Rich
To:
pvoytek@
crosslink.
net
Leukroth/
DC/
USEPAIU
cc:
Rob
Dewoskin/
RTP/
USEPA'US
©
EPA,
Michel
S@
EPA
Stevens/
RTP/
USEPNUS@
EPA,
Paul
CampanellalDC/
USEPA/
US
©
EPA
John
02/
28/
2003
10:
38
AM
Schaeffer/
DC/
USEPA/
US
©
EPA
Subject:
TOE
Technical
Oonsult
Mtg
EPA
requests
a
technical
consultation
meeting
with
the
HAP
Task
Force
to
discuss
progress
on
the
Tier
I
Program
Review
for
the
l,
l,
2~
trichloroethane
(
TOE)
enforceable
consent
agreement
(
ECA)
.
Since
most
of
the
scientist
involved
will
be
attending
the
Society
of
Toxicology
(
SOT)
meeting
in
Salt
Lake,
UT
I
suggest
that
we
could
meet
on
Wednesday,
March
12th
following
the
last
afternoon
SOT
session
(
4:
30
­
6:
00
pm).

Attached
is
a
tentative
agenda,
overview
of
the
EPA
preliminary
findings,
and
a
discription
of
discussion
topics
relevant
to
the
TCE
alternative
testing
program.

Please
let
me
know
if
this
is
acceptable
to
the
HAP
Task
Force
and
who
D
will
be
attending
the
meeting.
3l2O3TCEJCmtgAgenda.
wpd
OPPT­
2002­
0056­
0064
RECEIVED
OPPT
NCIC
2003
JUN24
8:
05AM
Technical
Consultation
Meeting
on
1,1,2­
Trichloroethane
(
TCE)
EPA
Tier
I
Program
Review
Update
DATE
/
TIME:
February
12,
2003
4:
30p.
m.
­
6:
00p.
m.

LOCATION:

PURPOSE:
Society
of
Toxicology
Meeting,
Salt
Lake
City,
UT
EPA
will
describe
preliminary
findings
on
the
Tier
I
Program
Review
activity
for
1,1,
2­
trichioroethane
and
engage
in
scientistto
scientist
discussions
with
the
HAP
Task
Force
on
clarifying
questions
and
the
nature
and
scope
of
Tier
II
testing
under
the
Enforceable
Consent
Agreement
for
1,1
,2­
Trichloroethane.

I.
Introductions
TENTATIVE
AGENDA
Rich
Leukroth
/
Peter
Voytek
II.
Overview
of
the
ORD
Program
Review
Activity
III.
Discussion
Topics
Rob
Dewoskin
(
see
attachment)

IV.
Next
Steps
Meeting
Handout
February
12,
2003
Technical
Consultation
Meeting
for
1,1,2­
Trichioroethane
Tier
I
Program
Review
Overview
ofORD
Preliminary
Findings
EPA's
Tier
I
Program
Review
for
1,1,2­
trichioroethane
(
TCE)
is
focused
on
four
reports
submitted
by
the
HAP
Task
Force
in
accordance
with
the
Enforceable
Consent
Agreement
(
ECA)
for
TCE.
The
on­
going
Program
Review
notes
that
the
PKIMECH
data
and
Tier
I
toxicity
studies
appear
to
have
been
conducted
in
accordance
with
the
protocols
and
specifications
as
described
in
the
ECA.
The
available
study
records
are
sufficient
to
allow
an
evaluation
ofthe
quality
ofthe
studies
and
the
data.
The
TCE
PBPK
model
is
chemical­
specific,
and
is
based
on
the
current
understanding
of
the
kinetics
ofTCE.
The
species,
dose
level,
exposure
regimens,
and
vehicles
used
are
relevant
for
the
toxicity
data
that
are
the
object
of
the
Tier
II
extrapolations.
The
Tier
I
Program
Review
PK!
MECH
data
demonstrated
that
periodicity
was
achieved
in
the
studies
that
support
the
model.
The
EPA
preliminary
review
identified
five
topics
for
discussion
at
a
technical
consultation
meeting
with
the
HAP
Task
Force.

