From Manganism to Manganese-Induced Parkinsonism:
A Conceptual Model Based on the Evolution of Exposure
Roberto G. Lucchini•Christopher J. Martin•
Brent C. Doney
Received: 2 October 2009/Accepted: 19 November 2009/Published online: 10 December 2009
? US Government 2009
Parkinson’s disease. Manganese exposure scenarios in the
last century generally have changed from the acute, high-
level exposure conditions responsible for the occurrence of
manganism to chronic exposure to much lower levels. Such
chronic exposures may progressively extend the site of
manganese deposition and toxicity from the globus pallidus
to the entire area of the basal ganglia, including the sub-
stantia nigra pars compacta involved in Parkinson’s dis-
ease. The mechanisms of manganese neurotoxicity from
chronic exposure to very low levels are not well under-
stood, but promising information is based on the concept of
susceptibility that may place individuals exposed to man-
ganese at a higher risk for developing Parkinsonian dis-
turbances. These conditions include mutations of genes
which play important pathogenetic roles in both Parkin-
sonism and in the regulation of manganese transport and
metabolism. Liver function is also important in manganese-
related neurotoxicity and sub-clinical impairment may
increase the risk of Parkinsonism. The purpose and scope
Manganism is a distinct medical condition from
of this report are to explore the literature concerning
manganese exposure and potential subclinical effects and
biological pathways, impairment, and development of
diseases such as Parkinsonism and manganism. Inhalation
and ingestion of manganese will be the focus of this report.
Parkinsonian disorders ? Occupational exposure ?
Manganism ? Manganese poisoning ?
Cases of manganese intoxication have occurred worldwide
for almost two centuries, causing a severe, debilitating
referred to as manganism. Manganese is an essential ele-
ment; in humans, homeostatic mechanisms are present to
constantly adjust absorption and excretion rates in order to
maintain the physiological ranges and avoid both defi-
ciency and intoxication (Roth 2006). Although manganism,
which typically follows acute, high-level exposure, is the
most obvious clinical manifestation of manganese neuro-
toxicity, subclinical and sub-functional declines in neuro-
psychological tests, mainly related to motor coordination of
fine movements, have been documented in the context of
lower level exposure. Chronic lifetime exposure to very
low levels is currently hypothesized as a possible risk
factor for the onset of Parkinson’s disease. These three
manifestations may be associated with a continuum of
dysfunction (Martin 2006).
The purpose and scope of this review article are to
explore the literature concerning manganese exposure and
potential subclinical effects and biological pathways,
of diseases suchas
R. G. Lucchini
Department of Experimental and Applied Medicine,
Section of Occupational Health and Industrial Hygiene,
University of Brescia, Brescia, Italy
C. J. Martin
Institute of Occupational and Environmental Health,
West Virginia University School of Medicine,
Morgantown, WV, USA
B. C. Doney (&)
Centers for Disease Control and Prevention,
National Institute for Occupational Safety and Health,
Morgantown, WV 26505, USA
Neuromol Med (2009) 11:311–321
Parkinson’s disease and manganism. Inhalation and
ingestion of manganese will be the focus of this report.
The Classical Features of ‘‘Manganism’’
James Couper (1837) is credited with the first clear
description of the adverse neurological effects of manga-
nese in five Scottish men employed grinding manganese
dioxide ore in 1837. At that time, the industrial use of
manganese was limited, and in Couper’s case series, the
application was to generate ‘bleaching powder.’ Several of
Couper’s observations deserve mention. The most promi-
nent and earliest symptom was described as paraplegia,
with the lower extremities being markedly more affected
than upper extremities. As a result, ‘‘the patient staggers,
and inclines to run forward when he attempts to walk.’’
Facial expression was vacant, with drooling and difficulty
speaking. Couper remarked specifically on the absence of
any tremor, any deficiency of intellect or any abnormalities
in sensation. The first two cases, for whom exposure was
more prolonged, failed to improve even 1 and 7 years
following cessation of exposure. The latter three cases,
removed promptly from exposure when staggering was
noted, were described as having fully recovered.
