EPA-540/1-86-057
e 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
vvEPA
HEALTH EFFECTS ASSESSMENT
FOR MANGANESE (AND COMPOUNDS)
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EPA/540/1-86-057
September 1984
HEALTH EFFECTS ASSESSMENT
FOR MANGANESE (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 Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the United 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 1t 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 prelimin-
ary Interim assessment of adverse health effects associated with manganese
(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 In 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. 1981. Multimedia Criteria for Manganese and Compounds.
Environmental Criteria and Assessment Office, Cincinnati, OH.
Internal draft.
U.S. EPA. 1982a. Health Assessment Document for Manganese.
Environmental Criteria and Assessment Office, Cincinnati, OH.
External review draft. EPA 600/8-83-013A. NTIS PB83-217786.
U.S. EPA. 1984. Health Assessment Document for Manganese. Final
Report. Environmental Criteria Assessment Office, Cincinnati, OH.
EPA-600/8-83-013F. . NTIS PB 84-229954
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
systemic toxicants (toxicants for which cancer Is not the endpolnt of con-
cern). The first, the AIS or acceptable Intake subchronic, 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 lifespan). 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 1n ambient air or water where lifetime exposure Is
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronic human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
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The AIC, acceptable Intake chronic, Is similar 1n concept to the ADI
(acceptable dally Intake). It Is an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980) for a discussion of
this concept]. The AIC 1s route specific and estimates acceptable exposure
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 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of carc1nogen1dty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that Is 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 If 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.
Data concerning the toxlcologlcal consequences of oral exposure to
manganese are limited to subchronlc evaluations 1n rodents. An oral AIS
(36.8 mg/day) was estimated based on a subchronlc rat study that showed
effects on serum testosterone levels. An oral AIC of 15.4 mg/day was
estimated from a 2-year study 1n rats 1n which slightly altered brain bio-
chemistries were observed.
More extensive Information 1s available concerning Inhalation effects of
manganese. An Inhalation AIC of 21 yg/day was calculated based on the
determination that occupational exposure to 300 vg/m3 1s the lowest
level associated with mild signs of manganlsm. Because manganism can occur
after a relatively short exposure period, 21 vg/day was also adopted as
the Inhalation AIS for manganese. A CS of 37.6 was calculated for the
obvious neurotoxlc signs of manganlsm noted 1n workers at 500 vg/m3.
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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 was»the Project
Officer. The final documents In 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
vl
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TABLE OF CONTENTS
1.
2.
' 3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE ,
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . ,
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
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
1
4
. . . 4
6
. . . 7
7
. . . 7
12
18
. . . 18
. . . 19
, , . 23
. . . 23
. . . 24
, , . 24
. . . 25
, , , 25
. . . 25
. . . 25
, , 25
. . . 25
. . . 25
. . . 25
. . . 26
. . . 29
V11
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 31
6.1. SU8CHRONIC EXPOSURE (AIS) 31
6.1.1. Oral 31
6.1.2. Inhalation 33
6.2. CHRONIC EXPOSURE (AIC) 33
6.2.1. Oral 33
6.2.2. Inhalation 34
6.3. CARCINOGENIC POTENCY (QT*) 35
6.3.1. Oral 35
6.3.2. Inhalation 35
7. REFERENCES 36
APPENDIX: Summary Table for Manganese and Compounds 55
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LIST OF ABBREVIATIONS
ADI
AIC
AIS
BCF
bw
CAS
CNS
CS
EMG
GI
LOAEL
MED
MTD
NOAEL
ppm
RBC
RVd
RVe
SGOT
SGPT
STEL
TLV
TWA
Acceptable dally Intake
Acceptable Intake chronic
Acceptable Intake subchronlc
B1oconcentrat1on factor
Body weight
Chemical Abstract Service
Central nervous system
Composite score
Electromyogram
Gastrointestinal
Lowest-observed-adverse-effect level
Minimum effective dose
Maximum tolerated dose
No-observed-adverse-effect level
Parts per million
Red blood cells
Dose-rating value
Effect-rating value
Serum glutamlc oxalacetlc transamlnase
Serum glutamlc pyruvlc transamlnase
Short-term exposure limit
Threshold limit value
Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Manganese Is a metal belonging to the first Transition Series of the
periodic table. Elemental manganese has a CAS Registry number of 7439-
96-5. Although manganese can exist In all the valence states from -3 to +7
(Cotton and Wilkinson, 1980), the Inorganic chemistry of manganese Is dom-
inated by compounds 1n the +2, +4 and +7 valence states. The primary
examples of manganese 1n the 0 valence state are metal and alloys and the
carboxy compound. Selected physical properties of a few environmentally
significant manganese compounds are given 1n Table 1-1.
The principal sources of manganese 1n the atmosphere are natural pro-
cesses Including continental dust, volcanic gas and dust, and forest fires.
The atmospheric flux of manganese due to burning of forests and wood fuel
may exceed the combined flux due to other natural and anthropogenic sources.
The main anthropogenic sources of manganese are Industrial emissions and
combustion of fossil fuels (Lantzy and MacKenzle, 1979). In the atmosphere,
manganese 1s expected to be present 1n partlculate form (U.S. EPA, 1982a).
The two main mechanisms that may determine the fate of atmospheric manganese
are tropospheMc chemical reactions and physical removal processes. Atmos-
pheric manganese may undergo photochemical and thermal reaction (U.S. EPA,
1982a). Thus, manganese dioxide may react with S0_ or N0? 1n the atmos-
phere, forming MnSO, and Mn(NO»)0, respectively. Although such reac-
*r O t
tlons may change the chemical nature of manganese, these reactions may not
be directly responsible for the removal of manganese from the atmosphere.
Manganese aerosol may be removed from the air through dry fallout or wet
precipitation. It has been estimated that the atmospheric residence time
-1-
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TABLE 1-1
Selected Physical Properties of a Few Manganese Compounds3
Element/
Compound Formula
Manganese Mn
Manganese (II) MnCl2
chloride
Manganese (II) MnCOs
carbonate
Manganese (II) MnS04
sulfate
Manganese (II) MnO
oxide
Manganese (IV) Mn02
dioxide
Potassium KMn04
permanganate
Specific Water
Molecular Gravity/ Solubility
Weight Density
54.938 7.20 decomposes
125.84 2.977254 72.3 g/100 ml
at 25°C
114.95 3.125 6.5 mg/100 ml
at 25°C
151.00 3.25 52 g/100 ml
at 5°C
70.94 5.43-5.46 Insoluble5
86.94 5.026 Insoluble5
158.04 2.703 6.38 g/100 ml
at 20°C
Vapor
Pressure
1 mm at
1292°C
10 mm at
778°C
NA
NA
NA
NA
NA
Source: Weast, 1980
5No further data regarding solubility are available from Weast, 1980.
NA = Not available
-2-
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for manganese due to such physical removal processes Is ~7 days (CupHt,
1980).
The fate of manganese 1n aquatic systems may be determined by Us
ability to undergo chemical and microbiological reactions. In most natural
aquatic systems, manganese Is expected to be present predominantly In the
suspended partlculates and sediments as Mn00 and Mn_0A or both. A
£ O T"
small amount of manganese may remain as soluble Mn\\2. The maximum concen-
tration of soluble MnV may be limited by the solubility product of
MnCO» and, under certain reducing conditions, by the MnS solubility
•J
product. The concentration of soluble chelated manganese In aquatic systems
1s Hkely to be less than soluble free manganese Ions (U.S. EPA, 1982a).
Thus, although manganese may undergo spedatlon through chemical and micro-
biological reactions 1n systems, 1t may persist 1n aquatic systems for a
long period. .By analogy with aquatic Iron (U.S. EPA, 1981), the residence
time of aquatic manganese may be a few hundred years.
The BCF for manganese 1n a species of edible fish (striped bass) has
been reported to be <10 (U.S EPA, 1982a). Also, significant bloaccumulatlon
of manganese may not occur with organisms of higher tropic level.
Both chemical and microbiological Interactions may cause spedatlon of
manganese In soils; soil pH and oxidation-reduction potential of soil may
Influence the spedatlon process. It has been suggested that 1n add
water-logged soils, manganese passes freely Into solution and may leach Into
groundwater. Also, manganese can be leached readily from waste burial sites
and from other natural soils Into groundwater (U.S. EPA, 1982a).
-3-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
As is true of other nutritionally required trace elements, GI absorption
of manganese 1s controlled by homeostatlc mechanisms; extent of absorption
1s dependent upon availability, concentration In the diet, Interactions with
other metals or other dietary constituents, and age (U.S. EPA, 1982a).
Manganese 1s probably absorbed as the Mn*+ cation.
Limited quantitative data Indicated that under normal conditions GI
absorption of manganese Is low, averaging -3% of the Ingested manganese.
Early studies by Greenberg et al. (1943) with radlomanganese Indicated
absorption of 3-4% of the orally administered dose 1n rats. More recently,
Pollack et al. (1965) reported absorption of 2.5-3.5% of S4MnCl2 given
orally to rats.
In 11 healthy human subjects, Mena et al. (1969) determined absorption
of -3+0.5% by combining 100 yd of 54MnCl2 with 200 yg manganese
dlchlorlde (55MnCl2) as a carrier. Whole body counts were performed
dally for 2 weeks. In additional studies, 6 healthy manganese miners
retained 3%, six former manganese miners with chronic manganese poisoning
retained 4%, and 13 anemic subjects (type of anemia not specified) retained
7.5% of the radioactivity of S4MnCl? administered orally (Mena et al.,
1969). These studies did not consider the possibility of enterohepatic
redrculatlon or GI excretion of manganese.
In rats, Cikrt (1973) reported that enterohepatic circulation appeared
to be Important. Duodenal uptake of manganese that had been excreted into
the bile was -35%, whereas only 15% of an equivalent dose of manganese
dlchlorlde administered intraduodenally was absorbed. Cikrt (1973) con-
cluded that manganese subjected to hepatic metabolism and bile excretion was
present in a form more readily absorbed than manganese dlchlorlde.
-4-
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It 1s well documented that manganese and Iron compete for GI absorption.
Several studies have shown that manganese uptake from the gut Is Increased
1n Iron-deficient humans (Mena et al., 1969; Thomson et a!., 1971) and rats
(Pollack et al., 1965; D1ez-Ewald et al., 1968). Addition of dietary Iron
decreased manganese uptake from the gut In both humans and rats (Thomson et
al., 1971; Thomson and Valberg, 1972) and resulted 1n decreased whole body
retention of manganese (Kostlal et al., 1980). Addition of manganese to the
diets of Iron-deficient animals (Leach and Lllburn, 1978) or addition of
excessive manganese to the diets of normal animals (species not specified)
(U.S. EPA, 1982a) resulted 1n depressed blood hemoglobin concentrations,
which were reversed by dietary supplementation with Iron. In humans, Mena
et al. (1969) showed that Intestinal absorption of manganese was closely
associated with absorption of Iron; anemic subjects had a 2-fold greater
retention of manganese than did normal subjects.
Thomson and Valberg (1972) and Thomson et al. (1971) found that manga-
nese competes with Iron and cobalt for binding sites 1n the process of
uptake from the lumen Into the mucosal cells of the Intestine and 1n the
process of transfer across the mucosal cells Into the circulation. In
humans and rats, these Investigators have shown that manganese absorption 1s
by diffusion when high levels of Iron are present and by active transport
when Iron levels are normal or low. They also determined that the binding
sites for uptake from the lumen of the bowel are different from the binding
sites for transfer to the circulation, since changes 1n uptake occurred
without concomitant changes 1n transfer to the body. Gruden (1977a,b, 1979)
suggested that transmucosal transport of manganese was Influenced by Iron
more than was Intestinal uptake. C1krt and Vastal (1969) showed that trans-
port took place primarily across the mucosa of the duodenum and 1leum.
