Document ID: EPA-HQ-OPP-2004-0349-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-11-09T05:00Z

Page
1
of
13
Background
Document
for
FIFRA
Scientific
Advisory
Panel
"
The
N­
methyl
Carbamate
Cumulative
Risk
Assessment:
Strategies
and
Methodologies
for
Exposure
Assessment"

December
3,
2004
Key
Bridge
Holiday
Inn
Arlington
,
VA
Prepared
by:
Office
of
Pesticide
Programs
US
Environmental
Protection
Agency
Page
2
of
13
Table
of
Contents
I.
Purpose.........................................................................................................
3
II.
Brief
History:
Cumulative
Risk
Under
the
FQPA
...........................................
3
III.
Cumulative
Risk
Assessment
of
the
N­
Methyl
Carbamates.......................
5
A.
Overview
of
Activities
to
Date....................................................................
5
1.
Determining
the
Common
Mechanism
Group........................................
5
2.
Determining
the
Cumulative
Assessment
Group
...................................
5
B.
On­
Going
Activities....................................................................................
7
1.
Empirical
dose­
response
modeling........................................................
7
2.
Physiologically­
Based
Pharmacokinetic
Model
Based
Approach...........
8
3.
Developing
Exposure
Scenarios
..........................................................
11
4.
Next
Steps
...........................................................................................
12
IV.
Summary
.................................................................................................
12
V.
References..................................................................................................
13
Page
3
of
13
I.
Purpose
This
document
provides
the
members
of
the
FIFRA
Scientific
Advisory
Panel
(
SAP)
and
the
public
with
background
material
and
a
brief
historical
summary
of
cumulative
risk
assessment
for
the
December
3,
2004
FIFRA
Scientific
Advisory
Panel
(
SAP)
meeting.
The
document
discusses
the
general
framework
for
the
development
of
the
cumulative
risk
assessment
for
the
Nmethyl
carbamate
group
of
pesticides,
summarizes
the
procedures
used
to
identify
the
N­
methyl
carbamate
cumulative
assessment
group,
and
describes
anticipated
"
next
steps"
for
the
carbamate
cumulative
risk
assessment.
The
document
is
designed
to
provide
the
regulatory
context
for
the
white
paper
entitled
"
Designing
Exposure
Models
that
Support
PBPK/
PBPD
Models
of
Cumulative
Risk"
developed
by
the
LifeLife
Group
Inc
(
LLG).;
EPA
is
committed
to
the
continual
improvement
of
tools
and
methodologies
available
for
developing
risk
assessments;
the
concepts
discussed
in
this
background
document
and
the
accompanying
white
paper
are
an
important
component
in
promoting
further
progress
in
the
development
of
methods
to
evaluate
cumulative
risk.

The
December
3,
2004
meeting
of
the
FIFRA
SAP
is
the
first
of
what
will
be
several
meetings
concerning
the
development
of
a
cumulative
risk
assessment
for
the
N­
methyl
carbamate
class
of
pesticides.
A
second
meeting
of
the
SAP
is
anticipated
to
occur
in
February
2005
and
will
include
a
"
casestudy
example
for
which
advice
is
sought
by
the
Agency
on
several
issues
concerning
the
N­
methyl
carbamate
cumulative
risk
assessment.
The
anticipated
content
of
this
February
SAP
is
discussed
and
detailed
in
Attachment
1
of
this
document.

II.
Brief
History:
Cumulative
Risk
Under
the
FQPA
In
assessing
the
potential
health
risks
associated
with
exposure
to
pesticides,
EPA's
attention
has
historically
focused
on
single
pathways
of
exposure
(
e.
g.,
pesticide
residues
in
food,
water,
or
residential/
nonoccupational
uses)
for
individual
chemicals,
and
not
on
the
potential
for
individuals
to
be
exposed
to
multiple
pesticides
by
all
pathways
(
and
routes)
concurrently.
In
1993,
a
report
by
the
National
Research
Council
(
NRC)
made
several
recommendations
on
how
to
improve
the
assessment
of
health
risks
posed
by
pesticides
in
the
diets
of
infants
and
children
(
NRC,
1993).
One
recommendation
included
consideration
of
all
sources
of
dietary
and
non­
dietary
exposures
to
pesticides
and
assessment
of
risks
from
exposure
to
multiple
pesticides
that
cause
a
common
toxic
effect.
The
NRC
publication
provided
an
example
for
five
organophosphorus
pesticides.