Although not referenced by Couper, his report was only
20 years after James Parkinson’s seminal description of the
‘‘shaking palsy’’ (Parkinson 2002). However, many other
movement disorders clearly unrelated to manganese were
also described at this time, such as Wilson’s Disease in
1883 and Huntington’s Chorea in 1842 (Harper 2002;
Several decades after Couper’s first description, manga-
nese began to be used much morewidely in what remains by
far its most common application, as a metal essential to the
manufacture of steel alloy. In 1901, Von Jaksch (1909)
described a case with very similar symptoms, with the
exception of a marked tremor in the right hand. He is also
credited with coining the term ‘cock-walk’ for the peculiar
gait now closely associated with manganism. However, he
was initially unaware of Couper’s earlier work, and even
though occupational manganese exposure was documented,
definitive review of clinical, toxicological, and epidemio-
logical evidence available to date was published which not
only clearly and unequivocally implicated manganese as the
cause of this neurological disease, but also proposed diag-
nostic criteria (Edsall et al. 1919).
Later, psychiatric symptoms were described, termed
locura manganica or ‘manganese madness’ (Cotzias 1958).
Rodier (1955) described three clinical phases in an exten-
sive study of 115 cases among underground miners. A
prodromal phase was considered to consist largely of
subjective symptoms of general asthenia, anorexia and
apathy. There was an initial mental and sexual excitement
followed closely by impotence, which was considered the
most common symptom in this phase. Patients were
aggressive and deranged. Gait could be staggered in this
phase and speech slowed. The intermediate phase was
characterized by objective neurological symptoms with the
earliest symptom being disorders of speech consisting of
dysarthria, stuttering and eventual muteness. A loss of
facial expression was termed the ‘‘masque manganique.’’
Movements became clumsy and subjects exhibited labile
moods. A propensity to fall backwards was noted. In the
established phase, both subjective and objective symptoms
and signs progressed and there were obvious gait abnor-
malities with the cock-walk present in all cases. Tremor,
hypertonicity, and weakness were present. Dystonia of the
feet and hands as well as one case of torticollis were
described. Psychiatric symptoms were present in all stages.
Since these first works, a large number of additional
case reports and series of an extrapyramidal syndrome now
termed manganism have been described, with an estimated
400 published cumulative cases by 1973 (Smyth et al.
1973). Among the most closely studied cohorts are smelter
workers in Taiwan (Wang et al. 1989) and miners in Chile
(Schuler et al. 1957). Manganism has now been described
or suspected in a great variety of settings, both occupa-
tional and non-occupational, a spectrum summarized in
Table 1. The exposure absorption routes by the stages of
development are illustrated. Inhalational occupational
exposure is an important absorption route in adulthood.
Most frequently (as in Couper’s report), the exposures
exposure to the dust or fumes of manganese dioxide ores.
Some of these reports must be read critically. In some
instances, patients were exposed to several neurotoxic
agents. External measurements are generally unavailable
and therefore the level of exposure to manganese is not
complex and poorly understood relationship to external
levels (Smith et al. 2007). Unlike other neurotoxic metals,
Therefore, homeostatic mechanisms exist which regulate
levels within a narrow range and preclude a direct inference
between external exposure and levels within the body. Most
recently, the blood manganese–iron ratio has been reported
to more closely correlate with airborne manganese levels
may substantially influence this biomarker and diminish its
A second tool used to establish manganese overexposure
is the MRI, with the characteristic finding being a markedly
increased signal intensity on T1-weighted images of the
312 Neuromol Med (2009) 11:311–321
globus pallidus and midbrain. However, even though
clinical symptoms of manganism persist or progress, these
imaging findings normalize approximately 6 months after
cessation of exposure (Nelson et al. 1993). Moreover, MRI
findings appear to be non-specific with respect to clinical
manganism, being present in over 73% of active, yet
asymptomatic, welders in a Korean study (Kim et al.
1999a). The same MRI findings have also been observed in
the absence of clinical manganism in patients undergoing
hemodialysis (da Silva et al. 2007) and after surgery to
correct biliary atresia (Agarwal et al. 2008). Nevertheless,
with these caveats in mind, several themes emerge.
Firstly, there is striking variability in the clinical pre-
sentation of manganism. The onset of symptoms from the
time of exposure can vary from only a few months to over a
decade within the same occupational cohort. Psychiatric
symptoms are variably described, in some reports (such as
those of Couper) they are not mentioned at all, whereas in
later descriptions, they are prominent and early features.
