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AMERICAN JOURNAL OF INDUSTRIAL MEDICINE (2007)
Basal Ganglia Neurotransmitter Concentrations in
Rhesus Monkeys Following Subchronic Manganese
Sulfate Inhalation
Melanie F. Struve, BS, Brian E. McManus, BS, Brian A. Wong,
and David C. Dorman, DVM, PhD
PhD,
Background Manganese neurotoxicity in humans is recognized as a form of parkinsonism with lesions occurring predominantly within the globus pallidus, subthalamic nucleus,
putamen, and caudate nucleus.
Methods This study evaluated dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic
acid, serotonin, norepinephrine, 5-hydroxyindoleacetic acid, g-aminobutyric acid
(GABA), and glutamate concentrations in the globus pallidus, caudate, and putamen of
male rhesus monkeys exposed subchronically to either air or manganese sulfate (MnSO4)
at 0.06, 0.3, or 1.5 mg Mn/m3.
Results An approximate 1.5–6-fold increase (vs. air-exposed controls) in mean brain
manganese concentration was observed following subchronic MnSO4 exposure. A
marginally significant (P < 0.1) decrease in pallidal GABA and 5-hydroxyindoleacetic
acid concentration and caudate norepinephrine concentration occurred in monkeys
exposed to MnSO4 at 1.5 mg Mn/m3.
Conclusions Despite the presence of increased tissue manganese concentrations, highdose exposure to MnSO4 was associated with relatively few changes in basal ganglial
neurotransmitter concentrations. Am. J. Ind. Med. 2007. ß 2007 Wiley-Liss, Inc.
KEY WORDS: parkinsonism; neurochemistry; inhalation; macaca mulatta; manganese
INTRODUCTION
As an essential nutrient, manganese plays an important
role in blood sugar regulation, cellular energy, reproduction,
digestion, bone growth, and free radical defense mechanisms. Manganese metalloenzymes include arginase, glu-
CIIT Centers for Health Research, The Hamner Institutes for Health Sciences, Research
Triangle Park, North Carolina 27709
Contract grant sponsor: Afton Chemical Corporation.
*Correspondence to: Melanie F. Struve, CIIT Centers for Health Research, The Hamner
Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC
27709. E-mail: [email protected]
Accepted18 May 2007
DOI 10.1002/ajim.20489. Published online in Wiley InterScience
(www.interscience.wiley.com)
2007 Wiley-Liss, Inc.
tamine synthetase, phosphoenolpyruvate decarboxylase, and
manganese superoxide dismutase. Human dietary manganese deficiency has not been documented [Aschner et al.,
2005]. There have, however, been reports associating
reduced blood or serum manganese concentrations with
epilepsy [Dupont and Tanaka, 1985; Carl et al., 1986;
Davidson and Ward, 1988], although reports of seizures
associated with high blood manganese concentrations
[Gonzalez-Reyes et al., 2007] and studies failing to support
this observation have also been published [Ilhan et al., 2004].
Excessive manganese accumulation within the human
caudate nucleus, putamen, and globus pallidus is observed
following high-dose inhalation or oral exposure [Aschner
et al., 2005]. Clinically, manganese neurotoxicity (manganism) is categorized as a form of parkinsonism because
severely affected individuals demonstrate gait abnormalities,
postural instability, micrographia, dystonia, rigidity, and
2
Struve et al.
bradykinesia. Overt manganese neurotoxicity most often
results from the chronic inhalation of very high (>1 mg/m3)
concentrations of airborne manganese [Pal et al., 1999].
Pulmonary and reproductive toxicities have also been
reported in occupationally exposed workers [Martin, 2006].
Individuals receiving total parenteral nutrition and patients
with hepatobiliary insufficiency are also at increased risk for
manganese neurotoxicity [Aschner et al., 2005]. Brain
magnetic resonance imaging (MRI) studies revealing hyperintensities within the pallidum and other brain regions known
to accumulate manganese have been reported for people
exposed to high levels of manganese or with hepatobiliary
insufficiency [reviewed in Fitsanakis et al., 2006b].
