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12 Zinc SUMMARY Zinc functions as a component of various enzymes in the mainte- nance of the structural integrity of proteins and in the regulation of gene expression. Overt human zinc deficiency in North America is not common, and the symptoms of a mild deficiency are diverse due to zincâs ubiquitous involvement in metabolic processes. Factorial analysis was used to set the Estimated Average Requirement (EAR). The Recommended Dietary Allowance (RDA) for adults is 8 mg/ day for women and 11 mg/day for men. Recently, the median intake from food in the United States was approximately 9 mg/day for women and 14 mg/day for men. The Tolerable Upper Intake Level (UL) for adults is 40 mg/day, a value based on reduction in erythro- cyte copper-zinc superoxide dismutase activity. BACKGROUND INFORMATION Function Zinc has been shown to be essential for microorganisms, plants, and animals. Deprivation of zinc arrests growth and development and produces system dysfunction in these organisms. The biological functions of zinc can be divided into three categories: catalytic, structural, and regulatory (Cousins, 1996). There is extensive evi- dence in support of each of these functions, and there may be some overlap. 442
ZINC 443 Nearly 100 specific enzymes (e.g., EC 220.127.116.11 alcohol dehydroge- nase) depend on zinc for catalytic activity. Zinc removal results in loss of activity, and reconstitution of the holoenzyme with zinc usually restores activity. Examples of zinc metalloenzymes can be found in all six enzyme classes (Vallee and Galdes, 1984). Well-studied zinc metalloenzymes include the ribonucleic acid (RNA) polymerases, alcohol dehydrogenase, carbonic anhydrase, and alkaline phosphatase. Zinc is defined as a Lewis acid, and its action as an electron acceptor contributes to its catalytic activity in many of these enzymes. Changes in activity of zinc metalloenzymes during dietary zinc restriction or excess have not been consistent in experimental studies with humans or animals. The structural role of zinc involves proteins that form domains capable of zinc coordination, which facilitates protein folding to produce biologically active molecules. The vast majority of such proteins form a âzinc finger-likeâ structure created by chelation centers, including cysteine and histidine residues (Klug and Schwabe, 1995). Some of these proteins have roles in gene regulation as dioxy- ribonucleic acid binding transcription factors. Examples include nonspecific factors such as Sp1 and specific factors such as retinoic acid receptors and vitamin D receptors. These structural motifs are found throughout biology and include the zinc-containing nucleo- capside proteins of viruses such as the human immunodeficiency virus (Berg and Shi, 1996). The relationship of zinc finger protein bioactivity to zinc in the diet has not received extensive study. Zinc also provides a structural function for some enzymes; copper-zinc superoxide dismutase is the most notable example. In this instance, copper provides catalytic activity, whereas zincâs role is structural. Also of potential relevance as a structural role is the essentiality of zinc for intracellular binding of tyrosine kinase to T-cell receptors, CD4 and CD8Î±, which are required for T-lymphocyte development and activation (Huse et al., 1998; Lin et al., 1998). The role of zinc as a regulator of gene expression has received less attention than its other functions. Metallothionein expression is regulated by a mechanism that involves zincâs binding to the transcription factor, metal response element transcription factor (MTF1), which activates gene transcription (Cousins, 1994; Dalton et al., 1997). The number of genes that are activated by this type of mechanism is not known, however, because a null mutation for MTF1 is lethal during fetal development of mice, suggesting some critical genes must be regulated by MTF1 (GÃ¼nes et al., 1998). Zinc transporter proteins associated with cellular zinc accumulation and release may be among the metal response element-regulated family
444 DIETARY REFERENCE INTAKES of genes (McMahon and Cousins, 1998). Zinc has been shown to influence both apoptosis and protein kinase C activity (McCabe et al., 1993; Telford and Fraker, 1995; Zalewski et al., 1994), which is within the regulatory function. The relationship of zinc to normal synaptic signaling processes also falls within the regulatory role (Cole et al., 1999). The most widely studied MTF-regulated gene is the metallothionein gene. An unequivocal function has not been established, but this metalloprotein appears to act as a zinc traffick- ing molecule for maintaining cellular zinc concentrations (Cousins, 1996) and perhaps as part of a cellular redox system for zinc dona- tion to zinc finger proteins (Jacob et al., 1998; Roesijadi et al., 1998). Upregulation of metallothionein by specific cytokines and some hormones suggests a function that is critical to a stress response. Induction of metallothionein by changes in dietary zinc intake has received considerable attention in experiments with both animals and humans (reviewed in Chesters, 1997; Cousins, 1994). Erythro- cyte metallothionein concentrations decreased rapidly in humans fed a phytate-containing diet of very low zinc content (Grider et al., 1990). Erythrocyte metallothionein concentration appears to be a measure of severe zinc depletion, and the extent of a change in concentration can distinguish between low and adequate levels of zinc intake under experimental conditions (Thomas et al., 1992). Erythrocyte metallothionein and monocyte metallothionein messen- ger RNA concentrations increase with elevated zinc intake levels such as those encountered with dietary supplements (Grider et al., 1990; Sullivan et al., 1998). Studies of metallothionein concentra- tion in blood cells or plasma during large human dietary trials have not been undertaken. Consequently, the use of metallothionein as a static or functional indicator of zinc status needs further study. While knowledge of the biochemical and molecular genetics of zinc function is well developed and expanding, neither the relationship of these genetics to zinc deficiency or toxicity nor the function(s) for which zinc is particularly critical have been established. For example, explanations for depressed growth, immune dysfunction, diarrhea, altered cognition, host defense properties, defects in carbohydrate utilization, reproductive teratogenesis, and numerous other clinical outcomes of mild and severe zinc deficiency (Hambidge, 1989; King and Keen, 1999) have not been conclusively established. Physiology of Absorption, Metabolism, and Excretion Zinc is widely distributed in foods. Because virtually none of it is present as the free ion, bioavailability is a function of the extent of
ZINC 445 digestion. Digestion produces the opportunity for zinc to bind to exogenous and endogenous constituents in the intestinal lumen, including peptides, amino acids, nucleic acids, and other organic acids and inorganic anions such as phosphate. The vast majority of zinc is absorbed by the small intestine through a transcellular pro- cess with the jejunum being the site with the greatest transport rate (Cousins, 1989b; Lee et al., 1989; Lonnerdal, 1989). Absorption kinetics appear to be saturable, and there is an in- crease in transport velocity with zinc depletion. Paracellular trans- port may occur at high zinc intakes. Transit time also influences the extent of absorption to an extent that, in malabsorption syndromes, zinc absorption is reduced. Transfer from the intestine is via the portal system with most newly absorbed zinc bound to albumin. Considerable amounts of zinc enter the intestine from endogenous sources. Homeostatic regulation of zinc metabolism is achieved princi- pally through a balance of absorption and secretion of endogenous reserves involving adaptive mechanisms programmed by dietary zinc intake (King and Keen, 1999). Zinc depletion in humans is accom- panied by reduced endogenous zinc loss on the order of 1.3 to 4.6 mg/day, derived from both pancreatic and intestinal cell secretions. Strong evidence suggests zinc transporter proteins in the various tissues act in concert to obtain such adaptation, but evidence is lack- ing in humans (McMahon and Cousins, 1998). Measurement of true absorption, which eliminates the contribu- tion of endogenous zinc from calculations, shows that zinc depletion increases the efficiency of intestinal zinc absorption. Regulation of absorption may provide a âcoarse controlâ of body zinc, whereas endogenous zinc release provides âfine controlâ to maintain balance (King and Keen, 1999). An autosomal recessive trait, acrodermatitis enteropathica, is a zinc malabsorption problem of undetermined genetic basis. The mutation causes severe skin lesions and cognitive dysfunction (Aggett, 1989). The genetic defect suggests that one gene has a major influence on zinc absorption. Tracer studies have shown that zinc is metabolically very active with initial uptake by liver representing a rapid phase of zinc turn- over. Over 85 percent of the total body zinc is found in skeletal muscle and bone (King and Keen, 1999). While plasma zinc is only 0.1 percent of this total, its concentration is tightly regulated at about 10 to 15 Âµmol/L. Stress, acute trauma, and infection cause changes in hormones (e.g., cortisol) and cytokines (e.g., interleukin 6) that lower plasma concentration. Small changes in tissue pools could cause the decrease. In humans, plasma zinc concentrations are maintained without notable change when zinc intake is restricted
446 DIETARY REFERENCE INTAKES or increased unless these changes in intake are severe and pro- longed (Cousins, 1989a). Preliminary kinetic data indicate that the combined size of readily exchangeable zinc pools (i.e., those that exchange with zinc in plasma within 72 hours) decreases with dietary zinc restriction (Miller et al., 1994). Fasting results in increased plasma zinc concentration, an outcome that possibly reflects cata- bolic changes in muscle protein. Cyclic postprandial changes in plasma zinc concentration have been documented (King et al., 1994). In both cases, hormonally regulated events are the biochem- ical basis for the changes. Albumin is the principal zinc-binding protein in plasma from which most metabolic zinc flux occurs. Func- tional aspects of zinc tightly bound to Î±-2-macroglobulin have not been described. Plasma amino acids bind some zinc and could be an important source of zinc excretion. Zinc secretion into and excretion from the intestine provides the major route of endogenous zinc excretion. It is derived partially from pancreatic secretions, which are stimulated after a meal. Biliary secretion of zinc is limited, but intestinal cell secretions also con- tribute to fecal loss (Lonnerdal, 1989). These losses may range from less than 1 mg/day with a zinc-poor diet to greater than 5 mg/day with a zinc-rich diet, a difference that reflects the regulatory role that the intestinal tract serves in zinc homeostasis. Urinary zinc losses are only a fraction (less than 10 percent) of normal fecal losses (King and Keen, 1999). Zinc transporter activity may account for renal zinc reabsorption (McMahon and Cousins, 1998), and glucagon may help regulate it. Increases in urinary losses are con- comitant with increases in muscle protein catabolism due to starva- tion or trauma. The increase in plasma amino acids, which consti- tute a potentially filterable zinc pool, is at least partially responsible. Zinc loss from the body is also attributed to epithelial cell desqua- mation, sweat, semen, hair, and the menstrual cycle. Clinical Effects of Inadequate Intake Individuals with malabsorption syndromes including sprue, Crohnâs disease, and short bowel syndrome are at risk of zinc defi- ciency due to malabsorption of zinc and increased urinary zinc losses (Pironi et al., 1987; Valberg et al., 1986). In mild human zinc deficiency states, the detectable features and laboratory/functional abnormalities of mild zinc deficiency are diverse. This diversity is not altogether surprising in view of the biochemistry of zinc and the ubiquity of this metal in biology with its participation in an extra- ordinarily wide range of vital metabolic processes. Impaired growth
ZINC 447 velocity is a primary clinical feature of mild zinc deficiency and can be corrected with zinc supplementation (Hambidge et al., 1979b; Walravens et al., 1989). Other functions that respond to zinc sup- plementation include pregnancy outcome (Goldenberg et al., 1995) and immune function (Bogden et al., 1987). Evidence of the efficacy of zinc lozenges in reducing the duration of common colds is still unclear (Jackson et al., 2000). Severe zinc deficiency has been documented in patients fed intra- venously without the addition of adequate zinc to the infusates (Chen et al., 1991) and in cases of the autosomal recessively inherited disease acrodermatitis enteropathica (Walling et al., 1989). Because of the ubiquity of zinc and the involvement of this micronutrient in so many core areas of metabolism, it is not surprising that the fea- tures of zinc deficiency are frequently quite basic and nonspecific, including growth retardation, alopecia, diarrhea, delayed sexual maturation and impotence, eye and skin lesions, and impaired appetite. Clinical features and laboratory criteria are not always con- sistent. This inconsistency poses a major difficulty in the quest to validate reliable, sensitive clinical or functional indicators of zinc status that apply to a range of otherwise potentially useful labora- tory indicators such as alkaline phosphatase activity. A further major conundrum is posed by the impressive, yet appar- ently imperfect, homeostatic mechanisms that maintain a narrow range of zinc concentrations within the body in spite of widely diverse dietary intakes of this metal and in spite of differences in bioavailability. This situation applies, for example, to circulating zinc in the plasma, which consequently provides only an insensitive index of zinc status (King, 1990). Therefore, it has become increas- ingly apparent that homeostatic mechanisms fall short of perfection and that clinically important features of zinc deficiency can occur with only modest degrees of dietary zinc restriction while circulat- ing zinc concentrations are indistinguishable from normal. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR ZINC Principal Indicator The selection of zinc absorption (more specifically, the minimal quantity of absorbed zinc necessary to match total daily excretion of endogenous zinc) as the principal indicator for adult Estimated Average Requirements (EAR) has been based on the evaluation of a factorial approach to determining zinc requirements. Details of this
448 DIETARY REFERENCE INTAKES approach are discussed under âFindings by Life Stage and Gender GroupâAdults Ages 19 Years and Olderâ. A sufficient number of metabolic studies of zinc homeostasis have been reported to permit an estimation of dietary zinc requirements in adults. The first step in this approach is to calculate nonintestinal losses of endogenous zinc, that is, losses via the kidney and integument with smaller quantities in semen and menstrual losses. Although urinary zinc excretion decreases markedly with severe dietary zinc restriction (Baer and King, 1984), extensive data indicate that ex- cretion by this route is unrelated to dietary zinc intake over a wide range (4 to 25 mg/day) that is certain to encompass the dietary zinc requirements for adults. Data regarding this lack of relation between intake and integumental and semen losses of zinc are more limited. Therefore, nonintestinal losses of endogenous zinc have been treated as a constant in response to varied zinc intake. In contrast to excretion of zinc via other routes, excretion of endogenous zinc via the intestine is a major variable in the mainte- nance of zinc homeostasis and is strongly correlated with absorbed zinc. The second step in estimating dietary zinc requirements is to define this relationship (Figure 12-1). After it has been defined and adjusted by the constant for other endogenous losses, one can cal- culate the minimum quantity of absorbed zinc necessary to offset endogenous zinc losses (Figure 12-1). The dietary zinc intake corresponding to this average minimum quantity of absorbed zinc is the EAR. This value has been deter- mined from the plot of the asymptotic regression analysis of ab- sorbed zinc versus ingested zinc (Figure 12-2). Theoretically, given the results described in detail for adults below, balance could also be used as an indicator. However, review of all published data on zinc balance (and net [apparent] absorp- tion) studies in young adult men (excluding those studies that have included tracer data and are being utilized for the current factorial calculations) collectively revealed no correlation with dietary zinc. Presumably this lack of correlation reflects the vagaries of balance studies. The factorial calculations for adults are based on tracer/ metabolic studies in which participants were fed diets from which the bioavailability of zinc was likely to be representative of typical diets in North America or, in some instances, possibly greater than average.
