Neurodevelopmental impacts of prenatal drinking water exposure to manganese and other metals on children

Manganese
Exposure

1

Neurodevelopmental
impacts
of
prenatal
drinking
water
exposure
to
manganese

and
other
metals
on
children

Jeronda
Scott
and
Melissa
Miller

Clark
University

Manganese
Exposure

2

Neurodevelopmental
impacts
of
prenatal
drinking
water
exposure
to
manganese

and
other
metals
on
children

Jeronda
Scott
and
Melissa
Miller

Abstract

The
aim
of
this
paper
was
to
review
the
scientific
research
published
to
date
on
the

potential
effects
on
neurodevelopment
and
behavioral
disorders
in
children

exposed
to
manganese
and
other
metals
via
drinking
water
and
optimum

biomarkers
to
measure
exposure.
This
was
done
by
using
online
research
databases

such
as
Google
Scholar
and
PubMed,
etc.
It
was
found
that
there
is
an
association

between
exposure
to
manganese
and
neurodevelopmental
deficits
in
young

children,
and
that
there
are
large
gaps
in
the
body
of
research
that
must
be
done
to

better
understand
these
issues.
Improvements
to
exposure
limits
must
be
made.
We

hope
that
further
research
on
optimal
biomarkers,
such
as
dentine,
will
help
to

contribute
to
the
knowledge
of
negative
neurological
impacts
from
manganese

exposure.

1.
Introduction

Manganese
(Mn)
is
an
essential
nutrient
found
in
all
living
organisms
and
is

naturally
present
in
rocks,
soil,
water,
and
food
making
it
abundant
in
the

environment.
It
is
important
to
understand
its
potential
impacts
not
only
because
of

its
natural
abundance
but
also
because
it
is
a
recent
gasoline
additive
and
may
be

even
more
widespread
in
the
environment
in
the
future
(Schettler,
Solomon,
&

Manganese
Exposure

3

Valenti,
2000).
Mn
is
required
for
normal
amino
acid,
lipid,
protein,
and

carbohydrate
metabolism
(Erikson,Thompson,
&
Aschner,
2007)).
However,

overexposure
to
Mn
can
have
significant
neurotoxic
effects,
and
it
is
likely
that
there

is
a
greater
effect
on
fetuses,
newborns,
and
young
children.
Due
to
lack
of
research,

Mn
concentrations
in
drinking
water
are
not
currently
regulated
in
the
United

States.
Health
based
guidelines
for
the
maximum
level
of
Mn
in
drinking
water
have

been
established
by
the
EPA,
and
are
currently
set
at
300
µg/L
(U.S.
EPA
2004).

While
there
is
a
healthy
amount
of
research
analyzing
the
effects
of
postnatal
and

occupational
exposure
to
Mn,
there
is
a
lack
of
research
and
evidence
of
the
effects

of
Mn
exposure
on
a
more
vulnerable
group,
babies
in
utero
and
young
children.

The
Holliston
Health
Project
is
a
collaborative
initiative
to
examine
if

children
in
the
town
of
Holliston,
Massachusetts
are
being
exposed
to
detrimental

levels
of
chemicals,
and
if
this
exposure
is
leading
to
any
adverse
health
effects.
In

this
literature
review
we
closely
examine
Mn
and
other
heavy
metals
and
their

effects
on
children
from
in
utero
to
age
10.
The
purpose
of
this
literature
review
is
to

support
the
Holliston
Health
Project
by
providing
an
in-‐depth
look
at
the
state
of

research
for
a
variety
of
chemicals
and
their
potential
impact
on

neurodevelopmental-‐cognitive-‐behavioral
outcomes
from
exposure
during

pregnancy,
and
biomarkers
that
can
be
used
to
measure
those
exposures.

2.
Background

2.1
Manganese
Metabolism
in
Children

Manganese
Exposure

4

Mn
is
crucial
to
bone
and
tissue
development
as
well
as
the
immune
system.

However,
there
are
many
correlations
between
excessive
postnatal
exposure
to
Mn

and
interference
with
normal
brain
development
(Wasserman
et
al.
2006,
Bouchart

et
al.
2010,
Khan
et
al.
2011).
Too
much
exposure
can
cause
Mn
to
accumulate
in
the

brain,
particularly
the
central
nervous
system,
leading
to
neurological
damage.
Since

Mn
is
an
essential
element,
it
stands
that
there
should
be
a
level
above
which

negative
impacts
will
occur.

Infants
and
young
children
face
higher
risks
from
exposure
to
metals
than

adults
because
adults
have
fully
developed
homeostatic
mechanisms
which
limit

absorption
of
ingested
metals.
Because
infants
and
young
children
have
not

completely
developed
these
mechanisms,
their
bodies
are
unable
to
correctly

process
these
metals,
and
retention
of
metals
is
higher
in
infants
than
in
adults.

According
to
Lönnerdal
(1994)
bile
flow
is
low
in
infants,
which
may
result
in
a

lower
excretion
of
Mn
via
bile,
causing
higher
retention
of
Mn
in
tissue.
Moreover,

certain
tissue
sites
have
a
high
affinity
for
Mn,
and
although
these
sites
are
saturated

in
adults,
they
strongly
retain
Mn
in
infants
(Ljung
&
Vahter,
2007).

There
is
an
increasing
body
of
evidence
that
internal
and
external
exposures

to
chemicals
and
metals
cause
a
variety
of
physiological
impacts
at
different

developmental
stages.
As
a
consequence,
windows
of
vulnerability
open
when

susceptibility
to
environmental
chemicals
is
heightened.
Therefore
it
is
crucial
to

look
at
the
timing
of
exposures
in
addition
to
levels
of
exposure.
The
prenatal
period

is
specifically
important
when
examining
critical
windows
of
exposure.
During
in

utero
development
and
early
childhood,
the
tissues
and
organs
of
the
body
undergo

Manganese
Exposure

5

stages
of
rapid
development,
during
which
toxic
exposure
or
nutrient
deficiency
can

lead
to
long-‐term
effects.
(Andra,
Austin,
Wright,
&
Arora,
2015).

