Page
1
of
12
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
March
17,
2006
MEMORANDUM
SUBJECT:
Human
Studies
Review
Board:
Final
Weight
of
Evidence
Comparison
of
BMD
Estimates
from
Human
and
Animal
Toxicology
Studies
of
Oxamyl
and
Methomyl
for
the
Interspecies
Extrapolation
Factor
in
the
N­
Methyl
Carbamate
(
NMC)
Cumulative
Risk
Assessment.

DP
Barcode
D321872.
TXR
No.:
0054127
PC
Codes:
103801,
090301
FROM:
Elissa
Reaves,
Ph.
D.,
Toxicologist
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

THROUGH:
William
Hazel,
Branch
Chief
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

TO:
Tina
E.
Levine,
Ph.
D.,
Director
Health
Effects
Division
(
7509C)

This
document
presents
the
rationale
for
the
integration
of
RBC
ChE
inhibition
data
from
the
methomyl
and
oxamyl
human
studies
(
MRIDs
44721401,
and
44912301)
for
the
extrapolation
of
the
interspecies
factor
of
methomyl
and
oxamyl
in
the
N­
Methyl
Carbamate
(
NMC)
Cumulative
Risk
Assessment.
Page
2
of
12
Integration
of
Methomyl
and
Oxamyl
Human
Studies
into
the
N­
methyl
Carbamate
(
NMC)
Pesticide
Cumulative
Risk
Assessment
1.
Background:

The
Food
Quality
Protection
Act
(
FQPA)
was
passed
by
Congress
in
1996.
The
FQPA
made
key
changes
to
the
approaches
used
by
EPA
to
assess
pesticide
chemicals.
One
of
these
changes
was
the
requirement
to
consider
cumulative
risk
to
those
pesticides
which
act
by
a
common
mechanism
of
toxicity.
Pesticides
are
determined
to
have
a
"
common
mechanism
of
toxicity"
if
they
act
the
same
way
in
the
body­­
that
is,
the
same
toxic
effect
occurs
in
the
same
organ
or
tissue
by
essentially
the
same
sequence
of
major
biochemical
events.
OPP
established
the
N­
methyl
carbamate
pesticides
(
NMCs)
as
a
common
mechanism
group
and
in
accordance
with
FQPA
has
developed
a
preliminary
cumulative
risk
assessment
for
this
group
of
pesticides
(
USEPA,
2005).
Methomyl
and
oxamyl
are
members
of
the
NMC
common
mechanism
group.

OPP
has
developed
a
guidance
document
for
developing
cumulative
risk
assessments
under
FQPA
(
USEPA,
2002).
This
guidance
indicates
that
when
developing
a
multi­
chemical
hazard
assessment,
comparison
of
toxic
potency
should
be
made
using
a
uniform
basis
of
comparison,
by
using
to
the
extent
possible
a
common
response
derived
from
a
comparable
measurement
methodology,
species,
and
sex
for
all
the
exposure
routes
of
interest.
In
the
preliminary
cumulative
risk
assessment,
the
Agency
considered
RBC
and
brain
ChE
inhibition
as
potential
endpoints.
Plasma
cholinesterase
data
were
not
considered
since
the
primary
enzyme
in
plasma
is
butylcholinesterase
and
not
acetylcholinesterase.
Ultimately,
brain
ChE
data
from
acute
rat
toxicity
studies
measured
at
or
near
the
time
of
peak
effect
have
been
used
by
EPA
to
estimate
a
relative
potency
factor
(
RPF)
and
to
develop
the
points
of
departure
(
PoD)
for
extrapolating
cumulative
risk.
For
instance,
the
brain
BMD10
has
been
used
to
calculate
the
RPF
while
the
brain
BMDL10
establishes
the
PoD
in
the
preliminary
cumulative
risk
assessment.
Brain
data
have
been
selected
over
RBC
data
as
brain
ChE
inhibition
represents
a
direct
measure
of
the
target
tissue
(
as
opposed
to
blood
data
which
is
considered
a
surrogate
measure)
and
brain
ChE
inhibition
data
tend
to
have
less
variation
and
thus
confer
less
uncertainty
on
cumulative
risk
estimates.