When present, psychiatric and neurological components
are present in all phases of disease, with psychiatric
symptoms dominating in earlier and neurological symp-
toms in later stages.
Secondly, although symptoms may overlap, manganism
is a distinct entity from Parkinson’s disease at many levels
(Calne et al. 1994). Shared features include generalized
rigidity and bradykinesia. However, unlike the festinating
gait in Parkinson’s disease, the gait abnormality of man-
ganism is a cock-walk with an associated foot dystonia,
such that patients walk on the balls of the feet with the
heels elevated above the ground. Dystonia has also been
documented in other locations, unlike Parkinson’s disease.
In manganism, tremor is less prominent, postural, of higher
frequency and lower amplitude. Manganism patients are
more prone to fall backward.
Thirdly, the differences extend beyond signs and symp-
toms. Manganism patients do not show a sustained response
to dopamine replacement and functional imaging studies
using fluorodopa-labeled positron emission tomography
(PET) scans fail to show the pattern of reduced striatal
uptake which is uniformly present in Parkinson’s disease. In
primate studies of overexposure to manganese, the disease
resembles manganism, not Parkinson’s disease (Shinotoh
et al. 1995). On the rare occasions when tissue was available
from humans, pathological findings are also discordant
(Yamada et al. 1986).
Fourthly, based on a small series of four cases from the
Taiwanese cohort, the condition has been noted to pro-
gressively deteriorate for 10 years following removal from
exposure, followed by a plateau in the second decade
(Huang et al. 2007).
From Historical High Manganese Levels to Lifetime
Exposure: An Alternative Situation
From the time of Couper’s report, changes in exposure
have taken place all over the world although differences
persist between individual countries and among the
developed and the developing regions. From high expo-
sures for relatively short periods of time (mainly confined
to the workplace), exposure to hazardous substances like
manganese has progressively extended to the general
environment outside the workplace, although at much
lower levels. In occupational settings, airborne concentra-
tions of manganese in inhalable particles were easily above
a full-shift time-weighted average of 1 mg/m3, considered
as the minimum level able to cause manganism in sus-
ceptible individuals (WHO 1981). Today, the exposure
levels are generally around a time-weighted average value
of 200 lg/m3adopted by ACGIH?(2009) in most ferro-
alloy and mining operations (IEH/IOM 2004). In the gen-
eral environment, outdoor manganese concentrations are
approximately 40 ng/m3in urban areas (EPA 2003) but can
Table 1 Spectrum of case reports of manganism by exposure source and route
Exposure sourceRoute of exposureReference
Manganese fumes in a smelter with malfunctioning ventilation Inhalational Wang et al. (1989)
Dust of fungicide maneb (manganese ethylene-bis-dithiocarbamate) Inhalational Meco et al. (1994)
Welding in confined space without respiratory protection Inhalational Kenangil et al. (2006)
Potassium permanganate (KMnO4) used in manufacture
of the recreational drug methcathinone
Intravenous Stepens et al. (2008)
Increased dietary manganese absorption from sideropenia
secondary to polcythemia vera
Gastrointestinal Pratesi et al. (2008)
Excess manganese supplementation in patients receiving
long-term total parenteral nutrition
Gastrointestinal Fell et al. (1996)
Chronic liver failure Impaired clearanceKlos et al. (2005)
Manganese powder in a worker with hepatic dysfunction
from hepatitis C infection
Both inhalational and impaired clearance Schaumburg et al. (2006)
Neuromol Med (2009) 11:311–321 313
reach 300 ng/m3in the vicinity of sources such as ferro-
alloy facilities, coke ovens, and power plants (WHO 2004).
Concern has also been raised regarding the content of
manganese in drinking water and the associated neurobe-
havioral impairment in children (Wasserman et al. 2006;
Wright et al. 2006; Bouchard et al. 2007). Manganese
concentrations in Swedish groundwater used for drinking
water are on average 150 ± 510 lg/l, with maximum val-
ues as high as 30,000 lg/l. Around 20% of the 12,000
sampled wells had manganese concentrations exceeding the
Swedish recommended guideline value of 300 lg/l (Ljung
and Vahter 2007). In urban areas of the United States, the
median groundwater concentration of manganese was
found to be 150 lg/l, with the 99th percentile at 5600 lg/l.