Occupational exposure to manganese occurs primarily
through contact with dust or fumes generated during
manganese mining operations, cutting, and welding of steel,
or during the production of certain batteries and pesticides.
Inhalation is the most relevant route for workplace exposure
since dermal absorption is extremely limited and oral
absorption of manganese is under tight physiological
regulation with only a small fraction (2–5%) of the ingested
dose becoming systemically absorbed [Aschner et al., 2005].
Occupational studies have found tremor, reduced hand
steadiness, and slower finger-tapping speed in workers that
inhale manganese at concentrations below those associated
with overt manganese neurotoxicity [Olanow, 2004]. For
example, a cross-sectional study conducted by Roels et al.
[1992] in a Belgium dry alkaline battery plant revealed that
20–30% of the workers had subclinical neurobehavioral
dysfunction associated with inhalation exposure to particulate manganese dioxide (MnO2). The mean time-weighted
average (TWA) concentration of manganese in inhalable dust
was 1 mg Mn/m3 with an average duration of exposure of
5.3 years. An 8-year prospective investigation of the
manganese-exposed cohort identified the NOAEL and
LOAEL to be approximately 120 and 400 mg Mn/m3,
respectively [Roels et al., 1999]. The American Conference
of Governmental and Industrial Hygienists (ACGIH) threshold limit value (TLV) expressed as a time-weighted average
for manganese is 0.2 mg Mn/m3 (total dust).
Neuropathology associated with manganism generally
involves the globus pallidus and substantia nigra pars
reticulata, with less extensive involvement of the caudate
nucleus, putamen, subthalamic nucleus, and substantia nigra
pars compacta [Yamada et al., 1986]. These observations
suggest that the dopaminergic system is an important target
for manganese. In two patients with manganese toxicity,
striatal dopamine levels were reported to be markedly
decreased [Mena et al., 1970; Bernheimer et al., 1973].
Unlike individuals with Parkinson’s disease, manganism
patients do not respond to dopamine replacement [Koller
et al., 2004; Olanow, 2004]. Likewise, functional imaging
studies using fluorodopa-labeled positron emission tomography (PET) scans have failed to show reduced striatal
uptake of fluorodopa in patients with manganism [Olanow,
2004]. Neurochemical changes that occur in people following high-dose manganese exposure are poorly documented.
Thus, this study was conducted to improve our understanding
of neurochemical changes that occur in nonhuman primates
following high-dose manganese inhalation.
MATERIALS AND METHODS
Experimental Design
Male rhesus monkeys were exposed to air (n ¼ 6) or
MnSO4 at 0.06 (n ¼ 6), 0.3 (n ¼ 4), or 1.5 mg Mn/m3 (n ¼ 4)
for 65 exposure days. Exposures were conducted for 6 hr/day,
5 days/week. MnSO4 aerosol concentrations of 0.18, 0.92,
and 4.62 mg MnSO4/m3, corresponding to 0.06, 0.3, and
1.5 mg Mn/m3, were generated for this study. Control animals
were exposed to filtered air. Our lowest exposure MnSO4
concentration (0.06 mg Mn/m3) is below the current ACGIH
8-hr TLV for inhaled manganese of 0.2 mg Mn/m3. T1weighted MRI studies of the head were performed 3–4 days
prior to necropsy using the following anesthesia protocol.
