MEETING
SUMMARY
Title:
Technical
Consultation
Meeting
on
the
TCE
ECA
Date:
August
13,
2002
Time:
l:
3OPM­
3:
OOPM
Location:
EPA
Main
Campus,
RTP,
NC
Room
B­
249
Attendees:
For
EPA:
Richard
Leukroth
(OPPT/
CCD),
Michel
Stevens
(ORD/
I\
ICEA),
Rob
Dewoskin
(ORD/
NCEA),
Deirdre
Murphy
(OAR/
OAQPS),
and,
by
phone,
John
Schaeffer
(OPPT/
CCD).

For
HAP
Task
Force:
Peter
\
7
oytek,
and
Michael
Gargas
(Sapphire
Group)

The
meeting
began
about
1:
30
p.
m.
due
to
plane
delays.
A
copy
of
the
Agenda
is
attached
(Appendix
1).

Following
introductions,
Rich
Leukroth
(RL)
commended
the
HAP
Task
Force
for
their
work
under
the
1,1
,2­
trichloroethane
(TCE)
enforceable
consent
agreement
(ECA)
and
indicated
that
this
was
a
technical
consultation
meeting
convened
at
the
request
of
the
HAP
Task
Force.
The
purpose
of
this
technical
consultation
was
to
provide
an
opportunity
for
the
HAP
Task
Force
to
preview
the
Tier
I
Program
Review
deliverables
under
the
TCE
ECA.
These
deliverables
were
reported
to
EPA
in
two
documents
entitled:
"Pharmacokinetics
of
1,1
,2~
Trichloroethanein
Rats
and
Mice
by
Battelle
Pacific
Northwest
Laboratories"
and
"Physiologically
Based
Pharmacokinetic
Model
Development,
Simulations,
and
Sensitivity
Analysis
for
Repeated
Exposure
to
1,1
,2­
Trichloroethane."
The
receipt
of
these
documents,
along
with
other
information
relevant
to
the
TCE
ECA,
marks
the
conclusion
ofthe
HAP
Task
Force
Tier
I
and
Tier
I
Program
Review
testing
activities
under
the
TCE
ECA.
The
next
step
in
the
ECA
Testing
Program
will
be
the
EPA
Program
Review.
RL
indicated
that,
while
EPA
was
not
prepared
to
discuss
EPA's
Program
Review
activity,
these
presentations
and
discussions
would
inform
EPA's
decision
which
will
be
conveyed
to
the
HAP
Task
Force
by
letter
at
the
conclusion
of
the
Program
Review
process.
In
conjunction
with
this,
RL
indicated
that
EPA
intends
to
publish
a
Federal
Register
solicitation
notice
announcing
the
Program
Review
and
requesting
comments
on
the
above
mentioned
reports.
Peter
Voytek
(PV)
presented
an
overview
of
the
TCE
Tier
I
Program
Review
HAP
Task
Force
deliverables.
He
described
the
purpose,
goals
and
objectives
for
developing
pharmacokinetics
and
mechanistic
data
(PKIMECH)
on
TCE
and
extending
the
existing
Gargas
model
for
TCE.
PY
explained
how
new
data
lead
to
further
refining
the
model
to
include
consideration
for
suicide
inhibition.
A
copy
of
these
presentation
overheads
is
attached
(Appendix2).