Because
data
from
rat
studies
provide
the
basis
for
potency
determination,
the
Agency
must
consider
interspecies
extrapolation
(
ie,
animal
to
human)
in
its
cumulative
risk
assessment.
As
such,
human
data
may
be
used
by
the
Agency
to
inform
the
pesticide­
specific
interspecies
extrapolation.
In
the
specific
case
of
methomyl
and
oxamyl
MRIDs
44721401
and
44912301
are
available,
respectively.
Page
3
of
12
2.
Executive
Study
Summaries:

Methomyl:

TABLE
1.
Study
design
Doses
of
methomyl
administered
(
mg/
kg
bw)
and
number
of
male
volunteers
Session
Numbers
0
(
Placebo)
0.1
0.2
0.3
0.5
1
1
1
2
1
4
1
3
1
4
1
(
dropped)*

4
1
5
Total
Volunteers
=
19
4
5
5
5
0
Data
obtained
from
p.
34,
MRID
44721401.
*
No
dosing
at
0.5
mg/
kg
occurred
in
Session
3
as
>
40%
RBC
inhibition
was
obtained.

In
a
non­
guideline,
ascending
acute
oral
toxicity
study
(
MRID
44721401),
19
healthy
human
male
volunteers,
ages
18
­
40
years,
were
each
given
a
single
oral
dose
of
a
methomyl
formulation
(
Lannate
®
SP,
approximately
89%
a.
i.,
batch
#:
T
101397­
00)
in
a
capsule
at
doses
of
0,
0.1,
0.2,
or
0.3
a.
i.
mg/
kg
bw
following
a
"
standard"
breakfast,
and
observed
for
two
nights
and
one
follow­
up
visit
7
(
±
2)
days
post­
dose.
Volunteers
were
admitted
to
the
clinic
the
afternoon
prior
to
the
morning
dosing
and
were
requested
to
fast
for
9
hours
prior
to
breakfast.
The
study
was
conducted
as
a
double­
blinded
ascending­
dose
escalation
clinical
trial,
and
each
male
was
treated
at
one
of
four
dosing
sessions.
All
volunteers
remained
under
close
medical
and
nursing
supervision
throughout
the
study.
Parameters
evaluated
were
physical
examination
and
urinalysis
at
screening
and
24
hours
post­
dosing;
vital
signs
(
i.
e.,
blood
pressure
and
heart
rate),
salivary
quantity
by
weight
(
secreted
within
5
minutes),
and
pupillometry
at
screening,
16
hours
pre­
dosing,
30
minutes
pre­
dosing,
and
1,
2,
3,
4,
8,
and
24
hours
post­
dosing;
oral
temperature
at
screening,
16
hours
predosing
30
minutes
pre­
dosing,
2,
4,
and
24
hours
post­
dosing;
12­
lead
electrocardiogram
(
ECG)
recorded
at
screening,
30
minutes
pre­
dosing,
30
minutes
post­
dosing,
and
2,
3,
and
24
hours
post­
dosing;
continuous
ECG
monitoring
from
30
minutes
pre­
dosing
through
3
hours
post­
dosing;
hematology
and
clinical
chemistry
at
screening,
30
minutes
pre­
dosing,
and
24
hours
postdosing
and
plasma
and
red
blood
cell
(
RBC)
cholinesterase
activities
at
screening,
16
hours
pre­
dosing,
30
minutes
pre­
dosing,
every
15
minutes
for
the
first
2
hours
post­
dosing,
and
then
hourly
through
8
hours,
at
24
hours,
and
one
week
later.

Four
volunteers
(
one
volunteer
at
each
concentration)
throughout
the
4
Sessions
demonstrated
a
greater
than
40%
inhibition
of
RBC
cholinesterase
activity
from
that
individual's
baseline
(
Session
1:
0.1
mg/
kg,
­
43.5%
at
8hrs
post­
dose;
Page
4
of
12
Session
2:
0.2
mg/
kg,
­
40.6%
at
45
minutes
post­
dosing
and
headache
at
105
minutes
post­
dosing;
Session
3:
0.3
mg/
kg,
­
43%
at
45
minutes
post­
dosing;
Session
4:
0.2
mg/
kg,
­
41%
at
75
minutes
post­
dosing).
RBC
cholinesterase
activity
returned
to
baseline
by
6
hours
post­
dosing
in
all
volunteers
with
the
exception
of
one
volunteer
receiving
0.1
mg/
kg
(
8
hrs
post­
dosing).

