EPA-540/1-86-048
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
oEPA
HEALTH EFFECTS ASSESSMENT
FOR ZINC (AND COMPOUNDS)
-------
EPA/540/1-86-048
September 1984
HEALTH EFFECTS ASSESSMENT
FOR ZINC (AND COMPOUNDS)
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Haste and Emergency Response
Washington, DC 20460
U.S. M
77 West
*.. '•". .:
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DISCLAIMER
This report has been funded wholly or 1n part by the UnHed States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and H has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Vnterlm assessment of adverse health effects associated with zinc (and
compounds). All estimates of acceptable Intakes and carcinogenic' potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document Is current up
to September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The fol-
lowing Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. _Amb1ent Water Quality Criteria for Z1nc.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-079. NTIS PB 81-117897.
U.S. EPA. 1983b. Reportable Quantity for Z1nc (and Compounds).
Prepared by the Environmental Criteria and Assessment Office, Cin-
cinnati, OH, OHEA for the Office of Solid Haste and Emergency
Response, Washington, DC.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope .tending to generate conservative (I.e., protective) estimates. _Never-
theless, the Interim values presented reflect the relative degree of'"hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants In ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
111
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significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable expo-
sure for a given route with the Implicit assumption that exposure by other
routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained In U.S. EPA (1983a).
For compounds for which there 1s sufficient evidence of carclnogenlclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-]*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
There 1s a considerable body of Information concerning the toxicology of
orally administered zinc 1n both humans and experimental animals. A synthe-
sis of the available human data supported by the experimental animal Infor-
mation resulted 1n an oral AIS and AIC estimate of 14.9 mg/day. This value
represents an estimated additional acceptable Increment beyond background
dietary exposures. Based on oral studies 1n humans, a CS of 17.6 was
derived.
The data base for Inhalation exposure 1s much more limited. No adequate
animal data were located pertinent to either subchronlc or chronic Inhala-
tion exposures. An AIS of 7.1 mg/day and an AIC of 0.7 mg/day have been
estimated based on the TkV for zinc chloride. Z1nc chloride- 1s the zinc
compound with the lowest TLV • except for zinc chromates. Protection from
potential carcinogenic effects of zinc chromates 1s not Implied by the AIS
and AIC estimates. Data were Inadequate to develop suggested exposure
limits for the zinc chromates.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball wasithe Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
,
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIHEN 1 AL«W\NIMAt S . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
BIOASSAYS *+,
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
1
... 3
... 3
. .- . 4
6
6
... 6
19
, . , 20
... 20
... 22
... 24
... 24
... 25
25
28
... 28
... 28
... 29
29
... 30
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 32
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 32
6.1.1. Oral 32
6.1.2. Inhalation -. 34
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 34
6.2.1. Oral 34
6.2.2. Inhalation 35
6.3. CARCINOGENIC POTENCY (q-j*) 36
7. REFERENCES 37
APPENDIX: Summary Table for Zinc (and Compounds) 48
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LIST OF TABLES
No. TUIe Page
3-1 Oral ToxIcHy of 21nc Sulfate 1n Humans 8
3-2 Oral ToxIcHy Studies of Z1nc and Its Compounds 12
5-1 Regulatory Standards and Criteria for 21nc 31
1x
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LIST OF ABBREVIATIONS
ADI
AIC
AIS
BCF
bw
CAS
CS
GI
- LOAEL
MED
NOAEL
NOEL
ppm
RDA
RVd
RVe
STEL
TLV
TWA
UF
Acceptable dally Intake
Acceptable Intake chronic
Acceptable Intake subchronlc
B1oconcentrat1on factor
Body weight
Chemical Abstract Service
Composite score
Gastrointestinal
Lowest-observed-adverse-effect level
Minimum effective dose
No-observed-adverse-effec-t level
No-observed-effect level
Parts per million
Recommended dally allowance
Dose-rating value
Effect-rating value
Short-term exposure limit
Threshold limit value
Time-weighted average
Uncertainty factor
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Z1nc Is a metal belonging to group 118 of the Periodic Table, Elemental
zinc has a CAS Registry number of 7440-66-6. It occurs In nature In the
zero valence (metal and alloys) and +2 valence (compounds) states. Besides
a variety of Inorganic compounds, zinc forms a number of compounds with
organic Ugands. Both organic and Inorganic zinc compounds have a variety
of uses (Lloyd and Showak, 1984; Lloyd, 1984). Zinc forms simple covalent,
1on1c and stable covalent complex compounds with other Ions, groups or
Ugands. The element 1s amphoteMc In nature and forms both addle and
basic salts (Lloyd, 1984).
In the atmosphere, zinc 1s expected to be present as dust and fumes from
zinc production facilities, lead smelts, brass works, automobile emissions,
fuel combustion. Incineration and soil erosion (Lloyd and Showak, 1984).
The atmospheric fate of zinc has not been comprehensively studied. Any
chemical Interaction of zinc compounds 1n the atmosphere may result 1n
speclatlon, that 1s, conversion of zinc Into a stable species such as zinc
«
oxide, and not Us removal through decomposition as frequently occurs with
organic compounds. The atmospheric Interactions are minimal for partlcu-
lates with large aerodynamic diameters because of their short air residence
time (F1shbe1n, 1981). However, zinc 1s found 1n the atmosphere at the
highest concentrations 1n smallest particles (<3 ym In aerodynamic diam-
eter) (F1shbe1n, 1981). Z1nc oxide emitted from high-temperature processes
(e.g., brass foundries, galvanizing, smelting and welding processes) may
have particle sizes 1n the range of 0.01-0.4 vm (NIOSH, 1975). Therefore,
these smaller particles may have a long residence time, although no estimate
for the atmospheric lifetime for zinc 1s available at this time.
-1-
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Z1nc Introduced Into the aquatic environment Is partitioned Into sedi-
ments through sorptlon onto hydrous Iron and manganese oxides, clay
minerals and organic material; a small part may be partitioned Into the
aquatic phase through spedatlon Into soluble zinc compounds. Precipitation
of the sulflde 1s an Important control on the mobility of zinc 1n reducing
environments, and precipitation of hydroxides, carbonate or basic sulfate
may occur at high zinc concentration. Formation of complexes with organic
and Inorganic Ugands may Increase the mobility of zinc 1n aquatic media,
but these complexes also have a tendency to be absorbed more strongly onto
the sediments. Sorptlon of zinc 1s probably the dominant fate of zinc In
the aquatic environment (Callahan et a!., 1979).
Information regarding the fate of zinc 1n soil 1s Inadequate. However,
zinc 1s likely to be strongly sorbed onto soil. Soil conditions not
amenable for the sorptlon of zinc may lead to the leaching of zinc. The
tendency of zinc to be sorbed 1s affected by the pH and salinity of soils.
Decrease of pH (<7) and Increase of soil salinity favors desorptlon (U.S.
EPA, 1980b). In a study of groundwater from New Jersey, Page (1981)
detected zinc 1n 100/4 of the samples. This Indicates that leaching of zinc
from soil may be prevalent.
The BCFs for zinc 1n aquatic organisms have been determined by several
Investigators (U.S. EPA, 1980b). BCFs for zinc 1n edible portions of
aquatic organisms have been found to vary from 43 1n soft-shell clam, Hya
arenarla. to 16,700 In oyster, Crassostrea vlrqlnlca (U.S. EPA, 1980b).
-2-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
This discussion of oral absorption of zinc and compounds 1s taken pri-
marily from U.S. EPA (1980b). According to the U.S. EPA (1980b), GI absorp-
tion of zinc Is dependent 1n part upon the zinc status of the organism.
This Is a reasonable conjecture, 1n that zinc levels In the body are rigidly
controlled by various homeostatlc mechanisms. Also, 1t appears that dietary
levels of other nutrients may Influence the kinetics of zinc absorption.
The fact that zinc 1s excreted, 1n part, through the GI tract complicates
quantHatlon of zinc uptake. It 1s also likely that the anl.on associated
with zinc, chelatlon or other complexlng moieties may Influence GI
absorption.
Spencer et al. (1965) demonstrated that 65Zn as the chloride was
rapidly absorbed by human volunteers. Peak plasma values were obtained
within 4 hours. Apparent absorption ranged from 20-80% with a mean of 50%.
