Document ID: EPA-HQ-OW-2002-0021-0134
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-05-15T04:00Z

Health
Effects
Support
Document
for
Manganese
2
Health
Effects
Support
Document
for
Manganese
Prepared
for:

U.
S.
Environmental
Protection
Agency
Office
of
Water
(
4304T)
Health
and
Ecological
Criteria
Division
Washington,
DC
20460
www.
epa.
gov/
safewater/
ccl/
pdf/
manganese.
pdf
EPA
822­
R­
03­
003
February
2003
iii
Manganese
 
February
2003
FOREWORD
The
Safe
Drinking
Water
Act
(
SDWA),
as
amended
in
1996,
requires
the
Administrator
of
the
Environmental
Protection
Agency
to
establish
a
list
of
contaminants
to
aid
the
agency
in
regulatory
priority
setting
for
the
drinking
water
program.
In
addition,
SDWA
requires
EPA
to
make
regulatory
determinations
for
no
fewer
than
five
contaminants
by
August
2001.
The
criteria
used
to
determine
whether
or
not
to
regulate
a
chemical
on
the
CCL
are
the
following:

The
contaminant
may
have
an
adverse
effect
on
the
health
of
persons.

The
contaminant
is
known
to
occur,
or
there
is
a
substantial
likelihood
that
the
contaminant
will
occur,
in
public
water
systems
with
a
frequency
and
at
levels
of
public
health
concern.

In
the
sole
judgment
of
the
administrator,
regulation
of
such
contaminant
presents
a
meaningful
opportunity
for
health
risk
reduction
for
persons
served
by
public
water
systems.

The
Agency's
findings
for
all
three
criteria
are
used
in
making
a
determination
to
regulate
a
contaminant.
The
Agency
may
determine
that
there
is
no
need
for
regulation
when
a
contaminant
fails
to
meet
one
of
the
criteria.
The
decision
not
to
regulate
is
considered
a
final
agency
action
and
is
subject
to
judicial
review.

This
document
provides
the
health
effects
basis
for
the
regulatory
determination
for
manganese.
In
arriving
at
the
regulatory
determination,
data
on
toxicokinetics,
human
exposure,
acute
and
chronic
toxicity
to
animals
and
humans,
epidemiology,
and
mechanisms
of
toxicity
were
evaluated.
In
order
to
avoid
wasteful
duplication
of
effort,
information
from
the
following
risk
assessments
by
the
EPA
and
other
government
agencies
were
used
in
development
of
this
document:

U.
S.
EPA
1994a.
U.
S.
Environmental
Protection
Agency.
Drinking
Water
Criteria
Document
for
Manganese.
Office
of
Health
and
Environmental
Assessment,
Cincinnati,
OH
CEAO­
CIN­
D008,
prepared
September,
1993,
revised
March
31,
1994.

ATSDR.
2000.
Agency
for
Toxic
Substances
and
Disease
Registry.
Toxicological
Profile
for
Manganese
(
Update).
Department
of
Health
and
Human
Services.
Atlanta,
GA.
Available
at
http://
www.
atsdr.
cdc.
gov.

U.
S.
EPA
1996a.
U.
S.
Environmental
Protection
Agency.
Integrated
Risk
Information
System
(
IRIS):
Manganese.
Available
at
http://
www.
epa.
gov/
iris.
Last
revised
December
1,
1996.

In
addition,
primary
references
of
studies
published
in
peer­
reviewed
scientific
journals
relevant
to
human
risk
assessment
of
manganese
were
also
used
in
preparing
this
Drinking
Water
iv
Manganese
 
February
2003
Support
Document
for
Manganese.
Recent
studies
of
manganese
were
identified
by
literature
searches
conducted
in
1999
and
2000.

Generally
a
Reference
Dose
(
RfD)
is
provided
as
the
assessment
of
long­
term
toxic
effects
other
than
carcinogenicity.
RfD
determination
assumes
that
thresholds
exist
for
certain
toxic
effects
such
as
cellular
necrosis.
It
is
expressed
in
terms
of
milligrams
per
kilogram
per
day
(
mg/
kg­
day).
In
general,
the
RfD
is
an
estimate
(
with
uncertainty
spanning
perhaps
an
order
of
magnitude)
of
a
daily
exposure
to
the
human
population
(
including
sensitive
subgroups)
that
is
likely
to
be
without
an
appreciable
risk
of
deleterious
effects
during
a
lifetime.

The
carcinogenicity
assessment
for
manganese
includes
a
formal
hazard
identification.
Hazard
identification
is
a
weight­
of­
evidence
judgment
of
the
likelihood
that
the
agent
is
a
human
carcinogen
via
the
oral
route.

Guidelines
that
were
used
in
the
development
of
this
assessment
may
include
the
following:
the
Guidelines
for
Carcinogen
Risk
Assessment
(
U.
S.
EPA,
1986a),
Guidelines
for
the
Health
Risk
Assessment
of
Chemical
Mixtures
(
U.
S.
EPA,
1986b),
Guidelines
for
Mutagenicity
Risk
Assessment
(
U.
S.
EPA,
1986c),
Guidelines
for
Developmental
Toxicity
Risk
Assessment
(
U.
S.
EPA,
1991a),
Proposed
Guidelines
for
Carcinogen
Risk
Assessment
(
1996b,
1999b),
Guidelines
for
Reproductive
Toxicity
Risk
Assessment
(
U.
S.
EPA,
1996c),
and
Guidelines
for
Neurotoxicity
Risk
Assessment
(
U.
S.
EPA,
1998a);
Recommendations
for
and
Documentation
of
Biological
Values
for
Use
in
Risk
Assessment
(
U.
S.
EPA,
1988);
and
Health
Effects
Testing
Guidelines
(
OPTS
series
870,
1996
drafts;
U.
S.
EPA
40
CAR
Part
798,
1997);
Peer
Review
and
Peer
Involvement
at
the
U.
S.
Environmental
Protection
Agency
(
U.
S.
EPA,
1994b);
Use
of
the
Benchmark
Dose
Approach
in
Health
Risk
Assessment
(
U.
S.
EPA,
1995).

The
chapter
on
occurrence
and
exposure
to
manganese
through
potable
water
was
developed
by
the
Office
of
Ground
Water
and
Drinking
Water.
It
is
based
primarily
on
unregulated
contaminant
monitoring
(
UCM)
data
collected
under
SDWA.
The
UCM
data
are
supplemented
with
ambient
water
data
as
well
as
information
on
production,
use,
and
discharge.
v
Manganese
 
February
2003
ACKNOWLEDGMENTS
This
document
was
prepared
under
the
U.
S.
EPA
contract
No.
68­
C­
02­
009,
Work
Assignment
No.
B­
02
with
ICF
Consulting,
Fairfax,
Virginia.
The
Lead
U.
S.
EPA
Scientist
is
Julie
Du,
Ph.
D.,
Health
and
Ecological
Criteria
Division,
Office
of
Science
and
Technology,
Office
of
Water.
vi
Manganese
 
February
2003
TABLE
OF
CONTENTS
FOREWORD
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
iii
ACKNOWLEDGMENTS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
v
LIST
OF
TABLES
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
ix
1.0
EXECUTIVE
SUMMARY
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
1­
1
2.0
IDENTITY:
CHEMICAL
AND
PHYSICAL
PROPERTIES
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
2­
1
3.0
USES
AND
ENVIRONMENTAL
FATE
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
1
3.1
Production
and
Uses
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
1
3.2
Sources
and
Environmental
Fate
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
4
4.0
EXPOSURE
FROM
DRINKING
WATER
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
1
4.1
Introduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
1
4.2
Ambient
Occurrence
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
1
4.3
Drinking
Water
Occurrence
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
4
4.4
Results
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
10
4.5
Conclusion
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
11
5.0
EXPOSURE
FROM
ENVIRONMENTAL
MEDIA
OTHER
THAN
WATER
.
.
.
.
.
.
.
.
.
5­
1
5.1
Food
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
1
5.1.1
Concentrations
of
Manganese
in
Food
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
1
5.1.2
Intake
of
Manganese
From
Food
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
1
5.2
Air
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
5
5.2.1
Concentration
of
Manganese
in
Air
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
5
5.2.2
Intake
of
Manganese
in
Air
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
11
5.3
Soil
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
12
5.3.1
Concentration
of
Manganese
in
Soil
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
12
5.3.2
Intake
of
Manganese
in
Soil
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
12
5.4
Other
Media
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
12
5.5
Summary
of
Exposure
to
Manganese
in
Media
Other
Than
Water
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
12
6.0
TOXICOKINETICS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
1
6.1
Absorption
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
1
6.2
Distribution
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
7
6.3
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
11
6.4
Excretion
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
12
7.0
HAZARD
IDENTIFICATION
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
1
7.1
Human
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
1
7.1.1
Case
Reports
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
1
vii
Manganese
 
February
2003
7.1.2
Short­
term
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
3
7.1.3
Long­
Term
and
Epidemiological
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
4
7.1.4
Beneficial
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
9
7.2
Animal
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
10
7.2.1
Acute
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
10
7.2.2
Short­
Term
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
12
7.2.3
Subchronic
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
14
7.2.4
Neurotoxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
16
7.2.5
Developmental/
Reproductive
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
25
7.2.6
Chronic
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
33
7.2.7
Carcinogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
34
7.3
Other
Key
Data
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
37
7.3.1
Mutagenicity/
Genotoxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
37
7.3.2
Immunotoxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
41
7.3.3
Hormonal
Disruption
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
41
7.3.4
Physiological
or
Mechanistic
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
42
7.3.5
Structure­
Activity
Relationship
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
45
7.4
Hazard
Characterization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
45
7.4.1
Synthesis
and
Evaluation
of
Major
Noncancer
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
45
7.4.2
Synthesis
and
Evaluation
of
Carcinogenic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
48
7.4.3
Mode
of
Action
and
Implications
in
Cancer
Assessment
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
49
7.4.4
Weight
of
Evidence
Evaluation
for
Carcinogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
50
7.4.5
Sensitive
Populations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
50
7.4.6
Potential
Childhood
Sensitivity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
50
7.4.7
Other
Potentially
Sensitive
Populations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
52
8.0
DOSE­
RESPONSE
ASSESSMENT
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
8­
1
8.1
Dose­
Response
for
Noncancer
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
8­
1
8.1.1
RfD
Determination
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
8­
1
8.1.2
RfC
Determination
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
8­
3
8.2
Dose­
Response
for
Cancer
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
8­
4
9.0
RISK
DETERMINATION
AND
CHARACTERIZATION
OF
RISK
FROM
DRINKING
WATER
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
1
9.1
Regulatory
Determination
for
Chemicals
on
the
CCL
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
1
9.1.1
Criteria
for
Regulatory
Determination
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
1
9.1.2
National
Drinking
Water
Advisory
Council
Recommendations
.
.
.
.
.
.
.
.
.
.
.
.
9­
2
9.2
Health
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
2
9.2.1
Health
Criterion
Conclusion
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
3
9.2.2
Hazard
Characterization
and
Mode
of
Action
Implications
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
3
9.2.3
Dose­
Response
Characterization
and
Implications
in
Risk
Assessment
.
.
.
.
.
9­
5
9.3
Occurrence
in
Public
Water
Systems
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
6
9.3.1
Occurrence
Criterion
Conclusion
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
6
9.3.2
Monitoring
Data
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
7
9.3.3
Use
and
Fate
Data
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
8
viii
Manganese
 
February
2003
9.4
Risk
Reduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
9
9.4.1
Risk
Reduction
Criterion
Conclusion
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
9
9.4.2
Exposed
Population
Estimates
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
9
9.4.3
Relative
Source
Contribution
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
10
9.4.4
Sensitive
Populations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
10
9.5
Regulatory
Determination
Decision
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
11
10.0
REFERENCES
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
10­
1
APPENDIX
A:
Abbreviations
and
Acronyms
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
A­
1
APPENDIX
B:
Complete
NIRS
Data
for
Manganese
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
B­
1
ix
Manganese
 
February
2003
LIST
OF
TABLES
Table
2­
1.
Chemical
and
Physical
Properties
of
Manganese.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
2­
2
Table
2­
2.
Chemical
and
Physical
Properties
of
Manganese
Compounds.
.
.
.
.
.
.
.
.
.
.
.
.
.
2­
3
Table
3­
1.
Imports
of
Manganese
and
Ferromanganese
to
the
United
States
(
thousand
metric
tons,
gross
weight).
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
1
Table
3­
2.
Manganese
Manufacturers
and
Processors
by
State.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
2
Table
3­
3.
Summary
of
Uses
for
Selected
Manganese
Compounds.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
3
Table
3­
4.
Environmental
Releases
(
in
pounds)
for
Manganese
in
the
United
States,
1988
 
1998.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
6
Table
3­
5.
Environmental
Releases
(
in
pounds)
for
Manganese
Compounds
in
the
United
States,
1988
 
1998.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
7
Table
4­
1.
Manganese
Detections
and
Concentrations
in
Streams
and
Ground
Water.
.
.
.
4­
5
Table
4­
2.
Manganese
Detections
and
Concentrations
in
Bed
Sediments
and
Aquatic
Biota
Tissues
(
all
sites).
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
5
Table
4­
3.
Manganese
Occurrence
in
Ground
Water
PWS
of
NIRS
Survey.
.
.
.
.
.
.
.
.
.
.
.
4­
8
Table
4­
4.
Occurrence
Summary
of
Ground
and
Surface
Water
Systems
by
State
for
Manganese.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
9
Table
5­
1.
Manganese
Concentrations
in
Selected
Foods
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
2
Table
5­
2.
Average
Concentrations
of
Manganese
in
Ambient
Air
Sampled
from
1953
 
1982
5­
6
Table
5­
3.
Manganese
Levels
in
Air
of
Canadian
Urban
Locations
as
Determined
by
Personal
Exposure
Monitoring
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
6
Table
5­
4.
Ambient
Air
Concentrations
of
Manganese
in
Relation
to
Traffic
Density,
Montreal,
Canada
1981
 
1994.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
8
Table
5­
5.
Estimated
Atmospheric
Mn
Concentration
in
Relation
to
the
Combustion
of
MMT
in
Gasoline.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
9
Table
5­
6.
Mean
Manganese
Exposures
from
3­
day
Indoor,
Outdoor
and
Personal
Air
Samples.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
10
Table
5­
7.
Summary
of
Human
Exposure
to
Manganese
in
Media
Other
than
Water
.
.
.
5­
13
Table
6­
1.
Normal
Manganese
Levels
in
Human
and
Animal
Tissues
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
8
Table
7­
1.
Mean
Neurological
Scores
of
Residents
in
Three
Areas
of
Northwest
Greece
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
5
Table
7­
2.
Mean
Neurological
Scores
of
Residents
in
Germany
Exposed
to
Different
Levels
of
Manganese
in
Well
Water.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
8
x
Manganese
 
February
2003
Table
7­
3.
LD
50
Values
for
Manganese
Compounds.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
11
Table
7­
4.
Neurological
Effects
of
Oral
Exposure
to
Manganese
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
17
Table
7­
5.
Developmental
Effects
of
Exposure
to
Manganese.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
26
Table
7­
6.
Reproductive
Effects
of
Exposure
to
Manganese.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
32
Table
7­
7.
Follicular
Cell
Tumor
Incidence
in
B6C3F
1
Mice.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
35
Table
7­
8.
Summary
of
Carcinogenicity
Studies
Reporting
Positive
Findings
for
Selected
Manganese
Compounds
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
35
Table
7­
9.
Pulmonary
Tumors
in
Strain
A
Mice
Treated
with
Manganese
Sulfate
.
.
.
.
.
7­
36
Table
7­
10.
Genotoxicity
of
Manganese
In
Vivo.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
37
Table
7­
11.
Genotoxicity
of
Manganese
In
Vitro.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
39
Table
9­
1.
Comparison
of
Average
Daily
Intake
from
Drinking
Water
and
Other
Media
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
10
1­
1
Manganese
 
February
2003
1.0
EXECUTIVE
SUMMARY
The
U.
S.
Environmental
Protection
Agency
(
EPA)
has
prepared
this
Health
Effects
Support
Document
to
assist
in
determining
whether
to
establish
a
National
Primary
Drinking
Water
Regulation
(
NPDWR)
for
manganese.
At
high
doses
by
inhalation,
manganese
is
very
toxic,
as
seen
by
occupational
exposure
in
miners.
On
the
other
hand,
manganese
is
essential
for
normal
physiological
function
of
animals
and
humans.
The
Food
and
Nutrition
Board
of
the
National
Academy
of
Science
(
NAS)
sets
an
adequate
intake
for
manganese
at
2.3
mg/
day
for
men
and
1.8
mg/
day
for
women,
and
an
upper
limit
for
daily
intake
at
11
mg
for
adults
(
IOM,
2002).
Manganese
has
a
low
aesthetic
threshold
in
water.
Based
on
staining
and
taste,
EPA
has
set
a
secondary
level
for
manganese
at
0.05
mg/
L
which
is
below
the
level
that
may
present
a
health
concern.
Available
data
suggest
that
regulation
of
manganese
in
public
water
does
not
present
a
meaningful
basis
for
health
risk
reduction.
EPA
will
present
a
determination
and
further
analysis
in
the
Federal
Register
Notice
covering
the
Contaminant
Candidate
List
proposals.

Manganese
(
Chemical
Abstracts
Services
Registry
Number
7439­
96­
5)
is
an
abundant
elemental
metal
that
does
not
exist
naturally
in
its
pure
form,
but
rather
is
found
as
a
component
of
over
100
minerals.
It
is
also
an
essential
nutrient,
and
a
certain
level
of
intake
is
necessary
for
good
health.
The
NAS
has
determined
that
the
Adequate
Intake
for
manganese
(
AI)
is
1.8
to
2.3
milligrams
per
day
for
an
adult
woman
and
man,
respectively,
although
others
have
argued
that
it
may
be
higher.
Manganese
occurs
naturally
in
soil,
air,
water,
and
food
at
low
levels.

Manganese
and
manganese
compounds
are
used
mostly
in
the
production
of
manganeseiron
alloy
through
a
smelting
process.
They
are
also
used
in
fertilizer,
fungicide,
livestock
feed,
and
in
unleaded
gasoline
as
an
anti­
knock
additive
in
the
form
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT).
Any
of
these
uses
may
result
in
substantial
releases
of
manganese
to
the
environment.
Manganese
is
listed
as
a
Toxic
Release
Inventory
(
TRI)
chemical,
with
releases
to
soil
constituting
most
of
the
on­
site
releases,
although
air,
surface
water
and
ground
water
are
also
important
sinks
for
manganese
release.

Human
exposure
to
manganese
occurs
primarily
through
ingestion
of
foods
containing
manganese.
These
include
many
nuts,
grains,
fruits,
legumes,
tea,
leafy
vegetables,
infant
formulas,
and
some
meat
and
fish.
The
relatively
high
levels
of
manganese
in
nuts,
grains,
and
many
plant
products
and
infant
formulas
are
not
well
absorbed
upon
ingestion
because
these
foods
also
contain
inhibitors
of
manganese
absorption
such
as
phytates,
fiber,
plant
protein
and
polyphenolic
compounds
(
tannins).
Manganese
absorption
is
affected
by
other
factors
including
age
(
neonate
compared
to
the
adult),
chemical
species
of
manganese,
dose,
and
route
of
exposure
in
addition
to
the
dietary
factors
mentioned
above.
Human
exposure
to
manganese
may
also
occur
through
inhalation
of
manganese
dust,
intake
of
soil
containing
manganese
compounds,
or
drinking
water
contaminated
with
manganese.

The
primary
target
of
manganese
toxicity
is
the
nervous
system,
and
common
symptoms
of
toxic
exposure
include
ataxia,
dementia,
anxiety,
a
"
mask­
like"
face,
and
manganism,
a
syndrome
similar
to
Parkinson's
disease.
These
effects,
when
observed,
are
generally
the
result
1­
2
Manganese
 
February
2003
of
very
high
exposures
via
inhalation,
as
might
occur
in
an
industrial
setting,
and
are
not
seen
among
the
general
population
exposed
to
low
or
moderate
manganese
levels.
Manganese
has
very
low
toxicity
by
oral
ingestion
and
reports
of
adverse
effects
by
this
route
are
rare.
Because
manganese
is
an
essential
nutrient,
concern
for
toxic
over­
exposure
must
be
balanced
against
the
potentially
negative
effects
of
nutritional
deficiency
resulting
from
under­
exposure.

An
epidemiological
study
performed
in
Peloponnesus,
Greece
(
Kondakis
et
al.,
1989)
showed
that
lifetime
consumption
of
drinking
water
containing
naturally
high
concentrations
of
manganese
oxides
may
lead
to
neurological
symptoms
and
increased
manganese
retention
(
through
the
concentration
of
manganese
in
hair)
for
people
over
50
years
old.
For
the
group
consuming
the
highest
concentration
(
around
2
mg/
L)
for
more
than
ten
years,
the
authors
suggested
that
some
neurologic
impairment
may
be
apparent.
The
study
raises
concerns
about
possible
adverse
neurological
effects
following
chronic
ingestion
from
drinking
water
at
doses
within
ranges
deemed
essential.
However,
the
study
did
not
examine
manganese
intake
data
from
other
routes/
sources
(
i.
e.,
dietary
intake,
inhalation
from
air,
etc.),
precluding
its
use
as
a
basis
for
the
RfD.

Another
long­
term
drinking
water
study
in
Germany
(
Vieregge
et
al.,
1995)
found
no
neurological
effects
in
people
older
than
50
years
of
age
who
drink
water
containing
0.3
to
2.16
mg/
L
of
manganese
for
more
than
ten
years.
However,
this
study
also
lacks
exposure
data
from
other
routes
and
sources,
and
the
manganese
concentration
range
in
water
is
very
wide.
Thus,
the
study
cannot
be
used
for
quantitative
assessment.

A
small
Japanese
community
(
total
25
individuals)
ingested
high
levels
of
manganese
in
contaminated
well
water
(
that
leaked
from
dry
cell
batteries
buried
near
the
wells)
over
a
threemonth
period
(
Kawamura
et
al.,
1941).
Manganese
intake
was
not
determined
at
the
time
of
intoxication,
but
when
assayed
months
later,
it
was
estimated
to
be
close
to
29
mg/
L
(
i.
e.,
58
mg/
day
or
approximately
1
mg/
kg­
day
assuming
a
body
weight
of
60
kg).
Symptoms
included
lethargy,
increased
muscle
tonus,
tremor,
mental
disturbances,
and
even
death.
Autopsies
revealed
macroscopic
and
microscopic
changes
in
the
brain
tissue.
In
contrast,
six
children
(
1­
to
10­
yr­
old)
were
not
intoxicated
as
were
the
adults
by
this
exposure.
The
elderly
were
more
severely
affected.
Some
effects
may
have
resulted
from
factors
other
than
manganese
exposure.

There
is
no
information
available
on
the
carcinogenic
effects
of
manganese
in
humans,
and
animal
studies
have
reported
mixed
results.
Based
on
the
1999
Draft
Guidelines
for
Carcinogen
Risk
Assessment,
there
is
"
Inadequate
Information
to
Assess
Human
Carcinogenic
Potential"
for
manganese
(
U.
S.
EPA,
1999b).
According
to
the
1986
Guidelines,
EPA
considered
manganese
to
be
not
classifiable
with
respect
to
carcinogenicity,
Group
D
(
U.
S.
EPA,
1986b).
Data
from
oral
exposure
suggest
that
manganese
has
a
low
developmental
toxicity.

In
various
surveys,
manganese
intakes
of
adults
eating
western­
type
and
vegetarian
diets
ranged
from
0.7
to
10.9
mg
per
day
(
Freeland­
Graves,
1994;
Gibson,
1994
as
cited
by
IOM,
2002).
Depending
on
individual
diets,
a
normal
intake
may
be
well
over
10
mg
per
day,
especially
from
a
vegetarian
diet
(
Schroeder
et
al.,
1966).
Thus,
from
the
dietary
surveys
taken
together,
EPA
concludes
that
an
appropriate
reference
dose
(
RfD)
for
manganese
is
10
mg/
day
1­
3
Manganese
 
February
2003
(
0.14
mg/
kg­
day,
U.
S.
EPA,
1996a).
This
RfD
is
unique,
with
an
uncertainty
factor
(
UF)
of
1
applied
to
a
human
chronic
NOAEL
of
0.14
mg/
kg­
day.
The
UF
of
1
is
used
because
the
NOAEL
(
with
no
apparent
LOAEL)
is
based
on
chronic
human
dietary
intake
surveys,
not
the
typical
toxicity
studies,
and
because
of
the
essentiality
of
the
trace
element.

EPA
derived
a
health­
related
benchmark
for
evaluating
the
occurrence
data,
called
the
health
reference
level
(
HRL),
of
0.30
mg/
L.
The
HRL
is
six
times
the
s­
MCL
of
0.05
mg/
L.
The
HRL
is
based
on
the
dietary
RfD
and
application
of
a
modifying
factor
(
MF)
of
three
for
drinking
water
as
recommended
by
IRIS
(
U.
S.
EPA,
1996a),
and
on
an
allocation
of
an
assumed
20%
relative
source
contribution
from
water
ingestion
as
opposed
to
total
manganese
exposure.
The
modifying
factor
accounts
for
concerns
raised
by
the
Kondakis
study
(
1989),
the
potential
for
higher
absorption
of
manganese
in
water
compared
to
food,
consideration
of
fasting
individuals,
the
concern
for
infants
with
potentially
higher
absorption
and
lower
excretion
rates
of
manganese,
and
the
potential
for
increased
susceptibility
to
neurotoxic
effects
of
ingested
manganese
as
compared
to
adults.
For
example,
Dorman
et
al.
(
2000)
reported
that
rat
pups
dosed
for
21
days
postnatally
with
11
or
22
mg
Mn/
kg­
day
(
by
mouth
in
drinking
water)
exhibited
significant
increases
in
the
startle
response
compared
to
controls.
Significant
increases
in
striatal
DA
(
dopamine)
and
DOPAC
(
dihydroxyphenylacetic
acid)
concentrations,
in
the
absence
of
pathological
lesions,
were
also
observed
in
the
high­
dose
treated
neonates.
Because
manganese
is
an
essential
nutrient
in
developing
infants,
the
potential
adverse
effects
from
manganese
deficiency
may
be
of
greater
concern
than
potential
toxicity
from
over­
exposure.
Potentially
sensitive
sub­
populations
include
children,
the
elderly,
pregnant
women,
irondeficient
individuals,
and
individuals
with
impaired
liver
function.

Exposure
to
manganese
in
drinking
water
is
ubiquitous
in
the
United
States.
Data
from
the
National
Inorganics
and
Radionuclide
Survey
(
NIRS),
conducted
between
1984
and
1986
by
EPA,
were
used
to
characterize
manganese
occurrence
in
public
water
systems
(
PWSs).
Although
somewhat
out
of
date,
these
data
indicate
that
occurrence
estimates
are
relatively
high,
with
approximately
68%
of
ground
water
PWSs
(
an
estimate
of
approximately
40,000
systems
nationally)
showing
detections
of
manganese,
affecting
about
55%
of
the
ground
water
PWS
population
served
(
approximately
47.5
million
people
nationally).
The
median
levels
for
detects
and
the
99th
percentile
concentration
for
all
samples
were
0.01
milligram
per
liter
(
mg/
L)
and
0.63
mg/
L,
respectively.
Based
on
this
survey
information
(
which
consisted
only
of
ground
water
and
not
surface
water
sampling),
and
using
supplemental
surface
water
levels
from
Safe
Drinking
Water
Act
(
SDWA)
compliance
monitoring
data
from
five
States,
EPA
concluded
that
population
exposure
to
manganese
in
PWSs
is
potentially
high.

When
the
detected
concentrations
are
evaluated
at
a
draft
health
reference
level
(
HRL)
of
0.3
mg/
L,
approximately
6.1%
of
the
NIRS
PWSs
have
detections
>
½
HRL
(>
0.15
mg/
L),
consisting
of
about
3,600
ground
water
PWSs
nationally,
and
affecting
approximately
4.6%
of
the
population
served
(
estimated
at
four
million
people
nationally).
The
percentage
of
NIRS
PWSs
with
detections
>
HRL
of
0.3
mg/
L
is
approximately
3.2%
(
about
1,920
ground
water
PWSs
nationally),
affecting
2.6%
of
the
population
served
(
estimated
at
approximately
2.3
million
people
nationally).
It
is
important
to
note,
however,
that
when
average
daily
drinking
1­
4
Manganese
 
February
2003
water
intakes
for
manganese
are
compared
with
intakes
from
a
normal
diet,
drinking
water
accounts
for
a
relatively
small
proportion
of
total
manganese
intake.
2­
1
Manganese
 
February
2003
2.0
IDENTITY:
CHEMICAL
AND
PHYSICAL
PROPERTIES
Manganese
is
an
abundant
element
which
makes
up
about
0.1%
of
the
earth's
crust
(
ATSDR,
2000).
Although
the
elemental
(
metal)
form
of
manganese
does
not
occur
naturally
in
the
environment,
manganese
is
a
component
of
over
100
minerals
(
ATSDR,
2000).
The
most
common
mineral
forms
include
manganese
dioxide,
manganese
carbonate,
and
manganese
silicate
(
ATSDR,
2000).
Manganese
exists
in
11
oxidative
states,
with
the
most
common
valences
being
2+,
4+,
and
7+
(
U.
S.
EPA,
1994a).
Although
there
is
no
recommended
daily
allowance
(
RDA)
for
manganese,
it
is
essential
for
the
proper
function
of
several
enzymes
and
is
necessary
for
normal
bone
structure
and
brain
function
(
U.
S.
EPA,
1994a).
The
chemical
and
physical
properties
of
elemental
manganese
are
presented
in
Table
2­
1.
Chemical
and
physical
properties
for
manganese
compounds
are
summarized
in
Table
2­
2.
2­
2
Manganese
 
February
2003
Table
2­
1.
Chemical
and
Physical
Properties
of
Manganese.

Property
Information
Chemical
Abstracts
Services
(
CAS)
Registry
No.
7439­
96­
5
Chemical
Formula
Mn
Atomic
Number
25
Molecular
Weight
54.94
Synonyms
Elemental
manganese;
Colloidal
manganese;
Cutaval;
Magnacat;
Tronamang
NIOSH
Registry
of
Toxic
Effects
of
Chemical
Substances
(
RTECS)
No.
009275000
Hazardous
Substances
Data
Bank
(
HSDB)
No.
00550
Boiling
Point
1,962oC
Melting
Point
1,244oC
Vapor
Pressure
(
at
1,292oC)
1
mm
Hg
Density
(
at
20oC)
7.21
 
7.44
g/
cm3
Water
Solubility
Decomposes
Acid
Solubility
Dissolves
in
dilute
mineral
acids
Sources:
ATSDR
(
2000);
U.
S.
EPA
(
1994a);
ChemIDplus
(
2000)
2­
3
Manganese
 
February
2003
Table
2­
2.
Chemical
and
Physical
Properties
of
Manganese
Compounds.

Name
CAS
Registry
No.
Synonyms
Valence
Chemical
Formula
Molec.

Wt.
Specific
Gravity
or
Density
Melting
Point
(
oC)
Boiling
Point
(
oC)
Soluble
in
Water?

Methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
12108­
13­
3
Pi­
methylcyclopentadienylmanganese
tricarbonyl;
Tricarbonyl(
methylcyclopentadienyl)

manganese;
Tricarbonyl(
2­
methylcyclopentadienyl)
manganese;

Tricarbonyl(
eta(
5)­
methylcyclopentadienyl)
manganese;
Manganese,

tricarbonyl
(
methyl­
pi­
cyclopentadienyl);

Manganese,
tricarbonyl((
1,2,3,4,5­
eta)­
1­
methyl­

2,4­
cyclopentadien­
1­
yl);
Manganese,

tricarbonyl(
2­
methylcyclopentadienyl);

pi­(
Methylcyclopentadienyl)
manganese
tricarbonyl;

2­
Methylcyclopentadienylmanganese
tricarbonyl;

(
Methylcyclopentadienyl)
tricarbonylmanganese;

Methylcymantrene
+
1
CH
3
C
5
H
4
Mn(
CO)
3
218.09
1.39
1.5
233
No
Manganous
carbonate
598­
62­
9
Carbonic
acid,
manganese(
2+)
salt;

Manganese(
2+)
carbonate;

Manganese
carbonate;

Manganese(
II)
carbonate;

Natural
rhodochrosite
+
2
MnCO
3
114.95
3.125
Decomposes
NS
Yes
Manganous
chloride
7773­
27­
01­
5
Manganese
chloride;

manganese
dichloride;

manganese
bichloride;

manganese(
II)
chloride
+
2
MnCl
2
125.84
NS
650
1190
Yes
Manganous
acetate
15243­
27­
3
­­
+
2
Mn(
C
2
H
3
O
2)
2B4H
2
O
245.08
1.589
NS
NS
Yes;
Cold
H
2
O
Table
2­
2.
Chemical
and
Physical
Properties
of
Manganese
Compounds.
(
continued)

Name
CAS
Registry
No.
Synonyms
Valence
Chemical
Formula
Molec.

Wt.
Specific
Gravity
or
Density
Melting
Point
(
oC)
Boiling
Point
(
oC)
Soluble
in
Water?

2­
4
Manganese
 
February
2003
Manganous
acetate
638­
38­
0
Acetic
acid,
manganese(
II)
salt;

Diacetyl
manganese;

Manganese(
2+)
acetate;

Manganese
acetate;

Manganese
diacetate;

Manganese(
II)
acetate;

Manganous
acetate;

Octan
manganaty
+
2
Mn(
C
2
H
3
O
2)
2
173.02
1.74
NS
NS
Decomposes
Manganese
ethylenebisdithiocarbamate
12427­
38­
2
Carbamic
acid,
ethylenebis(
dithio­,
manganese
salt;
Carbamodithioic
acid,
1,2­
ethanediylbis­,

manganese(
2+)
salt;

1,2­
Ethanediylbis(
carbamodithioato)
(
2­)­

manganese;

Manganous
ethylenebis(
dithiocarbamate);

Maneb
+
2
(
CH
2
NHCS
2)
2
Mn
265.24
NS
NS
NS
Moderately
Manganous
oxide
1344­
43­
0
Manganese
monoxide;

Manganese
oxide;

Manganese
protoxide
+
2
MnO
70.94
5.43
 
5.46
1,945
NS
No
Manganous
phosphate
10124­
54­
6
Manganese
orthophosphate;

Phosphoric
acid,
manganese
salt
+
2
Mn
3(
PO
4)
2
259.78
NS
NS
NS
NS
Manganous
sulfate
7785­
87­
7
Manganese
sulfate;

Sulfuric
acid,
manganese
(
II)
salt
+
2
MnSO
4CH
2
O
169.01
2.95
Stable;

57
 
117
NS
NS
Manganous
difluoride
7782­
64­
1
Manganese
difluoride
Manganese
fluoride;

Manganese
fluorure
+
2
MnF
2
92.93
3.98
856
NS
Yes
Manganous
trifluoride
7782­
53­
1
­­
+
2
MnF
3
111.93
3.54
Decomposes
600
NS
Decomposes
Manganese
borate
12228­
91­
0
Boron
manganese
oxide;

Tetraboron
manganese
heptaoxide
+
2
MnB
4
O
7
C8H
2
O
354.17
NS
NS
NS
No
Table
2­
2.
Chemical
and
Physical
Properties
of
Manganese
Compounds.
(
continued)

Name
CAS
Registry
No.
Synonyms
Valence
Chemical
Formula
Molec.

Wt.
Specific
Gravity
or
Density
Melting
Point
(
oC)
Boiling
Point
(
oC)
Soluble
in
Water?

2­
5
Manganese
 
February
2003
Manganese
formate
­­
­­
NS
Mn(
CHO
2)
2C2H
2
O
181.00
1.953
Decomposes
NS
Yes
Manganese
glycerophosphate
1320­
46­
3
1,2,3­
Propanetriol,
mono(
dihydrogen
phosphate),

manganese(
2++)
salt
Glycerol,
dihydrogen
phosphate,
manganese(
2+)

salt;
Manganese(
2+)
1,2,3­
propanetriol
mono(
dihydrogen
phosphate);
Manganese(
2+)

glycerol
dihydrogen
phosphate
+
2
MnC
3
H
7
O
6
P
225.00
NS
NS
NS
Slightly
in
Cold
H
2
O
Manganous
hydroxide
­­
Pyrochaotite
+
2
Mn(
OH)
2
88.95
3.258
(
13
BC)
Decomposes
NS
Slightly
in
Cold
H
2
O
Manganous
nitrate
10377­
66­
9
Manganese
dinitrate;

Nitric
acid,
manganese(
2+)
salt
+
2
Mn(
NO
3)
2C4H
2
O
215.01
1.82
25.8
129.4
Yes
Manganous
sulfide
­­
­­
+
2
MnS
87.00
3.99
Decomposes
NS
Slightly
in
Cold
H
2
O
Manganese
dioxide
1313­
13­
9
Manganese
peroxide;

manganese
binoxide;

manganese
black;

battery
manganese;

pyrolusite
+
4
MnO
2
86.94
5.026
535
NS
No
Potassium
permanganate
7722­
64­
7
Permangnaic
acid;

potassium
salt;

chameleon
mineral
+
7
KMnO
4
158.03
2.7
Decomposes
240
NS
Yes
Sources:
ATSDR
(
2000);
U.
S.
EPA
(
1994a);
ChemIDplus
(
2000).

Log
K
ow
and
threshold
information
was
not
available
for
manganese
compounds.

NS
=
Not
Specified
3­
1
Manganese
 
February
2003
3.0
USES
AND
ENVIRONMENTAL
FATE
The
uses
and
environmental
fate
of
manganese
in
air,
water,
and
soil
have
been
extensively
reviewed
by
ATSDR
(
2000)
and
U.
S.
EPA
(
1994a).
Information
from
these
documents
and
other
sources
is
summarized
below.

3.1
Production
and
Uses
Manganese
is
a
naturally
occurring
element
that
constitutes
approximately
0.1%
of
the
earth's
crust.
It
does
not
occur
in
the
environment
in
its
pure
metal
form,
but
is
ubiquitous
as
a
component
of
over
100
minerals,
including
many
silicates,
carbonates,
sulfides,
oxides,
phosphates,
and
borates
(
ATSDR,
2000).
Manganese
occurs
naturally
at
low
levels
in
soil,
water,
air,
and
food.
Of
the
heavy
metals,
manganese
is
surpassed
in
abundance
only
by
iron
(
ATSDR,
2000).

In
the
United
States,
most
manganese
ore
is
smelted
to
produce
ferromanganese,
which
is
a
manganese­
iron
alloy
(
ATSDR,
2000).
The
latter
is
used
primarily
in
the
production
of
steel
to
improve
stiffness,
hardness,
and
strength.
The
ore
is
mined
in
open
pit
or
shallow
underground
mines,
though
little
has
been
mined
in
the
U.
S.
since
1978
(
ATSDR,
2000;
USGS,
2000).
Almost
all
of
the
manganese
ore
used
in
steel
production
in
the
United
States
is
imported
(
see
Table
3­
1;
ATSDR,
2000).
Large
quantities
of
ferromanganese
are
imported
as
well
(
USGS,
2000).
Table
3­
2
provides
further
information
by
State
of
the
widespread
manufacture
and
processing
of
manganese.

Table
3­
1.
Imports
of
Manganese
and
Ferromanganese
to
the
United
States
(
thousand
metric
tons,
gross
weight).

Compound
1984
1988
1995
1996
1997
1998
1999
^

manganese
ore
308
499
394
478
355
332
535
ferromanganese
330
449
310
374
304
339
325
years
1984
and
1988:
ATSDR,
(
1997)
years
1995
to
1999:
USGS,
(
2000)
^
estimated
Manganese
compounds
are
produced
through
reactions
of
various
elements
and
compounds
with
either
manganese
ores
or
ferromanganese
(
ATSDR,
2000).
Some
common
manganese
compounds
include
manganese
chloride,
manganese
sulfate,
manganese
(
II,
III)
oxide,
manganese
dioxide,
and
potassium
permanganate
(
ATSDR,
2000).
Uses
of
these
compounds
are
varied,
implying
widespread
environmental
release.
Significantly,
approximately
80%
of
the
potassium
permanganate
used
in
the
United
States
is
expended
in
wastewater
and
drinking
water
treatment
(
U.
S.
EPA,
1984).
Manganese
dioxide
is
used
in
the
production
of
matches,
dry­
cell
batteries,
fireworks,
and
as
a
precursor
for
other
manganese
compounds.
Manganese
chloride
is
also
used
as
a
precursor
for
manganese
compounds.
A
large
proportion
(
60%)
of
U.
S.
manganese
sulfate
is
used
as
a
fertilizer,
while
the
remainder
is
used
in
varnish,
3­
2
Manganese
 
February
2003
Table
3­
2.
Manganese
Manufacturers
and
Processors
by
State.

Statea
Number
of
facilities
Range
of
maximum
amounts
on­
site
in
thousands
of
Activities
and
usesc
AL
60
0­
50,000
1,2,3,6,7,8,9,12
AR
29
0­
50,000
1,2,3,5,7,8,9,12,13
AZ
8
1­
1,000
1,4,5,7,8,9,10,12
CA
55
0­
500,000
1,2,3,4,5,6,7,8,9,10,11,12,13
CO
14
1­
10,000
2,3,4,9,12
CT
16
1­
1,000
2,3,9,10
DE
1
10­
100
1,5,8
FL
26
0­
10,,
000
8,9,10,13
GA
42
0­
10,000
1,2,3,5,7,8,9,10,12,13
HI
1
10­
100
9
IA
51
0­
10,000
1,2,3,5,7,8,9,10,12
ID
3
1­
1,000
9
IL
121
0­
50,000
1,2,3,4,5,8,9,10,11,12,13
IN
161
0­
50,000
1,2,3,4,5,6,7,8,9,10,11,12,13
KS
30
1­
500,000
1,3,4,5,8,9,12,13
KY
63
0­
500,000
1,2,3,4,5,6,7,8,9,10,12,13
LA
17
0­
10,000
1,2,3,5,7,8,9,10,12,13
MA
26
0­
1,000
1,2,3,4,5,9,10
MD
17
1­
50,000
2,4,9,10,13
ME
8
1­
100
1,3,9
MI
128
0­
10,000
1,2,3,4,5,6,7,8,9,10,12,13
MN
28
0­
10,000
8,9,10,12
MO
49
0­
10,000
1,5,8,9,12
MS
23
0­
50,000
8,9,13
MT
1
100,000­
500,000
1,2,3,4,5,6,7
NC
57
0­
10,000
1,2,3,5,8,9,10,11,12,13
ND
5
1­
100
2,3,9
NE
18
0­
10,000
1,2,3,8,9,12,13
NH
4
1­
1,000
8,9
NJ
27
1­
10,000
1,2,3,4,7,8,9,10
NM
1
10­
100
9
NV
2
100­
50,000
2,3,7
NY
63
0­
10,000
1,2,3,4,5,7,8,9,10,12,13
OH
231
0­
500,000
1,2,3,4,5,6,7,8,9,10,12,13
OK
48
0­
10,000
1,2,3,4,5,6,8,9
OR
17
1­
10,000
2,3,9,12,13
PA
179
0­
100,000
1,2,3,4,5,7,8,9,10,11,12,13
PR
5
0­
1,000
9
RI
5
1­
1,000
2,3,9,10
SC
57
0­
10,000
1,2,3,5,7,8,9,10,13
SD
7
1­
100
9,13
TN
54
0­
50,000
1,2,3,4,5,6,7,8,9,10,12,13
TX
85
0­
10,000
1,2,3,4,5,6,8,9,10,12,13
UT
23
1­
100,000
2,3,7,9,12,13
VA
23
0­
1,000
1,3,5,7,8,9
VT
1
10­
100
9
WA
27
0­
1,000
1,2,3,6,8,9
WI
126
0­
50,000
1,2,3,5,6,7,8,9,10,12,13
WV
15
1­
500,000
8,9,10,13
WY
2
0­
1,000
1,5
aPost
office
State
abbreviations
used
bData
in
TRI
are
maximum
amounts
on­
site
at
each
facility
cActivities/
Uses
1.
Produce
8.
Formulation
component
2.
Import
9.
Article
component
3.
On­
site
use/
processing
10.
Repackaging
4.
Sale/
distribution
11.
Chemical
processing
aid
5.
Byproduct
12.
Manufacturing
aid
6.
Impurity
13.
Ancillary/
other
uses
7.
Reactant
source:
ATSDR
(
2000)
compilation
of
1996
TRI
data
fungicides,
and
as
a
livestock
feed
supplement.
An
organic
manganese
compound,
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT),
was
used
as
an
anti­
3­
3
Manganese
 
February
2003
knock
additive
in
unleaded
gasoline
before
it
was
banned
in
1977.
However,
a
1995
court
decision
required
EPA
to
reregister
MMT
and
its
use
is
ongoing
(
ATSDR,
2000).

The
uses
of
manganese
compounds
vary
widely
depending
on
the
chemical
form.
Table
3­
3
summarizes
key
uses
of
selected
manganese
compounds.

Table
3­
3.
Summary
of
Uses
for
Selected
Manganese
Compounds.

Compound
Use
Methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
Fuel
additive
Manganous
carbonate
Ferrites;
animal
feeds;
ceramics;
acid
soluble
manganese
source
Manganese
chloride
Catalyst
in
organic
compound
chlorination;
trace
mineral
supply
for
animal
feed;
brick
colorant;
dye;
drycell
batteries;
linseed
oil
drier;
disinfecting;
purifying
natural
gas
Manganous
acetate
Mordant
in
dyeing;
drying
agent
for
paint
and
varnish;
bister
Manganese
ethylenebisdithiocarbamate
Agricultural
fungicide
Manganese
oxide
Ferrites;
ceramics;
fertilizer;
livestock
feed
additive
Manganese
phosphate
Ingredient
of
proprietary
solutions
for
phosphating
iron
and
steel
Manganese
sulfate
Livestock
feed
additive;
fertilizer;
glazes;
varnishes;
ceramics;
fungicides
Manganous
trifluoride
Fluorinating
agent
in
organic
chemistry
Manganese
borate
Drying
agent
for
varnish
and
oil;
linseed
oil
drier;
leather
industry
Manganous
nitrate
Porcelain
colorants;
manufacture
of
reagent
grade
manganese
dioxide
Manganese
dioxide
(
electrolytic
manganese,
pyrolusite)
Dry­
cell
batteries;
matches;
fireworks;
porcelain;
glass
bonding
materials;
amethyst
glass;
manufacturing
manganese
steel;
oxidizer
Potassium
permanganate
Oxidizing
agent;
water
and
air
disinfectant;
antialgal
agent;
metal
cleaning,
tanning,
and
bleaching
agent;
fresh
flower
and
fruit
preservative
Sources:
U.
S.
EPA
(
1994a);
ATSDR
(
2000);
Merck
(
1983).
3­
4
Manganese
 
February
2003
3.2
Sources
and
Environmental
Fate
Manganese
compounds
are
widely
distributed
in
air,
soil,
and
water.
Sources
of
atmospheric
manganese
include
industrial
emissions,
fossil
fuel
combustion,
and
erosion
of
manganese­
containing
soils.
Volcanic
eruptions
can
also
contribute
to
levels
of
manganese
in
air.
Almost
80%
of
industrial
emissions
of
manganese
are
attributable
to
iron
and
steel
production
facilities.
Power
plant
and
coke
oven
emissions
contribute
about
20%.
Although
soil
erosion
is
considered
an
important
source
of
atmospheric
manganese,
quantitative
data
for
contributions
from
this
source
are
not
available.
Due
to
generally
low
vapor
pressure,
manganese
compounds
in
air
exist
primarily
as
suspended
particulate
matter.
Because
particle
size
is
small,
atmospheric
manganese
distribution
can
be
widespread.
These
particles
will
eventually
settle
out
via
the
process
of
dry
deposition
into
surface
waters
or
onto
soils.
Little
information
is
available
on
the
chemical
reactions
of
atmospheric
manganese,
but
it
is
expected
to
react
with
sulfur
and
nitrogen
dioxide.
The
half­
life
of
manganese
in
air
is
only
a
few
days
(
ATSDR,
2000).

The
fuel
additive
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
is
expected
to
contribute
to
urban
air
concentrations
of
manganese
compounds.
The
fuel­
enhancing
properties
of
MMT
were
first
discovered
in
the
1950s,
and
the
compound
has
been
used
as
an
additive
in
leaded
and
unleaded
gasoline
since
the
1970s
in
the
United
States
and
Canada
(
Lynam
et
al.,
1999).
MMT
was
banned
for
use
in
unleaded
gasoline
in
the
United
States
in
1977
in
accordance
with
provisions
in
the
Clean
Air
Act,
which
stated
that
all
gasoline
additives
that
were
not
"
substantially
similar"
to
gasoline
were
required
to
obtain
a
waiver
proving
that
the
additive
did
not
"
cause
or
contribute
to
the
failure
of
emission
control
systems"
(
Lynam
et
al.,
1999).
The
U.
S.
EPA
lifted
this
ban
under
court
order
in
1995,
and
MMT
has
been
used
freely
since
that
time.

Gasoline
without
MMT
contains
virtually
no
manganese
(
Lynam
et
al.,
1999).
The
currently
allowed
maximum
level
of
MMT
in
unleaded
fuel
is
0.03125
gram
of
manganese
per
U.
S.
gallon
of
gasoline
(
0.0083
g/
L
or
10.4
ppm).
The
amount
of
manganese
emitted
from
the
tailpipe
of
an
automobile
using
MMT­
containing
fuel
depends
upon
the
type
of
engine,
driving
cycle,
and
age
of
the
vehicle.
Estimates
for
manganese
in
vehicular
exhaust
vary
between
4%
and
41%
of
the
manganese
consumed
(
Ardeleanu
et
al.,
1999).
The
remaining
fraction
apparently
remains
in
the
vehicle
(
Ardeleanu
et
al.,
1999).
Early
analysis
of
emissions
suggested
that
manganese
from
combustion
of
MMT
is
emitted
primarily
as
manganese
tetroxide
(
Mn
3
O
4)
(
Ter
Harr
et
al.,
1975d
as
cited
in
Lynam
et
al.,
1995).
However,
more
recent
testing
suggests
that
when
very
low
levels
of
MMT
are
combusted
(
i.
e.,
concentrations
comparable
to
the
currently
allowed
levels),
manganese
is
emitted
primarily
as
manganese
phosphate
and
sulfate.
The
reported
valence
of
the
emitted
manganese
is
+
2.2,
with
a
mass
median
aerodynamic
diameter
of
1
to
2
microns
(
Ethyl
Corporation,
1997;
Ressler
et
al.,
1999;
Wong
et
al.,
1998;
all
as
cited
in
Lynam
et
al.,
1999).
Uncombusted
MMT
rapidly
decomposes
to
manganese
oxide,
carbon
dioxide,
and
organic
compounds
in
the
atmosphere
and
has
a
half­
life
of
only
a
few
seconds
in
the
presence
of
sunlight
(
Lynam
et
al.,
1999;
Zayed
et
al.,
1999a).
Data
on
the
occurrence
of
manganese
in
air
resulting
from
combustion
of
MMT
and
other
sources
are
presented
in
Section
4.2.
3­
5
Manganese
 
February
2003
Manganese
is
listed
as
a
Toxic
Release
Inventory
(
TRI)
chemical.
In
1986,
the
Emergency
Planning
and
Community
Right­
to­
Know
Act
(
EPCRA)
established
the
TRI
of
hazardous
chemicals.
Created
under
the
Superfund
Amendments
and
Reauthorization
Act
(
SARA)
of
1986,
EPCRA
is
also
sometimes
known
as
SARA
Title
III.
The
EPCRA
mandates
that
larger
facilities
publicly
report
when
TRI
chemicals
are
released
into
the
environment.
This
public
reporting
is
required
for
facilities
with
at
least
10
full­
time
employees
that
annually
manufacture
or
process
more
than
25,000
pounds,
or
use
more
than
10,000
pounds,
of
TRI
chemical
(
U.
S.
EPA,
1996e,
2000a).

Under
these
conditions,
facilities
are
required
to
report
the
pounds
per
year
of
manganese
released
into
the
environment
both
on­
and
off­
site.
The
on­
site
quantity
is
subdivided
into
air
emissions,
surface
water
discharges,
underground
injections,
and
releases
to
land
(
see
Table
3­
4).
For
manganese,
releases
to
land
constitute
most
of
the
on­
site
releases,
with
an
abrupt
decrease
occurring
in
1989.
It
is
unclear
whether
this
sharp
decrease
is
real
or
a
function
of
changes
in
TRI
reporting
requirements
in
the
late
1980s
and
early
1990s
(
see
discussion
below).
Land
releases
have
fluctuated
modestly
since
that
year
with
no
trend
evident.
Air
emissions
are
also
an
important
mode
of
on­
site
release.
Though
the
first
four
years
of
record
for
air
emissions
are
markedly
higher,
no
trend
is
apparent
for
the
remainder.
Surface
water
discharges
and
underground
injections
are
less
significant
on­
site
releases,
with
underground
injections
sharply
decreasing
in
1994.
Low
levels
of
underground
injection
have
continued
to
the
present.
Off­
site
releases
of
manganese
are
considerable.
Though
in
1990
there
was
a
large
drop
when
compared
to
previous
years,
the
late
1990s
showed
a
steady
increase
in
pounds
released.
These
TRI
data
for
manganese
were
reported
from
49
States,
excluding
Alaska
(
U.
S.
EPA,
2000b).

Only
1%
of
environmental
manganese
is
released
to
water
(
Table
3­
4).
The
primary
sources
for
surface
and
ground
water
releases
are
industrial
facility
effluent
discharge,
landfill
and
soil
leaching,
and
underground
injection.
Manganese,
in
the
form
of
potassium
permanganate,
may
be
used
in
drinking
water
treatment
to
oxidize
and
remove
iron,
manganese,
and
other
contaminants
(
ANSI/
NSF,
2000),
in
addition
to
its
use
in
industrial
wastewater
purification
and
odor
abatement
(
ATSDR,
2000;
U.
S.
EPA,
1984).
Transport
and
partitioning
of
manganese
in
water
is
dependent
on
the
solubility
of
the
manganese
form.
The
chemical
form
is
controlled
by
factors
such
as
pH,
oxidation­
reduction
potential
(
Eh),
and
the
available
anions.
Often,
manganese
in
water
will
settle
into
suspended
sediments.
Little
information
is
available
on
the
biodegradation
of
manganese­
containing
compounds
in
water,
but
factors
such
as
pH
and
temperature
are
important
for
microbial
activities.
Data
for
occurrence
of
manganese
in
drinking
water
are
presented
in
Section
4.3.

Approximately
91%
of
environmental
manganese
is
released
to
soil.
The
main
source
of
this
release
is
land
disposal
of
manganese­
containing
wastes.
The
ability
of
manganese
compounds
to
adsorb
to
soils
and
sediments
is
contingent
upon
the
cation
exchange
capacity
and
organic
content
of
the
soil
or
sediment.
Adsorption
can
vary
widely
based
on
differences
in
these
two
factors.
Oxidative
microbial
activity
may
increase
the
precipitation
of
manganese
minerals
and
increase
the
dissolution
of
manganese
in
subsurface
environments.
Occurrence
data
for
manganese
in
soils
are
presented
in
Section
5.3.
3­
6
Manganese
 
February
2003
TRI
data
are
also
available
for
the
release
of
manganese
compounds
(
Table
3­
5).
Releases
to
land
again
constitute
the
largest
proportion
of
on­
site
releases.
With
the
exception
of
1997
and
1998,
releases
to
land
have
generally
decreased
over
the
period
of
record.
Air
emissions
are
also
an
important
mode
of
release
and
no
trends
are
evident
in
the
data.
Significantly,
surface
water
discharges
and
underground
injections
are
much
more
substantial
for
the
compounds
than
for
elemental
manganese,
and
have
been
generally
increasing
(
dramatically
in
some
years)
since
the
early
1990s.
These
data
must
be
interpreted
with
caution,
however,
as
they
reflect
changes
in
the
requirements
for
reporting
releases.
In
1998,
only
releases
of
75,000
lbs/
yr
were
required
to
be
reported;
this
value
is
now
25,000
lbs/
yr.
Therefore,
although
the
values
may
seem
to
be
increasing,
they
are
likely
comparable
to
past
releases
that
were
previously
unreported.
Further,
the
TRI
data
are
meant
to
reflect
releases
and
should
not
be
used
to
estimate
general
exposure
to
a
chemical
(
U.
S.
EPA,
2000c,
d).

Increases
in
surface
water
discharges
and
underground
injections
of
manganese
compounds
have
contributed
to
increases
in
total
on­
and
off­
site
releases
in
recent
years.
The
latter
have
returned
to,
or
exceeded,
the
higher
levels
seen
in
the
late
1980s
and
early
1990s.
Off­
site
releases,
a
large
component
of
total
releases,
are
also
at
their
highest
levels
since
reporting
began
in
1988.
These
TRI
data
for
manganese
compounds
were
reported
from
all
50
States
(
U.
S.
EPA,
2000b).

Table
3­
4.
Environmental
Releases
(
in
pounds)
for
Manganese
in
the
United
States,
1988
 
1998.

Year
On­
Site
Releases
Off­
Site
Releases
Total
On­
&
Off­
Site
Releases
Air
Emissions
Surface
Water
Discharges
Underground
Injection
Releases
to
Land
1998
970,658
260,403
3
9,995,895
15,967,545
27,194,504
1997
751,743
146,364
7
9,920,481
16,209,483
27,028,078
1996
816,733
117,571
8
10,111,563
15,191,636
26,237,511
1995
699,897
117,277
17
8,279,054
12,753,204
21,849,449
1994
818,600
89,332
10
8,452,582
14,076,682
23,437,206
1993
901,827
243,999
504
7,530,152
12,150,694
20,827,176
1992
721,047
235,307
304
6,543,600
11,997,270
19,497,528
1991
1,113,160
143,105
272
9,906,511
14,590,589
25,753,637
1990
1,168,809
139,358
881
9,031,215
11,364,721
21,704,984
1989
2,444,211
150,965
556
7,984,172
20,559,164
31,139,068
1988
1,586,675
321,993
255
20,229,826
20,087,660
42,226,409
source:
U.
S.
EPA
(
2000b)
3­
7
Manganese
 
February
2003
Table
3­
5.
Environmental
Releases
(
in
pounds)
for
Manganese
Compounds
in
the
United
States,
1988
 
1998.

Year
On­
Site
Releases
Off­
Site
Releases
Total
On­
&
Off­
site
Releases
Air
Emissions
Surface
Water
Discharges
Underground
Injection
Releases
to
Land
1998
1,566,352
4,471,582
7,755,610
52,820,578
45,269,882
111,884,004
1997
1,549,505
4,202,876
14,412,830
50,141,026
47,233,186
117,539,423
1996
1,828,684
2,119,241
15,630
40,334,426
33,543,677
77,841,658
1995
2,928,644
1,627,184
3,590
41,832,058
25,994,951
72,386,427
1994
3,060,424
857,825
5,930
38,228,464
25,840,954
67,993,597
1993
2,324,442
685,737
8,740
47,763,821
22,780,860
73,563,600
1992
2,079,044
733,728
22,569
63,490,137
17,297,544
83,623,022
1991
1,531,832
709,557
15,327
66,559,047
27,250,630
96,066,393
1990
2,276,084
721,787
2,842
83,331,787
35,789,554
122,122,054
1989
1,847,528
907,866
1,005,518
85,191,013
33,004,908
121,956,833
1988
1,801,463
681,469
6,816,070
84,227,842
20,670,921
114,197,765
source:
U.
S.
EPA
(
2000b).

Although
the
TRI
can
be
useful
in
giving
a
general
idea
of
release
trends,
the
data
are
far
from
exhaustive
and
have
significant
limitations.
For
example,
only
industries
which
meet
TRI
criteria
(
at
least
10
full­
time
employees
and
manufacture
and
processing
of
quantities
exceeding
25,000
lbs/
yr,
or
use
of
more
than
10,000
lbs/
yr)
are
required
to
report
releases.
These
reporting
criteria
do
not
account
for
releases
from
smaller
industries.
Threshold
manufacture
and
processing
quantities
also
changed
from
1988
to
1990
(
dropping
from
75,000
lbs/
yr
in
1988
to
50,000
lbs/
yr
in
1989
to
its
current
25,000
lbs/
yr
in
1990),
creating
possibly
misleading
data
trends.
Finally,
the
TRI
data
are
meant
to
reflect
releases
and
should
not
be
used
to
estimate
general
exposure
to
a
chemical
(
U.
S.
EPA,
2000c,
d).

In
summary,
manganese
and
many
of
its
compounds
are
naturally
occurring
and
found
at
low
levels
in
soil,
water,
air,
and
food.
Furthermore,
manganese
compounds
are
produced
in
the
United
States
from
manganese
ore
and
are
in
widespread
use.
Most
ferromanganese
is
used
in
steel
production,
while
other
manganese
compounds
are
used
in
a
variety
of
applications
from
fertilizers
and
industrial
products
to
water
treatment.
Recent
statistics
regarding
import
for
consumption
indicate
production
and
use
are
substantial
(
Table
3­
1).
Manganese
and
its
compounds
are
also
TRI
chemicals
(
Tables
3­
4
and
3­
5).
Industrial
releases
have
been
reported
since
1988
in
all
50
States.
Off­
site
releases
constitute
a
considerable
amount
of
total
releases,
with
releases
to
land
being
the
most
significant
on­
site
releases.
4­
1
Manganese
 
February
2003
4.0
EXPOSURE
FROM
DRINKING
WATER
4.1
Introduction
This
chapter
examines
the
occurrence
of
manganese
in
drinking
water.
No
complete
national
database
exists
regarding
the
occurrence
of
unregulated
or
regulated
contaminants
in
drinking
water
from
public
water
systems
(
PWSs)
collected
under
the
Safe
Drinking
Water
Act
(
SDWA).
In
this
chapter,
existing
federal
and
State
data
that
have
been
screened
for
quality,
completeness,
and
representativeness
are
aggregated
and
analyzed.
Populations
served
by
PWSs
exposed
to
manganese
are
also
estimated,
and
the
occurrence
data
are
examined
for
special
trends.
To
augment
the
incomplete
national
drinking
water
data
and
aid
in
the
evaluation
of
occurrence,
information
on
the
use
and
environmental
release,
as
well
as
ambient
occurrence
of
manganese,
is
also
reviewed.

4.2
Ambient
Occurrence
To
understand
the
presence
of
a
chemical
in
the
environment,
an
examination
of
ambient
occurrence
is
useful.
In
a
drinking
water
context,
ambient
water
is
source
water
existing
in
surface
waters
and
aquifers
before
treatment.
The
most
comprehensive
and
nationally
consistent
data
describing
ambient
water
quality
in
the
United
States
are
being
produced
through
the
United
States
Geological
Survey's
(
USGS)
National
Ambient
Water
Quality
Assessment
(
NAWQA)
program.
NAWQA,
however,
is
a
relatively
young
program
and
complete
national
data
are
not
yet
available
from
the
entire
array
of
sites
across
the
nation.

Data
Sources
and
Methods
The
USGS
instituted
the
NAWQA
program
in
1991
to
examine
water
quality
status
and
trends
in
the
United
States.
NAWQA
is
designed
and
implemented
in
such
a
manner
to
allow
consistency
and
comparison
among
representative
study
basins
located
around
the
country,
facilitating
interpretation
of
natural
and
anthropogenic
factors
affecting
water
quality
(
Leahy
and
Thompson,
1994).

The
NAWQA
program
consists
of
59
significant
watersheds
and
aquifers
referred
to
as
"
study
units."
The
study
units
represent
approximately
two­
thirds
of
the
overall
water
usage
in
the
United
States
and
a
similar
proportion
of
the
population
served
by
public
water
systems.
Approximately
one­
half
of
the
nation's
land
area
is
represented
(
Leahy
and
Thompson,
1994).

To
facilitate
management
and
make
the
program
cost­
effective,
approximately
one­
third
of
the
study
units
at
a
time
engage
in
intensive
assessment
for
a
period
of
3
to
5
years.
This
is
followed
by
a
period
of
less
intensive
research
and
monitoring
that
lasts
between
5
and
7
years.
This
way,
all
59
study
units
rotate
through
intensive
assessment
over
a
ten­
year
period
(
Leahy
and
Thompson,
1994).
The
first
round
of
intensive
monitoring
(
1991
 
96)
targeted
20
watersheds
and
the
second
round
monitored
16
basins
beginning
in
1994.
4­
2
Manganese
 
February
2003
Manganese
is
an
analyte
for
both
surface
and
ground
water
NAWQA
studies,
with
a
Minimum
Reporting
Level
(
MRL)
of
0.001
mg/
L.
Manganese
occurrence
in
bed
sediments
and
aquatic
biota
tissue
is
also
assessed,
with
MRLs
of
4
mg/
kg
and
0.1
mg/
kg,
respectively.
Additional
information
on
analytical
methods
used
in
the
NAWQA
study
units,
including
minimum
reporting
levels,
are
described
by
Gilliom
and
others
(
1998).

Manganese
data
from
the
first
two
rounds
of
intensive
NAWQA
monitoring
have
undergone
USGS
quality
assurance
checks
and
are
available
to
the
public
through
their
NAWQA
Data
Warehouse
(
USGS,
2001).
EPA
has
analyzed
these
data
after
further
data
quality
review
and
occurrence
results
are
presented
below.
The
descriptive
statistics
generated
from
the
manganese
NAWQA
data
broadly
characterize
the
frequency
of
manganese
detections
by
sample
and
by
site.
Furthermore,
detection
frequencies
above
a
Health
Reference
Level
(
HRL)
of
0.3
mg/
L
are
also
presented
for
all
samples,
and
by
site.
The
HRL
is
a
preliminary
health
effect
level
used
for
this
analysis
(
see
Section
4.3
for
further
discussion
of
the
HRL
and
its
development).
The
median
and
99th
percentile
concentrations
are
included
as
well
to
characterize
the
spread
of
manganese
concentration
values
in
ambient
waters
sampled
by
the
NAWQA
program.

Results
Typical
of
many
inorganic
contaminants,
manganese
occurrence
in
ambient
surface
and
ground
waters
is
high
(
Table
4­
1).
This
is
to
be
expected,
considering
that
manganese
constitutes
approximately
0.1%
of
the
earth's
crust
(
of
the
heavy
metals,
it
is
surpassed
in
abundance
only
by
iron),
and
the
element
and
its
compounds
are
used
in
many
products.
Significantly,
potassium
permanganate
is
used
in
wastewater
and
drinking
water
treatment.