Several
years
after
the
publication
of
the
NRC
report,
Congress
passed
FQPA
in
1996
which
instructed
EPA
to
base
its
assessment
of
the
risk
posed
by
the
pesticide
chemical
on
aggregate
(
i.
e.,
total
food,
drinking
water,
residential,
and
other
non­
occupational)
exposure
to
the
pesticide;
FQPA
also
required
EPA
Page
4
of
13
to
consider
available
information
concerning
the
combined
toxic
effects
to
human
health
that
may
result
from
dietary,
residential,
or
other
non­
occupational
exposure
to
chemicals
that
have
a
common
mechanism
of
toxicity
(
i.
e.,
cumulative
risk).
OPP
has
developed
a
guidance
document
for
developing
cumulative
risks
assessments
under
FQPA
(
USEPA,
2002a).
This
guidance
document
states
that
cumulative
risk
assessments
differ
from
the
single­
chemical
aggregate
risk
assessments
both
in
focus
and
intent
and
that
the
objectives
of
a
CRA
are
to:

Define
the
characteristics
of
the
exposure
to
a
group
of
chemicals
that
act
by
a
common
mechanism
of
toxicity

Estimate
multichemical,
multipathway
risks
reflecting
real­
world
exposure
to
pesticides,
including
the
changing
patterns
of
residue
levels
as
they
relate
to
differences
in
location,
time,
and
co­
occurrence

Identify
significant
contributors
to
risk

Characterize
the
confidence
in
the
conclusions
and
the
uncertainties
encountered
in
the
assessment

Facilitate
a
greater
understanding
of
the
potential
results
of
changes
in
pesticide
uses
and
possible
mitigation
activities.

Based
on
the
above
guidance
and
principles,
OPP
released
the
revised
cumulative
risk
assessment
for
the
organophosphorus
pesticides
(
OP)
in
June
2002
(
USEPA
2002b).
In
this
assessment,
OPP
developed
and
demonstrated
in
detail
the
methods
and
parameters
that
should
be
considered
in
estimating
cumulative
risk
associated
with
common
mechanism
pesticides
by
multiple
pathways
of
exposure.
Various
aspects
of
the
hazard
and
dose­
response
assessment
and
the
exposure
analyses
were
presented
to
both
the
SAP
and
the
public
for
comment
numerous
times
over
the
course
of
several
years.
Both
the
SAP
and
the
public
provided
helpful
and
insightful
comments
and
ideas
which
were
incorporated
into
the
revised
documents.
OPP
is
currently
developing
a
cumulative
risk
assessment
for
the
N­
methyl
carbamate
class
of
pesticides.
The
SAP
meeting
scheduled
for
December
3,
2004
is
the
first
in
a
series
of
scientific
peer
reviews
expected
for
the
cumulative
risk
assessment
of
the
N­
methyl
carbamate
pesticides.
Page
5
of
13
III.
Cumulative
Risk
Assessment
of
the
N­
Methyl
Carbamates
A.
Overview
of
Activities
to
Date
1.
Determining
the
Common
Mechanism
Group
The
first
step
of
producing
a
cumulative
risk
assessment
is
to
identify
a
group
of
chemicals
that
produce
a
common
toxic
effect(
s)
by
a
common
mechanism
of
toxicity.
OPP
has
developed
a
general
framework
for
identifying
the
chemicals
that
belong
to
that
group
(
USEPA,
1999).
The
cumulative
guidance
states
that,
in
determining
this
common
mechanism
group
(
CMG),
careful
attention
should
be
given
to
a
variety
of
factors
including
the
mechanism
of
toxicity,
the
time
dimensions
of
the
toxic
effects
and
exposure,
and
the
pesticide
exposure
patterns
and
treatment
scenarios.
Thus,
assessing
the
potential
for
two
or
more
carbamate
pesticides
to
act
by
the
same
mechanism
involves
the
consideration
of
three
principles:
1)
they
cause
the
same
critical
effect(
s);
2)
they
act
on
the
same
molecular
target
at
the
same
target
tissue;
and
3)
they
act
by
the
same
biochemical
mechanism
of
action
perhaps
because
they
share
a
common
toxic
intermediate
(
Mileson,
1998).
OPP
found
that
the
three
principles
were
met
for
the
ChE­
inhibiting
carbamates
and
judged
that
cholinesterase
(
ChE)
inhibition
was
a
scientifically
accepted
mechanism
of
action
for
the
carbamates
which
provides
a
sufficient
basis
for
determining
a
common
mechanism
of
toxicity
for
grouping
carbamate
pesticides
(
USEPA,
1999b).