Michael
Gargas
(MG)
presented
an
overview
ofthe
pharmacokinetic
studies
conducted
and
reviewed
the
results
for
female
rat
and
mouse
data.
MG
indicated
that
these
studies
were
conducted
to
facilitate
route­
to­
route
extrapolation
(parameter
estimates,
periodicity,
validation)
in
female
rats
and
mice,
inform
interpretation
and
extrapolation
ofa
corn
oil
gavage
cancer
bioassay,
and
a
drinking
water
gavage
study
for
immunotoxicity.
These
data
will
also
be
used
to
facilitate
route­
to­
route
extrapolations
for
new
studies
to
be
performed
under
Tier
II
of
the
TCE
ECA
testing
program.
MG
described
the
PBPK
model
structure
and
explained
model
optimization
and
validation
procedures
related
to
this
work.
The
inhalation
studies
performed
under
Tier
I
testing
were
used
to
validate
route­
to­
route
extrapolation
ofpharmacokinetic
data.
He
pointed
out
that
animal
recovery
from
exposure
was
evident
during
the
exposure­
free
weekend
periods.
MG
highlighted
data
indicating
that
at
sufficient
doses
(>
200
mg/
kg/
d)
metabolism
in
female
mice
is
believed
to
be
inhibited
by
enzyme
destruction
by
a
bound,
reactive
intermediate
(suicide
inhibition).
In
closing,
MG
provided
a
comparison
between
the
subchronic
inhalation
study
in
rats
conducted
under
Tier
I
ECA
testing
with
a
subchronic
drinking
water
study
in
mice
(White
et
a!.,
1985)
to
explore
how
these
data
sets
might
be
interpreted
by
the
TCE
model.
A
copy
of
these
presentation
overheads
is
attached
(Appendix
3).

Discussion
focused
on
clarification
questions
regarding:
understanding
ofportal
ofentry
effects,
selection
ofdose
metrics,
goodness
offit
estimations,
model
optimization,
standard
deviations
around
the
curves,
understanding
the
female
mouse
data,
mechanism
for
the
suicide
inhibition,
mode
ofaction
of
TCE,
and
GLP
compliance.
The
HAP
Task
Force
indicated
that
they
were
preparing
a
manuscript
on
the
model
development
forjournal
publication
and
that
the
sub­
contractors
had
already
expressed
interest
in
publishing
the
Tier
I
studies.

RL
closed
the
meeting
by
thanking
the
HAP
Task
Force
for
providing
these
presentations
and
encouraged
the
publication
of
the
Tier
I
study
results
and
model
development.
He
explained
that
the
EPA
Program
Review
is
getting
under
way
and
that
comments
received
in
response
to
the
Federal
Register
notice
solicitation
are
expected
to
inform
EPA's
Program
Review
decision.
In
closing
he
commented
that
including
public
process
into
the
Program
Review
would
most
likely
extend
the
time
needed
by
the
Agency
to
conclude
this
activity.

The
meeting
adjourned
at
about
3:
1
5
PM.

Prepared
by:
Richard
Leukroth
Date
:
Time:
AGENDA
Technical
Consultation
Meeting
on
the
TCE
ECA
August
13,
2002
1:
00
PM
­
3:
00
PM
Location:
EPA
Main
Campus,
RTP,
NC
Room
B­
249
Purpose:
HAP
Task
Force
presentations
at
this
meeting
will
provide
an
overview
ofthe
Tier
I
Program
Review
Testing
and
model
development
under
the
TCE
ECA
and
give
EPA
staff
an
opportunity
to
clarify
questions
about
the
PKIMECH
data
and
model
simulations.

1.
Introductions
2.
Tier
I
HAP
Task
Force
Overview
3.
Review
of
PBPK
Modeling
Results
4.
Discussion
Rich
Leukroth
(EPA)

Peter
Voytek
(HAP
Task
Force)

Mike
Gargas
(Sapphire
Group)

5.
Next
Steps
EPA
TIER
1
PROGRAM
REVIEW
A.
PK/
MECH
DATA
REVIEW
B.
PBPK
MODELING
REVIEW
C.
VALIDITY
OF
ORAL­
TOINHALATION
EXTRAPOLATIONS
REPORTS
PHARMACOKINETICS
OF
1,1,2­
TRICIILOROETHANE
IN
RATS
AND
MICE
[SUBMITTED
10/
31/
01]

PHYSIOLOGICALLY
BASED
PHARMACOKINETIC
MODEL
DEVELOPMENTAND
SIMULATIONS
[SUBMITTED
6/
11/
02]
PURPOSE
REFINE
EXISTING
MODEL
TO
BETTER
EXTRAPOLATE
FROMORAL
TO
INHALATION
ROUTE
ORAL~
HOH]==>
INHALATION
ACUTE
NEUROTOXICITY
(ORAL)
SUBCHRONIC
NEUROTOXICITY
(ORAL)
DEVELOPMENTAL
TOXICITY
(ORAL)
REPRODUCTIVE
TOXICITY
(ORAL)
IMMUNOTOXICITY
(ORAL)