Other early studies (NRC, 1978) also Indicated wide variations In absorption
rates of Ingested zinc. Stoklnger (1981), on the other hand, concluded that
only very small amounts of zinc are absorbed by laboratory animals.
Dietary protein levels have been shown to Influence uptake of zinc. In
studies of z1nc-def1c1ent human subjects, zinc uptake was enhanced by simul-
taneous administration of protein (NRC, 1978). Zinc associated with animal
proteins (meat, milk, eggs) seemed to be more easily absorbed, making these
foods good sources of dietary zinc. High dietary levels of phytate, a com-
plex organic phosphorus-containing compound 1n cereal products, have been
shown to reduce absorption of zinc, especially If large amounts of calcium
are present. Breads and cereal grain food products may, therefore, be less
valuable sources of dietary zinc. Arvldsson et al. (1978) added 65Zn to
-3-
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bread during baking, and 1n 11 human subjects determined GI absorption to
average 25X with a range of 12.2-39.1%. Repeating the experiment 1 month
later yielded similar results. In these studies phytate seemed to have
IHtle Influence on zinc uptake. Sandstead et al. (1978) suggested that
dietary fiber content may Influence uptake of zinc.
The homeostatlc regulators of zinc absorption may Involve several pro-
teins and Iow-molecular-we1ght compounds. Hetalloth1one1n, a low-molecular-
welght metal-binding protein In the Intestinal mucosa, may bind with zinc
and facilitate absorption (Richards and Cousins, 1977). Z1nc-b1nd1ng
.Ugands with molecular weights lower than metallothloneln have been found 1n
animals. Evans et al. (1975) proposed that such compounds were produced 1n
the pancreas, and that through the pancreatic secretion, they could complex
with zinc 1n the GI tract and enhance absorption.
That the z1nc-b1nd1ng Ugands that facilitate absorption may be species-
specific was suggesled by Ecknert et al. (1977); these authors showed that
zinc 1n human breast milk was associated with Iow-molecular-we1ght frac-
tions, but that In cow's milk, zinc was associated with h1gh-molecularwe1ght
fractions, as analyzed by gel chromatography. Presumably, zinc absorption
1n human Infants 1s enhanced by binding to Iow-molecular-we1ght Ugands, and
1n calves by binding to h1gh-molecular-we1ght Ugands. These species dif-
ferences 1n z1nc-b1nd1ng Ugands were offered as a possible explanation for
the occurrence of acrodermatlt1s enteropathlca, a zinc deficiency syndrome,
which occasionally appears 1n human Infants after weaning from breast milk.
2.2. INHALATION
No quantitative studies of Inhalation absorption of zinc or Us com-
pounds could be found 1n the available literature. The fate of Inhaled
particles containing zinc depends on particle size and solubility, and on
-4-
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the functional state of the lungs. Experiments on human subjects (Sturgls
et a!., 1927; Drinker et al., 1927a) revealed that both zinc oxide fumes and
zinc oxide powder with very small partlculate size were deposited 1n the
alveoli. Increased serum and plasma levels of zinc were evidence for pul-
monary absorption. It should be emphasized, however, that an undetermined
amount of Inhaled partlculate zinc oxide was subjected to GI absorption by
ciliary clearance and swallowing.
-5-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
Z1nc 1s an essential trace element In human and animal nutrition. In
the body It 1s found In high concentrations In male reproductive organs,
pancreatic Islets, muscle, kidney, liver and bone. It 1s essential for the
activity of some enzymes (U.S. EPA, 1980b). The human RDA of zinc for
adults Is 15 mg (NAS, 1980). Z1nc appears to be toxic only at levels at
least an order of magnitude greater than the RDA; toxlclty appears to result
from an overload of the homeostatlc mechanism for absorption and excretion
of zinc.
3.1. SUBCHRONIC
3.1.1. Oral. Much of the early research on zinc toxlclty was not useful
for risk assessment, because the studies were of too short duration or the
dose or range of doses used did not result 1n effects that allowed defini-
tions of NOELs, NOAELs or LOAELs. Only those studies that are useful 1n
risk assessment are presented here.
Acute toxlclty has been produced from foods stored In galvanized con-
tainers. Brown et al. (1964) reported zinc levels of -1000 ppm 1n chicken
with tomato sauce and spinach stored -24 hours 1n galvanized vats. In
another Instance (Brown et al., 1964), storage of fruit punch 1n galvanized
containers resulted In zinc levels of 2200 mg/i. Symptoms reported were
severe diarrhea, abdominal cramping, nausea and vomiting. The concentration
of cadmium, which occurs quite commonly In galvanized surfaces, was not
determined.
Lethargy was observed In a 16-year-old boy who Ingested 12 g of zinc 1n
peanut butter over a 2-day period In the belief H would accelerate wound
-6-
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healing (Murphy, 1970). Treatment with dlmercaprol resulted 1n a rapid
decrease of blood levels of zinc to subnormal levels and a rapid correction
of the boy's lethargic condition.
Anemia was observed 1n three children who were excreting >1 mg zinc/2.
of urine (Chunn, 1973). These children reportedly played with toy cars made
from a zinc alloy. Placing a toy car 1n warm water resulted 1n zinc levels
of 1.8 mg/i. It was hypothesized that these children Ingested bath water
when playing with toy cars 1n the tub.
Studies of regulated zinc Intake 1n humans are summarized 1n Table 3-1.
PoMes et al. (1967) administered 150 mg of zinc as the sulfate to 10 young
men for 43-61 days to accelerate wound healing after surgical removal of
pllonldal cysts. The subjects complained of some gastric discomfort, but no
other 111 effects were reported. Wound healing was accelerated, compared
with healing In 10 operated and nonsupplemented controls. Assuming a body
weight of 70 kg, the administered dose, 2.14 mg/kg/day constituted a LOAEL
1n this study.
Greaves and Sklllen (1970) reported on 18 patients given 150 mg of zinc
as zinc sulfate for 16-26 weeks to accelerate healing of venous ulceratlons
on the legs. Plasma zinc levels were elevated slightly after treatment
(0.94 pretreatment versus 1.4 mg/j. post-treatment); other clinical labora-
tory Investigations were conducted that Indicated no 111 effects from sup-
plemented zinc. In this study, 2.14 mg/kg/day appeared to define a NOAEL.
Similarly, 135 mg zinc/day as zinc sulfate for 18 weeks, given to 13
patients with leg ulcers, failed to cause alterations 1n blood counts, liver
function tests or urine chemistries (Hallbrook and Lanner, 1972). Placebo
treatments were given to 14 patients who served as a control group. Serum
levels of zinc 1n treated patients Increased from an average of 0.95 mg/s.
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TABLE 3-1
Oral loxlctty of Zinc Sulfate In Humans*
CD
I
Species/Strain Sex
Human with f
non-responsive
coeltac
disease
Human with M
sickle cell
anemia age 26
Humans with MS
sickle cell
anemia
Humans with H.F
sickle cell
anemia and leg
ulcers
Humans with 17F.
chronic venous 3H
leg ulcerallon
(duration >2
years)
Humans with H.f
chronic venous
ulcers 100-1000
sq mm In slie
Number at
Start
1
1
13
17 treated.
17 placebo
(double
blVnd)
20 treated
treated:
3 H.10 F.
age 40-84;
placebo:
S H.9 F.
age 43-80
Vehicle/ Dosage/Exposure
Physical State
capsules ISO mg Zn/day (220
mg 7nS04.7H20 3x/
day) x 26 months
capsules ISO mo, In/day (220
mg ZnSOi-7ll20 3x/
day) x 2 years
capsules ISO mg 7n/day (220
«g /nS04- 711^,0 3x/
day) x 6 months
capsule ISO mg Zn/day as
?nS04./llnO (220 mg
3x/day x 6 months)
capsule ISO mg Zn/day (220
mg ZnS04-7M20 3x/
day) >4 months)
effervescent 200 mg ?n sulfate
tablets 3x/day (600 mg/day
total) x 18 weeks
equivalent to 13S
mg Zn/day according
to U.S. [PA. 19BOb
Dose Response
(mg Zn/kg/day)
2.14 Profound hypochromtc mtcrocyllc
anemia, neulropenla, hypocupremla;
treatment with transfusion.
withdrawal of Zn. and Cu supple-
mentation, returned blood param-
eters to normal.
2.14 llypochromlc wlcrocyllc anemia.
