Page
1
of
5
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
7
April
2005
MEMORANDUM
Subject:
Transmission
of
Background
Materials
for
the
Session
of
the
May
5­
6,
2005
FIFRA
Scientific
Advisory
Panel
Entitled
"
A
Comparison
of
the
Results
of
Studies
on
Pesticides
from
1­
or
2­
year
Dog
Studies
with
Dog
Studies
of
Shorter
Duration"

To:
Myrta
Christian,
Designated
Federal
Official
FIFRA
SAP
Office
of
Science
Coordination
and
Policy
(
7101C)

From:
Karl
Baetcke,
Ph.
D.,
Senior
Scientist
Office
of
Pesticide
Programs,
Health
Effects
Division
(
7509C)

Whang
Phang,
Ph.
D.
Toxicologist
Office
of
Pesticide
Programs,
Health
Effects
Division
(
7509C)

Vicki
Dellarco,
Ph.
D.
Senior
Scientist
Office
of
Pesticide
Programs,
Health
Effects
Division
(
7509C)

Through:
Tina
Levine,
Acting
Director
Office
of
Pesticide
Programs,
Health
Effects
Division
(
7509C)

Attached
is
the
document
"
A
Comparison
of
the
Results
on
Pesticides
from
1­
or
2­
year
Dog
Studies
with
Dog
Studies
of
Shorter
Duration"
The
purpose
of
this
document
is
to
describe
a
retrospective
analysis
of
the
results
of
dog
studies
submitted
to
the
Office
of
Pesticide
Programs
in
support
of
the
registration
or
reregistration
of
pesticides.
Under
the
current
CFR
Part
158
toxicology
data
requirements,
a
90­
day
Page
2
of
5
and
a
1­
year
non­
rodent
(
dog)
study
(
guidelines
82­
1
and
83­
1)
are
required
for
all
food
use
pesticides
and
for
pesticides
with
nonfood
uses
if
use
of
the
pesticide
product
is
likely
to
result
in
repeated
human
exposure
to
the
product
over
a
significant
portion
of
the
human
life­
span.
Over
the
last
three
decades
the
Agency
has
received
the
results
of
a
large
number
of
dog
studies
in
support
of
the
registration
of
pesticides.
The
Agency
has
conducted
a
retrospective
analysis
of
dog
studies
that
provided
the
basis
for
the
selection
of
reference
doses
(
RfD's)
in
order
to
determine
whether
the
requirement
for
both
a
subchronic
and
a
chronic
dog
study
continues
to
be
justified.
The
analysis
involved
a
comparison
of
the
results
of
13­
week
studies
and
1­
or
2­
year
studies
or
a
comparison
of
interim
data
(
90­
days
or
less)
from
1­
year
dog
studies
with
the
data
from
1­
year
in
the
same
study.
The
Office
of
Pesticide
Programs
will
be
soliciting
comments
from
the
FIFRA
Scientific
Advisory
Committee
on
this
retrospective
analysis
of
the
results
of
dog
studies
and,
specifically,
on
the
soundness
of
this
retrospective
analysis
and
whether
the
analysis
supports
the
continuation
of
the
requirement
for
both
subchronic
and
chronic
dog
studies
or
whether
consideration
should
be
given
to
a
modification
of
the
current
requirements
for
dog
studies
(
see
Charge
below).

Attachments:
Document
For
Review
With
Respect
to
Charge
 

OPPTS
March
2005
Draft
Document
on
"
Comparison
of
the
Results
on
Pesticides
from
1­
or
2­
year
Dog
Studies
with
Dog
Studies
of
Shorter
Duration"
(
Enclosed)

Background
Material
 
(
reprints)


EPA
is
currently
obtaining
permission
from
journal
publishers
to
copy
articles
referenced
in
EPA's
document
submitted
for
review
by
the
SAP.
Permission
to
copy
all
pertinent
articles
is
expected
shortly
and
copies
will
the
be
forwarded
under
separate
cover.

Charge
to
the
Panel:
Please
provide
comment
and
advice
on
the
following
questions.