ORAL
[CORN
OILJ==>
INHALATION
CANCER
BIOASSAY
(CORN
OIL)

DETERMINE
STEADY­
STATE
BLOOD
CONCENTRATIONS
AT
REPEATED
INHALATION
EXPOSURES
DETERMINE
STEADY­
STATE
BLOOD
CONCENTRATIONS
AT
REPEATED
ORAL
(HOH)
DOSES
DETERMINE
STEADY­
STATE
BLOOD
CONCENTRATIONS
AT
REPEATED
ORAL
(CORN
OIL)
DOSES
DETERMINE
METABOLIC
PARAMETERS
AND
PARTITION
COEFFICIENTS
REVISED
MODEL
WITH
NEW
PARAMETERS/
PARTITION
COEFFICIENTS
VALIDATE
REVISED
MODEL
RATS
6HR/
DAY
6HR/
DAY
6HR/
DAY
BLOOD
A
SAMPLES—
+
WEEK
4*
4,6,6.25,8
HRS
4
6,6.25,8
HRS
~dosingstarted
at
0
hrs
(initiation
of
daily
dosing)
6HRIDAY
6HR/
DAY
4,6,6.25,8
HRS
GAVAGE
CORN
OIL
DAYS
1
2
3
MICE
365
MG/
KG/
DAY
365
MG/
KG/
DAY
365
MG/
KG/
DAY
4
365
MG/
KG/
DAY
5
365
MG/
KG/
DAY
RATS
94.2
MG/
KG/
DAY
94.2
MG/
KG/
DAY
94.2
MG/
KG/
DAY
BLOOD
SAMPLES*
0.5,
1,
2,
8
HRS
0.5
1,
2,
8
HRS
*dosing
started
at
0
hrs
(initiation
of
daily
dosing)
94.2
MG/
KG/
DAY
94
2
MG/
KG/
DAY
0.5,
1,
2,
8
HRS
INHALATION
DAYS
1
2
3
4
MICE
6HRIDAY
6HR/
DAY
6HR/
DAY
6HR/
DAY
6HR/
DAY
GAVAGE
HON
DAYS
1
2
3
4
5
MICE
97
MG/
KG/
DAY
97
MG/
KG/
DAY
97
MG/
KG/
DAY
97
MG/
KG/
DAY
97
MG/
KG/
DAY
RATS
1.66
MG/
KG/
DAY
1.66
MG/
KG/
DAY1.66
~
MG/
KG/
DAY~
1.66
MG/
KG/
DAY
BLOOD
+
+
SAMPLES
0.1,
0.2,
0.5,
1
HAS
0.1,
0.2,0.5,1
HAS
0.1,
0.2,
P~
1HRS
*dosing
started
at
0
hrs
(initiation
of
daily
dosing)

SUICIDE
INHIBITION
112
TRICHLOROETHANE
<:::::::;::>
ENZYME
SUBSTRATE
COMPLEX:::::::>
METABOLITE
+
ENZYME
ENZYME
SUBSTRATE
COMPLEX
::::~:>
ENZYME
INACTIVATION
SYNTHESIS
OF
NEW
ENZYME
Pharmacokinetic
Modeling
of
1,1,2­
ICE
for
Route­
to­
Route
Extrapolation
Under
the
HAPs
Test
Rule
Presented
by
Michael
L.
Gargas,
Ph.
D.
Managing
Principal
The
Sapphire
Group
August
13,
2002
Research
Triangle
Park,
NC
Outline
°
Overview
of
Pharmacokinetic
Studies
Conducted
°
Review
of
Results
°
Pharmacokinetics
of
1,1,2­
TOE
in
the
Female
Rat
°
Pharmacokinetics
of
1,1,2­
TOE
in
the
Female
Mouse
Comparison
of
dose
metrics
in
subchronic
studies
°
Next
Steps
a
1
Overview
of
Pharmacoki
netic
Studies
Conducted
°
Studies
conducted
to
facilitate
route­
toroute
extrapolation
(parameter
estimates,
periodicity,
validation)
°
Studies
conducted
in
female
rats
and
mice
°
Corn
oil
gavage
studies:
interpretation
and
extrapolation
of
cancer
bioassay
°
Aqueous
gavage
studies:
interpretation
and
extrapolation
of
existing
immunotoxicity
study
(by
drinking
water)
Inhalation
studies:
validate
route­
to­
route
extrapolation
of
pharmacokinetic
data
4
Model
Optimization
and
Validation
°
Vmax
and
absorption
rate
from
oil
determined
from
corn
oil
gavage
studies
°
KM
and
absorption
rate
from
water
determined
from
aqueous
gavage
studies
°
Metabolic
rate
constants
validated
against
inhalation
data
Pharmacokinetic
Studies
in
Rats:
Corn
Oil
Gavage
18
16
~Day1
—.—
Day3
14
2
—Model
~
10­

