MEMORANDUM
FROM:
William
L.
Jordan
Senior
Policy
Adviser
Office
of
Pesticide
Programs
(
7501P)

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
April
4
 
6,
2006,
Meeting
of
the
Human
Studies
Review
Board
We
appreciate
the
opportunity
to
offer
comments
on
the
draft
report
on
the
first
meeting
of
the
Human
Studies
Review
Board
(
HSRB),
held
April
4
 
6,
2006.
In
general,
the
report
reflects
the
oral
comments
made
during
the
meeting
and
provides
useful
additional
clarifications.
We
also
thank
the
Board
members
for
the
extraordinary
efforts
they
made
to
prepare
for
the
meeting,
to
provide
such
useful
commentary,
and
to
produce
a
completed
report
so
soon
after
the
meeting.

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
from
the
meeting.
In
addition,
OPP
has
identified
places
in
the
text
of
the
draft
report
that
appear
to
contain
typographical
or
other
minor
editorial
errors.

This
memorandum
does
not
purport
to
state
how
EPA
plans
to
act
on
the
HSRB's
recommendations.
We
will
report
to
the
Board
at
a
future
meeting
how
OPP
has
acted
on
its
recommendations.

Major
comments
OPP
has
major
comments
on
the
portions
of
the
report
dealing
with
amitraz
and
azinphos­
methyl.

1.
Amitraz
The
Board's
recommendations
concerning
the
use
of
the
results
of
the
available
human
studies
on
amitraz
appear
to
be
inconsistent.
On
page
5,
the
HSRB
states
in
the
summary
section
for
amitraz
under
Scientific
Considerations:

"
The
results
from
the
single
oral
dose
study
are
informed
by
the
human
metabolism
study
such
that
the
single
oral
dose
study
is
appropriate
for
developing
a
point
of
departure
for
acute
and
chronic
dietary
risk
and
short­
term
oral
exposure."
and
later
on
the
same
page:

"
The
combined
results
from
the
single
oral
dose
study
and
the
human
metabolism
study
were
not
appropriate
for
developing
a
point
of
departure
for
chronic
dietary
risk,
short­
term
oral
exposure,
or
inhalation
risk."

Substantively
identical
statements
appear
in
the
body
of
the
report
on
p.
62.
These
two
statements
appear
to
contradict
each
other
with
respect
to
whether
the
combined
results
from
the
two
amitraz
studies
may
be
used
for
developing
a
point
of
departure
for
chronic
dietary
risk
and
short­
term
oral
exposure.

Based
on
the
rationale
presented
in
the
body
of
the
report,
we
surmise
that
the
Board
may
have
meant
to
say
that
the
available
human
studies
could
be
used
for
acute
dietary
risk
assessment,
but
should
not
be
used
to
develop
a
point
of
departure
for
exposure
intervals
longer
than
one
day,
i.
e.,
for
chronic
dietary
risk,
short­
term
oral
exposure,
and
inhalation
risk.
In
its
explanation
for
the
recommendation
not
to
use
the
amitraz
data
for
assessing
the
risk
of
chronic
dietary
exposure,
the
Board
cited
the
possibility
that
amitraz
may
not
be
fully
eliminated
from
the
body
in
one
day,
and
thus
that
the
effects
produced
by
the
single,
higher
dose
of
amitraz
used
in
the
metabolism
study
might
occur
if
a
lower
dose
of
amitraz,
such
as
that
used
in
the
single
oral
dose
study,
were
repeated
on
successive
days.

As
reflected
in
OPP's
Weight
of
Evidence
assessment,
EPA
and
the
Board
reached
essentially
the
same
conclusions
with
respect
to
using
the
available
amitraz
human
studies
to
derive
a
point
of
departure
for
acute
dietary
risk.
If
it
is
correct
that
the
Board
recommends
not
using
the
human
data
for
the
chronic
dietary
risk,
short­
term
oral
exposure
and
inhalation
exposure,
it
should
be
noted
that
OPP's
WOE
assessment
reached
a
different
conclusion.
OPP
agrees
with
the
Board's
observations
that
the
available
human
studies
only
provide
insights
into
how
humans
respond
to
a
single
dose
of
amitraz,
and
that
the
human
studies,
by
themselves,
do
not
contain
data
to
characterize
the
effects
of
multiple
days
of
exposure.

