December
9
and
10,
2003
FIFRA
SAP
MEETING
AGENDA
December
5,
2003
Page
1
of
5
FIFRA
SCIENTIFIC
ADVISORY
PANEL
(
SAP)
OPEN
MEETING
December
9
and
10,
2003
FIFRA
SAP
WEB
SITE
http://
www.
epa.
gov/
scipoly/
sap/
OPP
Docket
Telephone:
(
703)
305­
5805
Proposed
Science
Policy:
PPAR­

Agonist­
Mediated
Hepatocarcinogenesis
in
Rodents
and
Relevance
to
Human
Health
Risk
Assessments
TUESDAY,
DECEMBER
9,
2003
HOLIDAY
INN
NATIONAL
AIRPORT
2650
JEFFERSON
DAVIS
HIGHWAY
ARLINGTON,
VIRGINIA
22202
703­
684­
7200
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
­
Gary
E.
Isom,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
40
AM
Administrative
Procedures
by
Designated
Federal
Official
­
Mr.
Steven
Knott

8:
45
AM
Welcome
­
Mr.
Joseph
Merenda,
Jr.
(
Director,
Office
of
Science
Coordination
and
Policy,
Office
of
Prevention,
Pesticides
and
Toxic
Substances,
EPA)


8:
50
AM
Opening
Remarks
­
Mr.
William
Jordan
(
Office
of
Pesticide
Programs,
Office
of
Prevention,
Pesticides,
and
Toxic
Substances,
EPA)


9:
00
AM
Introduction
and
Background
­
Margaret
Stasikowski,
M.
P.
H.
(
Health
Effects
Division,
Office
of
Pesticide
Programs,
EPA)


9:
10
AM
Presentation
on
PPAR 
Agonist­
Induced
Rodent
Tumors:
Modes
of
Action
and
Human
Relevance
­
Jeff
Peters,
Ph.
D.
(
Penn
State
University)


9:
50
AM
Break

10:
05
AM
Proposed
Science
Policy:
PPAR­

Agonist­
Mediated
Hepatocarcinogenesis
in
Rodents
and
Relevance
to
Human
Health
Risk
Assessments
­
Elizabeth
Mendez,
Ph.
D.
(
Health
Effects
Division,
Office
of
Pesticide
Programs,
EPA)


10:
45
AM
Public
Comments

12:
00
PM
Lunch

1:
00
PM
Public
Comments
Continued
December
9
and
10,
2003
FIFRA
SAP
MEETING
AGENDA
December
5,
2003
Page
2
of
5

2:
00
PM
Questions
to
the
Panel
OVERVIEW:

Developments
in
the
area
of
research
on
peroxisome
proliferating
chemicals
have
led
to
a
reevaluation
of
the
state
of
the
science
to
characterize
the
mode(
s)
of
action
(
i.
e.,
PPAR 
agonism)
and
the
human
relevance
of
rodent
tumors
induced
by
PPAR 
agonists.
Recently,
the
ILSI
Risk
Science
Institute
(
ILSI
RSI)
convened
a
large
expert
technical
group
(
ILSI
document,
2003)
to
evaluate
new
information
on
the
association
between
PPAR 
agonism
and
the
induction
of
tumors
by
peroxisome
proliferating
chemicals.
OPPTS
considered
the
2003
ILSI
report
as
well
as
the
pertinent
scientific
literature
in
developing
its
proposed
science
policy.
Please
provide
comments
and
advice
on
the
following
questions.
In
addressing
these,
questions
consider
the
completeness
of
the
data
sets
evaluated.