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Other elements (cadmium, nickel) have been shown to enhance retention of
manganese 1n laboratory animals (LassHer et al., 1969, 1970; Burch et al.,
1975; Schroeder et al., 1974; Schroeder and Nason, 1976).
Age appears to be Inversely related to manganese absorption and reten-
tion. Mena et al. (1974) reported that Intestinal absorption In Infant and
young rats was -4-fold greater than absorption 1n adult animals. Rabar
(1976) and Kostlal et al. (1978) observed much higher manganese absorption
1n artificially fed suckling rats (-40%) than 1n adult animals (<4%). Adult
rats fed a milk diet absorbed more manganese (6.4%) than those on a "normal"
diet (0.05%), Indicating that both age and diet affected the degree of
manganese absorption and retention.
2.2. INHALATION
Following Inhalation exposure, manganese absorption Into the bloodstream
occurs only 1f particles are sufficiently small to be able to reach the
alveoli (WHO, 1980). -Larger particles are removed by mucodllary clearance.
Water solubility of Individual manganese compounds greatly Influences the
degree of absorption from the pulmonary alveoli.
Mena et al. (1969) exposed 21 human volunteers to nebulized solutions or
suspensions of 54Mn-labeled manganese chloride or manganese oxide (concen-
tration and duration of exposure not specified). About 40-70% of the
manganese deposited 1n the lungs was recovered In the feces within 4 days,
Indicating relatively little pulmonary absorption of manganese (U.S. EPA,
1982a). Quantitative studies of manganese absorption following Inhalation
exposure 1n animals could not be located 1n the available literature.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In a discussion reviewing the acute toxldty of manganese
and Its compounds, the U.S. EPA (1982a) Indicated that toxldty associated
with oral exposure was likely to be less than toxldty associated with
parenteral routes of administration. Toxldty also varied with the chemical
form; manganese cations are more toxic than the anlonlc form and the
bivalent cation appears to be ~3 times more toxic than the trlvalent cation
(U.S. EPA, 1975). Relatively water-Insoluble compounds (manganese oxide)
tend to be less toxic than more water-soluble compounds (Holbrook et al.,
1975). From acute toxldty data, the U.S. EPA (1982a) concluded that rats
are more sensitive to manganese and Its compounds than are mice or guinea
pigs. Finally, 1t appears that pretreatment with small amounts of metal can
Induce tolerance to higher, even lethal, doses (Yoshlkawa, 1974), perhaps by
Induction of the synthesis of proteins Involved 1n the metabolism of the
metal (Jones et al., 1979).
Pertinent data regarding the toxldty to humans of subchronlc oral
exposure to manganese or Its compounds could not be located In the available
literature. Subchronlc oral exposure of animals has not been well studied.
One of the two common syndromes associated with chronic Inhalation
exposure 1n humans Involves the CNS. Most of the subchronlc oral studies 1n
animals were designed to Investigate the effects of manganese on CNS func-
tion. These studies are summarized 1n Table 3-1. To Investigate this syn-
drome In animals, Wassermann and Wassermann (1977) exposed rats to manganese
at 2000 ppm In the diet for 10 weeks. Treatment did not result 1n signs of
extrapyramldal neurologic disease. Klmura et al. (1978) found that feeding
2000 ppm manganese chloride (564 ppm manganese) for 3 weeks resulted 1n a
-7-
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TABLE 3-1
Subchronlc Oral Studies with Manganese
Species
Rat
Rat
Rat
Compound
manganese
chloride
MnCl2
Hn304
Exposure
2000 ppm Hn In diet for
10 weeks
2000 ppm (564 ppm Hn)
In diet for 3 weeks
50. 400. 1100 or 3550
ppm Hn In diet through
gestation and 224 days
of age
Dose of Hn:
mg/kg/day
100a
28.2«
2.25. 18. 50 or
160
Effects
no evidence of extrapyramldal
disease _
slight decrease In brain serotonin,
Increased circulating serotonin.
decreased blood pressure
no signs of extrapyramldal
neurologic disease
I
Reference
Wassermann and Wassermann.
1977
Klmura et al
Carter et al
Rehnberg et
1981. 1982;
1982
., 1978
.. 1980;
al.. 1980.
Laskey et al.,
I
00
I
House
Rat
Rat
Rat
Rat
Rat
Hn304
HnCl2
HnCI?
HnCl2
MnCl2
1050 ppm Hn In diet from
day 15 of gestation until
male offspring reached
90 days of age
0, 350. 1050 or 3500 ppm
Hn In diet from day 1 of
gestation to offspring
age of 224 days
200 ppm In drinking water
for 10 weeks
5000 ppm (2180 ppm Hn)
In drinking water for
7 months
10.000 ppm (4360 ppm Hn)
In drinking water for
2 months
0.01 or 5.0 mg Hna\\/
mi In drinking water
for 8 months
136.5a reduced fresh organ weights of
testes and secondary sex glands
17.5. 52.5 or testes weight In males unaffected;
175a serum testosterone decreased at 1050
ppm level; male reproductive perfor-
mance unaffected; fertility In 3500
ppm females depressed
20b proliferated endoplasmlc retlculum,
prominent Golgl, multiple rough
endoplasmlc clsternae In liver
306 no signs of extrapyramldal disease,
moderate pyknosls of neurons In
caudate nucleus, decreased brain
levels of dopamlne and homovantlllc
acid
-600 Increased concentration of
-r-amlnobutyrlc acid In the brain
0, 10 or 500b spontaneous motor activity; signifi-
cantly Increased In 1st month,
decreased In 7th and 8th months;
effect not dose-related
Gray and Laskey, 1980
Laskey et al., 1982
Wassermann and Wassermann,
1977
Bon111a and Dlez-Ewald,
1974
Bonllla, 1978a,b
Bonllla, 1984
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TABLE 3-1 (eont.)
Species
Rat
Compound
MnCl2
Exposure
0.01 mg/ml
water for
In drinking
12 months
Dose of Nn:
mg/kg/day
0.44C
Effects
ultrastructural alteration
synapse and neuronal soma
of post-
and
Reference
1
Nakashlma,
1983
Rat
NnCl2«4H20 0. 1, 10 or 20 mg/ml
In drinking water from
conception up to 120 days
of age
0. 22, 220 or
440d
neuronal atrophy; decreased brain
dopamlne content
rate of body weight gain: markedly
depressed In 20 mg/ml rats; these
rats not used In other studies; no
effect on 1 or 10 mg/ml rats
organ weights: unaffected at 1 or 10
mg/ml at 60 days
organ protein content: unaffected
at 1 or 10 mg/ml at 60 days
monoamlne oxldase activity In various
organs: unaffected at 1 or 10 mg/ml
at 60 days
behavioral response to amphetamine
administration: greatly (p<0.05)
reduced In 1 mg/ml rats at 80 days
of age (only level tested)
synaptosomal uptake of amines: signi-
ficantly (p<0.005) Increased uptake
of dopamlne (but not of several other
neurotransmltter amines) In 10 mg/ml
rats (only level tested) at 80 days of
age; temporary decrease In dopamlne
uptake In 1 mg/ml rate at 70-90 days
but not 100-120 days of age (only level
tested)
Leung et al.. 1982a,b;
Lai et al.. 1982 a.b
Calculated by applying the assumption that rats eat food equivalent to 55C of their body weight/ day or mice eat food equivalent to 13X
of their body weight/day; concentration of Nn provided by Investigator
^Calculated by applying the assumption that rats weigh 0.35 kg and drink 35 ml of water dally; concentration of Nn provided by Investigator
cCalcu1ated as b above, corrected for Nn as 44X of MnCl2
^Calculated as b above, corrected for Nn as 22X of MnCl2-4H20
-------
slight decrease in brain serotonin in rats. Exposure of rats to 5000 ppm
manganese chloride in drinking water (2180 ppm manganese) for 7 months
failed to trigger signs of extrapyramidal disease, but did result in
moderate pyknosis of some neurons in the caudate nucleus and significantly
decreased brain concentrations of dopamine and homovanillic acid (Bonilla
and Diez-Ewald, 1974).
High levels of manganese have been associated with depressed reproduc-
tive performance in both male and female animals. Gray and Laskey (1980)
exposed mice to a casein-based diet containing 1050 ppm manganese as
Mn.O. from day 15 of pregnancy. Male offspring were maintained on the
same diet from birth until 90 days of age when they were killed and
examined; Interim kills were also conducted. Wet weights of preputial
glands, seminal vesicles and testicles measured at 58, 73 and 90 days after
birth were lower In exposed animals than in control animals. In a follow-up
study to evaluate the effects of exposure to Mn00, and concurrent iron
o 4
deficiency on reproductive development, groups of Long-Evans rats were
exposed to 0, 350, 1050 or 3500 ppm manganese added to a normal or an
Iron-deficient diet (Laskey et al., 1982). Exposure was initiated on day 1
of gestation and continued through offspring age of 224 days. Testes
weights were unaffected at all dose levels. A decrease In serum testos-
terone was noted 1n males exposed to 1050 ppm, but no interference with
reproductive performance was noted. Fertility 1n females exposed to 3500
ppm was depressed as measured by the percent of rats pregnant after mating.
Excessive intake of manganese was suspected as a cause of depressed
hemoglobin levels associated with chronic manganese poisoning 1n humans.
Matrone et al. (1959) found that 2000 ppm manganese depressed hemoglobin
formation in both rabbits and piglets. Hartman et al. (1955) found that
-10-
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2010 ppm manganese 1n the diet of lambs Interfered with hemoglobin regenera-
tion. Carter et al. (1980) exposed groups of Long-Evans rats to diets con-
taining 50 (normal dietary level), 400, 1100 or 3550 ppm manganese. At each
dietary level of manganese some rats were maintained on a normal Iron and
some on an Iron-deficient diet. Exposure was during the prenatal and post-
natal periods. Among the normal Iron-fed groups, no effects on erythrocyte
count, mean cell volume or hematocMt were associated with manganese. At
1100 ppm manganese, statistical analysis revealed a significant decrease In
serum creatlnlne and Increases 1n serum calcium and phosphorus. Rats aged
24-100 days developed a mlcrocytlc anemia on the low-Iron diets, which was
exacerbated by higher levels of manganese.
Manganese has been associated with decreased blood pressure related to
elevated blood levels of serotonin released from different tissues. Klmura
et al. (1978) determined that dietary exposure to 564 ppm manganese produced
a significant Increase 1n circulating serotonin and a concomitant decrease
1n blood pressure. Details of protocol were not reported.
Wassermann and Wassermann (1977) gave rats drinking water with an extra
dose of 200 ppm manganese chloride to study ultrastructural changes In the
liver associated with exposure to levels of manganese known to be nontoxlc.
Details of protocol were not reported. These authors Interpreted the
finding of proliferated smooth and rough endoplasmlc retlculum, prominent
Golgl apparatus and the occurrence of multiple rough endoplasmlc dsternae
as an adaptive process to Increased exposure to manganese chloride. Only
hemoslderosls in the Kupfer cells was noted in monkeys given 345 mg manga-
nese/kg bw (duration of exposure unspecified) (Pentschew et al., 1963).
