Applying the DRI Framework to Non-Chronic Disease Endpoints Case Studies Focusing on Adequacy Status Endpoints

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1 Applying the DRI Framework to Non-Chronic Disease Endpoints Case Studies Focusing on Adequacy Status Endpoints Allison A. Yates, Ph.D., R.D. Director, Beltsville Human Nutrition Research Center USDA/ARS

2 Three Basic Premises when Applying DRI Framework No decision is not an option There is a continuum of adequacy Quantitative determination of adequacy must be based on validated biomarker/data (evidence-based component)

3 Key Components of DRI Framework Criterion of adequacy and excess based on decreasing risk of disease or condition, or validated biomarker with strong evidence EAR set based on reliable dose response so that half of individuals are still inadequate Primary endpoint data used should be from more than one lab UL based on chronic intake and serious adverse effect

4 Case Studies Vitamin C as example of an antioxidant with a known continuum of adequacy Iodine as example of deficiency state of public health significance Vitamin K as example of poorly characterized intake & requirements resulting in AI

5 Panel on Dietary Antioxidants and Related Compounds NORMAN I. KRINSKY, chair, Tufts University School of Medicine GARY R. BEECHER, USDA Beltsville Human Nutrition Research Center RAYMOND F. BURK, Vanderbilt University Medical Center ALVIN C. CHAN, University of Ottawa JOHN W. ERDMAN, University of Illinois at Urbana-Champaign ROBERT A. JACOB, USDA Western Human Nutrition Research Center ISHWARLAL JIALAL, University of Texas Southwestern Medical Center LAURENCE W. KOLONEL, University of Hawaii JAMES R. MARSHALL, University of Arizona SUSAN TAYLOR MAYNE, Yale University School of Medicine ROSS L. PRENTICE, University of Washington, Seattle KATHLEEN B. SCHWARZ, Johns Hopkins Hospital DANIEL STEINBERG, School of Medicine, University of California, San Diego MARET G. TRABER, Oregon State University, Corvallis

6 Dietary Antioxidants and Related Compounds: Statement of Work Develop working definition of dietary antioxidants Review scientific literature regarding the antioxidant nutrients and selected components of food that may influence the bioavailability of those nutrients Develop dietary reference levels of intake for the selected nutrients and other food components Address the safety of high intakes of the selected nutrients and other food components Provide guidance in uses of the developed reference intakes

7 Dietary Antioxidant Definition A dietary antioxidant is a substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiological function in humans

8 Vitamin C Endpoints Scurvy Bleeding Gums Excess [Urinary Excretion] Capacity to Repair [100% Neutrophil Saturation] Chronic Diseases? // XXX? Increasing Intake of Vitamin C, mg/d

9 Diseases Associated with Increased Levels of ROS and RNS Age-related eye disease Atherosclerosis Cancer Coronary heart disease Inflammatory bowel disease Neurodegenerative disease Respiratory diseases Rheumatoid arthritis Diabetes

10 Possible Biomarkers for Vitamin C Inhibition of superoxide in neutrophils Oxidative DNA and chromosome damage Immune markers Common cold Relationship to chronic disease outcomes Cardiovascular disease Cancer Cataracts

11 What Were We Looking For? Scientifically valid experiments Measurements of relevant biomarkers Reliable intake data In vivo, rather than in vitro, experiments Strength of evidence Role in health

12 What Were We Not Looking For? Strictly observational data Strictly antioxidant-type functions Over-reliance on animal data Associations, rather than causation

13 Vitamin C Inhibition of Superoxide Produced by Neutrophils % Inhibition of Superoxide Production by Activated Neutrophils Arrows represent range of normal plasma vitamin C concentrations Extracellular Ascorbate Concentration (µmol/l) Anderson and Lukey, Ann NY Acad Sci, 498: , 1987

14 Vitamin C Concentration in Neutrophils DRIs for Vitamin C, Vitamin E, Selenium, and Carotenoids, IOM, 2000

15 Rationale for Recommendation for Vitamin C No accepted methodology comparing vitamin C intake and in vivo antioxidant effect Vitamin C functions as an antioxidant in leukocytes, no data relating this to vitamin C intake Leukocyte ascorbate levels reflect liver and body pool ascorbate

16 Criteria, EARs, and RDAs for Vitamin C - Adults (mg/day) Life Stage Criterion EAR RDA 19y+ Males Near max. neutrophil saturation y+ Females Extrapolation from data on men Preg, 18y Extrapolation from data on men + fetal needs based on young infant needs Preg, 19-50y Lact, 18y Extrapolation from data on men + human milk content Lact, 19-50y Extrapolation from data on men + human milk content Dietary Reference Intakes for Vitamin C, etc., IOM, 2000

17 Research Recommendations for Vitamin C Establishment of a reliable functional biomarker of vitamin C nutriture Valid assessment of vitamin C requirements for children 1 18 years Interaction of vitamin C and iron in vivo following supplementation Effect of vitamin C supplements in pregnancy on fetus Effect of vitamin C supplements in preventing chronic diseases

18 Vitamin C Intake for Men and Women Who Don t Smoke (Food and Supplements) EAR for women = 60 mg for men = 75 mg women below EAR = 10.5% men below EAR = 20.7%

