EPA
FMC
Meeting
Agenda
EPA
FMC
Meeting
Agenda
EPA
FMC
Meeting
Agenda
°°
Introductions
Introductions
°
Human
health
risk
assessment
Human
health
risk
assessment
 
Human
risk
rationales
Human
risk
rationales
 
Technical
comments
on
Technical
comments
on
BMDs
BMDs
and
and
UFs
UFs
 
Human
studies
Human
studies
°
Benefits
Benefits
 
In
In­
progress
BEAD
assessments
progress
BEAD
assessments
 
USDA
input
USDA
input
 
EPA
alternatives
and
benefits
analysis
EPA
alternatives
and
benefits
analysis
°
Path
forward
Path
forward
 
Timetable
Timetable
 
Subsequent
meetings
Subsequent
meetings
Human
Health
Risk
Assessment
Human
Health
Risk
Human
Health
Risk
Assessment
Assessment
Explanation
of
Key
FMC
Comments
on
Phase
4
Risk
Assessment
Explanation
of
Key
FMC
Comments
Explanation
of
Key
FMC
Comments
on
Phase
4
Risk
Assessment
on
Phase
4
Risk
Assessment
°
Additional
5X
database
UF
is
not
Additional
5X
database
UF
is
not
necessary
necessary
°
Interspecies
UF
can
be
reduced
Interspecies
UF
can
be
reduced
°
Worker
risk
Worker
risk
 
Dermal
absorption
factor
reduction
to
Dermal
absorption
factor
reduction
to
3.5
percent
versus
6
percent
3.5
percent
versus
6
percent
 
Point
of
departure
should
be
reevaluated
Point
of
departure
should
be
reevaluated
?

Not
presented
1X
Not
presented
0.026
mg/
kg
Human
oral
study
During
Phase
5
During
Phase
5
Mid
Apri
Mid
April
to
to
early
May
2006
early
May
2006
0.00006
mg/
kg
5X
Brain
vs
RBC
10X
10X
0.03
mg/
kg
CCA
rat
study
Phase
4
Phase
4
after
after
March
2006
March
2006
aPAD
aPAD
Additional
UF
Additional
UF
Interspecies
Interspecies
UF
UF
Intraspecies
Intraspecies
UF
UF
Acute
Acute
endpoint
endpoint
Study
used
Study
used
0.00025
mg/
kg
10X
LOAEL
to
NOAEL
10X
10X
0.25
mg/
kg
(
LOAEL)

Chronic
dog
Phase
2
Phase
2
through
through
March
2
March
2006
06
Human
Health
Oral
Endpoints
Have
Undergone
Numerous
Changes
Human
Health
Oral
Endpoints
Have
Human
Health
Oral
Endpoints
Have
Undergone
Numerous
Changes
Undergone
Numerous
Changes
Human
Health
Dermal
Endpoints
Have
Undergone
Numerous
Changes
Human
Health
Dermal
Endpoints
Human
Health
Dermal
Endpoints
Have
Undergone
Numerous
Changes
Have
Undergone
Numerous
Changes
?

0.0017
mg/
kg
0.014
mg/
kg
Acute
dermal
Acute
dermal
dose
dose
N/
A
Not
presented
1X
Not
presented
0.17
mg/
kg
Human
dermal
study
During
Phase
5
During
Phase
5
Mid
Apri
Mid
April
to
to
early
May
2006
early
May
2006
6%
None
10X
10X
0.01
mg/
kg
Padilla/
FMC
rat
combined
data
Phase
4
Phase
4
after
after
March
2006
March
2006
Dermal
Dermal
absorption
(%)

absorption
(%)

Additional
UF
Additional
UF
Interspecies
Interspecies
UF
UF
Intraspecies
Intraspecies
UF
UF
Acute
Acute
endpoint
endpoint
Study
used
Study
used
6%

3X
LOAEL
to
NOAEL
10X
10X
0.25
mg/
kg
(
LOAEL)