Detection
frequencies
are
consistently
greater
for
surface
water
than
for
ground
water,
possibly
because
surface
waters
are
more
likely
to
act
as
sinks
for
anthropogenic
releases
of
manganese.
Median
concentrations
are
also
generally
higher
for
surface
water
(
median
concentration
for
all
sites
is
0.016
mg/
L
in
surface
water
and
0.005
mg/
L
in
ground
water).
However,
manganese
detection
frequencies
>
HRL
are
consistently
higher
in
ground
water,
and
99th
percentile
ground
water
concentrations
are
as
much
as
eight
times
larger
than
corresponding
99th
percentile
surface
water
concentrations.
Locally
high
concentrations
in
ground
water,
higher
than
any
seen
in
surface
water,
are
not
surprising
given
the
possibility
of
long
contact
times
between
ground
water
and
rocks
enriched
in
manganese
at
a
given
location.
Contact
times
between
surface
waters
and
naturally
occurring
manganese
are
orders
of
magnitude
shorter,
hence
concentrations
are
lower.
Furthermore,
surface
waters
subject
to
large
anthropogenic
inputs
of
manganese
are
more
easily
diluted
by
waters
integrated
from
other
parts
of
the
watershed,
where
manganese
concentrations
may
be
lower.

Table
4­
1
illustrates
that
low­
level
manganese
occurrence
is
ubiquitous.
Surface
water
detection
frequencies
by
site
are
greater
than
95%
for
all
land
use
categories.
Median
concentrations
and
HRL
exceedances
(
by
site)
are
greater
in
urban
and
agricultural
basins
compared
to
basins
characterized
as
mixed
land
use
or
forest/
rangeland.
This
distribution
of
manganese
occurrence
is
probably
influenced
by
the
wide
use
of
manganese
compounds
in
both
industry
and
agriculture.
Mixed
land
use
basins
are
generally
larger
than
either
urban
or
4­
3
Manganese
 
February
2003
agricultural
basins,
and
the
lower
occurrence
in
these
basins
may
reflect
some
dilution
of
the
contaminant.
The
99th
percentile
concentrations
for
surface
water
range
from
0.4
mg/
L
to
0.8
mg/
L.
The
frequency
of
detections
exceeding
the
MRL
and
HRL
by
site
for
all
sites
are
approximately
96.9%
and
10.2%,
respectively.
These
figures
indicate
that,
although
manganese
is
nearly
ubiquitous
in
surface
water,
detections
at
levels
of
public
health
concern
are
relatively
low.

For
ground
water,
detections
by
site
are
higher
in
urban
and
forest/
rangeland
areas
than
in
mixed
or
agricultural
lands.
Over
80%
of
urban
and
forest/
rangeland
sites
reported
detections,
while
approximately
63
to
64%
of
mixed
and
agricultural
land
use
sites
detected
manganese.
The
finding
that
ground
water
manganese
occurrence
is
higher
in
forest/
rangeland
areas
than
in
either
mixed
or
agricultural
sites
may
result
from
natural
variation
in
manganese
occurrence
in
soil
and
rock.
Urban
areas
have
the
highest
median
and
99th
percentile
concentrations
(
0.015
mg/
L
and
5.6
mg/
L,
respectively),
as
well
as
the
highest
detection
frequencies
(
by
site:
85.3%)
and
HRL
exceedances
(
both
by
sample
and
by
site:
17.2%
and
21%,
respectively)
of
manganese
in
groundwater.
These
results
suggest
that
urban
releases
of
manganese
and
manganese
compounds
can
leach
to
ground
water.

Detection
frequencies
and
HRL
exceedances
by
site
for
all
ground
water
sites
are
approximately
70.1%
and
13.8%,
respectively.
Again,
these
figures
suggest
that,
while
manganese
occurrence
in
ground
water
is
high,
detections
at
levels
of
public
health
concern
are
relatively
low.

Manganese
was
detected
at
100%
of
NAWQA
stream
bed
sediment
sampling
sites.
The
median
and
99th
percentile
concentrations
in
bed
sediments
are
1.1
mg/
kg
(
dry
weight)
and
9.4
mg/
kg
(
dry
weight),
respectively.
The
occurrence
of
manganese
in
stream
sediments
is
pertinent
to
drinking
water
concerns
because,
though
many
manganese
compounds
are
either
insoluble
or
have
low
solubility
and
are
transported
in
water
as
suspended
sediment,
some
desorption
of
the
compound
from
sediments
into
water
will
occur
through
equilibrium
reactions,
although
in
very
low
concentrations.

In
aquatic
biota
tissue,
detections
are
also
100%
of
all
samples
and
sites
(
Table
4­
2).
However,
concentration
percentiles
for
tissues
are
substantially
lower
than
for
bed
sediments:
the
median
for
biotic
tissue
is
0.01
mg/
kg
(
dry
weight)
and
the
99th
percentile
is
2.9
mg/
kg
(
dry
weight).
Significant
manganese
concentrations
in
aquatic
biota
tissues
would
imply
a
potential
for
bioaccumulation.
Although
manganese
was
detected
in
aquatic
biota
tissues
at
100%
of
samples
and
sites,
low
concentration
percentiles
suggest
that
the
element
does
not
bioaccumulate
appreciably.
4­
4
Manganese
 
February
2003
4.3
Drinking
Water
Occurrence
National
Inorganic
and
Radionuclide
Survey
(
NIRS)

In
the
mid­
1980s,
EPA
designed
and
conducted
the
National
Inorganic
and
Radionuclide
Survey
(
NIRS)
to
collect
national
occurrence
data
on
a
select
set
of
radionuclides
and
inorganic
chemicals
being
considered
for
National
Primary
Drinking
Water
Regulations.
The
NIRS
database
includes
36
inorganic
compounds
(
IOC)
(
including
10
regulated
IOCs),
2
regulated
radionuclides,
and
4
unregulated
radionuclides.
Manganese
was
one
of
the
36
IOCs
monitored.

The
NIRS
provides
contaminant
occurrence
data
from
989
community
PWSs
served
by
ground
water.
The
NIRS
does
not
include
surface
water
systems.
The
selection
of
this
group
of
PWSs
was
designed
so
that
the
contaminant
occurrence
results
are
statistically
representative
of
national
occurrence.
Most
of
the
NIRS
data
are
from
smaller
systems
(
based
on
populationserved
and
each
of
these
statistically
randomly
selected
PWSs
was
sampled
a
single
time
between
1984
and
1986.

The
NIRS
data
were
collected
from
PWSs
in
49
States.
Data
were
not
available
for
the
State
of
Hawaii.
In
addition
to
being
statistically
representative
of
national
occurrence,
NIRS
data
are
designed
to
be
divisible
into
strata
based
on
system
size
(
population
served
by
the
PWS).
Uniform
detection
limits
were
employed,
thus
avoiding
computational
(
statistical)
problems
that
sometimes
result
from
multiple
laboratory
analytical
detection
limits.
Therefore,
the
NIRS
data
can
be
used
directly
for
national
contaminant
occurrence
analyses
with
very
few,
if
any,
data
quality,
completeness,
or
representativeness
issues.

Supplemental
IOC
Data
One
limitation
of
the
NIRS
study
is
a
lack
of
occurrence
data
for
surface
water
systems.
To
provide
perspective
on
the
occurrence
of
manganese
in
surface
water
PWSs
relative
to
ground
water
PWSs,
SDWA
compliance
monitoring
data
that
were
available
to
EPA
were
reviewed
from
States
with
occurrence
data
for
both
kinds
of
systems.

The
State
ground
water
and
surface
water
PWS
occurrence
data
for
manganese
used
in
this
analysis
were
submitted
by
States
for
an
independent
review
of
the
occurrence
of
regulated
contaminants
in
PWSs
at
various
times
for
different
programs
(
U.
S.
EPA,
1999a).
In
the
U.
S.
EPA
(
1999a)
review,
occurrence
data
from
a
total
of
14
States
were
noted.
However,
because
several
States
contained
data
that
were
incomplete
or
unusable
for
various
reasons,
only
12
of
the
14
States
were
used
for
a
general
overview
analysis.
From
these
12
States,
8
were
selected
for
use
in
a
national
analysis
because
they
provided
the
best
data
quality
and
completeness
and
a
balanced
national
cross­
section
of
occurrence
data.
These
eight
were
Alabama,
California,
Illinois,
Michigan,
Montana,
New
Jersey,
New
Mexico,
and
Oregon.
4­
5
Manganese
 
February
2003
Table
4­
1.
Manganese
Detections
and
Concentrations
in
Streams
and
Ground
Water.

Detection
frequency
>
MRL*
Detection
frequency
>
HRL*
Concentration
percentiles
(
all
samples;
mg/
L)

%
samples
%
sites
%
samples
%
sites
median
99th
Surface
Water
urban
99.1
%
99.6
%
4.6
%
13.0
%
0.036
0.7
mixed
92.4
%
98.5
%
1.3
%
6.4
%
0.012
0.4
agricultural
96.3
%
97.2
%
3.7
%
12.3
%
0.019
0.7
forest/
rangeland
90.9
%
96.4
%
5.0
%
6.6
%
0.011
0.8
all
sites
94.0
%
96.9
%
3.0
%
10.2
%
0.016
0.7
Ground
Water
urban
74.7
%
85.3
%
17.2
%
21.0
%
0.015
5.6
mixed
56.9
%
62.9
%
8.9
%
9.0
%
0.002
1.3
agricultural
61.4
%
64.0
%
11.9
%
12.8
%
0.004
1.6
forest/
rangeland
75.3
%
81.3
%
10.9
%
13.8
%
0.012
2.9
all
sites
64.1
%
70.1
%
12.8
%
13.8
%
0.005
2.9
*
The
Minimum
Reporting
Level
(
MRL)
for
manganese
in
water
is
0.001
mg/
L
and
the
Health
Reference
Level
(
HRL)
is
0.3
mg/
L.
The
HRL
is
a
preliminary
health
effect
level
used
for
this
investigation.

Table
4­
2.
Manganese
Detections
and
Concentrations
in
Bed
Sediments
and
Aquatic
Biota
Tissues
(
all
sites).

Detection
frequency
>
MRL*
Concentration
percentiles
(
all
samples;
mg/
kg
dry
weight)

%
samples
%
sites
median
99th
sediments
100
%
100
%
1.1
9.4
aquatic
biota
tissues
100
%
100
%
0.01
2.9
*
The
Minimum
Reporting
Levels
(
MRLs)
for
manganese
in
sediments
and
biota
tissues
are
4
µ
g/
g
and
0.1
µ
g/
g,
respectively.
4­
6
Manganese
 
February
2003
Only
the
Alabama,
California,
Illinois,
New
Jersey,
and
Oregon
State
data
sets
contained
occurrence
data
for
manganese.
The
data
represent
more
than
37,000
analytical
results
from
about
4,000
PWSs
mostly
during
the
period
from
approximately
1993
to
1997,
though
some
earlier
data
are
also
included.
The
number
of
sample
results
and
PWSs
vary
by
State.

Data
Management
The
data
used
in
the
State
analyses
were
limited
to
only
those
data
with
confirmed
water
source
and
sampling
type
information.
Only
standard
SDWA
compliance
samples
were
used;
"
special"
samples,
"
investigation"
samples
(
investigating
a
contaminant
problem
that
would
bias
results),
or
samples
of
unknown
type
were
not
used
in
the
analyses.
Various
quality
control
and
review
checks
were
made
of
the
results,
including
follow­
up
questions
to
the
States
providing
the
data.
Many
of
the
most
intractable
data
quality
problems
encountered
occurred
with
older
data.
These
problematic
data
were,
in
some
cases,
simply
eliminated
from
the
analysis.
For
example,
when
the
number
of
data
with
problems
were
insignificant
relative
to
the
total
number
of
observations,
they
were
dropped
from
the
analysis
(
for
further
details
see
U.
S.
EPA,
1999a).

Occurrence
Analysis
The
summary
descriptive
statistics
presented
in
Table
4­
3
for
manganese
are
derived
from
analysis
of
the
NIRS
data.
Included
are
the
total
number
of
samples,
the
percent
samples
with
detections,
the
99th
percentile
concentration
of
all
samples,
the
99th
percentile
concentration
of
samples
with
detections,
and
the
median
concentration
of
samples
with
detections.
The
percentages
of
PWSs
and
population
served
indicate
the
proportion
of
PWSs
and
PWS
population
served
whose
analytical
results
showed
a
detection(
s)
of
the
contaminant
(
simple
detection,
>
MRL)
at
any
time
during
the
monitoring
period;
or
a
detection(
s)
greater
than
half
the
Health
Reference
Level
(
HRL);
or
a
detection(
s)
greater
than
the
HRL.
The
HRL
used
for
this
analysis
is
0.30
mg/
L.

The
HRL
was
derived
for
contaminants
not
considered
to
be
"
linear"
carcinogens
by
the
oral
route
of
exposure.
EPA
derived
the
HRL
using
an
RfD
approach
as
follows:
HRL
=
(
RfD
×
70
kg)/
2
L
×
RSC,

where:
RfD
=
Reference
Dose;
an
estimated
dose
(
mg/
kg­
day)
to
the
human
population
(
including
sensitive
subgroups)
that
is
likely
to
be
without
an
appreciable
risk
of
deleterious
effects
during
a
lifetime.
It
can
be
derived
from
a
NOAEL,
LOAEL,
or
benchmark
dose,
with
uncertainty
factors
generally
applied
to
reflect
limitations
of
the
data
used;

70
kg
=
The
assumed
body
weight
of
an
adult;

2
L
=
The
assumed
daily
water
consumption
of
an
adult;
4­
7
Manganese
 
February
2003
RSC
=
The
relative
source
contribution,
or
the
level
of
exposure
believed
to
result
from
drinking
water
when
compared
to
other
sources
(
e.
g.,
air),
and
is
assumed
to
be
20%
unless
noted
otherwise.

EPA
used
only
the
best
available
peer
reviewed
data
and
analyses
in
evaluating
adverse
health
effects.
Health
effects
information
is
available
for
manganese
in
the
Integrated
Risk
Information
System
(
IRIS).
IRIS
is
an
electronic
EPA
data
base
containing
reviewed
information
(
both
inside
and
outside
of
the
Agency)
on
human
health
effects
that
may
result
from
exposure
to
various
chemicals
in
the
environment.
These
chemical
files
contain
descriptive
and
quantitative
information
on
RfDs
for
chronic
noncarcinogenic
health
effects
and
hazard
identification,
as
well
as
slope
factors
and
unit
risks
for
carcinogenic
effects.

In
Table
4­
3,
national
occurrence
is
estimated
by
extrapolating
the
summary
statistics
for
manganese
to
national
numbers
for
systems,
and
population
served
by
systems,
from
the
Water
Industry
Baseline
Handbook,
Second
Edition
(
U.
S.
EPA,
2000e).
From
the
handbook,
the
total
number
of
ground
water
community
water
systems
(
CWSs)
plus
ground
water
non­
transient,
non­
community
water
systems
(
NTNCWSs)
is
59,440,
and
the
total
population
served
by
ground
water
CWSs
plus
ground
water
NTNCWSs
is
85,681,696
persons
(
see
Table
4­
3).
To
arrive
at
the
national
occurrence
estimate
for
the
HRL,
the
national
estimate
for
ground
water
PWSs
(
or
population
served
by
ground
water
PWSs)
is
simply
multiplied
by
the
percentage
for
the
given
summary
statistic
[
i.
e.,
the
national
estimate
for
the
total
number
of
ground
water
PWSs
with
detections
at
the
HRL
of
0.30
mg/
L
(
40,388)
is
the
product
of
the
percentage
of
ground
water
PWSs
with
detections
(
68%)
and
the
national
estimate
for
the
total
number
of
ground
water
PWSs
(
59,440)].

In
Table
4­
4,
occurrence
data
on
manganese
directly
submitted
by
the
States
of
Alabama,
California,
Illinois,
New
Jersey,
and
Oregon
for
A
Review
of
Contaminant
Occurrence
in
Public
Water
Systems
(
U.
S.
EPA,
1999a)
were
used
to
augment
the
NIRS
study
which
lacked
surface
water
data.
Included
in
the
table
are
the
same
summary
statistics
as
shown
in
Table
4­
3,
with
additional
information
describing
the
relative
distribution
of
manganese
occurrence
between
ground
water
and
surface
water
PWSs
in
the
5
States.

The
State
data
analysis
was
focused
on
occurrence
at
the
system
level
because
a
PWS
with
a
known
contaminant
problem
usually
has
to
sample
more
frequently
than
a
PWS
that
has
never
detected
the
contaminant.
The
results
of
a
simple
computation
of
the
percentage
of
samples
with
detections
(
or
other
statistics)
can
be
skewed
by
the
more
frequent
sampling
results
reported
by
the
contaminated
site.
The
system
level
of
analysis
is
conservative.
For
example,
a
system
need
only
have
a
single
sample
with
an
analytical
result
greater
than
the
MRL,
i.
e.,
a
detection,
to
be
counted
as
a
system
with
a
result
"
greater
than
the
MRL."

When
computing
basic
occurrence
statistics,
such
as
the
number
or
percent
of
samples
or
systems
with
detections
of
a
given
contaminant,
the
value
(
or
concentration)
of
the
MRL
can
have
important
consequences.
For
example,
the
lower
the
reporting
limit,
the
greater
the
number
of
detections
(
Ryker
and
Williamson,
1999).
As
a
simplifying
assumption,
a
value
of
half
the
MRL
is
often
used
as
an
estimate
of
the
concentration
of
a
contaminant
in
samples/
systems
4­
8
Manganese
 
February
2003
Table
4­
3.
Manganese
Occurrence
in
Ground
Water
PWS
of
NIRS
Survey.

Frequency
Factors
Health
Reference
Level
=
0.3
mg/
L
National
System
&
Population
Numbers1
Total
number
of
samples/
systems
989
59,440
99th
percentile
concentration
(
all
samples)
0.63
mg/
L
­­

Minimum
Reporting
Level
(
MRL)
0.001
mg/
L
­­

99th
percentile
concentration
of
detections
0.72
mg/
L
­­

Median
concentration
of
detections
0.01
mg/
L
­­

Total
population
1,482,153
85,681,696
Occurrence
by
Samples/
System
National
Extrapolation
HRL
=
0.3
mg/
L
Ground
water
PWSs
with
detections
(>
MRL)
Range
of
sampled
States
67.9%
8.3
 
100%
40,388
NA
Ground
water
PWSs
>
½
HRL
Range
of
sampled
States
6.1%
0
 
31.6%
3,606
NA
Ground
water
PWSs
>
HRL
Range
of
sampled
States
3.2%
0
 
21.0%
1,923
NA
Occurrence
by
Population
Served
Ground
water
PWS
population
served
with
detections
Range
of
sampled
States
55.4%
0.3
 
100%
47,502,000
NA
Ground
water
PWS
population
served
>
½
HRL
Range
of
sampled
States
4.6%
0
 
89.2%
3,940,000
NA
Ground
water
PWS
population
served
>
HRL
Range
of
sampled
States
2.6%
0
 
89.2%
2,256,000
NA
1
Total
PWS
and
population
numbers
are
from
EPA
MRL
=
minimum
reporting
level
HRL
=
health
reference
level
March
2000
Water
Industry
Baseline
Handbook.
PWS
=
public
water
system
 
=
no
data
NA
=
not
applicable
whose
results
are
less
than
the
MRL.
However,
for
these
occurrence
data
this
is
not
straightforward.
This
is
in
part
related
to
State
data
management
differences
as
well
as
real
differences
in
analytical
methods,
laboratories,
and
other
factors.

The
situation
can
cause
confusion
when
examining
descriptive
statistics
for
occurrence.
Because
a
simple
meaningful
summary
statistic
is
not
available
to
describe
the
various
reported
MRLs,
and
to
avoid
confusion,
MRLs
are
not
reported
in
the
summary
table
(
Table
4­
4).
4­
9
Manganese
 
February
2003
Table
4­
4.
Occurrence
Summary
of
Ground
and
Surface
Water
Systems
by
State
for
Manganese.

Frequency
Factors
Alabama
California
Illinois
New
Jersey
Oregon
Total
number
of
samples
Number
of
ground
water
samples
Number
of
surface
water
samples
1,343
934
409
31,998
29,923
2,075
344
275
69
3,196
2,795
401
172
90
82
Percent
samples
with
detections
Percent
ground
water
samples
with
detections
Percent
surface
water
samples
with
detections
30.2%
28.1%

35.0%
16.5%
17.5%

1.9%
44.2%
50.2%

20.3%
39.7%
40.6%

33.7%
39.5%
61.1%

15.9%

99th
percentile
concentration
(
all
samples)
0.13
mg/
L
0.71
mg/
L
0.96
mg/
L
0.42
mg/
L
1.6
mg/
L
Minimum
reporting
level
(
MRL)
Variable1
Variable1
Variable1
Variable1
Variable1
99th
percentile
concentration
of
detections
0.56
mg/
L
1.52
mg/
L
57
mg/
L
0.89
mg/
L
6.7
mg/
L
Median
concentration
of
detections
0.02
mg/
L
0.15
mg/
L
0.04
mg/
L
0.02
mg/
L
0.05
mg/
L
Total
number
of
PWSs
Number
of
ground
water
PWSs
Number
of
surface
water
PWSs
434
365
69
2,516
2,293
223
227
160
67
1,179
1,147
32
84
54
30
Total
population
served
Ground
water
population
Surface
water
population
3,662,222
1,820,214
1,837,743
45,388,246
27,840,774
30,675,992
1,995,394
724,635
1,270,179
7,472,565
2,386,396
3,687,076
1,306,283
301,440
1,117,782
Occurrence
by
System
PWSs
with
detections
(>
MRL)
Ground
water
PWSs
with
detections
Surface
water
PWSs
with
detections
46.5%
41.6%
72.5%
28.2%
29.8%
11.7%
41.4%
50.6%
19.4%
53.5%
52.3%
96.9%
46.4%
55.6%
30.0%

Health
Reference
Level
(
HRL)
=
0.3
mg/
L
PWSs
>
½
HRL
Ground
water
PWSs
>
½
HRL
Surface
water
PWSs
>
½
HRL
1.8%
1.4%
4.4%
17.2%
18.5%
3.6%
9.3%
11.9%
3.0%
5.8%
5.7%
9.4%
13.1%
20.4%
0.0%

PWSs
>
HRL
Ground
water
PWSs
>
HRL
Surface
water
PWSs
>
HRL
0.9%
0.6%
2.9%
10.1%
10.9%
1.8%
4.4%
5.0%
3.0%
2.5%
2.5%
3.1%
6.0%
9.3%
0.0%

Occurrence
by
Population
Served
PWS
population
served
with
detections
Ground
water
PWS
population
with
detections
Surface
water
PWS
population
with
detections
71.9%

50.9%

73.4%
49.3%

66.2%

10.5%
36.5%

66.3%

19.5%
85.7%

70.4%

100.0%
58.0%

41.8%

56.8%

Health
Reference
Level
(
HRL)
=
0.3
mg/
L
PWS
population
>
½
HRL
Ground
water
PWS
population
>
½
HRL
Surface
water
PWS
population
>
½
HRL
5.9%
0.8%

0.7%
34.8%
52.6%

4.4%
16.5%
29.1%

9.4%
15.3%
10.4%

23.3%
4.6%
19.9%

0.0%

PWS
population
>
HRL
Ground
water
PWS
population
>
HRL
Surface
water
PWS
population
>
HRL
2.4%
0.1%
0.6%
27.2%
42.8%
4.2%
14.7%
24.2%
9.4%
9.1%
4.9%
14.5%
3.2%
14.0%
0.0%

1
See
text
for
details
PWS
=
public
water
system
MRL
=
minimum
reporting
level
HRL
=
health
reference
level
4­
10
Manganese
 
February
2003
The
situation
can
cause
confusion
when
examining
descriptive
statistics
for
occurrence.
Because
a
simple
meaningful
summary
statistic
is
not
available
to
describe
the
various
reported
MRLs,
and
to
avoid
confusion,
MRLs
are
not
reported
in
the
summary
table
(
Table
4­
4).

Additional
Drinking
Water
Data
From
1996
AWWA
Survey
To
augment
the
SDWA
drinking
water
data
analysis
described
above,
results
from
a
1996
American
Water
Works
Association
(
AWWA)
survey
are
reviewed.
The
survey,
called
WATER:/
STATS,
is
a
cooperative
project
of
AWWA
and
AWWA
Research
Foundation.
The
WATER:/
STATS
survey
database
stores
results
from
the
1996
WATER:/
STATS
survey
of
water
utilities
in
the
United
States
and
Canada
in
terms
of
facilities,
scale
of
operation,
and
major
inputs
and
outputs.
A
total
of
794
AWWA
member
utilities
responded
to
the
survey
with
ground
water
and/
or
surface
water
information.
However,
the
actual
number
of
respondents
for
each
data
category
varies
because
not
all
participants
in
the
survey
responded
to
every
question.

4.4
Results
The
NIRS
data
in
Table
4­
3
show
that
approximately
68%
of
ground
water
PWSs
(
an
estimate
of
approximately
40,000
systems
nationally)
had
detections
of
manganese,
affecting
about
55%
of
the
ground
water
PWS
population
served
(
approximately
47.5
million
people
nationally).
At
an
HRL
of
0.30
mg/
L,
approximately
6.1%
of
the
NIRS
PWSs
had
detections
>
½
HRL
(
about
3,600
ground
water
PWSs
nationally),
affecting
approximately
4.6%
of
the
population
served
(
estimated
at
3.9
million
people
nationally).
The
percentage
of
NIRS
PWSs
with
detections
>
HRL
of
0.30
mg/
L
was
approximately
3.2%
(
about
1,900
ground
water
PWSs
nationally),
affecting
2.6%
of
the
population
served
(
estimated
at
approximately
2.3
million
people
nationally)
(
Table
4­
3).

Drinking
water
data
for
manganese
from
the
supplemental
individual
States
vary
among
States
(
Table
4­
4).
Manganese
has
not
been
required
for
monitoring
under
SDWA,
though
these
States
had
obviously
conducted
some
monitoring.
The
number
of
systems
with
manganese
data
for
Illinois
and
Oregon
is
far
less
than
the
number
of
PWSs
in
these
States.
Hence,
the
extent
to
which
these
data
are
representative
is
unclear.
Alabama,
California,
and
New
Jersey
have
substantial
amounts
of
data
and
PWSs
represented.
Because
the
NIRS
data
only
represent
manganese
occurrence
in
ground
water
PWSs,
the
supplemental
State
data
sets
provide
some
perspective
on
surface
water
PWS
occurrence.
For
example,
the
median
concentration
of
detections
for
the
States
ranged
from
0.02
mg/
L
to
0.15
mg/
L,
higher
than
the
NIRS
data
(
0.01
mg/
L).
For
detections
by
PWSs,
3
of
the
5
States
(
California,
Illinois,
and
Oregon)
had
higher
ground
water
PWS
detections.

For
simple
detections,
the
supplemental
State
data
show
a
range
from
30%
to
56%
of
ground
water
PWSs
(
Table
4­
4).
These
figures
are
lower
than
the
NIRS
ground
water
PWS
results:
68%
>
MRL
(
Table
4­
3).
The
supplemental
State
data
show
considerably
greater
percentages
of
simple
detections
for
surface
water
PWSs,
with
higher
variability
as
well:
12%
 
97%
>
MRL.
Comparisons
made
between
data
for
simple
detections
need
to
be
viewed
4­
11
Manganese
 
February
2003
with
caution
because
of
differences
in
MRLs
between
the
State
data
sets
and
the
NIRS
study,
and
among
the
States
themselves
(
see
Section
4.3).

The
supplemental
State
data
sets
indicate
ground
water
PWS
detections
>
HRL
of
0.30
mg/
L
between
0.6%
and
11%
(
Table
4­
4).
Again,
this
range
brackets
the
NIRS
national
average
of
PWS
>
HRL
of
0.30
mg/
L
(
3.2%)
(
Table
4­
4).
Notably,
surface
water
PWSs
showed
fewer
exceedances
of
the
HRL
than
ground
water
PWSs
at
this
higher
concentration;
ranging
from
0%
to
3.1%.

Reviewing
manganese
occurrence
by
PWS
population
served
shows
that
from
0.1%
 
43%
of
the
States'
ground
water
PWS
populations
were
served
by
systems
with
detections
>
HRL
of
0.30
mg/
L
(
Table
4­
4).
Comparatively,
2.6%
of
the
NIRS
ground
water
PWS
population
served
experienced
detections
>
HRL
of
0.30
mg/
L
(
Table
4­
3).
Populations
served
by
surface
water
PWSs
with
detections
>
HRL
of
0.30
mg/
L
ranged
from
0%
 
14.5%
among
the
five
supplemental
States.
Population
figures
for
the
supplemental
States
are
incomplete
and
are
only
reported
for
those
systems
in
the
database
that
have
reported
their
population
data.
For
manganese,
approximately
80%
of
the
PWSs
reporting
occurrence
data
for
these
5
States
also
reported
population
data.

Occurrence
in
AWWA
PWSs
The
AWWA
sponsored
1996
WaterStats
Survey
showed
manganese
occurrence
above
levels
at
which
health
effects
are
expected
to
be
realized
to
be
relatively
similar
to
that
reported
in
the
NIRS
data
and
the
supplemental
State
data.
Approximately
11%
of
the
participating
ground
water
PWSs
(
serving
about
5.1
million
people)
had
maximum
detections
of
manganese
in
raw
water
greater
than
the
HRL
of
0.30
mg/
L.
The
99th
percentile
of
concentration
and
the
median
concentration
were
9.0
mg/
L
and
0.09
mg/
L,
respectively.
Surface
water
PWSs
showed
comparable
results
with
approximately
12.8%
of
survey
respondents
(
serving
about
to
10.5
million
people)
having
maximum
detections
of
manganese
in
raw
water
greater
than
the
HRL
of
0.30
mg/
L.
The
99th
percentile
of
concentration
and
the
median
concentration
in
raw
surface
waters
were
3.08
mg/
L
and
0.092
mg/
L,
respectively.

In
finished
ground
water
samples,
approximately
3%
of
survey
respondents
(
serving
close
to
1.7
million
people)
had
maximum
detections
of
manganese
greater
than
the
HRL
of
0.30
mg/
L.
The
99th
percentile
concentration
and
the
median
concentration
were
0.80
mg/
L
and
0.021
mg/
L,
respectively.
For
finished
surface
water
samples,
approximately
1.5%
of
survey
respondents
(
about
1.7
million
people)
reported
maximum
detections
greater
than
the
HRL
of
0.30
mg/
L.
The
99th
percentile
concentration
and
the
median
concentration
in
finished
surface
water
samples
were
0.64
mg/
L
and
0.013
mg/
L,
respectively.

4.5
Conclusion
Manganese
and
its
compounds
are
TRI
chemicals.
Industrial
releases
have
been
recorded
since
1988
in
all
50
States.
Off­
site
releases
constitute
a
considerable
amount
of
total
releases,
with
releases
to
land
being
the
most
significant
on­
site
releases.
4­
12
Manganese
 
February
2003
Low­
level
manganese
occurrence
in
ambient
waters
and
bed
sediments
monitored
by
the
USGS
NAWQA
program
is
ubiquitous,
with
detections
approaching
100%
of
surface
water
sites
and
greater
than
62%
of
ground
water
sites.
Stream
bed
sediments
and
aquatic
biota
tissues
show
detections
of
100%
by
sample
and
by
site.
Urban
basins
generally
have
more
surface
and
ground
water
manganese
detections
greater
than
the
HRL
than
basins
in
other
land
use
categories,
and
higher
median
and
99th
percentile
concentrations.
Although
manganese
detection
frequencies
are
high
in
ambient
waters,
stream
bed
sediments,
and
aquatic
biota
tissue,
manganese
occurrence
at
levels
of
public
health
concern
is
low.

Manganese
has
been
detected
in
ground
water
PWS
samples
collected
through
the
NIRS
study.
Occurrence
estimates
are
relatively
high
with
approximately
68%
of
all
samples
showing
detections
affecting
about
55%
of
the
national
population
served.
The
99th
percentile
concentration
of
all
samples
is
0.63
mg/
L.
Exceedances
of
the
HRL
at
0.30
mg/
L
affect
2.6%
of
the
ground
water
PWS
population
served,
or
approximately
2.3
million
people
nationally.

Additional
SDWA
data
from
the
States
of
Alabama,
California,
Illinois,
New
Jersey,
and
Oregon,
including
both
ground
water
and
surface
water
PWSs,
were
examined
through
independent
analyses
and
also
show
substantial
levels
of
manganese
occurrence.
These
data
provide
perspective
on
the
NIRS
estimates
that
only
include
data
for
ground
water
systems.
The
supplemental
State
data
show
ground
water
systems
reported
higher
manganese
detections
in
3
of
the
5
States
(
California,
Illinois,
and
Oregon).
If
national
data
for
surface
water
systems
were
available,
the
occurrence
and
exposure
estimates
would
be
substantially
greater
than
from
NIRS
alone.
5­
1
Manganese
 
February
2003
5.0
EXPOSURE
FROM
ENVIRONMENTAL
MEDIA
OTHER
THAN
WATER
5.1
Food
5.1.1
Concentrations
of
Manganese
in
Food
Table
5­
1
summarizes
mean
manganese
concentrations
in
234
foods
analyzed
by
the
Food
and
Drug
Administration
(
FDA).
Nuts
and
grains
contain
the
highest
manganese
concentrations,
with
values
as
high
as
40
to
50
mg/
kg
reported.
Fruits,
vegetables,
fish,
poultry,
meat,
and
eggs
tend
to
have
intermediate
concentrations.
Manganese
levels
in
milk
tend
to
be
low,
with
concentrations
of
10
and
30
micrograms
per
liter
(:
g/
L)
reported
for
human
and
cow's
milk,
respectively.
In
contrast,
values
of
50
to
300
:
g/
L
have
been
reported
for
infant
formula
(
Collipp
et
al.,
1983).

Manganese
has
been
detected
in
the
muscle
of
fresh
bluefin
tuna
(
Thunnus
thynnus).
Hellou
et
al.
(
1992)
as
reported
in
ATSDR
(
2000),
analyzed
concentrations
in
14
tuna
samples
using
inductively
coupled
plasma
mass
spectrometry.
The
level
of
manganese
varied
from
0.16
to
0.31
micrograms
per
gram
(:
g/
g)
dry
weight,
with
a
mean
value
of
0.22
:
g/
g
dry
weight.

Black
tea
samples
from
the
United
Kingdom
(
UK)
were
found
to
have
mean
manganese
concentrations
of
4.6
mg/
L,
40%
of
which
was
bioavailable
(
Powell
et
al.,
1998).

The
issue
of
bioavailability
is
important
to
consider
when
assessing
manganese
levels
in
foods,
and
is
discussed
further
in
the
next
section.
For
instance,
the
actual
absorption
of
manganese
from
ingested
tea
is
limited
by
the
presence
of
polyphenolic
compounds
(
tannins)
in
the
tea
which
bind
manganese
(
Freeland­
Graves
and
Llanes,
1994).
This
explains
the
low
bioavailabilty
of
manganese
in
tea.
Likewise,
the
relatively
high
levels
of
manganese
in
fruits,
nuts,
grains,
and
vegetables,
as
well
as
in
soy­
based
infant
formula
(
discussed
in
Section
5.1.2),
are
limited
in
their
bioavailability
by
the
presence
of
phytic
acids,
oxalic
acids,
and
fiber
in
these
foods
(
U.
S.
EPA,
1996a).
In
addition,
high
levels
of
calcium
or
magnesium
ingestion
may
inhibit
manganese
absorption,
while
persons
with
diets
that
are
deficient
in
iron
may
experience
increased
manganese
absorption
(
U.
S.
EPA,
1996a).

5.1.2
Intake
of
Manganese
From
Food
General
Population
Manganese
is
an
essential
nutrient.
It
is
very
unevenly
distributed
in
foods.
Although
manganese
is
rich
in
tea,
whole
grains,
legumes,
and
nuts,
it
is
found
in
negligible
amounts
in
meats,
dairy
products,
sweets,
refined
grains,
and
most
fruits.
Thus,
many
individuals
who
do
not
consume
whole
grains,
nuts,
certain
fruits
(
pineapple),
green
leafy
vegetables,
and
tea
will
consume
a
"
low
manganese"
diet
­
less
than
2
mg
per
day
(
Davis
et
al.,
1992).
In
addition,
women
tend
to
consume
less
food
than
men;
hence
their
intakes
of
individual
nutrients,
including
manganese,
are
often
lower
than
those
of
men
(
Pennington
et
al.,
1989).
5­
2
Manganese
 
February
2003
The
Food
and
Nutrition
Board
set
an
adequate
intake
level
(
AI)
for
manganese
at
2.3
mg/
day
for
men
and
1.8
mg/
day
for
women
(
IOM,
2002;
Trumbo
et
al.,
2001).
The
current
recommendations
for
infants
and
children
are
0.003
to
0.6
mg/
day
and
1.2
to
1.9
mg/
day,
respectively
(
IOM,
2002).
An
adequate
intake
level
is
defined
as
"
a
recommended
intake
value
based
on
observed
or
experimentally
determined
approximations
or
estimates
of
nutrient
intake
by
a
group
(
or
groups)
of
healthy
people
that
are
assumed
to
be
adequate
­
used
when
an
RDA
cannot
be
determined."
Some
nutritionists
feel
that
this
level
may
be
too
low.
Freeland­
Graves
et
al.
(
1987),
as
cited
in
U.
S.
EPA
(
1996a),
have
suggested
a
range
of
3.5
to
7
mg/
day
for
adults
based
on
a
review
of
human
studies.

Dietary
habits
have
evolved
in
recent
years
to
include
a
larger
proportion
of
meats
and
refined
foods
in
conjunction
with
a
lower
intake
of
whole
grains
(
Freeland­
Graves,
1994;
U.
S.
EPA,
1996a).
The
net
result
of
such
dietary
changes
includes
a
lower
intake
of
manganese.
A
significant
number
of
adult
Americans,
particularly
women,
may
consume
suboptimal
amounts
of
manganese
(
ATSDR,
2000;
Pennington
et
al.,
1986).
On
the
other
hand,
it
is
not
known
whether
infants
may
ingest
more
than
the
AI
for
their
age
group
as
a
result
of
the
high
manganese
content
of
prepared
infant
foods
and
formulas.

Table
5­
1.
Manganese
Concentrations
in
Selected
Foodsa
TYPE
OF
FOOD
RANGE
OF
MEAN
CONCENTRATIONS
(
mg/
kg)

Nuts
and
nut
products
18.21
 
46.83
Grains
and
grain
products
0.42
 
40.70
Legumes
2.24
 
6.73
Fruits
0.20
 
10.38
Fruit
juices
and
drinks
0.05
 
11.47
Vegetables
and
vegetable
products
0.42
 
6.64
Desserts
0.04
 
7.98
Infant
foods
0.17
 
4.83
Meat,
poultry,
fish
and
eggs
0.10
 
3.99
Mixed
dishes
0.69
 
2.98
Condiments,
fats,
and
sweeteners
0.04
 
1.45
Beverages
(
including
tea)
0.00
 
2.09
Soups
0.19
 
0.65
Milk
and
milk
products
0.02
 
0.49
a
Adapted
from
ATSDR
(
2000)
and
Pennington
et
al.
(
1986).
5­
3
Manganese
 
February
2003
Based
on
various
surveys,
the
Food
and
Nutrition
Board
(
IOM,
2002)
concluded
that
the
average
manganese
intake
of
adults
eating
western­
type
and
vegetarian
diets
ranged
from
0.7
to
10.9
mg/
day
(
IOM,
2002),
and
the
median
intakes
for
women
and
men
ranged
from
1.6
to
2.3
mg/
day
(
IOM,
2002).
The
total
dietary
manganese
intake
among
individuals
may
vary
greatly
depending
upon
dietary
habits.
Individual
intake
estimates
for
Canadian
adult
male
blue­
collar
workers
(
n
=
28)
and
garage
mechanics
(
n
=
37),
as
determined
by
analysis
of
dietary
records,
ranged
from
1.0
to
14
mg/
day
(
Loranger
and
Zayed,
1995).
The
mean
values
in
this
study
for
manganese
intake
by
blue­
collar
workers
and
mechanics
were
3.7
and
2.9
mg/
day,
respectively.
It
should
be
noted
that
FDA's
Total
Diet
Study
menus
used
to
measure
the
levels
of
several
nutritional
elements
including
manganese
from
1982
to
1986
in
Pennington
et
al.
(
1989)
reflect
"
typical"
American
diets
and
contain
less
manganese
than
the
diets
consumed
by
Canadian
males.

The
Food
and
Nutrition
Board
also
set
a
tolerable
upper
intake
level
(
UI)
for
manganese
at
11
mg
per
day
for
adults,
based
on
the
upper
range
of
manganese
intake
for
adults
(
see
review
by
Greger,
1999).
An
UI
is
defined
as
"
the
highest
level
of
daily
nutrient
intake
that
is
likely
to
pose
no
risk
of
adverse
health
effects
for
almost
all
individuals
in
the
general
population.
As
intake
increases
above
the
UL,
the
risk
of
adverse
effects
may
increase."
For
shorter
duration,
Davis
and
Greger
(
1992)
reported
that
women
given
daily
supplements
of
15
mg
manganese
for
90
days
experienced
no
adverse
effects
other
than
a
significant
increase
in
lymphocyte
manganese­
dependent
superoxide
dismutase
(
Greger,
1998,
1999;
IOM,
2002).

Based
on
a
conservative
range
for
manganese
intake
of
2
to
10
mg/
day,
U.
S.
EPA
(
1996a)
estimated
a
dietary
manganese
intake
of
28.6
to
126
micrograms
per
kilogram
per
day
(:
g/
kgday
For
children,
assuming
a
manganese
intake
of
1.28
:
g/
calorie
(
U.
S.
EPA,
1984;
ATSDR,
2000)
and
a
caloric
intake
of
1,000
calories/
day
for
a
10
kg
child,
the
estimated
average
daily
intake
would
be
128
:
g/
kg­
day.

Groups
with
Potential
for
High
Manganese
Intake
from
Food
Groups
with
potential
for
high
intake
of
dietary
manganese
include
vegetarians,
heavy
tea
drinkers,
and
infants.
Vegetarians
may
consume
a
larger
proportion
of
manganese­
rich
nuts,
grains,
and
legumes
in
their
diet
than
the
general
population
(
U.
S.
EPA,
1996a).
Manganese
intake
by
North
American
vegetarians
has
been
estimated
to
be
as
high
as
10
mg
Mn/
day
(
Gibson,
1994).
However,
many
components
of
vegetarian
diets,
including
phytates,
tannins,
oxalates,
and
fiber,
inhibit
manganese
uptake
from
the
gastrointestinal
tract.
Consequently,
the
bioavailability
of
manganese
in
vegetarian
diets
is
uncertain.
Johnson
et
al.
(
1991)
studied
the
absorption
of
radiolabelled
manganese
from
various
plant
foods
in
adult
men
and
women,
and
reported
that
mean
fractional
absorption
values
from
lettuce
and
spinach
were
5.20
and
3.81%,
respectively.
Mean
fractional
absorption
from
sunflower
seeds
was
significantly
less
(
1.71%),
while
that
from
wheat
was
2.16%.
All
percent
absorption
values
from
plant
food
were
significantly
less
than
mean
values
from
MnCl
2
dissolved
in
water,
which
ranged
from
7.74
to
10.24%.
5­
4
Manganese
 
February
2003
Heavy
tea
drinkers
may
have
a
higher
manganese
intake
than
the
general
population.
An
average
cup
of
tea
may
contain
0.4
to
1.3
mg
manganese
(
ATSDR,
2000).
Consumption
of
three
cups
of
tea
per
day
would
therefore
have
the
potential
to
double
manganese
intake
for
some
individuals.
Again,
however,
it
is
likely
that
the
high
level
of
tannins
in
tea
will
result
in
reduced
manganese
absorption
(
Freeland­
Graves
and
Llanes,
1994).

Infants
may
ingest
high
levels
of
manganese
from
infant
formulas
or
prepared
baby
foods,
although
manganese
absorption
in
infants
is
influenced
by
several
variables,
and
the
degree
to
which
absorption
levels
may
be
a
health
concern
is
unknown.
Infant
formulas
contain
50
to
300
:
g/
L
manganese
(
Collipp
et
al.,
1983),
compared
to
human
milk
which
contains
7
to
15
:
g/
L
manganese
(
U.
S.
EPA,
1996a).
Assuming
an
intake
of
742
milliliters
(
mL)
of
breast
milk/
day
(
U.
S.
EPA,
1996a),
a
breast­
fed
infant
would
have
an
estimated
daily
manganese
intake
of
5.2
to
11.1
:
g/
day.
An
infant
consuming
the
same
volume
of
infant
formula
would
have
an
estimated
daily
manganese
intake
of
37.1
to
223
:
g/
day.
Assuming
an
average
weight
of
6
kg
for
an
infant
of
age
6
months,
the
weight­
adjusted
average
daily
intake
would
range
from
0.87
to
1.85
:
g/
kgday
for
breast­
fed
infants.
The
corresponding
weight­
adjusted
intake
for
a
formula­
fed
infant
would
be
6.2
to
37.2
:
g/
kg­
day.
Generally,
solid
foods
are
introduced
at
the
age
of
4
months.
Once
solid
foods
are
introduced,
the
dietary
intake
of
manganese
increases
so
substantially
that
the
contribution
of
Mn
intake
from
milk
becomes
less
significant.

In
assessing
infant
exposure
to
manganese,
however,
one
must
also
consider
constituents
of
infant
formula
and
of
breast
milk
which
may
affect
manganese
bioavailability.
For
instance,
formula
made
from
soy
protein
contains
high
levels
of
phytic
acids
and
vegetable
proteins
which
probably
decrease
the
manganese
bioavailability.
If
the
formula
is
also
iron­
fortified,
manganese
bioavailability
may
be
further
decreased,
although
studies
on
the
inhibitory
influences
of
iron
have
produced
conflicting
results
(
Freeland­
Graves,
1994).
Davidsson
et
al.
(
1989a)
measured
absorption
of
radiolabelled
manganese
in
adult
humans
given
human
milk,
cow's
milk,
or
soy
formula
and
found
that
fractional
manganese
absorption
from
human
milk
(
8.2%)
was
significantly
higher
than
absorption
from
cow's
milk
(
2.4%)
and
soy
formula
(
0.7%).
Manganese
in
infant
formula
is
in
the
divalent
state,
the
absorption
of
which
cannot
be
regulated
by
the
lactoferrin
receptors
in
the
gut;
breast
milk
manganese
is
in
the
trivalent
form
bound
to
lactoferrin,
and
its
absorption
is
thus
regulated
(
U.
S.
EPA,
1996a).
Davidsson
et
al.
(
1989a)
suggested
that
the
lactoferrin
in
human
milk
as
well
as
the
higher
calcium
content
in
cow's
milk
contributed
to
the
difference
in
absorption.
Dorner
et
al.
(
1989)
observed
similar
differences
in
fractional
manganese
retention
in
infants
as
those
observed
by
Davidsson
et
al.
(
1989a)
in
adults.
In
the
infant
study,
a
higher
percentage
of
manganese
was
retained
from
ingested
breast
milk
(
41%)
than
from
cow's­
milk
formula
(~
19%).
Therefore,
many
factors
probably
control
manganese
absorption
from
infant
formula,
and
firm
conclusions
are
difficult
to
make
in
the
absence
of
more
direct
data.
Keen
et
al.
(
1986)
demonstrated
that
fractional
manganese
uptake
from
human
breast
milk
and
cow's
milk
were
relatively
high
(~
80%
and
~
89
%,
respectively),
whereas
uptake
from
soy
formula
was
lowest
(~
60%)
in
rat
pups.

It
should
be
noted
that
Davidsson
et
al.
(
1989a)
performed
their
studies
in
adults;
manganese
body
burden
in
infants
may
be
additionally
influenced
by
the
fact
that
the
biliary
excretion
system,
which
is
the
primary
route
of
manganese
excretion,
is
not
completely
5­
5
Manganese
 
February
2003
developed
in
neonates
(
Lönnerdal,
1994).
Studies
in
rats
have
further
demonstrated
that
young
animals
absorb
significantly
more
manganese
in
the
gut
than
do
mature
animals
(
Lönnerdal
et
al.
1987).
Also,
animal
studies
have
shown
that
manganese
crosses
the
blood­
brain
barrier
in
neonates
at
a
rate
4
times
higher
than
that
in
adults
(
Mena,
1974).
However,
the
relevance
of
these
studies
to
humans
is
unknown,
and
few
direct
absorption
data
for
manganese
in
human
infants
are
available.
In
this
context,
it
is
noteworthy
that
Collipp
et
al.
(
1983)
reported
hair
manganese
levels
that
increased
significantly
from
birth
(
0.19
:
g/
g)
to
6
weeks
(
0.865
:
g/
g)
and
4
months
(
0.685
:
g/
g)
of
age
in
infants
given
formula,
while
infants
given
breast
milk
exhibited
no
significant
increase
(
0.330
:
g/
g
at
4
months).
This
study
also
reported
that
the
average
hair
manganese
level
in
children
exhibiting
learning
disabilities
was
significantly
increased
(
0.434
:
g/
g)
compared
to
those
that
exhibited
normal
learning
ability
(
0.268
:
g/
g).

5.2
Air
5.2.1
Concentration
of
Manganese
in
Air
General
Population
Table
5­
2
summarizes
nationally
aggregated
data
collected
between
1953
and
1982
for
manganese
concentrations
in
ambient
air
of
nonurban,
urban,
and
source­
dominated
locations.
Average
manganese
concentrations
for
nonurban
areas
ranged
from
a
high
value
of
60
nanograms
per
cubic
meter
(
ng/
m3)
determined
in
1953
 
1957
to
a
low
of
5
ng/
m3
in
1982.
Average
concentrations
for
urban
areas
ranged
from
110
to
33
ng/
m3
over
the
same
period.
Average
levels
in
source­
dominated
locations
varied
widely,
ranging
from
a
high
reading
of
8,300
ng/
m3
during
the
1965
 
1967
measurement
period,
to
concentrations
of
130
to
140
ng/
m3
in
1982.
Although
differences
in
sample
collection
and
analytical
methods
complicate
interpretation,
these
data
suggest
that
manganese
concentrations
in
ambient
air
decreased
over
the
time
period
of
record
(
U.
S.
EPA,
1984).
This
change
has
been
attributed
to
installation
of
emissions
controls
in
the
metals
industry
(
ATSDR,
2000).
More
recently,
U.
S.
EPA
(
1990)
has
proposed
an
average
annual
background
concentration
of
40
ng/
m3
for
urban
areas,
based
on
data
for
24­
hour
average
concentrations
in
102
cities
across
the
U.
S.

Multiple
local
studies
have
estimated
airborne
manganese
concentrations.
A
series
of
Canadian
studies
evaluated
total
airborne
manganese
concentrations
in
the
home
and
workplace
(
Sierra
et
al.,
1995;
Zayed
et
al.,
1994,
1996).
Table
5­
3
summarizes
the
results
of
these
studies.
Concentrations
of
manganese
were
determined
by
use
of
personal
sampling
devices.
Mean
levels
of
manganese
measured
in
homes
ranged
from
7
to
12
ng/
m3.
Mean
workplace
concentrations
ranged
from
12
to
44
ng/
m3
for
non­
automotive
workers
(
primarily
office
workers)
and
taxi
drivers.
Automotive
workers,
such
as
auto
mechanics,
experienced
mean
workplace
levels
ranging
from
250
to
448
ng/
m3.
Sample
sizes
for
these
studies
ranged
from
9
to
35
individuals.
5­
6
Manganese
 
February
2003
Table
5­
2.
Average
Concentrations
of
Manganese
in
Ambient
Air
Sampled
from
1953
 
1982a.

SAMPLING
LOCATION/
YEAR
CONCENTRATION
(
ng/
m3)

1953
 
1957
1965
 
1967
1982
Nonurban
60
12
5
Urban
110
73
33
Source­
dominated
No
data
250
 
8,300
130
 
140
a
Source:
ATSDR
(
2000)
and
U.
S.
EPA
(
1984).

Table
5­
3.
Manganese
Levels
in
Air
of
Canadian
Urban
Locations
as
Determined
by
Personal
Exposure
Monitoring.

OCCUPATION
LOCATION
DURATION
N
MEAN
(
ng/
m3)
RANGE
(
ng/
m3)
REFERENCE
Garage
worker
Work
5
days
10
250
9
 
2,067
Zayed
et
al.
(
1994)
Garage
worker
Home
2
days
10
7
4
 
27
Taxi
driver
Work
5
days
10
24
6
 
69
Taxi
driver
Home
2
days
10
11
4
 
22
Auto
Mechanic
Work
4
weeks
35
448
10
 
6,673
Sierra
et
al.
(
1995)
Auto
Mechanic
Home
4
weeks
35
12
6
 
63
Nonautomotive
Work
4
weeks
30
44
11
 
1,862
Nonautomotive
Home
4
weeks
30
8
5
 
87
Office
worker
Work
7
days
23
12
2
 
44
Zayed
et
al.
(
1996)
Taxi
driver
Work
7
days
9
28
8
 
73
5­
7
Manganese
 
February
2003
Automotive
fuels
in
Canada
and
the
U.
S.
contain
the
antiknock
agent
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT).
The
allowable
level
of
MMT
in
Canadian
gasoline
is
0.062
grams
per
gallon
(
g/
gal),
which
is
double
the
allowable
limit
of
0.031
g/
gal
in
the
U.
S.
(
Davis
et
al,
1998).
Combustion
of
MMT
releases
manganese
to
the
atmosphere
in
the
form
of
manganese
oxides,
phosphates,
and
sulfates
(
see
Section
3.2
above),
and
these
compounds
may
constitute
a
significant
source
of
manganese
contamination
in
urban
environments.
In
Canada,
a
car
exhaust
study
determined
that
4
to
41%
of
Mn
in
gasoline
is
emitted
from
the
tailpipe,
depending
on
the
vehicle
and
driving
cycle
(
Ardeleanu
et
al.,
1999).
The
fraction
not
emitted
to
the
atmosphere
appears
to
remain
in
the
engine
(
Ardeleanu
et
al.,
1999).

Levels
of
unburned
MMT
in
air
resulting
from
emission
of
residual
MMT
in
vehicular
exhaust
or
evaporative
emissions
(
e.
g.,
at
gas
stations)
are
expected
to
be
low.
Although
data
are
limited,
Zayed
et
al.
(
1999a)
reported
concentrations
ranging
from
0.4
ng/
m3
to
12
ng/
m3
when
measured
in
five
different
microenvironments
in
Montreal,
Canada.
The
highest
average
concentration
of
MMT
in
ambient
air
was
measured
at
gas
stations.

Use
of
MMT
in
gasoline
has
resulted
in
public
health
concerns
related
to
the
potential
health
effects
of
increased
manganese
exposure.
As
a
result,
determination
of
the
extent
to
which
MMT
contributes
to
environmental
levels
of
manganese
(
and
ultimately
to
human
exposure)
has
been
an
area
of
active
research.
Several
studies
in
Montreal,
Canada
have
examined
manganese
concentrations
in
ambient
air
in
relation
to
motor
vehicle
traffic
(
Table
5­
4).
Loranger
et
al.
(
1994a)
found
ambient
manganese
concentrations
to
be
significantly
correlated
with
traffic
density.
Areas
of
intermediate
and
high
traffic
densities
had
ambient
manganese
concentrations
above
the
natural
background
level
in
Montreal
of
40
ng/
m3
(
Loranger
and
Zayed,
1994;
Loranger
et
al.,
1994a).

Loranger
et
al.
(
1995)
summarized
modeling
and
empirical
data
relating
atmospheric
manganese
concentrations
to
combustion
of
gasoline
containing
varying
concentrations
of
MMT
(
Table
5­
5).
Estimated
increases
predicted
by
studies
listed
in
the
table
but
conducted
prior
to
1990
were
characterized
by
Loranger
et
al.
(
1995)
as
being
of
limited
use
due
to
insufficient
information
on
methodology.
Based
on
an
estimated
background
level
of
40
ng/
m3
(
calculated
by
taking
the
average
of
data
from
102
U.
S.
cities),
U.
S.
EPA
(
1990)
predicted
that
the
potential
increase
in
ambient
background
manganese
from
the
use
of
MMT
would
be
0.05P,
where
P
is
the
fraction
of
total
manganese
in
fuel
that
is
emitted
in
vehicular
exhaust.

Canadian
studies
have
addressed
the
fraction
of
total
manganese
concentration
in
air
associated
with
particulates
of
respirable
size.
Zayed
et
al.
(
1996)
reported
respirable
manganese
(
MnR)
and
total
manganese
(
MnT)
concentrations
determined
by
personal
exposure
monitoring
of
taxi
drivers
and
office
workers.
Mean
concentrations
of
MnR
were
10
and
15
ng/
m3
for
office
workers
and
taxi
drivers,
respectively.
Mean
concentrations
of
MnT
were
12
and
28
ng/
m3
for
the
same
respective
groups.
Loranger
and
Zayed
(
1997a)
measured
concentrations
of
MnR
and
MnT
at
two
sites
in
Montreal
with
different
vehicle
traffic
densities.
MnR
and
MnT
concentrations
adjacent
to
a
heavily
traveled
(>
100,000
vehicles/
day)
road
were
24
and
50
5­
8
Manganese
 
February
2003
Table
5­
4.
Ambient
Air
Concentrations
of
Manganese
in
Relation
to
Traffic
Density,
Montreal,
Canada
1981
 
1994.

TRAFFIC
DENSITY
(
vehicles/
day)
Mn
(
ng/
m3)
REFERENCE
<
15,000
<
40
(
50%
of
samples)
Loranger
et
al.
(
1994a)

>
15,000
>
40
(
50%
of
samples)
Loranger
et
al.
(
1994a)

4,900
26
Loranger
et
al.
(
1994b)

75,000
36
Loranger
et
al.
(
1994b)

<
15,000
20
Loranger
and
Zayed
(
1994)

<
30,000
50
Loranger
and
Zayed
(
1994)

>
100,000
60
Loranger
and
Zayed
(
1994)

117,585
54
Loranger
et
al.
(
1995)

117,585
29
 
37
Loranger
et
al.
(
1995)

Source:
Zayed
et
al.
(
1999b)

ng/
m3,
respectively.
Values
for
MnR
and
MnT
at
a
site
with
lower
traffic
density
(
10,000
to
15,000
vehicles/
day)
were
15
and
27
ng/
m3,
respectively.
Zayed
et
al.
(
1999a)
measured
mean
concentrations
of
respirable
manganese
ranging
from
18
to
53
ng/
m3
in
five
microenvironments
in
Montreal.
The
overall
mean
concentrations
of
respirable
and
total
manganese
were
36
±
7
ng/
m3
and
103
±
32
ng/
m3,
respectively.
These
data
indicate
that
approximately
35
to
90%
of
total
manganese
in
urban
air
is
respirable.

Personal
exposures
(
expressed
as
concentration
in
air)
to
airborne
manganese
were
measured
before
and
after
the
introduction
of
MMT
into
20%
of
the
diesel
fuel
used
in
London
(
Pfeifer
et
al.,
1999).
Concentrations
of
manganese
encountered
by
office
workers
and
taxi
drivers
(
10
subjects/
occupation)
were
measured
during
2­
week
periods
in
both
1995
(
before
MMT
introduction)
and
1996
(
after
MMT
introduction).
Manganese
concentrations
reported
for
office
workers
ranged
from
2
to
239
ng/
m3
and
from
4
to
147
ng/
m3
in
1995
and
1996,
respectively.
Taxi
drivers
experienced
exposure
to
concentrations
of
4
to
44
ng/
m3
and
9
to
36
ng/
m3
in
1995
and
1996,
respectively.
Thus,
neither
occupational
group
experienced
apparent
exposure
to
increased
Mn
after
the
introduction
of
MMT
to
gasoline.
The
greater
exposure
of
office
workers
to
airborne
manganese
when
compared
to
taxi
drivers
was
an
unexpected
result.
The
higher
intake
by
office
workers
was
attributed
to
manganese
enrichment
(
approximately
10­
fold
greater
than
in
the
general
environment)
of
the
particulate
matter
in
subway
tunnels.
When
5­
9
Manganese
 
February
2003
Table
5­
5.
Estimated
Atmospheric
Mn
Concentration
in
Relation
to
the
Combustion
of
MMT
in
Gasoline.

Mn
concentration
in
gasoline
Estimated
concentration
from
MMT
source
ng/
m
3
Ambient
air
concentration
from
all
sources
ng/
m
3
Reference
mg/
L
g/
gal
132.0
0.5
­­
200
 
800
(
Mena,
1974)

33.0
0.125
335
1,200
 
1,500a
(
Piver,
1974)

33.0
0.125
­­
2
 
250b
(
Moran,
1975)

33.0
0.125
­­
20
 
3,400c
(
U.
S.
EPA,
1975)

33.0
0.125
­­
70
 
720d
(
U.
S.
EPA,
1975)

33.0
0.125
­­
730
 
10,000e
(
U.
S.
EPA,
1975)

33.0
0.125
­­
120
 
3,630f
(
U.
S.
EPA,
1975)

26.4
0.100
20
 
200g
<
1,000h
(
Ter
Haal
et
al.,
1975)

18.0
0.068
25i
<
500h
(
Cooper,
1984)

17.0
0.064
20
 
200
­­
(
Abbott,
1987)

16.5
0.063
70
 
140
90
 
3,800j
(
HWC,
1978)

16.5
0.063
20
­­
(
Pierson
et
al.,
1978)

8.3
0.031
17
­­
(
Ethyl
Corp.,
1990)

8.3
0.031
150k
55l
(
U.
S.
EPA,
1990)

8.3
0.031
10
 
20
50
 
60m
(
U.
S.
EPA,
1991b)

10.0
0.038
<
1
 
3n
34
(
Loranger
et
al.,
1995)

2
 
29o
­­

Source:
Table
adapted
from
Loranger
et
al.
(
1995).
a
Annual
average.
b
24­
hour
average.
c
EPA
model:
24­
hour
average;
beside
highway
(
1
 
500
m),
20%
emission
at
the
tailpipe.
d
Ethyl
corp.
model:
24­
hour
average,
beside
highway
(
1
 
500
m),
20%
emission
at
the
tailpipe.
e
EPA
model:
hourly
peak,
beside
highway
(
1­
500
m),
20%
emission
at
the
tailpipe.
f
Ethyl
corp.
model:
hourly
peak,
beside
highway
(
1­
500
m),
20%
emission
at
the
tailpipe.
g
Median
value
=
0.05,
near
roadway.
h
Median
value.
I
Beside
highways.
j
Maximum
monthly
average.
k
30%
emission
at
the
tailpipe,
mid­
size
car
(
20
mi/
US
gal).
l
Urban
annual
average
background
concentration
=
0.04
µ
g
 
3.
m
SCREAM
model,
background
concentration
=
0.04
µ
g
 
3.
n
CALINE4
and
ISCLT
models:
>
250
m
beside
expressway.
o
CALINE4
model:
<
250
m
beside
expressway.
­­
=
no
data
5­
10
Manganese
 
February
2003
combined
with
elevated
levels
of
particulates,
manganese
concentrations
were
estimated
to
be
two
orders
of
magnitude
higher
in
the
underground
microenvironment.
While
these
results
differed
from
previous
studies
where,
regardless
of
MMT
use,
taxi
driver
exposures
to
airborne
manganese
were
higher
than
office
workers'
exposures
(
Lynam
et
al.,
1994;
Zayed
et
al.,
1994;
Riveros­
Rosas
et
al.,
1997),
they
are
consistent
with
findings
cited
in
Lynam
et
al.
(
1999)
which
indicated
that
subway
system
commuters
in
Toronto,
Canada
had
higher
manganese
exposures
than
non­
subway
users.

The
Particle
Total
Exposure
Assessment
Methodology
(
PTEAM)
study
provided
information
on
levels
of
airborne
manganese
in
Riverside,
CA
[
findings
summarized
in
Davis
et
al.
(
1998)].
This
study
was
conducted
over
a
7­
week
period
in
Fall
1990,
and
utilized
personal
and
stationary
monitors
to
measure
indoor
and
outdoor
concentrations
of
manganese.
Study
directors
used
a
stratified
sampling
plan
to
select
178
individuals
over
the
age
of
10
to
represent
the
general
population
of
the
region.
Each
individual
was
monitored
over
two
12­
hour
periods.
Personal
exposure
measurements
of
manganese
associated
with
PM
10
(
particulate
matter
of
diameter
10
:
m
or
less)
indicated
that
approximately
half
of
the
population
in
Riverside
experienced
daily
exposure
to
concentrations
exceeding
35
ng/
m3.
Approximately
1%
of
the
population
experienced
personal
exposures
to
manganese
concentrations
above
220
ng/
m3.

Another
study
measured
concentrations
of
manganese
associated
with
PM
in
Toronto,
Canada
during
1995
 
1996
(
Pellizzari
et
al.,
1999).
Residential
indoor,
outdoor,
and
personal
air
samples
were
collected
over
3­
day
periods.
Table
5­
6
lists
the
mean
3­
day
PM­
associated
manganese
concentrations
by
sample
type.
Average
concentrations
for
manganese
associated
with
either
PM
10
or
PM
2.5
(
PM
of
diameter
2.5
:
m
or
less)
were
higher
in
personal
monitor
samples
than
in
indoor
or
outdoor
air.

Clayton
et
al.
(
1999)
simulated
annual
exposures
to
manganese
using
3­
day
personal
exposure
measurements
reported
by
Pellizari
et
al.
(
1999).
The
mean
manganese
exposure
concentration
for
non­
occupationally
exposed
populations
was
predicted
to
be
9.2
ng/
m3.
Approximately
0.4%
and
7.6%
of
the
exposed
population
were
estimated
to
have
annual
exposure
concentrations
greater
than
25
ng/
m3
and
15
ng/
m3,
respectively
(
Clayton
et
al.,
1999).

Table
5­
6.
Mean
Manganese
Exposures
from
3­
day
Indoor,
Outdoor
and
Personal
Air
Samples.

Sample
PM
10­
associated
Mn
(
ng/
m3)
a
PM
2.5­
associated
Mn
(
ng/
m3)

Personal
35.8
13.1
Indoor
Air
8.0
5.5
Outdoor
Air
17.5
9.7
Source:
Pellizzari
et
al.(
1999).
a
Estimated
from
Figure
4
in
Pellizarri
et
al.
(
1999).
5­
11
Manganese
 
February
2003
Populations
with
Potential
for
High
Exposure
Workers
in
certain
occupations
may
be
exposed
to
significantly
higher
manganese
concentrations
than
the
general
population.
Historically,
the
production
of
manganese
fumes
or
manganese­
containing
dusts
in
the
ferromanganese,
iron
and
steel,
dry
cell
battery
manufacturing,
welding,
and
mining
industries
may
result
in
workplace
concentrations
as
much
as
10,000­
fold
higher
than
average
ambient
levels
in
air
(
ATSDR,
2000).
ATSDR
(
2000)
has
noted
that
data
for
current
occupational
levels
of
manganese
exposure
are
not
available.
However,
to
be
in
compliance
with
Occupational
Safety
and
Health
Administration
(
OSHA)
regulations,
manganese
levels
in
the
workplace
should
not
exceed
the
OSHA
time­
weighted
average
Permissible
Exposure
Limit
(
PEL)
of
1
mg/
m3.