There
are
two
instances
of
rapid
brain
development
for
infants.
The
first
is

during
pregnancy,
and
the
second
occurs
several
months
after
birth.
The
fetus
is

especially
vulnerable
to
Mn
during
the
development
period
in
utero;
Mn
easily

crosses
the
placenta
through
active
transport
mechanisms,
where
it
results
in

increased
levels
in
fetal
circulation
(Andra
et
al.
2015).
Thus,
fetal
life
can
be

regarded
as
a
period
of
great
vulnerability
to
Mn,
even
at
low
environmental
levels.

Mn
specifically
targets
the
nervous
system,
and
for
a
developing
child,
this
can
mean

interruption
of
crucial
development
of
the
nervous
system
(Yu,
Zhang,
Yan,
&
Shen,

2014).

Since
the
central
nervous
system
develops
sequentially
and
are

interdependent,
any
interruption
in
the
fetal
development
may
lead
to
deficiencies

in
later
stages
of
development
(Rodríguez-‐Barranco,
et
al.
2013).
Beginning
as
soon

as
the
second
week
of
gestation,
the
outer
layer
of
the
embryo
begins
to
fold
to

develop
the
neural
tube,
the
early
beginnings
of
the
brain.
After,
the
central
nervous

system
begins
to
develop,
creating
100
billion
nerve
cells
and
1
trillion
glial
cells,

which
must
undergo
a
slew
of
changes
and
formations
during
the
process
of

development
(Sanders
et
al.
2015).
Because
these
developments
are
successive,
a

reliable
and
effective
biomarker
provides
the
possibility
of
determining
when

exposure
occurred,
and
what
interruptions
took
place,
which
can
then
determine

how
these
interruptions
affect
neurological
development.
The
timing
of

environmental
exposures
is
incredibly
important;
the
time
at
which
the
child
is

Manganese
Exposure

6

exposed
to
the
metal
is
equally
important
as
the
level
of
exposure.
(Andra
et
al.

2015)

2.2
Manganese
Guidelines
for
Drinking
Water
Quality

The
current
United
States
health-‐based
guideline
for
Mn
in
drinking
water
is

partly
based
on
debatable
assumptions,
without
deeper
research.
The
previous

guideline
value
of
500
µg/L
was
set
originally
in
1958
and
was
based
on
the
distinct

impairment
of
water
potability
by
excessive
Mn
concentrations
(WHO
2004).
Due
to

the
staining
properties
of
Mn,
the
guideline
value
was
lowered
to
100
µg/
in
the

World
Health
Organization’s
(WHO)
first
edition
guidelines
for
drinking
water

quality
(Ljung
et
al.
2007).
Various
countries
have
set
standards
for
Mn
of
0.05

mg/liter,
to
prevent
problems
with
discoloration
(WHO
2011).
At
concentrations

above
0.1mg/liter,Mn
gives
water
an
undesirable
taste
and
stains
plumbing
fixtures

and
laundry,
and
at
concentrations
as
low
as
0.02
mg/litre,
Mn
can
form
coatings
on

water
pipes
that
may
later
slough
off
as
a
black
precipitate
(U.S.
EPA.
2004).
Based

on
health
motives,
the
guideline
value
was
raised
to
500
µg/L
in
the
1993
second

edition
(WHO
2004).

Currently,
the
health-‐based
guideline
value
for
Mn
in
water
is
in
the
United

States
400
µg/L.
It
is
based
on
an
estimated
no
observed
adverse
effect
level

(NOAEL)
for
Mn
in
food.
The
NOAEL
of
11
mg
of
Mn
a
day,
is
partly
based
on
a

review
by
Greger
(1998),
who
studied
adults
with
Western
diets.
The
current

guideline
value
for
drinking
water
is
likely
low
enough
to
protect
adolescents
and

adults
but
not
younger
children.
Mn
is
often
considered
one
of
the
least
toxic
metals

Manganese
Exposure

7

via
the
oral
route
due
to
homeostasis
mechanisms
in
the
body
that
limit

gastrointestinal
absorption.
However,
with
the
growing
evidence
of
neurotoxicity

through
oral
routes,
especially
in
infants
and
young
children,
the
guideline
needs
to

be
reevaluated.
Infant
formula
already
contains
high
levels
of
Mn
(300
µg/L
on

average,
but
ranging
between
66
and
856
µg/L,
depending
on
the
brand).
If
formula

is
prepared
with
water
containing
acceptable
levels
of
Mn
based
on
WHO
guidelines,

it
is
highly
possible
that
infants
will
receive
an
unacceptable
dose
of
Mn.(Ljung
et
al.

2007).

3.
Methods

To
understand
the
state
of
the
research,
papers
were
found
from
a
wide

variety
of
subjects
and
compared.
Research
was
compiled
from
PubMed
and
Google

Scholar
using
combinations
of
search
terms
such
as
“manganese”,
“in
utero

exposure”,
“prenatal
exposure”,
“drinking
water”,
“neurodevelopment”,

“neurotoxin”,
“co-‐exposure”
and
so
on.
Additional
papers
were
also
found
through

citations
from
particularly
relevant
papers.

When
using
PubMed,
MeSH
terms
were
used
to
find
similar
papers
listed

under
the
same
topic.
MeSH
terms
that
were
particularly
useful
included

“pregnancy”
“manganese”
“drinking
water”
“neurodevelopment”
and

“women’s/children’s
health”.

Papers
that
were
selected
contained
material
that
demonstrated
relevance
to

our
research
question,
or
that
demonstrated
holes
in
the
current
state
of
research.

