Page
1
of
9
DRAFT
September
15,
2004
FIFRA
SCIENTIFIC
ADVISORY
PANEL
(
SAP)
OPEN
MEETING
OCTOBER
13­
15,
2004
FIFRA
SAP
WEB
SITE
http://
www.
epa.
gov/
scipoly/
sap/
OPP
Docket
Telephone:
(
703)
305­
5805
Docket
Number:
OPP­
2004­
0287
ISSUES
ASSOCIATED
WITH
DEPLOYMENT
OF
A
TYPE
OF
PLANTINCORPORATED
PROTECTANT
(
PIP),
SPECIFICALLY
THOSE
BASED
ON
PLANT
VIRAL
COAT
PROTEINS
(
PVCP­
PIPS)

WEDNESDAY,
OCTOBER
13,
2004
Holiday
Inn
­
National
Airport
2650
Jefferson
Davis
Highway
Arlington,
VA
22202
Telephone:
(
703)
684­
7200

8:
30
AM
Introduction
and
Identification
of
Panel
Members
 
Stephen
Roberts,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
45
AM
Administrative
Procedures
by
Designated
Federal
Official
­
Mr.
Paul
Lewis

8:
50
AM
Welcome
­
Mr.
Joseph
J.
Merenda,
Jr.
(
Director,
Office
of
Science
Coordination
and
Policy,
EPA)


8:
55
AM
Opening
Remarks
­
Mr.
Jim
Jones
(
Director,
Office
of
Pesticide
Programs,
EPA)


9:
00
AM
Opening
Remarks
­
Mr.
Dennis
Szuhay
(
Biopesticides
and
Pollution
Prevention
Division,
Office
of
Pesticide
Programs,
EPA)


9:
05
AM
PVCP­
PIPs:
The
Context
 
Elizabeth
Milewski,
Ph.
D.
(
Office
of
Science
Coordination
and
Policy,
EPA)
and
John
Turner,
Ph.
D.
(
Animal
Plant
Health
and
Inspection
Service,
USDA)


9:
35
AM
Gene
Flow
in
Viral
Coat
Protein
Transgenic
Plants
 
Anne
Fairbrother,
DVM,
Ph.
D.
(
National
Health
and
Environmental
Research
Effects
Laboratory,
ORD,
EPA)


10:
15
AM
BREAK

10:
30
AM
Viral
Interaction
in
Viral
Coat
Protein
Transgenic
Plants
 
Melissa
Kramer,
Ph.
D.
(
Office
of
Science
Coordination
and
Policy,
EPA)


11:
00
AM
Other
Considerations
­
Elizabeth
Milewski,
Ph.
D.
(
Office
of
Science
Coordination
and
Policy,
EPA)


11:
15
AM
Public
Comments
Page
2
of
9

12:
30
PM
LUNCH

1:
30
PM
Panel
Discussion
Gene
Flow
Concerns
about
the
transfer
of
virus
resistance
to
wild
or
weedy
relatives
include
the
assumption
that
such
resistance
might
confer
a
selective
advantage
to
a
wild
or
weedy
relative
that
could
increase
its
competitive
ability
and
potential
to
become
weedy
or
invasive.
The
Agency
would
like
the
panel
to
consider
the
evidence
supporting
this
assumption.

1.
What
scientific
evidence
supports
or
refutes
the
idea
that
plant
viruses
have
significant
effects
on
reproduction,
survival,
and
growth
of
plant
populations
in
natural
settings?
Is
there
scientific
evidence
that
plant
populations
freed
from
viral
pressure
could
have
increased
competitive
ability
leading
to
changes
in
plant
population
dynamics?

2.
Please
comment
on
the
validity
of
the
Agency
list
of
crops
that
have
no
wild
or
weedy
relatives
in
the
United
States
with
which
they
can
produce
viable
hybrids
in
nature
(
i.
e.,
tomato,
potato,
soybean,
and
corn).


