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Dietary Reference Intakes Research Synthesis Workshop Summary 9 Dietary Reference Intakes for Infants and Children1 This session focused on major research needs related to the setting of Dietary Reference Intakes (DRIs) for infants and children. Lindsay H. Allen of the Western Human Nutrition Research Center at the University of California, Davis, who served on the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and is a former Food and Nutrition Board member, addressed major issues related to setting DRIs for infants and children. Nancy F. Krebs,2 of the University of Colorado Health Sciences Center, a current Food and Nutrition Board member, focused on the use of zinc stable isotopes to inform the DRI process for these age groups. SETTING DIETARY REFERENCE INTAKES FOR CHILDREN Presenter: Lindsay H. Allen This presentation covered three main topics: (1) a summary of the derivation of the DRIs for infants and children and of related problems that may be solvable, (2) issues that have been identified from the application of DRIs for children in various settings and their implications, and (3) the major knowledge gaps that were identified in the series of reports 1 This chapter is based on a transcript and slides from the workshop. 2 Dr. Krebs acknowledged contributions from K. Michael Hambidge, Leland V. Miller, Jamie Westcott, Lei Sian, and Xiaoyang Sheng.
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Dietary Reference Intakes Research Synthesis Workshop Summary and comments on whether those gaps can be filled. Information on the derivation of the DRIs was included to help clarify research gaps. Derivation of DRIs for Infants No Estimated Average Requirements (EARs) were set for infants because of lack of appropriate data. Adequate Intakes (AIs) were set instead. Thus, methods are lacking to estimate the prevalence of inadequate intakes or to plan complementary feeding for infants. This poses a large problem in developing countries where there may be a need for fortified foods. Young Infants The AI for all the nutrients for infants in the first six months of age was obtained by multiplying the average daily volume of breast milk (780 mL) times the concentration of the nutrient in breast milk. One serious problem is the accuracy of the data on human milk composition. The reported nutrient values for human milk vary widely among and within different studies. Reasons include small numbers of subjects, changes in composition over the course of feeding and over the course of lactation, improper sampling, effects of supplement use and food fortification on milk composition, and analytical problems. All these problems could be overcome. A few examples illustrate the nature and extent of the limitations of data on human milk composition. For iron, the average concentration is said to be 0.35 mg/L, but the literature provides values ranging from 0.20 to 0.88 mg/L. The 0.35-mg value is approximately in the middle of that range. One new study from Sweden (Domellof et al., 2004), which has a large sample size relative to other studies, reports a value of 0.29 mg of iron per liter of breast milk, which, in practice, is considerably lower than the 0.35-mg value in current use. For vitamin A, an average of 485 µg/L is the value chosen, but the values considered ranged from 314 µg/L to 640 µg/L. The situation is similar for vitamin B12, for which a value of 0.42 µg/L was chosen. The lowest reported value, 0.31 µg/L, was from vegans; the highest value, 0.91 µg/L, was from Brazilian women who received prenatal supplements. Folate analysis also has been very controversial. Dr. Allen emphasized that erroneous estimates of
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Dietary Reference Intakes Research Synthesis Workshop Summary breast milk composition have a huge influence on the AIs during the first year after birth, and that this is a straightforward problem that could be remedied. Older Infants Several methods were used to derive the AI for infants in the second six months of age. When appropriate data were available, the AI was obtained by adding the estimated mean intake of the nutrient from solid food to the amount of that nutrient provided by 600 mL of breast milk. Dietary data on nutrients from solid foods were unavailable for many of the nutrients. Thus, in many cases, the AI was obtained by extrapolating up from the younger infants and/or down from older age groups (see “Extrapolation and Interpolation” section). The factorial method was used to set the AI for three nutrients, and a few other approaches were used as well. For example, serum 25-hydroxyvitamin D, or 25-(OH)D, concentration was used to set the AI for vitamin D, and that AI has since been questioned. In many cases, the values obtained using two or more methods were compared to examine face validity. Derivation of DRIs for Children Overview of Methods Used Many different methods were used to set EARs, Recommended Dietary Allowances (RDAs), and AIs for children as follows: Energy (from birth; total energy expenditure plus growth) Protein (nitrogen balance, protein deposition) Linoleic, linolenic acids (breast milk plus median intake from the Continuing Survey of Food Intake by Individuals [CSFII]) Vitamin D (from birth; serum 25-(OH)D) Calcium (factorial, balance) Phosphorus (factorial) Iron (factorial, assumes 10% bioavailability) Zinc (factorial) Fluoride (caries prevention)
