Document ID: EPA-HQ-OPP-2004-0182-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-10-11T04:00Z

Section
1.0
1
­
1
1.0
Insect
Resistance
Management
(
IRM)

More
than
150
comments
were
received
by
the
Agency
regarding
IRM
of
event
MON
863
corn
expressing
the
Bt
Cry3Bb1
protein.
Since
many
of
these
comments
addressed
similar
areas,
comments
were
grouped
and
summarized
rather
than
responding
to
them
individually.

General
Public
Comments
One
commenter
states
that
the
use
of
this
technology
will
continue
to
provide
an
improvement
in
agricultural
environments
by
reducing
the
use
of
pesticides.
Another
commenter
notes
that
transgenic
corn
is
making
it
easier
and
more
economical
to
provide
supplemental
food
that
increases
the
winter
survival
of
some
wildlife
and
that
biotechnologies
in
general
have
benefitted
wildlife
by
reducing
insecticides
and
improving
the
habitat
for
many
aquatic
and
terrestrial
species.
One
commenter
believes
that
reduced
insecticide
use
would
have
benefits
along
the
whole
insecticide
supply
chain
and
would
reduce
exposure
of
beneficial
insects
to
insecticide,
thereby
improving
ecological
balance.
Another
commenter
believes
corn
rootworm­
protected
corn
fits
in
well
with
current
integrated
pest
management
recommendations
and
is
an
important
step
towards
sustainable
agriculture.

One
commenter
quotes
Illinois
entomologist,
Michael
Gray,
and
suggests
that
IPM
alternatives
exist
and
the
extra
expense
of
Cry
3Bb
corn
would
not
be
justified.
The
commenter
states
that
less
than
10
percent
of
the
acres
planted
to
corn
following
soybeans
require
insecticide
treatment.
The
commenter
also
notes
that
area­
wide
corn
rootworm
population
suppression
systems
are
under
development
and
that
new
approaches
target
insects
at
multiple
stages
in
their
life
cycle
when
control
interventions
can
be
carried
out
economically
and
safely.
The
commenter
believes
that
these
strategies
may
prove
to
be
cost­
effective
and
adequate
to
restore
the
former
efficacy
of
the
corn­
soybean
rotation
in
management
of
corn
rootworms.

One
commenter
identifies
several
disadvantages
to
the
technology
including:
(
1)
early
availability
in
desired
hybrid
backgrounds;
(
2)
specificity
to
one
insect;
(
3)
IRM
requirements
may
be
too
restrictive
to
bring
value
to
farmer;
and
(
4)
the
need
to
market
the
product.

EPA's
Response
The
Agency
recognizes
the
potential
benefits,
including
pesticide
use
reduction,
that
may
result
from
the
adoption
of
MON
863
corn
(
see
the
Event
MON863
Bt
Cry3Bb1
Corn
Biopesticides
Registration
Action
Document
(
BRAD)
Section
E
titled
Benefits).

Resistance
Public
Comments
One
commenter
states
that
biotechnology
should
be
evaluated
with
emphasis
on
insect
resistance
management
and
impacts
to
nontarget
organisms.
The
same
commenter
believes
corn
rootworm­
protected
corn
can
be
a
useful
tool
to
counteract
resistance
that
has
developed.
One
commenter
states
that
MON
863
Section
1.0
1
­
2
may
benefit
farmers
and
the
environment,
but
will
not
provide
an
effective
control
strategy
unless
a
rigorous
and
cautious
IRM
program
is
adopted.
One
commenter
states
that
resistance
management
strategies
need
to
be
explored
in
carefully
designed,
small­
scale
field
trials
and
laboratory
trials
before
large­
scale
commercialization.

One
commenter
states
that
the
challenges
to
managing
resistance
to
Cry
3Bb
will
be
significant
and
cites
a
report
suggesting
the
potential
for
resistance
development
by
corn
rootworm
is
acute
and
unavoidable.
Another
commenter
states
that
the
history
of
corn
rootworm
adaptation
emphasizes
the
need
for
an
IRM
plan
for
MON
863.
The
commenter
notes
that
rootworms
developed
resistance
to
chlorinated
hydrocarbon
soil
insecticides
and
this
resistance
affected
most
of
the
Corn
Belt.
The
commenter
adds
that
farmers
switched
to
synthetic
pyrethroid
and
organophosphate
insecticides
and
that
resistance
has
been
found
in
organophosphate
methyl
parathion
and
carbaryl.
One
commenter
supporting
registration
of
MON
863
cites
concerns
with
the
increased
use
of
adult
control
programs
with
soil
insecticides,
leading
to
insecticide
resistance.

One
commenter
addresses
concerns
that
Bt
corn
will
make
insects
resistant
to
Bt
and
states
that
non­
Bt
refuges
could
delay
resistance
if
growers
use
the
refuges
properly.
The
commenter
adds
that
resistance
threatens
all
pesticides,
but
that
we
know
how
to
avoid
it.
The
commenter
further
states
that
if
rootworms
did
become
resistant
to
Bt
corn
it
would
not
threaten
the
use
of
Bt
against
other
pests
and
so
the
possibility
of
resistance
is
not
a
valid
argument
against
registering
Bt
products.

Another
commenter
states
that
the
criteria
Monsanto
provides
for
defining
resistance
are
not
sensitive
enough,
and
could
miss
cases
of
corn
rootworm
resistance.
In
particular,
the
commenter
believes
the
EPA
should
require
a
definition
of
resistance
that
includes
slope
as
well
as
LC50
and
that
resistance
should
depend
on
increased
corn
rootworm
survival
as
opposed
to
corn
root
damage.
The
commenter
is
also
concerned
that
farmers
use
the
same
methods
to
grow
MON
863
as
refuge
corn,
including
crop
rotation
history,
to
ensure
that
pest
management
practices
on
the
refuge
are
compatible
with
the
IRM
plan.

EPA's
Response
The
Agency
agrees
that
a
rigorous
IRM
plan
is
necessary
to
prolong
the
efficacy
of
field
corn
expressing
the
Cry3Bb1
protein.
Therefore,
an
acceptable
IRM
plan
was
necessary
prior
to
registering
Cry3Bb1
corn.
In
determining
an
appropriate
IRM
strategy,
the
Agency
reviews
data
collected
from
small­
scale
field
and
laboratory
trials
as
well
as
results
of
simulation
models
before
large­
scale
commercialization.
A
summary
of
the
information
considered
in
developing
an
IRM
strategy
for
MON
863
corn
can
be
found
in
the
Event
MON863
Bt
Cry3Bb1
Corn
Biopesticides
Registration
Action
Document
(
BRAD)
Section
D,
titled
Insect
Resistance
Management
(
pp.
IID
1
to
IID
19).

An
acceptable
IRM
strategy
is
intended
to
delay
the
onset
of
resistance
rather
than
guarantee
that
resistance
will
never
occur.
The
Agency
is
aware
that
populations
of
the
western
corn
rootworm
have
developed
resistance
to
certain
cultural
methods
(
e.
g.,
crop
rotation)
and
insecticides
including
soil­
applied
cyclodienes
and
organochlorines
as
well
as
organophosphate
and
carbamate
sprays.
However,
resistance
was
not
observed
for
12
to
20
years.
Published
research
has
shown
that
an
insect
must
ingest
a
Bt
Cry
protein
which
leads
to
the
toxin
binding
to
receptors
in
the
insects
midgut
epithelial
cells.
Ultimately,
pores
are
formed
in
the
cellular
membranes
and
homeostasis
of
cells
occurs.
The
binding
of
the
toxin
to
the
Section
1.0
1
­
3
midgut
receptor
is
critical
in
Bt
mode
of
action
and
only
occurs
in
susceptible
insects.
Due
to
host
specificity
and
specific
mode
of
action
of
Cry
proteins,
cross­
resistance
or
resistance
to
other
insecticides
triggered
by
Bt
resistance
is
not
a
concern.
The
potential
for
cross­
resistance
is
not
an
issue
for
MON
863
since
no
microbial
pesticides
or
plant
incorporated
protectants
(
PIPs)
are
currently
registered
for
corn
with
the
same
mode
of
action
as
Cry3Bb1,
and
corn
rootworm
(
CRW)
is
not
a
listed
pest
on
any
current
Bt
microbial
products.

The
Agency
agrees
that
the
implementation
of
appropriate
resistance
management
strategies
will
delay
the
potential
onset
of
resistance.
To
ensure
a
case
of
resistance
is
identified
a
resistance
monitoring
plan
is
required
by
the
Agency
(
see
BRAD
Resistance
Monitoring
Section
pp.
IID
9
to
IID
10).
If
resistance
is
observed,
the
Registrant
is
required
to
implement
an
Agency
approved
mitigation/
remedial
action
plan
to
eradicate
the
resistant
population
and
prevent
the
spread
of
resistance
(
see
BRAD
Remedial
Action
Section
pp.
11
and
IID
12).

On
August
28
and
29,
2002
the
Agency
convened
a
FIFRA
Scientific
Advisory
Panel
(
SAP)
to
provide
expert
input
regarding
IRM
of
MON
863
corn.
The
SAP
did
not
recommend
including
slope
as
a
definition
of
resistance.
Important
factors
should
be
considered
such
as
behavioral
resistance
and
physical
size
that
may
not
relate
to
the
slope
of
an
LD50.
For
instance,
corn
rootworm
that
are
physically
larger
than
others
may
take
longer
to
be
affected
(
behavior
and/
or
sublethal
and
non­
lethal
changes)
but
have
the
same
slope
for
the
survival
in
a
dietary
toxicity
study.
The
Agency
does
not
want
to
restrict
the
definition
of
resistance
to
exclude
these
factors,
especially
for
a
pest
which
has
already
shown
behavioral
adaptation
to
cultural
control
techniques.

IRM
Practicality
Public
Comments
One
commenter
supports
registration,
but
urges
sustainable
implementation
taking
into
consideration
the
ability
of
growers
to
adopt
recommendations.
Several
commenters
note
that
proper
stewardship,
including
managing
resistance,
is
crucial.
One
of
these
commenters
emphasizes
the
importance
of
compliance
with
IRM
requirements.
Several
commenters
addressed
the
need
for
flexibility
in
a
workable
and
consistent
IRM
plan,
noting
that
world
markets
may
be
driven
by
IRM
performance
and
if
the
IRM
plan
does
not
work
the
burden
will
be
on
the
farmers.

EPA's
Response
The
Agency
agrees
that
proper
product
stewardship
and
grower
compliance
are
imperative
to
an
IRM
plan.
Therefore,
the
Agency
requires
an
appropriate
grower
education
and
compliance
program
(
see
BRAD
Grower
Education
and
Compliance
Section
pp.
IID
12
and
IID
13).
Growers
are
required
to
sign
a
technology
use
agreement
that
outlines
IRM
requirements
and
acknowledges
the
growers
responsibility
to
comply
with
them
on
an
annual
basis.
An
annual
industry­
supported
survey
conducted
by
a
third
party
will
be
submitted
to
the
Agency
as
a
tool
to
monitor
grower
compliance.
Additional
education
efforts
are
also
recommended
to
target
non­
compliant
growers
and
access
to
the
technology
will
be
limited
for
growers
found
to
be
non­
compliant.
Section
1.0
1
­
4
The
Agency
as
well
as
the
August
2002
SAP
agree
that
there
is
a
need
for
flexibility
in
an
IRM
plan.
Therefore,
two
refuge
options
are
considered
acceptable;
refuges
may
be
planted
as
in­
field
strips
or
adjacent
blocks.
In
addition,
the
Agency
has
considered
the
growers
need
to
treat
refuges
with
soil
applied
insecticides
for
immature
corn
rootworm
and
the
potential
need
to
use
insecticides
to
control
corn
pests
other
than
the
corn
rootworm
(
see
BRAD
Refuge
Section
pg.
IID
9).

Market
Public
Comments
One
commenter
supports
registration,
but
expressed
concerns
with
the
introduction
of
the
product
into
the
market.
The
commenter
noted
the
importance
of
using
proper
protocols
and
differentiating
this
product
from
other
products
on
the
market.