ZINC 449 4.4 4.2 4.0 3.8 3.6 Excretion of Endogenous Zinc (mg Zn/day) 3.4 3.2 3.0 2.8 2.6 Men 2.4 Total Endogenous 2.2 Women 2.0 1.8 1.6 1.4 1.2 1.0 0.8 Intestinal Endogenous 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 Absorbed Zinc (mg Zn/day) FIGURE 12-1 The relationship between endogenous zinc excretion and absorbed zinc. Heavy line represents the linear regression of intestinal excretion of endoge- nous zinc (mg/day) versus absorbed zinc (mg/day) from means of ten data sets for healthy men ages 19 through 50 years. The bold dashed lines above and parallel to the regression line represent the total endogenous zinc losses for men and women in relation to zinc absorption. The faint dashed line is the line of perfect agreement or equality of endogenous zinc and absorbed zinc. The intersect of this line with that of total endogenous zinc excretion indicates the average minimum quantity of absorbed zinc necessary to match endogenous losses for men and women. SOURCE: Hunt JR et al. (1992), Jackson et al. (1984), Lee et al. (1993), Taylor et al. (1991), Turnlund et al. (1984, 1986), Wada et al. (1985). Secondary Indicators Physical Growth Response to Zinc Supplementation In contrast to studies on the effects of low-dose zinc supplements on clinical features (e.g., pneumonia, diarrhea [Bhutta et al., 1999]) and on nonspecific laboratory functional tests of zinc status (e.g., tests of neuro-cognitive function [Sandstead et al., 1998]) or im- mune status (Shankar and Prasad, 1998), studies of the effects of zinc supplementation on physical growth velocity in children are useful in evaluating dietary zinc requirements for several reasons.
450 DIETARY REFERENCE INTAKES 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 Men 3.8 Absorbed Zinc (mg/day) 3.6 3.4 Women 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Ingested Zinc (mg/day) FIGURE 12-2 Asymptotic regression of absorbed zinc and ingested zinc. Individual points are means for the same data sets in Figure 12-1. SOURCE: Hunt JR et al. (1992), Jackson et al. (1984), Lee et al. (1993), Taylor et al. (1991), Turnlund et al. (1984, 1986), Wada et al. (1985). First, confirmation of the effect of zinc supplements on growth velocity (linear growth and weight) in children with varying degrees of growth retardation has been shown in a number of studies from many countries (Brown et al., 1998; Umeta et al., 2000). Second, because a sufficient number of these studies have been undertaken in North America, growth is applicable as a functional/clinical indi- cator of zinc requirement in North American children (Gibson et al., 1989; Walravens and Hambidge, 1976; Walravens et al., 1983, 1989). Third, baseline dietary data typically included in these studies are adequate to use for group analyses. Size and Turnover Rates of Zinc Pools Strong positive correlations have been observed between dietary zinc content, especially the amount of absorbed zinc, and estimates of the size of the combined pools of zinc that exchange with zinc in
ZINC 451 plasma (Miller et al., 1994; Sian et al., 1996). Once links to clinical, biochemical, or molecular effects of zinc deficiency have been achieved and appropriate cut-off levels for different age groups and gender have been defined, pool size and turnover measurements may be of value in future refinements of EARs. Even simpler models involving the measurement of plasma zinc clearance may be useful in assessing zinc deficiency, but dietary data derived by such a method are not available at this time (Kaji et al., 1998; Nakamura et al., 1993; Yokoi et al., 1994). More detailed model-based compartmental analyses, when specifically applied to the evaluation of dietary re- quirements, also have the potential to contribute to a more precise understanding of zinc requirements (Miller et al., 1998; Wastney et al., 1986). Plasma and Serum Zinc Concentration While both plasma zinc concentration and serum zinc concentra- tion are used as indicators of zinc status, plasma zinc concentration is preferable because of the lack of contamination of zinc from the erythrocyte. Homeostatic mechanisms are effective in maintaining plasma zinc concentrations for many weeks of even severe dietary zinc restriction (Johnson et al., 1993; Wada et al., 1985). A number of studies have reported no association between dietary zinc intake and plasma or serum zinc concentration (Artacho et al., 1997; Kant et al., 1989; Neggers et al., 1997; Thomas et al., 1988). Payette and Gray-Donald (1991) did observe a significant correlation between dietary zinc intake and serum zinc concentration in noninstitution- alized elderly; however, the correlation was positive for men and negative for women. Discernible relationships have been reported between plasma zinc concentration and habitual dietary zinc in- take, even within the range typically occurring in North America. These relationships are of some utility in providing a supportive indicator of zinc requirements. For example, serum zinc concentra- tions of Canadian adolescent girls aged 14 to 19 years vary inversely with phytate:zinc molar ratios, and a greater percentage of lacto- ovo-vegetarians have serum zinc values below 70 Âµg/dL than do omnivores (Donovan and Gibson, 1995). Cut-off concentrations for lower limits have been established and depend on the time of day at which collections are made because of the substantial and cumula- tive effects of meals in lowering concentrations (King et al., 1994). The cut-off concentrations for prebreakfast samples is 70 Âµg/dL. Different cut-off concentrations are not considered necessary for different age groups or genders.
452 DIETARY REFERENCE INTAKES Insufficient and inconsistent data exist for plasma or serum zinc concentrations in apparently normal subjects whose habitual dietary zinc intakes straddle the vicinity of the average requirement, and therefore use of those concentrations for estimating an average requirement is limited. Furthermore, plasma and serum zinc con- centrations do not seem to be sufficiently sensitive to serve as a subsidiary indicator. Zinc Concentration in Erythrocytes Erythrocyte zinc concentration is depressed at moderately severe levels of dietary zinc restriction (Thomas et al., 1992), but the sensi- tivity of this assay is inadequate to provide more than a secondary supportive indicator of dietary zinc requirements. Sample prepara- tion may account for some of the lack of sensitivity. Results from experimental depletion studies (Baer and King, 1984; Bales et al., 1994; Grider et al., 1990; Ruz et al., 1992; Thomas et al., 1992) have been mixed, and the value of erythrocyte zinc concentrations as an indicator of zinc nutritional status is not well defined. Zinc Concentration in Hair Associations between low zinc concentration in hair and poor growth have been documented (Ferguson et al., 1993; Gibson et al., 1989; Hambidge et al., 1972; Walravens et al., 1983). In three of these studies, low zinc concentration in hair was used as a criterion for zinc supplementation in children and resulted in increased growth velocity. Low zinc concentrations in hair have been reported in Canadian children with low meat consumption (Smit-Vanderkooy and Gibson, 1987). Subjects whose habitual diets are high in phytate or who have very high phytate:zinc molar ratios have also been noted to have relatively low zinc concentrations in hair. However, there is a lack of uniformity in apparently low zinc concentrations in hair, and no lower cut-off values have been defined clearly for any age group or either gender. The use of zinc in hair as a support- ive indicator for establishing zinc requirements needs further re- search. Activity of Zinc-Dependent Enzymes With the large number of zinc-dependent enzymes that have been identified, it is perhaps remarkable that no single zinc-dependent enzyme has found broad acceptance as an indicator of zinc status or
ZINC 453 requirement. This state of affairs is attributable to a number of factors, including the homeostatic processes that maintain zinc occupancy of the catalytic sites of these enzymes and the lack of consistency in findings between studies. Other factors include a lack of sensitivity, the inaccessibility of optimal tissues to assay, or, simply, inadequate research. The lack of baseline dietary data also negates the potential value of some reports. Given these limitations, limited dose-response data, and inconsistent responses to dietary zinc (Bales et al., 1994; Davis et al., 2000; Paik et al., 1999; Ruz et al., 1992; Samman et al., 1996), the activities of zinc-dependent enzymes, in- cluding alkaline phosphatase, copper-zinc superoxide dismutase, and lymphocyte 5â²-nucleotidase, can at most serve as supportive indicators of dietary zinc requirements at this time. Although it is not consistently responsive to zinc intake, the activity of plasma 5â²- nucleotidase (Beck et al., 1997a), which is derived from the CD73 cell surface markers of B and T cells, merits specific recognition as a potential marker of zinc status (Failla, 1999). Metallothionein and Zinc-Regulated Gene Markers Erythrocyte metallothionein concentrations have been reported to be responsive to both increased and restricted dietary zinc (Grider et al., 1990; Thomas et al., 1992), but the sensitivity and precision of this index has not been thoroughly evaluated. Monocyte metallo- thionein messenger RNA responds rapidly to in vivo zinc supple- mentation (Sullivan et al., 1998) and merits additional research. Moreover, this approach points the way for future exploration of molecular markers of zinc status including, for example, a whole family of zinc transporters that are now being identified (Failla, 1999; McMahon and Cousins, 1998). Indexes of Immune Status Zinc is essential for the integrity of the immune system, and inade- quate zinc intake has many adverse effects (Shankar and Prasad, 1998). Though the immune system, which is thought to underlie several of the most important sequelae of mild zinc deficiency, is sensitive to even mild zinc deficiency, the effects on functional indexes of zinc status are not specific. At this time, therefore, changes in indexes of immune status with manipulation of dietary zinc can serve only as a limited indicator for dietary zinc requirements.
