Full text - Igitur

thunderclingΤεχνίτη Νοημοσύνη και Ρομποτική

13 Νοε 2013 (πριν από 3 χρόνια και 9 μήνες)

113 εμφανίσεις








Role of manganese in Parkinson’s disease.
Are welders at risk?














Renate Nawrocki

Utrecht University

July
, 2012


2


Abstract


Serious concerns exist among welders and occupational health investigators on the possible
association between
exposure to manganese via welding fumes and neurological effects. One
suggestion is that exposure to welding fumes is associated with the development of Parkinson’s
disease.

This report is a review of literature that focuses on issues related to welders ex
posure to
manganese and subsequent risk to develop Parkinson’s disease. Aspects of the essential element
manganese, its presence in welding processes and its transport routes to the brain are briefly
discussed. A description of the effects of manganese on
the central nerve system is presented
and the disorders related to the adverse effects of manganese are discussed. Next genetic factors
that play a role in early
-
onset Parkinson’s disease are summarized and explained and
neurological risks associated with
welding fume exposure are discussed.

The exact mechanisms of, and risks factors for, developing Parkinson’s disease are not yet fully
understood, but currently, a lot of research on most of the mechanisms involved is ongoing.
Nonetheless, sufficient eviden
ce exists pointing at an association between manganese exposure
and (the development of) Parkinson’s disease.

3


Table of Contents


Abstract












page

1. Introduction









4


2. Manganese










4

2.1 Manganese; an essential element







4

2.2 M
anganese homeostasis








4

2.3 Manganese intoxication








4


3. Manganese exposure in welding processes





5

3.1 Welding processes









5

3.2 Welding fumes; composition







6

3.3 Occupational exposure to manganese






6


4. Transport routes
for manganese







7

4.1 Gastro
-
intestinal tract








7

4.2 Respiratory tract









8

4.3 Olfactory nerve









8


5. Manganese neurotoxicity








9

5.1 Central nerve system








9

5.2 Clinical symptoms









10

5.3 Imaging techniques








10


6. Manganism, Parkinson’s disease or manganese induced parkinsonism

11


7. Genetic factors in early
-
onset Parkinson’s disease




12


8. Neurological risks associated with welding fume exposure



13


9. Concluding remark








13


Literature

4


1.

Introduction

Millions of workers worldwide are exposed to welding fumes. These welding fumes are complex
mixtures consisting of different metals, predominantly iron, and many contain a small
percentage of manganese (Mn). Most studies of health effects of
fumes in welders were focused
on the respiratory effects [Antonini, 2003]. However, for the first time in 1837, neurological
dysfunctions as adverse health effects due to acute exposure to high
-
levels of manganese were
described. The disorder from such exp
osures to m
anganese is known as manganism a disorder
of which c
linical symptoms resemble symptoms associated with Parkinson’s disease [Roth,
2009].

Parkinson’s disease (PD)
is a progressive age
-
related neurodegenerative disease,
commonly with an onset at a
ge 55. Only about5 % of PD cases are inherited, in the main cases
(also called ‘id
io
pathic’ PD) there is no genetic linkage.
Incidence of the illness increases with age
from 20/100,000 up to 120/100,000 at age 70.
Clinically, patients with PD show tremor a
t rest,
rigidity (especially of the patients’ limbs), bradykinesia (slowness of movement) and akinesia
(absence of normal voluntary movements) [Dauer, 2003].

Responsible for these symptoms is
a dopamine

(DA)

deficiency due to the
loss of
dopaminergic
neur
ons in the substantia nigra, a brain structure at the base of the forebrain

[Dauer, 2003].

Dopamine is an important neurotransmitter in the mammalian brain it controls several
functions including locomotor activity and motivation and reward [KEGG dopamine]
.

As treatment endogenous
do
p
a
mine
can be completed with dopamine precursor levodopa.
However, this medication only treats symptoms but do not halt neuron degeneration [Dauer,
2003].

Nowadays serious concern exists as to manganese can be a causing agent fo
r Parkinson’s disease
and, during the last decades much research was focused on the neurotoxic effects of manganese.

This report reviews mechanisms responsible for manganese uptake and deposition in the brain
related to neurotoxic effects, and other factor
s (e.g. genetic predisposition) that controls
manganism and Parkinsonism with focus on welders who are frequently exposed to manganese
containing welding fumes.

2. Manganese

2.1 Manganese; an essential element

Manganese is one of the elements present in
the Earth’s crust and is an essential trace element
for human health e.g. for normal brain development and function. In biological environments
manganese most commonly exists as Mn
2+,

Mn
4+

and Mn
7+
.