4.
Results

4.1
Biomarkers

Manganese
Exposure

8

A
biomarker
is
any
substance
or
metabolite
that
may
be
measured
in
the

body
to
estimate
external
exposure
levels
or
to
predict
the
potential
for
adverse

health
effects
or
disease.
There
is
a
great
need
for
an
effective
biomarker
to
analyze

health
impacts
from
prenatal
exposures,
but
they
are
often
difficult
to
find,
and
are

not
always
accurate;
no
specific
accurate
biomarker
for
Mn
has
been
determined.

Research
has
so
far
relied
on
urine,
umbilical
cord
blood
and
serum,
and
hair.
There

is
new
research
analyzing
the
usefulness
of
tooth
dentine,
which
shows
promise.

(Santamaria
2008,
Arora
et
al.
2015),

4.1.1Hair

Hair
is
a
common
biomarker
used
to
study
the
neurological
effects
of
Mn

contamination
on
young
children.
Using
hair,
Rodríguez-‐Barranco
et
al.
(2013),

found
that,in
relation
to
Mn,
results
of
a
meta-‐analysis
suggest
that
a
50%
increase

in
hair
levels
would
be
associated
with
a
0.7
IQ
decrease
of
children
aged
6-‐13.

There
are
other
studies
that
have
found
an
association
with
adverse
health
effects

on
children
using
hair.
However,
hair
reflects
past
exposure
and
exposure
over
the

past
few
months,
and
with
age,
Mn
concentrations
decrease
in
hair.
Researchers

(Sanders,
Henn,
&
Wright
2015)
suggested
that
hair
is
not
a
reliable
biomarker
due

to
the
potential
for
external
Mn
exposures
that
may
affect
Mn
levels
in
hair,
limiting

its
use
as
an
indicator
of
internal
dose,
and
that
it
also
may
be
affected
by
the
degree

of
pigmentation.

4.1.2
Urine
and
Blood

A
large
portion
of
the
research
on
Mn
exposure
and
its
neurological
and

behavioral
effects
have
measured
Mn
in
blood
or
urine.
There
are
several
tests

Manganese
Exposure

9

available
that
can
measure
Mn
levels
in
whole
blood,
serum,
or
urine.
However,
Mn

is
naturally
present
in
the
body,
thus
some
Mn
is
always
found
in
these
fluids

(Santamaria
2008).
Both
blood
and
urine
have
relatively
short
half-‐lives,
which

makes
them
more
indicative
of
recent
exposure,
rather
than
serving
as
a
marker
or

long-‐term
or
chronic
exposure.
Due
to
high
variability
of
the
results,
they
cannot
be

considered
as
suitable
biomarkers
of
exposure
(Apostoli
2000).
This
is
in
agreement

with
Droz
(1993)
who,
on
the
basis
of
pharmacokinetic
modeling,
stated
that
for

half-‐lives
below
10
h,
there
is
no
statistical
advantage
in
using
biological
monitoring.

According
to
Santamaria
(2008)
urinary
Mn
is
not
a
less
suitable
biomarker

because
it
is
primarily
excreted
in
the
bile,
and
only
approximately
1%
is
excreted
in

the
urine.
Blood
Mn
has
been
the
most
commonly
used
biomarker
of
exposure,
but

the
short
half-‐life
of
Mn
in
blood
may
miss
periods
of
peak
exposure
and
Mn
is
also

not
reliable
in
blood
due
to
well-‐regulated
by
homeostatic
mechanisms
in
adults

(Gunier
2013).
Change
in
dietary
intake
may
also
influence
blood
Mn
levels
which

may
invalidate
study
results
(Santamaria
2008).

Despite
urine
and
blood
not
being
ideal
biomarkers,
they
have
still
been

useful
in
contributing
to
the
increase
of
knowledge
of
Mn
exposure.
Many
studies

have
found
associations
using
urine
and
blood
as
biomarkers.
Yu
et
al.
(2014)

compared
levels
of
Mn
in
serum
from
umbilical
cord
blood
with
results
from

neonatal
behavioral
neurological
assessment
(NBNA).
They
found
that
high
Mn

levels
in
umbilical
cord
serum
were
correlated
with
poor
NBNA
performance.
Based

on
their
results,
they
determined
that
any
Mn
concentration
in
blood
over
50
ug/L
is

Manganese
Exposure

10

unsafe.
This
study
showed
that
prenatal
exposure
to
Mn
at
environmentally
relevant

level
was
significantly
and
negatively
associated
with
fetal
neurodevelopment.

4.1.3.
Dentine

It
is
widely
regarded
(Arora
et
al.,
Andra
et
al.,
Gunier
et
al.,
Hare
et
al.)
that,

despite
the
usefulness
of
urine,
umbilical
cord
blood,
and
hair,
there
is
a
need
to
find

a
more
effective
biomarker
for
Mn
exposure,
particularly
one
that
can
be
used

retrospectively.
In
determining
the
effects
of
Mn
exposure
in
utero,
it
is
important
to

find
a
reliable,
retrospective
biomarker
in
order
to
demonstrate
the
levels
of
Mn

exposure
during
development.

The
biomarkers
that
have
been
extensively
used
thus
far
(hair,
blood,
and

urine)
tend
to
be
unreliable
and
variable,
and
their
accuracy
is
limited
(kasperson).

They
fail
to
provide
exposure
timing,
levels
of
cumulative
exposure,
and
lack
the

potential
to
provide
information
on
the
specific
source
(Andra
et
al.
2015).
Blood

has
been
used
quite
frequently,
but
may
not
be
the
most
reliable
measurement
tool

because
fully
matured
bodies
regulate
Mn
concentrations
effectively
and
the
half-‐
life
of
Mn
is
brief.
Hair
has
also
been
useful,
but
can
easily
be
contaminated
by

external
environmental
factors.
For
these
reasons,
commonly
used
biomarkers
are

not
the
most
effective
measure
of
exposure.
(Gunier
et
al.
2013).

