Document ID: EPA-HQ-OPPT-2004-0079-0097
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-09-28T04:00Z

Fax­
On­
Demand:
Proposed
1:
1/
2003
Telephone:
(
202)
401­
0527
Item
XXXX
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(
AEGLs)

FOR
NITROGEN
DIOXIDE
(
CAS
Reg.
No.
10102­
44­
0)

PROPOSED
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
PREFACE
1
2
Under
the
authority
of
the
Federal
Advisory
Committee
Act
(
FACA)
P.
L.
92­
463
of
1972,
3
the
National
Advisory
Committee
for
Acute
Exposure
Guideline
Levels
for
Hazardous
Substances
4
(
NAC/
AEGL
Committee)
has
been
established
to
identify,
review
and
interpret
relevant
toxicologic
5
and
other
scientific
data
and
develop
AEGLs
for
high
priority,
acutely
toxic
chemicals.
6
7
AEGLs
represent
threshold
exposure
limits
for
the
general
public
and
are
applicable
to
8
emergency
exposure
periods
ranging
from
10
minutes
to
8
hours.
Three
levels
 
AEGL­
1,
AEGL­
2
9
and
AEGL­
3
 
are
developed
for
each
of
five
exposure
periods
(
10
and
30
minutes,
1
hour,
4
hours,
10
and
8
hours)
and
are
distinguished
by
varying
degrees
of
severity
of
toxic
effects.
The
three
AEGLs
11
are
defined
as
follows:
12
13
AEGL­
1
is
the
airborne
concentration
(
expressed
as
parts
per
million
or
milligrams
per
cubic
14
meter
[
ppm
or
mg/
m3])
of
a
substance
above
which
it
is
predicted
that
the
general
population,
15
including
susceptible
individuals,
could
experience
notable
discomfort,
irritation,
or
certain
16
asymptomatic,
non­
sensory
effects.
However,
the
effects
are
not
disabling
and
are
transient
and
17
reversible
upon
cessation
of
exposure.
18
19
AEGL­
2
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m3)
of
a
substance
above
20
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
21
irreversible
or
other
serious,
long­
lasting
adverse
health
effects
or
an
impaired
ability
to
escape.
22
23
AEGL­
3
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m3)
of
a
substance
above
24
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
25
life­
threatening
health
effects
or
death.
26
27
Airborne
concentrations
below
the
AEGL­
1
represent
exposure
levels
that
can
produce
mild
28
and
progressively
increasing
but
transient
and
nondisabling
odor,
taste,
and
sensory
irritation,
or
29
certain
asymptomatic,
non­
sensory
effects.
With
increasing
airborne
concentrations
above
each
30
AEGL,
there
is
a
progressive
increase
in
the
likelihood
of
occurrence
and
the
severity
of
effects
31
described
for
each
corresponding
AEGL.
Although
the
AEGL
values
represent
threshold
levels
for
32
the
general
public,
including
susceptible
subpopulations,
such
as
infants,
children,
the
elderly,
persons
33
with
asthma,
and
those
with
other
illnesses,
it
is
recognized
that
individuals,
subject
to
unique
or
34
idiosyncratic
responses,
could
experience
the
effects
described
at
concentrations
below
the
35
corresponding
AEGL.
36
37
38
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
2
TABLE
OF
CONTENTS
1
2
PREFACE
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1
3
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LIST
OF
TABLES
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5
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LIST
OF
FIGURES
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7
8
SUMMARY
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5
9
10
1.
INTRODUCTION
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9
11
12
2.
HUMAN
TOXICITY
DATA
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10
13
2.1.
Acute
Lethality
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10
14
2.2.
Nonlethal
Toxicity
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11
15
2.2.1.
Case
Reports
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11
16
2.2.2.
Epidemiologic
Studies
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13
17
2.2.3.
Experimental
Studies
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14
18
2.3.
Developmental/
Reproductive
Toxicity
.
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18
19
2.4.
Genotoxicity
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19
20
2.5.
Carcinogenicity
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19
21
2.6.
Summary
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19
22
23
3.
ANIMAL
TOXICITY
DATA
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19
24
3.1.
Acute
Lethality
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19
25
3.1.1.
Dogs
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20
26
3.1.2.
Rabbits
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20
27
3.1.3.
Guinea
Pigs
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21
28
3.1.4.
Rats
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21
29
3.1.5.
Mice
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23
30
3.2.
Nonlethal
Toxicity
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24
31
3.2.1.
Monkeys
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24
32
3.2.2.
Dogs
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25
33
3.2.3.
Rabbits
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25
34
3.2.4.
Sheep
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26
35
3.2.5.
Guinea
Pigs
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26
36
3.2.6.
Hamsters
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27
37
3.2.7.
Ferrets
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27
38
3.2.8.
Rats
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27
39
3.2.9.
Mice
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31
40
3.3.
Developmental/
Reproductive
Toxicity
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31
41
3.4.
Genotoxicity
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32
42
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
3
3.5.
Subchronic
and
Chronic
Toxicity/
Carcinogenicity
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32
1
3.6.
Summary
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2
3
4.
SPECIAL
CONSIDERATIONS
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4
4.1.
Metabolism
and
Disposition
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33
5
4.2.
Mechanism
of
Toxicity
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.
.
.
.
34
6
4.3.
Oxides
of
Nitrogen
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
35
7
4.4.
Other
Relevant
Information
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
35
8
4.4.1.
Species
Variability
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
35
9
4.4.2.
Susceptible
Populations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
36
10
4.4.3.
Concentration­
Response
Relationship
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
37
11
4.4.4.
Susceptibility
to
infection
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
37
12
13
5.
DATA
ANALYSIS
FOR
AEGL­
1
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
.
.
38
14
5.1.
Summary
of
Human
Data
Relevant
to
AEGL­
1
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
38
15
5.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
1
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
39
16
5.3.
Derivation
of
AEGL­
1
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
39
17
18
6.
DATA
ANALYSIS
FOR
AEGL­
2
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
39
19
6.1.
Summary
of
Human
Data
Relevant
to
AEGL­
2
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
40
20
6.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
2
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
40
21
6.3.
Derivation
of
AEGL­
2
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
41
22
23
7.
DATA
ANALYSIS
FOR
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
41
24
7.1.
Summary
of
Human
Data
Relevant
to
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
42
25
7.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
42
26
7.3.
Derivation
of
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
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.
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.
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.
.
.
.
.
.
.
42
27
28
8.
SUMMARY
OF
AEGLS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
43
29
8.1.
AEGL
Values
and
Toxicity
Endpoints
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
43
30
8.2.
Comparison
with
Other
Standards
and
Criteria
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
44
31
8.3.
Data
Adequacy
and
Research
Needs
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
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.
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.
.
.
46
32
33
9.
REFERENCES
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
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.
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.
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.
.
.
46
34
35
APPENDIX
A:
Derivation
of
AEGL
Values
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
.
57
36
37
APPENDIX
B:
Derivation
Summary
for
AEGL
Values
38
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
61
39
40
APPENDIX
C:
Time
Scaling
Category
Plot
41
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
65
42
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
4
LIST
OF
TABLES
1
2
Table
1.
Physicochemical
Data
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
10
3
Table
2.
Effects
of
acute
exposure
to
high
NO
2
concentrations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
11
4
Table
3.
Summary
of
NO
2
mortality
in
five
species
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
24
5
Table
4.
AEGL­
1
values
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
39
6
Table
5.
AEGL­
2
values
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
41
7
Table
6.
AEGL­
3
values
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
43
8
Table
7.
Summary
of
AEGL
values
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
44
9
Table
8.
Extant
standards
and
guidelines
for
Nitrogen
Dioxide
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
45
10
11
12
LIST
OF
FIGURES
13
14
15
Figure
1.
Category
plot
of
AEGL
values
and
effects
of
nitrogen
dioxide
16
on
humans
and
animals
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
66
17
18
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
5
SUMMARY
1
2
NO
2
is
an
irritant
to
the
mucous
membranes
and
may
cause
coughing
and
dyspnea
during
3
exposure.
After
less
severe
exposure,
symptoms
may
persist
for
several
hours
before
subsiding
4
(
NIOSH,
1976).
With
more
severe
exposure,
pulmonary
edema
ensues
with
signs
of
chest
pain,
5
cough,
dyspnea,
cyanosis,
and
moist
rales
heard
on
auscultation
(
NIOSH,
1976;
Douglas
et
al.,
6
1989).
Death
from
NO
2
inhalation
is
caused
by
bronchospasm
and
pulmonary
edema
in
association
7
with
hypoxemia
and
respiratory
acidosis,
metabolic
acidosis,
shift
of
the
oxyhemoglobin
dissociation
8
curve
to
the
left,
and
arterial
hypotension
(
Douglas
et
al.,
1989).
A
characteristic
of
NO
2
intoxication
9
after
the
acute
phase
is
a
period
of
apparent
recovery
followed
by
late­
onset
bronchiolar
injury
that
10
manifests
as
bronchiolitis
fibrosa
obliterans
(
NIOSH,
1976;
NRC,
1977;
Hamilton,
1983;
Douglas
11
et
al.,
1989).
In
addition,
experiments
with
laboratory
animals
indicate
that
exposure
to
NO
2
12
increases
susceptibility
to
infection
(
Henry
et
al.,
1969;
U.
S.
EPA,
1993).
13
14
For
AEGL­
1
a
concentration
of
0.5
ppm
was
adopted
for
all
time
points.
Although
the
15
response
of
asthmatics
to
NO
2
is
variable,
asthmatics
were
identified
as
a
potentially
susceptible
16
population.
The
evidence
indicates
that
some
asthmatics
exposed
to
0.3­
0.5
ppm
NO
2
may
respond
17
with
either
subjective
symptoms
or
slight
changes
in
pulmonary
function
of
no
clinical
significance.
18
In
contrast,
some
asthmatics
did
not
respond
to
NO
2
at
concentrations
of
0.5­
4
ppm.
Because
of
the
19
weight
of
evidence,
the
study
by
Kerr
et
al.,
(
1978;
1979)
was
considered
the
most
appropriate
as
the
20
basis
of
AEGL­
1
values.
They
reported
that
7/
13
asthmatics
experienced
slight
burning
of
the
eyes,
21
slight
headache,
and
chest
tightness
or
labored
breathing
with
exercise
during
exposure
to
0.5
ppm
22
for
2
hours;
at
this
concentration
the
odor
of
NO
2
was
perceptible
but
the
subjects
became
unaware
23
of
it
after
about
15
minutes.
No
changes
in
any
pulmonary
function
tests
were
found
immediately
24
following
the
chamber
exposure
(
Kerr
et
al.,
1978;
1979).
Therefore,
0.5
ppm
was
considered
a
no­
25
adverse­
effect
level
for
the
asthmatic
population.
Since
asthmatics
are
potentially
the
most
26
susceptible
population,
no
uncertainty
factor
was
applied.
27
28
Supporting
studies
for
AEGL­
1
report
findings
similar
to
the
key
studies.
Significant
group
29
mean
reductions
in
FEV
1
(­
17.3%
with
NO
2
vs
­
10.0%
with
air)
and
specific
airway
conductance
(­
30
13.5%
with
NO
2
vs
­
8.5%
with
air)
occurred
in
asthmatics
after
exercise
during
exposure
to
0.3
ppm
31
for
4
hours
and
1/
6
individuals
experienced
chest
tightness
and
wheezing
(
Bauer
et
al.,
1985).
The
32
onset
of
effects
was
delayed
when
exposures
were
by
oral­
nasal
inhalation
as
compared
to
oral
33
inhalation
and
may
result
from
scrubbing
within
the
upper
airway.
In
a
similar
study,
asthmatics
34
exposed
to
0.3
ppm
for
30
minutes
at
rest
followed
by
10
minutes
of
exercise
had
significantly
greater
35
reductions
in
FEV
1
(
10%
vs
4%
with
air)
and
partial
expiratory
flow
rates
at
60%
of
total
lung
36
capacity,
but
no
symptoms
were
reported
(
Bauer
et
al.,
1986).
In
a
preliminary
study
with
13
37
asthmatics
exposed
to
0.3
ppm
for
110
minutes,
slight
cough
and
dry
mouth
and
throat
and
38
significantly
greater
reduction
(
11%
vs
7%)
in
FEV
1
occurred
after
exercise;
however,
in
a
larger
39
study,
no
changes
in
pulmonary
function
were
measured
and
no
symptoms
were
reported
following
40
exposure
of
21
asthmatics
to
concentrations
up
to
0.6
ppm
for
75
minutes
(
Roger
et
al.,
1990).
41
42
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
6
Human
data
were
also
used
as
the
basis
for
AEGL­
2.
Three
healthy
male
volunteers
1
experienced
definite
discomfort
from
exposure
to
30
ppm
for
2
hours
(
Henschler
et
al.,
1960).
Three
2
individuals
exposed
to
30
ppm
for
2
hours
perceived
an
intense
odor
upon
entering
the
chamber,
but
3
the
odor
perception
quickly
diminished
and
was
completely
absent
after
25­
40
minutes.
One
4
individual
experienced
a
slight
tickling
of
the
nose
and
throat
mucous
membranes
after
30
minutes,
5
the
two
others
after
40
minutes.
From
70
minutes
on,
all
subjects
experienced
a
burning
sensation
6
and
an
increasingly
severe
cough
for
the
next
10­
20
minutes,
but
coughing
decreased
from
100
7
minutes
on.
However,
the
burning
sensation
continued
and
moved
into
the
lower
sections
of
the
8
airways
and
was
finally
felt
deep
in
the
chest.
At
this
time,
marked
sputum
secretion
and
dyspnea
was
9
noted.
Towards
the
end
of
the
exposure,
the
subjects'
reported
the
exposure
conditions
to
be
10
bothersome
and
barely
tolerable.
A
sensation
of
pressure
and
increased
sputum
secretion
continued
11
for
several
hours
after
cessation
of
exposure
(
Henschler
et
al.,
1960).
12
13
AEGL­
3
values
were
based
on
animal
data
and
supported
by
a
human
case
report.
Exposure
14
of
monkeys
to
50
ppm
for
2
hours
was
used
to
derive
the
AEGL­
3
values.
Monkeys
(
n
=
2­
6/
group)
15
were
exposed
to
10­
50
ppm
NO
2
for
2
hours
with
respiratory
function
monitored
during
exposure
16
(
Henry
et
al.,
1969).
NO
2
exposure
alone
resulted
in
a
markedly
increased
respiratory
rate
and
17
decreased
tidal
volume
during
exposures
to
50
and
35
ppm,
but
only
slight
effects
at
15
and
10
ppm.
18
Mild
histopathological
changes
in
the
lungs
were
noted
after
exposure
to
10
and
15
ppm,
however,
19
marked
changes
in
lung
structure
were
observed
after
exposure
to
35
and
50
ppm.
The
alveoli
were
20
expanded
with
septal
wall
thinning,
bronchi
were
inflamed
with
proliferation
or
erosion
of
the
surface
21
epithelium,
and
lymphocyte
infiltration
was
seen
with
edema.
In
addition
to
the
effects
on
the
lungs,
22
interstitial
fibrosis
(
35
ppm)
and
edema
(
50
ppm)
of
cardiac
tissue,
glomerular
tuft
swelling
in
the
23
kidney
(
35
and
50
ppm),
lymphocyte
infiltration
in
the
kidney
and
liver
(
50
ppm),
and
congestion
and
24
centrilobular
necrosis
in
the
liver
(
50
ppm)
were
observed.
25
26
The
proposed
AEGL­
3
values
are
supported
by
human
data
for
a
welder.
Pulmonary
edema,
27
confirmed
on
X­
ray,
resulted
from
exposure
to
approximately
90
ppm
for
up
to
40
minutes
28
(
Norwood
et
al.,
1966).
If
this
exposure
scenario
is
used
for
derivation
of
AEGL­
3
values
with
an
29
uncertainty
factory
of
3
the
values
are
nearly
identical
to
those
derived
using
the
data
in
the
monkey.
30
In
addition,
the
proposed
AEGL­
3
values
are
below
the
concentrations
at
which
lethality
first
31
occurred
in
five
animal
species:
75
ppm
for
4
hours
in
the
dog
and
1
hour
in
the
rabbit,
50
ppm
for
32
1
hour
in
the
guinea
pig,
and
50
ppm
for
24
hours
in
the
rat
and
mouse
(
Hine
et
al.,
1970).
In
33
general,
the
larger
animals,
including
humans,
are
less
susceptible
to
toxicity
from
NO
2
inhalation
than
34
are
the
rodents.
35
36
For
AEGL­
2
and
AEGL­
3,
the
10­
and
30­
minute,
and
1­,
4­,
and
8­
hour
AEGL
endpoints
37
were
calculated
from
Cn
×
t
=
k
using
n
=
3.5
(
ten
Berge
et
al.,
1986).
The
value
of
n
was
calculated
38
by
ten
Berge
et
al.
using
the
data
of
Hine
et
al.
(
1970)
in
five
species
of
laboratory
animal.
An
39
uncertainty
factor
of
3
was
applied
to
account
for
sensitive
populations
since
the
data
for
asthmatics
40
and
those
with
respiratory
disease
are
inconclusive.
Because
the
endpoint
in
the
monkey
study
is
41
below
the
definition
of
AEGL­
3
and
due
to
the
similarities
of
the
respiratory
tract
between
humans
42
NITROGEN
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7
and
monkeys,
additional
uncertainty
factors
are
not
considered
necessary.
Also,
the
mechanism
of
1
action
of
NO
2
does
not
vary
between
species
with
the
target
at
the
alveoli.
In
general,
the
larger
2
animals,
including
humans,
appear
to
be
less
susceptible
to
NO
2
than
the
rodents.
3
4
The
proposed
values
for
the
three
AEGL
classifications
for
the
four
time
periods
are
listed
5
in
the
table
below.
6
7
8
Summary
of
AEGL
Values
for
Nitrogen
Dioxide
9
Classification
10
10­
Minute
30­
Minute
1­
Hour
4­
Hour
8­
Hour
Endpointa
(
Reference)

AEGL
 
1b
11
(
Non­
12
disabling)
13
0.50
ppm
(
0.94
mg/
m3)
0.50
ppm
(
0.94
mg/
m3)
0.50
ppm
(
0.94
mg/
m3)
0.50
ppm
(
0.94
mg/
m3)
0.50
ppm
(
0.94
mg/
m3)
slight
burning
of
the
eyes,
slight
headache,
chest
tightness
or
labored
breathing
with
exercies
in
7/
13
asthmatics
(
Kerr
et
al.,
1978,
1979)

AEGL
 
2
14
(
Disabling)
15
20
ppm
(
38
mg/
m3)
15
ppm
(
28
mg/
m3)
12
ppm
(
23
mg/
m3)
8.2
ppm
(
15
mg/
m3)
6.7
ppm
(
13
mg/
m3)
burning
sensation
in
nose
and
chest,
cough,
dyspnea,
sputum
production
in
normal
volunteers
(
Henschler
et
al.,
1960)

AEGL
 
3
16
(
Lethal)
17
34
ppm
(
64
mg/
m3)
25
ppm
(
47
mg/
m3)
20
ppm
(
38
mg/
m3)
14
ppm
(
26
mg/
m3)
11
ppm
(
21
mg/
m3)
marked
irritation,
no
deaths,
in
monkeys
(
Henry
et
al.,
1969)