5.2.2
Intake
of
Manganese
in
Air
General
Population
U.
S.
EPA
(
1990)
has
calculated
an
average
annual
atmospheric
manganese
background
concentration
of
40
ng/
m3
for
urban
areas,
based
on
data
for
24­
hour
average
concentrations
in
102
cities
across
the
U.
S.
(
U.
S.
EPA,
1990).
Assuming
an
intake
of
15.2
cubic
meters
per
day
(
m3/
day)
(
U.
S.
EPA,
1996d),
the
average
estimated
daily
intake
for
a
70
kg
adult
would
be
8.7
ng/
kg­
day.
The
corresponding
average
daily
intake
for
a
10
kg
child
would
be
35
ng/
kg­
day
if
an
inhalation
rate
of
8.7
m3/
day
(
U.
S.
EPA,
1996d)
is
assumed.
Alternatively,
assuming
a
range
of
ambient
concentrations
from
2
to
220
ng/
m3
for
rural
and
urban
populations,
and
an
inhalation
rate
of
15.2
m3/
day,
the
estimated
daily
intake
range
for
a
70
kg
adult
would
be
0.43
to
47.8
ng/
kg­
day.
The
daily
intake
for
a
10
kg
child
would
range
from
1.74
to
122
ng/
kg­
day.
These
calculated
adult
intakes
are
in
general
agreement
with
intakes
calculated
by
others.
Loranger
and
Zayed
(
1997a)
predicted
a
total
manganese
dose
for
adults
of
1
to
50
ng/
kg­
day
predicted
for
two
urban
sites
in
Montreal,
Canada,
using
Monte
Carlo
simulation.
Zayed
et
al.
(
1999a)
calculated
intakes
of
5
to
15
ng/
kg­
day
based
on
measurements
of
respirable
manganese
concentrations
at
five
sites
in
Montreal.

Populations
with
Potential
for
High
Exposure
Historically,
workers
in
occupational
settings
such
as
manganese
mining
or
ferromanganese
smelting
have
experienced
the
potential
for
high
levels
of
manganese
exposure.
Published
estimates
of
current
occupational
exposure
levels
were
not
available
in
the
materials
reviewed
for
this
document.
However,
assuming
a
maximal
legal
concentration
of
1
mg/
m3
and
inhalation
of
10
m3
of
air
over
the
course
of
a
work
day,
adults
exposed
to
manganese
in
some
occupational
settings
may
have
a
daily
intake
as
high
as
143,000
ng/
kg­
day
(
ATSDR,
2000).
5­
12
Manganese
 
February
2003
5.3
Soil
5.3.1
Concentration
of
Manganese
in
Soil
Manganese
constitutes
approximately
0.1%
of
the
earth's
crust,
and
is
a
naturally
occurring
component
of
nearly
all
soils
(
ATSDR,
2000).
Natural
levels
of
manganese
range
from
less
than
2
to
7,000
mg/
kg,
with
a
geometric
mean
concentration
of
330
mg/
kg
(
Shacklette
and
Boerngen,
1984).
The
estimated
arithmetic
mean
concentration
is
550
mg/
kg.
Accumulation
of
manganese
occurs
in
the
subsoil
rather
than
on
the
soil
surface
(
ATSDR,
2000).
An
estimated
60
 
90%
of
soil
manganese
is
associated
with
the
sand
fraction
(
WHO,
1981,
as
cited
in
ATSDR,
2000).

5.3.2
Intake
of
Manganese
in
Soil
General
Population
No
published
reports
quantify
exposure
to
manganese
associated
with
soil
ingestion.
Assuming
a
concentration
range
of
<
2
to
7,000
mg/
kg
soil
and
average
ingestion
of
50
mg
of
soil/
day,
the
average
manganese
intake
of
a
70­
kg
adult
would
be
0.0014
to
5
:
g/
kg­
day.
The
corresponding
intake
for
a
10­
kg
child
consuming
100
mg
of
soil/
day
would
be
0.02
to
70
:
g/
kgday

Populations
with
Potential
for
High
Exposure
No
highly
exposed
populations
were
identified
with
respect
to
soil
intake.

5.4
Other
Media
No
published
reports
identify
other
sources
of
manganese
exposure.

5.5
Summary
of
Exposure
to
Manganese
in
Media
Other
Than
Water
Table
5­
7
summarizes
information
on
exposure
to
manganese
in
media
other
than
water.
Inspection
of
data
in
this
table
reveals
that
ingestion
of
food
contributes
a
major
proportion
of
manganese
exposure.
This
observation
is
consistent
with
the
findings
of
Loranger
and
Zayed
(
1995,
1997b),
who
estimated
that
food
contributed
95
to
99%
of
the
multimedia
dose
of
manganese
in
Canadian
studies.
The
contribution
of
soil
as
a
source
of
manganese
was
not
evaluated
in
the
1995
study
(
Loranger
and
Zayed,
1995).
However,
as
evident
from
Table
5­
7,
soil
ingestion
has
the
potential
to
contribute
substantially
to
intake
in
areas
with
naturally
high
or
anthropogenically
enriched
concentrations
of
soil
manganese.

EPA
has
derived
an
oral
reference
dose
(
RfD)
for
manganese
of
0.14
mg/
kg­
day
and
an
inhalation
reference
concentration
(
RfC)
of
5
×
10­
5
mg/
m3
(
see
Section
8.1).
These
values
can
be
converted
to
daily
doses
(
assuming
a
70
kg
adult
inhaling
15.2
m3/
day
of
air)
of
10
mg
and
7.6
×
10­
4
mg
manganese,
respectively.
Thus,
the
level
of
safe
exposure
determined
for
the
5­
13
Manganese
 
February
2003
inhalation
route
is
five
orders
of
magnitude
less
than
that
determined
for
the
oral
route,
reflecting
the
much
greater
toxicity
observed
for
inhaled
versus
ingested
manganese.
For
exposure
to
manganese
from
drinking
water,
EPA
recommends
applying
an
additional
modifying
factor
of
three
to
the
above
RfD,
yielding
0.047
mg/
kg­
day
(
U.
S.
EPA,
1996a).
This
recommendation
derives
from
concern
raised
by
the
Kondakis
study
(
1989)
(
see
Sections
7.1.3
and
8.1)
about
the
potential
for
higher
absorption
of
manganese
from
water,
and
also
from
consideration
of
potentially
higher
absorption
in
fasting
individuals
and
neonates,
the
latter
of
which
may
have
higher
absorption
rates
and
lower
excretion
rates
of
manganese
than
mature
individuals
(
U.
S.
EPA,
1996a).

For
drinking
water,
a
National
Secondary
Drinking
Water
Regulation
(
or
secondary
Maximum
Contaminant
Levels,
s­
MCL)
for
manganese
also
exists
(
0.05
mg/
L)
to
prevent
clothes
staining
and
taste
problems.
Secondary
standards
are
non­
enforceable
guidelines
regulating
contaminants
that
may
cause
aesthetic
effects
(
such
as
color,
taste
or
odor)
or
cosmetic
effects
(
such
as
skin
or
tooth
discoloration)
in
drinking
water.
EPA
recommends
s­
MCLs
to
water
systems
but
does
not
require
systems
to
comply.

Table
5­
7.
Summary
of
Human
Exposure
to
Manganese
in
Media
Other
than
Water
(
General
Population).

PARAMETER
EXPOSURE
MEDIUM
Food
Air
Soil
Adult
Child
Adult
Child
Adult
Child
Concentration
in
Medium
0.04
 
47
mg/
kg
40
ng/
m3
<
2
 
7,000
mg/
kg
Estimated
Average
Daily
Intake
(:
g/
kgday
28.6
 
126
0.87
 
37.2
(
infant)
128
(
child)
0.0087
0.034
0.0014
 
5.0
0.02
 
70
6­
1
Manganese
 
February
2003
6.0
TOXICOKINETICS
The
absorption,
distribution,
metabolism
and
excretion
of
manganese
in
the
body
are
reviewed,
discussed,
and
summarized
in
Greger
(
1999),
U.
S.
EPA
(
1984),
Kies
(
1987),
U.
S.
EPA
(
1993),
and
ATSDR
(
2000).
Age,
chemical
species,
dose,
route
of
exposure,
and
dietary
conditions
all
affect
manganese
absorption
and
retention
(
Lönnerdal
et
al.,
1987).
Uptake
of
dietary
manganese
appears
to
be
controlled
by
several
dose­
dependent
processes:
biliary
excretion,
intestinal
absorption,
and
intestinal
elimination.
Manganese
absorbed
in
the
divalent
form
from
the
gut
via
the
portal
blood
is
complexed
with
plasma
proteins
that
are
efficiently
removed
by
the
liver.
Absorption
of
manganese
via
inhalation,
intratracheal
instillation,
or
intravenus
infusions
bypasses
the
control
processes
by
the
gastrointestinal
tract.
After
absorption
to
the
blood
system
by
these
alternate
routes,
manganese
is
apparently
oxidized,
and
the
trivalent
manganese
binds
to
transferrin.
Transferrin­
bound
trivalent
manganese
is
not
as
readily
removed
by
the
liver,
as
are
protein
complexes
with
divalent
manganese.
Thus,
manganese
delivered
by
these
other
routes
would
be
available
for
uptake
into
tissues
for
a
longer
period
of
time
than
the
orally
administered
manganese,
leading
to
quantitative
differences
in
tissue
uptake
(
Andersen
et
al.,
1999).

6.1
Absorption
Human
Studies
The
following
sections
discuss
absorption
of
manganese
following
oral
exposure
only.
Recent
studies
show
that
significant
differences
exist
in
the
amounts
of
manganese
that
are
absorbed
across
different
exposure
routes,
with
inhaled
manganese
being
absorbed
more
rapidly
and
to
a
greater
extent
than
ingested
manganese
(
Roels
et
al.,
1997;
Tjälve
at
al.,
1996).

Past
manganese
intake
and
iron,
phosphorus,
and
calcium
intake
affect
manganese
absorption
in
humans.
Further,
phytate,
fiber,
and
polyphenols
(
tannins)
in
vegetable
diet
tend
to
decrease
manganese
absorption
(
Greger,
1999;
Greger
and
Snedeker,
1980).
Manganese
speciation
and
the
route
of
exposure
also
affect
its
absorption
(
Andersen
et
al.,
1999;
Tjalve
et
al.,
1996).

Mena
et
al.
(
1969)
investigated
gastrointestinal
absorption
of
manganese
in
11
healthy,
fasted
human
subjects.
The
subjects
received
100
:
Ci
of
54MnCl
2
with
0.200
mg
stable
55MnCl
2
(
0.087
mg
Mn)
as
a
carrier.
After
2
weeks
of
daily
whole
body
counts,
the
absorption
of
54Mn
was
calculated
to
average
approximately
3%.
Comparable
absorption
values
were
found
for
healthy
manganese
miners
and
ex­
miners
with
chronic
manganese
poisoning.
However,
enterohepatic
circulation
was
not
taken
into
account
in
this
study.
These
values
may
therefore
underestimate
absorption
(
U.
S.
EPA,
1993).

Thomson
et
al.
(
1971)
reported
a
higher
absorption
rate
of
54MnCl
2
in
segments
of
jejunum
and
duodenum
using
a
double­
lumen
tube.
The
mean
absorption
rate
in
eight
subjects
was
27
±
3%.
6­
2
Manganese
 
February
2003
Schwartz
et
al.
(
1986)
studied
the
absorption
and
retention
of
manganese
over
a
7­
week
period
in
seven
healthy
male
volunteers
aged
22
 
32
years.
Volunteers
consumed
3,100
 
4,400
kcal/
day
which
provided
levels
of
manganese
ranging
from
12.0
to
17.7
mg
Mn/
day.
Assuming
an
adult
body
weight
of
70
kg,
this
intake
corresponds
to
0.17
to
0.25
mg/
kg­
day.
During
weeks
2
to
4,
manganese
absorption
was
­
2.0
±
4.9%
of
the
intake.
During
weeks
5
to
7,
the
reported
absorption
was
7.6
±
6.3%.
Despite
the
high
level
of
intake,
net
retention
of
manganese
was
not
observed
in
these
individuals.
Fecal
loss
accounted
for
nearly
all
of
the
ingested
manganese,
and
in
some
cases
exceeded
the
intake.
A
portion
of
this
loss
likely
represents
biliary
secretion
of
previously
absorbed
manganese.

Sandström
et
al.
(
1986)
administered
450
mL
of
infant
formula
containing
0.050
mg
Mn/
L
to
eight
healthy
subjects,
aged
20
to
38
years.
The
average
absorption
for
seven
of
the
subjects
was
8.4
±
4.7%.
The
eighth
subject
was
diagnosed
with
iron
deficiency
anemia,
and
absorbed
45.5%.
Six
additional
subjects
received
2.5
mg
of
manganese
(
as
sulfate)
in
a
multielement
preparation.
The
mean
absorption
for
the
second
group
of
subjects
was
8.9
±
3.2%.

Davidsson
et
al.
(
1989b)
studied
whole­
body
retention
of
54Mn
in
adult
humans
after
intake
of
radiolabeled
infant
formula.
These
authors
observed
reproducible
retention
figures
at
day
10,
after
repeated
administrations
of
the
labeled
formula
to
six
subjects.
Absorption
ranged
from
0.8
 
16%.
This
range
corresponds
to
a
20­
fold
difference
between
the
highest
and
lowest
values.
The
mean
value
was
5.9
±
4.8%.
Retention
at
day
10
ranged
from
0.6
 
9.2%,
with
a
mean
value
of
2.9
±
1.8%
when
measured
in
14
healthy
individuals.
These
results
suggest
substantial
variation
in
absorption
between
individuals.

In
addition,
Davidsson
et
al.
(
1989a)
studied
manganese
absorption
from
human
milk,
cow's
milk,
and
infant
formulas
in
human
adults
using
extrinsic
labeling
of
the
foods
with
54Mn
or
52Mn
and
measurements
of
whole­
body
retention.
The
fractional
manganese
absorption
from
human
milk
(
8.2%
±
2.9%)
was
significantly
different
when
compared
with
cow's
milk
(
2.4%
±
1.7%)
or
soy
formula
(
0.7%
±
0.2%).
The
total
amount
of
absorbed
manganese,
however,
was
significantly
higher
from
the
cow's
milk
formula
as
compared
with
human
milk.

Several
studies
have
reported
a
greater
retention
of
manganese
in
the
neonate
than
in
adults.
In
a
study
of
the
nutritional
requirements
for
manganese
in
pre­
term
infants,
Zlotkin
and
Buchanan
(
1986)
showed
that
99%
of
the
manganese
given
intravenously
for
6
days
was
retained.
Mena
(
1969)
observed
that
healthy
adults
absorb
3%
of
ingested
manganese.
Lonnerdäl
et
al.
(
1987)
showed
that
manganese
uptake
from
brush
border
membranes
was
higher
in
14
day­
old
rats
than
in
18
day­
old
rats.
Although
Rehnberg
et
al.
(
1985)
found
that
younger
animals
had
a
slower
distal
intestinal
transit
time
than
older
animals
(
potentially
contributing
to
a
higher
proportional
uptake),
Bell
et
al.
(
1989)
showed
that
the
uptake
rate
was
similar
in
preand
post­
weanling
animals
suggesting
that
age­
dependent
differences
in
manganese
retention
were
not
due
to
immature
intestinal
transport
mechanisms.

Dorner
et
al.
(
1989)
studied
retention
of
manganese
in
breast­
fed
infants
compared
to
preterm
(~
34­
36
weeks
gestational
age)
or
full­
term
(
2­
17
weeks
postgestational
age)
infants
fed
cow's
milk
formulas.
This
study
is
unique
in
that
it
analyzed
potential
differences
in
infant
6­
3
Manganese
 
February
2003
development
on
the
intake
and
retention
of
manganese
from
different
dietary
sources.
The
authors
observed
that
full­
term
breast­
fed
infants
retain
approximately
41%
of
ingested
manganese
from
breast
milk
(
containing
6.2
µ
g
Mn/
L).
Manganese
intake
in
the
formula­
fed
infants
(
14.2
µ
g/
kg,
full­
term
and
15.0
µ
g/
kg,
pre­
term)
was
high
relative
to
that
of
breast­
fed
infants
(
1.06
µ
g/
kg).
Formula­
fed
infants
also
retained
a
higher
absolute
amount
of
manganese
from
their
diet
compared
to
breast­
fed
infants
(
0.06,
2.8,
and
0.43
µ
g/
kg
retained
in
pre­
term
formula­
fed,
full­
term
formula­
fed,
and
breast­
fed,
respectively).
These
data
indicate
that
the
percentage
of
manganese
retained
between
the
different
food
sources
is
not
comparable;
a
higher
percentage
of
ingested
manganese
from
breast
milk
is
retained
by
the
infant.
Nevertheless,
formula­
fed
babies
retain
a
larger
total
amount
of
manganese,
due
to
the
greater
amount
of
manganese
present
in
the
formula
(
77­
99
µ
g/
L).
The
data
also
indicate
that
pre­
term
infants
had
an
active
excretory
capacity
for
manganese
obtained
from
formula,
as
compared
to
full­
term
infants.

Because
human
breast
milk
contains
low
levels
of
manganese
(
4­
10
µ
g/
L;
Arnaud
and
Favier,
1995;
Collipp
et
al.
1983;
Dorner
et
al.
1989),
it
is
suggested
that
the
neonates'
propensity
to
retain
greater
amounts
of
manganese
was
an
adaptive
mechanism
to
insure
that
sufficient
amounts
were
available
to
the
developing
animal.
Regardless
of
the
mechanism
(
e.
g.,
increased
uptake
and/
or
decreased
elimination),
results
from
human
and
animal
studies
suggest
increased
manganese
retention
in
the
neonate.
Neurological
development
in
the
rat
is
incomplete
at
birth,
suggesting
that
there
may
be
differential
susceptibility
to
excess
levels
of
manganese
during
this
critical
developmental
period.
Although
much
of
the
nervous
system
is
complete
at
birth
in
humans,
there
is
evidence
that
some
discrete
neurological
functions
undergo
further
development
after
birth.
The
developmental
stage
in
humans
that
is
exactly
comparable
to
the
pre­
weanling
age
in
rats
is
unclear.
Although
results
from
animal
data
suggest
that
elimination
rates
reach
adult
levels
by
the
age
of
weaning,
the
comparable
period
in
human
development
at
which
manganese
uptake
and
elimination
reaches
that
of
an
adult
is
unknown.

Factors
that
Affect
Absorption
in
Humans
Bioavailability
of
ingested
manganese
is
an
important
issue
in
assessing
the
health
hazard
of
manganese.
Multiple
factors
have
been
reported
to
affect
the
absorption
of
manganese
by
humans,
including
chemical
form,
age,
dose,
route
of
exposure,
and
presence
or
deficiency
of
other
dietary
components
(
Greger,
1999;
Greger
and
Snedeker,
1980).
Thomson
et
al.
(
1971)
and
Gibbons
et
al.
(
1976)
reported
that
the
divalent
form
of
manganese
is
absorbed
most
efficiently.
However,
the
efficiency
of
absorption
also
varies
for
different
manganese
salts.
In
this
regard,
Bales
et
al.
(
1987)
reported
that
manganese
chloride
was
more
efficiently
absorbed
than
the
sulfate
or
acetate
salts.

Presence
of
other
dietary
components
may
influence
the
absorption
of
manganese.
Calcium,
for
example,
may
inhibit
the
absorption
of
manganese.
McDermott
and
Kies
(
1987)
suggested
that
this
inhibition
results
from
the
influence
of
calcium
on
GI
tract
pH.
Manganese
is
more
readily
absorbed
as
the
Mn(
II)
form.
As
the
pH
rises,
conversion
to
the
less
absorbable
Mn(
III)
and
Mn(
IV)
forms
is
favored,
and
uptake
is
decreased.
Alternatively,
calcium
and
manganese
may
compete
for
common
absorption
sites.
The
extent
to
which
calcium
effects
on
absorption
influence
net
manganese
balance
is
uncertain.
However,
Spencer
et
al.
(
1979)
did
not
6­
4
Manganese
 
February
2003
observe
any
significant
effect
of
dietary
calcium
levels
(
from
200
 
800
mg/
day)
on
manganese
balance
in
healthy
males.

A
strong
association
between
dietary
iron
and
manganese
uptake
has
been
noted
in
several
human
studies.
Thomson
et
al.
(
1971)
observed
that
iron
deficiency
increased
manganese
absorption.
Davis
and
Greger
(
1992)
reported
that
women
consuming
increased
levels
of
nonheme
iron
experienced
decreased
levels
of
serum
and
urinary
manganese.
Finley
et
al.
(
1994)
observed
that
serum
sodium
ferritin
concentration
was
negatively
associated
with
manganese
absorption
in
young
women
consuming
a
manganese­
adequate
diet.

Finley
(
1999)
demonstrated
that
iron
status
(
assessed
as
serum
concentrations
of
sodium
ferritin)
may
also
affect
manganese
absorption
and
retention.
Absorption
(
determined
by
regression
of
whole
body
54Mn
counts)
was
assessed
in
women
aged
20
to
45
years
who
were
categorized
as
having
high
(
upper
10%
of
normal
range,
mean
values
68
to
69
:
g/
L)
or
low
(
lower
10%
of
normal
range,
mean
values
8.7
to
8.9
:
g/
L)
serum
ferritin
levels.
Absorption
was
determined
under
conditions
of
high
(
9.5
mg
Mn/
day)
or
low
(
0.7
mg
Mn/
day)
dietary
manganese
intake.
Within
a
diet
group,
individuals
with
low
ferritin
absorbed
3­
to
5­
fold
more
manganese
(
as
a
percentage
of
dose)
than
individuals
with
high
ferritin.
Manganese
absorption
was
greatest
in
women
with
low
serum
ferritin
concentrations
consuming
the
low
manganese
diet.
The
level
of
dietary
manganese
had
no
significant
effect
on
absorption
in
women
with
high
ferritin
concentrations.

Phytate,
a
component
of
plant
protein,
may
also
interfere
with
manganese
absorption.
Davies
and
Nightingale
(
1975)
observed
a
decrease
in
manganese
retention
in
the
presence
of
phytate.
This
result
was
attributed
to
the
formation
of
a
stable
complex
between
manganese
and
phytate
in
the
intestinal
tract.
Bales
et
al.
(
1987)
reported
that
cellulose,
pectin,
and
phytate
reduced
the
plasma
uptake
of
manganese
in
human
subjects.
These
data
suggest
that
the
presence
of
these
components
contributes
to
the
decreased
bioavailability
of
manganese
from
vegetarian
diets.
However,
Schwartz
et
al.
(
1986)
found
no
significant
correlation
between
phytate
intake
and
manganese
absorption
in
healthy
males.

Ruoff
(
1995)
conducted
a
literature
review
to
determine
the
relative
bioavailability
of
manganese
from
water
versus
food.
The
calculated
ratio
following
evaluation
of
a
wide
variety
of
exposure
scenarios
in
non­
fasted
subjects
was
1.4.
However,
the
difference
in
absorption
between
the
two
media
was
not
statistically
significant.
The
ratio
for
fasted
subjects
was
2.0,
indicating
that
the
absorption
from
drinking
water
is
twice
that
from
foods
when
the
water
is
consumed
in
the
absence
of
partially
digested
foods
in
the
gastrointestinal
tract.
A
study
that
directly
measured
the
absorption
of
radiolabelled
manganese
from
various
manganese­
rich
plant
foods
given
to
adult
men
and
women
after
an
overnight
fast
reported
a
significantly
greater
percent
absorption
of
MnCl
2
from
water
compared
to
manganese
absorption
from
lettuce,
spinach,
sunflower
seeds,
or
wheat
(
Johnson
et
al.,
1991).
In
addition,
different
diets
may
have
different
levels
of
constituents
that
affect
manganese
absorption.
The
greater
levels
of
phytates,
tannins,
oxalates,
and
fiber
in
vegetarian
diets,
for
instance,
are
expected
to
have
an
inhibitory
effect
on
manganese
uptake
from
the
gastrointestinal
tract.
Johnson
et
al.
(
1991)
reported
mean
percent
absorption
values
from
lettuce
and
spinach
of
5.20
and
3.81%,
respectively,
and
from
6­
5
Manganese
 
February
2003
sunflower
seeds
and
wheat
of
1.71
and
2.16%,
respectively.
Mean
percent
absorption
values
from
MnCl
2
dissolved
in
water
only
(
controls)
ranged
from
7.74
to
10.24%.

Animal
Studies
There
are
studies
using
54Mn­
labeled
manganese
to
estimate
absorption
by
animals.
However,
these
studies
measured
the
apparent
absorption,
not
true
absorption.,
because
feeding
radioactive
isotopes
of
manganese
does
not
eliminate
the
problem
that
absorbed
manganese
is
very
rapidly
excreted
through
bile
into
the
feces
(
Malecki
et
al.,
1996).
Thus,
it
is
impossible
to
separate
non­
absorbed
manganese
from
secreted
manganese
without
elaborate
study
designs.
When
investigators
used
elaborate
methodology
in
which
54Mn
bound
to
albumin
was
injected
intraportally,
true
manganese
absorption
was
calculated
to
be
8.2%,
and
37%
of
the
absorbed
manganese
was
excreted
into
the
gut
(
Davis
et
al.,
1993).

Greenberg
et
al.
(
1943)
administered
a
single
oral
dose
containing
0.1
mg
of
54Mn­
labeled
manganese
(
as
chloride)
to
rats,
and
estimated
that
3
 
4%
was
absorbed
from
the
intestine.
Pollack
et
al.
(
1965)
administered
a
single
oral
dose
of
54Mn
as
chloride
with
5
:
mol
(
0.27
mg
Mn)
stable
carrier
to
fasted
rats
and
reported
2.5
 
3.5%
absorption
6
hours
after
administration.
In
separate
studies,
Rabar
(
1976)
and
Kostial
et
al.
(
1978)
administered
a
single
oral
dose
of
54Mn
as
chloride,
carrier
free,
to
post­
weaning
non­
fasted
rats
and
reported
0.05%
absorption
6
days
after
administration.
This
low
absorption
value
may
reflect
either
loss
of
absorbed
manganese
through
fecal
excretion,
or
the
fact
that
the
rats
were
not
fasted
(
U.
S.
EPA,
1984).

Cikrt
and
Vostal
(
1969)
showed
that
manganese
is
likely
to
be
absorbed
from
both
the
small
and
large
intestine
in
rats.
Factors
reported
to
influence
manganese
absorption
in
animals
include
dose,
chemical
form,
and
age.
With
respect
to
dose,
Garcia­
Aranda
et
al.
(
1983)
studied
the
intestinal
uptake
of
manganese
in
adult
rats
and
concluded
that
saturation
of
the
absorptive
process
occurred
at
higher
levels
of
intake.
Keen
et
al.
(
1986)
observed
that
when
suckling
rats
were
fed
0.5
mL
of
infant
formula
containing
5
or
25
mg
Mn/
mL,
retention
of
manganese
decreased
at
the
higher
concentration.

Tissue
levels
of
manganese
may
be
influenced
by
the
form
of
manganese
administered
in
the
diet.
Komura
and
Sakamoto
(
1991)
administered
manganese
in
soluble
(
manganese
acetate
or
manganese
chloride)
and
relatively
insoluble
(
manganese
dioxide
or
manganese
carbonate)
forms
to
male
ddY
mice.
Weight
gain
was
reduced
in
animals
receiving
the
more
soluble
forms.
Manganese
levels
in
the
liver
and
kidney
appeared
to
be
higher
in
animals
fed
manganese
acetate
or
manganese
carbonate.
The
statistical
significance
of
these
apparent
differences
was
not
determined.

Keen
et
al.
(
1986)
demonstrated
a
strong
effect
of
age
on
intestinal
manganese
uptake
and
retention.
Sprague­
Dawley
rat
pups
were
fasted
overnight
and
then
intubated
with
0.5
mL
of
human
milk
containing
0.005
mg
54Mn/
mL.
Manganese
retention
was
highest
($
80%)
in
pups
less
than
15
days
old.
In
older
pups
(
16
 
19
days
old),
the
average
retention
was
40%.
Keen
et
al.
(
1986)
also
administered
infant
formula
to
rat
pups.
Soy
formula
typically
contains
a
much
higher
level
of
Mn
than
does
human
milk.
The
amount
of
manganese
retained
in
14­
day
old
rat
6­
6
Manganese
 
February
2003
pups
was
25
times
higher
in
animals
given
soy
formula
when
compared
with
pups
receiving
human
milk.

Chan
et
al.
(
1987)
demonstrated
that
developmental
stage
has
a
significant
influence
on
the
absorption
of
manganese.
Manganese
absorption
decreased
in
rat
pups
from
age
9
days
to
20
days.
The
observed
decrease
in
manganese
absorption
was
correlated
with
a
switch
in
the
site
of
maximal
absorption.
The
duodenum
was
more
active
in
manganese
uptake
in
younger
rats,
while
the
jejunum
became
more
important
as
the
animals
matured.

Little
is
known
about
the
factors
that
determine
the
bioavailability
of
ingested
manganese
in
animals.
Chan
et
al.
(
1982,
1987)
reported
differences
in
the
concentration
and
chemical
form
of
manganese
found
in
different
milk
sources.
Human
milk
contained
only
0.008
±
0.003
mg
Mn/
L,
while
bovine
milk,
infant
formula
and
rat
milk
contained
0.030
±
0.005,
0.073
±
0.004,
and
0.148
±
0.018
mg
Mn/
L,
respectively.
However,
absorption
of
manganese
by
suckling
rats
from
these
four
types
of
milk
was
comparable,
suggesting
that
total
concentration
may
not
always
be
a
reliable
indicator
of
bioavailable
manganese.
Chan
et
al.
(
1982)
determined
that
the
chemical
form
of
manganese
in
infant
formula
is
very
different
from
that
in
human
or
cows'
milk.
Human
and
cow's
milk
contain
two
and
three
manganese­
binding
proteins,
respectively.
All
manganese
in
milk
from
these
sources
is
protein
bound,
while
the
manganese
in
infant
formulas
is
in
the
form
of
soluble
salts.
The
degree
to
which
the
association
of
manganese
with
protein
influences
absorption
is
unknown,
but
is
likely
to
be
important.

Lönnerdal
et
al.
(
1987)
reported
that
age,
manganese
intake
and
dietary
factors
affect
manganese
absorption
and
retention
in
rats.
Retention
is
very
high
during
the
neonatal
period
and
decreases
considerably
with
age.
Decreased
absorption
with
age
apparently
results
from
a
combination
of
decreased
intestinal
absorption
and
increased
excretion
in
the
bile.
In
young
rat
pups,
the
bioavailability
of
manganese
from
various
milk
sources
varied,
with
greater
absorption
occurring
from
human
and
cow's
milk
formula
than
from
soy
formula.
These
differences
were
less
pronounced
in
older
pups.

Several
studies
have
explored
the
interrelationship
among
manganese,
cobalt,
and
iron
uptake.
Thomson
et
al.
(
1971)
reported
that
iron
and
cobalt
compete
with
manganese
for
the
same
absorption
sites.
Competition
was
proposed
to
occur
during
uptake
from
the
lumen
into
mucosal
cells
and
in
the
transfer
from
mucosa
into
other
compartments.
Rehnberg
et
al.
(
1982)
administered
dietary
Mn
3
O
4
(
450,
1,150,
or
4,000
mg/
kg
Mn)
to
young
rats.
These
authors
amended
the
basal
diets
with
varying
levels
of
iron,
and
demonstrated
that
iron
deficiency
promoted
the
intestinal
absorption
of
manganese.
Conversely,
manganese
absorption
was
inhibited
by
large
amounts
of
dietary
iron.
Gruden
(
1984)
demonstrated
that
3­
week­
old
rat
pups
given
a
high
concentration
of
iron
(
0.103
mg
Fe/
L)
in
cow's
milk
absorbed
50%
less
manganese
than
pups
receiving
the
control
milk
(
0.005
mg
Fe/
mL).
This
difference
was
not
observed
in
rats
tested
at
8,
11,
14,
or
17
days
of
age,
suggesting
that
the
inhibition
of
manganese
absorption
by
iron
has
a
rapid
onset
during
the
third
week
of
life.
6­
7
Manganese
 
February
2003
6.2
Distribution
Human
Studies
Manganese
is
a
normal
component
of
human
tissues
and
fluids.
Information
about
the
distribution
of
manganese
in
humans
is
generally
derived
from
post­
mortem
analyses
of
various
organs
and
tissues.
The
patterns
observed
in
these
analyses
reflect
the
body
and
organ
burden
of
a
lifetime
intake
of
manganese.
Cotzias
(
1958)
and
WHO
(
1981)
reported
a
total
of
12­
20
mg
manganese
in
a
normal
70
kg
man.
Sumino
et
al.
(
1975)
reported
an
average
of
8
mg
among
15
male
and
15
female
cadavers
with
an
average
weight
of
55
kg.

The
highest
concentrations
of
manganese
in
the
body
of
persons
without
excessive
exposure
are
found
in
the
liver,
kidney,
pancreas,
and
adrenal
glands.
Intermediate
concentrations
occur
in
the
brain,
heart
and
lungs
(
Table
6­
1)
(
ATSDR,
2000).
The
lowest
concentrations
of
manganese
are
observed
in
bone
and
fat.
Some
data
suggest
that
tissues
rich
in
mitochondria
(
for
example,
liver,
kidney,
and
pancreas)
contain
higher
levels
of
manganese
(
Kato,
1963;
Maynard
and
Cotzias,
1955).

Manganese
levels
have
been
determined
in
human
serum
and
blood.
Serum
concentrations
in
healthy
male
and
female
subjects
in
Wisconsin
were
1.06
:
g/
L
and
0.86
:
g/
L,
respectively
(
Greger
et
al.,
1990;
Davis
and
Greger,
1992).
Blood
and
serum
levels
of
manganese
in
healthy
subjects
living
in
the
Lombardy
region
of
Italy
were
8.8
±
0.2
:
g/
L
and
0.6
±
0.014
:
g/
L,
respectively
(
Minoia
et
al.,
1990).

A
variety
of
factors
have
been
reported
to
influence
manganese
levels
in
blood
and
blood
fractions.
Hagenfeldt
et
al.
(
1973)
found
variations
in
plasma
manganese
concentrations
in
women
and
suggested
that
the
variation
may
be
due
to
hormonal
changes.
Horiuchi
et
al.
(
1967)
and
Zhernakova
(
1967)
found
no
difference
in
the
concentration
of
manganese
in
the
blood
of
men
and
women.
Slight
seasonal
(
lower
during
summer
and
autumn)
and
diurnal
(
lower
during
the
night)
variations
in
blood
manganese
concentrations
have
also
been
reported
(
U.
S.
EPA,
1984).

Three
studies
have
addressed
manganese
distribution
within
human
organs.
Perry
et
al.
(
1973)
investigated
manganese
concentrations
in
different
sections
of
the
liver
and
found
little
variation.
Larsen
et
al.
(
1979)
and
Smeyers­
Verbeke
et
al.
(
1976)
studied
the
regional
distribution
of
manganese
in
the
brain
and
reported
the
highest
concentrations
in
the
basal
ganglia.

Studies
by
Schroeder
et
al.
(
1966)
and
Widdowson
et
al.
(
1972)
indicate
that
placental
transfer
of
manganese
occurs
in
humans.
Manganese
levels
in
fetal
and
newborn
tissues
were
reported
to
be
similar
to
adult
levels,
with
the
exception
of
higher
concentrations
observed
in
fetal
bone.
6­
8
Manganese
 
February
2003
Table
6­
1.
Normal
Manganese
Levels
in
Human
and
Animal
Tissues.

Tissue
Tissue
concentrations
(:
g
Mn/
g
wet
weight)

Humans
Rats
Rabbits
A
B
C
D
Liver
1.68
1.2
2.6
 
2.9
2.1
Pancreas
1.21
0.77
­­
1.6
Adrenals
0.20
0.69
2.9
0.67
Kidney
0.93
0.56
0.9
 
1.0
1.2
Brain
0.34
0.30*
0.4
0.36
Lung
0.34
0.22
­­
0.01
Heart
0.23
0.21
­­
0.28
Testes
0.19
0.20
0.4
0.36
Ovary
0.19
0.19
­­
0.60
Muscle
0.09
0.09
­­
0.13
Spleen
0.22
0.08
0.3
0.22
Fat
­­
0.07
­­
­­

Bone
(
rib)
­­
0.06
­­
­­

Pituitary
­­
­­
0.5
2.4
Adapted
from
ATSDR
(
2000)
A
Tipton
and
Cook
(
1963)
B
Sumino
et
al.
(
1975)
C
Rehnberg
et
al.
(
1982)
D
Fore
and
Morton
(
1952)
*
Average
of
cerebrum
and
cerebellum
­­
No
data
Animal
Studies
Knowledge
of
manganese
distribution
patterns
in
animals
was
initially
derived
from
parenteral
exposure
studies
which
facilitated
the
use
of
radioactive
manganese
as
a
tracer.
The
distributions
of
parentally
(
injected)
and
orally
administered
manganese
are
very
different.
Cellular
uptake
of
manganese
is
affected
by
the
way
in
which
manganese
is
transported
in
the
plasma.
Injected
manganese
(
and
probably
inhaled
manganese
as
well),
which
is
transported
by
transferrin,
is
more
apt
to
accumulate
in
the
brain
and
cause
toxicity
than
orally
administered
manganese,
which
is
transported
from
the
gut
to
the
liver
by
albumin
(
Andersen
et
al.,
1999;
Davis
et
al.,
1993).
Davis
et
al.
(
1993)
demonstrated
that
the
distribution
pattern
of
albumin­
6­
9
Manganese
 
February
2003
bound,
but
not
transferrin­
bound,
intraportally­
injected
manganese
was
similar
to
that
of
orallyadministered
manganese.

Kato
(
1963)
and
Maynard
and
Cotzias
(
1955)
suggested
that
mitochondria­
rich
tissues
such
as
liver,
kidney,
and
pancreas
contain
higher
levels
of
manganese.
Distribution
studies
in
mice,
rats,
and
monkeys
have
subsequently
identified
liver,
kidney,
and
endocrine
glands
as
primary
sites
of
manganese
accumulation
following
parenteral
exposure.
Kato
(
1963),
for
example,
investigated
distribution
in
mice
using
radiolabeled
manganese.
High
levels
of
radioactive
manganese
were
found
in
the
liver,
kidneys,
and
endocrine
glands,
with
lesser
amounts
detected
in
brain
and
bone.
Dastur
et
al.
(
1969)
administered
an
intraperitoneal
dose
of
radioactive
manganese
to
rats,
and
subsequently
found
the
highest
concentrations
of
labeled
manganese
in
suprarenal,
pituitary,
liver,
and
kidney
tissue.
In
general,
these
results
are
in
agreement
with
the
patterns
of
manganese
distribution
observed
in
human
tissues.

Dastur
et
al.
(
1971)
observed
a
similar
pattern
of
distribution
in
monkeys
exposed
to
manganese
by
intraperitoneal
injection.
The
highest
concentrations
of
manganese
were
found
in
the
liver,
kidney
and
endocrine
glands,
as
observed
in
rodents.
Following
treatment,
manganese
levels
in
the
central
nervous
system
decreased
more
slowly
than
levels
in
other
tissues.
Suzuki
et
al.
(
1975)
injected
monkeys
subcutaneously
with
manganese,
and
subsequently
found
increased
tissue
concentrations
of
manganese
in
endocrine
and
exocrine
glands
(
thyroids,
parotids,
and
gall
bladder)
and
in
the
nuclei
of
cerebral
basal
ganglia.
Newland
et
al.
(
1989)
noted
substantial
accumulation
in
the
pituitary
gland
of
Macaca
fascicularis
and
Cebus
apella
monkeys
at
low
cumulative
doses.

Several
studies
have
addressed
regional
distribution
of
manganese
in
the
brain
following
parenteral
exposure.
Newland
and
Weiss
(
1992)
investigated
distribution
of
manganese
in
the
brain
of
monkeys.
Three
Cebus
monkeys
received
multiple
intravenous
doses
of
5
or
10
mg/
kg
of
manganese
chloride
over
the
course
of
450
days.
Magnetic
resonance
imaging
revealed
darkening
of
the
globus
pallidus
and
substantia
nigra.
This
result
is
consistent
with
accumulation
of
manganese
in
these
regions.

Scheuhammer
and
Cherian
(
1981)
reported
the
distribution
of
manganese
in
male
rat
brain
tissue
with
and
without
intraperitoneal
exposure
to
3
mg
Mn/
kg
as
manganese
chloride.
In
unexposed
rats,
the
highest
concentrations
of
manganese
were
found
in
the
hypothalamus,
colliculi,
olfactory
bulbs,
and
midbrain.
In
treated
rats,
all
brain
regions
showed
an
increase
in
manganese
concentration,
and
the
highest
manganese
concentrations
were
observed
in
the
corpus
striatum
and
corpus
callosum.

Autissier
et
al.
(
1982)
reported
that
rats
given
a
daily
intraperitoneal
dose
of
10
mg/
kgday
manganese
chloride
for
4
months
showed
significant
increases
in
the
accumulation
of
manganese
in
the
brain.
This
dose
was
equivalent
to
4.4
mg
Mn/
kg­
day.
The
study
showed
a
359%
increase
in
the
concentration
of
manganese
in
the
brain
stem,
a
243%
increase
in
the
corpus
striatum,
and
a
138%
increase
in
the
hypothalamus.

The
tissue
distribution
of
manganese
appears
to
be
affected
by
co­
exposure
to
other
metals.
Shukla
and
Chandra
(
1987)
exposed
young
male
rats
to
lead
(
5
mg/
L
in
drinking
water)
6­
10
Manganese
 
February
2003
and/
or
manganese
(
1
or
4
mg/
kg,
by
intraperitoneal
injection)
for
30
days.
Exposure
to
individual
metals
resulted
in
accumulation
in
all
brain
regions.
Co­
exposure
to
lead
and
manganese
resulted
in
increased
levels
of
both
metals,
particularly
in
the
corpus
striatum.
Administration
of
manganese
alone
led
to
dose­
dependent
increased
levels
in
liver,
kidney
and
testis.
Co­
exposure
to
lead
further
increased
manganese
accumulation
in
liver.
The
authors
concluded
that
the
interaction
of
metals
can
alter
tissue
distribution
of
manganese,
and
that
adverse
health
effects
may
result
from
co­
exposure
to
even
low
levels
of
metals.

The
chemical
form
in
which
manganese
is
injected
may
influence
the
subsequent
tissue
distribution
of
manganese.
Gianutsos
et
al.
(
1985)
demonstrated
that
blood
and
brain
levels
of
manganese
in
mice
are
increased
following
intraperitoneal
injection
of
manganese
chloride,
manganese
oxide,
or
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT).
However,
MnCl
2
administration
resulted
in
more
rapid
accumulation
and
ultimately
higher
levels
of
blood
and
brain
manganese.
It
was
suggested
that
the
differences
seen
among
the
three
manganese
compounds
result
from
the
oxide
and
MMT
forms
being
more
hydrophobic.
Hydrophobicity
may
cause
formation
of
a
depot
at
the
site
of
injection
that
retards
absorption.
Gianutsos
et
al.
(
1985)
also
demonstrated
that
the
exit
of
manganese
from
the
brain
is
a
slower
process
than
its
entry,
resulting
in
a
long
retention
period
and
potential
accumulation.
A
single
injection
of
0.4
mEq
Mn/
kg
resulted
in
a
significant
increase
(>
2­
fold)
in
brain
levels
within
1
 
4
hours.
The
increased
levels
were
maintained
for
at
least
21
days.
Brain
manganese
levels
were
especially
sensitive
to
a
repeated
dose
regimen.
Much
greater
accumulation
occurred
when
the
dose
was
divided
into
10
injections
given
every
other
day
as
compared
with
a
single
injection.
This
observation
may
help
explain
the
slow
onset
of
manganese
neurotoxicity:
acute
exposure
results
in
other
organs
serving
as
the
primary
target,
while
chronic
exposure
results
in
gradually
increasing
brain
levels
with
subsequent
neurotoxicity.

Distribution
of
manganese
has
also
been
investigated
in
oral
exposure
studies.
Chan
et
al.
(
1981)
administered
278
mg/
L
manganese
chloride
in
drinking
water
to
rats
for
two
years.
At
the
termination
of
the
study,
these
investigators
found
a
31%
increase
in
manganese
concentration
in
the
brain
and
a
45%
increase
in
the
liver
relative
to
control
values.
Assuming
a
body
weight
for
rats
of
0.35
kg
and
water
consumption
of
0.049
L/
day,
the
average
daily
dose
of
manganese
in
this
experiment
was
equivalent
to
17
mg/
kg­
day.

Some
oral
exposure
data
suggest
that
developmental
stage
may
influence
the
distribution
of
manganese.
The
brain,
for
example,
may
be
a
site
for
preferential
accumulation
of
manganese
in
neonates.
Kostial
et
al.
(
1978)
observed
that
rat
pups
showed
a
greater
accumulation
of
manganese
in
the
brain,
but
not
in
the
liver,
than
did
their
mothers.
The
data
of
Rehnberg
et
al.
(
1980,
1981,
1982)
indicate
that
the
neonatal
brain
reaches
higher
concentrations
of
manganese
than
other
tissues.
The
authors
suggested
that
this
pattern
reflects
a
response
to
a
nutritional
need
for
manganese
in
the
developing
brain.

Kontur
and
Fechter
(
1985)
demonstrated
placental
transfer
of
manganese
in
Long­
Evans
rats
exposed
via
drinking
water
throughout
gestation.
Transfer
was
limited,
with
only
0.4%
of
the
administered
manganese
accumulating
in
a
single
fetus.
Neonatal
pups
of
exposed
dams
had
significantly
increased
levels
of
manganese
in
the
forebrain.
However,
the
increase
was
not
associated
with
any
overt
signs
of
toxicity.
6­
11
Manganese
 
February
2003
Komura
and
Sakamoto
(
1993)
investigated
the
subcellular
distribution
of
Mn
and
the
binding
characteristics
of
Mn
to
brain
protein
in
male
mice
following
administration
of
different
forms
of
manganese.
Four
different
manganese
compounds
(
MnCl
2°
4H
2
O,
Mn(
CH
3
COO)
2°
4H
2
O,
MnCO
3,
or
MnO
2)
were
administered
in
the
diet
at
a
concentration
of
2,000
mg
Mn/
kg
for
12
months.
Each
treatment
group
included
6
male
mice.
The
control
group
received
a
diet
containing
approximately
130
mg
Mn/
kg
(
form
not
specified).
Assuming
a
food
factor
of
0.13,
the
control
and
treatment
dietary
levels
correspond
to
approximately
average
daily
doses
of
17
and
260
mg
Mn/
kg­
day,
respectively.
Cerebral
cortex
concentrations
of
Mn
were
significantly
higher
in
mice
receiving
the
relatively
insoluble
compounds
MnCO
3
and
MnO
2
than
in
controls.
The
subcellular
distribution
of
manganese
in
the
striatum
and
the
gel
chromatographic
profiles
of
manganese
were
similar
for
all
tested
manganese
compounds.

Roels
et
al.
(
1997)
reported
that
repeated
gavage
dosing
of
rats
(
once
weekly
for
4
weeks)
with
24.3
mg
Mn/
kg
(
5%
of
the
dose,
or
1.22
mg/
kg,
was
assumed
to
be
absorbed
by
the
study
authors)
as
MnCl
2
resulted
in
significantly
increased
concentrations
of
the
metal
in
blood
(
68%)
and
brain
cortex
(
22%)
compared
to
saline
controls
but
did
not
significantly
increase
striatal
or
cortex
Mn
concentrations.
Similar
administration
of
MnO
2
at
the
same
dose
level
did
not
result
in
significant
increases
of
Mn
in
blood
or
any
brain
tissue.
Further
studies
indicated
that
Mn
from
MnCl
2
was
absorbed
much
more
rapidly
and
reached
a
higher
peak
concentration
in
the
bloodstream
of
the
dosed
rats
than
did
MnO
2.
The
peak
Mn
blood
level
following
gavage
dosing
of
MnCl
2
was
roughly
twice
that
of
the
oxide
and
was
reported
1
hour
post­
dosing,
while
that
of
MnO
2
was
not
reported
until
144
hours
post­
dosing
(
Roels
et
al.,
1997).
These
data
indicate
that
administered
manganese
can
be
distributed
into
the
brain
and
the
kinetics
of
uptake
and
partitioning
depend
on
the
chemical
form
of
the
manganese
compound.

6.3
Metabolism
As
a
metallic
element,
manganese
does
not
undergo
metabolic
conversion
to
other
products.
However,
manganese
has
the
potential
to
exist
in
several
oxidation
states
in
biological
systems.
Circumstantial
evidence
from
the
study
of
manganese­
containing
enzymes
and
from
electron
spin
trapping
experiments
suggests
that
manganese
undergoes
conversion
from
Mn(
II)
to
Mn(
III)
within
the
body
(
ATSDR,
2000).
The
conversion
from
Mn(
II)
to
Mn(
III)
appears
to
be
catalyzed
by
the
"­
globulin
protein
ceruloplasmin
(
Andersen
et
al.,
1999).
This
reaction
may
be
enhanced
by
the
high
affinity
of
the
iron­
transporting
protein
transferrin
for
Mn(
III).

A
small
fraction
of
absorbed
manganese
is
present
as
the
free
ion.
However,
manganese
readily
forms
complexes
with
a
variety
of
organic
and
inorganic
ligands.
The
complexes
formed
include
1)
low
molecular
weight
complexes
with
bicarbonate,
citrate
or
other
ligands;
2)
an
exchangeable
complex
with
albumin;
and
3)
tightly
bound
complexes
with
proteins
such
as
transferrin
and
"
2­
macroglobulin.
In
addition,
manganese
can
assume
a
structural
role
in
metalloproteins
such
as
mitochondrial
superoxide
dismutase,
pyruvate
decarboxylase,
and
liver
arginase.
Manganese
also
plays
a
catalytic
or
regulatory
role
in
enzymatic
reactions
involving
select
hydrolases,
dehydrogenases,
kinases,
decarboxylases
and
transferases.
6­
12
Manganese
 
February
2003
6.4
Excretion
The
primary
route
for
elimination
of
manganese
is
to
the
feces
through
bile,
as
demonstrated
in
several
animal
studies
(
Weigand
et
al.,
1986;
Davis
et
al.,
1993;
Malecki
et
al.,
1996).
Fecal
manganese
concentration
reflects
both
unabsorbed
manganese
and
biliary
secretion
of
absorbed
manganese.

Human
Studies
The
primary
route
for
elimination
of
manganese
is
via
the
feces.
Fecal
manganese
concentration
reflects
both
unabsorbed
manganese
and
biliary
secretion
of
absorbed
manganese.

Price
et
al.
(
1970)
determined
the
excretion
pattern
for
preadolescent
girls
consuming
2.13
to
2.43
mg
Mn/
day.
Approximately
1.66
to
2.23
mg
Mn/
day
was
excreted
in
the
feces.
In
contrast,
only
0.01
to
0.02
mg/
day
was
excreted
in
the
urine.
Results
from
other
studies
confirm
the
importance
of
the
fecal
pathway
for
excretion.
WHO
(
1981)
and
Newberne
(
1973)
reported
that
human
excretion
of
manganese
in
urine,
sweat,
and
milk
is
minimal.
The
normal
level
of
manganese
found
in
urine
of
humans
has
been
reported
to
be
1
 
8
:
g/
L,
but
values
as
high
as
21
:
g/
L
have
also
been
reported
(
U.
S.
EPA,
1984).
Greger
et
al.
(
1990)
reported
urinary
excretion
levels
of
7.0
and
9.3
nmol
Mn/
g
creatine/
day
(
0.38
and
0.51
:
g
Mn/
g
creatinine/
day)
for
healthy
men
and
women,
respectively.
Urinary
excretion
of
manganese
was
not
responsive
to
oral
intake
levels
of
manganese
(
Davis
and
Greger,
1992).

A
number
of
studies
have
addressed
the
kinetics
of
manganese
excretion.
Humans
who
ingested
tracer
levels
of
radioactive
manganese
excreted
the
tracer
with
whole­
body
retention
half­
times
of
13
to
37
days
(
Mena
et
al.,
1969;
Davidsson
et
al.,
1989b;
Sandström
et
al.,
1986).
Sandström
et
al.
(
1986)
gave
volunteers
a
single
oral
dose
of
radioactive
manganese
and
reported
a
mean
biologic
half­
life
value
of
13
days
(
range
6
 
30
days)
for
14
subjects
monitored
on
postexposure
days
5
 
20,
and
a
mean
half­
life
of
34
days
(
range
26
 
54
days)
for
6
subjects
monitored
on
post­
exposure
days
20
 
50.
Two
additional
subjects
received
manganese
intravenously
and
experienced
a
much
slower
turnover.

Mahoney
and
Small
(
1968)
investigated
the
clearance
of
intravenously
injected
MnCl
2
by
humans.
These
investigators
observed
a
biphasic
clearance
pattern,
with
a
rapid
phase
that
lasted
4
days
and
a
slow
phase
that
lasted
39
days.
Schroeder
et
al.
(
1966)
reported
a
whole
body
turnover
rate
in
healthy
adults
of
about
40
days,
with
a
total
body
manganese
content
of
about
20
mg.

Cotzias
et
al.
(
1968)
injected
manganese
intravenously
and
reported
values
for
biological
half­
time
of
37.5
days
in
healthy
subjects,
15
days
in
healthy
miners,
and
28
days
in
subjects
with
chronic
manganese
poisoning.
These
researchers
also
found
that
clearance
by
healthy
subjects
averaged
25
days
from
the
liver,
54
days
from
the
head,
and
57
days
from
the
thigh,
as
measured
by
external
counting
with
a
collimator.
In
healthy
miners,
liver
clearance
averaged
13
days;
head
clearance
averaged
37
days;
and
thigh
clearance
averaged
39
days.
Subjects
with
6­
13
Manganese
 
February
2003
chronic
manganese
poisoning
cleared
manganese
from
the
liver
in
26
days,
from
the
head
in
62
days,
and
from
the
thigh
in
48
days.

Finley
(
1999)
demonstrated
that
iron
status
(
assessed
as
serum
concentrations
of
sodium
ferritin)
may
affect
manganese
excretion.
Biological
half­
life
(
determined
by
regression
of
whole
body
54Mn
counts)
was
assessed
in
women
aged
20
to
45
years
who
were
categorized
as
having
high
(
upper
10%
of
normal
range,
mean
values
68
to
69
:
g/
L)
or
low
(
lower
10%
of
normal
range,
mean
values
8.7
to
8.9
:
g/
L)
serum
ferritin
levels.
Biological
half­
life
was
determined
under
conditions
of
high
(
9.5
mg
Mn/
day)
or
low
(
0.7
mg
Mn/
day)
dietary
manganese
intake.
Subjects
with
low
ferritin
status
consuming
the
low
manganese
diet
had
a
mean
biological
halflife
that
was
more
than
twice
the
value
determined
for
high
ferritin
status
subjects
consuming
the
same
diet
(
36.6
days
versus
17.0
days).
There
was
no
effect
of
ferritin
status
on
mean
half­
life
for
subjects
consuming
the
high
manganese
diet
(
13.0
and
11.8
days
for
low
and
high
ferritin
status
groups,
respectively).

Animal
Studies
No
studies
of
excretion
following
oral
administration
of
manganese
in
animals
were
identified.

Greenberg
and
Campbell
(
1940)
reported
that
90.7%
of
a
1
mg
intraperitoneal
dose
of
radiolabeled
manganese
(
54Mn)
was
found
in
rat
feces
within
3
days.
In
a
subsequent
study,
Greenberg
et
al.
(
1943)
found
that
27.1%
of
a
0.01
mg
intraperitoneal
dose
of
radiolabeled
manganese
and
37.3%
of
a
0.1
mg
dose
were
collected
in
rat
bile
within
48
hours.
Tichy
et
al.
(
1973)
administered
a
0.6
:
g
dose
of
manganese
chloride
to
rats
and
reported
that
27%
was
excreted
into
the
bile
within
24
hours.

Klaassen
(
1974)
demonstrated
that
bile
is
the
main
route
of
manganese
excretion,
and
that
biliary
excretion
represents
a
major
homeostatic
mechanism
for
manganese
levels
in
the
body.
This
investigator
administered
intravenous
doses
of
0.3,
1.0,
3.0,
or
10.0
mg
Mn/
kg
to
rats,
rabbits
and
dogs.
Urinary
excretion
was
low.
As
the
dose
increased,
the
excretion
of
manganese
into
the
bile
also
increased.
The
concentration
of
manganese
in
bile
was
100
to
200
times
higher
than
in
plasma
at
the
three
lower
doses.
However,
at
the
10
mg
dose
there
was
no
further
increase
in
excretion
of
manganese
into
the
bile.
A
maximum
excretion
rate
of
8.5
:
g
Mn/
min/
kg
was
attained,
suggesting
that
a
saturable
active
transport
mechanism
may
exist
(
U.
S.
EPA,
1984).

Britton
and
Cotzias
(
1966)
and
Suzuki
(
1974)
found
that
an
increase
in
dietary
intake
of
manganese
decreased
biologic
half­
times.
Studies
also
indicate
that
the
biologic
half­
time
of
manganese
in
the
brain
of
rats,
mice
and
monkeys
is
longer
than
the
half­
life
in
the
body
(
Suzuki,
1974;
Dastur
et
al.,
1969,
1971).

In
developmental
studies
of
manganese
excretion,
neonatal
mice,
rats,
and
kittens
were
found
to
rapidly
accumulate
manganese
without
excreting
it
during
the
first
18
days
of
life
(
U.
S.
6­
14
Manganese
 
February
2003
EPA,
1984).
In
contrast,
when
lactating
rats
and
cats
were
given
excessive
doses
of
manganese
in
drinking
water
(>
280
mg/
L),
their
offspring
initiated
excretion
before
the
16th
day
of
life.

Although
human
and
animal
evidence
indicates
that
most
manganese
is
excreted
to
the
feces
in
bile,
alternative
routes
for
manganese
excretion
also
exist.
Experiments
conducted
by
Bertinchamps
and
Cotzias
(
1958),
Kato
(
1963),
and
Papavasiliou
et
al.
(
1966)
demonstrated
direct
excretion
of
manganese
through
the
intestinal
wall.
This
route
is
most
evident
in
the
presence
of
biliary
obstruction
or
following
high
doses
of
manganese.
Bertinchamps
et
al.
(
1966)
and
Cikrt
(
1973)
reported
that
in
rats
excretion
of
manganese
occurred
through
the
intestinal
wall
into
the
duodenum,
jejunum
and
terminal
ileum.
Burnett
et
al.
(
1952)
demonstrated
that
manganese
excretion
by
dogs
also
occurs
via
the
pancreatic
juice.
Other
potential
sources
of
fecal
manganese
include
intestinal
secretions
and
the
manganese
present
in
sloughed
off
intestinal
microvillus
cells.
The
fraction
of
total
excretion
attributable
to
these
alternative
pathways
has
not
been
reported,
but
is
expected
to
be
relatively
small
when
compared
to
biliary
secretion.
7­
1
Manganese
 
February
2003
7.0
HAZARD
IDENTIFICATION
7.1
Human
Effects
7.1.1
Case
Reports
General
Population
A
number
of
investigators
reported
the
toxicity
of
total
parenteral
(
TPN)
manganese
in
humans,
especially
on
changes
in
brain
MRI
scans
(
Ejima
et
al.,
1992;
Fell
et
al.,
1996;
Mirowitz
and
Westrich,
1992).
These
studies
emphasize
the
difference
in
the
effect
of
oral
and
parenteral
manganese.
When
administered
parenterally,
manganese
bypasses
the
typical
excretory
mechanisms
in
the
gastrointestinal
tract
and
liver
and
accumulates
in
the
brain
(
Mirowitz
and
Westrich,
1992).

In
addition,
there
are
a
limited
number
of
case
reports
describing
the
outcome
of
exposure
following
accidental
or
intentional
ingestion
of
manganese
from
potassium
permanganate,
a
strong
oxidizing
agent.
Unspecified
toxic
effects
were
reported
following
ingestion
of
2.4
mg/
kg­
day
potassium
permanganate
(
0.83
mg
Mn/
kg­
day)
by
a
woman
of
unknown
age
and
health
status.
This
information
was
reported
in
a
1933
French
study
cited
in
NIOSH
(
1984),
and
was
not
available
for
review.
Dagli
et
al.
(
1973)
described
a
case
in
which
oral
ingestion
of
a
300
mg
dose
of
potassium
permanganate
(
104
mg
Mn)
resulted
in
extensive
damage
to
the
distal
stomach
and
pyloric
stenosis.
Mahomedy
et
al.
(
1975)
described
two
cases
of
methemoglobinemia
following
ingestion
of
an
unspecified
amount
of
potassium
permanganate
which
had
been
prescribed
by
African
tribal
healers.
Development
of
methemoglobinemia
likely
reflects
the
chemical
oxidation
of
heme
iron.

Holzgraefe
et
al.
(
1986)
reported
neurological
effects
in
an
adult
man
who
ingested
approximately
1.8
mg/
kg­
day
of
potassium
permanganate
(
0.62
mg
Mn)
for
4
weeks.
A
syndrome
similar
to
Parkinson's
disease
developed
after
about
9
months.
However,
data
in
this
study
are
reported
to
be
insufficient
to
establish
causation
(
U.
S.
EPA,
1993).
Bleich
et
al.
(
1999)
published
a
14­
year
follow­
up
of
this
case
report.
Most
of
the
symptoms
originally
noted
(
including
rigor,
muscle
pain,
hypersomnia,
increased
libido,
sweating,
fatigue,
and
anxiety)
had
improved,
and
the
study
authors
noted
that
there
appeared
to
be
no
evidence
for
progression
of
the
parkinsonian
syndrome
as
described
by
others
(
Huang
et
al.,
1998).

Additional
case
reports
suggest
the
potential
for
manganese
toxicity
following
oral
exposure,
but
are
difficult
to
assess
quantitatively.
One
report
involved
a
59­
year­
old
male
who
was
admitted
to
the
hospital
with
classical
symptoms
of
manganese
poisoning,
including
dementia
and
a
generalized
extrapyramidal
syndrome
(
Banta
and
Markesbery,
1977).
The
patient's
serum,
hair,
urine,
feces,
and
brain
were
found
to
have
manganese
"
elevated
beyond
toxic
levels."
No
source
of
manganese
exposure
was
identified
for
this
individual.
Exposure
may
have
resulted
from
the
use
of
large
quantities
of
vitamin
and
mineral
supplements
for
4
to
5
years.
No
quantitative
data
were
provided
in
this
report.
7­
2
Manganese
 
February
2003
Manganese
intoxication
was
described
in
a
62
year­
old
male
who
received
total
parenteral
nutrition
that
provided
2.2
mg
of
manganese
(
form
not
stated)
daily
for
23
months
(
Ejima
et
al.,
1992).
This
level
corresponds
to
a
dose
of
approximately
0.023
mg
Mn/
kg­
day
for
a
70
kg
adult.
The
patient's
whole
blood
manganese
concentration
was
elevated.
The
patient
exhibited
dysarthria,
mild
rigidity,
hypokinesia
with
masked
face,
a
halting
gait,
and
severely
impaired
postural
reflexes,
and
the
diagnosis
of
this
condition
was
parkinsonism.
Assuming
an
average
absorption
of
roughly
5%
of
an
oral
dose,
the
intravenous
dose
of
2.2
mg
Mn/
day
would
be
approximately
equivalent
to
an
oral
intake
of
40
mg
Mn/
day
(
U.
S.
EPA,
1993).

Sensitive
Populations
Individuals
with
impaired
liver
function
or
bile
flow
may
represent
potentially
sensitive
subpopulations
for
manganese
exposure.
For
example,
Hauser
et
al.
(
1994)
reported
changes
in
brain
MRI
scans
in
liver
failure
patients
which
were
identical
to
those
observed
in
cases
of
manganese
intoxication.
The
patients
(
n=
3)
examined
exhibited
bilateral
signal
hyperintensity
in
the
globus
palladi
and
substantia
nigrae
in
T1­
weighted
MRI
and
increased
blood
manganese
levels
but
had
no
history
of
increased
exposure
to
manganese.
Hauser
et
al.
(
1994)
postulated
that
impaired
elimination
of
normal
dietary
manganese
could
result
in
manganese
intoxication.
Devenyi
et
al.
(
1994)
described
a
case
study
of
an
8
year­
old
girl
with
Alagille's
syndrome,
an
autosomal
dominant
disorder
characterized
by
neonatal
cholestasis,
intrahepatic
bile
duct
paucity,
and
end­
stage
liver
disease.
The
patient
exhibited
a
stable
peripheral
neuropathy,
and
for
a
period
of
2
months
exhibited
episodic,
dystonic
posturing,
and
cramping
of
her
hands
and
arms.
Whole
blood
manganese
level
was
elevated
(
27
:
g/
L,
in
contrast
to
a
normal
range
of
4
to
14
:
g/
L),
and
cranial
T1­
weighted
magnetic
resonance
imaging
(
MRI)
revealed
symmetric,
hyperintense
globus
pallidi
and
subthalamic
nuclei.
These
findings
were
interpreted
as
indications
of
manganese
toxicity.
Following
liver
transplantation,
the
patient's
manganese
levels
returned
to
normal,
her
neurological
symptoms
improved,
and
MRI
results
appeared
normal.
The
interpretation
of
this
series
of
events
was
that:
1)
progressive
liver
dysfunction
resulted
in
inadequate
excretion
of
manganese
into
the
bile,
2)
subsequent
accumulation
of
manganese
resulted
in
neurotoxicity,
and
3)
liver
transplantation
restored
biliary
excretion
and
alleviated
the
symptoms.

Manganese
has
been
identified
as
a
possible
etiologic
agent
in
the
occurrence
of
neurological
symptoms
associated
with
hepatic
encephalopathy
(
a
brain
disorder
associated
with
chronic
liver
damage).
Medical
evidence
supporting
an
etiologic
role
has
been
summarized
by
Layrargues
et
al.
(
1998).
Patients
with
chronic
liver
disorders
such
as
cirrhosis
experience
a
high
incidence
of
extrapyramidal
symptoms
resembling
those
observed
in
cases
of
occupational
manganism.
Manganese
concentration
increases
in
the
blood
and
brain
of
patients
with
chronic
liver
disease
and
these
changes
are
accompanied
by
pallidal
hyperintensity
on
T1­
weighted
MRI.
Autopsy
data
from
ten
patients
who
died
in
hepatic
coma
indicate
that
manganese
levels
are
2­
to
7­
fold
higher
in
the
globus
pallidus
of
cirrhotic
patients
when
compared
to
the
general
population.
Liver
transplantation
normalizes
the
pallidal
MR
signals
and
results
in
the
disappearance
of
extrapyramidal
symptoms.
Conversely,
transjugular
intrahepatic
portosystemic
shunting
(
a
procedure
which
increases
the
systemic
availability
of
manganese)
intensifies
the
pallidal
MR
signal
and
results
in
deterioration
of
neurological
function.
7­
3
Manganese
 
February
2003
7.1.2
Short­
term
Studies
General
Population
Kawamura
et
al.
(
1941)
reported
health
effects
resulting
from
the
ingestion
of
manganese­
contaminated
well
water
by
25
individuals.
The
source
of
contamination
was
identified
as
leachate
from
approximately
400
dry
cell
batteries
buried
near
the
drinking
water
well.
Chemical
analysis
also
revealed
high
levels
of
zinc
in
the
well
water.
The
length
of
exposure
to
manganese
was
estimated
to
be
2
to
3
months.
The
concentration
of
manganese
in
the
well
was
approximately
14
mg
Mn/
L
(
as
Mn
3
O
4)
when
analyzed
7
weeks
after
the
first
case
appeared.
This
level
corresponds
to
a
dose
of
approximately
28
mg
Mn/
day
(
assuming
a
daily
water
intake
of
2
L),
or
0.5
mg
Mn/
kg­
day
(
for
a
60
kg
adult).
When
reanalyzed
1
month
later,
the
manganese
concentration
had
decreased
by
about
50%.
Based
on
these
measurements,
retrospective
extrapolation
suggests
that
the
initial
exposure
level
may
have
been
28
mg
Mn/
L
or
higher.
Assuming
a
daily
water
intake
of
2
L,
and
an
additional
manganese
intake
from
food
of
at
least
2
mg/
day,
this
represents
a
dose
of
at
least
58
mg
Mn/
day.
This
intake
of
manganese
is
about
25
to
32
times
the
level
considered
to
be
safe
and
adequate
by
the
Food
and
Nutrition
Board
(
IOM,
2002).
Assuming
a
body
weight
of
60
kg
for
an
adult,
this
intake
level
corresponds
to
a
dose
of
0.93
mg
Mn/
kg­
day
from
drinking
water.
No
information
on
dietary
intake
was
available.