Issue
1:
Comparison
of
the
results
of
13­
week
and
chronic
dog
studies
OPP
has
concluded
that
there
is
evidence
that
little
qualitative
and
quantitative
value
is
added
by
requiring
both
a
13­
week
dog
study
and
a
1­
year
dog
study
to
support
the
establishment
of
chronic
oral
RfDs
for
pesticide
residues.

Question
1
­
.
Please
comment
on
the
adequacy
of
the
approach
used
and
the
comparisons
made
regarding
the
results
of
dog
studies
of
different
durations.
OPP
would
also
appreciate
recommendations
from
the
panel
on
improving
the
analysis
(
e.
g.,
figures
and
tables)
or,
if
needed,
discussion
of
additional
analyses
that
would
elucidate
the
validity
of
the
conclusions
made.
Page
3
of
5
Issue
2:
Examples
where
NOAELs
or
LOAELs
were
found
to
be
lower
in
chronic
dog
studies
than
in
13­
week
dog
studies
Nineteen
examples
(
Table
3,
Appendix)
were
initially
identified
where
NOAELs
or
LOAELs
were
found
to
be
lower
(>
1.5X)
in
chronic
dog
studies
than
in
13­
week
studies.
Further
analyses
showed
that
for
11
of
these
examples,
the
observed
differences
seem
to
be
associated
with
differences
in
dose
selection
or
interexperimental
variability
(
interim
data
from
1­
year
studies
indicated
the
same
NOAELs/
LOAELs
could
be
identified
at
13­
weeks).
For
the
remaining
8
pesticides
(
Table
1,
main
text),
there
are
rat
studies
that
would
provide
comparable
NOAELs/
LOAELs
to
the
chronic
dog
study
(
2
pesticides)
and,
for
3
pesticides,
data
were
insufficient
for
an
in­
depth
comparison
of
the
results
of
13­
week
and
chronic
dog
studies
or
the
data
were
inconsistent
with
current
biological
understanding.
Finally,
three
pesticides
were
identified
where
results
of
the
chronic
dog
study
seem
to
be
more
appropriate
for
selection
of
NOAELs/
LOAELs
that
would
be
used
for
derivation
of
a
chronic
RfD.

Question
2:
Please
comment
on
the
clarity
and
soundness
of
the
evaluations
presented
on
the
19
pesticides
where
NOAELs
or
LOAELs
appeared
to
differ
between
the
13­
week
and
chronic
studies.
Specifically,
do
theses
cases
detract
from
the
overall
conclusions
regarding
the
value
of
1­
year
dog
studies
in
RfD
selection.

Issue
3:
Recommended
durations
for
dog
studies
conducted
on
pharmaceutical
agents
versus
dog
studies
conducted
on
pesticides.

An
International
Conference
on
Harmonization
(
ICH)
workgroup
recommended
that,
in
the
case
of
pharmaceutical
agents,
the
animal
toxicity
database
should
include
a
dog
study
of
at
least
9
months
duration
(
DeGeorge
et
al.,
1999).
This
recommendation
appears
to
have
been
based
primarily
on
evidence
that
additional
toxicities
were
seen
from
9­
12
months
that
were
not
evident
at
6­
months.
EPA
understands
that
such
studies
are
often
conducted
with
dose
levels
in
the
range
of
dosages
anticipated
for
humans.
Therefore,
such
evidence
could
lead
to
an
adjustment
in
the
pharmacologically
active
doses
that
could
be
used
clinically
or
the
additional
toxicities
could
be
used
in
the
monitoring
of
clinical
parameters.
However,
it
appears
that
only
in
a
few
cases
did
the
additional
toxicities
seen
in
9­
12­
month
studies
led
to
a
revision
in
the
margin
of
safety
(
i.
e.,
the
ratio
of
no
observed
adverse
effect
level
to
the
anticipated
human
exposure,
in
this
case
exposure
to
a
pharmacologically
active
dose);
it
is
unclear
to
what
extent
margin
of
safety
estimates
for
pharmaceuticals,
in
general,
would
be
affected.

