EPA/600/8-87/022 F
JULY 1987
Summary Review of Health Effects
Associated With Zinc And Zinc Oxide
Health Issue Assessment
ENVIRONMENTAL CRITERIA AND ASSESSMENT
OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL
ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U. S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NC 27711
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Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
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Preface
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Abstract
Zinc is a dense, bluish-white, relatively soft metal used extensively in
the galvanizing of iron and steel. Zinc oxide, the most valued of the variety of
compounds formed by zinc is used principally in rubber products as an
activator in the vulcanization process and in the treatment of burns, .nfections,
3nd Snncdoccu?seSnaturally in the environment; however zinc may also enter
the environment as the result of mining and processing the production of z me
oxide and the manufacture and use of products contaming zinc oxide, he
combustion of coal and oil, the production of iron and steel, and the
man exposed to zinc through the ingestion of food
(between 8 and 18.6 mg/kg/day)' and drink (averaging up to 10 rng/day^
Based on annual average airborne zinc concentrations ,n areas throughout the
United States without mines or smelters of generally <1mg/m3, the
contribution, of zinc from inhaled air represents an ms.gnificant amount of
daily zinc exposure, averaging approximately 20 yg.
The literature on the toxic effects of z.ne is lim.ted. The most widely
known systemic effect resulting from acute inhalation of freshly formed I zinc
oxide fumes is a disease called "metal fume fever." Metal fume fever occurs
fn certain occupational settings and the exposure level at which toe fever
occurs is not known. Also, the ingestion of zinc levels above 400 parts per
million (ppm) produces acute gastrointestinal distress.
There is inadequate evidence to evaluate the carcinogen.c potential of
zinc or zinc oxide and no evidence suggesting that zinc is teratogen.a A
definite conclusion regarding the possible reproductive or mutagemc effect of
zinc cannot be drawn because of the lack of adequate studies.
IV
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Table of Contents
Preface
Abstract '.'.".'.'.' i 1 .'"
Authors, Contributors, and Reviewers !,!
List of Tables . v!
1. Summary and Conclusions "......' ........ .".'. V"
2. Background Information
2.1 Chemical Characterization and Measurement 5
2.2 Sources and Emissions 5
2.3 Environmental Release and Exposure ".'.'. K
2.3.1 Environmental Release a
2.3.2 Exposure .. *
2.4 Environmental Effects '.'.'.'.'.'.'.'.'.'.'.'.'. Q
3. Health Effects
3.1 Pharmacokinetics and Metabolism ! IQ
3.1.1 Absorption in
3.1.2 Distribution ... o
3.1.3 Elimination '.'.'.'.'.'.'.'.'.'.'. ,3
3.2 Essentiality and Biochemical Role ....'.'.'. 14
3.3 Clinical Manifestions of Zinc Deficiency 1 s
3.4 Effects in Animals 7
3.4.1Acute Toxicity '.'.'.'.'.'.'.'.'.'.'. 17
3.4.1.1 Inhalation . . 17
3.4.1.2 Oral '.'.'.'.'.'.'.'. ,9
3.4.2Subchronic Toxicity pn
3.4.2.1 Inhalation . ™
3.4.2.2 Oral .'.' go
3.4.3Chronic Toxicity 22
3.5 Carcinogenesis 22
3.6 Mutagenicity 2^
3.7 Teratogenicity 04
3.8 Reproduction 04
3.9 Neurotoxicity . oc
3.10 Effects in Humans '.'.'.'.'.'.'.'.'. ?S
3.10.1 Inhalation Toxicity oc
3.10.20ral Toxicity .'.'.' £3
3.10.3Other Routes of Exposure '.'.'.'.'.'. 27
3.10.4Epidemiology 2/
4. References „
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Authors, Contributors, and Reviewers
This document was prepared by the Environmental Criteria and
Assessment Office EPA, Research Triangle Park, North Carolina (Beverly
Wafts' otthis^mL have been reviewed for scientific and technical
merit by the following scientists: Dr. Paul Mushak, Div,s,on of Environmental
Pathology University9 of North Caro.ina, Chape. ^-.^^S^JSSSS
Piscator Department of Environmental Hygiene, the Karolinska.InsMute.
S ockho m Sweden; and Robert D. Putman, Environmental Health ConsuKant,
7 Maple Street. Weston. Connecticut. In addition, it has been reviewed by
members of the Carcinogen Assessment Group (CAG). Reproductive Effects
Assessment Group (REAQ), and the Ensure Assessment Group W of
the Office of Health and Environmental Assessment (OHEA),
Washington, DC.
VI
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No.
2-1
2-2
3-1
3-2
3-3
3-4
List of Tables
Atmospheric emission factors Q
Acute toxicity values for fish 9
Typical zinc concentrations of normal tissues in four species 14
Recommended dietary allowances for zinc 15
Zinc metalloenzymes j Q
Groups involved, age, duration of work and timing of work
of the 66 workers exposed to the effect of zinc oxide-seen for
medical examination 29
VII
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1. Summary and Conclusions
«f «fli7C 'ia den!f ' bluish-wnite- relatively soft metal with an atomic weight
of 65.37. Zinc oxide, the most valued of the variety of compounds formed by
'
In 1984, the U.S. mine production of zinc totaled 252,768 metric tons
Domestic production of zinc oxide in 1984 totaled 150,623 metric tons Zinc
!t-n^ .f*6"5^ in the Salvanizing of iron and steel. Zinc oxide is used
prmcipa ly in rubber products as an activator in the vulcanization process
skin diseases e$ °f ^ OXide '* '" the treatment °f burns> Dions',
fr°m 10 to 30° k- Uncontaminated
Content
6 natural|V ^"^ing levels of zinc in the environment,
sources which enter the environment as contaminants.
Such sources include m.nes, smelters, production of zinc oxide and the
ma.±d «?* U!f ? Pr°,dUCtS Containin9 2inc oxide- the combustion of
coal and oN, the product,on of iron and steel, and the incineration of refuse
howeZ rt ^ I'6 ^ ar'e on ambient air levels around mines or smelters;
however, it has been estimated that 100 g of zinc is emitted to the
atmosphere per metric ton of zinc mined and milled. Air concentrations of
zmc have been reported to range from 0.27 to 15.7 yg/m3 over 24-hr
periods proximal to one U.S. smelter in 1977. The annual average around
that smelter m 1977 was 5.0 Vg/m3. However, average yearly or quarterty
aeTsw^m2^ 6H °f <' V9/m3 have been ^ported" for several other
areas with smelters; and m areas without mines or smelters, ambient air levels
of zinc generally average < 1 yg/m3.
High levels of zinc in surface waters represent industrial and urban
poHution from such sources as galvanized pipes, dumpings of plating baths
as 210 mnH9',hSurfeCt ^ haS bee" found to «>ntain zinc levels as high
frLtm T9 f feSf °f the dlsposal of zinc minin9 waste- Water leaving
treatment plants generally contains < 5 mg/L of zinc
i««.i?nC|'S tOXi(;-t0 aquatiC or9anisms and other wildlife at high exposure
ESS; J»n^UH °r9anism,s- zinc toxicity depends largely on the water
hardness and pH, as well as the exposure level
Several quantitative methods may be used for determining the
atmospheric and soil levels of zinc and zinc compounds. The analytic
JmS"68 fre?uentV "sed are X-ray fluorescence spectrometry (X-ray
emission spectrometry), neutron activation analysis, mass spectrometry
voltammetry, absorption spectrophotometry, atomic absorption spectrometry
atomic fluorescence spectrometry, and optical emission spectroscopy. The
e in Water ******
The body of a 70-kg man typically contains approximately 1 4 to 2 3 q
of zinc. Humans are mainly exposed to zinc through the ingestion of food
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and drink The zinc content of the average daily diet ranges from 8 to 18.6
ma/kq The ingestion of 2 liters of water per day could contribute up to 10
mq Jnc per dly The contribution of zinc from inhaled a,r represent an
SiqnmcanT amount of the daily zinc exposure, averaging approximately -20
uo Z nc may also be absorbed through skin during the adm.mstrat.on of
ointments Xining zinc oxide or from skin contact with dust containing jzmc
Inhaled zinc is absorbed across the alveolocaP.llary membrane; however
the fate of inhaled zinc will depend on the particle size and solubility as wen
as the functional state of the lungs. There are no quantrtative data on the
deooltion and absorption of inhaled zinc compounds, but experiments on
SmansinSe that both zinc oxide dust and fumes of very small particle
sizSare deposited in the alveoli. That inhaled zinc is absorbed was shown by
me finding of widespread distribution of zinc in the soft tissue and hver of a
man aSenta^ly exposed to radio.abled zinc dust from an expenmental
reactor and increased plasma and serum zinc levels in exposed workers
re O Jy aSstered zinc is absorbed at several loci in the gastrointes-
tinal tract particularly in the second portion of the duodenum The rate of
absorption depends on the level and form of zinc adm.nistered and the
oresence or absence of other substances. .
Zinc is mainly excreted via the gastrointestinal tract; approx.mately 70 to
80 percent of the ingested zinc is found in the stool. To a .lesser extent zinc
is eliminated via urine, sweat, hair, and skin. Urinary excret.on of zinc may be
SUbS^s6slu^S StaTSl the body attempts to control the zinc
balance homeostatically by regulating zinc absorption and fecal Breton.
The mechanism governing this homeostat,c regu ation is not well understood
however, available data suggest that several protems and some low
molecular-weight compounds may be involved.
Zinc is essential for the growth and development of both plants and
aninS and Seen included in the list of recommended dietary allowances
?RDA) for humans. A daily intake of 15 mg/day has been recommended for
adults and 10 mg/day for preadolescent children. In children ages 0.5 to 1.0
yea 5 mg/day has been recommended and 3 mg/day for infants ages 0 1 tc ,6
monhs A daily zinc intake of 20 and 25 mg/day is recommended for
pregnant and lasting women, respectively. Zinc deficiency in people can
result in dwarfism, anemia, hypogonadism, hepatosplenomegaly, rough and
dry sk in. and mental lethargy. From a public health perspective .much
greater concern generally exists in regard to zinc defiaency associated wrth
insufficient daily intake of the metal in contrast to toxic effects less often seen
in association with excessive intake resulting from higher level exposures to
re0 effects resulting from exposure to zinc is very
limited. The most widely known systemic effect resulftng from ^inhala-
tion of freshly formed zinc oxide fumes is a disease called metal fume
fever " Metal fume fever occurs in certain occupational settings and generally
strikes at the beginning of the work week when the worker has not been
exoosed for several days. It is characterized by headache, fever, hyperpnea,
naSS swealng andymuscle pains, which occur within a few hours after
exposu e and per-sist for 1 to 2 days. The exact acute exposure eve a
wh?ch metal fume fever occurs is not known, but it has been estimated that
metal fume fever generally does not occur at zinc oxide levels below 15
mgm3 aTthough some Eastern European literature reports the occurrence of
mete! ume fever in workers repeatedly exposed to «nc ox.de leves
averaging as low as 5 mg/m3 but ranging up to 58 mg/m3. Chrome
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respiratory infections, dermatitis, conjunctivitis, and gastritis were also
reported for the same workers. Other Eastern European literature reported an
increase in respiratory illnesses such as chronic bronchitis and diffuse
pneumosclerosis in workers exposed to zinc oxide levels of up to 5.1 mg/m3
However, in both reports, contributions from other substances in the
workplace air cannot be ruled out. Hypocalcemia was reported in workers
exposed to zinc oxide levels ranging from 2.44 to 7.15 mg/m3.
The National Institute for Occupational Safety and Health (NIOSH) has
sought to protect workers exposed to zinc oxide fumes by recommending an
exposure standard. Occupational exposure to zinc oxide fumes shall not
exceed concentrations greater than 5 mg zinc oxide/m3 determined as a TWA
exposure for up to a 10-hour workday, 40-hour workweek, with a ceiling of
15 mg zinc oxide/m3 as determined by a sampling time of 15 minutes The
Occupational Safety and Health Administration (OSHA) established an 8-
nour TWA permissible exposure limit of 5 mg zinc oxide/m3 and the
American Conference of Governmental Industrial Hygienists (ACGIH) has
adopted a threshold limit value (TLV) of 5 mg/m3.
Acute effects also result from exposure to zinc chloride, the major
component of smoke bombs. Inhalation of this smoke in confined areas has
resulted in severe pulmonary disease and death. No information is available
on the concentrations of zinc chloride which causes these effects.
The ingestion of zinc levels above 400 ppm is known to cause acute
gastrointestinal distress. Such conditions usually result from the ingestion of
food and/or drink which has been stored in galvanized containers. However
epigastric pain has been reported in subjects chronically exposed to mean
zinc oxide levels of 5 to 18 mg/m3 in an occupational setting. Available
information also suggests that the administration of 150 mg elemental
zinc/day for 6 weeks may have an adverse effect on the immunologic and
cardiovascular systems.
Zinc oxide has been shown to cause chromosomal damage in the form of
an increased frequency of hyperdiploid cells in the bone marrow of noninbred
white rats at concentrations of 0.1 and 0.5 mg/m3. An increase in the
frequency of structural aberrations of the chromosomes and hyperdiploid cells
was seen when human lymphocytes at the G0 stage of the cell cycle were
exposed to zinc acetate at concentrations of 7.0 to 200 pg/mL An
interpretation of this report is difficult because the category of aberrations'
referred to as hyperdiploid cells is not one generally used by cytogeneticists
in discussing this type of study. Additionally, the frequency of structural
aberrations at 20 ug/mL was slightly less than the frequency at 7 yg/mL
Zinc oxide was not mutagenic at levels of 100 to 5,000 jjg/plate in the
Salmonella reversion assay.
There are no data which suggest that a zinc level over that required for
normal growth and development is teratogenic. A greater risk of
malformations is expected in regard to zinc deficiency. Zinc also appears to
offer a degree of protection against the teratogenic effect of cadmium. There
are several animals studies and one human study which suggest that the
ingestion of high levels of zinc may have an adverse impact on reproduction
Three premature births and one stillbirth occurred in a small group of women
ingesting 40.5 mg zinc/day during the third trimester of pregnancy. However
no adverse effects on the outcome of pregnancies were observed in a group
of women supplemented with 81 mg zinc/day during the third trimester of
pregnancy.
There is no evidence suggesting that inhaled zinc or orally or parenterally
administered zinc induces tumor formation. The only positive carcinogenic
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response resulting from zinc exposure occurs following injection of zinc salts
into the testes of fowl and rats. Since this route of exposure is not likely to be
encountered by humans, the predictive value of these results for humans is
limited given the lack of carcinogenicity testing and epidemoologic studies.
The available evidence for zinc is considered to be inadequate to assess the
carcinogenic potential equivalent to a Group D weight of evidence. There are,
however, data which indicate that zinc is indirectly involved in tumor formation
as a growth promoter or inhibitor. In some animal studies, zinc-deficient
diets have been found to promote the development of chemically induced
cancers, whereas zinc-adequate and zinc-supplemented diets provide a
protective barrier against tumor formation. In other animal studies, zinc-
adequate or zinc-supplement diet facilitated the development of chemically
induced cancers. Also, examinations of cancerous tissues in humans have
shown that the zinc level deviates from that found in noncancerous tissue.
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2. Background Information
healthpffprnf Summary of the data ava«able on the
health effects of exposure to zinc/zinc oxide. Emphasis is olaced on
dressed inn, H ,
addressed, including general
States
wth
are
toxicity, teratoqenicitv
health effects d*»3£i Perspe his
qU3lity aSpSCtS °f Zinc/zinc °*ide inPfhe United
distnbution' fate- a"d concentrations associated
^
2.1 CHEMICAL CHARACTERIZATION AND MEASUREMENT
' bluish-white'
' ' ,
formed vzinr'f Z"l?f 'S ^ m°St valued of a" the Compounds
powder wfththPmnL , white or yellowish white, odorless, and tasteless
powder with the molecular formula ZnO and atomic weight of 81 37
soil ?eeve1s oqfUa±tatiVHmeih°dS may be used to -determine atmospheric and
em,8S,on speolroscopy (National Research Council, 1978) The
ol 2inc in ™aier
2.2 SOURCES AND EMISSIONS
or J" tF!f U2'ted States there are over 25 mines and smelters where zinc is
The U I awidhPrOCeSSfHd' J" 1984' 252'768 metric tons of 2inc werf mined n
me U.S., with a worldw.de mine production of 6,419000 metric tons
Domestic production of zinc oxide in 1984 totaled 150623 me c tons'
t Smelter Produ^on totaled 331.245 metri^tons (JoNy '
horizon Si SrfrtT HI", baSlC typ6S °' primary 2inc smelters " the
° d'stl lat'on units- verti'al retort distillation units,
(L'°yd and Showak-
Because of its electrochemical nature, zinc is used extensively to
galvamze iron and steel. The element also readily combines wlhothe°
metals .mpartmg the characteristics of workability at low temDeratC Ss-
COrrOSIOn resistance; and pleasing fmishes for use 2 SLasZg
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brass and other common alloys. Zinc displays a vigorous reducing power,
liberating hydrogen from sulfuric and hydrochloric acid. This property is the
basis for the use of zinc dust or mossy zinc in many commercial organic
chemical processes (National Research Council, 1978; Nriagu, 1980a).