Question
1
­
Rodent
PPAR
 
Mode
of
Action
for
Hepatocarcinogenesis
OPPTS
has
concluded
that
there
is
sufficient
weight
of
evidence
to
establish
the
mode
of
action
for
PPAR 
agonist­
induced
rodent
hepatocarcinogenesis.
It
is
proposed
in
the
OPPTS
document
that
PPAR 
agonists
activate
PPAR 
leading
to
an
increase
in
cell
proliferation
and
a
decrease
in
apoptosis,
and
eventually
further
clonal
expansion
of
preneoplastic
cells
and
formation
of
liver
tumors.
The
key
events
in
PPAR 
agonist­
induced
hepatocarcinogenesis
may
be
classified
as
either
causal
(
required
for
this
MOA)
or
associative
(
marker
of
PPAR 
agonism).

Please
comment
on
the
weight
of
evidence
and
key
events
for
the
proposed
mode
of
action
for
the
PPAR 
agonist­
induced
rodent
hepatocarcinogenesis.
Please
comment
on
the
adequacy
of
the
data
available
to
identify
the
key
events
in
the
PPAR 
MOA.
Discuss
whether
the
uncertainties
and
limitations
of
these
data
have
been
adequately
characterized.


3:
00
PM
Break

3:
15
PM
Question
to
the
Panel
Continued
Question
2
­
Relative
Sensitivity
of
Fetal,
Neonatal,
and
Adult
Rodent
OPPTS
has
provided
a
review
of
the
ontogeny
of
PPAR 
expression
and
peroxisomal
assemblage
during
fetal
and
postnatal
development
in
rodents
as
well
as
an
analysis
of
the
available
data
evaluating
effects
on
peroxisomal
proliferation,
peroxisomal
enzyme
activity,
and
liver
weights
following
exposure
to
PPAR 
agonists
during
fetal
and
postnatal
development
in
rats
and
mice
(
see
Section
V
of
the
OPPTS
Document).
Based
on
this
analysis,
OPPTS
concluded
that
fetal
and
neonatal
rats
do
not
exhibit
an
increased
sensitivity
to
PPAR 
agonistinduced
hepatocarcinogenicity
relative
to
the
adult
rodent.
Therefore,
any
conclusions
regarding
this
mode
of
action
in
adult
rodents
would
also
apply
to
young
rodents,
and
similarly
any
conclusions
regarding
the
relevance
of
this
mode
of
action
for
human
hepatocarcinogenesis
would
apply
to
the
young,
as
well
as
the
adults.
December
9
and
10,
2003
FIFRA
SAP
MEETING
AGENDA
December
5,
2003
Page
3
of
5
Please
comment
on
the
weight
of
the
evidence
approach
and
mechanistic
data
used
to
support
this
conclusion.


5:
30
PM
Adjournment
WEDNESDAY,
DECEMBER
10,
2003
HOLIDAY
INN
NATIONAL
AIRPORT
2650
JEFFERSON
DAVIS
HIGHWAY
ARLINGTON,
VIRGINIA
22202
703­
684­
7200
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
­
Gary
E.
Isom,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
40
AM
Administrative
Procedures
by
Designated
Federal
Official
­
Mr.
Steven
Knott

8:
45
AM
Follow­
up
from
Previous
Day's
Discussion
­
Margaret
Stasikowski,
M.
P.
H.
and
Elizabeth
Mendez,
Ph.
D.
(
Health
Effects
Division,
Office
of
Pesticide
Programs,
EPA)


9:
00
AM
Questions
to
the
Panel
Continued
Question
3
­
Human
Relevance
OPPTS
has
provided
an
analysis
of
a
variety
of
in
vitro
and
in
vivo
studies
on
the
key
events
pertaining
to
PPAR 
agonist­
induced
hepatocarcinogenesis
with
hamsters,
guinea
pigs,
non­
human
primates,
and
humans.
Based
on
the
weight
of
the
evidence,
OPPTS
concludes
that
although
PPAR 
agonists
can
induce
liver
tumors
in
rodents
and
while
PPAR 
is
functional
in
humans,
quantitatively,
humans
and
nonhuman
primates
are
refractory
to
the
hepatic
effects
of
PPAR 
agonists.