Leung et al. (1982a,b) and La1 et al. (1982a,b) exposed rats from con-
ception up to 120 days of age to drinking water containing 0, 1, 10 or 20
-11-
-------
mg/rns. of manganese chloride (MnClp^HpO). Effects on rate of body
weight gain, organ weights and protein content, enzyme activities, synapto-
somal uptake of neurotransmltter amines and behavioral response to ampheta-
mine administration were measured. Growth rate was markedly depressed only
1n the 20 mg/ms. group; hence, other parameters were evaluated only at the
1 and 10 mg/ma, level. The behavioral response to amphetamine was altered
1n rats at 1 mg/ms., and significant but transient alterations 1n synapto-
somal neurotransmltter uptake were noted at both the 1 and 10 mg/ma levels.
In a Japanese study available only as an English abstract, rats exposed
to drinking water containing 10 mg MnCl-'lH-O/mJ, for 12 months had
neuronal atrophy and ultrastructural alteration of the postsynapse and
neuronal soma (Nakashlma, 1983). In another experiment, H appeared that
spontaneous motor activity was altered 1n rats exposed to drinking water
that provided 0.1 or 5.0 mg Mn2\\/ma, for 8 months (Bonllla, 1984). Spon-
taneous activity of the treated rats was Increased during the first month
but decreased during the 7th and 8th months of treatment.
3.1.2. Inhalation. Although symptoms of chronic manganese poisoning 1n
humans can appear within 4-5 months after exposure to very high occupational
exposures (62.5-250 mg/m3) (Ansola et al., 1944a,b), manganese toxldty 1s
most likely to be observed after prolonged exposure. Because Inhalation
exposure to manganese 1s likely to be occupational, repeated Inhalation
exposure of humans to manganese will be discussed In Section 3.2.2.
Symptoms of extrapyramldal disease are a major manifestation of chronic
manganese toxldty 1n man. Small laboratory rodents such as mice, rats and
guinea pigs do not manifest neurological syndromes typical of those 1n man
(Hambldge and Lasslter, 1973; Cotzlas et al., 1964).
-12-
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Several Inhalation studies using manganese compounds have been performed
1n laboratory animals primarily to Investigate the effects on the lungs.
These studies are summarized In Table 3-2.
The study by UlMch et al. (1979a,b,c) Investigated the toxldty of
Mn-0A In rats and monkeys exposed to manganese at levels of 0.0116,
O ^
0.1125 or 1.152 mg/m3 continuously for 9 months. Several parameters of
toxldty (clinical observations, hematology, clinical blood chemistries,
pulmonary function, electromyograms, limb tremor, hlstopathology and tissue
manganese data) were evaluated 1n this extensive Investigation. Each treat-
ment group consisted of 15 male and 15 female Spraque-Dawley rats and 4 male
and 4 female squirrel monkeys. Body weight gains were accelerated In rats
of either sex exposed to 1.152 mg/m3. Hemoglobin concentrations and RBC
were slightly elevated 1n both rats and monkeys of either sex exposed to
1.152 mg/m3. It was unclear 1f the slightly elevated hemoglobin concen-
trations and RBC were related to exposure to Mn-O. or the low background
O H
level of carbon monoxide which resulted from the combination method used to
generate Mn.,0.. Among blood chemistries, only a slight (p<0.05) depres-
sion 1n serum phosphorus In high dose group male rats was associated with
exposure to Mn~0.. Organ weights were comparable among all groups of
U ^r
monkeys and rats. Hlstopathologlcal evaluations failed to reveal adverse
effects related to Mn 0. exposure. In particular, special staining of
the brain failed to reveal any alterations or degenerative changes.
Pulmonary function tests (dynamic compliance, pulmonary flow resistance,
respiratory rate, tidal volume and number of breaths required to reduce
expired air from 80% nitrogen to 154 nitrogen while breathing pure oxygen)
were performed on all monkeys at time 0 (pre-exposure), 1, 3, 6 and 9 months
of exposure, and on one-half of the monkeys (not killed for hlstologlcal
-13-
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TABLE 3-2
Effects of Subchronlc Inhalation Exposure to Compounds of Manganese
Species Compound
Rabbit HnO?
Cat Mn02
Cat Mn02
Guinea pig ferromanganese
Guinea pig ferromanganese
Rat Mn02
lj Mice Mn02
•>
i
Mice Mn02
Rat Mn304
Monkey ^1304
Concentration
of Manganese
10-20 mg/m*
10-20 mg/m3
10-20 mg/ra* ,
then 150 mg/ra*
2350 mg/m*
2350 mg/m*
50 mg, Intra-
tracheal
3 mg/m*
0.7 mg/m*
0.0116, 0.1125
or 1.152 mg/m*
0.0116, 0.1125
or 1.152 mg/m3
Exposure
4 hours/day, 3 months
21 hours/day. 15 months
21 hours/day. 15 months
4 hours/day for addi-
tional 15 months
8 hours/day, 6 months
8 hours/day, 7.5 months
single dose
22 hours/day, 2 weeks
22 hours/day. 2 weeks
continuous for 9 months
continuous for 9 months
TWA Dose*
(mg/kg/day)
2.6-5.3
3.3-6.7
6.4-8.1
419.0
419.0
142.9
4.6
1.1
0.008. 0.084
or 0.9
0.004. 0.045 or
or 0.461
Effects
1
No pathological changes In lungs
No pathological changes In lungs
No pathological changes In lungs
No pathological changes In lungs
Ferromanganese had no effect on
mortality Induced by challenge
with pneumococcl.
Most animals had normal pulmon-
ary histology; some had nodules
of dust, macrophages and thin
retlcular fiber.
Inflammatory changes, generally
reversible after 2 months, at
which time desquamatlon of bron-
chial epithelium was observed.
Same as above
No treatment-related effects on
pulmonary function, hematology,
EMG, clinical chemistry, histology
or CNS function. Elevated tissue
levels of Mn.
No treatment-related effects on
pulmonary function, hematology.
Reference
Ehrlshmann. 1935
Ehrlshmann. 1935
Ehrlshmann. 1935
Heine. 1943
Heine. 1943
Singh et al..
1977
Nlshlyama et al.,
1975
Nlshlyama et al. ,
1975
UlHch et al..
1979a.b.c
Ulrlch et al..
1979a.b,c
EMG, clinical chemistry, histology
or CNS function. Elevated tissue
levels of Mn.
-------
TABLE 3-2 (cont.)
Species Compound Concentration Exposure TWA Dosea Effects
(mg/kg/day)
Monkey ^0304 0.072 rog/m» continuous for 12 months 0.03 No behavioral or other vlsua1! mani-
festations of toxlclty.
Nonkey Mn304 0.36 mg/m' continuous for 23 weeks 1.4 No signs of toxlclty during treat-
ment or a 10-month post-treatment
observation period. Examination
of tissues revealed no treatment-
related changes.
Monkey Mn02 3 mg/m1 22 hours/day. 5 months . 1.1 Pulmonary congestion
Monkey HnO? 0.7 mg/m* 22 hours/day, 5 months 0.3 Less severe pulmonary congestion
appeared later.
Monkey Mn02 3 mg/m1 22 hours/day, 10 months 1.1 Elevated serum SGOT, SGPT, MAO, Ca,
Mg; elevated Mn In brain, lungs.
hide, bile and kidneys. 2/3
showed mild tremors of fingers
and decreased pinch force; reduced
i dexterity In movement of upper
-• limbs.
en
i
Monkey Mn02 0.7 mg/m' 22 hours/day, 10 months 0.3 Same as above, except no neuro-
logic signs. Clinical chemistries
and tissue levels of Nn were only
mildly affected.
Reference
Coulston and
Griffin, 1977
Coulston and
Griffin, 1977
Nlshlyama et al..
1975
Nlshlyama et al..
1975
Nlshlyama et al.,
1977
Nlshlyama et al..
1977
*TUA dose of manganese calculated from the following data: rabbit body weight 1.13 kg. Inhalation rate 1.6 m'/day; cat body weight 3.3 kg. Inhalation
rate 1.26 m'/day; guinea pig body weight 0.43 kg. Inhalation rate 0.23 mVday; rat body weight 0.35 kg, Inhalation rate 0.26 mVday; mouse body
weight 0.03 kg, Inhalation rate 0.05 re3/day; monkey body weight 3.5 kg. Inhalation rate 1.4 m'/day.
-------
examination after 9 months of exposure) after an additional 6-month recovery
period. Although low-dose group males had a significantly Increased tidal
volume and mid- and high-dose group males had significantly Increased airway
resistance, Ulrlch et al. (1979c) stated that "taken as a whole, the data
did not Indicate any adverse effects [that] could be attributed to the Mn
aerosol exposure."
A total of 112 EMG and 11mb tremor oscillograph records were evaluated.
Of these, 14 were considered to demonstrate possible abnormalities. The
distribution of these possibly abnormal records among pre-exposure animals
and control as well as treatment groups led Ulrlch et al. (1979c) to con-
clude that there was "no Indication of any exposure-related effect on elec-
tromyograms or 11mb tremor."
Tissue levels of manganese reflected exposure to Mn-O.. Rats showed
Increased (p<0.05) levels.of manganese 1n kidneys, lungs (mid- and high-dose
groups) and blood (high-dose groups). .Monkeys had elevated (p<0.05) levels
of manganese 1n the kidneys (mid- and high-dose groups), lung (low- and mid-
dose groups), spleen and blood (high-dose groups). Ulrlch et al.
(1979a,b,c) concluded that neither rats nor monkeys exhibited any signs of
toxlclty associated with Inhalation of 0.0116-1.152 mg manganese/m3 con-
tinuously for 9 months.
N1sh1yama et al. (1975) Investigated the pulmonary toxldty of MnO- In
monkeys by exposing them to manganese at levels of 3 or 0.7 mg/m3 for 22
hours/day for 5 months. Pulmonary congestion was observed at both dosages,
but at the lower dose 1t appeared later and was less severe. In this study,
0.3 mg/kg/day, associated with exposure to 0.7 mg/m3, appeared to be a
LOAEL. Subsequently, N1sh1yama et al. (1977) exposed three monkeys to 3 mg
manganese/m3 and two monkeys to 0.7 mg manganese/m3 (as MnO?), 22
-16-
-------
hours/day for 10 months to Investigate the biochemical and neurotoxlc
effects of long-term exposure. A control group of three monkeys was main-
tained. High-dose group monkeys exhibited elevated serum concentrations of
SCOT, S6PT, monoamlne oxldase, calcium and magnesium compared to controls.
Substantially elevated manganese levels were determined 1n brain, lung,
hide, hair, bile and kidney, compared to controls and low-dose group
monkeys. M1ld tremors of the fingers, decreased pinch force and reduced
dexterity of upper limbs were observed and considered to be evidence of
neurologic damage analogous to that observed 1n humans suffering from
chronic manganese toxldty. No neurologic signs were observed 1n the low-
dose group monkeys. Elevations 1n serum SGOT were similar to those observed
1n the high-dose group; S6PT and monoamlne oxldase were more elevated 1n
low-dose than high-dose or control group monkeys. Elevations of serum cal-
cium and magnesium 1n low-dose monkeys were slightly less than those
observed 1n high-dose monkeys, but considerably higher than those observed
1n control monkeys. Generally, tissue levels 1n low-dose monkeys were some-
what Intermediate between levels determined 1n high-dose and control
monkeys, except that pulmonary levels were similar 1n all exposed monkeys
and levels 1n hide and hair were similar to those of controls. In a subse-
quent report (presumably further results from the same study), these authors
reported that the monkeys exposed to 700 vg/m3 showed pathologic changes
In the lungs following 10 months of exposure (Suzuki et al., 1978). This
appears to represent the lowest reported LOAEL.