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Dietary Reference Intakes Research Synthesis Workshop Summary All others (extrapolation and/or interpolation) If the value being extrapolated was an AI, the child value also must be an AI, with all its limitations. Some of these methods may not have produced reasonable values (for example, see presentation on zinc by Dr. Nancy Krebs). Extrapolation and Interpolation Questions have been raised about the approaches used for extrapolating DRI values from one age group to another. Examination of this issue calls for a description of the methods used. Extrapolation up from the AI for infants ages 0 to 6 months to obtain an AI for infants ages 7 to 12 months was usually based on body weight, using body weight to the 0.75 power to correct for surface area changes, which are large during that period of life. Extrapolation down from the adult EAR to the child EAR used the equation: In this case the references weights were obtained from the Third National Health and Nutrition Examination Survey (NHANES III). Growth factors were based on the approximate proportional increase in protein requirements for growth (FAO/WHO/UNU, 1985). The growth factor value was 0.3 for children younger than 3 years of age and 0.15 for older children. These growth factor values were used for all the extrapolations, but they may not be appropriate for all nutrients because there is unevenness in the timing of the deposition of some nutrients. Some, such as protein and calcium, are deposited in large amounts during growth. Others, such as B vitamins, are not. Before this workshop, Dr. Stephanie Atkinson of McMaster University in Ontario, Canada, provided Dr. Allen with comments on interpolation and extrapolation and how this has been done in other countries from 13 reports and 1 review. Her comments were based on the paper
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Dietary Reference Intakes Research Synthesis Workshop Summary Determining Life Stage Groups and Extrapolating Nutrient Intake Values prepared by Drs. Anderson and Koletzko for an international meeting on dietary recommended intakes. The report from that meeting will be available in 2007 in the United Nations University’s Food and Nutrition Bulletin. Table 9-1 summarizes the approaches to extrapolation. Four major conclusions from the review are listed below: Use the new World Health Organization growth standards for weight, length-for-height, and body mass index (BMI) for ages 0 to 5 years. (The Institute of Medicine [IOM] used height and BMI data from NHANES III and later from the Centers for Disease Control and Prevention [CDC] for interpolation and extrapolation.) Base the extrapolation on body weight for nutrients that are not associated with metabolic rate. Use body weight0.75 for nutrients related to metabolic rate. Base cutoff points for age categories on biology. Derivation of Tolerable Upper Intake Levels Vitamins A, D, and K, fluoride, selenium, zinc, and iron were the only nutrients for which reliable data were available on which to derive the Tolerable Upper Intake Levels (ULs). Most of the ULs for children were obtained by extrapolating the adult UL value down, based on body TABLE 9-1 Extrapolations: Different Approaches Actual Weight Reference Weight Metabolic Weight Energy Interpolated Canada/United X X X States Caribbean X Germany/Austria/Switzerland ? European Union X X X Finland X France None? Mexico X United Kingdom X? SOURCE: Atkinson and Koletzko, Determining Life Stage Groups and Extrapolating Nutrient Intake Values. Food and Nutrition Bulletin (in press).
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Dietary Reference Intakes Research Synthesis Workshop Summary weight. Dr. Allen stated that the ULs for children probably are relevant only to nutrients obtained from supplements. For infants and children, the UL is very close to the AI—particularly for vitamin A and zinc. Problems Identified Upon Applying Selected Dietary Reference Intakes Inconsistencies Table 9-2 identifies nutrients for which the recommended intakes for 7- to 12-month-old infants are higher than those for 1- to 4-year-old children. These AIs were set by adding intake of the nutrient from complementary foods to the amount of the nutrient provided by 600 mL of breast milk. The reason for the inconsistency relates to the high content of specific nutrients in the complementary foods that were eaten by the 7- to 12-month-old U.S. infants. This inconsistency poses problems when trying to develop complementary food recommendations for developing countries. Another inconsistency is a very large increase in recommended intake of some nutrients going from 7 to 12 months up to 1 to 3 years (Table 9-3). The basis for these large increases is unclear. In practice, the application of these recommended intake values is very difficult. Usually, the period of 6 months to 4 years is viewed as a continuum in infant feeding, not a time of sharp changes in nutrient needs. TABLE 9-2 Inconsistency: Recommended Intakes for 7- to 12-Month-Old Infants Are Higher Than Those for 1- Through 3-Year-Old Children Nutrient Recommended Intake, by Age Group 7–12 months 1–3 years Vitamin A (µg RAE) 500 300 Vitamin C (mg) 50 15 Iodine (µg) 130 90 Iron (mg) 11 7 NOTE: RAE = retinol activity equivalent.