Technical
Consultation
Discussion
Topics
1)
Characterizing
variability
and
uncertainty
in
the
kinetic
data
and
the
model
simulations
EPA
Preliminary
Finding:
An
acceptable
PBPK
model
report
must
include
adequate
discussion
of
the
variability
in
the
kinetic
data
used
to
develop
the
model,
and
the
variability
and
uncertainty
in
the
model
with
respect
to
the
"
fit"
of
the
simulations
to
the
kinetic
data.
A
more
thorough
discussion
is
needed
to
support
scientifically
defensible
arguments
for
use
ofthe
PBPK
model
in
each
of
the
proposed
route­
to­
route
extrapolation.
Examples
of
criteria
for
characterizing
"
fit"
include
percent
match
for
AUC,
or
simulation
curves
that
fall
within
±
"
x"
number
of
standard
deviations
of
the
mean.

Preliminary
Recommendation:
The
HAP
Task
Force
can
provide
this
information
as
an
addendum
to
their
report.

1
Meeting
Handout
February
12,
2003
2)
Quality
review
of
the
pharmacokinetic
and
PBPK
data
and
reports.

EPA
Preliminary
Finding:
Overall,
PK,
and
PBPK
modeling
studies
submitted
by
the
HAP
Task
Force
under
this
ECA
appear
to
have
been
well
conducted
with
excellent
documentation.
However,
EPA's
preliminary
review
of
the
study
records
identified
a
few
reporting
errors.
For
example:
a)
in
the
PK
report,
Table
B­
2,
30
mm
andi
hour
reported
average
dose
values
appear
to
be
incorrect;
and
b)
in
the
PBPK
model
parameters
there
is
an
apparent
difference
between
the
value
reported
in
the
PK
report
for
the
spleen
:
air
partition
coefficient
(
page
43)
and
the
value
used
in
the
PBPK
model
(
page
53).

Part
VIII.
D.
of
the
ECA
agreement
states
that
"
all
testing
required
by
this
ECA
shall
be
conducted
in
accordance
with
the
EPA
Good
Laboaratory
Practice
(
GLP)
Standards
contained
in
40
CFR
part
792.
EPA
does
not
have
specific
GLP
guidelines
available
for
pharmacokinetic
(
PK)
and
PBPK
model
studies.
Some
of
the
GLP
requirements
(
e.
g.,
retention
of
records)
are
also
not
applicable
to
this
work.
Nonetheless,
the
GLPs
provide
for
noncompliance
with
specific
requirements
as
long
as
a
statement
(
signed
by
the
sponsor
and
study
director)
describing
the
differences
between
the
practices
used
in
the
study
and
those
required
by
part
792
is
included
in
the
submission
(
see
792.12
­
Statement
of
compliance
or
non­
compliance).

Preliminary
Recommendation:
To
ensure
the
quality
of
the
PK
and
PBPK
model
data
and
reports
submitted
to
EPA,
the
data
records
and
reports
should
undergo
a
quality
assurance
review.
A
signed
QA
statement
documenting
the
review
as
well
as
a
signed
GLP
compliance
statement
should
be
appended
to
the
report.

