Dietary Reference Intakes Research Synthesis: Workshop Summary (2007)

1

A.I.02

Epidemiological research that evaluates the impact of habitual (lifetime) nutrient intake on functional outcomes related to specific diseases is urgently needed in order to optimize nutrient recommendations.

Major Knowledge

2

A.I.03

Epidemiological research that evaluates the impact of habitual (lifetime) dietary calcium intake on peak bone mass and fracture risk is urgently needed in order to optimize calcium recommendations.

Major Knowledge

3

A.I.04

Epidemiological research that evaluates the impact of habitual (lifetime) dietary calcium intake on prostate cancer is urgently needed in order to optimize calcium recommendations.

Major Knowledge

4

A.I.05

Epidemiological research that evaluates the impact of habitual (lifetime) dietary calcium intake on renal stones is urgently needed in order to optimize calcium recommendations.

Major Knowledge

6

A.I.07

Epidemiological research that evaluates the role of habitual (lifetime) dietary magnesium intake in the development of hypertension, cardiovascular disease, and diabetes is urgently needed in order to optimize magnesium recommendations.

Major Knowledge

7

A.I.08

Research is needed to assess methods for determining individual risk of chronic disease risk of chronic disease outcomes so that associations with nutrient status can be better understood.

Major Knowledge

8

A.I.09

The potential relationship between allelic variation in the vitamin D receptor (VDR), bone vitamin D receptor (VDR), bone mineral density, and osteoporosis within and between population groups requires further elucidation in order to determine if VDR polymorphisms are a variable influencing life-long calcium intake needs.

Major Knowledge

9

A.I.10

For children ages 1 through 18 years, research is needed to evaluate the dietary intakes of the dietary intakes of calcium, phosphorus, magnesium, and vitamin D required to optimize bone mineral accretion, especially in relation to changing age ranges for the onset of puberty and growth spurts.

Major Knowledge

10

A.I.11

With respect to dietary intake needs for vitamin D, information is required by geographical and racial variables that reflect the mix of the Canadian and United States populations and the influence of sunscreens on intake requirements.

Major Knowledge

11

A.II.02

Calcium balance studies should be augmented with stable or radioactive tracers of calcium to estimate aspects of calcium homeostasis with changes in defined intakes (i.e., fractional absorption, bone calcium balance, and bone turnover rates).

Research Method

gate markers of osteopenia could be used in epidemiological studies.

13

A.II.04

Investigations should include assessment of the effect of ethnicity and osteoporosis and osteoporosis phenotype on the relationship between dietary calcium, desirable calcium retention, bone metabolism, and bone mineral content.

Knowledge Gaps

14

A.II.05

Investigations should include evaluation of the independent impact of diet, lifestyle (especially physical activity), and hormonal changes on the utilization of dietary calcium for bone deposition and growth in children and adolescents. These studies need to be done in populations for which the usual calcium intakes range from low to above adequate.

Knowledge Gaps

15

A.II.06

Investigations should include epidemiological studies of the interrelationships between calcium intake and fracture risk, osteoporosis, prostate cancer, and hypertension must be pursued to determine if calcium intake is an independent determinant of any of these health outcomes. Control of other factors potentially associated as other risk factors for these health problems is essential (for example, fat intake in relation to cancer and cardiovascular disease; weight bearing activity; and dietary components such as salt, protein, and caffeine in relation to osteoporosis). Such epidemiological studies need to be conducted in middle-aged as well as older adult men and women.

Major Knowledge

16

A.II.07

Carefully controlled studies are needed to determine the strength of the causal association between calcium intake vis-à-vis the intake of other nutrients and kidney stones in healthy individuals.

Knowledge Gaps

17

A.II.08

Because of their potential to increase the risk of mineral depletion in vulnerable populations, calcium–mineral interactions should be the subject of additional studies.

Knowledge Gaps

18

A.III.01

The model that relates absorbed phosphorus intake to serum phosphorus must be evaluated in clinical studies using oral phosphorus intakes, and investigated in children and adolescents as well as adults.

Major Knowledge

19

A.III.02

Bone mineral mass as a function of dietary phosphorus intake should be investigated at all stages of the life cycle.

Knowledge Gaps

20

A.III.03

The practical effect of phosphate-containing food additives on trace mineral status (iron, copper, and zinc) should be evaluated.

Knowledge Gaps

surveys that include estimates of intakes from food, water, and supplements in healthy populations in all life stages.

22

A.IV.03

Biochemical indicators that provide an accurate and specific marker(s) of magnesium status must be investigated in order to assess their ability to predict functional outcomes that indicate adequate magnesium status over prolonged periods.

Major Knowledge

23

A.IV.04

Basic studies need to be initiated in healthy individuals, including experimental magnesium depletion studies that measure changes in various body magnesium pools.

Major Knowledge

24

A.IV.05

Investigations should be conducted to determine the most valid units to use in expressing estimates of magnesium requirements (body weight, fat-free mass, or total body unit).

Major Knowledge

25

A.IV.06

Magnesium balance studies might be one indicator utilized as a marker of magnesium status. In magnesium balance studies, strict adherence to criteria suggested (IOM. 1997. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press. Chapter 6—Magnesium) would improve their application to dietary recommendations.

Research Method

26

A.IV.07

Investigations are needed to assess the interrelationships between dietary magnesium intakes, indicators of magnesium status, and possible health outcomes that may be affected by inadequate magnesium intakes. Possible health outcomes include hypertension, hyperlipidemia, atherosclerotic vascular disease, altered bone turnover, and osteoporosis.

Major Knowledge

27

A.IV.08

Based on the evidence of abnormal magnesium status and health outcomes [from research in Recommendation ID Code A.IV.07 (pg.249)], intervention studies to improve magnesium status and to assess its impact on specific health outcomes would be appropriate. Possible health outcomes include hypertension, hyperlipidemia, atherosclerotic vascular disease, altered bone turnover, and osteoporosis.

Knowledge Gaps

28

A.IV.09

The toxicity of pharmacological doses of magnesium requires further investigation.

Knowledge Gaps

29

A.V.01

Research is needed to evaluate how geographical and racial variables (that reflect the mix of the Canadian and American population) affect vitamin D status at various levels of vitamin D intake throughout the lifespan.

Knowledge Gaps

30

A.V.02

Research is needed to evaluate the influence of sunscreens on vitamin D status.

Knowledge Gaps

various intakes of vitamin D on circulating concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] during winter at a time when no vitamin D comes from sunlight exposure. During this time, the body adapts by increasing the renal metabolism of 25-hydroxyvitamin D [25(OH)D] to 1,25-dihydroxyvitamin D[1,25(OH)2D] and the efficiency of intestinal calcium absorption, thereby satisfying the increased calcium requirement by the rapidly growing skeleton.

32

A.V.04

It is very difficult to determine the reference values for vitamin D in healthy young adults aged 18 through 30 and 31 through 50 years in the absence of sunlight exposure because of their typically high involvement in outdoor activity and the unexplored contribution of sunlight to vitamin D stores. More studies are needed that evaluate various doses of vitamin D in young and middle-aged adults in the absence of sunlight exposure.

Knowledge Gaps

33

A.V.05

A major difficulty in determining how much vitamin D is adequate for the body’s requirement is that a normal range for serum 25-hydroxyvitamin D [25(OH) D] is 25 to 137.5 nmol/ liter (10 to 55 ng/ml) for all gender and life stage groups. However, there is evidence, especially in the elderly, that in order for the parathyroid hormone (PTH) to be at the optimum level, a 25-hydroxyvitamin D[25(OH)D] of 50 nmol/ liter (20ng/ml) or greater may be required. Therefore, more studies are needed to evaluate other parameters of calcium metabolism as they relate to vitamin D status including circulating concentrations of parathyroid hormone (PTH).

Knowledge Gaps

34

A.V.06

The development of methodologies to assess changes in body stores of vitamin D is needed to accurately assess requirements in the absence of exposure to sunlight. Such work would markedly assist in the estimation of reference values for all life stage groups.

Research Method

35

A.VI.01

Epidemiological studies (especially analytical studies) of the relationships among fluoride exposures from all major sources and the prevalence of dental caries and enamel fluorosis at specific life stages should continue for the purposes of detecting trends and determining the contribution of each source to the effects demonstrated.

Knowledge Gaps

37

A.VI.03

Studies are needed to define the effects of metabolic and environmental variables on the absorption, excretion, retention, and biological effects of fluoride. Such variables would include the composition of the diet (for example, calcium content), acid-base balance, and the altitude of residence.

Knowledge Gaps

38

B.I.01

Because of the difference in the bioavailability of food folate and the monoglutamate form of folate, it is recommended that both food folate and folic acid be included in tables and databases of food composition and in reports of intake. That is, the content or intake of naturally occurring food folate should be reported separately from that of folate provided by fortified foods and supplements.

Research Method

39

B.I.02

To fill information gaps, studies designed specifically to estimate average requirements in apparently healthy humans should be conducted for some micronutrients.

Major Knowledge

39.1

B.I.02.a

See Recommendation ID Code B.I.02.

Null

39.2

B.I.02.b

See Recommendation ID Code B.I.02.

Null

40

B.I.03

To fill information gaps, studies designed to generate usable data on the micronutrient needs of infants, children, adolescents, the elderly, and pregnant and lactating women should be conducted. Studies should use graded levels of nutrient intake and a combination of response indices.

Major Knowledge

40.1

B.I.03.a

See Recommendation ID Code B.I.03.

Null

40.2

B.I.03.b

See Recommendation ID Code B.I.03.

Null

40.3

B.I.03.c

See Recommendation ID Code B.I.03

Null

40.4

B.I.03.d

See Recommendation ID Code B.I.03.

Null

40.5

B.I.03.e

See Recommendation ID Code B.I.03.

Null

41

B.I.04

To fill information gaps, appropriately designed studies to determine the role of selected micronutrients in reducing the risk of certain chronic diseases should be conducted.

Major Knowledge

41.1

B.I.04.a

See Recommendation ID Code B.I.04.

Null

41.2

B.I.04.b

See Recommendation ID Code B.I.04.

Null

42

B.I.05

To fill information gaps, appropriately designed studies to determine the role of choline in reducing the risk of certain chronic diseases should be conducted.

Major Knowledge

43

B.I.06

To fill information gaps, studies designed to detect adverse effects of chronic high intakes of selected micronutrients should be conducted.

Major Knowledge

43.2

B.I.06.b

See Recommendation ID Code B.I.06.

Null

43.3

B.I.06.c

See Recommendation ID Code B.I.06.

Null

44

B.I.08

Conduct studies to provide the basic data for constructing risk curves and benefit curves across the exposures to food folate and to folate (folic acid) added to foods and taken as a supplement. Such studies would provide estimates of the risk of developing neural tube defects, vascular disease, and neurological complications in susceptible individuals consuming different amounts of folate. With the new U.S. regulations on the fortification of cereal grains with folate, it is now possible to investigate the health effects, both positive and negative, of folate fortification on folate intake and health status.

Major Knowledge

44.1

B.I.08.a

See Recommendation ID Code B.I.08.

Null

44.2

B.I.08.b

See Recommendation ID Code B.I.08.

Null

45

B.I.09

Conduct investigations of the magnitude of the effect of intake of folate, vitamin B6, vitamin B12, and related nutrients for preventing vascular disease and other chronic degenerative diseases. Possible mechanisms for the influence of genetic variation should also be investigated.

Major Knowledge

45.1

B.I.09.a

See Recommendation ID Code B.I.09.

Null

45.2

B.I.09.b

See Recommendation ID Code B.I.09.

Null

46

B.I.10

Conduct studies to overcome the methodological problems in the analysis of folate, including the development of sensitive and specific deficiency indicators and of practical, improved methods for analyzing the folate content of foods and determining its bioavailability.

Major Knowledge

47

B.I.11

Conduct studies to develop economical, sensitive, and specific methods to assess the prevalence, causes, and consequences of vitamin B12 malabsorption and deficiency and to prevent and treat these conditions. One reason these methods are especially needed is because it appears that vitamin B12 deficiency greatly increases the potential of folate to cause adverse effects.

Major Knowledge

47.1

B.I.11.a

See Recommendation ID Code B.I.11.

Null

48

B.I.12

Investigate how folate and related nutrients influence normal cellular differentiation and development, including embryogenesis and neoplastic transformation.

Major Knowledge

49.1

B.I.13.a

See Recommendation ID Code B.I.13.

Null

50

B.I.14

Investigate whether the folate requirement varies substantially by trimester of pregnancy. These investigations appear to be a priority from a public health perspective.