Thus,
OPP
concluded
that
the
pesticides
that
comprise
the
subgroup
of
N­
methyl
carbamates,
based
on
their
structural
characteristics
and
similarity
and
their
shared
ability
to
inhibit
acetylcholinesterase
by
carbamylation
of
the
serine
hydroxyl
group
located
in
the
active
site
of
the
enzyme,
should
be
designated
as
a
CMG
(
USEPA,
2001).

2.
Determining
the
Cumulative
Assessment
Group
Once
the
chemical
members
of
a
CMG
are
identified,
a
necessary
follow­
on
step
in
assessing
the
cumulative
risk
of
a
common
mechanism
group
(
here,
the
N­
methyl
carbamates)
involves
selecting
a
subset
of
these
CMG
chemicals
as
a
Cumulative
Assessment
Group
(
CAG).
As
the
risk
assessor
proceeds
with
the
cumulative
assessment,
it
is
important
to
determine
candidate
chemicals
and
uses,
routes,
and
pathways
from
the
CMG
that
may
cause
cumulative
effects.
As
described
in
the
Cumulative
Guidance
(
USEPA
2002a),
this
subset
of
CMG
Page
6
of
13
chemicals
is
selected
because
not
all
chemicals
grouped
by
common
mechanism
of
toxicity
should
necessarily
be
included
in
a
quantitative
cumulative
risk
assessment.
For
example,
initial
cumulative
assessments
should
not
attempt
to
quantify
risk
resulting
from
chemicals
with
low
hazard
potential
or
from
minor
exposure
scenarios,
but
should
instead
focus
on
those
chemicals
that
are
likely
to
be
risk
contributors.
Specifically,
the
CAG
 
and
consequently
the
cumulative
risk
assessment
 
should
exclude
those
chemicals,
those
chemical
uses,
and
those
exposure
scenarios/
routes/
pathways
for
which
risk
and
exposure
does
not
contribute
in
any
meaningful
or
substantive
ways
to
the
total
cumulative
risk
picture1.
Although
a
chemical(
s)
may
be
removed
from
the
quantification
of
risk,
the
rationale
for
such
decisions
should
be
transparently
explained.
Thus,
all
chemicals
that
were
grouped
by
a
common
mechanism
of
toxicity
should
be
accounted
for
(
qualitatively
or
quantitatively)
in
the
final
assessment
OPP
began
the
process
of
determining
the
members
of
the
CAG
by
identifying
those
carbamates
which
contained
the
N­
methyl
structural
moiety2.
OPP
then
further
narrowed
the
list
of
the
potential
CAG­
candidates
by
reviewing
OPP
databases
to
determine
those
CMG
members
that
have
active
food
or
residential
registrations.
Those
carbamates
which
have
neither
food
nor
residential
(
non­
food)
current
registrations
were
eliminated
from
further
consideration
for
inclusion
in
the
CAG.

Next,
OPP
investigated
the
presence,
pattern,
and
magnitudes
of
residues
in
the
USDA's
Pesticide
Data
Program
(
PDP)
database
through
2002.
Those
chemicals
for
which
PDP
did
collect
residue
data
but
did
not
detect
any
residues
were
eliminated
from
consideration
from
the
CAG
if
there
were
no
residential
uses.
No
chemicals
were
excluded
from
the
CAG
as
a
result
of
this
analysis.
Finally,
those
chemicals
that
are
currently
undergoing
phase­
out
or
cancellation
were
removed
from
the
CAG.
As
was
done
with
the
OP
assessment,
chemicals
currently
undergoing
phase­
out
or
cancellation
are
not
included
in
the
CAG
since
exposures
are
expected
to
be
zero
at
some
point
in
the
near
future.