OPP's
WOE,
however,
concluded
on
the
basis
of
the
available
animal
toxicity
data,
together
with
human
incident
information,
that
there
is
no
appreciable
difference
between
the
levels
of
toxicity
displayed
in
single
vs.
multiple­
day
exposures.
Further,
OPP
believes
that
the
draft
report
may
overstate
the
conclusions
to
be
drawn
from
the
amitraz
metabolism.
On
p.
62,
line
32,
the
draft
report
states:
"
Excretion
of
radiolabeled
metabolites
was
incomplete
(
62%)
at
24
hours."
The
metabolism
study
did
report
that
62%
of
the
radioactivity
was
detected
in
urine
collected
at
the
end
of
24
hours.
While
the
study
could
not
account
for
the
remainder
of
the
radioactivity,
OPP
believes
that
the
data
do
not
show
that
38%
of
the
radioactivity
was
retained
by
the
subjects,
especially
since
there
were
no
measurements
of
radioactivity
in
either
feces
or
expired
air
(
which
would
show
excretion)
or
blood
(
which
would
show
retention).
Thus,
the
metabolism
study
leaves
considerable
uncertainty
about
the
extent
of
excretion
of
a
single
oral
dose
of
amitraz
over
a
24
hour
period.
In
OPP's
view,
this
uncertainty
is
sufficiently
offset
by
the
evidence
from
animal
toxicity
testing
and
human
incidents
showing
comparability
in
toxicity
between
single
and
multiple­
day
exposures
to
justify
the
use
of
the
human
studies
for
chronic
dietary,
short­
term
oral,
and
inhalation
risk
assessments.

2.
Azinphos­
methyl
OPP
has
concerns
about
a
portion
of
the
draft
report
discussing
the
possible
causes
of
symptoms
experienced
by
subjects
in
the
28
day
oral
dosing
study
with
azinphos
methyl
(
AZM).
On
p.
34,
lines
39 
42,
the
report
states:

A
variety
of
symptoms
were
reported
over
the
course
of
the
study,
with
the
majority
occurring
in
the
subjects
administered
AZM.
The
conclusion
drawn
in
the
Agency's
Data
Evaluation
Record
(
Doherty
1999)
that
none
of
the
symptoms
likely
reflected
effects
of
AZM
is
not
verifiable,
nor
is
it
credible.

OPP
recognizes
that
the
data
available
from
the
28
day
oral
dosing
study
are
insufficient
to
show
definitively
whether
AZM
did
or
did
not
cause
the
reported
symptoms,
and
therefore
acknowledges
the
Board's
advice
that
no
firm
conclusion
should
be
reached
on
their
causation.
We
are
concerned,
however,
with
the
characterization
of
the
conclusions
reached
by
EPA's
science
reviewer.

We
suggest
the
following:

A
variety
of
symptoms
consistent
with
cholinesterase
inhibition
were
reported
in
both
the
control
(
2
of
4
subjects,
17
events)
and
AZM
dosed
groups
(
8
of
8
subjects,
53
events)
over
the
course
of
the
study.
There
was,
however,
no
statistically
significant
decrease
in
cholinesterase
activity
detected
in
AZMtreated
subjects;
no
increase
in
the
severity
of
the
symptoms
reported
by
the
treatment
group,
as
compared
to
the
control
group;
and
the
symptoms
in
the
AZM
treated
group
did
not
grow
worse
over
time
as
exposure
continued.
While
the
study
report
asserted
that
AZM
did
not
cause
these
symptoms,
there
was
insufficient
information
to
support
that
conclusion
and
some
concern
within
the
Board
that
some
of
the
symptoms
could
have
resulted
from
AZM
treatment.