Major Knowledge

50.1

B.I.14.a

See Recommendation ID Code B.I.14.

Null

50.2

B.I.14.b

See Recommendation ID Code B.I.14.

Major Knowledge

51

B.I.15

Develop indicators on which to base vitamin B6 requirements.

Major Knowledge

52

B.II.01

Priority should be given to studies useful for setting Estimated Average Requirements (EARs) for thiamin for children, adolescents, pregnant and lactating women, and the elderly. Future studies should be designed around the Estimated Average Requirement (EAR) paradigm, use graded levels of thiamin intake with clearly defined cutoff values for clinical adequacy and inadequacy, and be conducted for a sufficient duration. To do this, close attention should be given to the identification of indicators on which to base thiamin requirements.

Major Knowledge

53

B.II.02

If studies are designed to test high doses of thiamin for possible beneficial effects, the design should also provide for the careful investigation of possible adverse effects.

Research Method

54

B.III.01

Priority should be given to studies useful for setting Estimated Average Requirements (EARs) for riboflavin for children, adolescents, pregnant and lactating women, and the elderly. Future studies should be designed specifically around the Estimated Average Requirement (EAR) paradigm, use graded levels of riboflavin intake and clearly defined cutoff values for clinical adequacy and inadequacy, and be conducted for a sufficient duration.

Major Knowledge

55

B.III.02

Develop another functional test for riboflavin status to corroborate and augment the presently used flavin–adenine dinucleotide-dependent erythrocyte glutathione reductase (e.g., a test using a flavin mononucleotide-dependent erythrocyte enzyme such as the pyridoxine [pyridoxamine] 5′-phosphate oxidase).

Knowledge Gaps

56

B.III.03

Examine the effects of physical activity on the requirement for riboflavin.

Knowledge Gaps

57

B.IV.01

For niacin, data useful for setting the Estimated Average Requirement (EAR) for children, adolescents, pregnant women, and lactating women are scanty. To fill information gaps, additional research on niacin requirements is desired for children, adolescents, pregnant women, and lactating women.

Knowledge Gaps

namide adenine dinucleotide (NAD) needs for increased adenosine diphosphate (ADP) ribosylation resulting from oxidant– deoxyribonucleic acid (DNA) damage.

59

B.IV.03

Priority should be given to development of sensitive and specific blood measures of niacin status. Current assessments of niacin status and requirement are based solely on urinary metabolite measures; measurements of plasma metabolites such as the 2-pyridone derivatives may be productive. Two recent experimental studies have suggested erythrocyte nicotinamide adenine dinucleotide (NAD) as a functional blood measure of niacin status [Fu CS, Swendseid ME, Jacob RA, McKee RW. 1989. Biochemical markers for assessment of niacin status in young men: Levels of erythrocyte niacin coenzymes and plasma tryptophan. J Nutr 119(12):1949-1955; Ribaya-Mercado J, Russell R, Rasmussen H, Crim M, Perrone- Petty G, Gershoff S. 1997. Effect of niacin status on gastrointestinal function and serum lipids. FASEB J 11: A179. Abstract.], but further work is needed in clinical populations.

Major Knowledge

60

B.V.01

Priority should be given to studies useful for setting Estimated Average Requirements (EARs) for vitamin B6 for children, adolescents, pregnant and lactating women, and the elderly. Future studies should be designed around the Estimated Average Requirement (EAR) paradigm, use graded levels of nutrient intake and clearly defined cutoff values for clinical adequacy and inadequacy, and be conducted for a sufficient duration. To do this, close attention should be given to the identification of indicators on which to base vitamin B6 requirements.

Major Knowledge

60.1

B.V.01.a

See Recommendation ID Code B.V.01.

Null

61

B.VI.01

Investigations should be conducted to determine the mechanisms and magnitude of relationships of folate intake with risk reduction for the occurrence of neural tube defects (NTDs) and vascular disease and the influence of related factors (including genetic polymorphism) on these relationships. Targeted intervention programs need a clearer understanding of the mechanisms by which adequate folate intake ensures normal embryogenesis and may reduce vascular disease risk.

Major Knowledge

linked to metabolic function and traditional indices of folate status.

63

B.VI.03

Develop more precise and reproducible methods of analysis for the estimation of both blood and food folate and for the estimation of folate bioavailability. Improved methods would allow for comparison of status indicators among laboratories, revision of the food folate databases, and improved estimation of how dietary requirements are influenced by the food matrix and the source of folate (food or synthetic).

Research Method

64

B.VI.04

Identify and quantify adverse effects of high intakes of folate. Further investigation is needed on the effect of increasing folate intake from supplements and fortified foods on the onset and progression of vitamin B12 deficiency.

Major Knowledge

65

B.VI.05

Determine the mechanisms by which maternal folate sufficiency reduces the occurrence of neural tube defect (NTD) in the infant, including the establishment of which genes are responsible for the heritability and folate-responsiveness of NTD.

Knowledge Gaps

66

B.VI.06

Determine the effect of folate fortification on folate intake and occurrence of neural tube defect (NTD) and vascular disease. With the new U. S. regulations on the fortification of cereal grains with folate, it is now possible to investigate the health effects, both positive and negative, of folate fortification on folate intake and health status.

Major Knowledge

66.1

B.VI.06.a

See Recommendation ID Code B.VI.06.

Null

67

B.VI.07

Determine whether folate status affects the risk of birth defects other than neural tube defect (NTD) and of chronic diseases other than vascular disease (e.g., cancer). With the new U. S. regulations on the fortification of cereal grains with folate, it is now possible to investigate the health effects, both positive and negative, of folate fortification on folate intake and health status.

Major Knowledge

67.1

B.VI.07.a

See Recommendation ID Code B.VI.07.

Null

68

B.VII.01

Investigate the prevalence of vitamin B12 deficiency as diagnosed by biochemical, neurological, or hematological abnormalities (e.g., methylmalonic acid and holotranscobalamin II).

Major Knowledge

69

B.VII.02

Develop improved, economical, and sensitive methods to detect vitamin B12 malabsorption and deficiency before adverse neurological and hematological changes occur.

Major Knowledge

with food- bound malabsorption, research is needed on the form and amount of vitamin B12 that can normalize and maintain vitamin B12 stores. For vegetarians, information is needed about the absorption of vitamin B12 from dairy products, algae, and fortified food products.

71

B.VII.04

Investigate the feasibility, potential benefits, and adverse effects of fortification of cereal grain foods with vitamin B12 considering stability, identity of any degradation products, and bioavailability for normal individuals and those who malabsorb protein-bound vitamin B12.

Knowledge Gaps

72

B.VII.05

Investigate the contribution of bacterial overgrowth to elevated serum methylmalonic acid, to determine the variability of this indicator of vitamin B12 status.

Knowledge Gaps

73

B.VIII.01

To fill information gaps, further investigations about pantothenic acid as a nutrient are needed. Information gaps include human requirements, intake, bioavailability, toxicity, and metabolic effects. Research to date has indicated little cause for concern about the adequacy of pantothenic acid intake for healthy people; deficiency states can be produced only by actively interfering with the absorption or bacterial production pantothenic acid.

Major Knowledge

73.1

B.VIII.01.a

See Recommendation ID Code B.VIII.01.

Null

73.2

B.VIII.01.b

See Recommendation ID Code B.VIII.01.

Null

74

B.VIII.02

Investigate pantothenic acid requirements of different age groups, especially infants, children, and the elderly.

Major Knowledge

75

B.VIII.03

Investigate bioavailability of pantothenic acid from different foods and mixed diets and of the extent to which synthesis by intestinal bacteria contributes to meeting the requirement.

Major Knowledge

76

B.VIII.04

Using newer methods, such as high-pressure liquid chromatography, analyze pantothenic acid in foods. At present, pantothenic acid intakes are not calculated in national surveys such as the Third National Health and Nutrition Examination Survey (NHANES III) because of a lack of information on the pantothenic acid content of foods.

Major Knowledge

78

B.IX.01

There is a serious lack of data useful for setting Estimated Average Requirements (EARs) for biotin. Although the limited information seems to indicate that there is little cause for concern about the adequacy of biotin intake for healthy people, information on the human requirements, intake, bioavailability, toxicity, and metabolic effects of this compound is needed. Deficiency states can be produced only by actively interfering with the absorption or bacterial production of biotin.

Major Knowledge

78.1

B.IX.01.a

See Recommendation ID Code B.IX.01.

Null

78.2

B.IX.01.b

See Recommendation ID Code B.IX.01.

Null

79

B.X.01

To fill information gaps, investigations should be conducted to obtain sufficient human data to determine whether choline is essential in the human diet, how much choline is required if it is essential, and the public health impact of poor choline nutriture. Although choline can be formed in the human body from endogenous precursors, little is known about dietary intake and the relative amounts of choline derived from the diet and from endogenous synthesis. Additional information gaps include bioavailability, toxicity, and metabolic effects.

Major Knowledge

79.1

B.X.01.a

See Recommendation ID Code B.X.01.

Null

79.2

B.X.01.b

See Recommendation ID Code B.X.01.

Null

80

B.X.03

Investigate the effects of the use of graded levels of dietary intake of choline on parameters of health. This would include assessing plasma and tissue choline compounds and metabolites; plasma cholesterol and homocysteine concentrations; erythrocyte folate; and liver, renal, brain, and other organ function. Animal studies suggest that choline intake may affect long-term health.

Major Knowledge

80.1

B.X.03.a

See Recommendation ID Code B.X.03.

Null

81

B.X.04

Data on the composition of human food are needed for choline, phosphocholine, glycerophosphocholine, sphingomyelin, phosphatidylcholine, and betaine and the analytic sensitivity and specificity of methods for analysis of food composition need to be validated.

Research Method

82

B.X.05

Human studies on interrelationships among requirements for choline, methionine, folate, vitamin B6, and vitamin B12 to compare the homocysteine-lowering effects of combinations of these nutrients are needed.

Major Knowledge

synthesis of choline. It will be important to conduct studies on the bioavailability of choline and choline compounds and on the rate of de novo synthesis of choline in vivo.

84

B.X.07

Conduct studies using increasing levels of dietary intake of choline designed to assess toxicity for all organ systems, including heart, liver, brain and kidney; fishy body odor; and possible growth suppression in children from observational data and as determined by experimental studies in animal models.

Knowledge Gaps

85

B.XI.04

For many nutrients, further investigation should be conducted on the biochemical values that reflect abnormal function.

Major Knowledge

85.1

B.XI.04.a

See Recommendation ID Code B.XI.04.

Null

85.2

B.XI.04.b

See Recommendation ID Code B.XI.04.

Null

86

B.XI.05

For many of the B vitamins, further investigation should be conducted on the relationship of existing status indicators to clinical end points to allow their use for setting Estimated Average Requirements (EARs).

Major Knowledge

87

B.XI.06

For some of the B vitamins, new clinical end points of impaired function need to be identified and related to status indicators.

Knowledge Gaps

88

B.XI.07

The depletion–repletion research paradigms that are often used in studies of requirements, although not ideal, are still probably the best approach to determining vitamin requirements. However, these studies should be designed to meet three important criteria. See B.XI.07a, B.XI.07b, and B.XI.07c.

Research Method

88.1

B.XI.07.a

An indicator of vitamin status is needed for which a cutoff point has been identified, below (or above) which vitamin status is documented to be impaired. (In the case of folate, an erythrocyte level of 300 nmol/L [140 ng/mL] fits this criterion because lower levels are associated with megaloblastic changes in blood cells. In the case of vitamin B6 and several other B vitamins, however, there is little information relating levels of status indicators to functional sufficiency or insufficiency. Instead, the levels of indicators normally used to assess requirements are those exhibited by subjects on a baseline adequate diet—even though there is no information regarding whether this level of intake is greatly inexcess of adequate, barely adequate, or deficient.) The amount needed for restoration of biochemical status indicators to baseline values is not necessarily equivalent to the requirement for the nutrient.

Research Method

steady state to be reached. This can be very problematic because turnover rates of total body content for B vitamins range from less than 1 to about 3 percent per day, which suggests that long periods are needed for equilibrium. In the case of erythrocyte folate, theoretically the erythrocytes have to turn over completely (approximately 90 days). Study design should allow for examination of the effects of initial status on response to maintenance or depletion and repletion.

88.3

B.XI.07.c

Intakes used in repletion regimens should bracket the expected Estimated Average Requirement (EAR) intake to assess the EAR more accurately and to allow for a measure of variance. In addition, an accurate assessment of variance requires a sufficient number of subjects.

