1
FMC
Response
to
the
HSRB
Draft
report
dated
June
14,
2006
Re:
Carbofuran
1.
Introduction
On
May
2­
3,
2006
the
Environmental
Protection
Agency
Human
Studies
Review
Board
(
HSRB)
conducted
a
public
meeting
during
which
it
reviewed
the
following
carbofuran
human
studies:
Evaluation
of
the
Safe
Exposure
Levels
to
Carbamate,
Administered
Orally
to
Healthy
Adult
Normal
Male
Volunteers1,

MRID
No.
00092826;
Carbamate
(
Carbofuran)
Human
Dermal
Study2,
MRID
No.

00092827
(
hereafter
referred
to
as
Dermal
Study
1)
and
Comparison
of
Cholinesterase
Inhibition
and
Effects
of
Furadan
4F
and
FMC
35001
4
EC3,

MRID
No.
00092829
(
hereafter
referred
to
as
Dermal
Study
2).
The
HSRB
has
issued
a
proposed
final
draft
report
for
the
May
2­
3
HSRB
meeting,
and
is
scheduled
to
publicly
review
that
report
at
its
June
30th,
2006
meeting.
The
Agency's
Federal
Register
Notice
(
FR
Vol.
71,
No.
108,
pp.
32536­
32538)
in
this
regard
has
noted
that
interested
members
of
the
public
may
submit
relevant
written
or
oral
comments
for
the
HSRB
to
consider
during
the
advisory
process.

Accordingly,
FMC
Corporation
is
providing
the
following
written
comments
specifically
regarding
the
HSRB's
draft
report
conclusions
relative
to
the
carbofuran
human
studies.
FMC's
response
comments
herein
are
focused
on
the
human
oral
study,
and
will
make
only
limited
comments
relative
to
the
two
dermal
studies.

As
discussed
in
more
detail
below,
FMC
is
concerned
that
the
HSRB
has
judged
the
carbofuran
human
studies
 
and
in
particular
the
oral
study
 
as
scientifically
deficient
because
of
limitations
that
outweigh
the
strengths,
namely
small
sample
size,
the
lack
of
control
subjects
and
the
highly
variable
results
for
RBC.

Although
these
limitations
were
recognized
by
the
Agency
and
prior
peer
2
reviews,
their
conclusions
were
that
the
use
of
the
oral
studies
still
had
merit.

Importantly,
the
analysis
and
documentation
on
the
carbofuran
human
oral
study
that
EPA
presented
to
the
HSRB
was
not
yet
complete.
FMC
believes
that
it
would
be
inappropriate
for
the
HSRB
to
reject
completely
the
carbofuran
oral
study,
as
its
draft
report
does,
without
providing
EPA
an
opportunity
to
complete
and
present
its
analysis
of
these
studies.
For
example,
although
the
HSRB
correctly
noted
that
the
single
control
in
the
oral
study
is
a
limitation
of
that
study,

EPA's
BMD
methodology
 
which
also
utilizes
the
pre­
test
ChE
activity
levels
in
non­
control
subjects
as
surrogate
control
data
 
can
compensate
for
that
limitation.
The
HSRB
specifically
found
that
the
oral
study
met
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted,
further
supporting
the
conclusion
that
it
is
premature
to
reject
this
study
in
its
entirety.
For
the
reasons
presented
in
these
comments,
FMC
urges
the
HSRB
to
reconsider
its
conclusion
that
the
oral
study
should
not
be
used
either
as
a
point
of
departure
or
to
inform
the
interspecies
uncertainty
factor
for
carbofuran.
At
a
minimum,
the
HSRB
should
allow
EPA
to
complete
its
analysis
before
reaching
any
such
conclusions.

2.
Background:
Summary
of
EPA
Conclusions
presented
to
the
HSRB
In
its
review
and/
or
presentation
of
the
above
noted
studies
to
the
HSRB,

members
of
the
Agency's
Health
Effects
Division
noted
strengths,
uncertainties
and
limitations
of
each
of
the
studies6
and
concluded
that
these
studies
appropriately
could
be
used
as
a
point
of
departure
for
the
carbofuran
risk
assessment,
and
to
inform
the
interspecies
uncertainty
factor
in
the
carbamate
cumulative
assessment
 
conclusions
which
were
consistent
with
those
reached
by
EPA's
independent
peer
reviewers,
who
analyzed
these
studies
in
1997.

Specifically,
EPA's
Health
Effects
Division
found:

Conclusion:
Carbofuran
Human
Oral
Study:
3
"
Using
the
BMD
calculation,
the
BMDL10
of
0.026
mg/
kg
is
a
reasonable
Point
of
Departure
(
PoD)
for
possible
use
in
risk
assessment."

Furthermore,
the
Agency
noted
in
this
same
document
that
"
In
1997,
OPP
requested
an
external
peer
review
of
this
carbofuran
study.
Three
academic
scientists
reviewed
the
study
and
determined
it
was
an
appropriate
study
to
use
to
develop
an
RfD
and
also
commented
on
the
use
of
uncertainty
factors
in
deriving
an
RfD
(
Burnam,
1970(
sic))."