Several
commenters
challenge
the
claim
that
there
is
no
cause
for
alarm
if
resistance
to
Cry
3Bb
endotoxins
emerge
in
corn
rootworm
populations.
The
commenters
state
that
other
companies
will
commercialize
biopesticides
containing
an
endotoxin
much
like
Cry
3Bb
and
that
a
soil
applied
Bt
product
is
likely
to
result
from
the
phase
out
of
OP
and
carbamate
insecticides.
The
commenters
state
that
the
spread
of
resistance
to
synthetic
pyrethroid
insecticides
could
also
change
the
market.
The
commenters
add
that
a
resistance
to
one
Bt
endotoxin
will
reduce
the
selection
pressure
and
time
required
for
others
to
emerge
and
notes
that
EPA
and
USDA
must
assure
effective
resistance
management
plans
are
developed
and
adopted
with
the
introduction
of
any
Bt­
corn
events.

Two
commenters
suggest
local
sales
limits
to
assure
market
penetration
is
low,
noting
that
the
applicant
relies
on
assumptions
about
national
adoption
rates.
One
commenter
does
not
believe
the
current
lack
of
licensing
agreements
with
seed
companies
for
additional
varieties
should
be
used
to
predict
future
licensing.
The
commenter
believes
local
adoption
may
occur
more
quickly
than
national
adoption
and
states
that
the
applicant
has
not
considered
that
at
least
one
other
Bt
corn
variety
is
being
considered
and
may
impact
resistance.
The
same
commenter
states
that
the
existence
of
effective
chemical
alternatives
for
corn
rootworm
control
will
not
necessarily
slow
the
adoption
of
MON
863,
because
adoption
may
be
motivated
by
grower
convenience,
time
saving,
or
fewer
restrictions
on
crop
rotation.
Another
commenter
notes
that
new
and
existing
management
options
are
available
for
corn
rootworms
and
that
constraints
on
the
potential
market
share
of
transgenics
may
limit
adoption.
The
commenter
states
that
the
key
to
IRM
is
preventing
excessive
repetitive
use
of
technology
on
a
local
scale.

EPA's
Response
The
Agency
agrees
that
it
is
important
to
implement
appropriate
protocols
and
differentiate
MON
863
corn
from
other
products
on
the
market.
Therefore,
Monsanto
is
required
to
provide
growers
with
a
Product
Use
Guide
that
outlines
IRM
requirements.
In
addition,
growers
are
required
to
sign
a
technology
use
agreement
that
acknowledges
the
growers
responsibility
to
comply
with
requirements
outlined
in
the
Product
Use
Guide
on
an
annual
basis.
The
agreement
will
also
state
that
growers
received
the
Product
Use
Guide.
This
agreement
may
be
a
section
of
the
growers
order
sheet
or
some
other
document
or
format
(
see
BRAD
Grower
Education
and
Compliance
Section
pp.
IID
12
and
IID
13).
Section
1.0
1
­
5
Since
the
Agency
recognizes
the
benefits
of
Cry3Bb1
corn
(
See
BRAD
Section
E.
Benefits),
an
IRM
plan
that
would
delay
the
potential
for
corn
rootworm
resistance
was
required
prior
to
registration.
Limiting
sales
on
a
local
or
regional
level
was
considered
by
the
August
2002
SAP.
The
SAP
suggested
limiting
sales
of
MON
863
for
IRM
purposes
to
an
on­
farm
level
rather
than
by
region,
state
or
county.
The
Agency
concluded
that
additional
acreage
limitations
of
MON
863
beyond
the
20%
refuge
requirement
are
not
necessary
during
the
interim
registration
period.
Although
the
Agency
recognizes
alternatives
to
MON
863
exist
now
or
will
become
available
in
the
future,
each
registration
is
considered
individually.
Therefore,
the
use
of
MON
863
and
the
implementation
of
an
appropriate
IRM
strategy
is
based
on
current
uses
and
is
not
based
on
the
potential
of
new
pesticides
in
the
future
such
as
biopesticides
containing
an
endotoxin
much
like
Cry
3Bb
or
new
synthetic
pyrethroids.

Refuges
Public
Comments
One
commenter
refers
to
a
2001
study
of
western
corn
rootworm
and
notes
that
if
the
allele
is
recessive,
resistance
never
develops,
but
if
the
expression
of
the
allele
is
dominant,
then
resistance
will
occur
rapidly
after
adoption
of
the
technology
by
farmers.
The
same
commenter
notes
that
for
block
refuges
planted
within
a
field
and
at
different
locations
each
year,
the
development
of
resistance
should
be
closer
to
that
simulated
with
refuges
as
row
strips.

One
commenter
states
that
scouting
techniques,
extended
diapause,
and
oviposition
in
soybean
may
enable
the
use
of
transgenic
varieties
in
a
prescriptive
pest
management
approach.
The
commenter
notes
that
farmers
will
expect
the
option
of
protecting
corn
from
corn
rootworms
if
refuge
areas
are
required
and
encourages
the
use
of
adult
management
strategies
since
larvae­
targeted
insecticides
are
restricted
to
the
seed
furrow
and
allow
roots
outside
the
furrow
to
produce
adult
corn
rootworms.
One
commenter
believes
rotation
of
control
options
and
prescriptive
use
of
transgenics
based
on
scouting
should
be
considered
as
alternatives
to
planned
refuges
for
resistance
management.

EPA's
Response
Since
it
is
unknown
whether
the
resistance
allele
for
MON
863
corn
in
the
corn
rootworm
is
recessive
or
dominant,
simulation
models
were
considered
based
on
a
"
worst
case
scenario"
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp.
IID
5
to
IID
8).
Due
to
the
need
for
flexibility
in
refuge
options
to
ensure
grower
compliance,
the
Agency
has
not
stipulated
the
exact
placement
of
in­
field
refuges.
Until
further
research
has
been
conducted,
the
Agency
has
not
required
planting
refuges
within
the
field
as
blocks
in
different
locations
each
year.
However,
the
Agency
may
modify
requirements
for
refuge
placement
based
on
research
conducted
during
the
initial
interim
registration
period
(
see
BRAD
Conclusions
and
Recommendations
Sections
pp.
IID
14
to
IID
17
for
research
requirements).

The
Agency
encourages
scouting
fields,
use
of
economic
thresholds
and
the
implementation
of
integrated
pest
management
(
IPM)
approaches
for
all
pesticide
products
including
MON
863
corn.
However,
CRW
resistance
to
MON
863
is
not
expected
to
occur
during
the
interim
registration.
Therefore,
mandatory
scouting
or
prescriptive
use
of
MON
863
is
not
necessary
at
this
time.
According
to
Monsanto,
the
risk
of
resistance
will
be
reduced
by
encouraging
stakeholders
such
as
growers,
Extension
Agents
and
crop
Section
1.0
1
­
6
consultants
to
promote
and
practice
IPM.
For
instance,
scouting
fields
in
the
Fall
will
be
encouraged
and
planting
MON
863
on
acres
with
the
highest
risk
of
damage
will
be
promoted
(
MRID
455770­
01).

The
Agency
realizes
that
high
numbers
of
corn
rootworm
larvae
in
refuges
may
lead
to
unacceptable
levels
of
damage.
High
numbers
of
corn
rootworm
may
result
in
dramatically
reduced
yields
that
will
be
cost
prohibitive
to
farmers.
It
is
also
possible
that
refuge
corn
that
is
destroyed
by
corn
rootworm
damage
may
result
in
a
decreased
number
of
susceptible
insects
needed
to
mate
with
potentially
resistant
insects.
Therefore,
the
Agency
included
the
option
to
treat
refuges
with
seed
and
granular
insecticide
treatments
to
control
CRW
larvae.
However,
it
is
not
acceptable
to
treat
refuges
for
adult
CRW
control
since
these
treatments
may
diminish
the
effectiveness
of
the
refuge.
If
growers
spray
their
corn
fields
with
insecticides
to
control
pests
other
than
CRW,
then
all
acres
(
Bt
and
non­
Bt)
should
be
treated
identically
(
see
BRAD
Refuge
Section
pg.
IID
9).
Since
refuges
are
intended
to
produce
adults
susceptible
to
Cry3Bb1,
furrows
that
produce
adult
corn
rootworms
are
acceptable.

Dose
Public
Comments
One
commenter
believes
resistance
management
strategies
should
explore
low
dose
expression,
noting
that
no
effective
low
dose
expression
resistance
management
plans
have
been
developed
or
tested
with
transgenic
Bt
plants
yet.
The
commenter
also
raises
the
question
of
to
what
degree
the
low
dose
for
corn
rootworm
also
is
a
low
dose
for
other
nontarget
organisms.
Another
commenter
recommends
studies
to
determine
the
effective
dose
for
resistance
management.
The
same
commenter
proposes
additional
studies
focus
on
the
change
in
dose
in
the
roots
over
the
larval
period.

Another
commenter
believes
that
the
probability
of
rootworms
developing
resistance
to
Cry3Bb
during
an
interim
registration
period
appears
to
be
low.
The
commenter
notes
that
MON
863
is
not
a
high
dose
event
and
that
survivorship
may
be
linked
to
changes
in
larval
feeding
behavior
and
the
expression
of
Cry
3Bb
endotoxin
below
the
LC50.
The
commenter
adds
that
resistance
models
simulating
a
low
dose
product
and
low
market
penetration
predict
a
low
probability
of
resistance
evolution.

EPA's
Response
Identifying
the
level
of
dose,
as
related
to
selection
intensity,
is
crucial
when
determining
size
and
structure
of
a
refuge
needed
to
delay
CRW
resistance
to
MON
863
corn.
CRW
feeding
behavior
and
survival
and
root
expression
data
can
be
used
to
identify
the
dose
of
MON
863.
From
data
currently
available
it
can
be
concluded
that
MON
863
corn
does
not
provide
a
high
dose
for
CRW
control.
The
August
2002
SAP
suggested
that
it
is
not
necessary
to
determine
the
difference
between
a
low
and
moderate
dose.
It
is
adequate
to
differentiate
between
high
dose
and
non­
high
dose
products
when
determining
effective
refuge
size.
Therefore,
MON
863
should
be
characterized
as
a
non­
high
dose
product
(
see
BRAD
Dose
Section
pp.
IID
4
and
IID
5).

The
Agency
and
the
August
2002
SAP
agree
that
there
is
a
low
probability
that
corn
rootworm
will
develop
resistance
to
Cry3Bb1
during
an
interim
registration
period.
Section
1.0
1
­
7
Crop
Rotation
Public
Comments
Several
commenters
quote
the
motion
approved
by
the
NCR­
46
committee
which
states
that
NCR­
46
does
not
have
concerns
about
insecticide
resistance
management
by
allowing
a
Section
3
seed
increase
of
MON
863,
provided
that
corn
will
not
be
planted
the
following
year
in
a
field
used
for
seed
increase.

One
commenter
believes
that
rotating
the
seed
to
a
field
crop
other
than
corn
would
greatly
reduce
any
chance
of
producing
rootworm
adults
from
the
seed
increase
field.
The
same
commenter
is
concerned
that
problems
are
emerging
with
current
management
strategies,
particularly
adaptation
to
crop
rotation
and
increased
use
of
insecticides
to
deal
with
this
resistance.
The
commenter
cites
several
variables
that
reduce
the
efficacy
of
insecticides
and
states
that
insecticides
present
safety
issues.
The
commenter
believes
that
registrations
and
use
patterns
of
corn
rootworm
insecticides
may
change
as
a
result
of
reviews
by
EPA
under
the
Food
Quality
Protection
Act.

EPA's
Response
Although
Monsanto
does
not
plan
to
plant
a
refuge
for
inbred
seed
increase
fields,
they
will
treat
with
insecticides
that
will
probably
control
any
resistant
CRW
adults
that
may
emerge.
It
is,
therefore,
acceptable
to
plant
inbred
seed
increase
acres
without
a
refuge.

It
should
be
noted
that
the
request
for
public
comments
was
not
for
a
seed
increase
registration;
rather,
comments
were
being
requested
by
the
Agency
for
a
Section
3(
c)
full
commercial
registration.
It
should
also
be
noted
that
recommendations
made
by
the
NCR
46
technical
committee
were
considered
for
the
MON
863
registration
(
see
BRAD
Conclusions
and
Recommendations
Sections
pp.
IID
14
to
IID
17).
The
Agency
appreciates
the
concerns
regarding
the
corn
rootworms
ability
to
adapt
to
current
pest
control
methods.
The
corn
rootworms
adaptive
ability
was
considered
by
Monsanto
(
MRID
455770­
01)
and
reviewed
by
the
Agency.