Zinc oxide is principally used to activate the vulcanization of rubber. It
also helps protect rubber by its opaqueness to ultraviolet light and its high
thermal conductivity. A newer use of zinc oxide utilizes its photoconductive
and electrostatic properties in office photocopying applications (National
Research Council, 1978; Nriagu, 1980a). One of the oldest uses of zinc oxide
is in the treatment of burns, infections, and skin diseases (McKay, 198.};
National Research Council, 1978; Nriagu, 1980a). It is also used to give white
paints good concealing power, in the manufacture of opaque and certain
types of transparent glass, and in the manufacture of porcelain enamels for
sheet iron and vitreous, enamels for cast iron (National Research Council,
1978; Nriagu, 1980a).
2.3 ENV4RONMENTAL RELEASE AND EXPOSURE
2.3.1 Environmental Release
Although zinc is a moderately abundant element in nature, it does not
occur in the free state but instead is found as a salt or oxide. Zinc levels
occur around 70pg/kg in the earth's crust. Some zinc is present in part in
igneous and metamorphic rock as the sulphide sphalerate. In sedimentary
rock zinc is concentrated notably in shale and clays. It is also quite
concentrated in marine phosphorites (National Research Council, 1978;
Nriagu, 1980a). In soils, the zinc concentration ranges from 10 to 300 yg/kg^
Naturally occurring levels of zinc in fresh water and sea water are <10 and
from 1 to 27 vg/L, respectively (National Research Council, 1978; Lloyd and
Showak, 1984). Background ambient levels of zinc have been measured over
the South Pole and the Atlantic Ocean. An average concentration of 0.03
nq/m3 was found over the South Pole. Zinc levels over the Atlantic Ocean
ranged from 0.3 to 27 ng/m3 (U.S. Environmental Protection Agency, 1980;
Nriagu 1980a). In addition to the naturally occurring levels of zinc in air, zinc
is also' emitted to the atmosphere from such man-made sources as: zinc
mining milling, and concentrating; metallurgical processing; the production of
zinc compounds; and the manufacture and use of the products containing
zinc (National Research Council, 1978; U.S. Environmental Protection
Agency, 1980; Lloyd and Showak, 1984; Nriagu, 1980a).
Loss of zinc from mining is small, but some does occur during blasting,
ore handling, crushing, and wind loss from tailings. Only limited data were
found on the concentrations of atmospheric zinc near mines; however, it has
been estimated that 100 g of zinc is emitted to the atmosphere per metric ton
of zinc mined and milled (W. E. Davis and Associates, 1972; Lloyd and
Showak 1984; Nriagu, 1980a). On the basis of the 1984 total of 252,768
metric tons of zinc mined and milled in the U.S., the total zinc emissions to
the atmosphere from this process would be 25 metric tons.
During the smelting process zinc may be released to the atmosphere
during concentrate handling, open storage, and conveying. Roasting could
also create large amounts of zinc dust, but since this operation is enclosed,
the dust may be readily collected using particulate collecting devices which
recover >95 percent of the particulate matter (National Research Council,
1978- Nriagu 1980a; Lloyd and Showak, 1984). There are only limited data
on levels of atmospheric zinc near smelters. In 1977, a yearly mean zinc
level of 5 yg/m3 was found approximately 1.5 miles from a smelter in Kellogg,
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Idaho. The 24-hour values ranged from 0.27 to 157 pg/m3 (US
Environmental Protection Agency, 1980). The U.S. Environmental Protection
Agency (Hunt et al., 1984) reported average yearly or quarterly zinc
concentrations of < 1 yg/m3 in several areas with smelters. Table 2-1 lists
other emission factors and sources of zinc.
Available data on atmospheric levels of zinc have shown a general
decline. The National Air Sampling Network reported annual average airborne
zinc concentrations in areas throughout the U.S. without mines or smelters of
generally <1 yg/m3 (U.S. Environmental Protection Agency, Hunt et al
1984; National Research Council, 1978). Atmospheric zinc levels in the
Washington, D.C. area ranged from 0.05 to 0.1 yg/m3 (Kowalczyk et al
1982). Lee and von Lehmden (1973) reported atmospheric zinc levels in
urban are^s throughout the U.S. of 0.1 to 1.7 pg/m3. |n 1970, the average
atmospheric zinc level in urban areas in the U.S. ranged from 0 1 to 17
yg/m-i (Lee et al., 1972). Dyson and Quon (1976) reported average
atmospheric zinc levels in urban air in 1966 of 0.7 ng/m3.
Zinc levels in water are generally very low. High levels of zinc in surface
water represent industrial and urban pollution from such sources as
galvanized water pipes, dumping of planting baths, and zinc mining (National
,oo^\ Counci1- 1978= u-s- Environmental Protection Agency, 1980; Nriagu
1980a). In a 16-month study, Mink et al. (1971) found that a section of
Idaho s Couer d'Alene River system contained zinc levels of up to 21 mg/L as
the result of the disposal of zinc mining waste for a number of years The
U.S^ Department of Health, Education, and Welfare (currently the Department
of Health and Human Services) found that, of 2,595 drinking water samples 8
samples contained zinc levels above 5 mg/L, Water leaving treatment plants
generally contains less than 5 mg/L of zinc, but in cities with soft acidic water
the level of zinc increases in the distribution system. Therefore tap water
could contain zinc levels of around 5 mg/L (U.S. Environmental Protection
Agency, 1980).
Atmospheric workplace concentration limits have been established for
zinc oxide. The Occupational Safety and Health Administration (OSHA)
established an 8-hour time-weighted average (TWA) permissible exposure
imit of 5 mg zinc oxide/m3 and the American Conference of Governmental
Industrial Hygienists (ACGIH) has adopted a threshold limit value (TLV) of 5
mg/m-i. The National Institute for Occupational Safety and Health (NIOSH)
has recommended the following standard. Occupational exposure to zinc
oxide fumes shall not exceed concentrations greater than 5 mg zinc oxide/m3
determined as a TWA exposure for up to a 10 hour workday 40 hour
workweek, with a ceiling of 15 mg/m3 as determined by a sampling time of 15
minutes.
2.3.2 Exposure
Humans are exposed to zinc through the inhalation of air and the
mgestion of food and water. Zinc levels in air are generally < 1 yg/m3 (U S
Environmental Protection Agency, 1984; National Research Council 1978)
Assuming an individual inhales 20 m3 of air per day with an average zinc
concentration of 1 jig/m3, the daily zinc contribution from this source would
be 20 \tg.
There is a wide range of values published in'the literature on the zinc
content of various foods; however, in general, meat, milk products eqqs
shellfish (Halsted et al., 1974; National Research Council, 1978- US
Environmental Protection Agency, 1980; Nriagu, 1980b) and wheat germ
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TABLE 2-1. Atmospheric Emission Factors
Source
Mining (Zn + Cu + Pb)
Primary metal production
Zinc
Lead
Copper
Nickel
Aluminum
Secondary metal production
Zinc
Copper
Lead
Iron and steel
Ferroalloys and iron foundaries
End uses of zinc products inadvertent
sources
Coal combustion
Oil combustion
Wood combustion
Waste incineration
Rubber tire wear
Phosphate fertilizers
Grain handling
Emission Factor
100 g/metric ton
17,600 g/metric ton
110 g/metric ton
845 g/metric ton
845 g/metric ton
1 1 g/metric ton
9,000 g/metric ton
500 g/metric ton
300 g/metric ton
27 g/metric ton
54 g/metric ton
4.8 g/metric ton
0.025 g/metric ton
58 g/metric ton
500 g/metric ton
4.5 g/tire
15 g/metric ton
0.5 glmetric ton
Source: Nriagu (1980a).
(National Research Council, 1978) are the best sources of dietary zinc.
Halsted et al. (1974) reported a zinc content of standard hospital diets
(breakfast, lunch, and dinner) of 11.3 mg. The U.S. Environmental Protection
Agency (1980) reported a zinc dietary intake of 18 and 18.6 mg/day for males
ages 15 to 20 years old, respectively, whereas the daily dietary intake of girls
12 to 14 years old was 10 mg. Nriagu (1980b) reported daily zinc dietary
intakes of 8 to 14 mg.
Zinc levels in water are usually very low; however, due to contamination,
levels of 5 mg/L have been reported (U.S. Environmental Protection Agency,
1980). Assuming an individual ingests 2 liters of water per day containing 5
mg zinc/L, the daily intake of zinc from drinking water would be 10 mg.
2.4 ENVIRONMENTAL EFFECTS
Zinc levels above those needed for maximal plant growth may produce
toxic effects. Buchauer (1973) reported that the vegetation around two
smelters in Palmerton, PA was scrubby, with red and yellow foliage and
interveinal chlorosis. Depressed yield and leaf damage ranging from marginal
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necrosis to death was seen in legumes exposed to 3.2 and 6.25 pM zinc in a
!^9HCtUJ'fe SyStem (Carro" and Loneragan, 1968). Nriagu (1980a)
reported hat excessive levels of zinc curtails growth in plants by inhibiting
root development through restraint on both cell division and elongation
««, JS"« *toXiaty 3PP?rS }°, depend Iar9ely on the water hardness and PH,
Mnl 10™e,exP°sure level
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3. Health Effects
3.1 PHARMACOKINETICS AND METABOLISM/
3.1.1 Absorption
The absorption of zinc in humans and other mammals is similar. The site
of absorption depends on the form of presentation. Inhaled zinc is absorbed
across the alveolocapillary membrane; however, the fate of inhaled zinc wiM
depend on the particle size and solubility as well as the functional state of he
lungs Orally administered zinc is absorbed across the gut mucosa with the
major site of absorption in the second portion of the duodenum. Absorption
across the tissue and organ membranes normally follows gastrointestinal
absorption or parenteral administration. Zinc may also be absorbed across
the broken and unbroken epithelial membrane (National Research Council,
f rJr'eTre no quantitative data on the deposition and absorption of inhaled
zinc compounds, but experiments on humans indicate that both zinc oxide
dust and fumes of very small particle size are deposited in the a veoh (Bonne
and Bridges 1983; U.S. Environmental Protection Agency, 1980). That
inhaled zinc is absorbed was shown by the finding of widespread distribution
of zinc in the soft tissue and liver of a man accidentally exposed to
radiolabeled zinc dust from an experimental reactor (Newton and Holmes,
1966) and increased plasma and serum zinc levels in exposed workers
(Chmielewski et a!., 1974a,b; Hamdi, 1969; Klucik and Koprda, 1979; U.S.
Environmental Protection Agency, 1980). *•„„•„,
The absorption of orally ingested and parenterally administered zinc is
affected by several factors, some of which include: the amount of zinc
ingested, the zinc status of the organism, and the presence of other
substances (Lykken et at., 1986; Song and Adham, 1985; van RIJ ;and HaM.
1985; Prasad. 1978; National Research Council, 1978, Nriagu, 1980b; Rckel
et al' 1986; Furchner and Richmond, 1962).
A significant decrease in plasma, erythrocyte, and leukocyte zinc levels
has been seen after experimentally induced zinc deficiency. Following oral
zinc supplementation, values close to normal were obtained (Prasad et al.,
1978) Spencer et al. (1966) found that intravenously administered zinc is
rapidly distributed. Using radiolabeled zinc as an indicator, the zinc retention
after 30 days was >80 percent. The zinc status of the subjects was not
obtained prior to administration of the radiolabeled zinc. Istfan et al. (19BJ)
found that absorption of radiolabeled zinc increased linearly with an
increasing level of available zinc. . .
Valberg et al (1985) studied the rate of absorption and retention of zinc in
20 healthy subjects. Subjects ingested 25 mg radiolabeled zinc in metal free
water or in ground white turkey meat after overnight fasting. The absorption
and retention of radiolabeled zinc after 7 days was 42 percent for both
methods of administration. However, the rate of absorption, as shown by the
average increase in plasma zinc levels over a 4-hour period was significantly
10
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lower when zinc was administered in the solid test meal. The authors
believed that this finding was the result of the binding of zinc to food and the
slower rate of gastric emptying of the solid meal.
Hyperzincuria is associated with the consumption of alcohol. Dinsmore
et al. (1985) after orally administering alcoholic and nonalcoholic volunteers
50 mg zinc supplements via diet found significantly higher serum zinc levels
in the nonalcoholic volunteers. Under normal physiological conditions a
mutual inhibition also exists between zinc and folic acid (Ghishan et al 1986)
Zinc absorption is reduced if the diet contains large amounts of phytate or
phytic acids (Lowy et al.. 1986; Solomons et al., 1979; Reinhold 1971-
Remhold et al.. 1973, 1974; Turnlund et al.. 1984; Morris and Ellis 1980)'
Since phytic acid and phytates are found in plants and seeds, zinc from
plants is considered to be less available to monogastric animals than zinc
derived from animal protein. This was suggested to be a contributing factor
in the zinc deficiency seen in Iranian villagers who consumed a substantial
amount of unleavened bread high in phytate.
A biological antagonistic relationship exists between zinc and several
other metals. Generally calcium does not affect zinc absorption except in the
presence of phytate (Spencer et al.. 1984; Snedeker et al., 1982- National
Research Council, 1978; U.S. Environmental Protection Agency 1980) by
forming an insoluble calcium-zinc-phytate salt at the site of intestinal
absorption (Halsted et al., 1974; Forbes et al., 1983). There are, however
indications that high levels of calcium may affect zinc absorption when dietary
V^-fo of zmc are mar9'nal (Halsted et al.. 1974; National Research Council
1978; Spencer et al., 1984). As such, the high level of calcium (18.6 percent)
in clay ingested by Iranians with a history of geophagia may have been a
contributing factor to the zinc deficiency seen in that group (National
Research Council, 1978). Calcium has also been implicated in the formation
of irreversible sickle cells in sickle cell anemia patients. Data on the
interactions of zinc with calcium suggest that zinc may competitively inhibit
calcium leakage into the red blood cells and inhibit the formation of the
irreversible sickle cells (Prasad, 1978). Klucik and Koprda (1979) reported
that exposure to levels of,zinc ranging from an average of 0.5 mg/m3 to 7 14
mg/mJ produced signs of hypocalcemia in exposed workers. High levels of
orally administered zinc decreases the retention of copper and if administered
over an extended period of time will induce copper deficient anemia and
neutropenia (Festa et al., 1985; Fischer et al., 1883, 1984- L'Abbe and
Fischer, 1984). Mulhern et al. (1986) reported that excess dietary zinc (2000
ppm zinc/day) produced copper deficiency in the offspring of C57BL/6J mice
The offspring also developed alopecia by 5 weeks of age. In addition the
«m u reported tnat excess zinc causes alopecia in the monkey and mink
Whether excess zinc administered at certain stages of development will
produce alopecia in humans has not been determined. An increased
mgestion of zinc will offer protection against some of the toxic effects of lead
absorption (Nriagu, 1980a; Cerklewski and Forbes, 1976; EI-Gazzar et al
1977) by inhibiting lead absorption at the intestinal level (Cerklewski and
Forbes, 1976). A nonheme iron and zinc ratio of 2:1 slightly inhibits zinc
absorption (Solomons, 1986; Solomons and Jacob, 1981) by competing with
?«oo!n upper Smal1 intestine and delaying its absorption (Meadows et al
1983). However, Solomons (1986) suggested that there are sufficient sites for
both zinc and iron absorption when the total ion concentration does not
exceed 25 mg. Cadmium, a nonessential and toxic metal is associated with
zinc .in both geological and biological matter. The interaction between
cadmium and zinc has not been fully demonstrated; however renal
11
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concentrations of zinc have been shown to parallel those of cadmium up to
concentrations of 50 to 70 yg/g. There are also equ.moar amour, s of
cadmium and zinc in the kidney when cadm.um levels are low, but as
cadmium levels increase, the ratio of cadmium and zinc increases (U.b.
Environmental Protection Agency, 1980).