Dentine
in
baby
teeth
may
be
an
ideal
way
to
measure
in
utero
exposure
to
metals.

Unlike
other
the
biomarkers,
dentine
provides
exposure
data
that
is
comparable
to

data
from
a
longitudinal
study,
but
can
be
obtained
retroactively.
Dentine,
a
tissue
in

the
teeth,
begins
to
develop
as
early
as
the
second
trimester
(between
the
13th
and

19th
weeks
of
gestation),
and
then
enamel
and
dentine
begin
to
form
outward,

Manganese
Exposure

11

similarly
to
the
formation
of
growth
rings
on
trees
(Gunier
et
al.
2013).
Mn
is

absorbed
by
the
tissue
as
the
teeth
form.
Due
to
disturbances
caused
by
protein

matrix
deposition
during
birth,
the
teeth
form
a
neonatal
line,
and
that
line
can
be

used
to
distinguish
between
prenatal
and
postnatal
exposures.
Afterwards,
the
teeth

develop
daily
growth
lines,
which
create
an
image
of
daily
exposures
after
birth.

Measurements
of
Mn
exposures
from
this
point
until
almost
a
year
after
birth
can
be

taken,
which
can
be
used
to
characterize
both
prenatal
and
postnatal
exposures.

Analytical
technology
can
pinpoint
when
the
exposure
occurred,
and
how
much
of

the
exposure
was
incorporated
into
the
teeth
(Gunier
et
al.
2013,
Andra
et
al.
2015).

Both
Gunier
et
al.
and
Arora
et
al.
analyzed
the
usefulness
of
dentine
as
a
biomarker.

In
a
study
analyzing
the
distribution
of
Mn
in
primary
teeth,
Arora
et
al.
found
not

only
that
Mn
is
distributed
in
a
distinct
and
consistent
pattern,
but
also
that
Mn

leaves
a
distinct
high
concentration
area
in
the
prenatally
formed
dentine.
This

finding
suggests
that
deciduous
teeth
have
great
potential
as
a
useful
biomarker
for

prenatal
Mn
exposures
(Arora
et
al
2011).
Both
groups
used
laser-‐ablation-‐
inductively
coupled
plasma-‐mass
spectrometry
(LA-‐ICP-‐MS)
to
analyze
Mn

exposures
through
deciduous
teeth.
Gunier
et
al.
found
that
their
findings
using
LA-‐
ICP-‐MS
were
correlated
with
their
estimates
of
prenatal
environmental
exposures
to

Mn.
LA-‐ICP-‐MS
allowed
them
to
retroactively
gain
a
characterization
of
exposure
as

it
occurred

In
the
study
conducted
by
Gunier
et
al.,
it
was
found
that
Mn
levels
in
teeth

were
higher
during
the
second
trimester
than
the
third,
which
conflicts
with

findings
from
previous
studies
using
cord
blood
as
a
biomarker
that
found
highest

Manganese
Exposure

12

levels
near
the
end
of
pregnancy.
Dentine
reflects
direct
exposure
to
Mn,
and
while

there
are
fluctuations
in
Mn
concentrations
in
blood
during
pregnancy,
there
is
no

known
instability
in
tooth
mineralization.
This
pattern
found
by
Gunier
et
al.

suggests
that
fetal
uptake
of
Mn
in
the
second
trimester
is
higher
than
in
later
stages

of
pregnancy,
and
that
dentine
is
a
more
effective
measure
of
this
uptake.

Arora
et
al.
found
similar
results;
they
found
that
the
cord
blood
levels
of
Mn
were

significantly
positively
correlated
with
the
Mn
concentrations
in
dentine
adjacent
to

the
neonatal
line,
suggesting
that
dentine
is
an
effective
biomarker.
At
other
points

in
the
neonatal
line,
however,
there
is
not
an
association.
This
is
not
surprising;

deposits
of
Mn
in
dentine
are
a
direct
reflection
of
the
exposure,
while
cord
blood
is

only
a
direct
reflection
of
Mn
levels
in
the
fetus
at
the
time
of
birth.
Blood
Mn
can

vary
during
pregnancy,
and
has
a
half-‐life
of
approximately
four
days.
(Arora
et
al.

2013).

Gunier
et
al.
also
argues
that
previous
studies
measuring
Mn
exposures
with

enamel
instead
of
dentine
(Ericson
et
al.
2007)
are
less
effective
at
determining
the

timing
of
exposure
than
dentine
because
of
differences
in
formation;
dentine
is

mineralized
immediately
to
its
almost
final
stage,
while
enamel
is
mineralized

slowly
throughout
development
(Arora
et
al.
2013).
Arora
et
al.
agrees,
because

most
metals
being
incorporated
into
the
tooth
are
absorbed
after
all
of
the
enamel

matrix
is
formed
in
the
tooth,
and
therefore,
enamel
cannot
be
used
to
determine

the
timing
of
exposure.
More
research
should
be
conducted
to
analyze
the

differences
and
advantages
in
these
two
tissues
as
biomarkers

Manganese
Exposure

13

4.2
Effects
from
Exposure
through
Drinking
Water

Approximately
20%
of
drinking
water,
both
public
and
individual,
is
sourced

from
groundwater,
and
50%
of
United
States
citizens
receive
their
drinking
water

from
a
groundwater
source.
It
has
recently
been
recognized
that
groundwater
is

susceptible
to
contamination,
particularly
from
organic
chemicals
that
result
from

agricultural
activities
(Safe
Drinking
Water).
Mn
is
also
commonly
found
in

groundwater
because
of
the
weathering
and
leaching
of
rocks
or
minerals,
which

release
Mn
into
aquifers.
Although
there
is
currently
no
public
policy
regulating

drinking
water
concentrations
of
Mn,
the
EPA
has
released
a
health
advisory
for
its

adverse
neurological
effects
associated
with
oral
ingestion
and
has
set
a
health-‐
based
guideline
of
300
µg/L
(EPA
2004).
The
World
Health
Organization
has
set
its

own
guideline
as
400
µg/L,
slightly
higher
than
the
EPA
(WHO
2008).

