C H A P T E R
61
Zinc
HAROLD H. SANDSTEAD
ABSTRACT
Zinc (Zn) is ubiquitous, essential for life, and toxic
in excess. When diets provide adequate amounts of
bioavailable Zn and intakes of other nutrients are also
adequate homeostasis is maintained. When the con-
sumption of bioavailable Zn is insufficient, the risk of
deficiency increases. The worldwide prevalence of this
phenomenon is at least 20%. Excessive consumption
of bioavailable Zn and of exposure to Zn-containing
chemicals increase the risk of toxicity. The prevalence
of the former is unknown. The latter typically occurs in
association with industry; the likelihood is decreased
by the use of appropriate precautions. Low available
Zn in soil is common and if unmitigated decreases
agricultural production. Populations at risk of Zn defi-
ciency are also at risk of other deficiencies. Diets based
on cereal and legume products are rich in phytate and
other indigestible zinc-binding ligands, and diets based
on plant products that are low in Zn, such as roots,
tubers, and highly milled rice, are the major causes of
human Zn deficiency. Although Zn in animal flesh is
highly bioavailable, indigestible Zn-binding ligands in
diets suppress its availability. The physiological conse-
quences of Zn deficiency involve all systems.
Zinc toxicity is most common after habitual excessive
consumption of Zn-containing dietary supplements.
Bioavailability of dietary copper (Cu) is suppressed,
resulting in deficiency. Inadvertent consumption of Zn-
rich dental products over time, and the chronic pica of
articles composed of Zn also cause Cu deficiency. Acute
gastrointestinal illness can occur after consumption of
Zn-contaminated food or drink. Zinc toxicity associ-
ated with industry includes flu-like metal fume fever
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00061-5
from inhalation of Zn oxide fume. Exposure to highly
toxic Zn chloride fume can occur in industry, and from
the use of smoke bombs for crowd control.
1  IDENTITY AND PHYSICAL/CHEMICAL
PROPERTIES
The properties of zinc [Zn; Chemical Abstracts Ser-
vice (CAS) No. 7440-66-6] include atomic weight, 65.38;
atomic number, 30; valence, 2; density, 7.13 g/cm3;
Mohs’ hardness, 2.5; melting point, 419.5°C; boiling
point, 908°C; and electrical conductivity, 28.3% of the
international annealed copper standard. Crystalline
Zn is a bluish-white metal with a distorted hexagonal
close-packed structure. There are five stable isotopes,
64Zn (49%), 66Zn (28%), 68Zn (19%), 67Zn (4.1%), and
70Zn (0.62%), and 19 known radioactive isotopes. The
half-life of 65Zn is 243.8 days and that of 69Zn is 13.8 h
(Simon-Hettich et al., 2001; Choudhury et al., 2005).
Zinc reacts with oxygen to form Zn oxide (ZnO; CAS
No. 1314-13-2), chlorine to form Zn chloride (ZnCl2; CAS
No. 7646-85-7), and sulfur to form Zn sulfide (ZnS; CAS
No. 1314-98-3). In biological systems it is redox neutral
(Maret 2013). It is stable in dry air, but in moist air it is
coated with Zn oxide or basic carbonate. It is ampho-
teric and forms stable salts that are nonconducting, non-
magnetic, and white or colorless, except for those with
a chromophore group such as zinc chromate (ZnCrO4;
CAS No. 13530-65-9). At midrange pH, it forms hydrox-
ides [Zn(OH)2; CAS No. 20427-58-1] that have low solu-
bility in water, whereas at the extremes of pH solubility
is increased, releasing Zn ions at low pH and zincate
[tetrahydroxozincate ion, Zn(OH)42−] at high pH.
1369 Copyright © 2015 Elsevier B.V. All rights reserved.
1370 Harold H. Sandstead
2  ANALYTICAL METHODS
Zinc is ubiquitous; special care is required to avoid
contamination. The preparation of solid environmen-
tal samples may involve microwave-assisted mineral-
ization with concentrated acids. Water samples may
require solvent extraction in the presence of complex-
ing agents and chelating resin separation to preconcen-
trate Zn (Simon-Hettich et al., 2001).
Element-specific instrumental techniques accurately
measure Zn concentrations of 0.006 μg/L in water and
0.01 mg/kg in solid samples (Simon-Hettich et al.,
2001). Flame atomic absorption spectrometry (FAAS)
has a detection limit of about 5 μg/L and an optimal
concentration range of 50-2000 μg/L. Other methods
include atomic emission spectrometry (AES), X-ray
fluorescence, inductively coupled plasma (ICP)-AES,
inductively coupled plasma mass spectrometry (ICP-
MS), polarography, anodic stripping voltammetry, and
neutron activation analysis. ICP-AES and ICP-MS are
more sensitive than FAAS, and ICP-MS enables iso-
tope ratio analysis. Specific fluorophores facilitate the
observation of labile intra- and extracellular Zn ions
(Thompson 2005).
3  SOURCES OF HUMAN AND
ENVIRONMENTAL EXPOSURE
3.1  Commercial Uses
Fifty-five Zn-containing minerals are known
(Choudhury et al., 2005). Commercially, sphalerite
(Zn sulfide; CAS No. 1314-98-3) is the most important
Zn ore, and Zn oxide (CAS No. 1314-13-2) is the most
common Zn compound used in industry. From 2009
to 2013, the world production of Zn metal increased
from 11,281,000 to 13,138,000 tonnes (International
Lead Zinc Study Group, 2013). Zinc is used as a pro-
tective coating for other metals, in dye casting and the
construction industry, in noncorrosive alloys, and in
brass. Zinc oxide is used in the manufacture of rubber
and white pigment. Inorganic Zn compounds are used
in automotive equipment, storage and dry cell batter-
ies, and dental, medical, and household applications.
Organic Zn compounds are used as fungicides, topical
antibiotics, and lubricants (Simon-Hettich et al., 2001).
3.2  General Environment
Zinc is the 25th most abundant element, accounting
for about 0.02% by weight of the Earth’s crust (Simon-
Hettich et al., 2001). The average Zn content of rock in
the Earth’s crust is 78 mg/kg (Alloway 2008).
3.2.1 Atmosphere
Atmospheric Zn is mostly found in aerosols in the
oxidized form. Zinc-containing particles up to 5 mm
in diameter occur in industrial areas (Nriagu 1980).
Naturally occurring Zn from windborne dust, fires,
and volcanic emissions is about 45,000 tons/year
(Nriagu 1989).
3.2.2 Water
In water, zinc is typically present in particles
greater than 450 nm as a simple hydrated metal ion
[e.g. Zn(H2O)62+], simple inorganic complexes [e.g.
Zn(H2O)5Cl+], simple organic complexes (e.g. Zn
citrate; CAS No. 546-46-3), stable inorganic com-
plexes (e.g. Zn sulfide), stable organic complexes (e.g.
Zn humate), adsorbed on inorganic colloids to form
for example Zn+2Fe2O3, and adsorbed on organic col-
loids to form for example Zn+2-humic acid ­(Florence
1980). The pH of most freshwaters facilitates the
adsorption of Zn onto particulates. In sediment, Zn is
both suspended and in the sediment bed. Zinc binds
to organic material, especially when the pH exceeds
6.5. Zinc also adsorbs to kaolinite and illite clay as
hydroxy species in increasing amounts up to pH 10.5
(Farrah and Pickering 1977). Organic matter is oxi-
dized as it sediments, and because oxygen and nitrate
are limited, sulfate is the predominant terminal elec-
tron acceptor, thus forming Zn sulfide, which has low
solubility (Allen 1993).
In surface waters, natural Zn concentrations are
usually less than 10 μg/L, while in groundwater con-
centrations may be about 10-40 μg/L (Elinder 1986).
3.2.3 Soil
Zinc concentrations in soils are influenced to a large
degree by the weathering of rock, of which about 75%
are sedimentary (Alloway 2008). In many places, drift
deposits of sand, gravel, and other forms derived from
rock cover the underlying rock and are the parental
substances of agricultural soils. Weathering releases
about 915,000 tons/year of water-soluble compounds
of Zn. Soil conditions that underlie Zn deficiency
include low total Zn in sandy soils and weathered acid
tropical soils; neutral or alkaline soils, as in calcareous
or heavily limed soils; soils rich in sodium chloride;
organic soils, as in peat or muck; a high phosphate
content; waterlogged soils, as in rice paddies; and high
concentrations of magnesium and/or bicarbonate in
soils or irrigation water.
Humid, hot conditions increase weathering in the
tropics, resulting in the formation of acidic soils low
in Zn (Alloway 2008). The problem is worldwide.
 61 Zinc
Low Zn status is a major cause of low seed production
(cereals, legumes, nuts). Hidden Zn deficiency, before
signs of illness appear, is believed to account for a
decrease of about 20% in worldwide plant production
(Alloway 2008).
4  ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, AND TRANSFORMATION
4.1 Air
Zinc adsorbed onto small-diameter particles of low
density can be transported in the air over great dis-
tances (Han et al., 2002). There is no evidence of harm
from fallout at current levels. For example, fallout over
oceans provides Zn to sea creatures. Deposition in the
Greenland snow records the anthropogenic use of Zn.
For example, Zn fallout increased fivefold from 1800
to the 1960s, then decreased by about 40% by the 1990s
(Boutron 1995). Total worldwide emissions in the
1980s of about 132,000 tons/year (Nriagu and Pacyna
1988) decreased to about 52,000 tons/year in the 1990s
(Pacyna and Pacyna 2001).
4.2  Water and Sediment
In 1983-1984, the estimated total anthropogenic
emissions into aquatic environments were 77,000-
375,000 tons/year. Emissions later decreased in
some countries. For example, in the USA discharges
into surface water were about 386 tons in 1988, and
about 30 tons in 1993. In addition, findings from
Canada illustrate the effects of mining: active and
inactive mines resulted in high concentrations of
Zn, 900 mg/L, in acidic mine tailing ponds (Simon-
Hettich et al., 2001).
4.3 Soil
Soil factors that affect plant nutrition include total
Zn, pH, organic matter, limestone (CAS No. 1317-
65-3), redox conditions, microbes in the rhizosphere,
soil moisture, other trace elements, and the amount
of phosphorus and other nutrients (Adriano, 1986).
Zinc is present in five pools: water soluble; bound
to soil particles by an electrical charge; bound to
organic ligands; poorly exchangeable bound to clay
and insoluble metal oxides; and in weathering min-
erals (Alloway, 2008). The amphoteric nature of Zn
makes it poorly available at intermediate pH but
highly available at extremes of pH. Under normal
conditions, a small proportion of Zn is in solution.
Below pH 7.7, Zn ions predominate; above pH 7.7,
1371
ZnOH+ is the major form; and above pH 9.11, zinc-
ates [Zn(OH)4]2− are soluble (Kiekens, 1995). Low
molecular weight organic acids that bind Zn are also
an important source.
Plants extract Zn ion from the soil by adsorption
(Alloway, 2008). Low pH increases cation exchange,
and high pH increases chemisorption and complex-
ation to organic ligands. In clay, both reversible Zn ion
exchange and irreversible sorption to the mineral lat-
tice occur. The latter involves fixation of Zn in a hydro-
lyzed form and precipitation as Zn hydroxide. As a
result, Zn is less available to plants.
In limestone-based soils, Zn chemisorbs onto
calcium carbonate to form the highly stable Zn
hydroxycarbonate that suppresses Zn availability to
plants. At pH 8 and above, iron oxides precipitate
and coat carbonate minerals that firmly bind Zn.
Zinc coprecipitates with iron and manganese oxides,
and with franklinite. In addition, reducing condi-
tions that form Zn sulfide decrease the availability
of zinc to plants.
Zinc in industrial wastewaters tends to precipitate
as Zn hydroxide. At pH 9.5, the lowest soluble Zn
concentration is about 0.25 mg/L (Patterson et al.,
1977). During chemical extraction and acidification
of sewage sludge, organic and some insoluble inor-
ganic forms of zinc associate with the tetrasodium
pyrophosphate fraction that accounts for 18-52% of
total Zn. Zinc mobilization begins at pH 6.0, and
most is extracted by pH 2.0. Zinc is more easily
extracted from raw sludge than from dried forms
of activated and digested sludge. Mobilization of
Zn from liquid sludge begins at pH 4.0 (Rudd et al.,
1988) and increases when sludge is added to a clay
loam or a sandy loam soil, but is less effective in the
presence of clay (Sanders et al., 1987).
4.4 Biotransformation
The turnover of Zn in biosphere is essential for life.
Zinc enters the human food chain directly through
the consumption of plants and indirectly through
the consumption of animal products. Worldwide,
many soils are low in available Zn and Zn deficiency
in plants is common (Alloway 2008). Mitigation is
a major challenge. Industrial fallout has little effect.
Zinc toxicity toward plants is infrequent. In ani-
mals, the Zn content is controlled within a homeo-
static range by an array of importing, exporting, and
retention mechanisms (Maret 2013). The risk of Zn
deficiency is low among free-ranging animals, but
is increased among herbivores when their range is
constrained (Nielsen, 2012). The risk of human Zn
deficiency is discussed below.
1372 Harold H. Sandstead