Within the human body manganese is required for several e
nzymatic and cellular processes. As
part of enzymatic systems it is mostly bound to proteins forming metalloproteins. Manganese is
a cofactor for glial specific glutamine synthetase, superoxide dismutase, and other enzymes. The
total amount of Mn in human
adults is approximately 10
-
20 mg, predominantly stored in bones,
tissue concentrations in most adults range between 3 and 20 µM [Roth, 2006].


2.2 Manganese homeostasis

As noted above manganese is an essential trace mineral for normal brain development and

function. Up to 80% of the total amount of manganese in the body can be found in the brain. In
humans no significant changes in brain Mn concentration is observed during the development of
the foetus or during life. This suggests an efficient homeostatic
regulation of manganese
amounts in the body.

Manganese is naturally present in food. Nuts, cereals, fruits, grains and tea contain the highest
concentrations of Mn. It is also present in drinking water at low levels ranging between 0.001 to
0.1 mg/L [Santa
maria, 2010]. The average daily intake from food ranges from 2
-
9 mg/day,
[ATSDR, 2000] approximately 1
-
5% of the ingested Mn has its uptake route via the gastro
-
intestinal tract [Santamaria, 2010].

5

At normal dietary consumption homeostasis of manganese is
maintained by a balance between
the rate of transport across the enterocytes (uptake) and the removal by the liver and
subsequent excretion via the feces. Mn balance is managed by processes controlling cellular
uptake, retention and excretion. These proces
ses are in subtle balance.

As all organisms have systems for the export of cations it is plausible that for Mn such a system
exists, it is thought that manganese transport can occur via similar mechanisms as iron
[Ouintanar, 2008].

Even although it is an e
ssential element, it will have toxic effects when
present in excess .


2.3 Manganese intoxication

Overexposure to manganese via the respiratory tract can disturb this delicate balance leading to
manganese intoxication
,

which generally is considered to be an occupational disorder. Welders,
miners and others working in
a setting

in which Mn is
released

can
be overexposed to Mn due to
elevated atmospheric levels of manganese. The metal initially enters the body via inhalat
ion of
ambient air and then can gain access to the body via three important routes ending up in the
brain. Overexposure results in elevated manganese levels in the basal ganglia. Manganism is the
condition of injury of this part of the central nervous syst
em (CNS) as a result of these higher
levels of manganese. This neurological disorder displays symptoms as reduced response speed,
irritability, mood changes and intellectual deficits in the initial stage of the injury to more
prominent and irreversible ext
rapyramidal dysfunctions resembling Parkinson’s disease at later
stages [Aschner, 2007]. However, occupationally exposed individuals are not the only ones
suffering from manganese toxicity. Under normal circumstances Mn is removed from the body
by hepatic
elimination to maintain the homeostasis and Mn toxicity is also observed in patients
with liver failure. Classical symptoms of overexposure to manganese as tremor are also seen in
patients receiving parenteral nutrition [Roth, 2006].


3. Manganese exposure

in welding processes

Evidence exists that points at manganism and even parkinsonian disorders as a consequence of
overexposure to manganese. From past evidence welders and grinders are known as
occupationally exposed to high levels of manganese and at ris
k for manganism [Couper, 1837].
However, in the light of developing manganese
-
induced parkinsonism at chronic low dose
exposure to manganese still the following questions remain:

1.

to what extent are welders exposed to manganese nowadays when welding techni
ques
and occupational settings are modernized.

2.

To which forms and states of manganese are welders exposed?

3.

And what are the exposure doses?


3.1 Welding processes

Welding is a manufacturing method to join metallic components. Essentially, all metals can
be
welded. Over 80 different types of welding processes exist. Of these, shielded manual metal arc
welding (MMAW), gas metal arc welding (GMAW, also called Metal Inert Gas MIG)(Fig. 1), flux
-
cored arc welding (FCAW) and gas tungsten arc welding (GTAW) are
most commonly used
[Antonini, 2003].



6


Figure 1. Gas Metal Arc Welding (GMAW). The electric arc heats the consumable electrode and the metal pieces to
produce the weld. The weld is protected by shielding gasses.

(Modified after Antonini, 2003)

During ele
ctric arc welding processes an electric arc is created between a consumable electrode
and the base material. Temperatures in the arc rise above 4000
o
C and heat the metal pieces and
the metal from the electron wire. This makes both base metal and weld metal

to be joined with
liquid metal from the electrode wire. Shielding gases are added to reduce oxidation that occur
during the welding processes to protect the formed weld. These gases range from the completely
inert ones (argon, helium and their mixtures) t
o so
-
called active gases, which include carbon
dioxide and other gas mixtures. The gases may have interactions with the weld or fume. During
the welding process the consumable electrode is partially volatilized. Welding fumes consist for
the major part of
materials originating from the consumable electrode. As vaporized metals
react with air, metal oxides are produced and condense to particles of respirable sizes. Thus, the
electrode coating, shielding gases and base materials also contribute to the composi
tion of the
fume [Antonini, 2003].

