a neurobehavioral study of current and former welders exposed to manganese

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A neurobehavioral study of current and former welders

exposed to manganese

Dag G. Ellingsen a,*, Roman Konstantinov b, Rita Bast-Pettersen a,Ludmila Merkurjeva b, Maxim Chashchin b, Yngvar Thomassen a,

Valery Chashchin b

a National Institute of Occupational Health, P.O. Box 8149 Dep, N-0033 Oslo, Norwayb Northwest Public Health Research Centre, 191036 2-Sovetskaya, 4 St. Petersburg, Russia

Received 18 May 2007; accepted 28 August 2007

Available online 7 September 2007

bstract

Neurobehavioral functions were studied in 96 welders currently exposed to the geometric mean (GM) concentration of 121 mg/m3 (range

–2322) manganese (Mn) in welding fume (air-Mn) based on the individual mean from two successive days of sampling. They were compared to

6 age-matched referents. The arithmetic mean (AM) concentration of Mn in whole blood (B-Mn) was 8.6 mg/L versus 6.9 mg/L in the referents.

ssociations between the Digit Symbol and Finger Tapping test scores and B-Mn and air-Mn, respectively, were observed. The welders exposed to

he highest air-Mn concentrations (GM 423 mg/m3 range 204–2322) had statistically significantly poorer Finger Tapping test score as compared to

heir age-matched referents. The welders with the highest AM concentration of B-Mn (12.6 mg/L) scored statistically significantly poorer on the

igit Symbol test when compared to the age-matched referents (AM B-Mn 7.5 mg/L). The same neurobehavioral test battery was applied to 27

atients diagnosed, and financially compensated, as having welding related manganism. They were on average 44.9 (range 34–51) years old at the

ime of diagnosis, which on average was 5.8 years prior to this study. They had worked as welders for 23.1 years on average (range 15–30). The

ost affected neurobehavioral functions were associated with impaired Finger Tapping speed and Grooved Pegboard performance. The patients

ad no alterations in hand tremor as assessed by the CATSYS system, while a few subjects had noticeable tremor as assessed by the Static

teadiness test.

2007 Elsevier Inc. All rights reserved.

Available online at www.sciencedirect.com

NeuroToxicology 29 (2008) 48–59

eywords: Welding; Manganese; Neurobehavioral tests; Manganism

1. Introduction

High occupational exposure to manganese (Mn) can cause

manganism, a severe disorder of the central nervous system

(CNS) characterized mainly by movement disturbances and

psychiatric features (Couper, 1837; McMillan, 1999). Mangan-

ism has been diagnosed in workers employed in mining and

crushing of Mn ore, Mn alloy production, and in the production

of steel and dry cell batteries (Cook et al., 1974; Emara et al.,

1971; Huang et al., 1989; Rodier, 1955; Tanaka and Lieben,

1969).

* Corresponding author. Tel.: +47 23195205; fax: +47 23195205.

E-mail address: [email protected] (D.G. Ellingsen).

161-813X/$ – see front matter # 2007 Elsevier Inc. All rights reserved.

oi:10.1016/j.neuro.2007.08.014

There are few scientifically reported cases of manganism in

welders, although they probably constitute the highest number

of occupationally exposed workers. Their exposure to Mn may

originate from the steel, but more important from the welding

electrode and the flux. Particles in the respirable aerosol

fraction ranging from 10 to 100 nm near the welding arc and

agglomerates ranging from 0.5 to 2.0 mm in aerodynamic

diameter have been measured (Antonini et al., 2003;

Voitkevich, 1995).

Welders examined with magnetic resonance imaging had

increased amounts of Mn in the globus pallidus, midbrain and

putamen (Kim et al., 1999). Despite this, there are few studies

of currently exposed welders using neurobehavioral methods.

Slightly inferior motor functions (Siegl and Bergert, 1982;

Sjogren et al., 1996), but also severely impaired motor

functions (Bowler et al., 2003, 2006) have been reported.

mailto:[email protected]

http://dx.doi.org/10.1016/j.neuro.2007.08.014

D.G. Ellingsen et al. / NeuroToxicology 29 (2008) 48–59 49

Also slightly poorer cognitive test performance (Wang et al.,

2006) and severely impaired cognitive performance have been

reported (Bowler et al., 2003, 2006, 2007).

Studies of other Mn-exposed workers have shown altera-

tions in reaction time measures and in hand tremor test

parameters, and poorer performance on motor tests assessing

eye-hand coordination, motor speed or manual dexterity (Bast-

Pettersen et al., 2004; Beuter et al., 1994; Hochberg et al., 1996;

Iregren, 1990; Lucchini et al., 1995, 1999; Mergler et al., 1994;

Roels et al., 1987, 1992). There are also reports of reduced

cognitive performance, including memory functions and

increased prevalence of neuropsychiatric symptoms (Iregren,

1990; Lucchini et al., 1995, 1999; Mergler et al., 1994; Roels

et al., 1987). While these studies suggest neurobehavioral

alterations to result from Mn exposure, the exposure level

associated with the alterations is insufficiently established.

Manganese accumulates mainly in striatum, globus pallidus

and the subthalamic nuclei, with irreversible damage to the

nerve cells of these areas in Mn-intoxicated humans

(Normandin and Hazell, 2002; Pal et al., 1999). Increased

levels of Mn in the brain, however, were not measured in

clinically affected primates (Olanow et al., 1996). Manganism

resembles clinically other extrapyramidal disorders, in parti-

cular idiopathic Parkinson’s disease (PD) (Calne et al., 1994).

Neurodegeneration in PD occurs primarily in the substantia

nigra pars compacta. The nigrostriatal pathway is usually is

preserved in manganism (Pal et al., 1999).

Neurobehavioral tests are often used in epidemiological

studies to assess potential CNS effects of low Mn-exposure, but

neurobehavioral performance of patients with manganism has

hardly been described. Three stages of manganism has been

characterized in neurological terms; the prodromal phase was

dominated mostly by subjective symptoms; various neurolo-

gical signs appeared in the intermediate phase; while severe

disabling neurological signs appeared in the established phase

(Rodier, 1955).

Manganism among welders is considered a serious

occupational health problem in Russia. This work is part of

a larger study of welders’ exposure and health. Exposure

characteristics were described previously (Ellingsen et al.,

2006). This study was designed to assess the association

between exposure and nervous system function in current

welders, emphasizing motor system functions. A number of

patients diagnosed, and officially recognised in the Russian

insurance system many years previously as having welding

related manganism, were examined as well, in order to

contribute to the neurobehavioral characterization of the

disease.

2. Material and methods

2.1. Study design and participants

The study of currently exposed welders had a cross-sectional

pair-matched design restricted to men. The welders were

recruited from one facility producing heavy machinery and

from one shipyard, each employing several thousand workers.

The facilities had five and two welding departments,

respectively, and one department was randomly selected from

each. One shift of welders from each of the departments was

eligible for inclusion.