Research Method

89

B.XI.08

A relatively new and increasingly popular approach to determining requirements is kinetic modeling of body pools using steady state compartmental analyses. This approach is unlikely to supplant depletion–repletion studies because it has a number of drawbacks; for example,a number of assumptions that cannot be tested experimentally are often needed and estimates obtained for body pool sizes are inherently imprecise. Even if accurate assessments of body pool sizes were possible and were obtained, such information would be useful in setting a requirement only if the size of the bodypool at which functional deficiency occurs could be established. The amount of the nutrient needed for restoration of biochemical status indicators to baseline values is not necessarily equivalent to the requirement for the nutrient.

Research Method

89.1

B.XI.08.a

See Recommendation ID Code B.XI.08.

Null

89.2

B.XI.08.b

See Recommendation ID Code B.XI.08.

Null

89.3

B.XI.08.c

See Recommendation ID Code B.XI.08.

Null

89.4

B.XI.08.d

See Recommendation ID Code B.XI.08.

Null

90

B.XI.10

For some of the B vitamins, studies should examine whether the requirement varies substantially by trimester of pregnancy.

Major Knowledge

91

B.XI.18

A growing number of studies suggests that there are complex interrelationships among nutrients (e.g., vitamin B6, folate, vitamin B12 and perhaps choline, methionine, and riboflavin), but these are not well understood in relation to the maintenance of normal nutritional status and to the prevention of chronic degenerative disease. These interactions may affect the need for one or more of the nutrients.

Major Knowledge

of blood folate and for the analysis of folate content of food. For folate, as for some other micronutrients, there are serious limitations in the methods available to analyze laboratory values indicative of nutrient status and to determine the nutrient content of foods. These methodological limitations have slowed progress in conducting or interpreting studies of nutrient requirements for folate.

93

B.XI.21

To fill major knowledge gaps, compare the bioavailability of food folate from mixed diets and of folate in the form of folic acid (from supplements or fortification) consumed with food. This research should include an examination of the mechanisms by which bioavailability is altered by food matrices.

Major Knowledge

94

B.XI.23

Major gaps in knowledge include the mechanisms by which maternal folate sufficiency reducesthe occurrence of neural tube defect (NTD) in the infant (e.g., evaluation of whether increased NTD risk is due to folate deficiency or to the mode of action of folate sufficiency [does it act on mother, embryo, or both?]); the relative efficacy of food folate, folate added to food, and folate supplements in reducing neural tube defect (NTD) risk; the process, if any, by which folate influences the embryonic process of neurulation; and the genes that are responsible for the heritabilityand folate-responsiveness of neural tube defect (NTD). See B.XI.23.a.

Major Knowledge

94.1

B.XI.23.a

Genetic studies of the heritability and folate-responsiveness of neural tube defect (NTD) could include: (1) linkage analyses in suitable genetically homogeneous human populations to assess the etiologic relationship between neural tube defect (NTD) and a variety of genetic alterations (including the thermolabile variant of 5,10-methylenetetrahydrofolate reductase) and in the genes responsible for NTD in the curly tail mouse; (2) investigation of whether alterations in any of these genes produce neuraltube defect (NTD) when induced in mouse models, yield folate-responsive NTD in mouse models, and provide suitable markers for assessing NTD risk in human populations; and (3) identification of an animal model for common human neural tube defect (NTDs) that is responsive to relevant levels of folate.

Major Knowledge

95

B.XI.31

For B vitamins and choline as a group, only a few studies have been conducted that were explicitly designed to address adverse effects of chronic high intake. To allow sufficient data for deriving Tolerable Upper Intake Levels (ULs), additional research is required on the adverse effects of B vitamins and choline.

Knowledge Gaps

96

C.I.01

Because the various forms of vitaminE are not interconvertible and because plasma concentrations of alpha-tocopherol are dependent upon the affinity of the hepatic alpha-tocopherol transfer protein for the various forms, it is recommended that relative biological potencies of the various forms of vitamin E be reevaluated.

Major Knowledge

97

C.I.02

Until research is completed to reevaluate the relative biological potencies of the forms of vitamin E, the actual concentrations of each of the various vitamin E forms in food and biological samples should be reported separately, wherever possible.

Research Method

98

C.I.06

To fill information gaps, validated biomarkers to evaluate oxidative stress and the relationship between antioxidant intake and health and disease should be identified.

Major Knowledge

99

C.I.08

Conduct studies to provide the basic data for constructing risk curves and benefit curves across the exposures to dietary and supplemental in takes of vitamin C, vitamin E, selenium, and beta-carotene and other carotenoids. These studies should be followed by nested case-control studies to determine the relationship of the biomarkers of oxidative stress to chronic disease. Finally, full-scale intervention trials should be done to establish the preventive potential of a nutrient for chronic disease.

Major Knowledge

100

C.I.09

Conduct investigations of gender specificity of the metabolism and requirements for vitamin C, vitamin E, selenium, and beta-carotene and other carotenoids. For example, women and children with low intakes of selenium are at higher risk of Keshan disease than are men with similar intakes. Women are at higher risk of macular degeneration even at similar plasma concentrations of carotenoids.

Major Knowledge

100.1

C.I.09.a

See Recommendation ID Code C.I.09.

Null

101

C.I.10

Conduct studies to validate methods and possible models for estimating Dietary Reference Intakes (DRIs) in the absence of data for some life stage groups, such as children, pregnant and lactating women, and older adults.

Major Knowledge

102

C.I.11

Conduct research to determine the interactions and possible synergisms of vitamin C, vitamin E, selenium, and beta-carotene with each other, with other nutrients and food components, and with endogenous antioxidants. Multifactorial studies are needed to demonstrate in vivo actions as well as synergisms that have been shown to occur in vitro.

Major Knowledge

and treatment of specific viral infections or other infections.

104

C.I.13

Conduct investigations of the magnitude and role of genetic polymorphisms in the mechanisms of actions of vitamin C, vitamin E, selenium, and beta-carotene and other carotenoids.

Major Knowledge

105

C.II.01

Knowledge of vitamin C intakes needed to fulfill specific functional roles of ascorbate is needed to allow more accurate and precise determinations of the individual and average population requirements of vitamin C.

Major Knowledge

106

C.II.02

Some current candidates for specific functional roles of ascorbate that could be used as functional measures include pathways related to collagen and carnitine metabolism, oxidative damage, and oral health indices; however, research on new functions of vitamin C is needed.

Major Knowledge

107

C.II.03

Determination of vitamin C requirements based on antioxidant functions will require development of more reliable tests for in vivo oxidative damage and further understanding of the interactions of ascorbate with other physiological antioxidants.

Research Method

108

C.II.04

A practical method for measuring the vitamin C body pool is needed as a standard of comparison against proposed functional measures and measures of health or disease end points.

Research Method

109

C.II.05

Since the requirements for children ages 1through 18 years are extrapolated from the adult Estimated Average Requirements (EARs), it is critically important to conduct large-scale studies with children using state-of-the-art biomarkers to assess their vitamin C requirement.

Major Knowledge

110

C.II.06

Population studies on the relationship of vitamin C nutriture and chronic disease should focus more on individuals or populations who eat few fruits and vegetables and are marginally deficient in vitamin C.

Research Method

111

C.II.07

Attention also has to be given to methods for sorting out the effects of vitamin C intake from those of other dietary and lifestyle factors that may also affect disease risk.

Research Method

related in vivo reactions—for example, during simultaneous supplement ingestion, iron overload, and inflammation or tissue trauma where non-protein-bound iron may be released.

113

C.II.09

A small number of isolated reports raise concern that high vitamin C intakes during pregnancy may expose the fetus or neonate to risks of withdrawal symptoms, hemolysis, or oxidant damage. Further research is needed to confirm or refute these concerns.

Knowledge Gaps

114

C.III.01

Biomarkers are needed for use in assessment of vitamin E intake and vitamin E status. What are the determinants of plasma concentrations of alpha-tocopherol, and are these concentrations regulated? Are plasma alpha-tocopherol concentrations the best parameter for assessing adequate plasma vitamin E status in apparently healthy individuals? Does an alpha-tocopherol/lipid (e.g., total lipid, triacylglycerol, or cholesterol) ratio better reflect optimal plasma vitamin E status?

Major Knowledge

115

C.III.02

Since the Recommended Dietary Allowances (RDAs) for vitamin E for children ages 1 through 18 years are extrapolated from the adult RDAs, it is critically important to conductlarge-scale studies with children using state-of-the-art biomarkers to assess their vitamin E requirements.

Major Knowledge

116

C.III.03

Validate dietary intake instruments toassess intake of vitamin E. This methodology requires identification of the specific fats and oils consumed, in addition to careful tabulation of all of the foods consumed, because the vitamin E content of various fats and oils differs widely and because vitamin E is widely distributed in many foods. Most individual foodstuffs consumed account for less than 1 percent of the daily intake of alpha-tocopherol. Calories are frequently underreported, as is dietary fat, and the form and quantity of fat consumed are unknown. Better methods for estimating vitamin E intakes are needed.

Research Method

116.1

C.III.03.a

See Recommendation ID Code C.III.03.

Null

peroxidation or other manifestations of reactive oxygen species generation? Are there markers of oxidative stress that can be related to vitamin E status?

117.1

C.III.04.a

See Recommendation ID Code C.III.04.

Null

118

C.III.05

Information on the nutrient requirement, metabolism and kinetics of vitamin E is needed. (1) Can estimates of alpha-tocopherol requirements be made using stable isotopes? (2) Are balance studies feasible that measure intake and output of stable isotope-labeled vitamin E? (3) What are the tissue uptake and subcellular distributions of alpha-tocopherol in humans? (4) What is the mechanism by which these nutrients are taken up and regulated by the cells? (5) What is the turnover of alpha-tocopherol in various human tissues? (6) In which tissues is alpha-tocopherol degraded and how rapidly? (7) What are the major metabolic intermediates during degradation of alpha-tocopherol, and do they have biological function?

Knowledge Gaps

118.1

C.III.05.a

See Recommendation ID Code C.III.05.

Null

119

C.III.06

Determination of the effects of vitamin E intake on the prevention of chronic disease is needed. There is a great deal of suggestive or indirect evidence that vitamin E intakes above those that can reasonably be obtained from foods may confer health benefits. See C.III.06.a and C.III.06.b.

Knowledge Gaps

119.1

C.III.06.a

Before clinical intervention trials can be interpreted properly, more knowledge about the relationship of vitamin E dosage to level of protection, or level of protection to plasma cholesterol or lipoprotein levels, is needed.

Knowledge Gaps

120

C.III.07

Possible interactions between cholesterol-lowering treatments and antioxidant treatments (such as vitamin E) should be studied to find the best algorithm for preventive management of chronic disease.

Knowledge Gaps

121

C.III.08

More information is needed on the mechanisms of vitamin E function. It is unknown whether vitamin E functions solely as a relatively nonspecific antioxidant compound or whether it has some very specific modes of action, for which the precise structure of alpha-tocopherol is required.The mechanisms for regulation of tissue alpha-tocopherol are unknown. In fact, it is not known whether they are regulated at all. The relatively uniform concentrations in tissues from different individuals suggest that there may be regulation, but this may reflect differences in fat concentration.

Knowledge Gaps

122

C.III.09

The existence of alpha-tocopherol binding proteins in tissues other than the liver is being investigated. Do differences in depletion rates among various tissues reflect the functions of other tissue alpha-tocopherol binding proteins?

Knowledge Gaps

123

C.III.10

More information is needed on the other forms of vitamin E. What is the biological potency of forms of vitamin E other than alpha-tocopherol in humans? Does gamma-tocopherol have a role in humans? Does it function to act as a nitric oxide scavenger? What isthe metabolic fate of gamma-tocopherol in humans?

Knowledge Gaps

124

C.IV.01

Biomarkers for use in assessment of selenium status are needed to prevent selenium deficiency and selenium toxicity. The relationship of plasma selenoprotein concentrations to graded selenium intakes must be studied in a severely selenium-deficient population in order to establish a more precise dietary selenium requirement. Plasma selenium levels (and other measurements of the element) have to be carried out in subjects fed levels of selenium (both organic and inorganic forms) up to the Tolerable Upper Intake Level (UL). This could validate use of plasma selenium concentrations to assess high levels of selenium intake.

Major Knowledge

125

C.IV.02

Since the Recommended Dietary Allowances (RDAs) for selenium for children ages 1 through 18 years are extrapolated from the adult RDAs, it is critically important to conduct large-scale studies with children using state-of-the-art biomarkers to assess their selenium requirements.