3.2 Welding fumes; composition

A study comparing fumes of gas metal arc welding (GMAW) with stainless steel (SS) electrodes
and mild steel (MS) electrodes generated with use of an automated welding fume generation
system,

showed that both systems produced fumes containing Fe, Mn and Cu. Most particles
were between 0.56 and 0.1 µm in mean diameter. However particles of all sizes >
-

0.01 µm
diameter were generated. Particles in mild steel fume were found to be highly water
-
i
nsoluble.
[Leonard, 2010]. Analysis with inductive coupled plasma atomic emission spectroscopy (ICP
-
AES) revealed that 6.8% of the total metal content in GMAW
-
MS fume was manganese. [Sriram,
2010]. This is consistent with findings of Keane
et al
.
who

demon
strated that the total
manganese composition ranged from 7 to 15%.

To identify manganese species in welding fumes from GMAW processes used on stainless steel,
fumes were generated in a robotic welding system using three different metal transfer methods
and

four different shield gases. Results showed that manganese was generated in soluble form
and insoluble form and that different species were generated as Mn oxide, Mn
2+
,

Mn
3+
, Mn
4+

and
multiple manganese oxides. Dominant species is the acid
-
soluble Mn
2+

compound [Keane, 2010].

3.3 Occupational exposure to manganese

Welders are a heterogeneous group of workers employed in a variety of workplace conditions
including open, well ventilated or confined, poorly ventilated spaces. The complexity of these
conditions, combined with exposure to fumes generated from different w
elding processes makes
it difficult to assess the adverse health effects.
For a welder using gas metal arc welding with
mild steel electrodes (GMAW
-
MS) the predicted estimated daily worker exposure for manganese
concentrations is calculated 0.9 mg/m3 (time

weighted average) [Sriram, 2010].

The U.S. Occupational safety and health agency (OSHA)
sets enforceable permissible exposure
limits (PELs) to protect workers against the health effects of exposure to hazardous substances.
For manganese fume and manganes
e compounds the PEL
-
TWA is 5 mg/m3 (ceiling).

7


4. Transport routes for manganese

Transport of manganese into the brain is a complex process. In short, as illustrated in figure 2,
three important routes for manganese uptake exist: 1) ingestion of manganes
e and uptake by
the gastrointestinal tract, Mn is transported across enterocytes into the blood and subsequent
transported across the blood
-
brain
-
barrier; 2) Mn transport across the pulmonary epithelial
lining followed by its deposition into blood and subs
equent transport across the blood
-
brain
-
barrier; 3) direct uptake into the central nerve system of manganese deposited in the nasal
cavity via transport along the olfactory nerves [Roth, 2006]. Most prominent mechanisms
involved in Mn uptake into the brain

via ingestion and via the pulmonary epithelial cells are
illustrated in figure 3 and described in paragraphs 4.1 Gasto
-
intestinal tract and 4.2 Respiratory
tract. The dermal uptake route will not be considered.



Figure 2. Important routes for manganese
uptake into the brain. BBB: Blood
-
Brain
-
Barrier.

4.1 Gastro
-
intestinal tract

Manganese entering the body via ingestion by diet (dietary manganese) first passes the stomach,
and then enters the duodenum where it is transported across the enterocytes. There
appears to
be a link between Fe and Mn uptake and thus it is proposed that Mn uses the same routes as Fe.
Several mechanisms are responsible for transport of iron and manganese into cells. Iron is
absorbed at the apical surface of enterocytes after iron r
eduction to Fe(II) by the ferrireductase
cytochrome b. Reduction to Fe(II) is required for uptake into the cell via the divalent metal
transporter 1 (DMT
-
1; also known as NRAMP
-
2). Passage of iron out of the enterocyte into the
interstitial space requires
ferroportin and haephaestin. The transport protein ferroportin
exports the iron across the membrane and the ferroxidase hephaestin oxidizes the iron before it
enters the circulation. Within the plasma Fe(III) is bound to transferrin (Tf). Manganese follows

a similar pathway although the enzymes involved have not been identified.

Inhaled manganese deposited on pulmonary epithelial cells can be uptaken into the circulation
via the same mechanisms [Quintanar, 2007]
.

Subsequently, manganese has to pass the blo
od
-
brain
-
barrier (BBB) to enter cells of the central
nerve system (CNS). Several mechanisms for Mn transport across the BBB have been described
[Aschner, 2007]. Most prominent processes are: transport via the divalent metal tranporter
-
1
(DMT
-
1) and transpo
rt via Tf mediated endocytosis. At the membranes of the brain cells Fe(III)
-
Tf complexes as well as Mn(III)
-
Tf complexes bind to membrane Tf receptors (TfR) and undergo
endocytosis. In the endosome the low pH and metal
-
reductases help release the Fe and Mn

from
the metal
-
TfR complexes. The released Mn(II) then enters the cytosol via DMT
-
1. Alternatively,
Mn(II) can be directly transported via DMT
-
1

into the cell’
s

cytoplasma [Aschner, 2007;
Quintanar, 2008]
.