Chronic
dog
Phase
2
Phase
2
through
through
March
2
March
2006
06
Technical
Comments
on
Benchmark
Doses
and
UFs
Technical
Comments
on
Technical
Comments
on
Benchmark
Doses
and
Benchmark
Doses
and
UFs
UFs
Focus
of
Database
UF
Comments
Derivation
of
5X
Database
UF
Derivation
of
5X
Database
UF
Derivation
of
5X
Database
UF
Point
of
Departure
BMDL10
percent
0.03
mg/
kg
rat
pup
brain
data
10
x
UF
Intraspecies
10
x
UF
Interspecies
5
x
UF
Database
1
x
UF
FQPA
RBC
ChE
Inhibition
is
5
x
more
sensitive
than
brain
aPAD
0.00006
mg/
kg
RBC
BMD10
percent
0.03
mg/
kg
Combined
Dataset
EPA­
NHEERL
and
FMC­
time
Course
Studies
(
at
15
minutes)
Brain
BMD10
percent
0.15
mg/
kg
EPA­
NHEERL
Study
(
at
30
minutes)
Overall
Conclusions
Overall
Conclusions
Overall
Conclusions
°
Use
rat
pup
brain
BMDL
Use
rat
pup
brain
BMDL
10
10
ChEI
ChEI
of
0.031
of
0.031
mg/
kg
as
point
of
departure
for
dietary
mg/
kg
as
point
of
departure
for
dietary
risk
assessment
risk
assessment
 
No
significant
clinical
signs
at
this
dose
No
significant
clinical
signs
at
this
dose
°
A
5X
uncertainty
factor
for
brain
to
RBC
A
5X
uncertainty
factor
for
brain
to
RBC
ChEI
ChEI
is
unnecessary
is
unnecessary
 
Minimum
detectable
difference
for
RBC
Minimum
detectable
difference
for
RBC
ChEI
ChEI
is
is
20
percent
20
percent
 
The
BMD
The
BMD10
10
for
brain
is
similar
to
the
BMD
for
brain
is
similar
to
the
BMD20
20
for
for
RBC
RBC
19.1
20.9
23.4
Females
(
percent)

Females
(
percent)
20.0
21.9
24.5
Males
(
percent)

Males
(
percent)
N
=
12
N
=
10
N
=
8
Animals/
Dose
Animals/
Dose
Group
Group
RBC
RBC
ChE
ChE
Detectable
Difference
Detectable
Difference
Limit
of
Detection
for
RBC
ChE
Inhibition
Limit
of
Detection
for
RBC
Limit
of
Detection
for
RBC
ChE
ChE
Inhibition
Inhibition
°
RBC
RBC
ChE
ChE
levels
have
higher
background
levels
have
higher
background
variability
than
brain
variability
than
brain
°
Statistical
analysis
shows
20
percent
Statistical
analysis
shows
20
percent
effect
level
is
the
limit
of
detection
effect
level
is
the
limit
of
detection
 
Cannot
discern
10
percent
effect
from
Cannot
discern
10
percent
effect
from
background
background
Complications
in
Comparing
Brain
and
RBC
Cholinesterase
Complications
in
Comparing
Brain
Complications
in
Comparing
Brain
and
RBC
Cholinesterase
and
RBC
Cholinesterase
°
Comparison
of
brain
and
RBC
Comparison
of
brain
and
RBC
ChE
ChE
for
for
carbofuran
carbofuran
is
affected
by
the
availability
of
is
affected
by
the
availability
of
data
data
 
Brain
Brain
ChE
ChE
has
data
from
EPA
has
data
from
EPA­
NHEERL
study
with
NHEERL
study
with
earliest
time
point
of
30
minutes
earliest
time
point
of
30
minutes
 
RBC
RBC
ChE
ChE
has
data
from
two
studies
has
data
from
two
studies
°
EPA
EPA­
NHEERL
with
earliest
time
point
of
30
minutes
NHEERL
with
earliest
time
point
of
30
minutes
°
FMC
FMC­
time
course
with
earliest
time
point
of
15
minutes
time
course
with
earliest
time
point
of
15
minutes
 
The
only
direct
comparison
between
brain
and
RBC
The
only
direct
comparison
between
brain
and
RBC
with
more
than
one
dose
group
is
at
40
minutes
for
the
with
more
than
one
dose
group
is
at
40
minutes
for
the
EPA
EPA­
NHEERL
study
NHEERL
study
°
Carbofuran
Carbofuran
has
a
database
bias
because
only
has
a
database
bias
because
only
RBC
has
data
available
at
15
minutes
RBC
has
data
available
at
15
minutes
BMD10Brain
for
Carbofuran
BMD
BMD
10
10Brain
Brain
for
for
Carbofuran
Carbofuran
°
Derived
from
NMC
CRA
for
NMC
relative
Derived
from
NMC
CRA
for
NMC
relative
potency
assessment
potency
assessment
 