Conclusion:
Carbofuran
Dermal
Study
1
and
Dermal
Study
2:

"
Together,
the
two
dermal
studies
suggest
a
dermal
LOAEL
of
0.5
mg/
kg
based
on
RBC
ChEI
at
the
expected
peak
time
(
3­
4
Hours)
with
the
appropriate
recovery
over
the
next
six
hours.
Thus,
this
dose
may
be
used
as
a
PoD
for
an
appropriate
occupational
exposure
scenario."

In
this
same
document6
HED
further
concluded
the
following
in
regard
to
(
a)

single
chemical
assessment
and
(
b)
N­
methyl
carbamate
cumulative
assessment
respectively:

(
a)
"
OPP
HED
proposes
that
the
single
oral
dose
human
study
(
BMDL10
of
0.026)
be
used
directly
as
a
point
of
departure.
Based
on
RBC
ChE
inhibition
at
the
lowest
dose
tested
(
0.5
mg/
kg)
in
both
dermal
studies,
and
using
a
LOAEL
to
NOAEL
extrapolation
factor
of
3X,
the
point
of
departure
is
0.17
mg/
kg
for
worker
exposure."

(
b)
"
Because
data
from
rat
studies
provide
the
basis
for
potency
determination,
the
Agency
must
consider
interspecies
extrapolation
(
i.
e.,

animal
to
human)
in
its
cumulative
risk
assessment.
As
such,
human
data
may
be
used
by
the
Agency
to
inform
the
pesticide­
specific
interspecies
extrapolation.
In
the
specific
case
of
carbofuran,
MRID
00092826
[
i.
e.,
the
human
oral
dosing
study]
is
available."
4
Of
particular
note,
HED's
HSRB
Carbofuran
Weight­
of­
the
Evidence
(
WOE)

document6
noted
the
following
additional
points
that
are
relevant
in
response
to
the
HSRB's
draft
report
regarding
carbofuran.
In
the
"
Carbofuran
Human
Study
Summary"
section
(
page
16
of
19)
of
the
WOE
document,
HED
noted
the
following
relative
to
the
carbofuran
human
oral
study:

"
As
with
the
RBC
ChE
data
from
the
aldicarb,
methomyl,
and
oxamyl
human
studies
that
were
presented
to
the
HSRB
in
April
2006,
the
RBC
ChE
data
from
the
single
oral
carbofuran
human
study
also
is
being
utilized
by
the
Agency
to
inform
the
pesticide­
specific
interspecies
extrapolation."

"
The
measured
RBC
ChE
activity
from
the
oral
human
study
is
adequate
for
estimation
of
BMD
and
BMDL
estimates.
The
RBC
ChE
data
from
the
carbofuran
human
study
was
utilized
in
the
model
in
the
same
manner
as
the
RBC
data
from
the
oral
human
studies
for
aldicarb,
methomyl
and
oxamyl."

"
Based
on
the
FIFRA
SAP
(
2005)
approval
of
statistical
analyses
for
the
BMD
model,
the
single
RBC
BMD
estimate
for
carbofuran
indicates
similar
ChE
activity
in
males
and
females
(
0.031
mg/
kg,
M
and
F).
Comparison
of
the
rat
BMD
estimates
from
the
two
compartments
indicates
the
RBC
compartment
is
slightly
more
sensitive
than
the
brain.
The
RBC
ChE
data
from
the
human
study,
therefore,
would
also
be
expected
to
be
protective
of
brain
ChE
inhibition.
As
such,
the
BMD
estimate
from
the
carbofuran
human
study
provides
useful
information
into
the
sensitivity
of
RBC
ChE
inhibition
of
rats
compared
to
humans.

HED's
HSRB
Carbofuran
Weight­
of­
the
Evidence
(
WOE)
document6
noted
the
following
additional
points
in
the
"
Discussion"
section
(
page
16
of
19)
that,
when
considering
the
points
noted
above
from
the
Human
Study
Summary
section
of
5
the
WOE
document
are
particularly
relevant
in
response
to
the
HSRB's
draft
report
regarding
carbofuran:

"
Similar
to
the
approach
proposed
by
the
Agency
at
the
April,
2006
[
HSRB]
for
aldicarb,
methomyl,
and
oxamyl
for
informing
the
interspecies
extrapolation
factor
in
the
cumulative
risk
assessment,
the
carbofuran
human
study
may
also
inform
the
interspecies
extrapolation
factor
for
the
preliminary
cumulative
risk
assessment.
The
ratio
of
the
rat
BMD10
to
the
Human
BMD10
was
proposed
at
the
April
2006
HSRB.
The
Agency
is
proposing
to
use
the
same
approach
for
carbofuran
(
emphasis
added).

The
Agency
is
in
the
process
of
analyzing
both
the
rat
and
human
BMD10
data
to
determine
the
central
estimate
and
95%
confidence
interval
for
use
as
the
interspecies
extrapolation
factor.
(
emphasis
added)
­
­
­
­
The
interspecies
extrapolation
factor
resulting
from
the
formal
BMD
ratio
analysis
would
be
in
addition
to
the
other
uncertainty
factors
for
the
cumulative
risk
assessment
that
includes
intraspecies
variability
(
human
variability)
and
FQPA."