Animals were fasted overnight and then tranquilized with
ketamine (approximately 10–15 mg/kg, IM, Fort Dodge
Animal Health, Fort Dodge, IA). Animals were given
atropine (approximately 0.05 mg/kg, SQ, Phoenix Scientific,
Inc., St. Joseph, MO) to decrease bronchial secretions and
prevent bradycardia. This was followed by an intravenous
bolus of propofol (Gensia Sicor Pharmaceuticals, Inc.,
Irvine, CA) at an approximate dose of 1.25–2.5 mg/kg,
followed by slow intravenous propofol infusion at approximately 300 mg/kg/min (range 105–470 mg/kg/min) to
maintain a light plane of anesthesia for approximately 1–
2 hr. The in-life and necropsy portions of this study were
performed in accordance with the U.S. Environmental
Protection Agency’s Good Laboratory Practice (GLP)
Standards for Inhalation Exposure Health Effects Testing
(40 CFR Part 79.60).
Chemicals
Manganese (II) sulfate monohydrate (MnSO4H2O) was
obtained from Aldrich Chemical Company, Inc. (Milwaukee,
WI). Manganese sulfate is a relatively water-soluble, pale
pink, crystalline powder that contains approximately 32%
manganese. Unless otherwise noted, all other chemicals were
purchased from Sigma–Aldrich (St. Louis, MO).
Animals
This study was conducted under federal guidelines for
the care and use of laboratory animals [National Research
Council, 1996] and was approved by the CIIT Institutional
Animal Care and Use Committee. Twenty, 17–22 month
Neurotransmitters in Manganese-Exposed Monkeys
old, male rhesus monkeys were purchased from Covance
Research Products, Inc. (Alice, TX). Monkeys were 20–
24 months old at the start of the inhalation exposure.
Additional details concerning these animals, their husbandry,
and assessments have been previously published [Dorman
et al., 2005, 2006a,b]. Animals were observed daily by
trained veterinary and animal care staff.
Manganese exposures
Four 8-m3 stainless steel and glass inhalation exposure
chambers were used. Methods describing chamber monitoring as well as generation and characterization of the MnSO4
aerosol have been previously described [Dorman et al., 2004,
2005]. Based upon optical particle sensor measurements, the
overall average concentrations (SD) for the MnSO4
atmospheres were 0.19 0.01, 0.97 0.06, and 4.55 0.33 mg/m3 for the target concentrations of 0.18, 0.92, and
4.62 mg MnSO4/m3, respectively. The geometric mean
diameter, geometric standard deviation (sg), and calculated
mass median aerodynamic diameters (MMAD) of the
MnSO4 aerosols were determined to be 1.04 mm (sg ¼
1.51; MMAD ¼ 1.73 mm), 1.07 mm (sg ¼ 1.54; MMAD ¼
1.89 mm), and 1.12 mm (sg ¼ 1.58; MMAD ¼ 2.12 mm) for
the target concentrations of 0.18, 0.92, and 4.62 mg MnSO4/
m3, respectively.
Necropsy procedures
Necropsies were performed 18–23 hr after termination
of the final inhalation exposure. Food was withheld overnight
prior to necropsy. Monkeys were anesthetized with ketamine
(20 mg/kg, im, Fort Dodge Animal Health, Fort Dodge, IA)
and blood was collected from a peripheral vein using plastic
syringes with hypodermic needles. Monkeys were then
euthanized with pentobarbital (80–150 mg/kg, iv, Henry
Schein, Inc., Port Washington, NY) followed by exsanguination. Brains were removed, divided along the mid-sagittal
plane, and dissected into regions containing the caudate,
putamen, and globus pallidus. Anatomical structures were
identified using a monkey brain atlas [Martin and Bowden,
2000]. All samples were stored immediately in individual
plastic vials or bags, frozen in liquid nitrogen, and stored at
808C until chemical analyses were performed.
Brain manganese concentrations
Brain manganese concentrations were determined by
graphite furnace atomic absorption spectrometry with a
Perkin Elmer AAnalyst 800 atomic absorption spectrometer
equipped with AA WinLab software (version 4.1 SP), as
previously described [Dorman et al., 2004]. Samples (10–
30 mg) were digested in 16 M nitric acid (1 ml) prior to
3
manganese analysis using a CEM MARS5 Microwave
Accelerated Reaction System (CEM, Matthews, NC).