aSome
effects
may
be
delayed.
18
bThe
sweet
odor
of
NO
2
may
be
perceptible
to
most
individuals
at
this
concentration;
however,
adaptation
occurs
rapidly.
19
20
21
References
22
Bauer,
M.
A.,
Utell,
M.
J.,
Morrow,
P.
E.,
Speers,
D.
M.,
and
Gibb,
F.
R.
1985.
Route
of
inhalation
23
influences
airway
responses
to
0.30
ppm
nitrogen
dioxide
in
asthmatic
subjects.
Am.
Rev.
24
Respir.
Dis.
131:
A171.
25
26
Bauer,
M.
A.,
Utell,
M.
J.,
Morrow,
P.
E.,
Speers,
D.
M.,
and
Gibb,
F.
R.
1986.
Inhalation
of
0.30
ppm
27
nitrogen
dioxide
potentiates
exercise­
induced
bronchospasm
in
asthmatics.
Am.
Rev.
Respir.
28
Dis.
134:
1203­
1208.
29
30
Douglas,
W.
W.,
Hepper,
N.
G.
G.,
and
Colby,
T.
V.
1989.
Silo­
filler's
disease.
Mayo
Clin.
Proc.
31
64:
291­
304.
32
33
Hamilton,
A.
1983.
Nitrogen
compounds.
In:
Hamilton
and
Hardy's
Industrial
Toxicology,
4th
ed.
34
Boston:
John
Wright­
PSG,
Inc.
pp.
184­
186.
35
36
NITROGEN
DIOXIDE
NAC/
PROPOSED
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8
Henry,
M.
C.,
Ehrlich,
R.,
and
Blair,
W.
H.
1969.
Effect
of
nitrogen
dioxide
on
resistance
of
squirrel
1
monkeys
to
Klebsiella
pneumoniae
infection.
Arch.
Environ.
Health
18:
580­
587.
2
3
Henschler,
D.,
Stier,
A.,
Beck,
H.,
and
Neuman,
W.
1960.
Odor
threshold
of
a
few
important
4
irritant
gasses
(
sulfur
dioxide,
ozone,
nitrogen
dioxide)
and
observations
in
humans
exposed
5
to
low
concentrations.
Archiv
für
Gewerbepathologie
und
Gewerbehygiene
17:
547­
570.
6
(
translated
from
German)
7
8
Hine,
C.
H.,
Meyers,
F.
H.,
and
Wright,
R.
W.
1970.
Pulmonary
changes
in
animals
exposed
to
9
nitrogen
dioxide,
effects
of
acute
exposures.
Toxicol.
Appl.
Pharmacol.
16:
201­
213.
10
11
Kerr,
H.
D.,
Kulle,
T.
J.,
McIlhany,
M.
L.,
and
Swidersky,
P.
1978.
Effects
of
nitrogen
dioxide
on
12
pulmonary
function
in
human
subjects.
An
environmental
chamber
study.
Report:
ISS
13
EPA/
600/
1­
78/
025;
Order
no.
PB­
281
186,
20
pp.
14
15
Kerr,
H.
D.,
Kulle,
T.
J.,
McIlhany,
M.
L.,
and
Swidersky,
P.
1979.
Effects
of
nitrogen
dioxide
on
16
pulmonary
function
in
human
subjects:
An
environmental
chamber
study.
Environ.
Research
17
19:
392­
404.
18
19
NIOSH.
1976.
National
Institute
for
Occupational
Safety
and
Health.
NIOSH
criteria
for
a
20
recommended
standard....
occupational
exposure
to
oxides
of
nitrogen
(
nitrogen
dioxide
and
21
nitric
oxide).
U.
S.
Department
of
Health,
Education,
and
Welfare,
Washington,
D.
C.,
HEW
22
publication
No.
(
NIOSH)
76­
149,
195pp.
23
24
Norwood,
W.
D.,
Wisehart,
D.
E.,
Earl,
C.
A,
Adley,
F.
E.,
and
Anderson,
D.
E.
1966.
Nitrogen
25
dioxide
poisoning
due
to
metal­
cutting
with
oxyacetylene
torch.
J.
Occup.
Med.
8:
301­
306.
26
27
NRC.
1977.
National
Research
Council.
Medical
and
Biologic
Effects
of
Environmental
Pollutants.
28
Nitrogen
Oxides.
NRC,
National
Academy
of
Sciences,
Washington,
DC.
333pp.
29
30
Roger,
L.
J.,
Horstman,
D.
H.,
McDonnell,
W.,
Kehrl,
H.,
Ives,
P.
J.,
Seal,
E.,
Chapman,
R.,
and
31
Massaro,
E.
1990.
Pulmonary
function,
airway
responsiveness,
and
respiratory
symptoms
32
in
asthmatics
following
exercise
in
NO
2.
Toxicol.
Ind.
Health
6:
155­
171.
33
34
ten
Berge,
W.
F.,
Zwart,
A.,
and
Appelman,
L.
M.
1986.
Concentration­
time
mortality
response
35
relationship
of
irritant
and
systemically
acting
vapours
and
gases.
J.
Hazard.
Mat.
13:
301­
36
309.
37
38
U.
S.
EPA.
1993.
U.
S.
Environmental
Protection
Agency.
Air
Quality
Criteria
for
Oxides
of
39
Nitrogen,
Vol.
I­
III.
Office
of
Research
and
Development,
U.
S.
EPA,
Research
Triangle
40
Park,
NC.
41
42
NITROGEN
DIOXIDE
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1.
INTRODUCTION
1
2
Nitrogen
dioxide
(
NO
2)
is
the
most
ubiquitous
of
the
oxides
of
nitrogen
and
has
the
greatest
3
impact
on
human
health.
NO
2,
which
exists
as
an
equilibrium
mixture
of
NO
2
and
N
2
O
4
(
nitrogen
4
tetroxide),
is
a
reddish­
brown
gas
with
a
sweet
odor,
is
heavier
than
air,
and
reacts
with
water
(
U.
S.
5
EPA,
1993;
Mohsenin,
1994).
NO
2
is
shipped
under
pressure
and
the
equilibrium
between
NO
2
and
6
N
2
O
4
is
altered
with
change
in
pressure
with
N
2
O
4
becoming
predominant
at
very
high
pressures.
7
NO
2
is
a
free
radical
with
sufficient
stability
to
exist
in
relatively
high
concentrations
in
ambient
air
8
(
Mohsenin,
1994).
9
10
The
major
source
of
atmospheric
NO
2
is
from
the
combustion
of
fossil
fuels
for
heating,
11
household
appliances,
power
generation,
and
in
motor
vehicles.
Consequently,
the
chemical
is
a
12
major
component
of
smog
and
a
concern
for
indoor
air
quality.
Ambient
levels
in
urban
air
pollution
13
episodes
in
the
US
have
been
measured
between
0.1
and
0.8
ppm
as
a
maximum
hourly
average
with
14
short­
term
peaks
as
high
as
1.27
ppm.
Indoor
NO
2
concentrations
may
reach
a
maximum
1
hour
level
15
of
0.25
to
1.0
ppm
with
peak
levels
as
high
as
2­
4
ppm
where
gas
appliances
or
kerosene
heaters
are
16
used
(
Mohsenin,
1994).
17
18
NO
2
is
an
irritant
to
the
mucous
membranes
and
may
cause
coughing
and
dyspnea
during
19
exposure.
After
less
severe
exposure,
symptoms
may
persist
for
several
hours
before
subsiding
20
(
NIOSH,
1976).
With
more
severe
exposure,
pulmonary
edema
ensues
with
signs
of
chest
pain,
21
cough,
dyspnea,
cyanosis,
and
moist
rales
heard
on
auscultation
(
NIOSH,
1976;
Douglas
et
al.,
22
1989).
Death
from
NO
2
inhalation
is
caused
by
bronchospasm
and
pulmonary
edema
in
association
23
with
hypoxemia
and
respiratory
acidosis,
metabolic
acidosis,
shift
of
the
oxyhemoglobin
dissociation
24
curve
to
the
left,
and
arterial
hypotension
(
Douglas
et
al.,
1989).
A
characteristic
of
NO
2
intoxication
25
after
the
acute
phase
is
a
period
of
apparent
recovery
followed
by
late­
onset
bronchiolar
injury
that
26
manifests
as
bronchiolitis
fibrosa
obliterans
(
NIOSH,
1976;
NRC,
1977;
Hamilton,
1983;
Douglas
27
et
al.,
1989).
28
29
Selected
physicochemical
properties
of
nitrogen
dioxide
are
listed
in
Table
1.
30
31
NITROGEN
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10
TABLE
1.
PHYSICOCHEMICAL
DATA
FOR
NITROGEN
DIOXIDE
12
Parameter
3
Value
Reference
Common
name
4
nitrogen
dioxide
Synonyms
5
CAS
registry
no.
6
10102­
44­
0
Chemical
formula
7
NO2
Budavari
et
al.,
1996
Molecular
weight
8
46.01
Budavari
et
al.,
1996
Physical
state
9
reddish­
brown
gas
Budavari
et
al.,
1996
Vapor
pressure
10
720
torr
at
20

C;
800
mm
Hg
at
25

C
ACGIH,
1991;
U.
S.
EPA,
1990
Vapor
density
(
air
=
1)
11
1.58
Budavari
et
al.,
1996
Melting/
boiling
point
12
­
9.3

C/
21.15

C
Budavari
et
al.,
1996
Flamability
13
does
not
burn
Budavari
et
al.,
1996
Solubility
in
water
14
0.037
mL/
mL
at
35

C
Mohsenin,
1994
Conversion
factors
in
air
15
1
ppm
=
1.88
mg/
m3
1
mg/
m3
=
0.53
ppm
U.
S.
EPA,
1993
Reactivity
16
decomposes
in
water
forming
nitric
oxide
and
nitric
acid
Budavari
et
al.,
1996
17
18
19
2.
HUMAN
TOXICITY
DATA
20
2.1.
Acute
Lethality
21
22
Book
(
1982)
used
allometric
scaling
based
on
minute
volumes
and
LC
50
values
for
NO
2
for
23
5
animal
species
to
calculate
a
human
1­
hour
LC
50
of
174
ppm.
Concentrations
of
>
200
ppm
are
24
reported
to
induce
immediate
symptoms
of
bronchospasm
and
pulmonary
edema
and
may
cause
25
syncope,
unconsciousness,
and
quick
death
(
Douglas
et
al.,
1989).
26
27
Clinical
responses
to
"
acute"
inhalation
of
high
concentrations
of
NO
2,
as
summarized
by
28
NRC
(
1977)
and
based
on
occupational
exposures,
are
given
in
Table
2.
Durations
of
exposures
29
were
not
specified
except
for
the
statement
that
workers
in
a
nitric
acid
manufacturing
plant
in
Italy
30
were
exposed
to
average
concentrations
of
30­
35
ppm
for
an
unspecified
number
of
years
with
no
31
adverse
signs
or
symptoms.
32
NITROGEN
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1
Table
2:
Effects
of
acute
exposure
to
high
NO2
concentrations
2
Concentration
(
ppm)
3
Effect
0.4
4
approximate
odor
threshold
15­
25
5
respiratory
and
nasal
irritation
25­
75
6
reversible
pneumonia
and
bronchiolitis
150­
300+
7
fatal
bronchiolitis
and
bronchopneumonia
From
NRC,
1977.
8
9
A
man
died
after
entering
a
well
that
had
been
blasted
with
gelignite,
a
nitro­
glycerine
10
explosive
(
Derrick
and
Johnson,
1943).
The
individual
appeared
well
for
the
next
approximately
12
11
hours
at
which
time
he
was
taken
to
the
hospital
with
dyspnea;
he
later
fell
into
a
coma
and
died.
At
12
necropsy,
the
lungs
appeared
edematous
with
large
areas
of
hemorrhage.
About
29
hours
after
the
13
charge
had
been
fired,
concentrations
of
oxides
of
nitrogen
in
the
well
were
less
than
1
part
in
14
100,000.
15
16
2.2.
Nonlethal
Toxicity
17
2.2.1.
Case
Reports
18
19
Probably
the
most
well
known
manifestation
of
NO
2
toxicity
is
that
of
silo
filler's
disease.
In
20
a
silo,
the
gas
that
accumulates
above
the
silage
is
depleted
of
oxygen,
is
rich
in
carbon
dioxide,
and
21
contains
a
mixture
of
nitrogen
oxides,
mainly
NO
2
which
can
reach
concentrations
of
200
to
4000
22
ppm
within
2
days
(
Lowry
and
Schuman,
1956;
Douglas
et
al.,
1989).
The
term
silo
filler's
disease
23
was
first
used
by
Lowry
and
Schuman
in
1956
in
an
article
in
which
they
described
the
clinical
24
progression
of
the
disease:
inhalation
of
irritant
gas
from
a
silo;
immediate
cough
and
dyspnea
with
25
a
sensation
of
choking;
2­
3
week
period
after
exposure
of
apparent
remission;
second
phase
of
illness
26
accompanied
by
fever
with
progressively
more
severe
dyspnea,
cyanosis,
and
cough;
inspiratory
and
27
expiratory
rales;
discrete
nodular
densities
on
the
lung;
and
neutrophilic
leukocytosis
(
Lowry
and
28
Schuman,
1956).
Douglas
et
al.
(
1989)
reported
on
17
patients
examined
at
the
Mayo
clinic
between
29
1955
and
1987
after
exposure
to
silo
gas.
Acute
lung
injury
occurred
in
11
individuals
and
16
had
30
either
persistent
or
delayed
symptoms
of
dyspnea,
cough,
chest
pain,
eye
irritation
during
exposure,
31
and
rapid
breathing.
One
patient
died
and
at
autopsy
diffuse
alveolar
damage
with
hyaline
membranes
32
and
hemorrhagic
pulmonary
edema
and
acute
edema
of
the
airways
were
observed.
Bronchiolitis
33
fibrosa
obliterans
developed
in
one
patient
many
years
later;
however,
prophylactic
administration
34
of
corticosteroids
may
have
prevented
chronic
obstructive
pulmonary
disease
(
COPD)
in
the
other
35
patients.
Similar
case
reports
and
outcomes
of
silo
filler's
disease
and
industrial
exposures
were
36
described
in
earlier
literature
(
Grayson,
1956;
Lowry
and
Schuman,
1956;
Milne,
1969).
37
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A
case
was
reported
of
a
welder
who
developed
shortness
of
breath
and
chest
discomfort
1
during
the
use
of
an
acetylene
torch
for
metal­
cutting
in
a
poorly
ventilated
water
main;
the
worker
2
had
spent
approximately
30
minutes
welding
in
the
confined
space
before
being
forced
to
vacate.
3
Several
hours
later,
the
worker
became
so
short
of
breath
that
he
couldn't
sleep
that
night.
Chest
X­
4
ray
18
hours
after
exposure
revealed
pulmonary
edema
and
a
pulmonary
function
test
showed
42%
5
of
the
predicted
value
for
FVC.
The
individual
was
admitted
to
the
hospital
and
treated
with
6
antibiotics
and
oxygen.
The
patient
fully
recovered
by
21
days
after
exposure.
Simulation
of
the
7
accident
produced
an
NO
2
concentration
of
90
ppm
within
40
minutes
and
total
oxides
of
nitrogen
8
in
excess
of
300
ppm
(
Norwood
et
al.,
1966).
It
can
be
assumed
that
the
individual
was
exposed
to
9
at
least
90
ppm
during
the
welding
operation
and
that
the
outcome
could
have
been
more
severe,
or
10
even
fatal,
without
medical
intervention.
11
12
An
outbreak
of
NO
2­
induced
respiratory
illness
was
reported
among
players
and
spectators
13
at
two
high
school
hockey
games
(
Hedberg
et
al.,
1989).
Patients
presented
with
acute
onset
of
14
cough,
hemoptysis,
and/
or
dyspnea
during
or
within
48
hours
of
attending
the
hockey
game.
No
15
changes
in
lung
function
were
measured
10
days
and
2
months
after
exposure.
NO
2
concentrations
16
were
not
measured
in
the
arena
during
the
outbreak,
but
the
source
was
traced
to
a
malfunctioning
17
motor
on
the
ice
resurfacer.
Other
cases
of
respiratory
illness
in
hockey
players,
referees,
and
18
spectators
have
been
associated
with
elevated
nitrogen
dioxide
levels
in
the
arena
due
to
19
malfunctioning
resurfacers
or
ventilation
systems
or
combined
with
elevated
carbon
monoxide
levels
20
(
Smith
et
al.,
1992;
Soparkar
et
al.,
1993;
Morgan,
1995;
Karlson­
Stiber,
et
al.,
1996).
Attempts
to
21
measure
NO
2
concentrations
in
the
arenas
or
reconstruct
the
situations
were
described
by
the
authors
22
as
not
indicative
of
the
actual
exposure
scenario
which
resulted
in
adverse
effects.
23
24
Morley
and
Silk
(
1970)
described
a
number
of
cases
in
which
welders
involved
in
ship
repair
25
and
shipbuilding
were
exposed
to
nitrous
fumes.
Symptoms
included
dyspnea,
cough,
headache,
26
tightness/
pain
in
chest,
nausea,
and
cyanosis.
Most
patients
recovered
after
treatment
with
oxygen
27
and
antibiotics;
however,
one
man
died
43
days
later
from
viral
pneumonia.
For
two
individuals
28
admitted
to
the
hospital
with
cyanosis,
dyspnea,
and
pulmonary
edema,
the
concentration
of
NO
2
was
29
measured
at
30
ppm
during
a
40­
minute
welding
operation.
However,
the
authors
noted
that
7
other
30
individuals
present
at
the
time
were
unaffected.
31
32
A
railroad
tank
car
ruptured
at
a
chemical
plant
releasing
a
cloud
of
NO
2
in
a
small
community
33
(
Bauer
et
al.,
1998).
In
the
first
30
hours
after
the
release,
the
most
common
symptoms
reported
in
34
emergency
room
visits
were
headache,
burning
eyes,
and
sore
throat.
Most
air
samples
collected
3­
7
35
hours
after
the
release
showed
concentrations
of
0
ppm
with
one
sample
showing
1.4
ppm.
No
36
attempt
was
made
to
correlate
symptoms
with
estimated
exposure.
37
38
Acute
toxic
reactions
were
described
in
four
fireman
who
were
exposed
to
NO
2
which
39
originated
from
a
leak
in
a
chemical
plant
(
Tse
and
Bockman,
1970).
Concentrations
were
not
40
reported
and
exposure
durations
were
defined
as
"
barely
a
few
minutes"
to
"
about
ten
minutes".
41
Initial
responses,
which
cleared
within
several
days,
included
headache,
a
dry
hacking
cough,
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pulmonary
edema,
sinusitis,
and/
or
upper
respiratory
tract
irritation.
Four
to
six
weeks
after
1
exposure,
three
of
the
patients
developed
fever,
chest
tightness,
shortness
of
breath,
and
a
productive
2
cough;
these
subsided
and
the
patients
remained
asymptomatic.
The
fourth
patient
developed
chronic
3
pulmonary
insufficiency,
consisting
of
dyspnea
on
exertion,
despite
normal
chest
X­
ray.
4
5
Four
cases
of
exposure
to
unknown
concentrations
of
nitrous
fumes
were
reported
for
6
individuals
involved
either
in
the
use
of
an
oxyacetylene
burner,
during
a
leak
at
a
chemical
plant,
or
7
in
shotfiring
(
Jones
et
al.,
1973).
Three
patients
presented
with
pulmonary
edema,
one
of
which
8
progressed
to
bronchiolitis
obliterans;
the
fourth
patient
presented
with
clinical
features
of
9
bronchiolitis
obliterans.
All
recovered
completely
following
corticosteroid
treatment.
10
11
2.2.2.
Epidemiologic
Studies
12
13
Several
epidemiological
studies
associating
ambient
NO
2
exposure
with
an
increase
in
the
14
prevalence
of
respiratory
illness
have
been
inconclusive.
Increased
odds
ratios
(
1.2­
1.7)
were
found
15
for
bronchitis,
chronic
cough,
and
chest
illness
but
not
for
wheeze
and
asthma
in
children
from
six
16
U.
S.
cities
with
annual
average
NO
2
levels
0.0065­
0.0226
ppm
(
Dockery
et
al,
1989).
No
association
17
was
found
between
long­
term
differences
in
NO
2
levels
(
change
of
0.0106
ppm/
6­
week
average)
and
18
mean
annual
rates
of
respiratory
episodes
in
children
from
urban
and
rural
regions
in
Switzerland,
19
however
the
duration
of
symptoms
was
increased
(
Braun­
Fahrlaender
et
al.,
1992).
An
increase
in
20
the
cases
of
croup
in
children
was
associated
with
total
suspended
particulate
matter
and
NO
2
21
(
Schwartz
et
al.,
1991)
and
decreased
lung
function
in
children
was
linked
to
sulfur
dioxide
in
22
combination
with
NO
2
(
Mostardi
et
al.,
1981).
Symptoms
of
chronic
obstructive
pulmonary
disease
23
have
been
linked
to
exposure
to
total
oxidants
(>
0.1
ppm),
NO
2,
and/
or
sulfates,
but
not
to
NO
2
alone
24
(
Detels
et
al.,
1981;
Euler
et
al.,
1988).
Combined
effects
of
NO
2,
SO
2,
particulate
matter,
H
2
S,
and
25
other
pollutants
were
considered
as
contributing
factors
to
a
positive
association
between
the
26
occurrence
of
upper
respiratory
infections
and
living
in
polluted
areas
of
Finland
for
children
<
2
years
27
and
6
years
old
(
Jaakkola
et
al.,
1991).
28
29
In
a
more
recent
study,
children
from
12
communities
in
California
were
assessed
for
30
respiratory
disease
prevalence
and
pulmonary
function
(
Peters
et
al.,
1999a,
b).
Wheeze
prevalence
31
was
correlated
with
levels
of
both
acid
and
NO
2
in
boys,
whereas
regression
analysis
showed
that
NO
2
32
was
significantly
associated
with
lower
FVC,
FEV
1,
and
maximal
midexpiratory
flow
in
girls.
Similar
33
results
were
reported
for
eight
areas
of
Switzerland
in
which
a
10
µ
g/
m3
average
increase
in
NO
2
34
exposure
was
associated
with
decreases
in
FVC
(
Schindler
et
al.,
1998).
35
36
Epidemiological
studies
associating
indoor
NO
2
have
also
been
inconclusive.
One
study
found
37
no
evidence
for
any
short­
term
association
between
prevalence
of
respiratory
symptoms
in
infants
and
38
median
indoor
and
outdoor
NO
2
levels
of
6.8
and
12.6
ppb,
respectively
(
Farrow
et
al.,
1997).
Other
39
studies
found
a
significant
increase
in
the
occurrence
of
sore
throat,
colds,
and
absences
from
school
40
among
children
exposed
to
hourly
peak
levels
of

80
ppb
NO
2
from
unvented
gas
heating
in
the
41
classrooms
(
Pilotto
et
al.,
1997),
increased
respiratory
illness
in
children
from
homes
using
gas
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cooking
where
NO
2
concentrations
in
the
children's
bedroom
ranged
from
4­
169
ppb
(
Florey
et
al.,
1
1979),
and
slight
decreases
in
forced
vital
capacity
and
peak
expiratory
flow
among
adult
asthmatics
2
exposed
to
>
0.3
ppm
while
cooking
on
a
gas
range
(
Goldstein
et
al.,
1988).
Similar
to
these
findings,
3
Neas
et
al.
(
1991)
found
that
a
15
ppb
increase
in
household
annual
NO
2
mean
was
associated
with
4
an
increased
cumulative
incidence
of
attacks
of
shortness
of
breath
with
wheeze,
chronic
wheeze,
5
chronic
cough,
chronic
phlegm,
or
bronchitis
in
children.
6
7
As
part
of
a
review
of
the
National
Ambient
Air
Quality
Standards
(
NAAQS)
for
NO
2,
U.
S.
8
EPA
(
1995)
conducted
a
meta­
analysis
of
studies
which
examined
the
respiratory
effects
on
children
9
living
in
homes
with
gas
stoves.
Conclusions
drawn
from
that
analysis
were
that
children
ages
5­
12
10
years
old
had
an
increased
risk
of
about
20%
for
developing
respiratory
symptoms
and
disease
with
11
each
increase
of
0.015
ppm
in
estimated
2­
week
average
NO
2
exposure
(
mean
weekly
concentrations
12
in
bedrooms
0.008­
0.065
ppm)
and
that
no
evidence
for
increased
risk
was
found
for
infants
<
2
years
13
old.
Several
limitations
of
this
analysis
were
acknowledged
including
the
uncertainty
between
14
monitored
vs.
actual
exposure
concentration,
that
the
method
could
not
distinguish
between
peak
and
15
average
exposures,
the
confounding
effects
of
other
gas
combustion
by­
products,
and
in
context
of
16
the
NAAQS
review
that
indoor
exposures
do
not
mimic
outdoor
exposures
(
U.
S.
EPA,
1995).
17
18
Several
occupations
result
in
exposure
to
NO
2
concentrations
higher
than
ambient.
In
diesel
19
bus
garage
workers,
NO
2
concentrations
of

0.3
ppm,
along
with
respirable
particulates,
were
20
associated
with
work­
related
symptoms
of
cough,
itching,
burning
or
watering
eyes,
difficult
21
breathing,
chest
tightness,
and
wheeze;
but,
there
were
no
reductions
in
pulmonary
function
(
Gamble
22
et
al.,
1987).
In
contrast,
no
relationship
was
found
between
exposure
to
oxides
of
nitrogen
and
23
respiratory
symptoms
or
decline
in
FEV
1
among
British
coalminers
exposed
to
peak
NO
2
24
concentrations
up
to
14
ppm;
controls
were
matched
for
age,
dust
exposure,
smoking
habit,
coal
25
rank,
and
type
of
work
(
Robertson
et
al.,
1984).
No
differences
in
pulmonary
function
were
noted
26
among
shipyard
welders
exposed
to
average
concentrations
of
oxides
of
nitrogen
of
0.04
ppm
(
Peters
27
et
al.,
1973).
Slight
increases
in
prevalence
of
bronchitis
(
17.2%
vs
12.6%)
and
colds
(
37.5%
vs
28
30.7%)
were
noted
in
traffic
officers
exposed
to
automobile
exhaust
containing
mean
concentrations
29
of
0.045­
0.06
ppm
NO
2
(
Speizer
and
Ferris,
1973).
30
31
In
conclusion,
indoor
air
quality
may
be
more
significant
than
ambient
air
quality
to
the
32
prevalence
of
respiratory
illness
due
to
NO
2.
A
review
of
epidemiology
studies
which
assessed
33
ambient
quality
(
U.
S.
EPA,
1993)
yielded
that
there
is
insufficient
evidence
to
make
any
conclusion
34
about
the
long­
or
short­
term
health
effects
of
NO
2.
Further,
review
of
epidemiology
studies
that
35
assessed
indoor
air
quality,
found
that
meta
analysis
results
yielded
insufficient
evidence
to
conclude
36
that
NO
2
had
an
effect
on
infants
2
years
and
younger
while
several
considerations
limited
the
37
interpretation
of
the
positive
results
for
children
aged
5­
12
years.
38
39
2.2.3.
Experimental
Studies
40
41
Healthy
Subjects
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The
odor
threshold
for
NO
2
in
air
has
been
reported
as
0.4
ppm
for
recognition
and
4.0
ppm
1
for
<
100%
identification
(
NIOSH,
1976).
In
an
experimental
study,
the
odor
of
NO
2
was
perceived
2
by
3/
9
volunteers
exposed
to
0.12
ppm
and
by
8/
13
subjects
at
0.22
ppm.
At
concentrations
of

