Clinical aspects of trace elements: Zinc in human nutrition – Zinc ...downloads.hindawi.com/journals/cjgh/1995/523647.pdf · proper physiological and biochemical functioning. Defining

Clinical aspects of traceelements: Zinc in human

nutrition – Zinc requirementsMICHELLE M PLUHATOR MSC, ALAN BR THOMSON MD PHD FRCPC FACP FRS FACC, RICHARD N FEDORAK MD FRCPC

THIS REVIEW IS THE THIRD OF A

five-part series that examines zincin terms of its biochemistry and physi-ology, metabolism, dietary require-ments, nutritional assessment andstates of excess and deficiency.

Certain levels of essential nutrients,such as zinc, are required to maintainhuman life. If the body is consistentlyprovided with less than these requiredamounts, impaired function, diseaseand death can result. Every essentialnutrient has a unique range of tissueconcentration and intake necessary forproper physiological and biochemicalfunctioning. Defining these ranges ofsafe and adequate intake is the goal ofhuman nutrition research.

Although recommendations aboutdietary zinc intake have been pub-lished, zinc requirements and methodsfor determining zinc’s nutritional statuscontinue to be intensively studied. Be-cause of the body’s ability to adjust ho-meostatically to various levels of zincintake, it has been next to impossibleto determine what level of zinc intakeis just sufficient and below what levelthe body cannot compensate. Further,a clear lack of satisfactory biochemical

NUTRITION

MM PLUHATOR, ABR THOMSON, RN FEDORAK. Clinical aspects of traceelements: Zinc in human nutrition – Zinc requirements. Can J Gastroenterol1995;9(7):368-372. The body requires certain levels of essential nutrients,such as zinc, to maintain life. Intake less than the required levels can cause im-paired function, disease and death. Every essential nutrient has a unique range oftissue concentration and intake necessary for proper physiological and biochemi-cal functioning. Many criteria have been used to set dietary intake levels for nu-trients. For trace elements, however, a limited number of investigativeapproaches are currently employed by researchers due to inadequate informationon individual requirements and intake levels. Further, a clear lack of satisfactorybiochemical methods to measure zinc nutritional status continues to hinder for-mulation of dietary guidelines. Thus, many assumptions have to be made, andlarge safety margins have to be added to assumed daily requirements in order tocompensate for this absence of information. Numerous barriers to a full under-standing of what constitutes an adequate dietary recommendation for zinc stillexist. Zinc is incompletely absorbed, and this absorption can be greatly influ-enced by the chemical form in which zinc is bound; interactions with other nutri-ents also affect absorption. Part three of this five-part review presents the currentCanadian recommended nutrient intakes for zinc for various sex and age catego-ries and provides a rationale for the suggested values. The important nutrient in-teractions that affect the bioavailability of zinc, including those with phytates,copper, cadmium, tin and iron, are discussed. (Pour le résumé, voir page 369)

Key Words: Absorption, Enteral, Metabolism, Total parenteral nutrition, Zinc

Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton,Alberta

Correspondence: Dr RN Fedorak, Division of Gastroenterology, Department of Medicine,University of Alberta, 519 Robert Newton Research Building, Edmonton, Alberta T6G 2C2.Telephone 403-492-6941, fax 403-492-3744, e-mail [email protected]

Received for publication August 16, 1994. Accepted January 23, 1995

368 CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER/DECEMBER 1995

methods to distinguish among ade-quate, marginally deficient and defi-cient zinc states continues to hinderthe formulation of dietary guidelines.

Another barrier to the establish-ment of adequate dietary recommenda-

tions for zinc is its ionic form. Mosttrace elements, including zinc, occur inthe cationic form. Thus, they are in-completely absorbed, and their absorp-tion can be greatly influenced by thechemical form in which they are

bound, as well as by interactions withother nutrients. Such factors make itexceptionally difficult to recommendsafe and adequate levels of zinc intakefor a diverse population which con-sumes a variable diet.

This review presents the currentCanadian recommended nutrient in-takes of zinc for various sex and agecategories, with a rationale for thesesuggested values. A discussion of theimportant nutrient interactions affect-ing the bioavailability of zinc follows.