8





Figure 3. Most prominent mechanisms respon
sible for Mn and Fe
transport

into the brain. Tf: transferrin. TfR: Tf
-
receptor. DMT
-
1: divalent metal transporter
-
1.

(Modified after Quintanar, 2008)

4.2 Respiratory tract

In occupational welding settings
,

heavy metals as Mn

are evaporated during the welding
process. Mn found in welding fumes is present in multiple oxidation states. Acid
-
soluble Mn
2+

form is most common also Mn
3+

and Mn
4+

are generated [Keane, 2010]. During evaporation
manganese forms fume particles of differ
ent size. Out of the inhaled fume particles, particles
with size >5µ mainly deposit in the upper airway and are transported up to the mouth by
mucocillary elevator clearance where it is swallowed and subsequently enters the
gastrointestinal tract from wher
e Mn follows its way to the central nervous system via the
enterocytes. Mn containing particles ranging from 0.02 to 1 µm in size are commonly deposit in
the lower airway and follow the route of uptake to the central nervous system via the pulmonary
epithe
lial lining [Roth, 2006].

4.3 Olfactory nerve

The third mentioned route for manganese uptake is transport into the central nervous system
via the olfactory nerve. Inhaled manganese deposited in the olfactory mucosa situated in the
nasal cavity can directly

enter axons of chemoreceptive olfactory cells [Dorman, 2002]. Olfactory
cells have the capacity to transport large molecules using retrograde transport along their axons.
Axons of these olfactory cells bundle together to make the olfactory nerve
that
lead
s

to the
olfactory lobe. The olfactory lobe (also known as olfactory bulb) is located in the cerebrum and it
is the control center for smell [Borm, 2006].

On its way to the olfactory bulb the nerves pass through the narrow cribriform plate pores.
There, ax
ons of olfactory neurons narrow to a diameter of approximately 200 nm and thus for
olfactory transport particles should be <200nm in size. This means that nanoparticles (NP),
which are defined as particles with diameter size 0.1 µm consistent with ultrafin
e particles
(UFPs; PM 0.1), can pass. In rats it is demonstrated that inhaled solid Mn oxide particles with
diameter 31 nm were transported via the olfactory nerve mentioning that particle size is an
important factor that determines uptake efficiently via
the olfactory nerve [Elder, 2006]. Also for
the soluble manganese chloride and the poorly soluble MnHPO
4

it is demonstrated in rats that
these manganese forms could be taken up via the olfactory route to the olfactory bulb
[Brenneman, 2000; Dorman 2002]. H
owever, transport from the olfactory bulb into more distal
parts of the brain is not demonstrated. Manganese is demonstrated to be present in the striatum,
9

which is, together with the globus pallidus and subsantia nigra one of the brain structures that
are

found to be primary target sites for manganese neurotoxicity. The question that remains to
be elucidated is: what is the contribution of the olfactory route to elevate manganese levels in
the striatum, globus pallidus and substantia nigra


5. Manganese ne
urotoxicity

5.1 Central nerve system (CNS)

As mentioned above, the striatum, globus pallidus and substantia nigra are found to be primary
target sites for manganese neurotoxicity. These brain structures are components of the basal
ganglia, which are a grou
p of nuclei located at the base of the forebrain. They are strongly
connected with the cerebral cortex, thalamus and other brain areas. The main components of the
basal ganglia are the globus pallidus , striatum composed of caudate and putamen, substantia
nigra and the subthalamic nucleus (Fig. 4).



Figure 4. Main
components

of the basal ganglia; Globus pallidus, caudate, putamen, substantia nigra
and subthalamic nucleus.

(
http://www.dana.org/news/brainwork/)

Cells of the central nervous system form a com
plex network. Neurons are capable
of
transmitting
electrical or chemical signals via synapses. Neurotransmitters may initiate an
electrical response or a second messenger pathway that may either excite or inhibit the
postsynaptic neuron. Glutamate and γ
-
am
ino butyric acid (GABA) are important
neurotransmitt
e
rs. Glutamate is the most common neurotransmitter in the brain
,
most
ly

produced in the subthalamic nucleus. GABA is the major inhibitory neurotransmitter, occurring
in 30
-
40% of all synapses

and
most highly concentrated in the globus pallidus and the substantia
nigra. The primary monoamine neurotransmitters are dopamine, norepinephrine and
serotonine

[Alberts, 1989]
. Dopamine
is a slow neurotransmitter that is
released from one
synaptic terminal a
nd may act on many cells in the neighbourhood. DA released from a
presynaptic axon interacts with several receptor types in the central nerve system.