A
dose­
response
relationship
was
observed
in
all
dose
groups
for
plasma
and
RBC
cholinesterase
activity.
In
addition,
cholinesterase
activity
for
both
plasma
and
RBC
was
consistent
for
timing
of
peak
effect
and
time
to
recovery.
In
the
high
dose
group,
the
mean
percent
change
in
RBC
cholinesterase
activity
was
statistically
significantly
decreased
compared
to
placebo
activity
from
the
first
time
point
at
15
minutes
(­
18.6%)
to
4
hours
post­
dosing
(­
5.0%),
with
peak
inhibition
at
45
minutes
(­
35.2%)
and
recovery
at
6
hours
post­
dosing.
At
the
mid­
dose,
mean
percent
change
in
RBC
cholinesterase
activity
was
statistically
significantly
decreased
compared
to
placebo
activity
beginning
at
45
minutes
post­
dosing
(­
20.0%)
until
2
hours
post­
dosing
(­
16.2%),
with
peak
inhibition
at
1
hour
and
30
minutes
(­
27.9%)
and
recovery
at
3
hours
post­
dosing.
The
mean
percent
change
in
RBC
cholinesterase
activity
for
the
low
dose
(
0.1
mg/
kg)
was
statistically
similar
to
placebo
activity
at
all
time
points.
However,
at
60,
75,
and
90
minutes
post­
dosing,
the
percent
change
in
mean
RBC
cholinesterase
activity
was
­
14.6%
,
­
19.0%,
and
­
10.5%
of
the
mean
group
baseline
level,
respectively.
The
timing
of
the
mean
RBC
cholinesterase
activity
coincides
with
the
inhibition
of
RBC
cholinesterase
activity
in
the
mid­
and
high­
dose
groups.

The
mean
percent
change
in
plasma
cholinesterase
activity
was
statistically
significantly
decreased
compared
to
placebo
activity
in
the
high
dose
(
0.3
mg/
kg)
beginning
at
15
minutes
post­
dosing
(­
9.8%)
until
4
hours
post­
dosing
(­
8.1%),
with
peak
inhibition
at
45
minutes
(­
21.1%)
and
recovery
at
6
hours
post­
dosing.
In
the
mid­
dose
group
(
0.2
mg/
kg)
the
mean
percent
change
from
baseline
plasma
cholinesterase
activity
compared
to
placebo
was
statistically
significantly
decreased
beginning
at
45
minutes
post­
dosing
(­
11.5%)
until
2
hours
postdosing
(­
10.3%)
with
peak
inhibition
at
1
hour
45
minutes
(­
13.5%)
and
recovery
at
3
hours
post­
dosing.
Mean
percent
change
in
plasma
cholinesterase
activity
for
the
low
dose
(
0.1
mg/
kg)
was
statistically
similar
to
placebo
activity
at
all
time
points.
Plasma
cholinesterase
activity
was
only
statistically
significantly
decreased
at
2
hours
post­
dosing
(­
7.2%)
when
outliers
were
excluded.

Increases
in
saliva
weight
were
dose­
related
at
the
one­
hour
timepoint,
with
the
0.3
mg/
kg
volunteers
at
60.3%
above
baseline
weight,
suggesting
a
potentially
cholinergic
response
to
the
treatment.

Three
volunteers
had
increased
total
bilirubin
at
least
once
during
the
study.
The
first
volunteer
(
0.1
mg/
kg)
had
increased
total
bilirubin
at
30
minutes
pre­
dosing
only.
The
second
(
0.2
mg/
kg)
and
third
(
0.3
mg/
kg)
volunteer
had
increased
total
bilirubin
at
screening,
30
minutes
pre­
dosing,
and
24
hours
post­
dosing.
Page
5
of
12
No
dose
group
had
changes
in
pupillary
size,
respiratory
rate,
ECGs,
vital
signs,
hematology,
clinical
chemistry,
urinalysis,
or
clinical
signs
of
cholinergic
effects
(
with
the
exception
of
the
0.3
mg/
kg
individual
who
complained
of
a
transient
headache,
and
the
early
increase
in
salivation).

Under
the
conditions
of
this
ascending
oral
study,
the
NOAEL
for
methomyl
in
humans
is
<
0.1
mg/
kg.
The
LOAEL
is
0.1
mg/
kg,
based
on
decreased
peak
RBC
cholinesterase
activity
(­
19%).

The
Agency
generated
BMD
and
BMDL
estimates
based
on
the
RBC
ChE
data
from
this
study.
The
resulting
BMD10
is
0.035
mg/
kg
with
BMDL10
of
0.015
mg/
kg.
(
Please
refer
to
Table
3).

