bioinorganica del zinc

8/19/2019 Bioinorganica del zinc

1/34

A CONSPECTUS OF RESEARCH ON ZINC

REQUIREMENTS OF MAN

JA MES A. H ALSTED

Albany Medica l Co ll ege

A lb an y, N ew Yor k 1 22 08

J. CECIL SM ITH, JR.

Trace Elemen t Research Labora tory

Veterans Administ rat ion Hospital

Wash ington, D . C . 20422

an d

M. ISABEL IRWIN

Nutrit ion Insti tute

Agricultural Research Service

Unit ed S ta te s Departmen t o f Agri cu lt ure

BeltsviÃ¼e,Maryland 20705

Pages 345-378

THE JOURNAL OF NUTRITION

VO LUM E 1 4 N UM BER 3 MARC H 1974


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TABLE OF CONTEN TS

Introduction 347

Zinc in nature 347

Development of knowledge about zinc 348

Early discovery-uses in metallurgy 348

Chemistry 348

Biological essentiality 348

Biological functions 349

M ethods of measuring zinc 350

Zinc in food 350

Content in classes of foods 350

Content of typical meals or diets 351

Factors influencing content 352

M anufacturing techniques 352

Preparation of foods 352

M etabolic aspects of zinc in human nutrition 352

Distribution in the body 352

Plasma and serum 352

Red blood cells 352

Leucocytes 354

Hair 354

Absorption of zinc 354

Availability of zinc 355

Excretion of zinc 356

Binding of zinc to serum protein 357

Factors influencing the concentration of zinc in plasma .... 357

Relationship of zinc to endocrine functions 359

Interrelationships with other minerals 359

Calcium 359

Cadmium 359

Copper 360

Others 360

Interrelationships with vitamins 360

V itamin A 360

V itamin D 361

Riboflavin 361

Zinc deficiency 361

Animals 361

M anâ€”clinical and metabolic features 362

Parameters for assessing zinc status in man 363

Zinc toxicity 364

Human requirements for zinc 365

Conclusions 367

Acknowledgments 368

Literature cited . 368


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INTRODUCTION

The 1934 report by Todd et al. (300)

that zinc was necessary for l if e in animals

suggested that it was probably an essential

nutrient for man also. N evertheless the

ubiqui ty of zinc made i t seem unl ikely that

al terations in zinc metabol ism could lead

to significant problems in human nutrition

or clinical medicine. For example, in 1962

Underwood (303) stated that an uncom

plicated dietary deficiency of zinc has never

been observed in man. Since then, zinc

def iciency has been observed in man, and

thus, in 1971 Underwood (304) included

man among the species in whom a de

ficiency syndrome had been demonstrated.

This was the result of reports of primary

zinc deficiency in Egypt by Prasad et al.

(224, 226, 228) and in I ran by H alsted et

al. (80, 84). I n addition, Caggiano et al.

(27), in the U nited States, observed zinc

def iciency secondary to intestinal malab-

sorption. M ore recently, also in the United

States, Hambidge et al . ( 87) reported cases

of low hair zinc concentration and low

taste acuity that were responsive to zinc

supplementation.

The l iterature on the metabol ic aspects

of zinc is extensive (223) and is grow ing.

M uch of our knowledge of zinc has

stemmed however f rom cl inical observa

tions in plant, animal and, most recently,

human pathology. I t is still necessary to

rely on indirect information in estimating

human requirements for zinc and in de

lineating those factors that may accentuate

requi rements. This indi rect information

comes from all branches of available knowl

edge including geochemistry and the zinc

content of the earth's crust. Many bits of

information gleaned from widely disparate

experimental approaches, including those

from the few reported metabolic balance

studies and from cultural eating practices,

shed some light on the role of zinc in

human nutrition.

T he objective of this conspectus is to

bring together the information that bears

on human requirements for zinc, to show

how the information was obtained, and to

point out areas where research is needed.

ZIN C IN N ATURE

Z inc has been estimated to rank 25th in

abundance ( 305 ) and to make up 0.004 to

0.01% of the earth's crust (216, 305).

However, it is less abundant than titanium,

barium, zirconium, or vanadium (264) , ele

ments not yet shown to be essential to man.

A lthough zinc is ubiqui tous i t is unevenly

distributed in the earth's crust, ranging

from 10 to 300 ppm with a mean of 50

ppm (264). Rocks average 16 to 95 ppm

( 21 ). Shales have the highest concentration

and sandstone has the lowest.

Analysis of moon samples brought back

by the astronauts of A pollo 11, 12, and 14

revealed a much lower concentration of

zinc in both the rocks and soils than in

materials found on earth (39, 253, 254).

Specifically, igneous rock samples (basalt

and gabbro ) contained f rom 0.2 to 3.0 ppm

zinc (Apollo 11). E ight rocks returned by

A pollo 12 contained between 0.2 and 4.3

ppm zinc w ith a mean of slightl y less than

4.0 ppm. Lunar soil samples showed a

range of 4.0 to 8.2 ppm with a mean of

6.7 ppm zinc, l ess than 15% the mean con

centration of earth soil.

T he zinc content of certain land plant

species grown in the U nited States has

been summarized (100) . The contents vary

widely around a mean of 23 ppm. Some

land plants reportedly accumulate up to

16% of their ash weight as zinc (330).

Marine animals have a wide range of zinc

concentrations w ith oysters having the

highest level (21).

As an inorganic element, zinc is not de

stroyed but remains in cycle. This cycle

in its simplest form is from the rock ( soil)

-^plantsâ€”Â»animalsâ€”Â»soilr ocean. T here is

however a net loss of elemental zinc from

the soi l due to natural leaching and erosion

Received for puhllrntion February 7. 1972.

Requests (or reprints should be addressed to M .

Isabel Irwin.

7


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34 8

J. A . HALSTED, J. C . SMITH, JR. AND M. I. IRW IN

and because sewage is directed toward the

oceans. Thus, it is theoretically possible

that zinc and other trace elements may be

depleted from the soil. In a like manner,

c on sta nt remo va l o f c ro ps w ith ou t re ple tio n

results in deficiency of zinc in the soil.

M itchell (172) has calculated that the up

take of zinc by plants is relatively high

com pared w ith soil concentration. That is,

when a crop containing 100 ppm zinc is

removed from the soil, 1 ppm zinc is lost

from the surface soil (assuming a yield of

10 tons/acre). The feasibility of zinc-

enriched fertilizers as a method for soil

reple tion has bee n discussed by V iets (310).

DEVELOPM ENT OF KNOW LEDGE

ABOUT ZINC

Early d iscoveryâ€”uses in me ta llurgy

Zinc does not occur naturally in a free,

uncom bined state. It was discovered by ac

cident in the fourth century A .D . that brass

was produced when a certain earth (zinc

bearing) was heated with copper. In India

during the 13th century, m etallic zinc was

produced by reducing calamine (zinc

oxide plus a small percentage of ferric

oxide) with organic substances such as

w oo l (8 8). E be ne r o f N Ã¼ rn be rgis re po rte d

to have recognized zinc as a discrete ele

ment in 1509 (223). In 1746 Marggraf re

discovered the metal in Europe (88). Zinc

as a bipositive ion is com bined w ith sulfide

in the mineral sphalerite which contains

67 zinc. O ther na turally occurring zinc -

containing m inerals of the earth's crust in

clude zincite, ZnO; smithsonite ZnCO3;

willem ite, Zn2SiO4; and hem im orphite,

Zn4(OH)(Si2O7)-H2O.

Cliemistry

Zinc has an atomic number of 30 and an

atomic weight of 65.4. It has a relatively

low meltin g p oin t o f 4 19Â°.F ifte en iso to pe s

of zinc have been described ranging from

80Zn to 72Zn. Ten of these isotopes are not

stable. Their half-lives vary from 1.48

m inutes (61Zn) to 245 days (8SZn) (98).

Metallic zinc is a good reducing agent, is

amphoteric and will dissolve in m ineral

acids and strong bases. Zinc exists in solu

tion only in the oxidized state of Zn2t. The

soluble salts of zinc include chloride, bro

m ide, iodide , form ate, a cetate, su lfate, an d

nitrate (98). The insoluble salts include

carbona te, sulfide, hydroxide, a mm onium

phosphate, ox alate, and p hytate (98).

Today elemental zinc is obtained by

heating ores containing zinc to form zinc

oxide, reducing the oxide with carbon and

then distilling the metal. M etallic zinc is

b lu is h wh it e.

Biological essentiality

O ver 100 years ago (1869) R aulin (236),

a pupil of Pasteur, discovered that zinc w as

indispensable for the growth of a black

bread m old, A spe rgillus n iger. T his finding

was confirmed in 1911, 40 years later, by

Bertrand and Javillier (16). According to

B ertrand and de W olf ( 1 2-15 ) A spergillus

niger requires zinc in order to synthesize

phenylala nine, tryptopha n, and ty rosine as

w ell as sev eral enzym es. G ro wth of penicillin-producing fungi is greatly retarded by

zinc deficiency of the culture m edium ( 60 ).

E vidence in dicating that zinc is essential to

the growth of m icroorganisms has been

s ummariz ed re ce ntly ( 3 30 ).

In 1919 Birckner ( 18 ) reported that egg

yolk, human milk, and cow 's m ilk con

tained zinc and suggested that zinc was of

n utritiv e v alu e. S ho rtly th ere afte r, S ommer

and Lipman (278) demonstrated that zinc

was essential for plant life. Lutz (137)

noted that there had been reports from

time to time indicating that zinc was a

com mon and nearly universal constituent

of animal as well as plant tissues. He em

phasized that zinc was not present in

traces but in am ounts not greatly differ

ent from that found for other heavy m etals

such as iron. Analyses of many foods at

that time showed amounts somewhat

greater than in present day analyses, pre

sumably the result of contamination of

samp le s a nd le ss p re cise a na ly tic al m eth od s

than those used at present. A fter extensive

and meticulous analyses of tissues from

rats, cats, and m an, Lutz (137) calculated

that the human body contained a total of

2.2 g of zinc, an amount about half that of

iron. This value has been widely quoted.