Maximum
inhibition
assumed
to
be
30
minutes
Maximum
inhibition
assumed
to
be
30
minutes
°
Brain
10
percent
Brain
10
percent
ChE
ChE
inhibition
level
inhibition
level
selected
by
EPA
because:

selected
by
EPA
because:

 
At
or
near
the
limit
of
detection
At
or
near
the
limit
of
detection
 
Limit
of
detection
for
brain
data
verified
by
Limit
of
detection
for
brain
data
verified
by
power
calculation
power
calculation
BMD10RBC
for
Carbofuran
BMD
BMD
10
10RBC
RBC
for
for
Carbofuran
Carbofuran
°
Derived
from
NMC
CRA
for
Derived
from
NMC
CRA
for
carbamates
carbamates
relative
potency
assessment
relative
potency
assessment
 
Maximum
inhibition
assumed
to
be
15
minutes
Maximum
inhibition
assumed
to
be
15
minutes
°
10
percent
10
percent
ChE
ChE
inhibition
level
selected
inhibition
level
selected
by
EPA
by
EPA
 
Limit
of
detection
for
RBC
Limit
of
detection
for
RBC
ChE
ChE
Inhibition
was
Inhibition
was
not
considered
in
NMC
CRA
or
HED
March
not
considered
in
NMC
CRA
or
HED
March
2006
2006
EPA­
NHEERL
and
FMC­
Time
Course
Studies
Have
Different
Designs
EPA
EPA­
NHEERL
and
FMC
NHEERL
and
FMC­
Time
Course
Time
Course
Studies
Have
Different
Designs
Studies
Have
Different
Designs
13
time
points;

Earliest
time
point
at
15
min
7
time
points;

Earliest
time
point
at
30
min
1
time
point;

40
min
Number
of
time
Number
of
time
points
points
3
2
6
Number
of
doses
Number
of
doses
(
incl
(
including
uding
controls)

controls)
Multiple
time
points/
rat
by
modified
Ellman
method
Once/
rat
by
radiometric
method
Blood
samples
Blood
samples
Sprague­
Dawley
Long­
Evans
Rat
Rat
strain
train
FMC
FMC
Time
Time­
Course
Course
EPA
EPA­
NHEERL
NHEERL
Time
Time­
Course
Course
EPA
EPA­
NHEERL
NHEERL
Dose
Dose­
Response
Response
Note:
Combining
disparate
datasets
is
questionable
Most
Direct
Comparison
between
RBC
and
Brain
ChEI:
EPA­
NHEERL
Data
at
40
Minutes
Most
Direct
Comparison
between
Most
Direct
Comparison
between
RBC
and
Brain
RBC
and
Brain
ChEI
ChEI:
EPA
:
EPA­
NHEERL
NHEERL
Data
at
40
Minutes
Data
at
40
Minutes
Note:
Author
concluded
"
very
close
correspondence
between
brain
and
RBC"
ChEI
EPA­
NHEERL
Study
Maximum
Observed
Inhibition
EPA
EPA­
NHEERL
Study
NHEERL
Study
Maximum
Observed
Inhibition
Maximum
Observed
Inhibition
°
Earliest
non
Earliest
non­
zero
time
point
zero
time
point
measurement,
30
minutes,
had
maximum
measurement,
30
minutes,
had
maximum
observed
inhibition
effect
observed
inhibition
effect
FMC­
Time
Course
Study
Maximum
Observed
Inhibition
FMC
FMC­
Time
Course
Study
Time
Course
Study
Maximum
Observed
Inhibition
Maximum
Observed
Inhibition
°
Earliest
non
Earliest
non­
zero
time
point
measurement,

zero
time
point
measurement,

15
minutes,
had
maximum
observed
inhibition
15
minutes,
had
maximum
observed
inhibition
Maximum
RBC
Inhibition
is
Not
Comparable
Across
Studies
(
0.5
mg/
kg)