Major Knowledge

number of selenoproteins that have not yet been characterized. Therefore, the functions of known and new selenoproteins need to be determined.

127

C.IV.04

At present the recommendation for selenium intake has been set at the amount needed to achieve a plateau of the plasma selenoprotein glutathione peroxidase. Most residents in Canada and the United States can reach this level of selenium intake with their usual diet, but residents of many regions of the world have lower selenium intakes. Research is needed to determine the health consequences of selenium intakes inadequate to allow full selenoprotein expression.

Knowledge Gaps

128

C.IV.05

Limited evidence has been presented that intakes of selenium greater than the amount needed to allow full expression of selenoproteins may have chemopreventive effects against cancer. Controlled intervention studies are needed to fully evaluate selenium as a cancer chemopreventive agent.

Knowledge Gaps

129

C.V.01

Beta-carotene and other carotenoids have been shown to modulate a variety of intermediate end points. However, studies validating that changes in an intermediate end point are predictive of changes in a health outcome are critically needed.

Major Knowledge

130

C.V.02

Macular pigment optical density (MPOD) is a promising intermediate marker for age-related macular degeneration (AMD), and could be useful in studies of carotenoid requirements. However, human studies validating this end point prospectively are needed, as are studies demonstrating that changes in MPOD are predictive of changes in risk of macular degeneration.

Knowledge Gaps

131

C.V.03

Studies are needed on the effects of long-term depletion of beta-carotene and subsequent repletion, with an evaluation of validated intermediate end points.

Knowledge Gaps

132

C.V.04

Significantly more research is needed on health effects of dietary carotenoids other than beta-carotene. Possible associations between lycopene and decreased prostate cancer risk, between lutein and zeaxanthin and lowered risk of age-related macular degeneration (AMD), and between alpha-carotene or lutein and various cancers have to be evaluated in additional observational studies, in animal models, and in human intervention trials, if justified. Studies should consider not only the other carotenoids, but also the cis-versus trans-configuration of the carotenoid.

Major Knowledge

132.1

C.V.04.a

See Recommendation ID Code C.V.04.

Null

of which are ongoing. An examination is needed of health effects in populations with varying baseline risk profiles and, in particular, of studies evaluating interventions in populations with poor baseline nutritional status. Post-trial follow-up of completed beta-carotene trials is also needed.

134

C.V.06

Studies aimed at the identification of correlates of higher beta-carotene intake and plasma concentrations, which might help to explain the lower risks of cancer associated with carotene-rich diets, are needed.

Knowledge Gaps

135

C.V.07

Additional research is needed that targets putative mechanisms to explain a possible increase in lung cancer risk in heavy smokers taking high-dose beta-carotene supplements (animal studies, biochemical studies, and molecular studies). In particular, confirmation and extension of findings such as those of recent reports regarding lung metaplasia[Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell M. 1999. Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst 91(1):60-66.] and carotenoid oxidation products [Salgo MG, Cueto R, Winston GW, Pryor WA. 1999. beta-carotene and its oxidation products have differenteffects on microsome mediated binding of benzo[a]pyrene to DNA. Free Radic Biol Med 26(1-2):162-173.], and their relevance to cancer development in humans, are needed.

Knowledge Gaps

136

C.V.08

Surveys are needed that routinely assess and report dietary intakes of individual food carotenoids from large, representative population samples. Intakes from both foods and dietary supplements must be considered.

Research Method

137

C.V.09

Efforts should be directed toward evaluating equivalency and demonstrating efficacyof carotenoids in foods to meet vitamin A needs in vitamin A-deficient populations, in order to develop sustainable strategies to eradicate this worldwide public health problem.

Major Knowledge

137.1

C.V.09.a

See Recommendation ID Code C.V.09.

Null

138

C.VI.05

For many micronutrients, a priority should be the determination of the relationship of existing status indicators to clinical end points in the same subjects to determine if a correlation exists.

Major Knowledege

138.1

C.VI.05.a

See Recommendation ID Code C.VI.05.

Null

correlation exists.

140

C.VI.07

For some nutrients, eithernew clinical end points or intermediate end points of impaired function have to be identified and related to status indicators.

Major Knowledge

141

C.VI.08

For vitamin C, vitamin E, selenium, and carotenoids, either new clinical end points or intermediateend points of impaired function have to be identified and related to status indicators

Major Knowledge

142

C.VI.09

The depletion–repletion research paradigms that are often used in studies of requirements, although not ideal, are still probably the best approach to determining nutrient requirements. However, these studies should be designed to meet three importantcriteria. See C.VI.09a.C.VI.09b, and C.VI.09c.

Research Method

142.1

C.VI.09.a

An indicator of nutrient status is needed for which a cutoff point has been identified, below which nutrient status is documented to be impaired. (In the case of vitamin E, values are based on induced vitamin E deficiency and the correlation with hydrogen peroxide-induced hemolysis and plasma alpha-tocopherol concentrations, because there is little information relating levels of status indicators to functional sufficiency or insufficiency. Also with vitamin C, there is little information relating levels of status indicators to functional sufficiency or insufficiency, because dosedependent absorption and renal regulation of ascorbate allow body conservation during low intakes and limitation of plasma levels at high intakes.).

Research Method

142.2

C.VI.09.b

The depletion and repletion periods should be sufficiently long to allow a new steady state to be reached. (This can be very problematic for vitamin C because biological half-life ranges from 8 to 40 days and is inversely related to ascorbate body pool. For beta-carotene and other carotenoids, no long-term depletion– repletion studies with validated intermediate end points exist.) Study design should allow examination of the effects of initial status on response to maintenance ordepletion–repletion.

Research Method

142.3

C.VI.09.c

Repletion regimen intakes should bracket the expected Estimated Average Requirement (EAR) intake to assess the EAR more accurately and to allow for a measure of variance. In addition, an accurate assessment of variance requires a sufficient number of subjects.

Research Method

mester of pregnancy.

144

C.VI.13

To fill gaps in information on the nutrient requirements for vitamin C, vitamin E, selenium,and carotenoids, additional information is needed for groups at increased risk for oxidative stress, especially those who smoke or who are subjected to second-hand smoke, athletes, and individuals living at high altitudes.

Major Knowledge

145

C.VI.15

To fill information gaps, investigations should be conducted to advance the understanding of the health effects of carotenoids. Emphasis should be placed on bioavailability, toxicity, and health effects of carotenoids, since little information is available apart from beta-carotene.

Major Knowledge

146

C.VI.16

The only known validated function for carotenoids in humans is to act as a source of vitamin A in the diet. To fill information gaps, investigate the relative contribution of dietary provitamin A carotenoids to vitamin A status.

Major Knowledge

147

C.VI.17

Research to date has indicated little cause for concern about the adequacy of vitamin E intake for apparently healthy people; deficiency states can be produced only as a result of genetic abnormalities in alpha-tocopherol transfer protein, as a result of various fat malabsorption syndromes, or as a result of protein–energy malnutrition. However, investigation of the prevalence of these genetic abnormalities is needed.

Major Knowledge

148

C.VI.18

Investigate the health effects of nutrient-nutrient interactions. A growing number of studies suggest that there are complex interrelationships among nutrients, particularly those involved in protecting against oxidation (e.g., vitamin C, vitamin E, and selenium), but these are not well understood in relation to the maintenance of normal nutritional status and to the prevention of chronic degenerative disease. These interactions may affect the intake level for one or more of the nutrients.

Major Knowledge

149

C.VI.20

Develop assays for routine analysis of carotenoids. Although the analytical methodology for serum carotenoid status is becoming routine, methods for the analysis of the major dietary carotenoids remain as a limiting methodological factor.

Research Method

151

C.VI.23

Validate dietary intake instruments toassess intake of the major carotenoids in food.

Research Method

152

C.VI.24

To fill serious gaps in knowledge, investigate the relationship of intakes of vitamin C, vitamin E, selenium, and beta-carotene and other carotenoids to the risk of coronary heart disease, cancer, and other chronic degenerative diseases. An imbalance in oxidant stress and defenses can lead to the formation and excretion of oxidized products of nucleic acids, lipids, and proteins, which may play a role in chronic disease. Although interest is high and numerous studies have been conducted, additional investigations are needed.

Major Knowledge

153

C.VI.29

Vitamin E is known to protect ex vivo low-density lipoprotein oxidation, whereas beta-carotene offers no protection. Questions to be answered include the following: (1) what are the tissue uptake and subcellular distributions of beta-carotene in humans; (2) what is the mechanism by which beta-carotene is taken up and regulated by the cells; (3) what is the turnover of beta-carotene in the various tissues; (4) in which tissues is beta-carotene degraded and how rapidly; and (5) what are the major metabolic intermediates during degradation of beta-carotene and do they have biological function?

Knowledge Gaps

154

C.VI.30

Additional randomized clinical trials are needed to test whether or not supplementation with vitamin C, vitamin E, selenium, and/or beta-carotene and other carotenoids can reduce the risk of chronic disease. A number of clinical intervention trials involving more than 100,000 people are in progress. However, whether the results are positive or negative, additional studies will be necessary. See C.VI.30a, C.VI.30b, C.VI.30c, C.VI.30d, and C.VI.30e.

Major Knowledge

154.2

C.VI.30.b

Additional randomized clinical trials are needed to test whether ornot supplementation with vitamin C, vitamin E, selenium, and/or beta-carotene and other carotenoids can reduce the risk ofchronic disease. A number of clinical intervention trials involving more than 100,000 people are in progress. However, whether the results are positive or negative, additional studies will be necessary. If the results of ongoing clinical trials are positive, indicating that antioxidants do indeed offer protection, the relative importance of vitamin C, vitamin E, selenium, and beta-carotene will have to be sorted out, because they are being used in combination in several of the studies.

Major Knowledge

154.3

C.VI.30.c

Additional randomized clinical trials are needed to test whether or not supplementation with vitamin C, vitamin E, selenium, and/or beta-carotene and other carotenoids can reduce the risk of chronic disease. A number of clinical intervention trials involving more than 100,000 people are in progress. However, whether the results are positive or negative, additional studies will be necessary. If the results of ongoing clinical trials are positive, indicating that antioxidants do indeed offer protection, the issue of dose will arise. Most of these studies are using doses that may be unnecessarily high.

Major Knowledge

154.4

C.VI.30.d

Additional randomized clinical trials are needed to test whether or not supplementation with vitamin C, vitamin E, selenium, and/or beta-carotene and other carotenoids can reduce the risk ofchronic disease. A number of clinical intervention trials involving more than 100,000 people are in progress. However, whether the results are positive ornegative, additional studies willbe necessary. If the results of ongoing clinical trials are positive, indicating that antioxidants do indeed offer protection,the questions of who should be treated, atwhat dosage, and at whatage will have to be addressed, along with the impact of treatment on various subgroups (older adults, those who smoke, those with other chronic diseases such as diabetes, etc.).

Major Knowledge

going clinical trials are positive, indicating that antioxidants do indeed offer protection, it will be important to determine if combinations of antioxidants in various doses can further increase the beneficial effect.

155

C.VI.32

In cancer prevention studies, conduct additional randomized trials with vitamin E supplementation to confirmation or refutation the unexpected result of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finnish men.

Major Knowledge

156

C.VI.33

Data on the potential for beta-carotene to increase lung cancer rates in smokers are conflicting. Conduct additional randomized trials with beta-carotene supplementation to help resolve this issue.

Major Knowledge

157

C.VI.34

Because of inconsistent data, a Tolerable Upper Intake Level (UL) could not be established for beta-carotene, and due to a lack of sufficient data, ULs could not be set for other carotenoids from food. Thus, research is needed concerning the Tolerable Upper Intake Levels (ULs) for the carotenoids.

Major Knowledge

157.1

C.VI.34.a

See Recommendation ID Code C.VI.34.

Null

158

C.VI.35

Investigate the adverse effects of vitamin C, vitamin E, and selenium.

Knowledge Gaps

158.1

C.VI.35.a

See Recommendation ID Code C.VI.35.

Null

159

D.I.01

To fill information gaps, the specific role of selected micronutrients in human health should be investigated.

Major Knowledge

160

D.I.06

Conduct studies to identify and further understand the functional (e.g., cognitive function, regulation of insulin, bone health, and immune function) and biochemical end points that reflect sufficient and insufficient body stores of vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc.

Major Knowledge

161

D.I.07

Conduct studies to further identify and quantify the effects of interactions between micronutrients and interactions between micronutrients and other food components, the food matrix, food processing, and life stageon micronutrient (vitamin A, vitamin K, chromium, copper, iron, and zinc) bioavailability and therefore dietary requirement.