Those
receptors can be divided into two groups 1) D1
-
like receptors and D2
-
like receptors. Altogether
they

modulate intra
-
cellular Ca2+ levels and a number of Ca2+
-
dependent intracellular
signaling processes. Presynaptically localized D2
-
like receptors are responsible for synthesis
and release of dopamine [KEGG, dopamine].

10

The basal ganglia are part of the ex
trapyramidal system. This system is a neuronal network that
is part of the motor system involved in the coordination of movement and so responsible for
maintenance of muscle tone and posture. It also plays a role in coordinating voluntary
movements. Lesion
s of the extrapyramidal system are characterized by increased muscle tone
(rigidity), slowing of all motor activities (bradykinesia) and involuntary movements. (book,
concise pathology).

5.2 Clinical symptoms

Already in 1837 Dr. John Couper reported that o
verexposure to manganese in five Scottish ore
grinders result in serious health problems. Patients showed altered neurological dysfunctions of
the extrapyramidal system (tremor in the extremities, gait disturbance, whispering speech).This
was the first rep
ort of severe neurotoxicity in humans resulting from manganese over
-
exposure
now known as manganism. Clinical symptoms of manganism resemble the symptoms of
idiopathic Parkinson’s disease. Therefore it is difficult to distinguish manganism from idiopathic
Parkinson’s disease based on clinical features. However, in general development of manganism
can be divided into three stages
. The two disorders can be distinguished with use of the

characteristics of the initial stage
.
The initial stage is marked by both
emotional and cognitive
disturbances characterized by excessive excitement, mood changes, irritably and intellectual
deficits. Fine motor coordination, as evidenced by changes in handwriting performance, also
appeared to be affected in this stage. There is

some evidence that removal of the subject from
exposure to manganese at this initial stage may lead to a reversal of symptoms

[Roth, 2009].

Continued exposure subsequently leads to more significant neurological injury including
anorexia, weakness, more se
vere psychotic behavior, slurred speech, mask
-
like face and a
genera clumsiness. The final stage of the disease is characterized by more acute and
incapacitating neurological impairment including limb rigidity, mild tremors, cock
-
like walk
excessive saliva
tion, mild tremors, dystonic, gait disturbance and loss of balance, whereas the
latter and cock
-
like walk are not associated with idiopathic Parkinson’s disease and thus used
for diagnosis. [Roth, 2009]. The three stages overlap considerably.

Measurements
of manganese in blood or urine bear a complex and poorly understood
relationship to external measurements and are of little value in determining exposure levels.

5.3 Imaging techniques

With use of modern imaging techniques as magnetic resonance imaging (MR
I) and positron
emission tomography (PET) it is possible to gain more information on the conditions of brain
structures. These techniques are also used to confirm diagnoses. MRI shows a characteristic
increased signal intensity on the globus pallidus and t
he midbrain in cases of manganism

[Aschner, 2009].

Symptoms of Parkinson’s disease
are
results from the loss of dopamine generating cells in the
substantia nigra.
The c
ause of this cell loss is unknown (idiopathic) however it is thought that
interactions b
etween genetic and environmental factors such as
manganese
-
containing
pesticides and heavy metals as manganese are important risk factors in Parkinson’s disease or
related parkinsonian disorders. PET scan imaging demonstrates degeneration of cells in the
s
ubstantia nigra pars compacta in individuals with idiopathic Parkinson’s disease. Both, brain
structures, globus pallidus and the substantia nigra are closely interconnected with other
components of the basal ganglia [Lucchini, 2009]. It is likely that cli
nical features of both
disorders resemble, but in origin manganism and idiopathic Parkinson’s disease are distinct
disorders.

PET studies elucidate that in idiopatic PD dopaminergic neurons were degenerated
whereas in Mn
-
induced PD were not. In the latter
studies non
-
human primates were chronically
exposed to Mn and an inhibition of in vivo release of
do
pamine was measured while no lack of
dopamine neuron degeneration was showed
. It seemed that Mn disrupts presynaptic release
mechanisms.
[
Guilarte, 2010].



11


6. Manganism, Parkinson’s disease or manganese induced
parkinsonism


Parkinsonism is a syndrome characterized by tremors, rigidity, low movements and balance
problems caused by neurological diseases as idiopathic Parkinson’s disease or exposure to toxic
s
ubstances including manganese the latter known as manganese induced parkinsonism (Fig. 5).
Other causes for parkinsonism as drugs or (viral) infections are not mentioned in this figure.

In general, manganism occurs after exposure to acute high levels of ma
nganese though it also is
generally recognized that manganism appears after several years of chronic exposure to lower
manganese levels in occupational settings. Neurological symptoms of manganism may worsen
even years after cessation of chronic exposure [
Aschner, 2009].