As
discussed
in
more
detail
below,
the
Board
did
not
take
this
EPA
information
into
account
in
its
assessment.
The
certified
(
by
Dr.
Celia
B.
Fisher,
Chair)

"
Minutes
of
the
United
States
Environmental
Protection
Agency
(
EPA)
Human
Studies
Review
Board
(
HSRB)
May
2­
3,
2006
Public
Meeting,
issued
June
1,

2006,
specifically
noted
(
page
15
of
34)
the
following
relative
to
the
Agency's
BMD
analysis
of
the
carbofuran
human
(
oral)
study
data:

"
The
strength
of
the
BMD
modeling
was
using
all
the
data
points.

The
Board
did
not
see
the
calculations
but
would
have
considerable
uncertainty
about
this
analysis."
(
emphasis
added)

The
certified
minutes
also
footnote
(
page
6
of
36)
the
following
in
regard
to
the
Vice
Chair,
Dr.
William
S.
Brimijoin
and
Member
Dr.
Janice
Chambers:
6
"*
Recused
from
carbofuran
discussion
and
deliberation"

Consideration
of
the
above
noted
conclusions
and
procedural
aspects
of
the
HSRB's
review
of
the
carbofuran
human
studies,
and
specifically
the
human
oral
study,
are
expanded
upon
in
the
following
discussion
of
Procedural,
Ethical
and
Scientific
Considerations.

3.
Procedural,
Ethical
and
Scientific
Considerations
Relative
to
the
HSRB's
Draft
May
2­
3
EPA
Human
Studies
Review
Board
Meeting
a.
Procedural
Issues:

1.
Fairness
compared
to
treatment
of
other
active
ingredients.
Based
on
the
above
noted
citations
from
the
"
Human
Studies
Review
Board:
Carbofuran
Weight­
of­
the­
Evidence"
document,
complete
analyses
for
estimation
of
BMD's
and
BMDL's
were
available
for
aldicarb,
methomyl
and
and
oxamyl,
and
were
presented
to
the
HSRB.
Unfortunately,
HED
scientists
had
not
been
able
to
complete
a
comparable
analysis
for
carbofuran
by
the
time
they
went
before
the
HSRB,
which
was
confirmed
by
the
certified
minutes
of
the
HSRB's
Chairman.

Compounding
this
issue,
the
lead
EPA
scientist
who
had
conducted
the
benchmark
dose
analyses
(
Dr.
W.
Setzer)
was
not
able
to
be
present
at
the
HSRB
meeting,
and
thus
was
unable
to
address
issues
raised
by
the
Board.

Without
the
HED
scientists
having
a
full
opportunity
to
present
their
completed
analysis,
and
without
the
benefit
of
input
from
the
most
knowledgeable
EPA
scientist,
the
HSRB
has
made
final
recommendations
relative
to
the
use
of
the
carbofuran
human
oral
study,
namely
"
Collectively,
the
weaknesses
in
the
carbofuran
human
studies
conduct
and
outcomes
cast
doubt
on
the
utility
of
the
data
for
identifying
a
NOAEL
or
LOAEL
or
for
comparing
across
species
in
consideration
of
the
interspecies
uncertainty
factor
for
the
cumulative
risk
assessment.
Thus
the
HSRB
recommended
that
the
human
data
should
not
be
7
used
for
these
evaluations."
It
is
FMC's
strong
belief
that
the
Agency's
presentation
of
an
incomplete
analysis
to
the
HSRB,
(
especially
considering
that
similar
analyses
for
aldicarb,
methomyl
and
oxamyl
were
in
final
form
when
presented
to
the
HSRB)
and
the
Board's
drawing
of
conclusions
"
without
see[
ing]

the
calculations",
or
permitting
the
Agency
an
opportunity
to
present
and
discuss
a
completed
analysis,
did
not
permit
a
full
and
sound
scientific
consideration
of
the
usefulness
of
the
carbofuran
human
oral
study.
Indeed,
the
certified
minutes
of
the
HSRB
meeting
note
the
following
(
page
15
of
34)
as
being
stated
by
the
Agency's
Dr.
Anna
Lowit:

"
The
risk
assessment
is
a
calculation
of
risk
and
to
help
risk
managers
understand
fisk.
In
the
case
of
carbofuran,
the
Agency
can
rely
heavily
on
the
animal
data
base,
or
can
use
human
data
to
look
at
the
clinical
signs
from
the
human
data
as
a
LOAEL
or
NOAEL
and
describe
the
relative
confidence
we
have
in
these
values.
Conversely,
the
Agency
could
look
at
what
the
AChEI
data
was
indicating.
The
BMD
analysis
accounts
for
low
sample
sizes
and
low
numbers
of
doses."

EPA,
in
presenting
its
Scientific
Considerations
to
the
HSRB,
stated:

"
The
WOE
document
also
discusses
the
Agency's
conclusions
that
these
studies
are
useful
in
establishing
point
of
departure,
both
oral
and
dermal,

for
the
single
chemical
assessment
and
in
informing
the
interspecies
uncertainty
factor
for
the
cumulative
assessment.
Please
comment
on
the
scientific
evidence
that
supports
these
conclusions."