454 DIETARY REFERENCE INTAKES Hormones The biology of zinc is linked extensively to hormone metabolism. Notable examples are the zinc finger motifs of regulatory proteins required for hormonal signals to regulate gene transcription (Cousins, 1994; Klug and Schwabe, 1995). Zinc has been reported to have roles in the synthesis, transport, and peripheral action of hormones. Low dietary zinc status has been associated with low circulating con- centrations of several hormones including testosterone (Prasad et al., 1996), free T4 (Wada and King, 1986), and IGF-1 (Ninh et al., 1996). Zinc supplementation has been associated with an increase in both circulating IGF-1 concentration and growth velocity (Ninh et al., 1996). However, no studies have directly related hormone concentrations to decreases or increases in zinc intake. Circulating Hepatic Proteins Reductions in retinol binding protein, albumin, and pre-albumin concentrations have been reported with moderate dietary zinc re- striction (Wada and King, 1986). Serum zinc and retinol binding protein concentrations are significantly correlated in zinc-deficient Thai children (Udomkesmalee et al., 1990). Changes in circulating concentrations of these proteins with changes in dietary zinc may serve as minor supportive indicators. The relationship of such indi- cators to general malnutrition or to dietary deficiency that is not related to zinc status supports their being minor indicators for zinc requirements. FACTORS AFFECTING THE ZINC REQUIREMENT Bioavailability Bioavailability of zinc can be affected by many factors at many sites. The intestine is the major organ in which variations in bio- availability affect dietary zinc requirements. These effects occur through two key regulatory processes: absorption of exogenous zinc and reabsorption of endogenous zinc. Dietary factors that affect bioavailability can have an impact on each of these processes (Cousins, 1989b; Lonnerdal, 1989). Zinc absorption from foods and supplements has received extensive study. The environment within the gastrointestinal tract drastically influences zinc solubility and absorptive efficiency. The propensity of zinc to bind tenaciously to ligands provided by dietary
ZINC 455 constituents is accentuated at the near neutral pH in the intestinal lumen. The exact nature of the form in which zinc is needed for uptake has not been established. Some transporters responsible for transcellular zinc movement may require the free ion, but cotrans- port with small peptides and nucleotides has not been ruled out. Absorption of zinc, when consumed as a chelate, has not been in- vestigated extensively. The option for zinc to be absorbed by the paracellular route adds to the lack of a unified form or path of zinc absorption from foods. Furthermore, the methods used to assess zinc absorption have varied widely, including balance studies, intes- tinal perfusion, responses of plasma zinc to single meals or aqueous doses, and tracer studies with intrinsically or extrinsically stable or radioactive zinc isotopes (Sandstrom and Lonnerdal, 1989). Nutrient-Nutrient Interactions Iron Daily intake of iron at levels such as those found in some supple- ments could decrease zinc absorption (OâBrien et al., 2000; Solomons and Jacob, 1981; Valberg et al., 1984). This relationship is of some concern in management of iron supplementation during pregnancy and lactation (Fung et al., 1997). Recent studies of the mechanism of nonheme iron absorption suggest that upregulation of an iron transport protein occurs in iron deficiency (Gunshin et al., 1997). The comparable affinity of this transporter for zinc sug- gests that, during low iron intake, zinc absorption may be stimulated and suggests one possible locus for a zinc-iron interaction. The in- fluence of heme iron on zinc absorption has not received much attention. The activity of other divalent metal transporters may also affect zinc absorption. Calcium and Phosphorus The importance of calcium in the diet and the mass of the ele- ment that must be consumed daily to maintain maximum bone density suggest that special attention should be given to its poten- tial inhibitory effect on zinc absorption. Nutrition experiments with swine have shown conclusively that excess dietary calcium produces a decrease in zinc absorption, which leads to a skin condition called parakeratosis. Experiments in humans have been equivocal, with calcium phosphate (1,360 mg/day of calcium) decreasing zinc ab- sorption (Wood and Zheng, 1997) and calcium as the citrate-malate
456 DIETARY REFERENCE INTAKES complex (1,000 mg/day of calcium) having no statistically signifi- cant effect on zinc absorption (McKenna et al., 1997). Differences could be related to the calcium sources, techniques used, and the extent of luminal zinc solubility. At present, data suggest consump- tion of a calcium-rich diet does not have a major effect on zinc absorption at an adequate intake level of the nutrient. Calcium effects at low dietary zinc intakes have not been adequately investi- gated. Dietary phosphorus-containing salts over an extensive intake range have not been shown to influence zinc balance (Greger and Snedeker, 1980; Spencer et al., 1984). Other dietary sources of phos- phorus include phytate and phosphorus-rich proteins, for example, milk casein and nucleic acids, all of which bind zinc tenaciously and decrease zinc absorption. Copper Large-scale studies on the influence of dietary copper intake on zinc absorption and utilization have not been carried out with human subjects. Various experimental approaches with animals have not revealed a uniform influence of copper on intestinal zinc uptake (Cousins, 1985; Sandstrom and Lonnerdal, 1989). Rather, evidence for an interaction derives from the therapeutic effect of zinc in reduc- ing copper absorption in patients with Wilsonâs disease (Yuzbasiyan- Gurkan et al., 1992). This action includes the induction of intesti- nal metallothionein by zinc and the subsequent binding of excess copper by this metalloprotein, which may limit transcellular copper absorption. The relationship may have relevance in situations where zinc supplements are consumed with marginal dietary copper intake. Folate Folate bioavailability is enhanced when polyglutamate folate is hydrolyzed by the zinc-dependent enzyme, polyglutamate hydrolase, to the monoglutamate. This occurrence suggests a possible point of interaction. Some studies have shown a relationship between folate and zinc (Milne et al., 1984), with low zinc intake decreasing folate absorption/status. More recent evidence does not support any effect of low zinc intake on folate utilization and shows that folate supple- mentation does not adversely affect zinc status (Kauwell et al., 1995). Extensive studies on this potential relationship have not been car- ried out in women. Given that these nutrients have important func- tions in both fetal and postnatal development, the relationship re- quires further study.
ZINC 457 Protein Zinc binds tenaciously to proteins at near neutral pH. Conse- quently, the amount of protein in the diet is a factor contributing to the efficiency of zinc absorption. As protein digestion proceeds, zinc becomes more accessible for zinc transport mechanisms of intestinal cells. The relative abundance of zinc as small molecular weight complexes of low binding affinity enhances the process. Small changes in protein digestion may produce significant changes in zinc absorption (Sandstrom and Lonnerdal, 1989). These changes in absorption may explain the correlation between zinc deficiency symptoms and certain malabsorption disorders (Cousins, 1996). The markedly greater bioavailability of zinc from human milk than from cowâs milk is an example of how protein digestibility, which is much lower in casein-rich cowâs milk than in human milk, influences zinc absorption (Roth and Kirchgessner, 1985). In general, zinc absorption from a diet high in animal protein will be greater than from a diet rich in proteins of plant origin such as soy (King and Keen, 1999). Other Food Components Phytic Acid Plants contain phytic acid (myo-inositol hexaphosphate) for use as a storage form of phosphorus. Consequently, plant-based foods, particularly grains and legumes, have a significant phytic acid con- tent. Enzymatic action of yeast during the leavening of bread and other fermentations reduce phytate levels, whereas extrusion processes (used in preparation of some breakfast cereals), may not (Williams and Erdman, 1999). In Caco-2 cells, the metal binding property of phytic acid decreases proportionally as fewer than six phosphate groups are bound to each inositol molecule (Han et al., 1994). Phytate binding of zinc has been demonstrated as a contrib- uting factor for the zinc deficiency related to consumption of un- leavened bread seen in certain population groups in the Middle East (Prasad, 1991). The overall effect of phytate is to reduce zinc absorption from the gastrointestinal tract through complexation and precipitation (Oberleas et al., 1966). These chemical effects appear to be enhanced by simultaneous binding of calcium. Phytate binding in the intestinal lumen includes zinc of both food origin and endogenous origin. Since zinc homeostasis is controlled in part by endogenous secretions, consumption of phytate-rich foods may
458 DIETARY REFERENCE INTAKES be of practical importance as a factor that limits absorption and maintenance of zinc balance. While high-fiber-containing foods tend also to be phytate-rich, fiber alone may not have a major effect on zinc absorption. Picolinic Acid A metabolite of tryptophan metabolism, picolinic acid has a high metal binding affinity. Picolinate complexes of zinc and chromium are not formed in nature in appreciable amounts, but are sold com- mercially as dietary supplements. Zinc picolinate as a zinc source for humans has not received extensive investigation. In an animal model, picolinic acid supplementation promoted negative zinc bal- ance (Seal and Heaton, 1985), presumably by promoting urinary excretion. Algorithms To date, a useful algorithm for establishing dietary zinc require- ments based on the presence of other nutrients and food compo- nents has not been established, and much information is still needed to develop one that can predict zinc bioavailability (Hunt, 1996). Algorithms for estimating dietary zinc bioavailability will need to include the dietary content of phytic acid, protein, zinc, and possibly calcium, iron, and copper. The World Health Organization (WHO, 1996) developed zinc requirements from low, medium, and high bioavailability diets on the basis of estimates of fractional absorp- tion on single test meals with varying zinc and phytate content. The results of single test meals for measuring zinc absorption, however, may be different from the long-term response of zinc absorption, as has been shown to be the case for iron (see Chapter 9). FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 6 Months No functional criteria of zinc status have been demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of zinc are based on an Adequate Intake (AI) that reflects the observed mean zinc intake of infants exclusively fed human milk.
ZINC 459 Method Used to Set the Adequate Intake Using the method described in Chapter 2, an AI has been used as the goal for intake during the first 6 months of life. The AI is based on the maternal zinc supply to the infant exclusively fed human milk. There is an unusually rapid physiologic decline in the zinc con- centration of human milk and consequently in the zinc supplied to infants fed human milk during the first 6 months of lactation (Krebs et al., 1985, 1994, 1995; Moser and Reynolds, 1983) (Figure 12-3). Concentrations of zinc in human milk decline from approximately 4 mg/L at 2 weeks to 3 mg/L at 1 month, 2 mg/L at 2 months, 1.5 mg/L at 3 months, and 1.2 mg/L at 6 months postpartum (Krebs et al., 1995; see Table 12-1). With a standard volume of intake of 0.78 L/day (Chapter 2), calculated zinc intakes are 2.15 mg/day at 1 month, 1.56 mg/day at 2 months, 1.15 mg/day at 3 months, and 0.94 mg/day at 6 months (Table 12-1). Measured zinc intake of infants fed human milk was 2.3 mg/day at 2 weeks and 1 mg/day at 3 months (Krebs et al., 1994). 4.5 4 3.5 Milk Output (mg/d) 3 2.5 2 1.5 1 0.5 0 0 2 4 6 8 10 12 14 Time (months) FIGURE 12-3 Average zinc consumption from human milk during the first 12 months of lactation. SOURCE: Table 12-1.
460 DIETARY REFERENCE INTAKES TABLE 12-1 Zinc Concentration in Human Milk Maternal Intake Stage of Reference Study Group (mg/d) Lactation Picciano and Guthrie, 1976 50 women Not reported 6â12 wk Johnson and Evans, 1978 10 women Not reported 2 moâ2 y Vuori et al., 1980 15 women, 24â35 y 13.7 Â± 2.7 mg/d 6â8 wk 12.8 Â± 2.8 mg/d 17â22 wk Fransson and Lonnerdal, 1982 23 women Not reported Various s Moser and Reynolds, 1983 23 women, 30 y 9.4 1 mo 12.8 3 mo 9.6 6 mo Casey et al., 1985 11 women, 26â39 y Not reported 8d 14 d 21 d 28 d Casey et al., 1989 22 women 10.9 7d 1 mo 12 mo Sievers et al., 1992 10 women Not reported 17 d 35 d 56 d 85 d 117 d Anderson, 1993 6 women, 20â30 y Not reported Up to 5 m Krebs et al., 1995 71 women, 30 y 13â25.7 0.5 mo 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 7 mo 8 mo 9 mo Aquilio et al., 1996 14 women, 21â29 y Not reported 2â6 d 12â16 d 21 d Biego et al., 1998 17 milk samples Not reported Mature m a Zinc intake based on reported data or concentration (mg/L) Ã 0.78 L/day for 0â6 months postpartum and concentration (mg/L) Ã 0.6 L/day for 7â12 months postpartum.