Manganese induced parkinsonism is an additional appearance of manganese neurotoxicity. This
form was first described in a study among newly diagnosed cases of Parkinson disease. This
reported that in 15 out of 953 cases the age at diagnosi
s was 17 years earlier in welders than
non
-
welders. All other clinical features specific for idiopathic Parkinson’s disease were the same
between the two groups.




Figure 5. Features of manganism and parkinsonism and the association between manganism an
d manganese induced
parkinsonism.


Figure 5 also shows the occurrence of manganism and manganese induced parkinsonism with
an overlapping area indicating that both disorders may not only be seen as two isolated
conditions but that there exists mixed condit
ions.

Supporting evidence for the fact that mixed forms exists arise from a case of a 43 year old
woman diagnosed with Parkinson’s disease displaying elevated blood manganese levels
presumably from hepatic dysfunction. This patient showed abnormal positro
n emission
tomography with 6
-
(18F) fluorodopa (indicating Parkinson’s disease) and also segments of the
globus pallidum exhibited increased signal on T1
-
weighted magnetic resonance imaging
consistent with manganism [Racette, 2005].

As mentioned before, in

the brains the sites involved in manganism and Parkinsonism are
closely interconnected with regions of the basal ganglia. These regions are functionally joined to
each other by a complex neurochemical and anatomical networks consisting of both excitatory
and inhibitory pathways. In case of lifetime low manganese exposure the influx process occurs at
12

very low doses and relative slow rate and with an even slower efflux rate [Yokel, 2009]. In this
way manganese levels may not reach the concentration required
to cause manganism and
accumulation process may continue involving all the other sites including the substantia nigra
pars compacta. [Luccini, 2009].


7. Genetic factors in early
-
onset Parkinson’s disease

It is likely that genetic background alters an indi
viduals’ response to manganese exposure. The
fact that not all welders and other workers who are daily exposed to abnormally high
atmospheric levels of manganese develop manganism points out that differences in responses to
Mn overexposure is likely due to

underlying genetic variability. Note the case of a worker with
an exposure history of only three years before progressive symptoms of Mn toxicity showed up
and the above mentioned study in which two individuals showed an early onset of Parkinson’s
disease
.[resp. Roth, 2009; Racette, 2001]

Genes

related to early onset Parkinson’s disease are summarized in Table 1 and discussed
below.


Table 1. Genes associated with early onset of Parkinson’s disease and their protein products and functions

Gene

Protein

Function

Park2

Parkin

Neuroprotective

Park6

PINK1

Mitochondrial S/T protein kinase

Neuroprotective

Park7

DJ
-
1

Anti oxidant, RNA binding

neuroprotective

Park9

ATP13A2

Lysosomal ATPase

Neuroprotective


The Park2 gene codes for the neuroprotective parkin

protein. Loss of function of the parkin gene
is the most common cause of early
-
onset of juvenile parkinsonism. Parkin is an E3 ligase and
serves as mediator in the ubiquitination of specific proteins. Ubiqiutinated proteins become a
target for degradation

by the proteasome. Dependent on the alternate region different
substrates, as Divalent Metal Transporter 1 (DMT
-
1) are recognized [Giasson, 2001]. DMT
-
1 also
plays an important role in the transport of manganese [Roth, 2009]. Loss of function of parkin
pr
otein may result in disturbtion of manganese metabolism leading to an increased uptake of
manganese having manganese intoxication as adverse effect.

In mammalian cells mitochondria play an important role in ATP production, oxidative stress
response and apo
ptosis. Within the brains the PTEN
-
induced kinase 1 (PINK1) protein is mainly
found in the substantia nigra. PINK1 is believed to regulate mitochondrial functions of
dopaminergic cells in the substantia nigra by acting as a mitochondrial Ser/Thr protein ki
nase.
Thus,
when

the PINK1 (Park6) gene
is mutated dopaminergic neurons of the substanatia nigra
loss their mitochondrial functions. T
his may lead to elimination of defective proteins [Wang,
2011]

Also associated with early
-
onset Parkinson’s’ disease are m
utations in the DJ
-
1 gene. DJ
-
1 is
identified as a regulatory subunit of an RNA
-
binding protein. Yet the exact function of the DJ
-
1
protein is still unknown. In yeast DJ
-
1 homolog transcription is induced together with genes
involved in the oxidative stess
s response pointing at a role in protection against oxidative
damage. Loss of function of DJ
-
1 causes neurodegeneration, [Bonifata, 2003]
.

Characteristic in Parkinson’s disease is the accumulation of α
-
synuclein in so called Lewy bodies
within neuronal cel
ls in the substantia nigra. Overexpression of α
-
synuclein finally leads to
dopaminergic neuronal loss. Lysosomal membrane protein ATP13A2 (PARK9) mediates
clearance of accumulated and aggregated α
-
synuclein [Usenovic, 2012]. Thus co
-
expression of
ATP13A2 p
revents dopaminergic neuron loss.

