Page
1
of
4
FIFRA
SCIENTIFIC
ADVISORY
PANEL
(
SAP)
OPEN
MEETING
December
11
and
12,
2003
FIFRA
SAP
WEB
SITE
http://
www.
epa.
gov/
scipoly/
sap/
OPP
Docket
Telephone:
(
703)
305­
5805
PHYSIOLOGICALLY­
BASED
PHARMACOKINETIC/
PHARMACODYNAMIC
MODELING:
PRELIMINARY
EVALUATION
AND
CASE
STUDY
FOR
THE
N­
METHYL
CARBAMATE
PESTICIDES:
A
CONSULTATION
Thursday,
December
11,
2003
Sheraton
Crystal
City
Hotel
1800
Jefferson
Davis
Highway
Arlington,
Virginia
22202
703­
486­
1111
Please
note
that
all
times
are
approximate.


8:
30
AM
Meeting
Opening
­
Stephen
M.
Roberts,
Ph.
D.
(
Chair
of
the
FIFRA
SAP)


8:
35
AM
Introduction
of
Panel
Members
­
Christopher
Portier,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
40
AM
Administrative
Procedures
by
Designated
Federal
Official
­
Mrs.
Myrta
R.
Christian

8:
45
AM
Opening
Remarks
­
Mr.
Jim
Jones
(
Director,
Office
of
Pesticide
Programs,
Office
of
Prevention,
Pesticides,
and
Toxic
Substances,
EPA)


8:
55
AM
Introduction
and
Background
­
Randolph
Perfetti,
Ph.
D.
(
Office
of
Pesticide
Programs,
EPA)


9:
00
AM
Scope
and
purpose:
Anna
Lowit,
Ph.
D.
(
Office
of
Pesticide
Programs,
EPA)
PBPK/
PD
models
and
cumulative
risk
assessment:
Rory
Connolly,
Sc.
D.
(
CIIT
Centers
for
Health
Research)
Pharmacodynamic
modeling
of
the
N­
methyl
carbamate
pesticides:
Jerry
Blancato,
Ph.
D,
Curtis
Dary,
Ph.
D.
(
Office
of
Research
and
Development,
National
Exposure
Research
Lab,
EPA)


10:
00
AM
Break

10:
15
AM
Computer
implementations
and
simulation
examples:
Jerry
Blancato,
Ph.
D,
Fred
Power,
M.
S.
(
Office
of
Research
and
Development,
National
Exposure
Research
Lab,
EPA)
Model
evaluation:
R.
Woodrow
Setzer,
Ph.
D.
(
Office
of
Research
and
Development,
National
Health
and
Environmental
Effects
Laboratory,
EPA).
Page
2
of
4
Extrapolation
of
PBPK/
PD
models
from
laboratory
animals
to
humans
and
data
needs
for
the
PBPK/
PD
model(
s)
for
the
N­
methyl
carbamate
pesticides:
Rory
Connolly,
Sc.
D.
(
CIIT
Centers
for
Health
Research)
Conclusions
and
summary:
Anna
Lowit,
Ph.
D.
(
Office
of
Pesticide
Programs,
EPA)


12:
00
PM
Lunch

1:
00
PM
Public
Comments

2:
00
PM
Questions
to
the
Panel
1.
Development
of
the
Preliminary
PBPK/
PD
Model
Structure
Conceptually,
PBPK/
PD
models
offer
great
promise
in
cumulative
risk
assessment,
such
as
the
ability
to
incorporate
species,
sex,
or
age­
specific
information
on
biological
processes
and
the
explicit
consideration
of
pharmacokinetic
and
mechanistic
data.
At
present
time,
the
appropriate
pharmacokinetic
data
are
not
available
for
the
majority
of
Nmethyl
carbamate
pesticides.
The
Agency
has
developed
preliminary
model
structure
in
two
computer
languages
(
See
Section
III.
D,
Figures
2
and
3)
for
this
common
mechanism
group
based
on
information
available
at
the
present
time.
Specifically,
the
structure
of
the
preliminary
model
is
based
on:
limited
available
pharmacokinetic
data
from
the
literature;
AChE
inhibition
data
and
rat
metabolic
profiles
from
the
scientific
literature
and/
or
from
studies
submitted
for
pesticide
registrations;
and
previous
PBPK/
PD
models
developed
for
organophosphorus
chemicals.