Main criteria for inclusion were at least 1 year of

employment as a welder and currently employed. Referents

(turners/fitters) recruited from the same facilities were matched

1:1 with a welder based on age, with a maximum age difference

within a pair of �2 years.

Known alcohol (or drug) abuse, diabetes mellitus, any larger

damage of the dominant hand, current or previous diseases of

the CNS that is probably unrelated to Mn exposure (e.g. brain

tumours, transitory ischemic attacks) or serious kidney or liver

diseases were among the exclusion criteria. Subjects with

occupational exposure to organic solvents (>3 years) in jobs

like painters or spray-painters, ever employed at plants

producing solvents or occupational exposure to lead or mercury

for more than 1 year were also excluded. Individuals that had

been on sick leave for more than 14 days at the examination day

were not included.

In all, 132 welders worked in the selected departments, of

whom five were not available for inclusion (sick leave,

vacation) and 11 were excluded due to violation of the

exclusion criteria as recorded in the occupational health

service files (mainly due to high alcohol intake). Among the

remaining 116 eligible welders, 20 declined to participate

(82.8% participation rate). Thirty-nine percent stated always

to use respiratory protection when welding, 42% mostly, 11%

rarely and in 8% this information was missing. Among the

156 turners/fitters working in other departments that were

chosen for recruiting the referents, 14 were not available due

to sick leave or vacation. Twenty-two potential referents were

excluded (mainly due to high alcohol intake). Thus the

reference base consisted of 120 eligible potential referents, of

whom 24 refused to participate (participation rate 80.0%). We

are not aware of any occupational Mn exposure in the

referents.

The Northwest Public Health Research Centre (NWPHRC)

in St. Petersburg (Russia) had in their medical files recorded 74

patients with the diagnosis of manganism, officially recognised

as an occupational disease in the Russian insurance system

(List of Occupational Diseases, 1996). The aim was to examine

half of the patients, by considering every second individual

from an alphabetical list. Four patients were excluded, two were

not available, and four refused to participate. Thus, 87.1% of

the available 31 patients participated (N = 27). They were all

former welders and four were women. As the youngest patient

was 41 years old, the patients were compared to the participants

from the cross-sectional study above this age.

The neurobehavioral examinations, blood and urine sam-

pling, and a structured interview were carried out at the

occupational health clinics of the respective facilities and at the

NWPHRC for the patients. Personal air samples were collected

on day 1 and day 2. The neurobehavioral examinations and the

collection of biological samples were carried out on the third

day. Background characteristics for the participants are shown

in Tables 1 and 5.

Table 1

Background and exposure characteristics in current welders and referents

Welders (N = 96) Referents (N = 96) p

AMa Range AM Range

Age (years) 36.3 20–65 36.1 18–66 0.90

Education (years) 12.7 8–17 12.3b 8–19 0.20

Weight (kg) 78.5 47.3–118.2 75.7 50.2–113.5 0.09

Smokers (%)c 60.4 – 62.5 – 0.77

Cigarettes/day (no.) 9.5 0–40 10.6 0–30 0.41

Alcohol consumption (g/year) 7700 0–47,320 5300 0–72,800 0.07

Earlier concussions (%)c 12.5 – 6.3 – 0.22

Use of prescribed medication (%)c 9.4 – 11.5 – 0.81

Years exposed 13.5 1.0–40.0 – – –

Current air-Mn (mg/m3)d 121e 7–2322 – – –

B-Mn (mg/L) 8.6b 4.7–21.7 6.9 3.8–14.3 <0.001

B-Pb (mg/L)d 47b 18–141 37 16–208 0.001

U-Mn (mg/g cr.)d 0.17b,f 0.03–1.1 0.12 0.02–10.2 0.07

a AM: arithmetic mean.b One subject missing.c Prevalence.d GM: geometric mean.e AM = 238 mg/m3.f AM = 0.37 mg/g cr.

D.G. Ellingsen et al. / NeuroToxicology 29 (2008) 48–5950

The study was approved by the Ethics Committee of St.

Petersburg Pasteur Institute. An informed written consent was

obtained from each participant.

2.2. Neurobehavioral examinations

The participants with-in an age-matched pair were examined

by the same investigator, usually for 1.5–2 h. The same test

sequence was applied for all subjects, and the participants in a

matched pair were examined at the same time of the day.

2.2.1. Cognitive tests and subjective symptoms

Sixteen neuropsychiatric and neurological symptoms, such

as fatigue, concentration and memory difficulties, were

recorded using the questionnaire Q 16 (Lundberg et al.,

1997). Digit Symbol (WAIS) (Lezak, 1995) is a paper and

pencil test requiring psychomotor speed, attention, perceptual

organization, and visual short-term memory. The task is to

recode symbols into digits. The number of correctly recoded

symbols during 90 s was recorded. Digit Span (WAIS) is a test

of attentional capacity and short-term memory. The measure is

the maximum number of digits repeated after an oral

presentation, either in the same order as presented (forwards)

or in reverse order (backwards) (Lezak, 1995).

2.2.2. Motor tests

Finger Tapping (Lafayette Instrument Company) requires

the participant to press a tapping key with the index finger as

fast as possible (Reitan and Wolfson, 1985). The measure of

this manual version was the median number of presses based on

three trials of 10 s.

Foot Tapping (Matthews and Kløve, 1964) requires the

participant to press a lever with the foot as quickly as possible

for 10 s while standing. The measure was the mean number of

presses based on two trials.

Dynamometer (Lafayette Psychological Instruments Model

78010) (Reitan and Wolfson, 1985). The participant holds the

dynamometer in the palm of the hand and squeezes the stirrup

with the fingers as firm as possible. The measure was the

amount of pressure in kg. Grooved Pegboard (Matthews and

Kløve, 1964) is a test of motor speed and fine manipulative

dexterity consisting of a board containing a 5 � 5 set of slotted

holes angled in different directions and 25 pegs with a ridge that

are to be inserted as quickly as possible. The completion time

(in s) was recorded for each hand.

The CATSYS Postural Sway test (Danish Product Devel-

opment, 1996) consists of a platform with sensors mapping the

position of the force centre resulting from the participants

position. The participant is instructed to stand erect and keep

the balance during three administrations, each period for 60 s

(total test time 75 s): 1. Eyes open. 2. Blindfolded. 3.

Blindfolded, standing on the platform with a pad of foam

(2 cm) under their feet. Recorded were: weight (in kg); mean

sway: the mean of the distance from the geometrical centre of

all positions (in mm); transversal and sagittal sway: the mean of

recorded x and y values of the force centre in a coordinate

system with the mean force centre position as the origo (in

mm); sway area: the area of the smallest polygon that includes

all force centre positions (in mm2); sway intensity: the root

mean square of the accelerations recorded in the 0.1–10 Hz

band (mm); sway velocity: the average travel period of the force

centre, calculated by dividing the total length of the force centre

trajectory with the duration (mm/s). Condition 3 did not yield

additional significant information and is not reported.