In public water systems supplied by groundwater, approx-
imately 3% of the 982 sampled sources exceed the U.S.
health reference level of 300 lg/l (EPA 2003).
In addition to exposure intensity, health effects also
depend on lifetime exposure duration, which is constantly
increasing both due to increases in life expectancy and the
proportion of life spent working. In addition, health effects
depend upon exposure timing, the period of life when
exposure occurs, especially when the nervous system is the
target organ of toxicity (Grandjean and Landrigan 2006).
The brain needs manganese during the early phases of
development, as a constituent of important metalloenzymes
such as arginase, glutamine synthetase, pyruvate carbox-
ylase, and superoxide dismutase. Manganese exposure can
start before birth from the maternal exposure through
inhalation and ingestion of food items that may contain
higher manganese concentration from environmental pol-
lution. Therefore, excessive concentration of manganese
may cause an overload that is potentially harmful for the
fetus (Zota et al. 2009). Post-natal exposure can also be
relevant due to a relatively high concentration of manga-
nese in formulas (Aschner and Aschner 2005), with one
small primate study reporting an association with differ-
ences in neurobehavioral outcomes (Golub et al. 2005). In
order to provide manganese to the developing brain, the
intestinal absorption of this element is high (Do ¨rner et al.
1989), whereas the excretion rate is low due to the
incomplete development of the biliary pathway, responsi-
ble for manganese elimination (Lo ¨nnerdal 1994). However,
reassuring results were found in a recent study of 408
women living in an area of Bangladesh with elevated
manganese in drinking water, urine, and blood, since cor-
responding elevations in breast milk were not observed
(Ljung et al. 2009). According to the authors, elevated
maternal manganese exposure does not necessarily lead to
excessive exposure of breast-fed infants, stressing the
importance of breast feeding in high manganese areas.
Manganese exposure can continue during childhood and
adulthood from both environmental and occupational
exposure. According to each life stage, different absorption
routes and different potentials for increased exposure may
occur, consistently during an entire lifetime or during
discreet periods, leading to a final total body burden that
may result in neurotoxicity. The concept of lifetime
exposure is an important toxicological aspect to be con-
sidered for substances like manganese, which are charac-
terized by a cumulative mechanism of action (Lucchini and
Zimmerman 2009). Cumulative exposure can result in
delayed, long-term toxicity.
According to the principle of ‘‘fetal programming’’ of
the brain (Grandjean et al. 2007), prenatal exposure may be
of concern for late-onset neurodegenerative effects. The
occurrence of delayed effects can be explained by the
different mechanisms of transport across the blood–brain
barrier. A carrier-mediated brain influx and a diffusion-
mediated efflux cause manganese overload in the brain
with prolonged excessive exposure and prolonged very
low-level exposure (Yokel, this issue).
Cumulative toxicity may also derive from contemporary
exposure to multiple agents, a common scenario when
manganese exposure may occur together with other known
neurotoxicants such as pesticides and lead. According to
the ‘‘multi-hit’’ hypothesis, the brain may compensate less
efficiently when exposed to multiple neurotoxicants, lead-
ing to sustained and cumulative damage (Cory-Slechta
Taken together, this change in exposure scenario from
occupational settings to the general environment represents
an important background
approaching the relationship between current manganese
exposure and the subsequent neurotoxic effects. Currently,
overt, clinical manganism is a very rare event (Verschoor
and Verschoor 2009; Konstantinova et al. 2009), while low-
level prolonged manganese exposure remains of concern.
Studies of toxicity implicating manganese should be inter-
preted with these considerations in mind. This is particu-
larly related to inhaled manganese that can be transported
directly to the brain through nasal deposition and transport
along olfactory neurons (Dorman et al. 2002; Thompson
et al. 2007), especially when transported by ultrafine par-
ticles, such as welding fumes (Elder et al. 2006). Changes in
olfactory threshold and odor identification have been shown
in manganese exposed workers (Antunes et al. 2007; Luc-
chini et al. 1997) and the same tests are recognized as
predictive of Parkinson disease (Ponsen et al. 2009).
tobe considered when
From Manganism to Manganese-Induced
Parkinsonism: The Case of Welders
Manganese deposition takes place in the basal ganglia and
the globus pallidus of the brain because of a selective
314 Neuromol Med (2009) 11:311–321
affinity for such neuromelanin-rich areas (Verity 1999).