Coulston and Griffin (1977) exposed seven rhesus monkeys to 100
yg/m3 Mn-O. partlculate 24 hours/day for up to 66 weeks, and found
no exposure-related adverse effects.
-17-
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3.2. CHRONIC
3.2.1. Oral. Only one report of chronic oral exposure of humans to
manganese has been located 1n the available literature. Kawamura et al.
(1941) reported the case of water consumption from wells contaminated by
manganese from dry cell batteries burled nearby. After the outbreak of
chronic manganese Intoxication, water from the wells was tested and found to
contain 14.3 mg manganese/a. Over a period of 6 weeks, the concentration
was reported to have decreased to 4.2 mg/8.. A total of 16 people were
affected with symptoms of extrapyramldal dysfunction such as lethargy,
Increased muscle tone and spasms, tremors and mental disturbances. Elderly
people seemed to be most severely affected and children were least affected.
Autopsy of one case showed atrophy of the globus palUdum and disappearance
of Its neurons. Moderate congestion of the brain, spinal cord and menlnges
was observed. Menlngeal edema was particularly prominent 1n the area of the
occiput. Levels of manganese 1n well water during the outbreak were not
monitored.
The only chronic oral studies of manganese toxldty 1n laboratory
animals was the continuation of the drinking water studies in rats (see
Section 3.1.1.). In this experiment, rats were exposed to drinking water
containing MnCl2«4H20 at 1 mg/mj. from conception to termination at
>2 years of age (Leung et al., 1981; Lai et al., 1982c), to test the effects
of chronic manganese exposure on monoamlne oxidase and NAD-Hnked 1socitr1c
dehydrogenase activities in the brain of aged rats. Monoamlne oxidase
activity was marginally significantly elevated 1n young but not aged rats
treated with manganese in the cerebellum but not In five other regions of
the brain. The biological significance of this finding is doubtful.
-18-
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IsocHMc dehydrogenase activities did not appear to be affected by treat-
ment with manganese.
3.2.2. Inhalation. Several reports of chronic Inhalation exposure of
humans to manganese were located 1n the available literature. In most
cases, these reports do not contain sufficient exposure data to be useful In
risk assessment. These data are summarized 1n Table 3-2. The U.S. EPA
(1982a, 1984) provides an excellent review and discussion of the clinical
aspects of manganlsm (chronic manganese toxldty resulting from Inhalation
exposure). The brief discussion of manganlsm which follows 1s taken from
that document.
Effects of chronic manganese toxldty are most severe on the CNS. Signs
of toxldty can result from exposure to manganese aerosols for only a few
months (Ansola et al., 1944b), although exposure for longer periods of time
1s usually required. Damage may be 1s reversible 1f exposure 1s terminated
at an early stage. Barbeau et al. (1976), however, reported that symptoms
worsened In some patients after exposure had ceased. Cotzlas et al. (1968)
Indicated that elevated tissue levels of manganese are not necessary for
confirmation of chronic manganese toxldty.
Cotzlas (1962) described three phases of manganlsm. The first phase
begins Insidiously with anorexia, asthenia, abnormal psychotic behavior and
occasional criminal acts. Severe somnolence followed by Insomnia are noted.
Headache and leucocytopenla occur, which confuses differential diagnosis
with viral encephalitis. The second phase Initiates the onset of extrapyra-
mldal disease, clumsy articulation often resulting 1n muteness. A mask-like
face and general clumsiness and lack of skilled movements are characteris-
tic. The third phase 1s characterized by severe rigidity, and the limbs
manifest a "cogwheel" phenomenon. Tremors occur which become exacerbated by
-19-
-------
emotion, stress, fatigue or trauma. Indifference, Interrupted by laughing
or crying spells, occurs. Autonomlc dysfunction, manifested by excessive
salivation or sweating, often occurs.
As noted 1n Table 3-3, levels of manganese as low as 0.30 mg/m3 (fer-
romanganese plant, Sarlc et a!., 1977), 0.44 mg/m3 (welding fumes, Chandra
et al., 1981) and 0.5 mg/m3 (manganese mine, Schuler et al., 1957) have
been associated with neurological evidence of manganlsm.
Exposure to atmospheric manganese may also result In bronchitis and
pneumonltis 1n humans. The respiratory symptoms observed 1n the following
studies are considered to be due to the Inhalation of partlculate matter
rather than the Inhalation of manganese per set, because the respiratory
symptoms observed are not those of manganlsm and are those that result from
the Inhalation of partlculates not containing manganese (U.S. EPA, 1982b).
Nogawa et al. (1973) studied subjective symptoms and ventHatory func-
tion in 1258 junior high school students housed in a school 100 m from a
ferromanganese plant and in a similar group of 648 students housed 7 km
away. The following subjective symptoms were elevated in the manganese
exposed group: presence of sputum in winter on arising, presence of sputum
in summer, wheezing, clogged nose, frequent colds and throat symptoms.
Affected ventllatory parameters Included: lower mean values for forced
expiratory volume, lower mean values for 1 second capacity and lower ratios
of 1 second capacity to maximum expiratory flow.
M1ld signs of chronic bronchitis (raising phlegm In the morning and
during the day and/or night for at least 3 winter months for at least 2
years) were observed 1n a small percentage of workers exposed to dust
containing manganese at 0.005-0.040 mg/m3 in an electrode plant (SaMc and
Ludc-Pala1c, 1977).
-20-
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TABLE 3-3
Studies of Manganlsm In Humans and Exposure-Response Relationship
Type of Exposure
Ore crushing mill
Manganese mine
Manganese mine
Manganese mine
Ferromanganese
Industrial plants
Dry-cell battery
Ferromanganese dust
or manganese oxide
fumes
Ferromanganese
Ferromanganese
Ferromanganese plant
Junior high school
within 100 m of
ferromanganese plant
Electrode factory
Exposure Level
(mg Mn/m»)
<30
<30
62.5-250
250-450
0.5-46
0.45-0.6
<5
>5
6.8-42.2
2.1-12.9 (dust)
0.12-13.3 (oxide)
0.61-1.2
3.2-8.6
0.30-20.44
0. 003-0. Ollc
0.005-0.040
Duration of
Exposure
3.3 years average
NR
178 days
-1 month to 10 years
8.2 years
NR
NR
NR
7.5 years average
(1-16 years)
variable
NR
NR
NR
varied
27X <4 years
9.8X >20 years
NR
NR
Number of
Exposed
Workers
9
25
72
NR
370
994
38
117
36
71
NR
200
100
369
1258
students
102e
190f
Number Affected (%).
Pathological Findings
0 manganlsm
11 (44X) manganlsm
12 (16~5X) manganlsm
manganlsm - 150 cases observed
In workers In two mines
15 (4X) manganlsm
167 (16. 8X), some neurological
signs and symptoms
0
7 (6X) manganlsm
15 (12. 8X) suspected manganlsm
8 (22. 2X) neuropsychlatrlc
manifest
5 (7X) manganlsm
manganlsm
91 (45. 5X) neurological
abnormalities
40 (40X) slight neurological
abnormalities
62 (16. 8X) slight neurological
signs
NR: p<0.05 Increased Incidence
of symptoms related to the throat.
decreased lung function, compared
with 648 students In school 7 km
from factory**
11(10.8) chronic bronchitis'1
28(14.7) chronic bronch1t1sd
Reference
1
Fllnn et al.. 1940
Ansola et al., 1944a.b
Rodler, 1955
Schuler et al.. 1957
Gorodnova, 1967a
Tanaka and Lleben, 1969
Emara et al., 1971
Smyth et al., 1973
Kovaltchuk and
Brodskl. 1973a
Suzuki et al.,
1973a.b.cb
SaMc et al., 1977
Nogawa et al.. 1973
SaMc and Luclc-Palalc,
1977
-------
TABLE 3-3 (cont.)
Type of Exposure
Electrode plant
Welding fumes
Exposure Level
(mg Mn/m*)
0.002-0.030
(levels to which
the control popu-
lation was exposed)
0.44-0.99
0.5-0.8
0.88-2.6
Duration of
Exposure
NR
20.2 (mean years)
21.0 (mean years)
14.1 (mean years)
Number of
Exposed
Workers
190
20
20
20
Number Affected (X).
Pathological Findings
11 (5.8X) slight neurological
signs
5 (25X) slight neurological
signs
10 (SOX) slight neurological
signs
9 (45X) slight neurological
signs
1 Reference
Sarlc et al., 1977
Chandra et al., 1981
aOrlg1nal articles not available for review
''English abstract only
Determined by the U.S. EPA (1984) based on analogy to dustfall data from the United States. Later declared Invalid by the U.S. EPA (Stara.
1985).
U.S. EPA (Stara, 1985) has determined that the respiratory signs observed are due to the presence of Inhaled partlculate rather than
manganese per se.
eNonsmokers
^Total workers; Includes present, former and nonsmokers
NR = Not reported
-------
Lloyd-Davles (1946) reported a high Incidence of pneumonia In workers
employed 1n the manufacture of potassium permanganate 1n 1938-1945. Workers
also complained of bronchitis and upper respiratory Irritation. Based on
the MnO_ content of dust 1n the plant, the manganese content of the air
was estimated at 0.1-13.7 mg/m3. Almost all particles were
-------
Subsequently, Laskey et al. (1982) fed groups of female Long-Evans rats
Iron-sufficient or Iron-deficient diets containing 0, 350, 1050 or 3500 ppm
manganese as Mn-0.. A significant decrease In serum testosterone was
observed 1n male rats exposed to 1050 ppm manganese, but no reduction 1n
male fertility was noted. Female fertility, as measured by the percent of
pregnant rats, was reduced by exposure to 3500 ppm manganese In the diet,
but not by lower dietary concentrations.
Pertinent data associating terata with oral exposure to manganese could
not be located 1n the available literature.
3.3.2. Inhalation. Pertinent data associating inhalation exposure of
humans or animals to manganese with reproductive effects could not be
located in the available literature.
3.4. TOXICANT INTERACTIONS
As discussed 1n Section 2.1., Iron deficiency anemia results In greater
absorption of orally administered manganese (Mena et al., 1969). Since iron
and manganese compete with each other for absorption, It may be assumed that
iron deficiency may exacerbate the toxlcity of manganese. No other studies
of the Interactions of manganese with xenoblotics were located In the avail-
able literature.
-24-
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the cardnogenlcHy of manganese or Us com-
pounds 1n humans could not be located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. Furst (1978) administered manganese powder to F344 rats.
Groups of 25 rats of each sex received doses of 10 mg of manganese suspended
1n trloctanoln by gavage twice monthly for 12 months. When compared to the
Incidence of lymphosarcomas/leukemla and flbrosarcomas In vehicle-treated
controls, no Increase was noted 1n manganese-exposed rats. No other studies
of cardnogenlcHy due to oral exposure of animals to manganese or Us com-
pounds were located 1n the available literature.
4.2.2. Inhalation. Pertinent data regarding cardnogenlcHy 1n either
humans or laboratory animals related to Inhalation exposure to manganese or
Its compounds could not be located 1n the available literature.
4.3. OTHER RELEVANT INFORMATION
Few data concerning the mutagenldty of manganese or Us compounds have
been located 1n the available literature. Demerec and Hanson (1951) demon-
strated that MnCl_ caused a genetic reversion 1n a strain of Escher1ch1a
coll dependent upon streptomycin for Its growth. Similarly, Flessel (1977)
demonstrated that manganese was mutagenlc 1n experiments with Salmonella.
though details of protocol and results were lacking.