1
As
stated
in
the
Cumulative
Guidance
,
"
This
focus
on
likely
risk
contributors
is
important
...
since
a
large
number
of
chemicals
may
increase
the
complexity
and
uncertainty
with
no
substantial
change
in
total
exposure.
(
USEPA,
2002b).

2
Some
exceptions
were
made
as
described
in
additional
detail
in
the
Federal
Register
Notice.
For
example,
formetanate
hydrochloride
was
included
in
this
group
due
to
its
mode
of
action
rather
than
its
structural
similarity
to
the
N­
methyl
carbamates.
Page
7
of
13
Based
on
the
above
information,
OPP's
final
corrected
and
updated
proposed
list
of
N­
methyl
carbamates
which
OPP
expects
to
include
in
the
cumulative
risk
assessment
for
the
carbamate
pesticides
is
as
follows:

Aldicarb/
Aldoxycarb
Carbaryl
Carbofuran
Formetanate
HCl
Methiocarb
Methomyl
Oxamyl
Pirimicarb
Propoxur
Thiodicarb
These
carbamates
all
display
ChE­
inhibiting
activity,
have
current
active
registrations,
and
are
expected
to
contribute
to
the
carbamate
cumulative
risk
assessment
through
quantitatively
meaningful
exposure
scenarios.

B.
On­
Going
Activities
OPP
is
currently
working
with
EPA's
Office
Research
and
Development
to
develop
the
cumulative
hazard
assessment
using
different
approaches.

1.
Empirical
dose­
response
modeling
Work
is
on­
going
at
the
National
Health
and
Environmental
Effects
Research
Laboratory
(
NHEERL)
to
develop
use
empirical
approaches
to
develop
Relative
Potency
Factors
(
RPFs)
using
blood
and
brain
ChE­
inhibition
data
from
rat
toxicology
studies.
As
the
mechanism
of
action
for
this
group
is
AChE
inhibition
followed
by
rapid
recovery,
this
work
also
entails
quantitative
modeling
of
the
available
data
for
recovery
of
ChE­
inhibition.
In
the
RPF
approach,
the
toxic
potency
of
each
chemical
is
first
determined.
The
determination
of
toxic
potency
should,
to
the
extent
feasible
with
available
data,
be
conducted
on
a
uniform
basis
(
i.
e.,
same
measure
of
potency,
for
the
same
effect,
from
the
same
test
species/
sex
using
studies
of
comparable
methodology).
To
determine
relative
potency,
a
chemical
from
the
CAG
is
selected
to
serve
as
the
index
chemical.
The
index
chemical
is
used
as
the
point
of
reference
for
standardizing
the
common
toxicity
of
the
other
chemical
members
of
the
CAG.
Page
8
of
13
2.
Physiologically­
Based
Pharmacokinetic
Model
Based
Approach
In
addition
to
the
empirical
dose­
response
modeling
described
above,
the
cumulative
guidance
(
USEPA,
2002a)
describes
other
methods
including
the
use
of
physiologically­
based
pharmacokinetic/
dynamic
modeling
(
PBPK/
PD).
As
discussed
in
the
cumulative
guidance,
the
level
of
refinement
for
each
cumulative
risk
assessment
will
depend
on
several
factors;
specifically
included
among
these
is
the
availability
of
adequate
and
appropriate
data
for
the
particular
common
mechanism
group
of
interest.

The
FIFRA
SAP
has
previously
encouraged
OPP
to
consider
using
PBPK/
PD
models
(
FIFRA
SAP
2001,
2002)
in
developing
cumulative
risk
assessments.
In
December
2003,
EPA
discussed
with
the
FIFRA
SAP
aspects
of
a
draft
strategy
for
including
PBPK/
PD
modeling
into
its
cumulative
risk
assessment.
Key
issues
included
in
the
December
2003
review
included
the
key
data
needed
to
support
parameterization
of
a
PBPK/
PD
model
and
the
basic
structure
for
a
multi­
chemical
model
appropriate
for
the
Nmethyl
carbamate
pesticides.
This
common
mechanism
group
has
been
identified
as
good
case
study
for
the
application
of
PBPK/
PD
modeling
into
cumulative
risk
assessment.