Oxamyl:

TABLE
2.
Study
design
Doses
Administered
(
mg/
kg
bw)
and
number
of
male
volunteers
Session
Numbers
0
(
Placebo)
0.005
0.015
0.03
0.06
0.09
0.15
1
2
2
1
1
3
1
4
1
4
1
4
1
5
1
4
1
6
1
4
1
7
1
4
8
1
1
9
1
4
Total
Volunteers=
40
10
5
5
5
5
5
5
Data
obtained
from
p.
20,
MRID
44912301.

In
a
non­
guideline,
ascending
acute
oral
toxicity
study
(
MRID
44912301),
40
healthy
human
male
volunteers,
aged
19
­
39
years,
were
each
given
a
single
oral
dose
of
oxamyl
technical
(
approximately
97.6%
a.
i.,
batch
#:
DPX­
D140­
196)
in
a
gelatin
capsule
at
doses
of
0,
0.005,
0.015,
0.03,
0.06,
0.09,
or
0.15
a.
i.
mg/
kg
bw.
Volunteers
were
admitted
to
the
clinic
the
afternoon
prior
to
the
morning
dosing.
The
volunteers
were
fasted
for
9
hours
prior
to
breakfast.
Study
volunteers
were
dosed
approximately
5
minutes
following
a
"
standard"
breakfast,
and
observed
for
two
nights
and
one
follow­
up
visit
7
(
±
2)
days
post­
dose.
All
volunteers
remained
under
close
medical
and
nursing
supervision
throughout
the
study.
The
study
was
conducted
as
a
double­
blind
ascending­
dose
escalation
Page
6
of
12
clinical
trial,
and
each
male
was
treated
at
one
of
nine
dosing
sessions.
Volunteers
received
a
complete
screening
physical
examination,
testing
for
Hepatitis
B,
C,
and
HIV
infection,
and
drug­
screening
of
urine
within
14
days
of
study
commencement.
Blood
pressure
and
heart
rate
were
measured
at
screening
(
within
14
days
prior
to
dosing),
16
hours
pre­
dose
(
admission),
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8
,
and
24
hours
post­
dose.
Oral
temperature
was
recorded
at
screening,
16
hours
and
30
minutes
pre­
dose,
and
2,
4,
and
24
hours
post­
dose.
A
12­
lead
ECG
was
obtained
at
screening,
30
minutes
predose
and
30
minutes,
1,
2,
and
24
hours
post­
dose.
Hematology
and
clinical
chemistry
testing
was
performed
at
screening,
30
minutes
pre­
dose,
and
24
hours
post­
dose.
Urinalysis
was
conducted
at
screening
and
24
hours
postdose
Pupillometry
was
performed
16
hours
and
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8,
and
24
hours
post­
dose.
Saliva
was
collected
and
quantified
by
weight
16
hours
and
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8,
and
24
hours
post­
dose.
Plasma
and
red
blood
cell
cholinesterase
activity
were
assayed
at
screening,
and
2
days,
16
hours,
and
30­
minutes
pre­
dose,
and
at
0.25,
0.5,
0.75,
1.0,
1.25,
1.5,
1.75,
2,
3,
4,
6,
8,
12,
and
24
hours
post­
dose,
and
at
7
(
±
2)
days
postdose

Clinical
signs
were
reported
by
a
total
of
7
individuals
from
both
the
placebo
(
3
volunteers)
and
oxamyl
dose
groups
(
4
volunteers).
These
clinical
observations
did
not
correspond
with
peak
ChE
inhibition
and
were
therefore
not
considered
to
be
treatment
related.
Clinical
observations
from
the
placebo
volunteers
included
bleeding
gums,
headache,
fever,
tremor,
muscular
pains,
and
right
sided
groin
pain.
Symptoms
reported
by
the
two
volunteers
in
the
0.015
mg/
kg
dose
group
included
headache
(
pre­
dose),
brief
nausea
(
57
minutes
post­
dose
to
61
minutes),
and
abdominal
pain
(
46
hours
post­
dose
to
46.5
hours
post­
dose).
Examination
of
the
volunteer
with
the
brief
nausea
revealed
no
inhibition
of
cholinesterase
activity
or
effects
on
pupil
size
or
salivation
and
so
was
deemed
unlikely
related
to
the
test
compound.
An
earache
was
noted
by
one
volunteer
(
46
hours
post­
dose
to
46.5
hours
post­
dose)
of
the
0.03
mg/
kg
dose
group.
At
0.15
mg/
kg,
one
volunteer
experienced
a
headache
(
6
hours
50
minutes
lasting
15
hours
15
minutes)
and
increased
generalized
sweating
(
10
hours
50
minutes
lasting
3
hours
55
minutes).
Both
of
these
symptoms
were
considered
possibly
related
to
study
compound
but
further
investigation
revealed
the
time
course
of
symptoms
were
not
consistent
with
the
cholinesterase
activity
inhibition
observed.
Therefore,
the
adverse
events
were
not
likely
to
be
truly
related
to
the
test
compound.