Umeda and Nlshlmura (1979) Investigated the ability of MnCl2 and
potassium permanganate to cause chromosomal aberrations In C3H mouse mammary
carcinoma cells. Aberrations were noted 1n 5% of the cells exposed to
MnCl_ at a concentration of 10~3 M and In 17% of the cells exposed to a
concentration of 10~4 M potassium permanganate. DlkshHh and Chandra
(1978) failed to demonstrate chromosomal damage 1n spermatogonla or bone
-25-
-------
marrow cells of rats orally exposed to 50 yg MnClp/kg/day for 180 days.
Oorgenson et al. (1978) failed to demonstrate heritable translocatlon
defects In the offspring of F, males from male mice given manganese sul-
fate for 7 weeks before mating.
N1sh1oka (1975) reported a weakly positive effect for MnClp,
Mn(NO_)0, MnSO. and Mn'tChLCOOH) but a negative effect for
0 £ 't 0 u
KMnO. 1n a rec (recombination) assay using Bacillus subtllls strains H17
and M45. Negative results In the rec assay were reported for Mn(N03)2.
Mn(CH-COOH), and MnCl,, which was highly cytotoxlc (Kanematsu et al.,
O <. t
1980; Kada et al., 1980). Orgel and Orgel (1965) showed that divalent
manganese 1s also mutagenlc 1n the bacteMophage T4. Treatment of T4-1n-
fected E.. coll at concentrations of 10~2 M Increased the proportions of
rapid lyslc mutants from <0.04 to -1%.
Manganese was moderately effective 1n enhancing viral transformation of
Syrian hamster embryo cells (Casto et al., 1979). The composition of the
medium greatly Influenced the mutagenlc response. Hsle et al. (1979) found
that preparation of a medium deficient In divalent cations resulted 1n a
greater frequency of spontaneous mutations associated with MnCl_.
4.4. WEIGHT OF EVIDENCE
Furst (1978) administered a trloctanoln suspension of manganese powder
by gavage to rats twice monthly for 12 months. No statistically significant
Increase 1n the Incidence of neoplasla was found. In concurrent studies,
\
manganese powder, manganese acetylacetonate and manganese dioxide were
Injected Intramuscularly 1n rats and mice. Manganese acetylacetonate
appeared to cause a significantly Increased Incidence of Injection site
flbrosarcoma; mean latency period was 17 months.
-26-
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No other studies associating manganese or Its compounds with cardnogen-
1cHy 1n animals were located 1n the available literature. Stoner et al.
(1976) tested MnCl? for carclnogenlcHy 1n the strain A mouse lung tumor
system. Mice were Injected 1ntraper1toneally 3 times/week for 22 Injec-
tions. The dose levels used represented the MTD and 1:2 and 1:5 dilutions
of that concentration. Necropsy examinations 30 weeks after the first
Injection revealed no Increase 1n the Incidence of lung tumors compared to
untreated or physiological saline-treated controls. Urethane-treated (posi-
tive control) mice suffered a 100% Incidence of lung tumors.
DIPaolo (1964) Injected DBA mice either subcutaneously or IntrapeMtone-
ally with 0.1 ml of 1% MnCl. 1n aqueous solution twice weekly for 6
months. Although the Incidence of lymphosarcomas 1n treated mice appeared
to be Increased over the Incidence 1n negative controls and tumors appeared
earlier 1n treated mice than 1n control mice, the Incidence of tumors 1n
treated mice was not significantly different from that 1n the negative
controls.
Sunderman et al. (1974, 1976) failed to Induce Injection site tumors 1n
Fischer rats given single Intramuscular Injections of manganese powder.
Furthermore, these authors showed that addition of equlmolar amounts of
manganese dust to nickel subsulflde significantly depressed tumorlgenesls
due to nickel subsulflde. Under similar experimental conditions, Sunderman
et al. (1980) showed that manganese dust also Inhibited local sarcoma Induc-
tion by benzo[a]pyrene.
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The National Cancer Institute 1s conducting a cancer bloassay of manga-
nese sulfate given by gavage to rats and mice. Applying the criteria for
evaluating the overall weight of evidence for carclnogenlcity 1n humans
proposed by the Carcinogen Assessment Group of the U.S. EPA (Federal
Register, 1984), manganese Is best designated a Group 0 - Not Classified -
substance.
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5. REGULATORY STANDARDS AND CRITERIA
A summary of current regulatory standards and criteria for manganese and
Its compounds Is presented 1n Table 5-1. The ACGIH (1980) set the celling
limit for manganese dust at 5 mg/m3, based on reports of no cases of
manganlsm reported 1n 25 ore-handlers exposed to MnO. dust concentrations
of 1-5 mg/m3. On the basis of two Russian studies suggesting toxldty to
low levels of manganese cyclopentadlenyl tMcarbonyl, the ACGIH (1980) has
set the TLV for manganese from manganese cyclopentadlenyl tMcarbonyl at 0.1
mg/m3 manganese and the STEL at 0.3 mg/m3 manganese. For manganese
tetroxlde fume, the ACGIH (1980) has set the TLV at 1 mg/m3 manganese and
the STEL at 3 mg/m3 manganese. For 1984, the ACGIH (1983) has recommended
a TLV for manganese fume of 1 mg/m3 and a STEL of 3 mg/m3.
In Illinois, a much lower criterion 1n ambient air, 0.006 yg/m3, has
been recommended by the Illinois Institute of Environmental Quality (IIEQ,
1975).
The U.S. EPA (1976) has set the freshwater criterion at 0.05 mg/8.
based on the organoleptlc threshold for manganese, and the marine water
criterion at 0.1 mg/8, to protect consumers of seafood.
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TABLE 5-1
Regulatory Standards and Criteria
Standard or Criterion
Value
Reference
Mn dust:
Mn fume:
celling limit
TLV
STEL
5 mg/m3
1 mg/m3
3 mg/m3
ACGIH, 1980
ACGIH, 1983
Mn as cyclopentadlenyl
trlcarbonyl: TLV
STEL
Mn tetroxlde: TLV
STEL
Resplrable Mn for
occupational exposure
Ambient air criterion
Organoleptlc criterion 1n freshwater
Marine water criterion
0.1 mg Mn/m3
0.3 mg Mn/m3
1.0 mg Mn/m3
3.0 mg Mn/m3
0.3 mg/m3
0.006 yg/m3
0.05 mg/8.
0.1 mg/a.
ACGIH, 1980
ACGIH, 1980
WHO, 1980
IIEQ, 1975
U.S. EPA, 1976
U.S. EPA, 1976
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. As discussed 1n Section 3.1.1., reports of human toxlclty
to subchronlc oral exposure to manganese or Its compounds could not be
located 1n the available literature. Several references to subchronlc oral
exposure were found In U.S. EPA (1982a), but few were suitable for use In
risk assessment. Wassermann and Wassermann (1977) failed to produce symp-
toms of extrapyramldal disease In rats exposed to 2000 ppm manganese 1n the
diet. Proliferated endoplasmlc retlculum and other compensatory ultrastruc-
tural changes 1n the liver were noted 1n rats given 200 ppm MnCl2 1n the
drinking water. Klmura et al. (1978) associated slightly depressed brain
serotonin with 564 ppm manganese (as the chloride) 1n rats. Gray and Laskey
(1980) demonstrated retarded sexual development 1n male mice exposed to 1050
ppm manganese as Mn^. In a follow-up study, this level was shown to
cause decreased testosterone 1n male rats without Interference with repro-
ductive function (Laskey et al., 1982). In these studies, 1050 ppm manga-
nese 1n the diet constituted a LOAEL 1n mice (136.5 mg/kg/day) and rats
(52.5 mg/kg/day), assuming that mice and rats eat food equivalent to 13 and
5% of their body weight/day, respectively. Carter et al. (1980) reported a
decrease In serum creatlnlne and Increases 1n serum calcium and phosphorus
1n rats, associated with a dietary level of 1100 ppm manganese. In this
study, 1100 ppm manganese (55 mg/kg/day, food Intake equivalent to 5% of
body weight) represented a NOAEL.
Several studies of the effects of manganese on the brains of rats have
been performed (see Table 3-1). Bonllla and D1ez-Ewald (1974) observed mild
hlstologlcal changes In rats given MnCl2 1n the drinking water at 306 mg
Mn/kg bw/day. More recently, Bonllla (1984) observed alterations 1n spon-
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taneous motor activity of rats receiving 10 or 500 mg Mn/kg bw/day as
MnCl- 1n the drinking water. The alterations were not consistent and not
dose-related; they are probably not biologically significant or representa-
tive of a toxic response to manganese.
In another series of Investigations (Leung et a!., 1982a,b; Lai et al.,
1982a,b), rats were given drinking water from conception to 120 days of age
at levels of 1 or 10 mg/ml of MnCl2-4H20. Organ weights, protein
contents and monoamlne oxldase acH1v1t1es were unaffected at either level.
Significant alteration 1n dopamlne uptake at synaptosomes was noted at 10
mg/ms. and altered response to amphetamine-Induced hyperactlvHy was
observed at 1.0 mg/mi. H1stopatholog1cal examinations of the brain were
not performed 1n this study. The effects observed 1n the absence of signs
of toxldty or altered behavior were judged not to be adverse.
Nakashlma (1983) Indicated ultrastructural changes and neuronal atrophy
1-n rats treated with MnCl- at 0.01 mg/ma In the drinking water for 12
months. This study was available only as an English abstract and 1t 1s sus-
pected that the reported dosage 1s Incorrect. Applying the assumptions
footnoted 1n Table 3-1, this level results In a manganese Intake of 0.44
mg/kg bw/day. According to the NAS (1978), diets for laboratory rodents
should contain 50 ppm Mn. Assuming rats eat food equivalent to 5% of their
body weight/day, this level amounts to an Intake of 2.5 mg/kg bw/day. The
data of Nakashlma (1983) as reported 1n the English abstract are therefore
considered unreliable and are excluded from consideration 1n risk assessment.
The study by Laskey et al. (1982) was chosen to derive an oral AIS. The
animal dose of 52.5 mg/kg/day associated with decreased serum testosterone
but normal reproductive performance 1s multiplied by 70 kg, the assumed body
weight of man, and divided by an uncertainty factor of 100: a factor of 1 to
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account for Interspedes extrapolation because manganese 1s a required trace
element 1n the nutrition of rats and probably also 1n humans, a factor of 10
to extrapolate from a LOAEL to a NOAEL, and a factor of 10 to provide
greater protection to especially sensitive populations, such as those suf-
fering from Iron-deficiency anemia. The resultant AIS 1s 36.8 mg/man/day
for subchronlc oral exposure to manganese.
6.1.2. Inhalation. Studies of the toxldty of manganese as MnO 2 by
Inhalation exposure were primarily related to effects on the lungs
(Ehrlshmann, 1935; Ulrlch et a!., 1979a,b,c; N1sh1yama et al., 1975;
Coulston and Griff1n, 1977). The signs produced probably represent the
effects of partlculate matter, rather than manganese per se_, on the respira-
tory tract, since the signs observed were those of partlculate matter 1n the
air (U.S. EPA, 1982b) and were not those of manganlsm. Therefore, an AIS 1s
not calculated for manganese based on the respiratory signs observed In
these studies. Exposure of humans to manganese would probably result from
occupational or other anthropogenic exposure and would, therefore, poten-
tially be chronic. The AIC for Inhalation exposure, 21 yg/day, 1s there-
fore adopted as the AIS (see Section 6.2.2).