3:
00
PM
BREAK

3:
15
PM
Panel
Discussion
(
continued)

3.
Please
identify
other
crops
that
have
no
wild
or
weedy
relatives
in
the
United
States
with
which
they
can
produce
viable
hybrids
in
nature,
e.
g.,
papaya,
peanut,
and/
or
chickpea.

The
Agency
anticipates
the
need
to
evaluate
data
addressing
whether
transgenic
plant
species
are
capable
of
genetic
exchange
with
wild
or
weedy
plant
relatives.
In
general,
EPA
is
focused
on
the
potential
for
genetic
exchange
that
can
occur
in
the
field.
However,
evaluations
of
the
potential
for
genetic
exchange
are
likely
to
include
laboratory
studies
that
are
not
necessarily
an
accurate
indicator
of
plants'
ability
to
exchange
genetic
material
outside
the
lab.

4.
What
laboratory
techniques
used
to
achieve
genetic
exchange
between
species
(
e.
g.,
embryo
rescue,
use
of
intermediate
bridging
crosses,
protoplast
fusion)
are
not
indicative
of
possible
genetic
exchange
between
these
species
in
the
field?
Conversely,
what
techniques,
if
any,
used
in
laboratory
or
greenhouse
experiments
provide
the
most
reliable
indication
of
ability
to
hybridize
in
the
field?


4:
30
PM
ADJOURNMENT
Page
3
of
9
FIFRA
SCIENTIFIC
ADVISORY
PANEL
(
SAP)
OPEN
MEETING
OCTOBER
13­
15,
2004
FIFRA
SAP
WEB
SITE
http://
www.
epa.
gov/
scipoly/
sap/
OPP
Docket
Telephone:
(
703)
305­
5805
Docket
Number:
OPP­
2004­
0287
ISSUES
ASSOCIATED
WITH
DEPLOYMENT
OF
A
TYPE
OF
PLANTINCORPORATED
PROTECTANT
(
PIP),
SPECIFICALLY
THOSE
BASED
ON
PLANT
VIRAL
COAT
PROTEINS
(
PVCP­
PIPS)

THURSDAY,
OCTOBER
14,
2004
Holiday
Inn
­
National
Airport
2650
Jefferson
Davis
Highway
Arlington,
VA
22202
Telephone:
(
703)
684­
7200

8:
30
AM
Introduction
and
Identification
of
Panel
Members
 
Stephen
Roberts,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
35
AM
Administrative
procedures
by
Designated
Federal
Official
­
Mr.
Paul
Lewis

8:
40
AM
Follow­
up
from
Previous
Day's
Discussion
 
Melissa
Kramer,
Ph.
D.
(
Office
of
Science
Coordination
and
Policy,
EPA)


9:
00
AM
Panel
Discussion
(
continued)

EPA
recognizes
that
it
may
be
possible
to
genetically
engineer
a
plant
such
that
concerns
about
gene
flow
to
wild
or
weedy
relatives
are
significantly
reduced.
However,
according
to
the
2004
NRC
report,
Biological
Confinement
of
Genetically
Engineered
Organisms,
current
techniques
for
bioconfinement
(
e.
g.,
sterile
triploids,
male
sterility)
are
imperfect
and
are
not
guaranteed
to
eliminate
entirely
gene
flow
to
existing
wild
relatives.
Recent
modeling
studies
suggest
imperfections
in
bioconfinement
could
result
in
significant
levels
of
gene
introgression
in
compatible
plant
relatives
over
a
period
of
decades.

5.
Given
that
current
bioconfinement
techniques
are
not
100%
effective,
what
would
the
environmental
implications
be
of
extremely
low
transfer
rates
of
virus­
resistance
genes
over
time?