Major Knowledge

162

D.I.08

Conduct studies to further investigate the roles of arsenic, boron, nickel, silicon, and vanadium in human health.

Major Knowledge

micronutrients currently measured by U.S. and Canadian nutritional surveys, such as for iron and vitamin A. An example of such an impact is the evidence from national survey data that suggests that body mass index (BMI) and plasma glucose concentration are positively correlated with indicators of ironstatus. Such non-nutritional factors may markedly affect the interpretation of the survey data for certain subpopulations where the prevalence of non-nutritional factors is high.

163.1

D.I.09.a

See Recommendation ID Code D.I.09.

Null

164

D.II.01

Investigate effects of food matrices (e.g., carotenoids in milk and supplements) on the bioavailability of provitamin A carotenoids.

Knowledge Gaps

165

D.II.02

Investigate age-related differences in the bioavailability of vitamin A.

Knowledge Gaps

166

D.II.03

Define critical end points for population assessment for vitamin A and evaluation of their association with liver vitamin A stores.

Knowledge Gaps

167

D.II.04

Investigate the effect of dietary vitamin A and vitamin A status on turnover and utilization of vitamin A. Is there significant adaptation to low vitamin A intakes? Is vitamin A absorption increased in response to low vitamin A intake? Is catabolism upregulated as body stores increase?

Knowledge Gaps

168

D.II.05

Investigate the relationship of bioactive vitamin A indicators (e.g., retinoic acid) to dietary vitamin A intake.

Knowledge Gaps

169

D.II.06

Investigate effects of pregnancy and lactation on maternal vitamin A turnover.

Knowledge Gaps

170

D.II.07

Investigate the effect of the interaction of vitamin A with other nutrients and food processing on the bioavailability of vitamin A.

Knowledge Gaps

171

D.III.01

Conduct clinical studies of vitaminK supplementation aimed at elucidating the physiological significance of undercarboxylated osteocalcin; these studies should be designed so as to relate this indicator to overall bone health and integrity.

Knowledge Gaps

172

D.III.02

Investigate the function of all of the vitamin K-dependent proteins and their role in human physiology.

Knowledge Gaps

173

D.III.03

Investigate the possible role of vitamin K in promoting human health other than that mediated by the known Gla-containing vitamin K-dependent proteins.

Knowledge Gaps

174

D.III.04

Investigate further the bioavailability of dietary vitamin K.

Knowledge Gaps

176

D.IV.02

Investigate chromium absorption, metabolism, and requirements during pregnancy and lactation.

Knowledge Gaps

177

D.IV.03

Generate information on variability in chromium concentration in the food and water supply.

Knowledge Gaps

178

D.IV.04

Develop and validate a useful clinical indicator to identify persons with marginal chromium status and investigate effects of physiological levels of chromium supplementation in these patients.

Knowledge Gaps

179

D.IV.05

Investigate possible relationships between chromium status and insulin resistance, impaired glucose tolerance, and type 2 diabetes.

Knowledge Gaps

180

D.IV.06

Monitor any adverse effects of self-supplementation with chromium.

Knowledge Gaps

181

D.IV.07

Any research using supplementation with large-doses of chromium should be designed as controlled studies to assess both potential beneficial and potential adverse effects of large-dose supplementation of chromium.

Research Method

182

D.V.01

Investigate the specific health risks associated with marginal copper deficiency.

Knowledge Gaps

183

D.V.02

Conduct investigations to define the adverse effects of chronic high copper consumption for establishing Tolerable Upper Intake Levels (ULs) and to evaluate the health effects ofcopper supplements.

Knowledge Gaps

184

D.V.03

Conduct investigations to determine the involvement of low and high copper intakes on neurological and cognitive function.

Knowledge Gaps

185

D.VI.01

Investigate the correlation of community iodine intake with autoimmune thyroid disease and papillary thyroid cancer.

Knowledge Gaps

186

D.VI.02

Continually monitor U.S. urinary iodine by the National Health and Nutrition Examination Survey (NHANES) and include data on thyroid size in children, determined by ultrasound.

Research Method

187

D.VI.03

Investigate the role of iodine in fibrocystic breast disease.

Knowledge Gaps

188

D.VI.04

Investigate iodine nutrition and immune response.

Knowledge Gaps

189

D.VI.05

Investigate iodine nutrition in relation to other nutrients, particularly vitamin A, iron, and selenium.

Knowledge Gaps

190

D.VI.06

Investigate the effects of iodine concentration in water purification.

Knowledge Gaps

191

D.VI.07

Conduct investigations to further standardize thyroid volume by ultrasound and urinary iodine excretion in areas with different iodine intake.

Knowledge Gaps

in blood.

193

D.VII.02

Investigate the effect of iron absorption and dietary iron on phenotypic expressions in individuals with hereditary hemochromatosis.

Knowledge Gaps

194

D.VII.03

Conduct research to distinguish between hereditary hemochromatosis and iron overload.

Knowledge Gaps

195

D.VII.04

Conduct research to study the effect of limited iron intake during pregnancy on infant iron status during the first 6 months of life.

Knowledge Gaps

196

D.VII.05

Investigate the bioavailability of supplemental iron.

Knowledge Gaps

197

D.VII.06

Conduct research to foster concurrence on valid indicators for assessing the effect of iron deficiency anemia on cognitive development and function.

Knowledge Gaps

198

D.VII.07

Investigate the risk of cardiovascular disease for those with high stores of body iron.

Knowledge Gaps

199

D.VII.08

Investigate the relationship between high iron stores in men and the bioavailability of dietary iron and impaired regulation of iron balance.

Knowledge Gaps

200

D.VII.09

Investigate the relationship between iron consumption and oxidative cellular damage.

Knowledge Gaps

201

D.VII.10

Investigate integrative mechanisms of iron transporter proteins that influence gastrointestinal absorption in various dietary conditions and physiologic states.

Knowledge Gaps

202

D.VIII.01

Conduct investigations to identify functional indicators for manganese.

Knowledge Gaps

203

D.VIII.02

Conduct investigations to analyze the effects of graded levels of dietary manganese intake on leukocyte superoxide dismutase activity or another appropriate functional indicator to provide an appropriate basis for setting an Estimated Average Requirement (EAR).

Knowledge Gaps

204

D.IX.01

Investigate the bioavailability of molybdenum.

Knowledge Gaps

205

D.IX.02

Conduct investigations to gather further data to estimate an average requirement for molybdenum.

Knowledge Gaps

206

D.X.01

Investigate biomarkers of zinc status based on functional outcomes; these biomarkers may be gene products derived from zinc-influenced systems and may include transporter proteins that provide homeostatic regulation of zinc intake and cellular processing.

Knowledge Gaps

207

D.X.02

Investigate the relationship of oxidative stress to zinc status.

Knowledge Gaps

this relates to daily dietary zinc intake is not clear. Investigation is needed in this area.

209

D.X.04

Investigate the effectiveness and potential toxicity of zinc as a dietary supplement. On which systems should zinc’s potential effectiveness be based? Which systems become dysfunctional with excessive zinc intake?

Knowledge Gaps

210

D.X.05

Investigate the role of zinc in the various processes of the immune system, particularly those related to T-cell function at marginal zinc status.

Knowledge Gaps

211

D.X.06

Conduct investigations to generate quantitative data on human zinc homeostasis under a wide range of dietary conditions and at all ages using recent advances in zinc stable isotope methodology; these metabolic studies need to be long-term.

Knowledge Gaps

212

D.X.07

Conduct investigations to quantify what happens to zinc homeostasis as zinc intakes and absorption are increased and decreased beyond the range typically seen until recently; these metabolic studies need to be long-term.

Knowledge Gaps

213

D.XI.01

Conduct investigations to delineate a better understanding of species differences in biotransformation of arsenic and thetoxicity of arsenic.

Knowledge Gaps

214

D.XI.02

Investigate the role of arsenic in methyl metabolism and genetic expression.

Knowledge Gaps

215

D.XI.03

Identify a reliable indicator of arsenic status in humans.

Knowledge Gaps

216

D.XI.04

Because relatively low serum arsenic concentrations have been associated with vascular diseases and central nervous system injury, more systematic investigation of the possible role of arsenic in these disorders is needed.

Knowledge Gaps

217

D.XII.01

Investigate the relationship between dietary boron and vitamin D metabolism.

Knowledge Gaps

218

D.XII.02

Investigate whether boron influences the half-life of functional vitamin D metabolites.

Knowledge Gaps

219

D.XII.03

Investigate whether boron influences calcium metabolism as it relates to bone mineralization.

Knowledge Gaps

220

D.XII.04

Investigate the possible influence of boron on estrogen metabolism and function, particularly biological half-life, receptor–ligand interactions, and estrogen-inducible gene expression as related to bone mineral density.

Knowledge Gaps

221

D.XII.05

Investigate the possible role of boron in human neurophysiological and cognitive function in young as well as older populations; these investigations should include delineation of abiochemical or other physiological basis for the role of boron.

Knowledge Gaps

for nickel in humans.

222.1

D.XIII.01.a

See Recommendation ID Code D.XIII.01.

Null

223

D.XIII.02

Conduct investigations to identify a reliable indicator of nickel status for use in future studies of nickel deficiency.

Knowledge Gaps

224

D.XIII.03

Investigate the possible role of nickel in vitamin B12 and folate metabolism.

Knowledge Gaps

225

D.XIII.04

Investigate whether nickel nutrition should be a concern for pregnant women or people at risk for cardiovascular disease.

Knowledge Gaps

226

D.XIV.01

Investigate the physiological role of silicon and how this role relates to human health.

Major Knowledge

226.1

D.XIV.01.a

See Recommendation ID Code D.XIV.01.

Null

227

D.XIV.02

Investigate the possible role of silicon in atherosclerosis, hypertension, several bone disorders, Alzheimer’s disease, and other conditions common to the elderly because of the prevalence and cost of these disorders.

Knowledge Gaps

228

D.XIV.03

Conduct investigations to determine a reliable indicator of silicon status.

Knowledge Gaps

229

D.XV.01

Conduct investigations to determine the biochemical role of vanadium in both higher animals and humans.

Major Knowledge

229.1

D.XV.01.a

See Recommendation ID Code D.XV.01.

Null

230

D.XV.02

Conduct investigations to determine a reliable status indicator of vanadium for further work in humans.

Knowledge Gaps

231

D.XV.03

Investigate the efficacy and safety of the use of vanadium as a nutritional supplement.

Knowledge Gaps

232

D.XVI.05

For vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc, investigate the relationship of existing status indicators to clinical end points in the same subjects to determine if a correlation exists.

Major Knowledge

233

D.XVI.06

For some micronutrients, either new clinical end points or intermediate end points of impaired function have to be identified and related to status indicators.

Major Knowledge

234

D.XVI.07

For vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc, either new clinical end points or intermediate end points of impaired function have to be identified and related to status indicators.

Major Knowledge

are still probably the best approach to determining requirements for many of the trace minerals. However, these studies should be designed to meet three important criteria. See D.X VI.08a, D.XVI.08b, and D.XVI.08c.

235.1

D.XVI.08.a

An indicator of nutrient status is needed for which a cutoff point has been identified, below which nutrient status is documented to be impaired. (In the case of manganese, serum manganese concentrations appear to be sensitive to large variations in manganese intake; however, there is a lack of information to indicate that this indicator reflects manganese status.)

Research Method

235.2

D.XVI.08.b

The depletion and repletion periods and balance studies should be sufficiently long to allow a new steady state to be reached. (For iodine and chromium, long-term balance studies are lacking.) Study design should allow examination of the effects of initial status on response to maintenance or depletion–repletion.

Research Method

235.3

D.XVI.08.c

Repletion regimen intakes should bracket the expected Estimated Average Requirement (EAR) intake to assess the EAR more accurately and to allow for a measure of variance. In addition, an accurate assess ment of variance requires a sufficient number of subjects.

Research Method

236

D.XVI.11

For some of the micronutrients reviewed [list reviewed includes vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc], studies should examine whether the requirement varies substantially by trimester of pregnancy.

Major Knowledge

237

D.XVI.12

Data are lacking about gender specificity of the metabolism and nutrient requirements for some of the micronutrients reviewed [list reviewed includes vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc].

Major Knowledge

vitamin A are encouraged. With such data, more information can be obtained about the relative contribution of dietary provitamin A carotenoids and dietary preformed vitamin A to vitamin A nutrition.