The only other sim ilar work is that ofW iddowson et al. (325), who reported

human body zinc content to be between

1.4 and 2.3 g.

Som e plant diseases have been traced to

zinc deficiency, such as leaf rosette in


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RESEA RCH ON Z IN C REQU IREM EN TS OF M A N

349

apples, mottle leaf in citrus crops and prob

ably dwarf ing of trees. Agronomists have

traced zinc deficiency in plants to deficient

soils in parts of Californi a and Texas and

in the Ninety M ile Desert in South Aus

tral ia. These lands have been reclaimed for

productivity by zinc supplementation (305).

A lthough many attempts were made to

provide a controlled zinc-deficient diet, this

was not accomplished until 1934 when

Todd et al. (300) were successful in dem

onstrating that zinc is essential for growth

and development of rats. The disease of

swine, porcine parakeratosis, which had

been long recognized in animal husbandry,

was shown to be the result of zinc defi

ciency by Tucker and Salmon (302) in

1955. Their f indings led to the general prac

tice of supplementing animal feeds w ith

zinc. O 'Del l and Savage ( 193) showed that

zinc was essential for growth in birds also.

A t present, at least 15 animal species, man

included, have been shown to require

zinc.

A dwarfism syndrome in man was first

described by Lemann in 1910 (129). T his

syndrome was reported subsequently in

Turkey by Reimann (237) in 1956 and bv

Okcuoglu et al. (195) in 1968, in Portugal

by LeCour ( 128 ) , and in Morocco by Faure

(53). I n 1960 and 1961 Prasad et al. (224)

and H alsted and Prasad (83) published a

detai led cl inical description of 11 dwarfs

w ith extreme iron deficiency anemia who

were studied in a hospital at Palliavi Uni

versi ty, Shi raz, I ran. They suggested that

the endocrinopathies (growth and sexual

retardation) observed in the dwarfs

might be caused by zinc deficiency. Sub

sequent biochemical investigations (225,

226, 257) in similar dwarfs residing in

the Nile delta of Egypt demonstrated

abnormalities of zinc metabolism. Dai ly

oral supplementation with zinc sulfate

resulted in signif icantly more rapid growth

and sexual development. These findings

were confirmed in I ran by Halsted et

al. (80, 84) in a study on 17 nutritional

dwarfs. I n this study sexual function oc

curred in 224 Â ±72 days (mean Â ±so) innine dwarfs who were fed a wel l-balanced

hospital diet. In contrast, seven dwarfs, fed

the same diet plus 100 mg of zinc sulfate

dai ly, developed sexual function in 59 Â±40

days. In 6 months the mean growth incre

ment in the nine dwarfs fed the hospital

diet alone was 4.2 Â ±1.9 cm, whereas in

dwarfs who were fed the same diet plus

zinc sulfate, the growth increment was

10.5 Â±3.7 cm.The extreme degree of dwarfism and

total l ack of sexual development noted in

the above reports probably represent one

end of a spectrum, the other end being

represented by outwardly healthy but short

adolescents with delayed puberty and mild

anemia. Two studies have been publ ished

designed to determine whether oral zinc

supplementation of such mildly growth re

tarded individuals would cause a growth

response. Carter et al. (31) in Egypt gave

daily zinc supplementation for 5 months

with negative resul ts. Ronaghy et al . ( 251 )

in I ran administered a complete supple

ment that provided al l essential trace elements and vitamins with and without

added zinc to each of two groups. Those

receiving zinc developed sexually more

rapidly than those who did not (P < 0.02).

I t thus appears that zinc, in addition to

other essential nutrients and calories, may

be a limiting factor in normal growth and

well-being of certain populations in under

developed regions of the world.

B io l o gi c a l fu n c ti o n s

The biochemical functions in which zinc

has been implicated as necessary include:

1) enzymes and enzymatic function, 2) pro

tein synthesis, and 3) carbohydrate metab

olism.

K eilin and Mann in 1939 (116) and 1940

(117) f irst showed that zinc was an integral

and necessary component of carbonic an-

hydrase of red blood cells. Since then, at

least 18 metal loenzvmes have been shown

to contain zinc (202). Several enzvmes

necessary for cel lular oxidation, such as

human alcohol dehydrogenase, are zinc

dependent. M ore complete information on

the importance of zinc in enzymatic func

tion may be found in recent revi ews (160,

202).

Zinc has been shown to be related to

protein synthesis in microorganisms, ani

mals, and animal tissues. The synthesis of

both DNA (63, 132) and RNA (315, 321,

327) is inhibited when zinc is lacking.

Protein synthesis appears to be reduced or

altered in zinc-deficient rats (295, 326).


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J. A. HALSTED, J. C. SMITH, JR. AND M. I. IRWIN

Somers and Underwood (277), in a con

trolled study, found that the output of uri

nary nitrogen and sulfur w as significantly

higher in zinc-deficient lam bs than in con

trol anim als. This observation suggestedim paired protein or am ino acid utilization.

The data did not show whether the defect

was due to impaired tissue synthesis or to

increased catabol ism.

H su et al. ( 1 04 -107 ) recently elabo rated

on the relationship of zinc to protein syn

thesis. They showed that, in vivo, the in

corporation of 35S a mino acids into organ

and skin protein w as significantly altered

in z in c-d efic ie nt ra ts .

The role of zinc in carbohydrate m etab

olism is controversial. In 1937 Hove et al.

( 1 03 ) and m ore recently Quarterm an et al.

( 2 35 ) re po rte d d ec re as ed g lu co se to le ra nc e

in rats that w ere zinc defic ient. In c ontrast,

Macapinlac et al. (139) could find no dif

ference in fasting bloo d sugar, or in glucose

and insulin tolerance curves betw een zinc-

deficient rats and ad libitum controls.

Studies by M ills et al. (169) indicated that

zinc influences the membrane transport

and utilization of glucose. A lthough H ard

ing et al. (89) showed that the insulin

molecule contains 2 zinc atoms, it has not

been demonstrated that these are neces

sary for th.e biological activity of insulin.

K inetic studies by W eil et al. (322) have

indicated, however, that the stability of

zinc-free insulin is less than that of zinc

insulin. It is evident that the exact role of

zinc in carbohvdrate m etabolism has yet

to b e e lu cid ate d.

METHODS OF MEASURING ZINC

B ecause of the lack of precise analytical

procedures for the determ ination of zinc by

the earliest workers, zinc was assigned to

the category of a t race elem ent. The ele

m ent could be detected but not accurately

quantitated. As m ethods becam e m ore sen

sitive, the problem of contamination due

to the ubiquitous nature of zinc became

evident. For exam nle, blood for zinc analv-

sis is easilv contaminated bv the needles

and svringes used for venepuncture. V acu-

tainers, now widelv used to draw venous

blood, have been shown to be a source of

contamination (86, 91). The use of all-

plastic polyethy lene syring es 1 and certa in

sta in le ss ste el n ee dle s,2 h ow ev er, p re ve nts

contamination from these sources (81).

Anticoagulants also may be a source of

e xt ra neou s z in c.

Early analytical determ inations of zinc

relied upon gravim etric and volum etric

m ethods that were relatively insensitive.

Beam ish and W estland (7) have reviewed

such me thod s.

Am ong the m ore m odern techniques are

a tom ic abs orp tio n s pe ctro ph otometry , em is

sion spectrochem ical m ethods (173), and

X -ra y emis sio n sp ec tro gra ph y ( 1 ). O f th ese ,

atom ic absorption spectrophotom etry is at

present the most popular method for ana

lyzing zinc in biological sam ples (76, 249,

271). W alsh (318), an A ustralian physicist,

developed the method in 1955 and since

then several com mercial instrum ents have

becom e a vailable. T he general ad vantages

of this m ethod include: 1) simplicity and

ease of ope ration, 2 ) sensitivity, precision

and accuracy, and 3) cost. In its simplest

form the instrumentation consists of a

hollow cathode lamp (light source), a

flame atomizer, grating or prism , and a

photo detector. S am ple prep aration is a per

sistent problem in this m ethod because the

sample must be aspirated into the instru

ment. Dry ashing may result in losses of

zinc, presumably due to volatilization

( 2 96 ). A t presen t, the m ost popular m ethod

of preparing biological solid m aterial for

atom ic absorption analysis of zinc is acid

(w et) d ig estio n (2 74 ).

A lthough m any of the techniques for the

analysis of zinc are extrem ely sensitive,

each method is no better than the stan

dards available. The sam e standards rarely

have been used by different laboratories.

B iological reference standards are now

available from the U . S. N ational B ureau of

Standards.3 For an accurate com parison of

zinc analyses betw een laboratories it is im

p era tiv e th at a u niv ersa l re fe re nc e sta nd ard

b e u se d.

ZIN C IN FO OD

Con te nt in c la sse s o f fo od s

Classes of foods cannot be rigidly cate

gorized acco rding to zinc concentration be-

iP ee l-A -W ay S cien tific. S o. E l M onte , C aliforn ia

91733.

*Mono je ct -2 50 , She rwood Medi ca l I ndus tr ie s, I nc .,

Delano. Flor ida 32720 .

Â »U .S . N ati on al B ur ea u o f S ta nd ar ds , Wa sh in gt on ,

D . C . 2 0204 .