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. Although Kawamura et al. (1941) described an outbreak of
chronic manganese toxldty associated with contaminated well water, exposure
data were Insufficient for use 1n risk assessment. The only chronic study
1n animals was the continuation of the drinking water study 1n rats 1n which
monoamlne oxldase and IsocltMc dehydrogenase activities were measured 1n
aged rats treated for >2 years with MnCl2«4H20 at 1 mg/ma. (Leung et
al., 1981; Lai et al., 1982c). No adverse effects were observed. An AIC
can be calculated from these data. Applying the assumptions footnoted 1n
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Table 3-1, this exposure corresponds to a dose of 22 mg Mn/kg bw/day. An
AIC 1s calculated by multiplying the animal dose by 70 (the assumed body
weight of humans) and dividing by an uncertainty factory of 100: a factor
of 10 to reflect the unknown 1n extrapolating from rats to humans and
another factor of 10 to afford additional protection for unusually sensitive
members of the population. An AIC of 15.4 mg/day for a 70 kg human results,
which Is not >6.2 times the human adult dietary allowances for manganese
recommended by the NRC (1980).
6.2.2. Inhalation. Occupational Inhalation exposure to levels of manga-
nese as low as 0.3 mg/m3 (Sarlc et a!., 1977), 0.44 mg/m3 (Chandra et
al., 1981) or 0.5 mg/m3 (Schuler et al., 1957) were associated with neuro-
logic evidence of manganlsm (see Section 3.2.2.). A review of the epldeml-
ologlc data regarding manganlsm (the neurotoxlc syndrome associated with
manganese) Indicates that occupational exposure to >5000 yg/m3 Is
clearly related to occurrence of the syndrome. The evidence that manganlsm
occurs at atmospheric levels <500 yg/m3 1s judged to be equivocal and H
1s concluded that 300 yg/m3 1s the lowest level at which symptoms of
manganlsm had been documented. Accepting 300 yg/m3 as the threshold for
manganlsm 1n humans allows derivation of an AIC. The AIC Is calculated by
assuming that humans Inhale 10 m3 of air during the workday and by
expanding exposure from 5 to 7 days/week. An uncertainty factor of 100 1s
applied, a factor of 10 to convert from a LOAEL to a NOAEL and another
factor of 10 to afford greater protection for unusually sensitive Individu-
als. These calculations result 1n an AIC of 21 yg/day.
The toxldty of manganese was reviewed and a CS was calculated for
neural effects 1n animals, exposed both orally and by Inhalation, and for
manganlsm 1n occupationally exposed humans. A CS of 37.6, based on manga-
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nism 1n humans, was selected as most appropriately representing the toxldty
of manganese. A review of the human data Indicates that occupational expo-
sure to 500 yg/m3 was the lowest concentration clearly related to the
occurrence of symptoms. Assuming workers Inhale 10 m3 of air on the job
and work 5 days/week, this exposure converts to 3571 vg/day or 3.6
mg/day. This MED corresponds to an RV. of 4.7. The effects observed,
neurological symptoms of manganlsm, are assigned an RV of 8. A CS of
v
37.6 1s calculated as the product of RV. and RV .
d e
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Only one study (Furst, 1978) of the cardnogenldty of
orally administered manganese was located 1n the available literature. No
significantly Increased Incidence of cancer was associated with manganese In
this study; hence, no q * for oral exposure can be calculated.
6.3.2. Inhalation. Pertinent data regarding the cardnogenldty of
mangane-se 1n humans or animals exposed by Inhalation could not be located In
the available literature. A review of the reports of humans or animals
exposed to manganese by Inhalation for prolonged periods (see Section
3.2.2.) has failed to reveal cancer associated with exposure to manganese.
Therefore, no q,* for Inhalation exposure can be calculated.
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7. REFERENCES
AC6IH (American Conference of Governmental Industrial Hyg1en1sts). 1980.
Documentation of the Threshold Limit Values, 4th ed. ACGIH, Cincinnati, OH.
p. 250-251. (Cited In U.S. EPA, 1982a)
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents 1n the
Workroom Environment with Intended Changes for 1984. Cincinnati, OH.
Ansola, J., E. Ulberall and E. Escudero. 1944a. Intoxication by manganese
1n Chile (study on 64 cases). I. Environmental and etlologlcal factors.
Rev. Med. Chile. 72: 222-228. (Cited 1n U.S. EPA, 1982a)
Ansola, J., E. Ulberall and E. Escudero.. 1944b. Intoxication by manganese
1n Chile (study on 64 cases). II. Clinical aspects, Incapacity and medico-
legal reparations. Rev. Med. Chile. 72: 311-322. (Cited In U.S. EPA,
1982a)
Barbeau, A., N. Inou'e and T. Cloutler. 1976. Role of manganese 1n
dystonla. Adv. Neurol. 14: 339-352. (Cited In U.S. EPA, 1982a)
Bonllla, E. 1978a. Flamelln atomic absorption spectrophotometrlc determin-
ation of manganese In rat brain and other tissues. CUn. Chem. 24(3):
471-474. (Cited 1n U.S. EPA, 1984).
-36-
-------
BonHla, E. 1978b. Increased GABA content 1n candate nucleus of rats after
chronic manganese chloride administration. J. Neurochem. 31: 551-552.
(Cited 1n U.S. EPA. 1984).
Bonllla, E. 1984. Chronic manganese Intake Induces changes 1n the motor
activity of rats. Exp. Neurol. 84(3): 696-700.
Bonllla and D1ez-Ewald. 1974. Effect of L-DOPA on brain concentration of
dopamlne and homovanllUc add 1n rats after chronic manganese chloride
administration. J. Neurochem. 22: 297-299.
Burch, R.E., R.V. Williams, H.K.J. Hahn, M.M. Jetton and J.F. Sullivan.
1975. Tissue trace element and enzyme content 1n pigs fed a low manganese
diet. I. A relationship between manganese and selenium. J. Lab. Clln. Med.
86: 132-139. (Cited 1n U.S. EPA, 1982a)
Carter, S.D., J.F. He1n, 6.L. Rehnberg and J.W. Laskey. 1980. Chronic
manganese oxide 1ngest1on 1n rats: Hematologlcal effects. J. Toxlcol.
Environ. Health. 6: 207-216. (Cited 1n U.S. EPA, 1982a)
Casto, B.C., J. Meyers and J.A. DIPaolo. 1979. Enhancement of viral trans-
formation for evaluation of the carcinogenic or mutagenlc potential of
Inorganic metal salts. Cancer Res. 39: 193-198. (Cited 1n U.S. EPA, 1982a)
Chandra, S.V., G.S. Shukla, R.S. SMvastava, H. Singh and V.P. Gupta. 1981.
An exploratory study of manganese exposure to welders. Clln. Toxlcol. 18:
407-416. (Cited 1n U.S. EPA, 1982a)
-37-
-------
Clkrt, M. 1973. Enterohepatlc circulation of 64Cu, 52Mn and 203Hg In
rats. Arch. Toxlcol. 34: 51-59. (CUed In U.S. EPA, 1982a)
C1krt, M. and J. Vastal. 1969. Study of manganese resorptlon in vitro
through Intestinal wall. Int. J. Cl1n. Pharmacol. 2: 280-285. (Cited 1n
U.S. EPA, 1982a)
Cotton, F.A. and G. Wilkinson. 1980. Advanced Inorganic Chemistry. A
Comprehensive Text, 4th ed. John Wiley and Sons, Inc., NY. p. 736-749.
Cotzlas, 6.C. 1962. Manganese. In.: Mineral Metabolism: An Advanced
Treatise, 2B, C.L. Comar and F. Bronner, Ed. Academic Press, NY.
p. 403-442. (Cited 1n U.S. EPA, 1982a)
Cotzlas, G.C., P.S. PapavaslHou and S.T. Miller. 1964. Manganese 1n
melanlns. Nature, London. 201: 1228-1229. (Cited 1n U.S. EPA, 1982a)
Cotzlas, G.C., K. Horluchl, S. Fuenzallda and I. Mena. 1968. Chronic
manganese poisoning. Clearance of tissue manganese concentrations with per-
sistence of the neurological picture. Neurology. 18: 376-382. (Cited 1n
U.S. EPA, 1982a)
Coulston, F. and T. Griffin. 1977. Inhalation toxicology of airborne
partlculate manganese 1n rhesus monkeys. EPA 600/1-77-026. NTIS PB 268643.
-38-
-------
CupHt, L.T. 1980. Fate of Toxic and Hazardous Materials 1n the A1r
Environment. U.S. EPA, ESRL, ORD, Research Triangle Park, NC.
EPA-600/3-80-084. NTIS PB 80-221948.
Demerec, M. and J. Hanson. 1951. Mutagenlc action of manganous chloride.
Cold Spring Harbor Symp. Quant. B1ol. 16: 215-228. (CHed 1n U.S. EPA,
1982a)
D1ez-Ewald, M., L.R. Welntraub and W.H. Crosby. 1968. Interrelationship of
Iron and manganese metabolism. Proc. Soc. Exp. Blol. Med. 129: 448-451.
(CHed In U.S. EPA, 1982a)
D1ksh1th, T.S. and S.V. Chandra. 1978. Cytologlcal studies 1n albino rats
after oral administration of manganese chloride. Bull. Environ. Contam.
Toxlcol. 19: 741-746. (CHed In U.S. EPA, 1982a)
DIPaolo, J.A. 1964. The potentlatlon of lymphosarcomas In mice by manga-
nese chloride. Fed. Proc. 23: 393. (CHed In U.S. EPA, 1982a)
EhMshmann, 0. 1935. Untersuchungen uber die Aufnahme von Staub durch die
Atemwege. Z. Hyg. 117: 662-678. (Ger.) (CHed In U.S. EPA, 1982a)
Emara, A.M., S.H. El-6hawab1, O.I. Madkour and G.H. El-Sarma. 1971.
Chronic manganese poisoning 1n the dry battery Industry. Br. J. Ind. Med.
28: 78-82. (CHed 1n U.S. EPA, 1982a)
-39-
-------
Federal Register. 1984. Environmental Protection Agency. Proposed guide-
lines for carcinogenic risk assessment. Federal Register 49: 46294-46299.
Flessel, C.P. 1977. Metals as mutagens. Adv. Exp. Blol. Med. 91:
117-128. (Cited In U.S. EPA, 1982a)
FUnn, R.H., P.A. Neal, W.A. Relnhart, J.M. Dallavalle, W.B. Fulton and A.E.
Dooley. 1940. Chronic manganese poisoning In an ore-crushing mill. Public
Health Bull. No. 247. Washington, DC. p. 1-77. (Cited 1n U.S. EPA, 1982a)
Furst, A. 1978. TumoMgenlc effect of an organomanganese compound on F344
rats and Swiss albino mice: Brief communication. J. Natl. Cancer Inst. 60:
1171-1173. (Cited 1n U.S. EPA, 1982a)
Gorodnova, N.B. 1967. Clinical picture and cause of manganese poisoning at
simultaneous exposure to aerosols of manganese oxides formed by condensa-
tion, local vibrations and physical strain. Inst. G1g. Tr. Prof. Zabol.,
Sverdlovsk. (Cited 1n U.S. EPA, 1982a)
Gray, L.E., Jr. and J.W. Laskey. 1980. Mult1var1ate analysis of the
effects of manganese on the reproductive physiology and behavior of the male
house mouse. J. Toxlcol. Environ. Health. 6: 861-867. (Cited 1n U.S. EPA,
1982a)
-40-
-------
Greenberg, O.M., D.H. Copp and E.M. Cuthbertson. 1943. Studies 1n mineral
metabolism with the aid of artificial radioactive Isotopes. VII. The dis-
tribution and excretion, particularly by way of the bile, of Iron, cobalt,
and manganese. J. B1ol. Chem. 147: 749-756. (Cited 1n U.S. EPA, 1982a)
Gruden, N. 1977a. Interrelationship of manganese and Iron 1n rat's duoden-
um. Nutr. Rep. Int. 15: 577-580. (Cited 1n U.S. EPA, 1982a)
Gruden, N. 1977b. Suppression of transduodenal manganese transport by milk
diet supplemented with Iron. Nutr. Metab. 21: 305-309. (Cited In U.S.