19 Panel on Micronutrients ROBERT M. RUSSELL, Chair, USDA Human Nutrition Research Center on Aging, Tufts University JOHN L. BEARD, The Pennsylvania State University ROBERT J. COUSINS, University of Florida JOHN T. DUNN, University of Virginia GUYLAINE FERLAND, University of Montreal K. MICHAEL HAMBIDGE, University of Colorado Health Sciences Center SEAN LYNCH, Hampton VA Medical Center JAMES G. PENLAND, USDA Grand Forks Human Nutrition Research Center A. CATHARINE ROSS, The Pennsylvania State University BARBARA J. STOECKER, Oklahoma State University JOHN W. SUTTIE, University of Wisconsin JUDITH R. TURNLUND, USDA Western Human Nutrition Research Center KEITH P. WEST, Johns Hopkins School of Hygiene and Public Health STANLEY H. ZLOTKIN, The Hospital for Sick Children and University of Toronto

20 Iodine Essential component of the thyroid hormones involved in the regulation of various enzymes and metabolic processes

21 Three Basic Premises when Applying DRI Framework No decision is not an option There is a continuum of adequacy Quantitative determination of adequacy must be based on validated biomarker/data (evidence-based component)

22 Iodine Endpoints Cretinism, Mental Retardation Goiter Elevated TSH Levels Iodine Accumulation and Turnover Urinary Excretion > 100 µg/l Increasing Intake of Iodine, µ/d

23 Estimating the Average Requirement of Iodine for Adults Thyroid iodine accumulation (radioiodine) and turnover 96.5 µg/day, men & women, y, n = 18 (Fisher and Oddie, 1969) 91.2 µg/day, men & women from Arkansas, n = 274 (Fisher and Oddie, 1969) Absolute iodine uptake: 21 to 97 µg/day, n = 3 (DeGroot, 1966) Thyroid hormone secretion (method 1): µg/day Thyroid hormone secretion (method 2): µg/day Decision: Use turnover EAR adult = 95 µg/day Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

24 Criteria, EARs and RDAs for Iodine - Adults (µg/day) Life Stage Criterion EAR RDA 19-50y Iodine turnover > 51y Extrapolated from y Preg, 18y Balance data during pregnancy Preg, 19-50y Balance data during pregnancy Lact, 18y Age group + human milk content Lact, 19-50y Age group + human milk content

25 Estimating the Average Requirement of Iodine for Children y Iodine balance study (4 days) on nutritionally rehabilitated children 1.5 to 2.5y (Ingenbleek & Malvaux, 1974) Intake = 63.5 µg/day Balance = µg/day C.V. ~ 20% EAR = 65 µg/day If extrapolated from adults, EAR ~ 36 µg/day Decision: Use balance study as resulted in positive balance EAR 1-3y = 65 µg/day Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

26 Estimating the Average Requirement of Iodine for Children y Iodine balance study with 8 y old children (Malvaux, et al., 1969) Intake = 20 to 40 µg/day Balance = - 23 to 26 µg/day EAR = = 65 µg/day If extrapolated from adults, EAR ~ 47 µg/day Decision: Use balance study as resulted in higher estimate EAR 4-8 y = 65 µg/day Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

27 Estimating the Average Requirement of Iodine for Children y Iodine balance study with sixteen 9-13 y old boys & girls in Belgium (Malvaux, et al., 1969) Ave. Intake = 31 µg/day Ave. Balance = - 24 µg/day EAR = = 55 µg/day If extrapolated from adults, EAR ~ 73 µg/day Decision: Use adult extrapolation which resulted in higher estimate EAR 9-13 y = 73 µg/day Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

28 Estimating the Average Requirement of Iodine from Prevalence of Goiter Urinary iodine excretion ~ intake Estimate median urine volume/day/kg Estimate % dietary iodine excreted in urine (~ 92%) when adequate Obtain estimate of dietary intake that results in observed level of urinary iodine excretion: 2 For a 40 kg 10 year old, urinary excretion 92% intake, so urinary excretion of 100 µg/day results in 100 RDA = 125 µg/day Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

29 Estimating the Average Requirement of Iodine for Adolescents y Iodine balance study with ten y old boys & girls in Belgium (Malvaux, et al., 1969) Ave. Intake = 34 µg/day Ave. Balance = - 24 µg/day EAR = = 58 µg/day If extrapolated from adults, EAR ~ 95 µg/day Decision: Use adult extrapolation which resulted in higher estimate EAR y = 95 µg/day Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

30 Criteria, EARs, RDAs, and AIs for Iodine - Children (µg/day) Life Stage Criterion EAR RDA AI 0-6 mo Human milk content mo Extrapolated from 0-6 mo y Balance data on children y Balance data on children y Extrapolated from adults y Extrapolated from adults Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

31 Vitamin K Required as a coenzyme for the synthesis of proteins active in blood coagulation and bone metabolism

32 Three Basic Premises when Applying DRI Framework No decision is not an option There is a continuum of adequacy Adequacy must be based on validated biomarker/data (evidence-based component)

33 Vitamin K Endpoints ypoprothrom -binemia Plasma Factor VII Urinary GLA Residues Undercarboxylated Prothrombin, Osteocalcin Osteoporosis, Atherosclerosis Order of Endpoints not Identified 0 Increasing Intake of Vitamin K, µ/d

34 Criteria and AIs for Vitamin K Life Stage Criterion (µg/day) AI Male Female 0 6 mo Human milk content mo Extrapolated from 0-6 mo y Median intake from NHANES III y Median intake from NHANES III y Median intake from NHANES III y Median intake from NHANES III y Median intake from NHANES III Pregnancy, Lactation, see age group Dietary Reference Intakes for Vitamin A, etc., IOM, 2001

35 Three Basic Premises when Applying DRI Framework No decision is not an option There is a continuum of adequacy Quantitative determination of adequacy must be based on validated biomarker/data (important evidence-based component), whether for Calcium or Sulfate!

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