IRM
Data
Needs
Public
Comments
One
commenter
believes
EPA
should
request
that
the
SAP,
Monsanto,
and
academic
IRM
experts
develop
a
new
IRM
theory
applicable
to
MON
863
before
approving
MON
863
for
registration.
The
commenter
also
states
that
EPA
should
work
with
the
SAP
to
evaluate
approving
MON
863
under
a
prescription­
use
approach
designed
to
enhance
compliance
with
IRM
provisions
and
other
product­
use
requirements
and
limitations.
The
commenter
believes
this
approach
will
support
systematic
collection
of
high­
quality
data.

One
commenter
does
not
believe
that
the
applicant
provides
sufficient
data
to
support
the
proposed
IRM
Section
1.0
1
­
8
plan
for
MON
863.
The
commenter
states
that
the
applicant
should
be
required
to
develop
a
more
protective
IRM
plan
consulting
with
independent
experts,
identifying
and
addressing
data
gaps,
and
considering
current
means
of
resistance
management.

One
commenter
notes
that
the
applicant
does
not
offer
many
specific
commitments
regarding
data
collection
and
states
that
biological
data
is
needed
to
assess
the
effectiveness
of
the
proposed
refuge
strategy
and
to
determine
whether
other
approaches
to
IRM
would
be
more
effective.
The
commenter
believes
additional
data
is
needed
on
the
northern
corn
rootworm,
and
on
the
movement
and
mating
behavior
of
adult
corn
rootworm,
mechanisms
of
resistance,
initial
frequency
of
resistance
alleles,
levels
of
resistance
of
hetero­
and
homozygous
resistant
adults
and
larvae,
and
fitness
costs
associated
with
resistance.
The
commenter
suggests
EPA
work
with
the
NRC­
46
committee
to
evaluate
the
impacts
of
Bt
corn
on
current
corn
rootworm
management
strategies,
particularly
soybean/
corn
rotations.

The
same
commenter
states
that
the
applicant's
IRM
plan
should
incorporate
previously
submitted
recommendations
for
improving
compliance.
The
commenter
believes
the
applicants
mitigation
strategies
to
delay
the
spread
of
resistance
are
inadequate
and
suggests
a
more
comprehensive
national
IRM
plan
is
needed.
The
same
commenter
states
that
the
applicant
has
not
given
consideration
to
the
impacts
of
stacked
transgenes
on
resistance
management.
The
commenter
is
concerned
with
increased
corn
earthworm
resistance
due
to
stacking
of
MON
810
with
MON
863
and
suggests
that
EPA
restrict
gene
stacking.

One
commenter
remarks
that
the
single
corn
rootworm
generation
per
year
slows
the
potential
for
resistance
development,
but
notes
that
deviations
from
the
life
cycle,
such
as
extended
diapause
and
oviposition
outside
of
corn,
have
implications
that
should
be
considered
in
IRM
approaches.
The
commenter
notes
that
adult
corn
rootworm
emergence
patterns
are
variable
and
can
be
influenced
by
management
strategies.
The
commenter
states
that
the
effects
of
transgenic
events
on
the
synchrony
of
emergence
of
males
and
females
are
unknown,
but
could
result
in
selective
mating
and
increase
the
speed
of
resistance.
The
commenter
also
adds
that
a
realistic
product
duration
should
be
considered
in
IRM
options
and
suggests
that
preferred
longevity
of
corn
rootworm
susceptibility
be
clearly
defined.

The
commenter
provides
the
following
questions
for
EPA
to
consider:
1.
Since
dose
levels
have
not
been
defined
for
transgenic
events
against
corn
rootworms,
what
constitutes
high,
moderate,
and
low­
dose
events?
2.
How
can
the
effective
dosage
of
a
transgenic
event
be
measured
for
corn
rootworms?
3.
How
do
the
diversity
of
situations
that
have
triggered
resistance
development
previously
in
corn
rootworms
(
chlorinated
hydrocarbons,
crop
rotation,
adult
control
with
organophosphates)
relate
to
assumptions
about
resistance
to
transgene
events
and
IRM?
4.
What
can
be
done
to
develop
a
robust
plan
for
multiple
species,
for
multiple
events?
5.
What
are
baseline
toxicity
levels
for
all
corn
rootworm
species,
not
just
western
corn
rootworms?
6.
How
does
the
difficulty
of
rearing
corn
rootworms
and
conducting
bioassays
complicate
the
registration
of
events?
7.
What
are
the
appropriate
methodologies
to
use
to
monitor
for
corn
rootworm
resistance
to
rootworm
protected
transgenic
plants
(
laboratory/
field)?
8.
What
is
a
realistic
time
period
to
try
to
preserve
the
life
of
a
transgenic
event
by
preventing
resistance
through
IRM?
Section
1.0
1
­
9
EPA's
Response
The
Agency
agrees
that
SAP,
Monsanto,
and
academic
IRM
experts
should
be
consulted
to
develop
a
new
IRM
theory
applicable
to
MON
863
before
approving
MON
863
for
registration.
Therefore,
an
SAP
was
convened
on
August
28
and
29,
2002
to
comment
on
Monsanto's
IRM
plan
outlined
in
MRID
455770­
01.
An
SAP
report
was
published
on
November
6,
2002
and
can
be
viewed
at
http://
www.
epa.
gov/
scipoly/
sap/
2002/
august/
august2002final.
pdf.
From
data
currently
available
it
can
be
concluded
that
MON
863
corn
does
not
provide
a
high
dose
for
CRW
control.
The
August
2002
SAP
suggested
that
it
is
not
necessary
to
determine
the
difference
between
a
low
and
moderate
dose.
It
is
adequate
to
differentiate
between
high
dose
and
non­
high
dose
products
when
determining
effective
refuge
size.
Therefore,
MON
863
should
be
characterized
as
a
non­
high
dose
product
(
see
BRAD
Dose
Section
pp.
IID
4
and
IID
5).

Although
the
Agency
recognizes
the
importance
of
grower
compliance
(
see
BRAD
Grower
Education
and
Compliance
Section
pp.
IID
12
and
IID
13),
a
prescriptive
use
approach
was
not
required.
According
to
Monsanto,
the
risk
of
resistance
will
be
reduced
by
encouraging
stakeholders
such
as
growers,
Extension
Agents
and
crop
consultants
to
promote
and
practice
IPM.
For
instance,
scouting
fields
in
the
Fall
will
be
encouraged
and
planting
MON
863
on
acres
with
the
highest
risk
of
damage
will
be
promoted
(
MRID
455770­
01).

The
Agency
believes
there
is
sufficient
information
currently
available
to
ensure
corn
rootworm
resistance
to
Cry3Bb1
will
not
occur
during
an
interim
registration
(
see
BRAD
Chapter
D.
Insect
Resistance
Management).
To
further
ensure
the
delay
of
resistance,
the
Agency
is
requiring
the
use
of
non­
Bt
corn
refuges
(
see
BRAD
Refuge
Section
pg.
IID
9).
The
Agency
agrees
that
a
comprehensive
compliance
and
remedial
action
plan
are
needed
for
an
IRM
strategy
(
see
BRAD
Remedial
Action
and
Grower
Education
and
Compliance
Sections
pp.
IID
11
to
IID
13).
The
Agency
also
recognizes
the
importance
of
pest
biology
when
developing
an
IRM
strategy
(
see
BRAD
Pest
Biology
Section
pp.
IID
2
to
IID
4).
However,
more
data
is
needed
regarding
pest
biology
and
its
impact
on
an
IRM
strategy.
Therefore,
the
Agency
has
requested
additional
research
be
conducted
during
the
interim
registration
to
provide
the
needed
data
on
corn
rootworm
biology.
In
particular,
data
has
been
requested
on
movement,
mating
and
ovipositional
patterns
of
the
corn
rootworm
as
well
as
the
information
on
the
potential
for
rearing.
Data
has
also
been
requested
to
establish
baseline
toxicity
levels
for
all
corn
rootworm
species
(
see
BRAD
Conclusions
and
Recommendations
Sections
pp.
IID
14
to
IID
17).

This
registration
only
addressed
Cry3Bb1
expressed
in
field
corn.
Therefore,
stacked
products
were
not
considered.

Applicant
Responses
Public
Comments
The
applicant
responds
to
public
comments
on
the
IRM
plan
with
the
following
statements:
­
The
proposed
interim
IRM
plan
for
MON
863
has
been
designed
with
input
from
key
stakeholders,
including
academic,
government
and
industry
scientists,
crop
consultants
and
growers.
­
The
1998
EPA
SAP
recommended
a
refuge
and
high
dose
strategy
for
the
first
Bt
plant­
incorporated
Section
1.0
1
­
10
protectants,
but
the
Panel
emphasized
the
need
for
flexibility
in
resistance
management
plans
based
upon
pest
biology,
the
nature
of
the
response
to
the
Bt
crop,
and
economic
or
logistical
feasibility.
­
To
support
commercial
launch
of
this
product
a
research
strategy
is
in
place
with
stakeholders
to
balance
the
best
technical
information
and
grower
feasibility
to
increase
the
durability
of
CRW­
protected
hybrids.
The
IRM
plan
for
MON
863
hybrids
will
evolve
over
time
as
new
information
is
developed,
just
as
the
IRM
plan
for
YieldGard
Corn
Borer
evolved
over
time.
­
MON
863
presents
a
negligible
cross­
resistance
risk
to
other
Bt
events
that
work
via
a
different
mode
of
action.
­
MON
863
does
not
pose
an
unreasonable
cross­
resistance
risk
to
a
future,
hypothetical
Bt
microbial­
based
products
for
the
control
of
CRW
because
surface­
applied
Bt
microbial
formulations
cannot
be
adequately
applied
to
growing
root
tissues
to
assure
constant
coverage
of
root
tissue
for
a
prolonged
period
of
time
to
control
feeding
CRW
larvae.

In
response
to
comments
that
adaptation
of
CRW
populations
to
the
Cry3Bb1
protein
expressed
in
MON
863
could
limit
the
longevity
of
future
biopesticide
formulations
of
Cry3Bb,
other
Cry3Bb
events
or
Bt
events
with
a
different
mode
of
action,
the
applicant
provided
further
scientific
background:

The
Cry3Bb
protein
has
never
been
used
in
any
formulated
Bt
microbial­
based
product
to
control
CRW
larvae
for
two
important
reasons:
delivery
and
timing.
CRW
larvae
feed
on
corn
roots
over
a
largely
unpredictable
period
of
three
to
eight
weeks,
and
the
Bt
insecticidal
protein
must
be
ingested
to
elicit
a
pesticidal
physiological
response.
Thus,
in
order
for
CRW
larvae
to
come
into
contact
with
a
microbial
Bt
formulation,
it
would
need
to
be
applied
so
as
to
constantly
cover
the
root
tissue
and
remain
active
for
a
prolonged
period
of
time.
Neither
of
these
issues
can
be
addressed
with
current
Bt
microbial
formulation
technology.
Thus,
it
is
reasonable
to
assume
that
use
of
MON
863
will
not
pose
an
unreasonable
risk
to
a
future,
hypothetical
Bt
microbial­
based
product
for
the
control
of
CRW.
Studies
also
indicate
that
there
is
little
cross­
resistance
between
Bt
plant
and
foliar
sprays
with
similar
proteins
because
of
the
presence
of
other
critical
ingredients,
such
as
spores,
in
the
spray
formulations.

Corn
event
MON
863
produces
the
Cry3Bbl
protein
at
levels
sufficient
to
minimize
CRW
larval
root
damage.
Regulatory
approval
and
commercial
use
of
this
technology
will
require
the
deployment
of
a
scientifically
sound
and
feasible
IRM
plan
that
suppresses
the
emergence
of
insect
resistance
in
targeted
pest
populations.
In
the
event
that
future
Cry3Bbl
events
are
introduced,
EPA
will
require
and
determine
the
acceptability
of
appropriate
IRM
plans
for
all
products.