PBPK/
PD
models
are
data
and
resource
intensive.
Very
few
PBPK
models
have
been
used
by
EPA's
IRIS
program
(
Integrated
Risk
Information
System),
and
OPP
has
not
used
such
models
to
support
pesticide
registration
(
or
for
developing
cumulative
risk
assessments).
Scientists
from
OPP
and
ORD's
National
Exposure
Research
Laboratory
(
NERL)
are
collaborating
on
the
multichemical
PBPK/
PD
case
study
in
order
to
gain
experience
for
developing
a
PBPK/
PD
model
that
is
sufficiently
robust
for
regulatory
purposes.
OPP
is
developing
this
case
study
in
a
stepwise
manner
and
soliciting
scientific
peer
review
at
each
stage.
In
this
way,
the
learning
and
development
process
is
transparent
and
open
to
public
evaluation
and
participation.
With
this
case
study,
EPA
can
identify
critical
needs
and
begin
the
process
of
filling
these
so
that
in
the
future
the
necessary
tools
may
be
both
available
and
operational.
Tolerance
reassessment,
including
the
cumulative
risk
assessment
for
the
N­
methyl
carbamates,
must
be
completed
by
August
2006.
Given
the
early
stage
of
development
of
these
models,
it
is
not
known
to
what
extent
the
PBPK
model
can
be
used
for
cumulative
risk
assessment
of
the
N­
methyl
carbamates.
Page
9
of
13
Two
of
the
immediate
critical
needs
that
OPP
has
identified
for
development
and
use
of
these
models
are
the
generation
of
pharmacokinetic
data
for
the
pesticides
or
pesticide
classes
of
interest
and
the
development
a
"
link"
or
interface
between
the
models
currently
in
use
in
OPP
designed
to
provide
exposure
estimates
and
the
PBPK/
PD
models
currently
being
developed
by
ORD
and
others.
These
two
data
needs
are
discussed
in
more
detail
below.

Pharmacokinetic
Data
Pharmacokinetic
(
PK)
and
pharmacodynamic
(
PD)
data
provide
the
basis
for
the
development
and
evaluation
of
any
PBPK/
PD
model.
OPP
has
systematically
evaluated
the
availability
of
PK
and
PD
data
for
the
N­
methyl
carbamates
and
has
determined
that
for
the
majority
of
N­
methyl
carbamates
the
databases
are
not
sufficiently
complete
for
developing
compound
specific
PBPK/
PD
models.
PK
studies
typically
submitted
to
OPP
for
purposes
of
pesticide
registration
were
designed
to
evaluate
absorption,
distribution
in
tissues
and
organs,
metabolism
and
elimination
in
fluids
and
excreta.
The
study
protocols,
however,
were
not
specifically
designed
to
obtain
parameter
values
needed
for
developing
robust
PBPK/
PD
models.
For
example,
sample
collection
is
typically
not
targeted
or
specified
to
obtain
blood/
tissue
partition
coefficients
or
kinetic
rates
of
metabolism
or
AChE
inhibition
for
particular
chemicals
that
may
be
identified
with
the
critical
metabolic
pathways,
or
mechanisms
of
action.
Instead,
the
guidelines
are
designed
to
account
for
fractional
absorption,
distribution
of
mass
equivalents
in
tissue,
and
specific
identity
of
major
metabolites
in
fluids
and
excreta.
In
addition,
the
guidelines
require
absorption,
distribution,
metabolism,
and
elimination
(
ADME)
studies
be
initially
performed
only
for
the
oral
(
gavage)
route
of
administration.
Dermal
absorption
studies
are
only
conditionally
required.
Ideally,
oral,
dermal
and
intravenous
pharmacokinetic
studies
are
needed
to
quantitatively
distinguish
between
the
kinetics
of
distribution,
metabolism,
and
excretion
from
the
kinetics
of
each
absorption
route.
Lastly,
radiometric
measurements
of
tissue
concentrations
are
not
sufficient
to
identify
the
specific
metabolites
that
would
constrain
the
parameter
values
associated
with
chemical
ADME.
Therefore,
mass
balance
of
parent
chemical
and
metabolites
in
tissues
must
be
inferred
from
excretion
data
as
mass
equivalents
remaining.