HUMAN DIETARY ZINCREQUIREMENTS

Sources of dietary zinc: Zinc absorp-tion is affected by the amount of zinc inthe diet (1), age (2) and the presence ofinterfering substances (3). In an aver-age adult, 30 to 50% of the zinc pro-vided daily in the diet is absorbed (4).Major dietary sources of zinc are foodsof animal origin such as meat, fish,shellfish, poultry, eggs and dairy prod-ucts. Whole grain cereals are also goodsources of zinc; however, absorption ofzinc from these sources is reduced due tothe presence of interfering materialssuch as phytates and fibre. In Canada,an average mixed diet contains ap-proximately 5 mg zinc/1000 kcal (5).Recommended zinc intake: The appar-ent lack of readily accessible zinc stores(ie, virtually all the zinc in the body islocked away in bone and protein), cou-pled with a relatively high endogenousloss of the element, dictates that thebody experiences a constant need fordietary zinc to maintain plasma zincconcentrations (6). The recommendednutrient intake for zinc in Canada hasbeen established using a factorial ap-proach, whereby obligatory zinc lossesare divided by the fractional absorptionto obtain the required amount (7) (Ta-ble 1). The recommended zinc intakefor males and females over the age of 13years is 12 and 9 mg/day, respectively(7). This requirement is thought to en-compass the needs of the elderly be-cause it is not known whether zincrequirements change in later adult-hood. Studies have indicated that theamount of zinc absorbed by the body ap-pears to decline with age. For example,in a study by Turnlund et al (2), a group

Aspects cliniques, biochimiques et physiologiques des élémentstrace : zinc et nutrition humaine. Les besoins en zinc

RÉSUMÉ : L’organisme requiert certains taux d’éléments nutritifs essentiels,comme le zinc, pour rester en vie. Un apport insuffisant peut provoquer des dys-fonctions, des maladies et même la mort. Chaque élément nutritif essentiel doitêtre présent dans une concentration tissulaire spécifique et doit être pris en quan-tité adéquate pour le bon fonctionnement biologique et biochimique de l’organ-isme. De nombreux critères ont été utilisés pour teuter d’établir quel est l’apportalimentaire idéal de ces éléments nutritifs. Pour les éléments traces toutefois, lenombre d’approches expérimentales actuellement utilisées par les chercheurs estlimité à cause du manque de renseignements et de la variabilité des besoins et desapports. De plus, l’absence de méthodologie biochimique satisfaisante pour me-surer le statut nutritionnel en zinc continue de freiner la préparation des direc-tives diététiques. Ainsi, plusieurs suppositions doivent être faites et de bonnesmarges de sécurité ont été ajoutées aux exigences quotidiennes pour compenserces lacunes du savoir. De nombreuses barrières s’opposent toujours à la pleinecompréhension de ce qui constitue une recommandation diététique adéquatepour le zinc. Le zinc s’absorbe de façon incomplète et cette absorption peut êtregrandement influencée par la forme chimique à laquelle le zinc est lié. Les inter-actions avec d’autres aliments peuvent également en affecter l’absorption. Latroisième partie de cette synthèse en cinq volets présente les apports nutrition-nels recommandés au Canada pour le zinc, selon l’âge et le sexe et explique la rai-son d’être de ces recommandations. On y décrit les importantes interactionsnutritionnelles qui affectent la biodisponibilité du zinc, y compris les interactionsavec les phytates, le cuivre, le cadmium, l’étain et le fer.

TABLE 1Recommended dietary zinc intakes

Age (years) Sex

Canadian RNI:*

zinc mg/day

American RDA:†

zinc mg/day

0-0.3 Both 2.0 5.0

0.4-1 Both 3.0 5.0

1 Both 4.0 10.0

2-3 Both 4.0 10.0

4-6 Both 5.0 10.0

7-9 Both 7.0 10.0

10 Both 9.0 10.0

11 Males 9.0 15.0

Females 9.0 12.0

12 Males 9.0 15.0

Females 9.0 12.0

13+ Males 12.0 15.0

Females 9.0 12.0

Pregnancy 15.0 15.0

Lactation 15.0

First six months 19.0

Second six months 16.0

*Canadian values from reference 7;†American values from reference 8. RDA Recommended Dietary Al-

lowance; RNI Recommended Nutrient Intake

CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER/DECEMBER 1995 369

Zinc requirements

of healthy elderly men showed reducedfractional absorption of zinc comparedwith young control males fed the samediet. The endogenous fecal and urinarylosses of the elderly group were less thanthose of the young men. Thus, thelower zinc absorption of the elderly menwas sufficient to replace their endoge-nous losses. In this study, as well as inothers, the older group absorbed about55% the amount of zinc absorbed byyoung adults. As more research is dedi-cated to the zinc status of the elderly,perhaps changes in the recommendedzinc intake will be forthcoming.