EPA, 1982a)
Gruden, N. 1979. Dietary variations and manganese transduodenal transport
1n rats. Period. B1ol. 81: 567-570. (Cited In U.S. EPA, 1982a)
Hambldge, K.M. and J.W. Lasslter. 1973. Manganese toxlclty and catechola-
mlnes. In: Medical and Biologic Effects of Environmental Pollutants: Manga-
nese. Natl. Academy of Sciences, Washington, DC. p. 92-100. (Cited 1n
U.S. EPA, 1982a)
Hartman, R.H., G. Matrone and G.H. Wise. 1955. Effect of high dietary
manganese on hemoglobin formation. J. Nutr. 57: 429-439. (Cited In U.S.
EPA, 1982a)
Heine, W. 1943. Beobachtungen und experlmentelle Untersuchungen uber
Manganverglftungen und "Manganpneumonlen". Z. Hyg. Infektlonskrank. 125:
3-76. (Ger.) (Cited 1n U.S. EPA, 1982a)
-41-
-------
Holbrook, D.J., Jr., M.E. Washington, H.B. Leake and P.E. Brubaker. 1975.
Studies on the evaluation of the toxldty of various salts of lead, manga-
nese, platinum and palladium. Environ. Health Perspect. 10: 95-101.
(Cited In U.S. EPA, 1982a)
Hs1e, A.W., N.P. Johnson, D.B. Couch, et al. 1979. Quantitative mammalian
cell mutagenesls and preliminary study of the mutagenlc potential of metal-
lic compounds. In.: Trace Metals 1n Health and Disease, N. Kharasch, Ed.
Raven Press, NY. p. 55-70. (Cited 1n U.S. EPA, 1982a)
IIEQ (Illinois Institute of Environmental Quality). 1975. Airborne manga-
nese. Health effects and recommended standard. Environmental Health
Resource Center, IIEQ Doc. 75-18. p. 46. (Cited In U.S. EPA, 1982a)
Jones, M.M., J.E. Schoenhelt and A.D. Weaver. 1979. Pretreatment and heavy
metal LD5Q values. Toxlcol. Appl. Pharmacol. 49: 41-44. (Cited 1n U.S.
EPA, 1982a)
Jorgenson, T.Z., C.J. Rvshbrook, G.W. Newell and S. Green. 1978. In vivo
mutagenesls Investigations of four GRAS chemicals. Mutat. Res. 53: 205.
(Abstr.) (Cited 1n U.S. EPA, 1982a)
Kada, T., K. Hlrano and Y. Shlrasu. 1980. Screening of environmental chem-
ical mutagens by the rec-assay system with Bacillus subt111s. In: Chemical
Mutagens: Principles and Methods for Their Detection, Vol. 6, A. Hollaender,
Ed. p. 149-173. (Cited 1n U.S. EPA, 1982a)
-42-
-------
Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagenldty
studies on metal compounds. Mutat. Res. 77: 109-116. (Cited In U.S. EPA,
1982a)
Kawamura, R., H. Ikuta, S. Fukuzuml, et al. 1941. Intoxication by manga-
nese In well water. KHasato Arch. Exp. Med. 18: 145-169. (Cited 1n U.S.
EPA, 1982a)
Klmura, M., N. Yagl and Y. Itokawa. 1978. Effect of subacute manganese
feeding on serotln metabolism 1n the rat. J. Toxlcol. Environ. Health. 4:
701-707.
Kostlal, K., 0. Kello, S. Jugo, I. Rabar and T. Maljkovlc. 1978. Influence
of age on metal metabolism and toxldty. Environ. Health Perspect. 25:
81-86. (Cited 1n U.S. EPA, 1982a) -
Kostlal, K., I. Rabar, M. Blanusa and I. S1monov1c. 1980. The effect of
Iron additive to milk on cadmium, mercury and manganese absorption 1n rats.
Environ. Res. 22: 40-45. (Cited 1n U.S. EPA, 1982a)
Kovaltchuk, A.A. and B.O. Brodskl. 1973. Health of the workers In ferroal-
loys foundries. |n: Proceedings of a Conference on Occupational Hygiene and
Prevention of Occupational Disease 1n Ferroalloys Production. Inst. G1g.
Tr. Prof. Zabol., Sverdlovsk, p. 78-80. (Cited 1n U.S. EPA, 1982a)
-43-
-------
La1, J.C.K., T.K.C. Leung and L. Llm. 1982a. The ontogeny of acetylcho-
Unesterase activities 1n rat brain regions and the effect of chronic treat-
ment with manganese chloride. J. Neurochem. 39(6): 1767-9.
La1, J.C.K., T.K.C. Leung, J.F. Guest, A.N. Davlson and L. Llm. 1982b. The
effects of chronic manganese chloride treatment expressed as age-dependent,
transient changes In rat brain synaptosomal uptake of amines. J. Neuro-
chem. 38(3): 844-7.
La1, J.C.K., T.K.C. Leung and L. L1m. 1982c. Activities of the mltochond-
rlal NAD-Hnked 1soc1tr1c dehydrogenase 1n different regions of the rat
brain. Changes 1n aging and the effect of chronic manganese chloride
administration. Gerontology. 28(2): 81-5.
Lantzy, R.J. and F.T. MacKenzle. 1979. Atmospheric trace metals: Global
cycles and assessment of man's Impact. Geochlm. Cosmochlm. Acta. 43:
511-525.
Laskey, J.W., G.L. Rehnberg, J.F. Heln and S.D. Carter. 1982. Effects of
chronic manganese (Mn_0.) exposure on selected reproductive parameters
O *r
In rats. J. Toxlcol. Environ. Health. 9: 677-687.
Lasslter, J.W., W.J. MUler, F.M. Pate and R.P. Gentry. 1969. 54Mn
metabolism 1n rats as affected by dietary calcium and phosphorus. Presented
at the 33rd Annual Meeting of the American Institute of Nutrition, Federa-
tion of American Societies for Experimental Biology, Atlantic City, NJ,
April 13-18. (Cited 1n U.S. EPA, 1982a)
-44-
-------
LassHer, J.W., J.O. Morton and W.J. Miller. 1970. Influence of manganese
on skeletal development 1n the sheep and rat. In: Trace Element Metabolism
1n Animals, C.F. Mills, Ed. Livingstone, Edinburgh, p. 130-132. (Cited 1n
U.S. EPA, 1982a)
Leach, R.M., Jr. and M.S. LUburn. 1978. Manganese metabolism and Us
function. World Rev. Nutr. Diet. 32: 123-134. (Cited 1n U.S. EPA, 1982a)
Leung, T.K.C., J.C.K. La1 and L. Llm. 1981. The regional distribution of
monoamlne oxldase activities towards different substrates: Effects In rat
brain of chronic administration of manganese chloride and of aging. J.
Neurochem. 36(6): 2037-2043.
Leung, T.K.C., J.C.K. La1 and L. Llm. 1982a. The effects of chronic manga-
nese feeding on the activity of monoamlne oxldase 1n various organs of the
developing rat. Comp. Blochem. Physlol. C. 71C(2): 223-228
Leung, T.K.C., J.C.K. La1, M. Trlcklebank, A.M. Oavlson and L. L1m. 1982b.
Chronic manganese treatment of rats alters synaptosomal uptake of dopamlne
and the behavioral response to amphetamine administration. J. Neurochem.
39(5): 1496-9
Lloyd-Davles, T.A. 1946. Manganese pneumonltls. Br. J. Ind. Med. 3:
111-135 (Cited 1n U.S. EPA, 1984).
-45-
-------
Mandzgaladze, R.N. 1967. Some clinical and experimental data on the effect
of manganese compounds on sexual function. Vopr. G1g. Tr. Prof. 11:
126-130. (Eng. Abstr.) (Cited In U.S. EPA, 1982a)
Matrone, G., R.H. Hartman and A.J. Clawson. 1959. Studies of a manganese
Iron antagonism 1n the nutrition of rabbits and baby pigs. J. Nutr. 67:
309-317. (Cited 1n U.S. EPA, 1982a)
Mena, I., 0. Marln, S. Fuenzallda and G.C. Cotzlas. 1967. Chronic manga-
nese poisoning: Clinical picture and manganese turnover. Neurology. 17:
128-136. (Cited In U.S. EPA, 1982a)
Mena, I., K. Horluchl, K. Burke and G.C. Cotzlas. 1969. Chronic manganese
poisoning. Individual susceptibility and absorption of Iron. Neurology.
19: 1000-1006. (CHed 1n U.S. EPA, 1982a)
Mena, I., K. Horluchl and G. Lopez. 1974. Factors enhancing entrance of
manganese Into the brain: Iron deficiency and age. J. Nucl. Med. 15: 516.
(CHed 1n U.S. EPA, 1982a)
Nakashlma, S. 1983. The hlstopathologlcal alteration of the central ner-
vous system In rat following long-term administration of manganese chlor-
ide. Relation to the activity of tyroslne hydroxylase. Brain Nerve:
35(1): 91-9. (Taken from Chem Abstr. 98(17):138642r.)
NAS (National Academy of Sciences). 1978. Nutrient requirements of labora-
tory animals. Third ed. NAS, Washington, D.C. 96 p. (CHed 1n U.S. EPA,
1984)
-46-
-------
N1sh1oka, H. 1975. Mutagenlc activities of metal compounds 1n bacteria.
Mutat. Res. 31: 185-189. (CHed 1n U.S. EPA, 1982a)
N1sh1yama, K., Y. Suzuki, N. Fujll, H. Yano, T. Mlyal and K. Ohmlshl. 1975.
Effect of long-term Inhalation of manganese dusts. II. Continuous observa-
tion of the respiratory organs 1n monkeys and mice. Jap. J. Hyg. 30: 117.
(CHed 1n U.S. EPA, 1982a)
N1sh1yama, K., Y. Suzuki, N. Fuj11, H. Yano, K. Ohn1sh1 and T. M1ya1. 1977.
Biochemical changes and manganese distribution 1n monkeys exposed to manga-
nese dioxide dust. Tokushlma J. Exp. Med. 24: 137. (Taken from Chem.
Abst. 89 37611P)
Nogawa, K., E. Kobayashl and M. Sakamoto. 1973. Ep1dem1olog1cal studies on
disturbance of respiratory system caused by manganese air pollution. Report
1: Effects on respiratory system of junior high school students. Jap. J.
Pub. Health. 20: 315-326.
NRC (National Research Council). 1980. Recommended dietary allowances:
Manganese, 9th ed. Food and Nutrition Board. National Academy of Sciences,
Washington, DC. p. 154-156.
Orgel, A. and I.E. Orgel. 1965. Induction of mutations 1n bacteMophage T4
with divalent manganese. J. Mol. B1ol. 14: 453-457. (CHed 1n U.S. EPA,
1982a)
-47-
-------
Penalver, R. 1955. Manganese poisoning. The 1954 Ramazz1n1 oration. Ind.