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RESEARCH ON Z INC REQUI REM ENTS OF M AN

351

TABLE 1

Z in c c on ten ts o f selecte d fo od s1

Food i tem

Zinc

Meat p ro du cts

R oa st b ee f

B eef patty (raw )

Ch ic ken b re as t

C hi ck en th ig h

Da ir y p ro du ct s

Milk

C ream (half and half)

ma/100 g

wet w t

6.4

4.7

1.1

2.8

o Â«

4

BreadsWhiteRyeWhole

WheatVegetables

an druitsPeasPotatoesGreen

beansCarrotsTomatoesApricotsPeachesPearsApplesauceOrange

juiceApple

juice

GrapefruituiceBeveragesTeaCoffeeDecaf

coffee0.571.341.04O.fi )0.2(10.210.250.200.120.070.080.080.110.07

0.100.020.030.04

1 T ak en f rom Osi s et al. 197) .

cause of the variability of the zinc contents

of foods within each class. There is a wide

range of values published in the literature

for the same food because of the differ

ences in analysis, source, and variety. In

general, meat, eggs, m ilk products, and

shellfish ( o ysters in particular ) are the best

sources of zinc. Fruits and vegetables usu

ally are poor sources. Berfenstam ( 1 1 ) re

ported human m ilk to contain 3 to 5 ppm

( w et w eight ) w hich is com parable to cow 's

m ilk ( 1 89 ). M ore recent analyses of infant

foods showed that 22 mature human milk

sam ples contained a m ean zinc concentra

tion of 1.34 ppm and four commercially

prepared infant formulas, as consum ed,

contained 1.47 to 3.99 ppm (180). These

concentrations are markedly lower than

that of 20 ppm previously reported for

hum an colostrum (147). The im portance

of zinc in colostrum was demonstrated by

Nishim ura ( 1 84 ) who showed that zinc de

ficiency developed in suckling mice de

priv ed o f colo strum . O ral adm inistratio n of

zinc prevented the deficiency. M utch andHurley4 reported that dietary zinc de

ficiency in lactating fem ale rats resulted in

zinc deficiency in the suckling young due

to a lowered zinc content of the m ilk.

These studies suggest that consideration

be given to the adequacy of zinc in infant

formulas.

Content of typical m ea ls or diets

During the course of m etabolic balance

stu die s, O sis e t a l. (1 97 ) a na ly ze d n um ero us

diets. The average total zinc content of 138

diets used in metabolic balance studies

sam pled and analyzed over a 4-year period

was 12.2 mg/day. The zinc contents of a

standard hospital diet according to indi

vidual meals were: breakfast, 2.2 mg;

lunch, 4.7 mg; and dinner, 4.4 mg. Thus

the total zinc content of the daily standard

hospital diet was 11.3 m g, very sim ilar to

the m ean of the experim ental diets. M urph y

et al. (178) published analyses of trace

minerals in Type A school lunches col

lected from 300 schools in 19 states. The

average zinc content of these lunches,

served to sixth grade children, was 3.91

mg. The zinc content of selected foods as

reported by Osis et al. (197) is shown in

table 1.

An estimation of the zinc content of

several diets from other cultures was sum

marized by Eggleton in 1938 (47). The

diet of native sailors in the Dutch East

Indian Navy prior to 1874 was estim ated to

contain 7.3 m g of zinc. The diet consisted

mainly of meat (beef, pork, or fish) and

rice. (Its caloric content was not known.)

The Steffanssen all-meat diet (lean beef,

fatty tissue, liver, m arrow ) eaten by A rctic

explorers in the 1920's contained about 24

m g/day. The zinc content of a North China

diet was estimated as 9.5 mg/day. Grain

products and legumes furnished most of

the protein. Eggleton (47) estim ated that

the daily zinc intake of the poorest class of

Chinese in South China at that time was

Â«M utch, P . B. H ur ley. L . S. 1971) Z inc de

ficiency i n suck ling r at a. F ei l. Pr oc. 30, 043 Abstr .) .

Complete paper to be published in T he Journal of

Nutr i tion 1074.


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352

J. A. HA LSTED, J. C. SM ITH , JR. AN D M . I . IRW IN

l ess than 6 mg/day. He suggested that zinc

might be limiting at this level. The southern

China diet consisted mainly of polished

rice, sea fish, and cooked cabbage.

F a cto rs in flu en cin g zin c c on te nt o f fo od s

Ma nufa ctu ring tech niques. The r efining

of foods usual ly results in a decrease in the

zinc content. For example, Czerniejewski et

al. (40) found that during the milling

process of wheat for f lour, up to 80% of the

zinc may be lost. Schroeder et al. (263,

264) reported similar data. Thus, bread

made from white flour has a lower zinc

content than whole wheat bread (197).

Cornstarch contains much less zinc than

the whole corn kernel (165) . The possibly

deleterious ef fects of ref ining foods have

been discussed by M ertz (157) and

Schroeder (263).

P repa ra tion of foods. F ood pr epa ra tion

methods also affect zinc concentration. For

example, water added for cooking purposes

w il l vary markedly in zinc content among

di fferent regions, thus changing the zinc

level of the prepared food. Kopp ( 123 )

analyzed 380 samples of tap (finished)

water and reported the average zinc con

centration to be 79.2 /ig/liter. T he range

was from 3 to 2010 fig/liter. T he zinc con

tent of foods will also be affected by the

equipment and utensils used to prepare

and store the food. For instance, the cor

rosive action of acid foods in contact with

galvanized metal increases the zinc con

centration. This source of contamination,

however, has decreased with the increased

use of stainless steel , plastic, and plastic-

coated cooking utensils.

M ET ABOL IC A SPECT S OF Z IN C

IN H UM AN N UTRITION

D istr ib utio n in th e b od y

Several studies have been publ ished on

the distribution of zinc in tissues. Extensive

work on trace-element concentration in the

tissues of man has been carried out by

Tipton et al. (298). They analyzed, by

emission spectrography, 24 trace elements,

including zinc, in 10 different tissues of 162

adult subjects from various countries out

side the continental Uni ted States. About

half of the subjects had died from acci

dental causes, but the remainder had died

of various diseases. The tissues were col

lected from primitive A frican cultures,

L ebanon, I ndia, the Far East and Europe

(Switzerland and Scandinavia). T hese

samples represented people of a wide geographical distribution as well as with a

variety of dietary habits. Surprisingly, l ittle

variation was found in the zinc content.

The resul ts were simi lar to data obtained

by Perry et al. (211) from 150 healthy

A merican adults who died suddenly of

accidents.

Other data have been reported by Netsky

et al. (182), T ipton and Cook (297), Butt

et al. (25), Eggleton (47, 49), Galin et al.

(66), Schrodt et al. (262), and M cBean et

al. (148). T he results are summarized in

table 2. The distribution of stable zinc in

various tissues of rats (231) , calves (163) ,

and pigs (232) is included for comparisonin this table.

A highly signi ficant correlation among

dietary, plasma, and bone zinc contents

has been demonstrated in rats (274) . Often

the zinc concentrations of the k idney and

liver are not decreased when there is zinc

deficiency.

The concentrations of zinc in plasma or

serum, blood cells, and hair have been

extensively studied and will be considered

in more detail.

P la sma a nd ser um. Althoug h pla sma a nd

serum have usual ly been regarded as pos

sessing similar zinc concentrations (305,

311), Foley et al . (55) reported that seruminvariably has a higher zinc content than

plasma (about 16%). Thev attributed the

greater serum content to the l iberation of

zinc by disintegrated platelets, to a dilu

tion factor and to invisible hemolysis which

always occurs (268). I n a sense, serum is

always slightly contaminated by the zinc

contained in platelets and by hemolysis of

red cells.

Values for the concentrations of zinc in

plasma under normal conditions obtained

by di fferent laboratories using di fferent

methods are, with a few exceptions, in rea

sonably good agreement (table 3). T he

constancy of most estimates since 1965coincides with better methods for avoiding

contamination and with more precise ana

lytical methods.

Red blood cells. The r epor ted zinc con

tent of red blood cells varies from about


9/34

RESEARCH ON ZINC REQUIREM ENTS OF M AN

&5i gSe

1^


10/34

5

J. A . HALSTED, J. C. SMITH, JR. AND M. I. IRWIN

10 to 14 /tg/m l. Ross et al. (256) using the

dithizone method found that the red cells

of 48 norm al subjects contained 11.8 Â ±1.8

/x g zin c/g . A lso u sin g th e d ith iz on e m eth od ,

Prasad et al. (229) found a mean red cell

z in c c on te nt o f 1 3.7 Â ±1 .2 /Â ¿g /m lin a s tu dy

with 14 normal subjects. W hen samples of

the same blood were analyzed by atomic

absorption spcctrophotometry, a mean

value of 14.0 Â ±1.5 /Â ¿g/m lw as obtained.

Mansouri et al. (144) also using atomic

absorption spectrophotometry found a

m ean zinc content of 11.8 Â ±1.7 jÂ «.g/m ln

the red blood cells of 51 normal subjects.

In the same laboratory, M cBean and

Halsted (149) obtained a mean value of

10.1 Â±1.2 /ug/m l in 10 fasting controls.

After a meal, the mean value (10.1 Â±1.0

/ag/m l) w as not sig nificantly changed. D if

ferences in techniq ue, for instance in sp eed

of centrifugation, m ay account for part of

t he d if fe re nc e in e stima te s.

Leucocytes. The zinc content of leuco

cytes has been determ ined (44, 170, 214,

306) with general agreement that these

cells a re rich in zinc.

Hair. Hair zinc concentration has been

reported to be affected by zinc intake in

rats (242), swine (130), cattle and goats

(164,168), and in m an (87).