The CATSYS Maximum Frequency test (Danish Product

Development, 1996) was recorded for 12 s with a touch-

sensitive recording drum connected to a computer. The

participant is required to lightly hit the surface of the drum

in an alternating hand pronation–supination as close as possible

to a metronome beat increasing in frequency from 1.6 to 7.5 Hz.


The maximum frequency at which the sound could be followed

was recorded (in Hz).

2.2.3. Hand steadiness/hand tremor

The Kløve–Matthews Static Steadiness test is a stylus-and-

hole apparatus. In the CATSYS Tremor test, version 7.0

(Danish Product Development, 1996), the participant is

required to hold a tremor pen containing a biaxial micro-

accelerometer like an ordinary pen. The arm is bent at an angle

of 908 without any support for 10.2, 2 s to stabilize and 8.2 s for

recording. The tests have been described in detail (Bast-

Pettersen and Ellingsen, 2005).

2.3. Collection of biological samples and elemental

measurements

The participants were instructed to void the first morning

urine. Heparinized whole blood was collected between 8.30 and

9.30 the same morning. The samples were analysed by

inductively coupled plasma sector field mass spectrometry

using an Element 2 mass spectrometer (Thermo Electron,

Bremen, Germany). SeronormTM Trace Elements human whole

blood and urine quality control materials were used. Creatinine

in urine was measured according to Jaffe reaction. Analytical

and sampling details have been presented (Ellingsen et al.,

2006).

2.4. Air sampling and measurements

Current exposure to welding fumes was characterized by

full-shift samples collected with Millipore (25 mm) plastic

cassettes equipped with 5.0 mm pore-size polyvinyl chloride

membrane filters mounted underneath the welding helmet in the

breathing zone of each welder on two successive days. SKC

(SKC Ltd., Dorset, UK) pumps operated at a constant flow rate

of 2.0 L/min were used for the sampling. The samples were

analysed by inductively coupled plasma optical emission

spectrometry. Reference workroom air filters traceable to

international certified reference materials were used for the

quality assurance. Analytical and sampling details have been

presented (Ellingsen et al., 2006).

2.5. Estimates of exposure to manganese

The individual concentrations of U-Mn and B-Mn were used

as biological exposure measures. The mean Mn concentration

of the 2 days of air sampling preceding the collection of the

biological samples was used as an individual air exposure

estimate (air-Mn).

2.6. Statistics

Continuous variables that had a skewed distribution were

log-transformed if the skewness exceeded 2.0. For those

variables the geometric mean (GM) is presented. The

arithmetic mean (AM) is otherwise used. Analysis of variance

(ANOVA) was used for group comparisons of continuous

variables, and the least square difference (LSD) was calculated

when more than two groups were compared. For the

comparison of bilateral differences in neurobehavioral perfor-

mance, the Mann–Whitney test was applied because the

variables could not be log-transformed due to several 0-values.

The x2-test was applied for dichotomous variables.

Potential confounders were assessed by multiple linear

regression analysis (backward procedure) including exposure

status (1/0), age (in years), tobacco smoking (1/0), alcohol

consumption (g/year), use of medication (1/0), head injury with

concussion (Hinj) (1/0) and the concentration of B-Pb (log)

(mg/L) as independent variables. ‘‘Years of education’’ was

included when assessing Digit Span and Digit Symbol. If

exposure status was associated with the outcome variable, the

same regression models were used to study dose–response

associations, but exposure status was substituted with B-Mn

(mg/L), U-Mn (log) (mg/g cr.) or air-Mn (log) (mg/m3) in

separate models. In order to include all subjects for the

assessment of air-Mn, the referents were assigned a log-value of

0.001 for that variable. When a dose–response association was

observed, the welders were stratified into three equally large

groups according to the exposure variable in question (N = 32

in each stratified group), and compared with their pair-matched

(on age) referents within each stratum. A general linear model

was used to adjust for covariates between subgroups. Two-

tailed p-values < 0.05 were considered to be of statistical

significance. The statistical package SPSS1, version 11.5, was

used.

3. Results

3.1. Current welders

The current welders and their referents were comparable

with respect to age, education and current smoking habits

(Table 1). The exposed group had worked as welders for on

average 13.5 years, and their current GM exposure to air-Mn

was 121 mg/m3.

Although the performance on most motor tests was quite

similar, the AM Finger Tapping score was slightly poorer in the

welders than in the referents (Table 2). The AM scores for the

cognitive Digit Span test (forwards) were almost identical,

although the backwards performance and the AM Digit Symbol

test scores were significantly lower in the welders. The welders

reported more subjective symptoms, but the difference was not

significant.

The results of the hand tremor/hand steadiness tests were

somewhat contradictory. The TREMOR 7.0 test performance

was similar in the two groups (Table 3), but the welders

performed better on the Static Steadiness test (Table 2). The two

groups performed similar on the Postural Sway test (Table 3).

The welders performed slightly better on two of the parameters

under regular test conditions, but the difference disappeared

when blindfolded.

Exposure status (1/0) was assessed taking into account

potential confounders (see Section 2.6) in a multiple linear

regression analysis (results not shown). The performance for

Table 2

Neurobehavioral test results in current welders and referents


AMa Range AM Range

Q16, no. of subjective symptoms 3.6 1–13 2.9 0–14 0.13

Grooved Pegboard

Dominant hand (s) 63.7 37–120 63.0b 38–91 0.44

Non-dominant hand (s) 66.8c 34–116 67.0 44–110 0.94

Finger Tapping

Dominant hand (no.) 45.9 18–69 47.3 27–63 0.20

Dominant hand (no.)d 45.8 44.3–47.2 47.4 45.9–48.9 0.13

Non-dominant hand (no.) 41.3 14–72 43.2 26–59 0.051

Non-dominant hand (no.)d 41.2 39.9–42.5 43.3 42.0–44.6 0.03

Foot Tapping

Dominant foot (no.) 45.0 16–58 44.0 25–64 0.39

Non-dominant foot (no.) 43.2 13–58 42.4 25–64 0.45

Dynamometer

Dominant hand (kg) 54.4 36–71 53.2 10–71 0.40

Non-dominant hand (kg) 52.3 27–74 51.0 11–70 0.35

Static Steadiness

Dominant hand

Number 142 5–656 184 5–603 0.01

Time (s) 6.7 0.4–37.7 11.2 0.3–32.2 <0.001

Non-dominant hand

Number 157 14–624 204 25–808 0.01

Time (s) 9.0 0.3–41.8 13.3 1.0–44.3 0.001

Digit Span

Forwards (no.) 5.9 4–9 5.9 4–9 0.95

Backwards (no.) 3.8 1–8 4.2 3–7 0.01

Backwards (no.)d 3.8 3.6–4.0 4.3 4.1–4.5 0.003

Digit Symbol (no.) 46.7c 20–74 50.6 25–74 0.03

Digit Symbol (no.)d 46.5 44.3–48.6 50.8 48.7–53.0 0.005

For the adjusted results, the mean and 95% CI are presented.a AM: arithmetic mean.b Two subjects missing.c One subject missing.d The results are adjusted for factors shown in Table 4.