4
3
ppm,
the
volunteers
perceived
the
odor
for
1­
10
minutes,
but
the
duration
of
perception
was
not
4
directly
related
to
concentration.
The
olfactory
response
to
NO
2
returned
1­
1.5
minutes
after
5
cessation
of
exposure
(
Henschler
et
al.,
1960).
6
7
Low
level
exposures
of
healthy
individuals
to
NO
2
have
shown
no
effects
on
pulmonary
8
function
or
symptoms.
In
several
studies,
healthy
men
and/
or
women
were
exposed
to
0.6
ppm
NO
2
9
for
1­
3
hours
with
intermittent
or
continuous
exercise.
No
significant
effects
were
observed
in
any
10
study
on
pulmonary
function,
cardiovascular
function,
metabolism,
or
symptoms
of
exposure
11
(
Folinsbee
et
al.,
1978;
Adams
et
al.,
1987;
Frampton
et
al.,
1991;
Hazucha
et
al.,
1994).
No
changes
12
in
pulmonary
function
occurred
following
exposure
to
1.5
ppm
for
3
hours
or
to
a
baseline
of
0.05
13
ppm
with
intermittent
peaks
of
2
ppm,
however,
continuous
exposure
to
1.5
ppm
for
3
hours
resulted
14
in
a
slight
but
significantly
greater
fall
in
FEV
1
and
FVC
in
response
to
carbachol
(
Frampton
et
al.,
15
1991).
Pulmonary
function
was
not
affected
in
competitive
athletes
exposed
to
0.18
and
0.30
ppm
16
for
30
minutes
during
heavy
exercise
(
Kim
et
al.,
1991)
or
in
healthy
adults
exposed
to
0.3
ppm
for
17
4
hours
with
intermittent
exercise
(
Smeglin
et
al.,
1985).
18
19
Studies
at
higher
concentrations
of
NO
2
indicate
an
apparent
threshold
before
pulmonary
20
function
is
affected.
No
changes
in
pulmonary
function,
airway
reactivity,
or
indications
of
irritation
21
were
measured
in
healthy
adults
exposed
to
1
ppm
for
2
hours,
2
ppm
for
3
hours
(
Hackney
et
al.,
22
1978),
2
ppm
for
4
hours
(
Devlin
et
al.,
1992),
3
ppm
for
2
hours
(
Goings
et
al.,
1989)
or
to
2.3
ppm
23
for
5
hours
(
Rasmussen
et
al.,
1992).
Normal
subjects
exposed
to
2
ppm
for
1
hour
developed
an
24
increase
in
airway
reactivity
to
methacholine
challenge
without
changes
in
lung
volume
or
pulmonary
25
function
(
Mohsenin,
1988).
No
statistically
significant
effects
on
airway
resistance,
symptoms,
heart
26
rate,
skin
conductance,
or
self­
reported
emotional
state
were
found
in
healthy
volunteers
exposed
to
27
4
ppm
NO
2
for
1
hour
and
15
minutes
with
intermittent
light
and
heavy
exercise
(
Linn
and
Hackney,
28
1983).
However,
a
significant
decrease
in
mean
(
n
=
11)
alveolar
O
2
partial
pressure
by
8
mm
Hg
29
and
a
significant
increase
in
mean
(
n
=
11)
airway
resistance
from
1.51
to
2.41
cm
H
2
O/(
L/
s)
occurred
30
in
healthy
volunteers
exposed
to
5
ppm
for
2
hours
with
6/
11
individuals
responding
(
von
Nieding
31
et
al.,
1979).
32
33
Henschler
et
al.
(
1960)
performed
several
experiments
on
healthy,
male
volunteers.
They
34
reported
that
a
2­
hour
exposure
to
20
ppm
did
not
cause
any
irritation
as
long
as
several
exposures
35
to
lower
concentrations
occurred
during
the
preceding
days;
however,
exposure
to
30
ppm
for
2
36
hours
caused
definite
discomfort.
Three
individuals
exposed
to
30
ppm
for
2
hours
perceived
an
37
intense
odor
upon
entering
the
chamber
which
quickly
diminished
and
was
completely
absent
after
38
25­
40
minutes.
One
individual
experienced
a
slight
tickling
of
the
nose
and
throat
mucous
39
membranes
after
30
minutes,
the
two
others
after
40
minutes.
From
70
minutes
on,
all
subjects
40
experienced
a
burning
sensation
and
an
increasingly
severe
cough
for
the
next
10­
20
minutes,
but
41
coughing
decreased
from
100
minutes
on.
However,
the
burning
sensation
continued
and
moved
into
42
NITROGEN
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16
the
lower
sections
of
the
airways
and
was
finally
felt
deep
in
the
chest.
At
this
time,
marked
sputum
1
secretion
and
dyspnea
was
noted.
Towards
the
end
of
the
exposure,
the
subjects'
reported
the
2
exposure
conditions
to
be
bothersome
and
barely
tolerable.
A
sensation
of
pressure
and
increased
3
sputum
secretion
continued
for
several
hours
after
cessation
of
exposure
(
Henschler
et
al.,
1960).
4
5
In
a
similar
experiment
(
Henschler
and
Lütke,
1963)
groups
of
4
or
8
healthy,
male
volunteers
6
were
exposed
to
10
ppm
for
6
hours
or
to
20
ppm
for
2
hours.
All
subjects
upon
entering
the
7
chamber
noted
the
odor
which
diminished
rapidly.
At
20
ppm
minor
scratchiness
of
the
throat
was
8
felt
after
about
50
minutes
and
3/
8
experienced
slight
headaches
towards
the
end
of
the
exposure
9
period.
Methemoglobin
levels
remained
within
the
normal
range
in
all
subjects
after
exposure.
10
11
Biochemical
changes
in
bronchoalveolar
lavage
fluid
(
BALF)
and
blood
have
also
been
12
studied
following
exposure
of
healthy
adults
to
NO
2.
Exposures
to
2
ppm
for
4
(
Devlin
et
al.,
1992)
13
or
6
hours
(
Frampton
et
al.,
1992)
caused
an
influx
of
polymorphonuclear
leukocytes
in
BALF,
2.3
14
ppm
for
5
hours
resulted
in
a
decrease
in
serum
glutathione
peroxidase
activity
(
Rasmusen
et
al.,
15
1992),
1
and
2
ppm
for
3
hours
caused
a
decrease
in
RBC
membrane
acetylcholinesterase
activity,
16
2
ppm
for
3
hours
resulted
in
an
increase
in
peroxidized
RBC
lipids
and
glucose­
6­
phosphate
17
dehydrogenase
activity
(
Posin
et
al.,
1978),
and
exposure
to
3
or
4
ppm
for
3
hours
resulted
in
a
18
decrease
in
 ­
1­
protease
inhibitor
activity
but
not
in
overall
enzyme
levels
in
BALF
(
Mohsenin
and
19
Gee,
1987).
Following
exposure
to
2
ppm
for
4
hours,
neutrophilic
inflammation
was
detected
in
20
bronchial
washings
but
no
changes
in
inflammatory
cells
were
observed
in
endobronchial
biopsy
21
samples
(
Blomberg
et
al.,
1997).
Mucociliary
activity
was
completely
stopped
in
healthy
individuals
22
45
minutes
after
exposure
to
1.5
and
3.5
ppm
for
20
minutes
(
Helleday
et
al.,
1995).
23
24
Asthmatic
Subjects
25
26
Studies
on
the
effects
of
NO
2
on
pulmonary
function
in
asthmatics
are
inconclusive
and
27
conflicting.
No
consistent
changes
in
pulmonary
function
or
reported
symptoms
have
been
found
in
28
exercising
asthmatic
adults
and
adolescents
exposed
to
0.12
or
0.18
ppm
for
40
minutes
(
Koenig
et
29
al.,
1987),
0.12
ppm
for
1
hour
at
rest
(
Koenig
et
al.,
1985),
0.2
ppm
for
2
hours
with
intermittent
30
exercise
(
Kleinman
et
al.,
1983),
0.3
ppm
for
30
minutes
(
Rubinstein
et
al.,
1990),
1
hour
(
Vagaggini
31
et
al.,
1996),
or
4
hours
with
exercise
(
Morrow
and
Utell,
1989),
0.5
ppm
for
1
hour
at
rest
32
(
Mohsenin,
1987),
up
to
0.6
ppm
for
75
minutes
with
intermittent
exercise
(
Roger
et
al.,
1990),
and
33
up
to
1
ppm
for
4
hours
(
Sackner
et
al.,
1981).
No
statistically
significant
differences
between
34
control
and
NO
2
exposure
were
found
for
airway
resistance,
symptoms,
heart
rate,
skin
conductance,
35
or
self­
reported
emotional
state
for
asthmatics
exposed
to
4
ppm
for
75
minutes
with
intermittent
36
exercise
(
Linn
and
Hackney,
1984).
37
38
Kerr
et
al.
(
1978,
1979)
studied
of
the
effects
of
NO
2
on
pulmonary
function
as
well
as
39
reported
symptoms
which
were
not
included
in
many
other
studies.
The
subjects
were
asked
to
keep
40
note
of
symptoms
they
experienced
during
exposure
to
0.5
ppm
for
2
hours,
specifically
cough,
41
sputum,
irritation
of
mucus
membranes,
and
chest
discomfort.
At
this
concentration
the
odor
of
NO
2
42
NITROGEN
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was
perceptible
but
the
subjects
became
unaware
of
it
after
about
15
minutes.
Seven
of
13
asthmatics
1
reported
symptoms
with
exposure
compared
with
only
one
of
the
10
normal
subject
and
one
of
the
2
7
subjects
with
chronic
bronchitis.
In
the
group
of
asthmatics,
two
had
slight
burning
of
the
eyes,
one
3
had
a
slight
headache,
three
reported
chest
tightness,
and
one
had
labored
breathing
with
exercise
4
compared
with
slight
nasal
discharge
in
the
normal
and
chronic
bronchitis
individuals.
No
changes
5
in
any
pulmonary
function
tests
were
found
immediately
following
the
chamber
exposure.
6
7
Significant
group
mean
reductions
in
FEV
1
(­
17.3%
with
NO
2
vs
­
10.0%
with
air)
and
specific
8
airway
conductance
(­
13.5%
with
NO
2
vs
­
8.5%
with
air)
occurred
in
asthmatics
after
exercise
during
9
exposure
to
0.3
ppm
for
4
hours
and
1/
6
individuals
experienced
chest
tightness
and
wheezing
(
Bauer
10
et
al.,
1985).
The
onset
of
effects
was
delayed
when
exposures
were
by
oral­
nasal
inhalation
11
compared
to
oral
inhalation
and
may
result
from
scrubbing
within
the
upper
airway.
In
a
similar
12
study,
asthmatics
exposed
to
0.3
ppm
for
30
minutes
at
rest
followed
by
10
minutes
of
exercise
had
13
significantly
greater
reductions
in
FEV
1
(
10%
vs
4%
with
air)
and
partial
expiratory
flow
rates
at
60%
14
of
total
lung
capacity,
but
no
symptoms
were
reported
(
Bauer
et
al.,
1986).
In
a
preliminary
study
15
with
13
asthmatics
exposed
to
0.3
ppm
for
110
minutes,
slight
cough
and
dry
mouth
and
throat
and
16
significantly
greater
reduction
(
11%
vs
7%)
in
FEV
1
occurred
after
exercise,
however,
in
a
larger
17
study,
no
changes
in
pulmonary
function
were
measured
and
no
symptoms
were
reported
following
18
exposure
of
21
asthmatics
to
concentrations
up
to
0.6
ppm
for
75
minutes
(
Roger
et
al.,
1990).
The
19
mean
drop
in
FEV
1
for
asthmatics
during
a
3­
hour
exposure
with
intermittent
exercise
to
1
ppm
NO
2
20
(
2.5%)
was
significantly
greater
than
the
drop
during
air
(
1.3%)
exposure;
in
BALF,
levels
of
6­
keto­
21
prostaglandin
1 
were
decreased
and
levels
of
thromboxane
B
2
and
prostaglandin
D
2
were
increased
22
after
NO
2
exposure
(
Jörres
et
al.,
1995).
23
24
The
effects
of
NO
2
on
airway
hyperreactivity
in
asthmatics
have
also
been
inconclusive
among
25
studies.
Methacholine
responsiveness
in
asthmatics
was
not
increased
following
exposure
to
0.25
26
ppm
for
20
minutes
at
rest
plus
10
minutes
of
exercise
(
Jörres
and
Magnussen,
1991)
or
by
exposure
27
to
0.1
ppm
for
1
hour
at
rest
(
Hazucha
et
al.,
1983).
Exposure
to
0.1
ppm
for
1
hour
caused
a
slight
28
but
significant
increase
in
initial
specific
airway
resistance
and
enhanced
the
bronchoconstrictor
effect
29
of
carbachol
in
13/
20
asthmatics,
but
the
remaining
7
subjects
were
unaffected.
When
the
study
was
30
repeated
in
4
individuals
(
two
responders
and
two
non­
responders)
at
0.2
ppm,
the
results
were
31
variable
in
that
the
two
non­
responders
were
still
unaffected,
while
one
responder
had
an
equal
32
response
and
the
other
had
a
greater
response
to
carbachol
challenge
compared
with
their
responses
33
to
0.1
ppm
(
Orehek
et
al.,
1976).
Slight
but
significant
potentiation
of
airway
reactivity
in
asthmatics
34
occurred
from
NO
2
exposures
of
0.5
ppm
for
1
hour
followed
by
methacholine
challenge
(
Mohsenin,
35
1987),
0.3
ppm
for
40
minutes
followed
by
isocapnic
cold
air
hyperventilation
(
Bauer
et
al.,
1986),
36
0.2
ppm
for
2
hours
followed
by
methacholine
challenge
(
Kleinman
et
al.,
1983),
and
0.25
ppm
for
37
30
minutes
followed
by
isocapnic
hyperventilation
(
Jörres
and
Magnussen,
1990).
A
significantly
38
greater
fall
in
FEV
1
from
challenge
with
house
dust
mite
antigen
was
reported
for
asthmatics
as
39
compared
to
controls
(­
7.76%
vs
­
2.85%)
following
exposure
to
0.4
ppm
for
1
hour
(
Tunnicliffe
et
40
al.,
1994),
but
no
significant
changes
were
found
in
a
similar
study
using
a
6­
hour
exposure
(
Devalia
41
et
al.,
1994).
Exposure
of
asthmatics
to
0.4
ppm
for
3
hours
significantly
decreased
the
amount
of
42
NITROGEN
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18
inhaled
allergen
required
to
decrease
FEV
1
by
20%
but
no
changes
in
airway
responsiveness
occurred
1
following
exposure
to
0.2
ppm
for
6
hours;
these
results
suggest
a
concentration
threshold
rather
than
2
a
duration
effect
(
Jenkins
et
al.,
1999).
3
4
Folinsbee
(
1992)
conducted
a
meta­
analysis
of
twenty
studies
which
measured
airway
5
responsiveness
in
asthmatics
following
NO
2
exposure.
Eight
different
agents
were
used
in
these
6
studies
to
induce
non­
specific
airway
responsiveness
and
the
analysis
was
limited
to
exposures
in
the
7
range
of
0.2
to
0.3
ppm.
For
asthmatics,
the
fraction
of
subjects
with
an
increase
in
airway
8
responsiveness
was
significant
(
p

0.01)
following
exposures
at
rest,
but
not
with
exercise.
When
9
only
those
studies
which
used
a
cholinergic
agonist
were
analyzed
similar
results
were
found
in
that
10
a
greater
proportion
of
subjects
showed
an
increased
response
in
resting
exposures
than
in
exercising
11
exposures.
12
13
Subjects
with
Chronic
Lung
Disease
14
15
The
results
of
studies
on
the
effects
of
NO
2
on
pulmonary
function
in
patients
with
chronic
16
lung
disease
or
bronchitis
are
also
conflicting.
No
significant
differences
in
pulmonary
function
or
17
symptom
reporting
were
observed
in
patients
with
chronic
respiratory
illness
exposed
to
0.3
ppm
for
18
4
hours
at
rest
(
Hackney
et
al.,
1992),
in
patients
with
chronic
obstructive
pulmonary
disease
(
COPD)
19
exposed
to
NO
2
levels
up
to
2
ppm
for
1
hour
with
intermittent
exercise
(
Linn
et
al.,
1985),
and
in
20
patients
with
chronic
bronchitis
exposed
to
0.5
ppm
for
2
hours
with
exercise
(
Kerr
et
al.,
1978,
21
1979).
In
contrast
to
these
reports,
forced
expiratory
volume
of
COPD
patients
significantly
22
decreased
from
18.8
L
after
air
to
13.6
L
after
exposure
to
0.3
ppm
for
1
hour
(
Vagaggini
et
al.,
23
1996).
A
significant
reduction
in
forced
vital
capacity
that
progressed
during
exercise
(­
1.2
to
­
8.2%)
24
occurred
in
elderly
COPD
patients
exposed
to
0.3
ppm
for
4
hours
while
no
effects
were
seen
in
an
25
age
and
gender
matched
healthy
control
group
(
Morrow
and
Utell,
1989;
Morrow
et
al.,
1992).
26
27
The
effects
of
NO
2
on
respiratory
gas
exchange
was
investigated
in
patients
with
chronic
28
bronchitis.
Inhalation
of
4
and
5
ppm
for
15­
60
minutes
significantly
decreased
the
CO
diffusing
29
capacity
and
arterial
pO
2
with
no
progressive
changes
noted
over
time.
Exposure
to
5
ppm
over
15
30
minutes
resulted
in
an
average
decrease
in
CO
diffusion
capacity
of
3.8
mL/
min/
torr
and
a
decrease
31
in
arterial
pO
2
from
an
average
of
76.5
to
71.3
torr.
A
slight,
but
statistically
significant,
increase
in
32
airway
resistance
(
approximately
20­
30%
above
the
initial
value)
was
measured
for
exposure
33
concentrations
of
1.6­
5
ppm
for
5
minutes;
no
effects
occurred
at
or
below
1.5
ppm
(
von
Nieding
et
34
al.,
1973;
von
Nieding
and
Wagner,
1979).
35
36
2.3.
Developmental/
Reproductive
Toxicity
37
38
No
information
was
found
regarding
the
developmental
or
reproductive
toxicity
of
NO
2
in
39
humans.
40
41
2.4.
Genotoxicity
42
NITROGEN
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19
No
information
was
found
regarding
the
genotoxicity
toxicity
of
NO
2
in
humans.
1
2
2.5.
Carcinogenicity
3
4
No
information
was
found
regarding
the
carcinogenicity
of
NO
2
in
humans.
5
6
2.6.
Summary
7
8
In
humans,
NO
2
exposure
causes
immediate
irritation
with
pulmonary
edema
followed
by
a
9
latent
period
of
apparent
recovery.
A
second
phase
of
symptoms
can
occur
after
several
hours
with
10
the
development
of
bronchiolitis
obliterans.
An
estimation
of
the
concentration
causing
death
in
11
humans
is
approximately

150
ppm,
but
no
duration
of
exposure
was
given.
Most
case
reports
do
12
not
contain
concentrations
or
durations
of
exposure,
however,
welders
exposed
to
30
and
90
ppm
13
for
40
minutes
experienced
varying
degrees
of
dyspnea,
cough,
headache,
chest
tightness,
nausea,
and
14
cyanosis
with
hospitalization
required
for
pulmonary
edema,
confirmed
by
X­
ray,
at
the
higher
15
concentration
(
Norwood
et
al.,
1966;
Morley
and
Silk,
1970).
16
17
Epidemiological
studies
on
the
long­
term
effects
of
elevated
NO
2
have
been
conflicting.
It
18
is
likely
that
increases
in
respiratory
illnesses
are
due
to
NO
2
in
combination
with
other
pollutants
and
19
that
short­
term
peak
concentrations
are
more
detrimental
than
chronic,
low­
level
exposures.
20
Evidence
suggests
that
children
ages
5­
12
have
a
greater
risk
for
developing
respiratory
disease
from
21
long­
term
exposure
to
higher
concentrations,
but
that
infants
do
not.
22
23
Experimental
studies
with
both
healthy
and
asthmatic
individuals
are
inconclusive.
Negative
24
results
have
been
obtained
in
many
studies
with
exposures
up
to
4
ppm
for
1
hour,
however,
other
25
studies
report
positive
effects
on
pulmonary
function
at
lower
concentrations.
It
should
be
noted
that
26
in
the
studies
which
found
statistically
significant
changes
with
NO
2
exposure,
the
differences
were
27
<
10%
and
of
questionable
biological
significance
even
for
asthmatics.
However,
the
available
28
evidence
also
suggests
that
asthmatics
may
experience
an
increase
in
airway
responsiveness
from
29
concentrations
of
0.2­
0.3
ppm.
30
31
32
3.
ANIMAL
TOXICITY
DATA
33
3.1.
Acute
Lethality
34
35
Acute
lethality
data
were
located
for
several
species.
One
group
of
investigators
(
Hine
et
al.,
36
1970)
studied
the
effects
of
varying
concentration
and
duration
of
exposure
in
five
different
species
37
of
laboratory
animal;
these
results
are
described
separately
by
species
below
and
summarized
in
Table
38
3
at
the
end
of
this
section.
In
this
study,
deaths
generally
occurred
within
2­
8
hours
after
exposure
39
and
the
majority
within
24
hours.
Additional
data
from
rabbit,
rat,
and
mouse
studies
were
available
40
and
are
in
good
agreement
with
the
results
of
the
Hine
et
al.
study.
41
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3.1.1.
Dogs
1
2
Greenbaum
et
al.
(
1967)
exposed
mongrel
dogs
(
n
=
1/
exposure)
to
0.1%
(
1000
ppm)
NO
2
3
for
136
minutes,
0.5%
(
5000
ppm)
for
5­
45
minutes,
or
to
2%
(
20,000
ppm)
for
15
minutes.
All
4
dogs
died
that
were
exposed
to
either
0.5%
for
35
or
45
minutes
or
to
2%
for
15
minutes.
5
Respiration
became
shallow
and
gasping
with
deaths
due
to
pulmonary
edema.
Fluid
was
visible
in
6
the
tracheobronchial
tree
at
necropsy.
Cyanosis
due
to
methemoglobin
formation
(
78%)
was
noted
7
in
one
animal
given
2%
for
15
minutes.
At
concentrations
of
0.5%
and
2%,
arterial
pO
2
and
systemic
8
arterial
pressure
were
reduced.
The
authors
stated
that
pulmonary
edema
was
caused
by
the
action
9
of
nitrogen
dioxide
on
the
alveolar
lining
fluid,
forming
nitric
and
nitrous
acids
which,
in
turn,
cause
10
denaturing
of
proteins,
rupture
of
lysosomes,
and
the
development
of
chemical
pneumonitis.
11
12
Hine
et
al.
(
1970)
studied
the
effects
of
varying
concentration
and
duration
of
NO
2
exposure
13
on
mongrel
dogs.
Animals
(
n
=
1­
4)
were
exposed
to
5­
250
ppm
NO
2
for
periods
of
30
minutes
to
14
24
hours.
At
concentrations
of