< neutropenta. hypocuprenla, hypo-
ccruloplasmlnemla; all conditions
corrected by Cu supplementation.
2.14 Decreased ceruloplasmln levels In
7 of 13 relative to pretreatment
levels and 'normal* levels; In-
creasing to normal or high
normal when Cu supplements given.
2.14 Increase In serum Zn levels. In
rate of healing of ulcers, and In
Incidence of complete healing;
patients reported no symptoms of
toxlclty.
2.14 Complete healing In 13. partial
healing In S, 2 failed to complete
study; no effect on blood Mb
levels. UttC count (total and dif-
ferential) or clinical chemistry
Indicators of hepatic or renal
toxlclly.
1.93 Rale and frequency of healing
Increased by Zn In patients with
Initial low serum Zn levels; no
effect on body weight, blood
counts. Indicators of liver func-
tion or urlnalysls values; no
symptoms of loxlclty.
Reference
Porter
et al.. 1977
Prasad
et al., 1978
Prasad
et al.. 1978
Serjeant
et al.. 1970
Greaves and
Sktllen. 1970
Ha 11 book and
tanner. 1972
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TABLE 3-1 (cont.)
Species/Strain Sex
Humans with NS
chronic refrac-
tory rheumatoid
arthritis
Humans. 15-69 N.f
years old with
sickle cell
anemia; some
had Zn deft-
clency and
hypogonadhn
and growth
retardation or
chronic leg
ulcers
Number at Vehicle/
Start Physical State
12 treated; capsules
12 placebo;
both groups
received Zn
during the
2nd part of
the study
7 M. 2 f NS
Dosage/Exposure
ISO mg Zn/day (220
mg ZnSOfOM^O 3«/
day) for 12 weeks
(double blind).
followed by 150 mg
Zn/day for 12 weeks
660 mg Zn sulfate/
day for 4-60 weeks
Dose Response
(mg Zn/kg/day)
2.14 During both 12-week periods. Zn
produced significant Improve-
ments In clinical parameters
related to arthritis Including
reduction of soft tissue swelling
but no changes In bones (x-ray);
no effect on hcmatocrll, UBC count,
clinical chemistry and urlnalysts
values except slight decrease In
serum hlslldlne and Increase In
i serum alkaline phosphalase levels.
2.14 Improvement In condition, Includ-
1f heptahydrate Ing growth, sexual maturation, and
healing of ulcers; "no serious
toxic side effects'; some had
nausea after taking Zn on empty
stomach.
Reference
Slmkln. 1976
Prasad
et al.. 1975
•Source: Adapted from U.S. EPA. 1983b
lib - Hemoglobin
MS . Not specified
WBC - White blood cells
Zn - Zinc ,
-------
to 1.57 mg/l after 6 weeks of treatment, but no further Increases were
noted. Patients wHh an 1nH1al serum zinc level >1.1 mg/i experienced no
Increase 1n serum zinc throughout the 18-week treatment period. This study
defined a subchronlc oral NOAEL of 1.93 mg/kg/day.
Slmkln (1976) subjected 12 human patients with chronic refractory
rheumatoid arthritis to 12 weeks of treatment with 150 mg zinc as zinc sul-
fate. A placebo-treated group of 12 arthritis patients served as a control
1n this study. After the Initial 12 weeks, both groups were put on 150 mg
zinc for an additional 12 weeks. Evaluation of clinical parameters of
arthritis revealed significant Improvement In the patients' conditions, with
no effect on hematologlc, blood chemistry or urlnalysls parameters except
for a slight decrease 1n serum hlstldlne and a slight Increase 1n serum
alkaline phosphatase. No toxic manifestations were mentioned, and 2.14 mg
zlnc/kg/day was a NOAEL 1n this study.
Serjeant et al. (1970) divided 34 sickle cell anemia patients with leg
ulcers Into two groups of 17. The treatment group received zinc sulfate
capsules 3 times/day (equivalent to 2.14 mg zlnc/kg/day for an average
human), and the control group received a placebo 1n this double-blind study
that lasted for 6 months. An Increase 1n serum zinc levels, the rate of
ulcer healing and the Incidence of complete healing were reported. Patients
reported no symptoms of toxldty, and 2.14 mg zlnc/kg/day constituted a
NOAEL 1n this study. Prasad et al. (1975) reported on the administration of
2.14 mg zlnc/kg/day (as the sulfate) for 4-60 weeks to an unspecified number
of humans with sickle cell anemia, some of whom also had complications with
zinc deficiency, hypogonadlsm, growth retardation or chronic leg ulcers.
Improvement 1n clinical condition, Including growth, sexual maturation and
-10-
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healing of ulcers without signs of toxlclty, was noted. Some patients com-
plained of nausea after taking zinc on an empty stomach. Therefore, 2.14
zlnc/kg/day was considered to be a LOAEL 1n this study.
Studies of subchronlc oral exposure of animals to zinc, and Us com-
pounds abound 1n the available literature. Studies between 90 and 365 days
1n length were considered to be subchronlc. Data from these reports are
summarized 1n Table 3-2. Only those studies that affect risk assessment
will be discussed 1n detail here.
Drinker et al. (1927a) administered zinc acetate to 12-week-old male and
female rats. Individual rats were given 7.6, 14.4 or a TWA of 25.5 mg
zlnc/kg/day for 53, 48 or 47 weeks, respectively, and two rats served as
untreated controls. Administration was through the drinking water;
apparently water consumption was measured to arrive at dally Intake. No
effects on growth, hematologlc parameters, urlnalysls or gross or hlstologl-
cal appearance of the organs were noted at any dosage level.
Malta et al. (1981) fed diets containing 3000 or 30,000 ppm zinc sulfate
to both rats and mice. These diets contributed -95 or -950 mg zlnc/kg/day
to rats and -188 or -1880 mg/kg/day to mice, respectively, based on the
assumption that a rat weighs 0.35 kg and a mouse weighs 0.03 mg. At 3000
ppm, neither rats nor mice evidenced any effects of treatment; at 30,000 ppm
both rats and mice suffered from partial anorexia, retarded growth and
hematologlc abnormalities. In this study, 3000 ppm (95 mg/kg/day for rats;
188 mg/kg/day for mice) appeared to define a NOEL.
One study of the effects of subchronlc administration of zinc chloride
was found 1n the literature. Heller and Burke (1927) added 0, 2500 and 5000
ppm zinc to the diets of 4, 4 and 9 young rats, respectively, for the "full
growth period." The only effect reported was high mortality of offspring 1n
-11-
-------
TABLE 3-2
Oral Toxlclty Studies of line and Its Compounds'
Species/Strain Sex Number at
Start
Nice. Chester N.F NS
Beatly stock.
newborn Utters
(with dans);
some weanlings
to replace
losses
Vehicle/ Purity
Physical State
drinking water; NS
ZnS04
Dosage/Exposure Dose
(mg Zn/kg/day)
0. 1000 or 5000 0. 170 or 850b
ppm Zn added to
drinking water
for 1 year
t
Response
Inlercurrent disease
(ectromella) killed
some mice In all groups
during first 8 weeks;
dead and Infected Mice
were replaced with
weanlings; Zn had no
effect on weight gain.
tumor Incidence or
Mortality.
Reference
Walters and
Roe. 1965
Rats, young
H.F
Rats, *1ce
MS
treated:
2 M. 2 f;
control:
3 H. 1 F
NS
diet; ZnS04
NS
diet; ZnS04
NS
Nice. C3II
NS
NS
drinking water; NS
ZnS04
0.25X Zn added 125b
to diet for 3
generations. 4
litters (total)
(2SOO ppw)
3000 or 30.000
ppm of ZnS04
added to diet
fur 13 weeks
dose at 3000
ppm . 230-240
mtj/kg/day (rats)
or 450-460
Mj/kg/day (nice)
of ZnS04
500 mg Zn/l In 85b
water for up to
14 Months
-95 rats, and
-188 Mice at
3000 pom; not
estimated at
30.000 ppm
No effect on growth.
reproduction, or gross
appearance, weight.
and ash content of
organs; no signs of
toxlclty.
3000 ppm: maximum no-
effect level; 30.000
ppm: decreased food
Intake, retarded
growth, hematologlc
abnormalities (NS).
Microscopic evidence of
hypertrophy of adrenal
cortex and pancreatic
Islets and changes
characteristic of
hyperactlvlty In pitui-
tary; no change In
plasma Insulin and glu-
cose levels.
