/~­
Rich
Leukroth
To:
Rob
Dewoskin/
RTP/
USEPNUS
@
EPA,
Hugh
Barton/
RTP/
USEPAIUS@
EPA
~
 
05/
02/
2003
03
13
PM
cc
John
Schaeffer/
DC/
USEPA/
US@
EPA
Mtchei
Stevens/
RTP/
USEPA/
US
@
EPA
Subject:
RE
TOE
Program
Review
Attached
is
the
HAP
Task
Force
response
to
the
revised
Table
1
footnotes.
tend
to
agree
with
Peter
on
many
of
these
points.
We
cant
go
beyond
the
intent
of
the
ECA.
rn
not
convinced
that
we
need
a
comprehensive
understanding
of
the
mode
of
action
to
complete
this
testing
program
and
for
route
dosimetry
extrapolation.

Ill
be
out
of
the
office
until
next
Thursday
(
5/
8/
03).
In
the
interim
perhaps
you
folks
could
give
these
footnotes
another
look.
Hopefully
we
can
find
a
better
way
to
express
what
we
want
so
that
we
can
move
forward.

**
*******
*********
********
*****
***
*****
*******
****

Richard
W.
Leukroth,
Jr.
Environmental
Scientist
/
Toxicologist
Chemical
Control
Division
U.
S.
Environmental
Protection
Agency
Mail
Stop
7405;
Room
4328
S
1200
Pennsylvania
Avenue,
N.
W.
Washington,
DC
20460
Phone:
202­
564­
8167
FAX:
202­
564­
4765
E­
mail:
leukroth.
rich@
epa.
gov
Forwarded
by
Rich
Leukroth/
DO/
USEPNUS
on
05/
02/
03
03:
03
PM
Peter
Voytek
To:
Rich
Leukroth/
DO/
USEPAJUS@
EPA
<
pvoytek@
cross~
ink.
n
cc:
et>
Subject:

05/
02/
03
05:
49
PM
Rich,
the
deadline
times
are
fine­­
but
there
are
some
big
problems
with
the
wording
in
the
footnotes.
You
just
cant
throw
mode
of
action
around
unless
you
define
what
you
mean.
If
your
input
comes
from
the
RTP
people
maybe
we
need
to
have
a
conference
call
to
revisit
what
the
ECA
is
and
the
use
of
the
PBPK
model
regarding
route
to
route
extrapolation.
We
are
not
performing
a
risk
assessment
which
seems
to
be
somewhat
implicated
in
confusing/
misleading
footnotes
as
read
them.
See
attached.

As
a
positive
note
I
did
complete
the
review
of
the
Battelle
report.
I
recalculated
all
there
tables
and
appendices.
There
are
some
differences
which
need
to
he
corrected.
I
also
am
asking
for
some
addition
raw
data
from
them
to
be
included
in
the
modification.

Peter
0
revisedTbll
4~
28_
03wpc
RECEIVED
OPPT
NCIC
2003
JUN24
8:
05AM
OPPT­
2002­
0056­
0066
Table
1._
Required
Testing,
Test
Standards,
and
Reporting
Requirements
for
TCE
­

Mndification~/
Revigicrns
(?`
t~
to
Tier
II
Testing
and
Reporting
Activities
Tier
II
Testing
and/
or
Extrapolation
Reporting
Developmental
toxicity
(
oral)

Developmental
toxicity
extrapolation
of
oral
data
to
inhalation
Reproductive
toxicity
(
oral)

Reproductive
toxicity
extrapolation
of
oral
data
to
inhalation
Immunotoxicity
extrapolation
of
extant
oral
data
in
ECA
Appendix
E.
2
to
inhalation
~

Carcinogenicity
extrapolation
ofextant
oral
data
in
ECA
Appendix
E.
3
to
inhalation
~
40
CFR
§
799.9620
(
as
annotated
in
ECA
Appendix
0.3)

40
CFR
§
799.9370
(
as
annotated
in
ECA
Appendix
D.
4)

ECA
Appendix
C
40
CFR
§
799.93
80
(
as
annotated
in
ECA
Appendix
D.
5)

ECA
Appendix
C
ECA
Appendix
C
ECA
Appendix
C
1
Number
of
months
after
the
effective
date
of
this
Federal
Register
Notice,
which
announces
that
EPA
has
concluded
the
EPA
Program
Review,
when
the
final
report
is
due.
In
addition,
every
6
months
from
the
effective
date
ofthe
Order
until
the
end
ofthe
ECA
testing
program,
interim
reports
describing
the
status
ofall
testing
to
be
performed
under
the
Eca
for
TCE
must
be
submitted
by
the
Companies
to
EPA.
~­­­­­­­­­­­­­­­
­­­­­­­
­

Testing
Required
testing
Test
standard
Deadline
for
Segment
final
report'
~
Months~

40
CFR
§
799.9620
(
as
annotated
in
ECA
Appendix
D.
3)

ECA
Appendix
C
Acute
neurotoxicity
(
oral)

Acute
neurotoxicity
extrapolation
of
oral
data
to
inhalation
2
Subchronic
neurotoxicity
(
oral)

