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Dietary Supplements, Selenium and Chronic Disease Prevention Saverio Stranges, MD, PhD Clinical Sciences Research Institute University of Warwick Medical.

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Presentation on theme: "Dietary Supplements, Selenium and Chronic Disease Prevention Saverio Stranges, MD, PhD Clinical Sciences Research Institute University of Warwick Medical."— Presentation transcript:

1 Dietary Supplements, Selenium and Chronic Disease Prevention Saverio Stranges, MD, PhD Clinical Sciences Research Institute University of Warwick Medical School, UK

2 Outline Context on Dietary Supplements Context on Dietary Supplements Physiological Role of Selenium Physiological Role of Selenium Selenium and Human Health Selenium and Human Health Perspectives 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 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 1994: Dietary Supplement Health and Education Act 1994: Dietary Supplement Health and Education Act 1997-onwards: Dramatic increase in supplement sales $18.8 billion in onwards: Dramatic increase in supplement sales $18.8 billion in /2000: 52% of US adults take some 1999/2000: 52% of US adults take some type of dietary supplements (NHANES) 1990: Nutrition Labeling and Education Act

5 Dietary Supplement Use in US Adults ( 20 ys) NHANES Am J Epidemiol. 2004; 160: % of US adults take a dietary supplement 52% of US adults take a dietary supplement 35% take a multivitamin/multimineral (often with Se) 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

6 Dietary Supplement Use in US Adults ( 20 ys) NHANES Am J Epidemiol. 2004; 160: Any dietary supplement Multivitamin/ multimineral Selenium Vitamin E

7 Trends in Daily Use of Vitamin/Mineral Supplements - US Adults ( 18 ys) 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 2002: Directive 2002/46/EC - Food Supplements Directive 2004: Decreto Legislativo 169/2004 (Italy) 2004: Decreto Legislativo 169/2004 (Italy) 150 millions euros/year in dietary supplements (Italy) 150 millions euros/year in dietary supplements (Italy) 20-30% dietary supplement users (among adults) in Europe 20-30% dietary supplement users (among adults) in Europe

9 Dietary Supplements in the Market CategoryExample Single VitaminVitamin A, C, E Multiple VitaminsB complex, Centrum TM Single Mineralscalcium, zinc, selenium Multiple Mineralsiron and zinc, calcium and magnesium Vitamins + Minerals (VM)centrum TM with minerals VM + other productsOne-a-Day TM with Gingko Amino Acidslysine, methionine, tryptophan Fish Oilsomega-3 fatty acids Glandularspancreas, liver, organ extracts Fiberfiberwafers TM, florabiber TM Botanicals, herbsEchinacea, ginseng, St. Johns Wort Antacids as calcium suppl.Tums Antacid/Calcium Supplement TM

10 Why Do People Take Dietary Supplements? Balance a poor diet/promote optimal health, fitness Balance a poor diet/promote optimal health, fitness Prevent/manage minor ailments or chronic disease Prevent/manage minor ailments or chronic disease Distrust of conventional medicine Distrust of conventional medicine Media pressure Media pressure Co-responsibility of health professionals… Co-responsibility of health professionals…

11 Social Perception of Dietary Supplement Use Blendon JB et al. Arch Intern Med. 2001; 161: Supplements are good for health? Access is very important Supplements are adequately tested Stop using if ineffective

12

13 Use of Antioxidants among Physicians… Am J Cardiol. 1997; 79: Any Vitamin E β Carotene Vitamin C

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

15 The Beta-Carotene and Retinol Efficacy Trial Beta Carotene + Retinol (Vitamin A) Lung Cancer Incidence Mortality 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

17 Mortality in Randomized Trials of Antioxidant Supplements * *P <.05 * * * Bielakovic G. JAMA. 2007; 297:

18 Potential Benefits on Cancer Huang H-Y et al. Ann Intern Med. 2006; 145: and NPC…

19 Potential Benefits on Mortality Huang H-Y et al. Ann Intern Med. 2006; 145:

20 …Selene, Moon Goddess…

21 Physiological Role of Selenium Selenium is an essential trace mineral Selenium is an essential trace mineral Selenium is incorporated as seleno-cysteine (Sec) Selenium is incorporated as seleno-cysteine (Sec) At least 25 seleno-proteins in humans At least 25 seleno-proteins in humans Complex genetic mechanism encoded by the UGA codon Complex genetic mechanism encoded by the UGA codon