Accordingly,
considering
the
materialness
of
this
particular
request,
FMC
believes
it
is
reasonable,
and
prudent,
for
the
Agency
to
have
the
opportunity
to
complete
its
carbofuran
BMD
analysis
and
for
the
results
of
that
analysis
to
be
presented
to,
clearly
understood
and
fully
considered
by,
the
HSRB
before
the
Board
concludes
its
deliberations,
and
finalizes
its
report,
relative
to
the
carbofuran
human
oral
study.
8
2.
Improper
Recusal
of
Two
Knowledgeable
Board
Members.
Further,
FMC
Corporation
is
dismayed
by
the
recusal
of
two
individuals,
Drs.
Brimijoin
and
Chambers,
on
the
HSRB
from
both
discussion
and
deliberation
of
the
carbofuran
studies.
The
certified
minutes
footnote
(
page
6
of
36)
the
following
in
regard
to
the
Vice
Chair,
Dr.
William
S.
Brimijoin
and
Member
Dr.
Janice
Chambers:

"
Recused
from
carbofuran
discussion
and
deliberation"

The
HSRB
was
asked
to
consider
the
scientific
and
ethical
aspects
of
three
carbofuran
human
studies
(
one
oral
and
two
dermal)
conducted
in
1976­
1978.
In
1997,
EPA
contracted
with
Drs.
(
William)
Brimijoin
and
(
Janice)
Chambers
(
in
addition
to
Dr.
Carey
Pope)
to
be
two
of
three
independent
peer
reviewers
of
the
carbofuran
oral
study.
In
their
1997
peer
reviews,
Drs.
Brimijoin
and
Chambers
(
as
well
as
Dr.
Pope)
concluded
that
the
oral
study
was
the
proper
study
to
use
as
the
point
of
departure
for
calculating
the
reference
dose
for
carbofuran.

Based
on
these
independent
peer
reviews,
EPA
concluded
that
the
oral
study
was
ethical
and
should
be
accepted
for
regulatory
purposes.
In
its
April
2006
report
to
the
HSRB,
EPA
concluded
that
that
the
oral
study
was
ethical
and,

consistent
with
Drs.
Brimijoin
and
Chambers'
(
and
Pope)
earlier
recommendation,
should
be
used
as
the
point
of
departure
for
setting
carbofuran
health
benchmarks
and
for
determining
the
appropriate
uncertainty
factors
for
the
cumulative
assessment
of
carbamates.

Drs.
Brimijoin
and
Chambers
were
appointed
by
EPA
to
be
members
of
the
HSRB.
They
had
no
financial
interest
in
the
carbofuran
matter,
had
done
no
prior
work
for
FMC,
and
satisfied
all
of
the
other
ethical,
financial
and
technical
standards
for
appointment.
Moreover,
Drs.
Brimijoin
and
Chambers
were
experts
on
both
the
ethics
and
scientific
relevance
of
the
oral
study,
and
their
input
would
be
highly
useful
and
important
to
the
Board
as
a
whole.

Nevertheless,
for
reasons
that
are
not
clear,
these
two
members
either
recused
themselves
or
were
recused
from
the
HSRB's
consideration
of
the
carbofuran
studies.
9
The
recusal
was
both
improper
and
prejudicial
to
FMC.
There
was
no
basis
for
recusal
merely
because
Drs.
Brimijoin
and
Chambers
were
experts
in
the
oral
study
and
previously
had
been
asked
by
EPA
to
conduct
the
1997
independent
review.
This
was
neither
a
conflict
of
interest
nor
an
appearance
of
a
conflict.
To
the
contrary,
it
was
part
of
the
basis
of
their
expertise
which
made
them
uniquely
qualified
to
serve
on
the
HSRB.
Further,
their
specific
experience
with
the
carbofuran
studies
made
them
especially
qualified
to
participate
in
the
HSRB's
evaluation
as
to
whether
the
studies
should
now
be
considered
by
the
Agency
under
the
human
studies
guidelines.
(
Note:
This
recusal,
and
other
procedural
issues
were
previously
noted
in
a
letter
to
OPP
Director
Jim
Jones,
which
is
attached,
as
Exhibit
A,
to
these
response
comments).

b.
Ethical
Considerations:

FMC
agrees
with
the
HSRB
conclusions
concerning
the
ethical
considerations
for
the
oral
study,
namely:

"
For
the
oral
study,
there
was
no
evidence
that
the
study
failed
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted."

"
For
the
oral
human
toxicity
study,
there
was
no
clear
and
convincing
evidence
of
significant
deficiencies
in
the
ethical
procedures
that
could
have
resulted
in
serious
harm
(
based
on
the
knowledge
available
at
the
time
the
study
was
conducted)
nor
that
information
provided
to
participants
seriously
impaired
their
informed
consent."