5  ENVIRONMENTAL LEVELS AND HUMAN
EXPOSURE
5.1 Air
Zinc concentrations are usually highest in urban
and industrial areas (Simon-Hettich et al., 2001). Back-
ground concentrations may range from 10 to 300 ng/
m3. In European rural areas and cities, zinc levels of
0.4-300 ng/m3 and 10-2400  ng/m3, respectively, are
reported. Indoor urban air Zn concentrations are about
0.1-1.0 μg/m3.
5.2 Water
Human consumption of Zn from drinking water is
usually negligible. For example, the estimated world-
wide Zn content of fresh clean water and drinking
water in 1992 (Zuurdeeg 1992) was 3.25 μg/L (range
0.64-16.6). On the other hand, acid corrosion of galva-
nized pipes was observed to result in concentrations
of 2 mg/L in standing water over a period of several
hours (Schroeder et al., 1967).
5.3 Soil
Worldwide, mining and smelting discharge about
1-3 million tons of mostly nondispersed Zn onto
land. In addition, fertilizer and atmospheric fall-
out account for about 689-2054 × 103 tons/year, and
­agricultural and animal wastes, sewer sludge, and
fly ash contribute 640-1914 × 103 tons/year (Simon-­
Hettich et al., 2001). The major impacts are local.
Worldwide, these sources have little impact on
Zn-deficient soils, except where Zn fertilizers are
­ found Zn intakes similar to those of adults, although
applied (Alloway 2008).
The zinc content of soils is affected by weathering
and varies widely. Average concentrations of noncon-
taminated soils were reported to be 40-90 mg/kg, with
a range of 1-2000 mg/kg (Adriano 1986). Discharges
from industrial sources also contribute to local and
more distant Zn concentrations in the soil. High con-
centrations damage susceptible plants (­Shuman et al.,
2001; Palazzo et al., 2003). Zinc in sewage sludge is
available to plants and inhibits their uptake of cad-
mium (Chaney 1988). Zinc in composted sewage
sludge ranges from 101 to 49,000 mg/kg dry weight,
with a mean of about 1700 mg/kg (Chaney 1983). Soil
Zn is introduced into the human food chain through
(1) plants and (2) animals that consume plants. The
bioavailability of Zn from food and the metabolic pro-
cesses that facilitate Zn status are unrelated to soil Zn
levels.
Certain clays consumed during geophagia adsorb
Zn from the alkaline chyme of the small intestine and
thus contribute to Zn deficiency (Halsted et al., 1972;
Çavdar et al., 1983).
5.4 Diet
The Zn content of foods varies widely (Table 1).
Reported Zn intakes in several industrialized coun-
tries and in India vary widely, from 3.1 to 18.6 mg
­(Campbell-Brown et al., 1985; Simon-Hettich et al., 2001).
A national survey in the United States found the Zn
intakes shown in Table 2. For comparison, a 2000-2001
survey of British adults, aged 19-64 years, found mean
Zn intakes of 10.7 ± 5.75 mg in men and 7.9 ± 3.54 mg
in women (Office for National ­ Statistics, 2002). In
addition, a survey of boys and girls aged 15-18 years
11-14-year-old boys and girls had intakes of 7.7 mg