22 Selenium Metabolism Papp LV. Antioxid. Redox Signal. 2007; 9:

23 Physiological Functions of Selenium Redox Homeostasis (e.g., glutathione peroxidases, thioredoxin reductases ) Redox Homeostasis (e.g., glutathione peroxidases, thioredoxin reductases ) Thyroid Hormone Metabolism (iodothyronine 5-deiodinase) Thyroid Hormone Metabolism (iodothyronine 5-deiodinase) Reproduction/Testosterone Biosynthesis Reproduction/Testosterone Biosynthesis Membrane Integrity Membrane Integrity Immune Function/Prostacyclin Production Immune Function/Prostacyclin Production

24 The Human Selenoproteome Papp LV. Antioxid Redox Signal. 2007; 9:

25 Bioavailability of Selenium Geographical variations in soil selenium content Geographical variations in soil selenium content Plant foods are the major dietary sources Plant foods are the major dietary sources Meats, seafood, and bread are common sources Meats, seafood, and bread are common sources 55 µg/day: recommended intake (RDA) to optimize GPx activity 55 µg/day: recommended intake (RDA) to optimize GPx activity µg/L: plasma Se levels to optimize GPx activity µg/L: plasma Se levels to optimize GPx activity 400 µg/day: tolerable upper intake level (UL) 400 µg/day: tolerable upper intake level (UL) Increasing use of Se-enriched foods and fertilizers Increasing use of Se-enriched foods and fertilizers

26 Foodµgµg% Daily Value Brazil nuts, 1 ounce Daily Value (DV) for Selenium Tuna, light, canned in oil, drained, 3 ounces 6395 Beef, cooked, 3½ ounces 3550 Cod, cooked, 3 ounces 3245 Turkey, light meat, roasted, 3½ ounces 3245 Chicken Breast, meat only, roasted, 3½ ounces 2030 Noodles, enriched, boiled, 1/2 cup 1725 Macaroni, elbow, enriched, boiled, 1/2 cup 1520 Egg, whole, 1 medium 1420 Cottage cheese, low fat 2%, 1/2 cup 1215 Rice, white, enriched, long grain, cooked, 1/2 cup 1215 Rice, brown, long-grained, cooked, 1/2 cup 1015 Bread, enriched, whole wheat, 1 slice 1015 Dietary Sources of Selenium High Good

27 …Strategies to Increase Selenium Intake…

28 Rayman MP. Lancet 2000; 356: Optimal GPx activity Dietary Selenium Intake Worldwide (90s)

29 Selenium Status in Italy Sesana G et al. Sci Total Environ ;120: μg/L

30 μg selenium/L plasma US Average 100 µg Se/day RDA 55 µg Se/day China 10 µg Se/day Plasma Selenium and Selenoproteins Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79 High-Dose (UL) 400 µg Se/day

31 Selenium and Human Health Where Did it Begin…? Keshan Keshan Disease Research Group. Chin Med J. 1979; 92:

32 Keshan Disease, Endemic Cardiomyopathy

33 Diseases Related to Selenium Selenium Deficiency Keshan disease (endemic cardiomyopathy) Keshan disease (endemic cardiomyopathy) Viral Infections (HIV) and immune disease Viral Infections (HIV) and immune disease Reproduction-related disorders (miscarriage, male infertility) Reproduction-related disorders (miscarriage, male infertility) Selenium Status/Supplements and Chronic Disease Cancer, all-cause mortality Cancer, all-cause mortality Cardiovascular disease Cardiovascular disease Metabolic disease: type 2 diabetes, serum lipids Metabolic disease: type 2 diabetes, serum lipids

34 Cancer Incidence- Mortality

35 Selenium Status & Cancer Mortality Clark LC et al. Arch Environ Health 1991; 46: InadequateVariable Adequate

36 Geographic Studies: Selenium Levels in Forage Crops* 10% higher cancer mortality for major cancer sites in low-Se areas *L C Clark et al., 1991

37 The Nutritional Prevention of Cancer (NPC) Trial Clark LC et al. JAMA 1996; 276: Arizona Cancer Center Selenium Supplementation and Chronic Disease Prevention

38 NPC Study Population Multi-center, double-blind, randomized, placebo-controlled Multi-center, double-blind, randomized, placebo-controlled 1,312 residents from Eastern United States 1,312 residents from Eastern United States Previous history of non-melanoma skin cancer Previous history of non-melanoma skin cancer Mean age, 63 years; range, years; ¾ males Mean age, 63 years; range, years; ¾ males 200 μg selenium per day (as selenium yeast)or placebo 200 μg selenium per day (as selenium yeast) or placebo Blinded phase of the trial: Compliance: 79.3% Compliance: 79.3%

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

40 Plasma Selenium Concentrations during NPC

41 NPC Findings ( , 6.4 years follow-up) * * *P < Clark LC et al. JAMA 1996; 276: Selenium Group (200 μg/day) vs. placebo

42 Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11: NPC Findings: Cancer Incidence ( , 7.4 years follow-up)