Heller and
Burke. 1927
Malta et al..
1981
Aughcy
et al., 1977
-------
TABLE 3-2 (cont.)
Species/Strain Sex
Rait. 12 weeks M.F
old at start;
-250 g H and
200 g F plateau
weight
NtMber at
Start
I/dose
level and
2 controls
Vehicle/ Purity
Physical State
drinking water; NS
In acetate
Dosage/Exposure
1.9 Kg/day for
53 weeks (M).
3.6 i»g/day for
48 weeks (N).
4.4 mg/day for
29 weeks plus
6.3 Rig/day for
18 weeks |F)
(S.I mg/day 1UA)
Dose
(mq Zn/kg/day)
H: 7.6 or 14.4
f: 25.5 (TWA)
Response
No effect on growth.
blood lib levels. RBC
or WBC counts, urinary
excretion of albumin
or sugar, or gross or
hlstologtcal appearance
of organs.
Reference
Drinker
et al.. 1927a
Rats. 200-325 g
plateau weight
H.F
Rats, young
H.F
Parents:
treated.
3 H. 3 t ;
control.
3 H. 3 F.
Offspring:
treated.
4 H. 1 F;
control.
9 H. 12 F
0.25X Zn:
2 H. 2 F;
0.5X Zn:
2 H. 7 F
control
3 H. 1 F
drinking water;
Zn acetate
diet;
Zn chloride
NS 3 F given Zn ace-
tate or citrate
for 29 weeks be-
fore mating and
Zn acetate or
•alate after
Mating through
rearing of 2
litters; 3 N
given Zn malate
or acetate as
for female
above; all
parents received
Zn acetate
either before
or after mating;
5 offspring (H
and F) received
Zn acetate until
60 days of age
NS 0.25X Zn added
to diet for 3
generations
through "full
growth" of each
Parents: 1.75-
16.5 mg Zn/dayb;
5.4-47 mg/kg/day.
Offspring: NS
0. 125 or 250b
No overt signs of
toxlclty; no effect on
body weight or repro-
duction of parents or
on growth of offspring.
No effect on growth.
reproduction, or gross
appearance, weight, and
ash content of organs;
no signs of toxlclty;
high Mortality of off-
spring at high dose
only, not specifically
attributed by authors
to Zn treatment.
Thompson
et al.. 1927
Heller and
Burke. 1927
-------
1ABIE 3-2 Jconl.)
Species/Strain
Hals, young.
40-50 g
Sex Number at
Start
H.F ambiguous;
>3 F and
2 H/dose
level
Vehicle/
Physical State
diet;
In carbonate
Purity
{•puri-
ties
<0.024X
Dosage/Exposure
0.1, 0.5 or l.OX
7n In diet for
39 weeks (1000.
SOOO or 10.000
ppn)
Dose
(mg Zn/kg/day)
SO. 250 or 500C
Response
0.1X: no effect on
growth, reproduction,
blood Hb levels, BBC
count. 0.5X: no effect
on growth or RBC count.
Reference
Sutlon and
Nelson, 1937
Rats, young
Rats. 200 g
(parents)
H.f
M.F
treated:
4 H. 4 F;
control:
5 N. 3 F
parents:
treated.
3 H. 1 F;
rontrol
3 H. 3 F;
offspring:
treated.
3 H. 3 F;
From Zn
malate
parents;
control.
9 M.12 F
diet; Metallic MS
suspended In NS
3X yum acacia
solution (drink-
Ing water); ZnO
0.25X In added
to diet for
3 generations;
through "full
growth* of each
1 F given Zn
citrate for 29
weeks before
waling and ZnO
through rearing
of 2 litters,
2 N given ZnO
given ZnO and
1 H given Zn
•alatc before
mating as above
and ZnO through
string of 2nd
litter; off
sprIng received
ZnO through 60
days of age
125C
parents: 6.5-30
Mg Zn/dayc; 32.5-
190 Mg/kg/day;
offspring NS
but Mb level decreased
below normal and as
compared with controls
by 30 weeks; some pups
In first litter were
stillborn and no live
young were born after
this; no pregnancies
after 5 Months (lib and
fertility returned to
normal when ZnC03 no
longer given). IX: most
animals failed to grow
and some died within 4
weeks; Hb and HOC count
Markedly decreased
starting at -3 weeks;
abnormal RBC; no repro-
duction occurred.
No effect on growth.
reproduction, or gross
appearance, weight,
ash content of organs;
no signs of toxlclly.
No overt signs of
toxlclty. no effect on
body weight or repro-
duction of parents but
1 Male given ZnO before
Mating was sterile and
19 of 20 offspring from
Zn-treated parents did
not survive through
weaning*'; growth of
offspring (from Zn
malate parents)
unaffected by ZnO.
Heller and
Burke, 1927
Thompson
et al., 1927
-------
TABLE 3-2 (conl.)
Species/Strain Sex
Rats, young H.F
Rats. 5-7 weeks N
old. plateau
weight 200-250 g
Cats. 2.8-4.8 kg 5 N.
at start 5 F
Number at Vehicle/ Purity
Start Physical State
treated: diet; 7nO NS
2 H. 3 f:
control:
3 H. 1 F
treated: suspended In NS
total of 3.5X gun acacia
11. I/dose solution (drink-
level Ing water); ZnO
except 3
at high-
est dose;
control: 6
10 treated; food; ZnO 99.799*
apparently
no controls;
coMpared
with values
from the
literature.
pretreatmenl
urlnalysls
values, and
?n levels In
7 normal cats
Dosage/Exposure Dose
(•g 7n/kg/day)
0 or 0.5X Zn 250b
added to diet
for 3 genera-
tions through
"full growth"
of each
2.7-34.4 mg 12-153
Zn/dayc x 34-36
weeks
200-B5B OK) ZnO/ 33.B-223.B (1UA)
day (TWA) nixed
with food x
10-53 weeks
(actual range •
175-1000 mg/day)
Response
Slight depression of
growth, food consump-
tion MS. no effect on
reproduction or gross
appearance, weight, and
ash content of organs;
no signs of toxlclly.
No effect on growth;
decreased water con-
sumption at higher
dosages; no effect on
blood lib levels. RBC
or WBC counts, urinary
excretion of albumin
or sugar, or gross
htstologlcal appearance
of organs; slight but
not significant Increase
In tissue but not blood
Zn levels.
No signs of toxlclly;
7 cats receiving <76.4
mg Zn/kg/day gained
weight, 3 cats receiv-
ing >132.7 mg Zn/kg/day
(lb-21 weeks) lost W
of their body weight
and ate less; RBC and
WBC counts, blood Mb
levels and urlnalysls
findings were normal;
the 3 high-dose cats
had Hbrollc pancreas
glands, no other gross
or microscopic evidence
of Zn damage In tissues
of any treated cat ;
dose-related Increase
In Zn levels of liver.
pancreas and kidney and
uniform Increase In Zn
levels; Increase In
blood Zn levels In
higher dose group only.
Reference
Heller and
Burke. 1927
Drinker
et al.. 1927a
Drinker
et al.. 1927b
-------
TABLE 3-2 (conl.)
Species/Strain
Dogs. 10 kg
average weight
during experi-
ment
Dogs, beagle
skelelally
mature, IS 16
months old at
start
Sex Number at Vehicle/
Start Physical State
IN. 2 treated, food; ZnO
IF apparently
no controls;
compared
with values
from the
literature.
pretrealment
urtnalysls
values, and
Zn levels In
9 normal dogs
N 4 treated; drinking water
22 control acidified to
(possibly pll 5 with IIC1;
not con- ZnO
current)
Purity Dosage/Exposure Dose
(mg Zn/kg/day)
99.799X IN: 500 mg ZnO/ N: 36,1
day x 19 weeks; f : 76.5
If: 1000 mg
ZnO/day x 15
weeks mixed
with food; IN:
500 mg ZnO/day
x 3 weeks (died
of distemper)
i
NS 0 ppm Zn x 2 0 or 2.5
months, then
100 ppm Zn In
drinking water
x 9 months
Response
No signs of toxlclty.
slight weight gain; RBC
and UBC counts and url-
nalysls findings were
normal; no gross or
microscopic evidence of
Zn damage In tissues;
average of Zn levels
from all 3 dogs was
Increased In liver.
kidney, pancreas, bone
and bone marrow but not
In blood and other
tissues.