ZINC 461 Intake Stage of Milk Concentration Estimated Zinc Intake Lactation (mg/L) of Infants (mg/d)a rted 6â12 wk 1.7 1.33 rted 2 moâ2 y 1.8 1.40 7 mg/d 6â8 wk 1.89 1.47 8 mg/d 17â22 wk 0.72 0.56 rted Various stages 1.1 0.86 1 mo 2.6 2.03 3 mo 1.3 1.01 6 mo 1.1 0.86 rted 8d 4.74 3.69 14 d 3.88 3.03 21 d 3.71 2.89 28 d 2.98 2.32 7d 4.7 3.66 1 mo 2.9 2.26 12 mo 0.5 0.39 rted 17 d 3.6 2.81 35 d 2.6 2.03 56 d 1.7 1.33 85 d 1.3 1.01 117 d 1.2 0.94 rted Up to 5 mo 1.1â3.4 0.86â2.65 0.5 mo 4 3.12 1 mo 2.75 2.15 2 mo 2 1.56 3 mo 1.5 1.17 4 mo 1.4 1.09 5 mo 1.2 0.94 6 mo 1.2 0.94 7 mo 0.8 0.48 8 mo 0.9 0.52 9 mo 0.8 0.48 rted 2â6 d 2.2 1.72 12â16 d 2.3 1.79 21 d 2.3 1.79 rted Mature milk 2 1.6
462 DIETARY REFERENCE INTAKES In order to match the zinc intake of the infant in early weeks (Figure 12-3), the AI is set at 2.0 mg/day (2.5 mg/L Ã 0.78 L/day). This amount appears to be generous at ages 4 to 6 months when evaluated by zinc intake from human milk at this age, and human milk has been shown to result in weight gain and body lengths similar to those of infants provided complementary foods at 4 to 6 months (Dewey et al., 1999). A positive association between zinc content of human milk at 5 months and changes in the weight-for- age Z scores for the 5- to 7-month interval have, however, been documented (Krebs et al., 1994). There is also some evidence, how- ever, that growth-limiting zinc deficiency can occur in infants prin- cipally fed human milk after the age of 4 months (Walravens et al., 1992). Factorial estimates of requirements (i.e., 2.1 mg/day at 1 month and 1.54 mg/day at 5 months) are consistent with this AI for infants ages 0 through 6 months. These factorial estimates are based on measurements of zinc intake of infants fed human milk, fractional absorption, and endogenous losses (Krebs et al., 1996). Integu- mental and urine losses are from published calculations (Krebs and Hambidge, 1986). Also consistent with this AI is an earlier report that physical growth of male infants fed a zinc-fortified cow milk formula (5.8 mg/L) was greater than that of infants receiving the same formula but with a zinc concentration of 1.8 mg/L, which provided about 1.4 mg/day of zinc (Walravens and Hambidge, 1976). Zinc AI Summary, Ages 0 through 6 Months AI for Infants 0â6 months 2.0 mg/day of zinc Special Considerations The zinc concentration in cow milk ranges from 3 to 5 mg/L (Lonnerdal et al., 1981) which is greater than the average concen- tration in human milk (Table 12-1). Singh and coworkers (1989) reported that approximately 32 percent of zinc in cow milk is bound to casein and the majority of the remaining zinc (63 percent) is bound to colloidal calcium phosphate. The absorption of zinc from human milk is higher than from cow milk-based infant formula and cow milk (Lonnerdal et al., 1988; Sandstrom et al., 1983). The zinc bioavailability from soy formulas is significantly lower than from milk-based formulas (Lonnerdal et al., 1988; Sandstrom et al., 1983).
ZINC 463 Infants and Children Ages 7 Months through 3 Years Evidence Considered in Estimating the Average Requirement Intake from Human Milk. Zinc nutriture in later infancy is quite different from that in the younger infant. It is likely that neonatal hepatic stores, which may contribute to metabolically usable zinc pools in early postnatal life, have been dissipated (Zlotkin and Cherian, 1988). Human milk provides only 0.5 mg/day of zinc by 7 months postpartum (Krebs et al., 1994), and the concentration declines even further by 12 months (Casey et al., 1989). It is apparent, there- fore, that human milk alone is an inadequate source of zinc after the first 6 months. As a result, extrapolation from human milk in- take during the 0 through 6 months postpartum period, which yields 2.4 mg/day, does not reflect adequate zinc intake during the second 6 months. Intake from Human Milk and Complementary Foods. Data from the Third National Health and Nutrition Examination Survey indicate that the median intake of zinc from complementary foods is 1.48 mg/day (n = 45) for older infants consuming human milk. Thus, the average zinc intake from human milk and complementary foods is estimated to be approximately 2 mg/day (0.5 + 1.48). Factorial Analysis. Excretion of endogenous zinc is used to esti- mate the physiological requirement of zinc in older infants and young children. The Estimated Average Requirement (EAR) for zinc is determined by dividing the physiological requirement by the fractional zinc absorption. Apart from some data on excretion of zinc in the urine (Alexander et al., 1974; Cheek et al., 1968; Ziegler et al., 1978), direct measurements of endogenous zinc excretion are not available for older infants, children, or adolescents. These endogenous zinc losses (intestinal, urinary, and integumental), therefore, are estimated by extrapolation from measured values for either adults (see âAdults Ages 19 Years and Olderâ) or younger infants. These extrapolations have been based on a reference weight. Intestinal losses vary directly with the quantity of zinc absorbed (see âAdults Ages 19 Years and Olderâ). The average intestinal excretion of endogenous zinc in infants aged 2 to 4 months who receive human milk is approximately 50 Âµg/kg/day (Krebs et al., 1996). There is a âcriticalâ level of intestinal excretion of endogenous zinc
464 DIETARY REFERENCE INTAKES in adults at which the quantity of absorbed zinc is equal to the total endogenous zinc losses. This critical level, derived from all available sets of data for adult men, yields an average excretion of 34 Âµg/kg/ day of zinc and is used for children beyond 1 year of age and adoles- cents. Therefore, 50 Âµg/kg/day is used for older infants and 34 Âµg/ kg/day for children aged 1 through 3 years. It is recognized that this is an approximation, not only because of the extrapolation of values but also because intestinal excretion of endogenous zinc is strongly correlated with zinc absorption. Urinary losses of zinc are approximately 7.5 Âµg/kg/day for both men and women (see âAdults Ages 19 Years and Olderâ). After early infancy, excretion rates for children on a body weight basis seem to differ very little from adult values (Krebs and Hambidge, 1986). No data are available on the integumental losses in children, so estimates for children are derived from data in adult men (Johnson et al., 1993), which provide an estimate of 14 Âµg/kg/day of zinc. There- fore, the estimated total endogenous excretion of zinc is 64 Âµg/kg/ day for older infants and 48 Âµg/kg/day for children aged 1 through 3 years. Requirements for Growth. These requirements have been estimated from chemical analyses of infants and adults, which give an average concentration of 20 Âµg/g wet weight of zinc (Widdowson and Dick- erson, 1964). It is assumed that each gram of new lean and adipose tissue requires this amount of zinc. The average amount of new tissue accreted for older infants and young children is 13 and 6 g/ day, respectively (Kuczmarski et al., 2000). With the estimates above, the total amount of absorbed zinc re- quired for infants ages 7 through 12 months is 836 Âµg/day (Table 12-2). The corresponding value for children ages 1 through 3 years is 744 Âµg/day (Table 12-3). Fractional Absorption of Dietary Zinc. Fractional absorption probably has the greatest variation of any of the above physiological factors, depending as it does on numerous factors including quantity of ingested zinc, nutritional status, and bioavailability. Although a âcrit- icalâ average fractional absorption of 0.4 has been derived from the data sets used for adult men (see âAdults Ages 19 Years and Olderâ), a more conservative value of 0.3 is used for preadolescent children. This value is based on studies of infants and young children reported by Fairweather-Tait and coworkers (1995) and Davidsson and co- workers (1996). To calculate the dietary zinc requirement based on
ZINC 465 TABLE 12-2 Requirement for Absorbed Zinc for Infants Aged 7 through 12 Months Intestinal losses 50 Âµ g/kg/day Ã 9 kg = 450 Âµ g/day Urinary and integumental losses 14 Âµ g/kg/day Ã 9 kg = 126 Âµ g/day Requirement for growth 13 g/day Ã 20 Âµg/g = 260 Âµ g/day Required absorbed zinc = 836 Âµ g/day TABLE 12-3 Requirement for Absorbed Zinc for Children Aged 1 through 3 Years Intestinal losses 34 Âµ g/kg/day Ã 13 kg = 442 Âµ g/day Urinary and integumental losses 14 Âµ g/kg/day Ã 13 kg = 182 Âµ g/day Requirement for growth 6 g/day Ã 20 Âµ g/g = 120 Âµ g/day Required absorbed zinc = 744 Âµ g/day the fractional zinc absorption, it is assumed that the older infant continues to be fed human milk between 7 and 12 months of age along with complementary foods. The fractional absorption of zinc from human milk continues to approximate 0.5 (Abrams et al., 1997). Based on an average intake of 500 Âµg/day from human milk and a fractional absorption of 0.5, the amount of zinc ingested from milk is approximately 250 Âµg/day. Therefore the estimated absorbed zinc required from complementary foods is 586 Âµg/day (836 â 250). Applying a fractional absorption of 0.3, zinc intake required from complementary foods is 1.95 mg/day (586 Ã· 0.3). Therefore, the EAR for infants ages 7 through 12 months is 2.5 mg/day (0.5 + 1.95). For children ages 1 through 3 years, a fractional absorption of 0.3 is used to estimate the required dietary zinc resulting in an EAR of 2.5 mg/day (744 Ã· 0.3), after rounding. Extrapolation from Adults. An average requirement of 2.3 and 3.0 mg/day for older infants and young children, respectively, is calcu- lated with use of the method described in Chapter 2 that extrapo- lates from the adult EAR based on body size. Growth. Limited dietary zinc data are available for children in this age group. In a 6-month, placebo-controlled, randomized zinc sup- plementation study (Walravens et al., 1989), a major criterion for
466 DIETARY REFERENCE INTAKES inclusion was a weight-for-age less than the tenth percentile in appar- ently healthy young children with no organic disease and no detect- able family dynamic issues that might explain failure to thrive. Com- pared with placebo-treated control subjects, the zinc-supplemented children had a significantly greater increase in mean weight-for-age Z-scores. Inspection of the individual data points indicated that 87.5 percent of zinc-supplemented subjects had an increase in weight- for-age Z-scores compared with 52 percent of control subjects. These results indicate that 35.5 percent of 10 percent, or 3.6 percent of the overall population in this age group, had growth-limiting zinc deficiency. The calculated mean dietary intake at baseline for the placebo-treated children was 4.1 Â± 0.8 mg/day (standard deviation [SD]) of zinc. Subtraction of two SDs from this population mean gives an EAR of 2.5 mg/day. It is likely that this calculation errs on the low side because of the variability associated with 24-hour recall dietary information and because some children with weight-for-age greater than the tenth percentile are also likely to have mild growth- limiting zinc deficiency. Hence this value corresponds reasonably well with the EAR determined from the factorial approach. Zinc EAR and RDA Summary, Ages 7 Months through 3 Years EAR for Infants 7â12 months 2.5 mg/day of zinc EAR for Children 1â3 years 2.5 mg/day of zinc The Recommended Dietary Allowance (RDA) for zinc is set by using a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, the zinc RDA is 120 percent of the EAR). The calculated RDA is rounded to the nearest 1 mg. RDA for Infants 7â12 months 3 mg/day of zinc RDA for Children 1â3 years 3 mg/day of zinc