Brain neurotransmitter concentrations
Monoamine neurotransmitter (dopamine, 3,4-dihydroxyphenylacetic acid [DOPAC], homovanillic acid [HVA],
serotonin [5-HT], 5-hydroxyindoleacetic acid [5-HIAA],
and norepinephrine) concentrations were determined using
modifications of the methods described by Ali and Slikker
[1994]. Approximately 10–50 mg of brain tissue were
homogenized with a 20-fold volume of an aqueous solution
containing 0.2 N perchloric acid (PCA) with 3,4 dihydroxybenzyl-amine (DHBA) at 1000 ng DHBA/ml and homoserine (500 mg/ml) as internal standards. Tissue samples in
aqueous PCA were placed in ice and sonicated for
approximately 4–8 s using a Branson 450 digital sonifier
(Danbury, CT). The homogenized sample was then centrifuged for 10 min at 10,000g (12,000 rpm) at 48C. Sample
supernatants were diluted as needed prior to analysis. Tissue
monoamine concentrations were determined by using
reverse-phase high-pressure liquid chromatography with
electrochemical detection (HPLC-EC). An HPLC-EC system consisting of a Waters 717Plus refrigerated autosampler
(Waters Corporation, Milford, MA), ESA 580 HPLC pump
(ESA Biosciences, Inc., Chelmsford, MA), SSI pulse dampener, ESA model 5020 guard cell, and ESA Coulochem II
Model 5200A electrochemical detector equipped with an
ESA analytical electrochemical cell Model 5011 was used.
The HPLC was equipped with a Supelco Discovery C18
analytical column (10 cm 4.6 mm, 5 mm) and a Supelguard
Discovery C18 guard column (2 cm 4.0 mm, 5 mm). The
mobile phase was 7 mM phosphate buffer and 11% methanol
at pH 3.0. Chromatograms were analyzed using EZChrom
Elite for the ESA Chromatography Data System. Representative standard curves were developed for each monoamine
of interest using commercially available high-purity standards purchased from Sigma–Aldrich or a similar vendor.
g-Aminobutyric acid (GABA) and glutamic acid concentrations were determined by using reverse-phase HPLCEC with pre-column derivatization of the amino acids
with o-phthaldialdehyde (OPA) and 2-mercaptoethanol
(b-ME) prior to detection using procedures described in
ESA Application Note 70-0160 (http://www.esainc.com/
applications/application_notes.htm#GABA). An HPLC-EC
system consisting of an ESA Model 540 refrigerated autosampler, ESA 580 HPLC pump, SSI pulse dampener, and
ESA CoulArray Model 5600 electrochemical detector and
thermal chamber equipped with twin ESA analytical electrochemical cells (Model 6210) was used. The HPLC was
equipped with a Waters Xterra MS C18 2.5 mm (3.0 mm 5.0 mm) HPLC column. The mobile phase was 20% methanol
and 3.5% acetonitrile in 100 mM sodium phosphate dibasic
buffer at pH 6.7. Chromatograms were analyzed using ESA
4
Struve et al.
CoulArray Chromatography Data Software System. Representative standard curves were developed using commercially
available high-purity standards purchased from Sigma–Aldrich.
controls) in mean caudate manganese concentration was
observed following subchronic exposure to MnSO4 at
0.3 mg Mn/m3. Treatment-related clinical signs were not
observed.