239

D.XVI.15

There is increasing evidence to suggest that the interaction between micronutrients [list reviewed includes vitamin A, vitamin K, arsenic, boron,chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc] and other food components affect micronutrient absorption and metabolic utilization (bioavailability), but these interactions are not well understood in relation to the maintenance of normal nutritional status. These interactions may affect the dietary requirement for one or more of the micronutrients.

Major Knowledge

240

D.XVI.16

To fill information gaps, further research is needed to evaluate the metabolic role of arsenic, boron, nickel, silicon, and vanadium in human health. There is evidence that the five trace minerals have a role in some physiological processes in some species. For boron, silicon, and vanadium, measurable responses of human subjects to variation in dietary intake have been demonstrated. However, the available data are not as extensive and the responses are not as consistently observed as they are for the other micronutrients.

Major Knowledge

241

D.XVI.17

For some micronutrients [list reviewed includes vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc], serious limitations exist in the methods available to analyze laboratory values indicative of micronutrient status, to determine the micronutrient content of foods, or both. Standardization of indicators in relation to functional outcome is also needed. These methodological limitations have slowed progress in conducting or interpreting studies of micronutrient requirements.

Major Knowledge

241.1

D.XVI.17.a

See Recommendation ID Code D.XVI.17.

Null

241.2

D.XVI.17.b

See Recommendation ID Code D.XVI.17.

Null

242

D.XVI.18

Serious limitations exist in the methods available to determine chromium content of foods. This methodological limitation has slowed progress in generating data on chromium intake in North America and nutrient requirements. Develop improved, expedient methods for measuring chromium in food samples.

Research Method

gress in conducting or interpreting studies of nutrient requirements. Conduct studies to further standardize thyroid volume and urinary iodine excretion to varying levels of iodine consumption.

244

D.XVI.20

Further studies are needed for identifying the best indicator for assessing the effect of iron deficiency anemia on cognitive development. These methodological limitations have slowed progress in conducting or interpreting studies of nutrient requirements.

Major Knowledge

245

D.XVI.21

Potential sources of error in self-reported in take data include underreporting of portion sizes and frequency of intake, omission of foods, and inaccuracies related to the use of food composition tables and data bases. Develop an acceptable method for adjusting intakes based on under reporting.

Research Method

245.1

D.XVI.21.a

See Recommendation ID Code D.XVI.21.

Null

246

D.XVI.22

Research is needed on the relationships of micronutrient in take to chronic disease. There are major gaps in knowledge linking the in take of specific micronutrients and the prevention or retardation of certain chronic diseases common in North America. For some micronutrients Estimated Average Requirements (EARs) are based on indicators other than functional ones.

Major Knowledge

247

D.XVI.23

A number of studies have been conducted to evaluate the role of vitamin K in maintenance of bone health. Additional studies are needed to understand the role of vitamin K in the prevention and retardation of chronic diseases common in North America such as osteoporosis.

Major Knowledge

248

D.XVI.24

A number of studies have demonstrated a beneficial effect of chromium on insulin action and circulating glucose levels. Additional research is needed to relate the intake of chromium to the prevention and reversal of diabetes, a chronic disease common in North America.

Major Knowledge

249

D.XVI.25

When sufficient information was available, Estimated Average Requirements (EARs) were based on functional indicators. For some micronutrients functional indicators were not apparent and Estimated Average Requirements (EARs) were based on other types of indicators. Additional research is needed to identify functional indicators of nutrient requirements for these micronutrients.

Major Knowledge

needed concerning the Tolerable Upper Intake Levels (ULs) for vitamin K, arsenic, chromium, and silicon.

251

D.XVI.31

There was a lack of data from humans to establish a Tolerable Upper Intake Level (UL) for boron, molybdenum, and vanadium, and therefore a UL was based on animal data. Thus, human research is needed concerning the Tolerable Upper Intake Levels (ULs) for boron, molybdenum, and vanadium.

Knowledge Gaps

252

E.I.01

To fill information gaps, studies designed specifically to estimate average requirements for fiber and fat in presumably healthy humans should be conducted.

Major Knowledge

253

E.I.02

To fill information gaps, studies designed to generate data on the needs of macronutrients of infants, children, adolescents, the elderly, and pregnant and lactating women should be conducted.

Major Knowledge

254

E.I.03

To fill information gaps, multidose, long-term studies to determine the role of specific macronutrients in reducing the risk of certain chronic diseases should be conducted.

Major Knowledge

255

E.I.04

To fill information gaps, studies designed to detect adverse effects of chronic high intakes of specific macronutrients should be conducted. There are major gaps in knowledge linking the intake ofsome macronutrients and the prevention and retardation of certain chronic diseases common in North America. Because the relationship between macronutrient intake and risk of chronic disease is a trend, it is difficult to ascertain the optimal range of intake for each macronutrient.

Major Knowledge

255.1

E.I.04.a

See Recommendation ID Code E.I.04.

Null

256

E.I.05

Conduct long-term, dose–response studies to help identify the requirement of individual macronutrients that are essential in the diet (e.g., indispensable amino acids and n-6 and n-3 poly unsaturated fats) for all life stage and gender groups. It is recognized that it is not possible to identify a defined intake level off at for maintaining health and decreasing risk of disease; however, it is recognized that further information is needed to identify acceptable ranges of intake for fat, as well as for protein and carbohydrate that are based on prevention of chronic disease and maintaining health.

Major Knowledge

256.1

E.I.05.a

See Recommendation ID Code E.I.05.

Null

258

E.I.07

Conduct studies designed to determine protein and energy needs during pregnancy. Do requirements vary substantially by trimester of pregnancy?

Major Knowledge

258.1

E.I.07.a

See Recommendation ID Code E.I.07.

Null

259

E.I.08

Conduct investigations to gather information on the form, frequency, intensity, and duration of exercise and physical activity that is successful in managing body weight in both children and adults.

Major Knowledge

260

E.I.09

Conduct long-term studies on the role of glycemic response in preventing chronic diseases, such as diabetes and coronary heart disease, in healthy individuals

Major Knowledge.

261

E.I.10

Conduct studies to investigate the levels at which adverse effects occur with chronic high intakes of macronutrients (carbohydrate, fiber, protein, and total fat).

Major Knowledge

261.1

E.I.10.a

See Recommendation ID Code E.I.10.

Null

262

E.II.01

Expand the number of available doubly labeled water studies for the determination of total energy expenditure (TEE) in certain age and gender categories, particularly in young children 3 to 5 years of age, adolescent boys, and adult men and women 40 through 60 years of age.

Major Knowledge

262.1

E.II.01.a

See Recommendation ID Code E.II.01.

Null

263

E.II.02

Develop reliable methods to track dietary energy intakes in population groups.

Research Method

264

E.II.03

Identify biological markers of risk of excess weight gain in children and young adults.

Knowledge Gaps

265

E.II.04

Develop methods suitable for free-living population-based studies or develop applications to measure physical activity levels in order to classify children and adults into sedentary, low active, active, and very active levels of physical activity.

Research Method

266

E.II.05

Conduct additional studies to determine whether and which dietary composition patterns facilitate permanent weight loss in adults and children.

Knowledge Gaps

267

E.II.06

Develop practical, accurate means to assess body composition in populations.

Research Method

268

E.II.07

Conduct investigations to describe physical activity patterns consistent with normal health and development of children that are applicable across age, gender, and ethnic backgrounds.

Major Knowledge

268.1

E.II.07.a

See Recommendation ID Code E.II.07.

Null

270

E.II.09

Conduct investigation to identify factors affecting the changes in total energy expenditure (TEE) during pregnancy. Do requirements vary substantially by trimester of pregnancy? Develop equations to predict the basal metabolic rate (BMR) throughout pregnancy to better predict the energy requirements of nonobese, overweight, and obese pregnant women.

Major Knowledge

270.1

E.II.09.a

See Recommendation ID Code E.II.09.

Null

271

E.II.10

More information is needed on the energy requirements of over weight and obese adults and children. It would be desirable for this additional total energy expenditure (TEE) information to be collected in studies that also document physical activity patterns, so that the relationship between activity and TEE can be further evaluated.

Major Knowledge

271.1

E.II.10.a

See Recommendation ID Code E.II.10.

Null

272

E.II.11

Conduct additional research on the extent to which energy expenditure changes when a hypocaloric diet is consumed, and whether dietary composition affects the extent of change in energy expenditure.

Knowledge Gaps

273

E.II.12

Identify dietary components, in dependent of energy, that could favorably affect body composition.

Knowledge Gaps

274

E.III.01

Conduct additional research to elucidate the metabolic and long-term health differences resulting from the ingestion of high versus low glycemic index carbohydrates using larger, diverse sample sizes and whole-food diets.

Knowledge Gaps

275

E.III.02

Conduct investigations to determine if the energy density approach to weight reduction is effective in the long-term.

Knowledge Gaps

276

E.III.03

Conduct experimental studies to determine whether there is a metabolic effect of sugars in enhancing energy expenditure or in suppressing fat intake at a fixed level of energy.

Knowledge Gaps

277

E.III.04

Conduct research to determine the effect of low glycemic index foods and low glycemic-load diets on serum lipids and other risk factors for chronic disease and complications, especially in high-risk groups.

Knowledge Gaps

bulk) and its relationship to these end points.

279

E.IV.03

Conduct a dose–response study to determine the amount of fiber that needs to be ingested to promote optimum laxation so that this could form the basis for a recommendation for fiber intake and provide a basis for determining functional fibers.

Major Knowledge

280

E.IV.04

Attempt to relate changes in the colonic microflora due to fiber ingestion to functional end points (e.g., decreased irritable bowel syndrome, increased laxation).

Major Knowledge

281

E.IV.05

Conduct longer-term studies on low energy-dense food sources (high in dietary fiber) and satiety and weight control to see if switching to a higher fiber diet will help with weight maintenance or promote adherence to reduced calorie diets for weight reduction.

Major Knowledge

282

E.IV.06

Examine the relation between dietary fiber intake, energy intake, and long-term body weight in existing prospective epidemiological studies in addition to intervention studies.

Major Knowledge

283

E.IV.07

Conduct long-term studies on the effects of both viscous and whole-grain cereal fibers on coronary heat disease and diabetes risk factors studies.

Major Knowledge

284

E.V.01

Conduct studies that examine the effects of alterations in the level of total fat in the context of a low saturated fatty acid diet on blood lipid concentrations and glucose– insulin homeostasis in individuals with defined metabolic syndromes, such as type 1 and type 2 diabetes.

Knowledge Gaps

285

E.V.02

Conduct randomized and blinded long-term (greater than 1 year) studies on the effect of dietary fat versus carbohydrate on body fatness.

Knowledge Gaps

286

E.V.03

Conduct investigations to further examine intakes of saturated fats at which significant risk of chronic diseases canoccur.

Knowledge Gaps

287

E.V.04

Examine the indicators for and risk of chronic disease at low levels of saturated fatty acid intake.

Knowledge Gaps

288

E.V.05

Conduct investigations to assess energy balance in free-living individuals who have implemented a diet high in monounsaturated fatty acids versus a diet lower in monounsaturated fatty acids (and higher in carbohydrate).

Knowledge Gaps

290

E.V.07

Conduct studies to evaluate cardiovascular disease risk status and risk of other chronic diseases in individuals consuming a high monouns aturated fatty acid diet versus a diet lower in monounsaturated fatty acids (and higher in carbohydrate).

Knowledge Gaps

291

E.V.08

Conduct an evaluation of the nutritional adequacy and nutrient profile of free-living individuals following a self-selected high monounsaturated fatty acid.

Knowledge Gaps

292

E.V.09

Conduct studiesthat assess the effects of a high monounsaturated fatty acid diet on endothelial function and atherogenesis.

Knowledge Gaps

293

E.V.10

In metabolic and large observational studies, compare the benefits of alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) across a range of n-6 polyunsaturated fatty acid intakes.

Knowledge Gaps

294

E.V.11

Using good biomarkers for low density lipoprotein (LDL) oxidation and cancer susceptibility, assess the potential adverse effects of diets at levels of n-6 polyunsaturated fatty acids greater than 10 percent of energy.

Knowledge Gaps

295

E.V.12

Conduct studies that assess the effects of a high n-6 polyunsaturated fatty acid diet on markers of endothelial function and inflammation.

Knowledge Gaps

296

E.V.13

Conduct additional research to address the potentially important relationships between theamount of n-3 and n-6 fatty acids and glucose tolerance suggested by studies of fatty acidcomposition in affected individuals.

