Page
1
of
44
Preliminary
N­
Methyl
Carbamate
Cumulative
Risk
Assessment
Preliminary
N­
Methyl
Carbamate
Cumulative
Risk
Assessment
FIFRA
Scientific
Advisory
Panel
August
23­
26,
2005
FIFRA
Scientific
Advisory
Panel
August
23­
26,
2005

Session
1
°
Public
Comments
°
Hazard
Assessment

Session
2
°
Drinking
Water
Exposure
Assessment

Session
3
°
Food
&
Residential
Exposure
Assessment

Session
4
°
Model
Results
Comparison,
Cumulative
(

Multipathway
Analysis,
&
Risk
Characterization
Sessions
Roadmap
Page
2
of
44
Page
3
of
44
Session
4
Preliminary
N­
Methyl
Carbamate
Cumulative
Risk
Assessment:

Model
Results
Comparison,

Cumulative
(
Multi­
pathway)
Analysis,

&
Risk
Characterization
Session
4
Preliminary
N­
Methyl
Carbamate
Cumulative
Risk
Assessment:

Model
Results
Comparison,

Cumulative
(
Multi­
pathway)
Analysis,

&
Risk
Characterization
Health
Effects
Division
Office
of
Pesticide
Programs
Health
Effects
Division
Office
of
Pesticide
Programs
Page
4
of
44
Preliminary
N­
Methyl
Carbamate
Cumulative
Hazard
Assessment:

Risk
Characterization
Preliminary
N­
Methyl
Carbamate
Cumulative
Hazard
Assessment:

Risk
Characterization
David
Miller
Health
Effects
Division
Office
of
Pesticide
Programs
David
Miller
Health
Effects
Division
Office
of
Pesticide
Programs
Page
5
of
44
Risk
Characterization

Introduction
and
Overview

Timeframes
of
exposure

Conclusions
Page
6
of
44
Risk
Characterization

NMC
CRA
complicated,
multi­
faceted
risk
assessment
°
Includes
many
datasets
from
different
sources
and
with
different
quality

Key
decisions
not
yet
made:

°
FQPA
10X
decisions
°
Interspecies
factors
°
Percentile(
s)
of
regulation

Sensitivity
analyses
still
on­
going
Page
7
of
44
Risk
Characterization

Integration
of
hazard
and
exposure
assessments

Dynamic
nature
of
exposure,
cholinesterase
inhibition,
and
recovery

Current
limitations
in
data
and
models

Efforts
to
improve
methods:

°
December
2003:
Physiologically­
Based
Pharmacokinetic/
Pharmacodynamic
Modeling:

Preliminary
Evaluation
and
Case
Study
for
the
NMethyl
Carbamate
Pesticides
°
December
2004:
The
N­
Methyl
Carbamate
Cumulative
Risk
Assessment:
Strategies
and
Methodologies
for
Exposure
Assessment
°
February
2005:
Carbaryl
PBPK/
PD
as
part
of
the
N­
Methyl
Carbamate
Cumulative
Risk
Assessment:
Pilot
Cumulative
Analysis
Page
8
of
44
Risk
Characterization

RPF
Method
combined
with
probabilistic
exposure
models
(

DEEMCalendex
 
,
LifeLife
 
,
CARES
 
)

°
Sum
exposures
over
24
hour
periods

Goal:

°
To
provide
an
appropriate
characterization
of
the
risk
using
existing
tools

Presentation
will
focus
on
example
analyses
to
look
at
timeframes
of
exposure
Page
9
of
44
Timeframe
of
Common
Mechanism
Endpoint

Recovery
from
AChE
inhibition
caused
by
the
N­
methyl
carbamates
is
relatively
rapid
(
minutes
to
hours)


Session
1
focused
on:

°
Dose­
time
empirical
modeling
with
rat
acute
cholinesterase
data
provides
robust
estimates
of
BMD10/
BMDL10
°
Half
life
to
recovery
estimates
indicate
that
recovery
varies
among
chemicals
and
that
for
some,
is
dose
dependant

Generally
range
from
<
1
to
6
hours

4
half­
lives:
~
4
to
24
hours
Page
10
of
44
Time
Frames
of
Exposure

All
three
models
(
DEEM­
Calendex
 
,

LifeLife
 
,
CARES
 
)

°
Sum
exposures
through
food
consumption
over
a
24
hour
period
using
FCID
data
°
Add
in
exposures
through
water
and
residential
sources
over
a
24
hour
period

It
may
be
important
to
consider
the
intra­
day
timing
of
these
exposures
used
to
model
daily
risk
Page
11
of
44
Time
Frames
of
Exposure

