Bioinorganica Del Zinc

A CONSPECTUS OF RESEARCH ON ZINC
REQUIREMENTS OF MAN
JAMES A. HALSTED
J. CECIL SMITH, JR.

Trace Element Research Laboratory
Veterans Administration Hospital
Washington, D. C. 20422
and
M. ISABEL
IRWIN
Nutrition Institute
Agricultural Research Service
United States Department of Agriculture
Beltsvie,Maryland 20705
(Pages 345-378)
THE JOURNAL
OF NUTRITION
VOLUME 104,
3, MARCH 1974
NUMBER
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Albany Medical College

Albany, New York 12208
TABLE OF CONTENTS
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352
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354
354
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359
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363
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365
367
368
368
Introduction
Zinc in nature
Development of knowledge about zinc
Early discovery-uses in metallurgy
Chemistry
Biological essentiality
Biological functions
Methods of measuring zinc
Zinc in food
Content in classes of foods
Content of typical meals or diets
Factors influencing content
Manufacturing techniques
Preparation of foods
Metabolic aspects of zinc in human nutrition
Distribution in the body
Plasma and serum
Red blood cells
Leucocytes
Hair
Absorption of zinc
Availability of zinc
Excretion of zinc
Binding of zinc to serum protein
Factors influencing the concentration of zinc in plasma ....
Relationship of zinc to endocrine functions
Interrelationships with other minerals
Calcium
Cadmium
Copper
Others
Interrelationships with vitamins
Vitamin A
Vitamin D
Riboflavin
Zinc deficiency
Animals
Manclinical and metabolic features
Parameters for assessing zinc status in man
Zinc toxicity
Human requirements for zinc
Conclusions
Acknowledgments
Literature cited .
INTRODUCTION
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.
The 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.
ZINC IN NATURE
Zinc 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.
Although
it is unevenly
distributed zinc
in istheubiquitous
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 Apollo 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 from 0.2 to 3.0 ppm
zinc (Apollo 11). Eight rocks returned by
Apollo 12 contained between 0.2 and 4.3
ppm zinc with a mean of slightly 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, less than 15% the mean con
centration of earth soil.
The zinc content of certain land plant
species grown in the United 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 with 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)
-^plantsanimalssoil
or ocean. There is
however a net loss of elemental zinc from
the soil due to natural leaching and erosion
Received for puhllrntion February 7. 1972.
Requests (or reprints should be addressed to M.
Isabel Irwin.
347
The 1934 report by Todd et al. (300)

that zinc was necessary for life in animals
suggested that it was probably an essential
nutrient for man also. Nevertheless the
ubiquity of zinc made it seem unlikely that
alterations in zinc metabolism 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
deficiency 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 Iran by Halsted et
al. (80, 84). In addition, Caggiano et al.
(27), in the United States, observed zinc
deficiency secondary to intestinal malabsorption. More 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 literature on the metabolic aspects
of zinc is extensive (223) and is growing.
Much of our knowledge of zinc has
stemmed however from clinical observa
tions in plant, animal and, most recently,
human pathology. It is still necessary to
rely on indirect information in estimating
human requirements for zinc and in de
lineating those factors that may accentuate
requirements.
This indirect information
comes from all branches of available knowl
edge including
geochemistry
and thebitszinc
content
of the earth's
crust. Many
of
348
J. A. HALSTED,
J. C. SMITH, JR. AND M. I. IRWIN
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,
constant removal of crops without repletion
results in deficiency of zinc in the soil.
Mitchell (172) has calculated that the up
take of zinc by plants is relatively high
compared with 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 zincenriched fertilizers as a method for soil
repletion has been discussed by Viets (310).
DEVELOPMENT
OF KNOWLEDGE
ABOUT ZINC
Cliemistry
Zinc has an atomic number of 30 and an
atomic weight of 65.4. It has a relatively
low melting point of 419.Fifteen isotopes
of zinc have been described ranging from
80Zn to 72Zn. Ten of these isotopes are not
stable. Their half-lives vary from 1.48
minutes (61Zn) to 245 days (8SZn) (98).
Metallic zinc is a good reducing agent, is
amphoteric and will dissolve in mineral
acids and strong bases. Zinc exists in solu
tion only in the oxidized state of Zn2t. The
soluble salts of zinc include chloride, bro
mide, iodide, formate, acetate, sulfate, and
Biological essentiality
Over 100 years ago (1869) Raulin (236),
a pupil of Pasteur, discovered that zinc was
indispensable for the growth of a black
bread mold, Aspergillus niger. This finding
was confirmed in 1911, 40 years later, by
Bertrand and Javillier (16). According to
Bertrand and de Wolf ( 12-15 ) Aspergillus
niger requires zinc in order to synthesize
phenylalanine, tryptophan, and tyrosine as
well as several enzymes. Growth of penicil
lin-producing fungi is greatly retarded by
zinc deficiency of the culture medium ( 60 ).
Evidence indicating that zinc is essential to
the growth of microorganisms has been
summarized recently (330 ).
In 1919 Birckner ( 18 ) reported that egg
yolk, human milk, and cow's milk con
tained zinc and suggested that zinc was of
nutritive value. Shortly thereafter, Sommer
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
common and nearly universal constituent
of animal as well as plant tissues. He em
phasized
zinc wasnotnotgreatly
present
"traces" butthatin amounts
differin
ent from that found for other heavy metals
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
samples and less precise analytical methods
than those used at present. After extensive
and meticulous analyses of tissues from
rats, cats, and man, 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 similar work is that of
Widdowson et al. (325), who reported
human body zinc content to be between
1.4 and 2.3 g.
Some plant diseases have been traced to
zinc deficiency, such as leaf rosette in
Early discoveryuses in metallurgy

Zinc does not occur naturally in a free,
uncombined 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, metallic zinc was
produced by reducing calamine (zinc
oxide plus a small percentage of ferric
oxide) with organic substances such as
wool (88). Ebener of Nrnbergis reported
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 combined with sulfide
in the mineral sphalerite which contains
67% zinc. Other naturally occurring zinccontaining minerals of the earth's crust in
clude zincite, ZnO; smithsonite ZnCO3;
willemite, Zn2SiO4; and hemimorphite,
Zn4(OH)(Si2O7)-H2O.
nitrate (98). The insoluble salts include

carbonate, sulfide, hydroxide, ammonium
phosphate, oxalate, and phytate (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. Metallic zinc is
bluish white.
RESEARCH ON ZINC REQUIREMENTS OF MAN
zinc was essential for growth in birds also.

At 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). This
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). In 1960 and 1961 Prasad et al. (224)
and Halsted and Prasad (83) published a
detailed clinical description of 11 dwarfs
with extreme iron deficiency anemia who
were studied in a hospital at Palliavi Uni
versity, Shiraz, Iran. 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. Daily
oral supplementation
with zinc sulfate
resulted in significantly more rapid growth
and sexual development. These findings
were confirmed in Iran by Halsted et
al. (80, 84) in a study on 17 nutritional
dwarfs. In this study sexual function oc
curred in 224 72 days (mean so) in
nine dwarfs who were fed a well-balanced
hospital diet. In contrast, seven dwarfs, fed
the same diet plus 100 mg of zinc sulfate
daily, developed sexual function in 59 40
days. In 6 months the mean growth incre
ment in the nine dwarfs fed the hospital

diet alone was 4.2 1.9 cm, whereas in
dwarfs who were fed the same diet plus
zinc sulfate, the growth increment was
10.5 3.7 cm.
The extreme degree of dwarfism and
total lack 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 published
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 results. Ronaghy et al. ( 251 )
in Iran administered a complete supple
ment that provided all essential trace ele
ments 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).
It 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.
Biological functions
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.
Keilin and Mann in 1939 (116) and 1940
(117) first showed that zinc was an integral
and necessary component of carbonic anhydrase of red blood cells. Since then, at
least 18 metalloenzvmes have been shown
to contain zinc (202). Several enzvmes
necessary for cellular oxidation, such as
human alcohol dehydrogenase, are zinc
dependent. More complete information on
the importance of zinc in enzymatic func
tion may be found in recent reviews (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).
apples, mottle leaf in citrus crops and prob