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Dietary Reference Intakes Research Synthesis Workshop Summary TABLE 9-3 Inconsistency: Large Increases in Recommended Intakes Occur at Age 12 Months Nutrient Recommended Intake, by Age Group 7–12 months 1–3 years Folate (µg) 80 150 Calcium (mg) 270 500 Phosphorus (mg) 275 460 Vitamin K (µg) 2.5 30 High Recommended Fiber Intakes Following up on earlier comments about the AIs for fiber, Dr. Allen concurred that they probably are too high for children. Table 9-4 shows how the intake range for dietary fiber compares with the AI, by age group. Notably, the upper end of each range of reported intake is far below the AI. Dr. Allen asked, “Is it even possible to achieve the [fiber] AI in U.S. [and Canadian] children?” Questionable Estimates of the Prevalence of Inadequacy Despite the application of correct methods of analysis, some nutrients may be incorrectly identified as inadequate in the diets of children. Dr. Allen pointed out that there appears to be an inconsistency: 58 percent of the children ages 1 to 2 years in the CSFII had intakes less than the EAR for vitamin E, but fewer than 1 percent of them had inadequate intakes of any other nutrient (Devaney et al., 2004). Similarly, nearly 80 percent of school children in the CSFII had intakes of vitamin E less than the EAR, 36 percent had intakes of magnesium less than the EAR, and 20 percent had intakes of phosphorus less than the EAR (Suitor and Gleason, 2002). Although it has been suggested that the finding of a high prevalence of inadequacy of vitamin E might be a result of underestimation of vitamin E intakes (see Chapter 5 covering the DRIs for antioxidant nutrients), more information is needed on this topic. Do the findings for the U.S. school children suggest that the EARs for vitamin E, magnesium, and phosphorus are too high? Are inadequate intakes of vitamin E, phosphorus, and magnesium really the most common inadequacies in U.S. school children based on biological data?
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Dietary Reference Intakes Research Synthesis Workshop Summary TABLE 9-4 A Comparison of Dietary Fiber Intake with the Respective AI, by Age Group Age (years) AI (g/d) Intake range (g/d) 1–3 19 5–12a 4–8 25 6–18 9–13 26–31c 9–11b aFor 1- to 2-year-old children. bFor 10- to 12-year-old children. cValue depends on individual’s energy intake. Very High Prevalences of Intakes Greater Than the UL Analysis of CSFII intake data for certain nutrients has revealed a very high prevalence of intakes greater than the UL. For example, 90 percent of formula-fed infants ages 0 through 11 months exceed the UL for zinc, and 39 percent exceed the UL for vitamin A. High percentages of children ages 1 to 4 years exceeded the UL for zinc, vitamin A, and sodium, but less than 1 percent exceeded the UL for other nutrients. Do these findings represent a problem with intakes, the ULs, or both? Knowledge Gaps Identified In the full set of DRI reports, 43 knowledge gaps were identified that pertained to infants, children, and/or adolescents. Of these, 11 essentially said that studies are needed to set child and adolescent EARs for a range of vitamins using graded levels of intake and clearly defined cutoff points (i.e., biomarkers) for adequacy and inadequacy and that these studies should be conducted over a sufficient duration. With few exceptions, such studies have not been done at all. Thus, the question is, Is it feasible to address this research need relating to children? Possible Approaches to Fill Knowledge Gaps Vitamin Requirements Some suggested approaches for improving knowledge of vitamin requirements include the following:
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Dietary Reference Intakes Research Synthesis Workshop Summary Test responses to interventions in populations with a high prevalence of deficiency. Many studies have been conducted, and more are underway. Possibly feed the nutrient in doses slightly below and above the EAR long enough to see changes in biomarkers. This approach would be expensive, time-consuming, and difficult. Conduct studies with stable isotopes (e.g., deuterated retinol, deuterated vitamin D) or nanotracers (14C-folate and 14C-tocopherol, 14C-vitamin B12) by accelerator mass spectrometry. Stable isotope studies could be used for several purposes, including the following: To estimate the percent absorption from breast milk and food To conduct kinetic modeling (this requires a time series; for example, Haskell et al.  used a population-based plasma kinetics approach to look at vitamin A stores and requirements in Peruvian children) To estimate the intake that maintains pool size (see, for example, information on the paired deuterated-retinol-dilution technique [Haskell, et al., 2004]) Mineral Requirements Studies with stable isotope tracers could improve knowledge of mineral requirements, for example: Measure bioavailability. Absorption of 58Fe from breast milk equals 16 percent in Swedish infants (Domellof et al., 2002). Measure the effects of foods on breast milk iron absorption (Abrams et al., 2005) based on erythrocyte incorporation. Measure absorption, excretion, pool size, and turnover to determine requirements, as with zinc (Krebs et al., 2006). Feasible ways to determine the intakes of calcium, phosphorus, magnesium, and vitamin D needed to maximize bone mineral accretion among 1- to 18-year-old children include the following: Studies of calcium, phosphorus, and magnesium balance and retention at varying levels of intake. Based on the adult experience,