"
For
the
oral
study
there
was
no
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical
(
e.
g.,
intended
to
seriously
harm
participants
or
that
informed
consent
was
not
obtained)."
10
For
the
above
noted
reasons,
there
is
no
ethical
basis
for
the
HSRB,
or
the
Agency,
to
recommend
against
the
use
of
the
carbofuran
human
oral
study.

c.
Scientific
Considerations:

The
scientific
reasons
cited
for
the
weaknesses
outweighing
the
strengths
of
the
carbofuran
human
oral
study
were
the
small
sample
size,
the
lack
of
control
subjects,
and
the
highly
variable
results
for
RBC.
As
a
result,
the
HSRB
members
had
varying
opinions
on
the
use
of
the
human
oral
study
as
noted
in
the
certified
minutes
(
e.
g.,
"
For
the
reasons
cited
above
the
Board
reached
a
decision
that
the
quantitative
use
of
the
oral
carbofuran
study
was
poor
science.

From
a
qualitative
perspective,
it
may
be
helpful
as
a
point
of
departure
for
NOAEL/
LOAEL
determination",
page
11
of
34
of
the
certified
minutes;
"
The
carbofuran
study
doesn't
help
identify
information
at
the
lower
dose
levels
and
­
­

there
simply
wasn't
enough
power
in
the
data.
­
­
The
data
may
have
some
qualitative
value.
­
­
Part
of
the
science
needed
is
to
see
how
the
BMD
methodology
works.
­
­
The
Board
suggested
the
Agency
use
much
caution
regarding
the
scientific
validity
of
this
data."
pages
15
and
16
of
the
certified
minutes).
However,
the
draft
HSRB
report
states
that
the
carbofuran
human
oral
study
should
not
be
used
for
the
BMD10,
or
NOAEL/
LOAEL
determinations
(
Page
21
of
36
of
the
draft
May
2­
3,
2006
Human
Studies
Review
Board
Meeting
Report).
Thus
the
decisions
reached
in
the
discussion
during
the
HSRB
meeting
as
indicated
in
the
minutes
from
the
meeting,
do
not
match
what
was
written
in
the
draft
final
report.

Although
there
was
only
one
"
control"
subject
in
the
human
oral
study,
each
subject
had
pre­
dosing
cholinesterase
determinations
as
well.
In
the
section
below,
these
pre­
dose
cholinesterase
levels
are
compared
to
the
one
control
value
and
are
found
to
be
similar.
The
EPA
proposed
to
use
the
human
study
for
determination
of
a
BMD10
as
was
done
with
the
rat
data.
An
alternative
is
to
use
the
data
to
lower
the
UF
for
interspecies
variability.
In
either
case,
use
of
the
11
additional
control
data
from
the
carbofuran
human
oral
study
(
and
the
human
dermal
studies)
adds
to
the
confidence
of
the
data.
This
analysis
shows
that
the
data
are
relatively
consistent
and
should
be
used
to
characterize
the
effects
of
oral
administration
of
carbofuran
in
humans.

Use
of
Human
data
to
Calculate
BMD10
Values
As
noted
in
the
Introduction
above,
there
are
oral
and
dermal
studies
on
human
volunteers
following
acute
exposure
to
carbofuran
(
Arnold
19761,
19772,
19783).

These
human
studies
were
evaluated
as
a
part
of
the
Weight
of
Evidence
evaluation
by
the
EPA6.
EPA's
interim
BMD
analysis
of
these
human
data
calculated
a
BMD10
of
0.038
mg/
kg
and
BMDL10
of
0.026
mg/
kg6.
.
(
Note:
The
WOE
document
uses
both
0.025
mg/
kg
and
0.026
mg/
kg
for
the
BMDL10.
For
consistency,
the
value
0.026
is
used
in
this
response
document).

EPA's
WOE
evaluation
proposed
that
for
single
chemical
assessment
the
BMDL10
of
0.026
mg/
kg
can
be
used
directly
as
a
PoD.
An
important
limitation
of
the
human
oral
study
that
is
relevant
for
the
ChEI
measurement
is
that
the
number
of
subjects
is
low.
There
were
two
subjects
for
both
the
low­
(
0.05
mg/
kg)
and
mid­
dose
(
0.1
mg/
kg)
groups,
four
subjects
for
the
high­
dose
(
0.25
mg/
kg)
group,
and
only
one
concurrent
control.
BMD
analyses
of
the
carbofuran
human
oral
study1
RBC
ChEI
data
at
1
hour
were
conducted
using
OPCumRisk
that
modeled
the
exponential
dose
response.
4
To
address
the
limitation
related
to
the
single
subject
placebo
group,
the
pre­
test
ChE
activity
levels
measured
in
the
study
(
t=
0)
for
the
treated
subjects
were
used
as
a
surrogate
measure
of
control
group
response
and
variability.
As
shown
in
Table
1
below,
the
RBC
ChE
level
for
the
subject
receiving
the
placebo,
308
U/
L,
is
comparable
with
the
pretest
levels
with
a
mean
activity
of
323
±
71
and
a
range
of
237 
462
U/
L
at
Time
0.
12
Table
1.
Summary
statistics
of
RBC
ChE
inhibition
levels
Control
Group
Data
N
Mean
Standard
Deviation
Coefficient
of
Variation
Human
Oral
Study1
Placebo
1
308
NA*
NA
Human
Oral
Study1
Pre­
test
(
t=
0)(
for
8
treated
and
1
placebo)
9
323
71
22
Mean
based
on
mean
from
Dermal
Study
23
pre­
test
and
StDev
based
on
coefficient
of
variation
of
Human
Oral
Study
pre­
test
9
377
83
22
*
Not
applicable.