Health
effects
reported
by
Kawamura
et
al.
(
1941)
included
lethargy,
increased
muscle
tonus,
tremor
and
mental
disturbances.
Out
of
25
people
examined,
15
had
symptoms.
Five
cases
were
considered
severe,
2
cases
were
categorized
as
moderate
and
8
cases
were
described
as
mild.
The
most
severe
symptoms
were
observed
in
the
elderly.
Younger
people
were
less
affected,
and
symptoms
of
intoxication
were
absent
in
young
children
(
age
1
to
6
years).
Three
deaths
occurred,
including
one
from
suicide.
Upon
autopsy,
the
concentration
of
manganese
in
the
brain
of
one
person
was
found
to
be
2
to
3
times
higher
than
concentrations
measured
in
two
control
autopsies.
Extreme
macroscopic
and
microscopic
changes
were
seen
in
the
brain
tissue,
especially
in
the
globus
pallidus.
The
authors
also
reported
elevated
levels
of
zinc
in
the
well
water,
but
concluded
that
the
zinc
appeared
to
have
no
relation
to
the
observed
symptoms
or
tissue
pathology.
This
conclusion
was
largely
based
on
the
observation
of
morphological
changes
in
the
corpus
striatum
which
are
characteristic
of
manganese
poisoning,
but
are
not
a
feature
of
zinc
poisoning.

While
toxicity
in
the
Kawamura
et
al.
(
1941)
study
is
attributed
to
manganese,
several
aspects
of
the
observed
health
effects
are
inconsistent
with
traits
of
manganism
observed
in
humans
following
chronic
inhalation
exposure.
Inconsistencies
include
the
rapid
onset
of
symptoms
and
rapid
progression
of
the
disease.
Two
adults
who
came
to
tend
the
members
of
one
family
developed
symptoms
within
2
to
3
weeks.
The
course
of
the
disease
was
very
rapid,
progressing
in
one
case
from
initial
symptoms
to
death
in
3
days.
Some
survivors
recovered
prior
to
significant
decreases
in
the
manganese
concentration
of
the
well
water
which
resulted
when
the
batteries
that
caused
the
contamination
were
removed
from
the
site.
This
pattern
contrasts
with
the
longer
latency
period
and
irreversible
damage
caused
by
inhalation
exposure
to
manganese.
These
observations
may
represent
differences
in
the
pharmacokinetics
of
ingested
7­
4
Manganese
 
February
2003
versus
inhaled
manganese,
but
there
is
little
information
to
support
this
conclusion.
Although
these
individuals
were
clearly
exposed
to
high
levels
of
manganese,
it
is
possible
that
additional
factors
contributed
to
the
observed
effects
(
U.
S.
EPA,
1993;
ATSDR
2000).

Sensitive
Populations
Study
data
for
sensitive
populations
were
not
identified
in
the
materials
reviewed
for
preparation
of
this
document.

7.1.3
Long­
Term
and
Epidemiological
Studies
General
Populations
Kondakis
et
al.
(
1989)
conducted
an
epidemiologic
study
of
manganese
in
drinking
water
in
northwest
Greece.
Three
areas
with
different
levels
of
manganese
in
the
drinking
water
supply
were
chosen
for
this
study.
Area
A
had
manganese
concentrations
of
3.6
to
14.6
:
g/
L,
Area
B
had
concentrations
of
81.6
to
252.6
:
g/
L,
and
Area
C
had
concentrations
of
1,800
to
2,300
:
g/
L.
The
total
population
in
the
study
areas
ranged
from
3,200
to
4,350
people.
The
study
included
only
individuals
over
the
age
of
50
drawn
from
a
random
sample
of
10%
of
all
households.
The
sample
sizes
were
62,
49,
and
77
for
areas
A,
B,
and
C,
respectively.
The
study
authors
reported
that
"
all
areas
were
similar
with
respect
to
social
and
dietary
characteristics,"
but
few
details
were
provided.
Kondakis
et
al.
(
1989)
determined
whole
blood
and
hair
manganese
concentrations
in
samples
collected
from
study
participants.
The
mean
concentration
of
manganese
in
hair
was
3.51,
4.49
and
10.99
:
g/
g
dry
weight
for
areas
A,
B
and
C,
respectively.
Concentrations
in
hair
differed
significantly
between
areas
C
and
A
(
p
<
0.001).
No
significant
differences
in
whole
blood
manganese
levels
were
observed
among
the
three
areas.
However,
manganese
concentration
in
blood
is
not
considered
to
be
a
reliable
indicator
of
manganese
exposure
(
U.
S.
EPA,
1993).

Kondakis
et
al.
(
1989)
also
administered
a
neurological
examination
which
evaluated
the
presence
and
severity
of
33
symptoms
(
e.
g.,
weakness/
fatigue,
gait
disturbances,
tremors,
dystonia)
in
all
subjects.
The
results
of
the
neurological
examination
were
expressed
as
a
composite
score.
A
higher
neurological
score
indicated
an
increased
frequency
and/
or
severity
of
the
33
evaluated
symptoms.
Results
for
the
three
geographic
areas
are
summarized
in
Table
7­
1.
Mean
scores
for
both
sexes
combined
were
2.7
(
range
0
 
21)
for
Area
A;
3.9
(
range
0
 
43)
for
Area
B;
and
5.2
(
range
0
 
29)
for
Area
C.
The
authors
indicated
that
the
difference
in
mean
scores
for
Area
C
versus
Area
A
was
statistically
significant
(
Mann­
Whitney
Test,
z
=
3.16,
p
=
0.002,
for
both
sexes
combined),
suggesting
neurologic
impairment
in
people
living
in
Area
C.
In
a
subsequent
analysis,
logistic
regression
indicated
a
significant
difference
between
areas
A
and
C
when
both
age
and
sex
were
taken
into
account
(
Kondakis,
1990).
7­
5
Manganese
 
February
2003
Table
7­
1.
Mean
Neurological
Scores
of
Residents
in
Three
Areas
of
Northwest
Greece
with
Different
Levels
of
Manganese
in
Drinking
Water
(
range
is
given
in
parentheses).

Subject
Area
A
(
3.6
 
14.6
:
g
Mn/
L)
Area
B
(
81.6
 
252.6
:
g
Mn/
L)
Area
C
(
1,800
 
2,300
:
g
Mn/
L)

Males
2.4
(
0
 
21)
1.6
(
0
 
6)
4.9
(
0
 
29)

Females
3.0
(
0
 
18)
5.7
(
0
 
43)
5.5
(
0
 
21)

Both
2.7
(
0
 
21)
3.9
(
0
 
43)
5.2
(
0
 
29)

Source:
Kondakis
et
al.
(
1989)

Limitations
to
the
Kondakis
study
have
been
noted
by
ATSDR
(
2000).
These
include:
1)
lack
of
clearly
detailed
descriptions
of
neurological
signs
and
symptoms
that
reportedly
increased
following
manganese
exposure,
and
2)
failure
to
describe
procedures
for
avoiding
bias
when
evaluating
subjective
neurological
scoring
parameters.
An
additional
shortcoming
of
this
study
is
the
lack
of
quantitative
exposure
data
(
U.
S.
EPA,
1996a).
The
individuals
examined
by
Kondakis
et
al.
(
1989)
also
consumed
manganese
in
their
diet.
The
initial
estimate
of
dietary
intake
was
10
to
15
mg/
day
based
on
high
intake
of
vegetables
(
Kondakis,
1990).
This
figure
was
subsequently
revised
to
an
estimate
of
5
to
6
mg
Mn/
day
(
Kondakis,
1993),
but
data
were
not
provided
to
substantiate
this
estimate.
Lack
of
dietary
intake
and
water
consumption
data
prevents
determination
of
a
quantitative
dose­
response
relationship
for
manganese
toxicity
in
this
study.
Nevertheless,
this
study
raises
concern
for
adverse
neurological
effects
at
estimated
doses
that
are
not
far
from
the
range
of
essentiality
(
U.
S.
EPA,
1996a).

Although
conclusive
evidence
is
lacking,
some
investigators
have
linked
increased
intake
of
manganese
with
violent
behavior.
Gottschalk
et
al.
(
1991)
found
significant
increases
in
the
level
of
manganese
in
the
hair
of
convicted
felons
(
1.62
±
0.173
ppm
in
prisoners
compared
with
0.35
±
0.020
ppm
in
controls).
The
study
authors
suggested
that
"
a
combination
of
cofactors,
such
as
the
abuse
of
alcohol
or
other
chemical
substances,
as
well
as
psychosocial
factors,
acting
in
concert
with
mild
manganese
toxicity
may
promote
violent
behavior."
The
number
of
potential
variables
indicates
that
caution
should
be
exercised
in
interpretation
of
these
data.

Results
from
studies
of
an
Aboriginal
population
in
Groote
Eylandt
have
been
cited
as
additional
evidence
for
a
relationship
between
elevated
manganese
exposure,
violent
behavior,
and
adverse
health
effects.
The
soil
on
this
Australian
island
is
exceptionally
high
in
manganese
(
40,000
to
50,000
mg/
kg),
and
the
fruits
and
vegetables
grown
in
the
region
are
reported
to
contain
elevated
concentrations
of
manganese.
High
alcohol
intake,
anemia,
and
a
diet
deficient
in
zinc
and
several
vitamins
(
Florence
and
Stauber,
1989)
may
contribute
to
increased
uptake
and
retention
of
manganese.
The
proportion
of
arrests
in
this
native
population
is
the
highest
in
Australia,
and
high
incidences
of
stillbirths
and
congenital
malformations,
as
well
as
a
high
occurrence
of
Parkinson­
like
neurobehavioral
syndrome,
have
been
observed
(
Cawte
and
Florence,
1989;
Kilburn,
1987).
Clinical
symptoms
consistent
with
manganese
intoxication
are
present
in
about
1%
of
the
inhabitants.
Quantitative
data
on
oral
intake
have
not
been
reported,
7­
6
Manganese
 
February
2003
but
elevated
concentrations
of
manganese
have
been
determined
in
the
blood
and
hair
of
the
Aborigines
(
Stauber
et
al.,
1987).
However,
Stauber
et
al.
(
1987)
did
not
find
a
correlation
between
hair
levels
of
manganese
and
the
severity
of
neurological
symptoms
in
individuals.

A
study
of
the
neurologic
status
of
the
Aborigines
in
Groote
Eylandt
identified
two
general
syndromes.
One
syndrome
is
characterized
by
muscle
atrophy
and
weakness,
while
the
other
is
characterized
by
ataxia
and
oculomotor
disturbances
(
Kilburn,
1987).
Although
an
association
of
adverse
health
effects
with
elevated
manganese
exposure
is
suggested
by
these
observations,
the
small
population
of
Groote
Eylandt
and
the
difficulty
in
defining
an
appropriate
control
population
have
prevented
the
identification
of
statistically
significant
trends
(
U.
S.
EPA,
1993).

Several
of
the
studies
above
utilized
hair
analysis
as
a
method
for
estimating
exposure
to
manganese.
ATSDR
(
2000)
has
outlined
several
potential
limitations
to
the
use
of
hair
analysis.
The
normal
cycle
of
hair
growth
and
loss
restricts
its
usefulness
to
a
period
of
a
few
months
following
exposure.
External
contamination
of
hair
by
dye,
bleaching
agents,
or
other
materials
may
result
in
values
which
are
not
representative
of
absorbed
doses.
The
affinity
of
manganese
for
pigmented
tissue
may
result
in
variation
of
manganese
concentration
with
hair
color.

Goldsmith
et
al.
(
1990)
investigated
a
Parkinson's
disease
cluster
within
southern
Israel.
The
prevalence
of
the
disease
was
increased
among
persons
50
to
59
years
old,
suggesting
an
early
onset
of
the
disease.
Well
water
and
soils
in
the
region
reportedly
contained
high
levels
of
manganese,
although
no
quantitative
data
were
provided.
In
addition,
the
manganese­
containing
fungicide
Maneb
was
commonly
used
in
the
area.
However,
several
factors
limit
the
use
of
this
study
for
evaluation
of
the
human
health
effects
of
excess
manganese
exposure.
Lack
of
environmental
concentration
data
prevented
reliable
estimation
of
exposure
rates.
Potentially
confounding
factors
included
the
high
levels
of
aluminum,
iron,
and
other
metals
in
the
soil
and
water,
and
the
use
of
the
herbicide
paraquat
in
the
area
(
ATSDR,
2000).
Paraquat
is
structurally
related
to
N­
methyl­
4­
phenyl­
1,2,3,6­
tetrahydropyridine
(
MPTP),
a
piperidine
derivative
which
causes
irreversible
symptoms
of
parkinsonism
in
humans.

Vierrege
et
al.
(
1995)
investigated
the
neurological
impact
of
chronic
manganese
exposure
via
drinking
water
in
a
cross­
sectional
study
of
two
proband
cohorts
in
rural
northern
Germany.
The
study
population
was
drawn
from
the
county
Herzogtum
Lauernburg
in
the
northernmost
province
of
Germany.
This
region
is
characterized
by
agricultural
and
forestry
activities
but
no
steel
or
mining
industry.
Many
of
the
residents
of
this
area
draw
their
drinking
water
from
wells,
and
by
law,
the
well
water
is
routinely
monitored
for
chemicals
and
bacteria.
A
survey
was
conducted
in
1991
and
was
combined
with
a
cross­
sectional
investigation
of
a
randomly
selected
group
of
right­
handed
residents
aged
40
years
or
older
who
had
used
their
wells
as
the
primarily
source
of
drinking
water
for
a
minimum
of
10
years
(
range
10
to
40
years).
Complete
documentation
of
manganese
monitoring
results
for
six
years
prior
to
the
investigation
was
required
for
study
eligibility.
Participants
were
assigned
to
two
groups
on
the
basis
of
manganese
concentration
in
their
well
water.
Group
A
included
individuals
who
continually
ingested
well
water
containing
between
0.300
and
2.160
mg
Mn/
L.
Group
B
included
individuals
whose
well
water
manganese
concentration
had
never
exceeded
0.050
mg/
L.
7­
7
Manganese
 
February
2003
Detailed
information
on
medical
history,
employment
history,
diet,
alcohol
consumption,
drug
use
and
smoking
was
collected
by
interview.
Individuals
in
Group
A
were
matched
to
individuals
in
Group
B
with
respect
to
age,
sex,
nutritional
habits,
and
drug
intake.
Criteria
for
exclusion
from
the
study
included
history
of
employment
in
the
steel
industry,
adherence
to
dietary
restrictions,
history
of
CNS­
relevant
drug
use,
diabetes
mellitus,
history
of
stroke,
or
treatment
for
psychiatric
disorders.
Conditions
that
could
affect
performance
on
the
neurological
assessment
tests
(
neurorthopedic
impairment
of
hand­
finger
function
or
poor
vision)
were
also
grounds
for
exclusion
from
the
study.

A
total
of
164
eligible
subjects
was
identified.
Of
these,
49
subjects
were
excluded
for
failure
to
meet
the
health
or
water
monitoring
criteria.
Group
A
included
41
subjects
(
21
male
and
20
female)
with
a
mean
age
(
±
standard
deviation)
of
57.5
±
10.3
years
(
range
41
to
84
years).
Group
B
included
74
subjects
with
a
mean
age
of
56.9
±
11.8
years
(
range
41
to
86)
years.
No
dietary
differences
were
evident
between
the
two
groups.
Neurological
status
was
assessed
by
experienced
personnel
blinded
to
the
group
status
of
the
subjects.
Each
participant
was
evaluated
for
neurotoxicological
symptoms
by
use
of
a
modified
German
version
of
a
standardized
symptoms
list.
Signs
of
parkinsonism
were
evaluated
by
the
Columbia
University
Rating
Scale
(
CURS).
Fine
motor
ability
(
each
hand)
was
assessed
using
a
conventional
apparatus
("
Motorische
Leistungsserie,"
MLS)
and
application
of
aiming,
steadiness,
line
pursuit,
and
tapping
tests.
Manganese
status
was
evaluated
by
determination
of
manganese
in
blood.
The
concentration
of
manganese
in
hair
or
nails
was
not
determined.

The
results
of
neurological
evaluations
are
summarized
in
Table
7­
2.
There
were
no
significant
differences
between
groups
for
the
mean
item
scores
on
the
standardized
symptoms
list
or
the
CURS.
MLS
test
results
were
obtained
for
36
group
A
subjects
(
18
male
and
18
female,
mean
age
56.4
±
8.4
years,
range
41
to
72
years)
and
67
Group
B
subjects
(
35
men
and
32
women,
mean
age
55.1
±
9.9
years,
range
41
to
72
years).
Results
of
participants
older
than
72
years
were
not
included
in
the
statistical
analysis
of
MLS
data
because
normative
information
from
the
general
population
have
an
upper
age
limit
of
72
years.
No
significant
differences
were
observed
between
groups
for
any
test
when
results
were
standardized
to
age­
corrected
values.
Mean
blood
manganese
concentrations
were
8.5
±
2.3
:
g/
L
and
7.7
±
2.0
:
g/
L
for
groups
A
and
B,
respectively.
The
blood
manganese
values
did
not
differ
significantly
and
both
fell
within
the
normal
range
for
the
general
(
non­
occupationally
exposed)
population.
Separate
analyses
for
possible
confounding
factors
did
not
reveal
differences
in
clinical
or
instrumental
test
outcomes
related
to
high
or
low
consumption
of
alcohol,
mineral
water,
coffee,
tea,
tobacco,
vegetables,
or
fruit.
Where
cases
of
parkinsonism
(
n
=
3)
were
encountered
in
this
study,
they
occurred
in
the
low
exposure
group
(
Group
B)
and
were
considered
to
be
typical
Parkinson's
disease
and
thus
unrelated
to
manganese
exposure.
The
authors
of
this
study
concluded
that
there
was
no
evidence
of
an
association
between
consumption
of
high
concentrations
of
manganese
in
well
water
and
neurological
impairment
(
including
those
suggestive
of
parkinsonism).

Three
potential
limitations
related
to
the
ecologic
design
of
this
investigation
were
noted
by
Vieregge
et
al.
(
1995).
First,
the
investigators
could
not
control
for
possible
migration
of
subjects
with
manganese­
induced
neurological
disorders
from
the
study
area
prior
to
the
investigation.
However,
Vieregge
et
al.
(
1995)
stated
on
the
basis
of
inquiries
and
general
experience
in
the
region
that
a
migration
effect
was
unlikely
to
be
significant.
7­
8
Manganese
 
February
2003
Table
7­
2.
Mean
Neurological
Scores
of
Residents
in
Germany
Exposed
to
Different
Levels
of
Manganese
in
Well
Water.

Assessment
Measure
Exposure
Group
Group
A
(
High)
Group
B
(
Low)

Neurotoxicological
Symptom
Questionnaire
Item
Number
3.2
±
3.0a
3.9
±
3.1
CURS
Parkinsonism
Item
Number
1.2
±
1.0
1.7
±
2.0
MLS
Aiming
Duration
(
sec)
104.8
±
9.1b
102.9
±
10.0
MLS
Steadiness
Errors
(
number)
103.9
±
103.9
103.1
±
7.9
Duration
of
errors
(
sec)
100.8
±
10.6
100.2
±
10.5
MLS
Line
Pursuit
Errors
(
number)
106.4
±
7.6
106.6
±
8.0
Duration
of
errors
(
sec)
102.3
±
8.1
103.1
±
10.6
Total
duration
(
sec)
104.3
±
12.6
100.7
±
15.5
MLS
Tapping
Rate
(
number)
103.1
±
7.2
103.9
±
10.5
a
Mean
±
standard
deviation
b
MLS
test
results
are
for
right
hand
Second,
although
possible
confounding
by
several
dietary
items
or
groups
was
evaluated
and
found
to
be
non­
evident,
confounding
effects
of
nutrition
(
particularly
in
subjects
working
outside
their
home
residence)
could
not
be
completely
excluded.
Finally,
blood
manganese
levels
are
thought
to
primarily
reflect
current
body
burden
of
manganese
rather
than
exposure.

Iwami
et
al.
(
1994)
reported
that
the
incidence
of
motor
neuron
disease
(
MND)
in
a
small
town
in
Japan
was
positively
correlated
with
a
significantly
increased
manganese
concentration
in
local
rice
and
a
low
magnesium
concentration
in
the
drinking
water.
This
study,
however,
did
not
provide
good
estimates
of
overall
exposure
to
manganese
in
either
the
control
population
or
the
population
with
MND.

Adverse
neurological
effects
(
decreased
performance
in
school
and
in
neurobehavioral
exams
of
the
WHO
core
test
battery)
were
reported
in
11­
to
13­
year­
old
children
who
were
exposed
to
excess
manganese
through
ingestion
of
well
water
and
from
wheat
fertilized
with
sewage
water
(
He
et
al.
1994;
Zhang
et
al.
1995).
The
exposed
group
consisted
of
92
children
pair­
matched
to
92
controls
from
a
nearby
area.
The
groups
were
matched
for
age,
sex,
grade,
family
income
level,
and
parental
education
level;
further,
both
groups
lived
on
farms.
The
average
manganese
concentration
of
the
drinking
water
of
the
exposed
group
was
0.241
mg/
L
compared
to
the
control
level
of
0.04
mg/
L.
Although
the
study
authors
had
drinking
water
data
7­
9
Manganese
 
February
2003
from
a
3­
year
period,
it
was
not
clear
how
long
the
children
were
exposed
prior
to
the
study.
Further,
the
exposure
data
were
not
well­
characterized;
therefore
it
was
not
possible
to
establish
a
cause­
effect
link
between
ingestion
of
excess
manganese
and
preclinical
neurological
effects
in
children.

Sensitive
Populations
Study
data
for
sensitive
populations
were
not
identified
in
the
materials
reviewed
for
preparation
of
this
document.

7.1.4
Beneficial
Effects
Manganese
is
a
naturally­
occurring
element
that
is
required
for
normal
physiological
functioning
in
all
animal
species
(
U.
S.
EPA,
1996a).
Manganese
plays
a
role
in
bone
mineralization,
metabolic
regulation,
protein
and
energy
metabolism,
protection
of
cells
from
oxidative
stress,
and
synthesis
of
mucopolysaccharides
(
ATSDR,
2000).
Many
of
these
roles
are
achieved
by
participation
of
manganese
as
a
catalytic
or
regulatory
factor
for
enzymes,
including
hydrolases,
dehydrogenases,
kinases,
decarboxylases
and
transferases.
In
addition,
manganese
is
a
structural
component
of
the
metalloenzymes
mitochondrial
superoxide
dismutase,
pyruvate
carboxylase,
and
liver
arginase.
Additional
information
on
the
biochemical
and
nutritional
roles
of
manganese
in
human
health
is
available
in
Wedler
(
1994)
and
Keen
et
al.
(
1999).
At
present,
the
optimal
levels
of
oral
manganese
exposure
have
not
been
well
defined
for
humans
(
Greger,
1999).

Overt
signs
of
manganese
deficiency
have
been
demonstrated
in
multiple
animal
species
(
Keen
et
al.,
1999).
Biochemical
effects
observed
in
manganese­
deficient
animals
include
alterations
in
carbohydrate,
protein,
and
lipid
metabolism.
Physiological
outcomes
associated
with
deficiency
include
impaired
growth
(
Smith
et
al.,
1944),
skeletal
abnormalities
(
Amdur
et
al.,
1944;
Strause
et
al.,
1986),
impaired
reproductive
function
in
females,
and
testicular
degeneration
in
males
(
Boyer
et
al.,
1942).
The
molecular
basis
for
these
effects
has
not
been
established
with
certainty,
but
may
be
related
to
the
participation
of
manganese
in
numerous
enzymatic
reactions.
In
addition,
the
effect
of
manganese
deficiency
on
mitochondrial
superoxide
dismutase
activity
has
functional
consequences.
Manganese­
deficient
rats
experience
more
oxidation
of
mitochondrial
membranes
of
the
heart
and
more
formation
of
conjugated
dienes
than
manganese­
adequate
rats
(
Malecki
and
Greger,
1996).
In
another
study,
Gong
and
Amemiya
(
1996)
observed
ultrastructural
changes
suggestive
of
oxidative
damage
in
the
retinas,
of
rats
fed
a
manganese­
deficient
diet
for
12
to
30
months.

Manganese
is
ubiquitous
in
human
foods,
and
outright
manganese
deficiency
has
not
been
observed
in
the
general
population.
However,
observations
reported
by
Doisy
(
1973)
and
Friedman
et
al.
(
1987)
indicate
that
manganese
is
an
essential
element
for
humans.
Doisy
(
1973)
reported
a
decreased
level
of
clotting
proteins,
decreased
serum
cholesterol,
reddening
of
black
hair,
retarded
growth
of
hair
and
nails,
and
scaly
dermatitis
in
a
subject
inadvertently
deprived
of
manganese.
Friedman
et
al.
(
1987)
administered
a
manganese­
deficient
diet
to
seven
men
for
39
days.
Five
of
the
seven
subjects
exhibited
dermatitis
at
the
end
of
the
manganese­
deficient
7­
10
Manganese
 
February
2003
period.
The
development
of
dermatitis
was
attributed
to
decreased
activity
of
manganeserequiring
enzymes
that
are
required
for
skin
maintenance.
The
symptoms
cleared
rapidly
when
manganese
was
restored
to
the
diet.

7.2
Animal
Studies
This
section
presents
the
results
of
manganese
toxicity
studies
in
animals.
The
first
four
subsections
provide
study
results
by
duration
of
exposure.
In
general,
acute
studies
are
those
which
address
exposure
durations
of
24
hours
or
less.
Short­
term
studies
have
exposure
durations
greater
than
24
hours
but
less
than
approximately
90
days.
The
exposure
duration
of
subchronic
studies
is
typically
90
days,
and
chronic
studies
are
those
in
which
exposure
is
longer
than
90
days.
Some
studies
may
fall
into
more
than
one
exposure
category
since
they
measure
impacts
over
several
exposure
periods.
The
discussion
of
acute,
short­
term,
subchronic
and
chronic
studies
summarizes
observed
toxicological
effects
on
all
body
systems.
The
remaining
subsections
of
Section
7.2
provide
toxicological
data
related
to
specific
organ
systems
and
types
of
endpoints,
including
neurotoxicity,
developmental
and
reproductive
toxicity,
and
carcinogenicity.

7.2.1
Acute
Toxicity
Oral
Exposure
LD
50
values
determined
for
selected
manganese
compounds
are
summarized
in
Table
7­
3.
Oral
LD
50
values
among
the
water
soluble
manganese
compounds
ranged
from
400
to
475
mg
Mn/
kg
for
manganese
chloride,
and
from
379
to
810
mg
Mn/
kg
for
potassium
permanganate.
An
LD
50
of
836
mg
Mn/
kg
was
reported
for
manganese
acetate.

Age
may
be
a
factor
in
susceptibility
to
acute
manganese
toxicity.
Kostial
et
al.
(
1978)
found
that
MnCl
2
produced
the
greatest
oral
toxicity
in
the
youngest
and
oldest
groups.
Roth
and
Adleman
(
1975)
proposed
that
the
increased
susceptibility
of
older
rats
may
result
from
a
decrease
in
adaptive
responsiveness,
which
is
characteristic
of
the
aging
process.
Increased
susceptibility
of
younger
rats
may
reflect
high
intestinal
absorption
and
body
retention
of
manganese.

Parenteral
Exposure
Manganese
compounds
administered
by
parenteral
routes
generally
result
in
mortality
at
lower
doses.
LD
50
values
for
the
intraperitoneal
route
ranged
from
14
to
64
mg
Mn/
kg.
Franz
(
1962)
and
Bienvenu
et
al.
(
1963)
conducted
comparative
intraperitoneal
toxicity
studies,
and
found
that
manganese
is
less
toxic
than
many
other
metals.
Jonderko
(
1965)
found
increased
serum
calcium
and
decreased
inorganic
phosphorous
in
rabbits
exposed
intramuscularly
to
3.5
mg
Mn/
kg.
Details
on
the
compound
and
the
duration
of
exposure
were
not
available.
7­
11
Manganese
 
February
2003
Table
7­
3.
LD
50
Values
for
Manganese
Compounds.

Compound
Species
Route
LD
50
(
mg
Mn/
kg)
Reference
Manganese
acetate
rat
oral
836
Smyth
et
al.
(
1969)

Manganese
chloride
rat
oral
425
Shigan
and
Vitvickaja
(
1971)

rat
oral
475
Kostial
et
al.
(
1978)

rat
oral
410
Holbrook
et
al.
(
1975)

mouse
oral
450
Shigan
and
Vitvickaja
(
1971)

guinea
pig
oral
400
Shigan
and
Vitvickaja
(
1971)

rat
i.
p.
38
Franz
(
1962);
Holbrook
et
al.
(
1975)

mouse
i.
p.
56
Franz
(
1962);
Holbrook
et
al.
(
1975)

mouse
i.
v.
16
Larsen
and
Grant
(
1997)

Manganese
dioxide
rat
oral
2,197
Holbrook
et
al.
(
1975)

Manganese
sulfate
mouse
i.
p.
44
Bienvenu
et
al.
(
1963)

Manganese
sulfate,
tetrahydrate
mouse
i.
p.
64
Yamamoto
and
Suzuki
(
1969)

Manganese
nitrate
mouse
i.
p.
56
Yamamoto
and
Suzuki
(
1969)

Methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
rat
oral
10
Hanzlik
et
al.
(
1980)

rat
oral
12
Hinderer
(
1979)

rat
oral
12
Hysell
et
al.
(
1974)

mouse
oral
48
Hinderer
(
1979)

Potassium
permanganate
mouse
oral
750
Shigan
and
Vitvickaja
(
1971)

rat
oral
379
Smyth
et
al.
(
1969)

rat
oral
750
Shigan
and
Vitvickaja
(
1971)

guinea
pig
oral
810
Shigan
and
Vitvickaja
(
1971)

i.
p.
=
intraperitoneal
i.
v.
=
intravenous
7­
12
Manganese
 
February
2003
Baxter
et
al.
(
1965)
measured
physiological
parameters
in
manganese­
treated
rats
weighing
100
to
550
g.
Measurements
were
made
1
to
72
hours
after
subcutaneous
administration
of
5
to
150
mg
of
manganese
as
MnCl
2
in
saline.
Levels
of
hemoglobin,
hematocrit,
and
mean
corpuscular
volume
were
significantly
increased
in
rats
receiving
150
mg
Mn/
kg.
A
measurable
response
in
these
parameters
occurred
at
50
mg
Mn/
kg,
while
the
peak
increase
in
these
parameters
occurred
at
12
and
18
hours
after
dosing.
The
maximum
response
occurred
at
170
to
300
mg
Mn/
kg.
Necrotic
changes
were
noted
in
hepatic
tissue
18
hours
after
a
single
dose
of
170
mg
Mn/
kg.

Pancreatic
endocrine
function
is
affected
by
acute
manganese
exposure.
Baly
et
al.
(
1985)
injected
rats
intraperitoneally
with
40
mg
Mn/
kg.
Manganese
injection
resulted
in
a
decrease
in
plasma
insulin
levels,
an
increase
in
plasma
glucose
levels,
and
a
transitory
increase
in
glucagon
concentration.

Larsen
and
Grant
(
1997)
administered
a
single
intravenous
dose
of
150,
200,
300,
or
400
:
mol/
kg
manganese
chloride
in
saline
to
male
mice
(
5/
group).
These
doses
correspond
to
8.2,
11,
16,
and
22
mg
Mn/
kg,
respectively.
These
study
authors
reported
an
LD
50
value
of
300
:
mol/
kg
(
16
mg
Mn/
kg).

7.2.2
Short­
Term
Studies
Oral
Exposure
Matrone
et
al.
(
1959)
orally
administered
2,000
ppm
manganese
as
MnSO
4
CH
2
O
to
6­
month­
old
anemic
rabbits
for
6
weeks.
The
investigators
also
administered
125
ppm
Mn
as
MnSO
4
CH
2
O
to
anemic
newborn
pigs
for
27
days.
In
each
case,
the
investigators
observed
decreased
hemoglobin
content
in
the
blood
of
treated
animals.
Hemoglobin
depression
in
baby
pigs
fed
up
to
2,000
ppm
manganese
was
overcome
by
a
dietary
supplement
of
400
ppm
iron.

Kimura
et
al.
(
1978)
provided
rats
with
diets
supplemented
with
564
mg/
kg
of
manganese
as
MnCl
2
for
3
weeks.
Assuming
a
food
consumption
factor
of
0.05
above
the
dietary
background,
this
corresponds
to
a
daily
dose
of
28
mg
Mn/
kg­
day.
The
study
authors
reported
that
brain
serotonin
levels
were
decreased
in
manganese­
treated
rats.
Monoamine
oxidase
activity
was
unchanged,
but
L­
amino­
acid
decarboxylase
activity
in
the
brain
was
decreased
by
manganese
treatment.
Histopathological
analysis
of
the
brain
was
not
conducted.
Blood
serotonin
levels
were
increased
in
treated
rats,
and
this
change
was
accompanied
by
decreased
blood
pressure.

Shukla
et
al.
(
1978)
administered
a
dose
of
16
mg
MnCl
2
C4H
2
O/
kg
(
4.4
mg
Mn/
kg)
in
drinking
water
(
dose
calculated
by
investigators)
to
rats
for
30
days
and
evaluated
the
effect
on
hepatic
enzyme
activity.
Treated
rats
revealed
significantly
decreased
succinic
dehydrogenase,
alcohol
dehydrogenase,
and
$­
amylase
activity
when
compared
with
controls.
In
contrast,
manganese
exposure
resulted
in
significantly
increased
activities
of
monoamine
oxidase
(
MAO),
adenosine
triphosphatase,
arginase,
glutamate­
pyruvate
transaminase
(=
alanine
7­
13
Manganese
 
February
2003
aminotransferase,
or
ALT),
ribonuclease,
glucose­
6­
phosphatase,
and
"­
amylase
activity
in
the
livers
of
treated
rats.

Hietanen
et
al.
(
1981)
also
studied
the
effect
of
manganese
on
hepatic
and
extrahepatic
enzyme
activities.
Male
Wistar
rats
were
exposed
to
0.5%
Mn
(
as
MnCl
2)
in
the
drinking
water
for
1,
4,
or
6
weeks.
Assuming
an
average
body
weight
of
0.35
kg
and
average
water
consumption
of
0.049
L/
day
(
U.
S.
EPA,
1986d),
this
corresponds
to
an
exposure
of
0.7
mg
Mn/
kg­
day.
Changes
in
the
activity
of
several
enzymes,
including
aryl
hydrocarbon
hydroxylase,
ethoxycoumarin
O­
deethylase,
and
epoxide
hydrase,
were
observed
at
1
week
but
not
at
6
weeks.
Enzyme
activities
were
increased
in
the
liver,
and
decreased
in
the
intestines
and
kidney.

In
a
14­
day
oral
exposure
study,
NTP
(
1993)
administered
diets
containing
0,
3,130,
6,250,
12,500,
25,000,
or
50,000
ppm
manganese
sulfate
monohydrate
to
F344
rats
(
5/
sex/
dose).
All
rats
survived
the
exposure
period.
Statistically
significant
differences
in
manganese­
treated
rats
included
reduced
body
weight
gain
(
57%
decrease)
and
final
body
weight
(
13%
decrease)
in
the
high­
dose
males
when
compared
to
the
control
group.
Decreased
leukocyte
and
neutrophil
counts
and
reduced
liver
weight
were
observed
in
high­
dose
males
and
females.
The
high­
dose
groups
also
exhibited
diarrhea
during
the
second
week
of
the
study.
Manganese
concentrations
in
the
livers
of
animals
receiving
the
50,000
ppm
diet
were
more
than
twice
those
of
the
controls.
The
NOAEL
and
LOAEL
values
based
on
decreased
weight
gain
(
males)
and
hematological
changes
were
approximately
650
and
1,300
mg
Mn/
kg­
day,
respectively.

NTP
(
1993)
also
administered
diets
containing
0,
3,130,
6,250,
12,500,
25,000,
or
50,000
ppm
manganese
sulfate
monohydrate
to
B6C3F
1
mice
(
5/
sex/
dose)
for
14
days.
However,
study
animals
were
poorly
randomized
at
the
beginning
of
the
study,
and
no
effects
clearly
attributable
to
manganese
exposure
were
identified.

Parenteral
Exposure
Singh
et
al.
(
1974;
1975)
administered
6
mg
Mn/
kg­
day
(
as
MnSO
4°
4H
2
O)
intraperitoneally
to
male
IRTC
rats
for
25
days.
Histopathological
analysis
of
the
livers
revealed
mild
congestion
of
central
veins
and
sinusoids,
and
some
focal
necrosis
in
treated
animals.

Scheuhammer
and
Cherian
(
1983)
reported
toxic
effects
in
the
pancreas
resulting
from
intraperitoneally
injected
manganese.
The
exposure
duration
was
30
days.
Adverse
effects
included
a
pancreatitis­
like
reaction.
The
authors
suggested
that
this
reaction
was
potentiated
by
the
presence
of
manganese
in
the
peritoneal
cavity,
and
would
not
occur
as
readily
with
manganese
administered
by
the
oral
route.

Khandelwal
et
al.
(
1984)
administered
6
mg
Mn/
kg­
day
(
as
MnCl
2°
4H
2
O)
intraperitoneally
to
male
IRTC
rats
for
28
days.
Activity
of
succinic
dehydrogenase
and
cytochrome
oxidase
in
liver
tissue
were
decreased
after
28
days
of
manganese
treatment.

Khan
et
al.
(
1997)
administered
16
mg/
kg­
day
MnCl
2°
4H
2
O
in
saline
intravenously
to
male
beagle
dogs
(
3/
group).
Treatment
duration
was
up
to
4
hours/
day
for
4
days.
Two
of
the
three
dosed
animals
were
in
moribund
condition,
and
were
sacrificed
for
ethical
reasons
(
one
on
7­
14
Manganese
 
February
2003
day
3
and
one
on
day
4).
The
third
treated
dog
died
on
day
4.
Symptoms
prior
to
death
included
vomiting,
diarrhea,
tremors,
lethargy,
reduced
food
intake,
reduced
blood
pressure
with
reflex
tachycardia,
and
severe
hepatotoxicity.

7.2.3
Subchronic
Studies
Oral
Exposure
Mitochondria­
rich
organs,
such
as
the
liver
and
pancreas,
are
hypothesized
to
be
most
affected
by
excess
manganese
exposure.
Wassermann
and
Wassermann
(
1977)
reported
ultrastructural
changes
of
the
liver
cells
in
rats
exposed
to
200
mg/
L
of
manganese
chloride
in
their
drinking
water
for
10
weeks.
Assuming
water
consumption
of
0.049
L/
day
and
an
average
body
weight
of
0.35
kg
(
U.
S.
EPA,
1986d),
this
level
of
exposure
corresponds
to
an
average
daily
dose
of
approximately
12
mg
Mn/
kg­
day.
Increased
metabolic
activity
was
inferred
from
an
increased
amount
of
rough
endoplasmic
reticulum,
the
occurrence
of
multiple
rough
endoplasmic
cisternae
and
prominent
Golgi
apparatus,
and
large
Golgi
vesicles
filled
with
osmiophilic
particles
in
the
biliary
area
of
the
liver
cell.
The
authors
attributed
this
apparent
increase
in
metabolic
activity
to
biochemical
processes
related
to
the
nutritional
requirement
for
manganese,
and
homeostatic
processes
triggered
by
increased
exposure.
They
noted
that
other
observed
liver
effects,
including
the
presence
of
glycogenosomes
in
the
biliary
area,
groups
of
collagen
fibers
in
the
Disse's
spaces,
and
degenerative
changes
in
some
centrilobular
liver
cells,
may
either
be
direct
toxic
phenomena
or
secondary
responses
to
the
effect
exerted
by
manganese
on
other
target
tissues.
ATSDR
(
2000)
evaluated
these
data
and
designated
12
mg
Mn/
kg­
day
as
the
NOAEL
in
this
study.

Carter
et
al.
(
1980)
exposed
young,
iron­
deficient
rats
to
400
to
3,550
ppm
Mn
as
Mn
3
O
4
for
32
weeks
(
route
not
specified).
Manganese
treatment
resulted
in
decreased
hemoglobin
levels.

Leung
et
al.
(
1982)
administered
1,000,
10,000,
or
20,000
mg
MnCl
2°
4H
2
O/
L
in
drinking
water
to
female
Wistar
rats.
Exposure
was
initiated
at
conception
by
administration
of
manganese­
containing
drinking
water
to
the
dams,
and
continued
through
age
60
days.
The
estimated
doses
were
38.9,
389,
and
778
mg
Mn/
kg­
day
(
U.
S.
EPA,
1993).
Treated
rats
exhibited
liver
necrosis
and
ultrastructural
alterations
that
resembled
human
cholestasis.
A
LOAEL
of
38.9
mg
Mn/
kg­
day
was
identified
in
this
study
based
on
hepatic
necrosis.

In
a
13­
week
study,
NTP
(
1993)
administered
diets
containing
0,
1,600,
3,130,
6,250,
12,500,
or
25,000
mg/
kg
manganese
sulfate
monohydrate
above
basal
levels
to
F344
rats
(
10/
sex/
dose).
The
concentration
of
manganese
in
the
control
diets
was
approximately
92
mg/
kg.
Mean
daily
intake
of
manganese
sulfate
monohydrate
ranged
from
98
mg/
kg­
day
(
32
mg
Mn/
kgday
for
the
low­
dose
to
1,669
mg/
kg­
day
(
542
mg
Mn/
kg­
day)
for
the
high­
dose
males.
For
females,
the
range
was
114
mg/
kg­
day
(
37
)
for
the
low­
dose
group
and
1,911
mg/
kg­
day
(
621
mg
Mn/
kg­
day)
for
the
high­
dose
group.
No
rats
died
during
the
study,
and
no
clinical
or
histopathology
findings
were
attributed
to
manganese
exposure.
Females
receiving
diets
with
$
6,250
mg/
kg
manganese
sulfate
experienced
decreased
body
weight
gain.
Absolute
and
relative
liver
weights
were
decreased
in
males
receiving
diets
with
$
1,600
mg/
kg,
and
in
7­
15
Manganese
 
February
2003
females
in
the
highest
dose
group
only.
Hematological
effects
were
also
reported.
All
groups
of
exposed
males
exhibited
a
significantly
increased
neutrophil
count.
Lymphocyte
counts
were
decreased
in
males
receiving
$
6,250
mg/
kg
in
the
diet
and
females
in
the
three
highest
dose
groups.
The
low
dose
of
1,600
mg/
kg
(
about
32
mg
Mn/
kg­
day)
was
identified
as
the
LOAEL
for
this
study,
based
on
effects
on
liver
weight
and
neutrophil
counts
in
male
rats.

In
a
concurrent
13­
week
study,
NTP
(
1993)
administered
diets
containing
0,
3,130,
6,250,
12,500,
25,000,
or
50,000
mg/
kg
manganese
sulfate
monohydrate
above
basal
levels
to
B6C3F
1
mice
(
10/
sex/
dose).
The
concentration
of
manganese
in
the
control
diets
was
approximately
92
mg/
kg.
Mean
daily
intake
of
manganese
sulfate
monohydrate
ranged
from
328
mg/
kg­
day
(
107
mg
Mn/
kg­
day)
for
the
low­
dose
to
8,450
mg/
kg­
day
(
2,746
mg
Mn/
kg­
day)
for
the
high­
dose
group.
No
deaths
were
attributed
to
manganese
exposure.
All
groups
of
male
mice
and
female
mice
in
the
highest
dose
group
exhibited
significantly
decreased
body
weight
gain.
Relative
and
absolute
liver
weights
were
decreased
in
males
in
the
highest
dose
group.
Both
sexes
receiving
the
50,000
mg
Mn/
kg
diet
exhibited
decreased
hematocrit
and
hemoglobin
concentration.
The
NTP
report
suggests
that
these
findings
may
indicate
microcytic
anemia,
which
may
have
resulted
from
a
sequestration
or
deficiency
of
iron.
Males
receiving
$
25,000
ppm
also
exhibited
significantly
lower
leukocyte
counts,
although
this
finding
was
of
questionable
relevance
to
manganese
exposure.
No
clinical
findings
were
attributed
to
manganese
exposure.
The
LOAEL
for
this
study
was
3,130
mg/
kg­
day
(
107
mg
Mn/
kg­
day),
based
on
significantly
decreased
body
weight
gain
in
male
mice.

Komura
and
Sakamoto
(
1991)
supplemented
mouse
diets
with
different
chemical
forms
of
manganese.
Male
mice
(
8/
group)
were
exposed
either
to
a
control
diet
containing
130
mg
Mn/
kg,
or
a
diet
supplemented
with
an
additional
2,000
mg
Mn/
kg
as
MnCl
2°
4H
2
O,
Mn(
CH
3
COO)
2°
4H
2
O,
MnCO
3,
or
MnO
2.
Assuming
an
average
food
consumption
of
13%
of
body
weight,
the
average
daily
dose
from
the
control
diet
was
approximately
17
mg
Mn/
kg­
day,
while
the
average
daily
dose
from
the
manganese
enriched
diet
was
276
mg
Mn/
kg­
day.
The
duration
of
treatment
was
100
days.
The
mice
were
tested
for
spontaneous
motor
activity
after
30
days.
Blood
and
tissues
were
analyzed
at
the
termination
of
the
experiment.
No
significant
difference
in
food
intake
among
groups
was
seen.
Body
weight
gain
and
red
and
white
blood
cell
count
was
decreased
in
groups
that
received
Mn(
CH
3
COO)
2°
4H
2
O
or
MnCl
2.
Motor
activity
was
reduced
in
the
MnCO
3
group.
Tissue
manganese
concentrations
in
groups
receiving
supplemental
manganese
was
2
to
3
times
that
of
controls.
A
LOAEL
of
276
mg
Mn/
kg­
day
was
identified
in
this
study
based
on
decreased
weight
gain
and
hematological
effects.

Parenteral
Exposure
Suzuki
et
al.
(
1975)
administered
250,
500,
or
1,000
mg
of
MnO
2
in
saline
to
monkeys
(
Macaca
mullata)
by
subcutaneous
injection.
Injections
were
given
once
a
week
for
9
weeks.
The
study
authors
reported
a
body
weight
of
4
kg
for
monkeys
used
in
the
study.
Estimated
timeaveraged
doses
correspond
to
5.6,
11,
and
23
mg
Mn/
kg­
day.
At
autopsy,
manganese­
treated
monkeys
had
irregular
arrangement
of
hepatic
cords
and
lymphocytic
infiltration.

7.2.4
Neurotoxicity
7­
16
Manganese
 
February
2003
Occupational
studies
of
miners,
industrial
workers,
and
agricultural
workers
have
established
injury
to
the
central
nervous
system
as
the
chief
health
effect
associated
with
inhalation
exposure
to
manganese.
High
level
exposure
by
this
pathway
typically
results
in
a
suite
of
neurological
effects
collectively
termed
manganism.
Chronic
manganism
associated
with
inhalation
exposure
is
characterized
by
an
extrapyramidal
syndrome
with
symptoms
that
are
somewhat
similar
to
those
observed
in
Parkinson's
disease.
One
characteristic
difference
is
the
"
cock­
walk"
of
the
manganism
patient,
in
which
the
patient
walks
on
his
toes
with
his
spine
erect
and
elbows
flexed.
Further,
manganism
patients
do
not
often
exhibit
the
"
resting
tremor"
that
Parkinson's
patients
do,
and
they
have
a
propensity
for
losing
their
balance
and
falling
backwards.
The
clinical
course
of
manganism
occurs
in
three
phases:
an
initial
phase
of
subjective
and
nonspecific
symptoms;
an
intermediate
phase
of
evolving
neurological
symptoms
related
to
speech,
dexterity,
facial
expression,
and
movement;
and
an
established
phase
characterized
by
persistent,
often
irreversible
neurological
deficits
(
Chang,
1996).
While
MRI
scans
of
the
brains
of
humans
and
non­
human
primates
exposed
to
excess
manganese
indicate
that
the
metal
deposits
in
the
globus
pallidus
and
to
a
lesser
extent
in
the
substantia
nigra,
degenerative
lesions
are
limited
to
the
globus
pallidus
(
Calne
et
al.,
1994).
An
important
question
in
the
evaluation
of
health
effects
associated
with
manganese
in
drinking
water
is
whether
similar
neurotoxicological
effects
occur
following
exposure
by
the
oral
route.

Oral
Exposure
studies
of
the
neurotoxic
effects
of
manganese
exposure.
A
single
study
exists
for
evaluation
of
manganese
exposure
in
primates
by
the
oral
route.
Gupta
et
al.
(
1980)
administered
25
mg
MnCl
2
C4H
2
O/
kg
orally
to
four
male
rhesus
monkeys
daily
for
18
months.
This
level
is
equivalent
to
an
average
daily
dose
of
6.9
mg
Mn/
kg­
day.
Animals
were
maintained
on
monkey
pellets,
two
bananas/
day,
and
tap
water.
The
monkeys
developed
muscular
weakness
and
rigidity
of
the
lower
limbs.
Histological
analysis
revealed
degenerated
neurons
in
the
substantia
nigra
and
scanty
neuromelanin
granules
in
some
of
the
pigmented
cells.

Bonilla
and
Diez­
Ewald
(
1974)
noted
that
chronic
exposure
of
rats
to
manganese
chloride
produces
a
marked
decrease
in
brain
biogenic
amines,
particularly
dopamine.

Singh
et
al.
(
1979)
administered
manganese
(
16
mg/
kg
in
a
10%
sucrose
solution)
alone
or
in
combination
with
ethanol
to
groups
of
20
male
albino
rats
for
30
days.
Exposure
to
manganese
alone
led
to
a
72%
increase
in
manganese
concentration
in
the
brain
(
3.13
:
g/
g
dry
weight
versus
1.82
:
g/
g
for
controls).
This
outcome
was
not
altered
by
ethanol
exposure.
There
were
no
morphologic
changes
in
the
brain
tissue
of
any
group.
Significant
alterations
in
activity
were
reported
for
several
brain
enzymes.
Manganese
exposure
resulted
in
significant
increases
in
monoamine
oxidase
(
p
<
0.001),
adenosine
triphosphatase
(
p
<
0.001),
ribonuclease
(
p
<
0.001),
and
glutamate­
oxaloacetate
transaminase
(=
aspartate
aminotransferase,
or
AST;
p
<
0.001).
Significant
decreases
were
observed
for
succinic
dehydrogenase
(
p
<
0.02
and
deoxyribonuclease
(
p
<
0.001).
Concurrent
exposure
to
ethanol
resulted
in
a
synergistic
effect
with
some
7­
17
Manganese
 
February
2003
Table
7­
4.
Neurological
Effects
of
Oral
Exposure
to
Manganese.

Species
Compound
Route
Dose
Duration
CNS
Effects
Reference
Behavioral
Histological
Biochemical
Mouse
MnCl
2
drinking
water
3
:
g
MnCl
2/
mL
6
months
+
NS
+
Chandra
et
al.
(
1979)

Mouse
MnCl
2
diet
1%
MnCl
2
(
1
month),

4%
MnCl
2
(
5
months)
6
months
NS
NS
+
Gianutsos
and
Murray
(
1982)

Mouse
MnO
2
diet
1
mg
MnO
2/
g
7.5
months
­
NS
NS
Morganti
et
al.
(
1985)

Rat
MnCl
2
drinking
water
5
mg
MnCl
2/
mL
7
months
NS
NS
+
Bonilla
and
Diez­
Ewald
(
1974)

Rat
MnCl
2
gavage
1,
10,
20
mg
Mn/
kg­
day
Birth
 
24
days
old
NS
NS
+
Deskin
et
al.
(
1980)

Rat
MnCl
2
!
4H
2
O
gavage
10,
15,
20
mg
Mn/
kg­
day
Birth
 
24
days
old
NS
NS
+
Deskin
et
al.
(
1981)

Rat
MnCl
2
!
4H
2
O
drinking
water
1
mg
MnCl
2
!
4H
2
O/
mL
12
months
+
NS
+
Chandra
and
Shukla
(
1981)

Rat
MnCl
2
!
4H
2
O
drinking
water
1
mg
MnCl
2
!
4H
2
O/
mL
28
months
NS
NS
+
Leung
et
al.
(
1981)

Rat
MnCl
2
!
4H
2
O
drinking
water
1
mg
MnCl
2
!
4H
2
O/
mL
over
2
years
NS
NS
+
Lai
et
al.
(
1981)

Rat
MnCl
2
!
4H
2
O
drinking
water
1
mg
MnCl
2
!
4H
2
O/
mL
4
months
NS
­
+
Lai
et
al.
(
1982a)

Rat
MnCl
2
gavage
150
mg
Mn/
kg
42
days
+
NS
+
Kristensson
et
al.
(
1986)
Table
7­
4
(
continued)

Species
Compound
Route
Dose
Duration
CNS
Effects
Reference
Behavioral
Histological
Biochemical
7­
18
Manganese
 
February
2003
Rat
MnCl
2
!
4H
2
O
drinking
water
1
mg
MnCl
2
!
4H
2
O/
mL
65
weeks
+
NS
NS
Nachtman
et
al.
(
1986)

Rat
MnCl
2
!
4H
2
O
drinking
water
4,360
mg
Mn/
L
60
 
265
days
NS
NS
+
Eriksson
et
al.
(
1987)

Rat
MnCl
2
gavage
25,
50
mg
MnCl
2
!
4H
2
O
/
kg­
day
14
or
21
days
NS
NS
+
Kontur
and
Fechter
(
1988)

Rat
MnCl
2
!
4H
2
O
gavage
0.357
Mn
mg/
kg­
day
30
days
+
NS
NS
Oner
and
Senturk
(
1995)

Rat
Not
specified
10%
sucrose
16
Mn
mg/
kg
30
days
NS
NS
+
Singh
et
al.
(
1979)

Monkey
MnCl
2
!
4H
2
O
diet
25
mg
MnCl
2
!
4H
2
O/
kg
18
months
+
+
NS
Gupta
et
al.
(
1980)

Notes:
NS
=
Not
studied
Source:
U.
S.
EPA,
1993
7­
19
Manganese
 
February
2003
enzymes
and
an
antagonistic
effect
with
others.
No
mechanism
was
proposed
to
explain
the
pattern
observed
in
the
presence
of
ethanol.

Chandra
et
al.
(
1979)
evaluated
the
neurological
effects
of
manganese
in
mice
exposed
from
birth.
Neonatal
mice
were
initially
exposed
by
nursing
from
dams
given
5
mg/
mL
MnCl
2
in
their
drinking
water.
After
weaning
at
25
days,
the
mice
received
manganese
in
their
drinking
water.
Average
exposures
to
manganese
were
determined
to
be
0.030
mg
Mn/
day
for
60
days,
0.036
mg
Mn/
day
through
the
90th
day,
0.075
mg
Mn/
day
through
the
120th
day
and
0.090
mg
Mn/
day
for
the
interval
between
150
and
180
days.
Assuming
a
body
weight
of
0.03
kg
at
adulthood,
the
average
daily
dose
at
the
termination
of
the
experiment
was
approximately
3
mg
Mn/
kg­
day.
Elevated
levels
of
striatal
dopamine,
norepinephrine,
and
homovanillic
acid
were
observed
at
60
and
90
days
of
age,
with
a
concomitant
increase
in
spontaneous
locomotor
activity.
Exposure
past
90
days
did
not
influence
motor
activity.
Chandra
et
al.
(
1979)
proposed
that
the
hyperactivity
observed
in
these
mice
was
an
early
behavioral
effect
of
excess
manganese
exposure
that
resulted
from
elevated
dopamine
and
norepinephrine
levels.
The
study
authors
further
suggested
that
the
observed
hyperactivity
may
be
comparable
to
the
psychomotor
excitement
observed
in
the
early
stages
of
human
manganism.

Gray
and
Laskey
(
1980)
found
that
dietary
exposure
to
1,100
mg/
kg
manganese
(
as
Mn
3
O
4)
in
rats
for
2
months
produced
only
reduced
reactive
locomotor
activity.
Assuming
a
body
weight
of
0.35
kg,
this
level
of
exposure
corresponds
to
an
average
daily
dose
of
55
mg
Mn/
kg­
day.
Deskin
et
al.
(
1980)
studied
neurochemical
alteration
induced
by
manganese
chloride
in
neonatal
CD
rats.
Rats
were
intubated
with
daily
doses
of
1,
10,
or
20
mg
Mn/
kg­
day
from
birth
to
24
days
old.
Neurochemical
components
were
subsequently
analyzed
in
the
hypothalamus
and
corpus
striatum.
Administration
of
10
and
20
mg
Mn/
kg­
day
resulted
in
significantly
elevated
manganese
concentrations
in
both
regions,
but
neurochemical
alterations
were
observed
only
in
the
hypothalamus.
These
alterations
included
a
decrease
in
dopamine
concentration
and
turnover.
The
highest
dose
of
manganese
also
resulted
in
a
significant
decrease
in
hypothalamic
tyrosine
hydroxylase
activity,
and
an
increase
in
monoamine
oxidase
activity.
Visible
signs
of
toxicity
were
not
observed
in
any
group.

Deskin
et
al.
(
1981)
intubated
rats
with
daily
doses
of
10,
15
or
20
mg
Mn/
kg­
day
(
as
MnCl
2
C4H
2
O)
from
birth
to
24
days
old.
The
authors
reported
a
significant
elevation
of
serotonin
levels
in
the
hypothalamus,
but
not
the
striatum,
following
exposure
to
20
mg
Mn/
kg.

Chandra
and
Shukla
(
1981)
exposed
male
albino
rats
to
1,000
mg/
L
MnCl
2°
4H
2
O
(
436
mg
Mn/
L)
in
drinking
water.
Assuming
water
consumption
of
0.049
L/
day
and
an
average
adult
body
weight
of
0.35
kg,
this
level
of
exposure
corresponds
to
an
average
daily
dose
of
61
mg
Mn/
kg­
day.
Levels
of
catecholamines,
homovanillic
acid,
manganese,
and
the
activity
of
monoamine
oxidase
were
determined
in
the
corpus
striatum
at
time
intervals
up
to
360
days.
The
investigators
found
initial
increases
in
dopamine,
norepinephrine,
and
homovanillic
acid
levels.
This
initial
increase
was
followed
by
a
period
of
normal
levels.
After
300
days,
a
decrease
in
all
levels
was
observed.
These
changes
were
not
correlated
with
the
tissue
concentration
of
manganese.
The
authors
suggested
that
the
decreased
locomotor
activity
observed
during
later
periods
of
manganese
exposure
may
be
related
to
lowered
dopamine
and
norepinephrine
levels
in
the
brain,
and
that
this
stage
of
chronic
toxicity
may
correspond
to
the
later
neurologic
phase
of
7­
20
Manganese
 
February
2003
motor
dyskinesia
in
humans.
Ali
et
al.
(
1981)
conducted
concurrent
behavioral
studies,
and
found
an
initial
increase
in
spontaneous
locomotor
activity
followed
by
a
decrease
during
later
periods
of
manganese
exposure.

Lai
et
al.
(
1981)
exposed
female
Wistar
rats
to
1,000
mg/
L
MnC1
2
C4H
2
0
(
280
mg
Mn/
L)
in
drinking
water.
Exposure
was
initiated
at
mating.
Pups
were
exposed
in
utero
by
administration
of
manganese
in
drinking
water
to
dams
via
maternal
milk
during
nursing,
and
by
inclusion
in
drinking
water
after
weaning.
Groups
of
rats
were
exposed
to
manganese
for
over
2
years
and
were
either
2
months
or
24
to
28
months
of
age
at
examination.
Assuming
a
body
weight
of
0.35
kg
and
water
consumption
of
0.049
L/
day,
the
average
daily
dose
for
rats
at
adulthood
was
approximately
39
mg
Mn/
kg­
day.
The
brains
were
dissected
and
analyzed
for
activity
of
glutamic
acid
decarboxylase
(
GAD),
choline
acetyltransferase
(
ChAT),
and
acetylcholinesterase
(
AChE).
GAD,
ChAT,
and
AChE
are
neurochemical
markers
for
the
GABA
and
cholinergic
systems,
and
had
previously
been
implicated
in
manganese
toxicity
(
Sitaramayya
et
al.,
1974;
Bonilla,
1978a,
b).
Adverse
effects
of
chronic
manganese
exposure
on
the
activity
of
GAD,
ChAT,
or
AChE
were
not
apparent
in
2­
month­
old
rats.
The
study
authors
reported
that
lifetime
exposure
to
manganese
produced
effects
that
counteracted
age­
related
decreases
in
GAD,
ChAT,
and
AChE.

Leung
et
al.
(
1981)
analyzed
the
same
groups
of
rats
used
by
Lai
et
al.
(
1981)
for
monoamine
oxidase
(
MAO)
activity.
MAO
is
a
key
enzyme
in
oxidative
degradation
of
neurotransmitter
amines.
The
only
effect
observed
following
exposure
of
2­
month­
old
rats
to
manganese
was
a
small
decrease
in
the
neurotransmitter
serotonin
in
the
cerebellum.
No
significant
differences
were
observed
in
manganese­
treated
24­
to
28­
month­
old
rats.

Lai
et
al.
(
1982a)
examined
the
effects
of
manganese
exposure
on
male
Wistar
rats.
The
rats
were
initially
exposed
to
manganese
in
utero.
Following
weaning,
the
rats
were
exposed
to
1,000
mg
MnCl
2
C4H
2
O/
L
(
280
mg
Mn/
L)
in
drinking
water
for
either
70
to
90
days
or
100
to
120
days
after
birth.
Assuming
an
adult
weight
of
0.35
kg,
and
water
consumption
of
0.049
L/
day,
this
level
corresponds
to
a
dose
of
approximately
39
mg
Mn/
kg­
day.
Levels
of
dopamine,
noradrenaline,
serotonin,
and
choline
were
determined.
A
significant
decrease
was
seen
in
the
uptake
of
dopamine
by
synaptosomes
isolated
from
the
hypothalamus,
striatum
and
midbrain
in
70­
to
90­
day­
old
rats.
No
effect
was
observed
in
the
100­
to
120­
day­
old
rats.
Choline
levels
were
higher
in
70­
to
90­
day­
old­
exposed
rats
and
lower
in
100­
to
120­
day­
old­
exposed
rats
when
compared
with
controls.
The
authors
suggested
that
this
finding
may
reflect
involvement
of
both
the
dopaminergic
and
cholinergic
systems
in
manganese
toxicity.
They
concluded
that,
although
the
rat
may
not
serve
as
an
ideal
model
for
understanding
the
neurotoxic
effects
of
manganese,
neurochemical
effects
are
discernible
when
analyses
are
made
at
the
appropriate
period.

Lai
et
al.
(
1982b)
investigated
the
effect
of
manganese
exposure
on
the
developmental
profile
of
acetylcholinesterase
activity
in
different
regions
of
the
brain.
Female
Wistar
rats
were
exposed
to
manganese
chloride
tetrahydrate
provided
in
drinking
water
at
a
concentration
of
1,000
mg/
L.
Exposure
was
initiated
at
conception.
Male
offspring
were
weaned
onto
drinking
water
containing
1,000
mg/
L
manganese
chloride
tetrahydrate
and
exposed
for
up
to
60
days.
Enzyme
activity
in
the
cerebral
cortex,
striatum,
midbrain,
pons
and
medulla,
hypothalamus,
and
7­
21
Manganese
 
February
2003
cerebellum
was
determined
at
5,
12,
20,
30,
and
60
days
after
birth.
The
developmental
profile
of
the
enzyme
differed
in
the
various
regions.
Activity
was
detected
earlier
in
the
more
caudal
regions,
except
in
the
cerebellum
where
there
was
no
increase.
Exposure
to
manganese
from
conception
did
not
influence
the
developmental
profile
of
acetylcholinesterase
activity.

Gianutsos
and
Murray
(
1982)
studied
changes
in
the
concentrations
of
dopamine
and
GABA
in
mice
exposed
to
MnCl
2
in
the
diet.
A
1%
concentration
of
MnCl
2
was
administered
in
the
diet
to
an
unspecified
number
of
male
CD­
1
mice
for
1
month.
This
level
of
exposure
corresponds
to
568
mg
Mn/
kg­
day.
The
concentration
was
increased
to
4%
for
an
additional
5
months.
During
this
period,
the
average
daily
dose
was
2,272
mg
Mn/
kg­
day.
Dopamine
content
in
the
striatum
and
in
the
olfactory
tubule
at
6
months
was
reduced
compared
with
controls
(
p
<
0.05).
GABA
content
of
the
striatum
was
increased
(
p
<
0.05).
Apparent
increases
in
the
substantia
nigra
area
and
a
decrease
in
the
cerebellum
were
not
statistically
significant.
No
changes
in
neurotransmitter
levels
were
observed
when
assays
were
conducted
after
1
 
2
months
of
exposure.

Morganti
et
al.
(
1985)
conducted
a
behavioral
study
using
male
ICR
strain
Swiss
mice.
The
mice
were
fed
powdered
Charles
River's
RMH
300
diet
that
contained
1,000
mg
MnO
2/
kg.
This
dietary
concentration
corresponds
to
approximately
632
mg
Mn/
kg.
The
mice
consumed
5
g
of
food
daily.
Assuming
a
body
weight
of
0.03
kg
(
U.
S.
EPA,
1986d),
this
level
of
exposure
corresponds
to
an
average
daily
dose
of
105
mg/
kg­
day.
Neurobehavioral
evaluation
began
after
16
weeks
of
feeding
and
continued
at
2­
week
intervals
for
30
weeks.
The
endpoints
evaluated
were
open
field
and
exploratory
behavior,
passive
avoidance
learning,
and
rotarod
performance
(
a
measurement
of
balance
and
coordination).
Multivariate
analysis
of
variance
(
2
treatments
and
8
samples
by
week
of
exposure)
was
used
to
test
for
intergroup
differences.
No
significant
behavioral
differences
were
apparent
in
any
treatment
group.
In
contrast,
Morganti
et
al.
(
1985)
observed
significant
effects
in
mice
exposed
to
manganese
by
inhalation
for
7
hours/
day,
5
days/
week,
at
levels
greater
than
50
mg
Mn/
m3.
The
duration
of
exposure
was
16
to
32
weeks.
This
level
of
inhalation
exposure
was
considered
by
the
authors
to
be
comparable
to
the
oral
exposure.