Data analysis and statistics
Brain Neurotransmitter Concentrations
The data for quantitative, continuous variables were
compared for the exposure and control groups by tests for
homogeneity of variance (Levene’s test), analysis of variance
(ANOVA), and Dunnett’s multiple comparison procedure for
significant ANOVA. In the event the Levene’s test was
significant, then the data were transformed using a natural log
(ln) transformation. If the Levene’s test remained significant
then the data were analyzed by nonparametric statistics
(Wilcoxon/Kruskal–Wallis). Statistical analyses were performed using JMP Statistical Software (SAS Institute, Inc.,
Cary, NC). A probability value of <0.01 was used for
Levene’s test, while unless otherwise noted, <0.05 was used
as the critical level of significance for all other statistical
tests. Unless otherwise noted, data presented are mean
values standard error of the mean (SEM).
Putamen, caudate, and globus pallidus glutamate and
GABA concentrations following the end of the 13-week
exposure are presented in Table I. A statistically significant
decrease (vs. controls) in pallidal GABA concentration, at
P < 0.1, was observed in monkeys exposed to MnSO4 at
1.5 mg Mn/m3. Putamen, caudate, and globus pallidus
monoamine neurotransmitter concentrations following the
end of the 13-week exposure are presented in Table II.
Statistically significant decreases (vs. controls) in pallidal
5-HIAA concentration and caudate norepinephrine concentration, at P < 0.1, were observed in monkeys exposed to
MnSO4 at 1.5 mg Mn/m3. Putamen neurotransmitter
concentrations were unaffected by MnSO4 exposure.
DISCUSSION
RESULTS
Brain Manganese Concentrations
The results of these analyses have been previously
published [Dorman et al., 2006a] and are presented in Table I.
As reported, a statistically significant increase (vs. controls)
in mean pallidal and putamen manganese concentration was
observed following subchronic exposure to MnSO4 at
0.06 mg Mn/m3. A statistically significant increase (vs.
Manganese poisoning in humans and other primates
produces neuropathological changes in the basal ganglia,
especially in the internal segment of the globus pallidus,
caudate, and putamen [Yamada et al., 1986; Eriksson et al.,
1987, 1992a,b]. In humans, these lesions are localized preand post-synaptically to the dopaminergic nigrostriatal
pathway and are associated with the resultant development
of dystonia [Barbeau, 1984]. This observation has led to
several hypotheses concerning the mode of action of
TABLE I. Mean (SEM) Regional Brain Manganese (mg Mn/g Tissue Wet Weight), and GABA and Glutamate Levels (mg/g Tissue Wet Weight) in Monkeys
Exposed to MnSO4 by Inhalation for 6 hr/day, 5 days/week, for13 weeks (65 Exposure Days)
Endpoint
Manganese
GABA
Glutamate
MnSO4 exposure concentration
(mg/m3)
Putamen
Caudate
Globus pallidus
0
0.06
0.3
1.5
0
0.06
0.3
1.5
0
0.06
0.3
1.5
0.36 0.01
0.58 0.04*
0.75 0.05*
1.81 0.14 *
257 18
228 10
242 19
223 10
951 80
986 19
967 62
998 10
0.34 0.02
0.47 0.04
0.69 0.03*
1.72 0.10*
249 23
227 20
222 26
201 14
1181 48
1172 23
1143 55
1214 25
0.48 0.04
0.80 0.04*
1.28 0.15 *
2.94 0.23 *
619 46
587 64
681 31
415 98{
434 89
375 73
306 10
450 134
Group sizes were 6, 6, 4, and 4 for the 0, 0.06, 0.3, and 1.5 mg Mn/m3 exposure groups, respectively.
*Significantly different from control, P < 0.05.
{
Significantly different from control, P < 0.1.