Maximum
RBC
Inhibition
is
Not
Maximum
RBC
Inhibition
is
Not
Comparable
Across
Studies
Comparable
Across
Studies
(
0.5
mg/
kg)

(
0.5
mg/
kg)

Note:
Combining
these
data
causes
instability
in
the
model
estimates
NMC
CRA
BMD10
Estimate
for
RBC
was
Based
on
Combined
Data
Set
NMC
CRA
BMD
NMC
CRA
BMD
10
10
Estimate
for
RBC
Estimate
for
RBC
was
Based
on
Combined
Data
Set
was
Based
on
Combined
Data
Set
°
NMC
CRA
dose
NMC
CRA
dose­
response
response­
time
model
time
model
 
Non
Non­
linear
statistical
model
that
estimates
the
BMD
and
linear
statistical
model
that
estimates
the
BMD
and
recovery
half
recovery
half­
life
values
across
separate
dose
life
values
across
separate
dose­

response
relationships
for
each
study,
sex,
and
time
response
relationships
for
each
study,
sex,
and
time
point
measurements
point
measurements
 
BMD
estimated
from
the
dose
BMD
estimated
from
the
dose­
response
relationship
response
relationship
across
each
time
measurement
across
each
time
measurement
°
Time
of
maximum
observed
Time
of
maximum
observed
ChE
ChE
inhibition
is
a
inhibition
is
a
key
factor
in
the
dose
key
factor
in
the
dose­
response
model
response
model
 
Different
assumptions
for
time
of
maximum
inhibition
Different
assumptions
for
time
of
maximum
inhibition
were
used
for
RBC
and
brain
(
15
minutes
versus
were
used
for
RBC
and
brain
(
15
minutes
versus
30
minutes)

30
minutes)
Traditional
BMD
Modeling:
Dose­

Response
Model
for
One
Time
Point
Traditional
BMD
Modeling:
Dose
Traditional
BMD
Modeling:
Dose­

Response
Model
for
One
Time
Point
Response
Model
for
One
Time
Point
NMC
CRA
Model
is
Unique:

Estimates
Across
Time
and
Dose
Unlike
Traditional
BMD
Models
NMC
CRA
Model
is
Unique:

NMC
CRA
Model
is
Unique:

Estimates
Across
Time
and
Dose
Estimates
Across
Time
and
Dose
Unlike
Traditional
BMD
Models
Unlike
Traditional
BMD
Models
1.5
0.5
0.8
0.11
0.30
0.19
20
20
20
RBC
RBC
Combined
EPA­
NHEERL
only
FMC­
time
course
only
 

0.16
10
Brain
Brain
EPA­
NHEERL
Brain
:
RBC
Brain
:
RBC
Ratio
Ratio
BMD
BMD
(
mg/
kg)

(
mg/
kg)

Effect
Effect
Level
Level
(
percent)

(
percent)

Data
Set
Data
Set
BMD
Estimates
Using
Dose­

Response­
Time
Model
(
NMC
CRA)

BMD
Estimates
Using
Dose
BMD
Estimates
Using
Dose­

Response
Response­
Time
Model
(
NMC
CRA)

Time
Model
(
NMC
CRA)
Limitations
of
NMC
CRA
Approach
Limitations
of
NMC
CRA
Approach
Limitations
of
NMC
CRA
Approach
°
Model
convergence
issues
Model
convergence
issues
 
Gets
different
results
dependent
on
different
starting
Gets
different
results
dependent
on
different
starting
values
values
 
Lack
of
documentation
on
this
issue
Lack
of
documentation
on
this
issue
°
Scarcity
of
data
at
early
time
points
impacts
Scarcity
of
data
at
early
time
points
impacts
model
results
model
results
°
Combining
datasets
exacerbates
issues
with
Combining
datasets
exacerbates
issues
with
approach
approach
 
Differences
in
study
designs
result
in
different
model
Differences
in
study
designs
result
in
different
model
results
(
time
points,
dose
selection
and
measurement
results
(
time
points,
dose
selection
and
measurement
method)

method)

 
High
variability
of
study
results
impacts
model
results
High
variability
of
study
results
impacts
model
results
0.50
1.3
0.32
0.12
20
20
RBC
RBC
EPA­
NHEERL,

