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TABLE 1 Dietary Reference Intakes for Zinc by Life Stage Group DRI values (mg/day) EARa RDAb AIc ULd males females males females Life stage group 0 through 6 mo 2 4 7 through 12 mo 2.5 2.5 3 3 5 1 through 3 y 2.5 2.5 3 3 7 4 through 8 y 4.0 4.0 5 5 12 9 through 13 y 7.0 7.0 8 8 23 14 through 18 y 8.5 7.3 11 9 34 19 through 50 y 9.4 6.8 11 8 40 ≥ 51 y 9.4 6.8 11 8 40 Pregnancy 14 through 18 y 10.5 12 34 19 through 50 y 9.5 11 40 Lactation 14 through 18 y 10.9 13 34 19 through 50 y 10.4 12 40 a EAR = Estimated Average Requirement. b RDA = Recommended Dietary Allowance. c AI = Adequate Intake. d UL = Tolerable Upper Intake Level. Unless otherwise specified, the UL represents total intake from food, water, and supplements.

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PART III: ZINC 403 ZINC Z inc is crucial for growth and development. It facilitates several enzy- matic processes related to the metabolism of protein, carbohydrates, and fats. Zinc also helps form the structure of proteins and enzymes, and is involved in the regulation of gene expression. The adult requirements for zinc are based on metabolic studies of zinc absorption, defined as the minimum amount of dietary zinc necessary to offset total daily losses of the nutrient. The Tolerable Upper Intake Level (UL) is based on a zinc-induced decrease in copper absorption that is manifest as a reduction in erythrocyte copper–zinc superoxide dismutase activity. DRI values are listed by life stage group in Table 1. Foods rich in zinc include meat, some shellfish, legumes, fortified cereals, and whole grains. Overt human zinc deficiency is rare, and the signs and symp- toms of mild deficiency are diverse due to zinc’s ubiquitous involvement in metabolic processes. There is no evidence of adverse effects from intake of natu- rally occurring zinc in food. The adverse effects associated with chronic intake of supplemental zinc include acute gastrointestinal effects and headaches, im- paired immune function, changes in lipoprotein and cholesterol levels, reduced copper status, and zinc–iron interactions. ZINC AND THE BODY Function Zinc is essential for proper growth and development. Its biological functions can be divided into catalytic, structural, and regulatory. Zinc serves as a catalyst for nearly 100 specific enzymes, including alcohol dehydrogenase, alkaline phosphatase, and RNA polymerases. It is necessary for the structure of certain proteins, some of which are involved in gene expression as deoxyribonucleic acid–binding transcription factors. Examples include retinoic acid receptors and vitamin D receptors. Zinc also provides a structural function for some en- zymes, the most notable of which is copper–zinc superoxide dismutase. Addi- tionally, zinc plays a role in gene expression and has been shown to influence both apoptosis and protein kinase C activity.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 404 Absorption, Metabolism, Storage, and Excretion During digestion, zinc is absorbed by the small intestine through a transcellular process, with the jejunum being the site with the greatest transport rate. The mechanism of absorption appears to be saturable and there is an increase in transport velocity with zinc depletion. The absorbed zinc is bound to albumin and transferred from the intestine via the portal system. More than 85 percent of the body’s total zinc is stored in the skeletal muscle and bone; only about 0.1 percent of total body zinc is found in the plasma. However, the body tightly regulates plasma zinc concentrations to keep them steady at about 10–15 mmol/L. Factors such as stress, acute trauma, and infec- tion can cause plasma zinc levels to drop. In humans, plasma zinc concentra- tions will remain relatively stable when zinc intake is restricted or increased, unless these changes in intake are severe and prolonged. This tight regulation also means that small amounts of zinc are more efficiently absorbed than large amounts and that people in poor zinc status can absorb the nutrient more effi- ciently than those in good status. Zinc is excreted from the body primarily through the feces. Normal zinc 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. Zinc loss through the urine represents only a fraction (less than 10 percent) of normal zinc losses, although urinary losses may increase with conditions such as starvation or trauma. Other modes of zinc loss from the body include skin cell turnover, sweat, semen, hair, and menstruation. DETERMINING DRIS Determining Requirements The adult requirements for zinc are based on factorial analysis of metabolic studies of zinc absorption. Zinc absorption is defined for this purpose as the minimum amount of absorbed zinc necessary to match total daily zinc losses. The dietary intake corresponding to this average minimum quantity of absorbed zinc is the EAR. Special Considerations Children aged 3 years and under: The absorption of zinc from human milk is higher than from cow milk–based infant formula and cow milk. The zinc bioavailability from soy formulas is significantly lower than from milk-based formulas. Zinc nutriture in later infancy is quite different from that in the younger infant. Human milk provides only 0.5 mg/day of zinc by 7 months postpartum,