Ali
et
al.
(
1985)
studied
the
effect
of
dietary
protein
on
manganese
neurotoxicity.
Rats
received
either
a
normal
diet
(
21%
casein)
or
a
low
protein
diet
(
10%
casein).
Half
of
each
dietary
group
served
as
a
control
while
the
other
half
received
MnCl
2
C4H
2
O
(
3,000
mg
Mn/
L)
in
the
drinking
water
for
90
days.
Assuming
an
adult
body
weight
of
0.35
kg
and
water
consumption
of
0.049
L/
day,
this
corresponds
to
an
average
daily
dose
of
420
mg/
kg­
day.
The
low­
protein
diet
was
associated
with
decreased
levels
of
brain
dopamine
(
DA),
norepinephrine
(
NE),
and
serotonin.
Manganese
exposure
resulted
in
a
marked
increase
in
DA
and
NE
levels,
which
were
more
pronounced
in
the
low­
protein
group.
A
significant
decrease
in
serotonin
levels
following
manganese
exposure
occurred
only
in
the
low­
protein
group.
Weaned
F
1
pups
of
treated
rats
exhibited
the
same
pattern
of
effects.
The
study
authors
concluded
that
protein
deficiency
can
increase
vulnerability
of
rats
to
the
neurotoxic
effects
of
manganese.

Nachtman
et
al.
(
1986)
studied
the
behavioral
effects
of
chronic
manganese
exposure.
Male
Sprague­
Dawley
rats
were
administered
0
or
1
mg
MnCl
2
C4H
2
O/
mL
in
drinking
water
for
65
weeks.
Assuming
a
body
weight
of
0.35
kg
and
water
consumption
of
0.049
L/
day,
this
7­
22
Manganese
 
February
2003
corresponds
to
an
average
daily
dose
of
39
mg
Mn/
kg­
day.
The
treatment
did
not
result
in
any
change
in
body
weight.
The
manganese­
exposed
rats
exhibited
a
significant
increase
in
locomotor
activity
during
weeks
5
to
7.
However,
the
effects
were
transient,
and
by
8
weeks
the
activities
had
returned
to
control
levels.
Treated
rats
examined
at
14
and
29
weeks
were
found
to
be
more
responsive
to
the
effects
of
d­
amphetamine
(
a
locomotor
stimulant
that
works
primarily
by
releasing
dopamine)
than
were
controls.
There
was
no
difference
between
manganese­
treated
rats
and
controls
at
41
or
65
weeks.
The
investigators
concluded
that
manganese
exposure
may
result
in
a
transient
increase
in
dopaminergic
function,
as
evidenced
by
increased
spontaneous
and
d­
amphetamine­
stimulated
locomotor
activity.

Kristensson
et
al.
(
1986)
studied
the
effect
of
manganese
on
the
developing
nervous
system
of
young
rats.
Starting
at
3
days
of
age,
Sprague­
Dawley
rats
received
a
daily
dose
of
150
mg
Mn/
kg­
day
(
as
MnCl
2)
by
gavage.
The
treatment
continued
until
the
rats
reached
44
days
of
age.
At
days
15
to
22
there
was
a
large
but
transient
increase
(
7­
to
40­
fold)
of
manganese
in
the
brain,
and
the
rats
displayed
a
rigid
and
unsteady
gait.
By
44
days,
the
rats
appeared
normal
and
brain
manganese
levels
had
declined
to
approximately
3
times
the
control
level.
Histological
analysis
revealed
no
abnormalities
in
the
brains
of
manganese­
exposed
rats.
Axonal
growth
and
the
axon­
myelin
relation
were
normal.
A
second
group
of
rats
was
treated
for
15
days.
At
this
time
point,
half
the
rats
were
sacrificed
and
half
were
maintained
untreated
until
sacrifice
at
60
days
of
age.
The
rats
were
subsequently
analyzed
for
brain
content
of
dopamine
and
its
metabolites,
including
2,4­
dihydroxyphenylacetic
acid
and
homovanillic
acid
(
HVA),
and
serotonin
and
its
major
metabolite
5­
hydroxyindolacetic
acid.
Only
HVA
levels
in
the
hypothalamus
and
striatum
were
affected
by
manganese
treatment.
Significantly
decreased
HVA
levels
were
seen
at
the
15­
day
sacrifice.
Similar
decreases
in
rats
treated
for
15
days
and
allowed
to
recover
until
60
days
of
age
were
not
observed.
The
investigators
concluded
that
divalent
manganese
has
a
very
low
degree
of
toxicity
for
the
developing
nervous
system
in
rats,
but
that
longer­
term
exposure
to
more
active
manganese
compounds
may
cause
severe
damage
to
certain
neurologic
pathways.
In
addition,
the
investigators
emphasized
that
rodents
may
not
be
appropriate
for
comparison
with
primates.
Unpublished
studies,
where
monkeys
exposed
to
manganese
oxide
developed
severe
motor
disturbances,
were
cited
as
the
basis
for
this
conclusion.

Eriksson
et
al.
(
1987)
studied
the
effect
of
long­
term
manganese
exposure
on
biogenic
amine
levels
in
rat
brain.
Starting
at
20
days
of
age,
groups
of
male
Sprague­
Dawley
rats
were
provided
with
drinking
water
containing
10
g/
L
manganese
chloride
(
MnC1
2
C4H
2
0)
for
60,
100,
165,
or
265
days.
This
concentration
corresponds
to
2,777
mg
Mn/
L.
Assuming
an
adult
body
weight
of
0.35
kg
and
water
consumption
of
0.049
L/
day,
this
level
of
exposure
results
in
an
average
daily
dose
of
approximately
390
mg
Mn/
kg­
day.
There
were
no
clinical
signs
of
toxicity.
Following
60
days
of
exposure,
manganese
concentration
in
the
striatum
was
estimated
to
be
1.3
to
2.0
mg/
kg,
in
contrast
to
control
levels
of
0.4
to
0.5
mg/
kg.
Levels
of
dopamine,
3,4­
dihydroxyphenylacetic
acid,
homovanillic
acid,
serotonin
and
5­
hydroxyindoleacetic
acid
were
determined
in
discrete
regions
of
the
caudate­
putamen.
Rats
exposed
for
60
and
165
days
showed
significantly
increased
levels
of
dopamine
(
DA)
and
3,4­
dihydroxyphenylacetic
acid,
but
these
alterations
were
not
seen
in
rats
exposed
for
100
or
265
days.
This
suggests
an
increased
synthesis
and
turnover
of
dopamine
that
is
reversible,
even
with
continuous
manganese
exposure.
7­
23
Manganese
 
February
2003
This
study
identifies
a
LOAEL
of
390
mg
Mn/
kg­
day
based
on
increased
levels
of
dopamine
at
60
days.

Kontur
and
Fechter
(
1988)
intubated
neonatal
Long­
Evans
rats
daily
with
0,
25,
or
50
mg/
kg­
day
manganese
chloride
(
MnC1
2
C
4H
2
0)
for
14
or
21
days.
These
doses
correspond
to
6.9
and
13.9
mg
Mn/
kg­
day.
The
level
of
manganese
in
the
brain
was
increased
at
both
14
and
21
days,
but
was
greater
at
14
days.
Monoamine
and
metabolite
levels
were
not
altered
in
any
brain
region
by
manganese
treatment.
The
study
authors
suggested
that
the
different
results
reported
by
different
laboratories
may
be
attributable
to
species
or
strain
differences,
the
dosing
regimen
or
vehicle,
the
route
of
administration,
or
the
time
points
chosen
for
testing.
These
data
suggest
a
NOAEL
of
6.9
mg
Mn/
kg­
day
for
this
study,
based
on
the
absence
of
effect
on
monoamine
levels.

These
collective
studies
suggest
that
preclinical
neurological
effects
are
possible
in
the
human
following
oral
exposure;
however,
there
are
dissimilarities
in
the
spectrum
of
responses
between
rodent
and
primate
models
of
toxicity
that
preclude
a
determination
of
the
oral
dose
range
that
might
be
expected
to
induce
these
preclinical
effects.
Further,
conflicting
data
concerning
responses
in
humans
and
confounding
factors
in
the
limited
human
epidemiological
studies
prevent
determination
of
any
dose­
response
effect
in
humans
exposed
to
manganese
excesses
via
ingestion.

Parenteral
Exposure
Although
deficiencies
exist
in
experimental
design
(
U.
S.
EPA,
1984),
primate
studies
by
parenteral
routes
of
exposure
have
reported
extrapyramidal
signs
and
histologic
lesions
similar
to
those
described
in
humans.
Mella
(
1924)
treated
four
rhesus
monkeys
with
MnCl
2
for
18
months.
Two
monkeys
served
as
controls.
The
treated
monkeys
received
gradually
increasing
doses
of
MnCl
2
by
intraperitoneal
injection
on
alternate
days.
The
doses
started
at
5
mg
and
reached
a
maximum
of
25
mg
per
injection.
The
monkeys
exhibited
uncontrolled,
involuntary
movements
(
chorea)
followed
by
rigidity,
disturbances
of
motility,
fine
hand
tremors,
and
finally,
contracture
of
the
hands.
Histological
changes
were
reported
in
the
putamen,
the
caudate,
and
the
globus
pallidus.

Suzuki
et
al.
(
1975)
exposed
monkeys
subcutaneously
to
39.5,
79.0
or
158.0
mg
Mn/
kg
as
MnO
2
once
a
week
for
9
weeks
and
found
the
latency
of
neurologic
signs
(
tremors,
excitability,
choreiform
movement,
loss
of
equilibrium,
and
contracture
of
hands)
inversely
related
to
cumulative
dose.
Signs
appeared
earlier
when
higher
doses
were
administered,
but
the
severity
of
symptoms
was
not
completely
dose­
related.
The
estimated
daily
doses
in
this
experiment
were
5.6,
11,
and
23
mg
Mn/
kg­
day.

Olanow
et
al.
(
1996)
reported
damage
to
the
globus
pallidus
and
substantia
nigra
in
monkeys
that
were
dosed
intravenously
with
doses
as
low
as
4.4
mg
Mn/
kg/
week
(
for
7
weeks).
The
brain
damage
was
accompanied
by
neuromuscular
toxicity
including
bradykinesia,
rigidity,
facial
grimacing,
and
abnormal
posturing
of
the
limbs.
Newland
and
Weiss
(
1992)
administered
repeated
daily
intravenous
doses
of
manganese
to
Cebus
monkeys
so
that
the
monkeys
received
cumulative
doses
of
5
or
10
mg/
kg
for
450
days.
The
dosings
were
separated
by
at
least
one
7­
24
Manganese
 
February
2003
week.
The
authors
observed
that
single
intravenous
doses
of
5
or
10
mg
Mn/
kg­
day
resulted
in
a
significant
increase
in
the
number
of
incomplete
responses
of
dosed
monkeys
to
a
spring­
loaded
test
device
that
measured
physical
exertion
through
a
rowing
motion.
The
increase
in
incomplete
responses
occurred
within
a
few
days
after
dosing
began.
Further,
action
tremor
was
observed
in
the
monkeys
who
had
received
cumulative
doses
of
40
mg/
kg
or
higher;
however,
dystonia
was
never
observed.

Eriksson
et
al.
(
1992)
subcutaneously
injected
two
monkeys
with
0.4
g
doses
of
MnO
2
(
0.253
g
Mn)
in
water.
Eleven
doses
were
administered
over
4
months,
followed
by
a
final
dose
at
12
months.
Both
animals
developed
an
unsteady
gait
and
exhibited
hypoactive
behavior.
PET
scans
indicated
that
degeneration
of
dopaminergic
nerve
endings
occurred
following
Mn
intoxication.

Additional
studies
have
examined
the
neurotoxic
effects
of
manganese
administered
by
parenteral
routes
in
non­
primate
species.
Mustafa
and
Chandra
(
1971)
and
Chandra
(
1972)
reported
paralysis
of
the
hind
limbs
in
rabbits
administered
169
mg
Mn/
kg
(
as
MnO
2)
intratracheally.
The
paralysis
developed
after
a
period
of
18
to
24
months.
Examination
of
the
of
affected
animals
brains
showed
widespread
neuronal
loss
and
neuronal
degeneration
in
the
cerebral
cortex,
caudate
nucleus,
putamen,
substantia
nigra
and
cerebellar
cortex.
These
findings
are
reminiscent
of
the
characteristic
histopathologic
and
neurologic
consequences
of
manganism
found
in
exposed
workers
(
U.
S.
EPA,
1993).
A
marked
decrease
in
brain
catecholamine
levels
and
related
enzyme
activity
was
also
noted.

Histopathologic
evaluations
of
exposed
rats
by
Chandra
and
Srivastava
(
1970),
Chandra
et
al.
(
1979)
and
Shukla
and
Chandra
(
1976)
found
scattered
neuronal
degeneration
in
the
cerebral
and
cerebellar
cortex.
Daily
intraperitoneal
administration
of
2
to
4
mg
Mn/
kg
for
#
120
days
appeared
to
be
the
threshold
for
the
appearance
of
microscopic
lesions.
These
studies
also
demonstrated
an
association
between
the
maximum
number
of
degenerated
neurons
and
maximum
manganese
concentration
in
the
brain.

Scheuhammer
(
1983)
treated
male
Sprague­
Dawley
rats
intraperitoneally
for
30
days
with
either
3.0
mg
Mn/
kg
or
an
equal
volume
of
0.9%
NaCl.
Assuming
an
average
adult
body
weight
of
0.35
kg,
this
treatment
corresponds
to
an
average
daily
dose
of
8.6
mg
Mn/
kg­
day.
Following
sacrifice,
the
pancreas
was
removed,
fixed
in
10%
buffered
formalin,
and
subsequently
processed
for
light
microscopy.
Significant
pathological
changes
were
observed
in
pancreatic
tissue
from
manganese­
exposed
rats.
The
changes
were
characterized
by
a
pancreatitis­
like
reaction
consisting
of
expanded
interacinar
spaces,
a
thickened
connective
tissue
capsule
with
invaginations
of
fibrotic
connective
tissue
septa
extending
into
the
body
of
the
gland,
the
presence
of
an
inflammatory
infiltrate
of
neutrophils,
lymphocytes,
macrophages,
and
the
separation
of
groups
of
acini
from
the
body
of
the
pancreas
with
occasional
destruction
of
acinar
cells.
Other
peritoneal
organs
did
not
exhibit
pathological
changes.
This
study
suggests
that
intraperitoneally
injected
Mn(
II)
exerts
a
selective
toxicity
on
pancreatic
tissue.
Therefore,
the
study
author
cautioned
against
use
of
intraperitoneal
injection
as
the
route
of
administration
for
chronic
Mn
neurotoxicity
studies.
7­
25
Manganese
 
February
2003
Brouillet
et
al.
(
1993)
administered
0,
0.5,
1,
or
2
:
mol
of
MnCl
2
in
deionized
water
to
male
rats
by
a
single
intrastriatal
injection.
Assuming
a
body
weight
of
0.35
kg
for
an
adult
rat,
these
doses
correspond
to
0,
0.077,
0.171,
and
0.314
mg
Mn/
kg.
Each
treatment
group
contained
9
to
10
rats.
The
lowest
dose
produced
a
significant
reduction
in
dopamine,
but
had
no
effect
on
the
other
neurochemical
markers
examined.
Doses
of
0.171
and
0.314
mg
Mn/
kg
produced
a
reduction
in
dopamine
levels,
changes
in
neurochemical
markers,
and
indications
of
impaired
oxidative
metabolism.

7.2.5
Developmental/
Reproductive
Toxicity
Developmental
Studies
Studies
are
limited
regarding
developmental
toxicity
in
humans
following
oral
exposures
to
manganese.
Kilburn
(
1987)
reported
an
increased
incidence
in
birth
defects
and
stillbirths
in
a
small
population
of
indigenous
peoples
in
Groote
Eylandt,
Australia.
Although
the
area
was
rich
in
manganese
deposits
and
ingestion
of
excess
amounts
of
the
metal
was
suspected,
the
study
suffered
from
a
lack
of
exposure
data,
small
sample
sizes,
and
no
suitable
control
group.
Further,
inhalation
exposure
to
manganese
could
not
be
ruled
out.
Studies
by
He
et
al.
(
1994)
and
Zhang
et
al.
(
1995)
suggest
that
oral
exposures
to
excess
manganese
can
possibly
result
in
increased
neurological
deficits
measured
as
poorer
performance
in
school
and
on
standardized
neurobehavioral
exams.
These
studies
also
suffer
from
a
lack
of
adequate
exposure
data
and
the
potential
presence
of
confounding
factors,
such
as
exposure
to
other
potential
neurotoxicants
and
possible
inhalation
exposure
to
manganese.

Developmental
studies
conducted
in
animals
are
summarized
in
Table
7­
5.
These
studies
suggest
that
manganese
is
a
potential
developmental
toxicant,
but
additional
studies
that
are
better
controlled
are
necessary
in
order
to
determine
how
potent
it
is.

Several
studies
have
reported
developmental
effects
in
animal
models
following
oral
administration
of
manganese.
Järvinen
and
Ahlström
(
1975)
exposed
female
rats
to
4,
24,
54,
154,
504,
or
1,004
mg
Mn/
kg
(
as
manganese
sulfate
heptahydrate)
in
the
diet
for
8
weeks
after
weaning
and
during
pregnancy.
No
signs
of
embryotoxicity
or
fetotoxicity
were
observed.
Increases
in
the
whole
body
content
of
manganese
in
fetuses
and
in
liver
manganese
content
of
the
dams
were
reported
at
dietary
levels
above
154
mg
Mn/
kg.
No
increase
in
liver
manganese
content
was
observed
in
non­
pregnant
females.
Chandra
and
Shukla
(
1978)
administered
bolus
doses
of
1
mg
Mn/
kg­
day
to
neonatal
rats
for
60
days.
Neuronal
degeneration
and
increased
monoamine
oxidase
were
reported
on
days
15
and
30
of
the
study,
but
no
clinical
or
behavioral
signs
of
manganese
neurotoxicity
were
reported.

Several
studies
have
measured
changes
in
brain
chemistry
in
neonatal
rats
following
oral
exposure
to
manganese.
Deskin
et
al.
(
1980,
1981)
dosed
rat
pups
via
gavage
with
MnCl
2
in
5%
7­
26
Manganese
 
February
2003
Table
7­
5.
Developmental
Effects
of
Exposure
to
Manganese.

Compound
Species
Route
Dose
(
mg
Mn/
kgday
Effect
Reference
MnSO
4
!
7H
2
0
Rat
(
female)
Oral
(
diet)
0
4
24
54
154
504
1,004
Increased
manganese
concentration
in
fetus
and
maternal
liver;
no
indications
of
embryo­
or
fetotoxicity
Järvinen
and
Ahlström
(
1975)

MnCl
2
Rat
Bolus
(
in
water)
1
Neuronal
degeneration;
increased
monoamine
oxidase;
no
indications
(
clinical
or
behavioral)
of
neurotoxicity
Chandra
and
Shukla
(
1978)

MnCl
2
Rat
Oral
(
gavage)
0
1
10
20
Decreased
dopamine;
decreased
tyrosine
hydroxylase;
increased
monoamine
oxidase
activity
(
all
changes
in
hypothalamus
only)
Deskin
et
al.
(
1980)

Mn
3
O
4
Mouse
(
Male)
Oral
(
diet)
1,050
Decreased
preputial
gland,
seminal
vesicle,
and
testes
growth
Gray
and
Laskey
(
1980)

MnCl
2
Rat
Oral
(
gavage)
0
10
15
20
Increased
hypothalamic
serotonin
Deskin
et
al.
(
1981)

Mn
3
O
4
Rat
Oral
(
diet)
0
350
1,050
3,500
Decreased
serum
testosterone;
decreased
sperm
count;
decreased
testes
weight;
prevented
normal
decrease
in
serum
FSH
Laskey
et
al.
(
1982)

MnCl
2
Rat
Oral
(
drinking
water)
240
Delayed
air
righting
reflex;
delayed
age
of
eye
opening;
delayed
development
of
auditory
startle
Ali
et
al.
(
1983)

Mn
3
O
4
Rat
Oral
(
drinking
water)
40
Decreased
chloline
acetyltransferase
activity
in
cerebellum
and
midbrain
Lai
et
al.
(
1984)

MnCl
2
Rat
Oral
(
drinking
water)
0
68
136
232
Decreased
water
consumption
and
decrease
in
weight
gain
in
two
highest
dose
groups;
no
changes
in
catecholamine
or
startle
response
in
the
exposed
pups
Kontur
and
Fechter
(
1985)

Mn
3
O
4
Rat
Oral
(
gavage)
0
71
214
Decreased
serum
testosterone
following
7
days
of
hCG
induction
Laskey
et
al.
(
1985)
Compound
Species
Route
Dose
(
mg
Mn/
kgday
Effect
Reference
7­
27
Manganese
 
February
2003
MnCl
2
Rat
(
male)
Oral
(
drinking
water)
150
Transient
ataxia;
decreased
striatal
and
hypothalamic
homovanillic
acid
concentrations
Kristensson
et
al.
(
1986)

MnCl
2
!
4H
2
0
Mouse
Subcutaneous
injection
0
0.56
1.1
2.2
4.4
Decreased
weight
gain/
food
consumption;
increased
late
resorptions;
reduced
fetal
body
weight;
increased
incidence
of
morphological
defects
Sanchez
et
al.
(
1993)

MnCl
2
Rat
(
female)
Rabbit
(
female)
Oral
(
gavage)
0
11
22
33
Delayed
skeletal
and
internal
organ
development
and
increased
external
malformations
in
rat
pups
delivered
by
Caesarean
section.
No
effects
in
rabbit
Szakmáry
et
al.
(
1995)

MnCl
2
Mouse
Subcutaneous
injection
50
Late
resorptions;
postimplantation
loss;
skeletal
anomalies;
reduced
fetal
body
weight
Colomina
et
al.
(
1995)

MnCl
2
Rat
Intravenous
0
0.27
×
10­
3
1.1
×
10­
3
2.2
×
10­
3
Increased
incidence
of
skeletal
malformations
including
angulated
or
irregularly
shaped
clavicle,
femur,
fibula,
humerus,
ilium,
radius,
scapula,
tibia,
and/
or
ulna
Treinen
and
Blazak
(
1995)

MnCl
2
Mouse
Intravenous
0.3
1.6
Increased
fetal
weight
at
low
dose;
decreased
fetal
weight
at
high
dose;
fetal
skeletal
abnormalities
at
high
dose
Grant
et
al.
(
1997)

MnCl
2
Rat
Oral
(
drinking
water)
0
350
1,420
Thinning
of
cerebral
cortex;
absence
of
convincing
brain
histopathological
or
behavioral
evidence
from
perinatal
manganese
exposure
on
the
brain
Pappas
et
al.
(
1997)

MnCl
2
Rat
Oral
(
drinking
water)
11
22
Decreased
body
weight
gain;
increased
response
to
auditory
stimulus
Dorman
et
al.
(
2000)
7­
28
Manganese
 
February
2003
sucrose
for
24
days
starting
on
the
first
postnatal
day.
The
administered
doses
in
the
earlier
study
were
0,
1,
10,
and
20
mg
Mn/
kg­
day.
Decreased
dopamine
levels
in
the
hypothalamus
were
reported
at
the
two
highest
doses,
and
decreased
tyrosine
hydroxylase
levels
and
increased
monoamine
oxidase
activity
(
perhaps
due
to
increased
levels
of
the
enzyme)
were
reported
in
the
hypothalamus
at
the
highest
dose.
No
other
changes
in
brain
chemistry
were
reported
in
the
hypothalamus,
and
no
other
brain
section
was
affected.
In
the
latter
study,
doses
of
0,
10,
15,
and
20
mg
Mn/
kg­
day
were
administered.
Hypothalamic
serotonin
was
observed
to
be
increased
at
the
highest
dose;
the
level
of
this
transmitter
was
unaffected
in
the
striatum.
Lai
et
al.
(
1984)
reported
small
decreases
in
choline
acetyltransferase
activity
in
the
cerebellum
and
midbrain
of
2­
month­
old
rats
that
had
been
exposed
to
40
mg
Mn/
kg­
day
from
conception,
throughout
gestation,
and
throughout
life.
Other
neuronal
enzymes
(
e.
g.,
glutamic
acid
decarboxylase,
acetylcholinesterase)
were
unaffected.

Kristensson
et
al.
(
1986)
dosed
3­
day
old
male
rat
pups
with
150
mg
Mn/
kg­
day
(
in
water)
for
41
days.
The
authors
reported
a
transient
ataxia
(
days
15­
22),
which
was
resolved
by
the
end
of
the
dosing
period,
in
the
pups.
Manganese
levels
in
the
blood
and
brain
(
brain
levels
were
increased
7­
40
fold)
were
elevated
significantly
over
controls
in
15­
and
20­
day
old
pups;
brain
levels
had
decreased
to
approximately
3­
fold
over
control
levels
in
43­
day
old
pups.
Homovanillic
acid
(
metabolite
of
dopamine)
concentrations
were
decreased
in
the
striatum
and
hypothalamus,
but
not
in
other
brain
regions;
no
other
monoamines
or
their
metabolites
were
affected.

A
few
studies
have
measured
reproductive
endpoints
in
the
developing
rodent.
Manganese
administered
to
pre­
weanling
male
mice
at
a
dose
of
1,050
mg
Mn/
kg­
day
beginning
on
postnatal
day
15
resulted
in
the
decreased
growth
of
reproductive
organs
(
preputial
gland,
seminal
vesicle,
and
testes)
measured
on
days
58,
73,
and
90
but
did
not
affect
body
growth
or
liver
or
kidney
weights
(
Gray
and
Laskey,
1980).
Laskey
et
al.
(
1982)
administered
dietary
manganese
at
doses
of
0,
350,
1,050,
and
3,500
mg
Mn/
kg­
day
to
male
and
female
rats
fed
a
diet
either
adequate
or
deficient
in
iron.
Males
and
females
were
mated
during
days
90­
100
of
the
study;
testes
weights
of
male
offspring
fed
the
iron­
deficient
diet
were
decreased
as
compared
to
controls
at
day
40
at
the
highest
two
doses
and
at
day
100
at
the
intermediate
dose.
While
40­
day­
old
weanling
rats
did
not
exhibit
any
treatment­
related
hormonal
changes,
exposed
rats
showed
a
dose­
related
decrease
in
serum
testosterone
at
60­
100
days
of
age
(
when
age­
related
increases
were
expected),
and
no
increase
in
serum
luteinizing
hormone
was
observed.
The
normal
decrease
in
serum
follicle
stimulating
hormone
(
FSH)
from
60
to
100
days
was
prevented
by
manganese
exposure.
Epididymal
sperm
count
was
decreased
by
the
treatment
only
when
given
with
the
iron­
deficient
diet.

In
an
additional
study
measuring
the
effects
of
manganese
exposure
on
the
developing
reproductive
system,
Laskey
et
al.
(
1985)
administered
0,
71,
and
214
mg
Mn
(
as
Mn
3
O
4)/
kg­
day
via
gavage
to
pre­
weanling
rats
on
postnatal
days
1­
21.
The
study
authors
measured
serum
levels
of
FSH,
LH,
and
testosterone
in
the
pups
at
21
or
28
days
of
age.
Manganese
exposure
did
not
affect
endogenous
or
stimulated
serum
levels
of
FSH
or
LH,
nor
did
it
affect
endogenous
or
acute
human
chorionic
gonadotropin
(
hCG)­
induced
serum
testosterone
at
2
hours.
Serum
testosterone
was
decreased
following
7
days
of
hCG
induction,
however.
The
delayed
decrease
7­
29
Manganese
 
February
2003
in
testosterone
was
hypothesized
by
the
study
authors
to
be
a
result
of
an
unknown
manganeseinduced
effect
on
the
Leydig
cell.

Ali
et
al.
(
1983)
evaluated
potential
changes
in
developmental
endpoints
in
rat
pups
after
administering
excess
manganese
in
drinking
water
to
pregnant
dams
fed
a
normal
or
low­
protein
diet.
Manganese
exposure
was
started
90
days
prior
to
mating
and
continued
throughout
gestation
and
nursing.
The
offspring
of
dams
who
had
ingested
240
mg
Mn/
kg­
day
exhibited
delayed
air
righting
reflexes.
Significant
delays
in
the
age
of
eye
opening
and
the
development
of
auditory
startle
were
reported
in
pups
from
dams
ingesting
protein­
deficient
diets.
No
decreases
in
body
weight
or
brain
weight
were
reported
in
the
offspring
of
rats
fed
normalprotein
diets.

Kontur
and
Fechter
(
1985)
exposed
pregnant
Long­
Evans
rats
to
0,
5,000,
10,000,
or
20,000
mg/
L
of
manganese
chloride
in
drinking
water
throughout
the
gestation
period.
Rats
in
the
10,000
and
20,000
mg/
L
groups
showed
reduced
water
intake
and
a
significant
decrease
in
weight
gain.
A
significant
decrease
in
birth
weight
was
observed
in
the
20,000
mg/
L
group.
At
one
day
of
age,
pups
from
the
10,000
and
20,000
mg/
L
groups
had
increased
manganese
levels
in
the
forebrain,
although
there
was
no
difference
in
the
extent
of
accumulation
between
the
two
groups.
The
increased
manganese
levels
were
not
associated
with
any
changes
in
catecholamine
function
or
startle
response
in
the
exposed
pups.
The
authors
concluded
that
manganese
is
not
particularly
toxic
to
developing
rats,
perhaps
as
a
result
of
limited
placental
transfer.

The
developmental
effects
of
manganese
have
also
been
evaluated
following
parenteral
administration.
Sánchez
et
al.
(
1993)
investigated
the
embryotoxic
and
teratogenic
potential
of
manganese
during
organogenesis.
Pregnant
Swiss
mice
received
daily
subcutaneous
injections
of
0,
2,
4,
8
or
16
mg/
kg­
day
of
MnCl
2
A4H
2
O
on
days
6
to
15
of
gestation.
These
doses
correspond
to
0,
0.56,
1.1,
2.2,
or
4.4
mg
Mn/
kg­
day,
respectively.
Dams
were
sacrificed
on
gestational
day
18.
Significant
reductions
in
weight
gain
and
food
consumption
were
reported
in
dams
receiving
8
mg/
kg­
day
and
above,
and
treatment­
related
deaths
were
reported
at
16
mg/
kgday
A
significant
increase
in
the
number
of
late
resorptions
was
observed
at
doses
of
4
mg/
kgday
and
higher,
and
reduced
fetal
body
weight
and
an
increased
incidence
of
morphological
defects
were
reported
at
doses
of
2.2
mg
Mn/
kg­
day
and
higher.
No
difference
was
seen
in
the
incidence
of
individual
or
total
malformations
in
treated
groups
when
compared
with
controls.
A
NOAEL
of
1.1
mg/
kg­
day
was
identified
by
the
study
authors
for
maternal
toxicity.
A
NOAEL
of
0.56
mg/
kg­
day
was
identified
for
embryo/
fetal
toxicity
Pappas
et
al.
(
1997)
assessed
behavioral,
neurohistological,
and
neurochemical
endpoints
in
rats
exposed
to
manganese
from
conception
to
weaning.
The
investigators
administered
0,
2,000,
or
10,000
mg
Mn/
L
as
manganese
chloride
in
drinking
water
to
female
rats
(
10/
group)
and
their
litters
from
conception
until
postnatal
day
(
PND)
30.
The
average
daily
consumption
of
manganese
during
gestation
was
350
and
1,420
mg/
kg­
day,
respectively,
for
the
two
manganese
treatment
groups.
No
effects
were
observed
on
pregnancy
or
birth
parameters
and
no
physical
abnormalities
were
evident
in
the
offspring
of
treated
dams.
The
findings
reflect
a
lack
of
effects
on
reproductive
capability.
Fifty
male
pups
from
each
treatment
group
were
subsampled
for
behavioral
tests
(
10
to
22
per
group),
histopathology
(
6
to
8
per
group)
and
neurochemical
7­
30
Manganese
 
February
2003
analyses
(
6
to
8
per
group).
The
rats
exposed
to
10,000
mg
Mn/
L
showed
a
2.5­
fold
increase
in
brain
cortical
Mn
levels.
They
also
experienced
reduced
weight
gain
during
PND
9
to
32,
and
were
hyperactive
at
PND
17.
Behavioral
tests
were
conducted
on
pups
from
all
groups
at
PND
17,
90
or
95.
No
significant
differences
in
performance
were
noted
for
the
radial
arm
maze,
elevated
plus
apparatus,
or
Morris
water
maze
behavioral
tests.
Both
doses
resulted
in
thinning
of
the
cerebral
cortex.
The
observed
thinning
may
have
been
a
consequence
of
either
perinatal
malnutrition
or
a
direct
effect
on
cortical
development.
Brain
monoamine
levels
and
choline
acetyltransferase
activity
were
unaffected
by
manganese
exposure.
Tyrosine
hydroxylase
immunohistochemistry
indicated
that
dopamine
neurons
of
the
substantia
nigra
were
intact.
Glial
fibrillary
acidic
protein
immunoreactivity,
an
indicator
of
neuronal
damage,
was
not
increased
in
cortex,
caudate
nucleus
or
hippocampus.
The
authors
emphasized
that
the
most
noteworthy
result
of
this
study
was
the
absence
of
convincing
histopathological
and
behavioral
evidence
for
persistent
effects
of
perinatal
manganese
exposure
on
the
brain.

Grant
et
al.
(
1997)
failed
to
observe
any
effects
of
manganese
exposure
on
weight
gain,
gross
malformations,
or
skeletal
malformations
in
the
offspring
of
pregnant
rats
dosed
via
gavage
with
22
mg
Mn/
kg­
day
on
gestational
days
6­
17.
Another
study
indicates
a
lack
of
persistent
developmental
effects
from
oral
manganese
exposure
during
gestation.
Szakmáry
et
al.
(
1995)
reported
the
developmental
effects
of
manganese
administered
via
gavage
to
pregnant
rats
throughout
gestation
and
to
pregnant
rabbits
through
organogenesis
(
gestation
day
6­
20)
at
doses
of
0,
11,
22,
and
33
mg/
kg­
day.
No
developmental
effects
in
the
rabbit
were
observed.
The
highest
dose
resulted
in
retardation
of
development
of
the
skeleton
and
internal
organs
of
the
rat,
as
well
as
a
significant
increase
in
external
malformations
(
e.
g.,
clubfoot)
in
pups
delivered
by
caesarean
section.
These
effects,
however,
were
not
observed
in
100­
day­
old
offspring
of
dams
that
had
been
similarly
dosed,
indicating
that
the
developmental
effects
were
self­
correcting.
Manganese
treatment
did
not
affect
the
following
endpoints
in
either
the
pup
group
that
was
surgically
delivered
or
the
group
born
live:
ears,
teeth,
eyes,
forward
motion,
clinging
ability,
body
posture,
correction
reflex,
or
negative
geotaxis
reflex.

In
a
more
recent
study,
Dorman
et
al.
(
2000)
dosed
neonatal
CD
rats
with
11
or
22
mg
Mn
(
in
water)/
kg­
day
for
21
days
from
birth
to
weaning.
The
high
dose
resulted
in
decreased
body
weight
gain
in
the
pups
and
affected
brain
neurochemistry.
Manganese
treatment
induced
a
significant
increase
in
the
amplitude
of
response
to
an
auditory
stimulus
but
did
not
affect
motor
activity,
performance
in
a
passive
avoidance
task,
or
brain
histopathology.

Colomina
et
al.
(
1995)
conducted
a
study
to
determine
which
gestation
day
is
most
critical
for
developmental
toxicity
of
manganese
in
mice.
The
investigators
administered
a
50
mg/
kg
dose
of
manganese
chloride
by
subcutaneous
injection
once
during
the
period
between
gestation
days
9
and
12.
Late
resorptions,
post­
implantation
loss,
and
skeletal
anomalies
increased
in
all
treatment
groups.
Significant
reductions
in
fetal
body
weight
occurred
following
exposure
on
gestation
day
9
or
10,
indicating
these
days
were
most
critical.

Treinen
and
Blazak
(
1995,
abstract
only)
dosed
female
Sprague­
Dawley
rats
(
15/
group)
intravenously
with
0,
5,
20,
or
40
nmol/
kg
MnCl
2
on
days
6
to
17
of
gestation.
These
doses
correspond
to
approximately
0,
0.27,
1.1,
or
2.2
:
g
Mn/
kg­
day.
Treatment
resulted
in
an
7­
31
Manganese
 
February
2003
increased
incidence
of
skeletal
malformations
(
doses
which
elicited
effects
were
not
reported).
The
observed
malformations
included
angulated
or
irregularly
shaped
clavicle,
femur,
fibula,
humerus,
ilium,
radius,
scapula,
tibia,
and/
or
ulna.

Grant
et
al.
(
1997)
administered
6
or
30
:
mol
MnCl
2/
kg­
day
to
female
mice
(
24/
group)
by
intravenous
injection
on
gestation
days
6
to
17.
These
doses
correspond
to
approximately
0.3
and
1.6
mg
Mn/
kg­
day.
The
experiment
was
terminated
on
gestation
day
20.
No
significant
differences
were
noted
in
manganese­
treated
mice
for
number
of
corpora
lutea,
implantation
sites,
pre­
or
post­
implantation
losses,
or
number
of
viable
fetuses
per
litter.
Fetal
weight
was
significantly
increased
(
p<
0.05)
at
the
lower
dose,
and
significantly
decreased
(
p<
0.05)
at
the
1.6
mg/
kg­
day
dose.
Skeletal
abnormalities
were
noted
in
the
fetuses
of
dams
receiving
the
higher
intravenous
dose.
In
contrast,
no
increase
in
skeletal
abnormalities
was
observed
in
the
fetuses
of
mice
administered
400
:
mol
of
MnCl
2
(
approximately
22
mg
Mn/
kg­
day)
by
oral
gavage
daily
from
days
6
to
17
of
gestation.

One
in
vitro
developmental
study
was
located.
Hanna
et
al.
(
1996,
abstract
only)
cultured
two­
stage
mouse
embryos
in
media
containing
varying
concentrations
of
essential
and
nonessential
minerals,
including
manganese.
Embryos
were
incubated
in
culture
media
containing
0.05
 
200
:
M
manganese
for
72
hours.
Both
essential
and
nonessential
minerals
were
embryotoxic
at
relatively
low
doses.

Reproductive
Studies
Some
inhalation
data
from
occupational
exposure
studies
suggest
that
male
reproductive
dysfunction
is
a
primary
endpoint
of
manganese
toxicity.
Toxicity
is
manifested
in
symptoms
including
loss
of
libido
and
impotence
(
U.
S.
EPA,
1996a).
Some
evidence
indicates
that
the
hypothalamus
and
pituitary
are
sites
of
manganese
accumulation
(
see
Section
6.2),
suggesting
disturbance
of
the
hypothalamic­
pituitary­
gonadal
axis
hormones
as
a
potential
mechanism
for
reproductive
effects.
No
human
reproductive
data
for
oral
manganese
exposure
are
available
in
the
current
literature.
Reproductive
studies
in
animals
orally
exposed
to
manganese
are
described
below.
Results
of
these
studies
are
summarized
in
Table
7­
6.

Chandra
and
colleagues
consistently
reported
degenerative
changes
in
the
seminiferous
tubules
in
the
testes
after
parenteral
exposure
of
rats
and
rabbits
to
manganese
(
Chandra,
1971;
Shukla
and
Chandra,
1977;
Imam
and
Chandra,
1975;
Chandra
et
al.,
1973,
1975).
However,
similar
changes
were
not
observed
in
subchronic
or
chronic
studies
in
mice
or
rats
(
NTP,
1993).

Gray
and
Laskey
(
1980)
exposed
male
mice
to
1,100
mg
Mn/
kg
as
Mn
3
O
4
in
a
casein
diet
from
gestation
day
15
to
90
days
of
age.
Assuming
a
food
consumption
factor
of
0.13
(
U.
S.
EPA,
1986d),
the
estimated
daily
dose
at
the
termination
of
the
study
would
be
approximately
143
mg/
kg­
day.
Sexual
development
was
retarded,
as
indicated
by
decreased
weight
of
testes,
seminal
vesicles
and
preputial
glands.
Reproductive
performance
was
not
evaluated.
7­
32
Manganese
 
February
2003
Laskey
et
al.
(
1982)
exposed
Long­
Evans
rats
to
0,
400,
1,100
or
3,550
mg
Mn/
kg
(
as
Mn
3
O
4)
in
the
diet
from
day
2
of
mother's
gestation
to
224
days
of
age.
Assuming
a
food
consumption
factor
of
0.05
(
U.
S.
EPA,
1986d),
the
average
daily
dose
at
the
termination
of
the
7­
33
Manganese
 
February
2003
Table
7­
6.
Reproductive
Effects
of
Exposure
to
Manganese.

Compound
Species
Route
Dose
Effect
Reference
Mn
3
O
4
Mouse
Oral
(
diet)
143
mg
Mn/
kgday
Decreased
weight
of
testes,
seminal
vesicles
and
preputial
glands
after
90
days.
Gray
and
Laskey
(
1980)

Mn
3
O
4
Rat
Oral
(
diet)
20
mg
Mn/
kgday
55
177
Dose­
related
decrease
in
serum
testosterone
concentration.
Reduced
fertility
at
3550
ppm
after
224
days.
Laskey
et
al.
(
1982)

Mn
3
O
4
Rat
Oral
(
gavage)
71
mg
Mn/
kgday
214
Decreased
body
and
testes
weights.
Reduction
in
serum
testosterone.
Laskey
et
al.
(
1985)

MnCl
2
Rat
i.
p.
8
mg/
kg­
day
Degenerative
changes
in
approx.
50%
of
seminiferous
tubules
after
150
and
180
days.
Chandra
(
1971)

MnCl
2
!
4H
2
0
Rat
i.
p.
15
mg/
kg­
day
Increased
Mn
in
testes;
decreased
nonprotein
sulfhydryls
and
decreased
activity
of
glucose­
6­
phosphate
dehydrogenase
and
glutathione
reductase
after
15
 
45
days.
Shukla
and
Chandra
(
1977)

MnCl
2
!
4H
2
0
Rabbit
i.
v.
3.5
mg/
kg
Inhibition
of
succinic
dehydrogenase
in
seminiferous
tubules
after
5
days.
Morphologic
changes
were
not
apparent.
Imam
and
Chandra
(
1975)

MnSO
4
Rat
i.
p.
6
mg
Mn/
kg
Increased
Mn
in
testes
after
25
 
30
days.
Degenerative
changes
in
10%
of
seminiferous
tubules.
Chandra
et
al.
(
1975)

MnO
2
Rabbit
i.
t.
250
mg/
kg
single
dose
Destruction
and
calcification
of
the
seminiferous
tubules
at
8
months.
Infertile
females.
Chandra
et
al.
(
1973)

i.
p.
=
intraperitoneal;
i.
v.
=
intravenous;
i.
t.
=
intratracheal
7­
34
Manganese
 
February
2003
study
was
0,
20,
55,
or
177
mg
Mn/
kg­
day.
The
investigators
observed
a
dose­
related
decrease
in
serum
testosterone
concentration
(
without
a
concomitant
increase
in
serum
luteinizing
hormone
concentration),
and
reduced
fertility
at
the
highest
dose.
Testes
weight,
number
of
ovulations,
resorption
and
preimplantation
deaths,
litter
size,
and
fetal
weights
were
unaffected
by
manganese
exposure.

Laskey
et
al.
(
1985)
conducted
studies
to
assess
the
effect
of
manganese
on
hypothalamic,
pituitary
and
testicular
function.
Long­
Evans
rat
pups
(
8/
litter)
were
dosed
by
gavage
from
day
1
to
day
21
with
a
50%
sucrose
solution
containing
particulate
Mn
3
O
4.
The
average
daily
dose
of
manganese
was
calculated
to
be
0,
71
or
214
mg
Mn/
kg­
day.
Assessments
of
the
hypothalamic,
pituitary,
or
testicular
functions
were
determined
by
measuring
the
endogenous
or
stimulated
serum
concentrations
of
follicle­
stimulating
hormone,
luteinizing
hormone,
and/
or
testosterone
at
21
or
28
days
of
age.
Body,
testes,
and
seminal
vesicles
weight
and
tissue
concentrations
of
Mn
were
also
evaluated.
Effects
attributed
to
manganese
included
slight
decreases
in
body
and
testes
weights,
and
a
reduction
in
serum
testosterone.
There
was
no
indication
of
hypothalamic
or
pituitary
dysfunction.
The
authors
suggested
that
the
decrease
in
testosterone
level
resulted
from
manganese­
induced
damage
of
Leydig
cells.

Studies
exist,
however,
that
report
no
adverse
reproductive
effects
in
female
rats
following
oral
manganese
exposure.
Pappas
et
al.
(
1997)
dosed
pregnant
rats
with
up
to
620
mg
Mn/
kg­
day
(
as
MnCl
2)
throughout
gestation.
No
treatment­
related
effects
were
reported
in
dam
health,
litter
size,
or
sex
ratios
of
the
pups.
The
study
did
not
include
more
extensive
analysis
of
female
reproductive
organs.
Grant
et
al.
(
1997)
administered
22
mg
Mn/
kg­
day
(
as
MnCl
2)
via
gavage
to
pregnant
dams
on
gestation
days
6­
17.
No
treatment­
related
effects
were
reported
in
dams
as
measured
by
mortality,
clinical
signs,
food
and
water
intake,
or
body
weights.

7.2.6
Chronic
Toxicity
NTP
(
1993)
investigated
the
chronic
toxicity
of
manganese
in
a
2­
year
oral
exposure
study.
Concentrations
of
0,
1,500,
5,000
or
15,000
mg/
kg
manganese
sulfate
monohydrate
were
administered
in
the
diet
to
male
and
female
F344
rats
(
70/
sex).
These
dietary
concentrations
resulted
in
doses
ranging
from
30
to
331
mg
Mn/
kg­
day
for
males,
and
26
to
270
mg
Mn/
kg­
day
for
females.
Ten
rats/
group
were
sacrificed
at
9
and
15
months.
Survival
of
males
in
the
highdose
group
was
significantly
decreased
starting
at
week
93
of
the
study,
and
death
was
attributed
to
advanced
renal
disease
associated
with
manganese
exposure.
Food
consumption
was
similar
for
all
groups.
However,
by
the
end
of
the
study,
high­
dose
males
exhibited
a
mean
body
weight
that
was
10%
lower
than
controls.
No
clinical
findings
or
effects
on
hematologic
or
clinical
chemistry
parameters
were
attributed
to
manganese
exposure
in
any
group.
Tissue
concentrations
of
manganese
were
elevated
in
the
livers
of
mid­
and
high­
dose
males,
concurrent
with
a
decrease
in
hepatic
iron
concentrations.
Renal
disease
in
high­
dose
males
was
the
only
pathological
effect
noted.
No
increases
in
tumor
incidence
were
attributed
to
manganese
exposure.

The
chronic
oral
toxicity
of
manganese
was
evaluated
in
mice
in
a
concurrent
study
conducted
by
NTP
(
1993).
Concentrations
of
0,
1,500,
5,000,
or
15,000
mg/
kg
manganese
7­
35
Manganese
 
February
2003
sulfate
monohydrate
were
administered
in
the
diet
to
B6C3F
1
mice
(
70/
sex)
in
a
2­
year
oral
exposure
study.
These
dietary
concentrations
were
reported
to
be
equivalent
to
doses
ranging
from
63
mg
Mn/
kg­
day
to
722
mg
Mn/
kg­
day
for
male
mice,
and
from
77
mg
Mn/
kg­
day
to
905
mg
Mn/
kg­
day
for
female
mice.
Interim
sacrifices
of
11
mice/
group
were
made
at
9
and
15
months.
No
clinical
findings
or
effects
on
survival
were
observed
in
any
group
of
mice.
Mean
body
weights
of
males
were
not
affected.
Female
mice
had
a
dose­
related
decrease
in
mean
body
weight
after
week
37.
The
final
mean
body
weights
for
the
low­,
mid­
and
high­
dose
females
were
6%,
9%
and
13%
lower
than
controls,
respectively.
No
differences
were
seen
in
food
consumption
for
any
group.
No
effects
were
reported
on
hematologic
parameters.
Tissue
concentrations
of
manganese
were
significantly
elevated
in
the
livers
of
all
exposed
females,
and
in
high­
dose
males.
Elevated
manganese
concentration
was
associated
with
decreased
hepatic
iron.

7.2.7
Carcinogenicity
The
carcinogenicity
of
ingested
manganese
was
evaluated
in
concurrent
2­
year
oral
exposure
studies
conducted
in
mice
and
rats
by
NTP
(
1993).
An
overview
of
these
studies
is
provided
below.
No
other
studies
of
manganese
carcinogenicity
via
the
oral
route
were
identified.

Groups
of
rats
were
exposed
to
dietary
levels
of
manganese
sulfate
monohydrate
that
resulted
in
intakes
ranging
from
30
to
331
mg
Mn/
kg­
day
for
males
and
26
to
270
mg
Mn/
kg­
day
for
females.
At
the
termination
of
the
study,
no
manganese­
related
increase
in
any
tumor
type
was
observed
(
NTP,
1993).

In
a
parallel
study,
NTP
(
1993)
administered
0,
1,500,
5,000,
and
15,000
mg/
kg
manganese
sulfate
monohydrate
in
the
diet
to
B6C3F
1
mice
(
70/
sex)
for
2
years.
These
dietary
concentrations
resulted
in
intakes
ranging
from
63
to
722
mg
Mn/
kg­
day
for
males
and
from
77
to
905
mg
Mn/
kg­
day
for
females.
The
estimated
manganese
intake
in
the
high­
dose
mice
was
approximately
107
times
greater
than
the
recommended
dietary
allowance.
Incidence
of
thyroid
follicular
cell
hyperplasia
was
significantly
greater
in
high­
dose
male
and
female
mice
than
in
controls.
The
incidence
of
follicular
cell
adenomas
is
summarized
in
Table
7­
7.
In
males,
tumors
were
observed
only
at
the
highest
dose
(
6%
incidence).
The
highest
incidence
of
tumors
in
females
was
also
observed
at
the
highest
dose.
No
significant
differences
in
tumor
incidence
relative
to
the
controls
were
observed
for
either
sex.
The
follicular
cell
tumors
were
seen
only
at
the
termination
of
the
study
(
729
days),
and
their
number
was
only
slightly
increased
relative
to
the
historical
control
range
in
female
B3C6F
1
mice
(
0
to
9%
historical
range
versus
10%
tumor
incidence
in
high­
dose
females).
Hence,
the
relevance
of
these
findings
to
human
carcinogenesis
is
questionable.
The
issues
of
concern
are:
1)
the
large
intake
of
manganese
required
to
elicit
a
response
seen
only
at
the
end
of
the
study,
and
2)
tumor
frequencies
that
are
not
significantly
different
from
historical
controls.
While
NTP
(
1993)
has
concluded
that
the
marginal
increase
in
thyroid
adenomas
of
the
mice
was
equivocal
evidence
of
carcinogenicity,
others
have
questioned
the
relevance
of
these
data
to
human
carcinogenicity
(
U.
S.
EPA,
1993).
7­
36
Manganese
 
February
2003
Table
7­
7.
Follicular
Cell
Tumor
Incidence
in
B6C3F
1
Mice.

Sex
Concentration
of
MnSO
4°
H
2
O
in
Diet
Control
Low
Medium
High
Males
0/
50
0/
49
0/
51
3/
50
Females
2/
50
1/
50
0/
49
5/
51
Source:
NTP
(
1992)

Other
studies
reporting
positive
results
for
carcinogenicity
are
summarized
in
Table
7­
8.
Stoner
et
al.
(
1976)
tested
manganese
sulfate
in
a
mouse
lung
adenoma
screening
bioassay.
These
investigators
exposed
6­
to
8­
week­
old
Strain
A/
Strong
mice
of
both
sexes
(
10/
sex)
to
6,
15
or
30
mg
MnSO
4/
kg
via
intraperitoneal
injection.
Doses
were
administered
three
times
a
week
for
a
total
of
21
injections.
The
cumulative
doses
were
132,
330
and
660
mg
MnSO
4/
kg.

Table
7­
8.
Summary
of
Carcinogenicity
Studies
Reporting
Positive
Findings
for
Selected
Manganese
Compounds
a.

Compound
Species
Route
Dose
Duration
(
weeks
intermittent
Results
Reference
Manganese
chloride
Mouse
Mouse
i.
p.

s.
c.
0.1
mL
of
1%

0.1
mL
of
1%

0%
(
control)
26
26
41%
­
Lymphosarcomas
67%
­
Lymphosarcomas
24%
­
Lymphosarcomas
DiPaolo
(
1964)

Manganese
sulfate
Mouse
i.
p.
660
mg/
kg
0
mg/
kg
8
67%
­
Lung
adenomas
31
 
37%
­
Lung
ademomas
Stoner
et
al.
(
1976)

Manganese
acety­
lacetonate
(
MAA)
Rat
i.
m.
1,200
mg/
kgb
0
mg/
kg
26
40%
(
males)
Fibrosarcomas
24%
(
females)
Fibrosarcomas
4
%
(
control
males
and
females)
Furst
(
1978)

i.
p.
=
intraperitoneal;
s.
c.
=
subcutaneous;
i.
m.
=
intramuscular
a
Source:
U.
S.
EPA
(
1984)
7­
37
Manganese
 
February
2003
These
doses
corresponded
to
42.9,
107.2
and
214.4
mg
Mn/
kg.
Observation
continued
for
22
weeks
after
the
dosing
period,
and
the
mice
were
sacrificed
at
30
weeks.
Table
7­
9
summarizes
the
results
of
this
study.
The
percentage
of
mice
with
tumors
was
elevated
at
the
highest
dose
level,
but
the
difference
was
not
significant
(
Fisher
Exact
test)
when
compared
with
the
vehicle
controls.
An
apparent
increase
in
the
average
number
of
pulmonary
adenomas
per
mouse
was
noted
both
at
the
middle
and
high
doses,
but
the
increase
was
significant
only
at
the
high
dose
(
660
mg
MnSO
4/
kg)
(
Student's
t­
test,
p
<
0.5).
Although
these
study
results
are
suggestive
of
carcinogenic
activity,
they
do
not
conclusively
meet
the
positive
response
criteria
(
increase
in
the
mean
number
of
tumors
per
mouse
and
an
observable
dose­
response
relationship)
for
the
interpretation
of
lung
tumor
data
in
this
mouse
strain
(
Shimken
and
Stoner,
1975).

Table
7­
9.
Pulmonary
Tumors
in
Strain
A
Mice
Treated
with
Manganese
Sulfate
a.

Total
Dose
Group
mg
MnSO
4/
kg
mg
Mn/
kg
Mortality
Mice
with
Lung
Tumors
(%)
Average
Number
Tumors/
Mouse
b
Value
c
Untreated
control
0
0
1/
20
6/
19
(
31)
0.28
±
0.07
NA
Solvent
control
(
0.85%
NaCl)
0
0
1/
20
7/
19
(
37)
0.42
±
0.10
NA
Treated
132
42.9
1/
20
7/
19
(
37)
0.47
±
0.11
NS
Treated
330
107.2
0/
20
7/
20
(
35)
0.65
±
0.15
NS
Treated
660
214.4
2/
20
12/
18
(
67)
1.20
±
0.49
0.05d
20
mg
urethane
e
0
0
2/
20
18/
18
(
100)
21.6
±
2.81
NR
a
Source:
Stoner
et
al.
(
1976)
b
X
±
S.
E.
c
Student
t­
test
d
Fisher
Exact
Test
p
=
0.068
e
Single
intraperitoneal
injection
NA
=
Not
applicable;
NS
=
Not
significant;
NR
=
Not
reported
Furst
(
1978)
injected
F344
rats
intramuscularly
with
manganese
acetylacetonate
and
observed
an
increased
incidence
of
fibrosarcomas
at
the
injection
site,
but
did
not
observe
increased
tumor
incidence
at
other
sites.
7­
38
Manganese
 
February
2003
7.3
Other
Key
Data
7.3.1
Mutagenicity/
Genotoxicity
In
Vivo
Studies
No
studies
or
reports
were
identified
which
describe
mutagenic
or
genotoxic
effects
in
humans
following
oral
exposure
to
manganese.
Table
7­
10
summarizes
the
results
of
the
most
recent
in
vivo
mutagenicity
and
genotoxicity
studies
in
animals.
Results
from
additional
studies
are
noted
in
the
text
below.

Studies
of
genotoxicity
in
animals
have
shown
mixed
results.
The
bone
marrow
cells
of
rats
receiving
a
50
mg/
kg
oral
dose
of
manganese
(
as
manganese
chloride)
showed
an
increased
incidence
of
chromosomal
aberrations
(
30.9%)
compared
with
those
of
control
animals
(
8.5%)
(
Mandzgaladze,
1966;
Mandzgaladze
and
Vasakidze,
1966).
However,
Dikshith
and
Chandra
(
1978)
administered
repeated
oral
doses
of
manganese
chloride
(
0.014
mg/
kg­
day)
to
male
rats
for
180
days
and
did
not
observe
significant
chromosomal
damage
in
bone
marrow
or
spermatogonial
cells.

Table
7­
10.
Genotoxicity
of
Manganese
In
Vivo.

Species
(
test
system)
Compound
End
Point
Route
Results
Reference
Nonmammalian
systems:

Drosophila
melanogaster
MnSO
4
Sex­
linked
recessive
lethal
Feeding
Injection
­
Valencia
et
al.
(
1985)

Drosophila
melanogaster
MnSO
4
Sex­
linked
recessive
lethal
Feeding
Injection
­
NTP
(
1993)

Drosophila
melanogaster
MnCl
2
Somatic
mutation
Soaking
larvae
­
Rasmuson
(
1985)

Mammalian
systems:

Albino
rat
(
bone
marrow
cells)
(
spermatogonial
cells)
MnCl
2
Chromosomal
aberrations
Oral
­
Dikshith
and
Chandra
(
1978)

Albino
mouse
MnSO
4
KMnO
4
Chromosomal
aberrations
Chromosomal
aberrations
Oral
Oral
+
+
Joardar
and
Sharma
(
1990)
7­
39
Manganese
 
February
2003
Joardar
and
Sharma
(
1990)
administered
oral
doses
of
manganese
sulfate
(
approximately
102,
202,
and
610
mg/
kg)
and
potassium
permanganate
(
65,
130,
and
380
mg/
kg)
to
male
Swiss
albino
mice
for
three
weeks.
Both
compounds
were
clastogenic,
with
manganese
sulfate
being
more
potent.
The
frequencies
of
chromosomal
aberrations
in
bone
marrow
cells
and
micronuclei
were
significantly
increased
by
both
salts.
There
was
also
a
statistically
significant,
dosedependent
enhancement
of
sperm­
head
abnormalities.
A
LOAEL
of
23
mg
Mn/
kg­
day
was
identified
for
this
effect
by
ATSDR
(
2000).

The
divalent
manganese
ion
(
Mn
II)
interacts
with
DNA
and
chromosomes
(
Kennedy
and
Bryant,
1986;
Yamaguchi
et
al.,
1986).
In
cultured
mammalian
cells,
both
MnCl
2
and
KMnO
4
produced
chromosome
aberrations,
including
breaks,
exchanges
and
fragments
(
Umeda
and
Nishimura,
1979).
DNA­
strand
breaks
have
also
been
induced
by
manganese
in
Chinese
hamster
ovary
calls
and
human
diploid
fibroblasts
(
Hamilton­
Koch
et
al.,
1986;
Snyder,
1988).
Tests
for
induction
of
chromosomal
aberrations
and
sister
chromatid
exchanges
in
cultured
Chinese
hamster
ovary
cells
were
positive
for
manganese
sulfate
monohydrate
in
the
absence
of
S9
metabolic
activation.
In
the
presence
of
S9,
only
the
sister
chromatid
exchange
test
was
positive
(
NTP,
1993).

Tests
for
mutagenicity
in
Drosophila
melanogaster
have
given
negative
results.
Manganese
sulfate
monohydrate
did
not
induce
sex­
linked
recessive
lethal
mutations
in
germ
cells
of
male
Drosophila
treated
by
feeding
or
injection
(
Valencia
et
al.,
1985,
as
reported
in
NTP,
1993).
Treatment
of
D.
melanogaster
with
manganese
chloride
by
soaking
did
not
induce
somatic
mutation
(
Rasmuson,
1985).

In
Vitro
Assays
Table
7­
11
summarizes
the
results
of
the
most
recent
in
vitro
mutagenicity
and
genotoxicity
studies.
Additional
results
from
early
studies
are
included
in
the
text
below.

Manganese
chloride
was
mutagenic
in
Escherichia
coli
(
Demerec
et
al.,
1951;
Durham
and
Wyss,
1957;
Zakour
and
Glickman,
1984),
Photobacterium
fischeri
(
Ulitzer
and
Barak,
1988)
and
Serretia
marcescens
(
Kaplan,
1962).
Both
positive
(
Nishioka,
1975)
and
negative
(
Kanematsu
et
al.,
1980)
results
have
been
reported
for
the
Bacillus
subtilis
recombination
assay.
Positive
(
Pagano
and
Zeiger,
1992;
Wong,
1988)
and
negative
results
(
Wong,
1988)
have
also
been
reported
for
manganese
chloride
in
the
Salmonella
typhimurium
reversion
assay.
Assays
in
mammalian
cell
lines
were
positive
for
gene
mutation
in
mouse
lymphoma
cells
(
Oberley
et
al.,
1982)
and
enhancement
of
transformation
in
Syrian
hamster
embryo
cells
(
Casto
et
al.,
1979).
An
assay
for
DNA
damage
in
human
lymphocytes
gave
negative
results
with
metabolic
activation,
and
positive
results
without
activation
(
De
Meo
et
al.,
1991).

Manganese
sulfate
gave
positive
results
in
the
T4
bacteriophage
mutation
test
(
Orgel
and
Orgel,
1965),
and
the
B.
subtilis
recombination
assay
with
S9
activation
(
Nishioka,
1975).
Pagano
and
Zeiger
(
1992)
obtained
positive
results
for
mutagenicity
in
S.
typhimurium
strain
TA97.
In
contrast,
manganese
sulfate
monohydrate
was
not
mutagenic
in
S.
typhimurium
strains
TA98,
TA100,
TA1535,
or
TA1537,
either
with
or
without
exogenous
metabolic
(
S9)
activation
7­
40
Manganese
 
February
2003
Table
7­
11.
Genotoxicity
of
Manganese
In
Vitro.

Results
Species
(
test
system)
Compound
End
Point
Strain
With
S9
Activation
Without
S9
Activation
Reference
Prokaryotic
organisms:

Salmonella
typhimurium
MnCl
2
Gene
mutation
TA98
TA102
TA1535
TA1537
­
­
­
­
­
­
­
+
Wong
(
1988)

Salmonella
typhimurium
MnSO
4°
H
2
O
Gene
mutation
TA97
TA98
TA100
TA1535
TA1537
­
­
­
­
­
­/+
­
­
­
­
Mortelmans
et
al.
(
1986)

Salmonella
typhimurium
MnSO
4
Gene
mutation
TA97
ND
+
Pagano
and
Zeiger
(
1992)

Salmonella
typhimurium
MnCl
2
Gene
mutation
TA100
TA102
ND
ND
­
+
DeMeo
et
al.
(
1991)

Photobacterium
fischeri
(
bioluminescence
test)
MnCl
2
Gene
mutation
(
restored
luminescence)
Pf­
13
(
dark
mutant)
ND
+
Ulitzur
and
Barak
(
1988)

Escherichia
coli
MnCl
2
Gene
mutation
KMBL
3835
ND
+
Zakour
and
Glickman
(
1984)

Bacteriophage
(
E.
coli
lysis)
MnSO
4
Gene
mutation
T4
ND
+
Orgel
and
Orgel
(
1965)

Bacillus
subtilis
(
recombination
assay)
MnCl
2
Mn(
NO
3)
2
MnSO
4
Mn(
CH
3
CO
O)
2
KMnO
4
Inhibition
of
growth
in
recombination
deficient
mutant
(
Rec­)
compared
to
wild
type
(
Rec+)
M45
(
Rec­)
ND
+
+
+

+
­
Nishioka
(
1975)

B.
subtilis
(
recombination
assay)
MnCl
2
Mn(
NO
3)
2
Mn(
CH
3
CO
O)
2
Inhibition
of
growth
in
recombination
deficient
mutant
(
Rec­)
compared
to
wild
type
(
Rec+)
M45
(
Rec­)
ND
­
­
­
Kanematsu
et
al.
(
1980)
Table
7­
11
(
continued)

Results
Species
(
test
system)
Compound
End
Point
Strain
With
S9
Activation
Without
S9
Activation
Reference
7­
41
Manganese
 
February
2003
Eukaryotic
organisms:

Fungi:
Saccharomyces
cerevisiae
MnSO
4
Gene
conversion,
reverse
mutation
D7
ND
+
Singh
(
1984)

Mammalian
cells:
Mouse
lymphoma
cells
MnCl
2
Gene
mutation
L5178Y
TK+/­
ND
+
Oberley
et
al.
(
1982)

Mammalian
cells:
Syrian
hamster
embryo
cells
MnCl
2
Enhancement
of
SA7
transformation
ND
+
Casto
et
al.
(
1979)

Mammalian
cells:
Human
lymphocytes
(
Single­
cell
gel
assay)
MnCl
2
DNA
damage
­
+
DeMeo
et
al.
(
1991)

Mammalian
cells:
Chinese
hamster
ovary
cells
MnSO
4
Chromosomal
aberrations
Sister
chromatid
exchange
­

+
+

+
NTP
(
1993)

Notes:
­
=
negative
results
+
=
positive
results
­/+
=
equivocal
results
ND
=
no
data
available
DNA
=
deoxyribonucleic
acid
MnSO
4°
H
2
O
=
manganese
(
II)
sulfate
monohydrate
Mn(
CH
3
COO)
2
=
manganous
acetate
MnCl
2
=
manganous
chloride
Mn(
NO
3)
2
=
manganous
nitrate
MnSO
4
=
manganous
sulfate
Rec
=
recombination
Source:
Modified
from
ATSDR
(
2000)
7­
42
Manganese
 
February
2003
when
assayed
by
Mortelmans
et
al.
(
1986).
Results
for
strain
TA97
were
negative
when
assayed
with
S9
activation,
and
equivocal
when
assayed
without
metabolic
activation.
Assays
in
eukaryotic
test
systems
were
positive
for
mutagenicity
in
S.
cerevisiae
(
Singh,
1984)
and
chromosomal
aberrations
in
Chinese
hamster
ovary
(
CHO)
cells
(
NTP,
1993).
Manganese
sulfate
gave
negative
results
when
assayed
for
induction
of
sister
chromatid
exchange
in
CHO
cells
(
NTP,
1993).