EPA
recognizes
that
concerns
about
gene
flow
to
wild
or
weedy
relatives
may
be
ameliorated
if
the
introduced
virus­
resistance
trait
would
give
little
or
no
selective
advantage
to
the
recipient
plant,
as
would
occur
if
the
plant
were
already
tolerant
or
resistant
to
the
virus
to
which
resistance
is
conferred.
It
is
obvious
that
such
resistance
does
exist
in
some
populations
because
traditional
breeding
for
resistance
relies
on
finding
a
source
of
resistance
within
related
cultivated
species,
old
varieties,
or
wild
species.
Page
4
of
9
6.
Please
comment
on
the
prevalence
of
tolerance
and/
or
resistance
to
viruses
in
wild
relatives
of
crops.


10:
00
AM
BREAK

10:
15
AM
Panel
Discussion
(
continued)

7.
Please
specify
techniques
that
do
or
do
not
provide
measures
of
tolerance
and/
or
resistance
that
are
relevant
to
field
conditions.

8.
How
do
environmental
or
other
factors
(
e.
g.,
temporal
variations)
affect
tolerance
and/
or
resistance?
Given
the
expected
variability,
what
measures
of
tolerance
and/
or
resistance
would
be
reliable?

9.
What
would
be
the
ecological
significance
if
a
plant
population
acquired
a
small
increase
in
viral
tolerance
and/
or
resistance
above
a
naturally­
occurring
level?

Based
on
the
hypothesis
that
concerns
about
the
consequences
of
gene
flow
to
a
wild
or
weedy
relative
in
the
United
States
may
be
negligible
in
certain
cases,
the
Agency
is
considering
whether
there
are
mechanisms
to
adequately
address
concerns
associated
with
gene
flow
so
that
certain
types
of
VCPs
would
be
of
such
low
risk
that
they
would
not
need
to
be
regulated
by
EPA.
Below
are
examples
of
three
conditions
(
modified
from
those
proposed
in
1994)
that
are
intended
to
significantly
reduce
any
potential
adverse
effects
of
gene
flow
with
plants
containing
a
PVCP­
PIP.

(
1)
The
plant
into
which
the
PVCP­
PIP
has
been
inserted
has
no
wild
or
weedy
relatives
in
the
United
States
with
which
it
can
produce
viable
hybrids
in
nature,
e.
g.,
corn,
tomato,
potato,
or
soybean;
or
(
2)
Genetic
exchange
between
the
plant
into
which
the
PVCP­
PIP
has
been
inserted
and
any
existing
wild
or
weedy
relatives
is
substantially
reduced
by
modifying
the
plant
with
a
scientifically
documented
method
(
e.
g.,
through
male
sterility);
or
(
3)
It
has
been
empirically
demonstrated
that
all
existing
wild
or
weedy
relatives
in
the
United
States
with
which
the
plant
can
produce
a
viable
hybrid
are
tolerant
or
resistant
to
the
virus
from
which
the
coat
protein
is
derived.

10.
Please
comment
on
how
necessary
and/
or
sufficient
these
conditions
are
to
minimize
the
potential
for
the
PVCP­
PIP
to
harm
the
environment
through
gene
flow
from
the
plant
containing
the
PVCP­
PIP
to
wild
or
weedy
relatives.
Would
any
other
conditions
work
as
well
or
better?


12:
00
PM
LUNCH

1:
00
PM
Panel
Discussion
(
continued)
Page
5
of
9
Viral
Interactions
Interactions
between
introduced
plant
virus
sequences
and
other
invading
viruses
in
transgenic
plants
(
e.
g.,
during
recombination
or
heterologous
encapsidation)
may
be
a
concern
to
the
extent
that
such
events
may
increase
in
frequency
or
be
unlike
those
expected
to
occur
in
nature.
It
has
been
hypothesized
that
such
events
could
lead
to
the
creation
of
viruses
with
new
disease
states
or
transmission
properties.
The
Agency
is
evaluating
the
circumstances
that
might
increase
the
potential
for
such
events
to
occur
and
the
potential
environmental
consequences
of
novel
viral
interactions
in
light
of
the
2000
NRC
report
which
stated
that,
"[
m]
ost
virus­
derived
resistance
genes
are
unlikely
to
present
unusual
or
unmanageable
problems
that
differ
from
those
associated
with
traditional
breeding
for
virus
resistance."
The
report
went
on
to
suggest
that
risks
might
be
managed
by
particular
ways
of
engineering
transgenes.
However,
under
either
of
the
1994
proposed
exemptions,
the
Agency
would
be
unable
to
ensure
that
such
strategies
were
implemented.
The
Agency's
literature
review,
"
Viral
interactions
in
viral
coat
protein
transgenic
plants,"
discusses
possible
ways
of
managing
these
potential
risks
in
detail.