TABLE 1  Zinc Content of Foods Commonly Consumed in the United States, per Common Measure
> 15 mg 5-10 mg 4-5 mg 3-4 mg 2-3 mg 1-2 mg < 1 mg

Oyster Beef Beef liver Lamb Lamb Pork loin Chicken breast
Peanut Butter Crunch® Lamb Beef Pork Pork Chicken dark meat Chicken liver

Product 19® Duck Lamb Veal Lobster Swordfish Salmon

Total® King Crab Pork Turkey dark meat Clams Shrimp Tuna
Wheaties® Captain Crunch ® Blue Crab Yogurt Mushroom Other finfish
Quaker Oats ® Rice Chex ® Skim milk White wheat flour Vegetables
Corn Chex ® White beans Navy beans White rice
Cheerios ® Chick peas Black beans Eggs
Whole-wheat flour Lentils Pinto beans Tofu
Corn meal All Bran ® Cheddar cheese
Nuts Blue cheese
Cottage cheese
Nuts

Source: Anon (2002).

 61 Zinc 1373

TABLE 2  Median Zinc Intake of Participants in NHANES-III

White Hispanic Black

n Median n Median n Median

Male
2-11 m 241 5.59 89 6.32 78 6.28
1-2 y 202 6.67 186 5.81 182 6.74
3-5 y 219 7.28 281 7.80 210 8.13
6-11 y 252 9.02 344 9.27 239 9.17
12-15 y 98 11.62 129 10.48 95 8.91
16-19 y 112 13.43 139 12.04 103 12.28
20-29 y 216 13.14 349 13.27 245 12.90
30-39 y 271 13.88 225 13.19 213 10.77
40-49 y 243 12.25 181 12.35 178 10.55
50-59 y 251 12.27 96 9.73 105 8.40
60-69 y 247 11.52 152 8.71 141 8.77
70-79 y 285 10.34 60 8.13 93 7.84
80 y + 250 9.06 19 7.74 21 7.04

Female
2-11 m 232 5.55 74 5.89 84 5.80
1-2 y 222 5.65 216 5.72 173 5.69
3-5 y 206 6.48 328 6.79 244 7.47
6-11 y 259 7.70 383 8.07 213 8.12
12-15 y 123 8.07 140 8.65 96 8.53
16-19 y 133 8.38 131 8.62 114 9.37
20-29 y 244 8.41 317 8.80 254 8.86
30-39 y 279 8.78 247 8.39 241 7.55
40-49 y 224 8.55 185 7.80 160 7.16
50-59 y 221 7.94 100 8.13 125 7.01
60-69 y 246 7.71 153 6.80 148 6.93
70-79 y 253 7.18 51 6.42 93 6.37
80 y + 251 6.59 23 5.26 35 5.92

m, months; NHANES, National Health and Nutrition Examination Survey; y, years

Source: Alaimo et al. (1994).

and 6.7 mg, respectively (Thane et al., 2004). However,
the Zn c­ ontent of food is only part of the story. Phytate
and other indigestible Zn-binding ligands bind Zn, thus
preventing its absorption (Hunt et al., 2008; Hambidge
et al., 2010). There is no evidence that humans adapt
to the various indigestible Zn-binding ligands in their
diets (Brune et al., 1989; Hunt et al., 2008).
5.4.1 Plants
Cereals and legumes are the major sources of dietary
Zn for the world’s poor (Gibson 1994). As affluence
increases, omnivorous diets become possible; in these,
cereals and legumes become less important sources of
Zn. In the USA, cereals and legumes are reported to
provide about 30% of dietary Zn (Walsh et al., 1994).
Milling decreases the Zn content of cereal-derived
foods (Table 1). For example, the Zn content of yellow
whole-grain cornmeal is 2.2 mg/cup (122 g) and that of
yellow degermed corn meal is 1.0 mg/cup (138 g); the
Zn content of cooked long-grain brown rice is 1.2 mg/
cup (195 g), and that of cooked long-grain white rice
is 0.5 mg/cup (175 g) (Gibson and Ferguson 2008).
Legumes are usually richer than refined cereals in
Zn. For example, the Zn content of beans ranges from
1.9 mg/cup (172 g) in cooked mature black beans to
2.5 mg/cup (164 g) in boiled chickpeas.
The removal of indigestible plant ligands by mill-
ing and/or fermentation improves Zn bioavailability
(Sandstrom and Sandberg 1992; Larsson et al., 1996),
but milling also removes Zn. Current knowledge sug-
gests phytate:Zn molar ratios of less than 5 are usu-
ally associated with higher intestinal absorption of Zn,
and that ratios greater than 15 are usually associated
with low Zn absorption (Hunt et al., 2008). Indigestible
Zn-binding ligands in the diet are excreted in the feces
(Dintzis et al., 1985).
5.4.2  Flesh Foods
Animal flesh is the best source of readily bioavail-
able Zn. In the United States, meat provides about
50% of dietary zinc (Walsh et al., 1994). Red meat is
the richest common source (Table 1). The preferential
1374 Harold H. Sandstead
consumption of poultry, finfish, and dairy prod-
ucts instead of red meat decreases Zn intake and can
increase the risk of Zn deficiency (Sandstead et al.,
1982). High dietary phytate and other indigestible Zn-
binding ligands in food prevent the absorption of Zn
from animal flesh (Hunt et al., 2008).
5.4.3  Dairy Products
Cow milk provides about 20% of the daily Zn
intake in the USA (Walsh et al., 1994). Adult absorp-
tion of a 65Zn tracer added to cow’s milk was 28%,
compared to 41% from human milk and 14% from
soy formula (Sandstrom et al., 1983). The low absorp-
tion of Zn from soy formula is related to its phytate
content.
5.4.4  Nutritional Supplements
The U.S. Food and Drug Agency classifies nutri-
tional supplements as food. A national survey during
2001-2006 of 18,758 subjects more than 1 year of age
found that consumption of nutrition supplements is
common among children aged 1-5 years, older adults,
and persons with higher education and income levels.
About 50% of the population and 70% of adults aged 71
years and older are consumers of dietary supplements,
and about 33% take multimicronutrient mixtures (Bai-
ley et al., 2011b). It has been suggested that among men
and women more than 60 years old the Zn status of
35-41% and 36-45%, respectively, might be improved
by supplements (Ervin and Kennedy-Stephenson,
2002). In contrast, only 6% of young Germans aged
2-18 years reported consuming supplemental minerals
(Sichert-Hellert and Kersting, 2004).
Current guidelines suggest that daily Zn intakes
greater than 40 mg in adults increase the risk of Cu defi-
ciency (Food and Nutrition Board 2006). Risk is higher
among the elderly: among persons aged less than 71
years, 11% of men and 7% and women exceeded the
guideline, while 16% and 11% of men and women
older than 71 years exceeded the guideline (Bailey
et al., 2011a). Although not specified, the guideline
must apply to persons consuming omnivorous diets
that are low in indigestible Zn-binding ligands; diets
rich in indigestible Zn-binding ligands suppress Zn
absorption (Hunt et al., 2008).
5.5  Work Environment
5.5.1 Inhalation
Exposure to metallic Zn and Zn compounds occurs
during Zn mining, smelting, and welding, as well as
other uses of Zn compounds (Simon-Hettich et al.,
2001). Toxicity from Zn oxide and Zn chloride are of
the greatest concern.
6  BIOLOGICAL MONITORING
6.1  Diet History
The collection of dietary information is an inva-
sive process that depends on the respondent’s mem-
ory, willingness, and ability to provide information
concerning the highly personal body function, i.e.
eating.
As far as Zn is concerned, history identifies the
foods available for consumption and the frequency
and amounts eaten. Collection of the latter data may be
difficult. Quantitative data allows the use of published
food composition data to estimate the amount of sub-
stances in foods that are of interest with respect to Zn.
Unfortunately, information concerning ­ Zn-binding
ligands in foods is limited.
When the collection of quantitative data is precluded
or unnecessary, the frequency of consumption of spe-
cific foods in the common cuisine provides useful data.
This approach identified correlations between the fre-
quency of red meat consumption and Fe nutriture in
women (Worthington-Roberts et al., 1988). These find-
ings were confirmed by a second study (Yokoi et al.,
2003, 2007): red meat intake was found to correlate sig-
nificantly with the size of the rapidly exchangeable Zn
pool; and sources of wheat bran correlated negatively
with the size of the Zn pool.
Diet history can also identify excess Zn consump-
tion in supplements, beverages, and other foods.
6.2  Physical Signs
The physical signs of Zn deficiency, other than
retarded growth and delayed development in chil-
dren, become increasingly evident with the passage of
time. Chemical and functional effects precede obvious
physical signs such as acrodermatitis (Kay et al., 1976;
Arakawa et al., 1976; Neldner et al., 1978) and demen-
tia (Henkin et al., 1975).
The prevalence of chronic Zn toxicity from diet
supplements or the pica of Zn-rich substances, e.g.
the U.S. 1 cent coin, is unknown. Physical findings
may include myeloneuropathy resembling that of
vitamin B12 deficiency (Kumar et al., 2005). Cardiac
arrhythmias also occur in human Cu deficiency
(Klevay et al., 1984; Reiser et al., 1985), a finding
confirmed in both experimental and farm animals
(Klevay, 2000).
 61 Zinc 1375