43 Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11: Duffield-Lillico AJ et al. J Natl Cancer Inst. 2003; 95: Cancer Cases Adjusted hazard ratios* SePlaceboHR 95% CI P Total Cancer Incidence Prostate Colorectal Total Cancer Mortality Non-melanoma skin *adjusted for age, gender, and smoking status at randomization NPC Findings: Cancer-Specific ( , 7.4 years follow-up)

44 NPC - Total Cancer Incidence ( , 7.4 years follow-up) Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11: Cases Cases Adjusted hazard ratios SePlaceboHR 95% CI P P, int Gender Female – Male – Smoking status Never – Former – Current – By baseline Se (ng/ml) (ng/ml) – – – >121.6 (ng/ml) –

45 NPC - Total Cancer Incidence ( , 7.4 years follow-up) Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11: Cases Adjusted* HR 95% CI P P trend Selenium Group By baseline Se (ng/ml) (ng/ml) – – >121.6 (ng/ml) – Placebo Group By baseline Se (ng/ml) (ng/ml) – – >121.6 (ng/ml) – *adjusted for age, gender, and smoking status at randomization

46 Int.PlaceboRR 95% CI P P, int Cancer Incidence Overall Gender0.02 Female Male Total Mortality Overall Gender0.11 Female Male SUMIVAX Trial, France 7.5 years follow-up, n=13,017 Hercberg S et al. Arch Intern Med. 2004;164: μg Selenium mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc

47 Cancer Incidence in the SUMIVAX Trial Hercberg S et al. Arch Intern Med. 2004;164: Overall Men Women

48 Selenium Status and Cancer Mortality NHANES III, 13,887 US adults Bleys J et al. Arch Inter Med. 2008; 168:

49 Selenium Status and All-Cause Mortality NHANES III, US Bleys J et al. Arch Inter Med. 2008; 168:

50 Selenium Status and All-Cause Mortality EVA Study, France 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) * * * *P < Salonen JT et al. Lancet. 1982; 2:175-9

53 Mateo GF et al. Am J Clin Nutr 2006; 84: Selenium Status and Peripheral Arterial Disease NHANES , US Bleys J, Navas-Acien A, Stranges S et al. (Submitted for publication)

54 Selenium Status and CVD Mortality NHANES III, 13,887 US adults Bleys J et al. Arch Inter Med. 2008; 168:

55 Mateo GF et al. Am J Clin Nutr 2006; 84: Meta-analysis of Observational Studies on Selenium and CHD Pooled RR in cohort studies: 0.85 ( )

56 Int.PlaceboRR 95% CI P P, int CHD Incidence Overall Gender0.44 Female Male Antioxidant Supplementation and CHD Incidence SUMIVAX Trial, France, 7.5 years follow-up Hercberg S et al. Arch Intern Med. 2004;164: μg Selenium mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc

57 Stranges S et al. Am J Epidemiol 2006; 163: Selenium Supplementation and CVD Incidence/Mortality NPC Trial ( ) *adjusted for age, gender, and smoking status at randomization CVD Cases Adjusted hazard ratios* SePlaceboHR 95% CI P All CVD All CHD ALL CVA CVD Mortality All-cause Mortality Participants without prevalent CVD at randomization (n = 1,004) Mean follow-up: 7.6 years

58 All Cardiovascular DiseaseAll Coronary Heart Disease All Cerebrovascular AccidentsCardiovascular Mortality Selenium Placebo NPC: Selenium Supplementation in CVD Primary Prevention

59 Stranges S et al. Am J Epidemiol 2006; 163: *adjusted for age, gender, and smoking status at randomization CVD Cases Adjusted hazard ratios* SePlaceboHR 95% CI P All CVD All CHD ALL CVA CVD Mortality All-cause Mortality Participants with prevalent CVD at randomization (n = 246) Mean follow-up: 5.5 years Selenium Supplementation and Recurrent CVD NPC Trial ( )

60 All Cardiovascular DiseaseAll Coronary Heart Disease Cardiovascular Mortality Selenium Placebo All Cerebrovascular Accidents NPC: Selenium Supplementation in CVD Secondary Prevention

61 Mateo GF et al. Am J Clin Nutr 2006; 84: Meta-analysis of Trials on Selenium and CHD

62 Type 2 Diabetes/Lipids

63 Ceriello A, Motz E. ATVB 2004; 24: The Common Soil Hypothesis Revisited

64 Selenium Supplementation and Incidence of Type 2 Diabetes NPC Trial ( ) To examine the efficacy of selenium supplementation in the primary prevention of type 2 diabetes 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 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) 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) 200 μg of selenium/day (n=600) or placebo (n=602)