The recommended daily zinc intakeis increased during pregnancy andlactation. Schraer and Calloway (9)calculated that, in order to allow for anormal pregnancy weight gain, anadditional 1.5 mg zinc would have tobe retained daily throughout thepregnancy. Given a reported dailyzinc intake of 8.9±3.2 mg by women inthe second trimester and applying asafety factor of 2 SD, the recommendedintake for pregnant women is 15 mg/day. For lactating women, an addi-tional 6 mg/day zinc is required to makeup for zinc losses to breast milk (10).This increase raises the zinc re-quirement for breast-feeding women to15 mg/ day (7).

The recommended dietary zinc in-take for infants is based on consump-tion of breast milk and is set at arecommended intake of 2.0 mg/day forinfants from birth to age four months.The requirement for formula-fed in-fants is likely higher because of thelower bioavailability of zinc in formulas(7). The zinc content of breast milk de-creases as postpartum time increases,from 2.6±0.2 �g/mL at one month to1.1±0.1 �g/mL at six months (11).Therefore, infants older than five or sixmonths may not receive adequate zinc

from breast milk alone. However, it hasbeen suggested that zinc requirementsare highest during the period of earlyinfancy and decrease during later in-fancy because of a decline in growth ve-locity (12). If this is so, breast-fedinfants likely receive adequate zincsupplies despite the decline in breastmilk’s zinc content. Due to the lack ofadequate data a linear require-ment:weight ratio has been assumed forchildren from six months to 13 years ofage (7). Thus, the requirement for chil-dren at five to 12 months is 3 mg/day,one to three years is 4 mg/day, four tosix years is 5 mg/day, seven to nineyears is 7 mg/day and 10 to 12 years is 9mg/day. This model does not recognizedifferences in sex until 13 years of age,when the adult recommended nutrientintake comes into effect.Zinc bioavailability: In addition to theamount of zinc provided by the diet, itsbiological availability is an importantnutritional consideration. For example,foods from animal sources enhance theabsorption and retention of zinc (7,13).Factors that particularly affect the bioa-vailability of zinc include the phytatefound in cereal grains, copper, cad-mium, tin and iron (4,7,13-15).

Phytic acid, the major form of phos-phorus found in cereal grains and leg-umes, has long been seen as a potentialantagonist of zinc absorption (16) (Ta-ble 2). Single-meal studies using radio-nuclide and stable isotope techniqueshave confirmed phytic acid’s negativeeffect on zinc absorption in humans.Turnlund et al (2), using levels ofphytic acid similar to those found inwhole grain and cereal-based diets, ob-served a significantly reduced absorp-tion of zinc with a liquid formula diet.Similar decreases in zinc absorptionwere observed when phytic acid wasadded to white bread (17) and to cow’smilk formula (18) at levels close tothose observed for wholemeal breadand soy-based formula, respectively.

The framework for understandingthe interaction between minerals andtrace elements was set by the studies ofHill and Matrone (19). These investi-gators suggested that minerals withsimilar chemical properties often en-gage in biological competition. The

zinc ion has parameters identical tothose of Cu+ and Cd2+, and thereforethese elements can be expected to in-teract with zinc. Such biological inter-actions between zinc and copper orcadmium are well-documented. Themolecular basis of this interaction ap-pears to be a competition for intracellu-lar binding to metallothionein (20).

Using 65Zn and whole-body count-ing in human subjects, Valberg et al(21) found that 5 mg copper had no ef-fect on the absorption of 0.5 mg zinc inwater. The normal human diet almostalways contains more zinc than copper.Thus, this interaction has little practi-cal nutritional significance (15). Con-versely, large quantities of oral zinc caninterfere with copper absorption and,because copper is necessary for iron me-tabolism, anemia may occur (22). Zincsupplementation may, however, pro-tect against detrimental effects of cop-per accumulation such as those foundin Wilson’s disease (23). Zinc acetate isbecoming well-established in the treat-ment of Wilson’s disease (24). Zincacts by inducing the production of in-testinal cell metallothionein, whichhas a high affinity for copper, blockingits absorption and causing its excretionin the feces. Doses of 50 mg zinc bid,taken separate from food, have beenshown to control abnormal copper bal-ances, block the uptake of orally ad-ministered 64Cu, control urine andplasma copper, prevent reaccumula-tion of hepatic copper and prevent theprogression of symptoms of coppertoxicosis (24).