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PART III: ZINC 405 and the concentration declines even further by 12 months. It is apparent, there- fore, that human milk alone is an inadequate source of zinc after the first 6 months. Vegetarian diets: Cereals are the primary source of dietary zinc for vegetarian diets. The bioavailability of zinc in vegetarian diets is reduced if phytate content in the diet is high, resulting in low zinc status (see “Dietary Interactions”). Zinc intake from vegetarian diets has been found to be similar to or lower than in- take from nonvegetarian diets. Among vegetarians, zinc concentrations in the serum, plasma, hair, urine, and saliva are either the same as or lower than in individuals consuming nonvegetarian diets. The variations found in these status indicators are most likely due in part to the amount of phytate, fiber, calcium, or other zinc absorption inhibitors in vegetarian diets. Even so, individuals consuming vegetarian diets were found to be in positive zinc balance. Yet, the requirement for dietary zinc may be as much as 50 percent greater for vegetarians, particularly for strict vegetarians whose major food staples are grains and legumes and whose dietary phytate:zinc molar ratio exceeds 15:1. This is due to poor absorption of zinc from vegetarian sources. Alcohol intake: Long-term alcohol consumption is associated with impaired zinc absorption and increased urinary zinc excretion. Low zinc status is ob- served in approximately 30–50 percent of people with alcoholism. Thus, with long-term alcohol consumption, the daily requirement for zinc will be greater than that estimated by the factorial approach. Criteria for Determining Zinc Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Average zinc intake from human milk 7 through 12 mo Factorial analysis 1 through 50 y Factorial analysis > 51 y Extrapolation of factorial data from 19 through 50 y Pregnancy 14 through 18 y Adolescent female EAR plus fetal accumulation of zinc 19 through 50 y Adult female average requirement plus fetal accumulation of zinc

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 406 Lactation 14 through 18 y Adolescent female EAR plus average amount of zinc secreted in human milk 19 through 50 y Adult female EAR plus average amount of zinc secreted in human milk The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all healthy people. Members of the general population should not routinely exceed the UL. The adverse effect of excess zinc on copper metabolism (i.e., reduced cop- per status) was chosen as the critical effect on which to base a UL for total daily intake of zinc from food, water, and supplements. The UL for zinc represents total intake from food, water, and supplements. According to data from the Third National Health and Nutrition Examina- tion Survey (NHANES III, 1988–1994), the highest reported zinc intake (from food) at the 95th percentile for all adults was 24 mg/day in men aged 19 to 30 years, which is lower than the UL. The 95th percentile of intake from food and supplements for adult men and nonpregnant women was approximately 25–32 mg/day; for pregnant and lactating women the 95th percentile of intake was 40 mg/day and 47 mg/day, respectively. The risk of adverse effects resulting from excess zinc intake appears to be low at these intake levels. DIETARY SOURCES Foods Zinc is widely distributed in foods. Zinc-rich foods include red meat, some seafood, whole grains, and some fortified breakfast cereals. Because zinc is mainly found in the germ and bran portions of grain, as much as 80 percent of total zinc is lost during milling. This is why whole grains tend to be richer in zinc than unfortified refined grains. Dietary Supplements According to U.S. data from the 1986 National Health Interview Survey (NHIS), approximately 16 percent of Americans took supplements containing zinc. The median total (food plus supplements) zinc intakes by adults who took the supplements were similar to those adults who did not. However, the use of zinc supplements greatly increased the intakes of those in the upper quartile of intake level compared with those who did not take supplements.

