Chloropicrin:
Weight
of
the
Evidence
for
Use
of
Human
Sensory
Irritation
Study
Elissa
Reaves,
Ph.
D.

Elissa
Reaves,
Ph.
D.

U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
June
27,
2006
June
27,
2006
2
Presentation
Overview
Presentation
Overview

Key
exposure
pathways
for
soil
fumigants

Chloropicrin
toxicology
database

Design
and
results
of
the
chloropicrin
human
sensory
irritation
study

Proposed
incorporation
of
Phase
3
of
human
study
in
risk
assessment
3
Overview:
Soil
Fumigants
Overview:
Soil
Fumigants

OPP
is
evaluating
the
risk
from
the
soil
fumigants:


Methyl
bromide

Methyl
iodide

Chloropicrin

Telone

Metam
sodium
&
Metam
potassium
(
degrade
to
MITC)


Dazomet
(
degrades
to
MITC)


Public
Technical
briefing
for
Soil
Fumigants
in
July,
2005
4
Overview:
Chloropicrin
Overview:
Chloropicrin

Exposure
pathways

Agricultural
settings,
greenhouses,
tree
replant
sites,

telephone
pole
applications,
empty
grain
and
potato
storage
fumigations

Can
be
used
as
an
indicator
chemical
or
as
a
warning
agent
when
used
at
2%
or
less
in
formulation

Major
pathway:
pre­
plant
soil
fumigant

Human
Health
Assessment:
Acute
Residential
Bystander
and
Occupational
Exposure
N
Cl
Cl
Cl
O
O
5
Overview:
Historical
use
of
Chloropicrin
Overview:
Historical
use
of
Chloropicrin

World
War
I

Used
for
sensory
irritant
properties
as
a
tearing
agent
and
lung
irritant

Incident
Data

Provide
support
for
the
irritating
properties
of
chloropicrin
 
Eye,
skin,
nose,
and
throat
irritation,
nausea,
cough,

dyspnea,
upper
respiratory
irritation,
chest
pain,
asthma
exacerbation

Insufficient
exposure
data
prevents
use
of
incident
data
in
quantitative
risk
assessment
6
Chloropicrin:
Toxicity
Profile
Chloropicrin:
Toxicity
Profile 
Animal
Animal

Robust
database
for
inhalation
studies

Studies
varying
from
30
minutes
to
108
weeks

Corrosive
to
skin
in
rodent
studies,
held
reserved
for
acute
primary
eye
and
dermal
sensitization
studies

Limited
port­
of­
entry
details
from
acute
studies

only
at
lethal
and
sub­
lethal
concentrations

No
information
on
progression
of
detection
to
irritation

Animal
data
suggest
port­
of­
entry
effects
occur
at
lower
concentrations
than
systemic
effects
7
Study
Design:
Chloropicrin
Human
Study
Study
Design:
Chloropicrin
Human
Study

3
Phases:
a
total
of
127
individuals

Mean
age
of
23
years
(
range,
18­
35
years)

Phase
Total
Subjects
Males
Females
Repeat
Participation
Phase
1
62
(
odor)

63
(
eye)
32
32
30
31
­­­

Phase
2
62
32
30
14
M
&
12
F
(
Phase
1)

Phase
3
32
15
17
1
M
(
Phase
1,
2),

1
M
(
Phase
2)
&

2
F
(
Phase
1,
2)
8
Phase
1
Design:
Chloropicrin
Human
Study
Phase
1
Design:
Chloropicrin
Human
Study

Objective:


Odor
detection,
eye
feel,
or
nasal
feel
from
brief
exposures

32
males,
30
females

Concentrations:
356,
533,
800,
1200
ppb

Duration:


 
Sniff :
1­
2
seconds,
both
nostrils

Eye:
25
seconds,
one
eye

Nose:
7
seconds,
one
nostril

Confidence
of
Feel:
1
(
very
low)
to
5
(
very
high)
9
Phase
1
Results:
Chloropicrin
Human
Study
Phase
1
Results:
Chloropicrin
Human
Study
Odor
Detection
Group
Analysis
Detecting
Subjects
Only
Logistic
Regression
Odor
Median
=

700
ppb
Odor
Median=
356
ppb
EC10=
215
ppb
EC50=
406
ppb
Eye
Detection
Eye
Median
=

900
ppb
Median
between
356
&
533
ppb
EC10=
38
ppb
EC50=
242
ppb
10
Overall
Phase
1:
Chloropicrin
Human
Study
Overall
Phase
1:
Chloropicrin
Human
Study

Strengths:


Pertinent
odor
&
eye
threshold
information

Informs
variability
of
responses
among
individuals

Similar
participation
of
males
and
females

Weaknesses:


No
severity
scores,
No
physiological
parameters

Length
of
sniff
duration
likely
varied
among
subject

Not
proposing
Phase
1
for
establishing
an
endpoint
for
risk
assessment
11
Phase
2
Design:
Chloropicrin
Human
Study
Phase
2
Design:
Chloropicrin
Human
Study

Objective:


Feel
in
the
eyes,
nose,
and/
or
throat
while
in
a
walk­
in
chamber

32
males
&
30
females

Concentrations:
0,
50,
75,
100,
150
ppb

Duration:


50
ppb
for
30
minutes

75,
100
and
150
ppb
for
20
minutes

Severity
of
feel
not
a
parameter
in
Phase
2
12
Phase
2
Design:
Chloropicrin
Human
Study
Phase
2
Design:
Chloropicrin
Human
Study

Response
judgment
(
score)
at
30
seconds
and
every
minute
until
end
of
exposure

Response
Score:


 
Yes 
or
 
No 
for
the
eyes,
nose,
and
throat

Confidence
of
response:

 
1=
not
certain
 
2=
moderately
certain
 
3=
very
certain

Subjects
free
to
leave
the
chamber
at
any
point
13
Hour
1
Hour
2
Hour
3
Hour
4
Hour
5
Hour
6
50
ppb
75
ppb
100
ppb
150
ppb
75­
minute
interval
75­
minute
interval
75­
minute
interval
Phase
2
Design:
Chloropicrin
Human
Study
Phase
2
Design:
Chloropicrin
Human
Study

Phase
2:
one
day
schedule
of
exposures

Minimum
of
45
minute
intervals
between
chloropicrin
exposures
14
Phase
2
Results:
Chloropicrin
Human
Study
Phase
2
Results:
Chloropicrin
Human
Study

Feel
in
the
eyes
was
more
sensitive
than
in
nose
and
throat

1
female
left
at
75
ppb,
again
at
150
ppb
with
1
male

1
female
and
1
male
left
at
150
ppb
(
different
day)


No
subjects
left
at
50
ppb
or
100
ppb

Ocular
median
75
ppb
15
Overall
Phase
2:
Chloropicrin
Human
Study
Overall
Phase
2:
Chloropicrin
Human
Study

Strengths:


More
appropriate
exposure
scenario
for
acute
bystander

Informs
the
timing
of
eye
and
nasal
detection

Informs
the
variability
of
responses
among
individuals

Study
design
employed
a
low
to
high
concentration

Blank
period
between
chloropicrin
exposures

Similar
participation
of
males
and
females
16
Overall
Phase
2:
Chloropicrin
Human
Study
Overall
Phase
2:
Chloropicrin
Human
Study

Weaknesses:


No
severity
scores

No
physiological
parameters

Durations
of
exposure
were
not
equal

Confidence
scores
different
than
in
Phase
1

Not
proposing
Phase
2
for
an
endpoint
in
risk
assessment
17
Phase
3
Design:
Chloropicrin
Human
Study
Phase
3
Design:
Chloropicrin
Human
Study

Objective:


Detection
and
severity
of
irritation
in
the
eyes,
nose,

and/
or
throat
while
in
a
walk­
in
chamber

15
males,
17
females

Concentrations:
0,
100,
150
ppb

Duration:


60
minutes

4
consecutive
days
to
same
concentration

Exposures
occurred
in
random
order
18
Phase
3
Design:
Chloropicrin
Human
Study
Phase
3
Design:
Chloropicrin
Human
Study

Physiological
Parameters:


Clinical
exam
of
eyes,
nose,
throat

Pulmonary
function
testing
 
FEV1
=
Forced
Expiratory
Volume
 
FVC
=
Forced
Vital
Capacity

Rhinomanometry

Nasal
Cytology

Ocular
Cytology

Exhaled
Nitric
Oxide
from:

 
lung
(
eNO)
and
nose
(
nNO)
19
Phase
3
Design:
Chloropicrin
Human
Study
Phase
3
Design:
Chloropicrin
Human
Study

Symptoms
rated
in
3
settings:

1.
While
in
the
chamber
(
scale
0
to
3);

2.
Before
and
after
exposure
in
the
chamber
and
at
the
beginning
and
end
of
the
exposure
week;

3.
At
the
beginning
and
end
of
a
cycle
of
exposures,

via
the
RQLQ
(
Rhinconjunctivitis
Quality
of
Life
Questionnaire)
20
Phase
3
Design:
Chloropicrin
Human
Study
Phase
3
Design:
Chloropicrin
Human
Study

Irritation
Severity
Scoring:


0
=
No
symptom

1
=
Mild;
symptom
present,
but
minimal
awareness,

easily
tolerated

2
=
Moderate;
symptom
definite
and
bothersome,

but
tolerated

3
=
Severe;
symptom
hard
to
tolerate
and
can
interfere
with
activities
of
daily
living
or
sleeping

Symptoms
rated
at
30
seconds
and
then
every
1
minute
until
the
end
of
60
minutes
21
Phase
3
Results:
Chloropicrin
Human
Study
Phase
3
Results:
Chloropicrin
Human
Study

No
subjects
left
the
chamber
prior
to
60
minutes

Eye
more
sensitive
than
nose
or
throat

Ocular
Irritation:


 
30%
of
subjects
reported
no
eye
irritation
at
any
time
or
concentration
during
the
60
minutes

 
15%
to
30%
of
subjects
varied
in
irritation
scores
of
2
(
moderate)
and
3
(
severe)
during
the
peak
response
period
(
30­
55
minutes)
at
either
100
or
150
ppb

At
0
ppb,
scores
varied
from
0,
1,
and
occasionally
2
22
Phase
3
Results:
Chloropicrin
Human
Study
Phase
3
Results:
Chloropicrin
Human
Study

Perceptual
effects:


Time
required
for
feeling
irritation
decreased
as
the
concentration
increased
from
100
to
150
ppb

Average
eye
severity
score
increased
with
increased
concentration

Physiological
effects
(
inflammation):


Change
in
nasal
nitric
oxide
(
nNO)


Change
in
upper
respiratory
air
flow
23
Phase
3
Results:
Chloropicrin
Human
Study
Phase
3
Results:
Chloropicrin
Human
Study

1
hour
after
exposure,
no
self­
reported
symptoms

1
hour
after
exposure,
physiological
changes
present

No
physiological
symptoms
the
following
day

Self­
reported
and
physiological
symptoms
did
not
progress
with
days/
weeks
of
exposure
24
Overall
Phase
3:
Chloropicrin
Human
Study
Overall
Phase
3:
Chloropicrin
Human
Study

Strengths:


Objective
and
subjective
irritation
scores

Repeated
measurements

Weaknesses:


Fewer
subjects
than
in
Phase
1
and
2

Lower
concentrations
as
in
Phase
2
not
examined
25
Point
of
Departure
(
PoD):
Chloropicrin
Point
of
Departure
(
PoD):
Chloropicrin
Human
Study
Human
Study

Phase
3
provides
physiological
parameters
that
support
eye
irritation
as
an
appropriate
endpoint
for
PoD

Proposing
Phase
3
of
human
study
for
establishing
an
endpoint
for
risk
assessment

TERA
BMC
Analysis:


Utilizes
Data
from
Phase
3
Chloropicrin
Human
Study

BMCL
10
=
73
ppb;
based
on
average
severity
score
of
1.5

Based
on
maximal
response
period
(
30­
55
minutes)
26
Chloropicrin
Charge
to
the
HSRB
Chloropicrin
Charge
to
the
HSRB
Chloropicrin
is
a
non­
selective
soil
fumigant
whose
primary
toxic
effect
is
sensory
irritation
in
which
stimulated
free
nerve
endings
mediate
sensations
and
clinical
signs
in
the
nose,
eyes,
throat,
and
upper
respiratory
tract.
Chloropicrin
is
a
unique
soil
fumigant
in
that
it
is
used
as
an
indicator
chemical
or
warning
agent
(
2%
or
less
by
weight
in
formulations).
The
Agency
is
developing
an
assessment
to
estimate
inhalation
risk
to
bystanders
and
workers
from
acute
exposures
to
chloropicrin.
27
Chloropicrin
Charge
to
the
HSRB
Chloropicrin
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
"
Weight
of
Evidence"
(
WOE)

document
and
Data
Evaluation
Records
(
DER)
for
chloropicrin
describe
the
study
design
of
the
acute
inhalation
human
toxicity
study.
The
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
inhalation
risk
to
bystanders
and
workers
exposed
to
chloropicrin.

Please
comment
on
whether
the
study
is
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
inhalation
exposure
to
chloropicrin.
28
Phase
2
Design:
Chloropicrin
Human
Study
Phase
2
Design:
Chloropicrin
Human
Study
Details
of
test
periods
and
concentrations
for
Phase
2
Exposure
Concentration:
N
(
Males)
N
(
Females)
Exposure
Duration
"
did
you
feel
in
the
nose,
eyes,
or
throat?"

blank
(
air)
32
30
30
min
50
ppb
chloropicrin
32
30
30
min
lunch
break
45
min
75
ppb
chloropicrin
32
30
20
min
blank
(
air)
32
29
30
min
100
ppb
chloropicrin
32
30
20
min
blank
(
air)
32
30
30
min
150
ppb
chloropicrin
32
30
20
min