Knowledge Gaps

297

E.V.14

Conduct randomized clinical trials of EPA+DHA, EPA (eicosapentaenoic acid), and DHA (docosahexaenoic acid) to evaluate their impact on cancer (i.e., colon, breast, prostate). The use of biomarkers for cancer susceptibility mayexpedite such studies.

Knowledge Gaps

298

E.V.15

Conduct randomized clinical trials of EPA+DHA, EPA (eicosapentaenoic acid), and DHA (docosahexaenoic acid) in treatment of inflammatory disorders (e.g., Crohn's disease, arthritis, psoriasis, asthma) and infections.

Knowledge Gaps

299

E.V.16

Conduct studies of EPA+DHA, EPA (eicosapentaenoic acid), and DHA (docosahexaenoic acid) supplementation in the elderly to prevent degenerative diseases of the central nervous system and retina, such as dementia, age-related macular degeneration (AMD), and night blindness.

Knowledge Gaps

301

E.V.18

Assess major sources of trans fatty acids currently in the marketplace; develop alternates similar to those developed for foods high in saturated fatty acids.

Knowledge Gaps

302

E.V.19

Conduct studies that distinguish trans fatty acid isomers from plants and animals with respect to the relative impact on blood lipid and lipoprotein concentrations.

Knowledge Gaps

303

E.V.20

In light of the wide variability of trans fatty acid intakes within food categories, develop a biochemical marker for trans fatty acid intake, in dependent of self-reported intake data.

Knowledge Gaps

304

E.VI.01

Conduct studies to identify possible mechanisms whereby early nutritional experiences, such as dietary cholesterol, affect the atherosclerotic process in adults and the sensitive periods in development when this may occur.

Knowledge Gaps

305

E.VI.02

Investigate the molecular mechanisms that regulate absorption of dietary cholesterol.

Knowledge Gaps

306

E.VI.03

Delineate specific genetic variants that contribute to wide interindividual variation in LDL (low density lipoprotein) cholesterol response to dietary cholesterol.

Major Knowledge

306.1

E.VI.03.a

See Recommendation ID Code E.VI.03.

Null

307

E.VI.04

Delineate dietary and constitutional factors (that is, non-genetic factors) that contribute to the wide interindividual variation in LDL (low density lipoprotein) cholesterol response to dietary cholesterol.

Major Knowledge

307.1

E.VI.04.a

See Recommendation ID Code E.VI.04.

Null

308

E.VI.05

Conduct studies to better define the relation between dietary cholesterol intakes and LDL (low density lipoprotein) cholesterol concentrations over a broad range of cholesterol intakes, from very low to high.

Knowledge Gaps

309

E.VI.06

Investigate the relationship between dietary cholesterol intakes and body pools of cholesterol.

Knowledge Gaps

310

E.VII.01

Conduct research on high protein intakes (greater than 145 mg nitrogen/kg body weight/day) in relationship to positive nitrogen balance and requirement estimates, metabolic and possible toxic effects in children and adults, and pathways impacted by these high intakes.

Knowledge Gaps

311

E.VII.02

Generate additional data on indispensable amino acid requirements for infants, children, and adolescents.

Major Knowledge

311.1

E.VII.02.a

See Recommendation ID Code E.VII.02.

Null

clude estimates of changes in efficiency of conversion of dietary protein for maintenance and tissue accretion. Do requirements vary substantially by trimester of pregnancy?

312.1

E.VII.03.a

See Recommendation ID Code E.VII.03.

Null

313

E.VII.04

Validate new methods, other than nitrogen balance, to determine protein requirements, particularly in regard to long-term health.

Research Method

313.1

E.VII.04.a

See Recommendation ID Code E.VII.04.

Null

314

E.VII.05

Investigate the role of the gastrointestinal system in the metabolism of amino acids, the nature of the amino acid losses, and the extent of synthesis of indispensable amino acids.

Knowledge Gaps

315

E.VII.06

Investigate adaptation mechanisms at various intakes of protein.

Knowledge Gaps

316

E.VII.07

To fill information gaps, investigate protein requirements in the elderly at various ages. Currently the protein data in the elderly are sparse. Available data for the very elderly, namely those from 80 to 100 years of age, consists of only two or three adults in their early eighties.

Knowledge Gaps

317

E.VII.08

To fill information gaps, investigate adverse effects of high intakes of amino acids. Tolerable Upper Intake Levels (ULs) could not be established for any of the amino acids (some of which are known to result in toxic effects at high doses) due to insufficient data on dose–response relationships.

Major Knowledge

317.1

E.VII.08.a

See Recommendation ID Code E.VII.08.

Null

318

E.IX.01

To fill information gaps, investigate the effect of exercise (i.e., endurance, resistance, other), frequency, intensity, and duration on body fatness in young and elderly adults and children.

Knowledge Gaps

319

E.IX.02

To fill information gaps, investigate the effects of exercise on substrate utilization and the roles of various energy depots (liver glycogen, muscle glycogen, adipose triacylglycerol, intramuscular triacylglycerol) in exercise and recovery in children, adults, and the elderly.

Knowledge Gaps

320

E.IX.03

Investigate whether the timing of meals and exercise can be used to optimize changes in, or to maintain favorable body mass index (BMI) and body composition of moderately and very active individuals.

Knowledge Gaps

322

E.IX.05

Identify the mechanisms by which acute and chronic physical activity change substrate utilization and body composition.

Knowledge Gaps

323

E.IX.06

Develop reliable, noninvasive, and clinically appropriate measurements of body composition, cardiovascular function, and physical fitness.

Knowledge Gaps

324

E.IX.07

Develop practical, yet reliable methods to assess habitual levels of physical activity.

Knowledge Gaps

325

E.X.03

To fill information gaps related to some of the macronutrients, investigations should be conducted on the biochemical values that reflect abnormal function.

Major Knowledge

326

E.X.04

For n-6 and n-3 polyunsaturated fatty acids, investigations should be conducted on the biochemical values that reflect abnormal function.

Major Knowledge

327

E.X.05

A priority should be to determine if there is a correlation between existing status indicators for macronutrients and clinical end points in the same subjects.

Major Knowledge

328

E.X.06

For some macronutrients, more data are needed using clinical end points or intermediate end points of impaired function to determine their requirements in regard to long-term health.

Major Knowledge

329

E.X.07

For indispensable amino acids more data are needed using clinical end points or intermediate end points of impaired function to determine their requirements in regard to long-term health.

Major Knowledge

330

E.X.08

For determining energy requirements, investigations should be conducted on the form, frequency, intensity, and duration of exercise that is consistent with a healthy body weight for all age groups.

Major Knowledge

331

E.X.09

Additional studies should be conducted using doubly labeled water studies for the determination of total energy expenditure (TEE) in certain life stage and gender categories.

Major Knowledge

332

E.X.10

Investigate the role of n-3 polyunsaturated fatty acids in the neurodevelopment of term infants.

Major Knowledge

333

E.X.11

Investigations of nutrient requirements should use graded levels of nutrient intake and a combination of response indexes.

Research Method

334

E.X.14

For some macronutrients, serious limitations exist in the methods available to analyze laboratory values indicative of energy balance and macronutrient status. These methodological limitations have slowed progress in conducting or interpreting studies of energy and macronutrient requirements.

Major Knowledge

adults and standardize and validate indicators in relation to functional outcome. Past methodological limitations have slowed progress in conducting or interpreting studies of energy and macronutrient requirements.

336

E.X.16

To better understand the relationship between fiber and colon cancer, further validate intermediate markers (such as polyp recurrence) and functional markers (such as fecal bulk) of fiber intake. Past methodological limitations have slowed progress in conducting or interpreting studies of energy and macronutrient requirements.

Major Knowledge

337

E.X.18

Reliable methods to track dietary energy intakes of populations need to be developed.

Research Method

338

E.X.19

Food composition tables and databases need to be expanded and revised to allow for further understanding of the relationship between macronutrient intake and health.

Research Method

339

E.X.20

A comprehensive database for the trans fatty acid content and glycemic index of foods consumed in North America is needed.

Research Method

340

E.X.22

Long-term, multidose clinical trials are needed to ascertain, for instance, the optimal range of total, saturated, and unsaturated fatty acids intake to best prevent chronic diseases such as coronary heart disease, obesity, cancer and diabetes.

Major Knowledge

341

E.X.23

Dose–response studies are also needed to determine the intake level of fiber to promote optimum laxation. To resolve whether or not fiber is protective against colon cancer in individuals or a subset of individuals, genotyping and phenotyping of individuals in fiber/colon cancer trials is needed.

Major Knowledge

342

E.X.24

Long-term clinical trials are needed to further understand the role of glycemic index in the prevention of chronic disease.

Major Knowledge

343

E.X.25

For some nutrients, such as saturated fat, trans fat, and cholesterol, biochemical indicators of adverse effects can occur at very low intakes. Clinical research should be conducted to ascertain clearly defined intake levels at which an onset of relevant health risks (e.g., obesity, coronary heart disease, and diabetes) occurs.

Major Knowledge

343.1

E.X.25.a

See Recommendation ID Code E.X.25.

Null

343.2

E.X.25.b

See Recommendation ID Code E.X.25.

Null

345

E.X.28

Conduct research to identify intake levels at which adverse effects begin to occur with the chronic consumption of high levels of protein and of the long chain n-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid).

Major Knowledge

346

E.X.29

To fill information gaps, studies designed specifically to estimate average requirements for macronutrients in presumably healthy humans should be conducted.

Major Knowledge

347

F.I.01

To fill information gaps, studies to generate data for estimating average requirements for electrolytes and water in presumably healthy humans should be conducted.

Major Knowledge

348

F.I.02

To fill information gaps, studies designed to generate evidence on the electrolyte and water needs of infants, children, adolescents, the elderly, and pregnant and lactating women should be conducted.

Major Knowledge

349

F.I.03

To fill information gaps, multidose trials to determine the effects of electrolyte and water intake on chronic diseases should be conducted.

Major Knowledge

350

F.I.04

There is a critical need for research on public health strategies that effectively reduce sodium intake and increase potassium intake in the general population.

Major Knowledge

350.1

F.I.04.a

See Recommendation ID Code F.I.04.

Null

351

F.II.01

Develop simple non- or minimally-invasive indexes of body hydration status (both hyperosmotic and isoosmotic).

Knowledge Gaps

352

F.II.02

Conduct controlled water balance studies in different subgroups of the population (i.e., children, elderly, and those with chronic illnesses) in different climatic conditions.

Knowledge Gaps

353

F.II.03

Develop capabilities to predict hourly and dailywater requirements based on metabolic rate, climatic conditions, and clothing for different subgroups of the population.

Knowledge Gaps

354

F.II.04

Conduct studies in water consumption and retention patterns due to meal schedule and diet.

Knowledge Gaps

355

F.II.05

Validate estimates of total water intake, both from food and fluids, in large-scale surveys.

Knowledge Gaps

356

F.II.06

Conduct additional studies on the effects of water deficits on cognitive performance.

Knowledge Gaps

358

F.II.08

Conduct investigations to better understanding of the relationship between body water deficits and heat stroke or cardiac arrest associated with intense physical activity.

Knowledge Gaps

359

F.II.09

Investigate the influence of hydration status on morbidity-associated fever and infection outcome.

Knowledge Gaps

360

F.II.10

Investigate the effects of hydration status and fluid intake on the occurrence of urinary tract infections. The effects of increased water intake as a means to prevent recurrent urinary tract infections could be tested in clinical trials.

Major Knowledge

360.1

F.II.10.a

See Recommendation ID Code F.II.10.

Null

360.2

F.II.10.b

See Recommendation ID Code F.II.10.

Null

361

F.II.11

Investigate the effects of hydration status and fluid intake on chronic diseases, such as kidney stones and gallstones (cholelithiasis), as well as the occurrence of specific cancers, including colon cancer and bladder cancer. The effects of increased water intake as a means to prevent recurrent kidney stones and urinary tract infections could be tested in clinical trials. The relationship between water intake and bladder cancer could be addressed in observational studies.

Major Knowledge

361.1

F.II.11.a

See Recommendation ID Code F.II.11.

Null

361.2

F.II.11.b

See Recommendation ID Code F.II.11.

Null

362

F.II.12

Investigate the effects of chronic overhydration, in the presence of adequate sodium intake, on health and cognitive ability.

Knowledge Gaps

363

F.II.13

Investigate the mechanistic effects by which dehydration can contribute to exertional heat injury and heat stroke.

Knowledge Gaps

364

F.III.01

Conduct dose–response trials testing the effects of different levels of potassium intake on blood pressure at different levels of sodium intake.