40
ppm,
signs
of
toxicity
included
lacrimation,
reddening
of
the
15
conjunctivae,
and
increased
respiration
which
became
labored
and
difficult
as
the
concentration
16
increased.
Mortalities
were
first
observed
at
75
ppm
for
4
hours
(
Table
3).
Terminally,
respiration
17
became
gasping
and
spasmodic
and
lung
edema
was
observed
at
necropsy.
Histological
observations
18
of
the
lungs
following
deaths
were
characterized
by
bronchiolitis,
desquamated
bronchial
epithelium,
19
infiltration
by
polymorphonuclear
cells,
and
edema.
20
21
3.1.2.
Rabbits
22
23
The
15­
minute
LC
50
for
the
rabbit
(
strain
not
specified;
n
=
5)
was
315
ppm.
Clinical
signs
24
of
toxicity
included
severe
respiratory
distress,
eye
irritation,
10­
15%
body
weight
suppression
for
25
two
days,
and
death;
time
to
death
varied
from
30
minutes
to
3
days.
Gross
pathology
revealed
26
darkened
areas
about
the
surface
of
the
lungs.
Histopathology
of
the
lungs
of
the
survivors
7
and
21
27
days
after
exposure
showed
lesions
consisting
of
focal
accumulation
of
intraalveolar
macrophages,
28
some
proliferation
of
the
alveolar
lining
epithelium,
and
varying
amounts
of
inflammatory
cells
29
(
Carson
et
al.,
1962).
30
31
Hine
et
al.
(
1970)
studied
the
effects
of
varying
concentration
and
duration
of
NO
2
exposure
32
on
rabbits
(
strain
not
specified).
Animals
(
n
=
2­
8)
were
exposed
to
5­
200
ppm
NO
2
for
30
minutes
33
up
to
24
hours.
At
concentrations
of

40
ppm,
signs
of
toxicity
included
lacrimation,
reddening
of
34
the
conjunctivae,
and
increased
respiration
which
became
labored
and
difficult
as
the
intoxication
35
increased.
Mortalities
were
first
observed
at
75
ppm
for
60
minutes
(
Table
3).
Terminally,
36
respiration
became
gasping
and
spasmodic
and
lung
edema
was
observed
at
necropsy.
Histological
37
observations
of
the
lungs
following
deaths
were
characterized
by
bronchiolitis,
desquamated
bronchial
38
epithelium,
infiltration
by
polymorphonuclear
cells,
and
edema.
39
40
In
a
similar
study,
rabbits
(
strain
not
specified;
n
=
3)
were
exposed
to
125,
175,
250,
400,
41
600,
or
800
ppm
NO
2
for
10
minutes
(
Meulenbelt
et
al.,
1994).
Two
of
three
animals
given
800
ppm
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died
7­
21
hours
after
exposure.
Lung
weights
were
significantly
higher
and
lung
homogenates
1
contained
greater
amounts
of
protein,
lactate
dehydrogenase
(
LDH),
glutathione
peroxidase,
and
2
glucose­
6­
phosphate
dehydrogenase
in
animals
exposed
to

250
ppm.
Bronchoalveolar
lavage
fluid
3
from
animals
receiving

175
ppm
contained
greater
amounts
of
protein,
albumin,
LDH,
and
4
angiotensin
converting
enzyme
activities
than
unexposed
controls
and
all
treated
groups
had
increased
5
numbers
of
neutrophilic
leucocytes.
Dose­
related
increases
in
severity
of
centriacinar
catarrhal
6
pneumonitis,
macrophage
influx,
and
neutrophilic
leucocytes
were
observed
on
histopathological
7
examination
of
the
lungs.
Edema
occurred
at

250
ppm,
subpleural
hemorrhaging
at

400
ppm,
and
8
desquamation
of
the
bronchiolar
epithelium
was
seen
at

600
ppm.
9
10
3.1.3.
Guinea
Pigs
11
12
Hine
et
al.
(
1970)
also
studied
the
effects
of
varying
concentration
and
duration
of
exposure
13
in
the
guinea
pig
(
strain
not
specified).
Animals
(
n
=
2­
6)
were
exposed
to
5­
200
ppm
NO
2
for
30
14
minutes
up
to
8
hours.
At
concentrations
of

40
ppm,
signs
of
toxicity
included
lacrimation,
15
reddening
of
the
conjunctivae,
and
increased
respiration
which
became
labored
and
difficult
as
the
16
intoxication
increased.
Mortalities
were
first
observed
at
50
ppm
for
1
hour
(
Table
3).
Terminally,
17
respiration
became
gasping
and
spasmodic
and
lung
edema
was
observed
at
necropsy.
Histological
18
observations
of
the
lungs
following
deaths
were
characterized
by
bronchiolitis,
desquamated
bronchial
19
epithelium,
infiltration
by
polymorphonuclear
cells,
and
edema.
20
21
To
determine
the
sensitivity
of
adult
and
neonate
animals
to
NO
2
inhalation,
Duncan­
Hartley
22
guinea
pigs
aged
5­
60
days
were
exposed
continuously
for
3
days
to
2
or
10
ppm
(
Azoulay­
Dupuis
23
et
al.,
1983).
A
total
of
17­
27
animals
were
studied
in
each
age
group
and
litter
exposures
prior
to
24
weaning
included
the
dam.
At
10
ppm,
clinical
signs
of
toxicity
in
adults
over
45
days
old
included
25
moving
with
difficulty,
reduced
food
and
water
consumption,
and
hyperventilation.
Body
weight
26
gains
were
decreased
until
21
days
and
body
weights
were
reduced
after
45
days
in
all
exposed
27
animals.
These
effects
were
most
pronounced
in
the
dams.
Mortality
in
the
high­
exposure
group
28
increased
with
age
with
4%
of
5­
day
olds,
up
to
60%
of
55­
day
olds,
and
67%
of
dams
dying.
29
Further,
most
of
the
older
animals
died
after
the
first
24
hours
of
exposure
whereas
the
younger
30
animals
died
later
in
the
3­
day
period.
At
2
ppm,
lung
histopathology
was
normal
until
animals
were
31
45
days
of
age
when
thickening
of
the
alveolar
walls,
infiltration
by
PMNs,
and
alveolar
edema
were
32
observed;
in
dams
bronchioles
were
devoid
of
cilia
in
some
areas.
At
10
ppm,
guinea
pigs
of
all
ages
33
were
affected
by
these
changes
which
were
more
pronounced
in
older
animals.
34
35
3.1.4.
Rats
36
37
Five­,
15­,
30­,
and
60­
minute
LC
50
values
for
the
male
rat
(
100­
120
g;
strain
not
specified;
38
n
=
10)
are
416,
201,
162,
and
115
ppm,
respectively.
Clinical
signs
of
toxicity
included
severe
39
respiratory
distress,
eye
irritation,
10­
15%
body
weight
suppression,
and
death;
time
to
death
varied
40
from
30
minutes
to
3
days.
Gross
pathology
revealed
darkened
areas
about
the
surface
of
the
lungs,
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and,
in
some
instances,
purulent
nodules
involving
the
entire
lungs
of
some
of
the
survivors
(
Carson
1
et
al.,
1962).
2
3
An
older
study
(
Gray
et
al.,
1954)
reported
LC
50
values
for
male
rats
(
200­
300
g;
strain
not
4
specified;
n
=
10)
of
1445
ppm
for
2
minutes,
833
ppm
for
5
minutes,
420
ppm
for
15
minutes,
174
5
ppm
for
30
minutes,
168
ppm
for
60
minutes,
and
88
ppm
for
240
minutes.
Deaths
were
attributed
6
to
pulmonary
edema.
The
differences
in
LC
50
values
between
this
study
and
Carson
et
al.
(
1962)
may
7
be
due
to
the
differences
in
size
and
age
of
the
rats
used
in
each.
8
9
Meulenbelt
et
al.
(
1992a,
b)
investigated
the
effects
of
both
concentration
and
duration
of
10
exposure
in
Wistar
rats.
The
effect
of
concentration
was
studied
by
exposing
6­
9
rats/
group
to
25,
11
75,
125,
175
or
200
ppm
NO
2
for
10
minutes.
No
signs
of
toxicity
were
observed
at
25
ppm.
12
Stertorous
respirations
were
heard
in
animals
exposed
to
175
and
200
ppm.
Rats
exposed
to

75
13
ppm
had
significantly
increased
lung
weight,
and
subpleural
hemorrhages
and
pale
discolorations
of
14
the
lung
were
observed
grossly.
Histologically,
the
lungs
from
these
animals
showed
atypical
15
pneumonia,
edema,
focal
desquamation
of
the
terminal
bronchiolar
epithelium,
increased
numbers
of
16
macrophages
and
neutrophilic
leucocytes,
and
interstitial
thickening
of
the
centriacinar
septa
(
175
and
17
200
ppm
only)
with
the
severity
increasing
at
the
higher
concentrations.
One
rat
died
14­
20
hours
18
after
exposure
in
both
the
175
ppm
and
200
ppm
groups.
Biochemical
changes
in
bronchoalveolar
19
lavage
fluid
included
concentration­
dependent
increases
in
protein
and
albumin
concentrations,
20
angiotensin
converting
enzyme
activity,
 ­
glucuronidase
activity,
and
neutrophilic
leukocytes.
21
22
Duration
of
exposure
was
investigated
by
exposing
6
rats/
group
to
either
175
ppm
for
10,
20,
23
or
30
minutes
or
to
400
ppm
for
5,
10,
or
20
minutes
(
Meulenbelt
et
al.,
1992a,
b).
Stertorous
24
respirations
were
heard
in
animals
for
all
exposure
times
of
both
concentrations
and
lung
weights
25
were
significantly
higher
than
the
controls
at
all
exposure
durations.
At
175
ppm,
5/
6
rats
died
in
the
26
20
and
30
minute
groups
and
at
400
ppm,
6/
6
rats
died
in
the
10
and
20
minute
groups.
Necropsy
27
revealed
foamy,
seroanguinous
fluid
in
the
trachea,
subpleural
bleeding,
and
pale
discoloration.
28
Histological
alterations
were
similar
to
those
described
above.
Methemoglobin
levels,
measured
after
29
exposure
to
175
ppm
for
10
minutes,
were
not
elevated,
but
plasma
nitrate
levels
were
significantly
30
higher
than
controls.
31
32
Hine
et
al.
(
1970)
also
studied
the
effects
of
varying
concentration
and
duration
of
exposure
33
in
Long­
Evans
rats.
Animals
(
n=
4­
31)
were
exposed
to
5­
250
ppm
NO
2
for
durations
of
30
minutes
34
up
to
24
hours.
At
concentrations
of

40
ppm,
signs
of
toxicity
included
lacrimation,
reddening
of
35
the
conjunctivae,
and
increased
respiration
which
became
labored
and
difficult
as
the
intoxication
36
increased.
Mortalities
were
first
observed
at
50
ppm
for
24
hours
(
Table
3).
Terminally,
respiration
37
became
gasping
and
spasmodic
and
lung
edema
was
observed
at
necropsy.
Histological
observations
38
of
the
lungs
following
deaths
were
characterized
by
bronchiolitis,
desquamated
bronchial
epithelium,
39
infiltration
by
polymorphonuclear
cells,
and
edema.
40
41
3.1.5.
Mice
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BALB/
c
mice
(
n
=
5­
7)
were
exposed
to
5,
20,
or
40
ppm
NO
2
for
12
hours
(
Hidekazu
and
1
Fujio,
1981).
Body
weights
were
markedly
decreased
1
and
2
days
after
exposure
to
20
and
40
ppm
2
and
3/
38
(
7.8%)
animals
exposed
to
40
ppm
died
within
2
days.
3
4
Hine
et
al.
(
1970)
studied
the
effects
of
varying
concentration
and
duration
of
exposure
in
5
Swiss­
Webster
mice.
Animals
(
n=
5­
14)
were
exposed
to
5­
250
ppm
NO
2
for
durations
of
30
6
minutes
up
to
24
hours.
At
concentrations
of

40
ppm,
signs
of
toxicity
included
lacrimation,
7
reddening
of
the
conjunctivae,
and
increased
respiration
which
became
labored
and
difficult
as
the
8
intoxication
increased.
Mortalities
were
first
observed
at
50
ppm
for
24
hours
(
Table
3).
Terminally,
9
respiration
became
gasping
and
spasmodic
and
lung
edema
was
observed
at
necropsy.
Histological
10
observations
of
the
lungs
following
deaths
were
characterized
by
bronchiolitis,
desquamated
bronchial
11
epithelium,
infiltration
by
polymorphonuclear
cells,
and
edema.
12
13
14
Table
3:
Summary
of
NO2
Mortality
for
Five
Species
15
Conc.
16
(
ppm)
17
Time
(
hr)
C
×
t
(
ppm­
hr)
Rat
Mouse
Guinea
Pig
Rabbit
Dog
50
18
1
6
24
50
300
1200
0/
17
0/
12
3/
10
0/
5
0/
5
5/
10
1/
6
4/
6
­
0/
4
0/
4
­
0/
1
0/
2
­

75
19
1
2
4
8
75
150
300
600
3/
31
1/
12
7/
12
12/
12
1/
6
2/
6
5/
6
6/
6
1/
4
3/
4
2/
4
4/
4
1/
8
0/
6
2/
8
6/
8
0/
2
0/
2
1/
3
1/
4
100
20
0.5
2
4
8
50
200
400
800
0/
5
8/
8
29/
29
­
2/
10
13/
14
10/
10
10/
10
1/
2
3/
4
­
­
1/
3
2/
4
3/
4
­
0/
2
1/
3
2/
2
­

150
21
0.5
1
2
4
75
150
300
600
2/
10
10/
13
10/
12
4/
4
­
­
­
­
3/
4
­
3/
3
­
­
1/
6
­
3/
4
­
2/
3
­
­

200
22
0.08
0.17
0.33
0.50
16.7
33.3
66.7
100
6/
12
8/
12
5/
5
4/
4
4/
6
6/
6
6/
6
­
2/
2
­
­
­
0/
2
1/
2
2/
4
­
­
­
2/
2
­

23
Data
from
Hine
et
al.,
1970,
p.
206;
deaths
generally
occurred
within
2­
8
hours
after
exposure
and
the
majority
within
24
hours.
24
25
26
3.2.
Nonlethal
Toxicity
27
3.2.1.
Monkeys
28
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Squirrel
monkeys
(
n
=
2­
6/
group)
were
exposed
to
10­
50
ppm
NO
2
for
2
hours
with
1
respiratory
function
monitored
during
exposure
(
Henry
et
al.,
1969).
Exposure
to
35
or
50
ppm
2
resulted
in
a
markedly
increased
respiratory
rate
and
decreased
tidal
volume
during
exposures
which
3
returned
to
normal
by
the
seventh
day
post
exposure.
Only
slight
effects
on
respiratory
function
were
4
noted
at
15
and
10
ppm.
Mild
histopathological
changes
in
the
lungs
were
noted
after
exposure
to
5
10
and
15
ppm,
however,
marked
changes
in
lung
structure
were
observed
after
exposure
to
35
and
6
50
ppm.
At
35
ppm,
areas
of
the
lung
were
collapsed
with
basophilic
alveolar
septa,
in
other
areas
7
the
alveoli
were
expanded
with
septal
wall
thinning,
and
the
bronchi
were
moderately
inflamed
with
8
some
proliferation
of
the
surface
epithelium.
At
50
ppm,
extreme
vesicular
dilatation
of
alveoli
or
9
total
collapse
was
observed,
lymphocyte
infiltration
was
seen
with
extensive
edema,
and
surface
10
erosion
of
the
epithelium
of
the
bronchi
was
observed.
In
addition
to
the
effects
on
the
lungs,
11
interstitial
fibrosis
(
35
ppm)
and
edema
(
50
ppm)
of
cardiac
tissue,
glomerular
tuft
swelling
in
the
12
kidney
(
35
and
50
ppm),
lymphocyte
infiltration
in
the
kidney
and
liver
(
50
ppm),
and
congestion
and
13
centrilobular
necrosis
in
the
liver
(
50
ppm)
were
observed.
14
15
3.2.2.
Dogs
16
17
Carson
et
al.
(
1962)
conducted
a
series
of
experiments
on
dogs
(
strain
not
specified;
n
=
2)
18
at
target
concentrations
of
NO
2
approximately
50%
and
25%
of
the
LC
50
for
the
rat
(
see
Sec.
3.1.5).
19
The
actual
analyzed
concentrations
varied
slightly,
but
were
within
10%
of
target.
For
the
50%
20
concentrations,
dogs
exposed
to
164
ppm
for
5
minutes,
85
ppm
for
15
minutes,
or
53
ppm
for
60
21
minutes
had
some
respiratory
distress
during
exposure,
a
mild
cough,
and
eye
irritation
all
of
which
22
cleared
within
two
days
after
exposure.
At
approximately
25%
of
the
rat
LC
50,
dogs
exposed
to
125
23
ppm
for
5
minutes,
52
ppm
for
15
minutes,
or
39
ppm
for
60
minutes
showed
only
mild
sensory
24
effects.
No
gross
or
microscopic
lesions
were
noted
in
any
dog.
25
26
Greenbaum
et
al.
(
1967)
exposed
mongrel
dogs
(
n
=
1)
to
0.1%
(
1000
ppm)
NO
2
for
136
27
minutes
or
to
0.5%
(
5000
ppm)
for
5­
45
minutes.
A
concentration
of
0.1%
did
not
cause
death
and
28
the
one
dog
exposed
to
this
concentration
remained
in
good
condition
throughout
the
exposure.
29
Exposures
to
0.5%
for
15
and
22
minutes
were
not
lethal
but
resulted
in
respiratory
distress
which
30
gave
rise
to
anxiety
for
about
2
hours
then
resolved
without
therapy.
Histopathologic
examination
31
of
the
lungs
was
not
performed
after
sacrifice.
32
33
No
treatment­
related
changes
in
behavior
or
clinical
signs
were
observed
in
mongrel
dogs
(
n
34
=
1)
exposed
to
10­
40
ppm
NO
2
for
6
hours
(
Henschler
and
Lütke,
1963).
35
36
Mongrel
dogs
(
number
of
animals
not
stated)
exposed
to
20
ppm
NO
2
for
up
to
24
hours
37
showed
minimal
signs
of
irritation
and
changes
in
behavior.
Microscopic
lesions
were
described
as
38
questionable
evidence
of
lung
congestion
and
interstitial
inflammation
for
up
to
48
hours
39
postexposure
(
Hine
et
al.,
1970).
40
41
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Pulmonary
ultrastructural
changes
were
examined
in
beagle
dogs
(
n
=
1)
exposed
to
3­
16
ppm
1
NO
2
for
1
hour
(
Dowell
et
al.,
1971).
Intraalveolar
edema
occurred
in
most
dogs
exposed
to

7
ppm
2
and
was
associated
with
impaired
surfactant
activity
and
lung
compliance.
Ultrastructural
alterations
3
included
wide­
spread
bleb
formation,
loss
of
pinocytic
vesicles,
and
mitochondrial
swelling
of
4
endothelial
cells.
Exposure
to
3
ppm
resulted
in
bleb
formation
in
the
alveolar
endothelium
(
observed
5
by
EM)
without
biochemical
or
physiological
changes.
6
7
3.2.3.
Rabbits
8
9
Rabbits
(
strain
not
specified;
number
of
animals
not
given)
exposed
to
20
ppm
NO
2
for
up
to
10
24
hours
showed
minimal
signs
of
irritation
and
changes
in
behavior.
Microscopic
lesions
were
11
described
as
questionable
evidence
of
lung
congestion
and
interstitial
inflammation
for
up
to
48
hours
12
postexposure
(
Hine
et
al.,
1970).
13
14
Rabbits
exposed
to
10
ppm
NO
2
for
2
hours
showed
accelerated
alveolar
particle
clearance
15
(
Vollmuth
et
al.,
1986)
and
altered
pulmonary
arachidonic
acid
metabolism
(
Schlesinger
et
al.,
1990).
16
Continuous
exposure
of
rabbits
to
3.6
ppm
NO
2
for
6
days
did
not
cause
morphological
changes
in
17
the
lungs
(
Hugod,
1979).
18
19
3.2.4.
Sheep
20
21
Lung
mechanics,
hemodynamics,
and
blood
chemistries
were
assessed
in
crossbred
sheep
(
n
22
=
5­
6)
exposed
by
nose­
only
or
lung­
only
(
to
mimic
mouth
breathing)
to
500
ppm
NO
2
for
15
23
minutes;
in
another
group
also
exposed
by
lung­
only,
bronchoalveolar
lavage
fluid
content
was
24
examined
after
a
20
minute
exposure
to
500
ppm
(
Januszkiewicz
and
Mayorga,
1994).
No
changes
25
in
hemodynamics
or
blood
chemistries
occurred
in
either
group.
Mean
inspired
minute
ventilation
26
was
significantly
increased,
resulting
in
increased
breathing
rate
and
decreased
mean
tidal
volume,
27
in
the
lung­
only
exposure
group,
but
not
the
nose­
only
group.
Both
nose­
only
and
lung­
only
28
exposure
groups
had
significantly
increased
lung
resistance
and
decreased
dynamic
lung
compliance.
29
Histopathologic
examination
of
tissue
from
the
lung­
only
exposed
group
revealed
exudative
fluid
30
distributed
in
a
patchy
lobular
pattern
with
mild
neutrophil
infiltration;
little
evidence
of
exudation
31
was
seen
in
the
nose­
only
exposed
group.
Epithelial
cell
number
and
total
protein
in
bronchoalveolar
32
lavage
fluid
were
significantly
increased
in
the
NO
2
exposed
animals
while
macrophage
number
was
33
decreased.
34
35
Airway
reactivity
to
aerosolized
carbachol
was
evaluated
in
crossbred
sheep
(
n
=
4­
10)
36
exposed
to
7.5
or
15
ppm
NO
2
for
2
hours
(
Abraham
et
al.,
1980).
Group
means
for
pulmonary
37
resistance,
bronchial
reactivity
to
carbachol,
or
static
lung
compliance
were
not
different
from
38
controls
at
either
concentration.
However,
following
exposure
to
7.5
ppm
NO
2,
5
of
9
animals
39
showed
an
increase
in
pulmonary
resistance
after
carbachol
exposure
of
57%
above
baseline
and
40
following
exposure
to
15
ppm
NO
2,
9
of
10
animals
responded
with
either
bronchoconstriction
or
41
hyperreactivity.
In
a
concurrent
experiment,
sheep
were
exposed
to
15
ppm
NO
2
for
4
hours
42
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(
Abraham
et
al.,
1980).
Mean
pulmonary
resistance
was
significantly
increased
from
the
preexposure
1
value,
but
there
were
no
changes
in
pulmonary
hemodynamics
or
clinical
signs
of
distress.
2
3
3.2.5.
Guinea
Pigs
4
5
Guinea
pigs
(
strain
not
specified;
number
of
animals
not
given)
exposed
to
20
ppm
NO
2
for
6
up
to
24
hours
showed
minimal
signs
of
irritation
and
changes
in
behavior.
Microscopic
lesions
were
7
described
as
questionable
evidence
of
lung
congestion
and
interstitial
inflammation
for
up
to
48
hours
8
postexposure
(
Hine
et
al.,
1970).
Guinea
pigs
exposed
to
9
and
13
ppm
for
2
hours
or
to
5.2
and
6.5
9
ppm
for
4
hours
had
significantly
increased
respiratory
rate
and
decreased
tidal
volume
with
complete
10
recovery
after
cessation
of
exposure
(
Murphy
et
al.,
1964).
11
12
Hartley
guinea
pigs
(
n
=
5­
16)
maintained
on
an
ascorbic
acid­
deficient
diet
had
increased
lung
13
lavage
fluid
protein
following
exposure
to
4.8
ppm
NO
2
for
3
hours
and
increased
wet
lung
weight,
14
increased
nonprotein
sulfhydryl
and
ascorbic
acid
content
of
the
lungs,
and
decreased
 ­
tocopherol
15
content
of
the
lungs
following
exposure
to
4.5
ppm
for
16
hours.
These
changes
were
not
seen
in
16
animals
maintained
on
normal
guinea
pig
diets
(
Hatch
et
al.,
1986).
17
18
Guinea
pigs
(
strain
not
specified;
n
=
12­
18)
were
exposed
to
20,
40,
or
70
ppm
NO
2
for
30
19
minutes
followed
by
a
30­
minute
exposure
to
aerosolized
albumin;
this
regimen
was
repeated
5­
7
20
times
at
intervals
of
several
days
(
Matsumura,
1970).
During
the
first
exposure
to
70
ppm,
labored
21
breathing,
though
not
severe,
was
observed
in
"
some"'
animals,
but
was
not
seen
with
subsequent
22
exposures.
Immediately
after
the
fifth
exposure
to
antigen,
one­
half
of
the
animals
in
the
70
ppm
23
group
showed
enhanced
airway
sensitization
(
anaphylactic
attacks).
No
effects
were
seen
at
20
or
24
40
ppm.
25
26
Changes
in
airway
responsiveness
to
histamine
were
investigated
in
Hartley
guinea
pigs
27
(
number
of
animals
not
given)
exposed
to
7­
146
ppm
NO
2
for
1
hour
(
Silbaugh
et
al.,
1981).
28
Pulmonary
function
measurements
and
histamine
challenge
tests
were
performed
2
hours
before
and
29
at
about
10
minutes,
2
and
19
hours
after
NO
2
exposure.
At
10
minutes
after
exposure,
increased
30
sensitivity
to
histamine
occurred
at
concentrations