EPA's
purpose
for
requiring
dog
studies
conducted
with
pesticides
is
to
identify
a
no
observed
adverse
effect
level
(
NOAEL)
and
the
lowest
observed
effect
level
(
LOAEL,
or
the
lowest
dose
that
produces
some
biologically
significant
evidence
of
Page
4
of
5
toxicity).
The
effects
at
the
LOAEL
are
used
to
characterize
the
toxicity
that
may
be
expected
to
occur
if
exposure
to
a
pesticide
exceeds
an
RfD.
The
NOAEL
is
used
to
derive
an
RfD,
which
represents
a
dose
that
is
unlikely
to
produce
adverse
health
effects
in
humans
exposed
to
environmental
residues
of
a
pesticide
at
or
below
the
RfD.
In
contrast,
dog
studies
performed
with
pharmaceuticals
are
designed
to
ascertain
whether
adverse
effects
may
occur
in
humans
administered
a
pharmaceutical
chemical
at
pharmacologic
doses
and
to
determine
margins
of
safety.

The
analysis
of
13­
week
and
1­
or
2­
year
dog
studies
conducted
on
172
pesticides
by
Spielmann
and
Gerbracht
(
2001)
and
the
results
of
the
analysis
of
77
studies
on
pesticides
by
the
Office
of
Pesticide
Programs
has
provided
evidence
that
the
NOAELs
and
LOAELs
observed
in
13­
week
and
1­
or
2­
year
dog
studies
generally
do
not
differ.
Further,
Spielmann
and
Gerbracht
(
2001)
found
that
for
only
7
of
141
pesticides
were
significant
new
effects
found
in
1­
or
2­
year
dog
studies
that
were
not
seen
in
13­
week
dog
studies
or
chronic
studies
with
rats.
Based
on
the
results
of
these
analyses
of
dog
studies
conducted
with
pesticides,
EPA
has
concluded
that
a
dog
study
of
13­
weeks
duration
provides
sufficient
data
for
an
evaluation
of
potential
chronic
toxicity
in
this
species
along
with
other
routinely
required
toxicity
studies.
(
Note
that
a
chronic
dog
study
is
only
one
of
several
studies
that
may
be
selected
for
the
derivation
of
a
chronic
RfD;
other
possibilities
include
a
2­
year
rat
study,
a
2­
generation
rat
reproduction
study,
and
an
18­
month
mouse
study)

Question
3A:
Given
the
somewhat
different
objectives
of
dog
studies
conducted
on
pharmaceutical
agents
and
on
pesticides
please
comment
on
the
extent
to
which
the
recommendations
of
the
International
Conference
on
Harmonization
workgroup
may
be
relevant
to
the
use
of
dog
studies
in
risk
assessments
with
pesticides
and
whether
the
results
of
studies
performed
specifically
on
pesticides
support
EPA's
conclusion
that
a
dog
study
of
13
weeks
duration
along
with
rodent
chronic
data
is
adequate
for
providing
an
assessment
of
chronic
toxicity
for
purposes
of
deriving
chronic
RfD's.

Question
3B:
EPA's
analysis
showed
that
there
was
no
additional
qualitative
hazard
information
provided
by
a
1­
year
dog
study
which
would
raise
significant
concerns
that
would
lead
to
the
application
of
uncertainty
factors
in
addition
to
the
standard
factors
when
deriving
an
RfD.
Please
comment
on
the
soundness
of
this
conclusion.
Page
5
of
5
Issue
4.
Refinement
of
the
13­
week
dog
study.

The
dog,
as
a
second
non­
rodent
species,
is
well
accepted
and
established
as
an
important
regulatory
data
requirement.

Question
4:
If
the
13­
week
dog
study
is
considered
adequate
for
hazard
identification,
how
could
the
best
use
be
made
of
this
13­
week
study
to
characterize
potential
human
health
effects
(
e..
g.,
increase
the
number
of
animals
evaluated,
measuring
additional
parameters
such
as
blood
pressure
and
ECG,
obtaining
toxicokinetic
data)?