ZINC 467 Children Ages 4 through 8 Years Evidence Considered in Estimating the Average Requirement Factorial Analysis. Factorial analysis is used to determine the EAR for children ages 4 through 8 years. The nonintestinal endogenous losses and requirement for growth are based on data previously discussed (see âInfants and Children Ages 7 Months through 3 Yearsâ). For this age group, the average intestinal losses are 34 Âµg/ kg/day of zinc and the amount of new tissue accreted is 7 g/day (Kuczmarski et al., 2000). Based on the summation of zinc losses and requirements for growth, the required amount of absorbed zinc for this age group is approximately 1.2 mg/day (Table 12-4). With a fractional absorption of 0.3 based on studies in infants and young children (Davidsson et al., 1996; Fairweather-Tait et al., 1995), the EAR is 4.0 mg/day of zinc. Extrapolation from Adults. The average requirement for zinc is 4 mg/day as determined by the method described in Chapter 2, which extrapolates from the adult EAR. Growth. Some dietary data are available from children aged 4 through 8 years whose growth percentiles were at the lower end of the normal range and who were subjects in placebo-controlled, randomized trials of dietary zinc supplementation. In each of two studies, one in Canada (Gibson et al., 1989) and the other in the United States (Walravens et al., 1983), zinc supplementation was associated with greater linear growth gain. Mean dietary intakes of the placebo-treated controls in the Canadian and U.S. studies were 6.4 and 4.6 mg/day of zinc, respectively. No growth response was observed with zinc supplementation of healthy children of either gender, unselected for growth, whose average calculated zinc in- take was 6.3 mg/day (Hambidge et al., 1979a). The SDs were too TABLE 12-4 Requirement for Absorbed Zinc for Children Aged 4 through 8 Years Intestinal losses 34 Âµ g/kg/day Ã 22 kg = 748 Âµ g/day Urinary and integumental losses 14 Âµ g/kg/day Ã 22 kg = 308 Âµ g/day Requirement for growth 7 g/day Ã 20 Âµ g/g = 140 Âµ g/day Required absorbed zinc = 1,196 Âµg/day
468 DIETARY REFERENCE INTAKES large (likely attributable to methodological limitations) to use these data with any confidence in setting an EAR. However, these data are consistent with the EAR derived from a factorial approach. Zinc EAR and RDA Summary, Ages 4 through 8 Years EAR for Children 4â8 years 4 mg/day of zinc The RDA for zinc is set by using a CV of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, the zinc RDA is 120 percent of the EAR). The calculated RDA was rounded to the nearest 1 mg. RDA for Children 4â8 years 5 mg/day of zinc Children Ages 9 through 13 Years Evidence Considered in Estimating the Average Requirement Factorial Analysis. Estimates used for factorial analysis are similar for boys and girls, and therefore calculations are used to estimate a single average requirement for both genders. With use of the same values as for younger children, an average accretion of 10 g/day of new tissue (Kuczmarski et al., 2000), and a reference weight of 40 kg, the required amount of absorbed zinc is 2.1 mg/day (Table 12-5). Based on a fractional absorption of 0.3 observed in infants and young children (Davidsson et al., 1996; Fairweather-Tait et al., 1995), the EAR is 7 mg/day. TABLE 12-5 Requirement for Absorbed Zinc for Children Aged 9 through 13 Years Intestinal losses 34 Âµ g/kg/day Ã 40 kg = 1,360 Âµg/day Urinary and integumental losses 14 Âµ g/kg/day Ã 40 kg = 560 Âµg/day Requirement for growth 10 g/day Ã 20 Âµg/g = 200 Âµg/day Required absorbed zinc = 2,120 Âµg/day
ZINC 469 Extrapolation from Adults. As determined by the extrapolation method described in Chapter 2, the average requirement for boys and girls is 6.7 and 5.6 mg/day of zinc, respectively. Zinc EAR and RDA Summary, Ages 9 through 13 Years EAR for Boys 9â13 years 7 mg/day of zinc EAR for Girls 9â13 years 7 mg/day of zinc The RDA for zinc is set by using a CV of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, the zinc RDA is 120 percent of the EAR). The calculated RDA is rounded to the nearest 1 mg. RDA for Boys 9â13 years 8 mg/day of zinc RDA for Girls 9â13 years 8 mg/day of zinc Adolescents Ages 14 through 18 Years Evidence Considered in Estimating the Average Requirement Factorial Analysis. Endogenous losses are calculated as for younger age groups by using the reference weights (see Chapter 2) with the addition of 100 Âµg/day of zinc to allow for calculated average se- men or menstrual losses (see âAdults Ages 19 Years and Olderâ, which follows). For this age group, a fractional absorption of 0.4 is used; it corresponds to the average âcriticalâ value for adult men from the data sets used in estimating adult requirements (see below). Gender differences are sufficient at this age for boys and girls re- quirements to be calculated separately. As determined by the sum- mation of average zinc losses and the zinc requirement for growth (Kuczmarski et al., 2000; Widdowson and Dickerson, 1964), the amount of absorbed zinc that is required for boys and girls is ap- proximately 3.4 and 3.0 mg/day, respectively (Table 12-6). On the basis of a fractional zinc absorption of 0.4 that was derived for men
470 DIETARY REFERENCE INTAKES TABLE 12-6 Requirement for Absorbed Zinc for Adolescent Boys and Girls Aged 14 through 18 Years Boys Girls Intestinal losses 34 Âµ g/kg Ã 64 kg = 34 Âµ g/kg Ã 57 kg = 2,176 Âµg/day 1,938 Âµg/day Urinary and 14 Âµ g/kg Ã 64 kg = 14 Âµ g/kg Ã 57 kg = integumental losses 896 Âµg/day 798 Âµg/day Semen or menstrual losses 100 Âµg/day 100 Âµg/day Requirement for 10 g/day Ã 20Âµg/g = 5 g/day Ã 20 Âµ g/g = growth 200 Âµg 100 Âµg/day Required absorbed zinc 3,372 Âµg/day 2,936 Âµg/day (see below), the EARs for adolescent boys and girls are calculated to be 8.5 and 7.3 mg/day of zinc, respectively. Extrapolation from Adults. Based on the extrapolation method de- scribed in Chapter 2, the average requirement for adolescent boys and girls is 9.5 and 6.4 mg/day, respectively. Zinc EAR and RDA Summary, Ages 14 through 18 Years EAR for Boys 14â18 years 8.5 mg/day of zinc EAR for Girls 14â18 years 7.3 mg/day of zinc The RDA for zinc is set by using a CV of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, the zinc RDA is 120 percent of the EAR). The calculated RDA is rounded up to the nearest 1 mg. RDA for Boys 14â18 years 11 mg/day of zinc RDA for Girls 14â18 years 9 mg/day of zinc
ZINC 471 Adults Ages 19 Years and Older Evidence Considered in Estimating the Average Requirement As discussed earlier, there are no adequately documented func- tional or simple laboratory indexes of zinc nutriture that can pro- vide a principal indicator of zinc requirements in adults. However, sufficient data are now available to apply a factorial approach to determine the EAR for adults. With this approach, the principal indicator selected is the minimal quantity of absorbed zinc that is adequate to replace endogenous zinc losses. The EAR is the average zinc intake that provides this quantity of absorbed zinc. An outline of these calculations follows. Step 1: Calculation of Endogenous Losses of Zinc via Routes Other than the Intestine. Urinary zinc excretion declines only with extreme dietary zinc restriction and is not correlated with zinc ingested by young adult men over a range of 4 to 25 mg zinc/day (Baer and King, 1984; Behall et al., 1987; Coudray et al., 1997; Hallfrisch et al., 1987; Holbrook et al., 1989; Hunt JR et al., 1992; Jackson et al., 1984; Johnson et al., 1982, 1993; Lee et al., 1993; Mahalko et al., 1983; Milne et al., 1983; Snedeker et al., 1982; Spencer et al., 1979; Turnlund et al., 1984, 1986; Wada et al., 1985). In men, therefore, zinc excretion via the kidney should be regarded as a constant in calculating zinc requirements, the average excretion being 0.63 mg/ day. Though fewer data are available, the same constancy appears to be true for combined integumental and sweat losses (Johnson et al., 1993) and losses in semen (Hunt CD et al., 1992; Johnson et al., 1993) for which the zinc losses average 0.54 and 0.1 mg/day, re- spectively. Therefore, losses of endogenous zinc via routes other than the intestine can be regarded as a constant over the range of dietary zinc intake that encompasses zinc requirements. This aver- age constant for men has been calculated to be 1.27 mg/day (0.63 + 0.54 + 0.1) of zinc. An equal quantity of zinc must be absorbed to match this loss. In 10 studies, the mean urinary loss of zinc from women was 0.44 mg/day (Colin et al., 1983; Greger et al., 1978; Hallfrisch et al., 1987; Hunt JR et al., 1992, 1998; Miller et al., 1998; Swanson and King, 1982; Taper et al., 1980; Turnlund et al., 1991; Wisker et al., 1991). Reported integumental losses for men are multiplied by 0.86 to adjust for the different average surface area of women, and accordingly the average total zinc endogenous losses are 0.46 mg/ day for women. Menstrual zinc losses are assumed to average 0.1
472 DIETARY REFERENCE INTAKES mg/day (Hess et al., 1977). Therefore, the calculated total loss of endogenous zinc for women via routes other than the intestine is 1.0 mg/day (0.44 + 0.46 + 0.10). Step 2: Relationship Between Excretion of Endogenous Zinc via the Intes- tine and Quantity of Zinc Absorbed. In contrast to other endogenous zinc losses, the quantity of endogenous zinc excreted via the intes- tine is positively correlated with the quantity of zinc absorbed over a wide range. This correlation is shown in Figure 12-1. This figure is based on 10 sets of balance data from seven studies (Hunt JR et al., 1992; Jackson et al., 1984; Lee et al., 1993; Taylor et al., 1991; Turnlund et al., 1984, 1986; Wada et al., 1985) of healthy young men, which also included isotopic tracer measurements of fractional zinc absorption. This correlation, in turn, allows for the quantifica- tion of daily zinc absorption and intestinal excretion of endoge- nous zinc. Importantly, this linear relationship, which indicates that for each milligram of zinc absorbed the intestine excretes approxi- mately 0.6 mg/day of endogenous zinc, has been demonstrated only for zinc absorption ranging from 0.8 to 5.5 mg/day. It is also noted that most of these data were relatively short-term, and these vari- ables were not examined while the participants were consuming habitual diets. However, the studies did extend as long as 6 months, a duration that suggests the observed relationship between absorp- tion and endogenous losses via the intestine is a long-term phenom- enon. Therefore, in contrast to other endogenous losses of zinc, losses from the intestine cannot be treated as a constant. To achieve balance, absorption must match the sum of nonintes- tinal and intestinal endogenous zinc losses. The minimum amount of zinc that must be absorbed before absorption matches the losses is determined in step 3 below. Corresponding data for women are both limited and divergent (Hunt JR et al., 1992, 1998; Sian et al., 1996; Turnlund et al., 1991). It has therefore been assumed that there are no significant gender differences for this relationship between absorbed zinc and intesti- nal excretion of endogenous zinc. Step 3: Determination of Minimal Zinc Absorption Required to Replace Total Endogenous Zinc Excretion. The sum of nonintestinal endoge- nous zinc losses (1.27 mg/day for men and 1.0 mg/day for women) is added to the linear regression line for excretion of endogenous zinc in the feces versus absorbed zinc (Figure 12-1). These âadjustedâ lines depict the quantitative relationship between absorbed zinc and total endogenous zinc losses for men and women.