Zinc may also be absorbed through both broken and unbroken sk.n
(Hallmans 1977; Derry et at.. 1983; Anteby et al., 1978; Hallmans and Lasek,
1985) Hallmans (1977) found that serum zinc levels increased in burn
patients treated with gauze containing zinc oxide. An increase in serum zinc
levels was seen in healthy subjects treated with a zinc oxide ointment, but the
increase was not statistically significant. It was theorized that zinc applied to
subjects topically with normal serum zinc concentrations is bound in the hair
follicules and slowly absorbed and stored or excreted resulting in no increase
in serum zinc concentrations. (Derry et al., 1983). A slight rise in serum zinc
has been seen in women using an intrauterine device containing copper and
zinc (Anteby et al., 1978).
Numerous studies indicate that the body attempts to control the zinc
balance homeostatically according to need by regulating the extent of
absorption of dietary zinc and the rate of fecal excretion of stable zinc
(National Research Council, 1978; Evans et al., 1973; Ansan et al., 975,
1976- Weigand and Kirchgessner, 1978; Nriagu, 1980b; Cousins, 1985.
Dinsmore et al 1985). The exact mechanisms involved in homeostatic
regulation have not been determined; however, recent information suggests
that zinc absorption across the brush border surface of the small intestine
may be partly regulated by a carrier-mediated diffusion mechanism which
responds homeostatically to the dietary zinc supply (Cousins, 1986; Menard
and Cousins 1983b). It has also been reported that many brush border
proteins are increased during zinc depletion (Menard et al., 1983); however,
this finding has not been confirmed by other researchers (Park et al. 1985).
Numerous other studies suggest that several proteins and low-mqlecular-
weiqht compounds may be involved in the absorption of zinc and other heavy
metals (Seal and Heaton. 1987; Wapnir and Stiel, 1986; Song and Adham,
1985- Wapnir et al., 1983; Lonnerdal et al., 1982; Menard and Cousins, 1983a;
Freeman and Taylor, 1977; Smith et al., 1978; Blakeborough et al., 1983;
°° In examining the reason for the accumulation of metals in mammalian
tissue a protein was discovered and termed metallothionem (Cousins, 1985).
This low-molecular-weight protein is characterized by a very special ammo
acid complex consisting mainly of cysteine and a lack of aromatic ammo
acids and histidine (Nordberg and Kojima, 1978; Kojima et al., 1976). A more
detailed discussion of the physical properties of metallothioneins are
contained in Kagi and Nordberg (1979) and Cousins (1985). Metallothipnems
have been isolated from intestine, liver, and kidney (Margoshes and Vallee,
1957- Kadi and Vallee 1960). More recently, a metallothionein-like protein
was 'isolated in the rat brain (Ebadi, 1984). The exact function of
metallothionein has not been determined; however, several functions have
been suggested. These include absorption and detoxification and hepatic
storage of heavy metals (Jackson et al., 1986; Bell, 1979; R-chards and
Cousins 1976; Cousins. 1985; Ebadi, 1984; Swerdel and Cous.ns, 1982;
Menard et al., 1981; Olafson, 1983; Kern et al., 1981; Quinones and Cousins,
1884; Gallant and Cherian, 1986; Banerjee et al., 1982).
12
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3.1.2 Distribution
-------
TABLE 3-1. TYPICAL ZINC CONCENTRATIONS OF
NORMAL TISSUES IN FOUR SPECIES
Tissue
Adrenal
Brain
Heart
Kidney
Liver
Lung
Muscle
Pancreas
Prostate
Spleen
Testis
Human
v&g
12
14
33
55
55
15
54
29
102
21
17
Monkey
V9'9
16
—
22
29
51
19
24
48
—
21
17
Rat
V9/9
—
18
21
23
30
22
13
33
223
24
22
Pig
V9/9
33
—
—
40
40
—
~
45
—
28
—
Source: Underwood (1971)
1978). Also, Binder et al. (1978) found that urinary excretion of zinc
decreases after the age of 20 years.
In addition to fecal and urinary excretion, zinc is also excreted in sweat
under conditions of extreme heat or exercise, via hair and milk, through
placental transfer to the fetus, and via skin sloughing (National Research
Council 1978). Molin and Wester (1976) found the zinc content of the
epidermis to be about 40 pg/g dry tissue by neutron activation analysis.
They estimated the daily loss of zinc by desquamation to be from 20 to 40
yg. The mean loss of zinc in sweat has been reported to be 4 percent of the
average daily intake (Jacob et al., 1981).
3.2 ESSENTIALITY AND BIOCHEMICAL ROLE
Over a hundred years ago zinc was shown to be an essential element in
the nutrition of Aspergillus niger. It was not until some years later that the
first indications of a function for zinc in plants and animals was uncovered.
Zinc is necessary for the growth and development of humans and is included
in the list of recommended dietary allowances (National Research Council,
1978; Krebs and Hambidge, 1986; U.S. Environmental Protection Agency,
1980) (Table 3.2). .
The essential nature of zinc is based on its role as an integral part of
some metalloenzymes, a cofactor in regulating the activity of zinc dependent
enzymes (Nriagu, 1980b). and as a structural and functional component of
biomembranes (Bettger and O'Dell, 1981). More than 20 zinc
14
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Table 3-2. Recommended Dietary Allowances for Zinc
Infants
Children
Men
Women
Pregnant
Lactating
Age
(years)
0.0-0.5
0.5-1.0
1-10
11-51 +
11-51 +
Zinc
(mg)
3
5
10
15
15
20
25
Source: National Research Council (1978).
metalloenzymes have been identified (Nriagu, 1980b) and over 100 enzymes
require zinc for maximum catalytic function (Cousins, 1986) (Table 3-3 lists
some of the zinc metalloenzymes). Zinc plays an important role in the
metabolism of proteins and nucleic acids and is essential for the synthesis of
DNA and nbosomal RNA. It also serves to stabilize the structure of some
™±L0enzymeS" ,T^US the level of available zinc maV Control metabolic
processes through the formation and/or regulation of the activity of zinc-
dependent enzymes (Nriagu, 1980b).
3.3 CLINICAL MANIFESTATIONS OF ZINC DEFICIENCY
. metabolic and biochemical defects responsible for the symptoms of
zinc deficiency are not fully understood. However, the manifestation of
^wt^2'"* i!ncy.SVmptoms mav be associated with the reduced
SlnL n ?T 6r ZmC C0ntainin9 enzymes. Typical symptoms of zinc
deficiency include: anorexia, pica, impaired taste acuity, mental lethargy
delayed sexual maturation in adolescence (Nriagu, 1980b) immune
dysfunction (Fraker et al., 1986; Sandstead et at 1982), dermS
emaciation, alopecia, ocular lesions, and retarded growth (Yamaguchi. 1984,:
Haisted et al 1974). Chronic, severe, and untreated zinc deficiency can be
fatal (Evans 1986). Prasad et al. (1963) found that in certain villages in Egypl
many people exhibited a syndrome characterized by dwarfism anemia
teCv^in?; hePatosPlenome9aly, rough and dry skin, and mental
5«SSy'«?K? deflc|ency was indicated by an abnormally low zinc content in
piasma, red blood cells, and hair.
LessPron
-------
Table 3-3. Zinc Metalloenzymes
Enzyme
RNA polymerase
RNA polymerase
DNA polymerase
Nucleotide pyrophosphatase
5'-Nucleotidase
Cyclic phosphodiesterase
Phosphomannose isomerase
Phosphoglucomutase
oc-D-Mannos/dase
3-i.acfamase
Protease
5'-Adenosine monophosphate
aminohyrrolase
Collagenase
Neutral protease
Dipeptidase
Phospholipase C
Dipeptidase
-------
Experimentally induced zinc-deficient subjects experienced
considerable weight loss. During the zinc depletion period thymidinekinase
activity was not detected and there was a reduction in plasma alkaline
phosphatase and plasma lactic dehydrogenase activity. Changes were also
noted in the RNA and DNA ratio in the connective tissue (Prasad et al 1978)
Whether zinc deficiency causes human reproductive or teratological
effects has not been established; however, the possibility has been suggested
based on the results of a number of animal studies (Lytton and Bunce 1986-
Styrud et al., 1986; Dreosti et al., 1986; Hurley and Swenerton, 1966- Hurley
and Mutch, 1973; Hurley et al., 1971; Apgar, 1971; Hurley and Shrader 1972)
Lytton and Bunce (1986) reported that female rats maintained on a low zinc
diet starting on day 10 of gestation usually experienced a prolonged fetal
delivery period with prolonged periods of abdominal straining. Also many
pups were either stillborn or died shortly after birth. Hurley and Mutch (1973)
found that rats maintained on zinc-deficient diets from day 6 to 14 of
pregnancy exhibited an increased number of stillbirths and a high incidence
of congenital malformations. Similar results were reported by Hurley et al
(1971). After maintaining rats on a zinc-deficient diet from day 0 to 21 of
pregnancy, they found that about half of the fetuses were resorbed and that
almost all of the remaining fetuses showed gross malformations.
A number of studies on the effects of zinc deficiency indicated that zinc
is necessary for normal neurological development and function (Dreosti et al
1986; Hurley et al., 1971; Hurley and Swenerton, 1966; Gordon et al 1982:
Lokken et al., 1973; Hurley and Shrader, 1972; Halas et al., 1979- Halas and
Sandstead, 1975; Golub et al., 1985; Sandstead, 1986). Hurley et al (1971)
reported severe neurological effects in the form of hydrocephalus
anencephalus, hydranencephalus and exencephalus in litters of zinc-
deficient mothers. Gordon et al. (1982) found that zinc-deficient rats were
slower to explore the observation area and only explored a small portion of
the area. Marginally zinc-deficient infant primates showed signs of lethargy
apathy, and hypoactivity (Golub et al., 1985). Similar findings have also beeri
reported in humans suffering from zinc deficiency (Prasad et al 1963- Henkin
et al., 1975).
Certain evidence suggests zinc is essential for immune function (National
Research Council, 1978; Sandstead et al., 1982; Bach, 1981; Beisel 1982-
Moynahan, 1975; Nriagu, 1980b). Successful results have been reported in
infants with acrodermatitis enteropathica after zinc therapy (Chandra et al
1983; Eckhert et al., 1977; Ecker and Schroeter, 1978; Nriagu 1980b)'
Patients with latrogenic zinc deficiency have developed a clinical picture
similar to that of acrodermatitis enteropathica which has been alleviated with
zinc therapy (Sandstead et al., 1982; Nriagu, 1980b). Chandra et al (1983)
reported that zinc deficiency increases vulnerability to Listeria Salmonella
Coxsackie virus, and other pathogens.
It has also been suggested that zinc deficiency stimulates the production
of endogenous free radicals in lung microsomes. The endogenous free
radicals may then react with tissue components initiating lipid peroxidation
and/or cross-linking of proteins leading to cell damage (Bray et al., 1986).
3.4 EFFECTS IN ANIMALS
3.4.1 Acute Toxicity
3.4.1.1 Inhalation. Lam et al. (1985) found functional, morphologic and
biochemical changes in the respiratory tract of guinea pigs exposed'to 5
17
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mg/m3 zinc oxide for 3 hours/day for 6 days. Vital capacity, functional
residual capacity, and alveolar volume were decreased following the last
exposure. Microscopic lesions in exposed animals consisted of f'™t'™
of the proximal portion of the alveolar ducts and adjacent alveoli charactenzed
by interstitial thickening, increased pulmonary macrophages and neutrophiis
in adjacent airspaces, and replacement of the alveolar squamous epithel urn
with cuboidal cells. In an earlier study, Lam et al. (1982) found that ventilation
and lung mechanics in guinea pigs exposed to 7.8 mg/mS zinc ox.de or a
single 3-hour exposure period were not significantly different from controls.
A significant decrease was, however, seen in the functional residual volume.
The pulmonary response to zinc oxide fumes of 23 guinea pigs was
studied by Amdur et al. (1982). The animals were exposed to approximately
1 mq/m3 of freshly formed zinc oxide. Respiratory measurements were made
every 5 minutes for a 30-minute preexposure period, a 1-hour exposure
and a 1-hour postexposure period. Pulmonary response measurements
included resistance, compliance, frequency, total volume, and minute volume.
The only statistically significant effect noted by the end of the exposure
period was a 9 percent decrease in compliance. One hour postexposure,
compliance had decreased 16 percent below control values. To further
examine the decrease in compliance, the experiment was repeated using /
quinea pigs The animals were again exposed to approximately 1 mg/m^ of
freshly formed zinc oxide for 1 hour, followed by a 2-hour postexposure
observation period. Unlike the first experiment, a statistically significant
decrease in compliance was not noted by the end of the exposure period.
However by the end of the first hour postexposure period, the compliance
had dropped 16 percent below control values. At the end of the second hour
postexposure period, the compliance had decreased to 27 percent below
control values. The decrease in compliance without a change in the airway
resistance noted in these experiments reflects a response in the periphery of
the lung, the primary site of deposition of submicron aerosols. ....
The ability of zinc oxide to alter pulmonary defenses was evaluated by
Hatch et al (1985). Ninety mice were treated with an intratracheal injection of
10 or 100 ug zinc oxide followed by exposure to group C Streptococcus sp.
The severity of the infection was quantitated by the resulting mortality over a
15 day period. A significant number of mortalities was noted in both
exposure groups (73 and 55 percent, respectively). .
An intratracheal injection of 0.5 mg zinc oxide produced morpho ogical
changes in pulmonary alveolar macrophages (RAM) in rats. One week after
exposure PAM contained a prominent nucleolus within a vagmated nucleus.
The resident pulmonary macrophages contained many electron dense
structures some of which were homogeneous and membrane bound, while
others of varying electron densities were in the proximity to lamellar
configurations. Membrane-bound electron dense structures were also seen
in the intercellular spaces among interstitial macrophages. The authors
hypothesized that the presence of electron dense structures along with
lamellar membranous formation in proximity to and within the intersti jal
macrophages suggested a transfer of paniculate matter from alveolar to the
resident interstitial macrophages. Accumulation of particulate matter within
the macrophages may interfere with the normal phagocytic function of these
macrophages, resulting in the metal fume fever (see Section 3.10.1)
associated with zinc toxicity (Migally et al., 1982).
Fischer et al. (1986) reported that zinc oxide is cytotoxic. Using the in
vitro bovine pulmonary macrophage assay system, the EC50 (effective
18
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concentration required to reduce phagocytosis to 50 percent of control
values) was 22 yg/ml.
Gupta et al. (1986) observed no signs of toxicity or symptoms of gross
morphological changes in the lungs of guinea pigs 7, 15, or 30 days after a 50
mg intratracheal injection of zinc oxide dust. However, an increase in alkaline
phosphatase activity was noted in the lung mitochondrial supernatant and
serum. A decrease in the activity of lactate dehydrogenase in the lunq
mitochondrial supernatant was noted on days 7 and 15 postexposure but
became normal after 30 days. No significant change was observed in the
activity of this enzyme in serum.
Conner et al. (1985) studied the irritancy potential of a combination of
zinc oxide and sulfur dioxide. Guinea pigs were exposed to 6 mg/m3 zinc
oxide mixed with 1 ppm sulfur dioxide for 3 hours a day for 6 days Total
lung capacity, vital capacity, functional residual volume, alveolar volume and
diffusing capacity were decreased following exposure and had not returned to
normal 72 hours after exposure. Morphological changes in the lungs were
limited to the centnacinar alveolar ducts and associated alveoli and consisted
of interstitial cellular infiltrate, increased numbers of macrophages in alveolar
ducts and alveoli, and replacement of squamous alveolar epithelium with
cuboidal cells. The severity and frequency of such lesions were lessened by
72 hours postexposure. Similar but more severe changes were seen after a
S!n9™"«hour exposure of 25 m9/m3 2inc oxide and sulfur dioxide (Conner et
T ,A *;?n™?f 3-?ute emPhVsema '" cattle was reported by Hilderman and
layior (1974). The episode occurred in a barn that was being remodeled
The cattle were exposed to zinc oxide fumes emitted during oxyacetylene
cutting and arc welding of galvanized pipe. Three heifers were severely
affected, and died within a short time. Autopsy findings showed severe
changes in the lungs with edema, emphysema, and hemorrhages Zinc
concentrations in liver, kidney, and lungs were not above normal values in the
two animals examined. In this case, a galvanized material was implicated but
the extremely severe condition caused by the fumes indicated either 'that
cattle are highly sensitive to zinc oxide fumes, or that other metals such as
cadmium, may have been involved.