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Dietary Reference Intakes Research Synthesis Workshop Summary however, this work is expected to lead to questions about whether maximal retention is the appropriate approach to use with calcium, for example. Studies using stable isotopes of calcium and magnesium to measure absorption, pools, excretion, and so on. Abrams and colleagues (2005) reported on dual calcium isotope tracer and timed urine collection—a very rapid way to look at calcium absorption. More data are needed on relationships of vitamin D intake and serum 25-(OH)D with parathyroid hormone, bone turnover markers, immune function, and bone mineral density. Although Dr. Allen indicated that the relationship between absorbed phosphorus and serum phosphorus probably could be determined, she questioned whether it is an important knowledge gap. Macronutrients Dr. Allen considers it feasible, timely, and important to address major knowledge gaps identified in the DRI Macronutrients Report (IOM 2002/2005) regarding activity factors for the management of body weight in children, total energy expenditure in children, measurement of the Physical Activity Level (PAL) in children, and diet composition patterns related to weight loss and accretion of lean tissue. Electrolytes and Water With regard to research recommendations in the DRI Electrolytes and Water Report (IOM, 2005), Dr. Allen considers it difficult to establish linkages of electrolyte needs and relationships of sodium and potassium in infancy with blood pressure and bone health later in life. Water turnover could be measured from the disappearance of deuterium from labeled water over time.
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Dietary Reference Intakes Research Synthesis Workshop Summary A Summary of Research Needs Related to Dietary Reference Intakes for Infants and Children In conclusion, Dr. Allen identified the following research that needs to be conducted related to DRIs for children: More analysis of breast milk, collected appropriately If extrapolating, use new World Heath Organization standards More nutrient intake data (especially from complementary foods) related to biomarkers that are validated in children Studies with stable isotopes and nanotracers to determine vitamin and mineral bioavailability, kinetic studies, and possibly change in pool size on different vitamin intakes Doubly labeled water studies to measure energy expenditure and water turnover Determination of vitamin D requirements based on relationships of intake with 25-(OH)D, parathyroid hormone, bone markers, and so on Although measuring food intake by infants and children is difficult, children need their own evidence-based DRIs. If DRI values for children are incorrect, this can result in incorrect identification of nutrient intake problems (either too little or too much), incorrect dietary recommendations for child feeding programs, and, potentially, adverse effects on health. THE USE OF ZINC STABLE ISOTOPES TO INFORM THE DIETARY REFERENCE INTAKE PROCESS FOR INFANTS AND CHILDREN Presenter: Nancy F. Krebs This presentation focused on two major topics: (1) the use of zinc stable isotopes in the estimation of zinc requirements in infancy and (2) the DRI process for setting the zinc UL for infants and children. The related DRI research recommendation involves the need for quantitative data on human zinc homeostasis under a wide range of dietary conditions
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Dietary Reference Intakes Research Synthesis Workshop Summary and at all ages (number 211-D).3 The type of study identified as particularly useful for this purpose was the use of stable isotope methodology to quantify responses to changes in intake and absorption over a long term. The presentation included a review of stable isotope methodologies for zinc (including dosing, collections, and data); issues particular to infants and young children (invasiveness, collections, constraints on study design); and considerations for refining estimates of zinc requirements and revisiting the UL for zinc. Advances in Understanding the Zinc Requirement Studies of Zinc Homeostasis in Children Figure 9-1 illustrates zinc homeostasis. Unlike other nutrients, a substantial amount of zinc is secreted into the gastrointestinal (GI) tract. Some of that zinc is reabsorbed, and some passes out into the stool. Urinary zinc content does not reflect dietary zinc intake. For infants and children, one needs to consider the accretion of zinc in new tissue. The DRI micronutrients panel used the factorial approach to determine the physiologic requirement for zinc and thus as a basis for the EAR. The amount that is absorbed needs to cover the losses from all sources plus the amount needed to account for the accretion of zinc in new tissue. Therefore, it is necessary to obtain data on the amount of zinc absorbed over an entire day rather than from a single “test meal.” Over the past few years, there has been a fundamental shift in the methods used to determine the physiologic requirement for zinc. 3 See Appendix C for the exact wording of the recommendation that corresponds to the identification number given, and see Appendix D for the name of the report that corresponds to the letter.