ably dwarfing of trees. Agronomists have
traced zinc deficiency in plants to deficient
soils in parts of California and Texas and
in the Ninety Mile Desert in South Aus
tralia. These lands have been reclaimed for
productivity by zinc supplementation (305).
Although 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 findings led to the general prac
tice
supplementing
feeds with
zinc. of
O'Dell
and Savage animal
( 193 ) showed
that
349
350
J. A. HALSTED, J. C. SMITH, JR. AND M. I. IRWIN
METHODS
OF MEASURING
ZINC
Because of the lack of precise analytical

procedures for the determination of zinc by
the earliest workers, zinc was assigned to
the category of a "trace" element. The ele
ment could be detected but not accurately
quantitated. As methods became more sen
sitive, the problem of contamination due
to the ubiquitous nature of zinc became
evident. For examnle, blood for zinc analvsis is easilv contaminated bv the needles
and svringes used for venepuncture. Vacutainers, now widelv used to draw venous
blood, have been shown to be a source of
contamination (86, 91). The use of allplastic polyethylene syringes 1 and certain
stainless steel needles,2 however, prevents
contamination from these sources (81).

Anticoagulants also may be a source of
extraneous zinc.
Early analytical determinations of zinc
relied upon gravimetric and volumetric
methods that were relatively insensitive.
Beamish and Westland (7) have reviewed
such methods.
Among the more modern techniques are
atomic absorption spectrophotometry, emis
sion spectrochemical methods (173), and
X-ray emission spectrography ( 1 ). Of these,
atomic absorption spectrophotometry is at
present the most popular method for ana
lyzing zinc in biological samples (76, 249,
271). Walsh (318), an Australian physicist,
developed the method in 1955 and since
then several commercial instruments have
become available. The general advantages
of this method include: 1) simplicity and
ease of operation, 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
photodetector. Sample preparation is a per
sistent problem in this method because the
sample must be aspirated into the instru
ment. Dry ashing may result in losses of
zinc, presumably due to volatilization
( 296 ). At present, the most popular method
of preparing biological solid material for
atomic absorption analysis of zinc is acid
(wet) digestion (274).
Although many of the techniques for the
analysis of zinc are extremely sensitive,
each method is no better than the stan
dards available. The same standards rarely
have been used by different laboratories.
Biological reference standards are now
available from the U. S. National Bureau of
Standards.3 For an accurate comparison of
zinc analyses between laboratories it is im
perative that a universal reference standard
be used.
ZINC IN FOOD
Content in classes of foods
Classes of foods cannot be rigidly cate
gorized according to zinc concentration beiPeel-A-Way Scientific. So. El Monte, California
91733.
*Monoject-250, Sherwood Medical Industries, Inc.,
Delano. Florida 32720.
U.S. National Bureau of Standards, Washington,
D. C. 20204.
Somers and Underwood (277), in a con

trolled study, found that the output of uri
nary nitrogen and sulfur was significantly
higher in zinc-deficient lambs than in con
trol animals. This observation suggested
impaired protein or amino acid utilization.
The data did not show whether the defect
was due to impaired tissue synthesis or to
increased catabolism.
Hsu et al. ( 104-107 ) recently elaborated
on the relationship of zinc to protein syn
thesis. They showed that, in vivo, the in
corporation of 35S amino acids into organ
and skin protein was significantly altered
in zinc-deficient rats.
The role of zinc in carbohydrate metab
olism is controversial. In 1937 Hove et al.
( 103 ) and more recently Quarterman et al.
( 235 ) reported decreased glucose tolerance
in rats that were zinc deficient. In contrast,
Macapinlac et al. (139) could find no dif
ference in fasting blood sugar, or in glucose
and insulin tolerance curves between zincdeficient rats and ad libitum controls.
Studies by Mills et al. (169) indicated that
zinc influences the membrane transport
and utilization of glucose. Although Hard
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.
Kinetic studies by Weil 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 metabolism has yet
to be elucidated.
RESEARCH ON ZINC REQUIREMENTS
TABLE 1
Zinc contents of selected foods1
Food item
Meat products
Roast beef
Beef patty (raw)
Chicken breast
Chicken thigh
Dairy products
Milk
Cream (half and half)
Zinc
ma/100 g
(wet wt)
6.4
4.7
1.1
2.8
o.:
OF MAN
351
of zinc in colostrum was demonstrated by

Nishimura ( 184 ) who showed that zinc de
ficiency developed in suckling mice de
prived of colostrum. Oral administration of
zinc prevented the deficiency. Mutch and
Hurley4 reported that dietary zinc de
ficiency in lactating female rats resulted in
zinc deficiency in the suckling young due
to a lowered zinc content of the milk.
These studies suggest that consideration
be given to the adequacy of zinc in infant
formulas.
0.40
Content of typical meals or diets

During the course of metabolic balance
studies, Osis et al. (197) analyzed numerous
WheatVegetables
diets. The average total zinc content of 138
diets used in metabolic balance studies
fruitsPeasPotatoesGreen
and
sampled and analyzed over a 4-year period
was 12.2 mg/day. The zinc contents of a
beansCarrotsTomatoesApricotsPeachesPearsApplesauceOrange
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 mg, very similar to
juiceApple
the mean of the experimental diets. Murphy
juice
et al. (178) published analyses of trace
minerals in "Type A" school lunches col
juiceBeveragesTeaCoffeeDecaf
Grapefruit
0.100.020.030.04
lected from 300 schools in 19 states. The
average zinc content of these lunches,
served to sixth grade children, was 3.91
coffee0.571.341.04O.fi!)0.2(10.210.250.200.120.070.080.080.110.07
mg. The zinc content of selected foods as
1 Taken from Osis et al. (197).
reported by Osis et al. (197) is shown in
table 1.
An estimation of the zinc content of
cause of the variability of the zinc contents
several diets from other cultures was sum
of foods within each class. There is a wide marized by Eggleton in 1938 (47). The
range of values published in the literature
diet of native sailors in the Dutch East
for the same food because of the differ
Indian Navy prior to 1874 was estimated to
ences in analysis, source, and variety. In contain 7.3 mg of zinc. The diet consisted
general, meat, eggs, milk products, and mainly of meat (beef, pork, or fish) and
shellfish ( oysters in particular ) are the best rice. (Its caloric content was not known.)
sources of zinc. Fruits and vegetables usu
The Steffanssen all-meat diet (lean beef,
ally are poor sources. Berfenstam ( 11 ) re
fatty
tissue, liver, marrow) eaten by Arctic
ported human milk to contain 3 to 5 ppm explorers in the 1920's contained about 24
( wet weight ) which is comparable to cow's
mg/day. The zinc content of a North China
milk ( 189 ). More recent analyses of infant diet was estimated as 9.5 mg/day. Grain
foods showed that 22 mature human milk products and legumes furnished most of
samples contained a mean zinc concentra
the protein. Eggleton (47) estimated that
tion of 1.34 ppm and four commercially
the daily zinc intake of the poorest class of
prepared infant formulas, as consumed,
Chinese in South China at that time was
contained 1.47 to 3.99 ppm (180). These
concentrations are markedly lower than
Mutch, P. B. & Hurley. L. S. (1971)
Zinc de
ficiency in suckling rata. Feil. Proc. 30, 043 (Abstr.).
that of 20 ppm previously reported for Complete
paper to be published in The Journal of
human colostrum (147). The importance
Nutrition 1074.
BreadsWhiteRyeWhole
352
less 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.
METABOLIC ASPECTS OF ZINC

