Supplement 2. Studies assessing exposure to manganese and neurodevelopmental/cognitive or behavioral outcomes.
Authors &
Study design Location
Year
Neurodevelopment / Cognition
Chung et al.
Prospective
South
2015 [68]
cohort
Korea
Sample
size
Exposure Measure
[Reported level]
Outcome
Measure
Confounders
Major Finding
232
Blood Mn at delivery
[Mean: 22.5 μg/L,
Median: 21.3 μg/L]
BSID-II at 6
mo
Inverted U-shape
association with PDI
(p<0.05) and MDI
(p=0.07). Threshold of
24-28 μg/L identified.
Yu et al. 2014
[67]
Prospective
cohort
China
933
Cord blood serum
Mn
[Median: 4.0 μg/L]
NBNA at 3
days old
Lin et al. 2013
[61]
Prospective
cohort
Taiwan
230
Cord blood Mn
[Median: 47.9 μg/L,
Range: 17.9-106.9
μg/L]
CDIIT at 2
yrs
Claus Henn et
al. 2010 [58]
Prospective
cohort
Mexico
448
Blood Mn at 1 and 2
yrs
[Mean12mo: 24.3 μg/L,
Median12mo 23.7
MDI and
PDI (BSIDII) at 1 and
2.5 yrs
Maternal age,
gestational age (days),
monthly income,
breastfeeding status,
maternal total caloric
intake, birth order,
residence, child’s
gender, and birth weight.
Maternal age, maternal
education* family
income, paternal
education, parents’
occupation, second-hand
smoke, gestational age,
child’s gender, birth
weight, Pb and Hg
exposure.
Maternal age, child’s
gender, environmental
tobacco smoke during
pregnancy and after
delivery, HOME, As and
Hg in cord blood.
Child’s gender, blood
lead, maternal IQ,
maternal education,
child’s hemoglobin,
Significant inverse
relationship with
NBNA score, behavior,
active tone, and general
reactions. Threshold of
5 μg/L identified.
Significant inverse
association with overall
score, cognitive, and
language
developmental
quotients.
Inverted U-shape
association with mental
development scores at 1
yr. No association with
μg/L]
Hair Mn
[Median: 11.48 μg/g,
Range: 0.52-55.74
μg/g]
IQ and
working
memory
(WISC), and
cognitive
flexibility
(WCST) at
7-12 yrs
Nonverbal
IQ (RCPM)
score at 612 yrs
5 cognition,
language,
and motor
domains
(BSID III)
at 1-4 yrs
gestational age
Maternal education
(WISC model) as well as
child’s age (Working
Memory model).
2-yr Mn levels.
Significant inverse
association with IQ
(vocabulary and block
design) and working
memory (digit span).
Child’s age and gender,
and parents’ education.
Significant inverse
association with IQ.
Child’s age (model 1) as
well as HOME,
hemoglobin, maternal
IQ, SES, hair Pb, marital
status, paternal
education, tester (full
model)
Unadjusted models
showed hair Mn was
significantly inversely
associated with
cognition and language,
which persisted among
girls when stratified.
No significant effects in
adjusted model.
Increasing Mn was
associated with
significant deficits in
thinking, reading,
calculations, and LQ in
the LDES. No
association with IQ.
Poorer performance on
the color test with low
Mn. 
No individual effect of
Carvalho et al.
2014 [57]
Crosssectional
Brazil
70
do Nascimento
et al. 2014
[59]
Crosssectional
Brazil
50
Hair Mn
[Rangehair: 0.09-11.5
μg/ga]
Rink et al.
2014 [64]
Crosssectional
Uruguay
60
Hair Mn
[Mean: 0.98 μg/g,
Range: 0.2-3.9 μg/g]
Bhang et al.
2013 [55]
Crosssectional
South
Korea
1001
Blood Mn
[Median: 14.14 μg/L]
IQ (WASI)
and
academic
function
(LDES) at
8-11 yrs
Child’s age, gender, and
IQ, region, maternal
education, maternal age
(model 1) as well as
urine cotinine (model 2),
and blood lead (model
3).
Lucchini et al.
Cross-
Italy
299
Blood Mn
FSIQ, VIQ,
Not reported.
[Mean: 111 μg/L,
Range: 40-241 μg/L]
2012 [62]
sectional
and PIQ
(WISC) at
11-14 yrs
6 verbal
memory and
learning
subscales
(CAVLT) at
7-11 yrs
TorresAgustin et al.
2012 [66]
CrossSectional
Mexico
174 (79
vs. 95)
Hair and blood Mn
[MedianHair: 12.6
μg/g, Medianblood: 9.5
μg/L (among
exposeda)]
Bouchard et
al. 2011 [56]
Crosssectional
Canada
362
Drinking water and
hair Mn
[Medianwater: 34 μg/L,
Rangewater: 1-2700
μg/L;
Rangehair: 0.1-21
μg/g]
FSIQ, VIQ,
PIQ (WASI)
at 6-13 yrs
Menezes-Filho
et al. 2011
[63]
Crosssectional
Brazil
83
FSIQ, VIQ,
PIQ (WISCIII) at 6-12
yrs
RiojasRodriguez et
al. 2010 [65]
Crosssectional
Mexico
172 (79
vs. 93)
Hair and blood Mn
[Meanblood: 8.2 μg/L,
Range: 2.7-23.4
μg/L;
Meanhair: 5.8 μg/L,
Range: 0.1-86.7
μg/L]
Blood and Hair Mn
[MedianHair: 12.6
μg/g, Medianblood: 9.5
μg/L (among
exposeda)]
FSIQ, VIQ,
PIQ (WISC)
at 7 -11 yrs
Mn.