40
ppm
but
returned
to
baseline
thereafter.
31
Concentration­
related
significantly
increased
breathing
frequencies
and
decreased
tidal
volumes
were
32
measured
at
10
minutes
(
exact
concentrations
not
specified)
and
remained
correlated
with
33
concentration
at
2
and
19
hours.
34
35
3.2.6.
Hamsters
36
37
Syrian
golden
hamsters
(
n
=
5)
were
administered
28
ppm
NO
2
for
6,
24,
or
48
hours
and
the
38
histopathological
changes
in
the
lungs
were
examined
by
light
and
electron
microscopy
(
Case
et
al.,
39
1982;
Gordon
et
al.,
1983).
The
bronchiolar
epithelium
showed
ciliary
loss
and
surface
membrane
40
damage,
loss
of
ciliated
cells,
and
epithelial
flattening
at
24
and
48
hours
and
epithelial
hyperplasia,
41
nonciliated
cell
hypertrophy,
and
loss
of
tight
junctions
between
type
I
pneumocytes
at
48
hours.
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3.2.7.
Ferrets
1
2
Weanling
domestic
ferrets
(
n
=
4­
6),
6
weeks
of
age,
were
exposed
to
5,
10,
15,
or
20
ppm
3
NO
2
for
4
hours
(
Rasmussen,
1992).
A
transient
inflammatory
response
was
evident
as
a
significantly
4
increased
number
of
neutrophils
in
the
lavage
fluid
up
to
48­
hours
postexposure
to
all
concentrations.
5
Morphometrically,
a
dose­
related
decreased
alveolar
size
and
thickened
alveolar
walls
indicative
of
6
exposure
were
observed
in
the
lungs.
7
8
3.2.8.
Rats
9
10
Pulmonary
injury
from
NO
2
as
indicated
by
increases
in
lung
weights
was
assessed
in
male
11
Fischer
344
rats
(
n
=
6­
12)
following
exposure
to
10,
25,
or
50
ppm
for
5,
15,
or
30
minutes
or
to
12
100
ppm
for
5
or
15
minutes
(
Stavert
and
Lehnert,
1990).
No
significant
changes
in
lung
weight
13
occurred
in
rats
exposed
to
10
ppm
for
30
minutes
or
to
25­
50
ppm
for
up
to
15
minutes.
Significant
14
increases
in
lung
wet
weight
and
right
cranial
lobe
dry
weight
were
found
following
exposure
to
50
15
ppm
for
30
minutes
or
to
100
ppm
for
5
and
15
minutes.
However,
histological
evidence
of
lung
16
injury
was
seen
in
animals
exposed
to
25
ppm
for
30
minutes,
50
ppm
for

5
minutes,
and
100
ppm
17
for
5
and
15
minutes.
This
was
described
as
accumulation
of
fibrin,
increased
numbers
of
18
polymorphonuclear
leukocytes
and
macrophages,
extravasated
erythrocytes,
and
type
II
pneumocyte
19
hyperplasia
the
severity
of
which
increased
with
concentration
and
duration
of
exposure.
20
21
In
a
more
expanded
study,
Lehnert
et
al.
(
1994)
determined
that
exposure
concentration
was
22
more
important
than
exposure
duration
in
the
severity
of
lung
injury.
Male
Fischer
344
rats
(
n
=
8­
23
12)
were
exposed
to
25,
50,
75,
100,
150,
200,
or
250
ppm
NO
2
for
durations
ranging
from
5­
30
24
minutes.
Lung
wet
weights
were
significantly
increased
following
exposures
to

150
ppm
for
5
25
minutes,
100
ppm
for
15
minutes,
and
75
ppm
for
30
minutes
and
further
increases
were
observed
26
as
exposure
duration
increased.
The
pulmonary
edematous
response
to
a
given
concentration
was
27
not
proportional
to
duration,
however,
increasing
concentrations
produced
proportional
increases
in
28
lung
wet
weight
when
similar
exposure
durations
were
compared.
Histologically,
fibrin
and
type
II
29
cell
hyperplasia
were
observed
following
5­
minute
exposures
to

50
ppm
the
severity
of
which
30
increased
proportionally
to
concentration.
As
further
confirmation
of
concentration­
dependent
lung
31
injury,
rats
were
exposed
to
1­
minute
bursts
of
500­
2000
ppm.
The
severity
of
the
resulting
32
pulmonary
edema
(
as
measured
by
lung
wet
weight)
was
directly
proportional
to
exposure
33
concentration.
The
authors
concluded
that
brief
exposures
to
the
high
concentrations
of
NO
2
are
34
more
injurious
than
longer
duration
exposures
to
lower
concentrations.
Dietary
taurine
(
an
35
antioxidant)
was
not
protective
against
the
increase
in
lung
wet
weight
and
exercise
potentiated
the
36
severity
of
the
pulmonary
edema.
37
38
The
concentration­
dependent
response
of
the
lung
to
NO
2
was
confirmed
in
another
study
in
39
which
Sprague­
Dawley
rats
(
n
=
5­
6)
were
exposed
to
3.6­
14.4
ppm
for
durations
of
6­
24
hours/
day
40
for
3
days
(
Gelzleichter
et
al.,
1992).
Increases
in
protein
content
and
cell
types
in
lavage
fluid
41
demonstrated
that
the
magnitude
of
lung
injury
was
a
function
of
exposure
concentration.
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Carson
et
al.
(
1962)
conducted
a
series
of
experiments
at
NO
2
concentrations
approximating
1
50%,
25%,
and
15%
of
the
rat
LC
50
levels.
At
the
50%
level,
rats
(
strain
not
specified;
n
=
30)
2
exposed
to
190
ppm
for
5
minutes,
90
ppm
for
15
minutes,
or
72
ppm
for
60
minutes
showed
signs
3
of
severe
respiratory
distress
and
eye
irritation
lasting
about
two
days;
lung­
to­
body
weight
ratios
4
were
significantly
increased
during
the
first
48
hours
after
exposure.
Pathological
examination
5
showed
darkened
areas
of
the
lungs,
pulmonary
edema,
and
an
increased
incidence
of
chronic
murine
6
pneumonia.
Rats
exposed
to
104
ppm
for
5
minutes,
65
ppm
for
15
minutes,
and
28
ppm
for
60
7
minutes
(
about
25%
of
the
LC
50
s)
showed
some
respiratory
distress
or
mild
signs
of
nasal
irritation
8
during
exposure
but
lung­
to­
body
weight
ratios
were
increased
only
at
the
104
and
65
ppm
levels.
9
No
gross
lesions
were
observed,
but
pulmonary
edema
was
seen
microscopically.
No
adverse
clinical
10
signs
of
toxicity
or
pathological
changes
were
seen
in
rats
exposed
at
15%
of
the
LC
50
(
74
and
33
11
ppm
for
5
and
15
minutes,
respectively).
12
13
Histological
changes
in
the
lungs
of
male
rats
(
strain
not
specified;
number
of
animals
not
14
given)
exposed
to
17
ppm
NO
2
were
examined
during
continuous
exposure
(
Stephens
et
al.,
1972).
15
After
2
hours
of
exposure,
there
was
some
precapillary
and
postcapillary
engorgement
in
the
alveoli.
16
Loss
of
cilia
and
occasional
alveolar
type
I
cell
swelling
were
detectable
by
4
hours,
the
terminal
17
bronchiolar
epithelium
had
become
uniform
by
16
hours,
maximal
macrophage
numbers
were
reached
18
by
24
hours,
cellular
hypertrophy
had
begun
by
48
hours,
and
mitotic
figures
became
more
prevalent
19
in
the
epithelium
of
the
terminal
bronchiole
between
16
and
48
hours.
Type
I
alveolar
cells
appeared
20
to
be
the
most
sensitive
to
NO
2
insult.
21
22
Results
similar
to
those
described
above
were
obtained
in
a
morphological
study
of
the
Wistar
23
rat
lung
(
number
of
animals
not
given)
following
exposure
to
20
ppm
NO
2
for
20
hours
(
Hayashi
et
24
al.,
1987).
Cytoplasmic
blebbing
occurred
in
a
small
number
of
type
I
cells
immediately
after
25
exposure.
Swelling
and
hyperplasia
of
type
II
cells
and
pinocytotic
vesicles
of
endothelial
cells
in
26
capillaries
followed
by
interstitial
edema
in
the
alveolar
walls
were
observed
between
days
5­
15
27
postexposure.
Twenty
days
after
exposure
the
lesions
lessened
and
the
lungs
appeared
normal
after
28
35
days.
Other
studies
have
confirmed
alveolar
and
interstitial
edema,
bronchiolitis,
bronchiolar
29
epithelial
cell
hyperplasia,
loss
of
cilia,
necrosis
of
type
I
cells,
and/
or
type
II
cell
hyperplasia
1­
3
days
30
after
exposure
to
26
ppm
NO
2
for
24
hours
(
Schnizlein
et
al.,
1980;
Hillam
et
al.,
1983)
or
to
20
ppm
31
for
24
hours
(
Rombout
et
al.,
1986).
32
33
Long­
Evans
rats
(
number
of
animals
not
given)
exposed
to
20
ppm
NO
2
for
up
to
24
hours
34
showed
minimal
signs
of
irritation
and
changes
in
behavior.
Microscopic
lesions
were
described
as
35
questionable
evidence
of
lung
congestion
and
interstitial
inflammation
for
up
to
48
hours
36
postexposure
(
Hine
et
al.,
1970).
37
38
The
effects
of
NO
2
on
the
lung
were
compared
between
Sprague­
Dawley
neonatal
and
adult
39
rats
(
number
of
animals
not
given).
Animals,
1­
40
days
old,
were
continuously
exposed
to
14
ppm
40
for
24,
48,
or
72
hours.
Prior
to
weaning
(
20
days
old),
exposure
resulted
in
only
minor
injury
and
41
loss
of
cilia
from
epithelial
cells
lining
the
terminal
airways.
Subsequent
to
weaning,
there
was
a
42
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progressive
increase
in
lung
injury
with
maximum
response
reached
at
about
35
days
of
age
(
Stephens
1
et
al.,
1978).
2
3
In
a
similar
study
to
determine
the
sensitivity
of
adult
and
neonate
animals
to
NO
2
inhalation,
4
Wistar
rats
(
number
of
animals
not
given)
aged
5­
60
days
were
exposed
continuously
for
3
days
to
5
2
or
10
ppm
(
Azoulay­
Dupuis
et
al.,
1983).
Litter
exposures
prior
to
weaning
included
the
dam.
No
6
clinical
signs
of
toxicity
or
deaths
were
observed
in
animals
of
any
age
except
for
body
weight
loss
7
in
dams
of
the
10
ppm­
group.
At
2
ppm,
lung
histopathology
was
normal
in
all
animals.
At
10
ppm
8
in
animals
45
days
old
and
older,
fibrinous
deposits
were
observed
in
the
alveoli
and
the
tracheal
and
9
bronchiolar
epithelia
were
occasionally
devoid
of
cilia.
10
11
Alterations
in
lavage
fluid
have
been
assessed
in
male
Long
Evans
rats
(
n
=
6)
following
12
exposure
to
10,
20,
30,
or
40
ppm
for
4
hours.
Cell­
free
lavage
fluid
contained
elevated
lactate
13
dehydrogenase
(
LDH),
malate
dehydrogenase
(
MDH),
isocitrate
dehydrogenase
(
IDH),
glucose­
6­
14
phosphate
dehydrogenase
(
GDH),
acid
phosphatase
(
AP),
and
aryl
sulfatase
(
AS)
after
exposure
to
15

30
ppm.
Total
protein
and
sialic
acid
were
increased
after
exposure
to

20
ppm.
Protein,
AP,
and
16
sialic
acid
concentrations
were
similar
to
plasma
indicating
transudation
into
the
airways
(
Guth
and
17
Mavis,
1985).
The
increases
in
LDH,
MDH,
and
GDH
were
significantly
attenuated
in
animals
18
maintained
on
diets
providing
1000
mg/
kg
of
 ­
tocopherol,
suggesting
that
lipid
peroxidation
is
19
involved
in
NO
2
induced
lung
injury
(
Guth
and
Mavis,
1986).
Antioxidants
in
the
lung
were
depleted,
20
lipid
peroxidation
products
were
elevated,
and
total
cell
count
in
BALF
and
alveolar
macrophage
21
count
were
decreased
while
epithelial
cell
count
was
increased
following
exposure
of
male
Sprague­
22
Dawley
rats
(
n
=
5)
to
200
ppm
for
15
minutes
(
Elsayed
et
al.,
2002).
Another
study
found
changes
23
in
fatty
acid
composition
of
alveolar
lavage
phospholipids
following
exposure
of
Wistar
rats
(
n
=
6)
24
to
20
ppm
NO
2
for
12
hours
(
Kobayashi
et
al.,
1984).
Increases
in
lavageable
protein,
25
polymorphonuclear
lymphocytes,
and
alveolar
macrophages
were
also
observed
following
exposure
26
of
male
Fischer
344
rats
(
n
not
given)
to
100
ppm
for
15
minutes
(
Lehnert
et
al.,
1994).
27
28
Changes
in
minute
ventilation,
V
E,
were
measured
in
male
Fischer
344
rats
(
n
=
12)
following
29
exposure
to
100,
300,
or
1000
ppm
NO
2
for
1­
20
minutes
(
Lehnert
et
al.,
1994).
In
general,
30
reductions
in
V
E
were
greater
with
the
higher
concentrations.
For
example,
reductions
of
about
7%
31
and
15%
were
measured
during
15­
and
20­
minute
exposure
to
100
ppm,
while
reduction
of
about
32
20%
and
28%
were
measured
during
1­
and
2­
minute
exposures
to
1000
ppm.
Similarly,
male
33
Sprague­
Dawley
rats
(
n
=
5)
exposed
to
200
ppm
for
15
minutes
showed
a
decrease
in
minute
34
ventilation
that
was
due
to
a
decline
in
tidal
volume
but
not
in
frequency
of
breathing
(
Elsayed
et
al.,
35
2002).
36
37
Male
Porton
rats
(
n
=
4)
were
exposed
to
an
atmosphere
of
oxides
of
nitrogen
that
was
38
produced
by
mixing
nitrogen
dioxide
and
nitric
oxide
(
Brown
et
al.,
1983).
Exposures
were
to
518
39
ppm
for
5
minutes
or
to
1435
ppm
for
1
minute.
No
clinical
signs
of
toxicity
were
observed
during
40
exposure
to
either
concentration
but
"
stertorous
respirations"
appeared
within
24
hours.
41
Histologically,
initial
lung
damage
showed
thickening
and
blebbing
of
the
alveolar
epithelium
followed
42
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by
a
latent
period
of
about
6
hours
after
which
development
of
edema
of
the
interstitium
and
alveolar
1
septum
was
observed.
The
early
changes
were
attributed
to
a
direct
oxidant
effect.
2
3
Changes
in
lung
immunity
have
been
described
as
increased
specific
IgE,
IgA,
and
IgG
titers
4
following
exposure
to
87
ppm
for
1
hour
(
Siegel
et
al.,
1997)
or
5
ppm
for
3
hours
(
Gilmour,
1995),
5
increased
number
of
IgG
anti­
sheep
red
blood
cell
antibody­
forming
cell
in
the
lung­
associated
lymph
6
nodes
(
Schnizlein
et
al.,
1980),
and
cell
proliferation
in
the
spleen
and
thoracic
lymph
nodes
(
Hillam
7
et
al.,
1983)
following
exposure
to
26
ppm
for
24
hours.
8
9
3.2.9.
Mice
10
11
Swiss­
Webster
mice
(
number
of
animals
not
given)
exposed
to
20
ppm
NO
2
for
up
to
24
12
hours
showed
minimal
signs
of
irritation
and
changes
in
behavior.
Histologically,
there
was
13
questionable
evidence
of
lung
congestion
and
interstitial
inflammation
for
up
to
48
hours
14
postexposure
(
Hine
et
al.,
1970).
The
voluntary
running
activity
of
mice
on
an
activity­
wheel
was
15
17%
and
80%
of
preexposure
levels
during
6­
hour
exposures
to
7.7
and
20.9
ppm,
respectively
16
(
Murphy
et
al.,
1964).
17
18
The
alveolar
septum
from
two
female
NMRI
mice
was
examined
microscopically
thirty­
six
19
hours
after
exposure
to
35
ppm
for
6
hours
(
Dillmann
et
al.,
1967).
Morphometric
measurements
20
found
that
the
arithmetic
mean
thickness
of
the
alveoli
was
approximately
1.5x
that
of
unexposed
21
controls.
No
changes
in
the
number
and
types
of
cells
present
were
observed
and
no
interstitial
22
edema
was
seen
with
ultrastructure
examination
by
electron
microscopy.
23
24
Male
CD­
1
mice
(
n
=
5­
9)
were
exposed
to
50­
140
ppm
NO
2
for
1
hour
and
biochemical
and
25
histological
responses
assessed
immediately
and
48­
hours
after
exposure
(
Siegel
et
al.,
1989).
26
Immediately
after
exposure
to
140
ppm,
cell
death
was
visible
in
the
terminal
bronchioles
and
there
27
were
significant
increases
in
protease
inhibitor
activity,
pulmonary
protein,
and
lung
wet
weight.
Two
28
days
after
exposure
to
140
ppm,
the
histological
damage
was
exacerbated
with
complete
obliteration
29
of
the
alveolar
structure,
progressive
edema
and
congestion
of
the
lungs,
hypertrophy
and
hyperplasia
30
of
the
epithelial
cells,
and
increased
numbers
of
intraalveolar
macrophages
and
neutrophils.
Also
two
31
days
after
exposure,
there
were
dose­
related
increases
in
 ­
glucuronidase,
lactate
dehydrogenase,
and
32
choline
kinase
activities
as
well
as
increased
protease
inhibitor
activity,
pulmonary
protein,
and
lung
33
wet
weight.
34
35
To
examine
the
effects
of
NO
2
on
gaseous
exchange
in
the
lung,
JCL:
ICR
mice
(
n
=
6)
were
36
exposed
to
5,
10,
or
20
ppm
for
24
hours
(
Suzuki
et
al.,
1982).
Significantly
increased
lung
wet
37
weight
and
lung
water
content
occurred
at
10
and
20
ppm.
In
animals
exposed
to
5
ppm,
the
gaseous
38
exchange
and
metabolic
rate
of
O
2
and
CO
2
were
accelerated
while
in
animals
exposed
to
10
and
20
39
ppm,
gaseous
exchange
in
the
lung
was
inhibited.
40
41
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Continuous
exposure
of
C56Bl/
6
mice
(
n
=
60)
to
20
ppm
NO
2
for
four
days
resulted
in
1
significantly
decreased
food
consumption
and
body
weight,
but
no
deaths
(
Bouley
et
al.,
1986).
2
3
3.3.
Developmental/
Reproductive
Toxicity
4
5
The
postnatal
effects
of
prenatal
exposure
to
NO
2
were
investigated
(
Tabacova
et
al.,
1985).
6
Pregnant
Wistar
rats
(
n
=
20)
were
exposed
to
0.265,
0.053,
0.53,
or
5.3
ppm
NO
2
for
6
hours/
day
7
throughout
pregnancy.
Maternal
effects
were
not
reported
or
discussed.
Pup
viability
and
body
8
weight
of
the
5.3
ppm­
group
were
significantly
(
p

0.05)
less
than
the
controls
on
lactation
day
21.
9
Exposure
to

0.53
ppm
resulted
in
developmental
delays
and
exposure
to

0.053
ppm
caused
10
disturbances
in
neuromotor
development.
Also
at
the
two
highest
concentrations,
hexobarbital
11
sleeping
time
was
increased
in
the
offspring
and
correlated
with
altered
biochemical
parameters
in
the
12
liver.
13
14
3.4.
Genotoxicity
15
16
Three­
week
old
male
Sprague­
Dawley
rats
were
exposed
by
inhalation
to
8,
15,
21,
or
27
17
ppm
NO
2
for
3
hours,
maintained
overnight
before
sacrifice,
and
lung
cells
isolated.
At
18
concentrations
of

15
ppm,
there
was
a
concentration­
related
increase
in
mutation
to
ouabain
19
resistance
in
lung
cells.
Concentration­
dependent
increases
in
chromosome
aberrations
were
20
observed
from
exposures
to
8
and
27
ppm
NO
2,
the
only
concentrations
analyzed
for
aberrations
21
(
Isomura
et
al.,
1984).
22
23
3.5.
Subchronic
and
Chronic
Toxicity/
Carcinogenicity
24
25
Respiratory
effects
in
humans
from
long­
term
environmental
exposures
to
NO
2
have
been
26
discussed
with
the
epidemiology
studies
in
Section
2.2.2.
27
28
The
effect
of
NO
2
on
promotion
of
lung
tumorigenesis
induced
by
N­
bis(
2­
hydroxypropyl)
29
nitrosamine
(
BHPN)
was
investigated
in
male
Wistar
rats
(
Ichinose
et
al.,
1991).
Animals
were
given
30
a
single
intraperitoneal
injection
of
0.5
g
BHPN/
kg
body
weight
at
6
weeks
of
age
and
exposed
to
31
0.04,
0.4,
or
4.0
ppm
NO
2
for
17
months.
The
incidence
of
pulmonary
tumors
in
rats
exposed
to
32
BHPN
plus
4
ppm
NO
2
was
12.5%
(
n.
s.)
with
adenomas
found
in
4/
40
rats
(
10%)
and
33
adenocarcinomas
found
in
1/
40
rats
(
2.5%).
One
adenoma
was
found
in
the
control
group
(
2.5%)
34
and
one
in
the
0.04
ppm
group,
but
none
in
the
0.4
ppm
group.
In
addition,
marked
bronchiolar
35
mucosal
hyperplasia
was
found
in
17/
40
rats
(
42.5%,
p

