Document ID: EPA-HQ-OPPT-2002-0029-0043
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-10-10T04:00Z

Comments
from
EDMVS
on
restricted
feeding
study

Difficult
to
evaluate
the
study
without
time
to
examine
the
data
in
advance,
but
generally
no
major
problems
with
study.

Effects
at
12%

reduction
in
BW
gain
(RBWG)
make
a
conclusion
of
no
effect
at
up
to
10%

questionable.

Another
unpublished
study
seems
to
confirm
no
RBWG
effects
on
PPS,
but
there
were
other
effects
on
reproductive
organs
(epididymal
and
SV
weights).

(VO
not
tested.)
Study
to
be
distributed
to
EDMVS.
Restricted
feeding
study
(2)

Much
discussion
on
need
for
pair­

feeding:
–
Not
needed
if
RBWG
<

10%
–
Not
clear
how
to
interpret
results
if
MTD
is
defined
as
10%

RBWG
–
Not
a
problem
if
EPA
requires
only
one
dose
in
the
pubertal
because
controls
can
be
pair­
fed.
Dose­
setting
issues

MTD
should
not
be
based
solely
on
RBWG.
Clinical
signs
can
be
the
basis.

Stay
below
signs
of
pain
and
distress.

Use
minimum
number
of
animals
commensurate
with
need,

usually
in
the
range
of
2
to
5.

Flexibility
in
dose­
setting
methods
is
needed.

Up/

down
procedure
is
fine
for
longer­
term
assays.
Acute
data
may
suffice
for
short­
term
assays.
Dose­
setting
issues
(2)

Use
all
possible
sources
of
data
when
guessing
at
initial
dose
(e.
g.,

HPV
data),
and
consider
using
in
vitro
data
if
no
other
info
is
available.

Be
aware
of
the
PK
and
other
differences
that
can
arise
by
mandating
gavage
as
route
of
exposure.

"There
is
no
substitute
for
good
judgment."
Dose­
setting
issues
(3)

Dose­
setting
must
be
part
of
protocol
validation,
but
there
is
also
a
need
to
know
what
happens
when
many
labs
use
identical
doses.

For
an
unknown
chemical
in
validation,

it
might
be
reasonable
to
have
all
labs
do
dose­
setting
independently,
with
a
committee
to
consider
all
the
results
and
decide
on
doses
to
test
in
the
assay
per
se.
Thyroid
endpoints
in
mammalian
2­

generation
assay

T3
not
useful;
thyroid
weight
useful

T4
very
useful
vs.
T4
not
helpful
beyond
weight
and
histopath

Consider
other
endpoints
(e.
g.,

auditory,
ocular)
for
thyroid
effects
on
neurodevelopment

Look
at
what
expert
review
for
perchlorate
RfD
said
were
useful
endpoints
for
thyroid.

Follow
up
on
the
germinal
epithelium
effects
Criteria
for
Screens

In
response
to
concerns
expressed
by
the
EDMVS
it
should
be
noted
that:
–
The
composition
of
the
Tier
1
battery
and
weight­
ofevidence
guidelines
will
be
updated
based
on
experience
with
the
assays
in
validation.
–
The
desire
for
redundancy
of
endpoints
in
separate
assays
in
the
battery
will
be
weighed
against
cost
and
animal
welfare
concerns.
ER
&

AR
Binding
Assays

EPA
will
proceed
with
the
validation
of
the
ER
uterine
cytosol
and
AR
prostate
cytosol
binding
assays
developed
by
EPA
taking
note
of
the
recommendations
for
challenge
chemicals
by
the
NIEHS
expert
panel.
ER
&

AR
Binding
Assays

Although
EPA
regards
the
ERTA
and
ARTA
as
assays
in
the
research
stage
(the
BRDs
could
not
recommend
a
protocol
or
assay
system
for
prevalidation
studies)
EPA
is
making
substantial
progress
in
the
development
of
stably
transfected
assays
for
both
ER
and
AR.
EPA
will
standardize
these
assays
and
investigate
options
for
their
validation
including
partnerships
with
industry
and
other
countries.