An
additional
BMD
analysis
based
on
the
pre­
test
ChEI
levels
from
Dermal
Study
2
was
also
conducted.
In
this
study,
the
mean
pre­
test
ChEI
level
for
20
subjects
was
377
U/
L,
which
is
higher
than
the
mean
value
of
323
for
the
Human
Oral
study.
This
analysis
was
conducted
to
evaluate
the
effect
on
the
BMD
estimate
of
assuming
higher
pre­
test
ChEI
levels
as
observed
in
Dermal
Study
2.
The
dose
response
models
have
adequate
model
fit
to
the
data
and
the
BMD10
and
BMD20
estimates
as
shown
in
Table
2.

Table
2.
OPCumRisk
BMD10
estimates
based
on
Arnold
(
1976,
1978)

Control
Group
Data
BMD10
BMDL10
p­
value
Human
Oral
Study1
Pre­
test
(
t=
0)
0.02605
0.0214
0.364
Mean
based
on
mean
from
Dermal
Study
2
pre­
test
and
StDev
based
on
coefficient
of
variation
of
the
Humans
Oral
study
pre­
test
0.02252
0.01917
0.83
EPA
BMD
analysis
of
Human
Oral
study1
reported
in
U.
S.
EPA
(
2006a)
5
0.038
0.025
Not
reported
by
EPA
These
BMD10
and
BMDL10
estimates
are
slightly
lower,
but
similar
to
the
values
proposed
in
the
EPA
Weight
of
Evidence6
evaluation
BMDL10
of
0.026
mg/
kg
which
shows
that
when
more
(
and
different)
control
subjects
are
used
in
the
calculation
of
the
BMD10,
it
does
not
significantly
change
the
value.
Although
the
13
number
of
subjects
is
low
and
there
is
variability
in
the
data,
the
human
oral
study
can
be
used
to
calculate
BMD10
values
that
are
reliable
enough
to
use
in
the
risk
assessment
process.

4.
Conclusion:

The
carbofuran
human
oral
study
was
reviewed
by
the
HSRB
on
May
2­
3,
2006.

The
HSRB
found
that
the
oral
study
met
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted
and
there
was
no
evidence
of
significant
deficiencies
in
the
ethical
procedures.
Although
the
study
has
some
scientific
deficiencies,
including
the
small
number
of
subjects,
small
number
of
controls
and
variability
in
the
RBC
cholinesterase
data,
the
Board
should
not
have
concluded
in
its
draft
document,
that
the
study
cannot
be
used
to
inform
the
risk
assessment
of
carbofuran.
Control
data
from
the
pre­
dose
measurements
from
the
study
subjects
in
the
oral
study
and
from
a
dermal
study
conducted
at
the
same
lab
show
that
the
control
values
are
all
in
the
same
range.
Calculation
of
a
benchmark
dose
uses
all
of
the
data
to
determine
the
value
that
would
result
in
10
percent
cholinesterase
inhibition.
This
is
a
more
powerful
way
to
use
the
limited
data,
than
use
to
determine
a
NOEL
or
LOAEL.
When
the
BMD10
is
calculated
from
the
human
oral
study
with
carbofuran,
the
values
range
from
0.022
to
0.038
mg/
kg.
These
values
compare
favorably
with
the
BMDL10
of
0.03
mg/
kg
from
the
rat
comparative
cholinesterase
study
which
is
the
proposed
basis
for
the
EPA
risk
assessment.

Therefore,
for
the
reasons
set
forth
above,,
the
human
oral
study
should
be
judged
to
meet
ethical
and
scientific
standards
and
thus
be
able
to
be
used
to
inform
the
hazard
and
risk
assessments
for
carbofuran.
This
conclusion
is
reached
setting
aside
the
procedural
considerations
noted
previously
in
this
Response
document.
Should
the
Agency
be
permitted
to
complete
its
interim
rat
and
human
BMD10
analyses,
FMC
believes
the
case
for
utilization
of
the
14
carbofuran
human
oral
study
would
be
even
more
convincing.
This
information,

in
combination
with
the
prior
independent
peer
reviews
of
the
Human
Oral
Study
should
be
reconsidered
by
either
the
HSRB,
including
Drs.
Brimijoin
and
Chambers,
or
another
panel
of
independent
reviewers.
15
References:

(
Reference
Number)
Citation
(
1)
Arnold,
J.
D.
1976.
Evaluation
of
safe
exposure
levels
to
carbamate,
administered
orally
to
healthy
adult
normal
male
volunteers.
Final
Report.
Quincy
Research
Center,
Kansas
City,
MO.

(
2)
Arnold,
J.
D.
1977.
Carbamate
(
carbofuran)
human
dermal
study.
Final
Report.
Quincy
Research
Center,
Kansas
City,
MO.

(
3)
Arnold,
J.
D.
1978.
Comparison
of
cholinesterase
inhibition
effects
of
furadan
4F
and
FMC
35001
4EC.
Final
Report.
Quincy
Research
Center,
Kansas
City,
MO.