Approximately
45%
of
wells
for
public
use
in
New
England
have
drinking
water

concentrations
of
Mn
greater
than
30
µg/L,
and
nationally,
and
close
to
5%
of

household
wells
in
the
United
States
have
concentrations
of
Mn
greater
than
300

µg/L
(Groschen
et
al.
2009,
U.S.
Geological
Survey
2009).

The
neurodevelopmental
and
behavioral
effects
of
children’s
exposure
to
Mn

in
drinking
water
are
varied,
but
well
established.
Water
Mn
has
been
significantly

negatively
associated
with
academic
performance
in
several
studies;
Zhang
et
al.

(1995)
found
children
with
elevated
hair
concentrations
of
Mn
had
poorer
school

records
than
their
peers,
and
performed
more
poorly
on
mathematics
and
language

tests,
while
Khan
et
al.
(2011)
found
that
concentrations
of
Mn
over
400
µg/L
were

Manganese
Exposure

14

significantly
negatively
associated
with
poor
performance
on
math
exams,
but
not

on
language
exams.
In
another
study,
it
was
found
that
children
exposed
to
water

with
high
Mn
concentrations
had
a
6.2
full
scale
IQ
point
difference
than
other

children
who
had
not
been
exposed
(Bouchard
et
al.
2010)3.
Wasserman
et
al.

(2006)
studied
an
area
in
which
80%
of
the
wells
in
the
study
area
had
Mn
levels

over
400
µg/L,
with
the
average
concentration
being
795
µg/L.
Children
exposed
to

the
contaminated
drinking
water
in
this
area
had
significantly
lower
Full-‐Scale,

Performance,
and
Verbal
raw
scores
on
the
Wechsler
Intelligence
Scale
for
Children.

A
separate
study
analyzing
the
effects
on
IQ
found
that,
with
a
median
water

concentration
of
Mn
of
34
µg/L,
there
was
a
significant
negative
association

between
IQ
and
exposure
to
Mn
(Bouchard
et
al.
2011).

He
et
al.
(1994)
tested
neurobehavioral
behaviors
of
92
children
aged
11-‐13

who
lived
in
an
area
with
high
levels
of
Mn
in
sewage
irrigation
and
a
control
area.

The
area
with
sewage
irrigation
had
significantly
higher
levels
of
Mn
in
the
drinking

water
during
the
study
period,
and
the
children
in
that
area
had
significantly
higher

concentrations
of
Mn
in
their
hair.
Mn
levels
in
hair
correlated
negatively
with

performance
on
a
number
of
neurobehavioral
tests.
The
concentrations
of
Mn
in
the

drinking
water
in
the
control
group
were
30-‐40
ug/L,
while
the
sewage
irrigation

group
had
levels
between
240-‐350
ug/L.

It
is
also
suggested
that
Mn
exposure
has
an
inverted
U-‐shaped
association

with
Mn
levels
and
blood
and
neurodevelopment,
suggesting
that
both
low
and
high

levels
can
be
detrimental
to
development
(Claus
Henn
et
al.
2010).

Manganese
Exposure

15

There
is
a
small
but
notable
body
of
literature
studying
the
effects
of
prenatal

exposure
to
Mn
in
drinking
water,
and
the
consequential
effects
on
the

neurodevelopment
of
the
child
through
early
childhood.
Gunier
et
al.
(2015)
and

Chung
et
al.
(2011)
enlisted
a
cohort
of
pregnant
women,
and
followed
their

children
as
they
grew
older
to
study
neurodevelopmental
effects.
Both
Gunier
et
al.

and
Chung
et
al.
found
that
there
were
significant
deficiencies
in
motor
development

related
to
exposure
to
water
Mn,,
and
while
Gunier
et
al.
found
additional

deficiencies
in
mental
development,
Chung
et
al.
did
not.
Also,
Gunier
et
al.
found

that
there
was
a
significant
relationship
between
prenatal
Mn
levels
and
6-‐month

mental
and
motor
development
for
children
born
to
mothers
with
low

concentrations
of
hemoglobin,
and
therefore
lower
iron
levels,
during
pregnancy.

Children
in
a
study
in
Bangladesh
were
found
to
be
significantly
more
likely

to
display
aggressive
behaviors
at
age
10
after
prenatal
Mn
exposure
from
drinking

water.
As
with
Gunier
et
al.’s
findings,
results
from
this
study
also
showed
that
there

was
a
tendency
for
lower
IQ
in
girls
who
were
born
to
mothers
with
low
iron
levels.

The
finding
that
prenatal
Mn
exposure
can
lead
to
behavioral
effects
in

childhood
is
supported
by
Ericson
et
al.
(2007)
who,
although
the
source
of
Mn
is

unknown,
found
that
there
is
an
association
between
Mn
deposits
in
tooth
enamel

and
behavioral
outcomes
in
childhood.
Levels
of
Mn
from
the
20th
week
of
pregnancy

were
significantly
and
positively
associated
with
measures
of
behavioral

disinhibition.