Comparatively
little
data
are
available
that
describes
the
genotoxic
potential
of
other
manganese
compounds.
Manganese
oxide
(
Mn
3
O
4)
was
not
mutagenic
in
S.
typhimurium
or
S.
cerevisiae
(
Simmon
and
Ligon,
1977).
Data
obtained
for
manganese
nitrate
(
Mn(
NO
3)
2)
in
the
B.
subtilis
recombination
assay
were
inconsistent
between
studies
(
Nishioka,
1975;
Kanematsu
et
al.,
1980).
Manganese
acetate
(
Mn(
CH
3
OO)
2)
was
mutagenic
in
the
B.
subtilis
recombination
assay
without
exogenous
metabolic
activation,
and
gave
negative
results
with
activation
(
Nishioka,
1975;
Kanematsu
et
al.,
1980).

7.3.2
Immunotoxicity
Immunotoxicity
and
lymphoreticular
effects
do
not
appear
to
be
significant
outcomes
of
oral
exposure
to
manganese.
A
single
report
describes
effects
in
this
category
following
oral
exposure.
NTP
(
1993)
administered
diets
containing
0,
1,600,
3,130,
6,250,
12,500,
or
25,000
mg/
kg
manganese
sulfate
monohydrate
to
F344
rats
(
10/
sex/
dose)
in
a
13­
week
study.
Based
on
measured
feed
consumption,
the
study
authors
determined
that
the
mean
intake
of
manganese
sulfate
monohydrate
ranged
from
110
to
1,700
mg/
kg­
day
(
equal
to
about
36
to
553
mg
Mn/
kgday
for
males,
and
from
115
to
2,000
mg/
kg­
day
(
equal
to
about
37
to
621
mg
Mn/
kg­
day)
for
females.
Increased
neutrophil
counts
were
noted
at
32
mg
Mn/
kg­
day
in
male
rats.
Decreased
leukocyte
counts
were
noted
at
155
mg
Mn/
kg­
day
in
female
rats.

Studies
in
animals
exposed
to
manganese
chloride
by
intraperitoneal
or
intramuscular
injection
suggest
that
manganese
can
affect
several
immunological
cell
types
(
ATSDR,
2000).
Observed
effects
include
stimulation
of
macrophage
and
natural
killer
cell
activity
in
mice
(
Rogers
et
al.,
1983;
Smialowicz
et
al.,
1985,
1987).
Other
effects
include
alteration
of
the
responsiveness
of
lymphoid
cells
to
mitogens
and
inhibited
antibody
production
in
response
to
a
T­
cell
antigen
(
Hart,
1978;
Lawrence,
1981;
Srisuchart
et
al.,
1987).
The
significance
of
these
findings
for
human
immune
function
is
presently
unknown.

7.3.3
Hormonal
Disruption
No
reports
describing
hormonal
disruption
associated
with
manganese
exposure
were
located.
7­
43
Manganese
 
February
2003
7.3.4
Physiological
or
Mechanistic
Studies
Biochemical
and
Physiological
Role
Manganese
is
a
naturally­
occurring
element
that
is
required
for
normal
physiological
functioning
in
all
animal
species
(
U.
S.
EPA,
1996a).
It
plays
a
role
in
bone
mineralization,
metabolic
regulation,
protein
and
energy
metabolism,
protection
of
cells
from
oxidative
stress,
and
synthesis
of
mucopolysaccharides
(
ATSDR,
2000).
Many
of
these
roles
are
achieved
by
participation
of
manganese
as
a
catalytic
or
regulatory
factor
for
enzymes,
including
hydrolases,
dehydrogenases,
kinases,
decarboxylases
and
transferases.
In
addition,
manganese
is
a
structural
component
of
the
metalloenzymes
mitochondrial
superoxide
dismutase,
pyruvate
carboxylase,
and
liver
arginase.
Studies
conducted
to
determine
the
biochemical
and
nutritional
roles
of
manganese
in
human
health
are
reviewed
in
greater
detail
by
Wedler
(
1994)
and
Keen
et
al.
(
1999).

The
frequency
of
occurrence
and
consequences
of
manganese
deficiency
are
issues
of
some
debate
(
Keen
et
al.,
1999).
However,
observations
reported
by
Doisy
(
1973)
and
Friedman
et
al.
(
1987)
suggest
that
manganese
is
an
essential
element
for
humans.
Doisy
(
1973)
reported
decreased
levels
of
clotting
proteins,
decreased
serum
cholesterol,
reddening
of
black
hair,
retarded
growth
of
hair
and
nails,
and
scaly
dermatitis
in
a
subject
inadvertently
deprived
of
manganese.
Friedman
et
al.
(
1987)
administered
a
manganese­
deficient
diet
to
seven
men
for
39
days.
Five
of
the
seven
subjects
exhibited
dermatitis
at
the
end
of
the
manganese­
deficient
period.
The
development
of
dermatitis
was
attributed
to
decreased
activity
of
manganeserequiring
enzymes
that
are
required
for
skin
maintenance.
The
symptoms
cleared
rapidly
when
manganese
was
restored
to
the
diet.

Manganese
deficiency
has
been
experimentally
induced
in
multiple
animal
species.
Outcomes
associated
with
manganese
deficiency
in
animals
include
impaired
growth
(
Smith
et
al.,
1944),
skeletal
abnormalities
(
Amdur
et
al.,
1944;
Strause
et
al.,
1986),
impaired
reproductive
function
in
females
and
testicular
degeneration
in
males
(
Boyer
et
al.,
1942),
ataxia
(
Hurley
et
al.,
1961),
altered
metabolism
of
carbohydrates
(
Baly
et
al.,
1988;
Hurley
et
al.,
1984)
and
lipids
(
Abrams
et
al.,
1976),
and
decreased
cholesterol
synthesis
and
excretion
(
Davis
et
al.,
1990;
Kawano
et
al.,
1987).
The
biochemical
basis
for
these
effects
has
not
been
established
with
certainty,
but
it
may
be
related
to
the
participation
of
manganese
in
numerous
enzymatic
reactions.

Low
serum
manganese
levels
are
associated
with
several
disease
states,
including
epilepsy,
exocrine
pancreatic
insufficiency,
multiple
sclerosis,
cataracts,
and
osteoporosis
(
Freeland­
Graves
and
Llanes,
1994).
In
addition,
the
metabolic
disorders
phenylketonuria
and
maple
syrup
urine
disease,
genetic
disorders
of
amino
acid
metabolism,
are
associated
with
poor
manganese
status
(
U.
S.
EPA,
1996a).
7­
44
Manganese
 
February
2003
Mechanisms
of
Neurotoxicity
The
central
nervous
system
(
CNS)
has
been
identified
as
the
major
target
of
manganese
toxicity
(
U.
S.
EPA,
1993;
ATSDR,
2000).
The
blood­
brain
barrier
(
BBB)
is
a
major
regulator
of
the
(
CNS)
milieu,
and
the
rate
and
extent
of
manganese
transfer
across
the
BBB
may
be
a
determinant
of
manganese
neurotoxicity
(
Aschner
and
Aschner,
1991).
The
mechanism
by
which
manganese
crosses
the
BBB
to
gain
access
to
neuronal
tissue
has
not
been
fully
elucidated,
but
may
be
a
function
of
binding
to
transferrin
(
Aschner
and
Aschner,
1991).
In
the
portal
circulation,
manganese
as
Mn(
II)
initially
binds
to
alpha­
2­
macroglobulin,
and
this
complex
cannot
cross
the
BBB.
The
Mn(
II)­
alpha­
2­
macroglobulin
complex
is
transported
by
the
bloodstream
to
the
liver
(
Tanaka,
1982),
where
a
small
fraction
of
the
circulating
Mn(
II)
may
be
oxidized
to
Mn(
III).
The
iron­
transporting
protein
transferrin
has
been
shown
to
also
bind
Mn(
III),
and
may
be
responsible
for
its
transport
into
the
brain.
The
observation
that
some
of
the
regions
of
the
brain
that
accumulate
manganese
(
e.
g.,
globus
pallidus,
striatum,
and
substantia
nigra)
receive
neuronal
input
from
the
transferrin­
rich
nucleus
accumbens
and
the
caudateputamen
supports
this
argument.
Both
of
these
regions
are
rich
in
transferrin
receptors.

Additional
evidence
for
the
transferrin
transport
hypothesis
was
provided
by
an
experiment
in
which
rats
were
given
a
6­
hour
intravenous
administration
of
ferric­
hydroxide
dextran
complex
(
Aschner
and
Aschner,
1990).
The
uptake
of
radiolabeled
manganese
into
the
brain
was
significantly
(
p
<
0.05)
inhibited
following
the
administration
of
the
iron
complex
as
compared
with
rats
administered
iron­
free
dextran.
It
was
concluded
that
iron
homeostasis
may
play
an
important
role
in
the
regulation
of
manganese
transport
across
the
BBB,
since
both
metals
are
transported
by
transferrin
and
may
be
competing
for
binding
sites.

Once
manganese
has
crossed
the
BBB,
several
neurotransmitter
systems
in
the
brain
appear
to
be
potential
targets
for
manganese
toxicity.
The
primary
targets
appear
to
be
the
monoamines,
including
dopamine,
noradrenaline
and
serotonin
(
Neff
et
al.,
1969;
Mustafa
and
Chandra,
1971).
The
amino
acid
neurotransmitter
(­
amino
butyric
acid
(
GABA)
may
also
be
affected
(
Gianutsos
and
Murray,
1982).
Effects
on
neurotransmitters
may
be
both
specific
and
highly
localized.
Manganese
neurotoxicity,
for
example,
is
reportedly
associated
with
a
selective
depletion
of
dopamine
in
the
striatum,
a
site
of
manganese
accumulation
(
Neff
et
al.,
1969;
Bernheimer
et
al.,
1973).

A
resemblance
exists
between
the
symptoms
of
manganism
and
Parkinsonism,
a
condition
characterized
by
loss
of
dopaminergic
neurons
in
the
substantia
nigra
and
globus
pallidus.
In
addition,
several
clinical
features
of
manganism
respond
favorably
to
therapy
with
Ldopa
in
a
manner
similar
to
patients
with
Parkinson's
disease
(
Mena
et
al.,
1970)
although
longterm
response
of
manganism
patients
to
L­
dopa
has
not
been
observed
(
ATSDR,
2000;
Calne
et
al.,
1994).
However,
despite
some
similarities
in
symptoms,
a
comparative
study
of
a
52­
yearold
worker
exposed
to
manganese
in
an
ore
crushing
plant
and
a
patient
with
Parkinson's
disease
did
not
reveal
any
similarity
in
neuropathology
(
Yamada
et
al.,
1986).
Barbeau
(
1984),
Calne
et
al.
(
1994),
and
Pal
et
al.
(
1999)
have
summarized
the
similarities
and
differences
between
manganism
and
Parkinsonism.
These
researchers
have
noted
that
manganism
characteristically
occurs
in
phases
of
increasing
severity
and
that
sufferers
exhibit
dystonia
(
disordered
tonicity
of
7­
45
Manganese
 
February
2003
muscles),
symptoms
of
extrapyramidal
dysfunction
such
as
bradykinesia
(
extreme
slowness
of
movements
and
reflexes),
monotonic
speech,
and
an
expressionless
or
even
grimacing
face.
Although
the
altered
gait
and
fine
tremor
are
common
to
both
Parkinsonism
and
manganism,
the
syndromes
are
different
in
that
manganism
patients
sometimes
have
psychiatric
disturbances
early
in
the
onset
of
the
syndrome,
have
a
tendency
to
fall
backwards,
do
not
have
the
Lewy
bodies
in
the
substantia
nigra
that
are
commonly
found
in
Parkinson's
patients.
Further,
fluorodopa
positron
emission
tomography
(
PET)
scans
are
normal
in
manganism
patients
but
not
in
individuals
with
Parkinson's
disease
(
ATSDR,
2000).

Mapping
studies
by
Yamada
et
al.
(
1986)
indicate
that
most
of
the
neuronal
degeneration
attributed
to
manganese
exposure
lies
close
to
monoamine
cell
bodies
and
pathways.
Histopathology
in
manganese­
exposed
primates
shows
more
widespread
deposition
of
the
metal,
with
intense
signaling
observed
in
both
the
globus
pallidus
and
substantia
nigra
using
MRI
(
Newland
and
Weiss,
1992).
Studies
in
humans
indicate
that
excess
manganese
in
the
brain
deposits
primarily
in
the
globus
pallidus
(
Fell
et
al.
1996;
Kafritsa
et
al.
1998;
Ono
et
al.
1995)
and
damage
to
the
human
brain
from
manganese
deposition
may
be
limited
to
that
region.
In
a
study
that
supports
these
findings,
the
globus
pallidus
exhibited
atrophy
in
an
autopsy
performed
on
a
worker
with
inhalation­
related
manganese
poisoning
(
Yamada
et
al.,
1986).

Although
there
is
consensus
that
the
monoaminergic
systems,
particularly
the
dopaminergic
system,
are
affected
by
excess
exposure
to
manganese,
the
precise
mechanism
of
action
remains
obscure.
One
hypothesis
proposes
that
oxidation
of
dopamine
plays
a
key
role
in
manganese
neurotoxicity.
Manganese
(
III)
has
been
shown
to
oxidize
dopamine
to
its
cyclized
O­
quinone
(
cDAoQ)
(
Archibald
and
Tyree,
1987).
This
irreversible
process
ultimately
results
in
decreased
dopamine
levels.
The
formation
of
cDAoQ
may
subsequently
initiate
the
generation
of
reactive
oxygen
species,
leading
to
oxidative
stress
and
cell
death
(
Segura­
Aguilar
and
Lind,
1989).
An
alternative
hypothesis
for
manganese
toxicity
proposes
an
effect
on
brain
cytochrome
P­
450
activity.
Liccione
and
Maines
(
1989)
demonstrated
a
high
sensitivity
of
rat
striatal
mitochondria
to
manganese­
induced
increases
in
cytochrome
P­
450
activity.
These
authors
speculated
that
the
increase
in
mixed
function
oxidase
activity
may
trigger
an
increase
in
the
formation
of
active
oxygen
species
(
e.
g.,
superoxide
anions)
that
exert
a
harmful
effect
on
dopaminergic
pathways.

Other
mechanistic
studies
have
identified
tyrosine
hydroxylase
(
TOH),
the
rate
limiting
enzyme
in
dopamine
synthesis,
as
a
potential
target
in
manganese­
induced
neurochemical
effects.
Bonilla
(
1980)
and
Chandra
and
Shukla
(
1981)
found
that
changes
in
TOH
activity
in
the
presence
of
manganese
closely
paralleled
dopamine
levels.
Qato
and
Maines
(
1985)
determined
that
alterations
in
the
activity
of
TOH
and
other
monooxygenases
may
be
related
to
manganeseinduced
alterations
in
brain
heme
metabolism.

Manganese
toxicity
may
be
selectively
associated
with
adverse
effects
on
mitochondria.
Maynard
and
Cotzias
(
1955)
originally
proposed
the
mitochondrion
as
the
target
organelle
for
manganese
cytotoxicity,
with
adverse
effects
expressed
primarily
as
disruption
of
Ca(
II)
homeostasis.
Mn(
II)
preferentially
accumulates
in
the
mitochondria
in
regions
of
the
brain
7­
46
Manganese
 
February
2003
associated
with
neurological
symptoms
and
manganism.
Once
inside
the
mitochondria,
Mn(
II)
disrupts
oxidative
phosphorylation.
The
fundamental
role
of
mitochondrial
energy
metabolism
in
manganese
neurotoxicity
has
been
highlighted
by
the
studies
of
Aschner
and
Aschner
(
1990)
and
Gavin
et
al.
(
1992),
as
cited
in
U.
S.
EPA
(
1996a)
and
ATSDR
(
2000).

The
results
of
Brouillet
et
al.
(
1993)
confirm
that
manganese
impairs
mitochondrial
oxidative
metabolism.
In
addition,
their
findings
indicate
that
manganese
neurotoxicity
involves
an
N­
methyl­
D­
aspartate
receptor­
mediated
process
similar
to
that
observed
for
some
other
mitochondrial
toxicants.
Manganese
may
thus
produce
neuronal
degeneration
by
an
excitotoxic
process
secondary
to
its
ability
to
disrupt
oxidative
energy
metabolism.

7.3.5
Structure­
Activity
Relationship
Information
on
structure­
activity
relationships
is
not
available
for
manganese.

7.4
Hazard
Characterization
7.4.1
Synthesis
and
Evaluation
of
Major
Noncancer
Effects
Manganese
is
an
ubiquitous
element
that
is
essential
for
normal
physiological
functioning
in
all
animal
species.
The
biochemical
basis
for
this
requirement
is
most
likely
the
participation
of
manganese
as
a
structural
component
or
catalytic
cofactor
for
many
enzymes.
The
Adequate
Intake
levels
for
manganese
range
from
0.003
to
0.6
mg/
day
for
infants
from
birth
to
6
months,
0.6
mg/
day
for
infants
from
7
months
to
1
year,
1.2
mg/
day
for
children
aged
1­
3
years,
1.5
to
1.9
mg/
day
for
children
aged
4­
13
years,
and
from
1.6
to
2.3
mg/
day
for
adolescents
and
adults
(
IOM,
2002).
Although
outright
manganese
deficiency
has
not
been
observed
in
the
general
population,
sub­
optimal
intake
may
be
of
concern
for
some
individuals.

In
contrast
to
the
beneficial
effects
of
manganese
as
a
nutrient,
excess
exposure
to
manganese
may
be
associated
with
toxic
effects.
At
present,
the
optimal
level
of
oral
exposure
to
manganese
is
not
well
defined
(
Greger,
1999).

Ingested
manganese
appears
to
be
primarily
absorbed
in
the
Mn(
II)
form,
and
may
compete
with
iron
and
cobalt
for
common
absorption
sites.
Absorption
varies
among
individuals
and
is
also
influenced
by
dietary
factors.
Absorption
of
3
to
10%
of
ingested
dietary
manganese
is
considered
to
be
representative
of
the
general
population
(
U.
S.
EPA,
1996a).
Iron
deficiency
enhances
the
absorption
of
manganese
in
animals
(
U.
S.
EPA,
1984).
Uptake
of
dietary
manganese
may
be
reduced
in
the
presence
of
other
dietary
components
such
as
calcium
and
phytate.

Once
absorbed,
manganese
has
the
potential
to
accumulate
in
mitochondria­
rich
tissues,
including
liver,
pancreas,
and
kidney.
Lesser
amounts
accumulate
in
brain
and
bone.
Manganese
is
efficiently
removed
from
the
blood
by
the
liver
and
released
into
bile.
Biliary
secretion
represents
the
major
pathway
for
manganese
transport
to
the
intestine,
and
studies
in
humans
indicate
that
manganese
is
primarily
excreted
in
the
feces.
The
rate
of
excretion
responds
7­
47
Manganese
 
February
2003
efficiently
to
increased
manganese
intake.
The
rate
of
biliary
secretion
acts
in
concert
with
absorptive
processes
to
establish
homeostatic
control
of
manganese
levels
in
the
body.
As
long
as
physiological
systems
are
not
overwhelmed,
humans
appear
to
exert
efficient
homeostatic
control
over
manganese
levels,
so
that
levels
in
the
body
are
kept
relatively
constant
despite
moderate
variations
in
intake.
Manganese
is
also
reabsorbed
in
the
intestine
through
enterohepatic
circulation
(
Schroeder
et
al.
1966).

While
it
is
apparent
that
exposure
to
excess
manganese
can
result
in
increased
tissue
levels,
the
interrelationships
between
oral
exposure
levels,
tissue
accumulation,
and
health
effects
in
humans
are
not
completely
understood.
Epidemiological
studies
of
workers
exposed
by
inhalation
to
manganese
dusts
and
fumes
have
identified
the
central
nervous
system
(
CNS)
as
the
primary
target
for
chronic
manganese
toxicity
by
the
inhalation
route
(
U.
S.
EPA,
1993).
Both
Mn(
III)
and
Mn(
II)
have
been
associated
with
the
neurotoxic
effects
of
manganese.
While
some
researchers
note
the
similarities
in
CNS
effects
occurring
following
manganese
exposure
and
in
Parkinson's
disease
(
dystonia,
rigidity,
bradykinesia),
there
are
significant
differences
in
the
two
diseases.
For
example,
manganism
patients
exhibit
a
less­
frequent
resting
tremor
than
do
Parkinson's
patients,
extrapyramidal
symptoms
including
fixed
expression
or
a
facial
grimace,
active
tremor
(
particularly
in
the
upper
body),
a
"
cock­
walk"
in
which
the
patient
walks
on
the
toes
with
the
back
stiff
and
the
elbows
flexed,
a
propensity
to
fall
backwards
(
especially
when
pushed),
and
a
failure
to
respond
to
dopaminomimetics
(
Barbeau,
1984;
Calne
et
al.,
1994;
Pal
et
al.,
1999).

Several
investigators
have
proposed
a
link
between
elevated
oral
manganese
intake
by
humans
and
neurological
symptoms
resembling
manganism
(
Kawamura
et
al.,
1941;
Kilburn,
1987;
Kondakis
et
al.,
1989;
Goldsmith
et
al.,
1990).
Results
from
these
studies
are
described
in
detail
in
Section
7.1.
In
each
case,
the
data
from
these
studies
were
insufficient
to
establish
that
manganese
was
the
causative
factor
(
ATSDR,
2000).
The
evidence
for
a
similar
pattern
of
neurotoxicity
in
humans
following
oral
exposure
is
therefore
considered
equivocal.

Numerous
studies
have
investigated
manganese
neurotoxicity
in
rodent
models.
However,
the
utility
of
rodent
studies
for
evaluating
the
potential
neurotoxic
effects
of
manganese
in
humans
has
been
questioned.
Although
biochemical
and
behavioral
evidence
of
neurological
effects
has
been
observed,
signs
of
impaired
motor
function
resembling
those
seen
in
humans
are
usually
not
detected.
In
particular,
studies
of
rodents
exposed
to
manganese
by
drinking
water
or
food
have
been
unable
to
produce
the
characteristic
signs
of
extrapyramidal
neurologic
disease
seen
in
humans.
In
contrast,
chronic
administration
of
manganese
to
monkeys
by
oral
(
one
study)
or
parenteral
routes
(
two
studies)
has
resulted
in
neurological
signs
consistent
with
chronic
manganism.
The
failure
to
reproduce
these
signs
in
rodent
studies
may
result
from
differences
in
manganese
accumulation
and
distribution
between
rodents
and
primates.
The
dietary
requirement
for
manganese
in
rodents,
for
example,
is
estimated
to
be
100
times
higher
than
in
humans.
In
addition,
neurotoxic
effects
in
humans
are
associated
with
manganese
accumulation
in
neuromelanin­
rich
regions
of
the
brain,
and
the
homologous
regions
in
rats
and
mice
lack
this
pigment.
Although
primates
are
likely
to
be
better
models
of
the
neurological
manifestations
of
manganese
intoxication
than
rodent
species,
sufficient
data
from
well­
designed
oral
studies
are
not
currently
available.
7­
48
Manganese
 
February
2003
An
additional
drawback
to
animal
studies
of
manganese
neurotoxicity
is
the
inability
to
identify
certain
psychological
or
neurobehavioral
signs.
Overt
neurological
impairment
in
humans
is
often
preceded
by
psychological
symptoms
such
as
irritability
and
emotional
lability.
Since
accurate
dose­
response
relationships
based
on
neurobehavioral
endpoints
are
generally
not
available
from
animal
studies,
neurochemical
responses
have
been
examined
as
alternative
indicators
of
neurotoxicity.
Such
studies
have
been
conducted
on
the
assumption
that
since
the
toxic
manifestations
of
chronic
manganese
exposure
resemble
Parkinsonism,
altered
biogenic
amine
metabolism
in
the
CNS
may
be
one
of
the
underlying
mechanisms.
However
the
patterns
of
neurochemical
response
reported
following
manganese
exposure
are
not
consistent
among
studies.
Although
manganese
exposure
is
generally
thought
to
result
in
decreased
dopamine
concentrations,
some
studies
report
increased
or
fluctuating
levels.
The
effect
of
manganese
on
dopamine
levels,
for
example,
appears
to
be
age­
dependent.
Neonatal
rats
and
mice
exposed
to
manganese
from
birth
to
15
or
30
days
of
age
have
an
increased
levels
of
dopamine
and
norepinephrine
in
the
brain
(
Chandra
et
al.,
1979;
Cotzias
et
al.,
1976;
Shukla
et
al.,
1980).
Further,
temporal
changes
in
dopamine
neurochemistry
have
been
observed
with
prolonged
or
continuous
manganese
treatment
and
it
is
not
established
how
these
time­
related
changes
affect
manganese­
induced
neurotoxicity.

Route
of
administration
is
also
an
issue
of
concern
in
evaluating
the
results
of
animal
studies.
Scheuhammer
(
1983),
for
example,
determined
that
intraperitoneal
injection
is
not
the
route
of
choice
for
studies
of
manganese
exposure
that
are
longer
than
30
days
in
duration,
especially
for
investigations
of
neurotoxicity.
Intraperitoneally
administered
manganese
appears
to
have
a
selectively
toxic
effect
on
the
pancreas.
This
effect
may
make
it
difficult
to
distinguish
between
subtle
neurochemical
changes
resulting
directly
from
manganese
exposure,
and
changes
that
are
secondary
to
cellular
damage
in
the
pancreas.
In
addition,
U.
S.
EPA
(
1984)
noted
that
results
from
parenteral
studies
are
of
limited
value
in
predicting
the
reproductive
hazards
of
ingested
manganese.
At
least
one
study
exists,
however,
that
shows
the
differential
uptake
and
distribution
of
manganese
administered
via
injection
compared
to
oral
dosing.
Roels
et
al.
(
1997)
investigated
the
uptake
and
distribution
of
manganese
(
as
either
MnO
2
or
MnCl
2)
in
rats
following
intra
peritoneal
injection
or
gavage
dosing.
Manganese
concentrations
were
not
increased
in
the
blood
or
brain
following
administration
of
4
weekly
doses
of
1.22
mg
Mn/
kg
of
the
dioxide
via
gavage;
following
i.
p.
dosing,
manganese
concentrations
were
significantly
increased
in
the
blood,
striatum,
cerebellum
and
cortex.
Steady­
state
blood
manganese
concentrations
were
increased
to
similar
levels
by
both
gavage
and
i.
p.
dosing
of
MnCl
2.
Gavage
dosing
of
the
dichloride
significantly
increased
the
cortex
manganese
concentrations,
but
not
that
of
the
other
two
regions.
Intra
peritoneal
dosing
of
the
compound
increased
the
manganese
levels
in
the
striatum
and
cortex,
but
not
the
cerebellum.
These
data
indicate
that
depending
on
the
compound,
injection
administration
of
manganese
results
in
higher
blood
and
brain
concentrations
of
the
metal
than
does
gavage
administration.

Toxic
effects
of
oral
manganese
exposure
have
also
been
reported
in
the
hematopoietic,
cardiovascular,
reproductive,
and
digestive
systems
in
animals.
Hematological
and
biochemical
outcomes
vary
depending
on
age
and
iron
status,
with
young
or
iron­
deficient
animals
more
likely
to
exhibit
adverse
effects.
Other
effects
observed
following
manganese
exposure
include
reduced
body
weight
and
reduced
liver
weight.
Animal
studies
suggest
that
manganese
is
not
a
potent
developmental
toxicant.
7­
49
Manganese
 
February
2003
Infants
have
been
identified
as
a
potentially
sensitive
subpopulation
for
excess
manganese
exposure.
This
determination
reflects
evidence
for
higher
levels
of
manganese
retention
in
the
brains
of
neonates
than
in
adults,
although
the
relationship
between
manganese
accumulation
in
the
neonatal
brain
and
toxicity
remains
unclear
(
U.
S.
EPA,
1993).
Additional
concerns
include
evidence
for
greater
extent
of
manganese
transport
across
the
blood­
brain
barrier,
the
high
concentration
of
manganese
in
some
infant
formulas,
and
evidence
suggestive
of
a
possible
link
between
manganese
exposure
and
learning
disabilities.
Although
a
causal
relationship
has
not
been
established
for
elevated
manganese
intake
and
learning
disabilities,
a
need
for
further
research
in
this
area
has
been
noted
(
U.
S.
EPA,
1993).

Other
potentially
sensitive
subpopulations
for
manganese
exposure
have
been
identified.
In
general,
these
are
groups
who
may
have
greater
potential
for
increased
body
burdens
due
to
increased
absorption
or
altered
clearance
mechanisms.
The
list
includes
pregnant
women,
elderly
persons,
iron­
or
calcium­
deficient
individuals,
and
individuals
with
impaired
liver
function.

7.4.2
Synthesis
and
Evaluation
of
Carcinogenic
Effects
The
carcinogenic
potential
of
ingested
manganese
has
not
been
systematically
evaluated
in
epidemiological
studies.

Data
from
animal
studies
are
also
limited.
Currently,
one
of
the
few
adequately
designed
investigations
is
the
2­
year
oral
exposure
study
conducted
by
the
National
Toxicology
Program
(
NTP,
1993).
Groups
of
F344
rats
(
70/
sex)
were
provided
with
diets
containing
0,
1,500,
5,000,
or
15,000
ppm
manganese
sulfate
monohydrate.
These
dietary
concentrations
were
reported
to
be
equivalent
to
an
intake
ranging
from
30
to
331
mg
Mn/
kg­
day
for
males,
and
26
to
270
mg
Mn/
kg­
day
for
females.
No
increase
in
any
tumor
type
could
be
attributed
to
manganese
exposure.

In
a
concurrent
study,
B6C3F
1
mice
were
administered
0,
1,500,
5,000,
or
15,000
mg/
kg
manganese
sulfate
monohydrate
(
NTP,
1993).
These
dietary
concentrations
were
reported
to
be
equivalent
to
an
intake
ranging
from
63
to
722
mg
Mn/
kg­
day
for
males
and
77
to
905
mg
Mn/
kg­
day
for
females.
Compared
to
controls,
the
incidences
of
thyroid
follicular
cell
hyperplasia
were
significantly
greater
in
high­
dose
males
and
in
females
at
all
dose
levels.
The
incidence
of
follicular
cell
adenomas
in
high­
dose
males
(
6%)
was
slightly
greater
than
the
range
of
historical
incidence
in
NTP
studies
of
follicular
cell
adenomas
in
male
B6C3F
1
mice
(
0
 
4%).
In
high­
dose
females,
the
incidence
of
follicular
cell
adenomas
(
10%)
was
also
slightly
above
the
historical
control
range
(
0
 
9%).
Follicular
cell
tumors
were
seen
only
at
the
termination
of
the
study
(
729
days).
NTP
(
1993)
reported
that
the
manganese
intakes
in
the
high­
dose
mice
were
107
times
greater
than
the
recommended
dietary
level.
While
NTP
(
1993)
concluded
that
these
data
provided
"
equivocal
evidence
of
carcinogenic
activity
in
mice,"
U.
S.
EPA
(
1993)
questioned
the
relevance
of
these
findings
to
human
carcinogenesis.
The
basis
for
concern
was
1)
the
large
dose
of
manganese
required
to
elicit
a
response
observed
only
at
the
end
of
the
study,
and
2)
tumor
frequencies
that
were
not
statistically
different
from
historical
controls.
7­
50
Manganese
 
February
2003
Three
additional
studies
address
the
carcinogenicity
of
manganese.
DiPaolo
(
1964)
found
that
a
larger
percentage
of
DBA/
1
mice
exposed
subcutaneously
and
intraperitoneally
to
manganese
chloride
developed
lymphosarcomas
when
compared
to
controls.
A
comprehensive
evaluation
of
these
data
was
not
possible,
however,
because
they
were
published
in
an
abstract
form
which
lacked
sufficient
experimental
detail.
Stoner
et
al.
(
1976)
found
a
higher
frequency
of
lung
tumors
in
strain
A/
Strong
mice
administered
manganese
sulfate
intraperitoneally
as
compared
to
controls.
Although
these
results
are
suggestive
of
carcinogenic
activity,
they
fail
to
meet
the
positive
response
criteria
for
the
interpretation
of
lung
tumor
data
in
this
strain
of
1)
an
increase
in
the
mean
number
of
tumors
per
mouse,
and
2)
an
observable
dose­
response
relationship
(
Shimkin
and
Stoner,
1975).
In
the
third
study,
Furst
(
1978)
injected
F344
rats
intramuscularly
with
manganese
acetylacetonate.
An
increased
incidence
of
fibrosarcomas
was
observed
at
the
injection
site.
Increased
tumor
incidence
was
not
observed
at
other
sites.
When
evaluated
as
a
group,
these
studies
do
not
provide
convincing
evidence
for
carcinogenicity
of
manganese.

Both
negative
and
positive
results
have
been
obtained
in
assays
for
the
genotoxic
effects
of
manganese.
Mutagenicity
assays
in
multiple
tester
strains
of
Salmonella
typhimurium
gave
predominately
negative
results
for
manganese
sulfate
monohydrate
and
manganese
chloride
when
tested
with
or
without
exogenous
metabolic
activation
by
S9
fraction
(
Wong,
1988;
DeMeo
et
al.,
1991;
Pagano
and
Zeiger,
1992;
NTP,
1993).
Neither
compound
induced
mutations
in
Drosophila
melanogaster
as
evaluated
by
sex­
linked
recessive
lethal
or
somatic
mutation
assays
(
Rasmuson,
1985;
Valencia
et
al.,
1985;
NTP,
1993).
Dikshith
and
Chandra
(
1978)
did
not
observe
increased
incidence
of
chromosomal
aberrations
in
rat
bone
marrow
or
spermatogonial
cells
following
oral
administration
of
manganese
chloride.

In
addition
to
the
negative
results
described
above,
positive
results
for
manganese
compounds
have
been
obtained
in
some
assays
for
genotoxicity.
Manganese
sulfate
induced
sister
chromatid
exchange
and
chromosomal
aberrations
in
vitro
in
Chinese
hamster
ovary
cells,
and
induced
chromosomal
aberrations
in
vivo
in
albino
mice
following
oral
administration
(
Joardar
and
Sharma,
1990).
Manganese
compounds
also
induced
or
enhanced
mutation,
transformation,
chromosomal
aberrations,
and
DNA
damage
in
some
assays
conducted
in
mammalian
cell
lines
(
Casto
et
al.,
1979;
Oberly
et
al.,
1982;
DeMeo
et
al.,
1991;
NTP,
1993),
bacteria
(
Orgel
and
Orgel,
1965;
Nishioka,
1975;
Zakour
and
Glickman,
1984),
and
yeast
(
Singh,
1984).
Although
these
results
suggest
that
manganese
may
have
genotoxic
potential,
there
are
presently
no
epidemiological
or
unequivocal
animal
data
to
suggest
that
manganese
is
carcinogenic.

7.4.3
Mode
of
Action
and
Implications
in
Cancer
Assessment
The
molecular
mechanisms
responsible
for
the
toxicity
of
manganese
have
not
been
identified
with
certainty.
Most
effort
has
focused
on
identification
of
mechanisms
mediating
the
toxic
effects
observed
in
the
central
nervous
system.
Multiple
researchers
have
proposed
that
elevated
levels
of
Mn(
II)
and
Mn(
III)
trigger
the
production
of
free
radicals,
reactive
oxygen
species,
and
other
cytotoxic
metabolites
in
brain
tissue.
Generation
of
these
reactive
species
is
hypothesized
to
occur
via
the
oxidation
or
turnover
of
intracellular
catecholamines,
impacts
on
7­
51
Manganese
 
February
2003
mitochondrial
metabolism,
or
stimulation
of
cytochrome
P­
450
activity.
Manganese
may
also
influence
transport
systems,
enzyme
activity
and
receptor
function
in
the
brain
and
other
organs.
At
the
present
time,
there
is
no
evidence
to
link
these
proposed
mechanisms
of
action
to
carcinogenic
potential.

7.4.4
Weight
of
Evidence
Evaluation
for
Carcinogenicity
The
U.
S.
EPA
considers
that
there
are
"
Inadequate
Information
to
Assess
Human
Carcinogenic
Potential"
for
manganese
(
U.
S.
EPA,
1999b).
In
the
past,
the
weight
of
evidence
for
manganese
carcinogenicity
resulted
in
Group
D
(
Not
Classifiable)
using
the
criteria
of
the
U.
S.
EPA
Guidelines
for
Carcinogen
Risk
Assessment
(
U.
S.
EPA,
1986a).
The
classification
of
Group
D
was
verified
on
May
25,
1988
by
the
cancer
risk
assessment
verification
endeavor
(
CRAVE)
Work
Group
of
the
U.
S.
EPA.
The
basis
for
this
determination
is
the
inadequacy
of
existing
studies
for
assessment
of
manganese
carcinogenicity
(
U.
S.
EPA,
1996a).

7.4.5
Sensitive
Populations
Sensitive
populations
are
defined
as
those
which
will
exhibit
an
enhanced
or
altered
response
to
a
chemical
when
compared
with
most
persons
exposed
to
the
same
concentration
of
chemical
in
the
environment.
Factors
that
can
contribute
to
this
altered
response
include
genetic
composition,
age,
developmental
stage,
health
status,
substance
use
history,
and
nutritional
status.
These
factors
may
alter
absorption
and
excretory
processes,
or
compromise
the
function
of
target
organs.
In
general,
the
elderly
with
declining
organ
function
and
infants
and
children
with
developing
organs
and
people
with
liver
malfunction
are
expected
to
be
more
sensitive
to
toxic
substances
than
healthy
adults.

7.4.6
Potential
Childhood
Sensitivity
Neonates
have
been
identified
as
a
potentially
sensitive
subpopulation
for
manganese
exposure.
This
determination
reflects
observations
in
human
(
Zlotkin
and
Buchanan,
1986)
and
animal
(
Keen
et
al.,
1986;
Kostial
et
al.,
1978;
Rehnberg,
et
al.,
1980)
studies
that
suggest
that
neonates
retain
higher
levels
of
administered
manganese
than
adults.

In
adults,
manganese
concentrations
are
retained
within
a
narrow
range
by
the
ability
of
excretion
systems
to
match
the
intake
of
this
element
(
Fechter,
1999).
The
process
responsible
for
manganese
excretion
is
generally
believed
to
require
a
significant
time
period
to
mature
into
the
adult
pattern,
with
adult
patterns
of
excretion
developing
at
about
the
time
of
weaning
(
Fechter,
1999).
During
this
period
of
development,
the
young
organism
might
be
susceptible
to
manganese
toxicity
if
exposed
to
high
levels
in
the
diet
or
via
environmental
contamination.

Data
with
respect
to
fetal
accumulation
are
not
numerous,
but
appear
to
consistently
demonstrate
that
manganese
is
transported
across
the
placenta
to
a
limited
extent
(
Fechter,
1999).
In
32
mother­
infant
pairs,
it
was
shown
that
the
mean
blood
manganese
level
in
the
newborn
was
three
times
higher
than
in
the
maternal
blood
(
Chan
et
al.,
1980).
Up
to
the
age
of
six
weeks,
infants'
erythrocyte
manganese
concentrations
are
higher
than
adults
by
about
7­
9%
(
Hatano
et
7­
52
Manganese
 
February
2003
al.,
1985).
When
all
available
data
are
examined,
it
appears
that
the
fetus
is
relatively
protected
from
manganese
accumulation
when
maternal
exposure
occurs
at
relatively
low
doses.
Under
conditions
of
high
maternal
exposure,
manganese
accumulation
also
appears
to
be
limited
(
Fechter,
1999).
The
mechanism
underlying
this
lack
of
accumulation
is
unknown,
but
may
reflect
increased
maternal
excretion,
limited
uptake
across
the
placenta,
or
fetal
elimination.

The
greatest
concern
for
developmental
susceptibility
has
been
generated
by
data
which
suggest
the
existence
of
a
period
prior
to
weaning
when
the
neonate
is
unable
to
eliminate
manganese.
Fechter
(
1999)
reassessed
data
in
the
published
literature
and
concluded
that
the
available
literature
does
not
support
a
toxicokinetic
basis
for
accumulation
in
the
fetal
or
neonatal
organism
[
relative
to
the
adult
organism],
under
conditions
of
excess
exposure
to
manganese.
While
the
available
data
indicate
that
manganese
does
reach
brain
tissue,
currently
available
evidence
does
not
support
a
clear
regional
distribution.

Kaur
et
al.
(
1980)
found
that
younger
neonates
and
19­
day
fetuses
were
more
susceptible
to
manganese
toxicity
than
older
rats.
Studies
with
54Mn
indicated
that
manganese
was
localized
to
the
liver
and
brain
in
younger
animals,
and
there
was
more
manganese
per
unit
weight
in
younger
animals
when
compared
with
older
animals.

Collipp
et
al.
(
1983)
found
that
hair
manganese
levels
in
newborn
infants
increased
significantly
from
birth
(
0.19
:
g/
g)
to
6
weeks
of
age
(
0.885
:
g/
g)
and
4
months
of
age
(
0.685
:
g/
g)
when
the
infants
were
given
formula.
In
contrast,
there
was
no
significant
increase
in
babies
who
were
breast­
fed
(
0.330
:
g/
g
at
4
months).
These
results
were
attributed
to
the
difference
in
manganese
content
between
infant
formula
and
breast
milk.
Human
breast
milk
is
relatively
low
in
manganese
(
7
to
15
:
g/
L),
while
levels
in
infant
formulas
are
3
to
100
times
higher.
Collipp
et
al.
(
1983)
further
reported
that
the
level
of
manganese
in
the
hair
of
learning
disabled
children
(
0.434
:
g/
g)
was
significantly
increased
in
comparison
to
samples
from
normal
children
(
0.268
:
g/
g).

There
is
at
least
one
study
reporting
different
responses
in
manganese­
treated
neonatal
animals
compared
to
treated
adults
(
Dorman
et
al.,
2000).
Pups
were
administered
MnCl
2
in
water
at
11
or
22
mg
Mn/
kg
for
21
days
by
mouth
and
were
dosed
starting
after
birth,
postnatal
day
1
(
PND
1),
until
weaning,
PND
21.
At
PND
21,
the
effect
of
manganese
treatment
on
motor
activity,
learning
and
memory
(
passive
avoidance
task),
evoked
sensory
response
(
acoustic
startle
reflex),
brain
neurochemistry,
and
brain
pathology
was
evaluated.
Manganese
treatment
at
the
highest
dose
was
associated
with
decreased
body
weight
gain
in
pups,
although
the
authors
indicated
absolute
brain
weight
was
not
significantly
altered.
There
were
no
statistically
significant
effects
on
motor
activity
or
performance
in
the
passive
avoidance
task.
However,
manganese
treatment
induced
a
significant
increase
in
amplitude
of
the
acoustic
startle
reflex.
Significant
increases
in
striatal
DA
and
DOPAC
concentrations
were
also
observed
in
the
highdose
treated
neonates.
No
pathological
lesions
were
observed
in
the
treated
pups.
No
effects
on
body
weight
or
behavior
were
observed
in
treated
adult
animals
in
this
study.
The
authors
indicated
that
these
results
suggest
that
neonatal
rats
are
at
greater
risk
than
adults
for
manganese­
induced
neurotoxicity
when
compared
under
similar
exposure
conditions.
This
study,
along
with
evidence
for
increased
absorption
and
reduced
elimination
in
the
neonate,
7­
53
Manganese
 
February
2003
suggests
that
the
very
young
may
be
more
susceptible
to
the
harmful
effects
of
manganese
exposure
due
to
differences
in
toxicokinetics.

Other
investigators
have
reported
an
association
between
elevated
hair
levels
of
manganese
and
learning
disabilities
in
children
(
Barlow
and
Kapel,
1979;
Pihl
and
Parkes,
1977).
Although
no
causal
relationship
has
been
established
for
learning
disabilities
and
manganese
intake,
further
research
in
this
area
is
warranted
(
U.
S.
EPA,
1993).
The
studies
by
He
et
al.
(
1994)
and
Zhang
et
al.
(
1995)
reported
increased
manganese
levels
in
hair
of
school­
age
children
exposed
to
excess
levels
of
manganese
in
drinking
water
and
food
stuffs.
These
studies
conflict
with
the
Kawamura
et
al.
(
1941)
study
which
showed
that
children
were
not
adversely
affected
by
ingesting
excess
levels
of
manganese.
The
more
recent
studies
differ
in
design,
however,
because
they
measured
early
preclinical
neurological
effects
of
manganese
overexposure.
The
older
studies
did
not
have
the
sensitivity
to
measure
such
effects;
this
may
explain
why
children
were
not
previously
identified
as
a
sensitive
population.
None
of
the
studies
in
children
provide
adequate
exposure
levels
or
properly
control
for
confounding
factors;
therefore,
they
are
not
strong
enough
to
indicate
that
children
are
more
sensitive
than
adults.
They
do
confirm
the
need
for
additional
studies
to
investigate
the
possibility
that
children
may
be
more
susceptible
than
adults
to
the
effects
of
manganese
overexposure.

High
levels
of
manganese
in
infant
formulas
may
also
be
of
concern
since
Lönnerdal
et
al.
(
1987)
reported
increased
absorption
and
retention
of
manganese
in
neonatal
animals.
Manganese
has
also
been
shown
to
cross
the
blood­
brain
barrier,
with
the
rate
of
penetration
in
animal
experiments
being
4
times
higher
in
neonates
than
in
adults
(
Mena,
1974).
Dieter
et
al.
(
1992)
stated
that
"
if
there
were
a
toxicological
limit
to
manganese
according
to
the
principles
of
preventive
health
care,
then
it
would
have
to
be
set
at
0.2
mg/
L
of
manganese
in
water
for
infants
as
a
group
at
risk."

7.4.7
Other
Potentially
Sensitive
Populations
U.
S.
EPA
(
1996a)
has
identified
additional
sensitive
subpopulations
for
manganese
exposure.
In
general,
these
are
groups
who
may
have
greater
potential
for
increased
body
burdens
due
to
increased
absorption
or
altered
clearance
mechanisms.
The
list
includes
pregnant
women,
elderly
persons,
iron­
or
calcium­
deficient
individuals,
and
individuals
with
impaired
liver
function.
8­
1
Manganese
 
February
2003
8.0
DOSE­
RESPONSE
ASSESSMENT
8.1
Dose­
Response
for
Noncancer
Effects
8.1.1
RfD
Determination
Choice
of
Principal
Study
and
Critical
Effect
Manganese
is
an
essential
trace
element
that
is
required
for
normal
physiologic
function
in
humans
and
animals.
Excess
exposure
to
manganese,
particularly
via
the
inhalation
route,
is
associated
with
neurotoxicological
symptoms
that
resemble
parkinsonism.
Thus,
derivation
of
the
RfD
must
consider
issues
of
both
essentiality
and
toxicity.

The
RfD
is
not
based
on
rodent
studies,
because
rodents
do
not
exhibit
the
same
neurologic
deficits
that
humans
do
following
exposure
to
manganese.
For
example,
manganese
at
high
doses
induces
parkinson­
like
symptoms
in
humans
and
primates,
but
not
in
rodents.
Because
of
the
species
difference
in
the
response
to
manganese
exposure,
rodents
are
not
good
models
for
manganese
toxicity
studies.
More
details
on
this
can
be
seen
in
IRIS
(
U.
S.
EPA,
1996a).

The
reference
dose
(
RfD)
is
based
on
the
extensive
information
available
for
the
dietary
intake
of
manganese
by
human
populations
(
U.
S.
EPA,
1996a).
Freeland­
Graves
et
al.
(
1987)
reviewed
human
studies
and
proposed
an
estimated
safe
and
adequate
daily
dietary
intake
of
3.5
to
7
mg
for
adults.
WHO
(
1973)
reviewed
data
on
adult
diets
and
concluded
on
the
basis
of
manganese
balance
studies
that
2
to
3
mg/
day
is
an
adequate
daily
intake
and
8
to
9
mg/
day
is
"
perfectly
safe."

Dose­
Response
Assessment
and
Method
of
Analysis
The
current
RfD
for
manganese
was
derived
from
information
gathered
in
dietary
surveys
of
manganese
exposure.
In
various
surveys,
manganese
intakes
of
adults
eating
western­
type
and
vegetarian
diets
ranged
from
0.7
to
10.9
mg
per
day
(
Freeland­
Graves,
1994;
Gibson,
1994
as
cited
by
IOM,
2002).
Depending
on
individual
diets,
a
normal
intake
may
be
well
over
10
mg
per
day,
especially
from
a
vegetarian
diet
Based
on
this
information,
the
U.
S.
EPA
(
1996a)
considers
a
dietary
intake
of
10
mg/
day
to
be
safe
for
a
70
kg
adult.
Thus,
the
resulting
dose
of
0.14
mg/
kg­
day
represents
a
NOAEL
for
chronic
human
consumption
of
manganese
in
the
diet
(
U.
S.
EPA,
1996a).

Application
of
Uncertainty
and
Modifying
Factors
U.
S.
EPA
(
1996a)
has
recommended
use
of
an
uncertainty
factor
of
1
for
derivation
of
the
manganese
RfD.
This
recommendation
is
based
on
the
following
considerations.
Manganese
is
an
essential
trace
element
for
human
health.
The
information
used
to
derive
the
RfD
was
collected
from
many
large
human
populations
consuming
normal
diets
over
an
extended
period
of
time.
The
available
data
suggest
that
as
long
as
physiological
systems
are
not
overwhelmed,
8­
2
Manganese
 
February
2003
humans
exert
effective
homeostatic
control
over
manganese
so
that
body
burden
is
kept
relatively
constant
when
concentration
of
manganese
in
the
diet
varies.

U.
S.
EPA
(
1996a)
has
recommended
the
use
of
a
modifying
factor
of
3
when
assessing
exposure
to
manganese
from
drinking
water.
U.
S.
EPA
(
1996a)
has
outlined
four
reasons
for
this
recommendation:

°
While
toxicokinetic
data
suggest
that
there
is
no
significant
difference
in
absorption
of
manganese
from
food
versus
water,
uptake
of
manganese
from
water
appears
to
be
greater
in
fasted
individuals.

°
The
study
by
Kondakis
et
al.
(
1989)
raises
concern
for
possible
adverse
health
effects
associated
with
a
lifetime
consumption
of
drinking
water
containing
2
mg/
L
of
manganese.

°
Evidence
exists
that
neonates
absorb
more
manganese
from
the
gastrointestinal
tract,
and
excrete
less
of
the
absorbed
manganese.
Additional
evidence
suggests
that
absorbed
manganese
more
easily
crosses
the
blood­
brain
barrier
in
neonates.
However,
this
evidence
comes
from
animal
studies;
similar
absorption
studies
in
human
neonates
have
not
been
performed,
although
Collipp
et
al.
(
1983)
observed
increased
hair
manganese
levels
in
infants
fed
prepared
formula
compared
with
infants
fed
breast
milk.

°
Infant
formula
typically
contains
a
much
higher
concentration
of
manganese
than
human
or
cows'
milk.
Powdered
formula
reconstituted
with
drinking
water
represents
an
additional
source
of
manganese
intake
for
a
potentially
sensitive
population.

These
potential
impacts
on
children,
when
considered
in
conjunction
with
the
likelihood
that
the
most
adverse
effects
of
manganese
(
e.
g.,
those
seen
in
manganese
miners
or
others
with
chronic
overexposure
to
inhaled
manganese)
are
likely
to
be
irreversible
and
not
manifested
for
many
years
after
exposure,
warrant
caution
until
more
definitive
data
are
available
(
U.
S.
EPA,
1996a).
Recent
data
indicate,
however,
that
in
contrast
to
the
symptoms
of
manganism,
preclinical
neurological
effects
of
inhalation
exposure
of
occupational
workers
to
excess
manganese
are
reversible
(
Roels
et
al.,
1999).
Similarly,
symptoms
of
oral
exposure
to
excess
manganese
in
compromised
individuals
(
e.
g.,
individuals
with
liver
disease
who
could
not
excrete
manganese
in
the
bile)
were
resolved
when
the
exposure
to
excess
manganese
was
decreased
(
Devenyi
et
al.,
1994;
Fell
et
al.,
1996).
These
data
indicate
that
the
human
body
can
recover
from
certain
adverse
effects
of
overexposure
to
manganese
if
the
exposure
is
stopped
and
the
body
can
clear
the
excess.
Significant
uncertainty
still
exists,
however,
concerning
at
what
level
of
manganese
intake
these
preclinical
neurological
symptoms
might
occur.
8­
3
Manganese
 
February
2003
The
RfD
for
chronic
exposure
to
manganese
in
drinking
water
is
therefore
calculated
as
follows:

RfD
=
0.14
mg/
kg­
day
=
0.047
mg/
kg­
day
1
×
3
where:

0.14
mg/
kg­
day
=
Chronic
NOAEL
for
dietary
manganese.

1
=
Uncertainty
factor.

3
=
Recommended
uncertainty
factor
for
exposure
in
drinking
water
8.1.2
RfC
Determination
The
inorganic
manganese
compounds
predominating
in
drinking
water
are
non­
volatile.
Inhalation
of
manganese
during
use
of
drinking
water
for
residential
activities
is
therefore
not
expected
to
be
a
significant
pathway
of
exposure
or
toxicity.

U.
S.
EPA
(
1996a)
has
derived
an
inhalation
Reference
Concentration
(
RfC)
for
manganese
of
5
×
10­
5
mg/
m3.

Choice
of
Principal
Study
and
Critical
Effect
The
RfC
for
manganese
(
U.
S.
EPA,
1996a)
was
derived
using
data
from
two
epidemiological
studies
of
workers
exposed
to
manganese
dioxide
dust
in
occupational
studies
(
Roels
et
al.,
1987;
Roels
et
al.,
1992).
The
critical
effect
was
impairment
of
neurobehavioral
function,
as
assessed
by
medical
questionnaire,
audio­
verbal
short­
term
memory,
visual
simple
reaction
time,
hand
steadiness,
and
eye­
hand
coordination.

Dose­
Response
Characterization
and
Method
of
Analysis
The
toxicity
data
for
manganese
were
evaluated
using
the
conventional
NOAEL/
LOAEL
approach.
Neither
of
the
principal
studies
identified
a
NOAEL.
The
LOAEL
from
the
Roels
et
al.
(
1992)
is
derived
from
an
occupational­
lifetime
integrated
respirable
dust
(
IRD)
concentration
of
manganese
dioxide
(
based
on
8­
hour
time­
weighted
average
[
TWA]
occupational
exposures
for
various
job
classifications,
multiplied
by
individual
work
histories
in
years).
This
LOAEL
is
expressed
as
mg
Mn/
m3­
year.
The
IRD
concentrations
ranged
from
0.040
to
4.433
mg
Mn/
m3­
year,
with
a
geometric
mean
of
0.793
mg
Mn/
m3­
year
and
a
geometric
standard
deviation
of
2.907.
The
geometric
mean
concentration
(
0.793
Mn/
m3­
year)
was
divided
by
the
average
duration
of
manganese
dioxide
exposure
(
5.3
years)
to
obtain
a
LOAEL
TWA
of
0.15
mg
Mn/
m3­
year.
The
LOAEL
(
Human
Equivalent
Concentration,
HEC)
is
0.05
mg/
m3.

The
LOAEL
identified
in
the
Roels
et
al.
(
1987)
study
is
based
on
an
8­
hour
TWA
occupational
exposure.
The
TWA
of
total
airborne
manganese
dust
ranged
from
0.07
to
8.61
mg/
m3,
and
the
median
was
0.97
mg/
m3.
The
LOAEL
(
HEC)
is
0.34
mg/
m3.
8­
4
Manganese
 
February
2003
Application
of
Uncertainty
and
Modifying
Factors
No
modifying
factor
was
used
in
derivation
of
the
RfC.
A
composite
uncertainty
factor
of
1,000
was
used
and
reflects
a
factor
of
10
for
protection
of
sensitive
individuals,
a
factor
of
10
for
use
of
a
LOAEL,
and
a
factor
of
10
for
database
limitations.
The
factor
of
10
for
database
limitations
reflects
an
exposure
period
of
less
than
chronic
duration,
lack
of
developmental
data,
and
potential
but
unquantified
differences
in
the
toxicity
of
different
forms
of
manganese.

8.2
Dose­
Response
for
Cancer
Effects
Manganese
has
in
the
past
been
classified
as
a
Group
D
chemical
 
NOT
CLASSIFIABLE
as
to
HUMAN
CARCINOGENICITY.
This
category
is
assigned
to
chemicals
for
which
there
is
inadequate
human
and
animal
evidence
of
carcinogenicity,
or
for
which
no
data
are
available.
There
are
presently
no
human
data
to
suggest
an
association
of
oral
manganese
exposure
with
increased
cancer
incidence.
Data
collected
from
a
2­
year
oral
exposure
study
in
rats
did
not
reveal
evidence
for
carcinogenic
activity
(
NTP,
1993).
Data
collected
from
a
2­
year
oral
exposure
study
in
mice
revealed
an
apparent
increase
in
tumor
incidence
at
the
highest
dose
administered,
but
only
near
the
end
of
the
study
(
NTP,
1993).
The
observed
increase
was
not
significantly
different
from
the
historical
control
incidence.
These
results
are
considered
to
be
equivocal.
Based
on
the
absence
of
any
significant
cancer
response,
a
quantitative
cancer
dose­
response
assessment
for
manganese
will
not
be
conducted.

Manganese
has
been
evaluated
using
the
criteria
of
the
U.
S.
EPA
Proposed
Guidelines
for
Carcinogen
Risk
Assessment
(
U.
S.
EPA,
1999b).
Based
on
available
data
manganese
is
classified
under
the
category
of
"
Data
are
inadequate
for
assessment
of
human
carcinogenic
potential."
This
descriptor
is
appropriate
when
there
is
a
paucity
of
data
on
carcinogenic
effects,
or
when
the
data
are
conflicting.
9­
1
Manganese
 
February
2003
9.0
RISK
DETERMINATION
AND
CHARACTERIZATION
OF
RISK
FROM
DRINKING
WATER
9.1
Regulatory
Determination
for
Chemicals
on
the
CCL
The
Safe
Drinking
Water
Act
(
SDWA),
as
amended
in
1996,
required
the
Environmental
Protection
Agency
(
EPA)
to
establish
a
list
of
contaminants
to
aid
the
Agency
in
regulatory
priority
setting
for
the
drinking
water
program.
EPA
published
a
draft
of
the
first
Contaminant
Candidate
List
(
CCL)
on
October
6,
1997
(
62
FR
52193,
U.
S.
EPA,
1997).
After
review
of
and
response
to
comments,
the
final
CCL
was
published
on
March
2,
1998
(
63
FR
10273,
U.
S.
EPA,
1998).
The
CCL
grouped
contaminants
into
three
major
categories
as
follows:

Regulatory
Determination
Priorities
­
Chemicals
or
microbes
with
adequate
data
to
support
a
regulatory
determination,

Research
Priorities
­
Chemicals
or
microbes
requiring
research
for
health
effects,
analytical
methods,
and/
or
treatment
technologies,

Occurrence
Priorities
­
Chemicals
or
microbes
requiring
additional
data
on
occurrence
in
drinking
water.

The
March
2,
1998
CCL
included
one
microbe
and
19
chemicals
in
the
regulatory
determination
priority
category.
More
detailed
assessments
of
the
completeness
of
the
health,
treatment,
occurrence
and
analytical
method
data
led
to
a
subsequent
reduction
of
the
regulatory
determination
priority
chemicals
to
a
list
of
12
(
one
microbe
and
11
chemicals)
which
was
distributed
to
stakeholders
in
November
1999.

SDWA
requires
EPA
to
make
regulatory
determinations
for
no
fewer
than
five
contaminants
in
the
regulatory
determination
priority
category
by
August,
2001.
In
cases
where
the
Agency
determines
that
a
regulation
is
necessary,
the
regulation
should
be
proposed
by
August
2003
and
promulgated
by
February
2005.
The
Agency
is
given
the
freedom
to
also
determine
that
there
is
no
need
for
a
regulation
if
a
chemical
on
the
CCL
fails
to
meet
one
of
three
criteria
established
by
SDWA
and
described
in
Section
9.1.1.

9.1.1
Criteria
for
Regulatory
Determination
These
are
the
three
criteria
used
to
determine
whether
or
not
to
regulate
a
chemical
on
the
CCL:

The
contaminant
may
have
an
adverse
effect
on
the
health
of
persons,

The
contaminant
is
known
to
occur
or
there
is
a
substantial
likelihood
that
the
contaminant
will
occur
in
public
water
systems
with
a
frequency
and
at
levels
of
public
health
concern,
9­
2
Manganese
 
February
2003
In
the
sole
judgment
of
the
administrator,
regulation
of
such
contaminant
presents
a
meaningful
opportunity
for
health
risk
reduction
for
persons
served
by
public
water
systems.

The
findings
for
all
criteria
are
used
in
making
a
determination
to
regulate
a
contaminant.
As
required
by
SDWA,
a
decision
to
regulate
commits
the
EPA
to
publication
of
a
Maximum
Contaminant
Level
Goal
(
MCLG)
and
promulgation
of
a
National
Primary
Drinking
Water
Regulation
(
NPDWR)
for
that
contaminant.
The
Agency
may
determine
that
there
is
no
need
for
a
regulation
when
a
contaminant
fails
to
meet
one
of
the
criteria.
A
decision
not
to
regulate
is
considered
a
final
Agency
action
and
is
subject
to
judicial
review.
The
Agency
can
choose
to
publish
a
Health
Advisory
(
a
nonregulatory
action)
or
other
guidance
for
any
contaminant
on
the
CCL
independent
of
the
regulatory
determination.

9.1.2
National
Drinking
Water
Advisory
Council
Recommendations
In
March
2000,
the
EPA
convened
a
Working
Group
under
the
National
Drinking
Water
Advisory
Council
(
NDWAC)
to
help
develop
an
approach
for
making
regulatory
determinations.
The
Working
Group
developed
a
protocol
for
analyzing
and
presenting
the
available
scientific
data
and
recommended
methods
to
identify
and
document
the
rationale
supporting
a
regulatory
determination
decision.
The
NDWAC
Working
Group
report
was
presented
to
and
accepted
by
the
entire
NDWAC
in
July
2000.

Because
of
the
intrinsic
difference
between
microbial
and
chemical
contaminants,
the
Working
Group
developed
separate
but
similar
protocols
for
microorganisms
and
chemicals.
The
approach
for
chemicals
was
based
on
an
assessment
of
the
impact
of
acute,
chronic,
and
lifetime
exposures,
as
well
as
a
risk
assessment
that
includes
evaluation
of
occurrence,
fate,
and
dose
response.
The
NDWAC
Protocol
for
chemicals
is
a
semi­
quantitative
tool
for
addressing
each
of
the
three
CCL
criteria.
The
NDWAC
requested
that
the
Agency
use
good
judgement
in
balancing
the
many
factors
that
need
to
be
considered
in
making
a
regulatory
determination.

The
EPA
modified
the
semi­
quantitative
NDWAC
suggestions
for
evaluating
chemicals
against
the
regulatory
determination
criteria
and
applied
them
in
decision
making.
The
quantitative
and
qualitative
factors
for
manganese
that
were
considered
for
each
of
the
three
criteria
are
presented
in
the
sections
that
follow.

9.2
Health
Effects
The
first
criterion
asks
if
the
contaminant
may
have
an
adverse
effect
on
the
health
of
persons.
Because
all
chemicals
have
adverse
effects
at
some
level
of
exposure,
the
challenge
is
to
define
the
dose
at
which
adverse
health
effects
are
likely
to
occur,
and
estimate
a
dose
at
which
adverse
health
effects
are
either
not
likely
to
occur
(
threshold
toxicant),
or
have
a
low
probability
for
occurrence
(
non­
threshold
toxicant).
The
key
elements
that
must
be
considered
in
evaluating
the
first
criterion
are
the
mode
of
action,
the
critical
effect(
s),
the
dose­
response
for
critical
effect(
s),
the
RfD
for
threshold
effects,
and
the
slope
factor
for
non­
threshold
effects.
9­
3
Manganese
 
February
2003
A
full
description
of
the
health
effects
associated
with
exposure
to
manganese
is
presented
in
Chapter
7
of
this
document
and
summarized
below
in
Section
9.2.2.
Chapter
8
and
Section
9.2.3
present
dose­
response
information.

9.2.1
Health
Criterion
Conclusion
The
available
toxicological
data
indicate
that
manganese
has
the
potential
to
cause
adverse
health
effects
in
humans
and
animals
at
high
doses.
The
primary
route
of
exposure
to
toxic
levels
of
manganese
is
through
the
inhalation
of
manganese
dust.
An
increased
potential
exists
for
inhalation
and
ingestion
exposure
to
manganese
as
a
result
of
the
use
of
MMT
in
fuels.
Zayed
et
al.
(
1999a)
measured
airborne
manganese
concentrations
(
as
MMT,
respirable,
and
total
manganese)
in
five
different
microenvironments
around
Montreal,
Canada.
The
authors
determined
that
the
average
daily
exposure
to
respirable
manganese
was
0.010
:
g/
kg­
day
and
had
a
low
contribution
to
air,
food,
and
water.
Oral
exposure
to
levels
of
toxicological
concern
is
rare.
In
humans,
neurological
effects
are
the
most
likely
manifestation
of
manganese
toxicity.
There
is
no
information
available
regarding
the
carcinogenicity
of
manganese
in
humans,
and
animal
studies
have
reported
mixed
results.
Manganese
is
classified
as
Group
D,
or
Not
classifiable
as
to
human
carcinogenicity.
The
Reference
Concentration
(
RfC)
for
manganese
is
5
x
10­
5
mg/
m3
(
U.
S.
EPA,
1998a)
which
is
derived
using
data
from
two
epidemiological
studies
of
workers
exposed
to
manganese
dioxide
dust
in
an
occupational
setting
(
Roels
et
al.,
1987;
Roels
et
al.,
1992).
The
critical
effect
was
impairment
of
neurobehavioral
function.
The
current
RfD
for
manganese
in
food
is
0.14
mg/
kg­
day;
and
for
drinking
water,
0.047
mg/
kg­
day.
Despite
the
fact
that
it
is
possible
for
manganese
to
elicit
some
toxic
effects
at
very
high
doses,
the
database
is
too
uncertain,
especially
related
to
children
and
other
sensitive
populations.
Based
on
the
occurrence
of
adverse
effects
in
humans
and
animals,
the
evaluation
for
Criterion
#
1
is
positive.

9.2.2
Hazard
Characterization
and
Mode
of
Action
Implications
The
primary
health
effect
of
manganese
exposure
is
neurotoxicity,
which
is
characterized
at
high
doses
by
ataxia,
increased
anxiety,
dementia,
a
"
mask­
like"
face,
general
extrapyrimidal
syndrome,
or
manganism,
a
syndrome
similar
to
Parkinson's
disease.
The
precise
mechanisms
of
manganese
neurotoxicity
are
not
known,
although
the
observed
effects
of
manganese
on
the
globus
pallidus
region
of
the
brain
suggest
that
a
likely
mechanism
involves
impairment
of
dopaminergic
function.
Preclinical
adverse
neurological
effects
have
been
reported
at
much
lower
doses
than
those
resulting
in
manganism,
however.
Therefore,
the
possibility
exists
that
any
potential
neurological
effects
resulting
from
environmental
exposures
to
manganese
would
likely
be
more
comparable
to
these
subtle,
though
potentially
significant,
changes
in
neurological
function.