Acute alimentary Zn toxicity is an unusual event 6.4  White Blood Cell Zinc
associated with drinking an acidic liquid such as lem-
Leukocyte and lymphocyte Zn concentrations more
onade that has been exposed to a galvanized container.
strongly reflect Zn status compared to plasma Zn
Signs and symptoms can include severe abdominal
(Prasad et al., 1978; Meadows et al., 1983). However,
distress and vomiting.
their isolation and analysis is technically demanding
The inhalation of Zn oxide fume by welders and
(Milne et al., 1985).
others working in conditions in which Zn is heated to a
high temperature results in a characteristic acute respi-
ratory illness of short duration with fever and flu-like 6.5  Hair Zinc
symptoms; it is associated with tolerance to continued
Low hair Zn concentrations were found in
exposure and reoccurs after later reexposure. A sec-
­n-deficient stunted Egyptian farm boys (Strain
Z
ond, potentially lethal respiratory illness occurs after
et al., 1966). In addition, low hair Zn concentrations
exposure to Zn chloride, usually from smoke bombs
were associated with reduced growth in children
designed for crowd control. In this case, respiratory
­(Hambidge et al., 1972; Ferguson et al., 1993; Cavan
distress is very severe.
et al., 1993). In contrast, premenopausal women with a
low rapidly exchangeable tissue Zn pool (Yokoi et al.,
6.3  Plasma/Serum Zinc 2003) did not display a decrease in hair Zn. In addi-
tion, the 6-7-year-old low-income Mexican-American
The concentration of the plasma Zn pool is about
children at risk of Zn deficiency had normal hair Zn,
1 mg/L (Wastney et al., 1986). Zinc functions within
while showing a significantly greater improvement in
cells; however, its status is not well reflected by
cell-mediated-immune functions after treatment with
plasma Zn (Lukaski and Penland, 1996). For exam-
Zn and a broad mixture of micronutrients than after
ple, although plasma Zn decreased substantially
treatment with other micronutrients alone (Sandstead
during chronic severe Zn deficiency (Pekarek et al.,
et al., 2008). Thus, the finding of low hair Zn concentra-
1979), it did not consistently decrease during preg-
tions can be useful diagnostically, but normal concen-
nancy in women whose offspring were affected
trations of hair Zn do not rule out Zn deficiency.
by fetal stunting, even though maternal leukocyte
Hair Zn is not commonly measured to ascertain
and muscle Zn levels were significantly decreased
excessive Zn exposure. During treatment for Zn defi-
(Meadows et al., 1981). In addition, 6-7-year-old
ciency, increases in the hair Zn concentration may
low-income Mexican-American children at risk of
occur (Pekarek et al., 1979).
Zn deficiency had normal concentrations of plasma
and hair Zn; however, their cell-mediated immune
functions improved significantly, compared to con- 6.6  Urine Zinc
trols, after treatment with Zn and a broad mixture
The daily urinary Zn excretion is about 7 mmol
of other micronutrients. Controls treated only with
(0.5 mg) (Milne et al., 1983). Losses increase dur-
other micronutrients showed significant improve-
ing catabolism (Cuthbertson et al., 1972), hemolysis
ment in some functions but not others (Sandstead
(Prasad et al., 1975), cirrhosis (Vallee, et al., 1959), and
et al., 2008).
diabetes mellitus (Cunningham et al., 1994). High Zn
The empirical lower limit of normal fasting plasma
exposure increased urinary Zn (Fuortes and Schenck,
Zn is 10.7 mmol/L (700 mg/L) (Pilch and Senti 1985).
2000; Main et al., 1982). Urinary Zn decreases during
Zinc kinetics of 33 premenopausal women not tak-
Zn deficiency (Prasad et al., 1963a). Experimental Zn
ing oral contraceptives confirmed this estimate (Yokoi
deficiency in men decreased urinary Zn to less than
et al., 2003). Men are reported to have higher concen-
150 mg daily, while plasma Zn remained greater than
trations of plasma Zn compared to premenopausal
700 mg/L (10.7 mmol/L) (Baer and King 1984).
women, infants, children, and the aged (Hotz et al.,
2003). Plasma Zn has a circadian rhythm: concentra-
tions are higher in the morning. In addition, concentra-
7  HUMAN ZINC NUTRITURE
tions decrease after meals, but increase after exercise;
Zn deficiency blunts the postexercise increase (Lukaski
7.1  Biological Importance of Zinc
et al., 1984). Oral daily administration of 400 or 800 μg
folate also reduced the postexercise increase in plasma Zinc is essential for most, if not all physiological
Zn (Milne et al., 1990). functions (Maret, 2013). Zinc status (Figure 1) is affected
In toxicity, plasma Zn may or may not increase by economics, availability of foods, choice, excessive
(Kumar and Jazieh, 2001). exposure, and other factors that affect homeostasis
1376
Percent of population at risk
100
of deficiency
50 Acceptable range of
exposure or intake
Normal
homeostasis
A B
Total exposure or intake
FIGURE 1  Zinc Nutriture Model. Percentage of population
subjected to deficiency and toxicity effects according to exposure/
intake. As intake drops below A, risk for deficiency increases; at ex-
tremely low exposures or intakes, all subjects will manifest deficien-
cy. As exposure or intakes increase beyond B, a progressively larger
proportion of subjects will exhibit effects of toxicity.
(Sandstead, 1991, 2011). Deviations from adequate
status increase the risk of deficiency or excess. Zinc
adequacy is most likely when a wide variety of foods
are consumed in an omnivorous diet, when factors that
interfere with absorption and/or retention are absent,
and when there is no excess.
In contrast to other transition elements, Zn is redox
neutral and readily binds to proteins with appropri-
ate amino acid motifs. More than 3000 proteins are
known to have such signatures (Andreini et al., 2006).
These include 933 enzymes, 957 transcription factors,
221 signaling proteins, 141 transport/storage proteins,
53 proteins with structural metal sites, 19 proteins
involved in DNA repair, replication, and translation,
427 Zn finger proteins of unknown function, and
456 other proteins of unknown function. Zinc binds
to the only known eukaryotic Zn ion sensor, metal
regulatory transcription factor 1/metal-response
element-binding transcription factor-1 (MTF-1) that
controls the gene expression of Zn storage proteins.
These 60-68 amino acid thioneins include 20-21 cys-
teines that constitute seven metal-binding sites with
different affinities for Zn and other divalent metals.
Metallothioneins are redox active: oxidation of sul-
fur releases Zn and other metals, while reduction of
dithiols facilitates the binding of Zn and other diva-
lent metals. In addition, certain proteins transiently
bind picogram amounts of Zn ions. This “free” Zn has
signaling and messaging functions (Haase and Maret
2005; Haase and Rink 2011).
Zinc functions in concert with other micronutrients.
For example, Zn has several roles in the methionine
cycle/transsulfuration pathway that also requires folate,
riboflavin, pyridoxine, cobalamine, choline/betaine
and methionine for the production of S-adenosyl methi-
onine (Maret and Sandstead, 2008). Another example is
the effect of Zn on endocrine function. Zinc-responsive
Harold H. Sandstead
stunting and hypogonadism, first described in Iranian
Percent of population at risk
100
and Egyptian farmers, is associated with endocrine
functions consistent with hypopituitarism (Sandstead,
of deficiency
50
2013). Other endocrine abnormalities include reversible
inactivation of thymulin in blood plasma (Dardenne
et al., 1984), impaired function of insulin receptors (Roth
and Kirchgessner, 1994; Maret, 2008), and suppressed
activity of insulin-like growth factor-I (IGF-I) (Roth and
Kirchgessner, 1994). It is not surprising therefore that Zn
WHO 97575
status affects most aspects of health (Maret and Sand-
stead, 2006). While very severe Zn deficiency causes
death, less severe deficiency suppresses resistance to
oxidative stress and inflammation (Bao et al., 2010), tis-
sue repair (Sandstead et al., 1970), immunity and resis-
tance to infections (Fraker and King 2004; Sandstead
et al., 2008), reproduction (Apgar, 1985), fetal growth
and development (Scholl et al., 1993; Goldenberg et al.,
1995; Velie et al., 1999), child and adolescent growth
(Brown et al., 2002; Sandstead, 2013), brain develop-
ment (Dvergsten et al., 1983, 1984; Dvergsten, 1984),
cognition (Halas et al., 1986; Sandstead et al., 1998), and
behavior (Halas and Sandstead, 1975; Halas et al., 1977).
Groups at greatest risk are low-income children (Sand-
stead et al., 1998, 2008), premenopausal women (Yokoi
et al., 2007), pregnant women (and fetuses) (Cherry
et al., 1989; Goldenberg et al., 1995), and the elderly
(Sandstead et al., 1982).
7.2  Body Composition
The Zn content of a “standard” 70-kg adult male is
about 2.5 g: about 60% is in muscle, 30% in bone, 8%
in skin and hair, 5% in liver, 3% in the gastrointestinal
tract and pancreas, and < 1% in other cells and blood
plasma (Wastney et al., 1986). Soft tissue Zn (mg/g
fresh tissue) ranges from about 12 in the adrenal glands
to 102 in the prostate (Tipton and Cook 1963). Zinc is
partially redistributed through cell turnover. Zinc is
lost in intestinal, pancreatic, renal, and skin secretions,
and in skin cells and hair.
7.3 Absorption
Zinc absorption is an active process facilitated by
zinc transporter ZIP4 (encoded by SLC39A4/ZIP4)
in the enterocyte apical membrane (Cousins 2010). In
Zn deficiency, the expression of ZIP4 and other ZIP
family genes is increased. When high amounts of Zn
are present in intestinal chime, enterocytes control
the amount, about 5-6 mg daily, available for trans-
fer into the body (Beiseigel et al., 2009; Hambidge
et al., 2010). Intracellular transporters, such as zinc
transporter 7 (ZnT7), mediate the movement of Zn
among compartments. Zinc induces the synthesis of
 61 Zinc 1377