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Dietary Reference Intakes Research Synthesis Workshop Summary FIGURE 9-1 Diagram depicting zinc homeostasis. NOTE: Zn = zinc. Stable isotopes are useful for measurements mainly in the GI tract processes. Such measurements include the following: Fractional absorption—the proportion of ingested zinc that actually is getting into the system The excretion of endogenous zinc secreted into the GI tract Estimated size of the rapidly exchanging pool, which makes up about 10 percent of total body zinc Despite considerable progress, much work still is needed in terms of validating what the findings really represent in terms of zinc status. Stable Isotope Methodological Considerations Historically, studies have posed many difficulties, two of which are collecting sufficiently large urine samples and complete fecal samples from infants, and avoiding contamination. Some advances that have been
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Dietary Reference Intakes Research Synthesis Workshop Summary particularly relevant to being able to do studies with stable isotopes in children relate to using urine for measures of fractional absorption with the so-called dual isotope tracer ratio technique. The use of this technique provides multiple measurements to average, rather than just one end point. Better instrumentation allows the use of spot urine, greatly reducing collection demands. Three different stable isotopes of zinc are available and can be used concurrently to track different processes and to look at different conditions in the same person. Fecal monitoring with an isotope of zinc plus the rare earth element dysprosium now makes it possible to measure the completeness of the fecal collection and also to obtain fractional absorption from a fecal sample more easily, without a requirement for an intravenous dose. Moreover, by using dysprosium in combination with isotopes and obtaining partial fecal and spot urine collections for 4 to 5 days, the endogenous fecal zinc excretion can be estimated. Better instrumentation now allows the use of lower doses. The cost of isotopes has decreased dramatically in the past 10 years. Thus, the major cost is the labor involved in the analyses. Examples of Applications of New Methods In well-nourished individuals at the lowest doses of zinc, fractional absorption is very high; it decreases steadily with increases in the dose. The high fractional absorption of a low dose is not due to zinc deficiency. Instead, it is due to a very small amount of zinc in the GI tract. With a low dose, even though there is a high fractional absorption, the amount actually getting absorbed is small. There is essentially a linear relationship of dietary zinc to absorbed zinc at the lower doses. For aqueous doses of zinc in the postabsorptive state, at an intake of about 20 mg of zinc, the amount absorbed levels off. Dr. Krebs’ group has extended this work, done some pharmacokinetics modeling, used a saturation response model extensively, and applied findings to other data. Figure 9-2 is a plot of zinc intake versus absorbed zinc in young infants. Fractional absorption is high for breast-fed infants, but the amount absorbed remains less than that of formula-fed infants. The UL for this age group is 5 mg/day—less than the amount consumed by all but one of the formula-fed infants. This kind of plotting can be informative in terms of bioavailability and requirements.
