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Dietary Supplements, Selenium and Chronic Disease Prevention

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1 Dietary Supplements, Selenium and Chronic Disease Prevention
Milan-NCI- 20/11/2008 Milan-IRCSS Multimedica – 21/11/2008 Saverio Stranges, MD, PhD Clinical Sciences Research Institute University of Warwick Medical School, UK

2 Outline Context on Dietary Supplements Physiological Role of Selenium
Selenium and Human Health Perspectives

3 Dietary Supplement “A dietary supplement is a preparation intended to supply nutrients (such as vitamins, minerals, or amino acids) that are missing or not consumed in sufficient quantity in a person's diet”

4 Context: Dietary Supplement Use in US
1990: “Nutrition Labeling and Education Act” 1994: “Dietary Supplement Health and Education Act” 1997-onwards: Dramatic increase in supplement sales $18.8 billion in 2003 The Dietary Supplement Health and Education Act of 1994 (1) assured consumer access to a wide range of dietary supplements. Dietary supplements of all varieties are now marketed in the United States, including single-ingredient products and various combinations of vitamins, minerals, botanicals, and other constituents. Media attention to supplements, including advertisements, informational articles, and studies reporting associations with health conditions, is considerable. Marketing data show a dramatic increase in supplement sales since 1997, which totaled approximately $18.8 billion in 2003. After receiving thousands of letters from supplement users in a heated advocacy campaign, Congress passed the Dietary Supplement Health and Education Act6 of 1994, which freed dietary supplement manufacturers from many existing Food and Drug Administration (FDA) regulations. In the Nutrition Labelling and Education Act7 of 1990, Congress gave the FDA the authority to require manufacturers of dietary supplements to provide evidence that their products were safe prior to sale and to approve the health claims made about these products before they could be used in marketing. After the 1994 legislation was enacted, the burden of proof concerning the safety of dietary supplements shifted. Instead of the manufacturer having to show that a supplement was safe, the FDA had to prove that it was unsafe. Also, as a result of the legislation, manufacturers have been able to make general health claims about products as long as they do not contain references to preventing or curing specific diseases. These supplements are now sold under the same oversight standard as vitamins and are categorized under a separate FDA category as "foods."8-9 Recently, the question of the need for stricter regulation of these products has been raised in editorials, medical journals, and articles in the media, particularly on the issue of safety and the specific health claims that can be made by the manufacturers.2, What has been missing in this growing debate over what the government's role should be in regulating dietary supplements are the views of the American public, both users and nonusers of these products. 1999/2000: 52% of US adults take some type of dietary supplements (NHANES)

5 Dietary Supplement Use in US Adults (≥ 20 ys)
52% of US adults take a dietary supplement 35% take a multivitamin/multimineral (often with Se) 1.1% (~2.5 millions) take Se supplements as single-ingredient Most supplements are taken daily for at least 2 years Fifty-two percent of adults reported taking a dietary supplement in the past month; 35% take a multivitamin/multimineral. More than 1% of the U.S. population take selenium supplements as single-ingredient, and more than 35% take multivitamin and multimineral supplements (2) that often contain selenium. NHANES Am J Epidemiol. 2004; 160:339-49

6 Dietary Supplement Use in US Adults (≥ 20 ys)
Fifty-two percent of adults reported taking a dietary supplement in the past month; 35% take a multivitamin/multimineral. More than 1% of the U.S. population take selenium supplements, and more than 35% take multivitamin and multimineral supplements (2) that often contain selenium. Any dietary supplement Multivitamin/multimineral Selenium Vitamin E NHANES Am J Epidemiol. 2004; 160:339-49

7 National Health Interview Survey. J Am Diet Assoc. 2004; 104:942-950
Trends in Daily Use of Vitamin/Mineral Supplements - US Adults (≥ 18 ys) To describe trends in use of specific vitamin and mineral (VM) supplements. DESIGN: The nationally representative National Health Interview Survey queried adult respondents about their use of VM supplements in 1987, 1992, and 2000.Statistical analysis Trends in use of VM supplements from 1987 to 2000 were determined using linear contrasts. RESULTS: The percentage of adults using any VM supplement daily increased from 23.2% (1987) to 23.7% (1992) to 33.9% (2000), following the Dietary Supplement Health and Education Act. This pattern was consistent for both sexes, all race/ethnic groups, and adults aged >or=25 years. The increase in the percentage of daily users of multivitamins, vitamin A, and vitamin E was 10.5, 1.2, and 7.3 percentage points, respectively, from 1987 to Increases in daily use of vitamin C (3.3 percentage points) and calcium (6.1 percentage points) occurred between 1992 and All trend analyses were significant at P<.001. In the 2000 National Health Interview Survey personnel queried the use of nonvitamin/nonmineral supplements for the first time. At that time, 6.0% of respondents reported using them daily. CONCLUSION: The increasing trend in supplement use over time and the notable use of nonvitamin/nonmineral supplements in 2000 indicates the continued need to monitor the use of all types of dietary supplements for purposes of dietary surveillance and nutrition-related research. National Health Interview Survey. J Am Diet Assoc. 2004; 104:

8 Context: Dietary Supplement Use in Europe
2002: Directive 2002/46/EC - Food Supplements Directive 2004: Decreto Legislativo 169/2004 (Italy) 150 millions euros/year in dietary supplements (Italy) 20-30% dietary supplement users (among adults) in Europe Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements The Food Supplements Directive [10] requires that supplements be demonstrated to be safe, both in quantity and quality. Some vitamins are essential in small quantities but dangerous in large quantities, notably Vitamin A. Consequently, only those supplements that have been proven to be safe may be sold without prescription. In practice, however, there appears to be little risk to supplement users of experiencing adverse side effects due to excessive intakes of micronutrients. [11] In Europe, it is also an established view that food supplements should not be labelled with drug/therapeutic claims but can bear health claims, although to a degree that differs from one member state to the other.

9 Dietary Supplements in the Market
Category Example Single Vitamin Vitamin A, C, E Multiple Vitamins B complex, CentrumTM Single Minerals calcium, zinc, selenium Multiple Minerals iron and zinc, calcium and magnesium Vitamins + Minerals (VM) centrumTM with minerals VM + other products One-a-DayTM with Gingko Amino Acids lysine, methionine, tryptophan Fish Oils omega-3 fatty acids Glandulars pancreas, liver, organ extracts Fiber fiberwafersTM, florabiberTM Botanicals, herbs Echinacea, ginseng, St. John’s Wort Antacids as calcium suppl. Tums Antacid/Calcium SupplementTM

10 Why Do People Take Dietary Supplements?
Balance a poor diet/promote optimal health, fitness Prevent/manage minor ailments or chronic disease Distrust of conventional medicine Media pressure Co-responsibility of health professionals… Food supplements are taken for many reasons, mostly as an insurance policy to make up for a poor diet and/or to promote optimal health and fitness. Supplements are also used in an attempt to enhance sports and athletic performance and prevent or manage minor ailment such as colds and skin, hair and nail problems, as well as more distressing conditions such as premenstrual syndrome and menopausal symptoms and diseases such as arthritis, CVD, cataract and age-related macular degeneration.

11 Social Perception of Dietary Supplement Use
This article presents the views of Americans on what the government's future role should be in regulating or overseeing the growing sales of dietary supplements for health purposes. Based on results of multiple national opinion surveys, including the views of both users and nonusers of supplements, we found that a substantial percentage of Americans surveyed reported that they regularly take dietary supplements as a part of their routine health regimen. However, they reported that they do not discuss the use of dietary supplements with their physicians because they believe that the physicians know little or nothing about these products and may be biased against them. Many users felt so strongly about the potential health benefits of some of these products that they reported that they would continue to take them even if they were shown to be ineffective in scientifically conducted clinical studies. However, there also was broad public support for increased government regulation of these products. We found that a majority of Americans surveyed supported the following: to require that the Food and Drug Administration review the safety of new dietary supplements prior to their sale; to provide increased authority to remove from sale those products shown to be unsafe; and to increase government regulation to ensure that advertising claims about the health benefits of dietary supplements are true. Supplements are good for health? Access is very important Supplements are adequately tested Stop using if ineffective Blendon JB et al. Arch Intern Med. 2001; 161:

12 The media bombardment… Many of these supplements promoted as “antioxidants”

13 Use of “Antioxidants” among Physicians…
A survey of 181 cardiologists listed in the American College of Cardiology directory was conducted to determine their coronary artery disease (CAD) risk profile and their intake of antioxidants. The survey reflected that the prevalence of CAD risk factors increases with age, as does the prophylactic intake of antioxidants (vitamin E was greater than vitamin C, and vitamin C was greater than beta carotene). Almost half (44%) of all respondents took prophylactic antioxidants themselves. In general, vitamin E was the most commonly used antioxidant vitamin among physicians (39%), followed by vitamin C (33%), and β carotene (19%). The greater frequency of intake of vitamin E is consistent with the reported benefit of this antioxidant. However, the frequency of intake of vitamin C and β carotene cannot be explained by the reported data. Data on the benefits of aspirin in patients with previous CAD and apparently healthy male physicians have also been widely disseminated. I observed that almost a similar percentage of respondents took routine aspirin (42%) as did antioxidants (44%). Twenty-eight percent of all respondents took both aspirin and antioxidants. I also examined the relation between perceived stress and use of antioxidants and aspirin in the hope that “stressed” cardiologists may be more prone to take agents that may have protective effect against CAD. However, the use of antioxidants was similar among those who perceived stress and in those who did not (43% and 42%, respectively) as was the use of aspirin (42% and 41%, respectively). It was intriguing that although 44% of all respondents used antioxidants themselves, a somewhat smaller percentage (37%) recommended antioxidants routinely to their patients with CAD. The reason for the disparity is not clear. Any Vitamin E β Carotene Vitamin C Am J Cardiol. 1997; 79:

14 BUT… It won’t hurt and might help, so why not take it?
Doctor, why should I take this pill? BUT…

15 CARETrial. N Engl J Med. 1996; 334:1150-5
The Beta-Carotene and Retinol Efficacy Trial Beta Carotene + Retinol (Vitamin A) Lung Cancer Incidence Mortality Background Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. Methods We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial — the Beta-Carotene and Retinol Efficacy Trial — involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. Results A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P = 0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. Conclusions After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos. CARETrial. N Engl J Med. 1996; 334:1150-5

16 Miller ER et al. Ann Intern Med 2005;142:37-46
Vitamin E Supplementation and Mortality Background: Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non–statistically significant increases in total mortality. Purpose: To perform a meta-analysis of the dose–response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials. Patients: participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d). Data Sources: PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and meta-analyses. No language restrictions were applied. Data Extraction: 3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available. Data Synthesis: 9 of 11 trials testing high-dosage vitamin E ( 400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per persons (95% CI, 3 to 74 per persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was –16 per persons (CI, –41 to 10 per persons; P > 0.2). A dose–response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d. Limitations: High-dosage ( 400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult. Conclusion: High-dosage ( 400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided. Miller ER et al. Ann Intern Med 2005;142:37-46

17 Mortality in Randomized Trials of Antioxidant Supplements
* * * * Context  Antioxidant supplements are used for prevention of several diseases. Objective  To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. Data Sources and Trial Selection  We searched electronic databases and bibliographies published by October All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials. Data Extraction  We included 68 randomized trials with 232 606 participants (385 publications). Data Synthesis  When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, ). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, ) and selenium (RR, 0.998; 95% CI, ) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, ). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, ), vitamin A (RR, 1.16; 95% CI, ), and vitamin E (RR, 1.04; 95% CI, ), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality. Conclusions  Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study. *P < .05 Bielakovic G. JAMA. 2007; 297:

18 Potential Benefits on Cancer
Background: Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States. Purpose: To synthesize studies on the efficacy and safety of multivitamin/mineral supplement use in primary prevention of cancer and chronic disease in the general population. Data Sources: English-language literature search of the MEDLINE, EMBASE, and Cochrane databases through February 2006 and hand-searching of pertinent journals and articles. Study Selection: Randomized, controlled trials in adults were reviewed to assess efficacy, and randomized, controlled trials and observational studies in adults or children were reviewed to assess safety. Data Extraction: Paired reviewers extracted data and independently assessed study quality. Data Synthesis: 12 articles from 5 randomized, controlled trials that assessed efficacy and 8 articles from 4 randomized, controlled trials and 3 case reports on adverse effects were identified. Study quality was rated fair for the studies on cancer, cardiovascular disease, cataracts, or age-related macular degeneration and poor for the studies on hypertension. In a poorly nourished Chinese population, combined supplementation with ß-carotene, -tocopherol, and selenium reduced the incidence of and mortality rate from gastric cancer and the overall mortality rate from cancer by 13% to 21%. In a French trial, combined supplementation with vitamin C, vitamin E, ß-carotene, selenium, and zinc reduced the rate of cancer by 31% in men but not in women. Multivitamin and mineral supplements had no significant effect on cardiovascular disease or cataracts, except that combined ß-carotene, selenium, -tocopherol, retinol, and zinc supplementation reduced the mortality rate from stroke by 29% in the Linxian study and that a combination of 7 vitamins and minerals stabilized visual acuity loss in a small trial. Combined zinc and antioxidants slowed the progression of advanced age-related macular degeneration in high-risk persons. No consistent adverse effects of multivitamin and mineral supplements were evident. Limitations: Only randomized, controlled trials were considered for efficacy assessment. Special nutritional needs, such as use of folic acid by pregnant women to prevent birth defects, were not addressed. Findings may not apply to use of commercial multivitamin supplements by the general U.S. population. Conclusions: Evidence is insufficient to prove the presence or absence of benefits from use of multivitamin and mineral supplements to prevent cancer and chronic disease. and NPC… Huang H-Y et al. Ann Intern Med. 2006; 145:

19 Potential Benefits on Mortality
Background: Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States. Purpose: To synthesize studies on the efficacy and safety of multivitamin/mineral supplement use in primary prevention of cancer and chronic disease in the general population. Data Sources: English-language literature search of the MEDLINE, EMBASE, and Cochrane databases through February 2006 and hand-searching of pertinent journals and articles. Study Selection: Randomized, controlled trials in adults were reviewed to assess efficacy, and randomized, controlled trials and observational studies in adults or children were reviewed to assess safety. Data Extraction: Paired reviewers extracted data and independently assessed study quality. Data Synthesis: 12 articles from 5 randomized, controlled trials that assessed efficacy and 8 articles from 4 randomized, controlled trials and 3 case reports on adverse effects were identified. Study quality was rated fair for the studies on cancer, cardiovascular disease, cataracts, or age-related macular degeneration and poor for the studies on hypertension. In a poorly nourished Chinese population, combined supplementation with ß-carotene, -tocopherol, and selenium reduced the incidence of and mortality rate from gastric cancer and the overall mortality rate from cancer by 13% to 21%. In a French trial, combined supplementation with vitamin C, vitamin E, ß-carotene, selenium, and zinc reduced the rate of cancer by 31% in men but not in women. Multivitamin and mineral supplements had no significant effect on cardiovascular disease or cataracts, except that combined ß-carotene, selenium, -tocopherol, retinol, and zinc supplementation reduced the mortality rate from stroke by 29% in the Linxian study and that a combination of 7 vitamins and minerals stabilized visual acuity loss in a small trial. Combined zinc and antioxidants slowed the progression of advanced age-related macular degeneration in high-risk persons. No consistent adverse effects of multivitamin and mineral supplements were evident. Limitations: Only randomized, controlled trials were considered for efficacy assessment. Special nutritional needs, such as use of folic acid by pregnant women to prevent birth defects, were not addressed. Findings may not apply to use of commercial multivitamin supplements by the general U.S. population. Conclusions: Evidence is insufficient to prove the presence or absence of benefits from use of multivitamin and mineral supplements to prevent cancer and chronic disease. Huang H-Y et al. Ann Intern Med. 2006; 145:

20 THE TRACE ELEMENT SELENIUM (Se) was discovered in 1817 by the Swedish chemist Berzelius, who named it after the moon goddess, Selene, in Greek. Selenium (Greek σελήνη selene meaning "Moon") was discovered in 1817 by Jöns Jakob Berzelius who found the element associated with tellurium (named for the Earth). …Selene, Moon Goddess…

21 Physiological Role of Selenium
Selenium is an essential trace mineral Selenium is incorporated as seleno-cysteine (Sec) At least 25 seleno-proteins in humans Complex genetic mechanism encoded by the UGA codon Selenium is a trace element; as selenocysteine, selenium is an essential component of the active sites of several enzymes, such as glutathione peroxidase, important to the protection of cellular components against oxidative and free radical damage; Membrane integrity: formation and normal development of spermatozoa UGA CODON (Termination/stop Codon)

22 Papp LV. Antioxid. Redox Signal. 2007; 9:775-806
Selenium Metabolism Dietary selenium metabolites are taken up into the cell, where, together with the existing intracellular pool, they become metabolized by different pathways, ultimately to yield selenide, which serves as the selenium source for Sec biosynthesis. (Se, selenium; GSSeSG, selenodiglutathione; CH3SeH methylselenol; H2Se selenide; SeMet, selenomethionine; Sec, selenocysteine; GSH, glutathione; TrxR, thioredoxin reductase; Trx, thioredoxin). Selenium has a unique metabolism that is complex. Absorption is not regulated and bioavailability of food selenium is usually high. This leads to 50–90% of dietary selenium being utilized. Homeostasis of the element is maintained by excretion. Methylation of selenium in liver and kidney produces compounds that enter the urine. When potentially toxic amounts of the element are ingested, volatile selenium metabolites give the breath a “garlicky” smell. Selenium function is exerted by selenoproteins. A selenoprotein contains 1 or more atoms of selenium per protein molecule. The chemical form of selenium in animal selenoproteins is selenocysteine. Synthesis and incorporation of selenocysteine into selenoproteins is a separate topic that will not be covered here (for review see Reference 5). However, incorporation of selenocysteine is genetically specified and is restricted to selenoproteins. Papp LV. Antioxid. Redox Signal. 2007; 9:

23 Physiological Functions of Selenium
Redox Homeostasis (e.g., glutathione peroxidases, thioredoxin reductases ) Thyroid Hormone Metabolism (iodothyronine 5’-deiodinase) Reproduction/Testosterone Biosynthesis Membrane Integrity Immune Function/Prostacyclin Production Selenium is a trace element; as selenocysteine, selenium is an essential component of the active sites of several enzymes, such as glutathione peroxidase, important to the protection of cellular components against oxidative and free radical damage; Membrane integrity: formation and normal development of spermatozoa

24 The Human Selenoproteome
The human selenoproteome. The 25 human selenoproteins are outlined and classified by their determined or potential function. Gpx3 and Sel P are markers of selenium status Papp LV. Antioxid Redox Signal. 2007; 9:

25 Bioavailability of Selenium
Geographical variations in soil selenium content Plant foods are the major dietary sources Meats, seafood, and bread are common sources 55 µg/day: recommended intake (RDA) to optimize GPx activity 70-90 µg/L: plasma Se levels to optimize GPx activity 400 µg/day: tolerable upper intake level (UL) Increasing use of Se-enriched foods and fertilizers Selenium is a trace element; as selenocysteine, selenium is an essential component of the active sites of several enzymes, such as glutathione peroxidase, important to the protection of cellular components against oxidative and free radical damage; Membrane integrity: formation and normal development of spermatozoa UGA CODON (Termination/stop Codon)

26 Dietary Sources of Selenium
Food µg % Daily Value Brazil nuts, 1 ounce 544 780 Daily Value (DV) for Selenium 70 100 Tuna, light, canned in oil, drained, 3 ounces 63 95 Beef, cooked, 3½ ounces 35 50 Cod, cooked, 3 ounces 32 45 Turkey, light meat, roasted, 3½ ounces Chicken Breast, meat only, roasted, 3½ ounces 20 30 Noodles, enriched, boiled, 1/2 cup 17 25 Macaroni, elbow, enriched, boiled, 1/2 cup 15 Egg, whole, 1 medium 14 Cottage cheese, low fat 2%, 1/2 cup 12 Rice, white, enriched, long grain, cooked, 1/2 cup Rice, brown, long-grained, cooked, 1/2 cup 10 Bread, enriched, whole wheat, 1 slice High Plant foods are the major dietary sources of selenium in most countries throughout the world. The content of selenium in food depends on the selenium content of the soil where plants are grown or animals are raised. For example, researchers know that soils in the high plains of northern Nebraska and the Dakotas have very high levels of selenium. People living in those regions generally have the highest selenium intakes in the United States (U.S.) [8]. In the U.S., food distribution patterns across the country help prevent people living in low-selenium geographic areas from having low dietary selenium intakes. Soils in some parts of China and Russia have very low amounts of selenium. Selenium deficiency is often reported in those regions because most food in those areas is grown and eaten locally. Selenium also can be found in some meats and seafood. Animals that eat grains or plants that were grown in selenium-rich soil have higher levels of selenium in their muscle. In the U.S., meats and bread are common sources of dietary selenium [9,10]. Some nuts are also sources of selenium. Selenium content of foods can vary. For example, Brazil nuts may contain as much as 544 micrograms of selenium per ounce. They also may contain far less selenium. It is wise to eat Brazil nuts only occasionally because of their unusually high intake of selenium. Selected food sources of selenium are provided in Table. *DV = Daily Value. DVs are reference numbers developed by the Food and Drug Administration (FDA) to help consumers determine if a food contains a lot or a little of a specific nutrient. The DV for selenium is 70 micrograms (ug). Most food labels do not list a food's selenium content. The percent DV (%DV) listed on the table indicates the percentage of the DV provided in one serving. A food providing 5% of the DV or less is a low source while a food that provides 10-19% of the DV is a good source. A food that provides 20% or more of the DV is high in that nutrient. It is important to remember that foods that provide lower percentages of the DV also contribute to a healthful diet. For foods not listed in this table, please refer to the U.S. Department of Agriculture's Nutrient Database Web site: High blood levels of selenium (greater than 100 μg/dL) can result in a condition called selenosis [62]. Symptoms of selenosis include gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage [2]. Selenium toxicity is rare in the U.S. The few reported cases have been associated with industrial accidents and a manufacturing error that led to an excessively high dose of selenium in a supplement [63,64]. The Institute of Medicine of the National Academy of Sciences has set a tolerable upper intake level (UL) for selenium at 400 micrograms per day for adults to prevent the risk of developing selenosis. Good

27 …Strategies to Increase Selenium Intake…
Bio-fortification of crops with selenium

28 Dietary Selenium Intake Worldwide (90’s)
Optimal GPx activity Serum or plasma measured since The Recommended dietary allowance is 55 µg/day Rayman MP. Lancet 2000; 356:

29 Selenium Status in Italy
118.8 μg/L Plasma selenium (Se) levels of 293 subjects (160 males and 133 females) living in Desio (a small town near Milan) were determined. Analyses were performed by graphite-furnace atomic absorption spectrophotometry with Zeeman background correction. Plasma samples were not subjected to any treatment before analysis and serum samples containing a certified Se content were used as reference materials to control the quality of the analytical determinations. Plasma Se levels were found to be distributed normally with an average value of μg/1 and a S.D. of 27.2 (95% of the subjects lie between 64.4 and μg/1). No statistically significant difference was found between males and females, and no correlation was found between plasma Se levels and age or smoking habits. The results of this study confirm those of previous studies [12,13] reporting no significant differences in plasma Se levels in humans with respect to sex and age. Also, no differences were observed between smokers and nonsmokers. Plasma Se levels obtained in this study are higher than those reported by other Italian authors who indicate average concentrations of 91.3 [12] and 81.0 ~g/l [14]. This difference can be explained on the basis of differences in the analytical methods used and the diverse diets and living regions of the subjects chosen for the study. In order to evaluate plasma Se levels in particular subjects (i.e. professionally exposed workers or dialysis patients), it is very important to have a reference value obtained in your own laboratory for the general population of the region from which the subjects under study originate. 12. G. Morisi, M. Patriarca, G. Marano, S. Giampaoli and F. Taggi, Age and sex specific reference serum selenium levels estimated for the Italian population. Ann. Ist. Super. Sanita', 25 (1989) 14. C. Minoia, E. Sabbioni, P. Apostoli, R. Pietra, L. Pozzoli, M. Gallorini, G. Nicolaou, L. Alessio and E. Capodaglio, Trace element reference values in tissues from inhabitants of the European Community. Sci. Total Environ., 95 (1990) Sesana G et al. Sci Total Environ ;120:

30 Plasma Selenium and Selenoproteins
μg selenium/L plasma Plasma selenium concentrations in several clinical situations. Each bar represents protein-bound selenium. Three components are shown: selenoprotein P, glutathione peroxidase, and selenomethionine in all methionine-containing proteins. The broken line indicates the plasma selenium concentration that is considered to be adequate in healthy subjects. The bars represent the following: A, healthy individual in the United States with average selenium intake (approximately 100 g selenium per day); B, healthy individual with lower, but adequate, intake (approximately 55 g per day, recommended dietary allowance, RDA); C, healthy individual with very high selenium intake as selenomethionine (approximately 400 g per day, tolerable upper intake level, UL); D, healthy but selenium-deficient individual from China (intake approximately 10 g per day). High blood levels of selenium (greater than 100 μg/dL) can result in a condition called selenosis [62]. Symptoms of selenosis include gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage [2]. Selenium toxicity is rare in the U.S. The few reported cases have been associated with industrial accidents and a manufacturing error that led to an excessively high dose of selenium in a supplement [63,64]. The Institute of Medicine of the National Academy of Sciences has set a tolerable upper intake level (UL) for selenium at 400 micrograms per day for adults to prevent the risk of developing selenosis. US Average µg Se/day RDA µg Se/day High-Dose (UL) µg Se/day China µg Se/day Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79

31 Selenium and Human Health Where Did it Begin…?
Keshan A cardiomyopathy known as Keshan disease occurs in children in some of the selenium-deficient areas in China (North-eastern provinces). Because the disease does not occur in every selenium-deficient child, it is postulated that a second stress, perhaps an infection, is needed to trigger the heart disease. Such a pathogenesis would be similar to mouse models in which selenium deficiency allows infecting RNA viruses to mutate to more pathogenic forms. The incidence of Keshan disease is very low at present but it was much higher before In the 1970s, Chinese investigators carried out a placebo-controlled study of selenium supplementation in children. Keshan disease continued to occur in the placebo group but ceased to occur in the treatment group. This proved that selenium deficiency was a necessary condition for the occurrence of Keshan disease. After the study, selenium was added to salt in high-risk groups, leading to a sharp decline in the incidence of Keshan disease. Keshan Disease Research Group. Chin Med J. 1979; 92:

32 Keshan Disease, Endemic Cardiomyopathy
Selenium was firmly established as an essential nutrient in 1973 when it was shown to be a constituent of the enzyme glutathione peroxidase. Until then, its status as a nutrient had rested largely on studies showing that vitamin-E-deficient animals could not tolerate being made selenium deficient. Clinical evidence indicating that selenium was essential for human beings appeared in Chinese scientists carried out a selenium supplementation study in children living in a selenium-deficient region. Selenium supplementation essentially abolished the occurrence of Keshan disease, a childhood cardiomyopathy that was often fatal. Thus, it became clear that selenium was an essential nutrient for humans and this was acknowledged in the 1980 Recommended Dietary Allowances of the National Academy of Sciences. A dietary intake of 50 µg to 200 µg per day was recommended as safe and adequate.

33 Diseases Related to Selenium
Selenium Deficiency Keshan disease (endemic cardiomyopathy) Viral Infections (HIV) and immune disease Reproduction-related disorders (miscarriage, male infertility) Selenium Status/Supplements and Chronic Disease Cancer, all-cause mortality Cardiovascular disease Metabolic disease: type 2 diabetes, serum lipids One example of disease associated with selenium deficiency is Keshan disease, a potentially fatal form of cardiomyopathy in north eastern provinces of China,

34 Cancer Incidence- Mortality

35 Selenium Status & Cancer Mortality
Inadequate Variable Adequate Preliminary studies: 1) Ecological observation by Dr. Clark. The potential protective effect of selenium status on the risk of developing cancer has been examined in animal and epidemiologic studies. This ecological study investigated the association between U.S. county forage selenium status and site- and sex-specific county cancer mortality rates ( ) using weighted least squares regression. Consistent, significant (p less than .01) inverse associations were observed for cancers of the lung, rectum, bladder, esophagus, and cervix in a model limited to rural counties and for cancers of the lung, breast, rectum, bladder, esophagus, and corpus uteri in a model of all counties. No consistent significant positive associations were observed in the rural county models. This remarkable degree of consistency for the inverse associations strengthens the likelihood of a causal relationship between low selenium status and an increased risk of cancer mortality. 2) Plasma selenium and skin neoplasms: a case-control study. Clark LC et al. Although experimental studies in animals show that selenium may prevent cancer, case-control studies of internal human cancers have been difficult to interpret because neoplastic tissue sequesters selenium. We therefore conducted a case-control study to examine the association between plasma selenium level and skin cancer, a neoplasm with minimal tumor mass at the time of diagnosis. The mean selenium level among patients with either basal cell epithelioma (N = 142), squamous cell carcinoma (N = 48), or both (N = 50), was micrograms/g. This was significantly lower than the mean plasma selenium level of the 103 control subjects, which was micrograms/g. The noncancer control groups were drawn from current clinic patients and past clinic patients. The logistic estimate of the odds ratio for the lowest versus the highest decile of selenium for all cases combined versus the group of current patient controls was 4.39; for all cases combined versus the past patient controls, the logistic estimate of the odds ratio was 5.81. Clark LC et al. Arch Environ Health 1991; 46: 37-42

36 Geographic Studies: Selenium Levels in Forage Crops*
Preliminary studies: 1) Ecological observation by Dr. Clark. The potential protective effect of selenium status on the risk of developing cancer has been examined in animal and epidemiologic studies. This ecological study investigated the association between U.S. county forage selenium status and site- and sex-specific county cancer mortality rates ( ) using weighted least squares regression. Consistent, significant (p less than .01) inverse associations were observed for cancers of the lung, rectum, bladder, esophagus, and cervix in a model limited to rural counties and for cancers of the lung, breast, rectum, bladder, esophagus, and corpus uteri in a model of all counties. No consistent significant positive associations were observed in the rural county models. This remarkable degree of consistency for the inverse associations strengthens the likelihood of a causal relationship between low selenium status and an increased risk of cancer mortality. 2) Plasma selenium and skin neoplasms: a case-control study. Clark LC et al. Although experimental studies in animals show that selenium may prevent cancer, case-control studies of internal human cancers have been difficult to interpret because neoplastic tissue sequesters selenium. We therefore conducted a case-control study to examine the association between plasma selenium level and skin cancer, a neoplasm with minimal tumor mass at the time of diagnosis. The mean selenium level among patients with either basal cell epithelioma (N = 142), squamous cell carcinoma (N = 48), or both (N = 50), was micrograms/g. This was significantly lower than the mean plasma selenium level of the 103 control subjects, which was micrograms/g. The noncancer control groups were drawn from current clinic patients and past clinic patients. The logistic estimate of the odds ratio for the lowest versus the highest decile of selenium for all cases combined versus the group of current patient controls was 4.39; for all cases combined versus the past patient controls, the logistic estimate of the odds ratio was 5.81. 10% higher cancer mortality for major cancer sites in low-Se areas *L C Clark et al., 1991

37 Selenium Supplementation and Chronic Disease Prevention
The Nutritional Prevention of Cancer (NPC) Trial OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], ), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, ). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, ]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, ]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, ]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made Clark LC et al. JAMA 1996; 276: Arizona Cancer Center

38 NPC Study Population Multi-center, double-blind, randomized, placebo-controlled 1,312 residents from Eastern United States Previous history of non-melanoma skin cancer Mean age, 63 years; range, years; ¾ males 200 μg selenium per day (as selenium yeast) or placebo Blinded phase of the trial: Compliance: 79.3% Skin cancer, a neoplasm with minimal tumor mass (selenium sequester, accumulation) at the time of diagnosis GEORGIA, SOUTH CAROLINA, FLORIDA, NORTH CAROLINA, CONNECTICUT

39 NPC Endpoints Primary Endpoint Secondary Endpoints
Recurrent skin basal (BCC) and squamous cell (SCC) carcinomas Secondary Endpoints All-cause mortality Total cancer mortality Total and site-specific cancer incidence (lung/prostate/colorectal) Cardiovascular disease (CVD) incidence and mortality Type 2 diabetes

40 Plasma Selenium Concentrations during NPC
High compliance with the intervention

41 NPC Findings (1983-1993, 6.4 years follow-up)
Selenium Group (200 μg/day) vs. placebo * * OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], ), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, ). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, ]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, ]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, ]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made *P < 0.001 Clark LC et al. JAMA 1996; 276:

42 NPC Findings: Cancer Incidence (1983-1996, 7.4 years follow-up)
The Nutritional Prevention of Cancer Trial was a randomized, clinical trial designed to evaluate the efficacy of selenium as selenized yeast (200 microg daily) in preventing the recurrence of nonmelanoma skin cancer among 1312 residents of the Eastern United States. Original secondary analyses through December 31, 1993 showed striking inverse associations between treatment and the incidence of total [hazard ratio (HR) = 0.61, 95% confidence interval (CI) = ], lung, prostate, and colorectal cancer and total cancer mortality. This report presents results through February 1, 1996, the end of blinded treatment. Effect modification by baseline characteristics is also evaluated. The effects of treatment overall and within subgroups of baseline age, gender, smoking status, and plasma selenium were examined using incidence rate ratios and Cox proportional hazards models. Selenium supplementation reduced total (HR = 0.75, 95% CI = ) and prostate (HR = 0.48, 95% CI = ) cancer incidence but was not significantly associated with lung (HR = 0.74, 95% CI = ) and colorectal (HR = 0.46, 95% CI = ) cancer incidence. The effects of treatment on other site-specific cancers are also described. The protective effect of selenium was confined to males (HR = 0.67, 95% CI = ) and was most pronounced in former smokers. Participants with baseline plasma selenium concentrations in the lowest two tertiles (<121.6 ng/ml) experienced reductions in total cancer incidence, whereas those in the highest tertile showed an elevated incidence (HR = 1.20, 95% CI = ). The Nutritional Prevention of Cancer trial continues to show a protective effect of selenium on cancer incidence, although not all site-specific cancers exhibited a reduction in incidence. This treatment effect was restricted to males and to those with lower baseline plasma selenium concentrations. Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:

43 NPC Findings: Cancer-Specific (1983-1996, 7.4 years follow-up)
Cases Adjusted hazard ratios* Se Placebo HR 95% CI P Total Cancer Incidence 105 137 0.75 0.03 Prostate 22 42 0.48 0.005 Colorectal 9 19 0.46 0.057 Total Cancer Mortality 40 66 0.59 0.008 Non-melanoma skin 1.17 The Nutritional Prevention of Cancer Trial was a randomized, clinical trial designed to evaluate the efficacy of selenium as selenized yeast (200 microg daily) in preventing the recurrence of non-melanoma skin cancer among 1312 residents of the Eastern United States. Original secondary analyses through December 31, 1993 showed striking inverse associations between treatment and the incidence of total [hazard ratio (HR) = 0.61, 95% confidence interval (CI) = ], lung, prostate, and colorectal cancer and total cancer mortality. This report presents results through February 1, 1996, the end of blinded treatment. Effect modification by baseline characteristics is also evaluated. The effects of treatment overall and within subgroups of baseline age, gender, smoking status, and plasma selenium were examined using incidence rate ratios and Cox proportional hazards models. Selenium supplementation reduced total (HR = 0.75, 95% CI = ) and prostate (HR = 0.48, 95% CI = ) cancer incidence but was not significantly associated with lung (HR = 0.74, 95% CI = ) and colorectal (HR = 0.46, 95% CI = ) cancer incidence. The effects of treatment on other site-specific cancers are also described. The protective effect of selenium was confined to males (HR = 0.67, 95% CI = ) and was most pronounced in former smokers. Participants with baseline plasma selenium concentrations in the lowest two tertiles (<121.6 ng/ml) experienced reductions in total cancer incidence, whereas those in the highest tertile showed an elevated incidence (HR = 1.20, 95% CI = ). The Nutritional Prevention of Cancer trial continues to show a protective effect of selenium on cancer incidence, although not all site-specific cancers exhibited a reduction in incidence. This treatment effect was restricted to males and to those with lower baseline plasma selenium concentrations. The Nutritional Prevention of Cancer Trial was a double-blind, randomized, placebo-controlled clinical trial designed to test whether selenium as selenized yeast (200 microg daily) could prevent nonmelanoma skin cancer among 1312 patients from the Eastern United States who had previously had this disease. Results from September 15, 1983, through December 31, 1993, showed no association between treatment and the incidence of basal and squamous cell carcinomas of the skin. This report summarizes the entire blinded treatment period, which ended on January 31, The association between treatment and time to first nonmelanoma skin cancer diagnosis and between treatment and time to multiple skin tumors overall and within subgroups, defined by baseline characteristics, was evaluated. Although results through the entire blinded period continued to show that selenium supplementation was not statistically significantly associated with the risk of basal cell carcinoma (hazard ratio [HR] = 1.09, 95% confidence interval [CI] = 0.94 to 1.26), selenium supplementation was associated with statistically significantly elevated risk of squamous cell carcinoma (HR = 1.25, 95% CI = 1.03 to 1.51) and of total nonmelanoma skin cancer (HR = 1.17, 95% CI = 1.02 to 1.34). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer continue to demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer. *adjusted for age, gender, and smoking status at randomization Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11: Duffield-Lillico AJ et al. J Natl Cancer Inst. 2003; 95:

44 NPC - Total Cancer Incidence (1983-1996, 7.4 years follow-up)
Cases NPC - Total Cancer Incidence ( , 7.4 years follow-up) Cases Adjusted hazard ratios Se Placebo HR 95% CI P P, int Gender  Female 23 20 1.20 0.66–2.20 0.55 0.14  Male 82 117 0.67 0.50–0.89 0.005 Smoking status  Never 25 26 0.81 0.47–1.41 0.46 0.76  Former 42 61 0.66 0.44–0.97 0.04  Current 38 50 0.86 0.56–1.31 0.47 By baseline Se ≤ (ng/ml) 27 54 0.51 0.32–0.81 0.007 105.3–121.6 34 46 0.70 0.44–1.09 0.11 >121.6 (ng/ml) 44 37 0.77–1.86 0.43 The Nutritional Prevention of Cancer Trial was a randomized, clinical trial designed to evaluate the efficacy of selenium as selenized yeast (200 microg daily) in preventing the recurrence of non-melanoma skin cancer among 1312 residents of the Eastern United States. Original secondary analyses through December 31, 1993 showed striking inverse associations between treatment and the incidence of total [hazard ratio (HR) = 0.61, 95% confidence interval (CI) = ], lung, prostate, and colorectal cancer and total cancer mortality. This report presents results through February 1, 1996, the end of blinded treatment. Effect modification by baseline characteristics is also evaluated. The effects of treatment overall and within subgroups of baseline age, gender, smoking status, and plasma selenium were examined using incidence rate ratios and Cox proportional hazards models. Selenium supplementation reduced total (HR = 0.75, 95% CI = ) and prostate (HR = 0.48, 95% CI = ) cancer incidence but was not significantly associated with lung (HR = 0.74, 95% CI = ) and colorectal (HR = 0.46, 95% CI = ) cancer incidence. The effects of treatment on other site-specific cancers are also described. The protective effect of selenium was confined to males (HR = 0.67, 95% CI = ) and was most pronounced in former smokers. Participants with baseline plasma selenium concentrations in the lowest two tertiles (<121.6 ng/ml) experienced reductions in total cancer incidence, whereas those in the highest tertile showed an elevated incidence (HR = 1.20, 95% CI = ). The Nutritional Prevention of Cancer trial continues to show a protective effect of selenium on cancer incidence, although not all site-specific cancers exhibited a reduction in incidence. This treatment effect was restricted to males and to those with lower baseline plasma selenium concentrations. In the current analysis of the NPC Trial, attempts to glean information on the nature of the effect modification of selenium treatment by baseline plasma selenium reveal a complex and confusing pattern, one that is not entirely consistent with our understanding of selenium as protective against cancer. Indeed, these results clearly indicate the lack of a protective effect among participants whose baseline plasma selenium concentrations were in the upper tertile. It is noteworthy that this group of participants was selected on the basis of residency in an area in which the selenium intake was likely to be lower than in other regions of the United States. Thus, these results provide little support for the use of 200 µg selenium/day to protect against cancer among average-risk individuals with plasma concentrations at or above the United States estimated average of 123 ng/ml (mean ± SD serum selenium in 16,693 subjects obtained from the Third National Health and Nutrition Examination Survey (NHANES III) was 123 ± 17 ng/ml (81) . In addition, among selenium-supplemented individuals, we observe a striking association; those with higher baseline concentrations experienced an elevated incidence of cancer. A pattern of modestly decreased incidence among placebo participants coupled with no risk gradient among treated participants seems somewhat plausible; however, the pattern we observed was clearly unpredicted and unsettling. It is critical that this effect be further evaluated in carefully controlled mechanistic studies. Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:

45 NPC - Total Cancer Incidence (1983-1996, 7.4 years follow-up)
Cases NPC - Total Cancer Incidence ( , 7.4 years follow-up) Adjusted* HR 95% CI P P trend Selenium Group By baseline Se 0.01 ≤ (ng/ml) 1.00 105.3–121.6 1.29 0.78–2.15 0.32 >121.6 (ng/ml) 1.88 1.15–3.05 Placebo Group 0.20 0.88 0.59–1.31 0.52 0.76 0.50–1.16 As a means of exploring the nature of this interaction, we present the HRs for total cancer according to baseline selenium status within treatment group. Table 6 presents these HRs, 95% CIs, and tests of statistical significance, relating baseline plasma selenium concentrations to the subsequent development of total cancer. HRs were calculated using three different exposure measures of baseline plasma selenium: (a) as a continuous variable (each unit = 10 ng/ml); (b) by the median value; and (c) by tertiles. A strong positive association between baseline plasma selenium and the incidence of total cancer is seen within the selenium group for the continuous, dichotomous, and trichotomous analyses of baseline selenium concentrations. When baseline plasma selenium is treated as a continuous variable, selenium supplementation increased total cancer incidence by 12% (HR = 0.12, 95% CI = 1.03–1.22, P = 0.005) for every unit (where 1 unit = 10 ng/ml) increase in baseline plasma selenium concentration. When selenium is treated as a dichotomous variable, the comparison of total cancers above the median with those below the median yielded a HR of 1.45 (95% CI = 0.98–2.15, P = 0.06). Using the first baseline selenium tertile as the referent group among selenium-supplemented subjects, the HR was 1.29 (95% CI = 0.78–2.15, P = 0.32) in the second tertile and 1.88 (95% CI = 1.15–3.05, P = 0.01) in the third tertile of baseline plasma selenium. The trend for this association was statistically significant (P = 0.01). Thus, the trichotomous analysis revealed that among selenium-supplemented participants, those in the third tertile experienced an almost 2-fold, statistically significant elevation of incidence compared with participants in the first tertile. The association of baseline plasma selenium and total cancer in the placebo group, albeit weak, was in the protective direction, with individuals of higher status showing a lower incidence of total cancer (Table 6) . There was a non-significant decrease in incidence of total cancer with increasing baseline selenium in increments of 10 ng/ml (HR = 0.97, 95% CI = 0.90–1.05, P = 0.49). The decrease in incidence was also non-significant when comparing the effects of baseline selenium above the median, as opposed to below the median (HR = 0.95, 95% CI = 0.68–1.34, P = 0.79). This non-significant reduction in total cancer incidence is again apparent in the comparison of tertiles of baseline plasma selenium. Using the first tertile as the referent group, the HR was 0.88 (95% CI = 0.59–1.31, P = 0.52) in the second and 0.76 (95% CI = 0.50–1.16, P = 0.20) in the third tertile. The P for trend in this trichotomous analysis was 0.20. *adjusted for age, gender, and smoking status at randomization Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:

46 SUMIVAX Trial, France 7.5 years follow-up, n=13,017
Int. Placebo RR 95% CI P P, int Cancer Incidence Overall 267 295 0.90 0.19 Gender 0.02  Female 179 171 1.04 0.53  Male 88 124 0.69 0.008 Total Mortality 76 98 0.77 0.09 0.11 36 35 1.03 0.92 40 63 0.63 BACKGROUND: It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. METHODS: The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of French adults (7876 women aged years and 5141 men aged years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium [as selenium-enriched yeast], , and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. RESULTS: No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], ]) but not in women (relative risk, 1.04 [95% CI, ]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, ] in men vs 1.03 [95% CI, ] in women; P = .11 for interaction). CONCLUSIONS: After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene. 100 μg Selenium + 120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc Hercberg S et al. Arch Intern Med. 2004;164:

47 Cancer Incidence in the SUMIVAX Trial
Overall Men BACKGROUND: It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. METHODS: The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of French adults (7876 women aged years and 5141 men aged years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium [as selenium-enriched yeast], , and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. RESULTS: No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], ]) but not in women (relative risk, 1.04 [95% CI, ]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, ] in men vs 1.03 [95% CI, ] in women; P = .11 for interaction). CONCLUSIONS: After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene. Women Hercberg S et al. Arch Intern Med. 2004;164:

48 Selenium Status and Cancer Mortality NHANES III, 13,887 US adults
Background: Selenium, an essential trace element involved in defense against oxidative stress, may prevent cancer and cardiovascular disease. The objective of this study was to evaluate the association between selenium and all-cause and cause-specific mortality in a representative sample of US adults. Methods: Serum selenium levels were measured in 13,887 adult participants in the Third National Health and Nutrition Examination Survey (NHANES III), recruited in 1988 to 1994 and followed up for up to 12 years. Results: Mean serum selenium level was ng/ml. The multivariate adjusted hazard ratios comparing the highest to the lowest serum selenium tertile were 0.83 (95% CI 0.72 – 0.96) for all cause mortality, 0.69 (95% CI 0.53 – 0.90) for cancer mortality, and 0.94 (95% CI 0.77 – 1.16) for cardiovascular mortality. The association between serum selenium and all-cause and cancer mortality was non-linear, with an inverse association at low selenium levels (< 130 ng/ml) and a modest increase in mortality at high selenium levels (> 150 ng/ml). There was no association between serum selenium and cardiovascular mortality. Conclusion: In a representative sample of the US population we found a non-linear association between serum selenium levels and all-cause and cancer mortality. Increasing serum selenium levels were associated with decreased mortality up to 130 ng/ml. Our study, however, raises the concern that higher serum selenium levels may be associated with increased mortality. Bleys J et al. Arch Inter Med. 2008; 168:

49 Selenium Status and All-Cause Mortality NHANES III, US
Background: Selenium, an essential trace element involved in defense against oxidative stress, may prevent cancer and cardiovascular disease. The objective of this study was to evaluate the association between selenium and all-cause and cause-specific mortality in a representative sample of US adults. Methods: Serum selenium levels were measured in 13,887 adult participants in the Third National Health and Nutrition Examination Survey (NHANES III), recruited in 1988 to 1994 and followed up for up to 12 years. Results: Mean serum selenium level was ng/ml. The multivariate adjusted hazard ratios comparing the highest to the lowest serum selenium tertile were 0.83 (95% CI 0.72 – 0.96) for all cause mortality, 0.69 (95% CI 0.53 – 0.90) for cancer mortality, and 0.94 (95% CI 0.77 – 1.16) for cardiovascular mortality. The association between serum selenium and all-cause and cancer mortality was non-linear, with an inverse association at low selenium levels (< 130 ng/ml) and a modest increase in mortality at high selenium levels (> 150 ng/ml). There was no association between serum selenium and cardiovascular mortality. Conclusion: In a representative sample of the US population we found a non-linear association between serum selenium levels and all-cause and cancer mortality. Increasing serum selenium levels were associated with decreased mortality up to 130 ng/ml. Our study, however, raises the concern that higher serum selenium levels may be associated with increased mortality. Bleys J et al. Arch Inter Med. 2008; 168:

50 Selenium Status and All-Cause Mortality EVA Study, France
BACKGROUND: Inadequate plasma selenium can adversely affect the maintenance of optimal health; therefore, reported decreases in plasma selenium in an aging population are cause for concern. To further examine this hypothesis, we explored the relationships between plasma selenium and mortality in an elderly population: the EVA (Etude du Vieillissement Artériel) study. METHODS: The EVA study was a 9-year longitudinal study with 6 periods of follow-up. During the 2-year period from 1991 to 1993 (EVA0), 1389 men and women born between 1922 and 1932 were recruited. The effects of plasma selenium at baseline on mortality were determined by Cox proportional hazards regression analysis, adjusting for the following variables: sociodemographic characteristics, dietary habits, health, and cognitive factors. RESULTS: During the 9-year follow-up, 101 study participants died. Baseline plasma selenium was higher in individuals who were alive at the end of follow-up [mean (SD), 1.10 (0.20) micromol/L] than in those who died during the follow-up [1.01 (0.20) micromol/L; P <10(-4)]. Mortality rates were significantly higher in individuals with low selenium [increments = 0.2 micromol/L; relative risk (RR) = 1.56 (95% confidence interval, )]. After we controlled for various potential confounding factors, this association remained significant [RR = 1.54 ( )]. When the underlying causes of death were considered, we found an association with cancer-related mortality [adjusted RR = 1.79 ( )]. CONCLUSIONS: Even if it is premature to present selenium as a longevity indicator in an elderly population, our results are in accordance those of large, interventional, randomized trials with selenium, which suggest that this essential trace element plays a role in health maintenance in aging individuals. Akbaraly NT et al. Clin Chem. 2005; 51:

51 CVD Incidence/Mortality

52 Selenium Status and CVD Eastern Finland
Low serum selenium (<45μg/l) Serum selenium (≥45μg/l) * * * 1982 by Salonen et al. A case-control study was conducted to investigate the association between serum selenium and risk of death from acute coronary heart disease (CHD) as well as risk of fetal and non-fetal myocardial infarction (MI). Case-control pairs came from a population of 11,000 persons examined in 1972 from two counties in eastern Finland, an area with an exceptionally high mortality from cardiovascular diseases. Cases were aged years and had died of CHD or other CVD or had a non-fetal MI during a seven-year follow-up. Controls were matched for sex, age, daily tobacco consumption, serum cholesterol, diastolic blood pressure, and history of angina pectoris. The mean serum selenium concentration for all cases was 51.8 micrograms/l and for all controls 55.3 micrograms/l (p less than 0.01). Serum selenium of less than 45 micrograms/l was associated with an adjusted relative risk of CHD death of 2.9 (p less than 0.01, 95% CI, ), a relative risk of CVD death of 2.2 (p less than 0.01, 95% CI, ), and a relative risk of fatal and nonfatal MI of 2.1 (p less than 0.001, 95% Ci, ). 22% (95% CI, 8-35%) of contrary deaths were attributable to serum selenium in the whole study population. *P < 0.001 Salonen JT et al. Lancet. 1982; 2:175-9

53 Selenium Status and Peripheral Arterial Disease
NHANES , US Background: Selenium, an antioxidant micronutrient, has been hypothesized to prevent atherosclerotic disease but data on the association of serum selenium with peripheral arterial disease are very limited. Methods: We conducted a cross-sectional study of the association of serum selenium with the prevalence of peripheral arterial disease among 2,062 men and women 40 years of age and older participating in the National Health and Nutrition Examination Survey (NHANES) 2003 – Serum selenium was measured using inductively coupled plasma-dynamic reaction cell-mass spectrometry. Peripheral arterial disease was defined as an ankle-brachial blood pressure index < 0.90. Results: The prevalence of peripheral arterial disease was 4.9%. The age-, sex-, and race-adjusted prevalence of peripheral arterial disease decreased with increasing serum selenium (p-value for linear trend 0.02), but there was an indication of an up-turn in risk in the highest quartile of serum selenium. The fully-adjusted odds ratios for peripheral arterial disease comparing selenium quartiles 2 – 4 to the lowest quartile were 0.75, 0.58, and 0.67, respectively. In spline regression models, peripheral arterial disease prevalence decreased with increasing serum selenium levels up to 150 – 160 ng/ml (80th – 91st percentiles of the serum selenium distribution), followed by a gradual increase at higher selenium levels. Conclusion: Our study was consistent with a U-shaped association between serum selenium and the prevalence of peripheral arterial disease. Prospective studies across populations with different levels of selenium intake and randomized trials stratified by baseline selenium status are needed to establish the optimal selenium intake to minimize the risk of chronic disease. Mateo GF et al. Am J Clin Nutr 2006; 84: Bleys J, Navas-Acien A, Stranges S et al. (Submitted for publication)

54 Selenium Status and CVD Mortality NHANES III, 13,887 US adults
Background: Selenium, an essential trace element involved in defense against oxidative stress, may prevent cancer and cardiovascular disease. The objective of this study was to evaluate the association between selenium and all-cause and cause-specific mortality in a representative sample of US adults. Methods: Serum selenium levels were measured in 13,887 adult participants in the Third National Health and Nutrition Examination Survey (NHANES III), recruited in 1988 to 1994 and followed up for up to 12 years. Results: Mean serum selenium level was ng/ml. The multivariate adjusted hazard ratios comparing the highest to the lowest serum selenium tertile were 0.83 (95% CI 0.72 – 0.96) for all cause mortality, 0.69 (95% CI 0.53 – 0.90) for cancer mortality, and 0.94 (95% CI 0.77 – 1.16) for cardiovascular mortality. The association between serum selenium and all-cause and cancer mortality was non-linear, with an inverse association at low selenium levels (< 130 ng/ml) and a modest increase in mortality at high selenium levels (> 150 ng/ml). There was no association between serum selenium and cardiovascular mortality. Conclusion: In a representative sample of the US population we found a non-linear association between serum selenium levels and all-cause and cancer mortality. Increasing serum selenium levels were associated with decreased mortality up to 130 ng/ml. Our study, however, raises the concern that higher serum selenium levels may be associated with increased mortality. Bleys J et al. Arch Inter Med. 2008; 168:

55 Meta-analysis of Observational Studies on Selenium and CHD
Background:It is hypothesized that low selenium concentrations are associated with an increased risk of cardiovascular disease and that selenium supplements prevent coronary heart disease. Objective:The objective was to perform a meta-analysis on the association of selenium biomarkers with coronary heart disease endpoints in observational studies and on the efficacy of selenium supplements in preventing coronary heart disease endpoints in randomized trials. Design:The MEDLINE and the Cochrane Library databases were searched for studies conducted from 1966 through Relative risks were pooled by using an inverse-variance weighted random-effects model. Results:Twenty-five observational studies (14 cohort and 11 case-control studies) that measured blood or toenail selenium concentrations and 6 randomized trials that evaluated supplements containing selenium met our inclusion criteria. The pooled relative risk in a comparison of the highest with the lowest selenium concentration categories was 0.85 (95% CI: 0.74, 0.99) in cohort studies and 0.43 (0.29, 0.66) in case-control studies. In observational studies, a 50% increase in selenium concentrations was associated with a 24% (7%, 38%) reduction in coronary heart disease risk. In randomized trials, the pooled relative risk in a comparison of supplements containing selenium with placebo was 0.89 (0.68, 1.17). Conclusions:Selenium concentrations were inversely associated with coronary heart disease risk in observational studies. Because observational studies have provided misleading evidence for other antioxidants, the validity of this association is uncertain. Few randomized trials have addressed the cardiovascular efficacy of selenium supplementation, and their findings are still inconclusive. Evidence from large ongoing trials is needed to establish low selenium concentrations as a cardiovascular disease risk factor. Currently, selenium supplements should not be recommended for cardiovascular disease prevention. Pooled RR in cohort studies: 0.85 ( ) Mateo GF et al. Am J Clin Nutr 2006; 84:

56 Antioxidant Supplementation and CHD Incidence SUMIVAX Trial, France, 7
Antioxidant Supplementation and CHD Incidence SUMIVAX Trial, France, 7.5 years follow-up Int. Placebo RR 95% CI P P, int CHD Incidence Overall 134 137 0.97 0.80 Gender 0.44  Female 27 23 1.17 0.57  Male 107 114 0.82 0.54 BACKGROUND: It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. METHODS: The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of French adults (7876 women aged years and 5141 men aged years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium [as selenium-enriched yeast], , and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. RESULTS: No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], ]) but not in women (relative risk, 1.04 [95% CI, ]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, ] in men vs 1.03 [95% CI, ] in women; P = .11 for interaction). CONCLUSIONS: After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene. 100 μg Selenium + 120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc Hercberg S et al. Arch Intern Med. 2004;164:

57 Selenium Supplementation and CVD Incidence/Mortality NPC Trial (1983-1996)
Participants without prevalent CVD at randomization (n = 1,004) Mean follow-up: 7.6 years CVD Cases Adjusted hazard ratios* Se Placebo HR 95% CI P All CVD 103 96 1.03 0.81 All CHD 63 59 1.04 ALL CVA 40 37 1.02 0.94 CVD Mortality 31 1.22 0.41 All-cause Mortality 110 111 0.95 0.71 Despite the documented antioxidant and chemopreventive properties of selenium, studies of selenium intake and supplementation and cardiovascular disease have yielded inconsistent findings. The authors examined the effect of selenium supplementation (200 microg daily) on cardiovascular disease incidence and mortality through the entire blinded phase of the Nutritional Prevention of Cancer Trial ( ) among participants who were free of cardiovascular disease at baseline (randomized to selenium: n = 504; randomized to placebo: n = 500). Selenium supplementation was not significantly associated with any of the cardiovascular disease endpoints during 7.6 years of follow-up (all cardiovascular disease: hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.78, 1.37; myocardial infarction: HR = 0.94, 95% CI: 0.61, 1.44; stroke: HR = 1.02, 95% CI: 0.63, 1.65; all cardiovascular disease mortality: HR = 1.22, 95% CI: 0.76, 1.95). The lack of significant association with cardiovascular disease endpoints was also confirmed when analyses were further stratified by tertiles of baseline plasma selenium concentrations. These findings indicate no overall effect of selenium supplementation on the primary prevention of cardiovascular disease in this population. *adjusted for age, gender, and smoking status at randomization Stranges S et al. Am J Epidemiol 2006; 163:

58 NPC: Selenium Supplementation in CVD Primary Prevention
All Cardiovascular Disease All Coronary Heart Disease All Cerebrovascular Accidents Cardiovascular Mortality Selenium Placebo Despite the documented antioxidant and chemopreventive properties of selenium, studies of selenium intake and supplementation and cardiovascular disease have yielded inconsistent findings. The authors examined the effect of selenium supplementation (200 microg daily) on cardiovascular disease incidence and mortality through the entire blinded phase of the Nutritional Prevention of Cancer Trial ( ) among participants who were free of cardiovascular disease at baseline (randomized to selenium: n = 504; randomized to placebo: n = 500). Selenium supplementation was not significantly associated with any of the cardiovascular disease endpoints during 7.6 years of follow-up (all cardiovascular disease: hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.78, 1.37; myocardial infarction: HR = 0.94, 95% CI: 0.61, 1.44; stroke: HR = 1.02, 95% CI: 0.63, 1.65; all cardiovascular disease mortality: HR = 1.22, 95% CI: 0.76, 1.95). The lack of significant association with cardiovascular disease endpoints was also confirmed when analyses were further stratified by tertiles of baseline plasma selenium concentrations. These findings indicate no overall effect of selenium supplementation on the primary prevention of cardiovascular disease in this population.