Digit Span (backwards), Digit Symbol and Finger Tapping

(non-dominant hand) were associated with exposure status.

These test results were further assessed by including B-Mn, U-

Mn (log) and air-Mn (log) into separate regression models

(Table 4). Air-Mn (log) was associated with several of the test

results and B-Mn was associated with the Digit Symbol test

performance.

Based on the regression equations in Table 4, the current

welders were stratified into three equally large groups

according to air-Mn or B-Mn, and compared with their age-

matched referents within each stratum. The 32 welders with the

highest B-Mn had poorer Digit Symbol test performance

( p = 0.01) than their 32 age-matched referents (adjusted for

education and age) (Fig. 1). Their respective AM B-Mn were

12.6 (range 8.7–23.5) mg/L and 7.5 (range 3.7–14.3) mg/L

( p < 0.001). Dose–response was also found between the Finger

Tapping test and the current air-Mn (Fig. 2). The welders

exposed to the highest air-Mn performed significantly poorer

on the Finger Tapping test for the non-dominant hand. The

difference was of borderline significance for the dominant hand

(adjusted for age and smoking). The lowest exposed welder

group had similar performance to their referents. Obvious

dose–response patterns could not be shown for the other

associations presented in Table 4.

3.2. Patients

Background data for the patients, and the current welders

and referents above 41 years of age participating in the cross-

sectional study are shown in Table 5. The patients were on

average 50.7 years old. Manganism had been diagnosed when

they on average were 44.9 years old.

The patients performed poorer than their referents on the

motor tests and the Digit Symbol test (Table 6). The cognitive

Digit Span test performance was quite similar across the three

groups. None of the TREMOR 7.0 test parameters discrimi-

nated between the groups (Table 7). However, the patients

scored somewhat poorer on Static Steadiness test (Table 6). The

Table 3

Results from the computerized CATSYS test battery in current welders and referents


AMa Range AM Range

TREMOR 7.0

Dominant handb

Tremor intensity (m/s2)c 0.13 0.06–0.71 0.14 0.07–0.46 0.69

Central frequency (Hz) 7.8 5.0–12.6 7.5 4.8–11.6 0.12

Frequency dispersion (Hz) 3.2 0.2–5.6 3.0 0.2–5.4 0.26

Harmonic index 0.86 0.68–0.98 0.86 0.70–0.98 0.47

Non-dominant hand

Tremor intensity (m/s2)c 0.14d 0.06–0.68 0.15d 0.07–0.45 0.41

Central frequency (Hz) 7.5d 1.6–12.6 7.8d 5.0–12.3 0.23

Frequency dispersion (Hz) 3.3d 0.2–6.1 3.1d 0.2–4.9 0.19

Harmonic index 0.85d 0.64–0.98 0.84d 0.67–0.97 0.70

Maximum frequency test

Dominant (Hz) 5.0d 1.0–7.5 5.4 1.0–7.5 0.09

Non-dominant (Hz) 5.1d 1.0–7.5 5.2d 1.0–7.5 0.83

Postural Sway test

Eyes openb

Transversal x (mm) 2.6 0.9–5.4 2.8 1.1–6.9 0.33

Sagittal y (mm)c 3.4 1.4–14.3 3.6 1.8–9.7 0.31

Sway area (mm2)c 182 36–948 219 67–1328 0.02

Mean sway (mm) 5.1 2.1–15.6 5.2 2.7–11.2 0.50

Intensity (mm)c 3.7 1.7–14.2 4.0 1.8–10.4 0.14

Sway velocity (mm/s) 8.8 4.6–20.6 9.6 4.9–23.2 0.045

Blindfoldede

Transversal x (mm) 3.3 1.4–11.2 3.3 0.9–6.1 0.93

Sagittal y (mm) 4.4 1.6–12.7 4.1 1.8–8.9 0.28

Sway area (mm2)c 295 70–3183 313 47–1293 0.51

Mean sway (mm) 6.1 2.8–15.3 5.9 2.3–11.6 0.45

Intensity (mm)c 5.1 2.5–21.6 5.1 2.7–8.7 0.56

Sway velocity (mm/s)c 12.1 5.8–53.4 13.2 5.6–21.3 0.10

a AM: arithmetic mean.b For this test 95 welders and 96 referents.c GM: geometric mean.d One subject missing.e For this test 93 welders and 95 referents.


patients also performed poorer on all test parameters for the

Postural Sway test (Table 7).

Tables 6 and 7 show the prevalence of patients scoring

poorer than the mean and 2 S.D. of the referents (or the 2nd

Table 4

Results from the multiple linear regression (backward procedure) analysisa assessi

Alfa Beta

Air-Mn

Finger Tapping

Dominant hand (no.) 55.6**** �0.79* Air-Mn (log)

Non-dominant hand (no.) 49.0**** �1.04** Air-Mn (log

Digit Symbol 51.7**** �2.1*** Air-Mn (log)

Digit Span backw. 4.1**** �0.20*** Air-Mn (log

B-Mn

Digit Symbol 51.7**** �0.66*** B-Mn � 0.5

a Model used; see Section 2.6.* p < 0.10.

** p < 0.05.*** p < 0.01.**** p < 0.001.

percentile for non-normally distributed variables). The pre-

valence of ‘‘abnormal’’ test scores was highest for the Finger

Tapping test, being 59.3% and 66.7% for the two hands,

respectively. Few patients scored below the cut-off points for

ng the impact of the exposure-related variables B-Mn, U-Mn and air-Mn

mult.r

� 0.20**** Age � 2.0* Smoking 0.34****

) � 0.11*** Age � 2.1** Smoking 0.30***

� 0.5**** Age + 1.4**** Edu 0.57****

) � 0.02*** Age � 0.0002* Alco + 0.08** Edu + 0.5* Hinj 0.37****

**** Age + 1.4**** Edu 0.56****

Fig. 1. The mean difference (and 95% CI) in the Digit Symbol test scores

(adjusted for age and education) between welders and referents matched for age

according to the level of B-Mn. The mean B-Mn (in mg/L) concentrations and

ranges are shown.

Fig. 2. The mean difference (and 95% CI) in the Finger Tapping test scores for

the dominant (dom.) and non-dominant (non-dom.) hand (adjusted for age and

smoking) between welders and referents matched for age according to the level

of air-Mn. The geometric mean air-Mn concentrations (in mg/m3) and ranges

are shown in brackets.


the TREMOR 7.0 parameters, although about 20% had poorer

performance on the Static Steadiness test. Greater than 90% of

the patients had more subjective symptoms than the cut-off

point.

In order to assess symmetry, the percentage difference in

neurobehavioral performance between the best and the poorest

hand/foot was calculated for all test variables applied

bilaterally. No statistically significant differences in bilateral

performance were found between the patients and the referents

for any of the tests (results not shown). The Pearson’s

correlation coefficients between the performances on the

dominant and the non-dominant side in the patients were 0.95

(Finger Tapping) (Fig. 3), 0.92 (Grooved Pegboard) and 0.93

(Foot Tapping) for the tests with the highest prevalence of

scores <2 S.D. (or 2nd percentile).