(
4)
U.
S.
EPA.
2002.
Revised
OP
cumulative
risk
assessment.
www.
epa.
gov/
pesticides/
cumulative/
rra­
op/.
U.
S.
Environmental
Protection
Agency,
Washington,
DC.

(
5)
U.
S.
EPA.
2006a.
Memorandum
from
A.
Lowit
to
J.
Liccione.
Benchmark
dose
analysis
of
cholinesterase
inhibition
data
in
neonatal
and
adult
rats
(
MRID
no.
46688914)
following
exposure
to
carbofuran.
January
19,
2006.

(
6)
U.
S.
EPA.
2006b.
Memorandum
from
J.
Liccione
to
T.
Levine,
Human
Studies
Review
Board:
Carbofuran
weight­
of­
the­
evidence
presentation
of
human
and
animal
toxicity
studies.
April
14,
2006.
16
EXHIBIT
A
June
27,
2006
HAND
DELIVERED
Mr.
Jim
Jones
Director,
Office
of
Pesticide
Programs
Environmental
Protection
Agency
1200
Pennsylvania
Ave.,
N.
W.
Washington,
D.
C.
20460
Re:
HSRB
Review
of
Carbofuran
Dear
Mr.
Jones:

I
am
writing
to
express
FMC's
concerns
arising
from
the
May
2­
3,
2006
meeting
of
the
Human
Studies
Review
Board
("
HSRB"),
and
their
implications
for
the
Agency's
regulation
of
carbofuran.
The
HSRB
meeting
was
subject
to
certain
procedural
irregularities
which
we
believe
could
taint
the
eventual
outcome
of
EPA's
reregistration
assessment
of
carbofuran.
For
this
reason,
FMC
asks
that
you
take
steps
to
cure
these
procedural
deficiencies
 
specifically
that
the
HSRB
be
asked
to
reconsider
the
carbofuran
human
studies
before
issuing
its
report,
with
the
opportunity
to
correct
the
deficiencies,
as
described
below.

The
HSRB
was
asked
to
consider
the
scientific
and
ethical
aspects
of
three
carbofuran
human
studies
conducted
in
1976­
1977,
one
oral
study
and
two
dermal
studies.
In
1997,
EPA
contracted
with
Drs.
William
Brimijoin
and
Janice
Chambers
to
be
two
of
the
three
independent
peer
reviewers
of
the
carbofuran
oral
study.
In
their
1997
peer
reviews,
Drs.
Brimijoin
and
Chambers
concluded
that
the
oral
study
was
the
proper
study
to
use
as
the
point
of
departure
for
calculating
the
reference
dose
for
carbofuran.
Based
on
this
independent
review,
EPA
concluded
that
the
oral
study
was
ethical
and
should
be
accepted
for
regulatory
purposes.
In
its
April
2006
report
to
the
HSRB,
EPA
concluded
that
that
the
oral
study
was
ethical
and,
consistent
with
Drs.
Brimijoin
and
Chambers'
earlier
recommendation,
should
be
used
as
the
point
of
departure
for
setting
carbofuran
health
benchmarks
and
for
determining
the
appropriate
uncertainty
factors
for
the
cumulative
assessment
of
carbamates.

Drs.
Brimijoin
and
Chambers
were
appointed
by
EPA
to
be
members
of
the
HSRB.
They
had
no
financial
interest
in
the
carbofuran
matter,
had
done
no
prior
work
for
FMC,
and
satisfied
all
of
the
other
ethical,
financial
and
technical
standards
for
appointment.
1
Moreover,
Drs.
Brimijoin
and
Chambers
were
experts
on
both
the
ethics
and
scientific
relevance
of
the
oral
study,
and
their
input
would
be
highly
useful
and
important
to
the
Board
as
a
whole.
Nevertheless,
for
reasons
that
are
not
clear,
these
two
members
either
recused
themselves
or
were
recused
from
the
HSRB's
consideration
of
the
carbofuran
studies.

1
The
HSRB
was
established
under
the
Federal
Advisory
Committee
Act
("
FACA"),
71
Fed.
Reg.
6137,
6156
(
Feb.
6,
2006),
and
the
HSRB
members
are
Special
Government
Employees
subject
to
the
relevant
ethical
and
other
requirements
of
18
U.
S.
C.
§
208.
17
The
recusal
was
both
improper
and
prejudicial
to
FMC.
There
was
no
basis
for
recusal
merely
because
Drs.
Brimijoin
and
Chambers
were
experts
in
the
oral
study
and
previously
had
been
asked
by
EPA
to
conduct
the
1997
independent
review.
This
was
neither
a
conflict
of
interest
nor
an
appearance
of
a
conflict.
To
the
contrary,
it
was
part
of
the
basis
of
their
expertise
which
made
them
uniquely
qualified
to
serve
on
the
HSRB.
Further,
their
specific
experience
with
the
carbofuran
studies
made
them
especially
qualified
to
participate
in
the
HSRB's
evaluation
as
to
whether
the
studies
should
now
be
considered
by
the
Agency
under
the
human
studies
guidelines.