59 Selenium Supplementation and Recurrent CVD NPC Trial (1983-1996)
Participants with prevalent CVD at randomization (n = 246) Mean follow-up: 5.5 years CVD Cases Adjusted hazard ratios* Se Placebo HR 95% CI P All CVD 56 65 0.79 0.21 All CHD 42 48 0.80 0.29 ALL CVA 14 17 0.76 0.45 CVD Mortality 30 28 1.06 0.81 All-cause Mortality 45 58 0.16 Despite the documented antioxidant and chemopreventive properties of selenium, studies of selenium intake and supplementation and cardiovascular disease have yielded inconsistent findings. The authors examined the effect of selenium supplementation (200 microg daily) on cardiovascular disease incidence and mortality through the entire blinded phase of the Nutritional Prevention of Cancer Trial ( ) among participants who were free of cardiovascular disease at baseline (randomized to selenium: n = 504; randomized to placebo: n = 500). Selenium supplementation was not significantly associated with any of the cardiovascular disease endpoints during 7.6 years of follow-up (all cardiovascular disease: hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.78, 1.37; myocardial infarction: HR = 0.94, 95% CI: 0.61, 1.44; stroke: HR = 1.02, 95% CI: 0.63, 1.65; all cardiovascular disease mortality: HR = 1.22, 95% CI: 0.76, 1.95). The lack of significant association with cardiovascular disease endpoints was also confirmed when analyses were further stratified by tertiles of baseline plasma selenium concentrations. These findings indicate no overall effect of selenium supplementation on the primary prevention of cardiovascular disease in this population. *adjusted for age, gender, and smoking status at randomization Stranges S et al. Am J Epidemiol 2006; 163:

60 NPC: Selenium Supplementation in CVD Secondary Prevention
All Cardiovascular Disease All Coronary Heart Disease Cardiovascular Mortality Selenium Placebo All Cerebrovascular Accidents Despite the documented antioxidant and chemopreventive properties of selenium, studies of selenium intake and supplementation and cardiovascular disease have yielded inconsistent findings. The authors examined the effect of selenium supplementation (200 microg daily) on cardiovascular disease incidence and mortality through the entire blinded phase of the Nutritional Prevention of Cancer Trial ( ) among participants who were free of cardiovascular disease at baseline (randomized to selenium: n = 504; randomized to placebo: n = 500). Selenium supplementation was not significantly associated with any of the cardiovascular disease endpoints during 7.6 years of follow-up (all cardiovascular disease: hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.78, 1.37; myocardial infarction: HR = 0.94, 95% CI: 0.61, 1.44; stroke: HR = 1.02, 95% CI: 0.63, 1.65; all cardiovascular disease mortality: HR = 1.22, 95% CI: 0.76, 1.95). The lack of significant association with cardiovascular disease endpoints was also confirmed when analyses were further stratified by tertiles of baseline plasma selenium concentrations. These findings indicate no overall effect of selenium supplementation on the primary prevention of cardiovascular disease in this population.

61 Meta-analysis of Trials on Selenium and CHD
Background: It is hypothesized that low selenium concentrations are associated with an increased risk of cardiovascular disease and that selenium supplements prevent coronary heart disease. Objective:The objective was to perform a meta-analysis on the association of selenium biomarkers with coronary heart disease endpoints in observational studies and on the efficacy of selenium supplements in preventing coronary heart disease endpoints in randomized trials. Design:The MEDLINE and the Cochrane Library databases were searched for studies conducted from 1966 through Relative risks were pooled by using an inverse-variance weighted random-effects model. Results:Twenty-five observational studies (14 cohort and 11 case-control studies) that measured blood or toenail selenium concentrations and 6 randomized trials that evaluated supplements containing selenium met our inclusion criteria. The pooled relative risk in a comparison of the highest with the lowest selenium concentration categories was 0.85 (95% CI: 0.74, 0.99) in cohort studies and 0.43 (0.29, 0.66) in case-control studies. In observational studies, a 50% increase in selenium concentrations was associated with a 24% (7%, 38%) reduction in coronary heart disease risk. In randomized trials, the pooled relative risk in a comparison of supplements containing selenium with placebo was 0.89 (0.68, 1.17). Conclusions:Selenium concentrations were inversely associated with coronary heart disease risk in observational studies. Because observational studies have provided misleading evidence for other antioxidants, the validity of this association is uncertain. Few randomized trials have addressed the cardiovascular efficacy of selenium supplementation, and their findings are still inconclusive. Evidence from large ongoing trials is needed to establish low selenium concentrations as a cardiovascular disease risk factor. Currently, selenium supplements should not be recommended for cardiovascular disease prevention. Mateo GF et al. Am J Clin Nutr 2006; 84:

62 Type 2 Diabetes/Lipids

63 The Common Soil Hypothesis Revisited
Insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (DM) are all linked to oxidative stress, which may represent the pathogenic mechanism linking these conditions to cardiovascular disease Ceriello A, Motz E. ATVB 2004; 24:

64 Selenium Supplementation and Incidence of Type 2 Diabetes NPC Trial (1983-1996)
To examine the efficacy of selenium supplementation in the primary prevention of type 2 diabetes 1,202 participants free of type 2 DM at randomization Self-reported diagnosis/medical records for type 2 DM ascertainment (for both incident and prevalent cases) 200 μg of selenium/day (n=600) or placebo (n=602) BACKGROUND: Findings from animal models suggest that selenium supplementation improves glucose metabolism. OBJECTIVE: To examine the effect of long-term selenium supplementation on the incidence of type 2 diabetes. DESIGN: Secondary analysis of a randomized, double-blind, placebo-controlled trial. SETTING: Areas of low selenium consumption of the eastern United States. PATIENTS: 1202 persons seen in dermatology clinics who did not have type 2 diabetes at baseline. INTERVENTION: Oral administration of selenium, 200 microg/d, or placebo. MEASUREMENTS: Incidence of type 2 diabetes. RESULTS: During an average follow-up of 7.7 years (SD, 2.7), type 2 diabetes developed in 58 selenium recipients and 39 placebo recipients (incidence, 12.6 cases per 1000 person-years vs. 8.4 cases per 1000 person-years, respectively; hazard ratio, 1.55 [95% CI, 1.03 to 2.33]). The lack of benefit of selenium supplementation on the incidence of type 2 diabetes persisted in analyses stratified by age, sex, body mass index, and smoking status. An exposure-response gradient was found across tertiles of baseline plasma selenium level, with a statistically significantly increased risk for type 2 diabetes in the highest tertile of baseline plasma selenium level (hazard ratio, 2.70 [CI, 1.30 to 5.61]). LIMITATIONS: Diabetes was a secondary outcome in the parent trial. Diagnoses of diabetes were self-reported but were validated in most participants. The sample was mostly older and white. CONCLUSIONS: Selenium supplementation does not seem to prevent type 2 diabetes, and it may increase risk for the disease.

65 Flow diagram of the NPC Trial, 1983-1996
Stranges S et. al. Ann Intern Med 2007; 147:

66 Characteristics of Participants at Randomization
Selenium Placebo Participants randomized (no.) 600 602 Age, years 63.4 (10.2) 63.0 (9.9) Education, years 12.9 (3.4) 12.9 (3.3) Gender, males (%) 74 75 Body mass index, kg/m2 25.6 (3.9) 25.5 (4.1) Smoking status (%) Never 34.0 30.0 Former 39.0 40.0 Current 27.0 Pack-years of smoking 56.8 (40.3) 56.6 (39.0) Plasma selenium, ng/ml Mean 114.4 (22.6) 114.0 (21.5) 33rd 105.6 104.8 50th 113.6 113.2 66th 122.4 121.2 No difference between treatment groups was statistically significant (P ≤ 0.05)

67 Cumulative Incidence of Type 2 Diabetes
Stranges S et. al. Ann Intern Med 2007; 147:

68 Incidence of Type 2 DM by Baseline Characteristics
Cases Incidence Adjusted hazard ratios* Se Placebo HR 95% CI P P, int Overall 58 39 12.6 8.4 1.55 0.03 Age (yrs.) 0.88  65 25 18 9.8 6.7 1.53 0.17 > 65 33 21 15.9 10.8 1.60 0.09 Gender 0.54 Female 9 8 6.8 6.3 1.38 0.51 Male 49 31 14.8 9.2 1.62 *mutually adjusted for other baseline covariates

69 Incidence of Type 2 DM by Baseline Characteristics
Cases Incidence Adjusted hazard ratios* Se Placebo HR 95% CI P P, int Smoking 0.53 Never 15 12 9.1 8.2 1.16 0.70 Former 30 18 17.2 10.0 1.67 0.09 Current 13 9 10.4 6.6 1.70 0.24 BMI 0.23 < 25 7.8 3.6 2.11 0.08 ≥ 25 40 17.5 14.7 1.25 0.36 *mutually adjusted for other baseline covariates

70 Incidence of Type 2 DM by Baseline Plasma Selenium
Cases Incidence Adjusted hazard ratios* Se Placebo HR 95% CI P P, int By median 0.028  113.4 26 25 11.1 10.7 1.04 0.89 > 113.4 32 14 14.1 6.1 2.50 0.005 By tertiles 0.038  105.2 18 11.6 11.3 1.13 0.72 10 8.8 6.5 1.36 0.63 > 121.6 11 17.5 7.3 2.70 0.008 *adjusted for age, BMI, gender, and smoking status at randomization

71 Summary of Results client.dssimon.com/viewvideo/acp28.wmv
No benefit from selenium supplementation on type 2 DM Potential adverse effects of long-term se supplementation Higher risk of type 2 DM at higher selenium concentrations client.dssimon.com/viewvideo/acp28.wmv client.dssimon.com/viewvideo/acp28.wmv

72 Limitations Strengths
Diabetes incidence was not a primary end-point of the trial Small number of diabetes cases Self-reported diagnosis Lack of biomarkers of glucose metabolism Lack of additional potential confounders Selected nature of participants (elderly, eastern US) Strengths Only trial with a long-term selenium supplementation High compliance with the intervention (80.3% s, 78.4% p)