Viral
interactions
may
occur
in
natural,
mixed
infections
which
are
common
in
plants.
Hypothetical
concerns
related
to
potential
adverse
effects
resulting
from
viral
interactions
between
infecting
viruses
and
PVCP­
PIPs
in
transgenic
plants
may
be
attributed
to
opportunities
for
interactions
not
expected
to
occur
in
nature.
EPA
is
interested
in
evaluating
the
significance
of
novel
viral
interactions
involving
a
viral
transgene.

11.
To
what
extent
are
novel
viral
interactions
(
e.
g.,
recombination,
heterologous
encapsidation)
involving
a
viral
transgene
an
environmental
concern?

Mixed
viral
infections
can
be
extremely
common
in
crops
and
other
plants.
However,
scientific
uncertainty
exists
as
to
whether
recombination
and
heterologous
encapsidation
would
occur
more
or
less
frequently
in
the
case
of
a
viral
transgene
and
an
infecting
virus
interaction
as
compared
to
such
interactions
in
mixed
infections
of
a
transgenic
plant's
non­
bioengineered
counterpart.

12.
What
conclusions
can
be
drawn
as
to
whether
the
likelihood
of
recombination
and/
or
heterologous
encapsidation
would
be
increased
or
decreased
in
a
transgenic
plant
compared
to
its
non­
bioengineered
counterpart?


3:
00
PM
BREAK

3:
15
PM
Panel
Discussion
(
continued)

A
number
of
methods
for
reducing
the
frequency
of
recombination
and
heterologous
encapsidation
have
been
identified.
While
the
effectiveness
of
these
techniques
has
been
verified
for
particular
cases,
their
applicability
to
all
PVCP­
PIPs
is
unclear.
Recognizing
that
it
would
be
difficult
for
a
product
developer
to
measure
rates
of
recombination,
heterologous
encapsidation,
or
vector
transmission
under
field
conditions,
Page
6
of
9
EPA
is
considering
whether
it
would
be
necessary
to
verify
that
such
methods
worked
in
any
particular
instance
by
measuring
rates
in
modified
versus
unmodified
plants.

13.
How
effective
is
deleting
the
3'
untranslated
region
of
the
PVCP
gene
as
a
method
for
reducing
the
frequency
of
recombination
in
the
region
of
the
PVCP
gene?
Is
this
method
universally
applicable
to
all
potential
PVCP­
PIP
constructs?
Would
any
other
methods
work
as
well
or
better?
Which
methods
are
sufficiently
effective
and
reproducible
such
that
actual
measurement
of
rates
to
verify
rate
reduction
would
be
unnecessary?

14.
Are
any
methods
for
inhibiting
heterologous
encapsidation
or
transmission
by
insect
vectors
universally
applicable
to
all
PVCP­
PIPs?
Which
methods
are
sufficiently
effective
and
reproducible
such
that
actual
measurement
of
rates
to
verify
rate
reduction
would
be
unnecessary?

15.
How
technically
feasible
would
it
be
to
measure
rates
of
recombination,
heterologous
encapsidation,
and
vector
transmission
in
PVCP­
PIP
transgenic
plants
in
order
to
show
that
rates
are
reduced?