Knowledge Gaps

365

F.III.02

Conduct additional dose–response trials evaluating the effect of potassium on salt sensitivity in subgroups of the population that are salt sensitive (e.g., African Americans, older persons, and persons with hypertension, chronic kidney disease, or diabetes).

Knowledge Gaps

366

F.III.03

Conduct randomized clinical trials to compare the effect of different potassium salts on blood pressure and other outcomes at different levels of sodium intake.

Knowledge Gaps

368

F.III.05

Conduct trials that test the efficacy of increased potassium intake (alone and in combination with reduced sodium intake) on preventing stroke. To the extent possible, dose–response clinical trials should be conducted.

Major Knowledge

368.1

F.III.05.a

See Recommendation ID Code F.III.05.

Null

368.2

F.III.05.b

See Recommendation ID Code F.III.05.

Null

369

F.III.06

Conduct trials that test the main and interactive effects of potassium and sodium intake on bone mineral density and, if feasible, bone fractures. To the extent possible, dose–response clinical trials should be conducted.

Major Knowledge

369.1

F.III.06.a

See Recommendation ID Code F.III.06.

Null

369.2

F.III.06.b

See Recommendation ID Code F.III.06.

Null

370

F.III.07

Conduct trials testing the main and interactive effects of sodium and potassium intake on the risk of kidney stones. To the extent possible, dose–response clinical trials should be conducted.

Major Knowledge

370.1

F.III.07.a

See Recommendation ID Code F.III.07.

Null

370.2

F.III.07.b

See Recommendation ID Code F.III.07.

Null

371

F.III.09

Conduct studies on the role of potassium intake during infancy and childhood on blood pressure later in life.

Major Knowledge

371.1

F.III.09.a

See Recommendation ID Code F.III.09.

Null

372

F.III.10

Conduct potassium balance studies during pregnancy.

Knowledge Gaps

373

F.III.11

Develop better estimates of potassium losses in sweat with various dietary, activity, and environmental conditions in diverse populations.

Knowledge Gaps

374

F.III.12

Develop food composition tables or databases for citrate and bicarbonate.

Research Method

375

F.III.14

Conduct trials to assess the effects of high potassium intake on serum potassium levels and blood pressure in the setting of early stages of renal insufficiency (with and without ACE [angiotensin converting enzyme] inhibitor therapy).

Knowledge Gaps

376

F.IV.02

Conduct a broad spectrum of research with the aim of facilitating changes in individual behavior toward salt consumption to achieve reduced sodium intakes for most individuals in the United States and Canada.

Knowledge Gaps

377

F.IV.03

Conduct research to develop reduced sodium food products that maintain flavor, texture, consumer acceptability, and low cost.

Knowledge Gaps

ioral change studies in individuals and community-based intervention studies.

378.1

F.IV.06.a

See Recommendation ID Code F.IV.06.

Null

379

F.IV.07

Develop alternative processing technologies to reduce the sodium content of foods, with a special emphasis on maintaining flavor, texture, consumer acceptability, safety, and low cost.

Major Knowledge

379.1

F.IV.07.a

See Recommendation ID Code F.IV.07.

Null

380

F.IV.08

Conduct a formal assessment of the feasibility of a large-scale, long-term clinical trial designed to assess the impact of sodium reduction on clinical cardiovascular outcomes. The results of this assessment should be published.

Major Knowledge

380.1

F.IV.08.a

See Recommendation ID Code F.IV.08.

Null

380.2

F.IV.08.b

See Recommendation ID Code F.IV.08.

Null

381

F.IV.09

Investigate the main and interactive effects of sodium and potassium intake on non-cardiovascular clinical outcomes, specifically bone mineral density, osteoporosis, and kidney disease progression. There is some evidence that increased dietary sodium intake and inadequate potassium intake increase urinary calcium excretion and affect calcium balance.

Major Knowledge

381.1

F.IV.09.a

See Recommendation ID Code F.IV.09.

Null

382

F.IV.10

Assess the genetic and dietary factors that affect salt sensitivity.

Knowledge Gaps

383

F.IV.11

Increased renin activity is a potential biochemical indicator of inadequate sodium intake. In predominantly short-term studies, a reduced sodium intake increased plasma renin activity, but the clinical relevance of increased plasma renin activity is uncertain. Studies should be conducted to investigate the clinical relevance of sodium-induced changes in plasma renin activity.

Major Knowledge

383.1

F.IV.11.a

See Recommendation ID Code F.IV.11.

Null

383.2

F.IV.11.b

See Recommendation ID Code F.IV.11.

Null

384

F.IV.12

Studies should be conducted to investigate the main and interactive effects of sodium and potassium intake on plasma renin activity.

Knowledge Gaps

385.1

F.IV.13.a

See Recommendation ID Code F.IV.13.

Null

385.2

F.IV.13.b

See Recommendation ID Code F.IV.13.

Null

385.3

F.IV.13.c

See Recommendation ID Code F.IV.13.

Null

386

F.IV.14

Develop practical tools to measure intakes of sodium and potassium and to assess total body levels of sodium and potassium.

Research Method

386.1

F.IV.14.a

See Recommendation ID Code F.IV.14.

Null

387

F.IV.15

Develop practical tools to define and measure salt sensitivity.

Knowledge Gaps

388

F.IV.16

Conduct investigations to better characterize salt sensitivity as a phenotype and determination of its relationship to cardiovascular outcomes.

Knowledge Gaps

389

F.IV.17

Investigate the influence of sodium intake during infancy and childhood on blood pressure later in life.

Major Knowledge

389.1

F.IV.17.a

See Recommendation ID Code F.IV.17.

Null

390

F.IV.18

Investigate the main and interactive effects of sodium and potassium intake on the age-related rise in blood pressure.

Knowledge Gaps

391

F.IV.19

Conduct sodium and potassium balance studies to provide estimates of electrolyte loss (sweat concentrations and total sweat loss) by physical activity level, climatic conditions, and dietary electrolyte intake in broad populations.

Knowledge Gaps

392

F.IV.20

Conduct sodium and potassium balance studies during pregnancy.

Knowledge Gaps

393

F.V.01

Investigate the relationship of urinary sulfate as a marker of sulfate absorption in evaluating adverse effects due to high intakes of sulfate.

Knowledge Gaps

394

F.V.02

Investigate sulfate supplementation of low-cysteine food products (e.g., casein-based enteral formula) to determine if supplementation improves growth or nitrogen balance.

Knowledge Gaps

395

F.V.03

Investigate sulfate needs during pregnancy, particularly the sulfate requirements of the growing fetus.

Knowledge Gaps

396

F.V.04

For sulfate, there is no indicator (i.e., biomarker) of inadequate intake. Evaluate using 3'-phosphoadenosine-5'-phosphosulfate or other biomarkers to determine dietary sulfate sufficiency.

Major Knowledge

396.1

F.V.04.a

See Recommendation ID Code F.V.04.

Null

397

F.V.05

Conduct investigations to generate better data on the relationship of diarrhea to sulfate intake in infants.

Knowledge Gaps

as whether and at what point adaptation occurs.

399

F.V.07

Conduct survey studies comparing high versus low sulfate water ingestion from public water supplies that appropriately control for other causes of intestinal disturbances.

Knowledge Gaps

400

F.V.08

Conduct studies to evaluate whether chronic exposure to high sulfur (both cystine and sulfate) ingestion predisposes individuals to ulcerative colitis. Investigate the role of hydrogen sulfide in the etiology of ulcerative colitis.

Knowledge Gaps

401

F.V.09

Assess the relationship between increased sulfate intake and risk of inflammatory bowel disease. Conduct studies to determine how much of the sulfate produced via turnover in metabolism reenters the bowel and thus may serve asan irritant or oxidant. The risk of inflammatory bowel disease might be addressed in the setting of a case-control study or possibly a large, prospective observational study.

Major Knowledge

401.1

F.V.09.a

See Recommendation ID Code F.V.09.

Null

401.2

F.V.09.b

See Recommendation ID Code F.V.09.

Null

402

F.V.10

Conduct absorption studies using acute and chronic sulfate doses.

Knowledge Gaps

403

F.V.11

Conduct analytical studies to determine sulfate, as well as total sulfur content, of foods.

Knowledge Gaps

404

F.VI.12

For water, plasma or serum osmolality is an acceptable indicator of hydration status; however, trials that rigorously control and test different levels of total water intake, rather than allowing ad libitum intakes, have not been performed. These studies should be performed.

Major Knowledge

405

F.VI.14

For water, potassium, and sodium, useful data are lacking for setting requirements for infants, children, adolescents, pregnant and lactating women, and the elderly. Studies to collect these data should be conducted.

Major Knowledge

406

F.VI.15

There is a paucity of data on the relationship of dietary sodium and potassium intakes early in life on blood pressure and markers of bone health during adulthood. Studies to collect these data should be conducted.

Major Knowledge

408

F.VI.17

Develop improved methods for the accurate measurement of total body water and electrolytes in free-living persons.

Research Method

409

F.VI.18

Develop improved methods for the accurate measurement of dietary intake of water and electrolytes in free-living persons. Potential sources of error in self-reported intake data include underreporting of portion sizes and frequency of intake, omission of foods and beverages, and use of food composition tables and databases.

Research Method

410

F.VI.19

Food composition tables and databases need to be continuously updated and expanded to include new foods and beverages and reformulated products. Inclusion of water and electrolytes in food composition tables and databases is important.

Research Method

411

F.VI.20

Develop practical tools to estimate sodium intake. For several reasons, assessment of sodium intake is problematic. Substantial additions can occur post-processing. In fact, many diet collection methods do not collect information on the salt (sodium chloride) added during cooking or eating. More importantly, there is large day-to-day variation in sodium intake. The most accurate method to assess dietary sodium is to measure several timed urinary collections. However, this approach is cumbersome and prone to collection errors. Hence, practical tools to estimate sodium intake are needed.

Research Method

412

F.VI.22

There is some evidence that increased dietary sodium intake and inadequate potassium intake increase urinary calcium excretion and affect calcium balance; to fill in knowledge gaps, additional investigations of effects of sodium and potassium intake on subclinical and clinical outcomes, such as bone mineral density and osteoporosis, are needed.

Major Knowledge

413

F.VI.32

Conduct studies that test the effects of reduced sodium and increased potassium intake, alone and combined, on clinical outcomes (e.g., stroke, bone mineral density, and kidney stones). To the extent possible, clinical trials should be conducted. A formal assessment of the feasibility of a sodium reduction trial with clinical cardiovascular outcomes should be undertaken. In the absence of trials, methodologically rigorous observational studies that concomitantly collect electrolyte intake, other dietary information, and genetic information should be conducted. There is some evidence that increased dietary sodium intake and inadequate potassium intake increase urinary calcium excretion and affect calcium balance.

Major Knowledge

414

F.VI.33

Conduct studies to assess the potential for increased potassium intake to mitigate the adverse consequences of excess sodium intake and, vice versa, the potential for a reduced sodium intake to mitigate the adverse consequences of inadequate potassium intake. Potential outcomes include blood pressure, salt sensitivity, bone demineralization, and decreased bone mineral density. There is some evidence that increased dietary sodium intake and inadequate potassium intake increase urinary calcium excretion and affect calcium balance.

Major Knowledge

414.1

F.VI.33.a

See Recommendation ID Code F.VI.33.

Null

415

F.VI.34

Conduct studies on the adverse effects of chronic, low-grade metabolic acidosis that results from an inadequate intake of potassium and its bicarbonate precursors. Potential clinical outcomes include decreased bone mineral density, osteoporosis, and kidney stones.

Major Knowledge

415.1

F.VI.34.a

See Recommendation ID Code F.VI.34.

416

F.VI.35

Conduct water, sodium, and potassium balance studies that enroll broad populations and that vary climate and physical activity levels. Populations of particular interest are children, as well as older persons with chronic, but stable, illnesses.

Major Knowledge

417

G.I.04

To fill knowledge gaps, conduct further investigations and collect better data on requirements for nutrients currently with an Adequate Intake (AI) (for age groups older than infants). Additional applications are possible when data are sufficient to allow Adequate Intakes (AIs) to be replaced with Estimated Average Requirements (EARs) (and thus Recommended Dietary Allowances [RDAs] can be set). Estimated Average Requirements (EARs) (rather than Adequate Intakes [AIs]) present more possibilities for assessing individual and group prevalence of inadequacy.

Major Knowledge.

417.1

G.I.04.a

See Recommendation ID Code G.I.04.

Null

417.2

G.I.04.b

See Recommendation ID Code G.I.04.

Null