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PART III: ZINC 407 TABLE 2 Qualitative Bioavailability of Zinc According to Diet Characteristicsa Bioavailability Dietary Characteristics High Refined diets low in cereal fiber and phytic acid, with adequate protein primarily from meats and fish Phytate/zinc molar ratio < 5 Medium Mixed diets containing animal or fish protein Vegetarian diets not based primarily on unrefined, unfermented cereal grains Phytate/zinc molar ratio 5–15 Low Diets high in unrefined, unfermented, and ungerminated cereal grains, especially when animal protein intake is negligible High-phytate soy protein products are the primary protein source Diets in which ≥ 50 percent of energy is provided by high-phytate foods (high extraction rate [90 percent] flours and grains, legumes) Phytate/zinc molar ratio > 15 High intake of inorganic calcium (> 1 g/day) potentiates the inhibitory effects of these diets, especially when animal protein intake is low a The phytate content of foods is provided by Hallberg and Hulthen (2000). The zinc content of foods is available from the U.S. Department of Agriculture at http://www.nal.usda.gov/fnic/foodcomp. Evidence of the efficacy of zinc lozenges in reducing the duration of com- mon colds remains unclear. Bioavailability The bioavailability of zinc can be affected by many factors at many sites and is a function of the extent of digestion. The intestine is the major organ in which variations in bioavailability affect dietary zinc requirements. Dietary substances such as phytate can reduce zinc bioavailability (see “Dietary Interactions”). To date, a useful algorithm for establishing dietary zinc requirements based on the presence of other nutrients and food components has not been established, and much information is still needed to develop one that can predict zinc bioavailability. Algorithms for estimating dietary zinc bioavailability will need to include the dietary content of phytic acid, protein, zinc, and possibly cal- cium, iron, and copper. (Characteristics associated with diets varying in zinc bioavailability are summarized in Table 2.) Dietary Interactions There is evidence that zinc may interact with certain other nutrients and dietary substances (see Table 3).

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 408 TABLE 3 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes NUTRIENTS THAT AFFECT ZINC Iron Iron may decrease In general, data indicate that high intakes of zinc absorption. supplemental iron inhibit zinc absorption if both are taken without food, but do not inhibit zinc absorption if they are consumed with food. This relationship is of some concern in the management of iron supplementation during pregnancy and lactation. Calcium and Calcium and phosphorus Dietary calcium may decrease zinc absorption, but phosphorus may decrease zinc there is not yet definitive evidence. Human studies absorption. have found that calcium phosphate supplements (1,360 mg/day of calcium) decreased zinc absorption, whereas calcium supplements in the form of a citrate– malate complex (1,000 mg/day of calcium) had no statistically significant effect on zinc absorption. Currently, data suggest that consuming a calcium-rich diet does not lower zinc absorption in people who consume adequate zinc. The effect of calcium on zinc absorption in people with low zinc intakes has not been extensively studied. Certain dietary sources of phosphorus, including phytate and phosphorus-rich proteins, such as milk casein, decrease zinc absorption. Protein Protein may affect The amount and type of dietary protein may affect zinc absorption. zinc absorption. In general, zinc absorption is higher in diets rich in animal protein versus those rich in plant protein. The markedly greater bioavailability of zinc from human milk than from cow milk is an example of how protein digestibility, which is much lower in casein-rich cow milk than in human milk, influences zinc absorption. Phytic acid Phytic acid, or phytate, Phytic acid, which is found in many plant-based and fiber may reduce zinc absorption. foods, including grains and legumes, binds to zinc and reduces its absorption in the gastrointestinal tract. Phytate binding of zinc has been demonstrated as a contributing factor for zinc deficiency related to the consumption of unleavened bread seen in certain population groups in the Middle East. Although high- fiber foods tend also to be phytate-rich, fiber alone may not have a major effect on zinc absorption.