Subchronic
neurotoxicity
extrapolation
of
oral
data
to
inhalation
2
ECA
Appendix
C
12
15
18
21
24
27
30
33
9
6
2
Quantitative
route­
to­
route
extrapolation
documented
graphically
and
with
tabular
data.
Different
dose
metrics
to
be
evaluated
initially
at
the
protocol
development
stage
and
then
in
the
context
of
the
finaLresults.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood
or
brain,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
andmetabolite,
as
amount
metabolized
in
the
liver
or
brain
per
day
normalized
to
organ
weight.
There
is
no
information
on
brain
metabolism.
To
get
this
brain
tissue
would
be
needed
to
assess
whether
metabolism
occurs
and
to
what
extent.
However,
the
model
can
predictamountthat­
en.
ters­
the
brain
on­
ly~
You
can't
say
anything
about
brain
metabolism.
From
the
acute
and
90
data
study
there
is
no
evidence
that
brain.
tissuels
altered
histologically.
Should
mode
of
action
[
Define
whatyou
mean
by
mode
of
action]
To
me
this
means
that
you
have
some
idea
of
what
is
happening
at
the
molecular
level,
Iam
unaw
re­
of­
any
data
for
1,1,2
that
identifies
specific
cell
types
or
macromolecules
resulting
in
eliciting
a
toxic
response.
First
of
all
you
would
need
some
indication
from
theacute
and
subchronic
studies
or
data
in
theliterature
that
some
molecule/
cell
type
is
targeted
and
maybe
responsible/
involved
in­
a
toxic
effect.
Ifsome
targetwas
potentially
identified
then
one
would
need
to
design
research
to
explore
mode
of
action.
This
could
take
years
(
e.
g.
methylene
chloride/
cancer/
species
differences­~.
This
goes
way
beyond
the
scope
ofthe
1,1,2­
ECA.
Remember
the
purpose
of
the
ECA
is
to
use
PBPK
to
obtain
equivalent
tissue
levels
from
external
doses
via
inhalation
and
ingestion
not
to
define
themechanism/
mode
of
action.
data
be
available
to
support
a
dose
metric
other
than
Cmax
orAUC
for
parent
compound(
e.
g.
time
above
a
critical
concentration
as
is
sometimes
used
in
pharmaceutical
applications)
that
dose
metric
will
be
derived
and
added
to
the
overall
evaluation.
The
choice
of
the
final
dose
metric
should
be
supported
with
mode­
of­
action
[
please
provide
an
example
of
mode
of
action
for
1,1,2­
with
references]
information
and
a
discussion
of
the
most
health
protective
[
I
da&
tkn~
wwhat
you
mean
by
"
health
protective."
Maybe
the
most
sensitive
dosimetric
to
obtain
conservative
external­
exposures???]

~
Quantitative
route­
to­
route
extrapolation
documented
graphically
and
with
tabular
data.
Different
dose
metrics
to
be
evaluated
initially
at
the
protocol
development
stage
and
then
in
the
context
ofthe
fmal
results.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.
The
choice
of
the
fmal
dose
metric
should
be
supported
with
mode­
of­
action
[
please
provide
an
example
of
mode
of
action
for
1,1,2­
with
references]
information
and
a
discussion
of
the
most
health
protective.
[
I
dou't
know
what
you
mean
by
"
health
protective."
Maybe
the
most
sensitive
dosimetric
to
obtain
conservative
external
exposures???]

"
Quantitative
route­
to­
route
extrapolation
based
on
the
data
of
Sanders
et
al.
(
1985)
documentedgraphically
and
with
tabular
data.
Dose
metrics
to
consider
include
parentcompound
in
venous
blood
or
spleen,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
or
spleen
per
day
normalizedto
organ
weight
Iwe
do
not
have
any
data
on
metabolism
in
spleen
 
you
can't
say
this!,
the
model
can
predict
levels
of
1,1,2­
in
this
organ].
The
choice
of
the
fmal
dose
metric
should
be
supported
with
mode­
of­
action
information
[
please
provide
an
example
of
mode
of
aetmnn
frsr
1,1,2­
with
references]
and
a
discussion
ofthe
most
health
protective.
[
I
don't
know
what
you
mean
by
"
health
protective."
Maybe
the
most
sensitive
dosimetric
to
obtain
conservative
external
exposures???]

~
Quantitative
route­
to­
route
extrapolation
based
on
the
data
of­
NCI
(
1978)
documented
graphically
and
with
tabular
data.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood
or
liver,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.
The
choice
of
the
final
dose
metric
should
be
supported
with
mode­
of­
action
information
[
please
provide
an
example
of
mode
of
action
for
1,1,2­
with
references]
and
a
discussion
of
the
most
health
protective.
[
I
don't
know
what
you
mean
by
"
health
protective."
Maybe
the
most
sensitive
dosimetric
to
obtain
conservative
external
exposures???
Dose­
response
analysis
to
be
performed
using
genotoxic
assumption
(
linear
extrapolation)
procedure.
[
What
has
this
got
to
do
with
anything??
All
the
cancer/
mutagenic
risks
that
I
ever
performed
at
EPA
assumed
no
threshold,
pretty
much
assuming
linearity
at
low
extrapolated
exposure
levels,
Again,
all
we
are
able
to
accomplish
is
equivalency
in
tissue
levels
via
inhalation
and
ingestion
doses.
In
otherwords,
get
equivalent
inhalation
doses
to
the
oral
doses
used
in
the
cancer
bioassay.
The
Agency
may
used
the
cancer
guidelines
for
extrapolating
to
lower
exposure
levels
without
utilizing
the
PBPK
model
or
elect
to
use
the
model
to
extrapolate
tissue
parent
concentrations
or
total
metabolite
at
lower
external
inhalation
exposures.
This
is
a
risk
assessment
decision
that
is
beyond
the
scope
ofthe
ECA
for
1,1,2­.
