Document ID: EPA-HQ-ORD-2004-0005-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-05-31T04:00Z

June
1,
2004
Supplemental
comments
submitted
by
Chemical
Products
Corporation
by
EDOCKET
This
letter,
submitted
by
Chemical
Products
Corporation
(
CPC),
comments
upon
the
Proposed
Oral
Reference
Dose
(
RfD)
for
Barium
and
Compounds
Discussion
Paper,
May
2004,
NCEA­
S­
1683,
and
the
Charge
to
Reviewers
of
this
document
contained
in
EPA
Docket
ORD­
2004­
0005
(
Document
ID
ORD­
2004­
0005­
0005).
The
comments
in
this
letter
supplement
the
comments
submitted
on
May
31,
2004.

The
discussion
paper
NCEA­
S­
1683,
on
page
22,
states,
"
For
the
derivation
of
the
proposed
RfD
it
was
determined
that
renal
lesions
in
chronically­
exposed
mice
provide
the
best
evidence
of
a
dose­
response
relationship
for
barium
toxicity.
For
this
reason,
the
chronic
mouse
study
conducted
by
NTP
(
1994)
is
selected
as
the
principal
study
and
chemically­
related
kidney
lesions
are
identified
as
the
critical
effect."

EPA's
OPPTS
published
a
toxicological
evaluation
for
barium
in
the
January
3,
1997
Federal
Register.
On
page
369
of
the
January
3,
1997
Federal
Register,
EPA
summarized
the
NTP
study
as
follows,
"
Based
on
the
renal
toxicity,
the
LOAEL
is
160
mg/
kg/
day
for
male
mice
and
200
mg/
kg/
day
for
female
mice.
The
No
Observed
Adverse
Effect
Level
(
NOAEL)
is
75
mg/
kg/
day
for
male
mice
and
90
mg/
kg/
day
for
female
mice."

Benchmark
dose
modeling
has
been
employed
in
discussion
paper
NCEA­
S­
1683
to
derive
a
proposed
RfD
that
is
significantly
below
a
high­
quality
chronic
NOAEL
derived
utilizing
100
animals
(
50
male
and
50
female);
the
question
of
whether
Benchmark
Dose
modeling
is
the
most
appropriate
for
this
situation
and
whether
it
is
being
correctly
applied
should
be
specifically
addressed
in
the
Charge
and
should
be
carefully
considered
by
the
Peer
Reviewers.

EPA's
draft
Benchmark
Dose
Technical
Guidance
Document,
EPA/
630/
R­
00/
001,
October
2000
states
at
Page14
("
a.
Design"),
"
In
general,
studies
with
more
dose
groups
and
a
graded
monotonic
response
with
dose
will
he
more
useful
for
BMD
analysis.
Studies
with
only
a
single
dose
showing
a
response
different
from
controls
may
not
be
appropriate
for
BMD
analysis,
though
if
the
one
elevated
response
is
near
the
BMR,
adequate
BMD
and
BMDL
computation
may
result
(
see
Kavlock,
et
a1,1996)."
In
this
case
there
is
only
a
single
dose
showing
a
response
significantly
different
from
controls,
as
stated
in
EPA's
notice
in
the
January
3,
1997
Federal
Register
at
page
369
and
shown
in
the
attached
tables
from
Apendices
C
and
D
of
NTP
Technical
Report
432
(
1994).
In
addition,
the
one
elevated
response
(
the
LOAEL
of
160
mg/
kg/
day
for
male
mice
and
200
mg/
kg/
day
for
female
mice)
is
not
near
the
BMR.
Therefore,
we
submit
that
BMD
analysis
is
not
appropriate
in
this
case;
the
NOAEL
of
75
mg/
kg/
day
should
be
the
basis
for
calculation
of
the
RfD.

In
the
same
document
(
EPA/
630/
R­
00/
001)
a
footnote
on
page
4
states,
"
Note
that
for
a
study
utilizing
6
animals
per
dose
group,
the
95%
upper
confidence
limit
(
UCL,)
on
an
observed
adverse
response
rate
of
0%
is
49%.
That
is,
NOAELs
chosen
on
the
basis
of
no
observed
response
in
6
animals
could
be
too
high
a
substantial
proportion
of
the
time.
The
95%
UCL,
s
for
groups
of
10,
20
and
50
animals
are
31%
,
17%,
and
7%,
respectively,
underscoring
the
importance
of
adequate
sample
sizes."
The
NOAELs
derived
from
the
NTP
Technical
Report
432
(
1994)
are
based
on
the
observed
response
in
100
animals
(
50
male
rats
or
mice
and
50
female
rats
or
mice).

If
I
can
answer
any
questions
about
this
letter,
please
telephone
me
at
770­
382­
2144.

Sincerely,

Jerry
A.
Cook
Technical
Director