The deposition is facilitated by the Dopamine Transporter
(DAT) (Anderson et al. 2007) and other manganese
transporters such as the divalent metal transporter DMT-1
(Roth, this issue), and/or store-operated calcium channels
(Yokel, this issue).
This small area is functionally responsible for the con-
trol of fine movements and mood state (Newland and
Weiss 1992) and thus explains the neuropsychiatric fea-
tures of classical manganism. The globus pallidus can be
considered as the critical target organ for manganese
according to a toxicological definition, meaning the site
that reaches a critical dose and therefore a critical adverse
effect, earlier than any other target organ (IUPAC 1993).
Manganism occurs when the inhaled airborne concentra-
tion exceeds a threshold, corresponding to at least 1 mg/m3
of manganese. The duration of exposure required to result
in the critical dose to the globus pallidus is not clear and
likely varies among individuals (WHO 1981).
As previously noted, the latency from the time of
exposure to manganese to first clinical effects can vary
from a few months to a decade. Therefore, although the
concentration and duration of exposure to manganese are
important, individual variability in susceptibility is also
relevant. In the context of manganism, other areas of the
basal ganglia such as the substantia nigra pars compacta,
known to be affected in Parkinson’s disease, are generally
spared as shown by the post-mortem studies (Perl and
Concern about the potential for an additional manifes-
tation of manganese neurotoxicity other than classical
manganism was first raised by a study reporting that among
953 newly diagnosed cases of Parkinson’s disease, the age
at diagnosis was 17 years earlier in 15 career welders than
non-welders (Racette et al. 2001). All other clinical fea-
tures, such as a response to dopamine replacement, were the
same between the two groups. Fluorodopa PET scans were
available for two of the affected welders and were reported
to show the abnormalities typical of Parkinson’s disease.
These findings extend beyond the concept of manganism as
a condition distinct from Parkinson’s disease.
Since then, several additional studies, both positive and
negative with respect to an association between occupation
as a welder and a risk for Parkinson’s disease, have been
published. One of the largest recent studies of mortality
data on over 4 million men included 49,174 deaths attrib-
uted to Parkinson’s disease (Stampfer 2009). Death cer-
tificates were abstracted and no information about
exposure, types of welding or materials, respirator use, or
engineering controls were available. No association with
employment as a welder was seen nor was death as a result
of Parkinson’s disease observed more frequently in
younger male welders. Nevertheless, this study has been
criticized for using an insensitive diagnosis for Parkinson’s
disease, which may be too restrictive for manganese-rela-
ted Parkinsonism. Other negative studies have been criti-
cized for being based on hospitalization, which is not a
common situation for Parkinsonian patients. Therefore, this
topic remains controversial, also because of the ‘‘healthy
worker effect’’ that may well reduce the incidence of
neurodegenerative diseases in the active workforce.
In a recent review, given the strong likelihood that
genetic background alters manganese pharmacokinetics
and pharmacodynamics and an individual’s response to
manganese exposure, the incorporation of genetic suscep-
tibility into the risk assessment for inhaled manganese has
been recommended to resolve these opposing viewpoints
(Curran et al. 2008). Regardless of the uncertainties, the
issue of manganese-related Parkinsonism among welders
has been important to raise the hypothesis that manganese
neurotoxicity may not be limited only to the globus palli-
dus and the nigro-striatal area.
Parkinsonism in Populations Environmentally Exposed
More recently, the hypothesis of an increased risk of Par-
kinsonian disturbances pointed out by manganese occupa-
tional studies (Gorell et al. 1999; Racette et al. 2001; Kim
et al. 2002; Racette et al. 2005) has prompted new epide-
miological research in environmentally exposed popula-
tions. A study was conducted in 1996 in the community of
Sauda, Norway, where the world’s largest ferroalloy plant
was active until 1923. A total number of 15 Parkinson’s
cases were observed among 5,294 inhabitants, equivalent
to a crude prevalence rate of 245.6/100,000 (Øygard et al.