No signs of toxlclty;
clinical chemistry and
hcmatologtc values un-
affected as compared
wllh controls; blood
Reference
Drinker
et al.. 1927b
Anderson and
Danylchuk,
1979
Inmunoreactlve para-
thyroid hormone wtthln
"normal" range and un-
changed from pretreat-
menl values; rib biop-
sies had no significant
differences (p<0.05) In
parameters of Havcrslan
bone remodeling from
pretrcatment levels ex-
cept those attributable
to normal aging, which
recurred also In control
dogs; no significant
Increase (p<0.05) In
bone Zn as compared with
pretrealmcnt levels or
levels In controls.
-------
lABLf 3-2 (cont.)
Species/Strain Sex Number at
Start
Pigs. Yorkshire N.f 3/group
4 weeks old.
7.5 kg at start
Vehicle/ Purity Dosage/Exposure Dose Response Reference
Physical State (mg Zn/kg/day)
diet containing NS 0 or 0.4X Zn IBS |low-Ca No signs of toxlctty; Hsu et al..
0.1* or 1.1X Ca; added to low- diet). 170 weight gain and feed 197S
ZnO or hlgh-Ca (htgh-Ca diet) efficiency decreased
diet x 9-13 by Zn when diet low In
weeks Ca (p<0.05); weight
gain (but not feed
efficiency) Increased
by Zn when diet high
In Ca (p
-------
rats In the high-dose group. No other effects of treatment were noted, and
the authors did not specifically attribute high mortality of offspring to
zinc treatment. Although the size of this study was too small to be con-
sidered In risk assessment, a NOEL of 2500 ppm (125 mg/kg/day) appeared to
be defined.
Of a number of studies Investigating the toxldty of zinc carbonate, the
study by Sutton and Nelso.n (1937) seemed to define the highest NOEL. About
five rats were fed diets fortified with 1000, 5000 or 10,000 ppm zinc (50,
250 or 500 mg/kg/day) for 39 weeks. At the lowest dose level, no effects on
growth, reproduction, hemoglobin concentration or erythrocyte count were
observed. At higher-dose levels, depression In hemoglobin concentration and
a high frequency of Interference with reproductive performance occurred.
Mortality occurred after 4 weeks on the high-dose diet.
The toxldty of zinc oxide has been examined 1n greater detail than has
the toxldty of other zinc compounds. Several studies on the toxldty of
zinc oxide are summarized In Table 3-2. Drinker et al. (1927a,b) Investi-
gated the toxldty of zinc oxide In several species. These authors sus-
pended zinc oxide In 3.5% gum acacia solution In drinking water, which sup-
plied 0 or 12-153 mg zlnc/kg/day to 6 control or 14 exposed rats for 34-36
weeks. It was Impossible to discern from this report exactly which rats
received exactly how much zinc. No adverse effects of any kind were noted
except for decreased water consumption at "higher dosages." Very conserva-
tively, then, a dose of 12 mg zlnc/kg/day 1n drinking water defined a NOEL
for rats 1n this study.
Drinker et al. (1927b) Incorporated zinc oxide Into the diet of 10 cats
for 10-53 weeks, which resulted 1n TWA zinc Intakes of 33.8-223.8 mg/kg/day.
No signs of toxldty were observed In cats receiving <76.4 mg/kg/day, and
-18-
-------
this level constltued a NOEL In cats 1n this study. Cats receiving >132.7
mg/kg/day experienced finicky appetites and loss of 14% of their body
weight. Cats receiving 223.8 mg zlnc/kg/day showed flbrotlc pancreas glands.
3.1.2. Inhalation. Subchronlc oral Inhalation In humans 1s almost exclu-
sively due to occupational exposure to the fumes or dusts of zinc or Its
compounds. Since zinc oxide 1s the compound used most 1n Industry, H has
been examined 1n most detail. Inhalation of vapors or dust of zinc or Us
compounds leads to a condition called metal fume fever. Although subchronlc
or even acute exposure to zinc oxide dust can cause metal fume fever, It 1s
discussed 1n connection with chronic toxldty 1n Section 3.2., since occupa-
tional Inhalation exposure 1s usually considered 1n relation to chronic
toxldty.
Few reports of subchronlc Inhalation exposure 1n animals were found 1n
the available literature. P1stor1us (1976) exposed unspecified numbers of
rats to a concentration of 15 mg zinc ox1de/m3 for 1, 4 or 8 hours/day,
presumably for 84 days (U.S. EPA, 1980b). Z1nc oxide partlculate size was
reportedly <1 ». "A number of lung function tests" were performed after
2, 4 and 7 weeks and at the end of the experiment. No differences 1n lung
function were observed between control and treatment groups, except for a
significant decrease 1n specific conductance and difference volume at the
end of 2 weeks. Continued exposure resulted 1n apparent recovery of these
parameters 1n treated animals. It was hypothesized that Increasing exposure
caused an Increase 1n pulmonary macrophages, which accelerated, clearing the
lung tissue of zinc oxide.
In another experiment, P1stor1us et al. (1976) exposed an unspecified
number of male and female rats for 1, 14, 28 or 56 days to zinc oxide dust
at a level of 14 mg/m3 for 4 hours/day, 5 days/week. Animals were killed
-19-
-------
24 hours after the last exposure, and zinc levels 1n lungs, Hver, kidneys,
tibia and femur were measured. A single exposure resulted 1n pulmonary
levels of 46 and 49 vq zinc 1n male and female rats, respectively. Pul-
monary levels of rlnc were highest after 1 and 14 days of treatment (1 and
10 exposures). No changes 1n hepatic, renal or skeletal levels of zinc were
noted, but control rats were not used 1n this study. After 28 and 56 days
of treatment (20 and 40 exposures), Inflammatory changes 1n the lungs,
Including Infiltration of leukocytes and macrophages, were observed. Frank
effects were observed at all levels of exposure.
3.2. CHRONIC
3.2.1. Oral. In humans, two case reports of chronic exposure to 150 mg
zinc/day for therapeutic reasons Illustrate the Intimate relationship
between zinc and copper (see Table 3-1). A profound hypochromlc mlcrocytlc
anemia associated with hypoceruloplasmlnemla, hypocupremla and neutropenla
developed In two patients given 150 mg zinc/day as the sulfate for -2 years.
Discovery of this condition prompted Prasad et al. (1978) to assay cerulo-
plasmln levels 1n all 13 of their sickle cell anemia patients who were
receiving zinc therapy. The mean ceruloplasmln level 1n these patients was
~50% what 1t had been before Initiation of zinc therapy. In seven of these
patients, ceruloplasmln was less than the lower limit of the normal range.
This clinical syndrome was rapidly reversed by discontinuing zinc therapy
and administering copper.
Only four studies of chronic exposure of animals to zinc were found 1n
the available literature (summarized 1n Table 3-2). In the first. Heller
and Burke (1927) added 0 or 5000 ppm zinc oxide to diets fed to two male and
three female rats for three generations through the "full growth" of each
generation. No effect on reproductive performance, gross appearance, weight
-20-
-------
or ash content of organs was noted. No manifestations of toxlclty occurred
except for a "slight" depression of food Intake and growth rate of FI(
F. and F.. offspring. The dosage employed, 250 mg zlnc/kg/day,
appeared to constitute a NOAEL 1n this study.
Heller and Burke (1927) also administered 2500 ppm zinc dust 1n the diet
to rats through the full growth of three generations. Assuming that a rat
consumes food equivalent to 5% of Its body weight, this dietary level cor-
responds to an Intake of 125 mg/kg/day. Initially, the treatment group con-
sisted of two males and two females, and the control group consisted of
three males and one female. Zinc-treated rats did not differ .from controls
1n growth, reproduction, or the gross appearance, weight or ash content of
heart, lungs, liver, spleen, kidneys or testicles. H1stopatholog1cal
examinations were not performed. No overt signs of toxlclty were observed.
The dose level of 125 mg/kg/day was a NOEL 1n this study.
Walters and Roe (1965) exposed unspecified numbers of Chester Beatty
mice to 0, IpOO or 5000 ppm zinc as the sulfate 1n drinking water for 1
year. Concurrent Infection with mouse pox virus caused mortality 1n all
groups during the first 8 weeks. Affected mice were replaced with wean-
lings. At these levels, corresponding to 0, 170 and 850 mg/kg/day, no
effect on weight gain, tumor Incidence or mortality occurred.