Event
MON
863
represents
a
negligible
risk
to
other
Bt
events
that
work
via
a
different
mode
of
action.
It
is
well
understood
that
Bt
proteins
having
similar
modes
of
action
are
at
a
greater
risk
of
exhibiting
cross­
resistance.
Conversely,
Bt
proteins
that
differ
in
their
mode
of
action
represent
a
minimal
risk
of
cross­
resistance.
It
is
for
this
reason
that
EPA
and
the
scientific
community
recommend
that
developers
of
Bt
crops
develop
and
express
Bt
proteins
with
differing
modes
of
action
as
a
means
to
further
reduce
the
likelihood
of
resistance
development
in
pest
populations.
Section
1.0
1
­
11
The
generally
recognized
mode
of
action
of
Bt
proteins
has
several
distinct
steps
after
ingestion
by
the
insect.
These
steps
include:
solubilization,
proteolytic
stability,
binding
to
the
insect
midgut
epithelium,
formation
of
ion
channels
in
the
insect
midgut
cells,
and
finally
lysis
of
these
cells.
Each
of
these
steps
is
governed
by
the
sequence­
dependent
structure
of
the
protein
and
the
insect­
specific
midgut
environment.
Thus,
the
more
two
proteins
differ
structurally,
the
more
likely
they
are
to
differ
in
their
mode
of
action
and
would
exhibit
differing
mechanisms
of
resistance.
The
sequence
dissimilarity
between
two
Bt
proteins
is
an
empirical
measure
of
their
likelihood
to
act
by
different
modes
of
action.
Recently
Cry34Abl
and
Cry35Ab1
have
been
listed
as
new
classes
of
novel
Cry
proteins,
which
require
them
to
share
less
than
45%
amino
acid
identity
with
any
other
known
Cry
protein
(
e.
g.,
Cry3Bbl).
The
Cry34
and
Cry35
proteins
expressed
in
CRW­
protected
events
under
development
by
Dow
AgroSciences
and
Pioneer
Hy­
Bred
International
function
as
a
binary
protein
active
against
CRW
larvae.
These
proteins
not
only
are
very
different
from
Cry3Bbl
in
amino
acid
sequence,
but
both
proteins
are
absolutely
required
for
CRW
activity.
Due
to
these
differences
in
protein
sequence
and
mode
of
action,
it
is
unlikely
that
Cry3Bb1
and
the
new
Cry34/
Cry35
binary
protein
have
similar
modes
of
action.

The
applicant
provides
the
following
benefits
relative
to
insect
resistance
management
for
MON
863:
­
Superior
pest
protection
will
greatly
reduce
the
use
of
insecticides
to
control
losses
from
corn
rootworm
and
reduce
human
and
animal
insecticide
exposure
on
the
farm
and
in
the
agro­
ecosystem.
­
The
proposed
interim
IRM
plan
incorporates
all
that
is
known
about
the
biology
of
the
target
pest
spectrum,
grower
feasibility
of
alternative
strategies,
product
dose,
as
well
as
other
available
pest
management
options
that
will
limit
overall
selection
pressure
from
MON
863
on
CRW
populations
during
the
interim
period.
­
The
proposed
interim
IRM
plan
identifies
important
areas
for
on­
going
research
and
is
intended
to
evolve
as
needed
over
time
based
on
the
latest
scientific
information.­
On­
going
research
will
be
used
to
design
a
long­
term
MM
plan
that
will
ensure
durability
of
MON
863
corn
hybrids.
­
The
proposed
interim
IRM
plan
for
MON
863
has
been
designed
with
input
from
key
stakeholders,
including
academic,
government
and
industry
scientists,
crop
consultants
and
growers.
­
The
interim
plan
does
not
rely
on
reduced
adoption
rates
as
an
MM
strategy,
as
this
approach
would
limit
grower
access
to
a
safe,
simple
and
effective
alternative
to
current
pest
management
practices
that
rely
heavily
on
insecticide
use.
­
An
appropriate
resistance
management
plan
can
be
developed
for
products
of
any
dose
level.
­
When
a
mathematical
model
was
applied
to
MON
863
and
CRW
Using
conservative
low
to
moderate
dose
parameters
and
assuming
incomplete
adoption
of
MON
863
during
the
interim
period,
the
durability
of
MON
863
was
predicted
to
extend
beyond
15
years.

The
applicant
responds
to
the
question
of
whether
an
IRM
strategy
designed
for
western
and
northern
corn
rootworm
is
applicable
to
other
corn
rootworm
species
stating
that
there
are
subtle
differences
in
the
biology
of
the
corn
rootworm
species
targeted
by
this
product,
but
they
should
not
be
at
any
greater
risk
for
resistance
development
during
the
period
that
this
interim
plan
is
in
effect.
The
applicant
adds
that
the
western
corn
rootworm
is
the
most
abundant
species
where
this
technology
will
be
used
and
has
shown
the
greatest
propensity
for
developing
resistance
to
other
insect
control
practices.
Section
1.1
1
­
12
EPA's
Response
The
Agency
agrees
with
the
comments
provided
by
Monsanto
and
summarized
above
with
one
exception
(
see
BRAD
Insect
Resistance
Management
Chapter).
It
is
unknown
whether
the
current
IRM
plan
will
extend
the
durability
of
MON
863
for
15
years.
Based
on
the
current
simulation
models
that
utilize
conservative
input
parameters,
a
20%
refuge
will
extend
the
durability
of
MON
863
corn
for
7
to
16
years
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp.
IID
5
to
IID
8).
In
addition,
the
Agency
recommends
gathering
more
information
on
biology
of
all
corn
rootworm
species
and
subspecies
to
verify
that
the
IRM
strategy
is
appropriate
for
western,
Mexican
and
northern
corn
rootworm.

1.1
Refuges
General
Public
Comments
Several
commenters
addressed
the
issue
of
overall
adequacy
of
the
IRM
plan.
One
commenter
states
that
the
applicant
may
underestimate
the
rate
of
MON
863
adoption
by
farmers,
has
not
considered
the
possible
impact
of
gene
stacking
on
the
efficacy
of
its
IRM
plan,
and
does
not
assure
that
farmers
will
adequately
comply
with
IRM
plan
requirements.
The
commenter
further
states
that
the
IRM
plan
should
consider
all
possible
means
to
prevent
resistance
and
not
be
limited
to
the
refuge
strategy,
in
particular
soybean/
corn
rotations
should
be
considered.

Another
commenter
states
that
the
interim
IRM
plan
is
flawed
and
describes
shortcomings,
including
dependence
on
the
marketplace
to
dictate
refuges,
an
inadequate
20
percent
grower­
established
refuge,
an
incorrect
definition
of
resistance,
inadequate
requirements
for
treating
refuges,
and
doubtful
assumptions
about
impacts
of
MON
863
on
continuous­
corn
acreage.
The
commenter
adds
that,
despite
slow
penetration
of
the
market
overall,
some
areas
may
have
adoptions
as
high
as
80
percent
of
corn
acres
so
that
the
defacto
unstructured
refuges
the
applicant
is
counting
on
would
be
lost.
The
commenter
believes
it
is
inappropriate
to
implement
a
resistance
management
plan
that
relies
on
the
marketplace
to
ensure
low
adoption
and
states
that
a
20
percent
refuge
may
allow
faster­
than­
predicted
resistance
evolution.

Another
commenter
states
that
IRM
must
be
closely
monitored
and
supports
the
proposal
for
20
percent
refuge
within
the
same
field
or
adjacent
field
with
similar
cropping
patterns.
The
commenter
also
notes
that
farmers
will
likely
apply
insecticide
in
the
refuges
and
states
that
refuge
requirements
that
minimize
the
handling
of
insecticides
would
be
beneficial.
The
same
commenter
states
that
crop
rotation
is
determined
by
many
factors
and
suggests
that
planting
adjacent
fields
with
similar
cropping
patterns
could
present
problems.

The
applicant
describes
alternative
strategies
and
available
control
tactics
considered
in
the
proposed
IRM
plan,
noting
that
growers
will
have
a
variety
of
pest
management
options
limiting
selection
pressure
on
corn
rootworm
populations.
The
applicant
also
states
that
other
management
options
will
prevail
initially
due
to
limited
availability
of
seed
and
grower
trials.

In
response
to
requests
for
discussion
on
whether
the
refuge
strategy
is
adequate
to
delay
resistance,
the
Section
1.1
1
­
13
applicant
states
that
the
IRM
plan
has
been
rigorously
examined
by
experts
and
that
the
conservative
nature
of
the
plan
is
further
reinforced
by
limited
initial
adoption
and
conservative
estimations
of
durability.
The
applicant
quotes
the
SAP
report
and
a
letter
submitted
by
NCR­
46
both
endorsing
the
plan.

EPA's
Response
The
Agency
realizes
that
grower
adoption
rates
may
be
underestimated.
Therefore,
the
simulation
models
and
overall
IRM
strategy
were
considered
on
the
basis
of
100%
grower
adoptions
which
is
clearly
an
overestimation.
In
addition,
corn/
soybean
rotations
versus
continuous
corn
is
considered
by
the
simulation
models
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp
IID
5
to
IID
8).
Since
continuous
corn
would
be
a
worst
case
scenario,
the
models
indicate
that
a
20%
refuge
is
adequate
to
delay
resistance
so
a
corn/
soybean
rotation
requirement
is
not
needed.
The
Agency
agrees
with
the
comment
that
a
20%
refuge
planted
adjacent
to
or
within
fields
is
adequate
to
delay
resistance
and
that
it
is
acceptable
to
apply
soil
applied
insecticides
to
refuge
acres
to
control
immature
corn
rootworm
(
See
BRAD
Refuge
Section
pg.
IID
9).
The
Agency
based
this
recommendation,
in
part,
on
simulation
models
utilizing
conservative
parameters
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp
IID
5
to
IID
8).
The
Agency
also
recognizes
the
need
to
monitor
for
resistance;
therefore,
a
resistance
monitoring
program
is
required
as
part
of
the
MON
863
IRM
strategy
(
see
BRAD
Monitoring
for
Resistance
Section
pp.
IID
9
to
IID
10).
Since
this
registration
is
for
Cry3Bb1
expressed
in
MON
863
corn,
stacked
genes
were
not
considered.

Dose
Public
Comments
One
commenter
believes
the
high­
dose
refugia
model
proposed
by
the
applicant
may
not
be
appropriate
because
MON
863
does
not
deliver
a
high
dose.

The
applicant
responds
to
questions
about
the
rationale
supporting
the
commercialization
of
a
low­
tomoderate
dose
product
by
describing
dose
considerations.
The
applicant
states
that
other
factors,
including
pest
biology,
refuge
size,
refuge
proximity,
agronomic
practices
and
grower
behavior
were
also
considered.
The
applicant
adds
that
considering
these
factors,
the
proposed
IRM
plan
is
conservative
and
acceptable
for
reducing
pest
adaptation
during
the
interim
period
and
beyond.

EPA's
Response
The
Agency
agrees
that
a
high­
dose/
refuge
model
is
not
appropriate
for
MON
863
corn
since
there
is
not
a
"
high
dose"
of
Cry3Bb1
expressed
(
see
BRAD
Dose
Section
pp.
IID
4
to
IID
5).
The
Agency
also
agrees
that
pest
biology,
refuge
size,
refuge
proximity,
agronomic
practices
and
grower
behavior
are
important
factors
to
be
considered
in
an
IRM
plan
(
see
BRAD
Refuge
Section
pg.
IID
9).
The
IRM
strategy
currently
recommended
is
based
on
conservative
parameters
and
current
knowledge
of
corn
rootworm
biology
(
see
BRAD
Pest
Biology
Section
pp.
IID
2
to
IID
4
and
Simulation
Models
of
Resistance
Section
pp
IID
5
to
IID
8).

Control
for
Refuges
Section
1.1
1
­
14
Public
Comments
A
few
commenters
addressed
the
control
strategies
for
refuge
corn.
One
commenter
states
that
the
IRM
lacks
detailed
requirements
ensuring
the
appropriate
makeup
and
treatment
of
refuges.
The
commenter
offers
several
suggestions
for
the
IRM
plan,
including
restricting
plantings
to
no
more
than
25
percent
of
the
corn
acreage
in
a
county,
requiring
at
least
30
percent
non­
Bt
refuges
to
accompany
MON
863
plantings,
and
requiring
that
refuges
be
planted
with
nonCry
3Bb
corn.
Another
commenter
is
concerned
that
farmers
use
the
same
methods
to
grow
MON
863
as
refuge
corn,
including
crop
rotation
history,
to
ensure
that
pest
management
practices
on
the
refuge
are
compatible
with
the
IRM
plan.
One
commenter
states
that
the
IRM
plan
would
include
20
percent
refuges,
and
that
growers
would
have
the
option
to
both
plant
insecticide­
treated
seed
and
spray
insecticides.

In
response
to
a
question
about
how
insecticide
use
in
the
refuge
and/
or
Bt
fields
affects
the
predictions
of
time
to
resistance,
the
applicant
states
that
empirical
evidence
suggests
that
insecticides
do
not
consistently
increase
or
decrease
the
number
of
surviving
insects
and
so
would
not
alter
the
model
predictions.
Responding
to
a
request
to
comment
on
what
conditions
would
allow
insecticide
use
in
refuges,
the
applicant
states
that
use
of
insecticides
is
essential
to
avoid
excessive
plant
lodging
and
yield
loss
in
the
refuge.