Therefore,
OPPTS
is
proposing
the
following
scientific
policy:

When
liver
tumors
are
observed
in
long
term
studies
in
rats
and
mice,
and
1)
the
data
are
sufficient
to
establish
that
the
liver
tumors
are
a
result
of
a
PPAR 
agonist
MOA
and
2)
other
potential
MOAs
have
been
evaluated
and
found
not
operative,
the
evidence
of
liver
tumor
formation
in
rodents
should
not
be
used
to
characterize
potential
human
hazard.

Please
comment
on
the
data
and
weight
of
evidence
regarding
the
hepatic
effects
of
December
9
and
10,
2003
FIFRA
SAP
MEETING
AGENDA
December
5,
2003
Page
4
of
5
PPAR 
agonists
in
humans,
and
please
comment
on
the
proposed
OPPTS's
science
policy
regarding
human
relevance.


10:
30
AM
Break

10:
45
AM
Question
to
the
Panel
Continued
Question
4
­
Data
Requirements
OPPTS
has
proposed
a
data
set
that
would
be
sufficient
to
demonstrate
that
PPAR 
agonism
is
the
mode
of
action
for
the
induction
of
rodent
liver
tumors.
The
data
set
includes
evidence
of
PPAR 
agonism
(
i.
e.
from
an
in
vitro
reporter
gene
assay),
in
vivo
evidence
of
an
increase
in
number
and
size
of
peroxisomes,
increases
in
the
activity
of
acyl
CoA
oxidase,
and
hepatic
cell
proliferation.
The
in
vivo
evidence
should
be
collected
from
studies
designed
to
provide
the
data
needed
to
show
dose­
response
and
temporal
concordance
between
precursor
events
and
liver
tumor
formation.

Please
comment
in
general
on
the
proposed
data
set
and
particularly
on
its
adequacy
to
demonstrate
that
a
PPAR 
agonist­
mediated
MOA
is
operating
in
rodent
hepatocarcinogenesis.


12:
00
PM
Lunch

1:
00
PM
Questions
to
the
Panel
Continued
Question
5
­
Other
Tumors
Induced
by
PPAR 
Agonists
Some
PPAR 
agonists
may
also
induce
pancreatic
acinar
cell
and
Leydig
cell
tumors
in
rats
and
modes
of
action
involving
agonism
of
PPAR 
have
been
proposed.
An
in
depth
analysis
of
these
tumors
is
provided
in
the
2003
ILSI
technical
panel
report.
Based
on
this
analysis,
OPPTS
agrees
that
the
data
available
to
date
are
insufficient
to
support
the
proposed
MOAs.

Thus,
OPPTS
is
proposing
the
following
science
policy:

Given
the
limited
evidence
available
to
support
that
a
chemical
may
induce
pancreatic
and
Leydig
cell
tumors
through
a
PPAR 
agonist
mode
of
action,
the
evidence
is
inadequate
at
this
time
to
support
a
linkage
between
PPAR 
agonism
and
formation
of
these
tumor
types.
Thus,
it
is
presumed
that
chemicals
that
induce
pancreatic
or
Leydig
cell
tumors
may
pose
a
carcinogenic
hazard
for
humans.

Please
comment
on
OPPTS's
conclusion
that
there
is
limited
evidence
that
a
chemical
may
induce
pancreatic
and
Leydig
cell
tumors
through
a
PPAR 
agonist
mode
of
action,
and
OPPTS's
proposed
science
policy
regarding
other
tumors
induced
by
PPAR 
agonists.
December
9
and
10,
2003
FIFRA
SAP
MEETING
AGENDA
December
5,
2003
Page
5
of
5

3:
00
PM
Adjournment
As
noted
above,
please
be
advised
that
agenda
times
are
approximate.
For
further
information,
please
contact
the
Designated
Federal
Official
for
this
meeting,
Mr.
Steven
Knott,
via
telephone:
(
202)
564­
8450;
fax:
(
202)
564­
8382;
or
email:
knott.
steven@
epa.
gov.
