MEMORANDUM
FROM:
Jack
E.
Housenger,
Associate
Director
Health
Effects
Division
Office
of
Pesticide
Programs
TO:
Paul
I.
Lewis
Designated
Federal
Official
for
the
Human
Studies
Review
Board
Office
of
the
Science
Adviser
SUBJECT:
OPP
Comments
on
the
Draft
Report
of
the
May
2
 
4,
2006,
Meeting
of
the
Human
Studies
Review
Board
We
appreciate
the
opportunity
to
offer
comments
on
the
draft
report
on
the
second
meeting
of
the
Human
Studies
Review
Board
(
HSRB),
held
May
2
 
4,
2006.
In
general,
the
report
captures
the
oral
comments
and
conclusions
made
during
the
meeting.
We
also
thank
the
Board
members
for
the
timeliness
in
preparing
the
report
recognizing
all
the
other
work
they
have
been
tasked
to
do.

Staff
in
the
Office
of
Pesticide
Programs
(
OPP)
has
carefully
reviewed
the
draft
to
identify
any
portions
that
are
either
unclear
or
inconsistent
with
our
notes
and
understandings
from
the
meeting.
This
memorandum
identifies
those
areas
in
the
draft
report
we
believe
could
benefit
from
rewording
and/
or
clarification
as
well
as
places
in
the
text
that
appear
to
contain
typographical
or
other
minor
editorial
errors.
It
does
not
purport
to
state
how
EPA
plans
to
act
on
the
HSRB's
recommendations.
OPP
will
report
to
the
Board
at
a
future
meeting
how
it
has
acted
on
its
recommendations.

1.
MITC
Page
3,
lines
3
 
6
The
Board
reached
it
decision
based
on
the
observation
that
eye
irritation
LOAELs
are
often
lower
than
respiratory
irritation
LOAELs
for
irritant
gases.

Page
27,
lines
2
 
5
Since
The
animal
studies
were
either
long­
term
inhalation
or
oral
studies
and
their
use
,
they
were
not
considered
for
a
point
of
departure
and
therefore
would
be
less
protective
of
human
health.
Thus,
therefore,
the
Board
recommended
the
eye
irritation
LOAL
LOAEL
as
a
point
of
departure.
2.
Chromium
Page
1,
lines
34
 
36
The
HSRB
concluded
there
was
insufficient
information
to
determine
whether
the
study
failed
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted.

This
summary
conclusion
is
worded
much
stronger
than
the
corresponding
conclusion
on
page
16,
lines
16
 
21
and
therefore
is
misleading
as
a
summary
of
the
Board's
stated
consensus
and
rationale
which
reads:

"
The
Board
based
these
two
determinations
on
its
conclusion
that
this
study
appeared
to
have
not
deviated
significantly
from
the
ethical
standards
prevailing
when
the
study
was
conducted.
However,
this
conclusion
was
based,
in
part,
on
a
process
that
was
hampered
by
a
lack
of
supporting
documentation
concerning
independent
ethical
review
by
the
study
investigators'
home
institutions.
The
Board
strongly
recommended
that
for
all
studies
submitted
to
the
HSRB,
the
Agency
make
a
good
faith
effort
to
obtain
such
documentation
in
the
future."

Page
9,
lines
41
 
44
At
the
public
meeting,
following
welcoming
remarks
from
Agency
officials,
Celia
B.
Fisher,
HRSB
Chair,
proposed
a
set
of
scientific
and
ethics
criteria
consistent
with
the
language
of
71
Federal
Register
6137
to
guide
Board
evaluation
of
each
protocol
completed
study.

Page
14,
line
12
The
study
sponsor
was
unknown,
but
is
likely
to
be
either
the
Chem
Risk
Division
of
McLaren/
Hart  .

Page
14,
line
36
The
Board
concurred
with
the
factual
observations
of
the
strengths
and
weaknesses
of
the
study,
as
detailed
in
USEPA
(
2006a).
However,
further
comments
were
raised
regarding:
1)
whether
the
documentation
and
process
of
study
subject
enrollment
was
sufficient
to
meet
prevailing
standards
of
voluntary
informed
consent
and
2)
whether
the
repeat
highdose
oral­
three
step
exposure
protocols
used
were
designed
to
minimize
risks
to
study
participants.
Page
16,
lines
1
 
3
Thus,
the
Board
believed
that
there
was
not
was
clear
and
convincing
evidence
that
these
studies
could
have
resulted
in
serious
harm
based
on
the
knowledge
available
to
the
investigators
at
the
time.

Page
27,
lines
2
 
5
Since
The
animal
studies
were
either
long­
term
inhalation
or
oral
studies
,
they
were
not
considered
for
a
point
of
departure
and
therefore
their
use
would
be
less
protective
of
human
health.
Therefore,
they
were
not
considered
for
a
point
of
departure.
Thus,
the
Board
recommended
the
eye
irritation
LOAL
LOAEL
as
a
point
of
departure.

3.
Carbofuran
Page
21,
lines
16
 
17
The
Agency
proposed
to
use
the
RBC
cholinesterase
data
for
determination
of
the
BMD10L
BMDL10.

Page
21,
lines
22
­
24
As
such,
although
a
BMD10L
BMDL10
could
be
calculated,
the
magnitude
of
the
error
in
the
derived
values
would
preclude
a
reliable,
meaningful
assessment.

Page
21,
lines
22
­
24
Therefore,
the
HSRB
reiterated
its
recommendation
that
the
human
data
should
not
be
used
for
calculation
of
the
BMDL10.

Page
18,
lines
29
 
31
Maximal
inhibition
of
RBC
cholinesterase
activity
at
this
dose
level
was
45
46
and
65%
in
the
2
subjects
(
4
hours),
whereas
plasma
cholinesterase
inhibition
was
maximal
at
24
hours
(
12
and
16
%,
respectively).

Page
20,
lines
31
 
33
The
weaknesses
included
the
small
sample
size,
the
lack
of
control
subjects,
the
highly
variable
results
for
RBC
cholinesterase
activity
and
the
inappropriate
application
methods
improper
dermal
loading
used
in
the
dermal
studies.
Page
25,
last
line
The
second
dermal
toxicity
study
was
considered
significantly
deficient
by
a
majority
of
all
Board
members
and
fundamentally
unethical
by
one
in
that
the
lack
of
information
provided
about
the
results
from
the
initial
dermal
toxicity
study
seriously
impaired
their
informed
consent.

4.
COMMENTARY
ON
SCIENTIFIC
STANDARDS
FOR
HUMAN
DOSING
STUDIES
Page
33
For
the
heading
"
Scientific
Standards
for
Human
Dosing
Studies",
it
is
unclear
whether
the
Board
intends
this
to
apply
only
to
toxicity
studies
or
all
human
dosing
studies.
Additionally,
it
is
unclear
whether
the
Board
intends
to
have
these
scientific
standards
be
applied
to
completed
studies,
proposed
studies
or
both.

Page
34,
lines
17
 
20
Scientific
Standards
for
Single
Dose
Level
Study
Board
definition
of
single
dose
level
study
­
individual
study
that
uses
one
dose
level
other
than
a
control
or
placebo,
irrespective
of
the
number
of
subjects,
or
frequency
of
dosing,
or
inclusion
of
a
control
or
placebo.