5:
00
PM
ADJOURNMENT
Page
7
of
9
FIFRA
SCIENTIFIC
ADVISORY
PANEL
(
SAP)
OPEN
MEETING
OCTOBER
13­
15,
2004
FIFRA
SAP
WEB
SITE
http://
www.
epa.
gov/
scipoly/
sap/
OPP
Docket
Telephone:
(
703)
305­
5805
Docket
Number:
OPP­
2004­
0287
ISSUES
ASSOCIATED
WITH
DEPLOYMENT
OF
A
TYPE
OF
PLANTINCORPORATED
PROTECTANT
(
PIP),
SPECIFICALLY
THOSE
BASED
ON
PLANT
VIRAL
COAT
PROTEINS
(
PVCP­
PIPS)

FRIDAY,
OCTOBER
15,
2004
Holiday
Inn
­
National
Airport
2650
Jefferson
Davis
Highway
Arlington,
VA
22202
Telephone:
(
703)
684­
7200

8:
30
AM
Introduction
and
Identification
of
Panel
Members
 
Stephen
Roberts,
Ph.
D.
(
FIFRA
SAP
Session
Chair)


8:
35
AM
Administrative
procedures
by
Designated
Federal
Official
­
Mr.
Paul
Lewis

8:
40
AM
Follow­
up
from
Previous
Day's
Discussion
 
Melissa
Kramer,
Ph.
D.
(
Office
of
Science
Coordination
and
Policy,
EPA)


9:
00
AM
Panel
Discussion
(
continued)

EPA
recognizes
that
scientific
disagreement
exists
as
to
the
likelihood
of
environmental
impacts
due
to
novel
viral
interactions
in
transgenic
plants
modified
with
PVCP­
PIPs.
The
Agency
is
considering
whether
there
are
available
mechanisms
to
adequately
address
concerns
associated
with
novel
viral
interactions
so
that
certain
types
of
PVCP­
PIPs
would
be
of
such
low
risk
that
they
would
not
need
to
be
regulated
by
EPA.
Below
are
examples
of
conditions
that
might
significantly
reduce
either
the
novelty
[(
1)
and
(
2)]
or
frequency
[(
3)
and
(
4)]
of
viral
interactions
in
PVCP­
PIP
transgenic
plants.

(
1)
The
genetic
material
of
the
PVCP­
PIP
is
translated
and/
or
transcribed
in
the
same
cells,
tissues,
and
developmental
stages
naturally
infected
by
every
virus
from
which
any
segment
of
a
coat
protein
gene
used
in
the
PVCP­
PIP
was
derived.

(
2)
The
genetic
material
of
the
PVCP­
PIP
contains
coat
protein
genes
or
segments
of
coat
protein
genes
from
viruses
established
throughout
the
regions
where
the
crop
is
planted
in
the
United
States
and
that
naturally
infect
the
crop
into
which
the
genes
have
been
inserted.
Page
8
of
9
(
3)
The
PVCP­
PIP
has
been
modified
by
a
method
scientifically
documented
to
minimize
recombination,
(
e.
g.,
deletion
of
the
3'
untranslated
region
of
the
coat
protein
gene).

(
4)
The
PVCP­
PIP
has
been
modified
by
a
method
scientifically
documented
to
minimize
heterologous
encapsidation
or
vector
transmission,
or
there
is
minimal
potential
for
heterologous
encapsidation
because
no
protein
from
the
introduced
PVCP­
PIP
is
produced
in
the
transgenic
plant
or
this
virus
does
not
participate
in
heterologous
encapsidation
in
nature.

16.
Please
comment
on
how
necessary
and/
or
sufficient
each
of
these
conditions
is
to
minimize
the
potential
for
novel
viral
interactions.
Please
address
specifically
what
combination
would
be
most
effective
or
what
conditions
could
be
modified,
added,
or
deleted
to
ensure
that
potential
consequences
of
novel
viral
interactions
in
PVCPPIP
transgenic
plants
are
minimized.