1992), which is higher than the average rates of Scandi-
navian countries, where a crude rate of 25/100,000 was
recently reported by Alves et al. (2009).
An epidemiological study investigated the risk of Par-
kinsonian disorders in the population of Toronto and
Hamilton, Ontario, in relation with industrial emissions of
manganese and the use of the organometallic compound
formed from manganese, methylcyclopentadienyl manga-
nese tricarbonyl (MMT) as fuel additive. Data sources were
represented by physicians’ diagnoses registered in the
Ministry of Health administrative databases, 1992–1999,
and prescriptions for L-Dopa containing medication. Sub-
jects were mapped to residence and homes were assessed in
relationship to distance from traffic, markers of traffic-
generated air pollution and neighborhood levels of ambient
manganese. Results have pointed out that in Hamilton, the
odds ratio for a physician’s diagnosis was 1.034 (1.00–
1.07) per 0.01 mg/m3increase in manganese in total sus-
pended particles. The estimate of ‘‘doubling exposure’’ for
Neuromol Med (2009) 11:311–321 315
a physician’s diagnosis was about 0.15 mg/m3manganese
in the ambient air. According to the authors, this study is
consistent with the theory that exposure to manganese may
add to the natural loss of neurons attributable to the aging
process (Finkelstein and Jerrett 2007).
A third epidemiological observation was based on a
study in the Italian province of Brescia, where the crude
prevalence of Parkinsonism among the 903,997 residents
was 296/100,000 and 407/100,000 when adjusted by age
and gender (Lucchini et al. 2007a). The frequency
increased to a standardized rate of 492/100,000 among the
residents in the vicinity of ferroalloy plants located in
Valcamonica, a pre-Alps valley in the North of the prov-
ince, whereas the plant in the South part of the province
had an open geographical setting. The data were also sig-
nificantly higher compared to both the average crude Ital-
ian rate of 157.7/100,000 and the European from 108 to
257/100,000 (Von Campenhausen et al. 2005). The Stan-
dardized Morbidity Ratio calculated for Parkinsonism was
significantly associated to the level of manganese in
deposited dust sampled in the same area.
Taken together, the three community studies support the
hypothesis that lifetime exposure to low manganese levels,
starting from pre-natal to older age, may be a risk factor for
Parkinsonism. Nevertheless, these studies cannot be con-
sidered as conclusive, especially because of the lack of
genetic assessment, which may be important with possible
gene–environment interaction that could explain the
existing variability of health outcomes. Therefore, more
epidemiological observations should be provided on this
matter, considering also co-exposures to other known
neurotoxicants for extrapyramidal functions such as pesti-
cides. A number of epidemiological observations are sup-
porting the role of manganese-based fungicides like
MANEB and MANCOZEB in the onset of Parkinsonism in
rural areas and among product applicators in agriculture
(Costello et al. 2009). Unfortunately, none of these studies
has assessed the possible role of manganese, although
exposure to manganese is known to derive from the use of
these products (Canossa et al. 1993). Interestingly, genetic
variability in the DAT resulted in an interactive effect with
occupational pesticide exposure in increasing the risk of
Parkinson’s disease (Ritz et al. 2009).
Manganese Neurotoxicity at High Acute Versus
Low Chronic Exposure: What Are the Possible
Taken together, current epidemiological observation indi-
cates that manganism and manganese-related Parkinsonism
may stand as two extreme conditions at the opposite sides
of the interactions between the exposure intensity and the
exposure duration. This can be represented by a Venn
diagram (Fig. 1), where overlapping conditions are in
between the two clinical entities, and with mixed condition
observable in populations like the welders. In this context,
the idea of a Parkinsonism ‘‘coincidentally’’ superimposed
on manganese exposure (Kim et al. 1999b) would be an
The exposure levels responsible for the two conditions
of manganism and manganese-related Parkinsonism can be
substantially different. As mentioned previously, mangan-
ism can occur at manganese airborne concentration above
1 mg/m3in inhalable particles (WHO 1981), whereas
manganese-related Parkinsonism may occur after lifetime
exposure to much lower exposure levels, possibly around
100 ng/m3of manganese in respirable particles (Lucchini
et al. 2007a; Finkelstein and Jerrett 2007).