One
commenter
disputes
the
assumption
that
a
majority
of
refuge
acres
will
not
be
treated
and
states
that
corn
rootworm
control
is
not
compatible
with
refuge
management
unless
it
is
applied
to
both
refuge
and
transgenic
areas.
The
commenter
also
states
that
refuge
design
should
include
consideration
of
the
amount
and
spatial
distribution
of
refuge
plus
the
potential
effect
management
practices
may
have
on
the
abundance
and
relative
phenology
of
susceptible
beetles.

EPA's
Response
Although
the
Agency
agrees
that
a
refuge
should
be
planted
with
non­
Cry3Bb
corn,
the
Agency
has
determined
that
a
20%
refuge
is
adequate
to
delay
resistance.
The
Agency
also
agrees
that
the
same
methods
to
grow
MON
863
as
refuge
corn,
including
crop
rotation
history,
should
be
implemented.
In
addition,
the
Agency
recognizes
the
growers
need
to
treat
refuges
to
control
corn
rootworm
larvae
and
to
treat
MON
863
corn
and
refuges
to
control
pests
other
than
the
corn
rootworm.
Therefore,
seed
and
granular
insecticide
treatments
to
control
corn
rootworm
larvae
are
acceptable
on
refuge
acres.
However,
it
is
not
acceptable
to
treat
refuges
for
adult
CRW
control
since
these
treatments
may
diminish
the
effectiveness
of
the
refuge.
If
growers
spray
their
corn
fields
with
insecticides
to
control
pests
other
than
corn
rootworm,
then
all
acres
(
Bt
and
non­
Bt)
should
be
treated
identically
(
see
BRAD
Refuge
Section
pg.
9).

Row
Strips
Public
Comments
One
commenter
states
that
for
block
refuges
planted
within
a
field
and
at
different
locations
each
year,
the
development
of
resistance
should
be
closer
to
that
simulated
with
refuges
as
row
strips
and
describes
supporting
data
from
a
2001
study
by
Onstad
et
al.
Section
1.1
1
­
15
Responding
to
questions
about
the
adequacy
of
in­
field
row­
strips
and/
or
immediately
adjacent
blocks
to
delay
resistance
during
a
three­
year
period,
the
applicant
states
that
both
options
can
be
used
and
should
be
available
to
growers.
For
the
width
of
in­
field
strips,
the
applicant
recommends
at
least
four
to
six
rows
wide.
The
applicant
adds
that
this
width
is
appropriate
for
corn
rootworm
and
provides
flexibility
for
growers,
but
is
the
least
favored
option.

EPA's
Response
The
2001
Onstad
et
al.
publication
was
considered
in
the
development
of
an
IRM
strategy
for
MON
863
corn
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp
IID
5
to
IID
8).
The
Agency
agrees
that
adjacent
block
or
in­
field
strips
are
acceptable
options
that
should
be
available
to
growers.
In
addition,
the
Agency
is
recommending
that
refuges
be
planted
as
at
least
six
consecutive
rows
(
see
BRAD
Refuge
Section
pg.
IID
9).

Hosts
Public
Comments
Regarding
EPA's
conclusion
that
alternate
hosts
should
not
be
considered
and
refuges
should
only
consist
of
non­
Bt
corn,
the
applicant
states
that
further
information
is
needed
to
assess
the
relative
value
of
noncorn
host
plants,
thus
they
have
not
been
included
as
refuge
in
the
IRM
plan.

EPA's
Response
The
Agency
agrees
that,
based
on
current
information,
non­
corn
hosts
are
not
acceptable
refuges
and
that
further
information
is
needed
to
assess
the
relative
value
of
alternate
host
plants
(
see
BRAD
Refuge
Section
pg.
IID
9).

Refuge
Research
Needs
Public
Comments
In
response
to
questions
about
research
needed
to
determine
placement
of
non­
Bt
corn
refuges,
the
applicant
states
that
the
most
important
research
need
is
to
understand
insect­
plant
interactions
and
dispersal
under
large­
scale
field
conditions.
The
applicant
adds
that
data
has
only
recently
been
generated
on
adult
and
larval
dispersal
with
MON
863
in
the
laboratory,
but
researchers
are
developing
techniques
to
study
dispersal
of
corn
rootworm
populations
under
commercial
conditions.

In
response
to
questions
about
additional
data
needs
on
mating
habitats,
ovipositional
patterns,
number
of
times
a
female
can
mate
and
fecundity,
the
applicant
states
that
research
to
date
with
MON
863
has
shown
that
changes
in
the
sex
ratio
among
survivors
will
eliminate
a
large
number
of
potential
matings
of
resistant
individuals,
and
that
emergence
delays
of
approximately
ten
days
will
increase
the
likelihood
that
resistant
females
would
mate
with
susceptible
males
dispersing
from
nearby
refuges.
The
applicant
further
states
Section
1.2
1
­
16
that
research
suggests
that
males
dispersing
from
nearby
refuges
will
already
be
present
in
large
numbers
and
compete
favorably
with
any
resistant
males
emerging
from
the
MON
863
field,
thereby
reducing
the
likelihood
of
resistance
development.

EPA's
Response
The
Agency
agrees
that
more
information
is
needed
on
corn
rootworm
adult
and
larval
movement
to
verify
the
appropriate
placement
of
refuges.
In
addition,
more
information
is
needed
on
dispersal,
mating
and
ovipositional
patterns,
fecundity
and
sex
ratio
(
see
BRAD
Conclusions
and
Recommendations
Sections
IID
14
to
IID
17).

1.2
Resistance
Defined
General
Public
Comments
One
commenter
states
that
the
plan's
definition
of
resistance
is
incorrect.
The
commenter
states
that
the
definition
is
similar
to
that
used
for
high
dose
Bt
crops
and
is
not
appropriate
for
MON
863,
and
that
the
definition
is
more
applicable
to
field
failure.
The
commenter
also
states
that
resistance
is
determined
by
both
the
LC50
of
the
line
and
the
slope
of
the
concentration­
survival
curve,
not
just
by
the
LC50.

In
response
to
a
request
for
discussion
of
an
appropriate
method
of
determining
suspected
and
confirmed
resistance
for
CRW,
the
applicant
states
that
Monsanto
will
investigate
reported
instances
of
product
failure
and
that
cases
of
suspected
resistance
will
undergo
laboratory
dose
response
and
whole
plant
assays.
The
applicant
indicates
that
a
mitigation
plan
will
be
implemented
if
resistance
is
confirmed.

The
applicant
responds
to
requests
for
comment
on
the
product
duration
or
longevity
of
CRW
susceptibility
considered
in
IRM
models
by
identifying
principle
factors
influencing
the
rate
of
resistance
development,
but
noting
that
current
models
do
not
incorporate
all
the
factors.
The
applicant
also
notes
that
the
longevity
of
any
management
tool
is
dependent
upon
the
extent
of
grower
adoption,
the
effectiveness
of
the
IRM
plan,
the
use
of
alternative
management
strategies,
the
relative
fitness
of
resistant
genotypes,
and
the
extent
of
grower
compliance
with
IRM
requirements,
all
of
which
are
also
missing
from
current
models.
The
applicant
adds
that
current
models
do
not
incorporate
current
or
future
management
options,
and
therefore
overestimate
the
risk
of
resistance.

The
applicant
also
addresses
the
question
of
how
insecticide
use
in
the
refuge
and/
or
Bt
fields
affects
the
predictions
of
time
to
resistance,
stating
that
empirical
evidence
suggests
that
insecticides
do
not
consistently
increase
or
decrease
the
number
of
surviving
insects
and
so
would
not
alter
the
model
predictions.

The
applicant
addresses
requests
for
a
discussion
on
whether
root
ratings
are
an
appropriate
indicator
of
suspected
resistance,
noting
that
unexpected
high
levels
are
one
indicator,
but
that
growers
will
more
likely
report
unacceptable
levels
of
plant
lodging
as
product
failure.
Section
1.2
Section
1
­
17
In
response
to
a
request
for
discussion
on
the
applicability
of
the
three
models
for
assessing
the
likelihood
of
CRW
developing
resistance,
the
applicant
states
that
the
models
developed
by
Drs.
Andow
and
Onstad
have
been
useful
for
prioritizing
research
but
they
have
not
been
useful
for
predicting
CRW
resistance
to
MON
863.
The
applicant
adds
that
the
models
were
developed
to
help
guide
the
research
program
and
to
develop
the
IRM
strategy,
but
their
predictions
must
be
viewed
cautiously.
The
applicant
states
that
the
model
developed
by
Dr.
Caprio
was
used
to
evaluate
the
durability
of
MON
863
in
a
qualitative
sense
by
examining
the
relative
impact
of
parameters
tested
in
the
other
models,
parameter
values
based
on
the
properties
of
MON863,
and
conservative
estimates
of
adoption,
dose
and
refuge
size.
The
applicant
also
provides
further
information
on
the
goals
and
outcomes
of
this
model.
The
applicant
listed
conservative
assumptions
used
in
all
three
models.

EPA's
Response
On
August
28
and
29,
2002
the
Agency
convened
a
FIFRA
Scientific
Advisory
Panel
(
SAP)
to
provide
expert
input
regarding
IRM
of
MON
863
corn.
The
SAP
did
not
recommend
including
slope
as
a
definition
of
resistance.
The
nature
of
resistance
takes
many
forms,
with
important
factors
considered
such
as
behavioral
resistance
and
physical
size
that
may
not
relate
to
the
slope
of
an
LC50.
For
instance,
corn
rootworm
that
are
physically
larger
than
others
may
take
longer
to
be
affected
(
behavior
and/
or
sublethal
and
non­
lethal
changes)
but
have
the
same
slope
or
the
survival
in
a
dietary
toxicity
study.
The
Agency
does
not
want
to
restrict
the
definition
of
resistance
to
exclude
these
factors,
especially
for
a
pest
which
has
already
shown
behavioral
adaptation
to
cultural
control
techniques.

The
initial
observation
of
unexpected
CRW
damage
or
suspected
resistance
will
likely
occur
by
the
grower.
Unexpected
damage
will
probably
be
observed
as
lodged
corn
plants.
Resistance
should
be
confirmed
by
a
standard
diet
bioassay
or
evaluation
of
root
node
injury.
An
insect
diet
bioassay
with
the
Cry3Bb1
protein
that
results
in
a
LC50
that
exceeds
the
upper
limit
of
the
95%
confidence
interval
of
the
LC50
established
from
baseline
measurements
of
susceptible
populations
could
be
used
to
confirm
resistance.
Alternatively,
resistance
may
be
confirmed
when
one
or
more
root
nodes
of
at
least
50%
of
Cry3Bb1
plants
grown
in
the
laboratory
are
destroyed.
Once
resistance
has
been
confirmed,
mitigation
measures
must
be
immediately
implemented
(
see
BRAD
Remedial
Action
Section
pp.
IID
11
and
IID
12).

A
model
was
run
by
Monsanto
that
utilized
conservative
parameters
including
an
initial
resistance
allele
frequencies
of
.01
and
.001,
RS
dominance
values
of
0.7
and
0.8
and
SS
survival
ranging
from
0.1
to
0.8.
Results
of
the
model
incorporating
these
conservative
input
parameters
(
e.
g.,
initial
allele
frequency
=
.01;
RS
dominance
value
=
0.8;
SS
survival
=
0.1)
suggested
that
CRW
resistance
to
Cry3Bb1
will
not
occur
for
at
least
seven
years
assuming
100%
MON
863
market
penetration
and
100%
IRM
compliance
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp.
IID
5
to
IID
8).
Section
1.3
Section
1
­
18
1.3
IRM
Plan
General
Public
Comments
One
commenter
believes
corn
rootworm­
protected
corn
provides
an
ideal
fit
with
current
integrated
pest
management
(
IPM)
recommendations
for
corn
rootworm
control.
Another
commenter
encourages
producers
to
implement
IRM
plans
when
planting
corn
rootworm­
protected
corn.
Another
commenter
states
that
Monsanto
recognizes
the
need
for
IRM
plans
and
intends
to
deploy
IRM
plans
involving
structured
refuges
at
the
time
of
commercialization.

One
commenter
points
out
that
there
will
always
be
non­
target
effects,
but
states
that
most
of
the
significant
questions
have
been
addressed.
The
commenter
also
states
that
positive
and
negative
impacts
must
be
compared
with
those
of
existing
technologies.