Studies
in
humans
and
animals
are
mixed,
but
most
animal
studies
indicate
that
children
are
a
potentially
sensitive
subpopulation
based
on
decreased
excretion
in
the
neonate
(
Lönnerdal,
1994).
Additional
potentially
sensitive
sub­
populations
include
the
elderly,
pregnant
women,
iron­
deficient
individuals,
and
individuals
with
impaired
liver
function.
9­
4
Manganese
 
February
2003
Because
the
primary
route
of
elimination
for
manganese
is
biliary
excretion,
persons
with
impaired
liver
function
may
be
especially
susceptible
to
manganese
toxicity
(
Layrargues
et
al.,
1998).
Persons
in
a
state
of
iron
deficiency
may
also
experience
greater
susceptibility
to
manganese
absorption
and
toxicity
(
Finley,
1999;
Finley
et
al.,
1994).
In
addition,
infants
and
neonates,
in
which
the
capacity
for
excretion
through
the
bile
is
not
fully
developed,
may
also
be
potentially
susceptible
to
manganese
toxicity
(
Lönnerdal,
1994).
Although
animal
studies
have
indicated
an
increased
potential
in
neonates
for
gastrointestinal
absorption
of
manganese,
as
well
as
decreased
excretion
potential,
the
degree
to
which
these
findings
apply
to
human
infants
is
unknown.
Dorman
et
al.
(
2000)
have
shown,
however,
that
there
is
increased
sensitivity
for
neurotoxic
effects
following
manganese
exposure
in
neonatal
rats
compared
to
adult
rats.
Because
manganese
is
an
essential
nutrient
in
developing
infants,
however,
the
potential
adverse
effects
from
manganese
deficiency
may
be
of
greater
concern
than
potential
toxicity
from
overexposure

An
added
complication
is
the
fact
that
many
inhibitors
of
manganese
absorption,
such
as
phytates
and
plant
fiber,
are
common
in
the
diet
and
may
thus
lower
the
actual
absorption
of
ingested
manganese.
Also,
manganese
absorption
from
foods
that
are
potentially
high
sources
may
be
inhibited
by
other
factors
such
as
the
presence
of
co­
occurring
plant
proteins
that
bind
manganese
and
decrease
its
bioavailability.
Thus,
although
the
manganese
content
in
the
soybased
formula
is
higher
than
manganese
content
in
human
milk,
the
actual
absorption
of
manganese
in
the
formula
may
not
be
substantially
greater
since
it
is
prepared
with
soy
milk,
which
is
high
in
phytate
and
vegetable
protein.
Data
exist,
however,
that
argue
against
this
possibility.
For
example,
Keen
et
al.
(
1986)
demonstrated
in
rat
pups
that
manganese
uptake
from
human
breast
milk
and
cow's
milk
was
higher
(~
80%
and
~
89
%,
respectively)
than
that
from
soy
formula
(~
60%),
but
the
absolute
amount
of
manganese
retained
from
soy
was
25
times
the
amount
retained
from
human
milk.
Dorner
et
al.
(
1989)
also
reported
increased
retention
of
manganese
in
full­
term
human
infants
fed
cow's­
milk
formulas
compared
to
breast­
fed
infants.
Human
milk
and
cow's
milk
contain
different
proteins
that
bind
manganese.
In
some
cases,
the
presence
of
these
proteins
may
enhance
manganese
transport
across
the
gut
wall
and
hence
increase
absorption.
If
infant
formula
is
prepared
with
contaminated
water,
then
it
is
possible
that
the
manganese
will
remain
in
a
soluble
form
which
may
be
more
easily
absorbed.
More
data
are
needed
on
the
various
factors
affecting
manganese
absorption
in
infants
before
a
confident
determination
can
be
made.
Other
instances
in
which
high
dietary
levels
of
manganese
may
not
necessarily
correspond
to
high
dose
levels
include
vegetarian
diets
(
many
vegetables
contain
high
manganese
levels
but
also
high
fiber
and
phytate
levels)
and
possibly
tea
drinkers
(
tea
also
contains
high
manganese
levels
accompanied
by
high
levels
of
tannin,
another
inhibitor
of
manganese
absorption).

Several
studies
have
explored
the
level
of
manganese
intake
which
may
be
considered
safe
in
humans.
The
Food
and
Nutrition
Board
(
IOM,
2002)
set
an
adequate
intake
level
for
manganese
of
2.3
mg/
day
for
men
and
1.8
mg/
day
for
women
(
IOM,
2002;
Trumbo
et
al.,
2001).
The
Food
and
Nutrition
Board
also
set
a
tolerable
upper
intake
level
of
11
mg
Mn/
day
for
adults
based
on
the
Greger
(
1999)
review,
which
suggested
that
people
eating
western­
type
and
vegetarian
diets
may
have
intakes
as
high
as
10.9
mg/
day
(
IOM,
2002).
Further,
for
short­
term
9­
5
Manganese
 
February
2003
duration,
Davis
and
Greger
(
1992)
found
that
daily
intake
of
15
mg/
day
for
90
days
resulted
in
no
adverse
effects
in
women;
the
only
effect
seen
was
an
increase
in
superoxide
dismutase
activity.

No
significant
exposure­
related
neurological
effects
were
seen
in
a
cohort
in
Germany
exposed
for
up
to
40
years
to
manganese
in
their
well
water
at
levels
as
high
as
2.160
mg/
L
(
0.3
to
2.160
mg/
L;
Vierrege
et
al.,
1995).
On
the
other
hand,
a
study
in
Greece
which
examined
older
populations
chronically
exposed
to
well
water
containing
up
to
around
2
mg/
L
found
effects
on
neurological
function
in
the
high­
exposure
group
(
Kondakis
et
al.,
1989);
however,
this
study
did
not
adequately
account
for
potential
bias
in
subjective
neurological
test
scores.
Neither
study
reported
the
dietary
or
other
sources
of
manganese
intake.

9.2.3
Dose­
Response
Characterization
and
Implications
in
Risk
Assessment
The
dose­
response
relationship
for
neurological
effects
of
manganese
by
ingestion
is
not
well­
characterized
in
animals
or
humans,
but
epidemiological
data
for
humans
indicate
that
intakes
as
high
as
11
mg/
day
(
0.16
mg/
kg­
day)
may
not
cause
adverse
effects
in
adult
humans.
Additional
evidence
suggests
a
safe
level
as
high
as
15
mg/
day
(
0.21
mg/
kg­
day
for
adult),
based
on
a
study
in
which
women
received
daily
supplements
of
15
mg
manganese
for
90
days
and
exhibited
only
an
increase
in
lymphocyte
manganese­
dependent
superoxide
dismutase,
but
no
measured
adverse
effects
(
Davis
and
Greger,
1992).
Characterizing
dose­
response
in
humans
is
complicated
by
the
fact
that
manganese
is
an
essential
nutrient,
and
therefore
some
minimal
level
of
intake
is
necessary
for
good
health.
There
are
many
reports
of
toxicity
to
humans
exposed
to
manganese
by
inhalation;
much
less
is
known,
however,
about
oral
intakes
resulting
in
toxicity.
Rodents
do
not
provide
a
good
experimental
model
for
manganese
toxicity
and
only
one
limited
study
in
primates
by
the
oral
route
of
exposure
is
available
(
Gupta
et
al.,
1980).

A
review
of
acute
animal
toxicity
studies
of
manganese
indicates
that
the
manganese
has
low
to
moderate
oral
toxicity.
For
example,
the
oral
LD
50
values
for
manganese
compounds
in
rats
are
in
the
range
of
400
to
2,000
mg
Mn/
kg.
Some
animal
studies
have
also
reported
developmental
and
reproductive
effects
at
high
doses
for
some
manganese
compounds,
but
most
data
from
oral
exposure
suggest
that
manganese
has
a
low
developmental
toxicity.

EPA
has
calculated
an
RfD
for
manganese.
The
RfD
for
manganese
in
food
is
0.14
mg/
kg­
day,
based
on
dietary
surveys
that
have
reported
that,
for
an
average
70
kg
adult,
having
a
daily
manganese
intake
of
10
mg
presents
no
adverse
effect.
For
drinking
water,
EPA
recommends
to
apply
a
modifying
factor
(
MF)
of
3
to
yield
a
value
of
0.047
mg/
kg­
day.
This
modifying
factor
is
meant
to
address
the
concern
raised
by
the
epidemiology
study
(
Kondakis
et
al.,
1989),
and
a
potential
higher
absorption
of
manganese
in
water,
especially
when
drinking
fluids
early
in
the
morning,
when
the
gut
is
empty.
EPA
has
medium
confidence
in
the
RfD
for
manganese.
9­
6
Manganese
 
February
2003
9.3
Occurrence
in
Public
Water
Systems
The
second
criterion
asks
if
the
contaminant
is
known
to
occur
or
if
there
is
a
substantial
likelihood
that
the
contaminant
will
occur
in
public
water
systems
with
a
frequency
and
at
levels
of
public
health
concern.
In
order
to
address
this
question,
the
following
information
was
considered:

°
Monitoring
data
from
public
water
systems
°
Ambient
water
concentrations
and
releases
to
the
environment
°
Environmental
fate
Data
on
the
occurrence
of
manganese
in
public
drinking
water
systems
were
the
most
important
determinants
in
evaluating
the
second
criterion.
EPA
looked
at
the
total
number
of
systems
that
reported
detections
of
manganese,
as
well
those
that
reported
concentrations
of
manganese
above
an
estimated
drinking
water
health
reference
level
(
HRL).
For
noncarcinogens
the
estimated
HRL
risk
level
was
calculated
from
the
RfD
assuming
that
20%
of
the
total
exposure
would
come
from
drinking
water.
For
carcinogens,
the
HRL
was
the
10­
6
risk
level.
The
HRLs
are
benchmark
values
that
were
used
in
evaluating
the
occurrence
data
while
the
risk
assessments
for
the
contaminants
were
being
developed.

The
available
monitoring
data,
including
indications
of
whether
or
not
the
contamination
is
a
national
or
a
regional
problem,
are
included
in
Chapters
4
of
this
document
and
are
summarized
below.
Additional
information
on
production,
use,
and
environmental
fate
are
found
in
Chapters
2
and
3.

9.3.1
Occurrence
Criterion
Conclusion
The
available
data
for
manganese
production
and
use
indicate
a
fairly
stable
trend
for
both.
While
release
of
manganese
to
surface
water
is
variable
within
a
wide
range
of
values,
release
of
manganese
compounds
to
surface
water
is
increasing.
Releases
of
manganese
and
manganese
compounds
to
land
are
generally
decreasing,
while
releases
of
manganese
to
air
are
decreasing
and
air
emissions
of
manganese
compounds
are
stable
(
Tables
3­
4
and
3­
5).
MMT
in
gasolines
provides
a
relatively
new
environmental
source
of
manganese
exposure.
Recent
testing
suggests
that
when
very
low
levels
of
MMT
are
combusted
(
i.
e.,
concentrations
comparable
to
the
currently
allowed
levels),
manganese
is
emitted
primarily
as
manganese
phosphate
and
sulfate.
Data
on
the
occurrence
of
manganese
in
air
resulting
from
combustion
of
MMT
and
other
sources
are
presented
in
Section
4.2.
Pfeifer
et
al.
(
1999)
determined
that
two
occupational
groups,
office
workers
and
taxi
drivers
were
exposed
to
comparable
concentrations
of
manganese
both
before
and
after
MMT
was
present
in
fuels.
These
data,
however,
are
counter
to
other
modeling
data
that
indicate
that
taxi
drivers
are
exposed
to
increased
concentrations
of
manganese
as
a
result
of
MMT
use
(
Lynam
et
al.,
1994;
Zayed
et
al.,
1994;
Riveros­
Rosas
et
al.,
1997).
Modeling
data
from
five
microenvironments
in
Canada
indicate
that
with
the
currently
acceptable
levels
of
MMT
allowed
in
fuel,
little
impact
to
air
and
surface
water
concentrations
of
9­
7
Manganese
 
February
2003
manganese
is
expected
from
the
use
of
MMT
in
fuels
(
Zayed
et
al.,
1999a).
Monitoring
data
indicate
that
manganese
is
infrequently
detected
in
public
water
supplies.
When
manganese
is
detected,
it
rarely
exceeds
the
HRL
or
a
value
of
one­
half
the
HRL.
Further,
because
manganese
is
an
essential
nutrient,
the
risks
of
over­
exposure
must
be
weighed
against
the
risks
of
manganese
deficiency.
Based
on
these
data,
it
is
unlikely
that
manganese
will
occur
in
public
water
systems
at
frequencies
or
concentration
levels
that
are
of
public
health
concern.
Therefore,
the
evaluation
for
Criterion
#
2
is
negative.

9.3.2
Monitoring
Data
Drinking
Water
Occurrence
data
for
manganese
in
drinking
water
are
presented
and
analyzed
in
Chapter
4
of
this
document.
Estimates
of
exposed
populations
are
derived
in
Section
4.3.
The
National
Inorganic
and
Radionuclide
Survey
(
NIRS)
data
represent
49
States.
Data
were
not
available
for
the
State
of
Hawaii.
Since
NIRS
data
lack
occurrence
information
for
surface
water
systems,
occurrence
data
on
manganese
exposure
from
the
States
of
Alabama,
California,
Illinois,
New
Jersey,
and
Oregon
were
used
to
obtain
information
on
surface
water.

At
a
health
reference
level
(
HRL)
of
0.3
mg/
L,
approximately
6.1%
of
the
NIRS
PWSs
had
detections
greater
than
one­
half
the
HRL
(
about
3,600
ground
water
PWSs
nationally),
affecting
approximately
4.6%
of
the
population
served
(
estimated
at
4.0
million
people
nationally).

The
percentage
of
NIRS
PWSs
with
detections
greater
than
the
HRL
of
0.3
mg/
L
was
approximately
3.2%
(
about
1,920
ground
water
PWSs
nationally),
affecting
2.6
%
of
the
population
served
(
estimated
at
approximately
2.3
million
people
nationally).

The
supplemental
State
data
sets
indicate
that
ground
water
PWS
detections
greater
than
the
HRL
of
0.3
mg/
L
are
between
0.6%
and
12%.
Again,
the
NIRS
national
average
is
within
this
range,
with
3.2%
of
PWSs
greater
than
the
HRL.
Notably,
surface
water
PWSs
showed
fewer
exceedances
of
the
HRL
than
ground
water
PWSs
at
this
higher
concentration,
ranging
from
0%
to
3%.
Extrapolating
national
population
exposures
from
these
limited
data
sets
is
not
possible
because
exposure
to
manganese
through
surface
water
is
not
quantified
beyond
the
five
States
shown.
However,
exposure
estimates
incorporating
surface
water
sources
would
certainly
be
larger
than
the
estimates
provided
here
for
groundwater
sources.

Ambient
Water
The
National
Ambient
Water
Quality
Assessment
(
NAWQA)
program
was
begun
in
1991
by
the
United
States
Geological
Survey
(
USGS)
to
monitor
water
quality
in
representative
study
basins
located
around
the
country.
This
program,
which
consists
of
59
significant
watersheds
and
aquifers,
was
described
in
Chapter
4
of
this
document
in
regard
to
its
use
for
monitoring
ambient
levels
of
manganese
in
surface
and
ground
waters.
The
Minimum
Reporting
Level
9­
8
Manganese
 
February
2003
(
MRL)
in
water
is
0.001
mg/
L,
while
the
MRLs
in
sediments
and
aquatic
biota
tissue
are
4
mg/
kg
and
0.1
mg/
kg,
respectively.

The
data
indicate
that
manganese
is
ubiquitous
in
surface
and
ground
waters,
presumably
as
a
result
of
its
natural
occurrence
in
the
earth's
crust.
The
frequency
of
detection
above
the
HRL
is
generally
higher
in
ground
water
than
in
surface
water,
but
the
median
concentration
in
sites
reporting
a
detection
is
higher
in
surface
water
(
0.016
mg/
L
in
surface
water
versus
0.005
mg/
L
in
ground
water).
Overall,
the
data
indicate
that,
while
manganese
is
nearly
ubiquitous
in
surface
and
ground
water,
detections
at
levels
of
concern
to
public
health
are
relatively
few.

Manganese
has
been
universally
detected
in
stream
sediments
and
aquatic
biota
tissues
at
low
levels.
Manganese
is
not
thought
to
bioaccumulate
in
tissues
to
any
significant
degree,
and
desorption
from
sediments
into
the
water
column
is
also
limited
by
the
insolubility
of
most
manganese
compounds.

9.3.3
Use
and
Fate
Data
Manganese
is
a
naturally
occurring
element
and
is
commonly
found
in
soil,
water,
air,
and
food,
generally
as
a
component
of
over
100
mineral
compounds.
Most
manganese
ore
is
imported
to
the
United
States,
with
the
amount
increasing
from
308
thousand
metric
tons
in
1984
to
535
thousand
metric
tons
in
1999.
Most
of
this
ore
is
smelted
to
produce
ferromanganese,
which
is
used
in
steel
production.
Manganese
compounds
have
a
variety
of
other
uses
in
industry
and
agriculture,
as
described
in
Table
3­
3
of
this
document.

Examination
of
data
from
the
Toxic
Release
Inventory
(
TRI),
shown
in
Tables
3­
4
and
3­
5
of
this
document,
indicates
that
releases
of
manganese
to
water
varied
between
89
thousand
and
2.4
million
pounds
for
the
period
1988
to
1998.
Data
for
manganese
compounds
reveal
an
increasing
trend
in
surface
water
discharges,
from
681
thousand
to
4.5
million
pounds
for
the
same
period.

Once
released
to
the
environment,
manganese
is
readily
deposited
in
the
soil
and
taken
up
by
plants,
whereupon
it
may
enter
the
food
chain.
Significant
bioaccumulation
is
not
expected
to
occur.
Manganese
is
an
essential
nutrient
in
the
diet,
so
some
minimal
intake
is
necessary
for
good
health.
Manganese
particles
may
also
become
airborne,
and
some
manganese
compounds
are
soluble
in
water.
Manganese
compounds
may
also
adsorb
to
sediment
surfaces
and
precipitate
out
of
solution.

Manganese,
in
the
form
of
potassium
permanganate,
may
be
used
in
drinking
water
treatment
for
oxidation
and
disinfection
purposes
(
ANSI/
NSF,
2000),
in
addition
to
its
use
in
industrial
wastewater
purification
and
odor
abatement
(
ATSDR,
2000;
U.
S.
EPA,
1984).
The
adsorption
properties
of
some
manganese
compounds
may
cause
them
to
be
more
prevalent
in
certain
types
of
soils
or
sediments.
9­
9
Manganese
 
February
2003
9.4
Risk
Reduction
The
third
criterion
asks
if,
in
the
sole
judgment
of
the
Administrator,
regulation
presents
a
meaningful
opportunity
for
health
risk
reduction
for
persons
served
by
public
water
systems.
In
order
to
evaluate
this
criterion,
EPA
looked
at
the
total
exposed
population,
as
well
as
the
population
exposed
above
the
estimated
HRL.
Estimates
of
the
populations
exposed
and
the
levels
to
which
they
are
exposed
were
derived
from
the
monitoring
results.
These
estimates
are
included
in
Chapter
4
of
this
document
and
summarized
in
Section
9.4.2
below.

In
order
to
evaluate
risk
from
exposure
through
drinking
water,
EPA
considered
the
net
environmental
exposure
in
comparison
to
the
exposure
through
drinking
water.
For
example,
if
exposure
to
a
contaminant
occurs
primarily
through
ambient
air,
regulation
of
emissions
to
air
provides
a
more
meaningful
opportunity
for
EPA
to
reduce
risk
than
regulation
of
the
contaminant
in
drinking
water.
In
making
the
regulatory
determination,
the
available
information
on
exposure
through
drinking
water
(
Chapter
4)
and
information
on
exposure
through
other
media
(
Chapter
5)
were
used
to
estimate
the
fraction
that
drinking
water
contributes
to
the
total
exposure.
The
EPA
findings
are
discussed
in
Section
9.4.3
below.

In
making
its
regulatory
determination,
EPA
also
evaluates
effects
on
potential
sensitive
populations,
including
the
fetus,
infants
and
children.
The
sensitive
population
considerations
are
included
in
Section
9.4.4.

9.4.1
Risk
Reduction
Criterion
Conclusion
Approximately
47.5
million
people
are
served
by
ground
water
public
water
systems
with
detections
greater
than
the
MRL.
More
than
2.3
million
of
these
individuals
are
served
by
systems
with
detections
greater
than
the
HRL.
Manganese
is
an
essential
nutrient
that
is
common
and
necessary
in
the
diet.
The
estimated
daily
exposure
to
manganese
from
public
water
systems
is
far
below
the
expected
daily
intake
from
the
diet,
and
also
far
below
the
level
determined
to
be
safe
and
adequate.
When
average
daily
intakes
from
drinking
water
are
compared
with
intakes
from
food,
air
and
soil,
drinking
water
accounts
for
a
relatively
small
proportion
of
manganese
intake.
On
the
basis
of
these
observations,
the
impact
of
regulating
manganese
concentrations
in
drinking
water
on
health
risk
reduction
is
likely
to
be
small.
Therefore,
the
evaluation
for
Criterion
#
3
is
negative.

9.4.2
Exposed
Population
Estimates
Estimates
of
exposed
populations
were
derived
in
Chapter
4.
National
population
estimates
for
manganese
exposure
were
derived
using
summary
statistics
from
the
National
Inorganic
and
Radionuclide
Survey
(
NIRS),
which
lacked
surface
water
data,
with
supplemental
surface
water
occurrence
data
that
had
been
separately
submitted
to
EPA
from
five
States.
An
estimated
47.5
million
people
in
the
U.
S.
are
served
by
public
water
systems
supplied
from
ground
water
with
detections
of
manganese
above
the
minimum
reporting
level
(
MRL).
An
estimated
4.0
million
people
(
4.6%
of
the
population)
are
served
by
ground
water
with
levels
above
one­
half
the
health
reference
level
(
HRL)
of
0.3
mg/
L,
and
an
estimated
2.3
million
people
9­
10
Manganese
 
February
2003
(
2.6
%
of
the
population)
are
served
by
ground
water
with
levels
above
the
HRL.
It
should
be
noted
that
these
estimates
are
based
on
very
limited
and
outdated
data.
The
possibility
exists
that
the
number
of
people
served
by
ground
water
with
Mn
levels
that
are
above
the
HRL
could
be
higher
than
these
estimates;
however,
the
data
are
lacking
at
this
time
to
develop
a
more
timely
assessment.

9.4.3
Relative
Source
Contribution
Relative
source
contribution
analysis
compared
the
magnitude
of
exposure
expected
via
drinking
water
to
the
magnitude
of
exposure
from
intake
of
manganese
from
other
media
such
as
food,
air,
and
soil.
To
perform
this
analysis,
intake
of
manganese
from
drinking
water
must
be
estimated.
Occurrence
data
for
manganese
are
presented
in
Chapter
4
of
this
document.
According
to
the
NIRS
data
(
Table
4­
1),
the
median
and
99th
percentile
concentrations
for
manganese
in
ground
water
public
water
supplies
were
above
the
MRL
of
0.001
mg/
L.
This
is
not
surprising
considering
the
ubiquity
with
which
manganese
is
present
in
the
earth's
crust.

Taking
the
median
concentration
of
detections
from
the
NIRS
data
(
0.01
mg/
L),
and
assuming
a
daily
intake
of
2
L
of
drinking
water
by
a
70
kg
adult,
the
average
daily
dose
would
be
0.02
mg/
person­
day
or
2.8
×
10­
4
mg/
kg­
day.
The
corresponding
dose
for
a
10
kg
child
consuming
1
L/
day
of
drinking
water
would
be
0.01
mg/
child­
day
or
1.0
×
10­
3
mg/
kg­
day.
These
values
are
far
below
those
expected
from
a
normal
diet
(
2.9
 
12.6
×
10­
2
mg/
kg­
day
for
adults,
1.3
×
10­
1
mg/
kg­
day
for
children,
see
Table
9­
1
below),
and
are
also
less
than
the
levels
determined
by
the
National
Academy
of
Sciences
to
be
safe
and
adequate.
The
NAS
determined
that
a
daily
intake
of
2.3
mg
Mn
is
adequate
for
men
and
1.8
mg
is
adequate
for
women,
while
the
daily
adult
intake
expected
from
drinking
water
containing
0.01
mg/
L
Mn
is
0.02
mg
Mn.
The
NAS
also
determined
that
a
daily
intake
of
1.9
mg
Mn
is
adequate
for
boys
and
1.6
mg
is
adequate
for
girls,
while
the
daily
intake
expected
from
drinking
water
containing
0.01
mg/
L
Mn
is
0.01
mg
for
children.
(
IOM,
2002).

Table
9­
1.
Comparison
of
Average
Daily
Intake
from
Drinking
Water
and
Other
Mediaa
Medium
Adult
(:
g/
kg­
day)
Child
(:
g/
kg­
day)

Drinking
Waterb
0.29
1.0
Food
28.6­
126
128.0
(
0.87­
37.2
for
infants)

Air
0.0087
0.034
Soil
0.0014
­
5.0
0.02
­
70
a
See
Chapter
5
for
derivation
of
intakes
from
media
other
than
water
b
based
on
median
values
9­
11
Manganese
 
February
2003
9.4.4
Sensitive
Populations
The
sensitive
populations
identified
for
manganese
include
persons
with
impaired
detoxification
and
excretory
function,
such
as
infants
and
the
elderly.
Individuals
with
damaged
or
impaired
liver
function
may
be
particularly
sensitive.

9.5
Regulatory
Determination
Decision
As
stated
in
Section
9.1.1,
a
positive
finding
for
all
three
criteria
is
required
in
order
to
make
a
determination
to
regulate
a
contaminant.
While
there
is
evidence
that
manganese
may
have
adverse
health
effects
in
humans
at
high
doses
through
inhalation,
the
evidence
for
adverse
effects
through
oral
exposure
at
low
or
moderate
levels
is
less
compelling.
Because
manganese
is
an
essential
nutrient,
concern
over
potential
toxic
effects
from
high
oral
exposure
must
be
balanced
against
concern
for
adverse
effects
from
manganese
deficiency
should
intake
be
too
low.
Manganese
has
been
found
to
occur
in
an
estimated
1,920
ground
water
public
water
systems
representing
more
than
2.3
million
people
exposed
(
2.6
%
of
the
population)
to
levels
at
or
above
0.3
mg/
L.
The
Agency
believes
that
a
meaningful
opportunity
for
health
risk
reduction
does
not
exist
for
persons
served
by
public
water
systems
because
the
average
dietary
intake
of
manganese
exceeds
the
contribution
normally
found
in
public
drinking
water
systems.
Thus,
based
on
the
evaluation
of
available
data
using
the
criteria
described
above,
the
regulatory
determination
is
"
Do
not
regulate".
10­
1
Manganese
 
February
2003
10.0
REFERENCES
Abbott,
P.
1987.
Methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
in
petrol:
The
toxicological
issues.
Sci.
Total
Environ.
67:
247­
255.

Abrams,
E.,
J.
W.
Lassiter,
W.
J.
Miller,
et
al.
1976.
Effect
of
dietary
manganese
as
a
factor
affecting
54Mn
absorbtion
in
rats.
Nutr.
Rep.
Int.
14:
561­
565
(
as
cited
in
ATSDR,
2000).

Ali,
M.
M.,
G.
S.
Shukla,
D.
K.
Saxena,
et
al.
1981.
Behavioral
dysfunctions
and
central
neurotransmitters
in
manganese
exposed
rats.
J.
Environ.
Biol.
2:
29­
39
(
as
cited
in
ATSDR,
2000).

Ali,
M.
M.,
R.
C.
Murthy,
D.
K.
Saxena,
et
al.
1983.
Effect
of
low
protein
diet
on
manganese
neurotoxicity:
I.
Developmental
and
biochemical
changes.
Neurobehav
Toxicol
Teratol
5:
377­
383.

Ali,
M.
M.,
R.
C.
Murthy,
S.
K.
Mandal,
et
al.
1985.
Effect
of
low
protein
diet
on
manganese
neurotoxicity:
III.
Brain
neurotransmitter
levels.
Neurobehav.
Toxicol.
Teratol.
7(
5):
427­
431.
Amdur,
M.
O.,
L.
C.
Norris
and
G.
F.
Heuser.
1944.
The
need
for
manganese
in
bone
development
by
the
rat.
Proc.
Soc.
Exp.
Biol.
Med.
59:
254­
255
(
as
cited
in
ATSDR,
2000).

Andersen,
M.
E.,
J.
M.
Gearhart,
H.
J.
Clewell,
III.
1999.
Pharmacokinetic
data
needs
to
support
risk
assessments
for
inhaled
and
ingested
manganese.
Neurotoxicology
20:
161­
172.

ANSI/
NSF.
2000.
American
National
Standards
Institute,
NSF
International.
Drinking
water
treatment
chemicals
­
Health
effects.
ANSI/
NSF
60­
2000.
Ann
Arbor,
MI.

Archibald,
F.
S.
and
C.
Tyree.
1987.
Manganese
poisoning
and
the
attack
of
trivalent
manganese
upon
catecholamines.
Arch.
Biochem.
Biophys.
2:
638­
650.

Ardeleanu,
A.,
S.
Loranger,
G.
Kennedy,
et
al.
1999.
Emission
rates
and
physico­
chemical
characteristics
of
Mn
particles
emitted
by
vehicles
using
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
as
an
octane
improver.
Water
Air
Soil
Pollut.
115:
411­
427.

Arnaud,
J.
And
A.
Favier.
1995.
Copper,
iron,
manganese
and
zinc
contents
in
human
colostrum
and
transitory
milk
of
French
women.
Sci
Total
Environ
159:
9­
15.

Aschner,
M.
and
J.
L.
Aschner.
1990.
Manganese
transport
across
the
blood­
brain
barrier:
relationship
to
iron
homeostasis.
Brain.
Res.
Bull.
24:
857­
860.

Aschner,
M.
and
J.
L.
Aschner.
1991.
Manganese
neurotoxicity:
Cellular
effects
and
blood­
brain
barrier
transport.
Neurosci.
Biobehav.
Rev.
15(
3):
333­
340.

ASNS.
1999.
Nutrient
Information:
Manganese.
American
Society
for
Nutritional
Sciences.
Available
at
http://
www.
nutrition.
org/
nutinfo.
10­
2
Manganese
 
February
2003
ATSDR.
2000.
Toxicological
Profile
for
Manganese
(
Final).
U.
S.
Department
of
Health
and
Human
Services,
Public
Health
Service,
Agency
for
Toxic
Substances
and
Disease
Registry,
Atlanta,
GA.

Autissier,
N.,
L.
Rochette,
P.
Dumas,
et
al.
1982.
Dopamine
and
norepinephrine
turnover
in
various
regions
of
the
rat
brain
after
chronic
manganese
chloride
administration.
Toxicology
24(
2):
175.

Bales,
C.
W.,
J.
H.
Freeland­
Graves,
P.
H.
Lin,
et
al.
1987.
Plasma
uptake
of
manganese:
Influence
of
dietary
factors.
In:
Kies,
C.,
ed.,
Nutritional
Bioavailability
of
Manganese.
Washington
D.
C.:
American
Chemical
Society,
pp.
112­
122.

Baly,
D.
L.,
B.
Lönnerdal
and
C.
L.
Keen.
1985.
Effects
of
high
doses
of
manganese
on
carbohydrate
homeostasis.
Toxicol.
Lett.
25:
95­
102.

Baly,
D.
L.,
B.
Lönnerdal
and
C.
L.
Keen.
1988.
Mechanism
of
decreased
insulinogenesis
in
manganese­
deficient
rats.
Decreased
insulin
mRNA.
FEBS
Lett.
239:
55­
58
(
as
cited
in
ATSDR,
2000).

Banta,
R.
G.
and
W.
R.
Markesbery.
1977.
Elevated
manganese
levels
associated
with
dementia
and
extrapyramidal
signs.
Neurology
27(
3):
213­
216.

Barbeau,
A.
1984.
Manganese
and
extrapyramidal
disorders
(
a
critical
review
and
tribute
to
Dr.
George
C.
Cotzias).
Neurotoxicology
5(
1):
13­
35
(
as
cited
in
ATSDR,
2000).

Barlow,
P.
J.
and
M.
Kapel.
1979.
Hair
metal
analysis
and
its
significance
to
certain
disease
conditions.
2nd
Annual
Trace
Metals
Health
Seminar,
Boston,
MA.

Baxter,
D.
J.,
W.
O.
Smith
and
G.
C.
Klein.
1965.
Some
effects
of
acute
manganese
excess
in
rats.
Proc.
Soc.
Exp.
Biol.
Med.
119:
966­
970.

Bell,
J.
G,
C.
L.
Keen,
and
B.
Lönnerdal.
1989.
Higher
retention
of
manganese
in
suckling
than
in
adult
rats
is
not
due
to
maturational
differences
in
manganese
uptake
by
rat
small
intestine.
J.
Toxicol.
Environ.
Health
26:
387­
398.
(
As
cited
in
ATSDR,
2000).

Bernheimer,
H.,
W.
Birkmayer,
O.
Hornykiewicz,
et
al.
1973.
Brain
dopamine
and
the
syndromes
of
Parkinson
and
Huntington:
Clinical,
morphological
and
neurochemical
correlations.
J.
Neurol.
Sci.
20:
415­
455.

Bertinchamps,
A.
J.
and
G.
C.
Cotzias.
1958.
Biliary
excretion
of
manganese.
Fed.
Proc.
17:
428.

Bertinchamps,
A.
J.,
S.
T.
Miller
and
G.
C.
Cotzias.
1966.
Interdependence
of
routes
excreting
manganese.
Am.
J.
Physiol.
211(
1):
217­
224.
10­
3
Manganese
 
February
2003
Bienvenu,
P.,
C.
Noire
and
A.
Cier.
1963.
Comparative
general
toxicity
of
metallic
ions.
A
relation
with
the
periodic
classification.
Rech.
Serv.
Sante
Armees,
Lyons,
France
256:
1043­
1044.

Bleich
S.,
D.
Degner,
R.
Sprung,
A.
Riegel,
W.
Poser,
and
E.
Ruther.
1999.
Chronic
manganism:
Fourteen
years
follow­
up.
J.
Neuropsych.
Clin.
Neuro.
11:
117.

Bonilla,
E.
and
M.
Diez­
Ewald.
1974.
Effect
of
L­
DOPA
on
brain
concentration
of
dopamine
and
homovanillic
acid
in
rats
after
chronic
manganese
chloride
administration.
J.
Neurochem.
22(
2):
297­
299.

Bonilla,
E.
1978a.
Flameless
atomic
absorption
spectrophotometric
determination
of
manganese
in
rat
brain
and
other
tissues.
Clin.
Chem.
24:
471­
472.

Bonilla,
E.
1978b.
Increased
GABA
content
in
caudate
nucleus
of
rats
after
chronic
manganese
chloride
administration.
J.
Neurochem.
31(
2):
551­
552.

Bonilla,
E.
1980.
L­
tyrosine
hydroxylase
activity
in
the
rat
brain
after
chronic
oral
administration
of
manganese
chloride.
Neurobehav.
Toxicol.
2:
37­
41.

Boyer,
P.
D.,
J.
H.
Shaw
and
P.
H.
Phillips.
1942.
Studies
on
manganese
deficiency
in
the
rat.
J.
Biol.
Chem.
143:
417­
425
(
as
cited
in
ATSDR,
2000).

Britton,
A.
A.
and
G.
C.
Cotzias.
1966.
Dependence
of
manganese
turnover
on
intake.
Am.
J.
Physiol.
211(
1):
203­
206.

Brouillet,
E.
P.,
L.
Shinobu,
U.
McGarvey,
et
al.
1993.
Manganese
injection
into
the
rat
striatum
produces
excitotoxic
lesions
by
impairing
energy
metabolism.
Exp.
Neurol.
120(
1):
89­
94
(
as
cited
in
ATSDR,
2000).

Burnett,
W.
T.,
Jr.,
R.
R.
Bigelow,
A.
W.
Kimball,
et
al.
1952.
Radio­
manganese
studies
on
the
mouse,
rat
and
pancreatic
fistula
dog.
Am.
J.
Physiol.
168:
620­
625.

Calne,
D.
B.,
N.
S.
Chu,
C.
C.
Huang,
et
al.
1994.
Manganism
and
idiopathic
parkinsonism:
similarities
and
differences.
Neurology
44:
1583­
1586.

Carter,
S.
D.,
J.
F.
Hein,
G.
L.
Rehnberg,
et
al.
1980.
Chronic
manganese
oxide
ingestion
in
rats:
hematological
effects.
J.
Toxicol.
Environ.
Health
6(
1):
207­
216.

Casto,
B.
C.,
J.
Meyers
and
J.
A.
DiPaolo.
1979.
Enhancement
of
viral
transformation
for
the
evaluation
of
the
carcinogenic
or
mutagenic
potential
of
inorganic
metal
salts.
Cancer
Res.
39:
193­
198.

Cawte,
J.
and
M.
T.
Florence.
1989.
A
manganic
milieu
in
North
Australia:
Ecological
manganism:
Ecology;
diagnosis;
individual
susceptibility,
synergism,
therapy,
prevention,
advice
for
the
community.
Int.
J.
Biosocial
Med.
Res.
11:
43­
56
(
as
cited
in
U.
S.
EPA,
1993).
10­
4
Manganese
 
February
2003
Chan
W.
Y.,
T.
Z.
Ramadan,
M.
Perlman,
A.
M.
McCaffree
and
M.
O.
Rennert.
1980.
Nutrition
Rep.
Int.
22:
939­
948.

Chan,
A.
W.
K.,
J.
C.
K.
Lai,
M.
J.
Minski,
et
al.
1981.
Manganese
concentration
in
rat
organs:
Effect
after
life­
long
manganese
treatment.
Biochem.
Soc.
Trans.
9:
229.

Chan,
W.
Y.,
J.
M.
Bates,
Jr.
and
O.
M.
Rennert.
1982.
Comparative
studies
of
manganese
binding
in
human
breast
milk,
bovine
milk
and
infant
formula.
J.
Nutr.
112(
4):
642­
651.

Chan,
W.
Y.,
M.
H.
Raghib
and
O.
M.
Rennert.
1987.
Absorption
studies
of
manganese
from
milk
diets
in
suckling
rats.
In:
Kies,
C.,
ed.,
Nutritional
Bioavailability
of
Manganese.
Washington,
D.
C.:
American
Chemical
Society,
pp.
80­
89.

Chandra,
S.
V.
and
S.
P.
Srivastava.
1970.
Experimental
production
of
early
brain
lesions
in
rats
by
parenteral
administration
of
manganese
chloride.
Acta
Pharmacol.
Toxicol.
28(
3):
177­
183.

Chandra,
S.
V.
1971.
Cellular
changes
induced
by
manganese
in
the
rat
testis
­
preliminary
results.
Acta
Pharmacol.
Toxicol.
29(
1):
75­
80.

Chandra,
S.
V.
1972.
Histological
and
histochemical
changes
in
experimental
manganese
encephalopathy
in
rabbits.
Arch.
Toxikol.
29(
1):
29­
38.

Chandra,
S.
V.,
R.
Ara,
N.
Nagar,
et
al.
1973.
Sterility
in
experimental
manganese
toxicity.
Acta
Biol.
Med.
Ger.
30(
6):
857­
862.

Chandra,
S.
V.,
D.
K.
Saxena
and
M.
Z.
Hasan.
1975.
Effect
of
zinc
on
manganese
induced
testicular
injury
in
rats.
Ind.
Health
13:
51­
56.

Chandra,
S.
V.,
and
G.
S.
Shukla.
1978.
Manganese
encephalopathy
in
growing
rats.
Environ
Res
15:
28­
37
(
as
cited
in
ATSDR,
2000).

Chandra,
S.
V.,
G.
S.
Shukla
and
D.
K.
Saxena.
1979.
Manganese­
induced
behavioral
dysfunction
and
its
neurochemical
mechanism
in
growing
mice.
J.
Neurochem.
33(
6):
1217­
1221.

Chandra,
S.
V.
and
G.
S.
Shukla.
1981.
Concentrations
of
striatal
catecholamines
in
rats
given
manganese
chloride
through
drinking
water.
J.
Neurochem.
36(
2):
683­
687.

Chang,
L.
W.
1996.
Toxico­
neurology
and
neuropathology
induced
by
metals.
In:
Chang,
L.
W.,
ed,.
Toxicology
of
Metals.
Boca
Raton,
FL:
CRC
Press,
Inc.,
pp.
511­
536.

ChemIDplus.
2000.
Division
of
Specialized
Information
Services,
National
Library
of
Medicine
(
NLM)
http://
chem.
sis.
nlm.
nih.
gov/
chemidplus/

Cikrt,
M.
and
J.
Vostal.
1969.
Study
of
manganese
resorption
in
vitro
through
intestinal
wall.
Int.
Z.
Klin.
Pharmakol.
Ther.
Toxikol
.
2(
3):
280­
285.
10­
5
Manganese
 
February
2003
Cikrt,
M.
1973.
Enterohepatic
circulation
of
64Cu,
52Mn
and
203Hg
in
rats.
Arch.
Toxikol.
31(
1):
51­
59.

Clayton,
C.,
E.
Pellizzari,
R.
Rodes,
et
al.
1999.
Estimating
distribution
of
long­
term
particulate
matter
and
manganese
exposures
for
residents
of
Toronto,
Canada.
Atmos.
Environ.
33:
2515­
2526.

Collipp,
P.
J.,
Chen,
S.
Y.,
and
Maitinsky,
S.
1983.
Manganese
in
infant
formulas
and
learning
disability.
Ann.
Nutr.
Metab.
27
(
6):
488­
494.

Colomina,
M.
T.,
J.
L.
Domingo,
J.
M.
Llobet,
et
al.
1995.
Embryotoxicity
and
fetotoxicity
of
manganese
in
mice:
variability
with
the
day
of
exposure.
Toxicologist
15(
1):
160
[
abstract].

Cooper,
W.
1984.
The
health
implications
of
increased
manganese
in
the
environment
resulting
from
the
combustion
of
fuel
additives:
a
review
of
the
literature.
J.
Toxicol.
Envir.
Hlth.
14:
23­
46.

Cotzias,
G.
C.
1958.
Manganese
in
health
and
disease.
Physiol.
Rev.
38:
503­
533.

Cotzias,
G.
C.,
K.
Horiuchi,
S.
Fuenzalida,
et
al.
1968.
Chronic
manganese
poisoning.
Clearance
of
tissue
manganese
concentrations
with
persistence
of
the
neurological
picture.
Neurology
18(
4):
376­
382.

Cotzias,
G.
C.,
S.
T.
Miller,
P.
S.
Papavasiliou,
et
al.
1976.
Interactions
between
manganese
and
brain
dopamine.
Med.
Clin.
North
Am.
60(
4):
729­
738.

Dagli,
A.
J.,
D.
Golden,
M.
Finkel,
et
al.
1973.
Pyloric
stenosis
following
ingestion
of
potassium
permanganate.
Digest
Dis.
18:
1091­
1094.

Dastur,
D.
K.,
D.
K.
Manghani,
K.
V.
Raghavendran,
et
al.
1969.
Distribution
and
fate
of
Mn54
in
the
rat,
with
special
reference
to
the
C.
N.
S.
Q.
J.
Exp.
Physiol.
54(
3):
322­
331.

Dastur,
D.
K.,
D.
K.
Manghani
and
K.
V.
Raghavendran.
1971.
Distribution
and
fate
of
54Mn
in
the
monkey:
Studies
of
different
parts
of
the
central
nervous
system
and
other
organs.
J.
Clin.
Invest.
50:
9­
20.

Davidsson,
L.,
A.
Cederblad,
B.
Lönnerdal,
et
al.
1989a.
Manganese
absorption
from
human
milk,
cow's
milk,
and
infant
formulas
in
humans.
Am.
J.
Dis.
Child
43(
7):
823­
827.

Davidsson,
L.,
A.
Cederblad,
B.
Lönnerdal,
et
al.
1989b.
Manganese
retention
in
man:
a
method
for
estimating
manganese
absorption
in
man.
Am.
J.
Clin.
Nutr.
49(
1):
170­
179.

Davies,
N.
T.
and
R.
Nightingale.
1975.
The
effects
of
phytate
on
intestinal
absorption
and
secretion
of
zinc,
and
whole­
body
retention
of
Zn,
copper,
iron
and
manganese
in
rats.
Br.
J.
Nutr.
34(
2):
243­
258.
10­
6
Manganese
 
February
2003
Davis,
C.
D.,
D.
M.
Ney
and
J.
L.
Greger.
1990.
Manganese,
iron
and
lipid
interactions
in
rats.
J.
Nutr.
120(
5):
507­
513
(
as
cited
in
ATSDR,
2000).

Davis,
C.
D.
and
J.
L.
Greger.
1992.
Longitudinal
changes
of
manganese­
dependent
superoxide
dismutase
and
other
indexes
of
manganese
and
iron
status
in
women.
Am.
J.
Clin.
Nutr.
55(
3):
747­
752
(
as
cited
in
ATSDR,
2000).

Davis,
C.
D.,
E..
A
.
Malecki,
and
J.
L.
Greger.
1992.
Interactions
among
dietary
manganese,
heme
iron,
and
non­
heme
iron
in
women.
Am.
J.
Clin.
Nutr.
56:
926­
932.

Davis,
C.
D.,
L.
Zech,
J.
L.
Greger.
1993.
Manganese
metabolism
in
the
rats:
An
improved
methodology
for
assessing
gut
endogenous
losses.
Proc.
Soc.
Exp.
Biol.
Med.
202:
103­
108.

Davis,
J.
M,
A.
M.
Jarabek,
D.
T.
Mage
and
J.
A.
Graham.
1998.
The
EPA
health
risk
assessment
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT).
Risk
Anal.
18(
1):
57­
70.

De
Meo,
M.,
M.
Laget,
M.
Castegnaro,
et
al.
1991.
Genotoxic
activity
of
potassium
permanganate
in
acidic
solutions.
Mutat.
Res.
260(
3):
295­
306
(
as
cited
in
ATSDR,
2000).

Demerec,
M.,
G.
Bertani
and
J.
Flint.
1951.
A
survey
of
chemicals
for
mutagenic
action
on
E.
coli.
Am.
Nat.
85:
119­
136.

Deskin,
R.,
S.
J.
Bursian
and
F.
W.
Edens.
1980.
Neurochemical
alterations
induced
by
manganese
chloride
in
neonatal
rats.
Neurotoxicology
2:
65­
73.

Deskin,
R.,
S.
J.
Bursian
and
F.
W.
Edens.
1981.
The
effect
of
chronic
manganese
administration
on
some
neurochemical
and
physiological
variables
in
neonatal
rats.
Gen.
Pharmacol.
12(
4):
279­
280.

Devenyi,
A.
G.,
T.
F.
Barron
and
A.
C.
Mamourian.
1994.
Dystonia,
hyperintense
basal
ganglia,
and
high
whole
blood
manganese
levels
in
Alagille's
syndrome.
Gastroenterology
106(
4):
1068­
1071
(
as
cited
in
U.
S.
EPA,
1999a).

Dieter,
H.
H.,
W.
Rotard,
J.
Simon,.
et
al.
1992.
Manganese
in
natural
mineral
waters
from
Germany.
Die
Nahrung
36:
477­
484.

Dikshith,
T.
S.
and
S.
V.
Chandra.
1978.
Cytological
studies
in
albino
rats
after
oral
administration
of
manganese
chloride.
Bull.
Environ.
Contam.
Toxicol.
19(
6):
741­
746
(
as
cited
in
ATSDR,
2000).

DiPaolo,
J.
A.
1964.
The
potentiation
of
lymphosarcomas
in
mice
by
manganese
chloride
[
Abstract].
Fed.
Proc.
23:
393.

Doisy,
E.
A.
1973.
Effects
of
deficiency
in
manganese
upon
plasma
levels
of
clotting
proteins
and
cholesterol
in
man.
Trace
Element
Metabolism.
In:
Hoekstra,
W.
G.,
J.
W.
Suttie,
A.
E.
10­
7
Manganese
 
February
2003
Ganther,
et
al.,
eds.
Animals­
2,
2nd
eds.
Baltimore:
University
Park
Press,
pp.
668­
670
(
as
cited
in
ATSDR,
2000).

Dorman,
D.
C.,
M.
F.
Struve,
D.
Vitarella,
F.
L.
Byerly,
J.
Goetz,
and
R.
Miller.
2000.
Neurotoxicity
of
manganese
chloride
in
neonatal
and
adult
CD
rats
following
subchronic
(
21­
day)
high­
dose
oral
exposure.
J
Appl
Tox
20:
179­
187.

Dörner,
K.,
S.
Dziadzka,
A.
Höhn,
E.
Sievers,
H.
D.
Oldgix,
G.
Schulz­
Lell,
and
J.
Schaub.
1989.
Longitudinal
manganese
and
copper
balances
in
young
infants
and
preterm
infants
fed
on
breastmilk
and
adapted
cow's
milk
formulas.
Br
J
Nutrition
61:
559­
572.

Durham,
N.
N.
and
O.
Wyss.
1957.
Modified
method
of
determining
mutation
rates
in
bacteria.
J.
Bacteriol.
74:
548­
552.

Ejima,
A.,
T.
Imamura,
S.
Nakamura,
et
al.
1992.
Manganese
intoxication
during
total
parenteral
nutrition
[
letter].
Lancet
339:
426.

Eriksson,
H.,
S.
Lenngren
and
E.
Heilbronn.
1987.
Effect
of
long­
term
administration
of
manganese
on
biogenic
amine
levels
in
discrete
striatal
regions
of
rat
brain.
Arch.
Toxicol.
59(
6):
426­
431.

Eriksson,
H.,
J.
Tedroff,
K.
A.
Thuomas,
et
al.
1992.
Manganese
induced
brain
lesions
in
Macaca
fascicularis
as
revealed
by
positron
emission
tomography
and
magnetic
resonance
imaging.
Arch.
Toxicol.
66(
6):
403­
710
(
as
cited
in
ATSDR,
2000).

Ethyl
Corporation.
1990.
The
case
for
an
environmentally
beneficial
fuel
additive.
Baton
Rouge,
USA.

Ethyl
Corporation.
1997.
Characterization
of
manganese
particulates
from
studies
performed
by
Lawrence
Livermore
National
Laboratory,
Southwest
Research
Institute,
Univ.
of
Minnesota,
Research
Triangle
Institute,
and
Ethyl
Research
and
Development.
September
10,
1997.
Submitted
to
U.
S.
EPA.
(
as
cited
in
Lynam
et
al.,
1999).

Fechter,
L.
D.
1999.
Distribution
of
manganese
in
development.
Neurotoxicology
20:
197­
201.

Fell,
J.
M.
E.,
A.
P.
Reynolds,
N.
Meadows,
et
al.
1996.
Manganese
toxicity
in
children
receiving
long­
term
parenteral
nutrition.
Lancet
347:
1218­
1221.

Finley,
J.
W.
1999.
Manganese
absorption
and
retention
by
young
women
is
associated
with
serum
ferritin
concentration.
Am.
J.
Clin.
Nutr.
70:
37­
43.

Finley,
J.
and
C.
D.
Davis.
1999.
Manganese
deficiency
and
toxicity:
Are
high
or
low
dietary
amounts
of
manganese
cause
for
concern?
Biofactors
10(
1):
15­
24.

Finley,
J.
W.,
P.
E.
Johnson
and
L.
K.
Johnson.
1994.
Sex
affects
manganese
absorption
and
retention
by
humans
from
a
diet
adequate
in
manganese.
Am.
J.
Clin.
Nutr.
60(
6):
949­
955.
10­
8
Manganese
 
February
2003
Florence,
T.
M.
and
J.
L.
Stauber.
1989.
Manganese
catalysis
of
dopamine
oxidation.
Sci.
Total.
Environ.
78:
233­
240.

Fore,
H.
and
R.
A.
Morton.
1952.
Manganese
in
rabbit
tissues.
Biochem.
J.
51:
600­
603
(
as
cited
in
ATSDR,
2000).

Franz,
R.
D.
1962.
Toxicities
of
some
trace
metals.
Naunyn­
Schmiedebergs
Arch.
Exp.
Path.
Pharmakol.
244:
17­
20.

Freeland­
Graves,
J.
1994.
Derivation
of
manganese
estimated
safe
and
adequate
daily
dietary
intakes.
In:
Mertz,
W.,
C.
O.
Abernathy
and
S.
S.
Olin,
eds.,
Risk
Assessment
of
Essential
Elements.
Washington,
D.
C.:
ILSI
Press,
pp.
237­
252.

Freeland­
Graves,
J.
H.,
C.
W.
Bales
and
F.
Behmardi.
1987.
Manganese
requirements
of
humans.
In:
Kies,
C.,
ed.,
Nutritional
Bioavailability
of
Manganese.
Washington,
D.
C.:
American
Chemical
Society,
pp.
90­
104.

Freeland­
Graves,
J.
H.
and
C.
Llanes.
1994.
Models
to
study
manganese
deficiency.
In:
Klimis­
Tavantzis,
D.
J.,
ed.,
Manganese
in
Health
and
Disease.
Boca
Raton,
FL:
CRC
Press,
Inc.,
pp.
59­
86.

Friedman,
B.
J.,
J.
H.
Freeland­
Graves,
C.
W.
Bales,
et
al.
1987.
Manganese
balance
and
clinical
observations
in
young
men
fed
a
manganese­
deficient
diet.
J.
Nutr.
117:
133­
143.

Furst,
A.
1978.
Tumorigenic
effect
of
an
organomanganese
compound
on
F344
rats
and
Swiss
albino
mice.
J.
Natl.
Cancer
Inst.
60(
5):
1171­
1173.

Garcia­
Aranda,
J.
A.,
R.
A.
Wapnir
and
F.
Lifshitz.
1983.
In
vivo
intestinal
absorption
of
manganese
in
the
rat.
J.
Nutr.
113(
12):
2601­
2607.

Gavin,
C.
E.,
K.
K.
Gunter
and
T.
E.
Gunter.
1992.
Mn2+
sequestration
by
mitochondria
and
inhibition
of
oxidative
phosphorylation.
Toxicol.
Appl.
Pharmacol.
115(
1):
1­
5
(
as
cited
in
ATSDR,
2000).

Gianutsos,
G.
and
M.
T.
Murray.
1982.
Alterations
in
brain
dopamine
and
GABA
following
inorganic
or
organic
manganese
administration.
Neurotoxicology
3(
3):
75­
81.

Gianutsos,
G.,
M.
D.
Seltzer,
R.
Saymeh,
et
al.
1985.
Brain
manganese
accumulation
following
systemic
administration
of
different
forms.
Arch.
Toxicol.
57(
4):
272­
275.

Gibbons,
R.
A.,
S.
N.
Dixon,
K.
Hallis,
et
al.
1976.
Manganese
metabolism
in
cows
and
goats.
Biochim.
Biophys.
Acta
444:
1­
10.

Gibson,
R.
S.
1994.
Content
and
bioavailability
of
trace
elements
in
vegetarian
diets.
Am
J
Clin
Nutr
59(
5
Suppl):
1223S­
1232S.
10­
9
Manganese
 
February
2003
Gilliom,
R.
J.,
D.
K.
Mueller,
and
L.
H.
Nowell.
1998.
Methods
for
comparing
water­
quality
conditions
among
National
Water­
Quality
Assessment
Study
Units,
1992­
95.
U.
S.
Geological
Survey
Open­
File
Report
97­
589.
Available
on
the
Internet
at:
URL:
http://
ca.
water.
usgs.
gov/
pnsp/
rep/
ofr97589/.
Last
modified
October
09,
1998.

Goldsmith,
J.,
Y.
Herishanu,
J.
Abarbanel,
et
al.
1990.
Clustering
of
Parkinson's
disease
points
to
environmental
etiology.
Arch.
Environ.
Health
45:
88­
94
(
as
cited
in
ATSDR,
2000).

Gong,
H.
and
T.
Amemiya.
1996.
Ultrastructure
of
retina
of
manganese­
deficient
rats.
Invest.
Ophthalmol.
Vis.
Sci.
37:
1967­
1974.

Gottschalk,
L.
A.,
T.
Rebello,
M.
S.
Buchsbaum,
et
al.
1991.
Abnormalities
in
hair
trace
elements
as
indicators
of
aberrant
behavior.
Compr.
Psychiatry
32(
3):
229­
237.

Grant,
D.,
W.
F.
Blazak
and
G.
L.
Brown.
1997.
The
reproductive
toxicology
of
intravenously
administered
MnDPDP
in
the
rat
and
rabbit.
Acta
Radiol.
38(
4
Pt
2):
759­
769.

Gray,
L.
E.,
Jr.
and
J.
W.
Laskey.
1980.
Mulitvariate
analysis
of
the
effects
of
manganese
on
the
reproductive
physiology
and
behavior
of
the
male
house
mouse.
J.
Toxicol.
Environ.
Health
6:
861­
867.

Greenberg,
D.
M.
and
W.
W.
Campbell.
1940.
Studies
in
mineral
metabolism
with
the
aid
of
induced
radioactive
isotopes.
IV.
Manganese.
Proc.
Natl.
Acad.
Sci.
26:
448­
452.

Greenberg,
D.
M.,
D.
H.
Copp
and
E.
M.
Cuthbertson.
1943.
Studies
in
mineral
metabolism
with
the
aid
of
artificial
radioactive
isotopes.
VII.
The
distribution
and
excretion,
particularly
by
way
of
the
bile,
of
iron,
cobalt,
and
manganese.
J.
Biol.
Chem.
147:
749.

Greger,
J.
L.
1998.
Dietary
standards
for
manganese:
Overlap
between
nutritional
and
toxicological
studies.
J.
Nutr.
128:
368S­
371S.

Greger,
J.
L.
1999.
Nutrition
versus
toxicology
of
manganese
in
humans:
Evaluation
of
potential
biomarkers.
Neurotoxicology
20:
205­
212.

Greger,
J.
L.
and
S.
M.
Snedeker.
1980.
Effect
of
dietary
protein
and
phosphorus
levels
on
the
utilization
of
zinc,
copper,
and
manganese
by
adult
males.
J.
Nutr.
110:
2243­
2253.

Greger,
J.
L.,
C.
D.
Davis,
J.
W.
Suttie,
et
al.
1990.
Intake,
serum
concentrations,
and
urinary
excretion
of
manganese
by
adult
males.
Am.
J.
Clin.
Nutr.
51(
3):
457­
461.

Gruden,
N.
1984.
The
influence
of
iron
on
manganese
metabolism
in
the
first
three
weeks
of
rat's
life.
Nutr.
Rep.
Int.
30:
553­
557.

Gupta,
S.
K.,
R.
C.
Murthy
and
S.
V.
Chandra.
1980.
Neuromelanin
in
manganese­
exposed
primates.
Toxicol.
Lett.
6:
17­
20.
10­
10
Manganese
 
February
2003
Hagenfeldt,
K.,
L.
O.
Plantin
and
E.
Diczfalusy.
1973.
Trace
elements
in
the
human
endometrium.
2.
Zinc,
copper
and
manganese
levels
in
the
endometrium,
cervical
mucus
and
plasma.
Acta
Endocrinol.
(
Copenh.)
72(
1):
115­
126.

Hamilton­
Koch,
W.,
R.
D.
Snyder
and
J.
M.
Lavelle.
1986.
Metal­
induced
DNA
damage
and
repair
in
human
diploid
fibroblasts
and
Chinese
hamster
ovary
cells.
Chem.
Biol.
Interact.
59(
1):
17­
28.

Hanna,
L.,
J.
M.
Peters,
L.
M.
Wiley,
et
al.
1996.
Comparative
effects
of
essential
and
nonessential
metals
on
preimplantation
mouse
embryo
development
[
abstract].
Faseb.
J.
10(
3):
A783.

Hanzlik,
R.
P.,
R.
Stitt
and
G.
J.
Traiger.
1980.
Toxic
effects
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
in
rats:
Role
of
metabolism.
Toxicol.
Appl.
Pharmacol.
56:
353­
360
(
as
cited
in
U.
S.
EPA,
1994).

Hart,
D.
A.
1978.
Evidence
that
manganese
inhibits
an
early
event
during
stimulation
of
lymphocytes
by
mitogens.
Exp.
Cell.
Res.
113:
139­
150
(
as
cited
in
ATSDR,
2000).

Hatano
S.,
K.
Aihara,
Y.
Nishi
and
T.
Usui.
1985.
Trace
elements
(
copper,
zinc,
manganese,
and
selenium)
in
plasma
and
erythrocytes
in
relation
to
dietary
intake
during
infancy.
J.
Pedia.
Gastroent.
Nutr.
4:
87­
92.

He,
P.,
D.
Liu,
G.
Zhang,
et
al.
1994.
[
Effects
of
high­
level
manganese
sewage
irrigation
on
children's
neurobehavior.]
Chung
Hua
Yu
Fang
I
Hsueh
Tsa
Chih]
28:
216­
218.
(
Chinese).

Hauser,
R.
A.,
T.
A.
Zesiewicz,
A.
S.
Rosemurgy,
C.
Martinez,
and
C.
W.
Olanow.
1994.
Manganese
intoxication
and
chronic
liver
failure.
Ann.
Neurol.
36:
871­
5.

Health
and
Welfare
Canada
(
HWC).
1978.
Methylcyclopentadienyl
manganese
tricarbonyl
(
MMT):
As
an
assessment
of
the
human
health
implications
of
its
use
as
a
gasoline
additive.
Environmental
Health
Directorate.
Health
Protection
Branch,
Ottawa,
Canada.
78­
EHD­
21.

Hellou,
J.,
L.
Fancy
and
J.
Payne.
1992.
Concentrations
of
twenty­
four
elements
in
bluefin
tuna,
Thunnus
thynnus,
from
the
Northwest
Atlantic.
Chemosphere
24(
2):
211­
218.

Hietanen,
E.,
J.
Kilpio
and
H.
Savolainen.
1981.
Neurochemical
and
biotransformational
enzyme
responses
to
manganese
exposure
in
rats.
Arch.
Environ.
Contam.
Toxicol.
10(
3):
339­
345.

Hinderer,
R.
K.
1979.
Toxicity
studies
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT).
Am.
Ind.
Hyg.
Assoc.
J.
40:
164­
167
(
as
cited
in
U.
S.
EPA,
1994).

Holbrook,
D.
J.,
Jr.,
M.
E.
Washington,
H.
B.
Leake,
et
al.
1975.
Studies
on
the
evaluation
of
the
toxicity
of
various
salts
of
lead,
manganese,
platinum,
and
palladium.
Environ.
Health
Perspect.
10:
95­
101.
10­
11
Manganese
 
February
2003
Holzgraefe,
M.,
W.
Poser,
H.
Kijewski,
et
al.
1986.
Chronic
enteral
poisoning
caused
by
potassium
permanganate:
A
case
report.
J.
Toxicol.
Clin.
Toxicol.
24:
235­
244
(
as
cited
in
ATSDR,
2000).

Horiuchi,
K.,
S.
Horiguchi,
N.
Tanaka,
et
al.
1967.
Manganese
contesnts
in
the
whole
blood,
urine
and
feces
of
a
healthy
Japanese
population.
Osaka
City
Med.
J.
13(
2):
151­
163
(
original
in
Japanese).

Huang,
C.­
C.,
N.­
S.
Chu,
C.­
S.
Lu,
R.­
S.
Chen,
and
D.
B.
Calne.
1998.
Long­
term
progression
in
chronic
manganism:
ten
years
of
follow­
up.
Neurology
50:
698­
700.

Hurley,
L.
S.,
D.
E.
Wolley
and
P.
S.
Timiras.
1961.
Threshold
and
pattern
of
electro
shock
seizures
in
ataxic
manganese­
deficient
rats.
Proc.
Soc.
Exp.
Biol.
Med.
106:
343­
346
(
as
cited
in
ATSDR,
2000).

Hurley,
L.
S.,
C.
L.
Keen
and
D.
L.
Baly.
1984.
Manganese
deficiency
and
toxicity:
effects
on
carbohydrate
metabolism
in
the
rat.
Neurotoxicology
5(
1):
97­
104
(
as
cited
in
ATSDR,
2000).

Hysell,
D.
K.,
W.
Moore,
Sr.,
J.
F.
Stara,
et
al.
1974.
Oral
toxicity
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
in
rats.
Environ.
Res.
7:
158­
168
(
as
cited
in
U.
S.
EPA,
1994).

Imam,
Z.
and
S.
V.
Chandra.
1975.
Histochemical
alterations
in
rabbit
testis
produced
by
manganese
chloride.
Toxicol.
Appl.
Pharmacol.
32(
3):
534­
544.

Institute
of
Medicine
(
IOM).
2002.
Dietary
Reference
Intakes:
Vitamin
A,
Vitamin
K,
Arsenic,
Boron,
Chromium,
Copper,
Iodine,
Iron,
Manganese,
Molybdenum,
Nickel,
Silicon,
Vanadium,
and
Zinc.
Washington
DC:
National
Academy
Press.
Pp.
10­
1
­
10­
22.

Iwami,
O.,
T.
Watanabe,
T.,
C.
S.,
Moon,
et
al.
1994.
Motor
neuron
disease
on
the
Kii
Peninsula
of
Japan:
excess
manganese
intake
from
food
coupled
with
low
magnesium
in
drinking
water
as
a
risk
factor.
Sci.
Total
Environ.
149:
121­
135
(
as
cited
in
ATSDR,
2000).

Järvinen,
R.
and
A.
Ahlström.
1975.
Effect
of
the
dietary
manganese
level
on
tissue
manganese,
iron,
copper,
and
zinc
concentrations
in
female
rats
and
their
fetuses.
Med.
Biol.
53:
93­
99.

Joardar,
M.
and
A.
Sharma.
1990.
Comparison
of
clastogenicity
of
inorganic
Mn
administered
in
cationic
and
anionic
forms
in
vivo.
Mutat.
Res.
240(
3):
159­
163.

Johnson,
P.
E.,
G.
I.
Lykken
and
E.
D.
Korynta.
1991.
Absorption
and
biological
half­
life
in
humans
of
intrinsic
54Mn
tracers
from
foods
of
plant
origin.
J.
Nutr.
121:
711­
717.

Jonderko,
G.
1965.
Calcium,
manganese,
inorganic
phosphorus,
sodium,
potassium
and
iron
level
in
the
blood
serum
in
the
acute
experimental
manganism.
Med.
Pr.
16(
4):
288­
292
(
original
in
Polish).
10­
12
Manganese
 
February
2003
Kafritsa,
Y.,
J.
Fell,
S.
Long,
et
al.
1998.
Long
term
outcome
of
brain
manganese
deposition
in
patients
on
home
parenteral
nutrition.
Arch.
Dis.
Child
79:
263­
265.

Kanematsu,
N.,
M.
Hara
and
T.
Kada.
1980.
Rec
assay
and
mutagenicity
studies
on
metal
compounds.
Mutat.
Res.
77:
109­
116
(
as
cited
in
ATSDR,
2000).

Kaplan,
R.
W.
1962.
Problems
testing
pharmaceutical
products,
additives
and
other
chemicals
for
their
mutagenic
action.
Naturwissen­
schaften
49:
457­
462
(
original
in
German).

Kato,
M.
1963.
Distribution
and
excretion
of
radiomanganese
administered
to
the
mouse.
Q.
J.
Exp.
Physiol.
48:
355­
369.