The
mean
percent
change
in
plasma
cholinesterase
activity
was
statistically
decreased
compared
to
placebo
in
the
high
dose
(
0.15
mg/
kg)
beginning
at
the
first
time
point
(­
14%,
15
min)
until
3
hours
post­
dosing
(­
8%),
with
peak
inhibition
at
45
minutes
post­
dosing
(
43%,
p<
0.001).
Plasma
cholinesterase
activity
returned
to
baseline
by
6
hours
post­
dosing.
For
the
group
exposed
to
0.09
mg/
kg,
plasma
cholinesterase
activity
was
significantly
inhibited
starting
at
75
minutes
post­
dosing
(­
12%
peak,
p=
0.026)
until
2
hours
post­
dosing
(­
10%,
Page
7
of
12
p=
0.039)
with
recovery
at
3
hours
post­
dosing.
Within
the
0.06
mg/
kg
dose
group,
the
maximum
plasma
cholinesterase
inhibition
was
­
7%
at
75
minutes
post­
dosing
(
non­
statistical,
p=
0.22).
Plasma
cholinesterase
activity
was
similar
to
placebo
in
the
0.005,
0.015
and
0.03
mg/
kg
dose
groups
at
all
time
points.
However,
when
the
linear
trend
was
tested
for
dose
at
each
time
point,
the
test
was
significant
for
every
time
point
except
at
4,
8,
12,
and
24
hours,
and
7
days
post­
dosing.
The
inclusion
or
exclusion
of
outlying
values
did
not
alter
the
results
for
plasma
cholinesterase
activity.

The
mean
RBC
cholinesterase
activity
of
the
high
dose
group
(
0.15
mg/
kg)
was
inhibited
significantly
beginning
at
30
minutes
(­
23%,
p<
0.001)
with
peak
inhibition
at
45
and
60
minutes
(­
28%
and
­
27%,
respectively
with
p<
0.001
for
both)
until
2
hours
post­
dosing
(­
8%,
p=
0.011)
and
recovery
to
baseline
by
3
hours
post­
dosing.
For
the
0.09
mg/
kg
dose
group,
the
mean
RBC
cholinesterase
activity
was
significantly
decreased
only
at
30
minutes
(­
7%,
p=
0.016)
with
recovery
following
at
45
minutes
post­
dosing.
RBC
cholinesterase
activity
was
statistically
similar
to
placebo
at
all
time
points
in
the
0.005,
0.015,
0.03,
and
0.06
mg/
kg
dose
groups.
Analysis
of
a
linear
trend
for
RBC
cholinesterase
activity
by
dose
at
varying
time
points
indicated
significance
from
30
minutes
until
105
minutes
post­
dosing.

Saliva
weight
when
examined
with
outliers
was
increased
in
the
two
highest
dose
groups
at
1
hour
post­
dosing
compared
to
the
placebo
group.
A
linear
trend
was
observed
for
saliva
weight
(
change
from
baseline),
which
increased
with
increasing
dose
and
was
only
significant
(
p=
0.002)
at
the
1
hour
time
point.
The
significance
of
saliva
weight
and
dose
was
not
achieved
at
any
other
time
point
during
the
study.

There
were
no
significant
decreases
in
minimum
pupil
size
and
recovery
pupil
size
relative
to
baseline
between
any
dose
level
and
placebo,
at
any
of
the
time
points.
Significant
increases
in
recovery
pupil
size
were
observed
at
2,4,
8
and
24
hour
post­
dosing
in
the
0.005
mg/
kg
group
when
compared
to
placebo.
However,
increases
in
pupil
size
are
contrary
to
the
expected
response
to
cholinergic
stimulation
by
the
test
substance.

Under
the
conditions
of
this
ascending
oral
dose
study
in
humans,
0.09
mg/
kg/
day
represents
a
level
where
7­
12%
plasma
and
RBC
ChE
inhibition
was
observed.
Three
of
5
volunteers
at
this
dose
(
0.09
mg/
kg/
day)
exhibited
greater
than
20%
plasma
ChE
inhibition.
Therefore,
0.06
mg/
kg/
day
is
considered
the
NOAEL.