10:
00
AM
BREAK

10:
15
AM
Panel
Discussion
(
continued)

Other
questions
In
1994
EPA
proposed
exempting
plant
viral
coat
proteins
from
the
requirement
of
a
food
tolerance
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
based
on
rationale
that
(
1)
virus
infected
plants
have
always
been
a
part
of
the
human
and
domestic
animal
food
supply
and
(
2)
plant
viruses
have
never
been
shown
to
be
infectious
to
humans
or
mammals.
The
safety
of
consuming
plant
virus
genes
has
been
supported
by
experimental
work
(
Chen
et
al.
2003;
Rogan
et
al.
2000;
Shinmoto
et
al.
1995)
and
expert
consultations
including
the
2000
NRC
report
which
concluded
that,
"
viral
coat
proteins
in
transgenic
pest­
protected
plants
are
not
expected
to
jeopardize
human
health
because
consumers
already
ingest
these
compounds
in
nontransgenic
food."
However,
EPA
recognizes
that
PVCP­
PIP
developers
may
wish
to
modify
the
PVCP­
PIP
construct
and
that
some
methods
of
mitigating
potential
risks
associated
with
recombination
and
heterologous
encapsidation
might
actually
require
them
to
do
so.
Such
modifications
might
result
in
changes
to
the
protein(
s)
produced
thus
creating
potential
food
safety
concerns,
e.
g.,
inadvertent
production
of
new
toxins
or
allergens
(
Day
1996).
Modifications
of
the
construct
and
alteration
of
the
proteins
produced
creates
the
potential
for
health
impacts
on
non­
target
species
as
well
as
humans.

17.
To
what
degree
and
in
what
ways
might
a
PVCP
gene
be
modified
(
e.
g.,
through
truncations,
deletions,
insertions,
or
point
mutations)
while
still
retaining
scientific
support
for
the
idea
that
humans
have
consumed
the
products
of
such
genes
for
generations
and
that
such
products
therefore
present
no
new
dietary
exposures?

18.
What
are
the
potential
adverse
effects,
if
any,
of
such
modifications
on
nontarget
species
(
e.
g.,
wildlife
and
insects
that
consume
the
PVCP­
PIP)?
Page
9
of
9
Modifications
of
the
construct
may
also
potentially
create
the
opportunity
for
novel
viral
interactions
because
the
inserted
virus
sequences
could
be
unlike
any
that
occur
naturally.

19.
To
what
degree
and
in
what
ways
might
a
PVCP
gene
be
modified
(
e.
g.,
through
truncations,
deletions,
insertions,
or
point
mutations)
before
it
would
be
a
concern
that
novel
viral
interactions
due
to
the
modifications
could
occur
because
the
PVCP
gene
would
be
significantly
different
from
any
existing
in
nature?

The
potential
risk
issues
identified
in
this
paper
are
specific
to
virus­
resistant
transgenic
plants.
However,
the
Agency
recognizes
that
it
may
be
necessary
to
evaluate
other
information
related
to
the
PVCP­
PIP.

20.
Would
any
additional
requirements
related
to
PVCP­
PIP
identity
and
composition
(
e.
g.,
demonstration
that
the
transgene
has
been
stably
inserted)
be
needed
for
significant
reduction
of
risks
associated
with
PVCP­
PIPs?

21.
Are
there
any
considerations
beyond
gene
flow,
recombination,
and
heterologous
encapsidation
as
posed
in
the
preceding
questions
that
the
Agency
should
consider
in
evaluating
the
risk
potential
of
PVCP­
PIPs
(
e.
g.,
synergy)?


3:
00
PM
ADJOURNMENT
Please
be
advised
that
agenda
times
are
approximate.
For
further
information,
please
contact
the
Designated
Federal
Official
for
this
meeting,
Mr.
Paul
Lewis,
via
telephone:
(
202)
564­
8450;
fax:
(
202)
564­
8382;
or
email:
lewis.
paul@
epa.
gov