Although
relevant
PK
data
are
not
available
for
most
of
the
N­
methyl
carbamates
at
this
time,
key
data
are
available
for
carbaryl.
As
discussed
in
Use
of
Pharmacokinetic
data
to
Refine
Page
10
of
13
Carbaryl
Risk
Estimates
from
Oral
and
Dermal
Exposure
(
USEPA,
2004),
metabolism
studies
specifically
designed
for
purposes
of
evaluating
pharmacokinetics
and
for
developing
a
PBPK/
PD
model
have
been
recently
performed
for
the
single
chemical
(
aggregate)
assessment
of
carbaryl.
These
metabolism
and
pharmacokinetic
studies
were
proposed
by
Bayer
CropScience
in
the
December
2003
and
completed
by
September
2004
following
consultation
with
OPP.
The
studies
included
evaluation
of
internal
dose
of
carbaryl
following
oral,
intravenous,
and
dermal
exposures
in
rats
using
low
and
high
doses.
These
studies
are
not
discussed
in
detail
here
but
instead
are
the
subject
of
a
separate
FIFRA
SAP
review
scheduled
to
occur
on
December
2,
2004.
The
carbaryl
pharmacokinetic
studies
provided
valuable
information
regarding
internal
dose(
s)
and
temporal
aspects
of
metabolism
and
excretion
not
available
from
the
typical
toxicology
studies
or
typical
guideline
metabolism
studies.
As
shown
by
the
completion
of
four
separate
studies
within
nine
months,
pharmacokinetic
data
can
developed
quickly
compared
to
other
typical
toxicology
studies
such
as
sub­
chronic
and
chronic
studies
Exposure
Assessment
Models
Another
critical
need
identified
by
OPP
regarding
the
use
of
PBPK/
PD
models
in
a
regulatory
setting
is
the
linkage
or
interface
between
exposure
assessment
and
PBPK/
PD
model(
s).
Typical
probabilistic
exposure
models
such
as
LifeLine,
CARES,
and
DEEM/
Calendex
estimate
distributions
of
exposure
for
exposure
scenarios
identified
by
the
model
user.
For
a
variety
of
reasons
including
computational
speed,
memory
and
storage
limitations,
and
perceived
utility,
the
output
of
these
models
are
typically
expressed
as
distributions
of
exposure
estimates
for
specified
populations
instead
of
specific,
exhaustive,
or
detailed
exposure
information
about
each
individual
in
the
exposure
simulation.
In
addition,
the
models
are
populated
by
data
that
is
often
grouped
or
summarized
in
some
way
or
presented
in
such
that
necessary
details
are
less
readily
extracted.
For
example,
the
three
exposure
models
in
current
use
by
OPP
(
Lifeline,
CARES,
and
DEEM/
Calendex)
use
consumption
data
derived
from
the
Food
Commodity
Intake
Database
(
FCID)
which
summarizes
exposures
through
food
on
a
daily
time­
step
basis,
not
on
a
smaller
time
step
which
is
more
relevant
for
PBPK
modeling
of
the
(
short­
lived)
Nmethyl
carbamates.
In
addition,
some
models
only
save
a
fraction
of
the
output
records
since
storage,
speed,
memory,
and
other
considerations
prohibit
saving
all
records
from
every
day
of
every
individuals
life.
An
important
advantage
of
using
PBPK
and
PBPK/
PD
models
is
the
capability
of
estimating
internal
Page
11
of
13
exposure(
s)
(
or
internal
dose)
and/
or
potential
toxic
effects
following
environmental
exposures.
PBPK/
PD
models,
as
indicated
above,
can
account
for
dynamic
biological
processes
such
as
absorption,
distribution,
metabolism,
and
excretion
which
may
be
occurring
simultaneously
depending
upon
the
exposure
history
of
the
individual
being
considered
and
the
toxicological
and
other
characteristics
of
the
chemical
being
considered.
These
models
can
estimate
temporal
aspects
of
internal
dose(
s)
at
the
target
site(
s).
In
order
to
take
advantage
of
the
capabilities
of
PBPK/
PD
models,
the
format
and
content
of
output
from
exposure
assessment
models
must
be
amenable
to
inputting
information
directly
into
PBPK/
PD
models.
In
other
words,
the
output
from
the
exposure
assessment
models
needs
to
include
specific,
detailed
information
about
individuals
(
e.
g.,
sex,
age,
body
weight)
in
addition
to
their
exposure
and
behavior
patterns
(
e.
g.,
timing
of
eating
events,
timing
of
outdoor
and
indoor
activities).
By
including
this
detailed
information,
the
PBPK/
PD
model
can
appropriately
estimate
the
temporal
aspects
of
internal
exposures
or
internal
doses
and
the
potential
toxic
outcome
for
different
population
groups.