IN HUMAN NUTRITION
Distribution in the body

Several studies have been published 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 United States. About
half of the subjects had died from acci
dental causes, but the remainder had died
Factors influencing zinc content of foods

Manufacturing techniques. The refining
of foods usually results in a decrease in the
zinc content. For example, Czerniejewski et
al. (40) found that during the milling
process of wheat for flour, 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 effects of refining foods have
been discussed by Mertz (157) and
Schroeder (263).
Preparation of foods. Food preparation
methods also affect zinc concentration. For
example, water added for cooking purposes
will vary markedly in zinc content among
different 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. The range
was from 3 to 2010 fig/liter. The 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 plasticcoated cooking utensils.
of various diseases. The tissues were col

lected from primitive African cultures,
Lebanon, India, the Far East and Europe
(Switzerland
and Scandinavia).
These
samples represented people of a wide geo
graphical distribution as well as with a
variety of dietary habits. Surprisingly, little
variation was found in the zinc content.
The results were similar to data obtained
by Perry et al. (211) from 150 healthy
American adults who died suddenly of
accidents.
Other data have been reported by Netsky
et al. (182), Tipton and Cook (297), Butt
et al. (25), Eggleton (47, 49), Galin et al.
(66), Schrodt et al. (262), and McBean et
al. (148). The 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 comparison
in this table.
A highly significant correlation among
dietary, plasma, and bone zinc contents
has been demonstrated in rats (274). Often
the zinc concentrations of the kidney 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.
Plasma and serum. Although plasma and
serum have usually been regarded as pos
sessing similar zinc concentrations (305,
311), Foley et al. (55) reported that serum
invariably has a higher zinc content than
plasma (about 16%). Thev attributed the
greater serum content to the liberation of
zinc by disintegrated platelets, to a dilu
tion factor and to invisible hemolysis which
always occurs (268). In 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 different laboratories using different
methods are, with a few exceptions, in rea
sonably good agreement (table 3). The
constancy of most estimates since 1965
coincides with better methods for avoiding
contamination and with more precise ana
lytical methods.
Red blood cells. The reported zinc con
tent of red blood cells varies from about
RESEARCH
ON ZINC REQUIREMENTS
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5^
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SIlliilll1-1!111!!igja3Mked
G) o)
"SSÔ
^
dlu^
valuH.sIt00lo-5a*oioA\fsMmoODH
mean
&5i"gSe
354
J. A. HALSTED,
10 to 14 /tg/ml. Ross et al. (256) using the

dithizone method found that the red cells
of 48 normal subjects contained 11.8 1.8
/xgzinc/g. Also using the dithizone method,
Prasad et al. (229) found a mean red cell
zinc content of 13.7 1.2 /g/mlin a study
with 14 normal subjects. When samples of
the same blood were analyzed by atomic
absorption spcctrophotometry,
a mean
value of 14.0 1.5 /g/mlwas obtained.
Mansouri et al. (144) also using atomic
absorption
spectrophotometry
found a
mean zinc content of 11.8 1.7 j.g/mlin
the red blood cells of 51 normal subjects.
In the same laboratory, McBean and
Halsted (149) obtained a mean value of
10.1 1.2 /ug/ml in 10 fasting controls.
After a meal, the mean value (10.1 1.0
/ag/ml) was not significantly changed. Dif

ferences in technique, for instance in speed
of centrifugation, may account for part of
the difference in estimates.
Leucocytes. The zinc content of leuco
cytes has been determined (44, 170, 214,
306) with general agreement that these
cells are 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 man (87).
Absorption of Zinc
As with iron, apparently only a small
percentage of ingested zinc is absorbed.
Absorption is difficult to ascertain precisely
and intake-output studies are not valid
Investigator
Reference
Year
Mean SD
Range
Not
Method
WolffVikbladhBerfenstamKoch
al.Vallee
et
al.SmitFuwa
et
al.Gofman
et
al.Butt et
al.Prasad
et
al.Kahn et
al.Sullivan
et
LankfordOlehy
&
al.Helwig
et
al.Parkeret
al.Rosneret
GorfienHalsted
&
al.Mahanand
et
al.Davies et
al.Halsted
et
malesand
for
femalesNewborn,
2(P)12023(P)12119(S)13929(S)122
1255Males,
2955 121
adultsAdults39
3(8)98
2(S)5140
6(S)510414(P)103
adults170
adults64
9(P)84
30(8)9412(S)93
5(P)9117(S)9010(S)13813(P)9613(P)94
adults23
adultsChildren,
(P)9513(P)9612(P)12020(S)92
SmithSinha
&
TABLE 3
Plasma or serum tine concentration in normal adults1
(ng/100 ml)
10815Males,
13Females,
95
1611Children,
8913Males,
9613Females,
9711100
18100
males 121
GabrieliMeret
&
1182145
females
3(S)696
90337
females
HankinLindeman
&
3Males,
males 94
96Females,
(P)119(8)10217(S)84-16370-170101-13972-11287-23486-10276-12572-11576-16063-14768
al.Kurz
et
8811
1102137
adults
al.Pekarek
et
1281799
children
males
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)(209)19501950
1 Zinc concentration has been found to be 16% higher in serum than in plasma in one study (21)8).
plasma.
4 A.A.S. ; atomic absorption spectrophotometry.
>SE.
! (S) ; serum.
RESEARCH
355
zinc. This was first shown in 1960 by O'Dell
and Savage (194). Later Oberleas et al.

( 186 ) showed that phytic acid added to an
animal protein diet depressed growth in
swine. Using 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'Dell (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. Likuski and Forbes
( 133 ) showed that phytic acid depressed
the availability 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 Iranian villagers
(often providing the major source of pro
tein), contains significantly more phytate
than urban breads which are leavened and
allowed to ferment (P < 0.001). Leavening
results in destruction of phytate. The omis
sion of the leavening process in Iranian
village breadmaking is presumably respon
sible for the high content of phytate.
The data suggesting that phytate en
hances the possibility of zinc deficiency in
man were strengthened by the reports from
Egypt (225, 226, 257) and Iran (83, 84)
that zinc deficiency occurred under condi
tions where unleavened bread was con
sumed in great amounts. Reinhold et al.
Availability of zinc
(244) tested the hypothesis that phytate
Edwards (46) using chicks studied the ingestin may result in zinc deficiency.
Three adult subjects were studied. During
availability of zinc from various com
pounds and ores. He reported that zinc an initial 16-day control period a diet pro
was most available from zinc sulfate, zinc viding approximately 0.7 g phytic acid was
fed. Following the control period, sodium
metal and zinc oxide, and least available
from sphalerite and franklinitc. Later phytate (4.5 g/day) was added to the diet
Roberson and Schaible (247) confirmed for 28 days yielding a total intake of about
2.5 g phytic acid/day. Then during the
these observations.
Other factors influence the absorption
next 32 days, no sodium phytate was fed,
but tanok replaced the low phytate bread
and retention of zinc and thus its avail
ability. Phytate (inositol hexaphosphate ), in the experimental diet. The tanok, a bread
which is present in cereal grains, markedly
consumed by villagers of Southern Iran,
impairs the availability (absorption)
of provided 2.6 to 3.4 g of phytate daily. Dur-
indicators because excretion of zinc is