ZINC 473 The intercept between the dashed line (line of equality for ab- sorbed zinc) and the gender-specific lines is then used to determine the minimal quantity of absorbed zinc required to replace endoge- nous zinc losses. With this approach, the calculated average total minimal quantity of absorbed zinc required for the men in these studies is 3.84 mg/ day (1.27 mg to match endogenous zinc losses from nonintestinal sources and, therefore, 2.57 mg/day to match intestinal endoge- nous zinc losses). The corresponding value for women is 3.3 mg/ day (1.0 mg/day to match endogenous zinc losses from nonintestinal sources and, therefore, 2.3 mg/day to match intestinal endogenous zinc losses). These calculated average minimal values for absorbed zinc are then used as the principal indicator for establishing an EAR in step 4. Step 4: Determination of the Average Zinc Intake Required to Achieve Absorption of the Quantity of Zinc Necessary to Match Total Endogenous Losses. The EAR is determined from the asymptotic regression of absorbed zinc on zinc intake (Figure 12-2) that was derived from the same data sets used for Figure 12-1. Thus, if 3.84 mg/day of absorbed zinc is required for men, the amount of ingested zinc, and therefore the EAR, is 9.4 mg/day. When this approach is used for women, the EAR is 6.8 mg/day. This value corresponds to aver- age fractional absorptions of 0.41 and 0.48 for men and women, respectively. A similar fractional absorption of 0.4 was observed for adult men fed experimental diets from which zinc bioavailability is likely to be favorable (August et al., 1989). Other Criteria for Men. Zinc deficiency has not been documented in healthy adult men in North America with the assessment methods currently in use. Some supportive data have been derived from one of the studies included in the factorial approach outlined above (Wada et al., 1985). This study included six men who received a diet containing 5.5 mg/day of zinc for an 8-week period. At the end of this period, several zinc-responsive biochemical changes had occurred, including declines in serum retinol binding protein, albumin, pre- albumin, and thyroxin concentrations (Wada and King, 1986). Other data from experimental zinc depletion studies are also con- sistent but at lower levels of intake (zinc intakes of 3 to 5 mg/day). These data include decreased erythrocyte metallothionein (Grider et al., 1990; Thomas et al., 1992) and zinc concentrations, decreased
474 DIETARY REFERENCE INTAKES 5â²-nucleotidase activity (Beck et al., 1997a), and various abnormali- ties of laboratory indexes of immune status (Beck et al., 1997b). Other Criteria for Women. Twenty-six percent of a group of appar- ently healthy Canadian omnivore women had prebreakfast serum zinc concentrations below the cut-off of 70 Âµg/dL (Gibson et al., 2000). The zinc intake of these subjects averaged 7.3 mg/day, which by this criterion is slightly above the EAR. These data are consistent with an EAR of 6.8 mg/day. Elderly. Reported values on the fractional absorption of zinc in the elderly have been quite variable (Couzy et al., 1993; Hunt et al., 1995; Turnlund et al., 1982, 1986), and no consistent evidence indi- cates that aging affects absorption adversely. Results of balance studies are again, predictably, variable (Bunker et al., 1982; Hallfrisch et al., 1987; Wood and Zheng, 1997). No evidence suggests that the zinc requirements of the elderly are higher than those of younger adults, but possible differences in zinc metabolism (Wastney et al., 1986) merit further investigation. Other Criteria for the Elderly. Zinc supplementation of 53 elderly men and women whose diet contained an average of 9.2 mg/day of zinc was not associated with any detectable benefits (Swanson et al., 1988). Specifically, there were no changes in circulating protein or immunoglobulin concentrations. In contrast, dietary zinc was positively correlated with serum albumin in a group of 82 elderly Canadians whose zinc intakes averaged 5 mg/day for women and 6.5 mg/day for men (Payette and Gray-Donald, 1991). Several stud- ies in which improvements in laboratory indexes of zinc status with zinc supplementation were reported did not, unfortunately, include information on habitual zinc intake (Boukaiba et al., 1993; Cakman et al., 1997; Duchateau et al., 1981; Fortes et al., 1998). Fifteen older men and women whose habitual dietary zinc averaged 8.8 mg/day had a significant decline in the activity of 5â²-nucleotidase activity after a 2-week period during which zinc intake was restricted to 4 mg/day (Bales et al., 1994). Subsequently, a 6-day supplemen- tation period in which total zinc intake averaged 28 mg/day was associated with a significant increase in 5â²-nucleotidase activity, but not beyond baseline levels. In 119 elderly women, serum IGF-1 con- centration was weakly correlated with dietary zinc over a range of 5 to 17 mg/day (Devine et al., 1998). A nonplacebo controlled study of zinc supplementation in 13 elderly subjects, part of a larger group of 180 subjects whose average calculated zinc intake was 9 mg/day,
ZINC 475 was reported to result in normalization of zinc in granulocytes and lymphocytes and improvement in various immune parameters (Prasad et al., 1993). Ethanol tolerance tests indicated a change in ethanol metabolism when dietary zinc intake of postmenopausal women was restricted to 2.6 mg/day (Milne et al., 1987). Zinc EAR and RDA Summary, Ages 19 Years and Older EAR for Men 19â30 years 9.4 mg/day of zinc 31â50 years 9.4 mg/day of zinc 51â70 years 9.4 mg/day of zinc > 70 years 9.4 mg/day of zinc EAR for Women 19â30 years 6.8 mg/day of zinc 31â50 years 6.8 mg/day of zinc 51â70 years 6.8 mg/day of zinc > 70 years 6.8 mg/day of zinc The RDA for zinc is set by using a CV of 10 percent (see Chap- ter 1) because information is not available on the standard devia- tion of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for zinc the RDA is 120 percent of the EAR). The calculated RDA was rounded to the nearest 1 mg. RDA for Men 19â30 years 11 mg/day of zinc 31â50 years 11 mg/day of zinc 51â70 years 11 mg/day of zinc > 70 years 11 mg/day of zinc RDA for Women 19â30 years 8 mg/day of zinc 31â50 years 8 mg/day of zinc 51â70 years 8 mg/day of zinc > 70 years 8 mg/day of zinc
476 DIETARY REFERENCE INTAKES Pregnancy Evidence Considered in Estimating the Average Requirement Factorial Approach. The average daily rates of zinc accumulation by maternal and embryonic/fetal tissues during the four quarters of pregnancy are 0.08, 0.24, 0.53, and 0.73 mg (Swanson and King, 1987). On the assumption of no compensatory change in intestinal excretion of endogenous zinc, it is concluded that increasing daily zinc absorption by these amounts is desirable. The average fractional absorption of zinc was 27 percent for non- pregnant women from eight studies in which dietary zinc averaged 10 mg/day (Fung et al., 1997; Hunt JR et al., 1992, 1998; Miller et al., 1998; Sian et al., 1996; Turnlund et al., 1991). Increases in frac- tional absorption during pregnancy have been reported to be non- significant (Fung et al., 1997), but this outcome may reflect inade- quate power of the study design. Therefore, increases in dietary zinc requirements during pregnancy are calculated to be the follow- ing: First quarter 0.08 Ã· 0.27 = 0.3 mg/day of zinc Second quarter 0.24 Ã· 0.27 = 0.9 mg/day of zinc Third quarter 0.53 Ã· 0.27 = 2.0 mg/day of zinc Fourth quarter 0.73 Ã· 0.27 = 2.7 mg/day of zinc To set a single EAR for pregnant women, the EAR is based on the additional requirement during the fourth quarter (2.7 mg/day) of pregnancy plus the EAR for nonpregnant adolescent girls and women. It should be noted, however, that the zinc requirement during the first quarter of pregnancy is only minimally greater than the preconceptional requirement. Other Criteria. Dietary supplementation reduced the decline in plasma/serum zinc concentration across pregnancy in a large cohort of Peruvian women whose dietary zinc intake was estimated to be 7 mg/day (Caulfield et al., 1999a), but not in North American women whose dietary zinc intake averaged 11 mg/day (Hambidge et al., 1983). Correlations observed between maternal biochemical indexes of zinc status and complications of pregnancy, delivery, and fetal development have been inconsistent. Gravid women with a zinc intake of 6 mg/day or less were found to have a high incidence of premature deliveries (Scholl et al., 1993). Increased gestational age at delivery and increased birth size
ZINC 477 have been reported to result from zinc supplementation of pregnant African-American women whose baseline dietary zinc intake was cal- culated to be 13 mg/day (Goldenberg et al., 1995). This calculated dietary zinc intake is notably high in comparison with other data for African-American women (Mares-Perlman et al., 1995). Without additional supporting documentation, it is difficult to reconcile the implications of the results of this study (with respect to dietary zinc requirements during pregnancy) with the EARs derived from a factorial approach. Nor is it easy to reconcile these findings with the results of other intervention studies. For example, no effect of zinc supplements on birth size was observed in a recent large-scale study of Peruvian women whose dietary zinc intake was estimated to be 7 mg/day (Caulfield et al., 1999b). There was, however, evidence of improved fetal neurobehavioral development (Merialdi et al., 1998). A report that zinc intakes of less than 7.5 mg/day during the third trimester are associated with lower zinc concentrations in human milk is consistent with the EAR (Ortega et al., 1997). Zinc EAR and RDA Summary, Pregnancy EAR for Pregnancy 14â18 years 10.0 mg/day of zinc 19â30 years 9.5 mg/day of zinc 31â50 years 9.5 mg/day of zinc The RDA for zinc is set by using a CV of 10 percent (see Chap- ter 1) because information is not available on the standard devia- tion of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for zinc the RDA is 120 percent of the EAR). The calculated RDA is rounded to the nearest 1 mg. RDA for Pregnancy 14â18 years 12 mg/day of zinc 19â30 years 11 mg/day of zinc 31â50 years 11 mg/day of zinc Lactation Evidence Considered in Estimating the Average Requirement Losses in Human Milk. Average concentrations of zinc in human milk decline physiologically from approximately 4 mg/L at 2 weeks
478 DIETARY REFERENCE INTAKES postpartum to 3 mg/L at 4 weeks, 2 mg/L at 8 weeks, 1.5 mg/L at 12 weeks, and 1.2 mg/L at 24 weeks (Krebs et al., 1995; Moser- Veillon and Reynolds, 1990). With use of a standard volume of 0.78 L/day of human milk secreted per day (Chapter 2), calculated zinc losses via the mammary gland are 2.15 mg/day at 4 weeks, 1.56 mg/ day at 8 weeks, 1.17 mg/day at 12 weeks, and 0.94 mg/day at 24 weeks. Postpartum involution of the uterus and decreased maternal blood volume should release approximately 30 mg of zinc that has been accumulated during pregnancy (King and Turnlund, 1989); that is, an average of approximately 1 mg/day for the first month. It is reasonable to assume that this endogenous zinc is available for reutilization. Thus, 1 mg/day is subtracted from the amount of zinc lost during the first 4 weeks of lactation. The loss of zinc for weeks 8, 12 and 24 are averaged: Week 4: (2.15 â 1.0) = 1.15 mg/day of zinc Week 8: (2.15 + 1.56) Ã· 2 = 1.85 mg/day of zinc Week 12: (1.56 + 1.17) Ã· 2 = 1.36 mg/day of zinc Weeks 12â24: (1.17 + 0.94) Ã· 2 = 1.05 mg/day of zinc The average calculated increased requirement for absorbed zinc during lactation is 1.35 mg/day. Reported values for fractional absorption of zinc for adult women outside the reproductive cycle averages 27 percent (Fung et al., 1997; Hunt JR et al., 1992, 1998; Sian et al., 1996; Turnlund et al., 1991). If this value were applied to the calculation of increased dietary zinc required during lactation (1.35 Ã· 0.27), the average dietary requirement would increase by 5 mg/day. However, the frac- tional absorption of zinc increases during lactation by 0.107 (Fung et al., 1997). Therefore, the fractional absorption would be increased to 0.716 (0.27 Ã· 0.377) to give an additional requirement of 3.6 mg/day (5 Ã 0.716). This value is added to the EAR for adolescent girls and women to set the EAR during lactation. Other Criteria. Typically, human milk zinc concentrations are not increased by the administration of a daily zinc supplement across lactation (Kirksey et al., 1979; Krebs et al., 1995; Moser-Veillon and Reynolds, 1990). In one study, however, a modest but statistically significant reduced rate of decline in zinc concentrations in milk across lactation was observed with a zinc supplement (Krebs et al., 1985). The dietary zinc in the placebo group averaged 10.7 mg/ day. In a subsequent study, in which the average dietary zinc was