Abs orp tio n o f Z in c

As with iron, apparently only a small

percentage of ingested zinc is absorbed.

Abs orp tio n is d iffic ult to a sc erta in p re cis ely

and intake-output studies are not valid

TABLE 3

P la sma o r s er um ti ne c on ce nt ra ti on in n orma l a du lt s1

( ng /1 00 m l)

Investigator

R efer ence Y ear

M e an Â ± SD

Range

Method

NotÂ«

WolffVikbladhBerfenstamKoch

etl.Vallee

etl.SmitFuwa

etl.Gofman

etl.Butt

etl.Prasad

etl.Kahn

etl.Sullivan

&ankfordOlehy

etl.Helwig

etl.Parker

etl.Rosner

&orfienHalsted

etl.Mahanand

etl.Davies

etl.Halsted

&mithSinha

&abrieliMeret

&ankinLindeman

etl.Kurz

etl.Pekarek

et al.(328)(311)(11)(122)(308)(272)(65)(67)(26)(229)(115)(292)(196)(92)(205)(255)(81)(143)(41)(85)(269)(156)(134)(125)(20

Â±(P)Â»120Â±23(P)121Â±19(S)139Â±29(S)122Â±

3(8)98Â±

2(S)5140Â±

6(S)5104Â±14(P)103

Â±(P)84

Â±30(8)94Â±12(S)93

Â±(P)91Â±17(S)90Â±10(S)138Â±13(P)96Â±13(P)94

(P)95Â±13(P)96Â±12(P)120Â±20(S)92Â±

3(S)696

(P)119(8)102Â±17(S)84-16370-170101-139â€”72-11287-23486-10276-12572-11576-1

fo ralesand

femalesNewborn,

125Â±5Males,

12 1±2955

adultsAdults39

adults170

adults64

adults23

adultsChildren,

108Â±15Males,

95±13Females,

16Â±11Children,

89Â±13Males,

96Â±13Females,

97Â±11100

m ale s 1 21±18100

females18Â±2145

females0Â±337

m ales 9 4±3Males,

96Females,

8811

adults10Â±2137

children28Â±1799

males

1 Z inc con cen tr at ion h as been f ou nd t o b e 16 h igher i n ser um t han i n p lasm a i n on e st ud y (21)8).

p lasm a. 4 A .A .S. ; at om ic ab sor pt ion sp ect rop hot om et ry. > SE .

(S) ; ser u m .


11/34


355

indicators because excretion of zinc is

nearly al l v ia the gut. Thus data indicating

an increased absorption may also be inter

preted as indicating a decreased excretion

and vice versa.Data on the site or sites of absorption in

man and on the mechanism(s) of absorption,

whether this be by active, passive or facul

tative transport, are meager. Pearson et al .

( 2 07 ) using the everted gut sac of the rat

provided evidence that zinc is actively ab

sorbed into the intestinal mucosa against a

concentration gradient. They reported that

zinc was most efficiently absorbed from the

distal gut segments. M ore recently, M eth-

fessel and Spencer (159) using 65ZnClo,

studied specific absorption sites in rats by

means of l igated intestinal sacs. They con

cluded that the absorption of 65Znwas sig

nificantly greater f rom the duodenum than

f rom the more distal segments of the smal l

intestine. Over a 2-hour observation period,

absorption was much less from the mid-

jejunum and i leum. Only minimal amounts

were observed f rom the stomach, cecum

and colon. These data suggest that si tes of

zinc absorption may be simi lar to those of

iron.

Becker and H oekstra (9) recently re

viewed the available information on intesti

nal absorption of zinc. They concluded that

zinc absorption is variable in extent and

is highly dependent upon a variety of fac

tors.' A mong the factors that they sug

gested might af fect zinc absorption were

body size, the level of zinc in the diet, and

the presence in the diet of other potentially

interfering substances such as calcium,

phytate, other chelating agents, and vi ta

min D .

Ava i la b il it y o f zi nc

Edwards (46) using chicks studied the

availability of zinc from various com

pounds and ores. H e reported that zinc

was most avai lable f rom zinc sul fate, zinc

metal and zinc oxide, and least available

from sphalerite and franklinitc. Later

Roberson and Schaible (247) confirmed

these observations.

Other factors inf luence the absorption

and retention of zinc and thus its avail

abi li ty . Phytate ( inositol hexaphosphate ) ,

which is present in cereal grains, markedly

impairs the availability (absorption) of

zinc. This was f irst shown in 1960 by O'Del l

and Savage (194). Later Oberleas et al.

( 186 ) showed that phytic acid added to an

animal protein diet depressed growth in

swine. U sing rats, Oberleas and Prasad( 190) demonstrated a close relationship

between zinc and the utilization of soybean

protein. Without zinc supplementation, rats

fed a 12% soybean diet gained less than

half as much as rats that were supple

mented with zinc. O'D ell (192) reported

that autoclaving soybeans destroyed most

of the phytic acid. In contrast, Lease ( 127)

autoclaved sesame meal and found no re

duction in phytate despite the fact that

there was a marked increase in zinc avail

ability to the chick. L ikuski and Forbes

( 133) showed that phytic acid depressed

the avai labi li ty of zinc whether the protein

source was pure amino acids or casein.

Such studies have a close relationship to

zinc in human nutrition because there is

strong evidence that phytate exerts a simi

lar effect in man. Reinhold (238, 239)

found that unleavened bread, consumed in

large amounts by the I ranian villagers

(often providing the major source of pro

tein) , contains significantly more phytate

than urban breads which are leavened and

al lowed to ferment (P < 0.001) . Leavening

results in destruction of phytate. The omis

sion of the leavening process in I ranian

village breadmaking is presumably respon

sible for the high content of phytate.

T he data suggesting that phytate en

hances the possibi li ty of zinc def iciency in

man were strengthened by the reports f rom

Egypt (225, 226, 257) and Iran (83, 84)

that zinc def iciency occurred under condi

tions where unleavened bread was con

sumed in great amounts. Reinhold et al.

( 244) tested the hypothesis that phytate

ingestiÃ ³n may result in zinc defi ciency.

Three adult subjects were studied. During

an initi al 16-day control period a diet pro

viding approximately 0.7 g phytic acid was

fed. Fol lowing the control period, sodium

phytate (4.5 g/day) was added to the diet

for 28 days yielding a total intake of about

2.5 g phytic acid/day. Then during the

next 32 days, no sodium phytate was fed,

but tanok replaced the low phytate bread

in the experimental diet. The tanok, a bread

consumed by vill agers of Southern I ran,

provided 2.6 to 3.4 g of phytate dai ly . Dur-


12/34

356

J. A. HALSTED, J. C. SM ITH, JR. AND M . I . IRW IN

ing the sodium phytate period (28 days)

zinc balances became significantly less posi

tive. Occasionally, negative balances were

observed. D uring the tanok period (32

days), zinc balances became more nega

tive. After these two experimental periods,

a white bread low in phytate was given to

two of the subjects for 32 days. During this

period of low phytate ingestion, zinc bal

ances became positive again in both sub

jects.

The avai labi li ty of z inc from foodstuf fs,

w ith major emphasis on the effect of phv-

tate, was rev iewed by Oberleas et al . ( 188)

in 1966. M ore recently Oberleas (185),

studying phytate-mineral complexes, sug

gested that the chelating properties of

phytate may induce a w ide variety of min

eral def iciencies depending on which ele

ment first becomes limiting. Chemical

studies indicate that phytate decreases zinc

avai labi li ty by forming an extremely insol

uble calcium-zinc-phytate salt at the pH

ranges found in the upper smal l intestine

where most minerals are absorbed (141,

187, 313). Judging from the information

now available on the deleterious effect of

phytate in cereals on optimum growth and

protein uti li zation, some amino acid sup

plementation programs may not be fully

successful without careful consideration of

the possibility of abnormal zinc metabolism

associated with cereal diets.

O ther factors that possibly may affect

the availability of zinc include the zinc

status of the organism, geophagia, the pres

ence of chelating agents (other than phy

tate) , and vi tamin D.

Zinc sta tus. H eth et a l. 96), wor kin g

with rats, and Prasad (222), studying hu

man subjects, observed that the proportion

of oral ly administered zinc lost in the feces

decreased when the animals or human sub

jects were zinc def icient. Prasad et al . ( 225 )

suggested, however, that this increased ap

parent absorption was probably due to de

creased excretion of zinc rather than to the

increased true absorption.

G eoph a gia . Minnich et a l. 171) found

that clay from T urkey inhibited iron ab

sorption in human subjects. Nearly al l sub

jects with severe nutritional dwarfism

studied in I ran gave a history of eating

large amounts of clay for many years. Be

cause the evidence indicated that zinc de

f iciency was the basic cause of this dwarf -

ism syndrome, it was logical to suspect that

Iranian clay might hinder zinc absorption.

Furthermore, when a solution of 6BZnwas

mixed with this clay, 97% of the radio

activity was removed from the solution.

W hen, however, I ranian clay was fed to

zinc-deficient rats, it proved to be a life-

saving source of zinc (274). A plausible

deduction, therefore, is that the subjects in

I ran may have sought zinc through the

ingestion of clay.

C hela ting a gents. C on sider able wor k ha s

been reported on the effect of chelating

agents on zinc absorption. Most of these

studies were carried out in animals and

have been summarized by V ohra and

K ratzer (314) and Maddaiah et al. (141).

The ability of EDTA(ethylenediaminetetra-

acetic acid) to complex readily with zinc

has led to i ts use in removing radioactive

zinc f rom the body (279 ) .