metallothionein, a cysteine-rich protein that binds 7.4 Excretion

or releases Zn depending on redox conditions. Zinc
Zinc is primarily excreted in the feces. Zinc in pan-
bound to metallothionein is not available for entry
creatic and intestinal secretions varies from 7 mmol
to the body and is returned to intestinal chime as
(0.5 mg) to greater than 45 mmol (3 mg) daily, and can
enterocytes turnover. Zinc released from metallo-
exceed dietary zinc (Sandstrom, 1997). Some secreted
thionein or other compartments into the cytosol
Zn is reabsorbed by the jejunum, ileum, and colon.
that is transported to the basolateral membrane
Zinc deprivation increases the percentage absorption
protein ZnT1 is then transported into the interstitial
and decreases fecal losses (Milne et al., 1983; Krebs and
fluid of the intestine from which it enters the portal
Hambidge, 2001).
circulation.
Sweat Zn reflects the Zn status (Milne et al., 1983).
Zinc absorption occurs throughout the small intes-
The Zn content of whole-body sweat of men living
tine and is greatest in the duodenum (Solomons, 1982).
in an air-conditioned environment and fed 8.3 mg Zn
In addition, the colon absorbs zinc (Sandstrom et al.,
daily in an omnivorous diet was about 0.49 mg daily.
1986). Fasting humans may absorb 60-70% of a tracer
The amount decreased to about 0.24 mg daily when the
dose of Zn in water (Sandstrom, 1997). Absorption
diet provided 3.6 mg Zn daily, and increased to about
from mixed omnivorous western diets is about 20-30%
0.62 mg daily when the diet provided 33.7 mg Zn daily.
(Hunt et al., 1995; Gallaher et al., 1988) (Table 3). Foods
Thus, sweat Zn can affect Zn balance.
rich in indigestible Zn-binding ligands have long been
known to suppress Zn absorption (Reinhold, 1971;
Reinhold et al., 1974; Sandstead, 1973; Committee,
7.5  Zinc Requirements
1973; Ismail-Beigi et al., 1977). It is now well estab-
lished that phytate-rich foods decrease the availability Absolute Zn requirement is related to anabolic reten-
of Zn from omnivorous diets (Hunt et al., 2008), and tion, and losses. Factorial estimates based on such data
that the daily dietary Zn requirement may double with by a World Health Organization (WHO) committee
each addtional 1000 mg dietary phytate (Hambidge and others are shown in Table 3. Included are amounts
et al., 2010). of zinc required relative to bioavailability using a coef-
Diseases that cause intestinal malabsorption ficient of variation (CV) of the absolute requirement of
increase the risk of zinc deficiency (McClain et al., 15% (the actual CV is unknown).
1985). In addition, a rare autosomal recessive muta- Substances that facilitate or inhibit Zn absorption
tion of ZIP4 (Wang et al., 2002) causes acrodermatitis determine dietary requirements. Facilitators include
enteropathica, a lethal illness of infants that begins animal proteins. In contrast, indigestible Zn-binding
after weaning from breast milk (Neldner et al., 1978). plant ligands and nonenzymatic browning ligands are

TABLE 3  Comparison of Factorial Estimates of Adult Zinc Requirements

Absolute needa Need if 20%
Source Group (mg/d) availableb 1.3c × 20% available Need if 30% available 1.3 × 30% available

WHO (Committee, Adults 2.2 11.0 14.3 7.3 9.5

1973)
Kingd (King and Adults 2.5 12.5 16.3 8.3 10.8
Turnlund, 1989)
UK (Anon, 1991) Men 2.2 11.0 14.3 7.3 9.5
Women 1.7 8.3 10.8 5.5 7.2
Canada (Committee, Men 2.1 10.5 13.7 7.0 9.1
1990) Women 1.8 9.0 11.7 6.0 7.8

The World Health Organization (WHO) estimate was based on the assumption that the Zn concentration of fat-free tissue is 30 μg/g, equiva-
lent to 2.0 g total Zn in soft tissue of a man or 1.2 g total Zn in soft tissue of a woman, as determined from a 40K-derived body cell mass. Bone
Zn was not included in the calculation because bone Zn is relatively sequestered from the exchangeable Zn pool. The Zn content of sweat was
based on a surface loss of 1 mg/L. The urinary excretion of Zn was based on reported normal levels.
aMinimal need = factorially calculated “absolute” requirement.
bAvailable = amount of zinc (mg/day) that is “bioavailable” (i.e. absorbed and used by the body each day).
c1.3 = the amount of zinc bioavailable plus two 15% coefficients of variation (2 × 15 = 30%) of the amount bioavailable.
dBased on more recent data than the WHO estimate.