nearly all via 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.
( 207 ) 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. More recently, Methfessel and Spencer (159) using 65ZnClo,
studied specific absorption sites in rats by
means of ligated intestinal sacs. They con
cluded that the absorption of 65Znwas sig
nificantly greater from the duodenum than
from the more distal segments of the small
intestine. Over a 2-hour observation period,
absorption was much less from the midjejunum and ileum. Only minimal amounts
were observed from the stomach, cecum
and colon. These data suggest that sites of
zinc absorption may be similar to those of
iron.
Becker and Hoekstra (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.' Among the factors that they sug
gested might affect 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 vita
min D.
OF MAN
356
J. A. HALSTED,
ficiency was the basic cause of this dwarfism 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.
When, however, Iranian clay was fed to
zinc-deficient rats, it proved to be a lifesaving source of zinc (274). A plausible
deduction, therefore, is that the subjects in
Iran may have sought zinc through the
ingestion of clay.
Chelating agents. Considerable work has
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 Vohra and
Kratzer (314) and Maddaiah et al. (141).
The ability of EDTA(ethylenediaminetetraacetic acid) to complex readily with zinc
has led to its use in removing radioactive
zinc from the body ( 279 ).
Vitamin D. Worker and Migicovsky (329)
found that the movement of zinc into the
bones of chicks was enhanced by vitamin
D. They effect
suggested
thatmetabolism
the site ofmight
the
vitamin's
on zinc
be "in the absorption mechanism." Later
Becker and Hoekstra (8) observed in
creased absorption of dietary zinc in rats
treated with vitamin D. Additional studies
with 65Zn convinced them that the in
creased absorption of zinc was not the pri
mary response but rather was the result of
an increased need for zinc secondary to in
creased skeletal growth.
Excretion of zinc
McCance and Widdowson (153) found
that regardless of whether zinc enters the
body orally or parenterally, it is excreted
almost wholly 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. Negli
gible amounts are excreted by the liver
into bile (153, 267). Urinary zinc excretion
in normal individuals and those with dis
eases was summarized by Roman (250).
In normal subjects, most of published
means ranged between 400 and 600 /g/24
hours.
Steele (284) recently reported data sug
gesting that renal handling of zinc is dif
ferent from that of other divalent cations.
ing the sodium phytate period (28 days)

zinc balances became significantly less posi
tive. Occasionally, negative balances were
observed. During 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 availability of zinc from foodstuffs,
with major emphasis on the effect of phvtate, was reviewed by Oberleas et al. ( 188 )
in 1966. More recently Oberleas (185),
studying phytate-mineral complexes, sug
gested that the chelating properties of
phytate may induce a wide variety of min
eral deficiencies depending on which ele
ment first becomes limiting. Chemical
studies indicate that phytate decreases zinc
availability by forming an extremely insol
uble calcium-zinc-phytate
salt at the pH
ranges found in the upper small 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 utilization, 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.
Other 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 vitamin D.
Zinc status. Heth et al. (96), working
with rats, and Prasad (222), studying hu
man subjects, observed that the proportion
of orally administered zinc lost in the feces
decreased when the animals or human sub
jects were zinc deficient. 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.
Geophagia. Minnich et al. (171) found
that clay from Turkey inhibited iron ab
sorption in human subjects. Nearly all sub
jects with severe nutritional dwarfism
studied in Iran gave a history of eating
large amounts of clay for many years. Be
cause the evidence indicated that zinc de
Binding of zinc to serum protein

Early work by Laurel on zinc binding
was summarized and amplified by Vikbladh
in 1951 (312). The portion of plasma zinc
bound 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 findings on zinc binding with serum
proteins have been confirmed by others
(22, 203, 305). The identity of the fraction
to which zinc is firmly bound has been the
subject of several studies. Surgenor et al.
(293) reported that zinc could combine
with a iglobulin ( transferrin ) in vitro.
Later Boyett and Sullivan (22) from 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 Vallee
(203) isolated alpha-2 macroglobulin 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 86Zn
incubated serum found that from 2 to 8%
of the total serum zinc was ultrafilterable.
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 ultrafilterable 65Zn
several fold. They suggested that this amino
acid bound fraction of zinc may play a
significant role in biological transport.
Factors influencing the concentration
of zinc in plasma
As noted in table 3 the mean plasma
zinc concentration reported in recent years
has been reasonably constant. Most of these
results were derived by atomic absorption
spectrophotometry, but the neutron acti
vation, fluorometric, and dithizone meth
ods have given similar values. The use of
polyethylene
materials, which became
available in the 1960's, has undoubtedly
aided in eliminating sources of contami
nation.
Little work has been done on the effects
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). No sig
nificant differences between males and
females have been reported (85).
Inconclusive data exist on the effect of
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 diuretic, either ethacrynic acid or
furosemide, 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 (zincuria) has been reported to accompany
nephrosis (52), diabetes (36, 154, 215),
postalcoholic 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/dayabout
seven times the amount excreted by their
healthy subjects.
Spencer and Samachson (282) noted
that urinary zinc excretion rose to high
levels during total starvation in extreme
obesity. They found a tenfold increase in
daily excretion during their ten 6-day bal
ance periods. Despite the urinary losses,
plasma zinc levels did not change.
Recently Fell et al. (54) studied urinary
zinc excretion by two patients after surgery
for total hip replacement. They adminis
tered 05Zn to the patient in sufficient time
before surgery to allow its incorporation
into the muscles. They found large in
creases in urinary excretion of 66Zn, total
zinc and nitrogen after surgery. The excre
tions rose to a maximum about 10 days
postoperation. The close correlation be
tween the excretion of 65Zn and 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, Fell et al.
(54) suggested that urinary zinc may pro
vide an index by which to estimate muscle
catabolism.
357
358
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 healing" (285).
At present there is conflicting evidence
on the effect of zinc on wound healing in
human subjects. Pories and Strain (219)
in 1966 reported that, with oral administra
tion of zinc sulfate heptahydrate, healing
time was apparently decreased. Their ob
servations included the measurement of
wound volume during the healing of pilonidal sinus tract excision wounds in two
unsupplemented patients and one zincsupplemented 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 healing 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 find
any difference in healing time between
zinc-treated and control patients. Likewise,
Myers and Cherry (181), studying 51
patients, 36 to 80 years old, with chronic
leg ulcers, and Barcia (5), with 20 young
men who underwent surgical treatment for
chronic pilonidal disease, failed to show an
improvement in healing time in those pa
tients who were treated with zinc. Pories
and
Strain (220)
in reviewing
suggested
that the
patient's these
initialstudies,
zinc
status may influence his response to zinctherapy. Holbkand Lanner (78), for
instance, observed significant differences in
healing 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 /g/100ml or
higher.
For many years there has been interest
in a possible relationship of zinc to malig6 Smith, J. C., Jr., McDaniel, E. G., McBean, L. D.,
Doft, F. S. & Halsted, J. A. (1971)
Effect of micro
organisms
upon zinc metabolism.
Proc. Western
Hemisphere
Nutr.
Cong., Bal Harbour,
Florida
(Abstr.).
meals on plasma zinc concentration. Davies