Vita min D . Wor ker a nd Mig icovsky 32 9)

found that the movement of zinc into the

bones of chicks was enhanced by vi tamin

D. They suggested that the site of the

vitamin's ef fect on zinc metabol ism might

be in the absorption mechanism. Later

Becker and Hoekstra (8) observed in

creased absorption of dietary zinc in rats

treated with vi tamin D. Addi tional studies

with 65Zn convinced them that the in

creased absorption of zinc was not the pri

mary response but rather was the resul t of

an increased need for zinc secondary to in

creased skeletal growth.

E xc re tio n o f zin c

McCance and Widdowson (153) found

that regardless of whether zinc enters the

body oral ly or parenteral ly, i t is excreted

almost whol ly via the feces. Animal experi

ments have shown that fecal excretion is

chiefly by way of the pancreatic juice re

gardless of the route of zinc intake. Negl i

gible amounts are excreted by the liver

into bi le (153, 267) . Urinary zinc excretion

in normal individuals and those with dis

eases was summarized by Roman (250).

I n normal subjects, most of published

means ranged between 400 and 600 /Â¿g/24

hours.

Steele (284) recently reported data sug

gesting that renal handling of zinc is dif

f erent f rom that of other divalent cations.


13/34


357

For instance, when saline-loaded subjects

were infused with a NaCl solution, zinc ex

cretion decreased, whereas that of calcium

and magnesium increased. Furthermore,

when a diureti c, either ethacrynic acid orfurosemide, was administered, urinary zinc

concentration decreased significantly while

the concentrations of calcium and mag

nesium increased. The mechanism govern

ing renal excretion of zinc is not clear.

Increased urinary zinc excretion (zinc-

uria) has been reported to accompany

nephrosis (52), diabetes (36, 154, 215),

postalcohol ic hepatic cirrhosis (229, 291,

307), and porphyria (213, 267). McCance

and Widdowson (153) found the urinary

zinc excretion in two patients with albu

minuria to be 3.3 and 2.0 mg/dayâ€”about

seven times the amount excreted by thei r

healthy subjects.Spencer and Samachson (282) noted

that urinary zinc excretion rose to high

levels during total starvation in extreme

obesi ty. They found a tenfold increase in

dai ly excretion during thei r ten 6-day bal

ance periods. Despi te the urinary losses,

plasma zinc levels did not change.

Recently Fel l et al . ( 54) studied urinary

zinc excretion by two patients after surgery

for total hip replacement. They adminis

tered 05Znto the patient in suf ficient time

before surgery to al low i ts incorporation

into the muscles. They found large in

creases in urinary excretion of 66Zn, total

zinc and nitrogen af ter surgery. The excre

tions rose to a maximum about 10 days

postoperation. The close correlation be

tween the excretion of 65Znand total zinc

suggested that the zinc was being with

drawn mainly from the skeletal muscles.

Because urinary total zinc was also closely

correlated with urinary nitrogen, Fel l et al .

(54) suggested that urinary zinc may pro

vide an index by which to estimate muscle

catabolism.

Bin din g o f zin c to ser um p ro tein

Early work by Laurel on zinc binding

was summarized and amplified by Vikbladh

in 1951 (312). T he portion of plasma zincbound to albumin was described as loosely

bound, whereas that associated with the

globulin fractions was more tightly bound

(312) . The relative amounts of loosely and

tightly bound zinc are at present some

what controversial, but it appears that most

is in a tightly bound form. The loosely

bound zinc complex according to Vikbladh

(312) is concerned with zinc transport.

These f indings on zinc binding with serumproteins have been confirmed by others

(22, 203, 305). The identi ty of the fraction

to which zinc is f irmly bound has been the

subject of several studies. Surgenor et al .

(293) reported that zinc could combine

w ith a ÃŸ iglobul in ( transferrin ) in vitro.

Later Boyett and Sul livan (22) f rom studies

of the distribution of protein-bound zinc

suggested that transferrin and alpha-2

macroglobulin may have an important role

in internal zinc exchange. Parisi and V allee

(203) isolated alpha-2 macroglobul in and

found that it contained 30 to 40% of the

total serum zinc. They suggested that

alpha-2 macroglobulin is the principal zinc

metalloprotein in human serum.

Prasad and Oberleas (227) using 86Z n

incubated serum found that from 2 to 8%

of the total serum zinc was ultraf il terable.

In their in vitro studies they found also that

several amino acids, specifically histidine,

glutamine, threonine, cystine, and lysine,

when added to predialyzed serum, in

creased the amount of ul traf il terable 65Zn

several fold. They suggested that this amino

acid bound fraction of zinc may play a

significant role in biological transport.

F a c to r s i nfl ue nc in g t he c on ce nt ra t io n

of zinc in pla sma

As noted in table 3 the mean plasma

zinc concentration reported in recent years

has been reasonably constant. M ost of these

results were derived by atomic absorption

spectrophotometry, but the neutron acti

vation, f luorometric, and dithizone meth

ods have given similar values. The use of

polyethylene materials, which became

avai lable in the 1960's, has undoubtedly

aided in el iminating sources of contami

nation.

L ittle work has been done on the ef fects

of age or sex differences on plasma zinc

levels. Somewhat higher levels have been

found in newborn infants and children

than in adults (11, 143), but another report

showed contradictory data (85). N o sig

nificant differences between males and

females have been reported (85) .

I nconclusive data exist on the effect of


14/34

358

J. A . HALSTED, J. C. SM ITH, JR. AN D M . I . IRW IN

meals on plasma zinc concentration. Davies

et al. (41) reported that the zinc level de

creased fol lowing intravenous or oral glu

cose loading, but this has not been con

firmed. In another study (149), the effectof a meal containing 3.92 mg of zinc on the

plasma zinc level was negl igible in 10 nor

mal individuals who had tasted 12 hours

prior to eating the meal. There are few

data on the ef fect of fasting on the plasma

zinc levels of man. A s noted previously,

Spencer and Samachson (282) reported no

change in plasma level in one obese patient

treated by total starvation despite a tenfold

increase in urinary zinc excretion.

Many factors, including pregnancy and

oral contraceptives, various diseases, and

stress, induce the lowering of the plasma

zinc concentration (41, 85). Whether this

ref lects zinc def iciency, a redistribution ofzinc, or an emergency cal l on avai lable ci r

culating zinc loosely bound to albumin is

not clear. Wacker et al. (316) in 1956

noted that serum zinc concentration was

lowered af ter an acute myocardial infarcÃ¬.

L indeman et al. (134) also noted that the

zinc level fel l rapidly after extensive sur

gery, myocardial infarcÃ¬,and acute infec

tions. I t rose to normal during convales

cence. Similarl y, after injection of endo-

toxin in man5 and rats (208) a sharp fall

in serum zinc level was noted. A s the in

fection subsided, the serum zinc level re

turned toward normal (208, 210, 319). I n

pulmonary tuberculosis and in varioustypes of chronic l iver diseases the plasma

zinc level was usual ly depressed, rising

toward normal as the patient recovered

(85).

Observations with burned and wounded

rats suggested to Strain et al. (288, 289)

that zinc was essential for wound heal ing.

O ther investigators using rats (258, 126,

191), cattle (166) , and hamsters (289) also

observed improved heal ing when zinc was

administered. Sandstead et al . ( 258) sug

gested that collagen formation is impaired

in conditions of zinc def iciency. Recently

Stephan and Hsu (285) found that in zinc-

defi cient rats, there was decreased DNAsynthesis as indicated by reduced thymi -

dine-methyl-3H incorporation into the DNA

of skin. They suggested that this observa

tion of impaired skin D NA synthesis to

gether with a previous observation of de

creased incorporation of 14C-labeled amino

acids in skin proteins of zinc deficient rats

( 105) might indicate a molecular basis for

the relationship of zinc to heal ing (285).

At present there is conf licting evidenceon the effect of zinc on wound healing in

human subjects. Pories and Strain (219)

in 1966 reported that, with oral administra

tion of zinc sul fate heptahydrate, heal ing

time was apparently decreased. Thei r ob

servations included the measurement of

wound volume during the healing of piloni-

dal sinus tract excision wounds in two

unsupplemented patients and one zinc-

supplemented patient. When the work was

extended to include 20 young men (217,

218), 10 of whom received zinc supple

ments, healing time was significantly re

duced in the supplemented group (45.8 vs.

80.1 days) . Studies on heal ing of leg ulcers

(72, 77, 78, 113, 266) also indicated sig

nificantly higher rates of healing in pa

tients to whom zinc was administered as

compared with nonsupplemented controls.

Other investigators, however, failed to find

that healing was accelerated after zinc

supplementation. Brewer et al. (23), for

instance, in a double blind study with 14

patients with decubitus ulcers did not f ind

any difference in healing time between

zinc-treated and control patients. Likewise,

M yers and Cherry (181), studying 51

patients, 36 to 80 years old, w ith chronic

leg ulcers, and Barcia (5), w ith 20 young

men who underwent surgical treatment forchronic pilonidal disease, failed to show an

improvement in healing time in those pa

tients who were treated w ith zinc. Pories

and Strain (220) in reviewing these studies,

suggested that the patient's initial zinc

status may inf luence his response to zinc-

therapy. HolbÃ¶Ã¶kand Lanner (78), for

instance, observed significant differences in

heal ing time between zinc treated and un

treated patients in a group whose indi

vidual serum zinc levels were less than

110 /ig/100 ml but not in a group whose

serum zinc levels were 110 /Â¿g/100ml or

higher.

For many years there has been interestin a possible relationship of zinc to mal ig-

6 Smith, J. C., Jr., M cDaniel, E. G., M cBean, L. D.,

Doft, F. S. & Halsted, J. A . (1971) Effect of micro

organisms upon zinc metabolism. Proc. W estern

Hemisphere Nutr. Cong., Bal Harbour, Florida

(Abstr.).