0.001)
in
the
BHPN
plus
4.0
ppm
NO
2
36
group.
37
38
3.6.
Summary
39
40
Five­
to
60­
minute
LC
50
values
for
the
rat
ranged
from
416
to
115
ppm,
respectively
in
one
41
study
(
Carson
et
al.,
1962)
and
from
833
to
168
ppm
in
another
study
(
Gray
et
al.,
1954).
The
15­
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minute
LC
50
for
rabbits
was
315
ppm
(
Carson
et
al.,
1962).
In
a
study
using
varying
concentration
1
and
duration
of
exposure,
the
first
mortalities
were
observed
in
dogs
at
75
ppm
for
4
hours,
in
rabbits
2
at
75
ppm
for
1
hour,
in
guinea
pigs
at
50
ppm
for
1
hour,
and
in
rats
and
mice
at
50
ppm
for
24
3
hours
(
Hine
et
al.,
1970).
Histological
alterations
of
the
lungs
following
death
included
bronchiolitis,
4
desquamated
bronchial
epithelium,
infiltration
by
polymorphonuclear
cells,
and
edema.
Enhanced
5
susceptibility
to
infection
was
shown
in
monkeys
following
exposure
to
50
ppm
for
2
hours
(
Henry
6
et
al.,
1969)
and
in
mice
following
exposure
to
2
or
3.5
ppm
for
3
hours
(
Ehrlich,
1978).
7
8
Pulmonary
edema
and
histological
alterations
induced
by
exposure
to
NO
2
have
been
9
characterized
in
dogs,
sheep,
guinea
pigs,
hamsters,
rats,
and
mice.
Numerous
studies
in
rats
have
10
confirmed
alveolar
and
interstitial
edema,
bronchiolitis,
bronchiolar
epithelial
cell
hyperplasia,
loss
11
of
cilia,
necrosis
of
type
I
cells,
and/
or
type
II
cell
hyperplasia
1­
3
days
after
exposure
to
26
ppm
NO
2
12
for
24
hours
(
Schnizlein
et
al.,
1980;
Hillam
et
al.,
1983)
or
to
20
ppm
for
20
(
Hayashi
et
al.,
1987)
13
or
24
hours
(
Rombout
et
al.,
1986).
14
15
Neonates
appear
less
sensitive
to
NO
2
than
adult
animals
with
progressive
increases
in
lung
16
injury
and
deaths
seen
in
older
rats
and
guinea
pigs
(
Stephens
et
al.,
1978;
Azoulay­
Dupuis
et
al.,
17
1983).
18
19
20
4.
SPECIAL
CONSIDERATIONS
21
4.1.
Metabolism
and
Disposition
22
23
Total
respiratory
tract
absorption
of
NO
2
by
humans
exposed
to
0.29­
7.2
ppm
for

30
24
minutes
during
quiet
respiration
and
during
exercise
has
been
measured
at
81­
90%
and
91­
92%,
25
respectively
in
healthy
adults
and
72%
and
87%,
respectively
in
asthmatics
(
U.
S.
EPA,
1993).
In
26
monkeys
exposed
to
0.30­
0.91
ppm
NO
2
for
<
10
minutes,
50­
60%
of
the
inspired
gas
has
been
27
shown
to
be
retained
during
quiet
respiration
with
distribution
throughout
the
lungs
(
Goldstein
et
al.,
28
1977).
While
the
isolated
rat
lung,
ventilated
with
5
ppm
for
90
minutes,
retained
36%
of
the
NO
2
29
(
Postlethwait
and
Mustafa,
1981),
the
majority
of
labeled
NO
2
(
exposure
parameters
not
specified)
30
was
retained
by
the
upper
respiratory
tract
of
the
rat
(
Russell
et
al.,
1991).
31
32
Pulmonary
absorption
of
NO
2
has
been
studied
using
in
vivo
and
in
vitro
models.
Uptake
33
appears
to
be
governed
by
the
reaction
between
inhaled
NO
2
and
constituents
of
the
pulmonary
34
surface
lining
layer
to
form
nitrite
(
Postlethwait
and
Bidani,
1990,
1994;
Saul
and
Archer,
1983).
35
NO
2
uptake
is
saturable
with
absorption
proportional
to
inspired
dose
(
Postlethwait
and
Bidani,
1994)
36
and
has
been
shown
to
increase
as
temperature
increases
to
a
maximum
of
10.6
µ
g
NO
2/
min
in
an
37
isolated
lung
model
(
Postlethwait
and
Bidani,
1990).
The
predominant
reaction
in
the
lungs
is
still
38
debated
and
may
involve
hydrogen
abstraction
by
readily
oxidizable
tissue
components
such
as
39
proteins
and
lipids
to
form
nitrous
acid
and
the
nitrite
radical
(
Postlethwait
and
Bidani,
1994)
or
it
40
may
be
reaction
with
water
to
form
nitrous
and
nitric
acids
(
Goldstein
et
al.,
1977).
41
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Distribution
of
inhaled
NO
2
or
its
metabolites
is
via
the
blood
stream
(
Goldstein
et
al.,
1977).
1
Nitrite
formed
in
the
lungs
is
oxidized
to
nitrate
by
interactions
with
RBCs
after
diffusion
into
the
2
vascular
space
(
Postlethwait
and
Mustafa,
1981).
Exposure
of
mice
to
40
ppm
NO
2
produced
slight
3
(
0.2%)
nitrosylhemoglobin
but
no
methemoglobin
(
Oda
et
al.,
1980)
and
an
increase
in
both
nitrite
4
and
nitrate
that
reached
equilibrium
in
10
and
30
minutes,
respectively
(
Oda
et
al.,
1981).
After
5
cessation
of
exposure,
nitrite
had
a
half­
life
of
several
minutes
and
nitrate
had
a
half­
life
of
about
1
6
hour
(
Oda
et
al.,
1981).
Urinary
excretion
of
nitrate
has
been
shown
to
be
linearly
related
to
the
NO
2
7
concentration
administered
via
inhalation
(
Saul
and
Archer,
1983).
8
9
4.2.
Mechanism
of
Toxicity
10
11
NO
2
is
an
irritant
to
the
mucous
membranes
and
may
cause
coughing
and
dyspnea
during
12
exposure.
After
less
severe
exposure,
symptoms
may
persist
for
several
hours
before
subsiding
13
(
NIOSH,
1976).
With
more
severe
exposure,
pulmonary
edema
ensues
with
signs
of
chest
pain,
14
cough,
dyspnea,
cyanosis,
and
moist
rales
heard
on
auscultation
(
NIOSH,
1976;
Douglas
et
al.,
15
1989).
Death
from
NO
2
inhalation
is
caused
by
bronchospasm
and
pulmonary
edema
in
association
16
with
hypoxemia
and
respiratory
acidosis,
metabolic
acidosis,
shift
of
the
oxyhemoglobin
dissociation
17
curve
to
the
left,
and
arterial
hypotension
(
Douglas
et
al.,
1989).
A
characteristic
of
NO
2
intoxication
18
after
the
acute
phase
is
a
period
of
apparent
recovery
followed
by
late­
onset
bronchiolar
injury
that
19
manifests
as
bronchiolitis
fibrosa
obliterans
(
NIOSH,
1976;
NRC,
1977;
Hamilton,
1983;
Douglas
20
et
al.,
1989).
21
22
Toxicity
from
acute
exposure
can
be
described
in
one
of
three
categories:
1)
immediate
death
23
after
very
heavy
exposure,
2)
delayed
symptoms
with
development
of
edema
within
48
hours,
and
24
3)
apparent
recovery
from
immediate
effects
but
later
chronic
chest
disease
of
varying
severity
(
NRC,
25
1977;
Hamilton,
1983).
Morphological
and
biochemical
changes
in
the
lungs
during
these
phases
26
were
studied
in
mice
exposed
to
140
ppm
for
1
hour
(
Siegel
et
al.,
1989).
Immediately
after
27
exposure,
cell
death
was
noted
in
areas
adjacent
to
the
distal
terminal
bronchioles,
and
protease
28
inhibitor
activity,
lung
protein
content,
and
lung
wet
weight
were
significantly
elevated.
Two
days
29
after
exposure,
the
histological
damage
was
exacerbated
with
complete
obliteration
of
the
alvoelar
30
structure,
progressive
edema
and
congestion
of
the
lungs,
hypertrophy
and
hyperplasia
of
the
31
epithelial
cells,
increased
numbers
of
intraalveolar
macrophages
and
neutrophils.
Also
two
days
after
32
exposure,
there
were
dose­
related
increases
in
 ­
glucuronidase,
lactate
dehydrogenase,
and
choline
33
kinase
activities
as
well
as
increased
protease
inhibitor
activity,
pulmonary
protein,
and
lung
wet
34
weight.
Pulmonary
injury
is
characterized
by
loss
of
ciliated
cells,
disruption
of
tight
capillary
35
junctions,
degeneration
of
type
I
cells,
and
proliferation
of
type
II
cells
(
Siegel
et
al.,
1989;
Elsayed,
36
1994).
37
38
The
predominant
reaction
in
the
lungs
involves
hydrogen
abstraction
by
readily
oxidizable
39
tissue
components
such
as
proteins
and
lipids
to
form
nitrous
acid
and
the
nitrite
radical
(
Postlethwait
40
and
Bidani,
1994;
U.
S.
EPA,
1995)
and
reaction
with
water
to
form
nitrous
and
nitric
acids
41
(
Greenbaum
et
al.,
1967;
Goldstein
et
al.,
1977).
This
reaction
can
lead
to
one
mechanism
by
which
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34
NO
2
causes
pulmonary
injury,
lipid
peroxidation.
NO
2
is
a
free
radical
that
can
attack
unsaturated
1
fatty
acids
in
the
cell
membrane
forming
carbon
and
oxygen
centered
radicals
in
a
chain
reaction
2
(
Ainslie,
1993;
Elsayed,
1994;
U.
S.
EPA,
1995).
This
theory
is
supported
by
studies
on
the
effects
3
of
antioxidants
on
NO
2
exposure
in
humans
and
animals.
Four­
week
supplementation
with
vitamins
4
C
and
E
before
exposure
to
4
ppm
for
3
hours
resulted
in
a
marked
decrease
in
the
amount
of
5
conjugated
dienes
and
attenuated
the
decrease
in
elastase
inhibitory
capacity
in
the
alveolar
lining
6
fluid
of
healthy,
human
volunteers
(
Mohsenin,
1991).
Guinea
pigs
maintained
on
an
ascorbic
acid­
7
deficient
diet
had
increased
lung
lavage
fluid
protein
following
exposure
to
4.8
ppm
NO
2
for
3
hours
8
and
increased
wet
lung
weight,
increased
nonprotein
sulfhydryl
and
ascorbic
acid
content
of
the
lungs,
9
and
decreased
 ­
tocopherol
content
of
the
lungs
following
exposure
to
4.5
ppm
for
16
hours.
These
10
changes
were
not
seen
in
animals
maintained
on
normal
guinea
pig
diets
(
Hatch
et
al.,
1986).
Rats
11
exposed
to
30
and
40
ppm
for
4
hours
had
elevations
of
lactate
dehydrogenase
(
LDH),
malate
12
dehydrogenase
(
MDH),
and
glucose­
6­
phosphate
dehydrogenase
(
GDH),
in
lavage
fluid
which
were
13
significantly
attenuated
in
animals
maintained
on
diets
providing
1000
mg/
kg
of
 ­
tocopherol
(
Guth
14
and
Mavis,
1986).
Another
study
found
changes
in
fatty
acid
composition
of
alveolar
lavage
15
phospholipids
following
exposure
of
rats
to
10
ppm
NO
2
for
12
hours
(
Kobayashi
et
al.,
1984).
16
17
4.3.
Oxides
of
Nitrogen
18
19
NO
2
exists
as
an
equilibrium
mixture
of
NO
2
and
N
2
O
4
but
the
dimer
is
not
important
at
20
ambient
concentrations
(
U.
S.
EPA,
1993).
The
two
compounds
are
phase­
related
forms
with
N
2
O
4
21
favored
in
the
liquid
phase
and
NO
2
favored
in
the
gaseous
phase.
An
equilibrium
distribution
is
22
reached
which
favors
the
lowest
energy
state
in
the
phase.
As
a
result
when
N
2
O
4
is
released
it
23
vaporizes
and
dissociates
into
NO
2,
making
it
nearly
impossible
to
generate
a
significant
concentration
24
of
N
2
O
4
at
atmospheric
pressure
and
ambient
temperatures,
without
generating
a
vastly
higher
25
concentration
of
NO
2.
Because
of
this
effect,
almost
no
inhalation
toxicity
data
are
available
on
N
2
O
4.
26
27
Another
oxide
of
nitrogen,
nitric
oxide
(
NO),
is
unstable
in
air
and
undergoes
spontaneous
28
oxidation
to
NO
2.
If
the
exposure
concentration
of
NO
is
not
high
enough
to
be
lethal
due
to
29
methemoglobin
formation,
the
victim
can
recover
completely.
On
the
other
hand,
concentrations
of
30
NO
2
that
are
not
rapidly
lethal
may
cause
more
persistent
effects
and
in
some
cases
cause
death
from
31
pulmonary
edema
after
a
delay
of
several
days
(
NIOSH,
1976).
In
photochemical
smog,
NO
2
absorbs
32
sunlight
of
wavelengths
between
290­
430
nm
and
decomposes
to
NO
and
O
(
U.
S.
EPA,
1993).
If
33
NO
is
of
concern,
reference
should
be
made
to
the
AEGL
technical
support
document
for
nitric
34
oxide.
35
36
4.4.
Other
Relevant
Information
37
4.4.1.
Species
Variability
38
39
Several
studies
indicate
that
there
is
a
size­
dependent
species
sensitivity
to
NO
2
with
larger
40
animals
apparently
less
sensitive
than
smaller
animals
such
as
rodents.
Dogs
showed
only
mild
signs
41
of
irritation
at
concentrations
that
caused
pulmonary
edema
in
rats
(
Carson
et
al.,
1962).
Dogs
also
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survived
exposures
to
1000
ppm
for
136
minutes
and
5000
ppm
for
up
to
22
minutes
(
Greenbaum
1
et
al.,
1967)
and
sheep
survived
exposures
to
500
ppm
for
15­
20
minutes
(
Januszkiewicz
and
2
Mayorga,
1994).
In
contrast,
15­
minute
and
1­
hour
LC
50
values
in
the
rat
ranged
from
201­
420
ppm
3
and
115­
168
ppm,
respectively
(
Gray
et
al.,
1954;
Carson
et
al.,
1962).
Based
on
the
data
available,
4
humans
are
not
more
sensitive
than
larger
laboratory
animals.
For
example,
irritation
was
reported
5
for
humans
exposed
to
30
ppm
for
2
hours
(
Henschler
et
al.,
1960),
in
dogs
exposed
to
20
ppm
for
6
24
hours
(
Hine
et
al.,
1970),
and
in
monkeys
exposed
to
35
ppm
for
2
hours
(
Henry
et
al.,
1969).
7
8
Elsayed
et
al.
(
2002)
examined
species
variability
through
dosimetry;
the
calculated
total
9
inspired
dose
from
experimental
measurements
in
rats
and
sheep
was
compared
to
the
theoretical
10
dose
of
an
average
human.
Whether
normalized
for
body
weight,
lung
volume,
or
alveolar
surface
11
area,
the
total
dose
was
rats
>>
sheep
>
humans.
One
explanation
for
these
differences
is
that,
upon
12
NO
2
exposure,
rats
exhibit
an
immediate
decrease
in
minute
ventilation
due
to
a
decrease
in
tidal
13
volume
with
no
change
in
respiratory
rate
while
the
larger
animals
show
an
increase
in
minute
14
ventilation
due
to
increased
respiratory
rate.
Taking
physiologic
and
anatomical
factors
into
15
consideration,
rats
had
a
much
higher
effective
dose
than
the
larger
animals
(
Elsayed
et
al.,
2002).
16
17
4.4.2.
Susceptible
Populations
18
19
For
chronic,
low­
level
exposures,
U.
S.
EPA
(
1995)
has
identified
two
populations
as
20
potentially
at
risk
from
NO
2
exposure:
children
ages
5­
12
and
persons
with
pre­
existing
respiratory
21
disease.
Conclusions
drawn
from
epidemiology
studies
were
that
children
ages
5­
12
years
old
had
22
an
increased
risk
of
about
20%
for
developing
respiratory
symptoms
and
disease
with
each
increase
23
of
0.015
ppm
in
estimated
2­
week
average
NO
2
exposure
(
mean
weekly
concentrations
in
bedrooms
24
0.008­
0.065
ppm)
and
that
no
evidence
for
increased
risk
was
found
for
infants
<
2
years
old.
This
25
conclusion
is
supported
somewhat
by
animal
data
in
which
adult
animals
were
more
sensitive
than
26
neonates
to
the
effects
of
NO
2
(
Azoulay­
Dupuis
et
al.,
1983;
Stephens
et
al.,
1978).
Reduced
27
ventilatory
reserves
may
prevent
individuals
with
respiratory
disease
from
resuming
normal
activity
28
following
exposure
to
NO
2
(
U.
S.
EPA,
1995).
However,
it
is
not
certain
whether
these
populations
29
are
also
at
particular
risk
from
acute
exposure
scenarios.
30
31
Taken
together,
the
data
summarized
in
section
2.2.3
indicate
that
some
asthmatics
exposed
32
to
0.3­
0.5
ppm
NO
2
may
respond
with
either
subjective
symptoms
or
slight
changes
in
pulmonary
33
function
of
no
clinical
significance.
Also
at
approximately
these
same
concentrations
of
NO
2
some
34
asthmatics
may
show
slight
hyperreactivity
to
a
bronchial
challenge,
but
the
response
is
not
more
35
severe
than
to
NO
2
alone
(
e.
g.
while
some
asthmatics
respond
to
a
bronchial
challenge
and
to
NO
2,
36
the
response
to
the
challenge
is
not
additively
increased
from
prior
exposure
to
NO
2).
In
contrast,
37
some
asthmatics
did
not
respond
to
NO
2
with
changes
in
pulmonary
function
or
symptoms
at
38
concentrations
of
0.5­
4
ppm.
The
responses
of
healthy
individuals
to
NO
2
exposures
are
also
variable
39
with
some,
but
not
all,
having
slight
changes
in
pulmonary
function
following
exposure
to
5
ppm.
40
All
reported
responses
in
both
asthmatic
and
healthy
subjects
at
the
concentrations
discussed
were
41
slight
and
of
questionable
biological
or
clinical
significance.
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Conclusions
regarding
differences
in
susceptibility
between
healthy
and
asthmatic
individuals
1
are
difficult
to
draw
from
the
available
data
because
of
the
high
variability
in
responses
among
both
2
classifications
of
individuals.
There
is
only
one
study
which
has
measured
the
responses
of
both
3
healthy
and
asthmatic
individuals
with
the
same
study
protocol
and
experimental
setup
(
Linn
and
4
Hackney,
1983).
Dose­
response
patterns
are
not
discernable
at
these
low
concentrations
and
clear
5
thresholds
are
not
apparent.
Some
individuals
reported
clinical
symptoms
in
the
absence
of
changes
6
in
pulmonary
function,
while
other
individuals
had
measurable
changes
in
pulmonary
function
tests
7
but
no
symptoms.
One
proposed
explanation
for
the
variability
in
the
responses
of
asthmatics
to
8
inhaled
NO
2
is
the
existence
of
a
subgroup
of
"
responders."
From
one
laboratory,
several
asthmatics
9
were
identified
as
equally
responsive
to
0.3
ppm
in
more
than
one
study
(
Bauer
et
al.,
1985;
1986).
10
However,
the
investigators
could
find
no
common
identifiers
for
these
"
responders"
such
as
degree
11
of
baseline
obstruction
or
their
inherent
airway
reactivity
to
carbachol
or
cold
air
(
Utell,
1989).
12
Although
some
individuals
may
respond
at
concentrations
below
which
others
might
show
a
13
measurable
response,
the
magnitude
of
the
reported
changes
was
not
biologically
or
clinically
14
significant
in
either
asthmatics
or
healthy
individuals.
15
16
4.4.3.
Concentration­
Response
Relationship
17
18
As
discussed
below
for
AEGL­
2
and
­
3
levels,
extrapolations
were
made
to
each
of
the
time
19
points
using
Cn
×
t
=
k
where
n
=
3.5
(
ten
Berge
et
al.,
1986).
The
value
of
n
was
calculated
by
ten
20
Berge
et
al.
based
on
the
data
of
Hine
et
al.
(
1970).
The
large
value
of
n
indicates
that
concentration
21
is
more
important
than
duration
for
the
effects
of
exposure
to
NO
2.
22
23
4.4.4.
Susceptibility
to
infection
24
25
To
determine
the
effects
of
NO
2
on
resistance
to
infection,
squirrel
monkeys
were
challenged
26
with
Klebsiella
pneumoniae
within
24
hour
after
exposure.
No
deaths
occurred
from
exposure
to
27
NO
2
alone,
however,
3/
3
monkeys
died
within
72
hours
after
50
ppm
NO
2
exposure
for
2
hours
28
followed
by
K.
pneumoniae
challenge;
massive
infection
was
present
in
the
lungs
and
other
organs.
29
Exposure
of
monkeys
to
10
ppm
for
2
hours
followed
by
K.
pneumoniae
challenge
3­
5
days
later
did
30
not
result
in
death
of
the
animals,
but
bacteria
were
still
present
in
lung
tissue
at
necropsy
up
to
46
31
days
after
challenge
indicating
reduced
clearence
(
Henry
et
al.,
1969).
32
33
Numerous
studies
have
reported
enhanced
susceptibility
of
mice
to
infectious
agents
following
34
exposure
to
NO
2.
Most
of
these
studies
have
been
reviewed
by
U.
S.
EPA
(
1993)
and
only
a
few
are
35
described
here.
A
single
3­
hour
exposure
to
2.0
or
3.5
ppm
NO
2
enhanced
the
susceptibility
of
three
36
strains
of
mice
to
streptococcal
pneumonia
and
influenza
infection
as
seen
by
excess
mortality
and
37
reduced
survival
time
(
Ehrlich,
1978).
Pulmonary
bacterial
defenses
against
Staphylococcus
aureus
38
were
suppressed
following
exposure
of
Swiss
mice
to
concentrations
of