et al. (41) reported that the zinc level de
creased following intravenous or oral glu
cose loading, but this has not been con
firmed. In another study (149), the effect
of a meal containing 3.92 mg of zinc on the
plasma zinc level was negligible in 10 nor
mal individuals who had tasted 12 hours
prior to eating the meal. There are few
data on the effect of fasting on the plasma
zinc levels of man. As 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
reflects zinc deficiency, a redistribution of
zinc, or an emergency call on available cir
culating zinc loosely bound to albumin is
not clear. Wacker et al. (316) in 1956
noted that serum zinc concentration was
lowered after an acute myocardial infarc.
Lindeman et al. (134) also noted that the
zinc level fell rapidly after extensive sur
gery, myocardial infarc,and acute infec
tions. It rose to normal during convales
cence. Similarly, after injection of endotoxin in man5 and rats (208) a sharp fall
in serum zinc level was noted. As the in
fection subsided, the serum zinc level re
turned toward normal (208, 210, 319). In
pulmonary tuberculosis and in various
types of chronic liver diseases the plasma
zinc level was usually 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 healing.
Other investigators using rats (258, 126,
191), cattle (166), and hamsters (289) also
observed improved healing when zinc was
administered. Sandstead et al. (258) sug
gested that collagen formation is impaired
in conditions of zinc deficiency. Recently
Stephan and Hsu (285) found that in zincdeficient rats, there was decreased DNA
synthesis as indicated by reduced thymidine-methyl-3H incorporation into the DNA
of skin. They suggested that this observa
tion
impaired
skin DNA
synthesis
to
getherof with
a previous
observation
of "de
359
nant disease. Ross et al. (256), using 65Zn establish more precisely the interrelation
in patients with neoplastic disease, found ships between zinc and endocrine function.
that uptake of zinc in leukemia leucocytes
Interrelationships with other minerals
was about one-half that of normal sub
Calcium. Tucker and Salmon (302) first
jects.
zinc content
ents inThe
Hodgkin's
disease of
hasblood
been constitu
reported
demonstrated that increasing the calcium
to be low (4). Davies et al. (42) and content of practical diets for swine en
Morgan (176) reported low plasma or hanced zinc-deficiency symptoms (skin
serum zinc levels in patients treated for lesions and growth retardation). Because
bronchogenic carcinoma. Smith et al. (275), the basal diets fed were relatively high in
however, found no differences in serum zinc, 34 to 44 ppm, this was an apparent
zinc levels between patients with untreated
demonstration of the antagonism of cal
bronchogenic carcinoma and normal con
cium to zinc. Numerous investigations with
trols. DeWys et al. (45) found that Walker swine using diets containing plant protein
256 sarcoma implanted in zinc-deficient
have confirmed the calcium-zinc antago
rats grew at a markedly reduced rate com
nism (35, 130, 131, 135, 136, 183, 286). In
pared with ones implanted in control, pair- contrast, when swine were fed animal pro
fed rats. These results suggest an increased
tein diets the deleterious effect of calcium
zinc requirement for tumor growth.
on zinc utilization was not demonstrable
The wide variety of pathological states
(10, 324). In 1960 (57) Forbes reviewed
in which plasma zinc concentration has the interrelationship of zinc and calcium.
been found to be depressed suggests that As pointed out by Forbes (58, 59) and
there may be several mechanisms involved more recently by O'Dell (192), the con
whereby zinc metabolism is altered in flicting results regarding the antagonistic
disease. On the other hand, there also may effect of calcium toward zinc can be ex
be a fundamental mechanism common to plained by the presence of phytate. That
all. It is attractive to speculate that zinc is is, excess calcium in the presence of phytate
required rapidly for enzyme formation or (which accompanies plant but not animal
protein synthesis when bodily insults occur, protein) results in decreased zinc absorp
and that the zinc that is loosely bound to tion, enhancing zinc deficiency. The inter
albumin is immediately available for these relationships of calcium, zinc, and phytic
purposes. Of interest is the fact that the acid in promoting growth of pigs are
zinc level rarely falls below 30 to 35% of shown in figure 1.'
the normal. This may correspond to that
It is doubtful whether the calcium an
amount loosely bound to albumin.
tagonism to zinc absorption plays an im
portant role in a well-balanced diet con
Relationship of zinc to endocrine functions
taining animal protein. Spencer et al. (283)
Endocrine abnormalities in human zinc could not demonstrate a calcium-zinc an
deficiency have been studied only in cases tagonism in human subjects fed meat as a
of nutritional dwarfism reported from protein source when calcium was varied in
Egypt (34, 226). Somewhat ambiguous re
the diet tenfold. However, the antagonism
sults were obtained in assessing growth may be a factor in diets high in plant pro
hormone, gonadotropin, adrenocortical, and tein, i.e., beans, peas, and cereal grains.
testicular function. In human pregnancy,
Cadmium. Cadmium and zinc have sev
plasma zinc concentration is usually de
eral similar chemical properties, including
pressed to about two-thirds that of normal a usual coordination number of 4, tetra(114). In a study with rats, McBean et al. hedral configuration,
and isoelectronic
(151) confirmed the findings, previously valence shells. In 1957 Pafizek (204)
observed in women (82), that depression
showed that the destructive effect of in
of plasma zinc concentration occurs when jected cadmium upon testicular tissue
contraceptive hormones are fed. McBean could be alleviated by zinc, and suggested
et al. (151) found that the estrogen com
that the injury was due to interference with
ponent of the contraceptive compounds
was responsible for the plasma zinc lower
9 By permission of the author B. L. O'Dell and the
ing effect. Additional work is needed to publisher American Journal of Clinical Nutrition.
360
J. A. HALSTED..J. C. SMITH, JR. AND M. I. IRWIN

-700
800
1Protein
600-Cn-
500-2
400-1
300-200-100-il1
CCP.A.,
added,%
1.4a,
1.5Zn,
%
ppm
S
C
C1.4
0
0
0 1.4nmiJî>ifiC
1.5 1.5 0.8 0.8 1.5
25 14 141414
114
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.
The interrelationships of zinc with other

minerals are obviously not limited to single
elements, i.e., zinc-copper or zinc-cad
mium. There have been some reports in
volving a simultaneous interaction of sev
eral minerals (99, 136, 177, 243, 287). No
information on such multiple interactions
in humans was found.
Interrelationships icith vitamins
Vitamin A. Early studies on dark adap
tation indicated that another nutrient might
be necessary for vitamin A utilization (206).
Observations of reduced plasma zinc con
centration in cirrhotic patients (85) sug
gested that this necessary nutrient might
be zinc. Studies with animals tended to
support this hypothesis. Stevenson and
Earle (286), for instance, reported that
zinc-deficient swine had depressed serum
vitamin A levels. These levels did not re
turn to normal even after massive oral
doses of vitamin A. Later, Saraswat and
Arora (260) reported that zinc supplemen
tation was necessary for maximum effi
ciency of vitamin A therapy in lambs that
were deficient in both zinc and vitamin A.
zinc function. Gunn et al. (74, 75), and

Mason and Young (146) confirmed the
antagonistic zinc-cadmium effects on testicular function.
In human nutrition, the zinc-cadmium
interrelationship
has not been demon
strated. Schroeder et al. (264) have elab
orated on the close association between
cadmium and zinc. Cadmium, a nonessential element, is invariably associated with
zinc in both geological and biological
matter.
Copper. In animal studies, excessively
high levels of zinc resulted in interference
with copper metabolism (70, 142). Studies
such as those by Hoefer et al. (101) and
Wallace et al. (317) indicated that the
severity of parakeratosis in swine 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). At
present the significance of these observa
tions is not understood.
When a diet composed entirely of meat
was fed to rodents, an anemia developed
that
responsive
to copper
(73,"meat
174,
175). was
It was
proposed
that this
anemia" resulted not only from a relative
excess of zinc over copper present in meat
but also from the lower calcium levels
found in meat. The meat anemia, however,
could be reduced or prevented by cook
ing the meat (174). This suggests that it
was not due simply to a high zinc-copper
ratio but that a heat labile factor may have
been involved. Hoekstra (102) has re
viewed this subject briefly.
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
toxic levels of zinc.
An interaction of zinc and molybdenum
was suggested by the investigations of
Gray and Ellis (71).