Not all above mentioned changes of genes involved in early
-
onset PD are linked to manganese.
For the latter yeast PARK9 is discovered to protect cells from manganese toxicity [Gitler, 2009].

13

8. Neurological risks associat
ed with welding fume exposure

Several epidemiological studies on the association between exposure to welding fumes and
neurological disorders are performed. Reviewed from literature 79 cases of probable/possible
and 19 additional cases of possible occupati
onal manganism were found among manganese
-
exposed workers involved in welding processes. Still epidemiologic evidence linking welding
exposures to Parkinson’s disease is controversial [Flynn, 2009].

It is thought that manganism is associated with acute hi
gh dose exposures to manganese as the
parkinsonian conditions are associated with chronic low dose exposures as depicted in figure 5.
Mn concentrations over 5 mg/ m
3

were measured in occupational settings of “high Mn exposed”
miners and plant workers. Thou
gh neurotoxic effects are seldom observed at exposure levels
below 5 mg Mn / m
3
, loss of neurologic function is reported with exposures below 0.2 mg/m3
[Santamaria, 2007].

From epidemiological studies in environmental exposed populations it is thought that

lifetime
exposure to very low manganese levels starting from pre
-
natal to older age may be a risk factor
for manganese induced parkinsonism indicated by a study conducted in 1996 in the community
of Sauda, Norway.

In this area where till 1923 a large fer
roalloy plant was active, the prevalence
rate of habitants with Parkinson’ disease is 245.6/100,000 which is higher than the average rate
of 25/100,000 of Scandinavian countries. Support for this comes from 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. 2009].

The
frequency increased to the standardized rate of 492/100,000 among the residents in the vicinity
of ferr
oalloy plants located in Valcamonica, a pre
-
Alps valley in the North of the province,
whereas the plant in the South part of the province had an open geographical setting. The data
were also significantly higher compared to both the average crude Italian r
ate of 157.7/100,000
and the European from 108 to 257/100,000 The standardized Morbidity Ratio for Parkinsonism
was significantly associated with the level of manganese in deposited dust samples in the same
area

[Lucchini, 2009]. All findings suggest that

cumulative exposure to low levels of manganese
can resul
t in delayed long
-
term toxicity. However it has to be taken into account that
simultaneously exposure to elevated levels of other metals as iron occurred.

9. Concluding remark

This report gives an o
verview of issues playing a role in the development of neurological
disorders in welders due to exposure to manganese containing welding fumes. It certainly is not
complete.

Parkinsons

disease is associated with degenerated dopaminergic neurons leading to a deficit of
dopamine. Chronic low dose exposure to manganese leads to Mn
-
induced parkinsonism
whereby dopamine deficiency seems to occur due to disruption of presynaptic release
mecha
nisms.
This means for welders as chronically exposed to manganese that it is not likely to
develop idiopathic Parkinsons disease. However, they are at risk in developing Mn
-
induced
Parkinson

with nearly similar clinical symptoms but not sensitive to treatm
ent with levodopa.
Altitudes for risk to develop either PD or Mn
-
induced PD remain unclear.

Fortunately, in addition to epidemiological and clinical studies many experimental research is
ongoing to elucidate mechanism involved in the onset of Parkinson dis
ease and the contribution
of manganese in the development of the disease.

O
verexposure
to manganese is also reported
in patients with liver failure and in children
receiving home parenteral nutrition [Linuma, 2003]. Further, concerns exists that industrial

emissions of manganese and the use of methylcyclopentadienyl manganese tricarbonyl (MMT)
as fuel additive are risk f
actors for Parkinson’s disease.

The fact that
other than occupational exposure scenarios to manganese occur

demonstrates the
importance for

further research.



14

Literature



Alberts B.

1989. Chapter 19. The nervous system.
Molecular biology of the cell.

Antonini, J
. 2003. Health effects of welding.
Critical reviews in Toxicology, 33 :
61
-
103.


Arvidson, B.
1994. A review of axonal transport
of metals.

Toxicology, 88 : 1
-
14.


Aschner, M.,
et al
.

2007.
Manganese: Recent advances in understanding its
transport and neurotoxicity.
Toxicology and applied Pharmacology, 221 : 131
-
147.

Aschner, M.

et al.
2009
.
Manganese and its role in Parkinson’s
disease: from
transport to neuropathology.

Neuromol Med., 11 : 252
-
266.


Bonifata, V.
et al.

2003. Mutations in the DJ
-
1 gene associated with autosomal
recessive early
-
onset parkinsonism.
Science, 299 : 256
-
259.

Borm, P.
et al.

2006. The potential risks of

nanomaterials: a review carried out
for ECETOC.
Particle and Fibre Toxicology, 3 : 11
.