ZINC 479 higher at 13.0 mg/day, there was no evidence of an effect of zinc supplementation on zinc concentration in milk. Zinc EAR and RDA Summary, Lactation EAR for Lactation 14â18 years 10.9 mg/day of zinc 19â30 years 10.4 mg/day of zinc 31â50 years 10.4 mg/day of zinc The RDA for zinc is set by using a CV of 10 percent (see Chap- ter 1) because information is not available on the standard devia- tion of the requirement. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for zinc the RDA is 120 percent of the EAR). The calculated RDA is rounded to the nearest 1 mg. RDA for Lactation 14â18 years 13 mg/day of zinc 19â30 years 12 mg/day of zinc 31â50 years 12 mg/day of zinc Special Considerations Vegetarianism Cereals are the primary source of dietary zinc for vegetarians (Gibson, 1994). The bioavailability of zinc in vegetarian diets is reduced if the phytate content in the diet is high (Gibson, 1994), and this may result in low zinc status (Freeland-Graves et al., 1980b). Absorption of zinc from vegetarian diets is lower than from non- vegetarian diets (Hunt et al., 1998; Kies, 1988); however, relatively minor changes to the diet can improve zinc absorption (Gibson et al., 1997; Harland et al., 1988). Vegetarian diets rich in calcium may negatively affect zinc bioavailability (Ellis et al., 1987). Zinc intake from vegetarian diets has been found to be both similar to intake from nonvegetarian diets (Alexander et al., 1994; Berglund et al., 1994; Donovan and Gibson, 1996; Johansson and Widerstrom, 1994; Kelsay et al., 1988; Levin et al., 1986; Srikumar et al., 1992) and lower than intake from nonvegetarian diets (Faber et al., 1986; Freeland-Graves et al., 1980a; Harland and Peterson, 1978; Hunt et al., 1998; Janelle and Barr, 1995). In most older adult and elderly populations, vegetarians have lower zinc intakes than non-
480 DIETARY REFERENCE INTAKES vegetarians (Brants et al., 1990; Hunt et al., 1988; Lowik et al., 1990). Among vegetarians, zinc concentrations in serum, plasma, hair, urine, and saliva are either the same as or lower than those of nonvegetarians (Anderson et al., 1981; Freeland-Graves et al., 1980a, 1980b; Hunt et al., 1998; Kadrabova et al., 1995; King et al., 1981; Krajcovicova-Kudlackova et al., 1995; Levin et al., 1986; Srikumar et al., 1992). The variations in these status indicators are most likely due to the amount of phytate, fiber, calcium, or other inhibitors of zinc absorption in the vegetarian diets. Individuals consuming vege- tarian diets were found to be in positive zinc balance (Ganapathy et al., 1981; Hunt et al., 1998). The requirement for dietary zinc may be as much as 50 percent greater for vegetarians and particularly for strict vegetarians whose major food staples are grains and legumes and whose dietary phytate:zinc molar ratio exceeds 15:1. At this time there are not sufficient data to set algorithms for establishing dietary require- ments for zinc on the basis of the presence and concentration of other nutrients and food components. Alcohol Long-term alcohol consumption is associated with impaired zinc absorption and increased urinary zinc excretion. Low zinc status is observed in approximately 30 to 50 percent of alcoholics. Thus, with long-term alcohol consumption, the daily requirement for zinc will be greater than that estimated via the factorial approach. INTAKE OF ZINC Food Sources The dietary sources of zinc vary widely. Zinc is abundant in red meats, certain seafood, and whole grains. Because zinc is mainly located in the germ and bran portions of grains, as much as 80 percent of the total zinc is lost during milling. Many breakfast cereals are fortified with zinc. Studies measuring zinc content in human milk are summarized in Table 12-1. Dietary Intake Data from nationally representative U.S. surveys are available to estimate zinc intakes (Appendix Tables C-25, C-26, D-4, E-9). Median intakes of zinc for adult men aged 19 to 50 years, based on the
ZINC 481 Third National Health and Nutrition Examination Survey and the Continuing Survey of Food Intakes by Individuals, were approxi- mately 14 mg/day (Appendix Tables C-25 and D-4). The median intakes for women in the same age range were approximately 9 mg/day. These values are similar to those found for zinc intakes of Canadian adults (Appendix Table F-3). Intake from Supplements In 1986, approximately 16 percent of Americans took supplements that contained zinc (Moss et al., 1989; see Table 2-2). The median total (food plus supplements) zinc intakes by adults taking supple- ments were similar to those of adults who did not take zinc supple- ments (Appendix Table C-26). Intake of zinc supplements, how- ever, greatly increased the intakes in the upper quartile compared to those who did not take zinc supplements. TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to indi- viduals who are receiving zinc under medical supervision. Hazard Identification Although no evidence of adverse effects from intake of naturally occurring zinc in food was found, the UL derived here applies to total zinc intake from food, water, and supplements (including for- tified food). Adverse effects associated with chronic intake of sup- plemental zinc include suppression of immune response, decrease in high-density lipoprotein (HDL) cholesterol, and reduced copper status.
482 DIETARY REFERENCE INTAKES Adverse Effects Acute Effects. Acute adverse effects of excess zinc have been reported. These include epigastric pain, nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches (Prasad, 1976; Samman and Roberts, 1987). Fosmire (1990) estimated that an emetic dose of zinc sulfate was approximately 1 to 2 g of the salt (225 to 450 mg of zinc). Gastrointestinal distress has been reported at doses of 50 to 150 mg/day of supplemental zinc (Freeland-Graves et al., 1982). Immunological Response. Intake of 300 mg/day of supplemental zinc as the sulfate for 6 weeks has been shown to cause some functional impairment in immunological response as well as significantly de- creased concentrations of HDL cholesterol (Chandra, 1984). Lipoprotein and Cholesterol. Two studies (Black et al., 1988; Hooper et al., 1980) have found that zinc at doses between 50 and 160 mg/ day decreased serum lipoprotein and cholesterol concentrations in men. Samman and Roberts (1988), however, reported no depres- sion of HDL concentrations in men at 150 mg/day of zinc and found some indication of a depression of low-density lipoproteins (LDL) in women. The different response to excess zinc in women was supported by an earlier study by Freeland-Graves and coworkers (1982). The reduction in HDL cholesterol concentration was shown to be transient and not dose related. Reduced Copper Status. Reduced copper status has been associated with increased zinc intake (Boukaiba et al., 1993; Burke et al., 1981; Festa et al., 1985; Fischer et al., 1984; Prasad et al., 1978; Samman and Roberts, 1988; Yadrick et al., 1989) (Table 12-7). In all studies in which the interaction of excess zinc and copper was measured, there was a consistent decrease in erythrocyte copper-zinc super- oxide dismutase (ESOD) activity, an erythrocyte enzyme indicative of copper status. Yadrick and coworkers (1989) reported this effect after total zinc intakes of about 60 mg/day (50-mg supplement plus 10 mg of dietary zinc) for up to 10 weeks. Although the clinical significance of the depressed ESOD activity is unknown, this marker enzyme is known to be a sensitive indicator of the effect of high zinc levels on copper homeostasis. Zinc-Iron Interactions. Zinc and iron are known to interact, and Whittaker (1998) has reviewed the available studies (also see âFac-
ZINC 483 tors Affecting the Zinc Requirementâ). The primary effect appears to be a decreased absorption of zinc at an iron:zinc ratio of 3:1 when the iron was administered in water. However, when iron was administered during a meal, no such effect was found. Similarly, when iron was present as heme iron, no effect was noted. One study found a 56 percent decline in iron absorption when the zinc:iron ratio was 5:1 and was administered in water (Rossander-Hulten et al., 1991). However, when this ratio of zinc and iron was adminis- tered in a hamburger meal, no effect on iron absorption was noted. Other Endpoints. No evidence was found of reproductive effects in humans from zinc intake. There is one case report of three pre- mature deliveries and one stillborn infant after excess zinc intake during pregnancy (Kumar, 1976). Because details on other contrib- uting factors were not provided, interpretation of these results is limited. There is insufficient evidence of carcinogenicity from human or animal studies. Summary Although there are no data indicating adverse interactions be- tween zinc and other nutrients when zinc is found in food, adverse nutrient interactions are present after feeding zinc in the form of dietary supplements. The adverse effect of excess zinc on copper metabolism (i.e., reduced copper status) was chosen as the critical effect on which to base a UL for total daily intake of zinc from food, water, and supplements in humans. This selection is based on (1) the consistency of findings from studies measuring the interaction of zinc and copper (Fischer et al., 1984; Samman and Roberts, 1988; Yadrick et al., 1989), (2) the sensitivity of ESOD activity as a marker for this effect, and (3) the quality and completeness of the database for this endpoint. The data on the effects of zinc on HDL cholesterol concentration were not consistent from study to study and there- fore were not used to derive a UL. Dose-Response Assessment Adults Data Selection. Data on reduced copper status in humans were used to derive a UL for zinc (Table 12-7). Studies measuring ESOD activity (which is a sensitive indicator of copper status) or other indicators
484 DIETARY REFERENCE INTAKES TABLE 12-7 Effect of Increasing Doses of Zinc (Zn) Intake on Copper (Cu) Status Study Subjects Zinc Intake (mg/d) Duration Prasad et al., 1978 1 black man, 150â200 2y 26 y w/sickle cell anemia Greger et al., 1978 14 girls, 12â14 y 7.4 (food) 30 d 13.4 (food) 30 d Burke et al., 1981 5 men, 6 women, 56â83 y 7.8 (fortified food) 30 d 23.26 (fortified food) 30 d Fischer et al., 1984 26 healthy adult men Placebo 6 wk 50 (as gluconate) 6 wk Festa et al., 1985 9 healthy men, 21â27 y 1.8 (food) 1 wk 4.0 (food) 1 wk 6.0 (food) 1 wk 8.0 (food) 1 wk 18.5 (food) 2 wk Samman and Healthy men and women 150 (as sulfate) 12 wk Roberts, 1988 Yadrick et al., 1989 18 healthy women, 25â40 y 50 (as gluconate) 10 wk Boukaiba et al., 1993c 44 older adults, 73â106 y Placebo 8 wk 20 8 wk a The authors note it was not possible to separate the effects of sickle cell disease and copper depletion. b Copper status was assessed by the activities of the copper-metalloenzymes, plasma ferroxidase (ceruloplasmin), and erythrocyte Cu,Zn-superoxide dismutase. No signifi- cant differences in the plasma copper levels or the ferroxidase activities between the supplemented and control groups could be detected at 2, 4, or 6 weeks. ESOD = erythro- cyte copper-zinc superoxide dismutase. of copper status (such as ceruloplasmin or serum copper concen- tration) were considered optimal for the dose-response assessment. Identification of a No-Observed-Adverse-Effect Level (NOAEL) and Lowest- Observed-Adverse-Effect Level (LOAEL). A LOAEL of 60 mg/day is based on the study of Yadrick and coworkers (1989) who evaluated copper status after supplemental intake of 50 mg/day as zinc glu-