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

66 No difference between treatment groups was statistically significant (P 0.05) Characteristics of Participants at Randomization CharacteristicsSeleniumPlacebo Participants randomized (no.) Age, years 63.4 (10.2) 63.0 (9.9) Education, years 12.9 (3.4) 12.9 (3.3) Gender, males (%) 7475 Body mass index, kg/m (3.9) 25.5 (4.1) Smoking status (%) Never Never Former Former Current Current Pack-years of smoking 56.8 (40.3) 56.6 (39.0) Plasma selenium, ng/ml Mean Mean (22.6) (21.5) 33 rd 33 rd th 50 th th 66 th

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 *mutually adjusted for other baseline covariates Cases Incidence Adjusted hazard ratios* Se PlaceboSePlaceboHR 95% CI P P, int Overall Age (yrs.) > 65 > Gender 0.54 Female Female Male Male

69 Cases Incidence Adjusted hazard ratios* Se PlaceboSePlaceboHR 95% CI P P, int Smoking 0.53 Never Never Former Former Current Current BMI 0.23 < 25 < *mutually adjusted for other baseline covariates Incidence of Type 2 DM by Baseline Characteristics

70 Incidence of Type 2 DM by Baseline Plasma Selenium *adjusted for age, BMI, gender, and smoking status at randomization Cases Incidence Adjusted hazard ratios* Se PlaceboSePlaceboHR 95% CI P P, int By median > > By tertiles > >

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

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

73 Se-Quintile 1 (< ng/ml) Se-Quintile 5 ( ng/ml) Cases/non-cases285/1,708311/1,266 Fully-adjusted OR 1.00 (reference) 1.57 (1.16–2.13) Selenium Status and Prevalent Diabetes NHANES III, 8,876 US adults 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 Czernichow S et al. Am J Clin Nutr. 2006; 84: μg Selenium mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc Baseline Plasma concentration β ± SE P ß-carotene, 0.5 µmol/L ß-carotene, 0.5 µmol/L –0.032 ± < Vitamin C, 4.9 µg/mL Vitamin C, 4.9 µg/mL –0.015 ± Vitamin E, 7.7 µmol/L Vitamin E, 7.7 µmol/L ± Selenium, 0.2 µmol/L Selenium, 0.2 µmol/L ± < Zinc, 1.8 µmol/L Zinc, 1.8 µmol/L –0.002 ±

75 Antioxidant Supplementation and Lipids SUMIVAX Trial, France, 7.5 years follow-up, n=12,741 Hercberg S et al. Lipids. 2005; 40: μg Selenium mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zincLipids Suppl vs. Placebo P Mean Cholesterol No difference Hypercholesterolemia Higher in Suppl (women) <0.05 Mean triglycerides Higher in Suppl (both sexes) <0.05 Hypertriglyceridemia Higher in Suppl (men) <0.05

76 Selenium Status and Lipids NHANES III, 5,452 US adults Bleys J, Navas-Acien A, Stranges S et al. Am J Clin Nutr. 2008; 88:416-23

77 Q1 <77.4 Q495.6 Q1 <113.7 Q Selenium Quartiles (µg/L) Stranges S et al. (under review) Total Cholesterol by Se Quartiles: UK NDNS 2000/01; US NHANES III

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

79 Biological Plausibility

80 Rayman MP. Lancet 2000; 356: Selenium Status in the NPC Trial vs. Europe

81 µg selenium/L plasma US Average 100 µg Se/day US RDA 55 µg Se/day China 10 µg Se/day Plasma Selenium and Selenoproteins Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79 NPC - Dose 200 µg Se/day

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

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

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

85 Benefits and Harms of Selenium Supplementation DiseaseBenefitsHarms Overall Mortality Unproved Cancer Incidence TotalPossible ProstatePossible ColorectalPossible Non-melanoma Skin Possible Cardio-metabolic CVDUnproved Type 2 Diabetes Possible HyperlipidemiaPossible

86 Prostate Cancer Selenium ? + -

87 Non-diabetics Diabetics …Diabetes and Prostate Cancer Risk… Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2006; 15: *P < * * * - 47% - 28%

88 …Diabetes and Prostate Cancer Risk… Hsing AW et al. Am J Clin Nutr 2007;86:843S-857S

89

90 Sel enium and Vitamin E C ancer Prevention T rial (SELECT) Cost: $175,000,000 Vitamin E (400 μg/day) Selenium (200 μg/day) +-T +-8,1008,10016,20016,200 8,1008,100 T16,20016,20032,400

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 Keshan The Nutritional Prevention of Cancer (NPC) Trial

93 Acknowledgments James R Marshall Mary E Reid Raj Natarajan Gerald F Combs Larry C Clark 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 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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