Table 5

Background characteristics and the mean concentrations of trace elements in whole b

referents above 41 years of age

Patients (N = 27) Welder

AMa Range AM

Age (years)b 50.7 41–58 46

Education (years) 10.0 8–13 12

Weight (kg) 78.5 61.4–98.8 78

Smokers (%)d 40.7 – 59

Cigarettes/day (no.) 5.6 0–20 9

Alcohol consumption (g/year)b 1670 0–8110 10,260

Concussions (%)d 0 – 16

Prescribed medication (%)d 25.9 – 16

Age at diagnosis (years) 44.9 34–51 –

Years since diagnosis 5.8 4–7 –

Years exposed 23.1 15–30 21

B-Mn (mg/L)e,f 8.7 5.2–19.1 8

B-Pb (mg/L)g,b,f 31.1 12.5–82.8 48

U-Mn (mg/g cr.)g,b,e,f 0.07 0.03–0.17 0

a AM: arithmetic mean.b p < 0.05 between patients and welders.c One subject missing.d Prevalence.e p < 0.05 between patients and referents.f p < 0.05 between welders and referents.g GM: geometric mean.

4. Discussion

Neurobehavioral functions were investigated in welders

currently exposed to welding fumes containing the GM of

121 mg/m3 of Mn. The welders had been exposed to welding

aerosols for 13.5 years on average. Patients diagnosed as having

welding-related manganism also were examined. Their

exposure, which had ceased on average 5.8 years prior to

the examinations, was on average 23.1 years. Reliable

quantitative data on their past exposure was not available.

The participation rates were high in all groups. Thus,

selection bias may be of little concern. The current welders and

the referents are blue-collar workers selected from the same

plants, and their socio-demographic background variables are

comparable. This may also be valid for the patients because

lood and urine in patients diagnosed with manganism, 42 current welders and 42

s (N = 42) Referents (N = 42) pANOVA

Range AM Range

.8 41–65 48.4 41–66 0.03

.5 8–17 12.0 8–19 <0.001

.3c 55.7–118.2 79.9 58.8–113.5 0.80

.5 – 52.4 – 0.31

.9 0–40 8.6 0–30 0.17

0–47,320 6450 0–72,800 0.004

.7 – 4.8 – –

.7 – 19.0 – 0.63

– – – –

– – – –

.4 1–40 – – –

.5 4.7–21.7 7.0 3.8–14.3 0.051

.4 18.0–141.4 35.8 16.1–208.0 0.01

.12 0.03–1.1 0.19 0.02–10.2 0.001

Table 6

Neurobehavioral test results in patients diagnosed with manganism, current welders and referents above 41 years of age

Patients (N = 27) Welders (N = 42) Referents (N = 42) pANOVA %a

AMb Range AM Range AM Range

Q16, symptoms (no.) 12.5c,d 9–16 4.3 1–13 3.4 1–14 <0.001 92.6

Grooved Pegboard

Dominant (s)e 106.2c,d 63–284 69.2 46–120 68.5 51–91 <0.001 59.3

Non-dominant (s)e 105.8c,d 72–303 71.4 51–116 73.0 51–110 <0.001 33.3

Finger Tapping

Dominant (no.) 26.5c,d 3–55 44.4 18–69 44.5 27–63 <0.001 59.3

Non-dominant (no.) 26.8c,d 2–53 40.0 14–72 41.5 26–53 <0.001 66.7

Foot Tapping

Dominant (no.) 27.6c,d 8–46 42.5 16–56 41.4 25–62 <0.001 40.7

Non-dominant (no.) 25.0c,d 6–48 40.7 13–55 39.4 25–63 <0.001 44.4

Dynamometerf

Dominant (kg) 31.3c,d 11–53 52.0 36–70 51.7 10–69 <0.001 30.4

Non-dominant (kg) 29.9c,d 7–53 50.6 27–74 49.0 11–70 <0.001 30.4

Static Steadiness

Dominant

Number 360c,d 20–1136 156 13–656 212 25–603 <0.001 18.5

Time (s) 20.5c,d 1.9–69.8 7.2 0.4–37.7 13.3 0.9–32.0 <0.001 22.2

Non-dominant

Number 348c,d 62–1121 170 26–624 221 28–808 <0.001 18.5

Time (s) 23.3c,d 4.7–75.0 10.2 0.3–41.8 15.4 1.0–41.8 <0.001 14.8

Digit Span

Forwards (no.) 5.3c 4–8 5.9c 4–9 5.6 4–7 0.14 0

Backwards (no.) 3.4 2–6 3.6 2–8 3.9 3–6 0.18 20.0

Digit Symbol (no.) 31.1c,d 17–50 41.4c 20–72 43.1d 25–65 <0.001 28.0

a The prevalence of patients scoring poorer than the mean and 2 standard deviations of the referents or the 2nd percentile for log-transformed variables.b AM: arithmetic mean.c p < 0.05 between patients and welders.d p < 0.05 between patients and referents.e GM: geometric mean.f N = 23, four female patients excluded.


they are all former welders recruited from the same

geographical area. The current welders had somewhat higher

alcohol consumption than the referents, but this potential

confounder had no statistically significant impact in the

regression modelling of the test results. The self-reported

Fig. 3. The association between the Finger Tapping test performance on the dominan

related manganism.

alcohol consumption is compatible with other cross-sectional

studies of Mn-exposed populations (Lucchini et al., 1999;

Roels et al., 1999).

The main results were the slightly poorer performance on the

Finger Tapping and the Digit Symbol tests of the currently

t and the non-dominant hand in 27 former welders diagnosed as having welding-

Table 7

Results on the CATSYS Sway test with eyes open and blindfolded, TREMOR 7.0 and the maximum frequency test in patients diagnosed with manganism, welders