Harding (1957) administered intratracheal instillations of 50 mg of zinc
stearate to rats. Approximately 50 percent mortality was noted after dosinq
buryivmg animals were sacrificed up to day 259 after instillation. Fibrosis
could not be detected. Harding also found that the zinc stearate disappeared
from the lungs of the survivors within 14 days after administration
Unlike Harding, Tarasenko et al. (1976) found pathological changes in the
lungs of surviving animals in the form of widespread plasmorrhagia in the
walls of small arteries and alveolar atelectasis foci alternating with foci of
chronic alveolar emphysema 2 months after a single 50 mg intratracheal dose
of zinc stearate. Still later, chronic alveolar emphysema and bronchitis were
S66P.
3.4.1.2 Oral. In an outbreak described by Allen (1968), cattle were
poisoned with dairy nuts which had been accidentally contaminated with zinc
oxide. The zinc content of the nuts was 20 g/kg. Based on a dairy nut
consumption of 7 kg/day, it is estimated that the cows consumed 150 g of
zinc/day. Exposure was only for a couple of days, but it resulted in severe
enteritis. On one farm 7 out of 40 cows were so severely affected that they
died or had to be slaughtered. The postmortem examination revealed severe
pulmonary emphysema, a flabby myocardium, blood spotting in the cortex
19
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and medulla of both kidneys, and marked degenerative changes in the liver.
The zinc cncentrations in the two livers analyzed were extremely high, 1,430
and 2,040 mg/kg (dry matter basis), and there were indications that copper
levels were lower than normal.
Breitschwerdt et al. (1986) described the clinical and laboratory findings
of three cases of acute oral zinc toxicosis in dogs. In two of the cases the
source of zinc was a metal nut high in zinc content (>98 percent). In the
third case, the animal had ingested a large amount of zinc oxide ointment
which had been applied to the perianal and scrotum areas to prevent moist
dermatitis secondary to fecal contamination. While only one dog succumbed
to the zinc toxicosis, all of the animals exhibited a loss of appetite, weakness,
depression, and vomiting. The zinc content in plasma and urine was also
elevated over that routinely found in healthy animals. Necropsy findings in
the dead animal were pulmonary peribronchial artenolar thrombosis,
enlargement of the right side of the heart, and various lesions of the kidneys.
The zinc content of the liver and kidney was 369 (average 26.2) and 295 ppm
(average 14.6 ppm), respectively.
3.4.2 Subchronic Toxiclty
3 4 2.1 Inhalation. In a study designed to determine the effect of
inhalation of zinc oxide particles of < 1 micron in size on rat lungs, Pistorius
(1976) exposed test animals to 15 mg/m3 zinc oxide for 1, 4, or 8 hours/day
for 84 days. There were no differences in lung function between controls and
exposed animals except for a decrease in specific conductance and another
lung function parameter termed "difference volume" (A-TGV-Vt) in the
exposed groups at the end of the second week of the experiment. The
conditions improved as the length of exposure increased. The author
believed the improvement in lung function with the extension of exposure to
be the result of an increase in macrophages, which in turn increased the
elimination of zinc from the lungs. In another study rats were exposed to 15
mg/m3 zinc oxide dust for 4 hours/day 5 days/week for 1, 14, 28, and 56
days Histological examination of the lungs showed core-shaped fresh
leukocytic inflammatory changes with numerous small leukocyte plugs in the
bronchus clearings and intraalveolar edema. After 14 days exposure isolated
foam and round cell cores appeared. The inflammatory changes decreased
by day 28 and 56; however, there were numerous alveolar macrophages
(Pistorius et al., 1976). . ,
Oberdorster and Hochrainer (1979) evaluated the effect of inhalation of
zinc oxide aerosol on the lung clearance mechanisms. Rats were exposed to
submicron zinc oxide aerosol (1 mg/m3) for 6 weeks followed by a 1-hour
exposure to 11.5 mg/m3 59pe as Fe203 (used as a marker). The rate of
clearance of 59Fe from the lungs of the zinc oxide exposed animals was
found to be twice that of the controls. On day 38 postexposure, 62 percent of
the initial lung 59pe was still present in the lungs of the zinc oxide exposed
animals The authors postulated that exposure to the zinc oxide aerosol over
the 6 week period affected the bronchial and alveolar clearance mechanism.
3422 Oral. Animals can tolerate high dietary levels of zinc without any
signs of a toxic effect. Ansari et al. (1976) administered from 1,200 to 8,400
ppm zinc oxide to rats via their diet for 21 days. No clinical signs of toxicity
were noted in any of the exposed groups. At the 1,000 ppm feeding level,
Sutton and Nelson (1937) found no adverse effects in rats or their offspring.
The National Research Council (1978) reported that dietary administration of
4000 to 7,500 ppm zinc produced a condition resembling iron deficiency
20
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anemia in young rats. Supplements of iron and copper increased the
hemoglobin concentration to normal levels.
In 1937, the University of Illinois was asked to identify a disease in two
suckling colts on a farm located near a zinc smelter. Autopsy examination of
the colts revealed parasitism, a form of arthritis, and abnormal amounts of
zinc in bone, liver, and urine. An abnormally high amount of zinc was also
found in the mother's milk. Based on these findings, Graham et al. (1940)
initiated a study to determine the effect of dietary zinc on pregnant mares and
mares nursing colts. Mares were administered 3.5 and 35 g of zinc lactate via
diet over a period of up to 2.5 years. These feeding levels were based on the
zinc content of the feed assumed to have been consumed by the mares while
suckling the affected foals. The results of the study did not demonstrate that
zinc, at the levels administered, would produce harmful effects in pregnant
mares or mares suckling colts. This led the authors to believe that the effects
seen in the two colts were caused by something other than zinc. However, it
should be pointed out that the zinc content in the milk from the experimen-
tal animals was Jess than that from the mares suckling the two infected colts.
The effects of subchronic exposure to zinc have also been studied in
several commercial animal species. Sampson et al. (1942) evaluated the
effect of ingestion of zinc lactate in pigs. In the first experiment shoats were
fed a basal diet plus 100 g of zinc lactate for 3 months. At the conclusion of
the experiment, none of the pigs showed any sign of an adverse effect. In the
second experiment weanling pigs were fed a basal diet plus 17.5 g of zinc
lactate for 9.5 months. The zinc-fed weanling pigs began losing their
appetite after only a few weeks on the diet. Symptoms of stiffness and
lameness were also noted. Autopsy findings revealed pathologic lesions in
the joints and an increased liver zinc content. This arthritic condition was
confirmed by Brink et al. (1959) and Hill et al. (1983) after feeding pigs from
500 to 8,000 mg/kg zinc. In addition to the arthritic condition characterized by
swollen joints, at feeding levels of 2,000 mg/kg and above, test animals
exhibited depressed weight gain and food consumption. There was also a
dosage-related increase in deaths (Brink et al., 1959). Postmortem
examination revealed extensive hemorrhaging in the axillary spaces and
intestine and marked gastritis with some ulceration.
In sheep, the ingestion of 240 mg zinc/kg as zinc oxide or zinc sulfate
administered three times a week for 4 weeks produced pancreatic damage in
all exposed animals. Animals ingesting zinc sulfate also experienced severe
diarrhea which commenced after a week of dosing and persisted throughout
the experiment. All animals in the zinc sulfate group died after day 13.
Postmortem examination revealed a reduction of the papillation of the rumen
wall and edema of the fundic folds of the abomasum. The liver had a finely
mottled surface and an orange brown color (Smith and Embling, 1984).
Dewar et al. (1983) studied the effects of excessive dietary zinc as zinc
oxide in chicks and hens. Chicks were maintained on a diet containing 2 000
4,000, or 6,000 mg/kg for 42 days or 1,000, 2,000, or 4,000 mg/kg for 28 days
while hens received 10,000 or 20,000 mg/kg for 4 days. Mortality was high in
chicks receiving 4,000 and 6,000 mg zinc/kg. Postmortem examination
revealed macroscopic abnormalities of the alimentary tract. In five chicks in
the 6,000 mg/kg group there was internal hemorrhaging from the descending
aorta or the thoracic aorta. Histological examination revealed gizzard and
pancreatic lesions in all exposed groups. There was no mortality reported for
the exposed hens; however, gizzard and pancreatic lesions were found in
both exposed groups.
21
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3.4.3 Chronic Toxicity
No information was found on the effects of chronic inhalation exposure to
zinc/zinc oxide in animals. However, a study on the oral administration of
subtoxic levels of zinc indicates a possible effect on the endocrmological
balance. Mice were administered 0.5 g/L zinc sulfate in drinking water for up
to one year. The animals maintained a healthy outward appearance during
the length of the study. Analysis of liver, spleen, and skin samples of zinc
supplemented animals did not show a significant increase in zinc content over
that of the controls. Histological examination revealed hypertrophy of the
adrenal cortex and the pancreatic islets. Since hypertrophy of the adrenal
cortex has been seen with an increased plasma level of certain pituitary
hormones, it was suggested that the administration of zinc over an extended
period of time may also cause hyperactivity of the pituitary (Aughey et al.,
1977) In an earlier study, Drinker et al. (1927b) found no evidence of toxic
effects in rats administered from 0.5 to 34.4 mg zinc/day as the oxide, citrate,
acetate, and malate for a period of 35 to 53 weeks.
3.5 CARCINCGENESIS
Under conditions of high gonadal activity, the injection of zinc salts into
the testes of fowl has induced testicular tumors (Sunderman, 1971; National
Research Council, 1978; U.S. Environmental Protection Agency, 1980; Nriagu,
1980b). Seminomas, interstitial cell tumors, and teratomas have also been
reported in rats after testicular injection of zinc salts (Nriagu, 1980b).
Conversely, the injection of zinc sulfate into the mammary glands of young
and sexually mature Marsh-Buffalo mice significantly delayed the onset and
incidence of mammary adenocarcinoma (Bischoff and Long, 1939).
There is no evidence that the inhalation, ingestion, or parenteral
administration of zinc induces the formation of tumors. There is, however, a
considerable amount of information which indicates that the administration of
zinc is indirectly involved in tumor formation as a growth promoter or inhibitor.
In a study by Wallenius et al. (1979), 4-nitro-quinoline-n-oxide-induced
cancer of the oral cavity in female rats appeared earlier in animals ingesting a
diet containing 200 mg/kg zinc than animals fed 15 or 50 mg/kg zinc. Fenton
and Burke (1985) found that TEPC plasmacytoma transplanted tumors were
somewhat smaller in mice maintained ort a zinc-deficient diet (0.5 yg/g)
compared to mice maintained on a zinc-adequate diet (50 pg/g). Mathur et
al. (1979) reported that zinc deficiency (5.9 mg/kg) promoted the development
of 4-nitro-quinoline-n-oxide-induced histological changes of the oral
cavity in rats. However, at the conclusion of the study there were no
differences in tumor formation between the animals fed the zinc-deficient
diet and the zinc-supplemented diet (260 mg/kg). Only moderate dysplasia
was seen in animals on the zinc-adequate diet (50 mg/kg). The authors
concluded that zinc deficiency facilitates the development of the initial
histological changes and supplementary zinc provides an initial protective
barrier against tumor formation, but once the protection is overcome, tumor
formation is accelerated. Fong et al. (1978) found that a zinc-deficient diet
(7 mg/kg) promoted the formation of methylbenzylnitrosamme (MBN)-
induced esophageal tumors. By the conclusion of the study, there was an
increased incidence of esophageal tumors in zinc-deficient animals over
animals maintained on the zinc-adequate diet (60 mg/kg). Similar results
were reported by Gabrial et al. (1982) after maintaining rats on a zinc-
deficient diet. In a more recent work, Fong et al. (1984) found that a zmc-
22
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deficient diet also promotes the formation of benzylmethylamine (BMA)-
induced esophageal tumors and NaN0.2-induced forestomach tumors. Van
Rensburg (1981), in a survey of 21 regions, found that in areas with high
incidences of esophageal cancer consumed diets were deficient in zinc,
magnesium, riboflavin, and nicotinic acid.
Many human studies have documented the level of zinc in both
cancerous and noncancerous tissues, and the zinc content has been found to
be both high and low with no definite pattern. Mulay et al. (1971) found a
higher zinc content in bronchogenic carcinoma and cancerous breast tissue
than in noncancerous bronchial and breast tissue. Lin et al. (1977) showed
that zinc concentrations in the esophagus in humans with esophageal cancer
were lower than normal. Zinc concentrations are normally very high in the
prostate, but levels are consistently lower in carcinomatous prostate tissues
(Lahtonen, 1985; Leake et al., 1984; Boddy et al., 1970; Feustel et al 1982-
Gyorkey et al., 1967; Schrodt et al., 1964; Habib et al., 1976). In the study by
Habib et al. (1976), zinc concentrations in the neoplastic tissue of the prostate
were less than half of those found in normal tissue or in hypertrophic
prostates; however, cadmium levels were higher in the neoplastic tissue than
in normal or hypertrophic tissue. High industrial exposure to cadmium has
been implicated as a possible factor in the development of prostatic cancer.
The only positive carcinogenic resonse resulting from zinc occurs
following injection of zinc salts into the testes of fowl and rats. The special
situation with regard to injection site tumor has been reviewed by several
authors. Gasso and Goldberg (1977)doubted the usefulness of the technique
if only injection site tumors developed. Tomatis (1977) reviewed 102
chemicals reviewed by IARC that had been tested using the subcutaneous
route. Based on the results by other routes, he concluded that
"administration of a chemical by the subcutaneous injection route produced
what one could call false negative results for six ( 5.6% ) of the 102 chemicals
tested, and if we accept all the crticism of this route of administration false
positive results for nine ( 8.7% ) of the 102 chemicals tested." Thus, with this
route a false positive result is a more likely result if only injection site tumors
are observed. Recently, Theiss ( 1982), again using the IARC data base
conclued that subcutaneous injection was most useful if the compound
produced tumors at a site distant from the site of injection. Therefore, by
analogy one could conclude that the testicular tumors resultimg from injection '
of zinc salts into the testes are of limited predictive value. In addition, with
zinc it is possible that the resulting testicular tumors could be influenced (i. e.
.promoted ) by the local displacement of cadmium from its carrier protein.
Because the carcinogenicity data in animals is derived from an artificial
exposure route and no other animal or human data exists to evaluate the
carcinogenic potential, the available evidence for zinc and zinc oxide is
considered to be inadequate, equivalent to a group O weight-of-evidence
using EPA's Cancer Risk Assessment Guidelines.
3.6 MUTAGENICITY
In its review of zinc's possible mutagenic effects, the National Research
Council (1978) found no literature suggesting that zinc or any of its
compounds are mutagens. However, Voroshilin ei al. (1978) reported
chromosomal damage in the form of an increased frequency of hyperdiploid
cells but not structural aberrations in the bone marrow of noninbred rats The
rats were exposed to 0.1 and 0.5 mg/m3 zinc oxide aerosol continuously for a
period of 5 months. In the same report, the authors also found an increase in
23
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the frequency of structural aberrations of the chromosomes and hyperdiploid
cells when human lymphocytes at the G0 stage of the cell cycle were
exposed to the action of zinc acetate at concentrations from 7.0 to 20.0
uq/mL An interpretation of this report is difficult because the category of
aberrations referred to as hyperdiploid cells is not one used by
cytogeneticists in this type of study. Additionally, in the in vitro s udy he
frequency of structural aberrations at 20 yg/mL was slightly less than the
frequency at 7 yg/mL (3.6 percent versus 4.0 percent, respectively), n a
recent study, Crebelli et al. (1985) found zinc oxide (1,000 to 5,000 yg/plate)
nonmutagenic in the Salmonella reversion assay.
3.7 TERATOGENICiTY
There are no data indicating that zinc is teratogenic. A greater risk of
malformations is expected in regard to zinc deficiency, as discussed in
Section 3.3. Zinc also appears to offer a degree of protection against the
teratogenic effect of cadmium. In a study by Perm and Carpenter (1968) an
increase in both unilateral and bilateral cleft lips and incomplete and complete
palatal clefts was seen in the offspring of hamsters administered cadmium
intravenously at levels of 2 and 4 mg/kg during the eighth day of gestation.
The simultaneous administration of zinc sulfate was found to reduce the
teratogenic effect of cadmium. This protective effect was also noted when
zinc was administered 15 minutes to 6 hours after the cadmium; however, the
malformations were slightly increased.
