November
6,
2003
MEMORANDUM
Subject:
Transmission
of
Background
Materials
for
the
Session
of
the
December
9­
10,
2003
FIFRA
Scientific
Advisory
Panel
Entitled
"
Proposed
Science
Policy:
PPAR 
Agonist­
Mediated
Hepatocarcinogenesis
in
Rodents
and
Relevance
to
Human
Health
Risk
Assessments"

To:
Steve
Knott,
Designated
Federal
Official
FIFRA
SAP
Office
of
Science
Coordination
and
Policy
(
7101C)

From:
Karl
Baetcke,
Ph.
D.,
Senior
Scientist
Office
of
Pesticide
Programs
Health
Effects
Division
(
7509C)

Jennifer
Seed,
Ph.
D.,
Branch
Chief
Office
of
Pollution
Prevention
and
Toxics
Risk
Assessment
Division
(
7403M)

Through:
Margaret
Stasikowski,
Director
Office
of
Pesticide
Programs
Health
Effects
Division
(
7509C)

Oscar
Hernandez,
Director
Office
of
Pollution
Prevention
and
Toxics
Risk
Assessment
Division
(
7403M)

Attached
is
the
document
"
Proposed
OPPTS
Science
Policy:
PPAR 
Agonist­
Mediated
Hepatocarcinogenesis
in
Rodents
and
Relevance
to
Human
Health
Risk
Assessments."
The
purpose
of
this
guidance
document
is
to
describe
the
approach
that
OPPTS
is
proposing
to
evaluate
the
scientific
information
regarding
the
mode
of
action
(
MOA)
of
PPAR 
agonists
in
rodent
hepatocarcinogenesis,
the
data
necessary
to
establish
the
MOA
for
PPAR 
agonist­
induced
rodent
liver
tumors
and
the
relevance
of
this
hepatic
MOA
in
humans
including
children.
The
Office
of
Prevention,
Pesticides
and
Toxic
(
OPPTS)
is
requesting
that
the
FIFRA
Scientific
Advisory
Panel
comment
on
the
soundness
of
this
proposed
science
policy
(
see
Charge
below).
Page
2
of
4
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.

Attachments:

Document
For
Review
With
Respect
to
Charge
 

OPPTS
October
2003
Draft
Document
Proposed
Science
Policy:
PPAR 
Agonist­
Mediated
Hepatocarcinogenesis
in
Rodents
and
Relevance
to
Human
Health
Risk
Assessments.
(
Enclosed)

Background
Material
 

ILSI
RSI
2003
PPAR 
Agonist­
Induced
Rodent
Tumors:
Mode(
s)
of
action
and
Human
Relevance.
(
Will
be
forwarded
separately)

Charge
to
the
Panel:

Please
provide
comment
and
advice
on
the
following
questions.
In
addressing
these
questions
consider
the
completeness
of
the
data
sets
evaluated.

Issue
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).

Question
1
­
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
been
adequately
characterized.
Page
3
of
4
Issue
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,
peroixsomal
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 
agonist­
induced
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.

Question
2
­
Please
comment
on
the
weight
of
the
evidence
approach
and
mechanistic
data
used
to
support
this
conclusion.

Issue
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
hepatocarcinogensis
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.

Question
3
­
Please
comment
on
the
data
and
weight
of
evidence
regarding
the
hepatic
effects
of
PPAR 
agonists
in
humans,
and
please
comment
on
the
proposed
OPPTS's
science
policy
regarding
human
relevance.
Page
4
of
4
Issue
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.

Question
4
­
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.

Issue
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.

Question
5
­
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.