4
ppm
for
4
hours
(
Jakab,
39
1987).
Significantly
decreased
pulmonary
bactericidal
activity
was
shown
in
Swiss
mice
infected
with
40
S.
aureus
then
exposed
to
7,
9.2,
and
14.8
ppm
NO
2
for
4
hours,
or
exposed
to
2.3
and
6.6
ppm
for
41
17
hours
prior
to
infection.
Histologically
the
lungs
of
mice
exposed
to

9.2
ppm
for
4
hours
showed
42
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vascular
hyperemia
while
those
from
mice
exposed
to

2.3
ppm
for
17
hours
had
minor
vascular
1
hyperemia
and
interstitial
edema
(
Goldstein
et
al.,
1973).
Enhanced
susceptibility
to
infection
was
2
observed
in
CD­
1
mice
exposed
to
5
ppm
for
6
hours/
day
on
two
consecutive
days
prior
to
3
inoculation
with
murine
cytomegalovirus,
followed
by
exposure
to
5
ppm
NO
2
for
6
hours/
day
for
4
four
consecutive
days;
there
was
no
histological
evidence
of
lung
injury
(
Rose
et
al.,
1989).
5
Continuous
exposure
of
mice
to
20
ppm
NO
2
for
4
days
resulted
in
impairment
of
acquired
resistance
6
(
decreased
ED
50)
of
C57Bl/
6
mice
immunized
prior
to
Klebsiella
pneumoniae
challenge
(
Bouley
et
7
al.,
1986).
8
9
Mice
have
also
been
used
extensively
as
a
model
for
immune
function
alterations
following
10
NO
2
exposure.
Decreases
in
splenic
and
thymic
weights,
cellularity,
plaque­
forming
cell
(
PFC)
11
responses,
and
hemagglutinins
(
HA),
along
with
decreased
body
weights,
were
observed
in
C56Bl/
6
12
mice
exposed
to
20
ppm
NO
2
for
48
hours
(
Azoulay­
Dupuis
et
al.,
1985).
Significant
suppression
13
of
primary
antibody
responses
(
HA
and
PFC)
were
also
seen
following
exposure
of
BALB/
c
mice
to
14
20
and
40
ppm
for
12
hours
(
Hidekazu
and
Fujio,
1981).
Other
effects
of
NO
2
on
cellular
and
15
humoral
immunity
have
been
reviewed
by
U.
S.
EPA
(
1993)
but
are
not
relevant
to
derivation
of
16
AEGL
values.
17
18
19
5.
DATA
ANALYSIS
FOR
AEGL­
1
20
21
AEGL­
1
is
the
airborne
concentration
(
expressed
as
parts
per
million
or
milligrams
per
cubic
22
meter
[
ppm
or
mg/
m3])
of
a
substance
above
which
it
is
predicted
that
the
general
population,
23
including
susceptible
individuals,
could
experience
notable
discomfort,
irritation,
or
certain
24
asymptomatic,
non­
sensory
effects.
However,
the
effects
are
not
disabling
and
are
transient
and
25
reversible
upon
cessation
of
exposure.
26
27
5.1.
Summary
of
Human
Data
Relevant
to
AEGL­
1
28
29
The
evidence
indicates
that
some
asthmatics
exposed
to
0.3­
0.5
ppm
NO
2
may
respond
with
30
either
subjective
symptoms
or
slight
changes
in
pulmonary
function
of
no
clinical
significance.
Also
31
at
approximately
these
same
concentrations
of
NO
2
some
asthmatics
may
show
slight
hyperreactivity
32
to
a
bronchial
challenge,
but
the
response
is
not
more
severe
than
to
NO
2
alone
(
e.
g.
while
some
33
asthmatics
respond
to
a
bronchial
challenge
and
to
NO
2,
the
response
to
the
challenge
is
not
additively
34
increased
from
prior
exposure
to
NO
2).
In
contrast,
some
asthmatics
did
not
respond
to
NO
2
at
35
concentrations
of
0.5­
4
ppm.
The
responses
of
healthy
individuals
to
NO
2
exposures
are
also
variable
36
with
some,
but
not
all,
responding
to
5
ppm.
37
38
Kerr
et
al.
(
1978;
1979)
reported
that
7/
13
asthmatics
experienced
slight
burning
of
the
eyes,
39
slight
headache,
chest
tightness,
or
labored
breathing
with
exercise
during
exposure
to
0.5
ppm
for
40
2
hours;
at
this
concentration
the
odor
of
NO
2
was
perceptible
but
the
subjects
became
unaware
of
41
it
after
about
15
minutes.
No
changes
in
any
pulmonary
function
tests
were
found
immediately
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following
the
chamber
exposure
(
Kerr
et
al.,
1978;
1979).
Significant
group
mean
reductions
in
FEV
1
1
(­
17.3%
vs
­
10.0%)
and
specific
airway
conductance
(­
13.5%
vs
­
8.5%)
occurred
in
asthmatics
after
2
exercise
during
exposure
to
0.3
ppm
for
4
hours
and
1/
6
individuals
experienced
chest
tightness
and
3
wheezing
(
Bauer
et
al.,
1985).
The
onset
of
effects
was
delayed
when
exposures
were
by
oral­
nasal
4
inhalation
compared
with
oral
inhalation.
This
delay
may
result
from
scrubbing
within
the
upper
5
airway.
In
a
similar
study,
asthmatics
exposed
to
0.3
ppm
for
30
minutes
at
rest
followed
by
10
6
minutes
of
exercise
had
significantly
greater
reductions
in
FEV
1
(
10%
vs
4%
with
air)
and
partial
7
expiratory
flow
rates
at
60%
of
total
lung
capacity,
but
no
symptoms
were
reported
(
Bauer
et
al.,
8
1986).
In
a
preliminary
study
with
13
asthmatics
exposed
to
0.3
ppm
for
110
minutes,
slight
cough
9
and
dry
mouth
and
throat
and
significantly
greater
reduction
(
11%
vs
7%)
in
FEV
1
occurred
after
10
exercise,
however,
in
a
larger
study,
no
changes
in
pulmonary
function
were
measured
and
no
11
symptoms
were
reported
following
exposure
of
21
asthmatics
to
concentrations
up
to
0.6
ppm
for
12
75
minutes
(
Roger
et
al.,
1990).
The
mean
drop
in
FEV
1
for
asthmatics
during
a
3­
hour
exposure
13
with
intermittent
exercise
to
1
ppm
NO
2
(
2.5%)
was
significantly
greater
than
the
drop
during
air
14
(
1.3%)
exposure
with
intermittent
exercise;
in
BALF,
levels
of
6­
keto­
prostaglandin
1 
were
decreased
15
and
levels
of
thromboxane
B
2
and
prostaglandin
D
2
were
increased
after
NO
2
exposure
(
Jörres
et
al.,
16
1995).
17
18
5.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
1
19
20
Animal
data
relevant
to
derivation
of
AEGL­
1
are
limited.
Slight
irritation
was
noted
in
21
squirrel
monkeys
exposed
to
10
and
15
ppm
for
2
hours
(
Henry
et
al.,
1969)
and
mild
sensory
effects
22
occurred
in
dogs
exposed
to
125
ppm
for
5
minutes,
52
ppm
for
15
minutes,
or
39
ppm
for
60
23
minutes
(
Carson
et
al.,
1962).
24
25
5.3.
Derivation
of
AEGL­
1
26
27
The
study
by
Kerr
et
al.,
(
1978;
1979)
was
considered
the
most
appropriate
to
use
as
the
basis
28
for
AEGL­
1
values.
Exposure
of
asthmatics
to
0.5
ppm
for
2
hours
resulted
in
clinical
signs
but
no
29
changes
in
pulmonary
function.
Therefore,
a
concentration
of
0.5
ppm
was
adopted
for
all
time
30
points
(
Table
4).
The
NAC
agreed
to
the
same
value
for
all
time
points
for
AEGL­
1
because
it
was
31
believed
that
these
effects
would
appear
immediately
and
would
not
progress
in
severity
with
32
continued
exposure.
In
addition,
animal
responses
to
NO
2
exposure
have
demonstrated
a
much
33
greater
dependence
upon
concentration
than
upon
time;
therefore,
extending
the
2­
hour
concentration
34
to
8
hours
should
not
exacerbate
the
human
response.
35
36
TABLE
4.
AEGL­
1
Values
for
Nitrogen
Dioxide
(
ppm
[
mg/
m3])
37
10­
minute
38
30­
minute
1­
hour
4­
hour
8­
hour
0.50
[
0.94]
39
0.50
[
0.94]
0.50
[
0.94]
0.50
[
0.94]
0.50
[
0.94]

40
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1
6.
DATA
ANALYSIS
FOR
AEGL­
2
2
3
AEGL­
2
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m3)
of
a
substance
above
4
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
5
irreversible
or
other
serious,
long­
lasting
adverse
health
effects
or
an
impaired
ability
to
escape.
6
7
6.1.
Summary
of
Human
Data
Relevant
to
AEGL­
2
8
9
Human
data
relevant
to
AEGL­
2
are
limited
but
consistent.
Henschler
et
al.
(
1960)
performed
10
several
experiments
on
healthy,
male
volunteers
and
found
that
exposure
to
30
ppm
for
2
hours
11
caused
definite
discomfort.
Three
individuals
exposed
to
30
ppm
for
2
hours
perceived
an
intense
12
odor
upon
entering
the
chamber
which
quickly
diminished
and
was
completely
absent
after
25­
40
13
minutes.
One
individual
experienced
a
slight
tickling
of
the
nose
and
throat
mucous
membranes
after
14
30
minutes,
the
two
others
after
40
minutes.
From
70
minutes
on,
all
subjects
experienced
a
burning
15
sensation
and
an
increasingly
severe
cough
for
the
next
10­
20
minutes,
but
coughing
decreased
from
16
100
minutes
on.
However,
the
burning
sensation
continued
and
moved
into
the
lower
sections
of
the
17
airways
and
was
finally
felt
deep
in
the
chest.
At
this
time,
marked
sputum
secretion
and
dyspnea
was
18
noted.
Towards
the
end
of
the
exposure,
the
subjects'
condition
was
described
as
bothersome
and
19
barely
tolerable.
A
sensation
of
pressure
and
increased
sputum
secretion
continued
for
several
hours
20
after
cessation
of
exposure
(
Henschler
et
al.,
1960).
In
a
similar
experiment
(
Henschler
and
Lütke,
21
1963)
groups
of
4
or
8
healthy,
male
volunteers
were
exposed
to
10
ppm
for
6
hours
or
to
20
ppm
22
for
2
hours.
All
subjects
upon
entering
the
chamber
noted
the
odor
which
diminished
rapidly.
At
20
23
ppm
minor
scratchiness
of
the
throat
was
felt
after
about
50
minutes
and
3/
8
experienced
slight
24
headaches
towards
the
end
of
the
exposure
period.
25
26
6.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
2
27
28
Several
animal
studies
are
relevant
to
AEGL­
2
derivation.
Hine
et
al.
(
1970)
noted
29
lacrimation,
reddening
of
the
conjunctivae,
and
increased
respiration
in
5
species
exposed
to

40
ppm
30
for
varying
durations.
Lethality
did
not
occur
until
concentrations
and
durations
reached
75
ppm
for
31
4
hours
in
the
dog
and
1
hour
in
the
rabbit,
50
ppm
for
1
hour
in
the
guinea
pig,
and
50
ppm
for
24
32
hours
in
the
rat
and
mouse.
At
20
ppm
for
24
hours,
all
species
showed
minimal
signs
of
irritation
33
and
changes
in
behavior
with
histopathological
lesions
described
as
questionable
evidence
of
lung
34
congestion
and
interstitial
inflammation.
35
36
Exposure
of
monkeys
to
35
ppm
for
two
hours
resulted
in
irritation
as
measured
by
changes
37
in
lung
function
and
microscopic
lesions
in
the
lung
(
Henry
et
al.,
1969).
The
histological
lesions
in
38
the
lung
were
characterized
by
Siegel
et
al.
(
1989)
following
exposure
of
mice
to
140
ppm
for
1
hour.
39
Carson
et
al.
(
1962)
conducted
a
series
of
experiments
in
dogs
and
rats.
Mild
irritation
and
some
40
respiratory
effects,
but
no
gross
or
microscopic
lesions,
were
noted
in
dogs
exposed
to
53
or
39
ppm
41
NITROGEN
DIOXIDE
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40
for
1
hour
while
rats
exposed
to
72
ppm
for
1
hour
showed
signs
of
severe
respiratory
distress
and
1
eye
irritation
as
well
as
gross
lesions
in
the
lung
and
evidence
of
infection.
2
3
Developmental
delays
and
disturbances
in
neuromotor
development
were
reported
for
rat
4
pups
following
maternal
exposure
(
Tabacova
et
al.,
1985).
However,
these
effects
were
reported
to
5
have
occurred
at
levels
near
ambient
concentrations
and
are
well
below
those
of
most
other
studies
6
in
both
humans
and
animals.
7
8
6.3.
Derivation
of
AEGL­
2
9
10
From
both
human
and
animal
data,
it
appears
that
a
concentration
of

30
ppm
NO
2
is
required
11
before
marked
irritation,
discomfort,
and
respiratory
effects
occur.
Therefore,
a
concentration
of
30
12
ppm
for
a
2­
hour
exposure
of
humans
(
Henschler
et
al.,
1960)
was
used
to
derive
AEGL­
2
values.
13
Values
scaled
for
the
derivation
of
the
10­
and
30­
minute
and
1­,
4­,
and
8­
hour
AEGL­
2
endpoints
14
were
calculated
from
Cn
×
t
=
k
using
n
=
3.5
(
ten
Berge
et
al.,
1986).
The
value
of
n
was
calculated
15
by
ten
Berge
et
al.
from
the
data
of
all
species
together
from
Hine
et
al.
(
1970).
An
uncertainty
factor
16
of
3
was
applied
to
account
for
sensitive
subpopulations.
It
is
felt
that
additional
uncertainty
factors
17
are
unnecessary
because
the
experimental
data
at
lower
concentrations
in
asthmatics
and
persons
with
18
respiratory
disease
are
inconclusive
and
the
effects
are
of
questionable
biological
significance.
19
Furthermore,
with
additional
uncertainty
factors
the
values
would
be
inconsistent
with
some
of
the
20
clinical
data
for
asthmatics,
e.
g.,
the
no­
adverse­
effect
concentration
of
4
ppm
in
the
study
by
Linn
21
and
Hackney
(
1984).
Proposed
AEGL­
2
values
are
presented
in
Table
5.
22
23
24
TABLE
5:
AEGL­
2
Values
for
Nitrogen
Dioxide
(
ppm
[
mg/
m3])
25
10­
minute
26
30­
minute
1­
hour
4­
hour
8­
hour
20
[
38]
27
15
[
28]
12
[
23]
8.2
[
15]
6.7
[
13]

28
29
These
levels
are
not
expected
to
cause
severe
effects
as
coal
miners
were
exposed
to
peak
30
NO
2
concentrations
of
14
ppm
without
adverse
consequences
(
Robertson
et
al.,
1984)
and
it
can
be
31
assumed
that
the
peak
levels
were
not
sustained
longer
than
a
few
minutes.
Similar
AEGL­
2
values
32
are
derived
using
the
exposure
of
140
ppm
for
1
hour
in
the
mouse
(
Siegel
et
al.,
1989)
and
an
33
uncertainty
factor
of
10
or
the
exposure
of
35
ppm
for
2
hours
in
the
monkey
(
Henry
et
al.,
1969)
34
and
an
uncertainty
factor
of
3.
If
the
animal
data
from
either
Hine
et
al.
(
1970)
or
Carson
et
al.
35
(
1962)
are
used
for
the
basis
of
derivation,
the
AEGL­
2
values
are
even
more
conservative
than
with
36
the
use
of
human
data.
37
38
39
7.
DATA
ANALYSIS
FOR
AEGL­
3
40
NITROGEN
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41
AEGL­
3
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m3)
of
a
substance
above
1
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
2
life­
threatening
health
effects
or
death.
3
4
7.1.
Summary
of
Human
Data
Relevant
to
AEGL­
3
5
6
A
welder
was
hospitalized
with
pulmonary
edema
after
exposure
to
approximately
90
ppm
7
for
30­
40
minutes
(
Norwood
et
al.,
1966).
It
is
possible
that
without
medical
intervention,
the
8
exposure
could
have
been
fatal.
9
10
Concentrations
of
NO
2
above
150
ppm
are
probably
fatal
to
humans
due
to
bronchospasm
11
and
pulmonary
edema
(
NRC,
1977;
Douglas
et
al.,
1989).
A
human
1­
hour
LC
50
of
174
ppm
was
12
estimated
from
data
in
5
animal
species
(
Book,
1982),
however,
this
is
not
considered
valid
13
experimental
data
on
which
to
base
AEGL­
3.
No
other
human
data
were
relevant
to
derivation
of
14
AEGL­
3.
15
16
7.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
3
17
18
Squirrel
monkeys
(
n
=
2­
6/
group)
were
exposed
to
10­
50
ppm
NO
2
for
2
hours
with
19
respiratory
function
monitored
during
exposure
(
Henry
et
al.,
1969).
NO
2
exposure
alone
resulted
20
in
a
markedly
increased
respiratory
rate
and
decreased
tidal
volume
during
exposures
to
50
and
35
21
ppm,
but
only
slight
effects
at
15
and
10
ppm.
Mild
histopathological
changes
in
the
lungs
were
22
noted
after
exposure
to
10
and
15
ppm,
however,
marked
changes
in
lung
structure
were
observed
23
after
exposure
to
35
and
50
ppm.
At
35
ppm,
areas
of
the
lung
were
collapsed
with
basophilic
24
alveolar
septa,
in
other
areas
the
alveoli
were
expanded
with
septal
wall
thinning,
and
the
bronchi
25
were
moderately
inflamed
with
some
proliferation
of
the
surface
epithelium.
At
50
ppm,
extreme
26
vesicular
dilatation
of
alveoli
or
total
collapse
was
observed,
lymphocyte
infiltration
was
seen
with
27
extensive
edema,
and
surface
erosion
of
the
epithelium
of
the
bronchi
was
observed.
In
addition
to
28
the
effects
on
the
lungs,
interstitial
fibrosis
(
35
ppm)
and
edema
(
50
ppm)
of
cardiac
tissue,
29
glomerular
tuft
swelling
in
the
kidney
(
35
and
50
ppm),
lymphocyte
infiltration
in
the
kidney
and
liver
30
(
50
ppm),
and
congestion
and
centrilobular
necrosis
in
the
liver
(
50
ppm)
were
observed.
31
32
Rats
exposed
to
72
ppm
for
60
minutes
(
approximately
50%
of
the
LD
50)
showed
signs
of
33
severe
respiratory
distress
and
eye
irritation
lasting
about
2
days;
lung­
to­
body
weight
ratios
were
34
significantly
increased
during
the
first
48
hours
after
exposure
(
Carson
et
al.,
1962).
35
36
Lethality
in
5
animal
species
first
occurred
at
exposure
concentrations
and
durations
of
75
37
ppm
for
4
hours
in
the
dog
and
1
hour
in
the
rabbit,
50
ppm
for
1
hour
in
the
guinea
pig,
and
50
ppm
38
for
24
hours
in
the
rat
and
mouse
(
Hine
et
al.,
1970).
In
general,
the
larger
animals,
including
39
humans,
are
less
susceptible
to
toxicity
from
NO
2
inhalation
than
are
the
rodents.
40
41
NITROGEN
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42
7.3.
Derivation
of
AEGL­
3
1
2
The
data
from
the
monkey
are
considered
as
the
best
available
for
derivation
of
AEGL­
3
3
values.
Signs
of
marked
irritation
and
severe
lung
histopathology
were
observed
from
exposure
to
4
50
ppm
for
2
hours.
This
exposure
scenario
was
extrapolated
to
the
10­
and
30­
minute
and
1­
4­,
5
and
8­
hour
time
points
using
the
equation
Cn
×
t
=
k
where
n
=
3.5
(
ten
Berge
et
al.,
1986).
The
6
value
of
n
was
calculated
by
ten
Berge
et
al.
from
the
data
of
all
species
together
from
Hine
et
al.
7
(
1970).
An
uncertainty
factor
of
3
was
applied
to
account
for
sensitive
subpopulations
since
the
data
8
for
asthmatics
and
those
with
respiratory
disease
are
inconclusive.
Because
the
endpoint
in
the
9
monkey
study
is
below
the
definition
of
AEGL­
3
and
due
to
the
similarities
of
the
respiratory
tract
10
between
humans
and
monkeys,
additional
uncertainty
factors
are
not
considered
necessary.
Also,
the
11
mechanism
of
action
of
NO
2
does
not
vary
between
species
with
the
target
at
the
alveoli.
In
general,
12
the
larger
animals,
including
humans,
appear
to
be
less
susceptible
to
NO
2
than
the
rodents.
AEGL­
3
13
values
for
NO
2
are
listed
in
Table
6.
14
15
16
TABLE
6:
AEGL­
3
Values
for
Nitrogen
Dioxide
(
ppm
[
mg/
m3])
17
10­
minute
18
30­
minute
1­
hour
4­
hour
8­
hour
34
[
64]
19
25
[
47]
20
[
38]
14
[
26]
11
[
21]

20
21
The
proposed
AEGL­
3
values
are
supported
by
human
data
from
the
welder.
Pulmonary
22
edema,
confirmed
on
X­
ray,
resulted
from
exposure
to
approximately
90
ppm
for
up
to
40
minutes
23
(
Norwood
et
al.,
1966).
If
this
exposure
scenario
is
used
for
derivation
of
AEGL­
3
values
with
an
24
uncertainty
factory
of
3
the
10­
and
30­
minute
and
1­,
4­,
and
8­
hour
values
are
45,
33,
27,
18,
and
25
15
ppm,
respectively.
Similar
results
are
obtained
using
the
exposure
of
rats
to
72
ppm
for
1
hour
26
(
Carson
et
al.,
1962)
and
an
uncertainty
factor
of
3.
In
addition,
the
proposed
AEGL­
3
values
are
27
below
the
concentrations
at
which
lethality
first
occurred
in
five
animal
species
(
Hine
et
al.,
1970).
28
29
30
8.
SUMMARY
OF
AEGLS
31
8.1.
AEGL
Values
and
Toxicity
Endpoints
32
33
The
derived
AEGL
values
for
various
levels
of
effects
and
durations
of
exposure
are
34
summarized
in
Table
7.
35
NITROGEN
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43
1
TABLE
7:
Summary
of
AEGL
Values
(
ppm
[
mg/
m3])
2
AEGL
Level
3
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
1
4
0.50
[
0.94]
0.50
[
0.94]
0.50
[
0.94]
0.50
[
0.94]
0.50
[
0.94]

AEGL­
2
5
20
[
38]
15
[
28]
12
[
23]
8.2
[
15]
6.7
[
13]

AEGL­
3
6
34
[
64]
25
[
47]
20
[
38]
14
[
26]
11
[
21]