15/34


359

nant disease. Ross et al. (256), using 65Zn

in patients with neoplastic disease, found

that uptake of z inc in leukemia leucocytes

was about one-half that of normal sub

jects. The zinc content of blood consti tu

ents in Hodgkin's disease has been reported

to be low (4). Davies et al. (42) and

M organ (176) reported low plasma or

serum zinc levels in patients treated for

bronchogenic carcinoma. Smith et al. (275),

however, found no differences in serum

zinc levels between patients with untreated

bronchogenic carcinoma and normal con

trols. DeWys et al. (45) found that Walker

256 sarcoma implanted in zinc-def icient

rats grew at a markedly reduced rate com

pared with ones implanted in control , pair-

fed rats. These results suggest an increased

zinc requirement for tumor growth.

The wide variety of pathological statesin which plasma zinc concentration has

been found to be depressed suggests that

there may be several mechanisms involved

whereby zinc metabolism is altered in

disease. On the other hand, there also may

be a fundamental mechanism common to

all. I t is attractive to speculate that zinc is

required rapidly for enzyme formation or

protein synthesis when bodily insults occur,

and that the zinc that is loosely bound to

albumin is immediately avai lable for these

purposes. Of interest is the fact that the

zinc level rarely falls below 30 to 35% of

the normal. T his may correspond to that

amount loosely bound to albumin.

Re la tio ns hip o f zin c to e nd oc rin e fu nc tio ns

Endocrine abnormal ities in human zinc

def iciency have been studied only in cases

of nutritional dwarfism reported from

Egypt (34, 226) . Somewhat ambiguous re

sults were obtained in assessing growth

hormone, gonadotropin, adrenocortical, and

testicular function. In human pregnancy,

plasma zinc concentration is usuall y de

pressed to about two- thirds that of normal

(114). I n a study with rats, M cBean et al.

( 151) conf irmed the f indings, previously

observed in women (82) , that depression

of plasma zinc concentration occurs when

contraceptive hormones are fed. McBean

et al. (151) found that the estrogen com

ponent of the contraceptive compounds

was responsible for the plasma zinc lower

ing effect. A dditional work is needed to

establish more precisely the interrelation

ships between zinc and endocrine function.

In te rr ela tio ns hip s with o th er m in er a ls

C a lcium. Tu cker a nd Sa lmon 302) fir st

demonstrated that increasing the calcium

content of practical diets for swine en

hanced zinc-deficiency symptoms (skin

lesions and growth retardation) . Because

the basal diets fed were rel atively high in

zinc, 34 to 44 ppm, this was an apparent

demonstration of the antagonism of cal

cium to zinc. Numerous investigations with

swine using diets containing plant protein

have conf irmed the calcium-zinc antago

nism (35, 130, 131, 135, 136, 183, 286). I n

contrast, when swine were fed animal pro

tein diets the deleterious ef fect of calcium

on zinc uti li zation was not demonstrable

(10, 324). I n 1960 (57) Forbes reviewedthe interrelationship of zinc and calcium.

As pointed out by Forbes (58, 59) and

more recently by O'D ell (192), the con

flicting results regarding the antagonistic

effect of calcium toward zinc can be ex

plained by the presence of phytate. That

is, excess calcium in the presence of phytate

(which accompanies plant but not animal

protein) results in decreased zinc absorp

tion, enhancing zinc def iciency. The inter

relationships of calcium, zinc, and phytic

acid in promoting growth of pigs are

shown in figure 1.'

I t is doubtful whether the calcium an

tagonism to zinc absorption plays an important role in a well-balanced diet con

taining animal protein. Spencer et al . (283)

could not demonstrate a calcium-zinc an

tagonism in human subjects fed meat as a

protein source when calcium was varied in

the diet tenfold. However, the antagonism

may be a factor in diets high in plant pro

tein, i.e., beans, peas, and cereal grains.

C a dmium. C a dmium a nd zinc ha ve sev

eral similar chemical properties, including

a usual coordination number of 4, tetra-

hedral conf iguration, and isoelectronic

valence shells. In 1957 Pafizek (204)

showed that the destructive effect of in

jected cadmium upon testicular tissue

could be al leviated by zinc, and suggested

that the injury was due to interference with

9 By permission of the author B. L. O'D ell and the

publ isher American Journal of C linical Nutri tion.


16/34

36 0

J. A. HALSTED..J. C . SMITH, JR. AND M. I. IRW IN

zinc function. Gunn et al. (74, 75), and

Mason and Young (146) confirmed the

antagonistic zinc-cadm ium effects on tes-

t icu lar function .

In hum an nutrition, the zinc-cadm ium

interrelationship has not been demon

strated. Schroeder et al. (264) have elab

orated on the close association between

cadm ium and zinc. Cadm ium , a nonessen-

tial elem ent, is invariably associated w ith

zinc in both geological and biological

matter.

Copper. In animal studies, excessively

high levels of zinc resulted in interference

w ith copper m etabolism (70, 142). Studies

such as those by Hoefer et al. (101) and

Wallace et al. (317) indicated that the

severity of parakeratosis in sw ine could be

alleviated by either zinc or copper, al

though zinc was usually more effective.

Ritchie et al. (246) reported that, in addi

tion to preventing parakeratosis in swine,

zinc gave protection against copper

toxicity.

The plasma zinc concentration was de

creased but copper concentration was in

creased in pregnant women (114) and in

those taking oral contraceptives (82). A t

present the significance of these observa

tio ns is n ot u nd ers to od .

W hen a diet composed entirely of meat

was fed to rodents, an anemia developed

that was responsive to copper (73, 174,

175). It was proposed that this meat

anem ia resulted not only from a relative

excess of zinc over copper present in m eat

but also from the lower calcium levels

found in m eat. The m eat anem ia, however,

could be reduced or prevented by cook

ing the meat (174). This suggests that it

was not due sim ply to a high zinc-copper

ratio but that a heat labile factor may have

been involved. Hoekstra (102) has re

v iewe d th is su bje ct b rie fly .

Others. In 1958 Sivarama Sasty and

Sarma (270) suggested that iron metab

olism was affected by toxic levels of zinc.

In addition, decreased concentrations of

iron in the liver were reported by Cox and

Harris (37), Magee and Matrone (142),

and Kinnamon (120) when rats were fed

to xic le ve ls o f z in c.

A n interaction of zinc and m olybdenum

was suggested by the investigations of

Gray and Ellis (71).

80 070 0

â€¢600-Cn-Â¿

500-2

400-1

300-200-100-il1

â€ ”Protein

S CCP.A.,

added, 0 0 0 1.4nmiJ^i>ifiC

C1.4

1.4Ã‡a,

1.5 1.5 0.8 0.8 1.5.5Zn,

ppm 25 14 141414

11 4

Fig. I Effect of phytic acid on growth rate of

pigs fed diets based on soybean (S) or casein

(C) with varying levels of calcium and zinc.

Phytic acid (P.A .) was added to the casein diet.

Reproduced from Amer. J. Clin. Nutr. (1969)

22, 1316, by permission of the author and pub

lisher.

T he interrela tionships of zinc w ith oth er

m inera ls are obviously not lim ited to single

elements, i.e., zinc-copper or zinc-cad

mium . There have been some reports in

volving a sim ultaneous interaction of sev

eral m inerals (99, 136, 177, 243, 287). No

inform ation on su ch m ultiple in teractionsin hu mans w as found.

I nt er re la ti on sh ip s i ci th v it am ins

Vitamin A. Early studies on dark adap

tation indicated that ano ther nutrient m ight

be nece ssary fo r vitam in A u tilization (206).

Observations of reduced plasm a zinc con

centration in cirrhotic patients (85) sug

gested that this necessary nutrient m ight

be zinc. Studies with animals tended to

support this hypothesis. S tevenson and

Earle (286), for instance, reported that

zinc-deficient sw ine had depressed serum

vitam in A levels. These levels did not re

turn to normal even after massive oraldoses of vitam in A. Later, Saraswat and

A rora (260) reported that zinc supplem en

tation was necessary for maximum effi

ciency of vitam in A therapy in lambs that

were deficient in both zinc and vitam in A.


17/34


361

M ore recently, Smith et al. (276) found in

rats that zinc was necessary for the mobili

zation of vitamin A from the liver into the

plasma. I n addition, retinal reductase, an

alcohol dehydrogenase of the retina in

volved in the metabolism of vitamin A , is

most probably a zinc metalloenzyme (307).

Vita min D . In 1 9 58 Whitin g a n d Be zea u

(324) reported that vitamin D decreased

the absorption and retention of zinc when

diets low in zinc were fed to pigs. W asser-

man (320) observed no significant change

in 8SZn absorption from the ligated du

odenum when rachitic chicks were fed

vitamin D .̂ As noted previously (page 356),

however, W orker and M igicovskv (329)

with chicks and Becker and I loekstra (8)

with rats observed that 7,inc absorption

and zinc uptake in the bones were en

hanced when vitamin D .Â ¡was fed. A posi

tive effect of vitamin D on zinc metabolism

was observed by others also (33, 118, 145).

Becker and Hoekstra (8) suggested that

the effect of vitamin D was primarily on

calcification and skeletal growth and that

the increased uptake of zinc bv the bone

was only a secondary effect. Chang et al.

(33), however, concluded from studios in

which bone growth and calcification of

rats were stimulated by either vitamin D

or protein that vitamin D probably exerts

an effect on zinc metabolism that is not

related to calci fi cation or bone growth.

Ribo fla vin. In 1 9 4 1, F o llis et a l. 5 6)

reported histological corneal lesions in

zinc-deficient rats and suggested that they

were apparently similar to lesions de

scribed by Bessey and Wolbach (17) in

uncompli cated ri bof lavin defi ciency in rats.