3.8 REPRODUCTION
It has been established that zinc deficiency may impair normal
reproduction or adversely affect the outcome of pregnancy in humans and
lower animal forms. However, excessive dietary zinc may also adversely
affect fertility (Samanta and Pal, 1986; White, 1955) and pregnancy (Sutton
and Nelson, 1937; Schlicker and Cox, 1968; Hill et al., 1983; Kumar, 1976^
Samanta and Pal (1986) reported that sperm motility was inhibited in rats fed
a diet containing 4,000 ppm zinc for 30 to 32 days. Of 18 females mated with
males from the zinc-exposure group, only 11 females conceived, whereas all
of the females (15) mated with control rats conceived. No strNbirths or
malformations were reported in either group. Sutton and Nelson (1937) found
that in most cases growth was retarded and no reproduction occurred after
feeding female rats 10.000 ppm zinc carbonate. At the 5,000 ppm feeding
level increased stillbirths occurred. Growth and reproduction were not
affected at the 1,000 ppm feeding level. The original females were remated.
At the 5 000 ppm level, no live young were born and, after 5 months the
females ceased to become pregnant. Hemoglobin values were found to
decrease with time in the 5,000 ppm group. Hemoglobin and red blood
corpuscles were diminished in those animals in the 10,000 ppm feeding
qroup Schlicker and Cox (1968) reported 100 percent resorption of fetuses
in rats fed 4,000 ppm zinc oxide beginning 21 days before gestation. Kumar
(1976) found a significant number of resorptions in rats receiving a total ot
ISO ppm zinc daily. In a brief statement this author also reported that three
premature births and one stillbirth occurred in a small group of women given
100 mg zinc sulfate (40.5 mg zinc) daily during the third trimester of
pregnancy. However, no premature births or stillbirths were reported in a
group of seven women receiving 200 mg zinc sulfate twice a day (81 mg
zinc/day) during the third trimester of pregnancy (Nnagu, 1980b). Also,
adverse effects on the outcome of pregnancies were not reported in a group
24
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of women supplemented with 20 mg zinc sulfate per day in addition to dietary
zinc intakes of from 9.3 to 11.3 mg/day (Hunt et al., 1985).
3.9 NEUROTOXICITY
It is known that zinc deficiency may have an adverse effect on the central
nervous system. However, recently it has been suggested that the ingestion
of excessive amounts of zinc may also exert toxic effects on the central
nervous system. Kozik et al. (1980) found morphological changes in the
ammonal cortex and basal ganglia in the form of shrunken neurocytes
accompanied by proliferated oligodendroglia, neuronal losses, and
degenerative changes and considerable vacuolization of the neurocytes of the
septum lucidum amygdaloid body in rats orally dosed with 100 mg zinc oxide
for 10 days. A reduction in the activity of acid phosphatase (acP), adenosine
triphosphatase (ATPase), acetylcholinesterase (AChE), and
butyrylthiocholinesterase (BuTJ) along with an increase of thiamine
pyrophosphatase (TPPase) and nonspecific esterase (NsE) activity was also
noted. The authors stated that the effects seen were rather low grade and
may be reversible. In a similar study, Kozik et al. (1981) found that the
ingestion of large doses of zinc oxide increased the production of
neurosecretion in the hypothalamus (supraoptic and paraventricular nuclei)
along with an increased release of antidiuretic hormone in the
neurohypophysis. Histological examination of cells of the hypothalamic nuclei
revealed enlargement of both the cells and their nuclei. Many neurocytes of
the supraoptic and paraventricular nucleus were also shrunken. Motor effects
suggestive of neurological disturbances in pigs during zinc intoxication have
also been reported (Hill et al., 1983).
3.10 EFFECTS IN HUMANS
The literature on adverse health effects in humans resulting from
exposure to excessive amounts of zinc is limited. One probable reason is
that zinc has generally been accepted as a beneficial substance, and adverse
effects, with the exception of those incurred under occupational settings have
generally not been expected or sought.
3.10.1 Inhalation Toxicity
In certain occupational settings, the inhalation of zinc oxide fumes
produces a disease known as metal fume fever. This disease is produced by
the inhalation of zinc oxide fumes when zinc is heated in an oxidizing
atmosphere to a temperature near its boiling point, as in smelting operations,
galvanizing, brass-founding, brazing, and oxyacetylene welding of
galvanized iron. Metal fume fever generally strikes at the beginning of the
work week when the worker has not been exposed for a couple of days and
so it has been called "Monday Fever." Further repeated exposure does not
cause any new symptoms, suggesting some type of adaptation. The
symptoms of this disease (headache, fever, hyperpnea, nausea, sweating
and muscle pains) occur within a few hours after exposure and may persist
for 1 to 2 days. The most prominent laboratory finding is leucocytosis. While
metal fume fever is most commonly caused by exposure to zinc oxide fumes
and/or dust, it may also be caused by exposure to other metals such as
manganese, copper, iron, cobalt, cadmium, antimony, lead, and beryllium
Most of our knowledge about metal fume fever and its relationship to zinc
oxide fumes comes from the beginning of the century (Drinker et al., 1927a,
1928; Sturgis et al., 1927). Many reviews on metal fume fever, often
25
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containing case reports, have also been published (Anseline, 1972; Armstrong
et al 1983; Wolf, 1975; Kemper and Trautman, 1972; Prasad, 1978; Hegsted
et al.! 1945; Kehoe, 1948; Rohrs, 1957; Summer and Haponick, 1981; Mueller
and Seger, 1985).
There are few data on the ambient levels of zinc oxide fumes that might
cause metal fume fever in man. Sturgis et al. (1927) exposed two people to
zinc oxide fumes at a dose corresponding to 600 mg zinc/m3. It was
calculated that the subjects inhaled 48 and 74 mg zinc, respectively. Both
subjects developed symptoms of metal fume fever. Batchelor et al., 1926;
Kemper and Trautman (1972); and Hammond (1944) reported that metal fume
fever does not occur at zinc oxide levels below 15 mg/m3.
Several theories have been postulated concerning the mechanism of
metal fume fever, but there is no definite evidence for any of the proposed
theories. McCord (1960) suggested that there is an allergic basis for the
mechanism of the fever. Mori et al. (1975) stated that catalytically active
metal oxide fumes produced by heating the metal within the proper
temperature range in the presence of carbon monoxide causes metal fume
fever by an oxidative action in the blood. Regardless of the mechanism of the
fever, the disease is likely caused only by metal particles of extremely small
size.' These penetrate deep into the alveoli, causing acute reactions there
(National Research Council, 1978; U.S. Environmental Protection Agency,
1980).
Acute pulmonary damage that can be lethal may occur after the
inhalation of zinc chloride, the major component in smoke coming from the
so-called "smoke bombs" often used in military exercises. Inhalation of
such smoke in confined spaces may rapidly lead to severe pulmonary
disease (Milliken et al., 1963; Schmahl, 1974; Schenker et al., 1981). Milliken
et al. (1963) reported on a fire fighter who died after being exposed to zinc
chloride smoke from a smoke generator during a demonstration. The subject
experienced difficulty in breathing, tachypnea, epigastric pain, nausea, and
fever followed by cyanosis, confusion, and coma. Postmortem examination
revealed advanced pulmonary fibrosis, acute cor pulmonale, and right
ventricular hypertrophy. Death was attributed to acute respiratory
insufficiency.
The effects of inhalation of zinc chloride in smoke from smoke bombs
have also been described by Schmahl (1974), who reported on 11 cases, of
which 2 had very severe reactions. There were no severe sequelae; however,
in one case it was almost 2 years before the lung function returned to normal.
3.10.2 Oral Toxicity
The hazards of ingesting foods and/or liquids stored in galvanized
containers are well known. Callender and Gentzkow (1937) reported on a
case of two companies of soldiers that dined separately who became ill after
consuming limeade which had been prepared and stored in galvanized iron
cans. Symptoms included gastrointestinal distress and diarrhea of mild
intensity. Analysis of the limeade prepared under the same conditions as that
in the poisoning incidents revealed a concentration of zinc oxide of 910 mg/L
and 15.6 mg/L of antimony. It was concluded that the amounts of zinc and
antimony present in the limeade were responsible for the poisonings. Brown
et al. (1964) reported on two cases of zinc poisoning in California. In the first
case, 300 to 350 people became ill after consuming food which had been
stored in galvanized containers. By simulating the preparation and storage of
the contaminated foods, the investigators estimated that the zinc
26
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concentration approached 1,000 ppm (wet weight). In the second case, 44
people became ill with nausea, vomiting, and diarrhea within 20 minutes after
consuming an alcoholic punch. Analysis of the punch revealed that it
contained 2,200 mg/L of zinc. A group of students in a home economics
class experienced chills, dizziness, nausea, vomiting, and headache after
consuming fruit punch which had been stored in a galvanized container
overnight. Punch samples from the storage container contained 443 ppm
zinc (Lapham et al., 1983).
Hooper et al. (1980) after orally administering 440 mg zinc sulfate/day
(160 mg elemental zinc/day) to healthy young males for 5 weeks found a 25
percent reduction in the high-density lipoprotein-cholesterol
(antiatherogenic lipoprotein) levels. The authors speculated that excessive
levels of orally administered zinc may be atherogenic in man. The effect of
moderate increases in dietary zinc on the high-density lipoprotein-
cholesterol level is not known.
In a later work, Chandra (1984) found a reduction in the high-density
lipoprotein-cholesterol level and an increase in the low-density
lipoprotein-cholesterol level in healthy adult males after oral administration of
150 mg elemental zinc/day for 6 weeks. A reduction in lymphocyte
stimulation to phytomemaglutinin and a reduction in polymorphonuclear-
migration in response to chemotactic migration and phagocytosis of bacteria
was also seen in these subjects. The results of this study indicate that oral
ingestion of excessive amounts of zinc by healthy individuals over an
extended period of time may have a deleterious effect on both the
immunologic and cardiovascular systems.
Murphy (1970) reported on a 16-year old boy who ingested 12 grams of
zinc over a 2 day period to hasten healing of a minor laceration. Three days
after ingestion the subject experienced difficulty in awakening after a full
night's sleep, light-headedness, slight staggering of gait, and difficulty in
writing. Follow-up examination 1 month later revealed no apparent
sequelae.
3.10.3 Other Routes of Exposure
Because it is an essential element, zinc is routinely added to parenteral
nutrition regimens; however, care must be taken to ensure against zinc
intoxication. Brocks et al. (1977) reported on a woman who suffered from a
case of acute zinc poisoning while receiving total parenteral nutrition. Over a
period of 64 hours she received 7.4 g of zinc sulfate. The patient became ill
with pulmonary edema, jaundice, vomiting, diarrhea, and oliguria. Her serum
zinc concentration was 4,184 pg/100 mL. In spite of treatment, renal function
did not improve and she remained oliguric. She died after 47 days of illness
with bronchopneumonia.
Gallery et al. (1972) reported on a patient who became ill with nausea,
vomiting, and fever during home hemodialysis. An investigation into the
cause of the illness disclosed that the patient was using rain water stored in
galvanized tanks for the dialysis. The water contained 625 yg zinc/100 mL.
3.10.4 Epidemiology
In 1926, Batchelor et al. made an extensive investigation of workers
exposed to zinc in a smelter in New Jersey. A total of 24 workers were
selected from a baghouse where zinc oxide was handled, from several zinc
oxide packing plants, from a plant handling metallic zinc, and from a lithopone
packing house. The length of exposure ranged from 2 to 35.5 years. In most
27
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work places the mean zinc concentrations were generally below 35 mg/m3,
except in the zinc dust plant, where concentrations of up to 130 mg/m3 were
measured.
The 24 subjects underwent careful examinations. A slight leukocytosis was
seen in 14 of the subjects. Hemoglobin readings ranged between 72 and 97
with the average being 81. Zinc in whole blood in the exposed groups
averaged 458 ug/100 mL, compared to 387 yg/100 mL in controls. In
exposed groups, 24-hour zinc elimination via feces averaged 46.8 mg, while
in controls the average was 9.32 mg. This finding indicated an exposure via
the gastrointestinal tract. The conclusion of the authors was that workmen
could be exposed to zinc compounds in a smelter for decades without any
symptoms or chronic disease. However, more recent surveys, discussed
below, do indicate hazards associated with high-level exposures to zinc
compounds in the workplace.
Chmielewski et al. (1974a,b) examined a group of workers in a shipyard
consisting of ship smiths, electric welders, ship's pipeline fitters, and
zincifying workers who were exposed to zinc oxide (see Table 3-4).
Exposure levels varied and in some cases exceeded the maximum
acceptable concentration (MAC) for zinc oxide in air (5 mg/m3). The highest
concentrations of zinc oxide during work were found at the stands of the
electric welders who worked in containers (maximum 58 mg/m3, mean 18
mg/m3), the ship's pipeline fitters working within the engine room of the ship
(maximum 40 mg/m3, mean 5 mg/m3), and the ship smiths employed in a
superstructure (maximum 50 mg/m3, mean 12 mg/m3). Interviews showed
that most of the smiths, welders, and fitters had experienced metal fume fever
several times. Frequent occurrences of chronic respiratory tract infections
were noted in the welders and fitters during the physical examination. Two
cases of an early stage of welder's pneumoconiosis were noted in the
welders' group. Chronic conjunctivitis and dermatitis occurred in all groups
examined. Chronic gastritis was noted in all groups examined; however,
because of the lack of a commonly accepted objective diagnostic criterion, an
unequivocal confirmation of this diagnosis could not be made. A statistically
significant increase in asparate aminotransferase activity was noted in the
welders and a statistically significant rise in alanine aminotransferase was also
noted in the welders and fitters. However, these workers were also exposed
to other hazardous compounds, such as nitrogen oxides.
Bobrishchev-Pushkin et al. (1977) studied the health status of 1,018
workers in the casting shops of three copper alloy production facilities. Four
hundred and fifty-one workers from the rolling shops were used as controls.
The average level of zinc oxide exposure in the casting shop was 2.1 mg/m3
(range of 0.2 to 5.1 mg/m3). Analysis of the health status of workers over a 5
year period showed an increased illness rate for the respiratory organs such
as subatrophic changes in the breathing passages, chronic bronchitis, and
diffuse pneumosclerosis. The frequency of illness with subatrophic and
atrophic rhinitis, rhinopharyngitis, and rhinopharyngolaryngitis increased with
the length of employment. The illnesses were noted in 15 percent of those
with an employment of 10 years, in 21 percent with 11 to 20 years of
employment, and in 35 percent of those employed for over 20 years; these
illnesses were 3 to 6 times higher than for controls. Chronic bronchitis was
diagnosed in 11 percent of exposed workers compared to 6 percent in
controls. However, workers were also exposed to other metals such as
copper, lead, and nickel.
A study of the mutagenic potential of urine from subjects occupationally
exposed to a variety of compounds, including zinc oxide in the rubber
28
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Table 3-4 Groups Involved, Age, Duration of Work and Timing of
Work of the 66 Workers Exposed to the Effect of Zinc Oxide- Seen
for Medical Examination
Number of
the workers
examined
20
13
15
18
Groups
examined
ship-
smiths
electric
welders
ship's
pipe-line
filters
zincifying
workers
Shop
k-3
k-3
R
I
Working
stand
super-
structure
super-
structure
container
engine-
room
zincifying
shop
Average
age of the
groups
pvstfnin&ri
C7Ad«//(//CU
(yr)
27.6
29.0
29.2
36.6
Mean
duration of
professional
work (yr)
7.0
8.0
7.9
14.5
Mean
duration of
exposure to
zinc oxide
(yr)
3.0
6.0
7.1
8.5
daily
(hr)
4.2
4.6
3.7
6.0
Source: Chmielewski et al. (1974b)
industry, was conducted by Crebelli et al. (1985). The urine samples were
found to not be mutagenic in the microtitre fluctuation assay with Salmonella
typhimurium strains TA1535, TA98, and TA100.
Klucik and Koprda (1979) found that everyone exposed to zinc oxide dust
in a zinc oxide factory showed signs of hypocalcemia. Exposure levels were
reported to average 0.5 mg/m3 for zinc melters and 2.44 to 7.15 mg/m3 for
zinc oxide packers; however, it was not indicated how these values were
obtained. Serum calcium levels of exposed subjects were significantly lower
and serum zinc was higher than in controls. X-rays revealed definite signs
of osteoporosis, loss of spongiosis in the vertebrae and pelvis of two of six
zinc oxide packers, of which one was thought to be due possibly to the age of
the subject (60 years). The authors suggested that with a higher zinc intake,
the zinc forces calcium from the bone, and the latter is then eliminated.
In a study on furnace operators exposed to zinc oxide fumes in a brass
foundry for a mean duration of 11 ±5 years, Hamdi (1969) found that
workers often complained of epigastric pain. These workers showed a
statistically significant increase in zinc concentration in whole blood, blood
corpuscles, and basal fasting gastric juice in comparison to nonexposed
subjects. The author suggested that the increased zinc content of the gastric
juice may have been responsible for the gastric complaints; however, it could
also be due to the presence of other substances used in the manufacture of
the alloys.