This
issue
 
the
linkage
between
exposure
assessment
and
PBPK/
PD
models­­­
is
the
topic
of
the
current
SAP
review
and
the
topic
of
the
conceptual
paper
developed
by
the
LifeLine
Group
entitled
"
Designing
Exposure
Models
that
Support
PBPK/
PBPD
Models
of
Cumulative
Risk."

3.
Developing
Exposure
Scenarios
Finally,
detailed
exposure
scenarios
for
all
of
the
uses
remaining
for
each
pesticide
in
the
CAG
are
developed.
This
includes
determination
of
potential
human
exposures
by
all
relevant
pathways,
durations,
and
routes
that
may
allow
simultaneous
exposures,
or
any
sequential
exposures
among
the
CAG
members
that
could
contribute
to
the
same
joint
risk
of
the
common
toxic
effect
(
i.
e.,
either
by
overlapping
internal
doses
or
by
overlapping
toxic
effects).
The
framework
for
estimating
combined
exposures
is
based
on
exposure
to
individuals,
representing
differing
attributes
of
the
population
(
e.
g.,
human
activity
patterns,
place
of
residence,
age)
that
link
pathways/
route
of
exposure
through
scenario
building.
Cumulative
risk
values
for
a
given
common
toxic
effect
are
calculated
separately
for
each
exposure
route
and
duration
and
then
combined.
To
the
extent
data
permit,
the
temporal
and
spatial
linkages
should
be
maintained
for
the
many
factors
defining
a
possible
individual
exposure.
A
decision
must
be
made
on
the
relative
importance
of
scenarios
and
the
need
for
their
inclusion
in
a
Page
12
of
13
quantitative
assessment,
as
well
as
on
the
populations
of
interest
and
locations
for
evaluation
in
the
assessment.
The
potential
for
cooccurrence
of
possible
exposure
scenarios
is
evaluated.
Spatial,
temporal,
and
demographic
considerations
are
major
factors
in
determining
whether
a
concurrent
exposure
is
likely
to
occur.
In
other
words,
all
exposure
events
need
to
occur
over
a
specific
interval
of
time;
events
need
to
agree
in
time,
place,
and
demographic
characteristics;
and
an
individual's
dose
needs
to
be
matched
with
relevant
toxicological
values
in
terms
of
route
and
duration.

4.
Next
Steps
As
described
in
detail
in
Attachment
1
(
Overview
of
Topics
for
February
2005
FIFRA
SAP
meeting),
EPA
is
planning
to
solicit
additional
comment
from
the
SAP
regarding
specific
topics
related
to
the
cumulative
risk
assessment
for
the
N­
methyl
carbamates
such
as
hazard
assessment,
PBPK/
PD
modeling
for
carbaryl,
groundwater
modeling,
and
the
integration
of
hazard
and
exposure.
The
preliminary
cumulative
risk
assessment
for
this
group
of
pesticides
is
expected
to
be
available
to
public
in
the
summer
of
2005.