The different forms of manganese neurotoxicity likely
recognize different underlying mechanism. Several inter-
pretations have been proposed, but they are mostly derived
by experimental models based on high exposure levels,
equivalent to those able to induce manganism in humans
(Gwiazda et al. 2007), and not suitable to reproduce
chronic low levels in humans.
Several authors have pointed out that the sites involved
in manganism, i.e. the globus pallidus, and Parkinsonism,
i.e. the substantia nigra pars compacta, are closely inter-
connected with other components of the basal ganglia, such
as the caudate and putamen, nucleus accumbens and sub-
thalamic nucleus (Weiss 2006). These regions are func-
tionally joined to each other by a complex neurochemical
and anatomical network consisting of both excitatory and
inhibitory pathways (Roth, this issue) (Fig. 2). Lifetime
manganese exposure may affect both the globus pallidus
and the subtantia nigra, because of the influx process
occurring at very low doses and at relatively slow rate, and
with an even slower efflux rate (Yokel, this issue) (Fig. 2).
Fig. 1 Venn diagram showing the occurrence of manganism, man-
ganese-induced Parkinsonism, and mixed conditions as a function of
exposure intensity and exposure duration
316 Neuromol Med (2009) 11:311–321
In this way, manganese levels in the globus pallidus may
not reach the critical concentration required to cause the
critical effects of manganism, and the accumulation pro-
cess may continue, involving all the other sites in the basal
ganglia, including the substantia nigra pars compacta (Park
et al. 2007).
Nevertheless, several aspects remain unclear. Manga-
nese can cause dopamine auto-oxidation (Verity 1999), but
manganese?? is an antioxidant able to inactivate the
oxidative properties of dopamine. On the other hand,
manganese toxicity in the globus pallidus is mainly direc-
ted to the GABAergic neurons (Gwiazda et al. 2007) and
the mechanism of toxicity at the globus pallidus probably
combines several simultaneous processes including influ-
ence on the glutamate transport (Roth, this issue). Selective
injuries of the globus palidus result in a reduction of the
dopaminergic neurons in the substantia nigra, mediated by
an increased activity of the subthalamic nucleus, which is
normally under tonic inhibition by the globus pallidus
(Wright and Arbuthnott 2007). Future studies are needed to
better characterize these interactions.
Individual Susceptibility Factors
Besides the mechanisms of direct toxicity in the basal
ganglia, the importance of inter-individual variability is
quite evident in all manganese exposure conditions.
According to Roth (this issue), genetic mutations of two
genes play an important role in rendering some individuals
more at risk for Parkinsonism when chronically exposed to
manganese. The ubiquitin E3 ligase parkin, which is
associated with early onset of Parkinson’s disease (Lesage
and Brice 2009), can also protect from manganese toxicity
(Higashi et al. 2004). A genetic interaction has also been
observed between a-synuclein, an important protein for
Parkinson’s disease, and PARK9, a yeast-ortholog of the
human gene ATP13A2, which is also important for Par-
kinson’s disease. Yeast PARK9 protects the cells from
manganese toxicity (Gitler et al. 2009). Mutations in these
genes may be ultimately important for the expression of
DMT1, therefore influencing the transport of manganese.
Other genetic markers of oxidative stress, susceptibility,
and disease are suggested by Curran et al. (2008) together
with the assessment of DNA methylation arrays. Although
these techniques provide a global view of epigenetic
changes, the differences in epigenomes across tissues may
diminish the predictive power of changes observable in
Interactions between manganese and iron have been
pointed out as important for manganese absorption and
transport across biological barriers (Roth and Garrick 2003;
Roth, this issue). Anemic condition can increase the man-
ganese uptake and should be considered as a potential
cause of hypersensitivity to manganese exposure.
Another condition able to increase the risk of Parkin-
sonism in manganese-exposed individuals may be repre-
sented by sub-clinical impairment of liver function.