This was the f irst suggestion of an apparent

similarity in the effect of riboflavin and

zinc def iciencies upon speci fi c tissues. More

recently, French investigators noted a

similarity in the effects of riboflavin and

zinc deficiency in rats (221). Specifically,

in deficiencies of either zinc or riboflavin,

simi lar bony mal formations were observed.

In addition, fetuses from riboflavin-de-

ficient females had lower body zinc con

tents than fetuses from ribof lavin-sufficient

mothers.

Z INC DEFICIENCY

Animals

I n animals, zinc deficiency has been de

scribed in rats (300), mice (43), swine

(302), chickens (193), turkeys (124),

cattle (162), goats (167), lambs (200),

dogs (248), Japanese quail (62), rabbits

(69), squirrel monkeys (138), hamsters

(20), and guinea pigs (152).

The signs and svmptoms of zinc de

ficiency are markedly similar in different

animals. T hey include dermatitis, emaci

ation, alopecia, ocular lesions, testicular

atrophy, retarded growth, and anorexia.

A ll of these conditions with the possible

exception of testicular lesions are reversed

by zinc supplementation (6,161).

Mal formati ons of embryos and/or f etuses

due to zinc deficiency were reported for a

number of species. Blamberg et al. (19)

reported gross malformati ons involving the

brain, vertebrae, limbs, beak, and head of

chick embryos produced from eggs laid

by zinc-def icient hens. K ienhol z et al. ( 119)

confirmed these findings. H urlev and co-

workers (108-111) demonstrated congeni

tal malformations in rat fetuses delivered

f rom zinc-defi cient f emales. The malforma

tions included a high incidence of short or

missing mandibles, clubbed feet, fused or

missing digits, cleft palate, and brain ab

normalities. Related studies bv A pgar (3)

and Hurley and Sw enerton (112) indicated

that female rats fed a zinc-deficient diet

during pregnancy cannot mobilize zinc

from tissue stores in amounts sufficient to

supply the needs of normal fetal develop

ment. Swenerton et al. (294) suggested

that the high incidence of gross congenital

malformations resulting from zinc defi

ciency may be caused by impaired DNA

synthesis. The evidence of a relationship

between zinc deficiency and congenital

malformations in the rat was reviewed in

1967 (2). T o our knowledge no congenital

malformations due to zinc deficiency have

been reported in humans. I t is of interest,

nevertheless, that a brother of one patient

with the dwarfism syndrome originally re

ported in 1961 (224) had pronounced bony

abnormal ities as well as extreme dwarf ism.

J


18/34

362

J. A. HALSTED, J. C. SM ITH, JR. A ND M . I . IRW IN

Behavioral impai rment was reported in

zinc-def icient adult rats (28, 29) . Perform

ance tests indicated that zinc-deficient rats

were inferior to zinc-suf ficient animals in

both learning ability and emotional sta

bility.

M a nâ € ” c li ni ca l a n d m et a bo li c fe a tu r es

I n man, the clinical aspects of zinc de

ficiency are similar to those described

above for animals. In summary, they consist

of severe iron def iciency anemia, hepato-

splenomegaly, short stature, infantile testes,

open epiphyses, spoon nai ls, f requently a

history of geophagia, and rough skin with

hyperpigmentation.

An interesting feature of the syndrome

is the rather prolonged rise in alkaline

phosphatase (a zinc-dependent enzyme)

which occurs when zinc is administered.

This could be due ei ther to a regeneration

of enzyme activity or to an increase in

bone grow th. I t was at first thought that

the syndrome was limited to males be

cause considerably higher concentrations of

zinc have been found in the testes than in

the ovaries. H owever, two well-docu

mented cases in females were included in

a recent report f rom Iran (84).

Ronaghy et al . ( 252) conducted a 6-year

follow-up study on the I ranian dwarfs in

whom zinc deficiency had first been sus

pected (224) . They found that the patients

remained well if they continued to eat a

wel l-balanced diet including meat. I f , how

ever, they resumed the vil lage diet in which

unleavened bread was predominant, their

symptoms of zinc deficiency reappeared.

Reinhold et al. (240) measured zinc,

calcium, phosphorus, and nitrogen intake

and output of 13 Iranian apparently healthy

vi llagers in a metabol ic ward ( table 4) . The

subjects were studied over a 6- to 7-day

period during which a well-balanced diet

was fed. The zinc data showed a wide

range of retention (â€”6.7 to 61.4%) . More

than half of the group had positive reten

tions greater than 25%. This observation

suggested to Reinhold et al. (240) that

these villagers had been depleted of zinc

previously.

Sandstead et al. (259) and Smit and

Pretorius (273 ) found very low serum zinc

levels in kwashiorkor. The latter workers

also found low urinary zinc excretion. A l-

TABLE 4

Zi nc b al an ce s tu di es o f a d ult I ra n ia n vil la ge rs 1

Subject

number12345678910111213SexM M M FM M FM FM FM FAgeVr3225382535473030243722

aiakg/dayN.A.0.070.070.18-0.060.03N.A.0.240.080.

15.4%-6.7-9.712.413.014.923.125.226

From Reinhold et al . (240) . ' AI weresufficiently healthy

to carry out normal activi ties of a v il lager . >Not avai lable

Alean for a 6 - to 7 -day period during which intakes in food

andiosses in excreta were measured. The hospital diet provided

2 400 calories, 75g ofprotein (15% from pulses, 21% from meat,Â¿8%from bread, and 36% from milk and cheese) , 80 to 120 e

of f at f rom butter and corn oi l, 24.6 mg of z inc, 1,031 mg of

calcium, and 1,513 mg of phosphorus.

though kwashiorkor is an extreme example

of protein-calori e malnutrition, zinc de

ficiency may be a secondary factor. To

date, littl e account of this possibili ty has

been taken.

Zinc deficiency, secondary to intestinal

malabsorption, recurrent infection and hy-

pogammaglobulinemia, has been reported

by Caggiano et al . ( 27) . One suspects that

zinc deficiency might be implicated in

growth retardation that may occur in cystic

f ibrosis, inf lammatory bowel disease, and

other malabsorption states, but these have

not yet been adequately investigated.

Reports by Henkin et al. (93-95) and

Schechter et al. (261) indicated that a de

crease in acuity of taste and/or smell may

occur spontaneously (idiopathic hypo-

geusia, hyposmia) or af ter the administra

tion of i/-penicillamine. These investigators

reported that this disorder may be cor

rected by the administration of ei ther cop

per or zinc.

Recently Hambidge et al . ( 87) reported

that 10 children over 4 years old in the

Denver area had hair zinc concentrations

of less than 70 ppmâ€”a level simi lar to that

reported for Egyptian adolescents suffering

f rom symptomatic zinc def iciency (290) .

Seven of the 10 children had a history of

poor appetite and eight had heights that


19/34


6

fell on or below the 10th percentile when

plotted on growth charts based on data

compi led by the Harvard School of Publ ic

Health and the Iowa Child W elfare Re

search Station. O f six children whose

taste acuity was measured, five showed

evidence of lowered acuity. A fter 1 to 3

months with dai ly dietary zinc supplemen

tation ( 1 to 2 mg ZnSO4/kg body weight ),

the taste acuity returned to normal and hair

zinc concentrations increased in the five

chi ldren. These chi ldren were from a group

of 338 subjects who were apparently

healthy Caucasians in the upper and mid

dle socioeconomic class.

Eggleton in 1938 (47) commenting on

a possible role of zinc defi ciency in beri

beri, said: A ttention is drawn, however,

to the fact that a diet producing beriberi

may supply minimal quantities of zinc,

and presumably also copper and manga

nese. To what extent shortage of minor ele

ments may be the cause of certain symp

toms usually associated with beriberi

remains to be shown, but i t is considered

possible that this shortage may account, in

part at least, for the pecul iar appearance of

the hair, the dry skin and the abnormal

f inger and toe nails . . . The integumentary

changes to which Eggleton referred also

are found in zinc-def icient dwarfs as wel l

as in animals with experimental or spon

taneous zinc def iciency. I t seems possible

that spoon nails (koilonychia) , long attrib

uted to chronic iron deficiency, might

actually be the result of associated zinc

deficiency.

PA RA M ET ERS FOR A SSESSI NG

ZINC STATUS IN M AN

Parameters that have been used in as

sessing zinc status in man are as fol lows:

1) plasma or serum concentration, 2) hai r

zinc concentration, 3) metabol ic balance

of zinc, 4) isotope turnover studies, 5) ex

cretion of urinary sulfate, and 6) response

of growth and sexual development to zinc

supplementation.

The simplest method is measurement of

plasma zinc concentration. As discussed

previously (pages 357-359), there are many

factors that influence the plasma zinc

level so that a lower than normal value

cannot be said to be more than suggestive

of zinc deficiency. I n some instances di

rectly after a stressful situation, such as the

injection of endotoxin, a myocardial infarct,

surgery, and other trauma, a very rapid

drop in the plasma zinc level occurs. I t ap

pears unl ikely that such a transiently low

level occurring so rapidly is a sign of zinc

deficiency. Nevertheless, demonstrable zinc

def iciency in man is accompanied by a low

plasma zinc concentration.

M easurement of a specif ic zinc-binding

protein, alpha-2 macroglobul in, possibly

may become a useful tool in assessment of

zinc def iciency. Boyett and Sul livan (22)

found a slight increase in this globulin

fraction in patients with alcoholic cirrhosis

as compared with normals. McBean et al .,7

studying a variety of diseases, found no

significant correlation, however, between

serum zinc and alpha-2 macroglobulin.