Source: Sandstead and Smith (1996)

1378 Harold H. Sandstead

of high importance: they suppress Zn absorption irre-
spective of facilitators of Zn absorption (Hunt et al.,
2008), and there is no evidence that humans adapt to
them (Brune et al., 1989; Hunt et al., 2008). Current evi-
dence suggests that phytate is the major Zn-binding
ligand in diets (Hambidge et al., 2010).
Zn requirements from experimental diets were
estimated using radioactive isotopic zinc tracers: the
net retention of orally administered 65Zn by whole-
body counting over a period of days was determined
and the log-transformed data regressed to baseline
(Lykken et al., 1983; Lykken 1983); Table 4 shows rep-
resentative data.
Requirements were also estimated using stable Zn
isotopes. Fractional retention of the orally admin-
istered stable isotope 67Zn was measured relative
to urinary excretion of intravenously administered
stable isotope 70Zn (Krebs and Hambidge, 2001). The
data were used to derive Dietary Reference Intakes
for zinc (Table 5), using a CV of 10% for the esti-
mated average requirement (Food and Nutrition
Board 2006).

TABLE 4  Fractional Zn Absorption from Total Diets, as Measured by Isotopic Techniques

Zn absorption,
Subjects Isotopes Diets Zn content μmol (mg) Phytate/Zn molar ratio % (± SD)

Young adults (Petterson Radioactive High fiber 163 (10.7) 7 27 ± 6

et al., 1994)
Young women (Knudsen Stable isotope Habitual 124 (8.1) 10 34 ± 9
et al., 1995) Radioisotope Lacto-ovo-vegetarian 139 (9.1) 14 26 ± 5
Omnivorous 169 (11.1) 5 33
Women (20-42y) (Hunt Radioisotope Vegetarian 169 (11.1) 5 33
et al., 1998)
Postmenopausal women Radioisotope “Low meat” 102 (6.7) 30 ± 4.6
(Hunt et al., 1995) “High meat” 198 (13.0) 28 ± 4.6

Source: Committee (2001).

TABLE 5  Dietary Reference Values for Zinc (mg/day)

United Kingdom
(Department of Health, 1991) European DRI (Commission
U.S. RDAa (Food and WHO DRI of the European Communities,
LNRI EAR RNI Nutrition Board, 2006) (Committee, 1996) 1993)

Infants
0-3 months 2.6 3.3 4.0 2.0 – –
4-6 months 2.6 3.3 4.0 3.0 – –
7-12 months 3.0 3.8 5.0 3.0 5.6 4.0
1-3 y 3.0 3.8 5.0 3.0 5.5 4.0
4-6 y 4.0 5.0 6.5 5.0 6.5 6.0
7-10 y 4.0 5.4 7.0 8.0 7.5 7.0

Males
11-14 y 5.3 7.0 9.0 8.0 12.1 9.0
15-18 y 5.5 7.3 9.5 11.0 13.1 9.5
19-50+ y 5.5 7.3 9.5 11.0 9.4 9.5

Females
11-14 y 5.3 7.0 9.0 8.0 10.3 9.0
15-18 y 4.0 5.5 7.0 9.0 10.2 7.0
19-50+ y 4.0 5.5 7.0 8.0 6.5 7.1
Pregnancy – – 11.0 7.3-13.3 – –

Lactation:
0-4 months – – – 12.0 12.7 + 5.0
4+ months – – – 12 11.7 + 5.0

DRI, Dietary Reference Intake; EAR, estimated average requirement; LNRI, lower reference nutrient intake; RDA, recommended daily allow-
ance; RNI, recommended nutrient intake.
aAge groups of the RDA do not coincide exactly with the age groups of the other standards.
 61 Zinc
7.6  Zinc Deficiency
Food balance data from the United Nations Food and
Agriculture Organization suggest that the worldwide
prevalence of Zn deficiency is at least 20% (Wuehler et al.,
2005). Low income results in a dependency on foods
derived from cereals, legumes, and other plants that are
rich in indigestible Zn-binding ligands or a dependency
on highly refined cereal products such as polished rice
that are low in Zn, and infrequent consumption of ani-
mal products rich in bioavailable Zn (Sandstead, 2011).
Independent of income is personal choice. For example,
in the USA diets designed for elderly were inadequate
in Zn when white chicken meat and finfish were substi-
tuted for beef and/or beef liver (Sandstead et al., 1982).
In addition, when premenopausal U.S. women chose
diets low in red meat and consumed foods rich in wheat
bran the size of the rapidly exchangeable tissue Zn pool
decreased (Yokoi et al., 2003, 2007), and when pregnant
women in the USA selected diets likely to be low in bio-
available Zn the risk of fetal malformations increased
(Velie et al., 1999).
Zn deficiency suppresses many functions: cell-
mediated immunity (Sandstead et al., 2008), pre-
vention of peroxidation (Bao et al., 2010), neuro-
psychological performance (Sandstead, 2012), nerve
conduction (Yokoi et al., 2003), fetal development
(Velie et al., 1999), fetal growth (Goldenberg et al.,
1995) and development (Cherry et al., 1989), child
growth (Walravens et al., 1983; Sandstead et al.,
1998), wound healing (Savlov et al., 1962; Nielsen and
Jemec, 1968; Larson et al., 1970), and various endo-
crine functions (Sandstead, 2013; Haase and Maret,
2005; Dardenne et al., 1982). As the severity of defi-
ciency increases, functions are increasingly deranged
and physical signs become evident. For example,
patches of hyperkeratotic dermatitis evolve into
generalized acrodermatitis (Kay et al., 1976). Bilat-
eral angular oral fissures and inflammation of lips
(cheilosis) occur, and lingual papillae may become
atrophic. Hair becomes highly pluckable and alope-
cia is evident; the texture, sheen, and pigment of hair
becomes abnormal. In very severe deficiency ataxia,
disorientation and psychosis are evident (Henkin
et al., 1975).
Conditioned or secondary Zn deficiency is caused
by many illnesses (Sandstead et al., 1976; McClain,
Kasarskis and Allen, 1985). Failure of absorption and/
or increased gastrointestinal losses of Zn from Crohn
disease, gluten enteropathy, cystic fibrosis, and other
malabsorption syndromes increase the risk of defi-
ciency. In populations at risk of dietary Zn deficiency,
such as Egyptian farmers (Sandstead, 2013), it is likely
that chronic intestinal bleeding from hookworm adds
1379
to the risk: erythrocytes are rich in Zn (Migasena et al.,
1984). In this regard, it is of interest that stunting and
retarded cognition have long been associated with
hookworm infection (Dock and Bass, 1910; Lemann,
1910; Waite, J. and Nelson, I. 1919). Risk also increases
when there are excessive losses of Zn in the urine from
hemolysis of erythrocytes (Prasad, 2002), or chronic
bleeding from schistosomiasis (Prasad et al., 1963b)
and menorrhagia (Yokoi et al., 2003). Increased uri-
nary Zn excretion also occurs in some renal diseases
­(Lindeman, 1989), cirrhosis of the liver and alcohol-
ism (Vallee et al., 1959), stress (McClain et al., 1993),
catabolism (Cuthbertson et al., 1972), and inflamma-
tion (Goldblum et al., 1987).
Other simultaneous micronutrient deficiencies
decrease the efficacy of Zn treatment (Sandstead,
1999). For example, treatment of Chinese children with
Zn and a broad mixture of micronutrients was more
efficacious than the micronutrients alone or Zn alone
for growth and neuropsychological functions (Sand-
stead et al., 1998).
7.7  Zinc Toxicity
7.7.1  Dietary and Supplement Intake
The risk of Zn toxicity and resulting Cu deficiency
increases when the consumption of Zn and Cu is not
proportionate (Sandstead, 1995). The likely mecha-
nism involves Zn-induced synthesis of metallothio-
nein that has a high-binding affinity for Cu. Copper
bound to metallothionein is returned to the intestinal
chyme with the turnover of enterocytes. Examples of
the “tolerable upper limit” of Zn consumption sug-
gested by the U.S. Institute of Medicine of the National
Academies are 4 mg in youngest infants, 12 mg in chil-
dren ages 4-8 years, 34 mg in adolescents (14-18 years),
and 40 mg for persons aged 19 years and older (Food
and Nutrition Board, 2006).
Relationships between dietary Zn and Cu in an
omnivorous experimental diet are shown in Table 6. The
copper requirement correlates directly with dietary Zn
and inversely with dietary protein (­Sandstead, 1982).
Under moderate conditions, Cu loss in sweat increases
the Cu requirement to about 0.34 mg daily (Jacob et al.,
1981). Thus, the Cu requirement is likely to be greater
than the 0.90 mg daily recommended for adults by
the U.S. Academy of Medicine (Food and Nutrition
Board 2006). Findings cited in Table 7 indicate some
of the effects of Cu deficiency induced by excess Zn
consumption. Not listed is myelopathy (Kumar et al.,
2004). It appears that a dietary Zn:Cu molar ratio
greater than 18 over an extended period is potentially
harmful (Sandstead, 1995).
1380 Harold H. Sandstead