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PART III: ZINC 409 TABLE 3 Continued Substance Potential Interaction Notes Picolinic Picolinic acid may promote Picolinic acid has a high metal binding affinity. People acid negative zinc balance. do not consume picolinic acid through food, but through dietary supplements, such as zinc picolinate or chromium picolinate. Zinc picolinate as a zinc source for humans has not received extensive investigation, but in an animal model, picolinic acid supplementation promoted negative zinc balance, presumably by promoting urinary zinc excretion. ZINC AFFECTING OTHER NUTRIENTS Copper Increased zinc intake may Reduced copper status has been associated with lead to reduced copper increased zinc intake. Doses of 60 mg/day (50 mg absorption. from supplements and 10 mg from food) for 10 weeks have shown this effect. This interaction also derives from the therapeutic effect of zinc in reducing copper absorption in patients with Wilson’s disease. Folate Low zinc intake may Some studies have shown that low zinc intake may decrease folate absorption. decrease folate absorption and folate status, whereas other studies have found that low zinc intake did not affect folate nutriture and that folate supplementation does not adversely affect zinc status. However, extensive studies on this potential relationship have not been carried out in women, and because both of the nutrients are important for fetal and postnatal development, further research is warranted. Iron Zinc may reduce High intakes of supplemental zinc may reduce iron iron absorption. absorption. One study found a 56 percent decline in iron absorption when a supplemental dose of zinc and iron (administered in water) contained five times as much zinc as iron. However, when the same dose was given in a hamburger meal, no effect on iron absorption was noted.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 410 INADEQUATE INTAKE AND DEFICIENCY Overt human zinc deficiency is rare. Because zinc is involved in so many core areas of metabolism, the signs and symptoms of mild deficiency are diverse and inconsistent. Impaired growth velocity is the primary clinical feature and can be corrected with zinc supplementation. Other functions that respond to zinc supplementation include pregnancy outcome and immune function. Other ba- sic and nonspecific signs and symptoms include the following: • Growth retardation • Alopecia • Diarrhea • Delayed sexual maturation and impotence • Eye and skin lesions • Impaired appetite It is noteworthy that zinc homeostasis within the body is such that zinc defi- ciency can occur with only modest degrees of dietary zinc restriction, while circulating zinc concentrations are indistinguishable from normal. Special Considerations Individuals susceptible to zinc deficiency: People with malabsorption syndromes, including sprue, Crohn’s disease, and short bowel syndrome are at risk of zinc deficiency due to malabsorption of zinc and increased urinary zinc losses. Ac- rodermatitis enteropathica, an autosomal recessive trait, is a zinc malabsorp- tion problem of an undetermined genetic basis. The mutation causes severe skin lesions and cognitive dysfunction. EXCESS INTAKE There is no evidence of adverse effects from the excess intake of naturally oc- curring zinc in food. The adverse effects associated with chronic intake of supple- mental zinc include suppression of the immune system, a decrease in high den- sity lipoprotein (HDL) cholesterol, and reduced copper status. Other adverse effects include the following: • Acute effects: Acute adverse effects of excess zinc include acute epigastric pain, nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches. Doses of 225–450 mg of zinc have been estimated to

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PART III: ZINC 411 cause vomiting. Gastrointestinal distress has been reported at doses of 50–150 mg/day of zinc • Impaired immune function: Intake of 300 mg/day of supplemental zinc for 6 weeks has been shown to cause impaired immune function SPECIAL CONSIDERATIONS Individuals susceptible to adverse effects: People with Menke’s disease may be distinctly susceptible to the adverse effects of excess zinc intake. Because Menke’s disease is a defect in the ATPase involved in copper efflux from enterocytes, supplying extra zinc will likely further limit copper absorption.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 412 KEY POINTS FOR ZINC Zinc functions as a component of various enzymes in the 3 maintenance of the structural integrity of proteins and in the regulation of gene expression. Factors such as stress, acute trauma, and infection can cause plasma zinc levels to drop. In humans, plasma zinc concentrations will remain relatively 3 stable when zinc intake is restricted or increased, unless these changes in intake are severe and prolonged. The adult requirements for zinc are based on metabolic studies 3 of zinc absorption, defined as the minimum amount of dietary zinc necessary to offset total daily losses of zinc. 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. The bioavailability of zinc in vegetarian diets is reduced if 3 phytate content in the diet is high, which may result in low zinc status. Zinc interacts with many other nutrients and dietary 3 substances. To date, a useful algorithm for establishing dietary zinc requirements based on the presence of other nutrients and food components has not been established, and much information is still needed to develop one that can predict zinc bioavailability. Zinc-rich foods include red meat, some seafood, whole grains, 3 and some fortified breakfast cereals. Whole grains tend to be richer in zinc than unfortified refined grains. This is because zinc, mainly found in the germ and bran portions of grains, is lost during the milling process. Overt human zinc deficiency is rare. 3 Because zinc is involved in so many core areas of metabolism, 3 the signs and symptoms of mild deficiency are diverse and inconsistent. Impaired growth velocity is the primary clinical feature and can be corrected with zinc supplementation. The signs and symptoms of zinc deficiency include impaired 3 growth, alopecia, diarrhea, delayed sexual maturation and impotence, eye and skin lesions, loss of appetite, altered immune function, and adverse pregnancy outcomes.

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PART III: ZINC 413 It is noteworthy that zinc homeostasis within the body is such 3 that zinc deficiency can occur with only modest degrees of dietary zinc restriction, while circulating zinc concentrations are indistinguishable from normal. People with malabsorption syndromes, including sprue, 3 Crohn’s disease, and short bowel syndrome are at risk of zinc deficiency due to malabsorption of zinc and increased urinary zinc losses. There is no evidence of adverse effects from the excess intake 3 of naturally occurring zinc in food. The adverse effects associated with chronic intake of excess supplemental zinc include acute gastrointestinal effects and headaches, impaired immune function, changes in lipoprotein and cholesterol levels.