Manganese is almost totally excreted via the biliary sys-
tem, and therefore any impairment of this pathway is
potentially able to cause manganese overload due to
insufficient elimination from the body. This is well known
in the case of cirrhotic patients showing manganese related
abnormalities, where the ‘‘liver encephalopathy’’ may be
partially explained by the excessive manganese in the brain
(Rovira et al. 2008). Milder liver abnormalities may
become highly important under conditions of lifetime
manganese exposure. Compatible results were obtained by
a further study on a targeted group of subjects selected
from the Italian study of Valcamonica where environ-
mental exposures to manganese are higher. A group of 65
patients and 52 controls from Valcamonica and 28 patients
and 14 controls from Brescia (a region of lower manganese
exposure) were examined for clinical and biochemical
indicators and exposure biomarkers. After adjusting for
age, gender, and illness duration, the clinical examination
of the Parkinsonian patients resident in the manganese
exposed areas showed a more severe phenotypic expression
as examined at the Unified Parkinson’s Disease Rating
Scale testing, together with a more pronounced deteriora-
tion of cognitive function as expressed by the Mini Mental
State, Token and Trial Making tests examination (Lucchini
et al. 2007b).
Fig. 2 Diagram showing specific brain regions where the manganism
occurs (Mn#: Globus Pallidus) and those where the manganese-related
Parkinsonism may occur (Mn*: putamen, Globus Pallidus, Substantia
Nigra pars compacta)
Neuromol Med (2009) 11:311–321317
The Parkinsonian patients resident in the exposed area
showed also significantly higher serum levels of Cu, Cu/
Zn, and AST/ALT ratios and lower serum Zn compared to
Parkinsonian patients resident in other areas and to healthy
controls from the same area. Within the Parkinsonian
patients, Cu, Cu/Zn ratio, AST/ALT ratio, and the duration
of illness correlated with the UDPRS scores. Manganese
concentrations in blood and urine were higher among the
residents in the exposed area and manganese in blood was
associated with both AST/ALT ratio (Lucchini et al. 2008;
Squitti et al. 2009) and serum cerulopasmin (Squitti,
These observations point out a possible role played by
sub-clinical liver impairment that may render manganese
exposed individuals at higher risk for Parkinsonism. In-
balance of copper and zinc is also important in manganese
exposure and was already observed in exposed workers (Li
et al. 2004, 2005) and non-human primates (Guilarte and
Chen 2007). These metals are both important in cellular
redox reactions; therefore, a dysregulation of their
homeostasis may potentiate the cellular damage resulting
from reactive oxygen species. Ceruloplasmin was found to
influence the disposition and neurotoxicity of manganese
(Jursa and Smith 2009). Therefore, underlying impaired
liver function likely influences the neurotoxicity of man-
ganese through a number of pathways.
In conclusion, manganism is a medical condition that dif-
fers from Parkinson’s disease according to clinical, path-
ological, and imaging parameters. The dynamic changes of
exposure scenarios have led to different situations from the
acute high exposure condition that was responsible for the
occurrence of manganism to the chronic exposure to much
lower levels of manganese is not likely to cause mangan-
ism. However, chronic exposure can progressively extend
the site of deposition and toxicity from the globus pallidus
to the entire area of the basal ganglia, including the sub-
stantia nigra pars compacta that is responsible for typical
Lifetime exposure to very low levels is now a more
common condition, one that can start prenatally and may
increase the risk of Parkinsonism in more sensitive sub-
populations. This assumption is based on the cumulative
mechanism of action of manganese that may entail delayed
long-term manifestation of the clinical damage but also on
co-exposures to other known neurotoxicants for extrapy-
ramidal functions such as pesticides.
The mechanisms of manganese neurotoxicity at chronic
exposure to very low levels are not sufficiently known, but
promising information is based on the condition of
susceptibility which may render individuals exposed to
manganese at a higher risk for developing Parkinsonian
disturbances. Such conditions include genetic mutations of
genes that play important pathogenetic roles in both Par-
kinsonism and in the regulation of manganese transport and
metabolism. Liver function is also important in manganese-
related neurotoxicity and sub-clinical impairment may also
increase the risk of Parkinsonism. Future research is nee-
ded to understand the development of manganism and the
impact manganese exposure in the occupational and com-
the authors and do not necessarily represent the views of the National
Institute for Occupational Safety and Health.
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