7
8
8.2.
Comparison
with
Other
Standards
and
Criteria
9
10
Standards
and
guidance
levels
for
workplace
and
community
exposures
are
listed
in
Table
8.
11
The
ACGIH
recommends
a
TLV
of
3
ppm
for
workers
(
ACGIH
2003)
while
the
OSHA
PEL
is
a
12
ceiling
of
5
ppm
(
OSHA,
1999).
The
NIOSH
IDLH
is
20
ppm
(
NIOSH,
1996)
which
is
exactly
13
between
the
30­
minute
AEGL­
2
and
AEGL­
3
values.
The
IDLH
is
reported
as
based
on
acute
14
inhalation
data
in
humans,
but
no
primary
references
were
listed
in
the
documentation.
ERPG
(
AIHA
15
2002)
were
under
consideration
but
had
not
been
derived
as
of
2002.
The
NRC's
1­
hour
EEGL
is
16
1
ppm
(
NRC
1985)
for
workplace
conditions.
The
occupational
exposure
limits
from
ACGIH,
17
Germany,
The
Netherlands,
and
Sweden
are
2­
5
ppm.
18
19
In
addition
to
the
standards
listed
in
Table
8,
air
quality
standards
have
also
been
developed
20
for
NO
2.
The
National
Ambient
Air
Quality
Standard
is
0.053
ppm
(
U.
S.
EPA,
1997)
with
21
Significant
Harm
Levels
of
2
ppm
for
a
1­
hour
average
and
0.5
ppm
for
a
24­
hour
average
(
U.
S.
22
EPA,
1987a).
The
Level
of
Concern
is
5
ppm
(
U.
S.
EPA,
1987b).
The
state
of
California
has
23
adopted
0.25
ppm
as
the
standard
for
a
1­
hour
exposure
to
protect
sensitive
individuals
(
Cal.
EPA,
24
1992).
25
26
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TABLE
8.
Extant
Standards
and
Guidelines
for
Nitrogen
Dioxide
1
2
Guideline
3
Exposure
Duration
10
minute
30
minute
1
hour
4
hour
8
hour
AEGL­
1
4
0.50
ppm
0.50
ppm
0.50
ppm
0.50
ppm
0.50
ppm
AEGL­
2
5
20
ppm
15
ppm
12
ppm
8.2
ppm
6.7
ppm
AEGL­
3
6
34
ppm
25
ppm
20
ppm
14
ppm
11
ppm
EEGL
(
NRC)
a
7
1
ppm
0.25
ppm
0.12
ppm
IDLH
(
NIOSH)
b
8
20
ppm
REL­
STEL
(
NIOSH)
c
9
1
ppm
PEL­
STEL
(
OSHA)
d
10
1
ppm
PEL­
TWA
(
OSHA)
e
11
5
ppm
(
C)

TLV­
TWA
(
ACGIH)
f
12
3
ppm
TLV­
STEL
(
ACGIH)
g
13
5
ppm
MAK
(
Germany)
h
14
5
ppm
MAK
Peak
Exposure
15
(
Germany)
i
16
5
ppm
MAC
(
The
17
Netherlands)
j
18
2.0
ppm
OEL­
LLV
(
Sweden)
k
19
2
ppm
OEL­
CLV
(
Sweden)
l
20
5
ppm
21
aEEGL
(
Emergency
Exposure
Guidance
Levels)
National
Research
Council
(
NRC
1985)
22
The
EEGL
is
the
concentration
of
contaminants
that
can
cause
discomfort
or
other
evidence
of
irritation
or
intoxication
23
in
or
around
the
workplace,
but
avoids
death,
other
severe
acute
effects
and
long­
term
or
chronic
injury.
24
25
bIDLH
(
Immediately
Dangerous
to
Life
and
Health,
National
Institute
of
Occupational
Safety
and
Health)
(
NIOSH
26
1996)
represents
the
maximum
concentration
from
which
one
could
escape
within
30
minutes
without
any
escape­
27
impairing
symptoms,
or
any
irreversible
health
effects.
The
IDLH
for
nitrogen
dioxide
is
based
on
acute
inhalation
28
toxicity
data
in
humans
(
Patty,
1963).
29
30
cNIOSH
REL­
STEL
(
Recommended
Exposure
Limits
­
Short
Term
Exposure
Limit)
(
NIOSH
2003)
is
defined
analogous
31
to
the
ACGIH
TLV­
STEL.
32
33
dOSHA
PEL­
STEL
(
Permissible
Exposure
Limits
­
Short
Term
Exposure
Limit)
(
NIOSH
2003)
is
defined
analogous
34
to
the
ACGIH­
TLV­
STEL.
35
36
eOSHA
PEL­
TWA
(
Occupational
Health
and
Safety
Administration,
Permissible
Exposure
Limits
­
Ceiling)
(
OSHA
37
1999)
is
defined
analogous
to
the
ACGIH­
TLV­
TWA,
but
is
for
exposures
of
no
more
than
10
hours/
day,
40
38
hours/
week.
(
C)
denotes
a
ceiling.
39
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
45
fACGIH
TLV­
TWA
(
American
Conference
of
Governmental
Industrial
Hygienists,
Threshold
Limit
Value
­
Time
1
Weighted
Average)
(
ACGIH
2003)
is
the
time­
weighted
average
concentration
for
a
normal
8­
hour
workday
and
2
a
40­
hour
workweek,
to
which
nearly
all
workers
may
be
repeatedly
exposed,
day
after
day,
without
adverse
effect.

34
gACGIH
TLV­
STEL
(
Threshold
Limit
Value
­
Short
Term
Exposure
Limit)
(
ACGIH
2003)
is
defined
as
a
15­
minute
5
TWA
exposure
which
should
not
be
exceeded
at
any
time
during
the
workday
even
if
the
8­
hour
TWA
is
within
the
6
TLV­
TWA.
Exposures
above
the
TLV­
TWA
up
to
the
STEL
should
not
be
longer
than
15
minutes
and
should
not
7
occur
more
than
4
times
per
day.
There
should
be
at
least
60
minutes
between
successive
exposures
in
this
range.

89
hMAK
(
Maximale
Argeitsplatzkonzentration
[
Maximum
Workplace
Concentration])
(
Deutsche
Forschungsgemeinschaft
10
[
German
Research
Association]
2002)
is
defined
analogous
to
the
ACGIH­
TLV­
TWA.
11
12
iMAK
Spitzenbegrenzung
(
Peak
Limit
[
Category
I,
1])
(
German
Research
Association
2002)
constitutes
the
average
13
concentration
to
which
workers
can
be
exposed
for
a
period
up
to
15
minutes
with
no
more
than
1
excursion
per
work
14
shift
and
a
minimum
of
1
hour
between
excursions.
15
16
jMAC
(
Maximaal
Aanvaaarde
Concentratie
[
Maximal
Accepted
Concentration])
(
SDU
Uitgevers
[
under
the
auspices
17
of
the
Ministry
of
Social
Affairs
and
Employment],
The
Hague,
The
Netherlands
2000)
is
defined
analogous
to
the
18
ACGIH­
TLV­
TWA.
19
20
kOEL­
LLV
(
Occupational
Exposure
Limits
­
Level
Limit
Value)
(
Swedish
National
Board
of
Occupational
Safety
and
21
Health,
1996)
is
an
occupational
exposure
limit
value
for
exposure
during
one
working
day.
22
23
lOEL­
CLV
(
Occupational
Exposure
Limits
­
Ceiling
Limit
Value)
(
Swedish
National
Board
of
Occupational
Safety
and
24
Health,
1996)
is
an
occupational
exposure
limit
value
for
exposure
during
a
reference
period
of
fifteen
minutes.
25
26
27
8.3.
Data
Adequacy
and
Research
Needs
28
29
Data
on
the
effects
of
NO
2
on
asthmatics
and
individuals
with
respiratory
disease
was
30
inconsistent
and
inconclusive.
Additional
studies
that
correlate
severity
of
disease
with
individual
31
responses
would
be
helpful.
32
33
34
9.
REFERENCES
35
36
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W.
M.,
Welker,
M.,
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M.,
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J.,
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A.,
and
Sackner,
M.
1980.
37
Cardiopulmonary
effects
of
short­
term
nitrogen
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72.
38
39
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In:
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of
40
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41
42
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2003.
American
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TLVs
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BEIs
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43
Documentation
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Values
for
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44
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46
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48
49
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
46
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2
9
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10
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33
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36
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43
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44
45
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47
48
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49
40
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50
51
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
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15
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35
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day
36
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39
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40
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42
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­
43
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47
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Effect
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48
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49
50
NITROGEN
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1:
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2003
48
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23
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Effects
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2
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16
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17
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18
19
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20
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of
domestic
concentrations
of
nitrogen
dioxide
on
airway
21
responses
to
inhaled
allergen
in
asthmatic
patients.
Lancet
344:
1733­
1736.
22
23
U.
S.
EPA.
1987a.
U.
S.
Environmental
Protection
Agency.
§
51.151
Significant
Harm
Levels,
p.
639.
Subpart
H
­
Prevention
24
of
Air
Pollution
Emergency
Episodes.
40
CFR.
25
26
U.
S.
EPA.
1987b.
U.
S.
Environmental
Protection
Agency.
Technical
Guidance
for
Hazards
Analysis.
Emergency
Planning
27
for
Extremely
Hazardous
Substances.
U.
S.
EPA,
FEMA,
and
U.
S.
DOT,
Washington,
DC.
28
29
U.
S.
EPA.
1990.
U.
S.
Environmental
Protection
Agency.
Health
and
Environmental
Effects
Document
for
Nitrogen
Dioxide.
30
Office
of
Health
and
Environmental
Assessment,
U.
S.
EPA,
Cincinnati,
OH.
133
pp.
31
32
U.
S.
EPA.
1993.
U.
S.
Environmental
Protection
Agency.
Air
Quality
Criteria
for
Oxides
of
Nitrogen,
Vol.
I­
III.
Office
of
33
Research
and
Development,
U.
S.
EPA,
Research
Triangle
Park,
NC.
34
35
U.
S.
EPA.
1995.
U.
S.
Environmental
Protection
Agency.
Review
of
the
National
Ambient
Air
Quality
Standards
for
Nitrogen
36
Dioxide.
Assessment
of
Scientific
and
Technical
Information.
OAQPS
Staff
Paper.
Office
of
Air
Quality,
U.
S.
EPA,
37
Research
Triangle
Park,
NC.
95
pp.
38
39
U.
S.
EPA.
1997.
U.
S.
Environmental
Protection
Agency.
§
50.11
National
Primary
and
Secondary
Ambient
Air
Quality
40
Standards
for
Nitrogen
Dioxide,
p.
8.
40
CFR.
41
42
Utell,
M.
J.
1989.
Asthma
and
nitrogen
dioxide:
A
review
of
the
evidence.
ASTM
STP
1024,
M.
J.
Utell
and
R.
Frank,
Eds.,
43
American
Society
for
Testing
and
Materials,
Philadelphia,
pp.
218­
223.
44
45
Vagaggini,
B.,
Paggiaro,
P.
L.,
Giannini,
D.,
Di
Franco,
A.,
Cianchette,
S.,
Carnevali,
S.,
Taccola,
M.,
Bacci,
E.,
Bancalari,
L.,
46
Dente,
F.
L.,
and
Giuntini,
C.
1996.
Effect
of
short­
term
NO
2
exposure
on
induced
sputum
in
normal,
asthmatic
and
47
COPD
subjects.
Eur.
Respir.
J.
9:
1852­
1857.
48
49
Vollmuth,
T.
A.,
Driscoll,
K.
E.,
and
Schlesinger,
R.
B.
1986.
Changes
in
early
alveolar
particle
clearance
due
to
single
and
50
repeated
nitrogen
dioxide
exposures
in
the
rabbit.
J.
Toxicol.
Environ.
Health
19:
255­
266.
51
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
56
von
Nieding,
G.,
Krekeler,
H.,
and
Fuchs,
R.
1973.
Studies
of
the
acute
effects
of
NO
2
on
lung
function:
influence
on
diffusion,
1
perfusion
and
ventilation
in
the
lungs.
Int.
Arch.
Arbeitsmed.
31:
61­
72.

23
von
Nieding,
G.
and
Wagner,
H.
M.
1979.
Effects
of
NO
2
on
chronic
bronchitics.
Environ.
Health
Perspect.
29:
137­
142.

45
von
Nieding,
G.,
Wagner,
H.
M.,
Krekeler,
H.,
Löllgen,
H.,
Fries,
W.,
and
Beuthan,
A.
1979.
Controlled
studies
of
human
6
exposure
to
single
and
combined
action
of
NO
2,
O
3,
and
SO
2.
Int.
Arch.
Occup.
Environ.
Health
43:
195­
210.
7
8
APPENDIX
A:
Derivation
of
AEGL
Values
1
2
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
58
Derivation
of
AEGL­
1
1
2
3
Key
Study:
Kerr
et
al.,
1978,
1979
4
5
Toxicity
endpoint:
slight
burning
of
the
eyes,
slight
headache,
chest
tightness
or
labored
6
breathing
with
exercise
in
7/
13
asthmatics
exposed
to
0.5
ppm
for
2
hours
7
8
Time
scaling:
Not
applied
9
10
Uncertainty
factors:
None
11
12
Modifying
factor:
None
13
14
Calculations:
None;
0.50
ppm
value
applied
across
AEGL­
1
exposure
durations
15
16
17
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
59
Derivation
of
AEGL­
2
1
2
Key
Studies:
Henschler
et
al.,
1960
3
4
Toxicity
endpoints:
burning
sensation
in
nose
and
chest,
cough,
dyspnea,
sputum
porduction
5
in
normal
volunteers
exposed
to
30
ppm
for
2
hours
6
7
Time
scaling:
C3.5
x
t
=
k;
the
value
of
n
was
calculated
by
ten
Berge
et
al.
(
1986)
from
8
the
data
of
Hine
et
al.
(
1970).
9
10
Uncertainty
factors:
3
for
intraspecies
variability
11
12
Modifying
factor:
None
13
14
Calculations:
C3.5
x
t
=
k
15
(
30
ppm/
3)
3.5
x
2
hours
=
k
16
6324.56
ppm
·
hours
=
k
17
18
10­
minute
AEGL­
2:
C
=
(
6324.56
ppm
·
hours/
0.167
hours)
1/
3.5
19
C
=
20
ppm
20
21
30­
minute
AEGL­
2:
C
=
(
6324.56
ppm
·
hours/
0.5
hour)
1/
3.5
22
C
=
15
ppm
23
24
1­
hour
AEGL­
2:
C
=
(
6324.56
ppm
·
hours/
1
hour)
1/
3.5
25
C
=
12
ppm
26
27
4­
hour
AEGL­
2:
C
=
(
6324.56
ppm
·
hours/
4
hours)
1/
3.5
28
C
=
8.2
ppm
29
30
8­
hour
AEGL­
2:
C
=
(
6324.56
ppm
·
hours/
8
hours)
1/
3.5
31
C
=
6.7
32
33
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
60
Derivation
of
AEGL­
3
1
2
Key
Studies:
Henry
et
al.,
1969
3
4
Toxicity
endpoint:
signs
of
marked
irritation,
but
no
deaths
in
monkeys
exposed
to
50
ppm
5
for
2
hours
6
7
Time
scaling
C3.5
x
t
=
k;
the
value
of
n
was
calculated
by
ten
Berge
et
al.
(
1986)
from
8
the
data
of
Hine
et
al.
(
1970).
9
10
Uncertainty
factors:
3
for
intraspecies
variability
11
12
Modifying
factor:
None
13
14
Calculations:
C3.5
x
t
=
k
15
(
50
ppm/
3)
3.5
x
2
hours
=
k
16
37,801
ppm
·
hours
=
k
17
18
10­
minute
AEGL­
3:
C
=
(
37,801
ppm
·
hours/
0.1667
hours)
1/
3.5
19
C
=
34
ppm
20
21
30­
minute
AEGL­
3:
C
=
(
37,801
ppm
·
hours/
0.5
hours)
1/
3.5
22
C
=
25
ppm
23
24
1­
hour
AEGL­
3:
C
=
(
37,801
ppm
·
hours/
1
hours)
1/
3.5
25
C
=
20
ppm
26
27
4­
hour
AEGL­
3:
C
=
(
37,801
ppm
·
hours/
4
hourss)
1/
3.5
28
C
=
14
ppm
29
30
8­
hour
AEGL­
3:
C
=
(
37,801
ppm
·
hours/
8
hours)
1/
3.5
31
C
=
11
ppm
32
33
APPENDIX
B:
Derivation
Summary
for
AEGL
Values
1
for
Nitrogen
Dioxide
2
(
CAS
No.
10102­
44­
0)
3
4
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
62
AEGL­
1
VALUES
1
10
minute
2
30
minute
1
hour
4
hour
8
hour
0.50
ppm
3
0.50
ppm
0.50
ppm
0.50
ppm
0.50
ppm
Key
Reference:
Kerr,
H.
D.,
Kulle,
T.
J.,
McIlhany,
M.
L.,
and
Swidersky,
P.
1978.
Effects
4
of
nitrogen
dioxide
on
pulmonary
function
in
human
subjects.
An
5
environmental
chamber
study.
Report:
ISS
EPA/
600/
1­
78/
025;
Order
no.
6
PB­
281
186,
20
pp.
7
8
Kerr,
H.
D.,
Kulle,
T.
J.,
McIlhany,
M.
L.,
and
Swidersky,
P.
1979.
Effects
9
of
nitrogen
dioxide
on
pulmonary
function
in
human
subjects:
An
10
environmental
chamber
study.
Environ.
Research
19:
392­
404.
11
Test
Species/
Strain/
Number:
Human
subjects;
sex
not
given;
13
asthmatics
with
12
exercise
13
Exposure
Route/
Concentrations/
Durations:
14
Inhalation:
0.5
ppm
for
2
hours
15
Effects:
slight
burning
of
the
eyes,
slight
headache,
chest
tightness,
or
labored
breathing
in
16
7/
13
subjects
17
Endpoint/
Concentration/
Rationale:
18
Mild
symptoms
of
discomfort
in
asthmatics.
19
Uncertainty
Factors/
Rationale:
20
Total
uncertainty
factor:
none
21
Interspecies:
NA;
human
data
used
22
Intraspecies:
1
­
asthmatics
were
used
as
the
test
population
23
Modifying
Factor:
none
24
Animal
to
Human
Dosimetric
Adjustment:
not
applicable
25
Time
Scaling:
Extrapolation
to
time
points
was
not
conducted.
26
Data
Quality
and
Support
for
the
AEGL
Values:
AEGL­
1
values
are
considered
conservative
27
and
should
be
protective
of
the
toxic
effects
of
NO
2
outside
those
expected
as
defined
under
28
AEGL­
1.
29
30
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
63
AEGL­
2
VALUES
1
10
minute
2
30
minute
1
hour
4
hour
8
hour
20
ppm
3
15
ppm
12
ppm
8.2
ppm
6.7
ppm
Key
Reference:
Henschler,
D.,
Stier,
A.,
Beck,
H.,
and
Neuman,
W.
1960.
Odor
4
threshold
of
a
few
important
irritant
gasses
(
sulfur
dioxide,
ozone,
5
nitrogen
dioxide)
and
observations
in
humans
exposed
to
low
6
concentrations.
Archiv
für
Gewerbepathologie
und
7
Gewerbehygiene
17:
547­
570.
8
Test
Species/
Strain/
Number:
human,
healthy
male,
10­
14
9
Exposure
Route/
Concentrations/
Durations:
0.5­
30
ppm
for
up
to
2
hours
10
Effects:
11
0.5
ppm:
metallic
taste
12
1.5
ppm:
dryness
of
the
throat
13
4
ppm:
sensation
of
constriction
14
25
ppm:
prickling
of
the
nose
15
30
ppm:
burning
sensation
in
nose
and
chest,
cough,
dyspnea,
sputum
production
16
Endpoint/
Concentration/
Rationale:
Humans
exposed
to
30
ppm
for
2
hours
experienced
17
pronounced
irritation
18
Uncertainty
Factors/
Rationale:
19
Total
uncertainty
factor:
3
20
Interspecies:
NA
human
data
used
21
Intraspecies:
3
­
Additional
uncertainty
factors
are
unnecessary
because
the
22
experimental
data
at
lower
concentrations
in
asthmatics
and
persons
23
with
respiratory
disease
are
inconclusive
and
of
questionable
24
biological
significance.
25
Modifying
Factor:
not
applicable
26
Animal
to
Human
Dosimetric
Adjustment:
not
applicable
27
Time
Scaling:
Cn
×
t
=
k
where
n
=
3.5
(
ten
Berge
et
al.,
1986)
28
Data
Quality
and
Support
for
the
AEGL
Values:
AEGL­
2
values
should
be
protective
of
the
29
toxic
effects
of
NO
2
outside
those
expected
as
defined
under
AEGL­
2.
The
values
are
30
supported
by
occupational
monitoring
data.
31
32
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
64
AEGL­
3
VALUES
1
10
minute
2
30
minute
1
hour
4
hour
8
hour
34
ppm
3
25
ppm
20
ppm
14
ppm
11
ppm
Key
Reference:
Henry,
M.
C.,
Ehrlich,
R.,
and
Blair,
W.
H.
1969.
Effect
of
nitrogen
4
dioxide
on
resistance
of
squirrel
monkeys
to
Klebsiella
pneumoniae
5
infection.
Arch.
Environ.
Health
18:
580­
587.
6
Test
Species/
Strain/
Number:
monkeys,
2­
6/
group
7
Exposure
Route/
Concentrations/
Durations:
Inhalation,
10,
15,
35,
50
ppm
for
2
hours
8
Effects:
9
50
ppm:
marked
increase
in
respiratory
rate
and
decrease
in
tidal
volume,
microscopic
10
lesions
in
lung
(
determinate
for
AEGL­
3)
11
35
ppm:
increase
in
respiratory
rate
and
decrease
in
tidal
volume,
microscopic
lesions
in
12
lung
13
10
and
15
ppm:
slight
changes
in
lung
function
14
Endpoint/
Concentration/
Rationale:
50
ppm
resulted
in
marked
effects
on
lung
function
but
15
no
deaths
16
Uncertainty
Factors/
Rationale:
17
Total
uncertainty
factor:
3
18
Interspecies:
1
­
because
the
endpoint
is
below
the
definition
of
AEGL­
3
and
due
19
to
the
similarities
of
the
respiratory
tract
between
humans
and
20
monkeys
21
Intraspecies:
3
­
to
account
for
sensitive
subpopulations
since
the
data
for
22
asthmatics
and
those
with
respiratory
disease
are
inconclusive.
23
Modifying
Factor:
not
applicable
24
Animal
to
Human
Dosimetric
Adjustment:
not
applicable
25
Time
Scaling:
Cn
×
t
=
k
where
n
=
3.5
(
ten
Berge
et
al.,
1986)
26
Data
Quality
and
Support
for
the
AEGL
Values:
The
study
is
of
high
quality
and
the
AEGL­
3
27
values
are
supported
by
human
data.
28
29
APPENDIX
C:
Time
Scaling
Category
Plot
1
for
Nitrogen
Dioxide
2
NITROGEN
DIOXIDE
NAC/
PROPOSED
1:
01/
2003
66
0.1
1.0
10.0
100.0
1000.0
ppm
0
60
120
180
240
300
360
420
480
Minutes
Human
­
No
Effect
Human
­
Discomfort
Human
­
Disabling
Animal
­
No
Effect
Animal
­
Discomfort
Animal
­
Disabling
Animal
­
Some
Lethality
Animal
­
Lethal
AEGL
Chemical
Toxicity
­
TSD
All
Data
Nitrogen
Dioxide
AEGL­
3
AEGL­
1
AEGL­
2
1
2
3
4
Figure
1:
Category
plot
of
AEGL
values
and
effects
of
nitrogen
dioxide
on
humans
and
animals
5
6
7