More recently, however, Aughey et al. (1977) administered 500 mg
z1nc/l as the sulfate 1n drinking water to mice for -14 months. Assuming
6 mi of water Intake and a body weight of 0.03 kg, zinc Intake of 100
mg/kg/day 1s calculated. Necropsy revealed microscopic evidence of hyper-
trophy of adrenal cortex and pancreatic Islets, and changes 1n the pituitary
characteristic of hyperactlvlty.
-21-
-------
3.2.2. Inhalation. Chronic exposure to zinc stearate, a fine powder used
1n the plastic and rubber Industries, may have been responsible for the
death of a factory worker exposed for 2S years (VotHa and Noro, 1957).
Necropsy revealed cause of death to be a diffuse pulmonary Mbrosls contain-
ing deposits of zinc. No quantitative determination of pulmonary zinc con-
tent was made. Weber et al. (1976) discussed the necropsy findings of a man
employed for the last 8 years of his life 1n a rubber factory. These
authors found flbrosls associated with a zinc content of 62 mg/kg dry lung
tissue. That this level Is within the normal limit for zinc Indicates the
ability of pathologic lesions to persist, even though zinc 1s cleared.
The most common syndrome 1n humans exposed to atmospheric zinc 1s known
as metal fume fever. This syndrome 1s described by NIOSH (1975) and Is
briefly summarized here. After 4-12 hours of exposure to fumes of zinc or
finely divided zinc oxide dust, a metallic taste 1s noted. This Is followed
by dryness and Irritation of the throat, coughing, dyspnea, weakness,
fatigue, aching muscles and joints, and a general malaise, similar to the
prodromal syndrome of Influenza. Fever then develops, typically associated
with chills. Body temperature usually reaches 38.9-40.0°C. The patient may
suffer from febrile shivering or rigors, which may become malar1a-l1ke 1n
Intensity. Profuse sweating follows, accompanied by a drop 1n body tempera-
ture and frequently by convulsions. Severe chest pains have also been
reported. Recovery Is usually complete within 24-48 hours (Drinker, 1922;
Kehoe, 1948; Rohrs, 1957; Flshburn and Zenz, 1969; Ansellne, 1972.)
A remarkable feature of metal fume fever 1s the rapid development of
tolerance, to which the term "tachyphylaxla" was given by McCord (1960).
The author stressed that this "Immunity" was both quickly gained and quickly
lost. The practical consequence of the phenomenon 1s the greater likelihood
-22-
-------
of experiencing metal fume fever following a weekend or vacation than during
midweek exposure; hence, the term "Monday-morning fever." This phenomenon
may be related to more rapid pulmonary clearance of zinc particles resulting
from enhanced phagocytosis by macrophages, following continued exposure to
zinc oxide particles.
One group of Investigators studied the quantitative aspects of metal
fume fever 1n considerable detail. Sturgls et al. (1927) exposed two male
subjects with a history of metal fume fever to amounts of zinc oxide fumes
that, based on their history, should precipitate the disease. Exposure for
10-12 minutes resulted 1n the retention of 24 and 37 mg of zinc followed by
onset of the syndrome 1n 7 and 4 hours, respectively, 1n the two subjects.
The white blood cell count of each subject peaked (-17,000 cells/mm3) at
about the same time that peak body temperature was obtained. Vital capac-
ity, measured every 4 hours, declined synchronously with the rise In body
temperature, reaching a declination of 18 and 54% In the two subjects.
Drinker et al. (1927c) later exposed these same two subjects to workroom
levels of zinc oxide fume for 2 or 3 consecutive days. Initial exposures
resulted In typical onset of metal fume fever. Subsequent exposures
resulted In milder attacks or no attacks at all, Indicating that "acquired
resistance" had occurred.
Subsequently, Drinker et al. (1927c) subjected five men and three women
to zinc oxide fumes 1n order to determine threshold levels that trigger zinc
fume fever. The exposure data were not specified 1n the document (NIOSH,
1975) from which this report was taken. The authors concluded, from measur-
ing zinc content of Inhaled and exhaled air, that -50'/4 of Inhaled zinc oxide
-23-
-------
Is retained 1n the lungs. They further postulated that slower and deeper
breathing resulted In a greater depth of penetration of zinc oxide Into the
alveoli and decreased the time to onset of zinc fume fever.
In continuing experiments, Drinker et al. (1927c) subjected seven male
and three female volunteers to different concentrations of zinc oxide 1n the
air for varying lengths of time. Although the treatment protocol was not
presented In the NIOSH (1975) document, these authors determined a dose-
response relationship and suggested that 15 mg z1nc/m3 be established as
the threshold HmH for an 8-hour workday.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. The U.S. EPA (1980b) stated that Cox et al. (1969) found
Increased concentrations of zinc and reduced concentrations of copper 1n the
liver and other tissues of fetuses from rats fed diets containing 4000 ppm
zinc during gestation. Ketcheson et al. (1969) fed diets containing up to
5000 ppm zinc to rats during gestation and observed reduced copper content
1n fetal livers. No malformations were observed In the fetuses In either of
these studies. Detailed Information on protocol was lacking.
Kumar (1976) stated that 1n "a small group" of women 1n the third tri-
mester of pregnancy supplemented their diets with 100 mg zinc sulfate (23 mg
z1nc)/day, three experienced premature deliveries and one delivered a still-
born Infant. This author (Kumar, 1976) then supplemented rats with "100 ppm
zinc orally" (experimental protocol and calculation of dosage not given).
Zinc-supplemented rats manifested a "significant Increase" 1n the number of
fetal resorptlons. Z1nc supplementation for pregnant women has been recom-
mended, but because of the known Interaction between zinc and copper,
-24-
-------
excessive zinc supplementation for prolonged times could have an adverse
effect on the fetus. It 1s also well-documented that zinc deficiency during
pregnancy may have an adverse effect on the fetus (NRC, 1978).
3.3.2. Inhalation. No reports of teratogenldty or fetotoxldty In man
or animals associated with Inhalation of zinc or Us compounds have been
found In the available literature.
3.4. TOXICANT INTERACTIONS
Z1nc has been shown to Interact with other metals 1n the body. These
Interactions have been presented 1n detail 1n U.S. EPA (1980b), to which the
reader Is referred, and only a brief summary will be presented here. Inter-
actions between cadmium and zinc have been discussed extensively In NRC
(1978). In general, exposure to cadmium may cause changes 1n the distribu-
tion of zinc, with accumulation occurring 1n the Hver and kidney. Eleva-
tion of dietary cadmium can precipitate zinc deficiency In some organs by
causing accumulation of zinc 1n the Hver and kidney, particularly If the
diet level of zinc 1s marginal. A case In point 1s the report of Lai
(1976), who found that oral exposure to cadmium could cause testlcular and
pulmonary lesions In rats on a marginal (5 ppm) but not an adequate (40 ppm)
zinc-fortified diet.
The Interactions of copper and zinc were alluded to In the discussions
of the studies of Prasad et al. (1978) and Porter et al. (1977), where zinc
was given therapeutlcally to sickle cell anemia patients. Murthy and
Petering (1976) administered 0, 2.5, 5.0, 10.0, 20 or 40 mg zinc acetate/1
of drinking water to Carworth rats for 60 days. The diet was 'artificially
low" 1n both zinc and copper. HematocrH and hemoglobin levels varied
Inversely with zinc dosage and directly with copper level 1n the diet.
Although these data were significant (p<0.05), all values remained within
-25-
-------
normal ranges. Klevay and Forbush (1976) suggested that the ratio of copper
and zinc 1n the American diet contributes to coronary heart disease. The
probability that copper nutrition In the typical American diet 1s suboptlmal
may have been responsible for this suggestion. Klevay (1973) found a direct
relationship between hypercholesterolemla 1n rats and the z1nc:copper ratio
In the diet. It has been shown (Petering et a!., 1977, Murthy and Petering,
1976) that copper status 1s a factor with regard to serum cholesterol levels.
NRC (1978) suggested that calcium 1n the diet may Interfere wUh zinc
uptake 1n the diet. Underwood (1977) reviewed the relationship between zinc
and calcium, and concluded that, unless zinc status Is marginal, calcium did
not Interfere with zinc uptake.