40
minutes
FMC
time
course,

15
minutes
 

0.16
10
Brain
Brain
EPA­
NHEERL
Brain
:
RBC
Brain
:
RBC
Ratio
Ratio
BMD
BMD
(
mg/
kg)

(
mg/
kg)

Effect
Effect
Level
Level
(
percent)

(
percent)

Data
Set
Data
Set
BMD
Estimates
Using
Traditional
Dose­
Response
Model
(
OPCumRisk)

BMD
Estimates
Using
Traditional
BMD
Estimates
Using
Traditional
Dose
Dose­
Response
Model
(

Response
Model
(
OPCumRisk
OPCumRisk)
Supporting
Information
from
Human
Data
Supporting
Information
from
Human
Supporting
Information
from
Human
Data
Data
0.0003
10
Intrasp,

10
Intersp*,

1
FQPA,
1
Db
BMDL10
from
rat
pup
brain
(
0.03
mg/
kg)
aPAD
aPAD
(
mg/
kg)

(
mg/
kg)

Uncertainty
Uncertainty
Factors
Factors
Approach
Approach
0.0008
10
Intrasp,

1
Intersp,

2.5
FQPA,
1
Db
BMDL10
from
human
RBC
FMC
1976
study
(
0.02
mg/
kg)
0.002
10
Intrasp,

1
Intersp,

2.5
FQPA,
1
Db
BMDL20
from
human
RBC
FMC
1976
study
(
0.04
mg/
kg)

Note:
Assumes
default
UF
Final
Conclusions
for
Database
UF
Final
Conclusions
for
Database
UF
Final
Conclusions
for
Database
UF
°
BMD
BMD
10
10
for
rat
pup
brain
for
rat
pup
brain
ChE
ChE
is
protective
is
protective
of
adverse
effects
for
RBC
of
adverse
effects
for
RBC
ChE
ChE
°
BMD
BMD
20
20
is
more
appropriate
when
is
more
appropriate
when
evaluating
RBC
evaluating
RBC
ChE
ChE
inhibition
in
rats
inhibition
in
rats
°
5X
database
UF
for
relative
sensitivity
of
5X
database
UF
for
relative
sensitivity
of
brain
and
RBC
brain
and
RBC
ChE
ChE
inhibition
in
rats
is
inhibition
in
rats
is
not
necessary
not
necessary
Interspecies
UF
Interspecies
UF
Interspecies
UF
°
The
interspecies
UF
should
be
reduced
The
interspecies
UF
should
be
reduced
because:

because:

 
EPA
has
already
concluded
the
rat:
human
ratio
EPA
has
already
concluded
the
rat:
human
ratio
is
approximately
1X
is
approximately
1X
 
EPA
adopted
a
similar
approach
for
other
EPA
adopted
a
similar
approach
for
other
carbamates
carbamates
 
Analysis
of
rat
and
human
Analysis
of
rat
and
human
BMDs
BMDs
shows
that
a
shows
that
a
10X
UF
is
not
needed
10X
UF
is
not
needed
Worker
Exposure
Worker
Exposure
Worker
Exposure
°
Point
of
departure
for
worker
exposure
Point
of
departure
for
worker
exposure
should
be
0.13
mg/
kg
based
on
acute
rat
should
be
0.13
mg/
kg
based
on
acute
rat
brain
brain
ChEI
ChEI
(
EPA
(
EPA­
NHEERL)

NHEERL)

 
Ratio
of
Brain:
RBC
values
center
around
one
Ratio
of
Brain:
RBC
values
center
around
one
 
Use
brain
Use
brain
ChEI
ChEI
as
point
as
point­
of
of­
departure
departure
 
Worst
Worst­
case
dermal
human
study
supports
0.17
case
dermal
human
study
supports
0.17
mg/
kg
for
point
of
departure
mg/
kg
for
point
of
departure
°
Dermal
absorption
factor
should
be
3.5%

Dermal
absorption
factor
should
be
3.5%

 
Based
on
Shah
et
al.
calculated
dermal
Based
on
Shah
et
al.
calculated
dermal
absorption
at
8
hours
(
instead
of
24
hours)

absorption
at
8
hours
(
instead
of
24
hours)
Benefits
and
Path
Forward
Benefits
and
Path
Forward
Benefits
and
Path
Forward