and referents above 41 years of age

Patients (N = 27) Welders (N = 42) Referents (N = 42) pANOVA %a

AMb Range AM Range AM Range

TREMOR 7.0

Dominant

Tremor intensity (m/s2)c 0.16 0.06–0.98 0.14 0.06–0.71 0.13 0.07–0.32 0.22 7.4

Central frequency (Hz) 7.4 3.1–11.6 7.8 5.5–12.6 7.2 5.2–11.6 0.27 14.8

Frequency dispersion (Hz) 2.8 1.0–4.4 3.1 0.2–5.4 2.8 0.2–4.9 0.36 0

Harmonic index 0.86 0.74–0.95 0.86 0.70–0.97 0.87 0.70–0.98 0.35 0

Non-dominant

Tremor intensity (m/s2)c 0.16 0.07–0.55 0.14 0.06–0.54 0.14 0.07–0.45 0.53 3.7

Central frequency (Hz) 7.4 3.1–12.1 7.5 1.6–10.9 7.9 5.0–12.3 0.41 11.1

Frequency dispersion (Hz) 3.0 0.7–4.9 3.4 1.0–6.1 3.0 0.7–4.6 0.13 7.4

Harmonic index 0.84 0.72–0.96 0.85 0.72–0.96 0.86 0.70–0.97 0.51 0

Maximum frequency

Dominant (Hz) 4.0d,e 1.0–7.5 4.9 1.0–7.5 5.7 3.0–7.5 <0.001 11.1

Non-dominant (Hz) 3.8d,e 1.0–6.7 4.8 1.0–7.5 5.4 2.7–7.5 <0.001 11.1

Postural Sway test

Eyes open

Transversal x (mm) 3.6d,e 1.8–6.0 2.8 1.1–5.4 2.7 1.1–5.3 0.003 29.6

Sway area (mm2)c 381d,e 104–1567 219 56–948 228 67–1328 0.003 4.0

Mean sway (mm) 7.8d,e 3.3–17.7 5.7 2.3–15.6 5.3 2.7–11.2 <0.001 29.6

Intensity (mm) 6.7d,e 2.8–13.9 4.5 1.8–14.2 4.4 1.8–10.4 <0.001 18.5

Sagittal y (mm)c 5.3d,e 2.3–17.1 3.9 1.7–14.3 3.7 1.9–9.7 0.003 14.8

Sway velocity (mm/s) 14.3d,e 6.0–32.2 9.6 4.8–20.6 10.0 5.2–23.2 <0.001 25.9

Blindfolded

Transversal x (mm) 5.0d,e 2.0–22.4 3.2 1.5–6.5 3.1 1.3–6.1 <0.001 29.6

Sway area (mm2)c 1077d,e 173–10,872 350 81–3183 319 72–1293 <0.001 29.6

Mean sway (mm) 10.6d,e 3.9–36.4 6.1 3.0–15.3 5.6 2.8–11.6 <0.001 33.3

Intensityc (mm) 10.16d,e 3.4–35.9 5.8 2.6–21.6 5.3 2.7–8.7 <0.001 55.6

Sagittal y (mm)c 8.0d,e 2.6–28.3 4.4 1.8–12.7 4.0 1.8–8.9 <0.001 51.9

Sway velocity (mm/s) 23.8d,e 8.6–93.3 13.9 7.2–53.4 13.6 5.8–21.3 <0.001 51.9

a The prevalence of patients scoring poorer than the mean and 2 standard deviations of the referents or the 2nd percentile for log-transformed variables.b AM: arithmetic mean.c GM: geometric mean.d p < 0.05 between patients and welders.e p < 0.05 between patients and referents.


exposed welders. Poorer performance was associated with

increasing air-Mn or B-Mn, which strengthens the evidence of

Mn being the causative agent. Poorer Finger Tapping test

performance has been reported in Mn-exposed populations

(Bowler et al., 2003, 2006; Chia et al., 1993; Iregren, 1990;

Lucchini et al., 1999). However, relationship between dose and

response are rare. Poorer performance was associated with a

current full-shift GM exposure to Mn in the welding aerosol of

423 mg/m3 (range 204–2322). That the patients’ performance

on the Finger Tapping test was relatively the poorest among all

areas tested adds evidence to suggest that Finger Tapping test

performance truly may be related to Mn-exposure in

chronically exposed welders.

The association between the Digit Symbol test and B-Mn

suggests impaired performance to be related to exposure from

welding resulting in 5.1 mg/L higher B-Mn on average than in

the referents. Poorer Digit Symbol performance has been

reported previously (Bowler et al., 2003, 2006; Chia et al.,

1993; Lucchini et al., 1999). Associations between Mn in

biological matrices and neurobehavioral performance has

rarely been observed. A dose–response relationship was not

found for the Digit Span test (backwards) when using stratified

analysis. Thus the overall group difference found for this test

should be interpreted with caution, especially because the

performance of the patients was similar to referents.

The currently exposed welders performed significantly

better on the Static Steadiness test when compared to the

referents. We have observed this phenomenon in welders

previously (Bast-Pettersen et al., 2000). The task of this test is

to keep a steady hand in a small space. This is similar to what

welders do during work, suggesting work practice to be of

importance. However, the results are in contrast to a recent

study that reported a very high prevalence of impairments in the

harmonic index of the CATSYS test battery when compared to

normative data of age and education matched participants from

another study (Bowler et al., 2007).

The poorer test performance in the welders is associated

with measures that may be regarded as indices of current


exposure. The duration of exposure did not contribute to the

statistical models. However, possible effects of cumulative

exposure cannot be ruled out. Previous studies have reported

signs of partial reversibility in neurological functions upon

removal from exposure (Olanow et al., 1996) which is in

accordance with Roels et al. (1999), who reported improved

performance in eye-hand coordination when exposure

decreased. This could suggest that some effects of exposure

partly may be reversible. In support of this view is the

observation that the current welders had higher serum prolactin

levels than the referents, but the patients had not (Ellingsen

et al., 2007). In contrast, Lucchini et al. (1999) reported in the

early states an association between cumulative exposure and

neurobehavioral test results. Whether neurotoxic effects are

related to low long-term exposure or instantaneous high peak

exposures has yet to be determined.

The mechanisms of Mn neurotoxicity are not completely

understood. The down-regulation of D1-receptors, increased

striatal dopamine transporter, reduced striatal dopamine nerve

endings and transient decreased D2-receptors in primates point

to an involvement of the dopaminergic system (Chen et al.,

2006; Eriksson et al., 1992a,b). Thus, it is of interest that Mn-

intoxicated workers clinically improved after treatment with

dopamine-agonists (Huang et al., 1989). The rate-limiting step

of the dopamine synthesis is dependent on the iron-containing

enzyme tyrosine hydroxylase (TH), converting tyrosine to L-

Dopa. Altered TH activity in several rat brain areas and

reversible alterations of the tyrosine hydroxylation after

administration of MnCl2 have been reported (Bonilla, 1980;

Daniels and Abarca, 1991; Deskin et al., 1980). Whether an

interaction between Mn and iron at the level of the dopamine

synthesis is of relevance for the neurotoxicity remains to be

elucidated.

The neurobehavioral test profile of the patients was

dominated by impaired motor speed and fine manipulative

dexterity. Few patients only had increased hand tremor or

impaired function of hand supination/pronation. Postural sway

under regular conditions was affected in only some of the

patients, but more patients appeared to be affected when

blindfolded. Immediate attention capacity was unaffected. A

slight impairment in short term memory may be present. The

patients have many subjective symptoms indicating a

neurasthenic clinical picture.

It is clinically challenging to differentiate between PD and

manganism. However, some features in these patients favour

the diagnosis of welding-related manganism. They received the

diagnosis when they were between only 34 and 51 years old,

which is comparable to the age at onset in a previous study of

welders (Racette et al., 2001). The occurrence of parkinsonism

in this age is rare. The incidence of 3 cases/100,000 years in the

age group 30–49 has been reported in the USA (Schrag and

Schott, 2006). There are about 17,000 welders in the St.

Petersburg area (V. Chashchin, personal communication).

Hand tremor was not significant on the CATSYS in the

patients, and the tremor frequency was similar to that of the

referents. Tremor at rest is one of the cardinal symptoms in PD.