ZINC DEFICIENCY
Animals
In 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. They include dermatitis,
emaci
ation, alopecia, ocular lesions, testicular
atrophy,
retarded
growth, and anorexia.
All of these conditions with the possible
exception of testicular lesions are reversed
by zinc supplementation
(6,161).
Malformations of embryos and/or fetuses
due to zinc deficiency were reported for a
number of species. Blamberg et al. (19)
reported gross malformations
involving the
brain, vertebrae, limbs, beak, and head of
chick embryos produced
from eggs laid
by zinc-deficient hens. Kienholz et al. (119)
confirmed these findings. Hurlev and coworkers (108-111)
demonstrated
congeni
tal malformations
in rat fetuses delivered
from zinc-deficient females. 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 Apgar (3)
and Hurley and Swenerton (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). To our knowledge no congenital
malformations
due to zinc deficiency have
been reported in humans. It is of interest,
nevertheless, that a brother of one patient
with the dwarfism syndrome originally re
ported in 1961 (224) had pronounced bony
abnormalities
as well as extreme dwarfism.
More 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. In addition, retinal reductase, an
alcohol dehydrogenase
of the retina in
volved in the metabolism of vitamin A, is
most probably a zinc metalloenzyme
(307).
Vitamin D. In 1958 Whiting and Bezeau
(324) reported that vitamin D decreased
the absorption and retention of zinc when
diets low in zinc were fed to pigs. Wasserman (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, Worker and Migicovskv
(329)
with chicks and Becker and Iloekstra (8)
with rats observed that 7,inc absorption
and zinc uptake in the bones were en
hanced when vitamin D.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 calcification or bone growth.
Riboflavin. In 1941, Follis et al. (56)
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
uncomplicated
riboflavin deficiency in rats.
This was the first suggestion of an apparent
similarity in the effect of riboflavin and
zinc deficiencies upon specific 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,
similar bony malformations
were observed.
In addition,
fetuses from riboflavin-deficient females had lower body zinc con
tents than fetuses from riboflavin-sufficient
mothers.
361
362
TABLE 4
Zinc balance studies of adult Iranian villagers1'
Subject
number12345678910111213SexMMMFMMFMFMFMFAgeVr32253825354730302437224017Weightk
gaiakg/dayN.A.0.070.070.18-0.060.03N.A.0.240.080.210.250.300.
15.4%-6.7-9.712.413.014.923.125.226.528.829.330
From Reinhold et al. (240). ' AI! were sufficiently healthy
to carry out normal activities of a villager.
>Not available
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, 75 g of protein (15% from pulses, 21% from meat,
8%from bread, and 36% from milk and cheese), 80 to 120 e
of fat from butter and corn oil, 24.6 mg of zinc, 1,031 mg of
calcium, and 1,513 mg of phosphorus.
though kwashiorkor is an extreme example

of protein-calorie malnutrition, zinc de
ficiency may be a secondary factor. To
date, little account of this possibility has
been taken.
Zinc deficiency, secondary to intestinal
malabsorption, recurrent infection and hypogammaglobulinemia, has been reported
by Caggiano et al. (27). One suspects that
zinc deficiency might be implicated in
growth retardation that may occur in cystic
fibrosis, inflammatory 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
hypogeusia, hyposmia) or after the administra
tion of i/-penicillamine. These investigators
reported that this disorder may be cor
rected by the administration of either 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 ppma level similar to that
reported for Egyptian adolescents suffering
from symptomatic zinc deficiency (290).
Seven of the 10 children had a history of
poor appetite and eight had heights that
Behavioral impairment was reported in

zinc-deficient adult rats (28, 29). Perform
ance tests indicated that zinc-deficient rats
were inferior to zinc-sufficient animals in
both learning ability and emotional sta
bility.
Manclinicaland metabolic features
In man, the clinical aspects of zinc de
ficiency are similar to those described
above for animals. In summary, they consist
of severe iron deficiency anemia, hepatosplenomegaly, short stature, infantile testes,
open epiphyses, spoon nails, frequently 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 either to a regeneration
of enzyme activity or to an increase in
bone growth. It 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. However, two well-docu
mented cases in females were included in
a recent report from Iran (84).
Ronaghy et al. (252) conducted a 6-year
follow-up study on the Iranian dwarfs in
whom zinc deficiency had first been sus
pected (224). They found that the patients
remained well if they continued to eat a
well-balanced diet including meat. If, how
ever, they resumed the village 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
villagers in a metabolic 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 (6.7to 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. Al-
RESEARCH
fell on or below the 10th percentile when

"plotted on growth charts based on data
PARAMETERS FOR ASSESSING

ZINC STATUS IN MAN
Parameters that have been used in as

sessing zinc status in man are as follows:
1) plasma or serum concentration, 2) hair
zinc concentration, 3) metabolic 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. In some instances di
363
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. It ap
pears unlikely that such a transiently low
level occurring so rapidly is a sign of zinc
deficiency. Nevertheless, demonstrable zinc
deficiency in man is accompanied by a low
plasma zinc concentration.
Measurement of a specific zinc-binding
protein, alpha-2 macroglobulin, possibly
may become a useful tool in assessment of
zinc deficiency. Boyett and Sullivan (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 investigators with 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 children. These subjects
had lower than normal plasma zinc levels,
but hair zinc concentrations were normal.
They 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, affect the zinc con
centration in hair.
Reinhold's zinc balance studies on Iranian
villagers (240) point to the value of the
balance method (table 4). His 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 limited
life expectancy. Richmond et al. (245) re
ported that the biological half-life of this
isotope in human subjects averaged 154
days. Zinc 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 intra7McBean, L. D., Smith, J. C, Bernard, B. H. &
Halsted, J. A. (1972) Serum zinc and alpha-macroglobulin concentration in patients with varimidis,
orders. Proc. IX Int. Congr. Nutr., Mexico City,
Mexico, September 2-9, 1972 (Abstr.).
compiled by the Harvard School of Public

Health and the Iowa Child Welfare Re
search Station." Of six children whose
taste acuity was measured, five showed
evidence of lowered acuity. After 1 to 3
months with daily 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
children. These children 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 deficiency in beri
beri, said: "Attention 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 it is considered
possible that this shortage may account, in
part at least, for the peculiar appearance of
the hair, the dry skin and the abnormal
finger and toe nails . . ." The integumentary
changes to which Eggleton referred also
are found in zinc-deficient dwarfs as well
as in animals with experimental or spon
taneous zinc deficiency. It seems possible
that spoon nails (koilonychia), long attrib
uted to chronic iron deficiency, might
actually be the result of associated zinc
deficiency.
OF MAN
364
J. A. HALSTED,
TABLE 5
Hair zinc concentration as reported by various investigators
zincppm2551396.41
InvestigatorEggletonReinhold
al.Strain
et
al.Eininians
et
al.KlevayMcBean
et
al.'MeanisD.
et
181
36.3'54 ZinconE.S.E.S.
62121
5s
10342 E.S.
120
5s163222127
49'17637l
19922'MethodDithizoneZincon
spectrography.
' A.A.S. ; atomic absorption spectrophotometry.
'Reference(48)(241)(290)(50)(121)(150)Mean
SE.Year193819661966196719701971E.S.;Subjects11
venously into patients with malignancy,

finding that it disappeared rapidly from
the plasma. Prasad's studies indicated that,
in zinc deficiency, plasma zinc turnover
was increased, the 24-hour exchangeable
zinc pool was decreased, cumulative excre
tion of 66Zn was low, and 6-hour plasma
65Zn disappearance was rapid. Spencer's
reports were limited to metabolic 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-35S. Somers and Underwood (277)
confirmed the significantly elevated sulfur
excretion in zinc-deficient lambs. The
mechanism suggested by Hsu and Anthony
( 104 ) was the inability of the zinc-deficient
animal to utilize sulfur-containing amino
acids for protein synthesis, with conse
quent excretion of sulfate. No reports of
similar work in man were found.
At present the critical test for zinc de
ficiency in man or animals is a definitive
response to oral supplementation with zinc
under controlled conditions. The data for
primary zinc deficiency in the cereal-eating
populations of Iran and Egypt now appear
unequivocal. No reports of similar studies
in other geographic locations have been
found.
ZINC TOXICITY
In comparison with the trace elements