A negative interaction has beenshown to occur between zinc and cad-mium. It has recently been proposedthat the use of tobacco products mayindirectly affect zinc status. Tobaccoproducts contain cadmium, a trace ele-ment toxic to all tissues, which com-petes with other elements, includingzinc, for binding sites on the intestinalmucosa (25). Smokers have also beenfound to have twice the cadmium tissueconcentration of nonsmokers. Thus,indirectly, cadmium from tobacco maydecrease zinc metabolism. Addition-ally, maternal smoking appears to im-pair the fetal zinc status (25). Kuhnertet al (26) related the birth weight of in-

TABLE 2Elemental antagonists to zinc absorp-tion

Phytic acid (phosphorus)

Copper

Cadmium

Tin

Iron

370 CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER/DECEMBER 1995

PLUHATOR et al

fants to zinc:cadmium ratios and postu-lated that cadmium released from ma-ternal smoking accumulates in theplacenta, tying up zinc and reducing fe-tus growth.

The levels of tin ordinarily found inthe human diet are low and unlikely tointerfere with zinc absorption (27).Food preserved in unlaquered canscan, however, contain considerableamounts of tin (27). Human metabolicbalance studies have shown that tinsupplements of 50 mg increase fecalzinc excretion (28) and radiozinc stud-ies have confirmed that tin reduced thezinc absorbed from both a test solutionand a meal (21). Solomons and co-workers (29) suggested that tin en-hanced zinc excretion because theyfound that the addition of up to 100 mgtin to an oral dose of 12.5 mg zinc hadno significant effect on plasma zinc up-take. While the level of tin used in thatstudy is much higher than that found inthe ordinary diet, such amounts arebiologically possible if several servingsof foods from unlaquered tin cans areingested within a short time (20,21).

Of greater importance is the com-petitive interaction between zinc andiron, which both have a mutual affinity

for the biological carrier transferrin. Astudy using bodily retention of 65Zn asan index of absorption found that bothinorganic and heme iron inhibited zincabsorption from 6 mg doses of zinc aszinc chloride (21). Inorganic iron,however, had no effect on 65Zn absorp-tion from an extrinsically labelled testmeal. Similar results regarding the dif-ferential effects of iron on zinc absorp-tion from aqueous solution ormeal-based sources have been observed(30). These effects exemplify the com-plex interactions that take place be-tween promoters and antagonists ofabsorption; it is important to know thata much higher fraction of zinc is ab-sorbed from an aqueous solution thanfrom food (30). Therefore, interactionswith iron may reduce the efficiency of azinc supplement, while the normal lev-els of iron enrichment found in foodsmay not significantly impair absorptionof the dietary zinc supply (27). Pharma-cological doses of iron are often givento individuals with high zinc require-ments such as pregnant women andteenagers (27). In addition, nutritionalformulas such as those for infants areoften enriched with iron. Thus, thenegative effect of iron on zinc absorp-

tion could have profound effects onvulnerable groups (27), and some as-pects of formula composition of dietarysupplementation may have to be re-thought taking this fact into account.

CONCLUSIONSIn view of the current incomplete

data on zinc intake and requirementsand the absence of a flawless method ofanalysis, it is very difficult to define hu-man zinc requirements. In addition,human zinc requirements cannot befully defined without consideration ofthe dietary source and amount becausethey both affect whole-body zinc utili-zation. An understanding of variationsin the efficiency with which zinc can beused from different dietary sources re-mains very limited. Once biochemicalmethods have been developed that suf-ficiently reveal changes in zinc status,epidemiological studies will be able toprovide much more useful informationregarding the relationship between die-tary habits and nutritional zinc status.Only then will truly accurate recom-mendations for the dietary intake ofzinc be available for all members of thehuman population.

REFERENCES1. Wada L, Turnlund JR, King JC. Zinc

utilization in young men fed adequateand low zinc intakes. J Nutr1985;115:1345-54.

2. Turnlund JR, Durkin N, Costa F,Margen S. Stable isotope studies of zincabsorption and retention in elderlymen. J Nutr 1986;116:1239-47.

3. Prasad AS. Clinical, biochemical andnutritional spectrum of zinc deficiencyin human subjects: an update. NutrRev 1983;41:197-208.

4. Guthrie HA. Micronutrient elements.In: Bagby RS, ed. IntroductoryNutrition, 7th edn. Toronto: TimesMirror/Mosby College Publishing,1989:289-335.

5. Kirkpatrick DC, Coffin DE. The tracemetal content of representativeCanadian diets in 1970 and 1971.Can Inst Food Sci Technol J1974;7:56-8.