One
commenter
states
that
any
resistance
management
plan
must
be
effective
against
all
corn
rootworm
species,
applicable
to
a
wide
variety
of
corn
production
systems,
and
readily
implementable
by
the
farmers.
The
commenter
believes
the
IRM
plan
meets
these
requirements,
but
should
address
the
unique
challenges
posed
by
Cry3Bb,
corn
rootworm
biology
and
ecology,
and
corn
rootworm
management.
The
commenter
notes
that
future
events
may
be
high
dose
and
require
different
IRM
plans.

The
applicant
quoted
the
SAP
report
and
noted
that,
in
addition
to
the
recommendation
of
refuge
plus
high
dose
strategy,
the
Subpanel
emphasized
the
need
for
flexibility
in
resistance
management
plans
based
upon
pest
biology,
the
nature
of
the
response
to
the
Bt
crop
and
economic
and
logistical
feasibility.
The
applicant
also
noted
that
the
IRM
plan
has
been
designed
with
input
from
academic
stakeholders,
government
and
industry
scientists,
crop
consultants,
and
growers
and
will
evolve
over
time
as
new
information
is
developed.

The
same
commenter
recommends
that
EPA
proceed
in
its
review
of
MON
863
with
the
assistance
of
the
SAP
in
establishing
performance
standards.
The
commenter
believes
acceptable
performance
standards
might
include:
1)
expression
levels
in
root
that
are
ten
times
or
more
higher
than
in
other
tissues;
2)
full
sequencing
of
transgenes
as
expressed
in
the
plant
to
serve
as
a
baseline
in
assessing
gene
silencing
and
instability
of
transgene
expression
over
multiple
generations;
3)
Understanding
the
genetics
of
resistance
in
pests
and
submission
of
an
IRM
plan
with
a
solid
prospect
of
preventing
resistance;
4)
at
least
a
10­
fold
"
Margin
of
Exposure"
for
all
nontarget
organisms
based
on
plausible
worst­
case
assumptions
regarding
exposures;
and
5)
clear
delineation
of
responsibilities
for
assuring
compliance
with
IRM
plans.

EPA's
Response
Monsanto
intends
to
encourage
stakeholders
such
as
growers,
Extension
Agents
and
crop
consultants
to
promote
and
practice
IPM.
For
instance,
scouting
fields
in
the
Fall
will
be
encouraged
and
planting
MON
863
on
acres
with
the
highest
risk
of
damage
will
be
promoted
(
MRID
455770­
01).

The
Agency
realizes
more
research
is
needed
to
determine
if
IRM
strategies
designed
for
western
corn
Section
1.3
Section
1
­
19
rootworm
and
northern
corn
rootworm
are
appropriate
for
Mexican
corn
rootworm.
Therefore,
research
on
various
aspects
of
corn
rootworm
pest
biology
as
it
relates
to
a
long­
term
IRM
strategy
will
be
conducted
during
the
interim
MON
863
registration
(
see
BRAD
Recommendations
Section
pp.
IID
16
and
IID
17).

The
Agency
agrees
with
the
August
2002
SAP
that
there
is
a
need
for
flexibility
in
an
IRM
plan.
Therefore,
two
refuge
options
are
considered
acceptable;
refuges
may
be
planted
as
in­
field
strips
or
adjacent
blocks
(
see
BRAD
Refuge
Section
pg.
IID
9).

The
Insect
Resistance
Management
chapter
of
the
MON
863
BRAD
summarizes
the
Agency's
reviews
of
Monsanto's
interim
IRM
plan.
The
IRM
chapter
also
includes
recommendations
for
research
needed
during
the
interim
registration
that
will
help
verify
whether
a
20%
refuge
is
adequate
to
delay
resistance
(
see
BRAD
Recommendations
Section
pp.
IID
6
and
IID
17).

IRM
Inadequacies
Public
Comments
Several
commenters
identified
specific
inadequacies
with
the
IRM
plan.
One
commenter
states
that
the
applicant
may
underestimate
the
rate
of
MON
863
adoption
by
farmers,
has
not
considered
the
possible
impact
of
gene
stacking
on
the
efficacy
of
its
IRM
plan,
and
does
not
assure
that
farmers
will
adequately
comply
with
IRM
plan
requirements.
The
commenter
further
states
that
the
IRM
plan
should
consider
all
possible
means
to
prevent
resistance
and
not
be
limited
to
the
refuge
strategy,
in
particular
soybean/
corn
rotations
should
be
considered.

Another
commenter
states
that
the
interim
IRM
plan
is
flawed
and
describes
shortcomings,
including
dependence
on
the
marketplace
to
dictate
refuges,
an
inadequate
20%
grower­
established
refuge,
an
incorrect
definition
of
resistance,
inadequate
requirements
for
treating
refuges,
and
doubtful
assumptions
about
impacts
of
MON
863
on
continuous­
corn
acreage.
The
commenter
further
believes
EPA
should
require
Monsanto
to
expand
and
revise
the
interim
IRM
plan
and
correct
deficiencies,
such
as
incomplete
monitoring
and
mitigation
plans,
incorrect
definition
of
resistance,
failure
to
address
northern
corn
rootworm
resistance
issues,
and
lack
of
modeling
to
address
the
use
of
insecticides
on
a
non­
high­
dose
refuge.
The
commenter
further
suggests
that
EPA
require
Monsanto
to
conduct
statistically
valid
research
and
modeling
to
fill
gaps.

The
commenter
also
identifies
the
following
flaws
with
the
IRM
plan:
1)
lack
of
modeling
results
that
address
the
use
of
insecticide
on
the
non­
high
dose
refuge;
2)
lack
of
clear
connections
between
grower
education
efforts
and
the
implementation
of
the
IRM
plan;
3)
failure
to
address
resistance
issues
associated
with
the
northern
corn
rootworm;
and
4)
inadequately
developed
monitoring
and
mitigation
plans.

The
same
commenter
believes
the
applicant's
claim
that
the
IRM
plan
is
conservative
may
be
misleading
in
some
instances.
In
particular,
the
commenter
states
that
Monsanto
claims
that
the
lack
of
beetle
exposure
to
Cry3Bb1
in
sprays
means
no
prior
selection
for
resistance.
The
commenter
adds
that
this
observation
does
affect
an
underlying
assumption
concerning
frequency
of
resistance
in
a
non­
conservative
direction,
leading
to
the
potentially
misleading
assumption
that
resistance
is
rarer
than
it
might
actually
be.
Also,
the
commenter
states
that
Monsanto
implies
that
CRW
resistance
to
MON
863
will
take
at
least
as
long,
if
not
Section
1.3
Section
1
­
20
longer,
to
develop,
particularly
in
light
of
adoption
of
IRM
plans,
however,
similar
CRW
survival
levels
in
the
presence
of
chemical
insecticides
will
likely
be
higher
for
Bt
than
for
insecticides
given
the
same
level
of
survival,
and
therefore
evolution
of
resistance
to
Bt
will
be
faster.
The
commenter
also
states
that
the
claim
that
mortality
caused
by
other
environmental
factors
will
exert
stronger
selective
pressure
on
corn
rootworm
than
MON
863
is
faulty
because
a
strong
mortality
force
is
not
necessarily
a
strong
selective
force.

Another
commenter
refers
to
recently
published
research
on
design
features
of
Bt­
transgenic
crop
resistance
management
plans
and
states
that
it
raises
unique
challenges
in
the
case
of
corn
rootworm.
According
to
the
commenter,
the
research
shows
that
refuges
need
to
be
separate
from
crop
fields
and
that
spraying
of
refuges
undermines
their
effectiveness.
The
commenter
notes
that
mating
occurs
during
the
adult
stage
of
the
rootworm
life
cycle
in
the
summer
months,
but
that
few
farmers
spray
cornfields
in
the
summer
for
adult
corn
rootworms.

Two
commenters
contrasted
ECB
and
corn
rootworm
resistance
management.
One
commenter
states
that
EPA
should
consider
the
impact
of
spraying
refuge
acres
for
ECB
to
the
corn
rootworm
resistance
management
plan.
Another
commenter
states
that
in
contrast
to
ECB
larval
movement,
corn
rootworm
larval
movement
is
limited
in
the
soil
and
may
permit
closer
integration
of
transgenic
and
non­
transgenic
corn
in
IRM
plans.
The
same
commenter
notes
that
migratory
behaviors
for
ECB
and
corn
rootworms
have
implications
on
the
selection
for
resistance,
its
spread
and
the
design
of
IRM
plans.
The
commenter
encourages
the
development
of
corn
rootworm­
specific
IRM
plans
including
refuge
options,
without
defacto
acceptance
of
the
ECB
plan.
The
same
commenter
recommends
that
the
IRM
plan
require
that
the
refuge
occur
in
the
same
field
as
the
transgenic
crop.

The
applicant
responds
to
comments
suggesting
there
is
insufficient
data
to
support
the
proposed
IRM
plan
by
stating
that
the
plan
includes
extensive
input
and
research
by
CRW
experts
from
academic
laboratories
across
the
U.
S.
The
applicant
states
that
this
input,
consideration
of
currently
available
data,
and
the
conservative
nature
of
the
plan
provide
a
reasonable
and
appropriate
strategy
for
limiting
pest
adaptation
during
the
interim
period.
The
applicant
adds
that
the
proposed
IRM
plan
is
intended
to
evolve
over
time
based
on
the
latest
scientific
information.

EPA's
Response
The
Agency
realizes
that
grower
adoption
rates
may
be
underestimated.
Therefore,
the
simulation
models
and
overall
IRM
strategy
were
considered
on
the
basis
of
100%
grower
adoptions
which
is
clearly
an
overestimation.
In
addition,
corn/
soybean
rotations
versus
continuous
corn
is
considered
by
the
simulation
models.
In
general,
the
current
simulation
model
summarized
in
the
Insect
Resistance
Management
Chapter
of
the
MON
863
BRAD
is
based
on
conservative
parameters
and
verifies
that
a
20%
refuge
is
adequate
to
delay
resistance
during
the
interim
registration
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp
IID
5
to
IID
8).
In
addition,
details
of
the
monitoring
for
resistance,
remedial
action
and
grower
education
and
compliance
plans
can
be
found
in
the
IRM
chapter.
During
the
interim
registration,
the
Agency
has
requested
Monsanto
develop
methods
to
improve
these
areas
of
their
IRM
plan.

Corn
rootworm
biology
was
considered
in
developing
the
IRM
plan
for
MON
863
corn
(
see
BRAD
Pest
Biology
Section
pp.
IID
2
to
IID
4).
In
addition,
the
Agency
recommends
gathering
more
information
on
Section
1.3
Section
1
­
21
biology
of
all
corn
rootworm
species
and
subspecies
to
verify
that
the
IRM
strategy
is
appropriate
for
western,
Mexican
and
northern
corn
rootworm.

The
Agency
requires
that
same
methods
to
grow
MON
863
as
refuge
corn,
including
crop
rotation
history,
should
be
implemented.
In
addition,
the
Agency
recognizes
the
growers
need
to
treat
refuges
to
control
corn
rootworm
larvae
and
to
treat
MON
863
corn
and
refuges
to
control
pests
other
than
the
corn
rootworm.
Therefore,
seed
and
granular
insecticide
treatments
to
control
corn
rootworm
larvae
are
acceptable
on
refuge
acres.
However,
it
is
not
acceptable
to
treat
refuges
for
adult
CRW
control
since
these
treatments
may
diminish
the
effectiveness
of
the
refuge.
If
growers
spray
their
corn
fields
with
insecticides
to
control
pests
other
than
corn
rootworm,
then
all
acres
(
Bt
and
non­
Bt)
should
be
treated
identically
(
see
BRAD
Refuge
Section
pg.
IID
9).

Resistance
should
be
confirmed
by
a
standard
diet
bioassay
or
evaluation
of
root
node
injury.
An
insect
diet
bioassay
with
the
Cry3Bb1
protein
that
results
in
a
LC50
that
exceeds
the
upper
limit
of
the
95%
confidence
interval
of
the
LC50
established
from
baseline
measurements
of
susceptible
populations
could
be
used
to
confirm
resistance.
Alternatively,
resistance
may
be
confirmed
when
one
or
more
root
nodes
of
at
least
50%
of
Cry3Bb1
plants
grown
in
the
laboratory
are
destroyed.
Once
resistance
has
been
confirmed,
mitigation
measures
must
be
immediately
implemented
(
see
BRAD
Remedial
Action
Section
pp.
IID
11
and
IID
12).
The
Agency
also
recognizes
the
need
to
monitor
for
resistance;
therefore,
a
resistance
monitoring
program
is
required
as
part
of
the
MON
863
IRM
strategy
(
see
BRAD
Monitoring
for
Resistance
Section
pp.
IID
9
to
IID
10).
Since
this
registration
is
for
Cry3Bb1
expressed
in
MON
863
corn,
stacked
genes
were
not
considered.