lead, cadmium, arsenic, and antimony, 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
mium, or arsenic (90). Zinc is noncumula
tive, and the proportion absorbed is
thought to be inversely related to the
amount ingested (64, 96). Vomiting, a
protective mechanism, occurs after inges
tion of large quantities or after extended
exposure to fumes containing zinc. In fact,
an oral dose of 2 g of zinc sulfate (454 mg
of zinc) has been recommended as an
emetic (155). In addition to severe vomit
ing, the symptoms of zinc toxicity in hu
mans include dehydration, electrolyte im
balance, stomach pain, nausea, lethargy,
dizziness, and muscular incoordination.
Acute 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 with 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
adults19
Chinese
male adult Iranian villagers
20 male control adult subjects
Iran)10
(Shiraz,
zinc deficient Egyptian male dwarfs
16 to 20 years
8 zinc-treated dwarfs 16 to 20 years
12 normal Egyptians 27 to 40 years
E.S.A.A.S.A.A.S.A.A.S.A.A.S.emission
years12
6 normal Rochester residents 23 to 37
old31
healthy village children 11 years
years14
Panamanian males 6 to 10
normal adults (Washington, D. C.)
75 Iranian village children 6 to 12 years
(growth retarded)Hair
365
RESEARCHON ZINC REQUIREMENTSOF MAN

over a 2-day period (179). Death is re
ported to have occurred after the ingestion
of 45 g of zinc sulfate ( 199 ). Toxic symp
toms, such as pulmonary distress, chills,
and fever, may be caused also by inhalation
of fumes
or dust
levels of
zinc
(201).
Thiscontaining
so-called high
"metal-fume
fever" usually has been seen in industrial
workers such as welders of galvanized
metal.
Numerous studies on the toxicity of zinc
in lower animals have been summarized
by Van Keen (309).
HUMAN REQUIREMENTS FOR ZINC
(TABLE 6)
zone method ( 97 ). With mean intakes that

ranged from 11.8 to 14.1 mg/day, the
young women retained from 5.1 to 8.8 mg/
day. Osis et al. (198) on the other hand,
observed much smaller retentions with
similar intakes. They studied one subject
whose mean zinc intake during four 6-day
periods ranged from 11.7 to 13.1 mg/day.
TABLE 6
Controlled studies on human requirements for zinc
SubjectsInfante
of
of
subjects10studies1
oldPreschool
5 to 8 days
oldSchool
3 to 6 years
368
13
children
oldAdolescentsNumber
7 to 12 years
0Xumber0Daily
Adults
men and women6164.9
>In rag/day except where otherwise stated.
intake10.20
retention1-0.85
1.19mg/kii3.80
to
to 0.08
mg/kg-2.70
3.390.5
to
5.874.6
to
daily
requirement10.300
to 0.307
(265)(51,
mg/kg6.2Reference(32)
to 9.2
to 3.8
13.85 to 18.35Daily 4.92 2.94Estimated
6.1
9.018.0to
to 14.1
to 22.0-0.8
0.0
-4.0 to 8.8
1.0to to 8.3(153.(153)
234)
(140)
198, 299, 301,

(68, 153, 299)323)
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. Adult subjects and
school children 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. All 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.
In the studies with adults, the intakes
varied from relatively low (about 5 mg/
day) to relatively high (about 22 mg/day).
McCance and Widdowson (153), for in
stance, reported data on two men and one

woman eating a specially formulated diet
that provided 4.9 to 6.1 mg of zinc/day.
Zinc analysis was carried out by the
method
described
by periods
Keilin of
and"about
Manna
(116). During
dietary
fortnight," balances of 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 from white flour, balances
rose slightly to range from 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 flour. 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.
In other studies in which moderate zinc
intakes (about 9 to 14 mg/day) were re
corded, retentions ranged from 4.0to 8.8
mg/day. The highest retentions with this
range of intake were recorded by Tribble
and Scoular (301). They studied a group
of 13 young women, 17 to 27 years old,
eating self-selected diets that were sampled
and analyzed for zinc by Hibbard's dithi-
366
A still lower mean balance was recorded

by Tipton et al. (299). They reported on
the mineral intake and excretion of two
young men, 23 and 25 years old, who re
corded their food intake and collected
samples of food, urine, and feces over a
50-week period. The samples were ana
lyzed for zinc by atomic absorption pho
tometry. One subject whose mean zinc in
take was 11 mg/day had a mean balance of
4.0mg/day. The second subject had a
mean intake of 18 mg of zinc/day. He re
tained 1.0 mg/day. This retention is in
reasonably close agreement with those ( 1.1
to 2.6 mg/day) reported by McCance and
Widdowson ( 153 ) in studies with similar
high intakes. It is much lower, however,
than those reported recently by Gormican
and Carli (68). They studied mineral bal
ances in five young men, 21 to 24 years old.
The men were given a liquid diet based on
milk solids, calves' liver, corn oil, and puri
fied carbohydrates for 28 days (four 7-day
periods). The zinc contents of food, feces,
and urine were determined by emission
spectroscopy. The average zinc intake was
19.5 mg/day with mean retention ranging
from 7.3 to 8.3 mg/day. The apparent dif
ferences in retention of zinc as indicated

by these studies may be due in part to
differences in dietary composition. The dif
ferences in retention may be due also to
differences in nutritional status among the
subjects. Fox (61) recently reviewed the
status of zinc and factors that affect its
requirement in human nutrition.
In studies with school children, the in
takes covered a range similar to that ob
served in studies with adults. Low to mod
erate intakes were reported by Engel et
al. (51). They studied a total of 36 girls, 7
to 10 years old, in groups of 12 in three
separate studies of 56, 48, and 36 days du
ration. The controlled diets provided from
4.6 to 9.2 mg of zinc/day. All subjects were
in apparent positive balance with these in
takes. When retentions were plotted against
intakes, the retentions during study 2 were
found to be much higher than those during
study 1 or 3. No explanation for this "un
usual behavior" was found. Using the data
from studies 1 and 3, Engel et al. (51)
plotted a regression line that, when ex
trapolated, indicated a mean endogenous
zinc loss of 0.874 mg/day and a minimum
requirement of 2.75 mg of zinc/day for
equilibrium. The regression calculation also
indicated that the children retained 31.8 %
of the dietary zinc. Assuming a dermal loss
of 0.874 mg/day and an allowance for
growth of 0.25 mg/day, Engel et al. (51)
calculated a daily dietary zinc requirement
of 6.2 mg for the pradolescentchild.
In a continuation of these studies Price
et al. (234) reported data obtained with
another group of 15 girls, 7 to 9 years old.
In this study, both protein and calcium
levels were adjusted in diets composed of
foods representative of those eaten by low
income groups in the southeastern United
States. The daily calcium intake was 0.26
or 0.62 g and the daily protein intake was
25 or 46 g. After a 6-day adjustment period,
the subjects were randomly assigned to the
four experimental diets for 30 days (five 6day periods). The variations in calcium
intake did not affect zinc retention. With
the low protein diets, the mean zinc intakes
were 4.83 and 4.53 mg/day, and the mean
retentions were 0.54 and 0.81 mg/day.
With the high protein diets, the mean
zinc intakes were 6.93 and 6.88 mg/day,
and the mean retentions were 1.99 and 1.79
With these intakes, the subject's retentions