29
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Zinc stearate, an organic compound of zinc encountered in the rubber
and plastics industry, is suspected of causing lung disease. Uotila and Noro
(1957) reported on the death of a man who had been employed in the rubber
industry for 29 years. The cause of death was determined to be chronic
pneumoconiosis. Histochemical examination of the lungs showed an
increased deposit of zinc; however, no quantitative determination of the zinc
content was made. The role of zinc stearate as the causative agent in
neumoconiosis has also been evaluated by Weber et al. (1976). Weber and
co-workers, as reported by the U.S. Environmental Protection Agency
(1980), described the autopsy findings in a man who, for the last 8 years of
his life, had been exposed to zinc stearate in the plastics industry.
Pneumoconiosis was given as the cause of death. The lungs contained 62
mg/kg zinc on a dry weight basis, which was within normal limits. The
authors concluded that zinc stearate could not have caused the fibrosis.
However, as pointed out by Harding (1957), zinc stearate is relatively rapidly
removed from the lungs; thus, a normal content of zinc does not exclude the
possibility that zinc may have contributed to the disease.
30
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4. References
Allen, G. S. (1968) An outbreak of zinc poisoning in cattle. Vet. Rec 83- 8-9
Amdur, N(O.; McCarthy, J. F.; Gill, M. W. (1982) Respiratory response of
guinea-pigs to zinc oxide fume. Am. Ind. Hyg. Assoc J 43- 887-889
Ansari, M. S.; Miller, W. J.; Lassiter, J. W.; Neathery, M. W.; Gentry, R. P.'
(1975) Effects of high but nontoxic dietary zinc on zinc metabolism and
adaptations in rats. Proc. Soc. Exp. Biol. Med. 150: 534-536
Ansari, M. S.; Miller, W. J.; Neathery, M. W.; Lassiter, J. W.; Gentry, R. P.;
Kincaid, R. L. (1976) Zinc metabolism and homeostasis in rats fed a wide
range of high dietary zinc levels. Proc. Soc. Exp. Biol. Med. 152- 192-
194.
Anseline, P. (1972) Zinc-fume fever. Med. J. Aust. 2: 316-318
Anteby, S. O.; Ben Bassat, H. A.; Yarkoni, S.; Aboulafia, Y.; Sadovsky, E.
(1978) The effect of intrauterine devices containing zinc and copper on
their levels in serum. Fertil. Steril. 29: 30-34.
Apgar, J. (1971) Effect of a low zinc diet during gestation on reproduction in
the rabbit. J. Anim. Sci. 33: 1255-1258
Armstrong, C. W.; Moore, L. W., Jr.; Hackler, R. L.;Miller, G. B., Jr.; Stroube,
R. B. (1983) An outbreak of metal fume fever: diagnostic use of urinary
copper and zinc determinations. JOM J. Occup. Med. 25: 886-888
Aughey. E.; Grant, L.; Furman, B. L.; Dryden, W. F. (1977) The effects of oral
zinc supplementation in the mouse. J. Comp. Pathol. 87: 1-14.
Bach, J. F. (1981) The multifaceted zinc dependency of the immune system
Today: 225-227.
Banerjee, D.; Onosaka, S.; Cherian, M. G. (1982) Immunohistochemical
localization of metallothionein in cell nucleus and cytoplasm of rat liver
and kidney. Toxicology 24: 95-105.
Batchelor, R. P.; Fennel, J. W.; Thomson, R.M.; Drinker, K. R. (1926) A
clinical and laboratory investigation of the effect of metallic zinc, of zinc
oxide, and of zinc sulphide upon the health of workmen. J. Ind. Hyg. 8:
322-363.
Beisel, W. R. (1982) Single nutrients and immunity. Am. J Clin Nutr
35(suppl.): 417-468.
Bell, J. U. (1979) A metallothionein-like protein in the hepatic cytosol of the
term rat fetus. Toxicol. Appl. Pharmacol. 48: 139-144
Bettger, W. J.; O'Dell, B. L. (1981) A critical physiological role of zinc in the
structure and function of biomembranes. Life Sci 28- 1425-1438
Bischoff, F.; Long, M. L. (1939) The local effect of zinc upon the development
of the Marsh-Buffalo adenocarcinoma. Am. J. Cancer 37- 531-535
Blakeborough, P.; Sailer, D. N.; Gurr, M. I. (1983) Zinc binding in cow's milk
and human milk. Biochem. J. 209: 505-512.
Bobrishchev-Pushkin, D. M.; Orlova, A. A.; Naumova. L. A.; Nikitina L S •
Nikolayeva, L. N.; Vernikova, A. A.; Yermolenko, A. Ye.; Khelkovskiy-
Sergeyev, N. A. (1977) Industrial hygiene and the health status of workers
in the production of copper alloys. Gig. Tr. Prof. Zabol. (8): 10-14
31
-------
Boddy. K.; East, B. W.; King, P. C.; Simpson, R. W.; Scott, R. (1970)
Preliminary studies of zinc metabolism in carcinoma of the prostate
gland. Br. J. Urol. 42: 475-480.
Bonner. F. W.; Bridges, J. W. (1983) Toxicological properties of trace
elements. In: Rose, J., ed. Trace elements in health: a review of current
issues. London, United Kingdom: Butterworth; pp. 1-20.
Boosalis, M. G.; Evans, G. W.; McClain, C. J. (1983) Impaired handling of
orally administered zinc in pancreatic insufficiency. Am. J. Clm. Nutr. 6i.
268-271.
Bray. T. M.; Kubow, S.; Bettger, W. J. (1986) Effect of dietary zinc on
endogenous free radical production in rat lung microsomes. J. Nutr. lib:
1054-1060. 0
Breitschwerdt, E. B.; Armstrong, P. J.; Robinette, C. L; Dillman, R. C.;
Karl M. L.; Lowry, E. C. (1986) Three cases of acute zinc toxicosis in
dogs. Vet. Hum. Toxicol. 28: 109-117. .
Brink. M. F.; Becker, D. E.; Terrill, S. W.; Jensen, A. H. (1959) Zinc toxicity in
the weanling pig. J. Anim. Sci. 18: 836-842.
Brocks, A.; Reid, H.; Glazner, G. (1977) Acute intravenous zinc poisoning. Br.
Med. J. 1: 1390-1391. „„„„,- ^
Brown. M. A.; Thorn, J. V.; Orth. G. L.; Cova, P.; Juarez, J. (1964) Food
poisoning involving zinc contamination. Arch. Environ. Health 8: 657-
660.
Brungs, W. A. (1969) Chronic toxicity of zinc to the fathead minnow,
Pimephales promelas rafinesque. Trans. Am. Fish. Soc. 98: 272-279.
Buchauer, M. J. (1973) Contamination of soil and vegetation near a zinc
smelter by zinc, cadmium, copper, and lead. Environ. Sci. Technol. 7:
131-135. . . .
Callender, G. R.; Gentzkow, C. J. (1937) Acute poisoning by the zinc and
antimony content of limeade prepared in a galvanized iron can. Mint.
Surg. 80: 67-71.
Carroll, M. D.; Loneragan, J. F. (1968) Response of plant species to
concentrations of zinc in solution: I. growth and zinc content of plants.
Aust. J. Agric. Res. 19: 859-868.
Cerklewski F. L.; Forbes, R. M. (1976) Influence of dietary zinc on lead
toxicity in the rat. J. Nutr. 106: 689-696.
Chandra R. K. (1983) Nutrition, immunity, and infection: present knowledge
and future directions. Lancet (8326): 688-691.
Chandra R K. (1984) Excessive intake of zinc impairs immune responses.
JAMA J. Am. Med. Assoc. 252: 1443-1446.
Chmielewski, J.; Jaremin, B.; Bartnicki, C.; Konieczka, R. (1974a) Evaluation
of occupational exposure to zinc oxide in the marine production-
shipyard: I. examination of the working environment and the stands under
exposure. Bull. Inst. Mar. Med. Gdansk 25: 43-51.
Chmielewski, J.; Jaremin, B.; Bartnicki, C.; Konieczka, R. (1974b) Evaluation
of occupational exposure to zinc oxide in the marine production shipyard:
II. examination of the state of health of the workers exposed to zinc oxide.
Bull. Inst. Mar. Med. Gdansk 25: 53-65.
Conner M W.; Rogers, A. E.; Amdur, M. O. (1982) Response of guinea pig
respiratory tract to inhalation of submicron zinc oxide particles generated
in the presence of sulfur dioxide and water vapor. Toxicol. Appl.
Pharmacol. 66: 434-442.
32
-------
Conner, M. W.; Lam, H. F.; Rogers, A. E.; Fitzgerald, S.; Amdur, M. O (1985)
Lung injury in guinea pigs caused by multiple exposures to submicron
in a humidified "
Cousins, R. J.
Ret 65-
Cousins R J.
in: Metal
GA. Clm.
Cousins R J
(1985) Absorption, transport, and hepatic metabolism of copper
a ^ tO metallothionein and ceruloplasmin. Physiol.
. (1986) Toward a molecular understanding of zinc metabolism
metabolism and disease: 9th ann. meet. NACB; 1985- Atlanta
Physiol. Biochem. 4: 20-30
.; Smith, K. T.; Failla, M. L; Markowitz, L. A. (1978) Origin of low
~ e'9ht Zinc-bindii9 complexes from rat intestine. Life Sci. 23-
.
.
Crebelli, R.; Paoletti, A.; Falcone, E.; Aquilina, G.; Fabri, G.; Carere A (1985)
Mutagenicity studies in a tyre plant: in vitro activity of workers' urinarv
concentrates and raw materials. Br. J. Ind Med 42- 481-487
Dav.es, N. T.; Nightingale, R. (1975) The effects of phytate on intestinal
absorption and secretion of zinc, and whole-body retention of Zn
copper, iron and manganese in rats. Br. J. Nutr 34- 243-258
Derry, J. E.; McLean, W. M.; Freeman, J. B. (1983) A study of the "
percutaneous absorption from topically applied zinc oxide ointment
JPEN J. Parenter. Enteral Nutr. 7: 131-135
Dewa£ W. A.; Wight, P. A. L.; Pearson, R. A.; Gentle, M. J. (1983) Toxic
effects of high concentrations of zinc oxide in the diet of the chick and
laying hen. Br. Poult. Sci. 24: 397-404.
Dinsrnore, W. W.; Callender, M. E.; McMaster, D.; Love, A H G (1985) The
absorption of zinc from a standardized meal in alcoholics and in normal
volunteers. Am. J. Clin. Nutr. 42: 688-693
'HE;-: Buckley- K- A-' Record- '- R- (1986) The teratogenic effect of
d®flPiencv and accompanying feeding patterns in mice. Nutr. Res. 6:
- 1 oo,
hn f> " (J928) Metal fume fever: V' results of the inhalation
by animals of zinc and magnesium oxide fumes. J. Ind Hvn 10- 56-72
Drinker, P.; Thomson, R. M.; Finn, J. L. (1927a) Metal fume fever IV '
threshold doses of zinc oxide, preventive measures, and the chronic
effects of repeated exposures. J. Ind. Hyg. 9- 331-345
Drinker, K. R.; Thompson, P. K.; Marsh, M. (I927b) An investigation of the
effect upon rats of long-continued ingestion of zinc compounds with
especial reference to the relation of zinc excretion to zinc intake. Am. J.
• nysioi. ol '. 284-306.
Dyson, W. L.; Quon, J. E. (1976) Reactivity of zinc oxide fume with sulfur
dioxide in air. Environ. Sci. Technol. 10: 476-481
Ebadi, M. (1984) The presence of metallothionein-like'protein (MTL) in rat
brain. Fed. Proc. Fed. Am. Soc. Exp. Biol. 43- 851
Ecker R. I.; Schroeter, A. L. (1978) Acrodermatitis and acquired zinc
deficiency. Arch. Dermatol. 114: 937-939
Vh; °UnCan' J" R': Hurley' L S" <1977> Zinc bir>ding:
human and bovine milk- Science (Washington, DC)
.
EI-Gazzar, R. M.; Finelli, V. N.; Boiano, J.; Petering, H. G. (1978) Influence of
dietary zinc on lead toxicity in rats. Toxicol. Lett V 227-234
Ehnder, C.-G.; Piscator, M. (1978) Cadmium and zinc relationships EHP
Environ. Health Perspect. 25: 129-132
33
-------
Blinder, C.-G.; Piscator, M.; Linnman, L. (1977) Cadmium and zinc
relationships in kidney cortex, liver, and pancreas. Environ. Res. 13:
432-440
Binder. C.-G.; Kjellstrom, T.; Linnman, L.; Pershageri, G. (1978) Urinary
excretion of cadmium and zinc among persons from Sweden. Environ.
Res. 15: 473-484.
Evans, G. W.; Grace, C. I.; Hahn, C. (1973) Homeostatic regulation of zinc
absorption in the rat. Proc. Soc. Exp. Biol. Med. 143: 723-725.
Failla, M. L; van de Veerdonk, M.; Morgan, W. T.; Smith, J. C., Jr. (1982)
Characterization of zinc-binding proteins of plasma in familial
hyperzincemia. J. Lab. Clin. Med. 100: 943-952.
Fenton, M. R.; Burke, J. P. (1985) Subcellular zinc distribution in livers and
tumors of plasmacytoma-bearing mice. Nutr. Res. 5: 1383-1391.
Perm, V. H.; Carpenter, S. J. (1968) The relationship of cadmium and zinc in
experimental mammalian teratogenesis. Lab. Invest. 18: 429-432.
Festa, M. D.; Anderson, H. L; Dowdy, R. P.; Ellersieck, M. R. (1985) Effect of
zinc intake on copper excretion and retention in men. Am. J. Clin. Nutr.
.41: 285-292.
Feustel, A.; Wennrich, R.; Steiniger, D.; Klauss, P. (1982) Zinc and cadmium
concentration in prostatic carcinoma of different histological grading in
comparison to normal prostate tissue and adenofibromyomatosis (BPH).
Urol. Res. 10: 301-303.
Fickel, J. J.; Freeland-Graves, J. H.; Roby, M. J. (1986) Zinc tolerance tests
in zinc deficient and zinc supplemented diets. Am. J. Clin. Nutr. 43: 47-
58.
Fischer, P. W. F.; Giroux, A.; L'Abbe, M. R. (1983) Effects of zinc on mucosal
copper binding and on the kinetics of copper absorption. J. Nutr. 113:
462-469.
Fischer, P. W. F.; Giroux, A.; L'Abbe, M. R. (1984) Effect of zinc
supplementation on copper status in adult man. Am. J. Clin. Nutr. 40:
743-746.
Fisher, G. L.; McNeil), K. L.; Democko, C. J. (1986) Trace element interactions
affecting pulmonary macrophage cytotoxicity. Environ. Res. 39: 164-
171.
Fong, L. Y. Y.; Sivak, A.; Newberne, P. M. (1978) Zinc deficiency and
methylbenzylnitrosamine-induced esophageal cancer in rats. JNCI J.
Natl. Cancer Inst. 61: 145-150.
Fong, L. Y. Y.; Lee, J. S. K.; Chan, W. C.; Newberne, P. M. (1984) Zinc
deficiency and the development of esophageal and forestomach tumors
in Sprague-Dawley rats fed precursors of _N-nitroso- _N-
benzylmethylamine. JNCI J. Natl. Cancer Inst. 72: 419-425.
Foote, J. W.; Delves, H. T. (1984) Albumin bound and ct2-macroglobulin
bound zinc concentrations in the sera of healthy adults. J. Clin. Pathol.
37: 1050-1054.
Forbes, R. M.; Erdman, J. W., Jr.; Parker, H. M.; Kondo, H.; Ketelsen, S. M.
(1983) Bioavailability of zinc in coagulated soy protein (tofu) to rats and
effect of dietary calcium at a constant phytate:zinc ratio. J. Nutr. 113:
205-210.
Fraker, P. J.; Gershwin, M. E.; Good, R. A.; Prasad, A. (1986)
Interrelationships between zinc and immune function. Fed. Proc. Fed.
Am. Soc. Exp. Biol. 45: 1474-1479.
Freeman, R. M.; Taylor, P. R. (1977) Influence of histidine administration on
zinc metabolism in the rat. Am. J. Clin. Nutr. 30: 523-527.
34
-------
Freeman, J. B.; Stegink, L. D.; Meyer, P. D.; Fry, L. K.; Denbesten, L. (1975)
Excessive urinary zinc losses during parenteral alimentation. J. Surq
Res. 18: 463-469.