Neurotransmitters in Manganese-Exposed Monkeys
5
TABLE II. Mean (SEM) Regional Brain Catecholamine Levels (mg/gTissue Wet Weight) in Monkeys Exposed to MnSO4 by Inhalation for 6 hr/day, 5 days/
week, for13 weeks (65 Exposure Days)
Transmitter (mg/g)
Dopamine
DOPAC
5-HIAA
5-HT
HVA
Norepinephrine
MnSO4 exposure concentration
(mg/m3)
Putamen
Caudate
Globus pallidus
0
0.06
0.3
1.5
0
0.06
0.3
1.5
0
0.06
0.3
1.5
0
0.06
0.3
1.5
0
0.06
0.3
1.5
0
0.06
0.3
1.5
56.46 4.51
63.56 1.92
64.37 3.24
63.80 0.76
1.96 0.45
1.85 0.30
1.71 0.30
1.54 0.13
1.06 0.10
0.85 0.07
1.01 0.17
0.70 0.13
0.27 0.04
0.27 0.02
0.29 0.08
0.29 0.04
93.8 6.4
81.6 4.0
93.7 8.7
83.8 8.4
1.42 0.09
1.47 0.08
1.45 0.03
1.53 0.12
64.72 4.31
61.48 4.25
61.49 4.10
64.82 2.39
2.19 0.36
1.89 0.17
2.22 0.37
1.63 0.09
0.59 0.06
0.49 0.06
0.82 0.13
0.39 0.02
0.52 0.10
0.38 0.07
0.45 0.09
0.49 0.15
63.0 8.5
61.6 6.9
68.0 11.0
63.6 9.0
0.88 0.04
0.73 0.08
0.92 0.10
0.65 0.05{
2.10 0.94
0.71 0.17
1.07 0.18
1.02 0.44
0.36 0.16
0.20 0.03
0.33 0.08
0.16 0.05
2.07 0.21
2.00 0.18
2.28 0.10
1.46 0.11{
0.56 0.07
0.55 0.11
0.80 0.11
0.50 0.12
68.2 7.6
53.2 8.5
56.5 4.4
49.1 13.7
0.56 0.16
0.58 0.17
0.77 0.26
0.59 0.22
Group sizes were 6, 6, 4, and 4 for the 0, 0.06, 0.3, and 1.5 mg Mn/m3 exposure groups, respectively.
{
Significantly different from control, P < 0.1.
manganese. One hypothesis focuses on manganese-induced
dopamine oxidation resulting in generation of reactive
oxygen species, oxidative stress, and secondary cytotoxicity
to dopaminergic neurons [Graham, 1984; Archibald and
Tyree, 1987; Simonian and Coyle, 1996; Hussain et al.,
1997]. Numerous studies conducted in rodents provide at
least partial support for this hypothesis. Rodent studies have
demonstrated that depletion of striatal dopamine and loss of
nigro-striatal dopaminergic neurons occur following highdose manganese exposure [Chandra et al., 1978; Gianutsos
and Murray, 1982; Komura and Sakamoto, 1991; Bonilla
et al., 1994; Pappas et al., 1997]. Studies conducted in
nonhuman primates result in similar findings. For example,
Eriksson and coworkers [Eriksson et al., 1987, 1992a]
reported reduced striatal and pallidal levels of dopamine and
DOPAC, but not homovanillic acid concentrations, and
reduced dopamine uptake sites and D1 receptors in monkeys
exposed to manganese oxide subcutaneously. In our study
however, we did not observe any statistically significant
changes in either dopamine or DOPAC levels in the MnSO4exposed monkeys. We did however observe marginally
statistically significant decreases (vs. controls, P < 0.1) in
pallidal 5-HIAA concentration and caudate norepinephrine
concentration in monkeys exposed to MnSO4 at 1.5 mg Mn/
m3. The toxicological significance of this observation is
unclear.
While research has focused on manganese-induced
effects on the dopaminergic system, there is evidence that
high brain manganese concentrations may also disrupt the
regulation of the GABA-ergic neurons [reviewed in Gwiazda
et al., 2002; Fitsanakis et al., 2006a]. Tomas-Camardiel et al.
[2002] have shown that high-dose manganese exposure can
decrease the levels of glutamic acid decarboxylase levels, an
enzyme involved in GABA synthesis regulation. This
observation has prompted the suggestion that manganese
neurotoxicity progresses with increasing cumulative dose,
whereby striatal GABA levels are adversely affected before
changes in dopamine levels occur [Fitsanakis et al., 2006a].