The
Agency
generated
BMD
and
BMDL
estimates
based
on
the
RBC
ChE
data
from
this
study.
The
resulting
RBC
BMD10
is
0.083
mg/
kg
with
BMDL10
of
0.069
mg/
kg.
(
Please
refer
to
Table
3).
Page
8
of
12
3.
Summary
of
Oxamyl
and
Methomyl
Study
Results:

The
human
toxicity
studies
for
both
oxamyl
and
methomyl
were
performed
in
a
dose­
escalating
fashion
that
provides
dose­
response
data
for
RBC
and
plasma
ChE.
Samples
were
taken
and
ChE
activity
measured
every
15
minutes
for
the
first
two
hours
post­
dosing,
then
hourly
through
8
hours,
at
24
hours,
and
one
week
later.
The
multiple
sampling
over
time
showed
the
progression
of
inhibition
of
ChE
activity
until
peak
inhibition
and
then
demonstrated
enzyme
recovery.

The
human
toxicity
studies
do
not
provide
brain
ChE
data,
for
obvious
reasons,
and
lack
plasma
and
RBC
ChE
inhibition
data
in
females.
The
blood
ChE
activity
(
plasma
and
RBC)
provided
in
the
human
studies
are
considered
appropriate
surrogate
measures
of
potential
effects
on
peripheral
nervous
system
(
PNS)
acetylcholinesterase
(
AChE)
activity,
and
of
potential
effects
on
the
central
nervous
system
(
CNS)
when
brain
ChE
data
are
lacking
(
USEPA
2000).
AChE
is
the
target
enzyme
for
the
cumulative
risk
assessment
and
is
the
primary
form
of
ChE
found
in
RBCs.
Butylcholinesterase
(
BChE),
on
the
other
hand,
is
the
primary
form
of
ChE
found
in
plasma.
BChE
is
considered
a
measure
of
exposure
but
has
not
been
shown
to
be
of
toxicological
significance.
RBC
ChE
data,
therefore,
is
being
utilized
by
the
Agency
to
inform
the
pesticidespecific
interspecies
extrapolation.

The
measured
RBC
ChE
activity
from
the
human
studies
is
adequate
for
estimation
of
BMD
and
BMDL
estimates.
The
male
RBC
ChE
data
from
both
the
methomyl
and
oxamyl
human
studies
were
utilized
in
the
dose­
response
model
in
the
same
manner
as
the
acute
rat
data
(
brain
and
RBC)
that
are
available
for
the
NMCs
of
the
cumulative
hazard
assessment
(
USEPA
2005).
The
BMD10
and
BMDL10
estimates
for
both
the
rat
(
RBC,
brain)
and
human
(
RBC)
are
included
in
Table
3
below.
Although
no
female
volunteers
were
measured
in
the
human
studies,
the
rat
data
indicate
no
sex
differences
in
ChE
activity
in
either
compartment
(
brain,
RBC).
Dose­
response
RBC
ChE
data
from
both
human
studies
indicate
a
lower
BMD
estimate
when
compared
to
rat
data.
For
example,
the
oxamyl
human
RBC
BMD10
is
0.08
mg/
kg
with
95%
confidence
interval
(
CI)
0.07
mg/
kg
to
0.11
mg/
kg.
The
corresponding
oxamyl
RBC
BMD10
in
the
rat
is
0.28
mg/
kg
with
95%
CI
of
0.14­
0.54
mg/
kg.
Likewise,
the
human
methomyl
RBC
BMD10
is
0.04
mg/
kg
with
0.01­
0.10
mg/
kg
95%
CI.
The
methomyl
rat
data
indicate
a
RBC
BMD10
of
0.34
mg/
kg
with
0.25­
0.45
mg/
kg
95%
CI.
As
such,
the
estimates
from
the
dose­
response
modeling
provide
useful
information
into
the
sensitivities
of
RBC
ChE
inhibition
of
rats
compared
to
humans.
Page
9
of
12
Table
3.
Oral
BMD10s
And
BMDL10s
Generated
from
Rat
ChE
(
RBC,
Brain)
and
Human
ChE
(
RBC)
Data
for
Oxamyl
and
Methomyl.