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Dietary Reference Intakes Research Synthesis Workshop Summary FIGURE 9-2 Zinc intake versus absorbed zinc in infants ages 2–4 months: Saturation response model. NOTE: Amax = maximum absorption; CI = confidence interval; Zn = zinc; CMF = cow milk formula; SEF = semielemental formula; BF = breast-fed (exclusively); BF/FF = breast-fed with formula intake (6 oz/day); Lo Fe = 4 mg/L iron-fortified formula; Hi Fe = 12 mg/L iron-fortified formula; BF w/Fe supp = exclusively breast-fed with daily iron supplement (15 mg/day). SOURCE: Adapted from Hambidge, et al (in press) A plot of the endogenous fecal zinc versus absorbed zinc over a day shows a good correlation between the two. In Figure 9-3, the breast-fed infants are represented by the symbols on the left. Homeostatic mechanisms, including the conservation of endogenous zinc, enable the breast-fed infants to achieve positive net zinc absorption. Absorption studies and application of the saturation–response curve to data provide information useful for predicting the effects of feeding different complementary foods to older infants, as shown in Figure 9-4. At 7 months of age, the breast milk alone provides less zinc than required. Feeding unfortified cereal is predicted to have little impact on the total amount of zinc absorbed. By adding meat (in this case, beef) one
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Dietary Reference Intakes Research Synthesis Workshop Summary dramatically increases both zinc intake and absorbed zinc, thus meeting the physiologic requirement. In the Zinc-Fortified Wheat Study in Peruvian Preschool Children (Lopez de Romana et al., 2005), absorption studies helped explain the lack of a statistically significant effect of treatment times duration. Zinc absorption studies of Chinese toddlers revealed that (1) homeostatic mechanisms were not enough to compensate for their low zinc intakes, (2) there is reason to suspect zinc deficiency, and (3) there is a need for intervention trials. Dr. Krebs indicated that examining intakes relative to the EAR may be quite useful in predicting absorption and, therefore, response to proposed interventions. The effects of phytate intake on zinc absorption are complex. Dr. Krebs and coworkers are using a trivariate model to examine zinc absorption as a function of intakes of both dietary zinc and phytate (model not yet published). FIGURE 9-3 Absorbed zinc versus endogenous fecal zinc: breast-fed and formula-fed infants. NOTE: Zn = zinc. SOURCE: Krebs NF, Westcott JE. 2002. Zinc and breast-fed infants: If and when is there a risk of deficiency? In: Davis MK, Isaacs CE, Hanson LA, Wright AL, eds. Integrating Population Outcomes, Biological Mechanisms and Research Methods in the Study of Human Milk and Lactation. New York: Kluwar Academic/Plenum Publishers. With kind permission of Springer Science and Business Media.
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Dietary Reference Intakes Research Synthesis Workshop Summary FIGURE 9-4 Absorbed zinc versus zinc intake at age 7 months: implications for complementary foods for breast-fed infants. NOTE: EAR = Estimated Average Requirement. SOURCE: Data from Hambidge et al., 2002; Jalla et al., 2006, Krebs et al., 2006 The DRI Process and the UL More attention should have been given to intake assessment prior to setting the UL for zinc for young children, according to Dr. Krebs and Dr. Michael Hambidge, who served on the panel on micronutrients. As has been reported by many, a large proportion of infants and young children have zinc intakes that exceed the UL for zinc—largely because of infant formula and food fortification. Dr. Krebs took the position that there is no evidence that adverse effects have resulted, and she called for prompt amendment of the zinc UL to address this discrepancy.
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Dietary Reference Intakes Research Synthesis Workshop Summary Concluding Remarks In conclusion, advances in stable isotope methodology have made it possible to conduct studies in diverse pediatric populations and settings. These methods can be taken to the field now. The application of stable isotopes to zinc homeostasis in infants and children suggest that absorption is characterized by a saturation–response model, the most important factors influencing zinc absorption are the quantity of zinc ingested and likely phytate (but not host status), homeostatic responses are insufficient to prevent dietary deficiency, and comparison of population intake to the current EAR for zinc seems to predict a response to interventions. Furthermore, it is important to link homeostatic responses to interventions with functional outcomes. DISCUSSION Throughout the workshop, many discussions included mention of the serious data gaps related to setting EARs for infants and children. During this discussion, Dr. Bier called for the convening of experts to develop modeling approaches and other approaches to radiotracers in a way that advances the pediatric field. For example, there is the need for reduced sampling algorithms that allow compartmental modeling. How does one develop those reduced sampling algorithms? How can multiple tracers be used to develop time series? Dr. Allen added that there is a big need to convene a group to examine methods that are most feasible, most ethical, and most convenient. Ethical considerations would include addressing the types of studies that should be allowable by institutional review boards.
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