TABLE 6  Copper Requirement (mg/day) of Adult Men Fed Mixed Diets of Common Foods Providing Four Levels of
Protein and Zinca,b
Protein, g 40 60 80 100

5 mg Zn 1.0 (0.73-1.28)c [6.7-3.8]d 0.95 (0.67-1.23) [7.3-3.9] 0.89 (0.61-1.17) [7.9-4.2] 0.83 (0.55-1.11) [8.9-4.4]
10 mg Zn 1.26 (0.98-1.54) [9.9-6.3] 1.20 (0.92-1.48) [10.6-6.6] 1.14 (0.86-1.42) [11.3-6.9] 1.08 (0.80-1.36) [12.2-7.2]
15 mg Zn 1.50 (1.22-1.78) [12.0-8.2] 1.45 (1.17-1.67) [12.5-8.8] 1.39 (1.11-1.67) [13.2-8.8] 1.33 (1.05-1.61) [13.9-9.1]
20 mg Zn 1.76 (1.48-2.04) [13.2-9.6] 1.70 (1.42-1.98) [13.7-9.8] 1.64 (1.36-1.92) [14.3-10.2] 1.58 (1.30-1.86) [15.0-10.5]

aCu intake = 0.87 + 0.49 (Cu balance) + 0.05 (Zn intake) − 0.02 (n intake); Intake = requirement when balance is in equilibrium.
bFor total requirement, add 0.34 mg to account for daily surface loss of Cu under moderate environmental conditions (Jacob et al., 1981).
c95% confidence interval.
dZn:Cu molar ratio.

Source: Sandstead (1982)

TABLE 7  Zinc and Copper Intakes, Effects on Copper Nutriture

Time Cu intake Zn intake Zn/Cu
n Gender (days) (mg/day) (mg/day) molar ratio Diet Response Reference

7 F 165 1.25 ± 0.20 ∼15 ∼11.7 Food Nil Johnson et al., 1988

24 M 77 1.03/2850 ∼25 23.7 Food: 20% of 4/24 Abn, ECG, ↓ ESOD Bhathena et al.,
 kcal energy fructose with ↑ fructose, ↓ pl leu- 1986; Holbrook
and met-enkephalins, et al., 1989; Reiser
↑ pl β-endorphins, et al., 1987; Reiser
↑ cholesterol et al., 1985
8 M 105-120 0.89 ± 0.09 19 20.8 Food 1/8 Abn ECG, 5/8 ↓  Klevay et al., 1986;
ESOD, 2/7 ↓ pl Cu, Klevay et al.,
4/8 ↓ RIDCp, 1/8 ↓ 1984; Milne et al.,
 ENZCp, 2/8 ↓ oral 1990
GTT, 1/8 ↑  cholesterol
11 M 42 0.79 ∼14.7 ∼18.1 Food and formula Nil Turnlund et al., 1990
8 F 84 ∼0.70 ∼16 ∼22.3 Food 8/8 ↓ ENZ Cp, ↑  stress BP Lukaski et al., 1988;
Milne et al., 1988
10 M 36 0.6/2500 11.9/2500 19.3 Food ↓ ENZCp, 4/10 ↓ ESOD, Nielsen et al., 1990
 kcal  kcal 4/10 ↓ MNC (Plt) CCO,
4/10 ↑ glutathione
6 M 48 0.6/2500 25.8/2500 41.9 Food, fructose 3/6 Abn ECG, ↓ ESOD, Milne and Nielsen,
 kcal kcal ↓ RIDCp 2003
12 F 105 0.64/2500 12/2500 18.3 Food 3/12 Abn ECG; 10/12 ↓ Plt Milne and Nielsen,
 kcal  kcal CCO, ↓ ESOD, ↓ Plt Cu, 1996
↓ EGPX, ↑ clotting
factors V and VIII
11 M 42 0.38 14.7 37.7 Food and formula ↓ pl Cu, ↓ ENZCp Turnlund et al., 1997
13 F 90 1.0/2000 53 51.6 ↓ Short-term general Penland et al., 1999
kcal recall, ↓ number
sequence recalla

Abn, abnormal; BP, blood pressure; ECG, electrocardiogram; EGPX, erythrocyte glutathione peroxidase; ENZCp, enzymatic activity of cerulo-
plasmin; ESOD, erythrocyte superoxide dismutase; Hgb, hemoglobin; MNC (Plt) CCO, monocyte (platelet) cytochrome c oxidase; pl, plasma;
RIDCp, radial immunodiffusion ceruloplasmin.
aContact Penland for more formation.

Source: In part from Milne (1998).