Kaur,
G.,
S.
K.
Hasan
and
R.
C.
Srivastava.
1980.
The
distribution
of
manganese­
54
in
fetal,
young
and
adult
rats.
Toxicol.
Lett.
5:
423­
426.

Kawamura,
C.
L.,
H.
Ikuta,
S.
Fukuzimi,
et
al.
1941.
Intoxication
by
manganese
in
well
water.
Kitasato
Arch.
Exp.
Med.
18:
145­
169.

Kawano,
J.,
D.
M.
Ney,
C.
L.
Keen,
et
al.
1987.
Altered
high
density
lipoprotein
composition
in
manganese­
deficient
Sprague­
Dawley
and
Wistar
rats.
J.
Nutr.
117:
902­
906
(
as
cited
in
ATSDR,
2000).

Keen,
C.
L.,
J.
G.
Bell
and
B.
Lönnerdal.
1986.
The
effect
of
age
on
manganese
uptake
and
retention
from
milk
and
infant
formulas
in
rats.
J.
Nutr.
116(
3):
395­
402.

Keen,
C.
L.,
J.
L.
Ensunsa,
M.
H.
Watson,
D.
L.
Baly,
S.
M.
Donovan,
M.
H.
Monaco,
and
M.
S.
Clegg.
1999.
Nutritional
aspects
of
manganese
from
experimental
studies.
Neurotoxicology
20:
213­
224.

Kennedy,
S.
D.
and
R.
G.
Bryant.
1986.
Manganese
deoxyribonucleic
acid
binding
modes:
Nuclear
magnetic
relaxation
dispersion
results.
Biophys.
J.
50:
669­
676.

Khan,
K.
N.,
J.
M.
Andress
and
P.
F.
Smith.
1997.
Toxicity
of
subacute
intravenous
manganese
chloride
administration
in
beagle
dogs.
Toxicol.
Pathol.
25(
4):
344­
350.

Khandelwal,
S.,
M.
Ashquin
and
S.
K.
Tandon.
1984.
Influence
of
essential
elements
on
manganese
intoxication.
Bull.
Environ.
Contam.
Toxicol.
32(
1):
10­
19.

Kies,
C.
1987.
Nutritional
Bioavailability
of
Manganese.
American
Chemical
Society,
Washington,
D.
C.

Kilburn,
C.
J.
1987.
Manganese,
malformations
and
motor
disorders:
findings
in
a
manganeseexposed
population.
Neurotoxicology
8(
3):
421­
429.

Kimura,
M.,
N.
Yagi
and
Y.
Itokawa.
1978.
Effect
of
subacute
manganese
feeding
on
serotonin
metabolism
in
the
rat.
J.
Toxicol.
Environ.
Health
4(
5­
6):
701­
707.
10­
13
Manganese
 
February
2003
Klaassen,
C.
D.
1974.
Biliary
excretion
of
manganese
in
rats,
rabbits,
and
dogs.
Toxicol.
Appl.
Pharmacol.
29(
3):
458­
468.

Komura,
J.
and
M.
Sakamoto.
1991.
Short­
term
oral
administration
of
several
manganese
compounds
in
mice:
physiological
and
behavioral
alterations
caused
by
different
forms
of
manganese.
Bull.
Environ.
Contam.
Toxicol.
46(
6):
921­
928.

Komura,
J.
and
M.
Sakamoto.
1993.
Subcellular
and
gel
chromatographic
distribution
of
manganese
in
the
mouse
brain:
Relation
to
the
chemical
form
of
chronically­
ingested
manganese.
Toxicol.
Lett.
66(
3):
287­
294
(
as
cited
in
ATSDR,
2000).

Kondakis,
X.
G.,
N.
Makris,
M.
Leotsinidis,
M.
Prinou,
and
T.
Papapetropopulos.
1989.
Possible
health
effects
of
high
manganese
concentration
in
drinking
water.
Arch.
Environ.
Health
44(
3):
175­
178.

Kondakis,
X.
G.
1990.
Professor,
University
of
Patras,
Greece.
Letter
to
S.
Velazquez,
U.
S.
EPA,
Cincinnati,
OH.
August
23
(
as
cited
in
U.
S.
EPA,
1993).

Kondakis,
X.
G.
1993.
Professor,
University
of
Patras,
Greece.
Letter
to
S.
Velazquez,
U.
S.
EPA,
Cincinnati,
OH.
June
7
(
as
cited
in
U.
S.
EPA,
1993).

Kontur,
P.
J.
and
L.
D.
Fechter.
1985.
Brain
manganese,
catecholamine
turnover,
and
the
development
of
startle
in
rats
prenatally
exposed
to
manganese.
Teratology
32(
1):
1­
11.

Kontur,
P.
J.
and
L.
D.
Fechter.
1988.
Brain
regional
manganese
levels
and
monoamine
metabolism
in
manganese­
treated
neonatal
rats.
Neurotoxicol.
Teratol.
10(
4):
295­
303.

Kostial,
K.,
D.
Kello,
S.
Jugo,
et
al.
1978.
Influence
of
age
on
metal
metabolism
and
toxicity.
Environ.
Health
Perspect.
25:
81­
86.

Kristensson,
K.,
H.
Eriksson,
B.
Lundh,
et
al.
1986.
Effects
of
manganese
chloride
on
the
rat
developing
nervous
system.
Acta
Pharmacol.
Toxicol.
(
Copenh.)
59(
5):
345­
348.

Lai,
J.
C.,
T.
K.
Leung
and
L.
Lim.
1981.
Brain
regional
distribution
of
glutamic
acid
decarboxylase,
choline
acetyltransferase,
and
acetylcholinesterase
in
the
rat:
effects
of
chronic
manganese
chloride
administration
after
two
years.
J.
Neurochem.
36(
4):
1443­
1448.

Lai,
J.
C.,
T.
K.
Leung,
J.
F.
Guest,
et
al.
1982a.
The
effects
of
chronic
manganese
chloride
treatment
expressed
as
age­
dependent,
transient
changes
in
rat
brain
synaptosomal
uptake
of
amines.
J.
Neurochem.
38(
3):
844­
847.

Lai,
J.
C.,
T.
K.
Leung
and
L.
Lim.
1982b.
The
ontogeny
of
acetylcholinesterase
activities
in
rat
brain
regions
and
the
effect
of
chronic
treatment
with
manganese
chloride.
J.
Neurochem.
39(
6):
1767­
1769
[
abstract].
10­
14
Manganese
 
February
2003
Lai,
J.
C.,
T.
K.
Leung,
and
L.
Lim.
1984.
Differences
in
the
neurotoxic
effects
of
manganese
during
development
and
aging:
Some
observations
on
brain
regional
neurotransmitter
and
nonneurotransmitter
metabolism
in
a
developmental
rat
model
of
chronic
manganese
encephalopathy.
Neurotoxicology
5:
37­
47.

Larsen,
L.
E.
and
D.
Grant.
1997.
General
toxicology
of
MnDPDP.
Acta
Radiol.
38
(
4
Pt
2):
770­
779.

Larsen,
N.
A.,
H.
Pakkenberg,
E.
Damsgaard,
et
al.
1979.
Topographical
distribution
of
arsenic,
manganese,
and
selenium
in
the
normal
human
brain.
J.
Neurol.
Sci.
42
(
3):
407­
416.

Laskey,
J.
W.,
G.
L.
Rehnberg,
J.
F.
Hein,
et
al.
1982.
Effects
of
chronic
manganese
(
Mn
3
O
4)
exposure
on
selected
reproductive
parameters
in
rats.
J.
Toxicol.
Environ.
Health
9(
4):
677­
687.

Laskey,
J.
W.,
G.
L.
Rehnberg,
J.
F.
Hein,
et
al.
1985.
Assessment
of
the
male
reproductive
system
in
the
preweanling
rat
following
Mn
3
O
4
exposure.
J.
Toxicol.
Environ.
Health
15(
2):
339­
350.

Lawrence,
D.
A.
1981.
Heavy
metal
modulation
of
lymphocyte
activities.
I.
In
vitro
effects
of
heavy
metals
on
primary
humoral
immune
responses.
Toxicol.
Appl.
Pharmacol.
57:
439­
451
(
as
cited
in
ATSDR,
2000).

Layrargues,
G.
P.,
C.
Rose,
L.
Spahr,
et
al.
1998.
Role
of
manganese
in
the
pathogenesis
of
portal­
systemic
encephalopathy.
Metab.
Brain
Dis.
13(
4):
311­
317.

Leahy,
P.
P.,
and
T.
H.
Thompson.
1994.
The
National
Water­
Quality
Assessment
Program.
U.
S.
Geological
Survey
Open­
File
Report
94­
70.
4
pp.
Available
on
the
Internet
at:
http://
water.
usgs.
gov/
nawqa/
NAWQA.
OFR94­
70.
html.
Last
updated
August
23,
2000.

Leung,
T.
K.,
J.
C.
Lai
and
L.
Lim.
1981.
The
regional
distribution
of
monoamine
oxidase
activities
towards
different
substrates:
effects
in
rat
brain
of
chronic
administration
of
manganese
chloride
and
of
ageing.
J.
Neurochem.
36(
6):
2037­
2043.

Leung,
T.
K.,
J.
C.
Lai
and
L.
Lim.
1982.
The
effects
of
chronic
manganese
feeding
on
the
activity
of
monoamine
oxidase
in
various
organs
of
the
developing
rat.
Comp.
Biochem.
Physiol.
71C
(
2):
223­
228.

Liccione,
J.
J.
and
M.
D.
Maines.
1989.
Manganese­
medicated
increase
in
the
rat
brain
mitochondrial
cytochrome
P­
450
and
drug
metabolism
activity:
Susceptibility
of
the
striatum.
J.
Pharmacol.
Exp.
Ther.
248:
222­
228.

Lönnerdal,
B.,
C.
L.
Keen,
J.
G.
Bell,
et
al.
1987.
Manganese
uptake
and
retention:
Experimental
animal
and
human
studies.
In:
Kies,
C.,
ed.,
Nutritional
Bioavailability
of
Manganese.
American
Chemical
Society,
Washington,
D.
C.
pp.
9­
20.
10­
15
Manganese
 
February
2003
Lönnerdal,
B.
1994.
Manganese
nutrition
of
infants.
In:
Klimis­
Tavantzis,
D.
J.,
ed.,
Manganese
in
Health
and
Disease.
CRC
Press,
Boca
Raton,
FL,
pp.
175­
191.

Loranger
S.
and
J.
Zayed.
1994.
Manganese
and
lead
concentrations
in
ambient
air
and
emission
rates
from
unleaded
and
leaded
gasoline
between
1981
and
1992
in
Canada:
A
comparative
study.
Atmos.
Environ.
28:
1645­
1651.

Loranger,
S.
and
J.
Zayed.
1995.
Environmental
and
occupational
exposure
to
manganese:
A
multimedia
assessment.
Int.
Arch.
Occup.
Environ.
Health.
67(
2):
101­
110.

Loranger,
S.
and
J.
Zayed.
1997a.
Environmental
contamination
and
human
exposure
to
airborne
total
respirable
manganese
in
Montreal.
J.
Air
Waste
Mngt.
Assoc.
47(
9):
983­
989
[
Abstract].

Loranger,
S.,
and
J.
Zayed.
1997b.
Environmental
contamination
and
human
exposure
assessment
to
manganese
in
the
St.
Lawrence
River
ecozone
(
Quebec,
Canada)
using
an
environmental
fate/
exposure
model:
GEOTOX.
Environ.
Res.
6(
1­
2):
105­
119.

Loranger,
S.,
J.
Zayed
and
E.
Forget.
1994a.
Manganese
contamination
in
Montreal
in
relation
with
traffic
density.
Water
Air
Soil
Pollut.
74:
385­
396.

Loranger,
S.,
G.
Demers,
G.
Kennedy,
et
al.
1994b.
The
pigeon
(
Columba
livia)
as
a
monitor
of
atmospheric
manganese
contamination
from
mobile
sources.
Arch.
Environ.
Contam.
Toxicol.
27:
311­
317.

Loranger,
S.,
J.
Zayed
and
G.
Kennedy.
1995.
Contribution
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
to
atmospheric
Mn
concentration
near
expressway:
dispersion
modeling
estimations.
Atmos.
Environ.
29:
591­
599.

Lynam
D.,
G.
Pfeifer,
B.
Fort,
et
al.
1994.
Atmospheric
exposure
to
manganese
from
use
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
performance
additive.
Sci.
Total
Environ.
146/
147:
103­
109.

Lynam,
D.
R.,
J.
W.
Roos,
G.
D.
Pfeifer,
et
al.
1999.
Environmental
effects
and
exposures
to
manganese
from
use
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
in
gasoline.
Neurotoxicology
20(
2­
3):
145­
150.

Mahomedy,
M.
C.,
Y.
H.
Mahomedy,
P.
A.
S.
Canhan,
et
al.
1975.
Methaemoglobinaemia
following
treatment
dispensed
by
witch
doctors.
Anaesthesia
30:
190­
193.

Mahoney,
J.
P.
and
W.
J.
Small.
1968.
Studies
on
manganese.
3.
The
biological
half­
life
of
radiomanganese
in
man
and
factors
which
affect
this
half­
life.
J.
Clin.
Invest.
47(
3):
643­
653.

Malecki
E.
A.
and
J.
L.
Greger.
1996.
Manganese
protects
against
heart
mitochondrial
lipid
peroxidation
in
rats
fed
high
levels
of
polyunsaturated
fatty
acids.
J.
Nutr.
126:
27­
33.
10­
16
Manganese
 
February
2003
Malecki,
E.
A.,
G.
M.
Radazanowski,
T.
J.
Radazanowski,
D.
D.
Gallahler,
and
J.
L.
Greger.
1996.
Biliary
manganese
excretion
in
conscious
rats
is
affected
by
acute
and
chronic
manganese
intake
but
not
by
dietary
fat.
J.
Nutr.
126:
489­
498.

Mandzgaladze,
R.
N.
and
M.
I.
Vasakidze.
1966.
The
effect
of
small
doses
of
manganese
compounds,
nitrogenous
organomercury
pesticides
and
some
anticoagulants
in
white
rat
bone
marrow
cells.
Vopr.
Gig.
Tr.
Profpatol.
10:
209­
212
(
original
in
Russian).

Mandzgaladze,
R.
N.
1966.
On
the
mutagenic
properties
of
manganese
compounds.
Vopr.
Gig.
Tr.
Profpatol.
10:
225­
226
(
original
in
Russian).

Matrone,
G.,
R.
H.
Hartman
and
A.
J.
Clawson.
1959.
Studies
of
a
manganese
iron
antagonism
in
the
nutrition
of
rabbits
and
baby
pigs.
J.
Nutr.
67:
309­
317.

Maynard,
L.
S.
and
G.
C.
Cotzias.
1955.
The
partition
of
manganese
among
organs
and
intracellular
organelles
of
the
rat.
J.
Biol.
Chem.
214:
489­
495.

McDermott,
S.
D.
and
C.
Kies.
1987.
Manganese
usage
in
humans
as
affected
by
use
of
calcium
supplements.
In:
Kies,
C.,
ed.,
Nutritional
Bioavailability
of
Manganese.
American
Chemical
Society,
Washington,
D.
C.
pp.
146­
151.

Mella,
H.
1924.
The
experimental
production
of
basal
ganglion
symptomatology
in
macacus
rhesus.
Arch.
Neurol.
Psych.
11:
405­
417.

Mena,
I.,
K.
Horiuchi
and
K.
Burke.
1969.
Chronic
manganese
poisoning:
Individual
susceptibility
and
absorption
of
iron.
Neurology
19:
1000­
1006.

Mena,
I.,
J.
Court,
S.
Fuenzalida,
et
al.
1970.
Modification
of
chronic
manganese
poisoning.
Treatment
with
L­
dopa
or
5­
OH
tryptophane.
N.
Engl.
J.
Med.
282(
1):
5­
10.

Mena,
I.
1974.
The
role
of
manganese
in
human
disease.
Ann.
Clin.
Lab.
Sci.
4(
6):
487­
491.

Merck.
1983.
The
Merck
Index,
10th
Ed.
Merck
&
Co.,
Inc.
Rahway,
N.
J.

Minoia,
C.,
E.
Sabbioni,
P.
Apostoli,
et
al.
1990.
Trace
element
reference
values
in
tissues
from
inhabitants
of
the
European
community.
I.
A
study
of
46
elements
in
urine,
blood
and
serum
of
Italian
subjects.
Sci.
Total
Environ.
95:
89­
105
(
as
cited
in
ATSDR,
2000).

Mirowitz,
S.
A.
and
T.
J.
Westrich.
1992.
Basal
ganglial
signal
intensity
alterations:
Reversal
after
discontinuation
of
parenteral
manganese
administration.
Radiol.
185:
535­
536.

Moran,
J.
1975.
The
environmental
implications
of
manganese
as
an
alternative
antiknock.
#
750926,
SAE
Publications
Division,
Michigan.
10­
17
Manganese
 
February
2003
Morganti,
J.
B.,
B.
A.
Lown,
C.
H.
Stineman,
et
al.
1985.
Uptake,
distribution
and
behavioral
effects
of
inhalation
exposure
to
manganese
(
MnO
2)
in
the
adult
mouse.
Neurotoxicology
6(
1):
1­
15.

Mortelmans,
K.,
S.
Haworth,
T.
Lawlor,
et
al.
1986.
Salmonella
mutagenicity
test.
II.
Results
from
the
testing
of
270
chemicals.
Environ.
Mutagen.
8
(
Suppl.
7):
1­
119
(
as
cited
in
NTP,
1993).

Mustafa,
S.
J.
and
S.
V.
Chandra.
1971.
Levels
of
5­
hydroxytryptamine,
dopamine
and
norepinephrine
in
whole
brain
of
rabbits
in
chronic
manganese
toxicity.
J.
Neurochem.
18(
6):
931­
933
(
as
cited
in
ATSDR,
2000).

Nachtman,
J.
P.,
R.
E.
Tubben
and
R.
L.
Commissaris.
1986.
Behavioral
effects
of
chronic
manganese
administration
in
rats:
locomotor
activity
studies.
Neurobehav.
Toxicol.
Teratol.
8(
6):
711­
715.

Neff,
N.
H.,
R.
E.
Barrett
and
E.
Costa.
1969.
Selective
depletion
of
caudate
nucleus
dopamine
and
serotonin
during
chronic
manganese
dioxide
administration
to
squirrel
monkeys.
Experimentia
25:
1140­
1141.

Newberne,
P.
M.
1973.
Input
and
disposition
of
manganese
in
man.
In:
Medical
and
Biologic
Effects
of
Environmental
Pollutants:
Manganese.
National
Academy
of
Sciences,
Washington,
D.
C.
pp.
77­
82.

Newland,
M.
C.,
T.
L.
Ceckler,
J.
H.
Kordower,
et
al.
1989.
Visualizing
manganese
in
the
primate
basal
ganglia
with
magnetic
resonance
imaging.
Exp.
Neurol.
106(
3):
251­
258.

Newland,
M.
C.
and
B.
Weiss.
1992.
Persistent
effects
of
manganese
on
effortful
responding
and
their
relationship
to
manganese
accumulation
in
the
primate
globus
pallidus.
Toxicol.
Appl.
Pharmacol.
113(
1):
87­
97.

NIOSH.
1984.
National
Institute
for
Occupational
Safety
and
Health.
Registry
of
Toxic
Effects
of
Chemical
Substances.
Prepared
by
Tracor
Jitco,
Inc.,
under
Contract
Number
210­
81­
8101.
Rockville,
MD.

Nishioka,
H.
1975.
Mutagenic
activities
of
metal
compounds
in
bacteria.
Mutat.
Res.
31:
185­
189
(
as
cited
in
ATSDR,
2000).

NTP.
1992.
Toxicology
and
Carcinogenesis
Studies
of
Manganese
(
II)
Sulfate
Monohydrate
(
CAS
no.
10034­
96­
5)
in
F344/
N
Rats
and
B6C3F
1
Mice
(
Feed
Studies).
Draft
Technical
Report.
NTP
Tech.
Rep.
Ser.
428.
National
Toxicology
Program,
Research
Triangle
Park,
NC.

NTP.
1993.
Toxicology
and
Carcinogenesis
Studies
of
Manganese
(
II)
Sulfate
Monohydrate
(
CAS
no.
10034­
96­
5)
in
F344/
N
Rats
and
B6C3F
1
Mice
(
Feed
Studies).
NTP
Tech.
Rep.
Ser.
428.
National
Toxicology
Program,
Research
Triangle
Park,
NC.
10­
18
Manganese
 
February
2003
Oberley,
T.
J.,
C.
E.
Piper
and
D.
S.
McDonald.
1982.
Mutagenicity
of
metal
salts
in
the
L5178Y
mouse
lymphoma
assay.
J.
Toxicol.
Environ.
Health
9:
367­
376
(
as
cited
in
ATSDR,
2000).

Olanow,
C.
W.,
P.
F.
Good,
H.
Shinotoh,
et
al.
1996.
Manganese
intoxication
in
the
rhesus
monkey:
A
clinical,
imaging,
pathologic,
and
biochemical
study.
Neurology
46:
492­
498.

Oner,
G.,
and
U.
K.
Senturk.
1995.
Reversibility
of
manganese­
induced
learning
defect
in
rats.
Food
Chem.
Toxicol.
33:
559­
563.

Ono,
J.,
K.
Harada,
and
R.
Kodaka.
1995.
Manganese
deposition
in
the
brain
during
long­
term
parenteral
nutrition.
J
Parent
Enter
Nutr
19:
310­
312
(
as
cited
in
ATSDR,
2000).

Orgel,
A.
and
L.
E.
Orgel.
1965.
Induction
of
mutations
in
bacteriophage
T4
with
divalent
manganese.
J.
Mol.
Biol.
14:
453­
457
(
as
cited
in
ATSDR,
2000).

Pagano,
D.
A.
and
E.
Zeiger.
1992.
Conditions
for
detecting
the
mutagenicity
of
divalent
metals
in
Salmonella
typhimurium.
Environ.
Mol.
Mutagen.
19(
2):
139­
146
(
as
cited
in
ATSDR,
2000).

Pal,
P.
K.,
A.
Samii,
and
D.
B.
Calne.
1999.
Manganese
neurotoxicity:
A
review
of
clinical
features,
imaging
and
pathology.
Neurotoxicology
20:
227­
238.

Papavasiliou,
P.
S.,
S.
T.
Miller
and
G.
C.
Cotzias.
1966.
Role
of
liver
in
regulating
distribution
and
excretion
of
manganese.
Am.
J.
Physiol.
211(
1):
211­
216.

Pappas,
B.
A.,
D.
Zhang,
C.
M.
Davidson,
et
al.
1997.
Perinatal
manganese
exposure:
behavioral,
neurochemical,
and
histopathological
effects
in
the
rat.
Neurotoxicol.
Teratol.
19(
1):
17­
25.

Pellizzari,
E.,
C.
Clayton,
C.
Rodes,
et
al.
1999.
Particulate
matter
and
manganese
exposures
in
Toronto,
Canada.
Atmos.
Environ.
33:
721­
734.

Pennington,
J.
A.,
B.
E.
Young,
D.
B.
Wilson,
et
al.
1986.
Mineral
content
of
foods
and
total
diets:
The
selected
minerals
in
food
survey.
J.
Am.
Diet
Assoc.
86:
876­
891.

Pennington,
J.
A.,
B.
E.
Young,
and
D.
B.
Wilson.
1989.
Nutritional
elements
in
the
U.
S.
diet:
Results
for
the
Total
Diet
Study,
1982­
1986.
J.
Am.
Diet
Assoc.
89:
659­
664.

Perry,
H.
M.,
Jr.,
E.
F.
Perry,
J.
E.
Purifoy,
et
al.
1973.
A
comparison
of
intra­
and
interhepatic
variability
of
trace
metal
concentrations
in
normal
men.
In:
Trace
Substances
in
Environmental
Health,
Proc.
Univ.
Missouri
7th
Annual
Conf.
University
of
Missouri,
Columbia,
MO.
pp.
281­
288.

Pfeifer
G.,
R.
Harrison
and
D.
Lynam.
1999.
Personal
exposures
to
airborne
metals
in
London
taxi
drivers
and
office
workers
in
1995
and
1996.
Sci.
Total
Environ.
235:
253­
260.
10­
19
Manganese
 
February
2003
Pierson,
W.,
D.
McKee,
W.
Brachaczek,
et
al.
1978.
Methylcyclopentadienyl
manganese
tricarbonyl:
effect
on
manganese
emissions
from
vehicles
on
the
road.
J.
Air
Pollut.
Control
Assoc.
28:
692­
693.

Pihl,
R.
O.
and
M.
Parkes.
1977.
Hair
element
content
in
learning
disabled
children.
Science
198:
204­
206.

Piver,
W.
1974.
Potential
dilemma:
The
methods
of
meeting
automotive
exhaust
emission
standards
of
the
Clean
Air
Act
of
1970.
Environ.
Health
Perspect.
8:
165­
190.

Pollack,
S.,
J.
N.
George,
R.
C.
Reba,
et
al.
1965.
The
absorption
of
nonferrous
metals
in
iron
deficiency.
J.
Clin.
Invest.
44:
1470­
1473.

Powell,
J.,
T.
Borden
and
R.
Thompson.
1998.
In
vitro
mineral
availability
from
digested
tea:
A
rich
dietary
source
of
manganese.
Analyst
123:
1721­
1724.

Price,
N.
O.,
G.
E.
Bunce
and
R.
W.
Engel.
1970.
Copper,
manganese
and
zinc
balance
in
preadolescent
girls.
Am.
J.
Clin.
Nutr.
23:
258­
260.

Qato,
M.
K.
and
M.
D.
Maines.
1985.
Regulation
of
heme
and
drug
metabolism
activities
in
the
brain
by
manganese.
Biochem.
Biophys.
Res.
Commun.
128(
1):
18­
24.

Rabar,
I.
1976.
Some
factors
influencing
manganese
metabolism
in
rats.
M.
Sc.
Thesis,
Univ.
Zagreb.,
Zagreb,
Yugoslavia.

Rasmuson,
A.
1985.
Mutagenic
effects
of
some
water­
soluble
metal
compounds
in
a
somatic
eye­
color
test
system
in
Drosophila
melanogaster.
Mutat.
Res.
157:
157­
162
(
as
cited
in
ATSDR,
2000).

Rehnberg,
G.
L.,
J.
F.
Hein,
S.
D.
Carter,
et
al.
1980.
Chronic
manganese
oxide
administration
to
preweanling
rats:
manganese
accumulation
and
distribution.
J.
Toxicol.
Environ.
Health
6(
1):
217­
226.

Rehnberg,
G.
L.,
J.
F.
Hein,
S.
D.
Carter,
et
al.
1981.
Chronic
ingestion
of
Mn
3
O
4
by
young
rats:
tissue
accumulation,
distribution,
and
depletion.
J.
Toxicol.
Environ.
Health
7(
2):
263­
272.

Rehnberg,
G.
L.,
J.
F.
Hein,
S.
D.
Carter,
et
al.
1982.
Chronic
ingestion
of
Mn
3
O
4
by
rats:
tissue
accumulation
and
distribution
of
manganese
in
two
generations.
J.
Toxicol.
Environ.
Health
9(
2):
175­
188.

Rehnberg,
G.
L.,
J.
F.
Hein,
S.
D.
Carter,
et
al.
1985.
Age­
dependent
changes
in
gastrointestinal
transport
and
retention
of
particulate
manganese
oxide
in
the
rat.
J
Toxicol
Environ
Health
16:
887­
899.
10­
20
Manganese
 
February
2003
Ressler,
T.,
J.
Wong,
and
J.
Roos.
1999.
Manganese
speciation
in
exhaust
particulates
of
automobiles
using
MMT
containing
gasoline.
J.
Synchroton
Radiation
(
as
cited
in
Lynam
et
al.,
1999).

Riveros­
Rosas
H.,
G.
Pfeifer,
D.
Lynam,
et
al.
1997.
Personal
exposure
to
elements
in
Mexico
City
air.
Sci.
Total
Environ.
198:
79­
96.

Roels,
H.,
R.
Lauwerys,
P.
Genet,
et
al.
1987.
Relationships
between
external
and
internal
parameters
of
exposure
to
manganese
in
workers
from
a
manganese
oxide
and
salt
producing
plant.
Am.
J.
Ind.
Med.
11:
297­
305
(
as
cited
in
U.
S.
EPA,
1999a).

Roels,
H.
A.,
P.
Ghyselen,
J.
P.
Buchet,
et
al.
1992.
Assessment
of
the
permissible
exposure
level
to
manganese
in
workers
exposed
to
manganese
dioxide
dust.
Br.
J.
Ind.
Med.
49(
1):
25­
34.

Roels,
H.
A.,
G.
Meiers,
M.
Delos,
et
al.
1997.
Influence
of
the
route
of
administration
and
the
chemical
form
(
MnCl
2,
MnO
2)
on
the
absorption
and
cerebral
distribution
of
manganese
in
rats.
Arch.
Toxicol.
71:
223­
230.

Roels,
H.
A.,
M.
I.
Ortega­
Eslava,
E.
Ceulemans,
A.
Robert
and
D.
Lison.
1999.
Prospective
study
on
the
reversibility
of
neurobehavioral
effects
in
workers
exposed
to
manganese
dioxide.
Neurotoxicology
20:
255­
271.

Rogers,
R.
R.,
R.
J.
Garner,
M.
M.
Riddle,
et
al.
1983.
Augmentation
of
murine
natural
killer
cell
activity
by
manganese
chloride.
Toxicol.
Appl.
Pharmacol.
70:
7­
17
(
as
cited
in
ATSDR,
2000).

Roos
J.
W.,
D.
L.
Denane,
B.
F.
Fort,
D.
G.
Grande,
and
K.
L.
Dykes.
The
effect
of
manganese
oxides
on
OBD­
II
catalytic
converter
monitoring.
SAE
Technical
Paper
Series
#
942056,
Warrendale,
PA
(
as
cited
in
Lynam
et
al.,
1999).

Roth,
G.
S.
and
R.
C.
Adleman.
1975.
Age­
related
changes
in
hormone
binding
by
target
cells
and
tissues:
Possible
role
of
altered
adaptive
responsiveness.
Exp.
Gerontol.
10:
1­
11.

Ruoff,
W.
L.
1995.
Relative
bioavailability
of
manganese
ingested
in
food
or
water.
In:
Proceedings:
Workshop
on
the
Bioavailability
and
Oral
Toxicity
of
Manganese.
Sponsored
by
the
U.
S.
Environmental
Protection
Agency,
Cincinnati,
OH.
August
30­
31,
1994
(
as
cited
in
U.
S.
EPA,
1999a).

Ryker,
S.
J.
and
A.
K.
Williamson.
1999.
Pesticides
in
Public
Supply
Wells
of
Washington
State.
U.
S.
Geological
Survey
Fact
Sheet
122­
96.

Sánchez,
D.
J.,
J.
L.
Domingo,
J.
M.
Llobet,
and
C.
L.
Keen.
1993.
Maternal
and
developmental
toxicity
of
manganese
in
the
mouse.
Toxicol.
Lett.
69(
1):
45­
52.

Sandström,
B.,
L.
Davidsson,
A.
Cederblad,
et
al.
1986.
Manganese
absorption
and
metabolism
in
man.
Acta
Pharmacol.
Toxicol.
(
Copenh.)
59(
Suppl
7):
60­
62.
10­
21
Manganese
 
February
2003
Scheuhammer,
A.
M.
and
M.
G.
Cherian.
1981.
The
influence
of
manganese
on
the
distribution
of
essential
trace
elements.
I.
Regional
distribution
of
Mn,
Na,
K,
Mg,
Zn,
Fe,
and
Cu
in
rat
brain
after
chronic
Mn
exposure.
Toxicol.
Appl.
Pharmacol.
61(
2):
227.

Scheuhammer,
A.
M.
1983.
Chronic
manganese
exposure
in
rats:
histological
changes
in
the
pancreas.
J.
Toxicol.
Environ.
Health
12(
2­
3):
353­
360.

Scheuhammer,
A.
M.
and
M.
G.
Cherian.
1983.
The
influence
of
manganese
on
the
distribution
of
essential
trace
elements.
II.
The
tissue
distribution
of
manganese,
magnesium,
zinc,
iron,
and
copper
in
rats
after
chronic
manganese
exposure.
J.
Toxicol.
Environ.
Health
12(
2­
3):
361­
370.

Schroeder,
H.
A.,
J.
J.
Balassa
and
I.
H.
Tipton.
1966.
Essential
trace
metals
in
man:
Manganese.
A
study
in
homeostasis.
J.
Chronic
Dis.
19(
5):
545­
571.

Schwartz,
R.,
B.
J.
Apgar
and
E.
M.
Wein.
1986.
Apparent
absorption
and
retention
of
Ca,
Cu,
Mg,
Mn,
and
Zn
from
a
diet
containing
bran.
Am.
J.
Clin.
Nutr.
43:
444­
455.

Segura­
Aguilar,
J.
and
C.
Lind.
1989.
On
the
mechanism
of
the
Mn3+­
induced
neurotoxicity
of
dopamine:
Prevention
of
quinone­
derived
oxygen
toxicity
by
DT
diaphorase
and
superoxide
dismutase.
Chem.
Biol.
Interact.
72(
3):
309­
324.

Shacklette,
H.
T.,
and
J.
G.
Boerngen.
1984.
Element
oncentrations
in
soils
and
other
surficial
materials
of
the
coterminous
United
States.
USGS
Paper
1270.
Washington,
DC:
US
Govern.
Printing
Office,
p.
6.

Shigan,
S.
A.
and
B.
R.
Vitvickaja.
1971.
Experimental
substantiation
of
permissible
residual
concentrations
of
potassium
permanganate
in
drinking
water.
Gig.
Sanit.
36:
15­
18.

Shimkin,
M.
B.
and
G.
D.
Stoner.
1975.
Lung
tumors
in
mice:
Application
to
carcinogenesis
bioassay.
Adv.
Cancer
Res.
21:
1­
58.

Shukla,
G.
S.
and
S.
V.
Chandra.
1976.
Manganese
induced
morphological
and
biochemical
changes
in
the
brain
of
iron
deficient
rats.
Ind.
Health
14:
87­
92.

Shukla,
G.
S.
and
S.
V.
Chandra.
1977.
Levels
of
sulfhydryls
and
sulfhydryl­
containing
enzymes
in
brain,
liver
and
testis
of
manganese
treated
rats.
Arch.
Toxicol.
37(
4):
319­
325.

Shukla,
G.
S.,
S.
Singh
and
S.
V.
Chandra.
1978.
The
interaction
between
manganese
and
ethanol
in
rats.
Acta
Pharmacol.
Toxicol.
(
Copenh.)
43(
5):
354­
362.

Shukla,
G.
S.,
M.
P.
Dubey
and
S.
V.
Chandra.
1980.
Managanese­
induced
biochemical
changes
in
growing
versus
adult
rats.
Arch.
Environ.
Contam.
Toxicol.
9(
4):
383­
391.

Shukla,
G.
S.
and
S.
V.
Chandra.
1987.
Concurrent
exposure
to
lead,
manganese,
and
cadmium
and
their
distribution
to
various
brain
regions,
liver,
kidney,
and
testis
of
growing
rats.
Arch.
Environ.
Contam.
Toxicol.
16(
3):
303­
310.
10­
22
Manganese
 
February
2003
Sierra,
P.,
S.
Loranger,
G.
Kennedy,
et
al.
1995.
Occupational
and
environmental
exposure
of
automobile
mechanics
and
non­
automotive
workers
to
airborne
manganese
arising
from
the
combustion
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT).
Am.
Ind.
Hyg.
Assoc.
J.
56(
7):
713­
716.

Simmon,
V.
F.
and
S.
Ligon.
1977.
In
vitro
microbiological
mutagenicity
studies
of
Ethyl
Corporation
compounds.
Interim
report.
Stanford
Research
Institute,
California.

Singh,
I.
1984.
Induction
of
gene
conversion
and
reverse
mutation
by
manganese
sulphate
and
nickel
sulphate
in
Saccharomyces
cerevisiae.
Mutat.
Res.
137:
47­
49
(
as
cited
in
ATSDR,
2000).

Singh,
J.,
R.
Husain,
S.
K.
Tandon,
et
al.
1974.
Biochemical
and
histopathological
alterations
in
early
manganese
toxicity
in
rats.
Environ.
Physiol.
Biochem.
4(
1):
16­
23.

Singh,
J.,
S.
V.
Chandra
and
S.
K.
Tandon.
1975.
Chelation
in
metal
intoxication
II:
In
vitro
and
in
vivo
effect
of
some
compounds
on
brain,
liver,
and
testis
of
rats
treated
with
manganese
sulphate.
Bull.
Environ.
Contam.
Toxicol.
14(
4):
497­
503.

Singh,
S.,
G.
S.
Shukla,
R.
S.
Srivastava,
et
al.
1979.
The
interaction
between
ethanol
and
manganese
in
rat
brain.
Arch.
Toxicol.
41(
4):
307­
316.

Sitaramayya,
A.,
N.
Nagar
and
S.
V.
Chandra.
1974.
Effect
of
manganese
on
enzymes
in
rat
brain.
Acta
Pharmacol.
Toxicol.
(
Copenh.)
35(
3):
185­
190.

Smeyers­
Verbeke,
J.,
P.
Bell,
A.
Lowenthal,
et
al.
1976.
Distribution
of
Mn
in
human
brain
tissue.
Clin.
Chim.
Acta
68(
3):
343­
347.

Smialowicz,
R.
J.,
R.
W.
Luebke,
R.
R.
Rogers,
et
al.
1985.
Manganese
chloride
enhances
natural
cell­
mediated
immune
effector
cell
function:
Effects
on
macrophages.
Immunopharmacology
9:
1­
11
(
as
cited
in
ATSDR,
2000).

Smialowicz,
R.
J.,
R.
R.
Rogers,
M.
M.
Riddle,
et
al.
1987.
Effects
of
manganese,
calcium,
magnesium,
and
zinc
on
nickel­
induced
suppression
of
murine
natural
killer
cell
activity.
J.
Toxicol.
Environ.
Health
20:
67­
80
(
as
cited
in
ATSDR,
2000).

Smith,
S.
E.,
M.
Medlicott
and
G.
H.
Ellis.
1944.
Manganese
deficiency
in
the
rabbit.
Arch.
Biochem.
Biophys.
4:
281­
289
(
as
cited
in
ATSDR,
2000).

Smyth,
H.
F.,
C.
P.
Carpenter,
C.
S.
Weil,
et
al.
1969.
Range­
finding
toxicity
data:
List
VII.
J.
Am.
Ind.
Hyg.
Assoc.
30:
470­
476.

Snyder,
R.
D.
1988.
Role
of
active
oxygen
species
in
metal­
induced
DNA
strand
breakage
in
human
diploid
fibroblasts.
Mutat.
Res.
193(
3):
237­
246.
10­
23
Manganese
 
February
2003
Spencer,
H.,
C.
R.
Asmussen,
R.
B.
Holtzman,
et
al.
1979.
Metabolic
balances
of
cadmium,
copper,
manganese,
and
zinc
in
man.
Am.
J.
Clin.
Nutr.
32(
9):
1867­
1875.

Srisuchart,
B.,
M.
J.
Taylor
and
R.
P.
Sharma.
1987.
Alteration
of
humoral
and
cellular
immunity
in
manganese
chloride­
treated
mice.
J.
Toxicol.
Environ.
Health
22:
91­
99
(
as
cited
in
ATSDR,
2000).

Stauber,
J.
L.,
T.
M.
Florence
and
W.
S.
Webster.
1987.
The
use
of
scalp
hair
to
monitor
manganese
in
aborigines
from
Groote
Eylandt.
Neurotoxicology
8(
3):
431­
435.

Stoner,
G.
D.,
M.
B.
Shimkin,
M.
C.
Troxell,
et
al.
1976.
Test
for
carcinogenicity
of
metallic
compounds
by
the
pulmonary
tumor
response
in
strain
A
mice.
Cancer
Res.
36(
5):
1744­
1747.

Strause,
L.
G.,
J.
Hegenauer,
P.
Saltman,
et
al.
1986.
Effects
of
long­
term
dietary
manganese
and
copper
deficiency
on
rat
skeleton.
J.
Nutr.
116:
135­
141
(
as
cited
in
ATSDR,
2000).

Sumino,
K.,
K.
Hayakawa,
T.
Shibata,
et
al.
1975.
Heavy
metals
in
normal
Japanese
tissues.
Amounts
of
15
heavy
metals
in
30
subjects.
Arch.
Environ.
Health
30(
10):
487­
494.

Suzuki,
Y.
1974.
Studies
on
excessive
oral
intake
of
manganese.
II.
Minimum
dose
for
manganese
accumulation
in
mouse
organ.
Shikoku
Acta
Med.
30:
32­
45.

Suzuki,
Y.,
T.
Mouri,
K.
Nishiyama,
et
al.
1975.
Study
of
subacute
toxicity
of
manganese
dioxide
in
monkeys.
Tokushima
J.
Exp.
Med
.
22:
5­
10.

Szakmáry,
E.,
G.
Ungvary,
A.
Hudak,
et
al.
1995.
Developmental
effect
of
manganese
in
rat
and
rabbit.
Cent
Eur
J
Occup
Environ
Med
1:
149­
159.

Tanaka,
Y.
1982.
Manganese:
Its
possible
significance
in
childhood
nutrition
in
relation
to
convulsive
disorders.
J.
Am.
Coll.
Nutr.
1:
113.

Ter
Haar,
G.,
M.
Griffing,
M.
Brandt,
D.
G.
Oderding,
and
M.
Kapron.
1975.
Methylcyclopentadienyl
manganese
tricarbonyl
as
an
antiknock:
Composition
and
fate
of
manganese
exhaust
products.
J.
Air
Pollut.
Control
Assoc.
25:
858­
860.

Thomson,
A.
B.,
D.
Olatunbosun
and
L.
S.
Valverg.
1971.
Interrelation
of
intestinal
transport
system
for
manganese
and
iron.
J.
Lab.
Clin.
Med.
78(
4):
642­
655.

Tichy,
M.,
M.
Cikrt
and
J.
Havrdova.
1973.
Manganese
binding
in
rat
bile.
Arch.
Toxikol.
30(
3):
227­
236.

Tipton,
I.
H.
and
M.
J.
Cook.
1963.
Trace
elements
in
human
tissue.
Part
II.
Adult
subjects
from
the
United
States.
Health
Phys.
9:
103­
145
(
as
cited
in
ATSDR,
2000).
10­
24
Manganese
 
February
2003
Tjälve,
H.,
J.
Henriksson,
J.
Tallkvist,
B.
S.
Larsson,
and
N.
G.
Lindquist.
1996.
Uptake
of
manganese
and
cadmium
from
the
nasal
mucosa
into
the
central
nervous
system
via
olfactory
pathway
in
rats.
Pharmacol.
Toxicol.
79:
347­
356.

Treinen,
K.
A.
and
W.
F.
Blazak.
1995.
Delvelopmental
toxicity
of
WIN
59010­
2
in
Sprague­
Dawley
rats.
Toxicology
15:
160­
161
[
Abstract].

Trumbo,
P.,
A.
A.
Yates,
S.
Schlicker
and
M.
Poos.
2001.
Dietary
reference
intakes:
Vitamin
A,
vitamin
K,
arsenic,
boron,
chromium,
copper,
iodine,
iron,
manganese,
molybdenum,
nickel,
silicon,
vanadium,
and
zinc.
J
Am
Diet
Assoc
101:
294­
301.

Ulitzur,
C.
E.
and
M.
Barak.
1988.
Detection
of
genotoxicity
of
metallic
compounds
by
the
bacterial
bioluminescence
test.
J.
Biol.
Chem.
2:
95­
99
(
as
cited
in
ATSDR,
2000).

Umeda,
M.
and
M.
Nishimura.
1979.
Inducibility
of
chromosomal
aberrations
by
metal
compounds
in
cultured
mammalian
cells.
Mutat.
Res.
67:
221­
223.

U.
S.
EPA.
1975.
Scientific
and
technical
assessment
report
on
manganese.
North
Carolina:
U.
S.
Environmental
Protection
Agency,
Office
of
Research
and
Development.
EPA
600/
6­
75­
002.

U.
S.
EPA.
1984.
Health
Assessment
Document
for
Manganese.
U.
S.
Environmental
Protection
Agency,
Office
of
Health
and
Environmental
Assessment,
Environmental
Criteria
and
Assessment
Office.
EPA
600/
8­
83­
013F.
Cincinnati,
OH.

U.
S.
EPA.
1986a.
Guidelines
for
Carcinogenic
Risk
Assessment.
U.
S.
Environmental
Protection
Agency.
Fed.
Reg.
51(
185):
33992­
34003.

U.
S.
EPA.
1986b.
Guidelines
for
the
Health
Risk
Assessment
of
Chemical
Mixtures.
U.
S.
Environmental
Protection
Agency.
Federal
Register
51(
185):
34014­
34025.

U.
S.
EPA.
1986c.
Guidelines
for
Mutagenicity
Risk
Assessment.
U.
S.
Environmental
Protection
Agency.
Federal
Register
51(
185):
34006­
34012.

U.
S.
EPA.
1986d.
Reference
Values
for
Risk
Assessment.
U.
S.
Environmental
Protection
Agency.
Prepared
by
the
Office
of
Health
and
Environmental
Assessment,
Environmental
Criteria
and
Assessment
Office.
Cincinnati,
OH.

U.
S.
EPA.
1988.
Recommendations
for
and
Documentation
of
Biological
Values
for
Use
in
Risk
Assessment.
U.
S.
Environmental
Protection
Agency,
Environmental
Criteria
and
Assessment
Office,
Office
of
Health
and
Environmental
Assessment,
Cincinnati,
OH.
EPA/
600/
6­
87­
008.
NTIS
PB88­
179874/
AS,
February
1988.

U.
S.
EPA.
1990.
Comments
on
the
use
of
methylcyclopentadienyl
manganese
tricarbonyl
in
unleaded
gasoline.
North
Carolina:
U.
S.
Environmental
Protection
Agency,
Office
of
Research
and
Development.
10­
25
Manganese
 
February
2003
U.
S.
EPA.
1991a.
Guidelines
for
Developmental
Toxicity
Risk
Assessment.
U.
S.
Environmental
Protection
Agency.
Federal
Register
56:
63798­
63826.

U.
S.
EPA.
1991b.
Summary
of
workshop
discussions
at
the
manganese
and
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
conference,
12­
15
March
1991.
North
Carolina:
U.
S.
Environmental
Protection
Agency,
Office
of
Research
and
Development.

U.
S.
EPA.
1993.
Drinking
Water
Criteria
Document
for
Manganese.
Final
Draft.
U.
S.
Environmental
Protection
Agency,
Environmental
Criteria
and
Assessment
Office,
Office
of
Health
and
Environmental
Assessment.
ECAO­
CIN­
D008.
Cincinnati,
OH.

U.
S.
EPA.
1994a.
Drinking
Water
Criteria
Document
for
Manganese.
U.
S.
Environmental
Protection
Agency,
Office
of
Water,
Research
and
Development.
September,
1993.
Updated:
March,
1994.

U.
S.
EPA.
1994b.
Peer
Review
and
Peer
Involvement
at
the
U.
S.
Environmental
Protection
Agency.
Signed
by
the
U.
S.
EPA
Administrator,
Carol
A.
Browner,
June
7.

U.
S.
EPA
1995.
Use
of
the
Benchmark
Dose
Approach
in
Health
Risk
Assessment.
U.
S.
Environmental
Protection
Agency.
EPA/
630/
R­
94/
007.

U.
S.
EPA.
1996a.
Manganese.
Integrated
Risk
Information
System.
(
IRIS).
U.
S.
Environmental
Protection
Agency.
Available
at
http://
www.
epa.
gov/
iris.
Last
revised
December
1,
1996.

U.
S.
EPA
1996b.
Proposed
Guidelines
for
Carcinogen
Risk
Assessment.
U.
S.
Environmental
Protection
Agency,
Office
of
Research
and
Development,
Washington,
D.
C.
EPA/
600/
P­
92/
003C.

U.
S.
EPA.
1996c.
Guidelines
for
Reproductive
Toxicity
Risk
Assessment.
U.
S.
Environmental
Protection
Agency,
Office
of
Research
and
Development,
Washington,
D.
C.
EPA/
630/
R­
96/
009.

U.
S.
EPA.
1996d.
Exposure
Factors
Handbook.
Vol.
I­
General
Factors.
EPA/
600/
8­
89/
043.
Washington,
DC.

U.
S.
EPA.
1996e.
Emergency
Planning
and
Community
Right­
to­
Know
Section
313,
List
of
Toxic
Chemicals.
Available
on
the
internet
at:
http://
www.
epa.
gov/
tri/
chemls2.
pdf.
Last
modified
March
23,
2000.
Link
to
site
at:
http://
www.
epa.
gov/
tri/
chemical.
htm
U.
S.
EPA.
1997.
U.
S.
Environmental
Protection
Agency.
Announcement
of
the
Draft
Drinking
Water
Contaminant
Candidate
List;
Notice.
Fed.
Reg.
62(
193):
52193.
October
6.

U.
S.
EPA.
1998.
U.
S.
Environmental
Protection
Agency.
Announcement
of
the
Drinking
Water
Contaminant
Candidate
List;
Final
Rule.
Fed.
Reg.
63(
274):
10273.
March
2.
10­
26
Manganese
 
February
2003
U.
S.
EPA.
1998a.
Guidelines
for
Neurotoxicity
Risk
Assessment.
U.
S.
Environmental
Protection
Agency.
Federal
Register
63(
93):
26926­
26954.

U.
S.
EPA.
1998b.
Science
Policy
Council
Handbook:
Peer
Review.
U.
S.
Environmental
Protection
Agency,
Office
of
Science
Policy,
Office
of
Research
and
Development,
Washington,
D.
C.
EPA/
100?
B­
98/
001.

U.
S.
EPA.
1999a.
A
Review
of
Contaminant
Occurrence
in
Public
Water
Systems.
EPA
Report/
816­
R­
99/
006.
U.
S.
Environmental
Protection
Agency,
Office
of
Water,
78
pp.

U.
S.
EPA.
1999b.
U.
S.
Environmental
Protection
Agency.
Guidelines
for
Carcinogen
Risk
Assessment.
National
Center
for
Environmental
Assessment,
Risk
Assessment
Forum,
Washington,
D.
C.
NCEA­
F­
0644.
July
1999.
Available
on­
line
at:
http://
www.
epa.
gov/
ncea/
raf/
car2sab.
htm
U.
S.
EPA.
2000a.
What
is
the
Toxic
Release
Inventory.
Available
on
the
Internet
at:
http://
www.
epa.
gov/
tri/
general.
htm
Last
modified
February
28,
2000.

U.
S.
EPA.
2000b.
TRI
Explorer:
Trends.
Available
on
the
Internet
at:
http://
www.
epa.
gov/
triexplorer/
trends.
htm
Last
modified
May
5,
2000.

U.
S.
EPA.
2000c.
TRI
Explorer:
Are
Year­
to­
Year
Changes
Comparable?
Available
on
the
Internet
at:
www.
epa.
gov/
triexplorer/
yearsum.
htm
Last
modified
May
5,
2000.

U.
S.
EPA.
2000d.
The
Toxic
Release
Inventory
(
TRI)
and
Factors
to
Consider
when
Using
TRI
Data.
Available
on
the
Internet
at:
http://
www.
epa.
gov/
tri/
tri98/
98over.
pdf.
Last
modified
August
11,
2000.
Link
to
site
at:
http://
www.
epa.
gov/
tri/
tri98
U.
S.
EPA.
2000e.
Water
Industry
Baseline
Handbook,
Second
Edition
(
Draft).
March
17.

USGS.
2000.
Mineral
Commodity
Summaries,
February,
2000
­
Manganese.
Available
on
the
Internet
at:
http://
minerals.
usgs.
gov/
minerals/
pubs/
commodity/
manganese/
420300.
pdf
USGS.
2001.
USGS
National
Water
Quality
Assessment
Data
Warehouse.
Available
on
the
Internet
at:
http://
infotrek.
er.
usgs.
gov/
pls/
nawqa/
nawqa.
home.
Last
updated
April
19,
2001
Valencia,
H.,
J.
M.
Mason,
R.
C.
Woodruff,
et
al.
1985.
Chemical
mutagenesis
testing
in
Drosophila.
III.
Results
of
48
coded
compounds
tested
for
the
National
Toxicology
Program.
Environ.
Mutagen.
7:
325­
348
(
as
cited
in
ATSDR,
2000).

Vieregge,
P.,
B.
Heinzow,
G.
Korf,
H.­
M.
Teichert,
P.
Schleifenbaum
and
H.­
U.
Mösinger.
1995.
Long
term
exposure
to
manganese
in
rural
well
water
has
no
neurological
effects.
Can.
J.
Neurol.
Sci.
22:
286­
289.

Wassermann,
D.
and
M.
Wassermann.
1977.
The
ultrastructure
of
the
liver
cell
in
subacute
manganese
administration.
Environ
Res.
14(
3):
379­
390.
10­
27
Manganese
 
February
2003
Wedler,
F.
C.
1994.
Biochemical
and
nutritional
role
of
manganese:
An
overview.
In:
Klimis­
Tavantzis,
D.
J.,
ed.,
Manganese
in
Health
and
Disease.
Boca
Raton,
FL:
CRC
Press,
Inc.,
pp.
1­
36
(
as
cited
in
ATSDR,
2000).

Weigand
E.,
M.
Kirchgessner,
and
U.
Helbig.
1986.
True
absorption
and
endogenous
fecal
excretion
of
manganese
in
relation
to
its
dietary
supply
in
growing
rats.
Biol.
Trace
Elem.
Res.
10:
265­
279.

WHO.
1973.
Trace
Elements
in
Human
Nutrition:
Manganese.
Technical
Report
Service,
532.
World
Health
Organization,
Geneva,
Switzerland.

WHO.
1981.
Environmental
Health
Criteria
17.
Manganese.
World
Health
Organization,
Geneva,
Switzerland.

Widdowson,
E.
M.,
H.
Chan,
G.
E.
Harrison,
et
al.
1972.
Accumulation
of
Cu,
Zn,
Mn,
Cr
and
Co
in
the
human
liver
before
birth.
Biol.
Neonate
20(
5):
360­
367.

Wong,
P.
K.
1988.
Mutagenicity
of
heavy
metals.
Bull.
Environ.
Contam.
Toxicol.
40:
597­
603
(
as
cited
in
ATSDR,
2000).

Yamada,
M.,
S.
Ohno,
I.
Okayasu,
et
al.
1986.
Chronic
manganese
poisoning:
A
neuropathological
study
with
determination
of
manganese
distribution
in
the
brain.
Acta
Neuropathol.
(
Berl.)
70:
273­
278.

Yamaguchi,
M.,
K.
Inomoto
and
Y.
Soketa.
1986.
Effect
of
essential
trace
metals
on
bone
metabolism
in
weanling
rats:
Comparison
with
zinc
and
other
metals'
actions.
Res.
Exp.
Med.
186:
337­
342.

Yamamoto,
H.
and
T.
Suzuki.
1969.
Chemical
structure
of
manganese
compounds
and
their
biological
effects.
Jap.
Assoc.
Ind.
Health,
Fukuoka
City,
Japan,
March
28­
31.

Zakour,
R.
A.
and
B.
W.
Glickman.
1984.
Metal­
induced
mutagenesis
in
the
lacI
gene
of
Escherichia
coli.
Mutat.
Res.
126:
9­
18
(
as
cited
in
ATSDR,
2000).

Zayed,
J.,
M.
Gerin,
S.
Loranger,
et
al.
1994.
Occupational
and
environmental
exposure
of
garage
workers
and
taxi
drivers
to
airborne
manganese
arising
from
the
use
of
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
in
unleaded
gasoline.
Am.
Ind.
Hyg.
Assoc.
J.
55(
1):
53­
58.

Zayed,
J.,
M.
Mikhail,
S.
Loranger,
et
al.
1996.
Exposure
of
taxi
drivers
and
office
workers
to
total
and
respirable
manganese
in
an
urban
environment.
Am.
Ind.
Hyg.
Assoc.
J.
57(
4):
376­
380.

Zayed,
J,
C.
Thibault,
L.
Gareau,
et
al.
1999a.
Airborne
manganese
particulates
and
methylcyclopentadienyl
manganese
tricarbonyl
(
MMT)
at
selected
outdoor
sites
in
Montreal.
Neurotoxicology
20(
2­
3):
151­
158.
10­
28
Manganese
 
February
2003
Zayed,
J.,
A.
Vyskocil
and
G.
Kennedy.
1999b.
Environmental
contamination
and
human
exposure
to
manganese­
contribution
of
methylcyclopentadienyl
manganese
tricarbonyl
in
unleaded
gasoline.
Int.
Arch.
Occup.
Environ.
Health.
72:
7­
13.

Zhang,
G.,
D.
Liu,
and
P.
He.
1995.
[
Effects
of
manganese
on
learning
abilities
in
school
children].
Chung
Hua
Yu
Fang
I
Hsueh
Tsa
Chih
29:
156­
158.

Zhernakova,
T.
V.
1967.
Correlation
between
iron,
manganese
and
copper
content
in
the
blood
serum
of
healthy
individuals.
Bull.
Exp.
Biol.
Med.
63:
47­
48.

Zlotkin,
S.
H.
and
B.
E.
Buchanan.
1986.
Manganese
intakes
in
intravenously
fed
infants:
Dosages
and
toxicity
studies.
Biol.
Trace
Elem.
Res.
9:
271­
279.
A­
1
Manganese
 
February
2003
APPENDIX
A:
Abbreviations
and
Acronyms
ACGIH
­
American
Conference
of
Governmental
Industrial
Hygienists
ATSDR
­
Agency
for
Toxic
Substances
and
Disease
Registry
CAS
­
Chemical
Abstract
Service
CCL
­
Contaminant
Candidate
List
CERCLA
­
Comprehensive
Environmental
Response,
Compensation
&
Liability
Act
CMR
­
Chemical
Monitoring
Reform
CWS
­
Community
Water
System
DWEL
­
Drinking
Water
Equivalent
Level
EPA
­
Environmental
Protection
Agency
EPCRA
­
Emergency
Planning
and
Community
Right­
to­
Know
Act
GW
­
ground
water
HA
­
Health
Advisory
HAL
­
Health
Advisory
Level
HRL
­
Health
Reference
Level
IOC
­
inorganic
compound
IRIS
­
Integrated
Risk
Information
System
MRL
­
Minimum
Reporting
Level
NAWQA
­
National
Water
Quality
Assessment
Program
NCOD
­
National
Drinking
Water
Contaminant
Occurrence
Database
NIOSH
­
National
Institute
for
Occupational
Safety
and
Health
NIRS
­
National
Inorganic
and
Radionuclide
Survey
NPDES
­
National
Pollution
Discharge
Elimination
System
NPDWR
­
National
Primary
Drinking
Water
Regulation
NTIS
­
National
Technical
Information
Service
NTNCWS
­
Non­
Transient
Non­
Community
Water
System
ppm
­
part
per
million
PWS
­
Public
Water
System
RCRA
­
Resource
Conservation
and
Recovery
Act
SARA
Title
III
­
Superfund
Amendments
and
Reauthorization
Act
SDWA
­
Safe
Drinking
Water
Act
SDWIS
­
Safe
Drinking
Water
Information
System
SDWIS
FED
­
the
Federal
Safe
Drinking
Water
Information
System
STORET
­
Storage
and
Retrieval
System
SW
­
surface
water
TRI
­
Toxic
Release
Inventory
UCM
­
Unregulated
Contaminant
Monitoring
UCMR
­
Unregulated
Contaminant
Monitoring
Regulation/
Rule
UMRA
­
Unfunded
Mandates
Reform
Act
of
1995
URCIS
­
Unregulated
Contaminant
Monitoring
Information
System
U.
S.
EPA
­
United
States
Environmental
Protection
Agency
A­
2
Manganese
 
February
2003
USGS
­
United
States
Geological
Survey
µ
g/
L
­
micrograms
per
liter
mg/
L
­
milligrams
per
liter
>
MCL
­
percentage
of
systems
with
exceedances
>
MRL
­
percentage
of
systems
with
detections
B­
1
Manganese
 
February
2003
NIRS
Data
­
Manganese
Occurrence
in
Public
Water
Systems
(
HRL
=
0.3
mg/
L)

State
#
Samples
#
Samples
>
MRL
%
Samples
>
MRL
#
Detects
>
1/
2
HRL
%
Detects
>
1/
2
HRL
#
Detects
>
HRL
%
Detects
>
HRL
Min
Detects
(
mg/
L)
Median
Detects
(
mg/
L)

AK
8
7
87.50%
2
25.00%
1
12.50%
<
0.00
0.50
0.50
0.02
0.05
AL
8
4
50.00%
0.00%
0.00%
<
0.00
0.05
0.05
0.00
0.01
AR
9
6
66.67%
0.00%
0.00%
<
0.00
0.06
0.06
0.00
0.01
AZ
14
5
35.71%
1
7.14%
1
7.14%
<
0.00
0.58
0.58
0.00
0.00
CA
60
26
43.33%
2
3.33%
1
1.67%
<
0.00
0.65
0.65
0.00
0.01
CO
10
7
70.00%
0.00%
0.00%
<
0.00
0.13
0.13
0.00
0.00
CT
23
18
78.26%
0.00%
0.00%
<
0.00
0.09
0.09
0.00
0.01
DE
10
10
100.00%
0.00%
0.00%
0.00
0.08
0.08
0.00
0.01
FL
56
29
51.79%
0.00%
0.00%
<
0.00
0.03
0.03
0.00
0.00
GA
23
9
39.13%
0.00%
0.00%
<
0.00
0.05
0.05
0.00
0.02
IA
28
22
78.57%
5
17.86%
4
14.29%
<
0.00
1.34
1.34
0.00
0.01
ID
12
1
8.33%
0.00%
0.00%
<
0.00
0.13
0.13
0.13
0.13
IL
46
34
73.91%
1
2.17%
1
2.17%
<
0.00
0.36
0.36
0.00
0.01
IN
19
18
94.74%
2
10.53%
1
5.26%
<
0.00
0.33
0.33
0.01
0.03
KS
6
3
50.00%
1
16.67%
1
16.67%
<
0.00
0.83
0.83
0.01
0.07
KY
8
6
75.00%
2
25.00%
1
12.50%
<
0.00
0.50
0.50
0.00
0.02
LA
26
24
92.31%
3
11.54%
0.00%
<
0.00
0.25
0.25
0.00
0.01
MA
7
6
85.71%
1
14.29%
0.00%
<
0.00
0.19
0.19
0.00
0.00
MD
6
5
83.33%
0.00%
0.00%
<
0.00
0.05
0.05
0.00
0.02
ME
7
6
85.71%
0.00%
0.00%
<
0.00
0.04
0.04
0.00
0.01
MI
25
22
88.00%
2
8.00%
0.00%
<
0.00
0.20
0.20
0.00
0.02
MN
19
17
89.47%
6
31.58%
4
21.05%
<
0.00
0.63
0.63
0.01
0.09
MO
21
16
76.19%
3
14.29%
1
4.76%
<
0.00
1.22
1.22
0.00
0.00
MS
26
21
80.77%
0.00%
0.00%
<
0.00
0.09
0.09
0.00
0.01
MT
11
5
45.45%
1
9.09%
1
9.09%
<
0.00
0.33
0.33
0.00
0.07
NC
44
33
75.00%
0.00%
0.00%
<
0.00
0.09
0.09
0.00
0.01
ND
19
19
100.00%
3
15.79%
2
10.53%
0.00
0.63
0.63
0.00
0.01
NE
19
10
52.63%
3
15.79%
2
10.53%
<
0.00
1.24
1.24
0.00
0.05
NH
10
8
80.00%
0.00%
0.00%
<
0.00
0.11
0.11
0.01
0.05
NJ
6
2
33.33%
0.00%
0.00%
<
0.00
0.09
0.09
0.01
0.05
NM
7
5
71.43%
1
14.29%
1
14.29%
<
0.00
0.38
0.38
0.00
0.02
NV
2
1
50.00%
0.00%
0.00%
<
0.00
0.00
0.00
0.00
0.00
NY
57
32
56.14%
4
7.02%
2
3.51%
<
0.00
0.40
0.40
0.00
0.03
OH
25
19
76.00%
0.00%
0.00%
<
0.00
0.13
0.13
0.00
0.02
OK
12
6
50.00%
0.00%
0.00%
<
0.00
0.08
0.08
0.00
0.00
OR
8
5
62.50%
1
12.50%
0.00%
<
0.00
0.17
0.17
0.00
0.01
PA
36
28
77.78%
7
19.44%
4
11.11%
<
0.00
0.86
0.86
0.00
0.02
PR
1
1
100.00%
0.00%
0.00%
0.01
0.01
0.01
0.01
0.01
RI
1
1
100.00%
0.00%
0.00%
0.03
0.03
0.03
0.03
0.03
SC
18
11
61.11%
0.00%
0.00%
<
0.00
0.07
0.07
0.00
0.01
SD
8
7
87.50%
2
25.00%
1
12.50%
<
0.00
0.72
0.72
0.00
0.06
TN
9
8
88.89%
0.00%
0.00%
<
0.00
0.08
0.08
0.00
0.00
TX
74
51
68.92%
0.00%
0.00%
<
0.00
0.13
0.13
0.00
0.02
UT
10
4
40.00%
0.00%
0.00%
<
0.00
0.02
0.02
0.00
0.00
VA
30
25
83.33%
0.00%
0.00%
<
0.00
0.13
0.13
0.00
0.01
VT
12
8
66.67%
2
16.67%
2
16.67%
<
0.00
0.33
0.33
0.00
0.00
WA
52
31
59.62%
3
5.77%
0.00%
<
0.00
0.18
0.18
0.00
0.01
WI
30
24
80.00%
1
3.33%
0.00%
<
0.00
0.18
0.18
0.00
0.02
WV
8
3
37.50%
1
12.50%
1
12.50%
<
0.00
0.76
0.76
0.00
0.10
WY
3
3
100.00%
0.00%
0.00%
0.02
0.09
0.09
0.02
0.02
Total
989
672
67.95%
60
6.07%
32
3.24%
<
0.00
0.63
1.34
0.00
0.01
The
Health
Reference
Level
(
HRL)
is
the
estimated
health
effect
level
as
provided
by
EPA
for
preliminary
assessment
for
this
work
assignment.

The
Health
Reference
Level
(
HRL)
used
for
Manganese
is
0.28
mg/
L.
This
is
a
draft
value
for
working
review
only.
Manganese
data
were
analyzed
using
two
different
HRLs
and
are,
therefore,
listed
separately.
Min
Value
(
mg/
L)
99%
Value
(
mg/
L)
Max
Value
(
mg/
L)

"%
>
HRL"
indicates
the
proportion
of
systems
with
any
analytical
results
exceeding
the
concentration
value
of
the
HRL.
PWS=
Public
Water
Systems;
GW=
Ground
Water
(
PWS
Source
Water
Type);
SW=
Surface
Water
(
PWS
Source
Water
Type);
MRL=
Minimum
Reporting
Limit
(
for
laboratory
analyses)
APPENDIX
B:
Complete
NIRS
Data
for
Manganese