Question
1.1
Please
comment
on
the
proposed
PBPK/
PD
model
structure
for
the
Nmethyl
carbamate
pesticides
as
described
in
the
document,
with
specific
consideration
of
the
biological
and
mechanistic
basis
for
this
structure.


3:
15
PM
Break

3:
30
PM
Questions
to
the
Panel
(
continued)

2.
Data
Needs
for
the
N­
Methyl
Carbamate
PBPK/
PD
Model
The
document
under
review
describes
an
iterative
process
for
model
development
where
the
model
developer
and
laboratory
scientist
work
collaboratively,
first
to
identify
and
then
to
fill
in
areas
where
data
or
information
are
missing
for
a
particular
chemical(
s).
At
the
present
time,
the
Agency
has
developed
a
preliminary
model
and
has
identified
areas
where
pharmacokinetic
and/
or
pharmacodynamic
data
are
not
available.
These
data
needs,
along
with
the
purpose
of
the
experiment
in
the
modeling
effort,
are
described
in
the
document.
Page
3
of
4
Question
2.1
Please
comment
on
the
adequacy
and
appropriateness
of
the
data
needs
identified
for
the
purpose
of
developing
PBPK/
PD
models
for
individual
Nmethyl
carbamates
and
also
for
developing
the
PBPK/
PD
model
for
the
common
assessment
group
as
a
whole.

Question
2.2
Typically,
parameter
estimation
is
performed
using
a
set
of
available
physiological,
pharmacodynamic,
and
pharmacokinetic
data.
Data
used
for
model
development
are
not
used
for
evaluating
model
reliability.
Instead,
separate
data
sets
are
used.
Given
the
considerable
resources
needed
to
conduct
in
vivo
pharmacokinetic
studies,
particularly
mixture
pharmacokinetic
studies,
identification
of
a
minimum
amount
of
data
needed
to
achieve
an
acceptable
level
of
residual
uncertainty
in
the
PBPK/
PD
model
for
the
common
assessment
group
is
preferred.
Please
comment
on
the
types
of
data
needed
to
evaluate
model
reliability.


5:
30
PM
Adjournment
Friday,
December
12,
2003
Sheraton
Crystal
City
Hotel
1800
Jefferson
Davis
Highway
Arlington,
Virginia
22202
703­
486­
1111
Please
note
that
all
times
are
approximate.


8:
30
AM
Meeting
Opening
­
Stephen
M.
Roberts,
Ph.
D.
(
Chair
of
the
FIFRA
SAP)


8:
35
AM
Introduction
of
Panel
Members
­
Christopher
Portier,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
40
AM
Administrative
Procedures
by
Designated
Federal
Official
­
Mrs.
Myrta
R.
Christian

8:
45
AM
Questions
to
the
Panel
3.
Model
Evaluation
and
Quality
Control
This
document
outlines
a
five­
step
approach
to
evaluating
a
PBPK/
PD
model
for
use
in
cumulative
risk
assessment.
These
steps
include:
1)
determining
and
stating
model
purpose,
2)
development
of
model
structure
based
on
characterization
of
the
biological
and
toxicological
profiles
of
the
individual
members
and
the
common
assessment
group
as
a
whole;
3)
description
of
the
mathematics
of
the
model;
4)
implementation
in
a
computer
language;
and
5)
estimation
of
parameters
and
evaluation
of
model
fit.
Page
4
of
4
Question
3.1
Please
comment
on
this
five­
step
approach
to
evaluating
PBPK/
PD
models,
with
particular
consideration
of
their
use
in
regulatory
settings.
Does
this
approach
encompass
the
main
issues
related
to
model
evaluation
and
quality
control?
If
not,
what
additional
issues
need
to
be
considered?


10:
30
AM
Adjournment
As
noted
above,
please
be
advised
that
agenda
times
are
approximate.
For
further
information,
please
contact
the
Designated
Federal
Official
for
this
meeting,
Mrs.
Myrta
R.
Christian,
via
telephone:
(
202)
564­
8450;
fax:
(
202)
564­
8382;
or
email:
christian.
myrta@
epa.
gov