7.7.2  Reference Dose

The U.S. Environmental Protection Agency
(­Dourson, 1994) suggested the lowest observed
adverse effect level (LOAEL) for Zn to be 60 mg daily. A
reference dose (RfD) of 0.33 mg/kg/day (23.1 mg daily
for a 70-kg man) was proposed. For comparison, the
“tolerable upper limit” for Zn consumption by adults
suggested in the USA is 40 mg daily (Food and Nutri-
tion Board, 2006).
A theoretical alternative approach that might be
useful estimates the LOAEL and the upper limit (UL)
for Zn relative to the dietary Zn:Cu molar ratio. Data
 61 Zinc
in Table 6 suggest the LOAEL for Zn to be 13.7 mg
when Cu intake is 0.83 mg (a Zn:Cu molar ratio of
16.1). This is near to 18, a level suggested to be unde-
sirable ­(Sandstead, 1995). In contrast, when Cu intake
is 1.5 mg Cu and Zn intake is 13.7 mg (a Zn:Cu molar
ratio of 8.9), the level of Zn is healthful. In the latter
case, the addition of a Zn supplement of 10 mg would
increase the Zn:Cu molar ratio to 15.4.
7.7.3  Poisoning from Ingestion of Zinc-Contaminated
Food, Drink, and Other Substances
Zinc-contaminated drinks containing up to
2500 mg/L, at a dose of about 325-650 mg Zn caused
nausea, abdominal cramping, vomiting, tenesmus,
and diarrhea with or without bleeding (Brown et al.,
1964). In contrast, Zn chloride ingestion caused pan-
creatitis and subsequent exocrine insufficiency (McK-
inney, Brent and Kulig, 1995). Ingestion of more than
1800 g Zn-containing coins by a mentally ill patient
over years resulted in Cu deficiency and high plasma
Zn (Kumar and Jazieh, 2001).
7.7.4  Poisoning from Inhalation
7.7.4.1  Zinc Oxide Fume
Metal fume fever (MFF) from the inhalation of Zn
oxide fume is also known as brassfounder’s ague, Zn
chills, Zn fever, Spelter’s shakes, and metal shakes.
According to the Commission for the Investigation
of Health Hazards of Chemical Compounds in the
Work Area (German Research Foundation, 2002),
about 3 million workers worldwide are at risk. The
illness is an acute, self-limited flu-like illness mani-
fested primarily by fever, chills, myalgia, nausea,
fatigue, and occasional shortness of breath. Appar-
ently less common are a sweet or metallic taste,
throat pain, thirst, dyspnea, chest pain, and X-ray-
identified lung opacities. The cause is inhalation of
finely dispersed particulates that are formed when
Zn oxide is volatilized as nanoparticles of less than
1.0 μm aerodynamic diameter (Gordon et al., 1992;
Gordon and Fine 1993) that, experiments suggest,
penetrate alveoli and induce inflammation (Fine
et al., 1997; Kim et al., 2010), and also are found in
arterial endothelial cells (Gojova et al., 2007). Toler-
ance occurs after repeated exposure and subsides
after 1-2 days when exposure stops; illness recurs
with reexposure.
Adequacy of guidelines that allow exposures of
5 mg/m3 8-h time-weighted average (TWA) threshold
limit value (TLV) for Zn oxide fume was examined
by the measurement of specific cytokines in blood
and bronchoalveolar lavage in 13 naive subjects. On
1381
separate days, 2.5 or 5 mg/m3 furnace-generated Zn
oxide fume in air was administered for 2 h. Mild fever
occurred after both levels of Zn oxide; plasma inter-
leukin-6 (IL-6) was increased 3 and 6 h after exposure
to 5 mg/m3, but tumor necrosis factor (TNF-α) did not
increase (Fine et al., 1997). Subjects repeatedly exposed
to Zn oxide fume displayed a significant decrease in
both percentage neutrophils and IL-6 concentration in
bronchoalveolar lavage fluid compared with baseline,
while clinical symptoms were “minimal” (Fine et al.,
2000). These findings were interpreted as consistent
with chronically exposed sheet metal workers being
tolerant to Zn oxide fume at the Occupational Safety
and Health Administration (OSHA) permissible expo-
sure limit.
Although MFF is not usually associated with long-
term sequelae, one study suggested that it might be
associated with occupational asthma (El-Zein et al.,
2005). In addition, a single report from England associ-
ated aseptic meningitis and pericarditis with a case of
MFF (Hassaballa et al., 2005). Furthermore, an appar-
ently unique report of 61 Egyptian unprotected work-
ers exposed to Zn oxide fume while dipping articles
into molten Zn over a period of years, found three
times as much dyspnea and six times as many muscle
cramps and twitches in the workers compared to 51
administrative personnel (El Safty et al., 2008). Workers
had lower serum ionized calcium concentrations than
controls. The mean serum Zn concentration of workers
was 87.57 ± 42.88 μg/dL, compared to 76.97 ± 14.17 in
administrative personnel. Some workers also had low
concentrations of serum Cu and nearly half had hemo-
globin concentrations less than 10 g/dL.
Consistent with guidance from the International
Labor Organization, Zn oxide fume and dust from Zn
mining, smelting, welding, and other activities are reg-
ulated in many countries at 5-10 mg/m3. Safety guide-
lines by the U.S. OSHA are available on the agency
website. A 5 mg/m3 8-h TWA exposure is suggested,
with a short-term exposure limit of 10 mg/m3, a 5 mg/
m3 10-h TWA limit, and a 15-min ceiling of 15 mg/m3.
The German Research Foundation (2002) also pub-
lished guidelines for Zn oxide fume. In contrast to the
OSHA, they suggest a TLV of 2 mg/m³ TWA. Other-
wise, their guidance is similar.
7.7.4.2  Zinc Chloride Fume
Inhalation of Zn chloride fume causes chemical pneu-
monia. Published examples testify to the severity of
illness. Two soldiers exposed briefly had minor symp-
toms for 10 days, and then rapidly deteriorated with
severe respiratory distress, pulmonary hypertension,
and death on the 25th and 32nd days (Homma et al.,
1992). Pathology in their lungs included interstitial and
1382 Harold H. Sandstead
intra-alveolar fibrosis, endothelial proliferation, and
vascular occlusions. Thirteen soldiers were exposed
for no longer than 5-10 min to smoke from smoke
bombs in the open air or to smoke that entered a house
(Kofoed-Enevoldsen et al., 1997). At first, there were
few complaints and all were treated intravenously with
hydrocortisone. The four believed to be exposed for
more than 1 min were treated systemically with hydro-
cortisone for 1 month: during the first 4 weeks their
lung carbon monoxide diffusion capacity decreased
substantially. Eight or more weeks later they continued
to complain of respiratory symptoms. Of 20 individuals
with low exposure, most showed pulmonary function
consistent with restrictive lung injury (Hsu et al., 2005).
Three to 21 days after exposure, high-resolution com-
puterized tomography (CT) of the lungs found patchy
or diffuse ground-glass opacities with or without con-
solidation. In 10 returning patients, pulmonary function
and CT scans were improved 27-66 days after exposure.
Guidelines for protection from Zn chloride fume are
available from the OSHA website.
8  EFFECTS EVALUATION
8.1  Homeostatic Model
Zinc is essential and, as shown in Figure 1, may be
adequate, deficient, or toxic in nature. In nature, Zn
is obtained from the diet. Homeostasis is maintained
by chemical mechanisms that control the absorption,
distribution, and excretion of Zn and other nutrients.
Zinc functions in concert with other nutrients, espe-
cially when all nutrients are present in proportionate
amounts. In nature, Zn deficiencies seldom occur alone.
8.1.1  Zinc Adequate Status
Zinc status is likely to be adequate when diets are
omnivorous, include a wide variety of foods, and
include animal flesh on a frequent basis, and when
consumption of foods rich in indigestible Zn-binding
ligands is limited. The consumption of such diets is
most likely to occur among the affluent. Some affluent
groups, especially the aged and those with underlying
illness, may benefit from judicious supplementation
with Zn and other micronutrients.
8.2  Risks to Human Health
8.2.1  Zinc Deficient Status
The worldwide prevalence of Zn deficiency appears
to be at least 20%. The poor are at greatest risk. As
income decreases, food variety and meat consumption
decrease, and dependence on foods rich in indigest-
ible Zn-binding ligands, or foods low in Zn such as
roots, tubers, and highly refined cereals such as rice
increases. Zn deficiency also occurs among the affluent
when dietary choice results in diets limited in bioavail-
able Zn. Other persons are at risk because of abnormal
physiology. Judicious use of Zn and other micronutri-
ents can benefit such persons.
8.2.2  Zinc Excess Status
8.2.2.1  Oral Excess
The uncontrolled consumption of Zn-containing
supplements increases risk Zn excess. Although about
40% of U.S. adults consume over-the-counter dietary
supplements, the prevalence of Zn excess is unknown.
Metallothionein induced by Zn excess avidly binds to
Cu. With enterocyte turnover, Cu is returned to the
intestinal chime. Infrequently, excess Zn is consumed
in Zn-contaminated food or drink, or during pica.
8.2.2.2  Inhalation Excess
Zinc oxide inhalation during welding, galvanizing,
brass smelting, and other industrial processes causes
MFF, a short-duration, flu-like illness that recurs after
a period of nonexposure and is usually of little appar-
ent consequence. In contrast, Zn chloride inhalation
causes a destructive, potentially lethal pneumonia.
8.3  Environmental Risk Assessment for Zn
Human exposure to excess Zn does not, for prac-
tical purposes, occur in the natural environmental.
Zinc from anthropogenic sources tends to be limited
to industrial settings, where it may affect workers.
General populations are little affected. Zinc released
into the environment is diluted, and with time forms
insoluble compounds in alkaline environments. Agri-
cultural soils are commonly low in available Zn, a
phenomenon of high importance for plant production
and for the health of herbivores living in Zn-limited
areas.
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