Brenneman, K.
et al.

2000. Direct olfactory transport of inhaled manganese
(54MnCl2) to the rat brain: toxicokinetic investigation in a unilateral nasal
occlusion mode
l.
Toxicology and applied pharmacology, 169 : 238
-
248.

Dauer, W. and Przedborski, S.

2003. Parkinson’s disease: Mechanisms and
models.
Neuron. 39 : 889
-
909.

Dorman, D.
et al.

2002.
Olfactory transport: a direct route of delivery of
inhaled manganese phosphate to the rat brain.
Journal of toxicology and
environmental health, Part A, 65 : 1493
-
1511.

Finkelstein, M. and Jerret, M.
2006. A study of the relationships between
Parkinson’s d
isease and markers of traffic
-
derived ad environmental
manganese air pollution in two Canadian cities.
Environmental Research 104 ;
420
-
432.

Flynn, M. and Susi, P.
2008.

Neurological risks associated with manganese
exposure from welding operations
-

A liter
ature review.
Int. J. Hyg. Environ.
Health, 212 : 459
-
469.

Giasson, B. and Lee, V.
2001. Parkin and the molecular pathways of
Parkinson’s disease.
Neuron, 31 : 885
-
888.

Gitler, A.
et al.

2009. α
-
Synuclein is part of a diverse and highly conserved
interacti
on network that includes PARK9 and manganese toxicity.
Nature
genetics, 41 : 308
-
315.

Guilarte, T.
2010. Manganese and Parkinson’s Disease: a critical review and
new findings.
Environmental Health Perspectives, 118 : 1071
-
1080
.

Keane, K.
et al.

2010.
Welding fumes from stainless steel gas metal arc
processes contain multiple manganese chemical species.

Journal of
environmental monitoring, 12 : 1133
-
1140.


KEGG Dopamine.
27 July 2012.
http://www.genome.jp/kegg/pathway/hsa/hsa04728.html

Leonard, S.
et al
.

2010.
Comparison of stainless and mild steel welding fumes
in generation of reactive oxygen species.
Particle and Fibre Toxicolgy, 7 : 32.


Linuma, Y.
et al
.
2003. Whole
-
blood manganese levels and brain manganese
accumulation in children receiving long
-
term home parenteral nutrition.
Pediatr.Surg. Int. 19 : 268
-
272.

15

Lucchini, R.
et al
.
2009.

From manganism to manganese
-
induced
parkinsonism: A conceptual model b
ased on the evolution of exposure.
Neuromol Med, 11 : 311
-
321
.


Quintanar, L.

2007. Manganese neurotoxicity: A bioinorganic chemist’s
perspective.
Inorganica Chimica Acta, 361 : 875
-
884.


Racette, B
. et al.

2001. Welding
-
related parkinsonism: Clinical feat
ures,
treatment, and pathophysiology.
Neurology, 56 : 8
-
13.


Racette, B
. et al.

2005.

[18F]FDOPA PET and clinical features in parkinisonism
due to manganism.
Movement disorders, 20 : 492
-
496.


Roth, J.

2006. Homeostatic and toxic mechanisms regulating mang
anese
uptake, retention, and elimination.
Biol Res, 39 : 45
-
57.


Roth, J.
2009. Are there common biochemical and molecular mechanisms
controlling manganism and parkinsonism.
Neuromol Med, 11 : 281
-
296
.

Santamaria, A.
et al.

2007. State
-
of
-
the
-
science
review does Manganese
exposure during welding pose a neurological risk?

Journal of toxicology and
environmental health, Part B, 10 : 417
-
465.

Santamaria, and Sulsky S.

2010. Risk assessment of an essential element:
Manganese.
Journal of toxicology and envi
ronmental health, 73 : 128
-
155.


Sen, S.
et al
. 2011. Manganese accumulation in the olfactory bulbs and other
brain regions of ‘asymptomatic’ welders.
Toxicological Sciences 121 : 160
-
167.

Sriram, K.
et al.

2010. Dopaminergic neurotoxicity following pulmonary
exposure to manganese in welding fumes.
Arch. Toxicol, 84 : 521
-
540.

Usenovic, M.
et al
.
2012. Deficiency of ATP13A2 leads to lysosomal
dysfunction, alpha
-
synuclein accumulation, and neurotoxicity.
J. N
eurosci. 32 :
4240
-
4246.

Wang, H.
et al.

2011. PARK6 PINK1 mutants are defective in maintaining
mitochondrial membrane potential and inhibiting ROS formation of substantia
nigra dopaminergic neurons.
Biochimica et biophysica Acta, 1812 : 674
-
684.

Yokel, R.

2009. Manganese flux across the Blood
-
Brain
-
Barrier.
Neuromol Med,
11 : 297
-
310.