ranged from 0.28 to 0.63 mg of zinc/day.
In an additional 24-day study, nine sub
jects ate a diet providing 12.3 mg of zinc/
day with either 200 or 1300 mg of calcium.
Four subjects with the low calcium diet
retained 0.73 mg of zinc/day whereas those
with the higher calcium diet retained 0.17
mg of zinc/day. The data indicated that
the difference in mean retention was due
mainly to a difference in mean fecal zinc
excretion. Zinc analysis was carried out by
atomic absorption spectrophotometry.
White and Gynne (323) also observed
low retentions in their study with nine
young women, 19 to 20 years old. The
women ate a controlled diet for 30 days
( six 5-day collection periods ). The average
zinc intake was 11.5 mg/day. Urinary losses
were too small to be accurately measured
by emission spectroscopy. Four women ab
sorbed 1 to 21% of the dietary zinc. Fecal
losses of four other subjects were greater
than the intakes. The average fecal excre
tion was 11.4 mg/day. White and Gynne
( 323 )"essentially
concluded in
that,
for zinc, the subjects
were
equilibrium."
RESEARCH
The one report available on zinc balance

in healthy infants suggests that neonates
behave differently from older children (32).
Cavell and Widdowson (32) determined
the zinc content of the meconium excreted
by six newborn infants during the first 24
hours of life. They found the mean zinc
excretion to be 0.66 mg/kg body weight.
Next, they measured zinc intake and out
put of 10 full-term neonates nourished
only by breast milk during days 6, 7, and
8 of life. Analysis of the breast milk from
the mothers of the babies indicated that
the zinc content varied considerably from
woman to woman (from 0.142 to 0.677
367
mg/100 ml ). The mean zinc content of the

milk was 0.408 mg/100 ml. The infants'
daily zinc intake also varied widely from
child to child (0.20 to 0.89 mg/kg) with a
mean daily intake of 0.67 mg/kg. All but
one baby were in negative balance and all
but two excreted more zinc in the feces
than they ingested in the milk. The bal
ances ranged from 0.85to 0.08 mg/kg
body weight (mean = 0.23 mg/kg).
Cavell and Widdowson (32) calculated
that the babies were losing more than 1%
of the body's total zinc each day. They
pointed out that these large losses could not
go on indefinitely without serious deple
tion. It is not known how long they con
tinue and how extensive the losses are.
CONCLUSIONS
The concept of possible or probable zinc
deficiency in man is relatively new, and the
deficiency syndrome, as yet, is not clearly
defined. Many of the manifestations of in
adequate zinc intake observed in animals
and poultry, such as reduced bone growth,
skeletal abnormalities, and retarded sexual
development (304) may be more difficult
to detect in human subjects because of
their slower growth pattern. The evidence
obtained in Egypt and Iran showing that
more rapid growth and sexual develop
ment could be induced in dwarfs by feed
ing a well-balanced diet plus zinc than by
feeding a well-balanced diet alone (80, 84,
257) suggests, however, that man's quali
tative zinc needs are similar to those of
other species.
At present we have few data on the
quantitative zinc needs of human subjects
at any age level. Most of the few studies
with healthy human subjects were con
ducted with young adults and school chil
dren. No reports were found of studies de
signed to determine zinc requirements of
healthy adolescents, pregnant and lactating
women, or elderly people.
The data that are available were ob
tained by the balance method. The studies
differed from each other in experimental
design and analytical technique. As might
be expected, the results also lacked agree
ment. In only two of these studies (51,
234) were allowances made for skin losses.
The balance study per se tells us whether
the subject was ingesting enough zinc to
mg/day. Price et al. (234) pointed out

that the low protein diets provided less
zinc than the approximate 6 mg/day rec
ommended by Engel et al. (51) for pr
adolescent girls. Assuming a sweat loss of
0.5 mg zinc/day (233), Price et al. (234)
suggested that the subjects would be
barely in positive zinc balance with the
low protein diets.
Much higher levels of zinc intake were
reported by Macy (140) who studied six
boys and one girl, 8 to 12 years old. In
experimental periods of about 55 consecu
tive days, zinc intakes ranged from 13.85
to 18.35 mg/day. The mean intake was
15.92 mg of zinc/day and the mean reten
tion was 4.92 mg/day. Macy (140) con
cluded that, "on the basis of body weight,
the children's intakes average 500 65
micrograms, and their retentions 154 88
micrograms per kilogram per day, indicat
ing a relatively high zinc requirement for
children and contradicting classification of
zinc as a trace element."
Intakes to provide similar retentions were
recommended for preschool children by
Scoular (265). She studied zinc intake and
output of three boys, 3 to 6 years old, in
12 successive 5-day periods. The zinc in
takes varied from 3.80 to 5.87 mg/day
(0.218 to 0.307 mg/kg body weight). Zinc
retention varied from 2.70mg to 3.39
mg/day (from -0.159 to 0.171 mg/kg).
Two of the boys had highest retentions
(0.171 and 0.123 mg/kg) with their high
est intakes (0.300 and 0.307 mg/kg). There
fore, Scoular (265) concluded that, "an in
gestion of not less than 0.300 to 0.307 mg of
zinc per kilogram of body weight is neces
sary for the preschool age child."
OF MAN
368
J. A. HALSTED,
tural practices and food processing tech

niques is not known.
Low plasma zinc concentrations have
been observed under various temporary
stress conditions (85, 134). In certain
chronic diseases, also, low blood zinc levels
are common. The significance of these low
concentrations is not clear. They may be
transient phenomena due to the redistribu
tion of zinc in the various body compart
ments. On the other hand, they may be the
result of inadequate dietary intake or of
decreased absorption or increased excre
tion associated with the stress condition.
If the latter is the cause, will increased zinc
intake correct the apparent deficiency? Al
though the literature suggesting that zinc
is beneficial in a variety of clinical dis
orders is growing, the conclusions are often
based on inadequately controlled studies.
More observations under carefully defined
conditions are needed.
In summary, much more information on
indices of marginal zinc deficiency and on
factors affecting availability and utilization
of dietary zinc is needed in order to make
sound recommendations on the nutritional
requirements and dietary allowances for
different population groups.
ACKNOWLEDGMENTS
The authors want to thank Dr. Herta

Spencer of the Veterans Administration
Hospital, Hies,Illinois, Dr. E. J. Under
wood of the University of Western Aus
tralia, and Dr. John G. Reinhold of the Uni
versity of Pennsylvania for their thoughtful
advice and criticism.
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A CONSPECTUS OF RESEARCH ON ZINC

J. CECIL SMITH, JR.

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Albany Medical College

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information gleaned from widely disparate

how the information was obtained, and to

Zinc has been estimated to rank 25th in

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The 1934 report by Todd et al. (300)

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

and because sewage is directed toward the

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Early discoveryuses in metallurgy

nitrate (98). The insoluble salts include

RESEARCH ON ZINC REQUIREMENTS OF MAN

zinc was essential for growth in birds also.

ment in the nine dwarfs fed the hospital

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apples, mottle leaf in citrus crops and prob

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

Because of the lack of precise analytical

contamination from these sources (81).

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Somers and Underwood (277), in a con

RESEARCH ON ZINC REQUIREMENTS

of zinc in colostrum was demonstrated by

Content of typical meals or diets

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

less than 6 mg/day. He suggested that zinc

METABOLIC ASPECTS OF ZINC

Distribution in the body

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Factors influencing zinc content of foods

of various diseases. The tissues were col

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

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

/ag/ml) was not significantly changed. Dif

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zinc. This was first shown in 1960 by O'Dell

and Savage (194). Later Oberleas et al.

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indicators because excretion of zinc is

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

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ing the sodium phytate period (28 days)

RESEARCH ON ZINC REQUIREMENTS OF MAN

Binding of zinc to serum protein

what controversial, but it appears that most

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For instance, when saline-loaded subjects

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

creased incorporation of 14C-labeled amino

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meals on plasma zinc concentration. Davies

RESEARCH ON ZINC REQUIREMENTS OF MAN

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

Fig. I Effect of phytic acid on growth rate of

The interrelationships of zinc with other

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