4.3
Risks
from
Metals

Manganese
Exposure

16

4.3.1
Lead

Lead
can
be
present
in
drinking
water
delivered
through
lead
pipes
or
pipes

joined
with
lead
solder
may
contain
lead.
Unlike
other
heavy
metals,
there
is

extensive
research
that
address
leads
adverse
health
effects
in
humans
and
early

life.
In
utero
exposure
to
lead
was
adversely
associated
with
cognitive
and
social

development
(Kim
2009,
Claus
Henn
2011,
WHO
2014).
There
is
no
known
level
of

lead
exposure
that
is
considered
safe

Young
children
in
particular
are
vulnerable
to
the
toxic
effects
of
lead
and

can
suffer
profound,
permanent
adverse
health
effects,
mainly
affecting
the

development
of
the
brain
and
nervous
system.
Pregnant
women
exposed
to
high

levels
of
lead
can
be
subject
to
miscarriage,
stillbirth,
premature
birth
and
low
birth

weight,
as
well
as
minor
malformations.
Young
children
are
specifically
vulnerable

because
they
absorb
4
-‐
5
times
as
much
ingested
lead
as
adults
from
a
given
source

(WHO,
2004).
Strong
evidence
suggests
that
lead
exposure
also
leads
to
subtle

neurological
effects,
developmental
delays,
and
behavioral
abnormalities
in

otherwise
normal-‐appearing
children.
(Schettler
et
al.
2000).
In
addition,
Wright
&

Baccarelli
(2009)
establish
that
co-‐exposure
to
Mn
and
lead
may
decrease

spontaneous
motor
activity
and
learning
ability
in
rats
as
compared
with
exposure

to
only
one
of
these
metals,
which
may
cause
damage
to
brain
development
during

pre-‐
and
post-‐natal
life.

4.3.2.
Arsenic

Arsenic
is
naturally
present
at
high
levels
in
groundwater
of
numerous

countries.
There
has
been
a
number
of
research
done
on
Arsenic
showing
that,

Manganese
Exposure

17

water
contaminated
with
high
levels
of
Arsenic
and
used
for
drinking,
food

preparation
and
irrigation
of
food
crops
poses
a
great
threat
to
public
health.

Arsenic
exposure
affects
almost
every
organ
system
in
the
body
including
the
brain.

Still,
there
is
limited
studies
on
the
effect
of
exposure
in
early
life.

In
lab
animals,
it
has
been
found
that
high
exposure
of
Arsenic
causes

malformations.
In
addition,
some
studies
suggest
that
arsenic
exposure
may
lead
to

spontaneous
abortion
and
stillbirth
and
may
affect
neurological
development,

particularly
the
development
of
hearing
(Schettler
et
al.
2000).
Drinking
water
is

one
of
the
main
pathways
of
arsenic
ingestion.
It
has
been
well
established
that

arsenic
exposure
negatively
correlates
with
neurodevelopment.
Studies
have
found

that
lowered
IQ
is
one
of
the
most
commonly
reported
significant
effect
(Tyler
&

Allan,
2014).
Results
of
meta-‐analysis
show
that
for
every
50%
increase
in
arsenic

levels,
there
could
be
a
0.5
decrease
in
the
IQ
of
children
aged
5-‐15
years

(Rodríguez-‐Barranco
et
al.
2013).

4.3.3.Trichloroethylene
(TCE)

There
is
a
wide
body
of
evidence
suggesting
connections
between
exposure
to

TCE
contamination
of
drinking
water
during
pregnancy
and
the
development
of

congenital
heart
defects
(Forand
et
al.
2011,
Watson
et
al.
2005).
In
a
study
in

Endicott,
New
York,
which
experienced
a
massive
chemical
spill
in
1979,
that

contaminated
the
drinking
water
supply
with
TCE,
44
children
that
lived
in
the
area

of
analysis
were
born
with
at
least
one
birth
defect
between
1983
and
2000,

including
cardiac
birth
defects.
The
increase
in
cardiac
defects
in
children
was

significant.
(Forand
et
al.
2011).

Manganese
Exposure

18

Additionally,
there
is
a
building
body
of
evidence
that
prenatal
exposure
to

TCE
impairs
neurodevelopment,
and
it
has
been
studied
well
in
rodents.
Noland-‐
Gerbec
et
al.
described
altered
brain
chemistry
in
the
offspring
of
rats
exposed
to

TCE
during
pregnancy,
and
another
study
found
that
prenatal
exposure
to
TCE

caused
increased
exploratory
and
locomotive
behaviors
in
rats
(Taylor,
et
al.
1985).

A
similar
study
found
that
maternal
ingestion
of
TCE
through
drinking
water
during

pregnancy
resulted
in
altered
social
behaviors,
particularly
autism-‐like
social

behaviors
and
increased
aggression
in
male
mice
(Blossom
2008).

In
humans,
exposures
to
TCE
in
water
during
pregnancy
have
been
linked
to

developmental
impacts
in
children.
In
1979,
4,100
gallons
of
1,1,1,-‐TCE
spilled
at
a

manufacturing
facility
in
Endicott,
New
York.
The
next
year,
groundwater
samples

revealed
a
large
amount
of
contamination
of
both
TCE
and
tetrachloroethylene,

along
with
a
number
of
other
volatile
organic
contaminants
in
addition
to

contaminants
from
previous
spills
and
incidents.

Populations
were
exposed
to
the

contamination
through
soil
vapor
intrusion
(SVI),
where
volatized
contaminants

rose
through
air
pockets
in
soil
into
nearby
building
structures.
It
was
found
that

women
living
in
areas
with
risk
of
exposure
to
TCE
from
SVI
experienced
low
birth

weight
(LBW)
or
were
small
for
gestational
age
(SGA),
possibly
as
a
result
of
growth

restriction
in
utero.
Similar
results
of
LBW
were
found
in
northern
New
Jersey
and

Tuscon,
Arizona,
both
of
which
also
had
groundwater
contaminated
with
TCE
(Bove

et
al.
1995,
Rodenbeck
et
al.
2000).
In
addition,
SGA
was
significantly
more

prevalent
in
a
retrospective
study
of
Woburn,
Massachusetts,
when
mothers
had

been
exposed
to
TCE
contaminated
drinking
water
(MDPH,
CDC,
and
MHRI
1996).