3a)
Choice
of
dose
metrics
and
dosing
regimens
EPA
Preliminary
Finding:
The
PBPK
model
report
provides
a
good
example
ofthe
potential
use
ofthe
model
for
a
route­
to­
route
extrapolation,
in
this
case,
for
a
drinking
water
exposure
to
an
inhalation
exposure
using
amount
metabolized
as
the
dose
metric.
Views
that
additional
examples
of
study
specific
route­
to­
route
extrapolation
curves
are
needed
to
adequately
review
how
the
PBPK
model
will
perform
for
the
specific
studies
and
dose
metrics
called
for
in
the
Tier
II
route­
to­
route
extrapolations.
The
utility
of
the
model
for
each
application
depends,
in
part,
on
the
choice
of
the
dose
metric
and
the
dose
regimen
used
in
the
simulation
(
e.
g.,
the
dose
pattern
used
to
simulate
a
drinking
water
exposure).
Such
route­
toroute
extrapolation
curves
could
readily
be
developed
specific
to
each
of
the
extant
Tier
II
studies
for
which
extant
data
is
available
(
immunotoxicity
and
carcinogenicity).
These
curves
will
provide
comparisons
among
different
dose
metrics
and
exposure
patterns,
and
will
support
a
more
scientifically
defensible
evaluation
of
the
utility
of
the
PBPK
model
for
each
application.
Meeting
Handout
February
12,
2003
3a)
Continued
Preliminary
Recommendation:
The
HAP
Task
Force
is
encouraged
to
proceed
with
these
reporting
activities
as
a
means
to
further
support
the
TCE
model
even
though
they
are
listed
as
Tier
II
ECA
activities.

3b)
EPA
notes
that
similar
route­
to­
route
extrapolation
curves
could
also
be
generated
based
for
the
dose
regimens
of
the
new
Tier
II
studies
(
neuro­,
developmental,
and
reproductive
toxicity)
prior
to
the
conduct
of
the
studies.
Such
simulations
could
include
considerations
for
different
dose
metrics.
Based
upon
the
results
of
the
Tier
I
Program
Review
Testing,
simulation
runs
prior
to
the
conduct
of
the
new
Tier
II
studies
could
lead
to
further
improvements
in
the
model
and
the
study
protocols.

Preliminary
Recommendation:
(
discussion
at
the
technical
consultation
meeting)

4)
Support
for
inclusion
of
suicide
inhibition
in
the
model
EPA
Preliminary
Finding:
The
HAP
Task
Force
has
incorporated
a
suicide
enzyme
inhibition
component
into
the
PBPK
model
as
a
means
to
explain
why
the
model,
as
originally
conceived,
could
not
predict
differences
observed
between
female
and
male
mice.
The
PBPK
report
lacks
adequate
data
to
support
this
hypothesis.

Preliminary
Recommendation:
The
hypothesis
of
suicide
enzyme
inhibition
in
female
mice
(
and
not
in
male
mice)
needs
additional
support.
A
study
to
consider
would
be
an
in­
vitro
microsomal
assay
for
P450
inhibition.

5a)
Route
specific
considerations
of
the
nasal
toxicity
observed
in
the
inhalation
studies
for
toxicity.

EPA
Preliminary
Finding:
EPA
notes
that
the
nasal
toxicity
observed
in
the
inhalation
studies
performed
under
Tier
I
testing
may
not
be
adequately
addressed
for
route
specific
toxicity.
The
relevance
of
the
olfactory
cytotoxicity
to
humans
needs
to
be
discussed,
as
well
as
the
impact
that
nasal
toxicity
might
have
on
study
outcomes
for
the
endpoints
of
interest
in
Tier
II,
in
contrast
to
an
oral
exposure
without
nasal
toxicity.

Preliminary
Recommendation:
(
discussion
at
the
technical
consultation
meeting)

3
Meeting
Handout
February
12,
2003
Sb)
Route
specific
considerations
of
the
nasal
toxicity
observed
in
the
inhalation
studies
on
the
kinetics.

EPA
Preliminaiy
Finding:
The
nasal
toxicity
may
not
be
adequately
addressed
for
route
specific
effects
on
the
kinetics
including
first
pass
effects
and
delivery
of
parent
compound
to
the
brain
compartment
(
i.
e.,
peak
concentrations
or
time
above
a
given
concentration).
First
pass
effects
can
be
evaluated
using
the
model
(
i.
e.,
comparison
of
bioavailability
for
different
exposure
routes).

Preliminary
Recommendation:
(
discussion
at
the
technical
consultation
meeting)

4