Rat
Human
Brain
RBC
RBC
Chemical
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
Oxamyl
F=
0.14
M=
0.18
F=
0.11
M=
0.14
0.28
0.16
0.08
0.07
Methomyl
0.49
0.33
0.34
0.26
0.04
0.02
BMD
estimates
are
presented
as
a
single
estimate
when
there
are
no
differences
between
sexes.
BMD
estimates
for
the
human
studies
are
for
males
only.
Human
RBC
data
obtained
from
MRIDs
44721401
and
44912301
for
methomyl
and
oxamyl,
respectively.
Methomyl
rat
brain
and
RBC
data
obtained
from
MRIDs
44472001,
44487501,
Padilla
et
al.
2005.
Oxamyl
rat
brain
and
RBC
data
obtained
from
MRIDs
44254401,
44472001,
Padilla
et
al.
2005.

4.
Discussion
There
are
a
variety
of
quality
studies
that
provide
ChE
inhibition
information
from
both
the
rat
and
human
studies
for
oxamyl
and
methomyl,
which
provide
information
about
dose
response.
For
purposes
of
the
cumulative
risk
assessment,
the
difficulty
lies
in
extrapolating
information
across
compartments
(
blood­
brain)
and
potential
uncertainty
surrounding
ChE
information
solely
from
males.
The
preliminary
NMC
cumulative
risk
assessment
relies
on
rat
brain
ChE
data
for
the
relative
potency
factors
(
RPFs)
and
points
of
departure
(
PoDs).
The
FIFRA
SAP
supported
the
Agency's
use
of
brain
ChE
data
in
August
2005
(
FIFRA
SAP
2005).

By
reviewing
and
outlining
the
available
data
for
oxamyl
and
methomyl,
it
becomes
apparent
that
a
couple
of
approaches
are
available
to
apply
the
interspecies
extrapolation
factor
for
the
preliminary
cumulative
risk
assessment.
Tables
4
and
5
below
highlight
for
oxamyl
and
methomyl
the
method
of
BMD10
ratio,
interspecies
factor,
confidence
interval,
and
the
pro's
and
con's
or
uncertainties
surrounding
these
options
for
interspecies
refinement.
The
first
approach
is
the
use
of
the
Agency's
default
10X
factor
for
interspecies
extrapolation.
The
second
approach
is
to
use
the
ratio
of
RBC
BMD10
rat
(
both
sexes)
to
RBC
BMD10
for
human
(
male).
The
uncertainties
surrounding
both
of
these
approaches
are
highlighted
in
the
tables
below.
It
should
also
be
noted
that
an
additional
approach
is
the
ratio
of
rat
brain
BMD10
to
human
RBC
BMD10.
This
option
would
compare
brain
data
relied
on
in
the
cumulative
risk
assessment
with
available
RBC
data
from
the
human
studies.
This
ratio
does
not
compare
ChE
data
from
the
same
compartment
and,
therefore,
is
less
appropriate
for
interspecies
extrapolation
for
either
methomyl
or
oxamyl.

At
the
present
time,
there
is
no
indication
from
the
available
rat
data
for
either
oxamyl
or
methomyl
to
suggest
a
sex
difference,
i.
e.
that
female
volunteers
Page
10
of
12
would
respond
differently
than
males
to
these
pesticides.
Given
the
similarity
between
brain
and
RBC
ChE
in
rats,
the
Agency
is
not
aware
of
any
biological
or
physiological
reason
that
human
brain
ChE
would
be
more
sensitive
than
the
rat
brain.
The
Agency,
therefore,
proposes
to
use
the
RBC
BMD10
ratios
for
rats
and
humans
for
oxamyl
and
methomyl
that
results
in
an
interspecies
extrapolation
of
3X
(
95%
CI
of
2­
7)
for
oxamyl
and
10X
(
95%
CI
of
3­
29)
for
methomyl.
These
interspecies
extrapolation
factors
are
in
addition
to
the
other
uncertainty
factors
for
the
cumulative
risk
assessment
including
10X
for
intraspecies
variability
(
human
variability)
and
FQPA
safety
factor.
Comparative
cholinesterase
assays
are
available
for
both
oxamyl
and
methomyl
in
which
specific
factors
will
be
developed
for
the
protection
of
potential
sensitivity
in
the
young.
Page
11
of
12
Table
4.
Comparison
of
the
Alternative
Choices
and
the
Resulting
Uncertainties
Surrounding
the
Refinement
of
the
Interspecies
Extrapolation
Factor
for
Oxamyl
in
the
NMC
Cumulative
Risk
Assessment
Option
of
Refinement
for
Interspecies
Factor
Resulting
Interspecies
Factor
Confidence
Interval
Pro's
Con's
or
Uncertainties
1.
Default
Factor
for
Risk
Assessment
10X
NA
1.
Standard
uncertainty
factor
for
interspecies
extrapolation.