Furchner, J. E.; Richmond, C. R. (1962) Effect of dietary zinc on the
absorption of orally administered Znes- Health Phys. 8: 35-40.
Gabrial, G. N.; Schrager, T. F.; Newberne, P. M. (1982) Zinc deficiency,
alcohol, and a retinoid: association with esophageal cancer in rats JNCI
J. Natl. Cancer Inst. 68: 785-789.
Gallant, K. R.; Cherian, M. G. (1986) Influence of maternal mineral deficiency
on the hepatic metallothionein and zinc in newborn rats. Biochem Cell
Biol. 64: 8-12.
Gallery, E. D. M.; Blomfield, J.; Dixon, S. R. (1972) Acute zinc toxicity in
haemodialysis. Br. Med. J. (5836): 331-333.
Gasaway, W. C.; Buss, I. O. (1972) Zinc toxicity in the mallard duck. J.
Wildlife Manage. 36: 1107-1117.
Ghavami-Maibodi, S. Z.; Collipp, P. J.; Castro-Magana, M.; Stewart, C.;
Chen, S. Y. (1983) Effect of oral zinc supplements on growth, hormonal
levels, and zinc in healthy short children. Ann. Nutr. Metab. 27: 214-219.
Ghishan, F. K.; Said, H. M.; Wilson, P. C.; Murrell, J. E.; Greene, H. L. (1986)
Intestinal transport of zinc and folic acid: a mutual inhibitory effect. Am J
Clin. Nutr. 43: 258-262.
Giroux, E. L.; Durieux, M.; Schechter, P. J. (1976) A study of zinc distribution
in human serum. Bioinorg. Chem. 5: 211-218.
Golub, M. S.; Gershwin, M. E.; Hurley, L. S.; Hendrickx, A. G.; Saito, W. Y.
(1985) Studies of marginal zinc deprivation in rhesus monkeys: infant
behavior. Am. J. Clin. Nutr. 42: 1229-1239.
Gordon, E. F.; Bond, J. T.; Gordon, R. C.; Denny, M. R. (1982) Zinc deficiency
and behavior: a developmental perspective. Physiol. Behav. 28- 893-
897.
Graham, R.; Sampson, J.; Hester, H. R. (1940) Results of feeding zinc to
pregnant mares and to mares nursing foals. J. Am. Vet. Med. Assoc. 97-
41-47.
Grasso, P.; Golberg, L. (1966) Subcutaneous sarcoma as an index of
carcinogenic potency. Food Cosmet. Toxicol. 4: 297-320.
Gupta, S.; Pandey, S. D.; Misra, V.; Viswanathan, P. N. (1986) Effect of
intratracheal injection of zinc oxide dust in guinea pias. Toxicoloav 38"
197-202. .
Gyorkey, F.; Min, K.-W.; Huff, J. A.; Gyorkey, P. (1967) Zinc and magnesium
in human prostate gland: normal, hyperplastic, and neoplastic. Cancer
Res. 27: 1348-1353.
Habib, F. K.; Hammond, G. L.; Lee, I. R.; Dawson, J. B.; Mason, M. K.; Smith,
P. H.; Stitch, S. R. (1976) Metal-androgen interrelationships in
carcinoma and hyperplasia of the human prostate. J. Endocrinol 71-
133-141.
Halas, E. S.; Sandstead, H. H. (1975) Some effects of prenatal zinc deficiency
on behavior of the adult rat. Pediatr. Res. 7: 300-319.
Halas, E. S.; Heinrich, M. D.; Sandstead, H. H. (1979) Long term memory
deficits in adult rats due to postnatal malnutrition. Physio) Behav 22-
991-997.
Hallmans, G. (1977) Treatment of burns with zinc-tape: a study of local
absorption of zinc in humans. Scand. J. Plast. Reconstr Sura 11- 155-
161.
35
-------
Hallmans. G.; Lasek, J. (1985) The effect of topical zinc absorption from
wounds on growth and the wound healing process in zinc-deficient rats.
Scand. J. Plast. Reconstr. Surg. 19: 119-125.
Halsted, J. A.; Smith. J. C., Jr.; Irwin, M. I. (1974) A conspectus of research on
zinc requirements of man. J. Nutr. 104: 345-378.
Hambidge, K. M.; Hambidge, C.; Jacobs, M.; Baum, J. D. (1972) Low levels of
zinc in hair, anorexia, poor growth, and hypogeusia in children. Pediatr.
Res. 6: 868-874.
Hamdi, E. A. (1969) Chronic exposure to zinc of furnace operators in a brass
foundry. Br. J. Ind. Med. 26: 126-134.
Hammond, J. W. (1944) Metal fume fever in the crushed stone industry. J.
Ind. Hyg. Toxicol. 26: 117-119.
Harding, H. E. (1957) Some enquiries into the toxicology of zinc stearate. Br.
J. Ind. Med. 15: 130-132.
Hatch. G. E.; Boykin, E.; Graham, J. A.; Lewtas, J.; Pott. F.; Loud, K.;
Mumford, J. L. (1985) Inhalable particles and pulmonary host defense: in
vivo and in vitro effects of ambient air and combustion particles. Environ.
Res. 36: 67-80.
Hegsted, D. M.; McKibbin, J. M.; Drinker, C. K. (1945) The biological,
hygienic, and medical properties of zinc and zinc compounds. Public
Health Rep. (suppl. 179): 1-44.
Henkin, R. I. (1971) Newer aspects of copper and zinc metabolism. In: Mertz,
W.; Cornatzer, W. E., eds. Newer trace elements in nutrition. New York,
NY: Marcel Dekker, Inc.; pp. 255-312.
Henkin. R. I.; Patten, B. M.; Re, P. K.; Bronzert, D. A. (1975) A syndrome of
acute zinc loss: cerebellar dysfunction, mental changes, anorexia, and
taste and smell dysfunction. Arch. Neurol. 32: 745-751.
Hilderman. E.; Taylor, P. A. (1974) Acute pulmonary emphysema in cattle
exposed to zinc oxide fumes. Can. Vet. J. 15: 173-175.
Hill. G. M.; Miller, E. R.; Stowe, H. D. (1983) Effect of dietary zinc levels on
health and productivity of gilts and sows through two parities. J. Anim.
Sci. 57: 114-122.
Hooper, P. L.; Visconti, L.; Garry, P. J.; Johnson, G. E. (1980) Zinc lowers
high-density lipoprotein-cholesterol levels. JAMA J. Am. Med. Assoc.
244: 1960-1961.
Hunt, W. F., Jr.; Faoro, R. B.; Duggan, G. M. (1984) Compilation of air toxic
and trace metal summary statistics. Research Triangle Park, NC: U. S.
Environmental Protection Agency, Office of Air Quality Planning and
Standards; EPA report no. EPA-450/4-84-015. Available from: NTIS,
Springfield, VA; PB84-245273.
Hunt, I. F.; Murphy, N. J.; Cleaver. A. E.; Faraji, B.; Swendseid, M. E.; Browdy,
B. L.; Coulson, A. H.; Clark, V. A.; Settlage, R. H.; Smith, J. C., Jr. (1985)
Zinc supplementation during pregnancy in low-income teenagers of
Mexican descent: effects on selected blood constituents and on progress
and outcome of pregnancy. Am. J. Clin. Nutr. 42: 815-828.
Hurley, L. S.; Mutch, P. B. (1973) Prenatal and postnatal development after
transitory gestational zinc deficiency in rats. J. Nutr. 103: 649-656.
Hurley, L. S.; Shrader, R. E. (1972) Congenital malformations of the nervous
system in zinc-deficient rats. Int. Rev. Neurobiol. Suppl. 1: 7-51.
Hurley, L. S.; Swenerton, H. (1966) Congenital malformations resulting from
zinc deficiency in rats. Proc. Soc. Exp. Biol. Med. 123: 692-696.
Hurley, L. S.; Gowan. J.; Swenerton, H. (1971) Teratogenic effects of
short-term and transitory zinc deficiency in rats. Teratology 4: 199-204.
36
-------
Istfan, N. W.; Janghorbani, M.; Young, V. R. (1983) Absorption of stable 70Zn
m healthy young men in relation to zinc intake. Am. J Clin Nutr 38-
187-194.
Jackson, M. J.; Holt, D.: Webb, M.; Carter, N. D. (1986) Physiological
zinc-binding proteins of medium molecular weight in the rat gut. Br. J.
* 'Uir. oo. ooy~o/ /.
Jacob, R. A.; Sandstead, H. H.; Munoz, J. M.; Klevay, L. M.; Milne D B
C1|fn81Nufrh°34b0dy SUrfaCe '°SS °f trace metals in normal m'ales- Am- J-
Jolly J. H. (1985) Zinc. In: Minerals yearbook 1984: v. I, metals and minerals
919 94^6°"' DC: U' S' Department of the lnterior- Bureau of Mines; pp.
Kagi, J. H.; Nordberg, M. (1979) Metallothionein. Basel, Switzerland-
Birkhauser.
Kagi, J. H.; Vallee, B. L. (1960) Metallothionein: a cadmium- and zinc-
containing protein from equine renal cortex. J. Biol. Chem. 235: 3460-
3465.
Kehoe, R. A. (1948) Metal fume fever. Am. Ind. Hyg. Assoc Q 9- 66-70
Kemper, F.; Trautmann, A. (1972) Inhalation of zinc oxide. Dtsch Med
Wochenschr. 97: 307.
Kern, S, R.; Smith, H. A.; Fontaine, D.; Bryan, S. E. (1981) Partitioning of zinc
and copper in fetal liver subtractions: appearance of metallothionein-like
L,-, Pr°te'ns durm9 development. Toxicol. Appl. Pharmacol. 59: 346-354
Kiilench, S.; Christiansen, C. (1984) Distribution of serum zinc between
albumin and ct2-macroglobulin estimated by ultracentrifugation Clin
Chim. Acta 142: 273-280.
Klucik, I.; Koprda, J. (1979) Hypokalcaemia in subjects exposed to long-term
effects of zinc oxide. Prac. Lek. 31: 234-237
Kojima, Y.; Berger, C.; Vallee, B. L.; Kagi, J. H. R. (1976) Amino-acid
sequence of equine renal metallothionein-IB. Proc. Natl. Acad. Sci. U
S. A. 73: 3413-3417.
Kowalczyk, G. S.; Gordon, G. E.; Rheingrover, S. W. (1982) Identification of
atmospheric particulate sources in Washington, D.C., using chemical
element balances. Environ. Sci. Technol. 16: 79-90
Kozik, M. B.; Maziarz, L.; Godlewski, A. (1980) Morphological and
histochemical changes occurring in the brain of rats fed large doses of
zinc oxide. Folia Histochem. Cytochem. 18: 201-206
Kozik, M. B.; Gramza, G.; Pietrzak, M. (1981) Neurosecretion of the
hypothalamo-hypophyseal system after intragastric administration of
zinc oxide. Folia Histochem. Cytochem. 19 115-122
Krebs, N. F; Hambidge. K. M. (1986) Zinc requirements and zinc intakes of
breast-fed infants. Am. J. Clin. Nutr. 43: 288-292.
Kumar, S. (1976) Effect of zinc supplementation on rats durinq preqnancv
Nutr. Rep. Int. 13: 33-36.
L'Abbe, M. R.; Fischer, P. W. F. (1984) The effects of dietary zinc on the
activity of copper-requiring metalloenzymes in the rat. J. Nutr. 114:
823-828.
Lahtonen, R. (1985) Zinc and cadmium concentrations in whole tissue and in
separated epithelium and stroma from human benign prostatic
hypertrophic glands. Prostate 6: 177-183.
Lam H. F.; Peisch, R.; Amdur, M. O. (1982) Changes in lung volumes and
diffusing capacity in guinea pigs exposed to a combination of sulfur
dioxide and submicron zinc oxide mixed in a humidified furnace Toxicol
Appl. Pharmacol. 66: 427-433.
37
-------
Lam H F • Conner, M. W.; Rogers, A. E.; Fitzgerald, S.; Amdur, M. O. (1985)
Functional and morphologic changes in the lungs of guinea pigs exposed
to freshly generated ultrafine zinc oxide. Toxicol. Appl. Pharmacol. 78.
pQ o Q
Lapham. S.i Vanderly, R.; Brackbill, R.; Tikkanen, M. (1983) Illness;associated
with elevated levels of zinc in fruit punch - New Mexico. MMWR Morb.d.
Mortal. Wkly Rep. 32: 257-258.
•Leake A • Chrisholm G. D.; Busuttil, A.; Habib, F. K. (1984) Subcellular
distribution of zinc in the benign and malignant human Prostate: evidence
for a direct zinc androgen interaction. Acta Endocrmol. 105: 281-^aa.
Lee R E Jr.; von Lehmden, D. J. (1973) Trace metal pollution in the
'environment. J. Air Pollut. Control Assoc. 23: 853-857_
Lee R E., Jr.; Goranson. S. S.; Enrione, R. E.; Morgan, G. B. (1972) Nabonal
air surveillance cascade impactor network. II. Size distribution
measurements of trace metal components. Environ. Sci. Technol. 6.
Lin H°j! Chan, W. C.; Fong, Y. Y.; Newberne, P. M. (1977) Zinc levels in
serum, hair and tumors from patients with esophageal cancer. Nutr. Rep.
Llovd T B- Showak, W. (1984) Zinc and zinc alloys. In: Kirk-Othmer
encyclopedia of chemical technology. 3rd ed. New York, NY: John Wiley
& Sons; pp. 807-851. . .
Lokken. P. M.; Halas, E. S.; Sandstead, H. H. (1973) Influence erf.zinc
deficiency on behavior. Proc. Soc. Exp. Biol. Med. 144: 680-682.
Lonnerdal, B.; Hoffman, B.; Hurley, L. S. (1982) Zinc and copper binding
proteins in human milk. Am. J. Clin. Nutr. 36: 1170-1176
Lowy, S. L.; Fisler, J. S.; Drenick, E. J.; Hunt, I. F:; Swendse.d, M. E.08B6)
Zinc and copper nutriture in obese men receiving very low calorie diets ot
soy or collagen protein. Am. J. Clin. Nutr. 43: 272-287.
Lykken, G. I.; Mahalko, J.; Johnson, P. Ev; Milne, D.; Sandstead, H. H.; Garcia
W J- Dintzis, F. R.; Inglett. G. E. (1986) Effect of browned and
unbrowned corn products intrinsically labeled with 65Zn on absorption of
65Zn in humans. J. Nutr. 116: 795-801.
Lytton F. D. C.; Bunce, G. E. (1986) Dietary zinc and parturition in the rat: I.
uterine pressure cycles. Biol. Trace Elem. Res. 9: 151-163.
Margoshes, M.; Vallee, B. L. (1957) A cadmium protein from equine kidney
cortex. J. Am. Chem. Soc. 79: 4813-4814.
Mathur, A.; Wallenius. K.; Abdulla, M. (1979) Influence of zinc on onset and
progression of oral carcinogenesis in rats. Acta Odontal. Scand. 37. 271-
284
McCord^ C. P. (1960) Metal fume fever as an immunological disease. Ind.
Med. Surg. 29: 101-107.
McKay M (1983) Topical dermatologic therapy. Primary Care 10. 513-5^4.
Meadows. N. J, Grainger. S. L, Ruse, W, Keeling. P W. N.; Thompson R.
P. H. (1983) Oral iron and the bioavailability of zinc. Br. Med. J. <&i.
Menard. M. P.; Cousins, R. J. (1983a) Effect of citrate, glutathione and
picolinate on zinc transport by brush border membrane vesicles from rat
intestine. J. Nutr. 113: 1653-1656.
Menard, M. P.; Cousins, R. J. (1983b) Zinc transport by brush border
membrane vesicles from rat intestine. J. Nutr. 113: 1434-144*!.
Menard, M. P.; McCormick, C. C.; Cousins, R. J. (1981) Regulation of
intestinal metallothionein biosynthesis in rats by dietary zinc. J. Nutr. 111:
1353-1361.
38
-------
Menard, M. P.; Oestreicher, P.; Cousins, R. J. (1983) Zinc transport by
isolated, vascularly perfused rat intestine and brush border vesicles In-
Inglett, G. C., ed. Nutritional bioavailability of zinc. Washington DC
Migally, N.; Murthy, R. C.; Doye, A.; Zambernard, J. (1982) Changes in'
pulmonary alveolar macrophages in rats exposed to oxides of zinc and
nickel. J. Submicrosc. Cytol. 14: 621-626
Milliken, J. A.; Waugh, D.; Kadish, M. E. (1963)'Acute interstitial pulmonary
fibrosis caused by a smoke bomb. Can. Med. Assoc J 88- 36-39
Mink, L. L.; Williams, R. E.; Wallace, A. T. (1971) Analysis of an aquatic"
^-environment receiving domestic and industrial effluent. In: Hemphill D
D., ed. Trace substances in environmental health-IV: [proceedings' of
University of Missouri's 4th annual conference on trace substances in
environmental health]; June; Columbia, MO. Columbia MO" University of
Missouri; pp. 69-84.
