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15 A Research Agenda The Panel on Micronutrients and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes were charged with developing a research agenda to provide a basis for public policy decisions related to recommended intakes of vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molyb- denum, nickel, silicon, vanadium, and zinc, and ways to achieve the recommendations. This chapter describes the approach used to develop the research agenda, briefly summarizes gaps in knowledge, and presents a prioritized research agenda. A section at the end of each nutrient chapter (Chapters 4 through 13) presents a priori- tized list of research topics for the nutrient. APPROACH The following approach resulted in the research agenda identi- fied in this chapter: 1. Identify gaps in knowledge to understand the role of the nutri- ents in human health, functional and biochemical indicators to assess nutrient requirements, methodological problems related to the assessment of intake of these micronutrients and to the assess- ment of adequacy of intake, relationships of nutrient intake to chronic disease, and adverse effects of nutrients; 2. Examine data to identify major discrepancies between intake and the Estimated Average Requirements (EARs) and consider pos- sible reasons for such discrepancies; 580
A RESEARCH AGENDA 581 3. Consider the need to protect individuals with extreme or dis- tinct vulnerabilities due to genetic predisposition or disease condi- tions; and 4. Weigh the alternatives and set priorities based on expert judg- ment. MAJOR KNOWLEDGE GAPS Requirements To derive an Estimated Average Requirement (EAR), the criterion must be known for a particular status indicator or combination of indicators that is consistent with impaired status as defined by some clinical consequence. For the micronutrients considered in this report, there is a dearth of information on the biochemical values that reflect abnormal function. A priority should be the determina- tion of the relationship of existing status indicators to clinical end- points in the same subjects to determine if a correlation exists. For some micronutrients, either new clinical endpoints or intermediate endpoints of impaired function need to be identified and related to status indicators. The depletion-repletion research paradigms and balance studies, although not ideal, are still probably the best approach to deter- mining requirements for many of the trace minerals. However, these studies should be designed to meet three important criteria: 1. 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 con- centrations 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.) 2. 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. 3. Repletion regimen intakes should bracket the expected 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. A relatively new and increasingly popular approach to determin-
582 DIETARY REFERENCE INTAKES ing requirements is kinetic modeling of body pools, using steady- state compartmental analyses. This approach is unlikely to supplant depletion-repletion studies because it suffers from a number of drawbacks. Several assumptions that cannot be tested experimentally are often needed, and the numbers obtained for body pool sizes are inherently imprecise. Even if accurate assessments of body pools were possible and were obtained, such information would be useful in setting a requirement only if one could establish the body pool size at which functional deficiency occurs. The amount needed for restoration of biochemical status indicators to baseline values is not necessarily equivalent to the requirement for the nutrient. For many of the nutrients under review, useful data are seriously lacking for setting requirements for infants, children, adolescents, pregnant and lactating women, and the elderly. Studies should use graded levels of nutrient intake and a combination of response in- dexes, and they should consider other points raised above. For some of these nutrients, studies should examine whether the requirement varies substantially by trimester of pregnancy. Data are lacking about gender issues with respect to metabolism and requirements of these nutrients. More information is needed on the vitamin A activity of caro- tenoids from plant foods and mixed meals, including meat. Field trials, studying the vitamin A efficacy of plant foods, are needed in which preformed vitamin A (positive control) is used at a supple- mentation level equivalent to plant food interventions. Assessment of the bioconversion and retinol molar equivalency ratio of caro- tenoids has mostly been conducted on single foods, rather than on a mixture of fruits and vegetables. Newer methods, such as stable isotopic methods, to evaluate the bioconversion of provitamin A carotenoids to 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. Further research is needed to evaluate the impact of non- nutritional factors on nutrient indicators. Evidence from national survey data provided in this report suggests that body mass index and plasma glucose concentration are positively correlated with indicators of iron status. Such non-nutritional factors may markedly affect the interpretation of the survey data for certain subpopula- tions where the prevalence of non-nutritional factors is high. There is increasing evidence to suggest that the interaction be- tween many of these nutrients and other food components affect nutrient absorption and metabolic utilization (bioavailability), but