Growers
should
be
required
to
sign
a
technology
use
agreement
that
outlines
IRM
requirements
and
acknowledges
the
growers
responsibility
to
comply
with
them
on
an
annual
basis.
The
agreement
will
also
state
that
growers
received
the
Product
Use
Guide.
This
agreement
may
be
a
section
of
the
growers
order
sheet
or
some
other
document
or
format
(
see
BRAD
Grower
Education
and
Compliance
Section
pp.
IID
12
and
IID13).

Dose
Public
Comments
One
commenter
states
EPA
should
reject
Monsanto's
IRM
plan
because
it
relies
on
an
unacceptable
lowto
moderate
toxin
dose.
The
commenter
further
states
that
the
IRM
would
include
20
percent
refuges
and
growers
would
have
the
option
to
both
plant
insecticide­
treated
seed
and
spray
insecticides
for
corn
rootworms
or
cutworms.
The
commenter
believes
that
the
applicant
ignores
recommendations
from
the
SAP
for
high
dose
refuge
strategies.

One
commenter
believes
the
high­
dose
refugia
model
proposed
by
the
applicant
may
not
be
appropriate
because
MON
863
does
not
deliver
a
high
dose.

EPA's
Response
The
high
dose/
refuge
strategy
recommended
by
the
February
1998
SAP
was
developed
for
lepidopteran­
Section
1.3
Section
1
­
22
active
Bt
corn.
The
August
2002
was
convened
to
address
MON
863
corn
and
identified
MON
863
corn
as
a
non­
high
dose
product.
The
SAP
acknowledged
that
"[
d]
ose,
as
related
to
selection
intensity,
is
important
in
determining
appropriate
refuge
size."
The
Panel
did
not
state
that
a
high
dose
was
necessary
for
corn
rootworm­
active
Bt
corn.
Since
there
in
not
a
high
dose
of
Cry3Bb1
to
control
corn
rootworm
in
MON
863
corn,
the
high
dose/
refuge
strategy
does
not
apply.

Durability
Public
Comments
One
commenter
objects
to
the
15­
year
goal
for
product
durability
and
states
that
the
only
prudent
goal
for
an
IRM
plan
is
to
prevent
resistance.

The
applicant
responds
to
requests
for
comment
on
the
product
duration
or
longevity
of
CRW
susceptibility
considered
in
IRM
models
by
identifying
principle
factors
influencing
the
rate
of
resistance
development,
but
noting
that
current
models
do
not
incorporate
all
the
factors.
The
applicant
also
notes
that
the
longevity
of
any
management
tool
is
dependent
upon
the
extent
of
grower
adoption,
the
effectiveness
of
the
IRM
plan,
the
use
of
alternative
management
strategies,
the
relative
fitness
of
resistant
genotypes,
and
the
extent
of
grower
compliance
with
IRM
requirements,
all
of
which
are
also
missing
from
current
models.
The
applicant
adds
that
current
models
do
not
incorporate
current
or
future
management
options,
and
therefore
overestimate
the
risk
of
resistance
(
See
BRAD
Simulation
Models
of
Resistance
Section
pp.
IID
5
to
IID
8).

EPA's
Response
An
IRM
strategy
is
not
intended
to
prevent
resistance
for
an
indefinite
period
of
time.
An
IRM
strategy
is
intended
to
delay
resistance.
Based
on
the
conservative
parameters
used
in
simulation
models,
a
20%
refuge
will
delay
corn
rootworm
resistance
to
MON
863
corn
for
at
least
seven
to
sixteen
years.
Since
the
models
assume
100%
market
penetration
and
are
based
on
conservative
parameters,
it
is
likely
that
resistance
will
be
delayed
longer
than
seven
to
sixteen
years.
Based
on
these
models,
the
Agency
has
determined
the
a
20%
refuge
is
adequate
to
delay
resistance
during
the
interim
registration
period.

Compliance
Public
Comments
One
commenter
states
that
the
IRM
provisions
to
ensure
compliance
are
inadequate.
The
commenter
does
not
believe
grower
education
is
adequate
to
ensure
compliance
and
that
additional
actions
including
penalties
are
needed.
The
same
commenter
states
that
the
applicant's
IRM
plan
should
incorporate
previously
submitted
recommendations
for
improving
compliance.
The
commenter
believes
the
applicants
mitigation
strategies
to
delay
the
spread
of
resistance
are
inadequate
and
suggests
a
more
comprehensive
national
IRM
plan
is
needed.

EPA's
Response
Section
1.3
Section
1
­
23
Growers
are
perhaps
the
most
essential
element
for
the
implementation
and
success
of
any
IRM
plan
as
they
will
ultimately
be
responsible
for
ensuring
that
refuges
are
planted
according
to
guidelines
and
that
Bt
fields
are
monitored
for
unexpected
pest
damage.
Therefore,
a
program
that
educates
growers
as
to
the
necessity
of
IRM
and
provides
guidance
as
to
how
to
deploy
IRM
should
be
an
integral
part
of
any
resistance
management
strategy.
The
October
2000
SAP
also
suggested
that
a
comprehensive
education
program
may
help
increase
IRM
compliance.
Ideally,
the
educational
messages
presented
to
growers
should
be
consistent
(
among
different
registrants
if
applicable
for
CRW)
and
reflect
the
most
current
resistance
management
guidelines.
Specific
examples
of
education
tools
for
growers
can
include
grower
guides,
technical
bulletins,
sales
materials,
training
sessions,
Internet
sites,
toll­
free
numbers
for
questions
or
further
information,
and
educational
publications.

To
avoid
confusing
or
discouraging
growers,
new
IRM
programs
should
be
kept
simple
and
consistent
with
existing
programs
so
that
growers
will
not
be
discourage
from
properly
implementing
IRM
or
from
growing
transgenic
crops.
Growers
should
be
required
to
sign
a
technology
use
agreement
that
outlines
IRM
requirements
and
acknowledges
the
growers
responsibility
to
comply
with
them
on
an
annual
basis.
The
agreement
will
also
state
that
growers
received
the
Product
Use
Guide.
This
agreement
may
be
a
section
of
the
growers
order
sheet
or
some
other
document
or
format.
An
annual
industry­
supported
survey
conducted
by
a
third
party
should
be
submitted
to
the
Agency
as
a
tool
to
monitor
grower
compliance.
Additional
education
efforts
should
target
non­
compliant
growers
and
access
to
the
technology
will
be
limited
for
growers
found
to
be
non­
compliant
(
see
BRAD
Grower
Education
and
Compliance
Section
pp.
IID
12
and
IID
13).

Adoption
Rates
Public
Comments
One
commenter
states
that,
despite
slow
penetration
of
the
market
overall,
some
areas
may
have
adoptions
as
high
as
80
percent
of
corn
acres
so
that
the
de
facto
unstructured
refuges
the
applicant
is
counting
on
would
be
lost.
The
commenter
believes
it
is
inappropriate
to
implement
a
resistance
management
plan
that
relies
on
the
marketplace
to
ensure
low
adoption
and
states
that
a
20
percent
refuge
may
allow
faster­
than­
predicted
resistance
evolution.
The
same
commenter
disputes
the
assumption
in
the
IRM
plan
about
MON
863'
s
effect
on
acreage
of
continuous
corn.
The
commenter
believes
incentive
payments
for
corn
production
will
prove
attractive
to
many
farmers
and
that
more
continuous
corn
will
increase
populations
of
some
rootworm
species.

In
response
to
suggestions
that
EPA
should
mandate
local
sales
limits
or
caps
to
assure
sufficiently
low
market
penetration,
the
applicant
states
that
the
interim
plan
does
not
rely
on
reduced
adoption
rates
as
an
IRM
strategy,
but
instead
considers
that
incremental
adoption
during
the
interim
period
reduces
selection
pressure
and
limits
pest
adaptation
while
additional
research
focused
on
CRW
biology
and
insect­
plant
interactions
is
underway.
The
applicant
adds
that
it
typically
requires
several
years
before
grower
demand
and
seed
availability
allow
for
peak
adoption.

In
response
to
the
question
of
whether
there
should
be
limitations
on
acres
planted
while
the
interim
IRM
plan
is
in
place,
the
applicant
states
that
acreage
limitations
are
not
appropriate
and
notes
that
conservatism
is
already
built
into
the
plan.
Section
1.3
Section
1
­
24
EPA's
Response
The
Agency
agrees
that
a
resistance
management
plan
should
not
be
based
on
potential
market
penetration.
Therefore,
the
simulation
models
of
resistance
that
demonstrate
the
adequacy
of
a
20%
refuge
are
based
on
100%
adoption
of
MON
863
by
corn
growers
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp.
IID
5
to
IID
8).

The
2002
SAP
suggested
limiting
sales
of
MON
863
for
IRM
purposes
to
an
on­
farm
level
rather
than
by
region,
state
or
county.
The
Agency
has
concluded
that
additional
acreage
limitations
of
MON
863
beyond
the
20%
refuge
requirement
are
not
necessary
during
the
three
interim
period.

Conditional
Registration
Public
Comments
One
commenter
notes
that
the
IRM
may
not
be
complete
with
respect
to
factors
that
could
influence
resistance
evolution,
but
states
that
the
conditional
registration
will
allow
the
scientific
community
to
begin
addressing
critical
issues.
The
commenter
states
that
revisions
can
be
made
to
the
plan
should
future
information
reveal
inadequacies.

Another
commenter
supports
a
conditional
registration
and
believes
that
enough
biological
information
is
available
to
support
the
revised
IRM
plan
on
an
interim
basis.
The
commenter
also
believes
the
IRM
plan
should
be
biologically
responsible
and
have
the
end
user
in
mind.
The
commenter
states
that
conditional
registration
would
allow
farmers
to
gain
experience
with
technology
on
a
limited
basis
and
permit
IRM
adjustments
to
be
made
to
address
the
needs
of
end­
users.

EPA's
Response
The
Agency
agrees
with
these
comments.
Section
1.4
Section
1
­
25
1.4
Data
Needs
and
Methods
General
Public
Comments
One
commenter
is
concerned
that
EPA
is
relying
too
heavily
on
data
provided
by
proponents
of
biotechnology.
Another
commenter
states
that
the
applicant
has
not
developed
the
data
necessary
for
a
long­
term,
effective
IRM
plan.
The
commenter
believes
data
is
lacking
in
a
number
of
areas,
including
the
dispersal
of
adult
CRW,
the
feeding
behavior
of
larvae,
the
effective
dose
of
MON
863,
and
rootworm
genetics.
The
same
commenter
recommends
that
EPA
require
the
applicant
to
expand
and
revise
the
interim
IRM
plan
to
correct
deficiencies,
such
as
incomplete
monitoring
and
mitigation
plans,
incorrect
definition
of
resistance,
failure
to
address
northern
corn
rootworm
resistance
issues,
lack
of
modeling
to
address
the
use
of
insecticides
on
a
non­
high­
dose
refuge.
The
commenter
also
recommends
EPA
require
the
applicant
to
conduct
statistically
valid
research
and
modeling
to
fill
gaps
that
prevent
the
development
of
effective,
long­
term
IRM
plans.

One
commenter
working
in
an
academic
environment
concedes
that
there
are
environmental,
ecological,
and
resistance
concerns
associated
with
the
introduction
of
Cry
3Bb
transgenic
corn.
The
commenter
notes,
however,
that
the
same
is
true
for
any
pest
control
technology
and
that
researchers
are
generating
data
addressing
these
concerns.
The
same
commenter
states
that
the
next
step
for
gathering
data
on
product
performance,
nontarget
impacts,
and
resistance
potential
is
on­
farm
trials,
which
are
only
possible
with
product
registration.

EPA's
Response
The
Agency
has
determined
that
a
20%
non­
Bt
corn
refuge
planted
adjacent
to
or
within
fields
will
ensure
resistance
does
not
develop
during
the
interim
registration.
The
Agency's
conclusion
is
based
on
information
provided
by
the
registrant,
public
comments,
published
research,
communication
with
expert
researchers
from
universities
and
the
August
2002
SAP.
During
the
interim
registration
period,
Monsanto
will
develop
the
necessary
data
to
verify
that
the
current
IRM
plan
will
ensure
that
resistance
is
delayed
(
see
BRAD
Conclusions
and
Recommendations
Sections
pp.
IID
14
to
IID17).
The
Agency
expects
that
this
data
will
be
developed
by
Monsanto's
research
scientists
as
well
as
university
collaborators.
For
all
pesticide
registrations,
it
is
the
registrants
responsibility
to
provide
appropriate
data
to
the
Agency
to
support
the
registration.