Molin, L.; Wester, P. O. (1976) The estimated daily loss of trace elements
from normal skin by desquamation. Scand. J. Clin. Lab. Invest. 36: 679-
682.
Mori, T.; Akashi, S.; Nukada, A. (1975) Effects of the inhalation of catalytically
active metallic oxide fumes on rabbits. Int. Arch. Occup. Environ. Health
ooi 29~39.
Morris, E. R.; Ellis, R. (1980) Bioavailability to rats of iron and zinc in wheat
bran: response to low-phytate bran and effect of the phytate/zinc molar
ratio. J. Nutr. 110: 2000-2010.
Moynahan, E. J. (1975) Zinc deficiency and cellular immune deficiency in
acrodermatitis enterophathica in man and zinc deficiency with thymic
hypoplasia in Fresian calves: a possible genetic link. Lancet (7937)- 710
Mueller, E. J.; Seger, D. L. (1985) Metal fume fever - a review J Emerq
Med. 2: 271-274. ' y'
Mulay, I. L; Roy, R.; Knox, B. E.; Suhr, N. H.; Delaney, W. E. (1971)
Trace-metal analysis of cancerous and non-cancerous human tissues
JNCI J. Natl. Cancer Inst. 47: 1-13.
Mulhern, S. A.; Stroube, W. B., Jr.; Jacobs, R. M. (1986) Alopecia induced in
young mice by exposure to excess dietary zinc. Experientia 42: 551-
9OO.
Murphy J. V. (1970) Intoxication following ingestion of elemental zinc. JAMA
J. Am. Med. Assoc. 212: 2119-2120.
National Research Council. (1978) Zinc. Baltimore, MD: University Park Press
Newton, D.; Holmes. A. (1966) A case of accidental inhalation of zinc-65 and
silver-IIOm. Radiat. Res. 29: 403-412.
Nordberg, M.; Kojima, Y., eds. (1978) Metallothionein and other low molecular
weight metal-binding proteins: report from the first international meeting
on metallothionen and other low molecular weight metal-bindinq
proteins; July 1978; Zurich, Switzerland. Zurich, Switzerland: International
Association on Occupational Health.
Nriagu, J. O., ed. (1980a) Zinc in the environment part I: ecoloqical cvclina
New York, NY: John Wiley & Sons.
Nriagu, J. O., ed. (1980b) Zinc in the environment part II: health effects New
York, NY: John Wiley & Sons.
Oberdoerster, G.; Hochrainer, D. (1979) Zinc oxide aerosols: generation, lung
clearance and effects on lung clearance. In: Stoeber, W.; Jaenicke R
eds. Aerosols in science, medicine and technology - the biomedicai
influence of the aerosol: proceedings of the 7th conference; October
Duesseldorf, Federal Republic of Germany. Mainz, Federal Republic of
Germany: Gesellschaft fuer Aerosolforschung pp. 132-137
39
-------
Ohno, H.; Doi, R.; Yamamura, K.; Yamashita, K.; lizuka, S.; Taniguchi, N.
(1985) A study of zinc distribution in erythrocytes of normal humans. Blut
50: 113-116. , _,
Olafson, R. W. (1983) Intestinal metallothionein: effect of parenteral and
enteral zinc exposure on tissue levels of mice on controlled zinc diets. J.
Nutr. 113: 268-275.
Park, J. H. Y.; Grandjean, C. J.; Antonson, D. L; Vanderhoof, J. A. (1985)
Effects of short-term isolated zinc deficiency on intestinal growth and
activities of several brush border enzymes in weanling rats. Pediatr. Res.
19: 1333-1336.
Pickering, Q. H.; Henderson, C. (1966) The acute toxicity of some heavy
metals to different species of warmwater fishes. Air Water Pollut. Int. J.
10: 453-463.
Piscator, M.; Lind, B. (1972) Cadmium, zinc, copper, and lead in human renal
cortex. Arch. Environ. Health 24: 426-431.
Pistorius, D. (1976) Early reactions of the rat lung to respiratory air containing
zinc oxide. Beitr. Silikose Forsch. Pneumokoniose 28: 69-77.
Pistorius, D.; Rosmanith, J.; Breining, H. (1976) Intake and distribution of zinc
in rat organisms after zinc oxide inhalation in male and female animals.
Beitr Silikose Forsch. Pneumokoniose 28: 92-101.
Pories, W. J.; Henzel, J. H.; Rob, C. G.; Strain, W. H. (1967) Acceleration of
healing with zinc sulfate. Ann. Surg. 165: 432-436.
Prasad, A. S. (1978) Zinc. In: Trace elements and iron in human metabolism.
New York, NY: Plenum Publishing Co.; pp. 251-346.
Prasad, A. S.; Miale, A., Jr.; Farid, Z.; Sandstead, H. H.; Schulert, A. R. (1963)
Zinc metabolism in patients with the syndrome of iron deficiency anemia,
hepatosplenomegaly, dwarfism, and hypogonadism. J. Lab. Clin. Med.
61: 537-549.
Prasad, A. S.; Rabbani, P.; Abbasii, A.; Bowersox, E.; Spivey Fox, M. R.
(1978) Experimental zinc deficiency in humans. Ann. Intern. Med. 89:
483-490.
Quinones, S. R.; Cousins, R. J. (1984) Augmentation of dexamethasone
induction of rat liver metallothionein by zinc. Biochem. J. 219: 959-963.
Rasmussen, A. I. (1982) Zinc depletion with dietary histidine in growing rats.
Fed. Proc. Fed. Am. Soc. Exp. Biol. 41: 781.
Reinhold, J. G. (1971) High phytate content of rural Iranian bread: a possible
cause of human zinc deficiency. Am. J. Clin. Nutr. 24: 1204-1206.
Reinhold, J. G.; Nasr, K.; Lahimgarzadeh, A.; Hedayati, H. (1973) Effects of
purified phytate and phytate-rich bread upon metabolism of zinc,
calcium, phosphorus, and nitrogen in man. Lancet (7798): 283-288.
Reinhold, J. G.; Parsa, A.; Karimian, N.; Hammick, J. W.; Ismail-Beigi, F.
(1974) Availability of zinc in leavened and unleavened wholemeal
wheaten breads as measured by solubility and uptake by rat intestine in
vitro. J. Nutr. 104: 976-982.
Richards, M. P.; Cousins, R. J. (1976) Metallothionein and its relationship to
the metabolism of dietary zinc in rats. J. Nutr. 106: 1591-1599.
Rohrs, L. C. (1957) Metal-fume fever from inhaling zinc oxide. AMA Arch.
Ind. Health 16: 42-47.
Samanta, K.; Pal, B. (1986) Zinc feeding and fertility of male rats. Int. J.
Vitam. Nutr. Res. 56: 105-107.
Sampson, J.; Graham, R.; Hester, H. R. (1942) Studies on feeding zinc to
pigs. Cornell Vet. 32: 225-236.
Sandstead, H. H. (1986) A brief history of the influence of trace elements on
brain function. Am. J. Clin. Nutr. 43: 293-298.
40
-------
Sandstead, H. H.; Henriksen, L. K.; Greger, J. L; Prasad, A. S.; Good R A
(1982) Zinc nutriture in the elderly in relation to taste acuity' immune
•response, and wound healing. Am. J. Clin. Nutr. 36: 1046-1059
Scnenker, M. B.; Speizer, F. E.; Taylor, J. O. (1981) Acute upper respiratory
symptoms resulting from exposure to zinc chloride aerosol. Environ. Res
25: 317-324. ,
Schlicker, S. A.; Cox, D. H. (1968) Maternal dietary zinc, and development
and zinc, iron, and copper content of the rat fetus. J. Nutr 95- 287-294
Schmahl, K. (1974) Klinik der Zinknebelvergiftung [Clinical signs in
zinc-chloride smoke intoxication]. Pneumonologie 150- 161-169
Schricker, B: R.; Forbes, R. M. (1978) Studies on the chemical nature of a low
molecular weight zinc binding ligand in rat intestine. Nutr. Rep. Int. 18:
159-166. ,
Schrodt, G. R.; Hall, T.; Whitmore, W. F., Jr. (1964) The concentration of zinc
in diseased human prostate glands. Cancer 17: 1555-1566
Schroeder, H. A.; Nason, A. P.; Tipton, I. H.; Balassa, J. J. (1967) Essential
trace metals in man: zinc. Relation to environmental cadmium. J. Chronic
UlS. id(j'. 1 79-210.
Seal, C. J.; Heaton, F. W. (1984) Zinc transfer among proteins in rat
duodenum mucosa. Ann. Nutr. Metab. 31: 55-60
Smith, B. L; Embling, P. P. (1984) The influence of chemical form of zinc on
the effects of toxic intraruminal doses of zinc to sheep JAT J ADD!
Toxicol. 4: 92-96. ' '
Smith, K. T.; Cousins, R. J.; Silbon, B. L.; Failla, M. L. (1978) Zinc absorption
and metabolism by isolated, vascularly perfused rat intestine. J. Nutr.
108: 1849-1857.
Snedeker, S. M.; Smith, S. A.; Greger, J. L. (1982) Effect of dietary calcium
and phosphorus levels on the utilization of iron, copper, and zinc by adult
males. J. Nutr. 112: 136-143.
Solomons, N. W. (1986) Competitive interaction of iron and zinc in the diet-
consequences for human nutrition. J. Nutr. 116: 927-935
Solomons, N. W.; Jacob, R. A. (1981) Studies on the bioavailability of zinc in
humans: effects of heme and nonheme iron on the absorption of zinc
Am. J. Clin. Nutr. 34: 475-482.
Solomons, N. W.; Jacob, R. A.; Pineda, O.; Viteri, F. E. (1979) Studies on the
bioavailability of zinc in man. Effects of the Guatemalan rural diet and of
the iron-fortifying agent, NaFeEDTA. J. Nutr. 109: 1519-1528
Song, M. K.; Adham, N. F. (1985) Metabolic influences on intestinal zinc
uptake in rats. Biochem. Arch. 1: 75-83
Spencer, H.; Rosoff, B.; Feldstein, A.; Cohn, S. H.; Gusmano, E. (1965)
Metabolism of zinc-65 in man. Radiat. Res. 24- 432-445
Spencer, H.; Kramer, L.; Norris, C.; Osis, D. (1984) Effect of calcium and
phosphorus on zinc metabolism in man. Am. J. Clin. Nutr. 40: 1213-
i21o.
Sturgis, C. C.;.Drinker, P.; Thomson, R. M. (1927) Metal fume fever: I clinical
observations on the effect of the experimental inhalation of zinc oxide by
two apparently normal persons. J. Ind. Hyg 9- 88-97
Styrud, J.; Dahlstrom, V. E.; Eriksson, U. J. (1986) Induction of skeletal
malformations in the offspring of rats fed a zinc deficient diet. Upsala J
Med. Sci. 91: 29-36.
Summer, W.; Haponik, E. (1981) Inhalation of irritant gases. Clin. Chest Med.
2; 273-287.
Sunderman, F. W., Jr. (1971) Metal carcinogenesis in experimental animals
Food Cosmet. Toxicol. 9: 105-120.
41
-------
Sutton, W. R.; Nelson, V. E. (1937) Studies on zinc. Proc. Soc. Exp. Biol.
Med. 36: 211-213. „,,•'• *
Swerdel, M. R.; Cousins, R. J. (1982) Induction of kidney metallothionem and
metallothionein messenger RNA by zinc and cadmium. J. Nutr. 112:
801-809.
Tarasenko. N. Y.; Shabalina, L. P.; Spiridonova, V. S. (1976) Comparative
toxicity of metal stearates. Int. Arch. Occup. Environ. Health 37: 179-
192- ^
Theiss, J. C. (1982) Utility of injection site tumors in assessing the
carcinogenic risk of chemicals to man. Toxicol. Pharmacol. 2: 213-222.
Tomatis L (1977) The value of long-term testing for the implementation of
primary prevention. In: Hiatt, H. H.; Watson, J. D.; Winsten, J. A., eds.
Origins of human cancer: book C, human risk assessment. Cold Spring
Harbor, NY: Cold Spring Harbor Laboratory; pp. 1339-1357. (Cold
Spring Harbor conferences on cell proliferation: v. 4).
Turnlund, J. R.; King, J. C.; Keyes, W. R.; Gong, B.; Michel, M. C. (1984) A
stable isotope study of zinc absorption in young men: effects of phytate
and -cellulose. Am. J. Clin. Nutr. 40: 1071-1077.
U S Environmental Protection Agency. (1980) Ambient water quality criteria
for zinc. Cincinnat, Ohio, Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office; EPA report no. EPA-
440/5-80-079. Available from: NTIS, Springfield, VA; PB-117897.
Underwood, E. J. (1971) Zinc. In: Trace elements in human and animal
nutrition. New York, NY: Academic Press; pp. 208-252.
Uotila, U.; Noro, L. (1957) Lo stearato di zinco come causa di pneumoloniosi
[Zinc stearate as a cause of pneumoconiosis]. Folia Med. 40: 245-249.
Valberg, L. S.; Flanagan, P. R.; Brennan, J.; Chamberlain, M. J. (1985) Does
the'oral zinc tolerance test measure zinc absorption? Am. J. Clin. Nutr.
41: 37-42.
van Rensburg, S. J. (1981) Epidemiologic and dietary evidence for a specific
nutritional predisposition to esophageal cancer. JNCI J. Natl. Cancer Inst.
67: 243-251.
Van Rij, A. M.; Hall, M. T. (1985) The effect of anesthetic agents on zinc
metabolism in the rat liver. Biol. Trace Elem. Res. 8: 231-235.
Voroshilin, S. I.; Plotko, E. G.; Fink, T. V.; Nikiforova, V. Ya. (1978)
Cytogenetic action of inorganic compounds of tungsten, zinc, cadmium,
and cobalt on human and animal somatic cells. Cytol. Genet. Engl.
Transl. 12: 46-48.
W E. Davis and Associates. (1972) National inventory of sources and
emissions: zinc - 1969. Research Triangle Park, NC: U. S.
Environmental Protection Agency, Office of Air Quality Planning and
Standards; EPA report no. APTD-1139. Available from: NTIS,
Springfield, VA; PB-210680.
Wallenius, K.; Mathur, A.; Abdulla, M. (1979) Effect of different levels of
dietary zinc on development of chemically induced oral cancer in rats.
Int. J. Oral Surg. 8: 56-62. .
Wapnir R A • Stiel, L. (1986) Zinc intestinal absorption in rats: specificity of
amino acids as ligands. J. Nutr. 116: 2171-2179.
Wapnir, R. A.; Khani, D. E.; Bayne, M. A.; Lifshitz, F. (1983) Absorption of zinc
by'the rat ileum: effects of histidine and other low-molecular-weight
ligands. J. Nutr. 113: 1346-1354.
Weber, J.; Einbrodt, H. J.; Wewer, B. (1976) Kann Zinkstearat eine
42
-------
Lungenfibrose ausloesen(Fallbericht) [Can zinc stearate induce lung
fibrosis (case report)]. Beitr. Silikose Forsch. Pneumokoniose 28: 105-
116.
Weigand, E.; Kirchgessner, M. (1978) Homeostatic adjustments in zinc
digestion to widely varying dietary zinc intake. Nutr. Metab. 22: 101-112.
White, I. G. (1955) The toxicity of heavy metals to mammalian spermatozoa
Austr. J. Exp. Biol. 33: 359-366.
Wolf, A. F. (1975) Occupational diseases on the lungs. Ann. Allergy 35: 165-
Xue-Cun, C.; Tai-An, Y.; Jin-Sheng, H.; Qiu-Yan, M.; Zhi-Min, H.;
Li-Xiang, L. (1985) Low levels of zinc in hair and blood, pica, anorexia,
and poor growth in Chinese preschool children. Am. J. Clin. Nutr. 42-
694-700.
Yamaguchi, M. (1984) Biochemical approach in analysis of heavy metal
toxicity. Esei Kagaky 30: 14-19.
Yunice, A. A.; King, R. W., Jr.; Kraikitpanitch, S.; Haygood, C. C.; Lindeman,
R. D. (1978) Urinary zinc excretion following infusions of zinc sulfate,
cysteine, histidine, or glycine. Am. J. Physiol. 235: F40-F45.
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