6. Keen CL, Gershwin ME. Zincdeficiency and immune function.Annu Rev Nutr 1990;10:415-31.

7. Health and Welfare Canada. NutritionRecommendations. Ottawa:Canadian Government PublishingCentre, 1990.

8. National Research Council.Recommended Dietary Allowances,10th edn. Washington: NationalAcademy Press, 1989.

9. Schraer KK, Calloway DH. Zincbalance in pregnant teenagers.Nutr Metab 1974;17:205-12.

10. American Academy of Pediatrics.Committee on Nutrition. Nutritionalneeds of low birth-weight infants.Pediatrics 1977;60:519-30.

11. Moser PB, Reynolds RD. Dietary zincintake and zinc concentrations ofplasma, erythrocytes and breast milk inantepartum and post-partum lactatingand nonlactating women: alongitudinal study. Am J Clin Nutr1983;38:101-8.

12. Krebs NF, Hambidge KM. Zincrequirements and zinc intakes ofbreast-fed infants. Am J Clin Nutr1986;43:288-92.

13. Ronaghy HA. The role of zinc inhuman nutrition. World Rev Nutr Diet1987;54:237-54.

14. Gordon EF, Gordon RC, Passal DB.Zinc metabolism: basic, clinical, andbehavioral aspects. J Pediatr1981;99:341-9.

15. Solomons NW. Factors affecting the

bioavailability of zinc. J Am Diet Assoc1982;80:115-21.

16. O’Dell BL, Savage JE. Effect of phytateon zinc availability. Proc Soc Exp BiolMed 1960;103:304-9.

17. Navert B, Sandstrom B, CederbladA. Reduction of the phytate contentof bran by leavening in breadand its effect on the absorptionof zinc in man. Br J Nutr1985;53:47-53.

18. Lonnerdal B, Cederblad A, DavidsonL, Sandstrom B. The effect ofindividual components of soy formulaand cow’s milk formula on zincbioavailability. Am J Clin Nutr1984;40:1064-70.

19. Hill CH, Matrone G. Chemicalparameters in the study of invivo and in vitro interaction oftransition elements. Fed Proc1970;29:1474-88.

20. Solomons NW. Biological availabilityof zinc in humans. Am J Clin Nutr1982;35:1048-75.

21. Valberg LS, Flanagan PR, ChamberlainMJ. Effects of iron, tin and copper onzinc absorption in humans. Am J ClinNutr 1984;40:536-41.

22. Patterson WP, Winkelmann M, Perry

CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER/DECEMBER 1995 371

Zinc requirements

MC. Zinc-induced copper deficiency:megamineral sideroblastic anemia.Ann Intern Med 1985;103:385-6.

23. Peereboom JWC. General aspects oftrace elements and health. Sci TotalEnviron 1985;42:1-27.

24. Brewer GJ, Yuzbasiyan-Gurkan V,Lee D. Use of zinc-copper metabolicinteractions in the treatment ofWilson’s Disease. J Am Coll Nutr1990;9:487-91.

25. Hennig B, McClain CJ, Diana J.Function of vitamin E and zinc inmaintaining endothelial integrity:

implications in atherosclerosis.Ann NY Acad Sci 1993;686:99-109.

26. Kuhnert BR, Kuhnert PM, Debanne S,Williams TG. The relationshipbetween cadmium, zinc andbirthweight in pregnant women whosmoke. Am J Obstets Gynecol1987;157:1247-51.

27. Oberleas D, Muhrer ME, O’Dell BL.Dietary metal-complexing agents andzinc availability in the rat. J Nutr1966;90:56-62.

28. Johnson MA, Baier MJ, Greger JL.Effects of dietary tin on zinc, copper,

iron, manganese metabolism ofadult males. Am J Clin Nutr1982;35:1332-8.

29. Solomons NW, Marchini JS,Duarte-Favaro RM, Vannuchi H,Dutra de Oliveira JE. Studies on thebioavailability of zinc in humans:intestinal interaction of tin and zinc.Am J Clin Nutr 1993;37:566-71.

30. Sandstrom B, Davidsson L, CederbladA, Lonnerdal B. Oral iron dietaryligands and zinc absorption. J Nutr1985;115:411-4.

368 CAN J GASTROENTEROL VOL 9 NO 7 NOVEMBER DECEMBER 1995

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Clinical aspects of trace elements: Zinc in human nutrition – Zinc ...downloads.hindawi.com/journals/cjgh/1995/523647.pdf · proper physiological and biochemical functioning. Defining