IV.
Summary
In
1996,
passage
of
the
Food
Quality
Protection
Act
(
FQPA)
imposed
OPP
the
requirement
to
consider
potential
human
health
risks
from
all
pathways
of
dietary
and
non­
dietary
exposures
to
more
than
one
pesticide
acting
through
a
common
mechanism
of
toxicity.
At
each
step
in
the
development
of
its
cumulative
risk
assessment
guidance
and
methodology,
OPP
has
solicited
scientific
peer
review.
In
2001,
EPA
established
the
N­
methyl
carbamate
pesticides
as
a
common
mechanism
group
based
on
their
structural
characteristics
and
also
similarity
and
shared
ability
to
inhibit
acetylcholinesterase
(
AChE)
by
carbamylation
of
the
serine
hydroxyl
group
located
in
the
active
site
of
the
enzyme.
In
early
2004,
EPA
announced
the
members
of
the
CAG
for
the
N­
methyl
carbamate
pesticides.
At
this
time,
work
is
on­
going
to
develop
the
cumulative
risk
assessment
for
this
group
of
pesticides.
EPA
is
committed
to
advancing
the
methodologies
and
approaches
used
in
its
cumulative
risk
assessments.
The
December
3,
2004
SAP
meeting
is
the
first
in
a
series
of
meetings
to
solicit
scientific
peer
review
on
different
aspects
of
the
cumulative
risk
assessment
for
the
N­
methyl
carbamates.
EPA
believes
that
incorporation
and
use
of
pharmacokinetic
and
mechanistic­
based
modeling
approaches
will
help
refine
and
improve
cumulative
risk
assessments.
The
current
review
of
the
issues
discussed
in
the
white
paper
developed
by
the
LifeLine
Group
is
a
key
step
in
the
development
of
such
approaches.
Page
13
of
13
V.
References
Mileson,
B.,
JE
Chambers,
WL
Chen,
W
Dettbarn,
M
Ehrich,
AT
Eldefrawi,
DW
Gaylor,
K
Hammernik,
E
Hodgson,
AG
Karczmar,
S
Padilla,
CN
Pope,
RJ
Richardson,
DR
Saunders,
LP
Sheets,
LG
Sultatos
and
KB
Wallace.
Common
Mechanism
of
Toxicity:
a
case
study
of
organophosphorus
pesticides.
Toxicological
Sciences
41,
p.
p.
8­
20.

NRC
(
National
Research
Council,
Committee
on
Pesticides
in
the
Diets
of
Infants
and
Children)
,
Pesticides
in
the
Diets
of
Infants
and
Children.
National
Academies
Press.
1993.

USEPA
(
1999)
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity,
www.
epa.
gov/
fedrgstr/
EPA­
PEST/
1999/
February/
Day­
05/
o­
p2781.
htm
USEPA,
1999b.
"
A
Science
Policy
on
a
Common
Mechanism
of
Toxicity:
The
Carbamate
Pesticides
And
the
Grouping
of
Carbamate
with
the
Organophosphorus
Pesticides;"
draft
document.
August
30,
1999.
http://
www.
epa.
gov/
scipoly/
sap/
1999/
september/
carbam.
pdf
USEPA,
2001a.
Memorandum
from
Marcia
Mulkey
to
Lois
Rossi.
"
Implementation
of
the
Determinations
of
a
Common
Mechanism
of
Toxicity
for
N_
Methyl
Carbamate
Pesticides
and
for
Certain
Chloroacetanilide
Pesticides."
July
12,
2001.
http://
www.
epa.
gov/
oppfead1/
cb/
csb_
page/
updates/
carbamate.
pdf
USEPA
(
2002a).
"
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
(
2002b).
Revised
Organophosphorus
Pesticide
Cumulative
Risk
Assessment.
Office
of
Pesticide
Programs,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
June
10,
2002.
http://
www.
epa.
gov/
pesticides/
cumulative/
rra_
op
USEPA
(
2004)
Use
of
Pharmacokinetic
Data
to
Refine
Carbaryl
Risk
Estimates
from
Oral
and
Dermal
Exposure.
November,
2004.
http://
www.
epa.
gov/
scipoly/
sap/
index.
htm