A RESEARCH AGENDA 583 these interactions are not well understood in relation to the mainte- nance of normal nutritional status. These interactions may affect the dietary requirement for one or more of the nutrients. Role of Nutrients in Human Health There is evidence that arsenic, boron, nickel, silicon, and vanadium have a role in some physiological processes in some species, and for boron, silicon, and vanadium, measurable responses of human sub- jects to variation in dietary intake have been demonstrated. How- ever, the available data are not as extensive and the responses are not as consistently observed as they are for the other micronutrients. Therefore, further research is needed to evaluate the metabolic role of these five trace minerals in human health. Methodology For some micronutrients, serious limitations exist in the methods available to analyze laboratory values indicative of micronutrient status or to determine the micronutrient content of foods, or both. Furthermore, the standardization of indicators in relation to func- tional outcome is needed. These methodological limitations have slowed progress in conducting or interpreting studies of nutrient requirements. Because of the difficulty in measuring chromium in food samples, data on chromium intake in North America are lim- ited. There is a need for further standardization of thyroid volume and urinary iodine excretion to varying levels of iodine consump- tion. Further studies are needed for identifying the best indicator for assessing the effect of iron deficiency anemia on cognitive devel- opment. Potential sources of error in self-reported intake data include underreporting of portion sizes and frequency of intake, omission of foods, and inaccuracies related to the use of food composition tables. At the current time, a method for adjusting intakes based on underreporting is not available and much work is needed to develop an acceptable method. Relationships of Intake to Chronic Disease There are major gaps in knowledge linking the intake of some micronutrients and the prevention and retardation of certain chronic diseases common in North America. Although a number of studies have been conducted to evaluate the role of vitamin K in mainte-
584 DIETARY REFERENCE INTAKES nance of bone health, its role is still not well understood. A number of studies have demonstrated a beneficial effect of chromium on insulin action and circulating glucose levels; however, further infor- mation is needed to relate the intake of chromium to the preven- tion and reversal of diabetes. Although information on vitamin K and chromium is insufficient, even less information is available for the other nutrients, and therefore EARs are based on indicators other than functional ones. Adverse Effects Considering these micronutrients as a group, only a few studies have been conducted that were explicitly designed to address ad- verse effects of chronic high intake. For four nutrientsâvitamin K, arsenic, chromium, and siliconâdata were insufficient to set a Tolera- ble Upper Intake Level (UL). Because of insufficient human data, the UL for three nutrientsâboron, molybdenum, and vanadiumâ were based on animal data. Thus, information on which to base a UL is extremely limited for some micronutrients. THE RESEARCH AGENDA Five major types of information gaps were noted: (1) a lack of data demonstrating a role of some of these nutrients in human health, (2) a dearth of studies designed specifically to estimate aver- age requirements in presumably healthy humans, (3) a lack of data on the nutrient needs of infants, children, adolescents, the elderly, and pregnant women, (4) a lack of studies to determine the role of these nutrients in reducing the risk of certain chronic diseases, and (5) a lack of studies designed to detect adverse effects of chronic high intakes of these nutrients. Highest priority is given to research that has the potential to pre- vent or retard human disease processes and to prevent deficiencies with functional consequences. The following four areas for research were assigned the highest priority (other research recommenda- tions are found at the ends of Chapters 4 through 13): â¢ studies to identify and further understand the functional (e.g., cognitive function, regulation of insulin, bone health, and immune function) and biochemical endpoints that reflect sufficient and in- sufficient body stores of these micronutrients; â¢ studies to further identify and quantify the effect of interactions between nutrients and interactions between micronutrients and
A RESEARCH AGENDA 585 other food components, the food matrix, food processing, and age on nutrient bioavailability and therefore dietary requirement; â¢ studies to further investigate the roles of arsenic, boron, nickel, silicon, and vanadium in human health; and â¢ studies to investigate the influence of non-nutritional factors (e.g., body mass index, glucose intolerance, infection) on the bio- chemical indicators for micronutrients such as iron and vitamin A that are currently measured by U.S. and Canadian nutritional sur- veys. Because of a lack of sufficient data, a Tolerable Upper Intake Level (UL) could not be established for vitamin K, arsenic, chromium, and silicon. Furthermore, there was a lack of data from humans to establish a UL for boron, molybdenum, and vanadium, and there- fore a UL was based on animal data. Thus, research is needed con- cerning the ULs for these micronutrients. However, it was con- cluded that higher priority should be given to the areas listed above because of low suspicion of toxicity at intakes consumed from food and supplements in the United States and Canada.