However, pure rest tremor is infrequent and a combination of

rest and postural tremor is more common (Bhidayasiri, 2005;

Koller et al., 1989). Postural tremor without visual feedback

discriminated better between PD patients and referents than rest

tremor (Beuter and Edwards, 1999). Tremor may occur in

manganism, but is not one of the main signs (Calne et al., 1994;

Mena et al., 1967). Few studies have used the CATSYS tremor

recording system in PD, but substantially higher tremor

intensity when compared to referents and also compared to our

patients has been reported (Biernat et al., 1999; Farkas et al.,

2006). A mixture of postural and resting tremor, lower central

frequency and a more narrow frequency dispersion in PD

compared to their referents was recorded by Farkas et al.

(2006). This was not found in our patients. Farkas et al. (2006)

reported a statistically significant different performance

between the better hand and the poorer hand in PD, but not

in their referents. The TI was 2.5 times higher in the more

affected hand than in the less affected hand in PD. Our patients

and the referents had only 1.3 times higher TI in the more

affected hand, suggesting that qualitative and quantitative

aspects of the hand tremor in our patients differ substantially

from PD.

The bilateral difference in motor performance of the patients

is about of the same magnitude as in the referents, indicating a

symmetrical manifestation of their disease. There is a common

recognition that asymmetric neurological performance is a

main feature of PD, but the causes for the unilaterality are

largely unknown (Djaldetti et al., 2006). This clinical

experience of PD has been studied rarely with neurobehavioral

tests.

The patients have a neurasthenic clinical picture, their major

subjective symptom being severe headache. Severe headache is

a frequently reported symptom in manganism (Rodier, 1955).

In contrast, it is unknown whether a specific mechanism of

headache exists in PD, and whether headache is more or less

frequent in PD than in a normal population (Ford, 1998). Thus,

it appears that headache, at least among the patients in this

study, is more prevalent than in PD.

We have previously reported that the patients have

significantly higher B-Mn as compared to the referents

(Ellingsen et al., 2006). This could suggest a substantial

previous exposure, but data on long-term accumulation of Mn

are rare. We have in these patients also measured biomarkers

indicating testicular dysfunction (Ellingsen et al., 2007).

Testicular pathology in combination with impairments of the

CNS is not known in PD. However, testicular pathology has

previously been observed in Mn-exposed animals at high

exposure (Chandra et al., 1973). This indicates that our patients

could have pathological changes which is not known to be

related to PD, in addition to their CNS affections.

In summary, associations between exposure and neurobe-

havioral performance have been shown in currently exposed

welders, and the most highly exposed subgroups differ

statistically significantly from their age-matched referents in

the Finger Tapping and Digit Symbol test performance. This

may indicate acute effects of exposure to Mn. The findings in

the patients are compatible with bradykinesia. Hand tremor was

not a prominent finding.


Acknowledgement

The study was carried out with financial support from

International Manganese Institute, Paris, France.

References

Antonini JM, Taylor MD, Zimmer AT, Roberts JR. Pulmonary responses to

welding fumes: role of metal constituents. J Toxicol Environ Health (Part A)

2003;67:233–49.

Bast-Pettersen R, Skaug V, Ellingsen D, Thomassen Y. Neurobehavioral

performance in aluminium welders. Am J Ind Med 2000;37:184–92.

Bast-Pettersen R, Ellingsen DG, Hetland SM, Thomassen Y. Neuropsycholo-

gical function in manganese alloy plant workers. Int Arch Occup Environ

Health 2004;77:277–87.

Bast-Pettersen R, Ellingsen DG. The Kløve–Matthews Static Steadiness test

compared with the DPD TREMOR; comparison of fine motor control task

with measures of tremor in smokers and manganese-exposed workers.

Neurotoxicology 2005;26:331–42.

Beuter A, Edwards R. Using frequency domain characteristics to discriminate

physiologic and Parkinsonian tremors. J Clin Neurophysiol 1999;16:

484–94.

Beuter A, Mergler D, deGeoffry A, Carriere L, Belanger S, Varghese L, et al.

Diadochokinesimetry: a study of patients with Parkinson’s disease and

manganese exposed workers. Neurotoxicology 1994;15:655–64.

Bhidayasiri R. Differential diagnosis of common tremor syndromes. Postgrad

Med J 2005;81:756–62.

Biernat H, Ellias SA, Wermuth L, Cleary D, De Oliveira Santos EC, Jørgensen

PJ, et al. Tremor frequency patterns in mercury vapour exposure, compared

with early Parkinson’s disease and essential tremor. Neurotoxicology

1999;20:945–52.

Bonilla E. L-Tyrosine hydroxylase activity in the rat brain after chronic oral

administration of manganese chloride. Neurobehav Toxicol 1980;2:37–41.

Bowler RM, Gysens S, Diamond E, Booty A, Hartney C, Roels HA. Neurop-

sychological sequelae of exposure to welding fumes in a group of occu-

pationally exposed men. Int J Hyg Environ Health 2003;206:517–29.

Bowler RM, Gysens S, Diamond E, Nakagawa S, Drezgic M, Roels H.

Manganese exposure: neuropsychological and neurological symptoms

and effects in welders. Neurotoxicology 2006;27:315–26.

Bowler RM, Roels HA, Nakagawa S, Drezgic M, Diamond E, Park R, et al.

Dose-effect relationships between manganese exposure and neurological,

neuropsychological and pulmonary function in confined space bridge

welders. Occup Environ Med 2007;64:167–77.

Calne DB, Chu N-S, Huang C-C, Lu C-S, Olanow W. Manganism and

idiopathic parkinsonism: similarities and differences. Neurology 1994;44:

1583–6.

Chandra SV, Aar R, Nagar N, Seth PK. Sterility in experimental manganese

toxicity. Acta Biologica et Medica Germanica 1973;30:857–62.

Chen M-K, Lee J-S, McGlothan JL, Furukawa E, Adams RJ, Alexander M, et

al. Acute manganese administration alters dopamine transporter levels in

the non-human primate striatum. Neurotoxicology 2006;27:229–36.

Chia SE, Foo SC, Gan SL, Jeyaratnam J, Tian CS. Neurobehavioral function

among workers exposed to manganese ore. Scand J Work Environ Health

1993;19:264–70.

Cook DG, Fahn S, Brait KA. Chronic manganese intoxication. Arch Neurol

1974;30:59–64.

Couper J. On the effects of black oxide of manganese when inhaled into the

lungs. Br Ann Med Pharm 1837;1:41–2.

Daniels AJ, Abarca J. Effect of intranigral Mn2+ on striatal and nigral synthesis

and levels of dopamine and cofactor. Neurotoxicol Teratol 1991;13:483–7.

Danish Product Development Ltd. (DPD). User’s manual. Snekkersten, Den-

mark: DPD; 1996.

Deskin R, Bursian SJ, Edens FW. Neurochemical alterations induced by

manganese chloride in neonatal rats. Neurotoxicology 1980;2:65–73.