Within the body, an Interesting relationship exists between zinc and
calcium. Beginning on the first day of gestation, female rats were given
zinc deficient (0.4 ppm) diets with or without calcium deficient (15 ppm)
diets (Hurley and Tao, 1972). Gravlda were examined on the 21st day of
gestation. Females deficient 1n both calcium and zinc had a larger number
of live fetuses/Utter than those deficient 1n zinc only. Of fetuses from
z1nc-def1c1ent/caldum adequate females, 83% exhibited malformations; from
the zinc- and calcium-deficient females, only 57/4 of fetuses showed malfor-
mation. Analysis of maternal femurs showed reduction of total ash, zinc and
calcium In females from the zinc- and calcium-deficient groups. These find-
Ings were Interpreted to suggest that calcium deficiency triggered maternal
osteolysls to meet fetal demands for calcium. Bony resorptlon also returned
zinc to the maternal circulation, which partially protected fetal rats from
teratogenldty Induced by zinc deficiency.
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Hamilton et al. (1978) studied the Intestinal absorption of zinc In
Iron-deficient mice, and found that zinc uptake from the gut was Inhibited
by adding Iron to the duodenal loop system used. These authors concluded
that zinc and Iron share mucosal binding sites.
Cerklewskl and Forbes (1976) fed diets containing 8, 35 or 200 pprn zinc
to rats challenged with 50 or 200 ppm lead 1n the diet. Rats on higher
dietary levels of zinc experienced a milder syndrome of lead toxlclty, had
lower tissue levels of lead and showed a lesser magnitude of hematologlcal
changes associated with lead toxldty. These authors concluded that dietary
zinc had a protective effect against toxlclty to Ingested lead and that the
site of activity was probably within the gut.
Since oral progestatlonal contraceptives have been associated with
altered zinc metabolism, Hess et al. (1977) measured urinary zinc output In
women using and not using oral contraceptives. During the latter course of
this study, these women received about 0.17 mg zinc/day In their diet, com-
pared with -10 mg/day before the study began. Urinary zinc excretion
decreased 83X 1n women using oral contraceptives and 62% 1n women not using
oral contraceptives. At the beginning of this study, urinary excretion of
zinc was about 0.36 and 0.4 mg, respectively, In women using and not using
oral contraceptives. These authors concluded that oral contraceptives prob-
ably have Uttle effect on zinc metabolism during adequate zinc Intake, but
may have a more pronounced effect 1f zinc Intake 1s low or marginal.
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data associating cancer 1n humans with zinc could not be
located 1n the available literature. Attempts have been made, however, to
relate zinc levels 1n tumorous tissue to the development of the tumors.
Most such attempts have met with frustration (NRC, 1978). In the prostate
gland, an organ ordinarily high 1n zinc, neoplasla has been shown to result
1n a zinc level <50J4 of normal (Hablb et a!., 1976).
4.2. BIOASSAYS
No bloassays of zinc or Us compounds for cardnogenldty could be
located 1n the available literature. The effect of dietary levels of zinc
upon development of cancer has been Investigated. Wallenlus et al. (1979)
exposed groups of female rats to diets containing 15, 50 or 200 ppm zinc.
The palatal mucosa was then painted with 4-n1tro-qu1nol1ne-n~ox1de 3 times/
week to Induce cancer. The animals were killed after cancer of the palate
became grossly visible. Animals exposed to 200 ppm dietary zinc developed
macroscoplcally detectable cancer earlier than rats exposed to the two lower
doses. Mathur et al. (1979) applied an Identical protocol to rats on diets
containing 5.9, 50 or 260 ppm zinc. Palatal mucosa was sampled at 3, 9, 13
and 23 weeks after exposure, at which time all rats were killed and
examined. After 3 weeks the animals on the z1nc-def1c1ent diet showed most
advanced hlstologlc changes. After 20 weeks, cancers were found In both the
zinc-deficient and zinc-supplemented groups. Rats on the adequate (50 ppm
zinc) diet only evidenced moderate dysplasla.
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One group of compounds, the zinc chromates, are suspected carcinogens.
Since the suspected carclnogenlcHy of these compounds 1s associated with
the chromate moiety rather than the element zinc, these compounds will not
be discussed In this document.
4.3. OTHER RELEVANT DATA
Pertinent data regarding mutagenldty of zinc or Us compounds could not
be located 1n the available literature.
4.4. WEIGHT OF EVIDENCE
IARC has not evaluated the risk to humans associated with oral or Inha-
lation exposure to zinc or Its compounds. Using criteria for evaluating the
overall weight of evidence of cardnogenlcHy 1n humans proposed by the
Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984), zinc
compounds are most appropriately classified as Group D - Not Classified
compounds.
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5. REGULATORY STANDARDS AND CRITERIA
A summary of regulatory standards and criteria for zinc and Us com-
pounds Is presented 1n Table 5-1. The ACGIH (1980) has recommended a TLV of
1 mg/m3 for zinc chloride, based apparently on Its corrosive and "harmful"
nature. An STEL of 2 mg/m3 Is suggested. For zinc chromates, a TLV of
0.05 mg/m3 1s recommended, primarily based on the suspicion that these
compounds are carcinogenic. The suggested TLV of 0.05 mg/m3 1s Identical
to the TLV for lead chromate. No STEL Is given. For zinc oxide fumes, a
TLV of 5 mg/m3 and a STEL of 10 mg/m3 are suggested, so that "the Inci-
dence of metal fume fever will be low and any attacks which may occur will
be mild." For zinc stearate, a TLV of 10 mg/m3 and a STEL of 20 mg/m3
are suggested, putting zinc stearate dust 1n the category of a nuisance dust
rather than a toxic compound.
The U.S. EPA (1980b) has recommended a level of 7.5 mg/l as the
ambient water quality criterion, primarily because consumption of 2 I of
water would provide 15 mg of zinc, an amount felt to be "well tolerated" on
the basis of long-term administration of zinc to patients to accelerate
wound healing. NAS (1974) recommended a drinking water standard of 5 mg/J.
based on organoleptlc effects.
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TABLE 5-1
Regulatory Standards and Criteria for Z1nc
Standard or Criterion
Value
Reference
Z1nc chloride
TLV
STEL
Swedish limit
Z1nc chromates*
TLV
Z1nc oxide, fume
TLV
STEL
USSR, Czechoslovakia,
East Germany, West Germany
Z1nc stearate
1 mg/m3
2 mg/m3
1 mg/m3
0.05 mg/m3
5 mg/m3
10 mg/m3
5 mg/m3
ACGIH, 1980
ACGIH, 1980
ACGIH, 1980
TLV
STEL
Z1nc oxide
TWA
Celling
Ambient water
quality criterion
Drinking water
criterion
10 mg/m3
20 mg/m3
5 mg/m3
5 mg/m3
15 mg/m3
7.5 mg/S.
5 mg/l
ACGIH, 1980
NIOSH, 1975
U.S. EPA, 1980b
NAS, 1974
*Based on suspected cardnogenlcKy of chromate moiety
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. Several studies of subchronlc oral administration of var-
ious compounds of zinc to animals and of the administration of zinc sulfate
to humans have been examined 1n Section 3.1. The human data are case
reports of the therapeutic use of zinc to accelerate normal or ulcer heal-
ing, to relieve the suffering of arthritis victims or to aid recovery of
sickle cell anemia patients. These authors (Porles et a!., 1967; Greaves
and Sklllen, 1970; Slrnkln, 1976; Serjeant et al.f 1970; Prasad et a!., 1975)
used oral encapsulated doses of zinc, -2.14 mg/kg/day (assuming a human body
weight of 70 kg), often divided Into 3 doses/day. Essentially, no adverse
effects were noted 1n any of these studies, except for mild nausea 1n some
patients who took their dosage on an empty stomach (Porles et a!., 1967;
Prasad et a!., 1975). Moderately elevated serum or plasma levels of zinc
were reported (Greaves and Sklllen, 1970; Hallbrook and Lanner, 1972;
Serjeant et a!., 1970), but only 1f pretreatment zinc serum levels were <1.1
mg/j, (Hallbrook and Lanner, 1972), Indicating the possibility of sub-
optimal zinc nutrition before treatment.
Several studies have been conducted using other zinc compounds (acetate,
chloride carbonate and oxide, as well as sulfate) 1n laboratory animals.