73 Selenium Status and Prevalent Diabetes NHANES III, 8,876 US adults
OBJECTIVE—The purpose of this study was to examine the relationship between serum selenium levels and the prevalence of diabetes among U.S. adults. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional analysis of 8,876 adults 20 years of age who participated in the Third National Health and Nutrition Examination Survey. Diabetes was defined as the presence of a fasting plasma glucose ≥ 126 mg/dl, a self-report of a physician diagnosis of diabetes, or current use of insulin or oral hypoglycemic medication. Serum selenium was measured by atomic absorption spectrometry. RESULTS—Mean serum selenium levels in participants with and without diabetes were and ng/ml, respectively. Age-, sex-, race-, and BMI-adjusted mean selenium levels were ng/ml in participants with diabetes and ng/ml in participants without diabetes (adjusted difference 2.1 ng/ml [95% CI 0.4–3.8]; P = 0.02). The multivariable adjusted odds ratio for diabetes comparing the highest to the lowest quintile of serum selenium was 1.57 [1.16–2.13]. However, the association between high serum selenium and the prevalence of diabetes was nonlinear, with no clear trend in quintiles 2–4. CONCLUSIONS—In a probability sample of the U.S. population, high serum selenium levels were positively associated with the prevalence of diabetes. Until findings from prospective studies and randomized controlled trials are available, selenium intake, including selenium supplementation, should not be recommended for primary or secondary diabetes prevention in populations with adequate selenium status such as the U.S. population. Se-Quintile 1 (< ng/ml) Se-Quintile 5 ( ng/ml) Cases/non-cases 285/1,708 311/1,266 Fully-adjusted OR 1.00 (reference) 1.57 (1.16–2.13) Bleys J et al. Diabetes Care. 2007; 30:

74 Antioxidant Supplementation and Glucose Levels SUMIVAX Trial, France, 7.5 years follow-up, n=3,146
Baseline Plasma concentration β ± SE P     ß-carotene, 0.5 µmol/L –0.032 ± 0.008 <0.0001     Vitamin C, 4.9 µg/mL –0.015 ± 0.007 0.0455     Vitamin E, 7.7 µmol/L 0.005 ± 0.007 0.5164     Selenium, 0.2 µmol/L 0.030 ± 0.008     Zinc, 1.8 µmol/L –0.002 ± 0.008 0.8108 Background: Observational data suggest a protective effect of several antioxidants on fasting plasma glucose (FPG) and type 2 diabetes. However, randomized trials have yielded inconsistent results. Objectives: The first objective was to assess the effect of 7.5 y of antioxidant supplementation on FPG at 7.5 y. The second objective was to examine the epidemiologic association of baseline dietary intakes or plasma antioxidants and FPG (at baseline and at 7.5 y). Design: Subjects (n = 3146) from the Supplementation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) primary prevention trial in France were randomly assigned to receive a daily capsule containing 120 mg vitamin C, 30 mg vitamin E, 6 mg ß-carotene, 100 µg Se, and 20 mg Zn or a placebo. Results: After 7.5 y, no significant difference was observed between age-adjusted mean FPG in men (P = 0.78) and women (P = 0.89) in either group. Baseline ß-carotene dietary intakes and plasma concentrations were inversely associated with FPG in multivariate mixed models (P = and P < , respectively). Baseline plasma vitamin C and selenium levels were negatively (P = ) and positively (P < ) associated, respectively, with FPG. Conclusions: Supplementation with antioxidants at nutritional doses for 7.5 y had no effect on FPG in men or women who followed a balanced diet. An inverse association of baseline ß-carotene dietary intake and plasma concentrations with FPG was found, probably because ß-carotene is an indirect marker of fruit and vegetable intakes. 100 μg Selenium + 120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc Czernichow S et al. Am J Clin Nutr. 2006; 84:

75 Antioxidant Supplementation and Lipids SUMIVAX Trial, France, 7
Antioxidant Supplementation and Lipids SUMIVAX Trial, France, 7.5 years follow-up, n=12,741 Lipids Suppl vs. Placebo P Mean Cholesterol No difference Hypercholesterolemia Higher in Suppl (women) <0.05 Mean triglycerides Higher in Suppl (both sexes) Hypertriglyceridemia Higher in Suppl (men) Antioxidant micronutrients have been reported to be associated with an improvement in the blood profile, but the results are not consistent. The aim of the present study was to assess the effects of antioxidant supplementation on changes in the serum lipid profile of adult participants in the SU.VI.MAX study. French adults (n = 12,741: 7,713 females aged yr, and 5,028 males aged yr) received daily antioxidant supplementation (120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 microg selenium, and 20 mg zinc) or a matching placebo. Median follow-up time was 7.5 yr. After 7.5 yr, no effect of supplementation on total cholesterol was observed in men or women after adjusting for baseline total cholesterol levels and lipid-lowering medications. The prevalence of hypercholesterolemia (> or =6.5 mmol/L) showed a trend toward being higher in women who received supplements compared with those who received the placebo (P= 0.06). In both sexes, the group receiving supplements exhibited higher mean serum TG concentrations than did the placebo group (P= 0.06 in men; P= 0.05 in women). The prevalence of hypertriglyceridemia (> or =2.3 mmol/L) was also significantly higher in men who received supplements (P= 0.03), but not in women. Our results suggest than long-term daily supplementation with low doses of beta-carotene, vitamins C and E, selenium, and zinc does not result in an improved lipid profile and could even adversely affect some blood lipids, possibly with a higher risk of hyperlipidemia in women. 100 μg Selenium + 120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc Hercberg S et al. Lipids. 2005; 40:335-42

76 Selenium Status and Lipids NHANES III, 5,452 US adults
Background: Selenium, an essential micronutrient, has received considerable attention for its antioxidant properties. Additionally, selenium may affect several cardiometabolic risk factors, such as glucose homeostasis and lipid levels. However, the effects of selenium intake on the 5 lipid profile in selenium-replete populations, such as the US, are largely unknown. Objective: To examine the relationship of serum selenium levels with serum lipids in a representative sample of US adults. Research Design and Methods: Cross-sectional analysis of 5,452 men and women ≥20 years old participating in the Third National Health and Nutrition Examination survey (NHANES III). Serum selenium was measured by atomic absorption spectrometry. Results: The multivariable adjusted differences in total-cholesterol, LDL-cholesterol, HDL cholesterol, apo B, and apo A1 comparing the highest to the lowest quartile of serum selenium were 16.6 (95% CI 11.6, 21.4), 10.9 (6.4, 15.4), 3.2 (1.6, 5.0), 8.9 (5.6, 12.2), and 6.9 (1.7, 12.1) mg/dl. Participants in the highest quartile of serum selenium had 10% higher levels of triglycerides compared to those in the lowest quartile (ratio of triglyceride levels 1.10, 95% CI 1.05 to 1.17). The difference in LDL-cholesterol / HDL-cholesterol and apo B / apo A1 ratios comparing the highest to the lowest selenium quartiles were 0.11 (-0.02, 0.25) and 0.03 (0.00, 0.06), respectively. Conclusion: High serum selenium was associated with high serum total cholesterol, LDL cholesterol, HDL-cholesterol, triglycerides, apo B, and apo A1 levels among US adults, a selenium-replete population. Experimental studies are needed to determine cause and effect relationships and the potential mechanisms underlying these associations. Bleys J, Navas-Acien A, Stranges S et al. Am J Clin Nutr. 2008; 88:416-23

77 Total Cholesterol by Se Quartiles:
UK NDNS 2000/01; US NHANES III Background: Recent findings raise concern about possible associations of high selenium exposure with diabetes and hyperlipidemia in the US, a population with high selenium levels. In the UK, a population with lower selenium levels, there is little data on the association of selenium status with cardio-metabolic risk factors in the general population. Objective: To examine the association of plasma selenium levels with blood lipids in a nationally representative sample of British adults. Methods: Cross-sectional analysis of 1,166 white participants (aged years) in the UK National Diet and Nutrition Survey. Plasma selenium was measured by inductively coupled plasma mass spectrometry (ICP-MS). Total and HDL cholesterol were measured in non-fasting plasma samples. Results: Mean plasma selenium levels were 87.1 ng/ml. The multivariate adjusted differences between the highest (≥95.60 ng/ml) and lowest (≤77.4 ng/ml) quartiles of plasma selenium were 0.38 (95% CI 0.17, 0.58) mmol/L for total cholesterol, 0.36 (0.16, 0.56) mmol/L for non-HLD cholesterol, and 0.02 (-0.04, 0.08) mmol/L for HDL cholesterol. Conclusion: High-normal selenium levels were associated with increased total and non-HDL cholesterol levels but not with HDL in the UK. Prospective and mechanistic evidence is necessary to assess causality and to evaluate the impact of this association on cardiovascular risk. Q <77.4 Q ≥95.6 Q <113.7 Q ≥134.7 Selenium Quartiles (µg/L) Stranges S et al. (under review)

78 Selenium Status and CVD Risk Factors Olivetti Heart Study
Jossa F et al. Atherosclerosis. 1991; 87:129-34

79 Biological Plausibility

80 Selenium Status in the NPC Trial vs. Europe
Serum or plasma measured since 1990 Rayman MP. Lancet 2000; 356:

81 Plasma Selenium and Selenoproteins
µg selenium/L plasma Plasma selenium concentrations in several clinical situations. Each bar represents protein-bound selenium. Three components are shown: selenoprotein P, glutathione peroxidase, and selenomethionine in all methionine-containing proteins. The broken line indicates the plasma selenium concentration that is considered to be adequate in healthy subjects. The bars represent the following: A, healthy individual in the United States with average selenium intake (approximately 100 g selenium per day); B, healthy individual with lower, but adequate, intake (approximately 55 g per day, recommended dietary allowance, RDA); C, NPC participants on supplementation (200 g per day, tolerable upper intake level, UL); D, healthy but selenium-deficient individual from China (intake approximately 10 g per day). NPC - Dose µg Se/day US Average µg Se/day US RDA µg Se/day China µg Se/day Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79

82 Humans Narrow therapeutic window of selenium
Inter-individual variability in selenium metabolism Pro-oxidative/apoptotic effects (methylselenol, ROS), which largely account for the Se-induced anti-cancer effects Hypothyroidism/body weight gain in high-selenium diets Adverse effects on growth hormone metabolism (low IGF-1) Upregulation of genes (FoXO) involved in insulin metabolism

83 Animal Models Over-expression of glutathione peroxidase activity
Enzyme over-expression may cause insulin resistance Release of glucagon with hyperglycemia at high doses Insulin-mimetic activities at low doses Selenium may accumulate in the pancreatic tissue

84 Perspectives Balance of benefits and harms of selenium supplementation
Consider dietary intake/selenium status of different populations Subtle toxicity for chronic high exposure Need to establish the optimal selenium intake to minimize risks Need for mechanistic studies/randomized trials High-quality prospective studies across different countries Concern on the widespread use of selenium supplements

85 Benefits and Harms of Selenium Supplementation
Disease Benefits Harms Overall Mortality Unproved Cancer Incidence Total Possible Prostate Colorectal Non-melanoma Skin Cardio-metabolic CVD Type 2 Diabetes Hyperlipidemia

86 Type 2 Diabetes Prostate Cancer Selenium ? + -

87 …Diabetes and Prostate Cancer Risk…
Non-diabetics Diabetics - 28% - 47% * * * Studies on the relationship between obesity and prostate cancer incidence are inconsistent. In part, this inconsistency may be due to a differential effect of obesity on low-grade and high-grade cancer or confounding of the association of obesity with prostate cancer risk by diabetes. We investigated the associations of obesity and diabetes with low-grade and high-grade prostate cancer risk. Data were from 10,258 participants (1,936 prostate cancers) in the Prostate Cancer Prevention Trial who all had cancer presence or absence determined by prostate biopsy. Multiple logistic regression was used to model the risk of total prostate cancer, and polytomous logistic regression was used to model the risk of low-grade and high-grade prostate cancer. Compared with men with body mass index < 25, obese men (body mass index 30) had an 18% [odds ratio (OR), 0.82; 95% confidence interval (95% CI), ] decreased risk of low-grade prostate cancer (Gleason <7) and a 29% (OR, 1.29; 95% CI, ) increased risk of high-grade prostate cancer (Gleason 7) or, alternatively, a 78% (OR, 1.78; 95% CI, ) increased risk defining high-grade cancer as Gleason sum 8 to 10. Diabetes was associated with a 47% (OR, 0.53; 95% CI, ) reduced risk of low-grade prostate cancer and a 28% (OR, 0.72; 95% CI, ) reduced risk of high-grade prostate cancer. Associations of obesity or diabetes with cancer risk were not substantially changed by mutually statistical controlling for each other. Obesity increases the risk of high-grade but decreases the risk of low-grade prostate cancer, and this relationship is independent of the lower risk for prostate cancer among men with diabetes *P < 0.001 Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2006; 15:

88 …Diabetes and Prostate Cancer Risk…
Despite the strong association of diabetes with obesity and insulin resistance, diabetes has been consistently linked to a reduced risk of prostate cancer in several prospective and case-control studies, although the magnitude of the association is modest. In a 2004 meta-analysis of 14 studies, the pooled relative risk between diabetes and prostate cancer was 0.91 (95% CI: 0.86, 0.96) (58). Since the 2004 report, 6 additional studies have been published showing a reduced risk of prostate cancer associated with diabetes. Although on the surface the lower prostate cancer risk among men with diabetes appears to be in conflict with the hypothesis that obesity and metabolic syndrome are associated with a higher risk of prostate cancer, a closer examination of the diabetes–prostate cancer association reveals additional support for the hypothesis that higher insulin concentrations and insulin resistance may increase the risk of prostate cancer. Diabetes is a complex disease, and insulin concentrations vary during its long natural history. Men with diabetes initially have higher concentrations of insulin as the result of insulin resistance but subsequently become insulin-deficient as a result of damaged pancreatic ß-cells. The lower prostate cancer risk associated with long-term diabetes has been attributed, in part, to the lower serum concentrations of insulin and testosterone among men with diabetes (67). Indeed, in a large follow-up study of >5000 prostate cancer cases, risk of prostate cancer was slightly increased during the first 3 y after diagnosis of diabetes (RR = 1.23; 95% CI: 0.92, 1.65) but was reduced among men with diabetes for 4 y (RR = 0.63; 95% CI: 0.56, 0.71) (64). Further supporting this result is the finding from the US Physicians Study of >1000 cases of prostate cancer that men with long-term diabetes tend to have a lower risk of prostate cancer, in particular, the more aggressive form of prostate tumors (66). Although the mechanisms underlying the link between diabetes and reduced prostate cancer risk are unclear, lower concentrations of insulin, testosterone, and insulin-like growth factor-I (IGF-I), as well as higher concentrations of estrogens, have been implicated. It is well established that obese men have lower concentrations of serum testosterone and sex hormone–binding globulin and higher concentrations of estrogen, which may be associated with lower risk of prostate cancer (29). In addition, insulin down-regulates IGF-binding protein I, thus increasing bioavailable IGF-1. Higher concentrations of IGF-1 are associated with an increased risk of prostate cancer (29); thus, lower concentrations of insulin among men with long-term diabetes are associated with lower concentrations of free IGF-1 and reduced risk of prostate cancer. Note that insulin concentrations per se may not sufficiently characterize the relation between diabetes and prostate cancer, because insulin sensitivity varies widely among individuals, and many patients who are insulin-resistant maintain their ability to secrete insulin (67). During the development of type 2 diabetes, ß-cell function is progressively lost. At the time of diabetes diagnosis, a substantial amount, up to 50%, of ß-cell function has already been lost. Thus, the duration and extent of diabetes and insulin action are more relevant in the pathogenesis of prostate cancer, although these factors are usually more difficult to measure in epidemiologic investigations. Large prospective studies that assess diabetes, insulin resistance, and sex hormones are needed to dissect the roles of these interrelated factors in prostate cancer. Hsing AW et al. Am J Clin Nutr 2007;86:843S-857S

89 FIGURE. Putative relations among obesity, metabolic syndrome, serum testosterone (T), and risk of prostate cancer. SHBG, sex hormone–binding globulin. Several mechanisms could explain the association of obesity and metabolic syndrome with prostate cancer risk, including the sex steroid hormone, insulin and IGF signaling, and inflammation pathways (Figure 8 ). Note that part of the speculative mechanisms presented in this figure, especially those related to the hypothesis that tumors become androgen-independent and can adapt to lower concentrations of testosterone, need confirmation in future studies. The sex steroid pathway The relation of prostate cancer with sex steroids and obesity is complex, and the underlying biological mechanisms are unclear. The current dogma regarding androgens and prostate cancer is that higher concentrations of androgens increase the risk of prostate cancer. Testosterone is metabolized intracellularly into dihydrotestosterone (DHT), and DHT then binds to the androgen receptor and its coactivators to form an intracellular complex that then binds to the androgen response elements in the prostate gene to initiate a cascade of androgen signaling (68). Thus, intuitively, obesity may protect against prostate cancer, because obese men have modestly lower concentrations of serum testosterone, substantially lower concentrations of sex hormone–binding globulin, and higher concentrations of estrogens (69–71). However, more recent data have shown that higher serum concentrations of total testosterone are associated with a reduced risk (OR = 0.26; 95% CI: 0.10, 0.61) of high-grade (Gleason 7) prostate cancer but with an increased risk (OR = 1.91; 95% CI: 0.89, 4.07) of low-grade tumors (29) and that estradiol is associated with a decreased risk of nonaggressive cancer but not aggressive cancer. These data underscore the complex interrelations between obesity and serum sex steroids and their differential effect on prostate cancer but further support the differential effect of obesity on subtypes of prostate cancer. The complex relations among these factors are shown in Figure 8 . As shown, obese men have an increased risk of high-grade prostate cancer and a lower concentration of serum testosterone, which has been shown to be associated with increased risk of high-grade tumors (29). One possible explanation for the association between lower concentrations of serum testosterone and an excess of high-grade tumors is that a subset of the tumors may be more androgen-independent and thereby do not need high androgen concentrations for progression. Whether these tumors are the result of a stronger genetic predisposition or other adverse factors needs to be clarified in future studies. An alternative explanation is through the interaction with metabolic syndrome. It has been shown that men with low serum concentrations of testosterone are at an increased risk of developing metabolic syndrome. Whether low concentrations of serum testosterone reflect the insulin-resistant state in these patients and whether insulin alone, in the absence of high serum testosterone, is sufficient to trigger progression of prostate cancer to higher-grade tumors need to be clarified. Similarly, a possible explanation for the observation that lower testosterone concentrations are associated with a reduced risk of low-grade tumors may be that this subset of tumors is slow-growing and does need androgen stimulation for progression. These hypotheses are preliminary and need to be tested in future studies, but they do provide some support for the importance of etiologic heterogeneity in prostate cancer, which needs to be taken into account in future studies designed to clarify the role of androgens, obesity, and metabolic syndrome in prostate cancer. The IGF pathway A potential mechanism for the link between metabolic syndrome and prostate cancer is through the IGF pathway. IGF-I plays an important role in cellular proliferation, differentiation, and reduction of apoptosis (72). Obesity is associated with increased free or bioavailable IGF-I (73), and several epidemiologic studies have reported a positive association between IGF-1 and prostate cancer risk (72), although data from recent studies after the start of the prostate-specific antigen screening era are much weaker. The inflammation pathway A plausible mechanism linking obesity and prostate cancer is chronic inflammation. Accumulating data support the hypothesis that chronic inflammation contributes to prostate carcinogenesis (73, 74). In addition, studies of genetic susceptibility have shown that variants of genes in the inflammation pathway, including MSR1, TNF- , and IL6, are associated with a higher risk of prostate cancer (75–77). It is now recognized that adipose tissue is an active organ that secretes a large number of proteins, including cytokines and hormone-like factors, such as leptin and adiponectin (75). It has been shown that obesity is associated with a state of low-grade chronic inflammation, with infiltrating macrophages within adipose tissue and elevated concentrations of inflammatory cytokines, including tumor necrosis factor- , interleukin-6, and C-reactive protein (78, 79). The subclinical inflammatory condition related to obesity promotes the production of proinflammatory factors involved in the pathogenesis of insulin resistance (80). Furthermore, in obesity, the proinflammatory effects of cytokines involve the nuclear factor- B (NF- B) and c-Jun N-terminal kinase (JNK) systems. Coincidentally, NF- B is a strong inducer of anti-apoptotic gene activity (BCL-XL) and cell cycle genes (cyclin D1) (81). The net result is dependent on the state of activity of the JNKs. Nuclear localization of NF- B is associated with prostate cancer (82). NF- B is important in immune cell activation, and loss of NF- B activity could alter immune surveillance for tumor cells (83). In a mouse model of colonic inflammation-associated cancer (84), loss of NF- B activation within colonic epithelial cells led to decreased tumor incidence, whereas loss of NF- B activation in myeloid cells decreased tumor size only. The hypothesis that inflammatory mediators could alter tumorigenesis is highly plausible, and the logical extension of this hypothesis is the speculation that increased NF- B via select cytokine pathways could lead to cell survival, as has been shown for several tumor cell types. In summary, the biological link between obesity and inflammation provides further support for the role of obesity in prostate cancer but adds additional complexity to the already confusing picture of the obesity-prostate cancer relation. FUTURE DIRECTIONS Worldwide, the prevalence of obesity is increasing, and in the United States, nearly two-thirds of adults are either overweight or obese. Given the rising epidemic of obesity and metabolic syndrome worldwide, especially in developing countries, and the potential links among obesity, androgen metabolism, diabetes, and inflammation, it is critical to understand better the complex relations between overall and abdominal obesity and prostate cancer risk and the role of chronic inflammation in obesity and the pathogenesis of prostate cancer. Clearly, to dissect these interrelated factors, future prospective studies should be sufficiently large, with better assessment of overall and abdominal obesity and with biochemical measures, such as insulin concentrations, sex steroids, and IGFs, to clarify the complex interplays of these factors on prostate cancer risk. Etiologic heterogeneity should be considered. Further refinement of prostate cancer classification, using biomarkers and genetic markers, coupled with a clearer understanding of the cellular and molecular pathways involved, should prove illuminating. Factors such as grade, stage, and aggressiveness of tumors should be assessed and incorporated into the analysis. Methodologic studies are also needed to gain a better understanding of the determinants of these biomarkers, including insulin, leptin, adipokines, IGFs, sex steroids, and inflammatory mediators, and to provide biological data to help interpret the results.

90 Selenium and Vitamin E Cancer Prevention Trial (SELECT)
(400 μg/day) Selenium (200 μg/day) + - T 8,100 16,200 32,400 Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm. Cost: $175,000,000

91 Review of Prostate Cancer Prevention Study Shows No Benefit for Use of Selenium and Vitamin E Supplements Initial, independent review of study data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), funded by the National Cancer Institute (NCI) and other institutes that comprise the National Institutes of Health shows that selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer. The data also showed two concerning trends: a small but not statistically significant increase in the number of prostate cancer cases among the over 35,000 men age 50 and older in the trial taking only vitamin E and a small, but not statistically significant increase in the number of cases of adult onset diabetes in men taking only selenium. Because this is an early analysis of the data from the study, neither of these findings proves an increased risk from the supplements and both may be due to chance.

92 The Nutritional Prevention of Cancer (NPC) Trial
Keshan The Nutritional Prevention of Cancer (NPC) Trial

93 Acknowledgments James R Marshall Mary E Reid Raj Natarajan
Gerald F Combs Larry C Clark† Richard P Donahue Joan M Dorn Jo L Freudenheim Maurizio Trevisan Ana Navas-Acien Joachim Bleys Eliseo Guallar

94 Acknowledgments James R Marshall Mary E Reid Raj Natarajan
Gerald F Combs Larry C Clark† Richard P Donahue Joan M Dorn Jo L Freudenheim Maurizio Trevisan Ana Navas-Acien Joachim Bleys Eliseo Guallar


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