If
exposure
to
N­
methyl
carbamates
during
a
24­
hour
period
is
from
a
single
event
or
from
events
closely
spaced
in
time 

 
then
the
approach
(
24­
hour
exposure)
used
in
this
preliminary
assessment
is
expected
to
provide
a
reasonable
approximation
of
the
risk
associated
with
these
exposures
Page
12
of
44
Time
Frames
of
Exposure
However,


If
exposure
to
N­
methyl
carbamates
during
a
24­
hour
period
is
from
multiple
exposure
events
that
are
widely
spaced
in
time,
then
recovery
from
AChE
inhibition
may
occur
between
events 

 
and
the
method
(
24­
hour
exposure)

used
in
this
preliminary
assessment
is
likely
to
overestimate
the
risk
Page
13
of
44
Time
Frames
of
Exposure

Potentially
important
for
all
three
exposure
pathways
°
Food
°
Water
°
Residential
Page
14
of
44
Time
Frames
of
Exposure:

Food

OPP
examined
DEEM
 
outputs
to
investigate
this
issue
°
Single
eating
events
or
multiple
events
°
Spacing
in
time
of
multiple
events

This
analysis
used:

°
DEEM
 
CEC
(
Critical
Exposure
Commodities)
report
°
FCID
Recipe
File
°
CSFII

Analysis
was
presented
at
February,
2005
SAP
of
the
CRA
Case
Study
Page
15
of
44
Time
Frames
of
Exposure:

Food

DEEM
 
CEC
Report
°
Individual
daily
food
exposure
records
from
the
upper
end
of
the
exposure
distribution
°
Records
identify

CSFII
individual

FCID
Food
Commodity
consumed

Residue
concentration
drawn

Amount
of
that
food
consumed

Fraction
of
total
exposure
Page
16
of
44
Time
Frames
of
Exposure:

Food

FCID
Recipe
File
°
Provides
recipes
used
by
USDA
and
EPA
to
link
food
commodities
as
reported
by
DEEM
CEC
to
actual
foods
as
eaten
as
reported
in
CSFII
Page
17
of
44
Time
Frames
of
Exposure:

Food

CSFII
Database
°
Individual
daily
food
intake
records
from
USDA's
national
food
survey
Records
identify

CSFII
individual

Identity
and
amount
food
eaten

Time
of
each
eating
occasion
Page
18
of
44
Time
Frames
of
Exposure:

Food

Comparison
of
DEEMTM
CEC
report
with
FCID
Recipe
File
and
CSFII
data
allows
us
to
determine:

°
Time
of
day
that
each
FCID
Commodity
was
consumed
°
Number
of
times
in
one
day
that
the
food
containing
the
commodity
was
reported
eaten
Page
19
of
44
Hypothetical
Example

As
reported
by
DEEM
CEC:

°
Consumption
of
240
grams
of
"
Beans,
Green,

Baked"
by
an
identified
10
kg
CSFII
individual
°
Green
Beans
contained
0.10
ppm
NMC
pesticide

OPP
would
use
FCID
recipe
file
and
CSFII
report
to
determine
that
consumption
is
due
to
green
bean
casserole
°
Two
separate
eating
occasions

1:
30
pm

6:
30
pm
Page
20
of
44
Time
Frames
of
Exposure:

Food

The
analysis
include
many
daily
exposure
records
representing
the
top
5
percentile
of
the
exposure
distribution
°
Approximately
8000
records
examined
at
>
95th
percentile
Time
Frames
of
Exposure
­­
Food
children
3­
5:
number
of
eating
occasions
sample
of
8005
records
from
top
5
percentile
exposure
73%

20%
5%
1%
1
eating
occasion
2
eating
occasions
3
eating
occasions
4
eating
occasions
35
records
for
5
eating
occasions
7
records
for
6
eating
occasions
No
records
with
more
than
6
eating
occasions
Page
21
of
44
Distribution
of
Time
Between
Eating
Events
0
50
100
150
200
250
300
350
400
450
500
1
2
3
4
5
6
7
8
9
10
11
12
13­
17
Hours
Between
Eating
Events
Number
of
Events
Page
22
of
44
Page
23
of
44
Time
Frames
of
Exposure:

Food

EPA
concluded
from
the
preliminary
analysis:

°
Approximately
2/
3
to
3/
4
of
records
represent
single
eating
events
°
Approximately
20%
of
records
represent
2
eating
events
°
<
5%
of
records
represent
3
or
more
eating
events
°
Records
at
the
high
end
of
the
distribution
are
due
predominantly
to
one
commodity
Page
24
of
44
Time
Frames
of
Exposure:

Food

EPA
further
concluded
from
the
analysis:

°
Approach
based
on
24­
hour
exposures
provides
reasonable
estimate
of
risk
from
Nmethyl
carbamates
from
food

From
the
February,
2005
SAP
Report:

°
"
The
default
assumption
of
eating
events
close
together
in
time
is
a
proper
approach
in
the
context
of
this
pilot
case
study
for
the
N­
methyl
carbamate
exposure
assessment"
Page
25
of
44
Time
Frames
of
Exposure:

Water

CSFII
does
not
provide
timing
information
associated
with
water
consumption
°
Risks
associated
with
exposure
through
the
water
pathway
may
be
overestimated
to
the
extent
that
consumption
of
water
occurs
throughout
the
day
°
Agency
is
seeking
high­
quality
data
which
describes
the
pattern
of
drinking
water
consumption
over
the
course
of
a
day
Page
26
of
44
Time
Frames
of
Exposure:

Water

Scenarios
can
be
generated
to
better
characterize
the
risk
assessment
and
improve
discussion
°
Hypothetical
cases
better
inform
risk
managers
about
the
effect
of
timing
of
drinking
water
consumption
events
and
the
reversibility
of
AChE
inhibition
on
risk
estimates

Potential
drinking
water
scenarios:

°
Upper
bound
risk
°
Intermediate
risk/
Intermittent
exposure
°
Lower
bound
risk
Page
27
of
44
Time
Frames
of
Exposure:

Water

Potential
drinking
water
scenarios:

°
Upper
bound
risk

All
water
consumed
in
a
single
event

Approach
in
the
preliminary
cumulative
risk
assessment
Page
28
of
44
Time
Frames
of
Exposure:

Water

Potential
drinking
water
scenarios:

°
Lower
bound
risk

At
or
near
continuous
consumption
throughout
waking
hours

Use
simple
steady­
state
PK
equations
Page
29
of
44
Time
Frames
of
Exposure:

Water

Potential
drinking
water
scenarios:

°
Intermediate
risk/
Intermittent
exposure

Consumption
varies
in
frequency,
timing,

and
amount
throughout
the
day

Age
group,
activity
level,
etc.


Use
simple
`
PK'
model
developed
by
EPA
to
test
simulations
Page
30
of
44
Time
Frames
of
Exposure:

Water

Basis
for
simple
`
PK'
model
°
Assumptions
were
evaluated
by
SAP
in
February,
2005
°
Dose­
time
empirical
modeling
Example
Suppose,
from
rat
data,
we
have
the
following
parameter
estimates:
0.3
1.5
0.25
0.5
Z
0.3
0.75
0.25
2
Y
0.3
0.5
0.25
4
X
P
TR
(
hours)

T*
(
hours)

BMD
(
mg/
kg)

Chemical
To
get
corresponding
human
parameters,
scale
the
rat
parameters.

For
example:

BMD:
Rat
 
Human
 
Sensitive
Human
(
10x
Inter;
10x
Intra
UFs)

Times:
Rat
 
Human
(
BW3/
4
scaling)

0.1
0.1
4
0.3
6.0
1.0
0.005
Z
0.3
3.0
1.0
0.02
Y
0.3
2.0
1.0
0.04
X
Page
31
of
44
Example
(
cont)

Suppose
an
adult
has
these
exposures
(
in
mg/
kg):
0.0025
0.001
0.008
Total
0.0005
0.004
18:
30
0.0025
0.0005
12:
00
0.004
8:
00
Z
Y
X
Time
Page
32
of
44
Example
(
cont)
Maximum
inhibition:
5.8%

Fraction
of
24hr
day
>
10%:
0%

Fraction
of
24hr
day
>
5%:
7.6%

Fraction
of
24hr
day
>
1%:
54%

Example
Response
Metrics
Result
of
Simplified
PK
Model
Total
Inhibition
X
Y
Z
0.00
0.02
0.04
0.06
0.08
0.10
Time
of
Day
(
24
hour
clock)

Fractional
AChE
Inhibition
11:
00
15:
00
19:
00
23:
00
Page
33
of
44
Page
34
of
44
Time
Frames
of
Exposure:

Water

These
analyses
may
be
useful
to
explore
the
effect
on
risk
of
"
spacing
out"
or
distributing
the
water
consumption
over
the
course
of
a
day
(
and
co­
exposure
from
food
+
water)

°
Permits
qualitative
evaluation
of
sensitivity
of
risk
estimates
to
intra­
day
oral
consumption
patterns
and
effect
of
reversibility
of
AChE
inhibition
Page
35
of
44
Time
Frames
of
Exposure:

Residential

As
with
food
and
water,
residential
exposures
modeled
to
occur
at
one
time
during
the
day

Risks
associated
with
exposure
through
the
residential
pathway
may
be
overestimated
to
the
extent
that
residential
exposures
occur
throughout
the
day

Agency
is
seeking
high­
quality
data
which
describes
the
pattern
of
residential
exposures
over
the
course
of
a
day
°
e.
g.
CHAD,
NHAPS