Manganese
Exposure

19

Analysis
of
the
public
drinking
water
contamination
in
New
Jersey
also

correlated
prenatal
trichloroethylene
exposure
with
a
number
of
adverse
effects

including
defects
in
the
central
nervous
system
and
neural
tube
development,
and

oral
clefts
(Bove
et
al.
1995).

There
is
still
limited
information
on
the
effects
of
TCE
exposure
during

pregnancy
on
neurological
development.

4.3.4Cadmium

Cadmium
is
a
scarce
element,
but
is
seventh
in
the
Agency
for
Toxic

Substances
and
Disease
Registry’s
list
of
elements
that
create
the
most
significant

risks
for
human
health
and
the
environment.
In
addition
to
its
neurological

impairment,
cadmium
is
toxic
to
the
digestive
system,
kidneys,
lungs
and
liver.
Only

four
studies
have
been
undertaken
to
study
the
neurodevelopmental
effects
of

cadmium
exposure
in
utero
(Cao
et
al.
2009,
Tian
et
al.
2009,
Wright
et
al.
2006,

Torrente
et
al.
2005).
Only
one
of
the
studies
(Tian
et
al.
2009)
found
significant

results;
they
found
that
children
with
higher
blood
levels
of
cadmium
at
birth
scored

lower
on
Full-‐Score
and
Performance
IQ
tests
at
four
years
of
age.
Both
Bao
et
al.

(2009)
and
Yousef
et
al.
(2011)
studied
the
behavioral
effects
of
prenatal
exposure,

but
only
Bao
et
al.
found
that
children
with
higher
levels
of
cadmium
in
their
hair

experienced
more
social
and
attention
problems.
Yousef
et
al.
found
that
there
was

no
significant
relationship
between
cadmium
exposure
and
ADHD.
The
information

on
cadmium
exposure
and
its
neurological
effects
is
conflicting
and
extremely

limited,
leaving
a
wide
gap
in
the
knowledge
of
understanding
the
effects
of
metals

on
neurological
development.

Manganese
Exposure

20

4.3.5.
Co
exposure

Co-‐exposure
to
multiple
neurotoxins
may
increase
their
toxicity,
but
few

studies
have
investigated
the
interactions
between
multiple
metals.
There
have

been
a
handful
of
studies
analyzing
the
interactions
between
lead
and
Mn,
all
of

which
conclude
that
the
combined
neurological
effects
are
greater
than
the
effects
a

single
exposure
would
cause.
It
is
important
to
acknowledge
the
potential
for

adverse
outcomes
from
co-‐exposure
during
early
childhood
because
of
the

particularly
vulnerable
developmental
periods.
Lead
and
Mn
co-‐exposure
may
cause

a
significant
risk
as
increased
levels
of
Mn
in
the
brain
may
cause
the
brain
to

produce
lead-‐binding
proteins,
increasing
the
exposure
to
lead.
Animal
studies
have

shown
that
co-‐exposure
to
Mn
and
lead
may
decrease
spontaneous
motor
activity

and
learning
ability
more
compared
with
exposure
to
only
one
of
these
metals,

which
may
impair
both
pre-‐
and
post-‐natal
neurodevelopment.
(Wright
2009)

Kim
et
al.
(2009)
found
an
association
between
co-‐exposure
to
lead
and
Mn

and
intelligence
in
school-‐aged
children.
Findings
indicated
that
in
utero
co-‐
exposure
to
environmental
Mn
and
lead
were
adversely
related
to

neurodevelopment
in
2
year-‐old
children,
and
reported
significant
negative

associations
between
lead
and
Mn
levels
and
full-‐scale
and
verbal
IQ.
These
results

are
similar
to
those
found
by
Henn
et
al.
(2008),
who
observed
that
joint
exposure

to
both
lead
and
Mn
were
correlated
with
mental
and
psychomotor
deficits.
These

were
higher
than
the
estimated
deficits
for
individual
lead
or
Mn
exposure.

5.
Discussion

Manganese
Exposure

21

The
body
of
literature
on
Mn
exposure
through
drinking
water
reveals
many

things
about
what
we
do
and
do
not
know.
We
know
that
there
are
associated

neurological
deficiencies
and
behavioral
changes
that
can
arise
from
possibly
even

low
level
exposures.
While
these
findings
are
important,
and
can
be
applied
to

public
policy
to
better
protect
pregnant
women
and
young
children,
they
also
shine

a
light
on
the
gaping
holes
in
the
research
that
need
to
be
addressed
for
us
to
better

understand
the
true
neurodevelopmental
impacts
associated
with
Mn
exposure.

The
results
from
these
studies
found
negative
impacts
associated
with
the

exposure
of
children
to
Mn,
but
they
all
had
different
methods
of
doing
so.
Different

neurological
tests
were
administered,
different
levels
of
exposures
were
measured,

and
different
biomarkers
were
used.
Consequently,
these
studies
have
found
a
slew

of
different
impacts,
ranging
in
type
and
severity.

The
lack
of
a
consistent
biomarker
is
another
factor
that
needs
to
be

addressed
to
better
understand
the
complex
issue
of
Mn
exposure.
Many
studies

that
have
been
conducted,
and
that
are
discussed
here,
use
hair
or
blood
to
measure

exposures.
These
biomarkers
are
highly
variable
and,
ultimately,
may
not
be
an

accurate
reflection
of
Mn
exposures.
Tooth
dentine
shows
a
great
amount
of

promise
to
overcome
the
shortcomings
of
biomarkers,
but
the
evidence
of
its
use

and
effectiveness
is
extremely
limited.
The
lack
of
a
consistent
and
accurate

biomarker
is
a
possible
contributor
to
why
there
are
still
no
concrete
answers
to
the

effects
of
prenatal
Mn
exposure.