Minor
Comments
EPA
has
the
following
minor
comments:

P.
1,
line
28
(
and
elsewhere):
Throughout
the
document
the
report
refers
to
sodium
cyanide
and
hydrogen
cyanide
in
ways
that
may
confuse
the
reader.
The
registered
pesticide
product
contains
the
active
ingredient,
sodium
cyanide.
When
mixed
with
water,
the
pesticide
produces
hydrogen
cyanide,
the
active
compound.
The
studies
reviewed
by
the
Board
involved
amygdalin,
which
breaks
down
into
hydrogen
cyanide
in
vivo.
Refer,
e.
g.,
to
p.
4,
lines
41,
45;
p.
5,
line
2;
p.
54,
line
32.

p.
1,
line
25:
revise
to
read:
".
.
.
procedures
that
could
have
resulted
.
.
.
."
p.
1,
line
28:
change
the
tense
of
verbs,
"
proposes"
to
"
proposed".

p.
2,
line
4
(
and
elsewhere):
The
standard
of
proof
for
rejecting
a
study
conducted
before
April
7
requires
"
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
.
.
.
."
(
emphasis
added).
The
draft
report
inaccurately
quotes
the
standard
as
"
clear
or
convincing
evidence."

p.
2,
line
35:
Change
to
read
"
affected
the
outcome
or
conclusions
of
this
study."

p.
4,
line
20­
21:
Revise
to
read
"
the
scientific
quality
of
either
the
ethephon
28
day
oral
toxicity
study
or
the
ethephon
16
day
human
oral
toxicity
study
.
.
.
."

p.
11,
line
3:
Cite
the
final
rule
as
(
71
Federal
Register
6137).

p.
11,
line
11:
Delete
repetitive
language
"
the
first
meeting
of
the
Board".

p.
11,
line
27:
The
Emanuel
(
2000)
article
does
not
appear
in
the
list
of
references
at
the
end
of
the
draft
report.
The
full
citation
is
"
Emanuel,
E.;
Wender,
D.;
Grady,
C.
(
2000)
What
Makes
Clinical
Research
Ethical?
JAMA
283:
2701­
2711."

p.
11,
line
35:
Delete
"
has".
The
purpose
of
this
and
similar
changes
is
to
make
clearer
that
the
report
reflects
the
Agency's
position
at
the
time
of
the
meeting,
as
opposed
to
the
time
of
the
report.

p.
12,
lines
4 
5:
Revise
to
read
".
.
.
on
which
the
Agency
proposed
to
rely
in
actions
under
the
pesticide
laws
and
studies
the
Agency
had
decided
not
to
use
.
.
.
."

p.
12,
line
19:
Cite
the
Notice
as
(
71
Federal
Register
12,194).

p.
12,
lines
27
and
30:
Should
the
"
i.
e.,"
be
"
e.
g.,"?

p.
12,
line
33:
Insert
a
right
parenthesis
after
the
word
"
consent."

p.
13,
lines
37 
41:
Revise
to
read
".
.
.
for
aldicarb
described
the
study
design
.
.
.
.
The
WOE
document
also
discussed
.
.
.
.
Regarding
the
aldicarb
human
study,
the
Agency
concluded
.
.
.
."

p.
20,
lines
34 
35:
Revise
to
read
".
.
.
and
the
criterion
not
to
escalate
the
dose
when
inhibition
of
RBC
cholinesterase
exceeded
40%."

p.
25,
line
23:
Revise
to
read
"
DER
for
oxamyl
described
the
study
.
.
.
."

p.
26,
line
21:
Revise
to
read
"
In
its
policy
on
the
use
.
.
.
."
p.
26,
lines
24­­
5:
Revise
to
read
"
as
a
surrogate
for
effects
on
the
peripheral
nervous
system
in
animals
and
for
effects
on
the
peripheral
and
central
nervous
systems
in
humans."