Our results are consistent with this hypothesis because a
marginally statistically significant decrease (vs. controls,
P < 0.1) in pallidal GABA concentration was observed in
monkeys exposed to MnSO4 at 1.5 mg Mn/m3. Glutamate
6
Struve et al.
regulation also appears to be affected by increased brain
manganese levels [reviewed in Fitsanakis et al., 2006a].
Interestingly, we did not observe any significant changes in
basal ganglial glutamate levels in our monkeys. Additional
work is currently underway to evaluate glutamine synthetase
levels in these samples.
The form of manganese used in this study (MnSO4) is
more soluble than the oxide forms present in most workplaces. Increased manganese particle solubility enhances
brain manganese delivery [Dorman et al., 2001]. In the
present study we observed manganese accumulation within
the globus pallidus, putamen, and caudate nucleus following
exposure to the lowest MnSO4 exposure concentration
(0.06 mg Mn/m3) used in this study. A greater than three
to fivefold increase (vs. air-exposed controls) in mean tissue
manganese concentration was observed in the globus
pallidus, putamen, and caudate of monkeys exposed
subchronically (65 exposure days) to MnSO4 at the highest
exposure concentration (1.5 mg Mn/m3). Our results
demonstrating manganese accumulation are consistent with
previous nonhuman primate inhalation studies [Coulston and
Griffin, 1977; Bird et al., 1984]. Moreover, brain MRI
hyperintensities seen in our MnSO4-exposed monkeys
[Dorman et al., 2006a] mimic those seen in heavily exposed
people [Fitsanakis et al., 2006b]. Thus, our exposure
conditions were sufficient to raise brain manganese concentrations to levels seen during manganese neurotoxicity.
Overall, subchronic high-dose MnSO4 inhalation in
rhesus monkeys was associated with relatively few changes
in basal ganglial neurotransmitter concentrations. This lack
of response may in part reflect the small sample size used,
however, our reanalysis of our data using a less stringent
significance level (P < 0.1) helps compensate for our
experimental design. This less stringent analysis identified
neurotransmitter changes in monkeys exposed to MnSO4 at
1.5 mg Mn/m3. Interestingly, however, we did not see any
change in brain neurotransmitter concentrations in monkeys
exposed to lower MnSO4 exposure concentrations (i.e.
<1 mg Mn/m3) despite the presence of elevated brain
manganese concentrations in these animals. Occupational
manganese neurotoxicity often requires prolonged exposure
and clinical manifestations may be delayed for up to
several years [Roels et al., 1987, 1992; Lucchini et al.,
1997, 1999; Martin, 2006]; thus results seen following
subchronic exposure may not reflect these more chronic
exposure scenarios. Our study provides additional evidence
that changes in basal ganglial neurotransmitter concentrations do not occur rapidly following subchronic manganese
inhalation at the current TLV.
Centers for Health Research staff for their contributions. We
also thank Dr. Eva Polston for her critical review of this
manuscript. This publication is based on a study sponsored
and funded by the Afton Chemical Corporation in satisfaction of registration requirements arising under Section 211(a)
and (b) of the Clean Air Act and corresponding regulations at
40 C. F. R. Subsections 79.50 et seq. These results were
presented at the International Workshop on Neurotoxic
Metals: Lead, Mercury, and Manganese from Research to
Prevention in Brescia, Italy on June 17–18, 2006.
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ACKNOWLEDGMENTS
Dorman DC, McManus BE, Parkinson CU, Manuel CA, James RA,
Struve MF, McElveen AM, Everitt JI. 2004. Nasal toxicity of
manganese sulfate and manganese phosphate in young male rats
following subchronic (13-week) inhalation exposure. Inhal Toxicol
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The authors would like to thank Paul Ross, Elizabeth
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