These data, summarized 1n Table 3-2, Indicate that NOELs ranged from 25.5 mg
zlnc/kg/day as the acetate (Drinker et al., 1927a) to 95-188 mg zlnc/kg/day
as the chloride (Heller and Burke, 1927). It 1s possible that administra-
tion 1n drinking water may result In greater toxldty than administration
through the diet. Many of these studies used small numbers of experimental
animals, often without controls; thus, these studies were not Ideally suited
for risk assessment. Since none of the animal studies demonstrated adverse
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effects at zinc dosage levels lower than the human dose of -2.14 mg/kg/day,
and since this dose 1n humans appeared to be very near an MED, this commonly
used therapeutic level of 2.14 mg/kg/day was chosen as a human MED from
which to derive an AIS. A UF of 10 Is Introduced to protect especially sen-
sitive populations, such as those with faulty copper nutrition. The human
AIS can be calculated by the formula AIS (mg/day) * MED (mg/kg/day) x 70
kg T UF. AIS a 14.9 mg/day. Rather than representing a total acceptable
Intake, this value 1s suggested as an additional allowable Increment beyond
that representing a baseline from dietary Intake.
The calculated AIS, 14.9 mg/day, 1s well within the NAS (1974) recom-
mendations that adults should have a dally Intake of 15 mg zinc/day, preg-
nant women should have an Intake of 20 mg/day, lactatlng women should
receive 25 mg/day and pre-adolescent children should receive 10 mg zinc/
day. As mentioned 1n Section 3.3., Kumar (1976) associated premature
delivery 1n women with zinc supplementation of -23 mg/day. This author then
reported fetal absorption 1n rats associated with supplementation with "100
ppm zinc." Unfortunately, no definitive diagnosis of the cause of the pre-
mature deliveries was mentioned. Furthermore, the nutritional competency of
the diets of the women who suffered premature delivery, or of the rats used
1n the study, was not mentioned. If supplementation with zinc can be
expected to result 1n fetal loss, one would have expected the studies by Cox
et al. (1969) and Ketcheson et al. (1969) to point up this phenomenon, as
they fed diets containing 4000-5000 ppm zinc, respectively, to gestatlng
rats. No mention of reduced Utter size was made by either of these studies.
Z1nc supplements containing 15 mg zinc/tablet have been available over
the counter to the general public for several years. Z1nc 1s a nutrient
that has been associated with Improved wound healing and fertility, and by
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some with Improved resistance to cancer. It seems reasonable that If 1t
existed, an association between zinc supplementation and premature delivery
would have surfaced by this time. The NRC currently recommends 40 ppm zinc
1n the diet (dry matter basis) for many classes of livestock (Underwood,
1977). Many private consultants and livestock nutritionists have routinely
formulated rations containing 50-200 ppm zinc, either for therapeutic rea-
sons or to Improve herd fertility. Fertility and reproductive performance
are constantly monitored 1n livestock operations, as these are major factors
that determine the economic well-being of livestock husbandmen. It seems
reasonable to assume that had reproductive performance suffered because of
zinc supplementation, this phenomenon would have been speedily Identified
and remedial action promptly taken. For these reasons, the report by Kumar
(1976), associating zinc supplementation with premature delivery, 1s not
considered 1n selecting the factors used to derive either an AIS or an AIC
for zinc.
6.1.2. Inhalation. No pertinent reports on subchronlc Inhalation tox-
1c1ty of zinc and Us compounds could be located In the available literature
that lend themselves to risk assessment. However, the TLV for zinc chloride
could be used to estimate an AIS (see Section 6.2.2.). Since the TLV Is
designed to protect workers on a chronic basis, It should be adequate to
protect the general population on a subchronlc basis. The TLV for zinc
chloride of 1 ppm would convert to an AIS value of 7.1 mg/day by applying an
uncertainty factor of 1.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. Few studies of chronic oral exposure of laboratory animals
to zinc or Us compounds were found 1n the available literature. The two
studies discussed 1n Section 3.2.1. Indicated only a slight depression 1n
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food Intake and growth of rats exposed to 250 mg zinc/kg/day (as the oxide)
1n the diet (Heller and Burke, 1927), and no evidence of toxldty 1n mice
exposed to 850 mg/kg/day (as the sulfate) 1n drinking water (Walters and
Roe, 1965). The case reports of Porter et al. (1977) and Prasad et al.
(1978) strongly Indicated that chronic human exposure to 2.14 mg/kg/day for
a prolonged period may result 1n a severe hypochromlc mlcrocytlc anemia,
hypoceruloplasm1nem1a and neutropenla. Copper nutrition of these patients
before treatment 1s not known. The fact that cessation of zinc therapy
followed by supplemental copper brought about a rapid reversal of these
undeslred effects emphasized the Intimate relationship between zinc and
copper nutrition. Since no data from experimental animals suggested a lower
MED than the data on humans generated by Porter et al. (1977) and Prasad et
al. (1978), their dosage of 2.14 mg/kg/day was chosen as the starting point
from which to derive an AIC. Again, a UF of 10 1s chosen to protect especi-
ally sensitive populations, primarily those with Inadequate copper nutri-
tion. As 1n Section 6.1.1., an AIC of 14.9 mg/day 1s obtained. This value
represents an additional Increment beyond background dietary exposures.
The U.S. EPA (1983b) calculated a CS for zinc based on the hypochromlc
mlcrocytlc amenla observed by two separate research teams (Porter et al.,
1977; Prasad et al., 1978) 1n humans treated with zinc sulfate to supply
zinc at 150 mg/day. This human MED corresponds to an RV of 2.2. The
hypochromlc mlcrocytlc anemia 1s assigned an RV of 8. A CS of 17.6
results as the product of RV and RV..
6.2.2. Inhalation. Pertinent data regarding the chronic Inhalation
studies of zinc or Its compounds 1n humans or animals that lend themselves
to risk assessment coulds not be located 1n the available literature. An
AIC for chronic Inhalation exposure can be derived 1n humans, based on the
-35-
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TLV recommendations set forth by the ACGIH (1980). The TLV for zinc
chloride was chosen because the ACGIH (1980) considered zinc chloride to be
the most damaging zinc compound of those tested. A TLV for zinc chloride of
1 mg/m3 would result 1n a dally Intake of 7.1 mg/day, assuming that a
workman Inhales 10 mVday and works 5 days/week. A UF of 10 1s applied to
protect especially sensitive populations. Division by 10 results In an AIC
of 0.7 mg/day.
6.3. UNIT CARCINOGENIC RISK (q^)
No bloassays of zinc by either oral or Inhalation exposure have been
performed. No reports of cancer 1n humans Induced by zinc or Us compounds
could be located 1n the available literature. It 1s therefore not possible
to calculate a q * or a 10~s risk level for zinc or Us compounds by
either oral or Inhalation Intake.
-36-
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Drinker, K.R., P.K. Thompson and M. Marsh. 19275. An Investigation of the
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P1stor1us, 0., et al. 1976. Aufnahme und Vertellung von Z1nk 1m Ratten-
organlsmus nach Z1nkox1d1nhalat1on b1e mannllchen und welgllchen Tleren.
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wound healing 1n man with zinc sulfate given by mouth. Lancet. 1: 121-124.
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low serum-copper during zinc therapy. Lancet, p. 774. (CHed 1n U.S. EPA,
1980b, 1983b)
Prasad, A.S., E.B. Schoomaker, J. Ortega, G.J. Brewer, D. Oberleas and F.J.
Oelshlegel, Jr. 1975. Z1nc deficiency 1n sickle cell disease. CUn. Chem.
21: 582-587. (CHed In U.S. EPA, 1983b)
Prasad, A.S., G.J. Brewer, E.B. Schoomaker and P. Rabbanl. 1978. Hypo-
cupremla Induced by zinc therapy In adults. J. Am. Med. Assoc. 240:
2166-2168.
Richards, H.P. and R.J. Cousins. 1977. Isolation of an Intestinal metallo-
thloneln Induced by parenteral zinc. Blochem. Blophys. Res. Commun. (CHed
In U.S. EPA, 1980b)
Rohrs, L.C. 1957. Metal-fume fever from Inhaling zinc oxide. Arch.
Intern. Med. 100: 44-49. (CHed 1n NIOSH, 1975)
-44-
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Sandstead, H.H., et al. 1978. Influence of dietary fiber on trace element
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U 5. Environment: \ '•'<•'
Region 5. library '
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