Assessment
complicated
by
potential
simultaneous
exposure
by
three
routes
Page
36
of
44
Time
Frames
of
Exposure

If
exposure
to
N­
methyl
carbamates
during
a
24­
hour
period
is
from
a
single
event
or
from
events
closely
spaced
in
time 

 
then
the
approach
(
24­
hour
exposure)
used
in
this
preliminary
assessment
is
expected
to
provide
a
reasonable
approximation
of
the
risk
associated
with
these
exposures
Page
37
of
44
Time
Frames
of
Exposure
However,


If
exposure
to
N­
methyl
carbamates
during
a
24­
hour
period
is
from
multiple
exposure
events
that
are
widely
spaced
in
time,
then
recovery
from
AChE
inhibition
may
occur
between
events 

 
and
the
method
(
24­
hour
exposure)

used
in
this
preliminary
assessment
is
likely
to
overestimate
the
risk
Page
38
of
44
Time
Frames
of
Exposure

The
risk
analyses
performed
in
the
current
Preliminary
N­
methyl
carbamate
cumulative
risk
assessment
sums
exposures
over
a
24
hour
period

With
the
understanding
that:

°
exposures
occur
over
the
course
of
a
day
°
some
degree
of
AChE
recovery
occurs
in
the
time
intervals
between
exposures
 
Page
39
of
44
Time
Frames
of
Exposure
 
OPP
is
asking
for
Panel
input
and
comment
on:


the
degree
to
which
risk
estimates
developed
from
attributing
total
daily
exposure
to
one
point
in
time
may
differ
from
those
that
would
result
from
alternate
modeled
scenarios
in
which
intra­
day
timing
is
considered

any
suggestions
that
the
Panel
might
have
with
respect
to
methods
or
techniques
for
refining
risk
estimates
to
take
into
account
intra­
day
timing
of
exposure
and
the
potential
value
of
this
pursuit.
Page
40
of
44
Session
4
Preliminary
Cumulative
Integration:

Questions
to
Panel
Session
4
Preliminary
Cumulative
Integration:

Questions
to
Panel
Health
Effects
Division
Office
of
Pesticide
Programs
Health
Effects
Division
Office
of
Pesticide
Programs
Page
41
of
44
Integration
Question
#
1

The
cumulative
risk
assessment
guidance
describes
key
principles
for
conducting
these
risk
assessments.
One
such
principle
is
the
need
to
consider
the
time
frame
of
both
the
exposure
(
e.
g.,
When
does
exposure
occur?
What
is
the
exposure
duration?)
and
of
the
toxic
effect
(
e.
g.,
What
are
the
time
to
peak
effects
and
the
time
to
recovery?
How
quickly
is
the
effect
reversed?).
EPA's
Preliminary
Cumulative
Risk
Assessment
for
the
N­
methyl
carbamates
describes
the
current
limitations
in
data
and
software
to
fully
characterize
the
dynamic
nature
of
exposure,
effect,
and
recovery
for
this
common
mechanism
group.
In
order
to
address
these
limitations,
OPP
performed
an
examination
of
the
exposure
patterns
for
records
from
the
high
end
of
exposure
distribution
and
found
that
a
large
fraction
(~
70%)

of
daily
records
contributing
to
the
upper
tail
of
the
food
exposure
distribution
represent
single
eating
occasions.

Regarding
drinking
water
and
residential/
nonoccupational
exposure,
EPA's
preliminary
assessment
provided
a
characterization
of
the
current
availability
regarding
datasets
and
models
and
a
description
of
the
impact
of
these
limitations
on
the
risk
estimates
from
specific
exposure
pathways
(
i.
e.,
drinking
water,
residential).
Page
42
of
44
Integration
Question
#
1
I1a.
Please
comment
on
clarity
and
adequacy
of
the
risk
characterization
provided
in
the
preliminary
cumulative
risk
assessment.
Are
there
important
aspects
with
respect
to
the
strengths
and
weaknesses
of
the
risk
characterization
other
than
the
ones
we
identified?
Page
43
of
44
Integration
Question
#
1
I1b.
Is
the
Panel
aware
of
additional
data
which
would
aid
the
Agency
in
its
cumulative
risk
characterization
for
the
N­
methyl
carbamate
pesticides?
For
example,
is
the
Panel
aware
of
any
available
data
on
the
timing
of
water
consumption
events
or
can
the
Panel
make
any
recommendations
regarding
reasonable
assumptions
that
could
be
made
to
help
characterize
the
estimated
risk?
Are
there
other
sensitivity
analyses
and
further
investigations
that
would
be
equally
or
more
important
than
the
ones
we
identified?
Page
44
of
44