p.
26,
line
42:
Revise
to
read
".
.
.
dosing
was
described
in
the
protocol."

p.
27,
line
3:
Revise
to
read
"
baseline
in
RBC
and
plasma
.
.
.
."

p.
28,
line
8:
Insert
concluding
period.

p.
29,
line
21:
The
correct
reference
is
Carley
2006c.

p.
31,
lines
32 
36:
The
observation
that
the
informed
consent
materials
described
cholinesterase
inhibition
as
a
side
effect
of
exposure
is
made
twice
in
this
passage.

p.
33,
line
30:
Revise
to
read
".
.
.
based
on
the
results
of
a
subchronic
rat
study
and
an
earlier
study
.
.
.
."

p.
33,
line
32:
Revise
to
read
".
.
.
and
regulatory
agencies
were
reluctant
to
.
.
.
."

p.
34,
line
9:
Revise
to
read
".
.
.
chosen
to
reduce
the
likelihood
of
confounding
factors."

p.
34,
line
23:
Replace
terminal
parenthesis
with
colon.

p.
34,
line
26:
Revise
to
read
"
Comparison
of
same
day
predosing
ChE
activities
with
ChE
activities
4
hours
after
dosing".
(
No
inhibition
was
observed.)

p.
34,
line
31:
Revise
to
read
"
.
.
.
however
there
have
been
no
consistent
sex
differences
in
sensitivity
with
regard
to
inhibition
of
plasma
or
RBC
cholinesterase
in
animal
studies."
(
At
higher
dose
levels
that
elicit
more
serious
toxicity,
there
gender­
related
differences
in
responses.)

p.
35,
lines
21 
22:
Revise
to
read:
".
.
.
in
other
studies
of
carbamates
and
organophosphates."
The
laboratory
which
conducted
the
AZM
study
had
performed
human
research
on
the
cholinesterase
inhibiting
effects
of
both
carbamates
and
organophosphates.

p.
39,
line
5:
Delete
"
a".

p.
40,
lines
31 
34:
This
discussion
of
the
degree
of
inhibition
of
cholinesterase
following
the
cessation
of
dosing
is
confusing.
The
data
show
cholinesterase
levels
were
17%
below
baseline.

p.
41,
line
5:
Revise
to
read
".
.
.
greatly
limit
the
value
of
this
study
.
.
.
."
p.
43,
table:
Correct
the
name
of
the
first
cited
study
to
"
Gledhill";
insert
closing
parenthesis
for
the
Gratz
study.

p.
45
line
41:
Revise
to
read
"
to
take
into
account
the
fact
that
.
.
.
."

p.
46,
line
45:
Delete
"(
3)"

p.
48,
lind
37:
Revise
to
read
"
One
subject
in
the
ethephon
group
was
asymptomatic."

p.
51,
lines
4 
6:
The
meaning
of
this
sentence
is
unclear;
a
word
may
be
missing
or
added.

p.
51,
lines
9­
11:
Revise
to
read
".
.
.
a
reference
dose
of
0.06
mg/
kg/
day
for
assessment
of
both
acute
and
chronic
dietary
risk
(
1.8
mg/
kg/
day
with
an
uncertainty
factor
of
10x
for
intraspecies
variability
and
a
3x
factor
for
use
of
a
LOAEL
 )".

p.
57,
line
21:
The
correct
citation
is
Carley
2006f.

p.
59,
line
32:
Insert
left
parenthesis
before
"
Campbell
1984)"

p.
62,
lines
21 
22:
Correct
the
text
to
read
"
and
no
quality
assurance
information
was
provided."

P.
65,
line
25:
Insert
right
parenthesis
after
the
word
"
volunteers."

p.
67,
lines
24,
28:
Add
the
first
initial
"
A."
to
the
author's
name
for
Dr.
Khasawinah.

p.
68,
line
44:
The
citation
is
incomplete.

p.
69,
line
11:
The
correct
date
of
the
Zendzian
article
cited
in
the
text
is
2000.