Hair zinc concentration has been studied

by several i nvestigators w ith varying re

sults (table 5). McBean et al. (150) could

find no correlation between plasma and

hair zinc concentration in growth-retarded

6- to 11-year-old chi ldren. These subjects

had lower than normal plasma zinc levels,

but hair zinc concentrations were normal .

T hey concluded that the zinc content of

hair was not a reliable indicator of body

zinc metabolism at the time of sampling.

Others ( 121, 212 ) have shown that various

factors, including age, af fect the zinc con

centration in hair.

Reinhold's zinc balance studies on Iranian

villagers (240) point to the value of thebalance method (table 4). H is data indi

cate that a zinc balance study, cumbersome

though it may be, is likely to shed light on

possible subclinical zinc deficiency.

Isotope turnover studies in man are

scarce, probably because the half-life of

65Znis 245 days making it an unacceptable

procedure except in patients with a l imited

lif e expectancy. Richmond et al. (245) re

ported that the biological half-life of this

isotope in human subjects averaged 154

days. Z inc isotope turnover studies have

been carried out by Ross et al. (256),

Prasad (225), and Spencer et al. (280, 281,

283) . Ross et al . ( 256) injected 65Zn intra-

7 McBean, L. D., Smith, J. C, Bernard, B. H. &

Halsted, J. A . (1972) Serum zinc and alpha-macro-

globulin concentration in patients with varimiÂ«dis,

orders. Proc. I X I nt. Congr. N utr., M exico City,

M exico, September 2-9, 1972 (Abstr.).


20/34

36 4

J. A . HALSTED, J. C . SMITH, JR. AND M. I. IRWIN

TABLE 5

Ha ir z in c concent ra ti on a s r epor te d b y var ious i nv es ti ga to rs

InvestigatorEggletonReinhold

etl.Strain

etl.Eininians

etl.KlevayMcBean

etl. 'MeanisD.

'Reference(48)(241)(290)(50)(121)(150)Mean

±SE.Year193819661966196719701971Â»E.S.;Subjects11

Chinesedults19

m ale a du lt Iran ian v illag ers

2 0 m ale co ntro l ad ult s ub jec ts

(Shiraz,ran)10

z in c d eficien t E gy ptian m ale d wa rfs

16 to 20 years

8 zinc-treated dw arfs 16 to 20 years

12 norm al Egyptians 27 to 40 years

6 norm al R ochester residents 23 to 37ears12

h ealth y villa ge ch ild ren 1 1 y ea rsld31

Panam anian males 6 to 10ears14

norm al adults (W ashington, D . C .)

75 Iranian village children 6 to 12 years

(g rowth retarded )Ha ir

zincppm255139Ãœ6.41

181±36.3 '54

Â±2121

Â±5s

103Â±42

120Â±s163Â±222127

Â±49'176Â±37l

199Â±22'MethodDithizoneZincon

ZinconE.S.Â»E.S.

E.S.

E.S.A.A.S.Â«A.A.S.A.A.S.A.A.S.emission

s pec tr og raphy. ' A .A .S. ; a tomic abs orpt io n s pec tr opho tomet ry .

venously into patients with m alignancy,

finding that it disappeared rapidly from

th e p lasm a. P rasad's stu dies indicated that,

in zinc deficiency, plasma zinc turnover

w as increased, the 24-hour exchangeable

zinc p ool w as decrease d, cum ula tive e xcre

tion of 66Zn was low , and 6-hour plasma

65Zn disappearance was rapid. Spencer's

reports w ere lim ited to m etabolic aspects

of zinc without consideration of zinc de

ficiency.

Hsu and Anthony (104) shewed that, in

zinc-deficient rats, urinary sulfate is

markedly increased after an injection of

cystine-35 S. S om ers a nd U nderw ood (277)

co nfirm ed the significantly ele vated su lfur

excretion in zinc-deficient lambs. The

m echanism suggested by H su and A nthony

( 1 04 ) w as th e in ab ility o f th e z in c-d efic ie nt

anim al to utilize sulfur-containing am ino

acids for protein synthesis, w ith conse

quent excretion of sulfate. No reports of

sim ila r w ork in m an w ere found .

At present the critical test for zinc de

ficiency in man or anim als is a definitive

response to oral supplem entation w ith zinc

under controlled conditions. The data for

p rim ary z in c d efic ie nc y in th e c ere al-e atin g

populations of Iran and Egypt now appear

unequivocal. N o reports of sim ilar studies

in other geographic locations have been

found.

Z IN C T OX IC IT Y

In comparison with the trace elements

lead, cadm ium , arsenic, and antim ony, zinc

is relatively nontoxic. Many of the toxic

effects ascribed to zinc by early investi

gators may be due actually to other con

taminating elements such as lead, cad

m ium , or arsenic (90). Zinc is noncum ula

tive, and the proportion absorbed is

thought to be inversely related to the

amount ingested (64, 96). Vomiting, a

protective m echanism , occurs after inges

tion of large quantities or after extended

exposure to fum es containing zinc. In fact,

an oral dose of 2 g of zinc sulfate (454 mg

of zinc) has been recommended as an

em etic (155). In addition to severe vom it

ing, the symptoms of zinc toxicity in hu

m ans include dehydration, electrolyte im

balance, stom ach pain, nausea, lethargy,

dizziness, and m uscular incoordination.

A cute renal failure caused by zinc chloride

poisoning was reported by Csata et al.

(38). The symptoms occurred within 3

hours after large quantities of zinc were

ingested.

There are reports in the literature indi

cating that the zinc content of acidic food

in contact w ith zinc-coated (galvanized)

containers for long periods possibly may

rise to toxic levels (24, 30). Toxic symp

toms were observed also after the volun

tary ingestion of 12 g of elemental zinc


21/34

RESEARCHON ZINC REQUIREM ENTSOF M AN

365

over a 2-day period (179). Death is re

ported to have occurred after the ingestion

of 45 g of zinc sulfate ( 1 99 ). T oxic symp

toms, such as pulmonary distress, chi lls,

and fever, may be caused also by inhalation

of fumes or dust containing high levels of

zinc (201). T his so-called metal-fume

fever usually has been seen in industrial

workers such as welders of galvanized

metal.

Numerous studies on the toxici ty of zinc

in lower animals have been summarized

by Van Keen (309).

H UM A N REQU IREM EN TS FOR Z IN C

(T ABL E 6)

The apparent enteroenteric circulation of

zinc makes precise estimation of absorption

and excretion impossible by a simple mea

surement of intake and output. Neverthe

less, the balance method has been the prin

cipal technique used in estimating zinc re

quirements of man. A dult subjects and

school chi ldren have been most studied.

There have been a few observations on

infants and preschool children. No reports

were found on zinc requirements of healthy

adolescents, pregnant or lactating women,

or of the elderly. A ll of the balance studies

with presumably healthy subjects indicated

that urinary zinc excretion was low and

not apparently related to intake. Fecal zinc

excretion tended to fluctuate with intake.

I n the studies with adults, the intakes

varied from relatively low (about 5 mg/

day) to relatively high (about 22 mg/day) .

M cCance and W iddowson (153), for in

stance, reported data on two men and one

woman eating a special ly formulated diet

that provided 4.9 to 6.1 mg of zinc/day.

Zinc analysis was carried out by the

method described by Keilin and M ann(116). D uring dietary periods of about a

fortnight, balances of â€”0.8to 0.0 mg zinc/

day were observed. When the zinc intake

was raised to 9.1 or 13.8 mg/day by add

ing zinc salts or by providing 40 to 50%

of the calories f rom whi te f lour, balances

rose slightly to range from â€”0.1to 2.7 mg/

day. For two subjects, the zinc intake was

increased to 19.6 and 22.0 mg/day by re

placing the white flour with 90% extrac

tion f lour. With these intakes, retentions of

1.1 and 2.6 mg/day were observed. The

possible effect of phytate in the high ex

traction flour on zinc absorption was not

discussed in this report.

I n other studies in which moderate zinc

intakes (about 9 to 14 mg/day) were re

corded, retentions ranged from â€”4.0to 8.8

mg/day. The highest retentions w ith this

range of intake were recorded by T ribble

and Scoular (301). T hey studied a group

of 13 young women, 17 to 27 years old,

eating self-selected diets that were sampled

and analyzed for zinc by H ibbard's dithi-

zone method (97) . Wi th mean intakes that

ranged from 11.8 to 14.1 mg/day, the

young women retained f rom 5.1 to 8.8 mg/

day. Osis et al. (198) on the other hand,

observed much smaller retentions with

simi lar intakes. They studied one subject

whose mean zinc intake during four 6-day

periods ranged f rom 11.7 to 13.1 mg/day.

TABLE 6

C on tr oll ed s tu di es o n h um an r eq uir em en ts fo r zi nc

SubjectsInfante

5 to 8 daysldPreschool

3 to 6 yearsldSchool

children

7 to 12yearsldAdolescentsNumber

of

subjects10

368

0Xumber

of

studies1

13

0Daily

intake10.20

to.19mg/kii3.80

to.874.6

to 9.2

13.85 to 18.35Daily

retention1-0.85

to 0.08

mg/kg-2.70

to.390.5

to 3.8

4.92 Â±2.94Estimated

daily

requirement10.300

to 0.307

mg/kg6.2Reference(32)

(265)(51,

234)

(140)

Adults

men and women6164.9

9.018.0to

6.1

to 14.1

to 22.0-0.8

-4.0

1.0to

0.0

to 8.8

to 8.3(153.(153)

198, 299, 301,

(68, 153, 299)323)

>In rag/day except where otherwise stated.


22/34

36 6

J. A. HALSTED, J. C. SMITH, JR. AND M. I. IRWIN

W ith these i

bioinorganica del zinc

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