The
recusal
resulted
in
the
absence
from
the
Board
of
the
persons
with
the
best
qualifications
to
review
the
carbofuran
human
studies.
As
a
result,
several
of
the
remaining
members
of
the
HSRB,
without
having
the
background
of
Drs.
Brimijoin
and
Chambers,
asked
significant
questions
about
the
studies
on
which
Drs.
Brimijoin
or
Chambers
could
have
provided
input
either
in
the
public
hearing
or
as
part
of
the
Board's
private
deliberations.
If
those
other
Board
members
conclude
that
such
questions
were
not
answered
satisfactorily,
the
Board
may
well
recommend,
contrary
to
EPA's
conclusions
and
presentation
at
the
hearing,
that
the
carbofuran
human
studies
not
be
used
either
as
a
point
of
departure
for
setting
health
benchmarks
or
for
determining
the
appropriate
uncertainty
factors
for
carbofuran.
One
source
of
this
adverse
result
is
the
improper
recusal
of
Drs.
Brimijoin
and
Chambers.

Compounding
this
prejudice,
FMC
was
provided
incorrect
information
by
the
HSRB's
designated
federal
officer
which
resulted
in
the
FMC
representatives
­­
Dr.
Donald
Carlson
and
Ms.
Jane
McCarty,
who
presented
oral
comments
and
answered
HSRB
inquiries
relative
to
the
FMC
human
studies
­­
missing
the
second
day
of
the
HSRB
meeting,
during
which
the
carbofuran
studies
were
further
debated.
At
the
conclusion
of
the
May
2,
2006
meeting,
FMC
representative
Dr.
Carlson
was
specifically
informed
by
the
designated
federal
officer
that
the
HSRB
would
not
address
the
carbofuran
human
studies
again
on
the
morning
of
May
3,
2006,
as
originally
indicated
on
the
meeting
agenda.
After
confirming
that
the
HSRB
had
completed
its
discussion
of
the
carbofuran
human
studies,
Dr.
Carlson
and
Ms.
McCarty
left
Washington,
D.
C.
on
the
evening
of
May
2,
2006
and
were
not
present
at
the
May
3,
2006
meeting.
FMC
later
learned
that,
despite
assurances
to
the
contrary,
the
HSRB
had
in
fact
returned
to
its
discussion
of
the
carbofuran
studies
on
the
morning
of
May
3,
2006
when
no
FMC
representative
was
present.
Had
FMC
been
present
at
the
May
3,
2006
meeting,
FMC
could
have
answered
any
additional
questions
that
may
have
been
relevant
to
the
Board's
deliberations.
2
Although
unintentional,
this
erroneous
representation
by
the
designated
federal
officer
violated
EPA
policy
and
basic
principles
of
fairness
and
due
process.
In
establishing
the
HSRB
as
a
FACA
committee,
EPA
determined
that
"
the
HSRB
will
be
required
to
use
procedures
that
ensure
transparency
in
its
operation
and
that
afford
opportunities
for
the
public
to
express
their
views
of
issues
being
considered
by
the
HSRB."
71
Fed.
Reg.
6137,
6156
(
Feb.
6,
2006).
Clearly,
FMC
was
deprived
of
its
full
opportunity
to
express
its
views
on
important
issues
that
could
affect
the
retention
of
its
carbofuran
registration.

The
combined
effect
of
these
two
procedural
defects
has
the
potential
to
be
extremely
damaging
to
FMC's
position.
FMC
believes
that
the
carbofuran
human
studies
are,
as
EPA
2
We
are
still
awaiting
a
copy
of
the
official
tape
of
the
May
2
and
3
sessions,
which
is
not
yet
available.
In
the
interest
of
time,
we
are
sending
this
letter
now.
If
the
tape
reveals
other
significant
issues
discussed
at
the
May
3
session
at
which
FMC
was
not
present,
FMC
will
send
you
a
follow
up
letter.
18
concluded,
not
unethical
and
highly
relevant
to
the
carbofuran
risk
assessment.
As
such,
they
may
influence
the
outcome
of
EPA's
reregistration
and
tolerance
reassessment.
However,
EPA
is
required
to
consider
the
views
of
the
HSRB
in
determining
whether
to
rely
on
the
human
studies,
and
if
those
views
are
the
result
of
a
flawed
process,
that
may
well
have
an
adverse
impact
on
EPA's
regulatory
position
and
on
FMC's
registration.

FMC,
therefore,
requests
that
EPA
remedy
these
procedural
deficiencies
by
asking
the
HSRB
to
reconsider
the
carbofuran
studies
with
Drs.
Brimijoin
and
Chambers
participating,
and
with
FMC
being
given
an
opportunity
to
address
the
issues
that
are
considered
by
the
Board.

We
ask
to
meet
with
you
to
provide
additional
details
on
this
matter.
Please
call
me
at
215­
299­
6183
to
schedule
a
meeting
to
discuss
our
concerns.
Thank
you
for
your
time
and
attention.

Sincerely,

Linda
W.
Froelich
Manager,
NA
Registration
and
Regulatory
Affairs
FMC
Agricultural
Products
Group
cc:
Don
Carlson
Jane
McCarty
Michael
Reilly
Ken
Weinstein,
Latham
&
Watkins
Claudia
O'Brien,
Latham
&
Watkins