Med. Surg. 24: 1-7. (Cited In U.S. EPA, 1982a)
Pentschew, A., F.F. Ebner and R.M. Kovatch. 1963. Experimental manganese
encephalopathy In monkeys. J. Neuropathol. Exp. Neurol. 22: 488-499.
(Cited In U.S. EPA, 1982a)
Pollack, S., J.N. George, R.C. Reba, R.M. Kaufman and W.H. Crosby. 1965.
The absorption of nonferrous metals 1n Iron deficiency. J. Clln. Invest.
44: 1470-1473. (Cited 1n U.S. EPA, 1982a)
Rabar, I. 1976. Some factors Influencing manganese metabolism 1n rats.
M.Sc. Thesis, University of Zagreb, Zagreb, Yugoslavia. (Cited 1n U.S. EPA,
1982a)
Rehnberg, G.L., J.F. He1n, S.D. Carter and J.W. Laskey. 1980. Chronic
manganese oxide administration to preweanllng rats: Manganese accumulation
and distribution. J. Toxlcol. Environ. Health. 6: 217-226. (Cited in U.S.
EPA, 1984).
Rehnberg, G.L., J.F. Hein, S.D. Carter, R.S. L1nko and J.W. Laskey. 1981.
Chronic ingestion of MN-04 by young rats: Tissue accumulation, distri-
bution, and depletion. J. Toxlcol. Environ. Health. 7: 263-272. (Cited 1n
U.S. EPA, 1984).
-48-
-------
Rehnberg, 6.L., J.F. He1n, S.O. Carter, R.S. L1nko and J.W. Laskey. 1982.
Chronic Ingestlon of MNgO. by rats: Tissue accumulation and distribu-
tion of manganese 1n two generations. J. Toxlcol. Environ. Health. 9:
175-188. (Cited 1n U.S. EPA, 1984).
Rodler, J. 1955. Manganese poisoning In Moroccan miners. Br. J. Ind. Med.
12: 21-35. (Cited In U.S. EPA, 1982a)
Sarlc, M. and S. Luc1c-Pala1c. 1977. Possible synerglsm of exposure to
airborne manganese and smoking habit 1n occurrence of respiratory symptoms.
in: Inhaled Particles, IV. W.H. Walton, Ed. Pergamon Press, New York. p.
773-779. (Cited 1n U.S. EPA, 1984).
Sarlc, M., A. Marklcevlc and 0. Hrustlc. 1977. Occupational exposure to
manganese. Br. J. Ind. Med. 34: 114-118. (Cited 1n U.S. EPA, 1982a)
Schroeder, H.A. and A.P. Nason. 1976. Interactions of trace metals 1n
mouse and rat tissues: Z1nc, chromium, copper, and manganese with 13 other
elements. J. Nutr. 106: 198-203. (Cited 1n U.S. EPA, 1982a)
Schroeder, H.A., M. MHchener and A.P. Nason. 1974. Life-term effects of
nickel 1n rats: Survival tumors, Interactions with trace elements and tissue
levels. J. Nutr. 104: 239-243. (Cited 1n U.S. EPA, 1982a)
Schuler, P., H. Oyanguren, V. Maturana, et al. 1957. Manganese poisoning.
Environmental and medical study at a Chilean mine. Ind. Med. Surg. 26:
167-173. (Cited 1n U.S. EPA, 1982a)
-49-
-------
Singh, J., J.L. Kaw and S.H. Zaldi. 1977. Early biochemical response of
pulmonary tissue to manganese dioxide. Toxicology. 8: 177-184. (Cited 1n
U.S. EPA, 1982a)
Smyth, L.T., R.C. Ruhf, N.E. Whitman and T. Dugan. 1973. Clinical manga-
nlsm and exposure to manganese 1n the production and processing of ferro-
manganese alloy. J. Occup. Med. 15: 101-109. (Cited 1n U.S. EPA, 1982a)
Stara, J.F. 1985. Non-carcinogenic health effects of manganese. U.S. EPA,
Cincinnati, OH. Memorandum to D.R. Patrick, OAQPS, Research Triangle Park,
NC. May 13.
Stoner, G.D., M.B. Sh1mk1n, M.C. Troxell, T.L. Thompson and L.S. Terry.
1976. Test for cardnogenldty of metallic compounds by the pulmonary tumor
response 1n strain A mice. Cancer Res. 36: 1744-1747. (Cited 1n U.S. EPA,
1982a)
Sunderman, F.W., Jr., T.J. Lau and L.J. Cralley. 1974. Inhibitory effect
of manganese upon muscle tumoMgenesIs by nickel subsulflde. Cancer Res.
34: 92-95. (Cited 1n U.S. EPA, 1982a)
Sunderman, F.W., Jr., K.S. Kasprzak, T.J. Lau, et al. 1976. Effects of
manganese on cardnogenldty and metabolism of nickel subsulflde. Cancer
Res. 36: 1790-1800. (Cited In U.S. EPA, 1982a)
-50-
-------
Sunderman, F.W., H.C. Reid, P.R. Allpass and S.B. Taubman. 1980. Manganese
Inhibition of sarcoma Induction by benzo(a)pyrene 1n Fischer rats. Proc.
Am. Assoc. Cancer Res. 21: 72. (Abstr.) (Cited In U.S. EPA, 1982a)
Suzuki, Y., K. N1sh1yama, Y. Suzuki, et al. 1973a. The effects of chronic
manganese exposure on ferromanganese workers (Part 1). Shlkoku Acta Med.
29: 412-424. (Jap. with Eng. abstract) (Cited 1n U.S. EPA, 1982a)
Suzuki, Y., K. Nlshiyama, Y. Suzuki, et al. 1973b. The effects of chronic
manganese exposure on ferromanganese workers (Part 2). Shlkoku Acta Med.
29: 433-438. (Jap. with Eng. abstract) (Cited In U.S. EPA, 1982a)
Suzuki, Y., K. N1sh1yama, Y. Suzuki, et al. 1973c. Blood and urinary
manganese 1n ferromanganese worker. Shlkoku Acta Med. 29: 425-432. (Jap.
with Eng. abstract) (Cited 1n U.S. EPA, 1982a)
Suzuki, Y., N. Fuj~11, H. Yano, T. Ohklta, A. Ichlkawa and K. Nlshiyama.
1978. Effects of the Inhalation of manganese dioxide dust on monkey lungs.
Tokushlma J. Exp. Med. 25: 119-125. (Cited 1n U.S. EPA, 1984).
Tanaka, S. and J. Lleben. 1969. Manganese poisoning and exposure 1n
Pennsylvania. Arch. Environ. Health. 19: 674-684. (Cited In U.S. EPA,
1982a)
Thomson, A.B.R. and L.S. Valberg. 1972. Intestinal uptake of Iron, cobalt,
and manganese 1n Iron-deficient rat. Am. J. Physlol. 223: 1327-1329.
(Cited 1n U.S. EPA, 1982a)
-51-
-------
Thomson, A.B.R., D. Olatunbosun, L.S. Valberg and J. Ludwlg. 1971. Inter-
relation of Intestinal transport system for manganese and Iron. J. Lab.
Clin. Med. 78: 642-655. (Cited 1n U.S. EPA, 1982a)
UlMch, C.E., W. Rlnehart and W. Busey. 1979a. Evaluation of the chronic
Inhalation toxldty of a manganese oxide aerosol. I. Introduction, experi-
mental design, and aerosol generation methods. Am. Ind. Hyg. Assoc. J. 40:
238-244. (Cited 1n U.S. EPA, 1982a)
UlMch, C.E., W. Rlnehart, W. Busey and M.A. Dorato. 1979b. Evaluation of
the chronic Inhalation toxldty of a manganese aerosol. II. Clinical
observations, hematology, clinical chemistry and hlstopathology. Am. Ind.
Hyg. Assoc. J. 40: 322-329. (Cited 1n U.S. EPA, 1982a)
UlMch, C.E., W. Rlnehart and M. Brandt. 1979c. Evaluation of the chronic
Inhalation toxldty of a manganese oxide aerosol. III. Pulmonary function,
electromyograms, 11mb tremor, and tissue manganese data. Am. Ind. Hyg.
Assoc. 3. 40: 349-353. (Cited 1n U.S. EPA, 1982a)
Umeda, M. and M. Nlshlmura. 1979. Induc1b1l1ty of chromosomal aberrations
by metal compounds In cultured mammalian cells. Mutat. Res. 67: 221-229.
(Cited In U.S. EPA, 1982a)
U.S. EPA. 1975. Scientific and Technical Assessment Report on Manganese.
ORO, Washington, DC. EPA 600/6-75-002.
-52-
-------
U.S. EPA. "1976. Quality Criteria 'for Water. Washington, DC. 256 p.
GPO-1977-0-222-904.
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45:79347-79357.
U.S. EPA. 1981. Multimedia Criteria for Manganese and Compounds. Environ-
mental Criteria and Assessment Office, Cincinnati, OH. Internal draft.
U.S. EPA. 1982a. Health Assessment Document for Manganese. Environmental
Criteria and Assessment Office, Cincinnati, OH. External review draft. EPA
600/8-83-013A. NTIS PB83-217786.
U.S. EPA. 1982b. Review of the National Ambient A1r Quality Standards for
Partlculate Matter: Asses-sment of Scientific and Technical Information.
Office of A1r Quality Planning and Standards, Research Triangle Park, NC.
PB82-177874.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid
Waste and Emergency Response, Washington, DC.
U.S. EPA. 1984. Health Assessment Document for Manganese. Environmental
Criteria and Assessment Office, Cincinnati, OH. May, 1984. EPA-600/8-
83-013F. NTIS PB84-229954
-53-
-------
Wassermann, D. and M. Wassermann. 1977. The ultrastructure of the liver
cell 1n subacute manganese administration. Environ. Res. 14: 379-390.
Weast, R., Ed. 1980. CRC Handbook of Chemistry and Physics, 61st ed. CRC
Press, Boca Raton, FL. p. B-117 to B-119, B-134, D-201.
WHO (World Health Organization). 1980. Recommended Health-based Limits 1n
Occupational Exposure to Heavy Metals: Manganese. Report of a WHO Study
Group. Technical Report Series 647, WHO, Geneva, Switzerland, p. 80-101.
{Cited 1n U.S. EPA, 1982a)
Yoshlkawa, H. 1974. Tolerance to acute metal toxlclty 1n mice having
received a dally Injection of Us low dose. Ind. Health. 12: 175-177.
(Cited In U.S. EPA, 1982a)
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APPENDIX
Summary Table for Manganese and Compounds
Species
Inhalation
AIS human
AIC human
Maximum human
^ composite
y score
Oral
AIS rat
AIC rat
Experimental
Dose/Exposure
300 yg/m3
occupational
300 yg/ma
occupational
500 yg/m3
occupational
(RVd=4.7)
52.5 mg/kg/day
22 mg/kg/day
Effect
threshold for
manganslm
threshold for
manganlsm
neurologic symptoms
of manganlsm
(RVe=8)
decreased serum
testosterone
slightly altered
Acceptable Intake Reference
(AIS or AIC)
21 yg/day Sarlc et al., 1977
21 yg/day Sarlc et al., 1977
37.6 Stara, 1985;
36.8 mg/day Laskey et al., 1982
15.4 mg/day Leung et al., 1981;
Isocltrate actlvl
ties In brain
La1 et al., 1982c
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