Djaldetti R, Ziv I, Melamed E. The mystery of motor asymmetry in Parkinson’s

disease. Lancet Neurol 2006;5:796–802.

Ellingsen DG, Dubeikovskaya L, Dahl K, Chashchin M, Chashchin V, Zibarev

E, et al. Air exposure assessment and biological monitoring of manganese

and other welding fume components in welders. J Environ Monit 2006;8:

1078–86.

Ellingsen DG, Chashchin V, Haug E, Chashchin M, Tkachenko V, Lubnina N,

et al. An epidemiological study of reproductive function biomarkers in male

welders. Biomarkers 2007;12(5):497–509.

Emara AM, El-Ghawabi. Madkour OI, El-Samra GH. Chronic manganese

poisoning in the dry battery industry. Br J Ind Med 1971;28:78–82.

Eriksson H, Gillberg P-G, Aquilonius S-M, Hedstrom K-G, Heilbronn E.

Receptor alterations in manganese intoxicated monkeys. Toxicology

1992a;66:359–64.

Eriksson H, Tedroff J, Thuomas KA, Aquilonius S-M, Hartvig P, Fasth KJ, et al.

Manganese induced brain-lesions in macaca fascicularis as revealed by

positron emission tomography and magnetic resonance imaging. Arch

Toxicol 1992b;66:403–7.

Farkas Z, Csillik A, Szirmai I, Kamondi A. Asymmetry of tremor intensity and

frequency in Parkinson’s disease and essential tremor. Parkinsonism Relat

Disord 2006;12:49–55.

Ford B. Pain in Parkinson’s disease. Clin Neurosci 1998;5:63–72.

Hochberg F, Miller G, Valenzuela R, McNelis S, Crump KS, Covington T, et al.

Late motor deficits of Chilean manganese miners: a blinded control study.

Neurology 1996;47:788–95.

Huang C-C, Chu N-S, Lu C-S, Wang J-D, Tsai J-L, Tzeng J-L, et al. Chronic

manganese intoxication. Arch Neurol 1989;46:1104–6.

Iregren A. Psychological test performance in foundry workers exposed to low

levels of manganese. Neurotoxicol Teratol 1990;12:673–5.

Kim Y, Kim KS, Yang JS, Park IJ, Kim E, Jin Y, et al. Increase in signal

intensities on T1-weighted magnetic resonance images in asymptomatic

manganese-exposed workers. Neurotoxicology 1999;20:901–8.

Koller WC, Vetere-Overfield B, Barter R. Tremors in early Parkinson’s disease.

Clin Neuropharmacol 1989;12:293–7.

Lezak MD. Neuropsychological assessment. New York: Oxford University

Press; 1995.

List of Occupational Diseases. Ministry of Health and Medical Industry of the

Russian Federation. Order no. 90, Appendix no., 1996.

Lucchini R, Selis L, Folli D, Apostoli P, Mutti A, Vanoni O, et al. Neurobe-

havioral effects of manganese in workers from a ferroalloy plant after

temporary cessation of exposure. Scand J Work Environ Health 1995;21:

143–9.

Lucchini R, Apostoli P, Perrone C, Placidi D, Albini E, Migliorati P, et al. Long

term exposure to ‘‘low levels’’ of manganese oxides and neurofunctional

changes in ferroalloy workers. Neurotoxicology 1999;20:287–98.

Lundberg I, Hogberg M, Michelsen H, Nise G, Hogstedt C. Evaluation of the

Q16 questionnaire on neurotoxic symptoms and a review of its use. Occup

Environ Med 1997;54:343–50.

Matthews CG, Kløve H. Instruction manual for the adult neuropsychological

test battery. Madison, WI: University of Wisconsin Medical School; 1964.

McMillan DE. A brief history of the neurobehavioral toxicity of manganese:

some un-answered questions. Neurotoxicology 1999;20:499–508.

Mena I, Marin O, Fuenzalida S, Cotzias GC. Chronic manganese poisoning.

Clinical picture and manganese turnover. Neurology 1967;17:128–36.

Mergler D, Huel G, Bowler R, Iregren A, Belanger S, Baldwin M, et al.

Nervous system dysfunction among workers with long-term exposure to

manganese. Environ Res 1994;64:151–80.

Normandin L, Hazell AS. Manganese neurotoxicity: an update of pathophy-

siologic mechanism. Metabol Brain Dis 2002;17:375–87.

Olanow CW, Good PF, Shinotoh H, Hewitt KA, Vingerhoets F, Snow BJ, et al.

Manganese intoxication in the rhesus monkey: a clinical, imaging, patho-

logic, and biochemical study. Neurology 1996;46:492–8.

Pal PK, Samii A, Calne DB. Manganese neurotoxicity: a review of clinical

features, imaging and pathology. Neurotoxicology 1999;20:227–8.

Racette BA, McGee-Minnich L, Moerlein SM, Mink JW, Videen TO, Perl-

mutter JS. Welding related parkinsonism; clinical features, treatment, and

pathophysiology. Neurology 2001;56:8–13.

Reitan RM, Wolfson D. The Halstead-Reitan Neuropsychological Test

Battery. In: Theory and clinical implication. Arizona: Neuropsychology

Press; 1985 .


Rodier J. Manganese poisoning in Moroccan miners. Br J Ind Med 1955;12:

21–35.

Roels H, Lauwerys R, Buchet JP, Genet P, Sarhan MJ, Hanotiau I, et al.

Epidemiological survey among workers exposed to manganese: effects on

lung, central nervous system, and some biological indices. Am J Ind Med

1987;11:307–27.

Roels HA, Ghyselen P, Buchet JP, Ceulemans E, Lauwerys RR. Assessment of

permissible exposure level to manganese in workers exposed to manganese

dioxide dust. Br J Ind Med 1992;49:25–34.

Roels HA, Ortega Eslava MI, Ceulemans E, Robert A, Lison D.

Prospective study on the reversibility of neurobehavioral effects in

workers exposed to manganese dioxide. Neurotoxicology 1999;20:

255–72.

Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of

early-onset parkinsonism. Lancet Neurol 2006;5:355–63.

Siegl P, Bergert K-D. Eine fruhdiagnostische Uberwachungsmetode bei Man-

ganexposition. Z Ges Hyg 1982;28:524–6 [in German].

Sjogren B, Iregren A, Frech W, Hagman M, Johansson L, Tesarz M, et al.

Effects on the nervous system among welders exposed to aluminium and

manganese. Occup Environ Med 1996;53:32–40.

Tanaka S, Lieben J. Manganese poisoning and exposure in Pennsylvania. Arch

Environ Health 1969;19:674–84.

Voitkevich V. Welding fume properties. In: Welding fumes—formation, proper-

ties and biological effects. Abington, England: Cambridge; 1995 p. 18–71.

Wang X, Yang Y, Wang X, Xu S. The effect of occupational exposure to metals

on the nervous system function in welders. J Occup Health 2006;48:100–6.

a neurobehavioral study of current and former welders exposed to manganese

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