ZINC 485 ake (mg/d) Duration Cu Intake (mg/d) Adverse Effects 2y Not provided Cu deficiency anemiaa Decreased serum Cu and ceruloplasmin 30 d 2.8 (food) No significant change 30 d 2.8 (food) No significant change d food) 30 d 2.33 (fortified food) Significant decrease in Cu retention ied food) 30 d 2.33 (fortified food) 6 wk Not provided No effect nate) 6 wk Significant decrease in ESOD activityb 1 wk 2.6 (food) No effect 1 wk 2.6 (food) No effect 1 wk 2.6 (food) No effect 1 wk 2.6 (food) No effect 2 wk 2.6 (food) Increase in Cu excretion/ decrease in retention ate) 12 wk Not provided Decrease in ESOD (women only) nate) 10 wk Not provided Significant decrease in ESOD activity 8 wk Not provided No effect 8 wk Significant decrease in serum Cu c Boukaiba et al. (1993) is a crossover study designed to determine the effects of low- dose zinc supplementation on food intake, nutritional status, immune and lipid in- dexes. The 16-week study period was divided into two experimental treatment periods, each lasting 8 weeks. Serum Zn concentrations were depressed. conate in 18 healthy women (aged 25 to 40 years) for 10 weeks. ESOD activity was significantly lower than pretreatment values. Although no dietary zinc or copper intakes were reported, a level of dietary zinc can be estimated at approximately 10 mg/day for women (aged 19 to 50 years) from the 1988â1994 Third National Health and Nutrition Examination Survey (Appendix Table C-26). A LOAEL of 60 mg/day was calculated by adding the supplemental
486 DIETARY REFERENCE INTAKES intake of 50 mg/day with the rounded estimate of dietary intake, 10 mg/day. Support for a LOAEL of 60 mg/day is provided by other studies showing altered copper balance after zinc supplementation (Fischer et al., 1984) (Table 12-7). Uncertainty Assessment. An uncertainty factor (UF) of 1.5 was select- ed to account for interindividual variability in sensitivity and for extrapolation from a LOAEL to a NOAEL. Because reduced copper status is rare in humans, a higher UF was not justified. Derivation of a UL. A LOAEL of 60 mg/day was divided by a UF of 1.5 to derive a UL of 40 mg/day for total intake of zinc from food, water, and supplements. UL = LOAEL = 60 mg/day = 40 mg/day UF 1.5 Zinc UL Summary, Ages 19 Years and Older UL for Adults â¥ 19 years 40 mg/day of zinc Infants, Children, and Adolescents Data Selection. There is only one case report of zinc-induced copper deficiency anemia in a young child (Botash et al., 1992): a 13-month- old girl was given 16 mg/day of zinc for 6 months followed by 24 mg/day for 1 month. There are no reports on the adverse effects of zinc on copper status in children or adolescents. The UL values for infants are based on a study by Walravens and Hambidge (1976). Identification of a NOAEL. Walravens and Hambidge (1976) fed 68 healthy, full-term infants either formula containing 1.8 mg/L of zinc (control) or the same formula supplemented with an additional 4 mg/L (total of 5.8 mg/L) of zinc for 6 months. No effects of zinc on serum copper or cholesterol concentrations or other adverse effects were found. Thus, 5.8 mg/L is the NOAEL selected. Multi- plying the NOAEL for infants 0 through 6 months of age by the estimated average intake of human milk of 0.78 L/day (Allen et al., 1991; Butte et al., 1984; Heinig et al., 1993) results in a NOAEL of 4.5 mg/day. Uncertainty Assessment. The length of the study by Walravens and
ZINC 487 Hambidge (1976) and the high number of infants justifies a UF of 1.0, given that there is no evidence that intakes from formula of 5.8 mg/L of zinc result in infant toxicity. Derivation of a UL. The NOAEL of 4.5 mg/day was divided by a UF of 1.0 to obtain a UL of 4 mg/day (rounded down) for infants ages 0 through 6 months. No adverse effects of zinc in children and adolescents could be found. Due to a dearth of information, the UL for young infants was adjusted for older infants, children, and ado- lescents on the basis of relative body weight as described in Chapter 2 and using reference weights from Chapter 1 (Table 1-1). Values have been rounded down. Zinc UL Summary, Ages 0 through 18 Years UL for Infants 0â6 months 4 mg/day of zinc 7â12 months 5 mg/day of zinc UL for Children 1â3 years 7 mg/day of zinc 4â8 years 12 mg/day of zinc 9â13 years 23 mg/day of zinc UL for Adolescents 14â18 years 34 mg/day of zinc Pregnancy and Lactation Because the UL is based on reduced copper status and because there are inadequate data to justify a different UL for pregnant and lactating women, the UL for pregnant and lactating women is the same as that for nonpregnant and nonlactating women. Zinc UL Summary, Pregnancy and Lactation UL for Pregnancy 14â18 years 34 mg/day of zinc 19â50 years 40 mg/day of zinc UL for Lactation 14â18 years 34 mg/day of zinc 19â50 years 40 mg/day of zinc
488 DIETARY REFERENCE INTAKES Special Considerations Individuals with Menkeâs disease may be distinctly susceptible to the adverse effects of excess zinc intake. Since Menkeâs disease is a defect in the ATPase involved in copper efflux from enterocytes, supplying extra zinc will likely further limit copper absorption (Yuzbasiyan-Gurkan et al., 1992). Brewer and coworkers (1993) demonstrated the effectiveness of zinc therapy in reducing copper accumulation in individuals with Wilsonâs disease. The UL is not meant to apply to individuals who are being treated with zinc under close medical supervision. Intake Assessment Utilizing the Third National Health and Nutrition Examination Survey data, the highest reported intake of dietary zinc at the ninety- fifth percentile for all adults was 24 mg/day in men aged 19 to 30 years (Appendix Table C-25), which is lower than the UL of 40 mg/ day. In 1986, approximately 17 percent of women and 15 percent of men consumed supplements that contained zinc (Moss et al., 1989; see Table 2-2). The ninety-fifth percentile intake of zinc coming from food and supplements for adult men and nonpregnant women was approximately 25 to 32 mg/day (Appendix Table C-26). For pregnant and lactating women, the zinc intake from food and sup- plements was approximately 40 and 47 mg/day, respectively, at the ninety-fifth percentile. Risk Characterization The risk of adverse effects resulting from excess zinc intake from food and supplements appears to be low at the highest intakes noted above. High intakes of zinc are due to the use of supplements, espe- cially during lactation and pregnancy. Doses approaching or equal to the UL are currently being tested in the treatment of diarrhea, pneumonia, and acute respiratory infections, especially in develop- ing countries. The UL is not meant apply to individuals who are receiving zinc for treatment purposes. RESEARCH RECOMMENDATIONS FOR ZINC â¢ Biomarkers of zinc status based on functional outcomes; these may be gene products derived from zinc-influenced systems and
ZINC 489 may include transporter proteins that provide homeostatic regula- tion of zinc intake and cellular processing. â¢ Information on the relationship of oxidative stress to zinc status; zinc is used therapeutically for treatment of some medical prob- lems, but how this relates to daily dietary zinc intake is not clear. â¢ Effectiveness and potential toxicity of zinc as a dietary supple- ment; on which systems should zincâs potential effectiveness be based, and which systems become dysfunctional with excessive zinc intake. â¢ The role of zinc and the immune system, particularly those related to T-cell function at marginal status. â¢ 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; quantification of 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. REFERENCES Abrams SA, Wen J, Stuff JE. 1997. Absorption of calcium, zinc, and iron from breast milk by five- to seven-month-old infants. Pediatr Res 41:384â390. Aggett PJ. 1989. Severe zinc deficiency. In: Mills CF, ed. Zinc in Human Biology. New York: Springer-Verlag. Pp. 259â279. Alexander D, Ball MJ, Mann J. 1994. Nutrient intake and haematological status of vegetarians and age-sex matched omnivores. Eur J Clin Nutr 48:538â546. Alexander FW, Clayton BE, Delves HT. 1974. Mineral and trace-metal balances in children receiving normal and synthetic diets. Quart J Med 169:89â111. Allen JC, Keller RP, Archer P, Neville MC. 1991. Studies in human lactation: Milk composition and daily secretion rates of macronutrients in the first year of lactation. Am J Clin Nutr 54:69â80. Anderson BM, Gibson RS, Sabry JH. 1981. The iron and zinc status of long-term vegetarian women. Am J Clin Nutr 34:1042â1048. Anderson RR. 1993. Longitudinal changes of trace elements in human milk dur- ing the first 5 months of lactation. Nutr Res 13:499â510. Aquilio E, Spagnoli R, Seri S, Bottone G, Spennati G. 1996. Trace element content in human milk during lactation of preterm newborns. Biol Trace Elem Res 51:63â 70. Artacho R, Ruiz-Lopez MD, Gamez C, Puerta A, Lopez MC. 1997. Serum concen- tration and dietary intake of Zn in healthy institutionalized elderly subjects. Sci Total Environment 205:159â165. August D, Janghorbani M, Young VR. 1989. Determination of zinc and copper absorption at three dietary Zn-Cu ratios by using stable isotope methods in young adult and elderly subjects. Am J Clin Nutr 50:1457â1463. Baer MT, King JC. 1984. Tissue zinc levels and zinc excretion during experimental zinc depletion in young men. Am J Clin Nutr 39:556â570.
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492 DIETARY REFERENCE INTAKES Davidsson L, Mackenzie J, Kastenmayer P, Aggett PJ, Hurrell RF. 1996. Zinc and calcium apparent absorption from an infant cereal: A stable isotope study in healthy infants. Br J Nutr 75:291â300. Davis CD, Milne DB, Nielsen FH. 2000. Changes in dietary zinc and copper affect zinc-status indicators of postmenopausal women, notably extracellular super- oxide dismutase and amyloid precursor proteins. Am J Clin Nutr 71:781â788. Devine A, Rosen C, Mohan S, Baylink D, Prince RL. 1998. Effects of zinc and other nutritional factors on insulin-like growth factor I and insulin-like growth fac- tor binding proteins in postmenopausal women. Am J Clin Nutr 68:200â206. Dewey KG, Cohen RJ, Brown KH, Rivera LL. 1999. Age of introduction of comple- mentary foods and growth of term, low-birth-weight, breast-fed infants: A ran- domized intervention study in Honduras. Am J Clin Nutr 69:679â686. Donovan UM, Gibson RS. 1995. Iron and zinc status of young women aged 14 to 19 years consuming vegetarian and omnivorous diets. J Am Coll Nutr 14:463â472. Donovan UM, Gibson RS. 1996. Dietary intakes of adolescent females consuming vegetarian, semi-vegetarian, and omnivorous diets. J Adolesc Health 18:292â300. Duchateau J, Delepesse G, Vrijens R, Collet H. 1981. Beneficial effects of oral zinc supplementation on the immune response of old people. Am J Med 70:1001â 1004. Ellis R, Kelsay JL, Reynolds RD, Morris ER, Moser PB, Frazier CW. 1987. Phytate:zinc and phytate x calcium:zinc millimolar ratios in self-selected diets of Americans, Asian Indians, and Nepalese. J Am Diet Assoc 87:1043â1047. Faber M, Gouws E, Spinnler Benade AJ, Labadarios D. 1986. Anthropometric measurements, dietary intake and biochemical data of South African lacto- ovovegetarians. S Afr Med J 69:733â738. Failla ML. 1999. Considerations for determining âoptimal nutritionâ for copper, zinc, manganese and molybdenum. Proc Nutr Soc 58:497â505. Fairweather-Tait SJ, Wharf SG, Fox TE. 1995. Zinc absorption in infants fed iron- fortified weaning food. Am J Clin Nutr 62:785â789. Ferguson EL, Gibson RS, Opare-Obisaw C, Ounpuu S, Thompson LU, Lehrfeld J. 1993. The zinc nutriture of preschool children living in two African countries. J Nutr 123:1487â1496. Festa MD, Anderson HL, Dowdy RP, Ellersieck MR. 1985. Effect of zinc intake on copper excretion and retention in men. Am J Clin Nutr 41:285â292. Fischer PWF, Giroux A, LâAbbe MR. 1984. Effect of zinc supplementation on copper status in adult man. Am J Clin Nutr 40:743â746. Fortes C, Forastiere F, Agabiti N, Fano V, Pacifici R, Virgili F, Piras G, Guidi L, Bartoloni C, Tricerri A, Zuccaro P, Ebrahim S, Perucci CA. 1998. The effect of zinc and vitamin A supplementation on immune response in an older popula- tion. J Am Geriatr Soc 46:19â26. Fosmire GJ. 1990. Zinc toxicity. Am J Clin Nutr 51:225â227. Fransson GB, Lonnerdal B. 1982. Zinc, copper, calcium, and magnesium in human milk. J Pediatr 101:504â508. Freeland-Graves JH, Bodzy PW, Eppright MA. 1980a. Zinc status of vegetarians. J Am Diet Assoc 77:655â661. Freeland-Graves JH, Ebangit ML, Hendrikson PJ. 1980b. Alterations in zinc absorp- tion and salivary sediment zinc after a lacto-ovo-vegetarian diet. Am J Clin Nutr 33:1757â1766. Freeland-Graves JH, Friedman BJ, Han WH, Shorey RL, Young R. 1982. Effect of zinc supplementation on plasma high-density lipoprotein cholesterol and zinc. Am J Clin Nutr 35:988â992.
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