Protein
Expression
Public
Comments
One
commenter
states
that
Monsanto's
intentions
are
unclear
regarding
future
combinations
of
the
Cry
3Bb
gene
with
the
Cry
1Ab,
Cry
1Ac,
or
other
Cry
proteins
for
European
corn
borer
(
ECB)
control.
The
commenter
provides
suggestions
for
combinations
and
engineered
expressions
and
states
that
the
alternative
strategies
would
have
profoundly
different
regulatory
consequences.
The
commenter
notes
that
one
alternative
crossing
parental
lines
each
with
a
single
Cry
gene
would
not
be
subject
to
regulatory
review
Section
1.4
Section
1
­
26
since
no
new
genetic
transformation
event
would
be
used,
but
that
another
alternative
of
a
single
event
expressing
two
Cry
proteins
would
require
the
development
and
review
of
new
data.
The
commenter
believes
these
different
regulatory
consequences
provide
evidence
that
the
regulations
are
out
of
step
with
the
practical
applications
of
biotechnology
and
states
that
EPA
should
clarify
additional
data
and
regulatory
review
that
may
be
needed.

EPA's
Response
This
registration
only
addressed
Cry3Bb1
expressed
in
field
corn.
Therefore,
stacked
products
were
not
considered.

Original
Data
Public
Comments
Another
commenter
notes
that
the
plan
assumes
universal
applicability
to
all
species
and
strains
of
corn
rootworms
despite
biological
and
ecological
differences.
The
commenter
adds
that
the
majority
of
research
has
been
conducted
on
western
corn
rootworms
in
classical
continuous
corn
situations
and
that
less
information
is
available
on
northern
corn
rootworms
in
classic
or
extended
diapause
situations.
The
same
commenter
suggests
that
differences
between
ECB
and
corn
rootworms
support
the
development
of
corn
rootworm­
specific
resistance
management
plans.
The
commenter
states
that
further
research
is
required
to
develop
a
robust
IRM
plan
and
provides
a
list
of
specific
topics
that
should
be
explored..
The
same
commenter
adds
that
interim
registration
is
needed
to
generate
necessary
data
to
develop
a
more
robust
IRM
plan.
The
commenter
notes
that
IRM
models
are
untested
and
have
not
been
validated,
but
states
that
the
revised
IRM
plan
provides
the
flexibility
needed
to
evaluate
IRM
deployment
strategies
and
to
address
rootworm
biology
questions
on
a
commercial
scale.
The
commenter
also
identifies
additional
data
needs.

EPA's
Response
The
Agency
recommends
gathering
more
information
on
biology
of
all
corn
rootworm
species
and
subspecies
to
verify
that
the
IRM
strategy
is
appropriate
for
western,
Mexican
and
northern
corn
rootworm.
Since
MON
863
corn
will
not
be
labeled
for
southern
corn
rootworm,
it
is
not
considered
in
the
IRM
strategy.
Additional
research
needs
are
outlined
in
the
Conclusions
and
Recommendations
Sections
of
the
IRM
chapter
in
the
MON
863
BRAD
(
pp.
IID
14
to
IID
17).

Resistance
Public
Comments
Another
commenter
states
that
the
applicant's
definitions
of
resistance
are
inappropriate
and
should
be
defined
using
slope
and
LC50,
as
well
as
increased
CRW
survival
on
MON
863
corn
compared
to
nonresistant
CRW.
Another
commenter
cites
a
2002
report
recommending
continued
research
on
management
strategies
to
slow
the
development
of
resistance
to
new
and
existing
pest
control
tools.

The
applicant
addresses
the
request
for
comment
on
the
appropriateness
of
the
following
input
parameters
Section
1.4
Section
1
­
27
of
these
simulation
models
for
CRW­
protected
field
corn:
resistance
allele
frequency,
dominance
of
the
heterozygote,
movement
of
the
males
and
females,
mating
and
ovipositional
behavior
and
other
genetic
and
behavioral
parameters.
The
applicant
states
that
these
parameters
have
been
incorporated
into
models,
but
urges
caution
in
using
models
for
predicting
product
longevity.
The
applicant
adds
that
some
of
the
parameters
can
be
estimated
based
upon
available
MON
863
data
but
other
parameters
can
only
be
input
based
upon
conservative
assumptions.

In
response
to
a
request
for
comment
on
the
Agency's
conclusions
regarding
refinements
to
Monsanto's
resistance
monitoring
program,
the
applicant
described
the
components
of
the
monitoring
plan
for
MON
863.
The
applicant
also
stated
that
populations
have
already
been
assayed
and
monitoring
following
commercialization
will
include
dose
response
assays
in
high
adoption
areas.
The
applicant
also
states
that
the
monitoring
plan
addresses
collection,
assay
techniques,
and
expenses.
The
applicant
notes
that
interpreting
results
from
laboratory
colonies
has
limitations.

EPA's
Response
The
August
2002
SAP
did
not
recommend
including
slope
as
a
definition
of
resistance.
The
nature
of
resistance
takes
many
forms,
with
important
factors
considered
such
as
behavioral
resistance
and
physical
size
that
may
not
relate
to
the
slope
of
an
LC50.
For
instance,
corn
rootworm
that
are
physically
larger
than
others
may
take
longer
to
be
affected
(
behavior
and/
or
sublethal
and
non­
lethal
changes)
but
have
the
same
slope
or
the
survival
in
a
dietary
toxicity
study.
The
Agency
does
not
want
to
restrict
the
definition
of
resistance
to
exclude
these
factors,
especially
for
a
pest
which
has
already
shown
behavioral
adaptation
to
cultural
control
techniques.

The
Simulation
Models
of
Resistance
Section
of
the
IRM
chapter
in
the
MON
863
BRAD
summarizes
the
parameters
included
Monsanto's
modified
Caprio
model
(
pp.
IID
5
to
IID
8).
These
parameters
are
considered
conservative
and
verify
that
a
20%
refuge
will
delay
corn
rootworm
resistance
to
MON
863
corn
for
at
least
seven
to
sixteen
years.

To
ensure
a
case
of
resistance
is
identified
a
resistance
monitoring
plan
is
required
by
the
Agency
(
see
BRAD
pp.
IID
9
to
IID
10
for
details
on
resistance
monitoring).
Detecting
shifts
in
the
frequency
of
resistance
genes
(
i.
e.,
susceptibility
changes)
through
resistance
monitoring
can
be
an
aggressive
method
to
detect
the
onset
of
resistance
before
widespread
crop
failure
occurs.
As
such,
the
utilization
of
sensitive
and
effective
resistance
monitoring
techniques
is
critical
to
the
success
of
an
IRM
plan.
Monitoring
techniques
such
as
discriminating
dose
concentration
assays
need
to
be
thoroughly
investigated
for
corn
rootworm
species
for
their
feasibility
as
resistance
monitoring
tools.
Section
1.5
Section
1
­
28
1.5
Expression
Levels
General
Public
Comments
Commenters
state
that
characterizing
the
expression
levels
as
"
moderate
to
low"
is
misleading.
These
commenters
said
that,
from
the
perspective
of
likely
environmental
impacts
and
potential
food
safety
risks,
the
expression
levels
are
actually
very
high.
One
commenter
states
that,
because
the
expression
levels
are
"
moderate
to
low"
and
because
the
corn
rootworm
has
already
demonstrated
its
ability
to
quickly
develop
resistance
to
multiple
pesticides,
the
proposed
use
of
MON
863
guarantees
the
quick
development
of
resistance
to
the
Cry
3Bb
proteins
in
corn
rootworms.

The
applicant
responds
to
concerns
that
the
characterization
of
Cy3Bb1
expression
level
in
MON
863
as
low
to
moderate
dose
is
misleading
with
the
following
background
information:
It
is
inappropriate
to
make
hazard
and
risk
assertions
based
upon
a
comparison
of
the
levels
of
Cry3Bb1
in
MON
863
corn
with
Cry
protein
levels
in
other
biotech
crops
because
human
and
environmental
safety
must
be
examined
on
a
case­
by­
case
basis
for
each
new
plant­
incorporated
protectant.
Cry3Bb1
failed
to
produce
any
adverse
effects
in
mammalian
toxicity
studies
conducted
at
maximum
attainable
concentrations.
It
was
on
this
basis
that
EPA
established
the
tolerance
exemption
for
Cry3Bbl
in
corn.
All
references
by
Monsanto
to
low
or
moderate
dose
have
been
made
in
the
context
of
defining
a
strategy
for
insect
resistance
management.
In
the
context
of
IRM,
the
level
of
Cry3Bbl
protein
expressed
in
MON
863
is
not
consistent
with
EPA's
definition
of
"
high
dose";
therefore,
MON
863
has
been
appropriately
described
as
"
low
or
moderate
dose."

The
applicant
also
states
that
MON
863
expresses
Cry3Bb1
at
much
less
than
a
high
dose
level
and
allows
a
large
number
of
individuals
to
survive.
The
applicant
also
states
that
the
large
and
highly
variable
impact
of
environmental
conditions
on
CRW
mortality
means
that
the
selection
for
physiological
resistance
to
the
Cry3Bb
protein
in
MON
863
will
likely
be
much
less
than
would
otherwise
be
expected.
The
applicant
adds
that
IRM
plans
can
be
developed
for
products
of
any
dose
level.

The
applicant
also
addresses
questions
about
what
techniques
should
be
used
to
determine
dose
for
Cry3Bb1,
providing
results
of
field
studies
showing
a
low
to
moderate
dose
and
suggesting
that
dose
can
be
assessed
by
examining
adult
emergence
compared
to
conventional
corn
under
field
conditions,
by
comparing
the
level
of
Cry3Bb1
plant
expression
to
the
LC50
of
purified
protein
determined
from
laboratory
artificial
diet
bioassays,
or
by
observing
larval
feeding
behavior
on
MON
863
roots
compared
to
conventional
corn
roots.

EPA's
Response
The
August
2002
SAP
has
identified
MON
863
corn
as
a
non­
high
dose
product
meaning
there
is
not
a
high
dose
of
Cry3Bb1
protein
to
control
the
corn
rootworm.
The
SAP
also
stated
that
it
does
not
matter
if
a
product
is
a
moderate
or
low
dose;
rather,
a
distinction
should
be
made
between
high
dose
and
non­
high
dose
products.
Simulation
models
were
created
based
on
a
non­
high
dose
product
and
verified
that
a
20%
refuge
will
delay
resistance
(
see
BRAD
Simulation
Models
of
Resistance
Section
pp.
IID
5
to
IID
8).
The
Section
1.5
Section
1
­
29
Agency
agrees
that
it
is
inappropriate
to
make
hazard
and
risk
assertions
based
upon
a
comparison
of
the
levels
of
Cry3Bb1
in
MON
863
corn
with
Cry
protein
levels
in
other
biotech
crops;
therefore,
a
risk
assessment
was
conducted
specifically
for
MON
863
corn.

Identifying
the
level
of
dose,
as
related
to
selection
intensity,
is
crucial
when
determining
size
and
structure
of
a
refuge
needed
to
delay
CRW
resistance
to
MON
863
corn.
CRW
feeding
behavior
and
survival
and
root
expression
data
can
be
used
to
identify
the
dose
of
MON
863.

According
to
the
August
2002
SAP,
comparing
measures
of
fitness
levels
of
susceptible
homozygotes
on
MON
863
and
non­
Bt
corn
would
provide
a
good
approximation
of
selection
intensity.
The
SAP
suggested
that
the
first
step
in
approximating
selection
intensity
would
be
to
measure
efficacy
of
MON
863
corn
against
CRW
larvae.
However,
the
Panel
pointed
out
that
selection
intensity
based
on
larval
efficacy
may
be
underestimated
if
sublethal
effects
or
fitness
costs
occur.
Selection
intensity
based
on
larval
survival
may
also
be
underestimated
if
density
dependent
mortality
is
occurring.
Resistant
colonies
of
CRW
should
be
developed
to
aid
in
determining
selection
intensity
(
see
BRAD
Dose
Section
pp.
IID
4
and
IID
5).