2.
Accounts
for
uncertainty
regarding
lack
of
ChE
brain
data
in
humans.

3.
Accounts
for
uncertainty
regarding
lack
of
ChE
data
in
female
volunteers.
1.
Ratio
of
RBC
BMDs
indicate
4X
factor.

2.
No
RBC
ChE
data
in
human
females.

2.
Ratio
of
RBC
BMD10
rat
vs.
human
RBC
BMD10
3X
2X
to
7X
1.
BMD10
ratio
is
based
on
the
specific
data
from
same
compartment
(
RBC)
in
rat
(
both
sexes)
and
human
(
male).

2.
Inhibition
of
RBC
ChE
in
rats
is
similar
between
sexes.
1.
Uncertainty
remains
regarding
lack
of
RBC
ChE
data
in
females.

2.
Uncertainty
remains
regarding
lack
of
brain
ChE
data
in
human
volunteers.
Page
12
of
12
Table
5.
Comparison
of
the
Alternative
Choices
and
the
Resulting
Uncertainties
Surrounding
the
Refinement
of
the
Interspecies
Extrapolation
Factor
for
Methomyl
in
the
NMC
Cumulative
Risk
Assessment
Option
of
Refinement
for
Interspecies
Factor
Resulting
Interspecies
Factor
Confidence
Interval
Pro's
Con's
or
Uncertainties
1.
Default
Factor
for
Risk
Assessment
10X
NA
1.
Standard
uncertainty
factor
for
interspecies
extrapolation.

2.
Is
supported
by
the
ratio
of
RBC
BMD10s
in
option
2
below.

3.
Rat
RBC
ChE
data
similar
between
sexes
and
as
sensitive
as
brain
ChE.
1.
Does
not
rely
on
species
specific
information.

2.
Uncertainty
remains
for
lack
of
RBC
ChE
data
in
female
volunteers.

3.
Uncertainty
remains
for
lack
of
brain
ChE
data
in
humans
(
male
and
female).

2.
Ratio
of
RBC
BMD10
rat
vs.
human
RBC
BMD10
9.5X
3X
to
29X
1.
BMD10
ratio
is
based
on
the
specific
data
from
same
compartment
(
RBC)
in
rat
(
both
sexes)
and
human
(
male).

2.
Inhibition
of
RBC
ChE
in
rats
is
similar
between
sexes
3.
RBC
ChE
as
sensitive
as
brain
ChE
in
rats.
1.
Uncertainty
remains
for
lack
of
brain
ChE
inhibition
in
humans
(
male
and
female)

2.
Uncertainty
exists
for
RBC
ChE
inhibition
in
females.

FIFRA
SAP
(
2005).
Meeting
Minutes
of
the
FIFRA
Scientific
Advisory
Panel
Held
August
23­
26,
2005.
SAP
Minutes
No.
2005­
04.
Preliminary
NMethyl
Carbamate
Cumulative
Risk
Assessment.
October
13,
2005.

Padilla
S.
et
al.
(
2005).
Time
Course
and
Dose
Response
Assessment
of
Cholinesterase
(
ChE)
Inhibition
in
Adult
Rats
Treated
Acutely
with
Carbaryl,
Methomyl,
Methiocarb,
Oxamyl,
or
Propoxur.
Presented
at
the
44
th
Annual
Meeting
of
the
Society
of
Toxicology;
New
Orleans,
LA.

USEPA
(
2000).
"
The
Use
of
Data
on
Cholinesterase
Inhibition
for
Risk
Assessments
of
Organophosphorous
and
Carbamate
Pesticides";
August
18,
2000.
Available:
http://
www.
epa.
gov/
pesticides/
trac/
science/
cholin.
pdf
USEPA
(
2002).
"
Guidance
on
Cumulative
Risk
Assessment
of
Pesticide
Chemicals
That
Have
a
Common
Mechanism
of
Toxicity."
January
14,

2002.
(
67
FR
2210;
January
16,
2002)
http://
www.
epa.
gov/
oppfead1/
trac/
science/#
common
USEPA
(
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Methyl
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Cumulative
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Office
of
Pesticide
Programs,
U.
S.
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Agency.
Washington,
DC.
http://
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epa.
gov/
scipoly/
sap/
index.
htm#
sept