Child’s gender, blood
lead, age, hemoglobin,
and maternal education.
Hair Mn was
significantly inversely
associated with longterm memory and
learning. Blood Mn had
a negative, but nonsignificant association.
Maternal verbal IQ,
Significant inverse
maternal education,
association with IQ
family income, home
scores for both hair
stimulation score, and
(FSIQ) and drinking
family structure (model
water Mn (FSIQ, PIQ,
A), as well as child’s age and VIQ).
and gender, test session
time, source of water,
iron level in tap water
(model B)
Maternal education and
Hair Mn was
child’s nutritional status. significantly inversely
associated with FSIQ
and VIQ. No
association with blood
Mn.
Child’s gender, blood
lead, age, hemoglobin,
and maternal education.
Hair Mn was
significantly inversely
associated with PIQ
VIQ and FSIQ. Blood
Mn had an inverse, but
non-significant
Kim et al.
2009 [60]
Crosssectional
South
Korea
261
Blood Mn
[Mean 14.3 μg/L,
Range: 5.3-29.0
μg/L]
FSIQ, VIQ
PIQ (WISC)
at 8-11 yrs
Child’s age, gender,
maternal education,
paternal education,
family income (model 2)
as well as maternal
smoking during
pregnancy, birth weight,
maternal age, smoking
status of child (model 3)
Behavior
Carvalho et al.
2014 [57]
Crosssectional
Brazil
70
Hair Mn
[Median: 11.48 μg/g,
Range: 0.52-55.74
μg/g]
Attention
(TAVIS-3R)
at 7-12 yrs
Maternal education and
child’s age
Bhang et al.
2013 [55]
Crosssectional
South
Korea
1001
Blood Mn
[Median: 14.14 μg/L]
Not reported.
Lucchini et al.
2012 [62]
Crosssectional
Italy
299
Blood Mn
[Mean: 111 μg/L,
Range: 40-241 μg/L]
Attention/A
DHD (ADS,
CCTT,
ADHD
rating scale,
and DISCIV) and
CBCL at 811 years
10 behavior
subscales
(CASS:L)
yrs 11-14
Not reported.
association FSIQ and
VIQ.
Significant inverse
association with VIQ
and FSIQ.
Significantly higher
commission error
(impaired performance)
with higher Mn tertiles.
Omission and
commission errors were
significantly associated
with gender.
Increasing Mn was
associated with higher
commission error
(impaired performance)
in the ADS test
(unadjusted). No
association with CBCL.
No individual effect of
Mn.
Khan et al.
2011 [71]
Crosssectional
Banglade
sh
201
Drinking water and
blood Mn
[Meanwater: 889 μg/L,
Range: 40-3442
μg/L; [Meanblood: 15.1
μg/L, Range: 6.333.9 μg/L]]
Abdullah et al.
2012 [69]
Case-control
USA
84
Yousef et al.
2011 [54]
Case-control
UAE
92
(18/74)
Farias et al.
2010 [70]
Case-cohort
Brazil
166
(106/74
taking
medicati
on)
Prenatal and postnatal ASD (ADItooth Mna
R), HDB
(DBD rating
scale) at 914 yrs
Blood Mn
ADHD
[Not reported; Range: (STI-CRS)
~0 – 2.5 μg/L]
at age 5-15
yrs
Serum Mn
ADHD[Mean: 5.2 vs. 2.8
DSM-IV at
μg/La]
7-15 yrs
a
CBCL-TRF
at 8-11 yrs
Water As (model 1) as
well as child’s gender,
BMI, maternal
education, arm
circumference, (model
2), as well as urinary
creatinine (model 3).
None reported.
None reported.
None reported.
Increasing water Mn
levels had a significant
association with
increased internalizing
and externalizing
behavior, and TRF. No
significant association
with blood Mn.
Marginally significant
association between
cases of ASD and
decreased postnatal Mn
compared to controls.
Significant increased
odds of ADHD with
increased Mn
Cases of ADHD not
taking medication had
significantly higher Mn
levels than cases with
ADHD taking
medication. Treatment
with methylphenidate
medication
significantly reduced
blood Mn.
See manuscript for detailed information.
ADHD attention deficit hyperactivity disorder, ADHD-DSM ADHD Diagnostic and Statistical Manual of Mental Disorders, ADI-R
Autism Diagnostic Interview-Revised, ADS Attention-Deficit/hyperactivity disorder Diagnostic System, ASD Autism spectrum
disorder, BSID Bayley Scales of Infant Development, CAVLT Children’s Auditory Verbal Learning Test, CASS:L Conners-Wells’
Adolescent Self-Report Scale Long Form, CBCL-TRF Teachers Report Form, CCTT Children’s Color Trails Test, CDIIT
Comprehensive Developmental Inventory for Infants and Toddlers, DBD Disruptive Behavior Disorders, DISC Diagnostic Interview
Schedule for Children Version IV, FSIQ Full scale IQ, HDB high levels of disruptive behavior, HOME Home Observation for
Measurement of the Environment, IQ intelligence quotient, LDES Learning Disability Evaluation scale, MDI mental development
index, NBNA Neonatal Behavioral Neurological Assessments, PDI psychomotor development index, PIQ Performance IQ, RCPM
Raven’s Colored Progressive Matrices, STI-CRS Short Ten-Item Conners’ Rating Scale, TAVIS Test of Visual Attention, VIQ Verbal
IQ, WASI Wechsler Abbreviated Scale of Intelligence, WCST Wisconsin card sorting test, WISC Wechsler Intelligence Scale for
Children.