There
is
an
incredibly
limited
amount
of
research
done
on
the
effects
of

drinking
water
Mn
concentrations
on
prenatal
and
early
childhood

Manganese
Exposure

22

neurodevelopment.
The
scientific
community
has,
in
multiple
papers,
acknowledged

that
this
is
an
extremely
vulnerable
population
and
an
area
of
research
that
needs
to

be
addressed.
Based
on
the
conclusions
that
children
are
incredibly
vulnerable

during
rapid
stages
of
prenatal
development,
and
that
Mn
is
a
commonly
known

toxicant
that
is
known
to
have
significant
negative
effects
in
school-‐age
children,
it

leads
one
to
believe
that
there
is
a
notable
risk
for
prenatal
Mn
exposure,

particularly
through
drinking
water.
Despite
this,
there
is
not
a
significant
body
of

research
to
support
this
line
of
thinking.

It
was
also
found
that
there
are
significant
negative
effects
associated
with

prenatal
exposures
to
other
metals.
Lead
is
well
established
in
this
sense,
and
there

is
a
lot
of
evidence
finding
that
there
are
significant
and
extremely
harmful
effects

from
prenatal
exposures
to
lead.
Arsenic,
Cadmium,
and
Trichloroethylene
are
all

also
acknowledged
as
being
extremely
toxic,
but
their
effects
on
prenatal

development
are
less
established.
Cadmium
is
best
associated
with
attention

disorders,
and
Arsenic
has
been
found
to
produce
lower
IQ,
and
TCE
is
linked
to

congenital
heart
defects
and
low
birth
weight.
Coexposures
can
cause
an
even
more

significant
effect
than
individual
exposures,
and
draws
attention
to
the
fact
that

there
are
a
large
amount
of
metals
and
chemicals
that
likely
have
negative
impacts

on
prenatal
or
early
childhood
development,
but
are
not
yet
understood.

Based
on
these
findings,
and
on
the
fact
that
neurodevelopmental
deficits
can

occur
from
such
low
exposures
to
metals,
particularly
Mn,
it
is
clear
that
the

measures
set
out
by
the
United
States
government
are
not
enough
to
adequately

protect
the
public.
Although
there
is
a
health
advisory
for
Mn,
it
is
not
considered
to

Manganese
Exposure

23

be
enough
of
a
risk
for
the
EPA
to
make
an
enforceable
limit
on
it.
The
WHO
has
a

tighter
guideline
for
an
acceptable
level
of
exposure
to
Mn
from
drinking
water
than

the
EPA
does,
and
the
exposures
in
a
number
of
the
studies
that
caused
significant

negative
cognitive
defects
in
children
occurred
from
exposures
that
were
even

lower
than
either
of
these
guidelines.
The
guidelines
for
Mn
have
not
been
updated

since
2004,
and
need
to
be
re-‐evaluated,
taking
into
account
this
new
research,
and

initiating
further
research
to
more
fully
understand
the
health
risks
that
are
faced

by
children
through
such
high
exposures
to
Mn.

6.
Conclusions

In
the
United
States,
approximately
6%
of
domestic
household
wells
have
Mn

concentrations
exceeding
300
µg
Mn/L,
which
is
the
current
EPA
lifetime
health

advisory
level
(Wasserman
et
al.
2006).
In
New
England,
45%
of
wells
for
public
use

have
Mn
concentrations
greater
than
30
µg/L.
According
to
a
2009
report
by
the
U.S.

Geological
Survey,
approximately
5%
of
domestic
household
wells
in
the
United

States
have
Mn
concentrations
greater
than
300
µg/L.
(U.S.
Geological
Survey
2009).

This
indicates
that
some
children
in
the
U.S.
are
at
risk
for
Mn-‐induced
neurotoxicity

due
to
drinking
water
exposure.

Too
much
exposure
can
cause
Mn
to
accumulate
in
the
brain,
in
particular

the
central
nervous
system,
leading
to
neurological
damage
and
long-‐term
effects.

Mn
retention
is
higher
in
infants
than
in
adults
meaning
Infants
and
young
children

face
higher
risks
from
exposure
to
heavy
metals
than
adults
due
to
underdeveloped

homeostasis
system
that
limit
the
absorption
of
Mn
ingested.
The
time
at
which
the

Manganese
Exposure

24

child
is
exposed
to
the
metal
has
been
shown
to
be
equally
important
as
the
level
of

exposure
(Andra
et
al.
2015).
Our
current
health-‐based
guideline
value
for
Mn
of

400
µg/L
in
drinking
water
is
based
partly
on
debatable
assumptions.
This
value
for

drinking
water
may
be
low
enough
to
protect
adolescents
and
adults,
but
not

younger
children.

Biomarkers
are
used
to
measure
to
estimate
external
exposure
levels
in
the

body,
to
date,
blood,
hair,
urine,
and
dentine
from
primary
teeth
have
been
used.

They’ve
contributed
to
our
increasing
body
of
knowledge
about
Mn
neurotoxicity.

However,
blood,
urine,
and
hair
have
been
found
to
be
unreliable
or
not
ideal

biomarkers.
They
fail
to
provide
exposure
timing,
levels
of
cumulative
exposure,
and

lack
the
potential
to
provide
information
on
the
specific
source
(Andra
et
al.
2015).

New
research
is
emerging
using
dentine
as
an
ideal
biomarker
to
measure
Mn

exposure,
and
it
is
showing
great
promise.
Dentine
reflects
direct
exposure
to
Mn

and
there
is
no
known
instability
in
tooth
mineralization.
There
is
a
growing
body
of

research
showing
an
association
between
Mn
exposure
and
its
neurological
effects

on
children.
Further
research
needs
to
be
done
on
optimum
biomarker
such
as

dentine,
measuring
exposure
limits
to
set
new
guidelines
to
protect
the
public
and

children
from
the
long
terms
effects
of
Mn
exposure.

Manganese
Exposure

25

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