°94
mg/
kg/
day
°Single
significant
difference
between
days
1
and
3
Pharmacokinetic
Studies
in
Rats:
Aqueous
Gavage
0_
Do
008
.
Dey
1
D4y3
007
­
DeyS
0/
006
—­
Model
~o_
03i
.~

002
001
L.

0.0
0.2
04
0.6
06
10
Time
(hr)

1
.66
mg/
kg/
day
Pharmacokinetic
Studies
in
Rats:
Inhalation
10
1

01j
0.07
—­~.—
­
~~­­­­~
~—
0
I
2
2
4
5
5
7
8
9
TIme
(ho)

.100
ppm,
6
h/
d­­
week
4
°Minimal
differences
between
days
1,
3
and
5
°Vmax
and
Km
derived
from
oral
studies
(validation)

4
Pharmacokinetic
Studies
in
Rats:
Summary
°
Periodicity
achieved
°
Few
statistically
significant
differences
among
days
1
,3
and
5
°
Constants
optimized
°
Ka
(water)
=
5.07/
hr
°
Ka
(corn
oil)
=
0.887/
hr
°
VmaxC
=
20.7
mg/
hr­
kg°
7
°
KM
=
0.412
mg/
L
Model
validated
against
inhalation
data
Pharmacokinetic
Studies
in
Mice:
Corn
Oil
Gavage,
Simulations
­Without
Enzyme
Inhibition
700
lo(,~
I(

­~
Day1
­
.

DayS
­­
Day
I
model
­
­­
­­
­­
Dao­
s~
04od5o~
ode(
4
0_
Ui
­.­­­­—­­­—­­­~­­­~—­­—~
—~~—­­­~­—­~
00
70
20
TO
40
50
00
70
60
Tune(
hil
a
365
mg/
kg/
day
°
Day
1
blood
concentrations
significantly
lower
4
than
days
3
and
5,
after
0.5
hr
I
U
~
4
~­­
—
Pharmacokinetic
Studies
in
Mice:
Aqueous
Gavage
Day
1
To
a
DayD
­~_­­
iiI
t~"
1.
..

Ii
I
—­
Model
DI
i


0007
­­­­­­~­~­­
_______

DO
02
04
0_
h
06
TO
Time
(Or)

.9.7
mg/
kg/
day
`No
apparent
inhibition
&
.&
`Metabolic
parameters
derived
from
oral
studies
Pharmacokinetic
Studies
in
Mice:
Corn
Oil
Gavage
700
ID
E
102
A~
A~
24
48
72
Time
(hi)
06
°SuiCide
inhibition
included
`365
mg/
kg/
day
120
6
Light
line:
inhalation.
Dark
line:
gavage
Recovery
evident
over
exposure­
free
weekend
Pharmacokinetic
Studies
in
Mice:
Inhalation
20
40
T)
m~
0
(hr)

°100
ppm,
6
hrs/
day,
week
4
`Many
significant
differences
between
day
1
and
days
3
and
5
Pharmacokinetic
Studies
in
Mice:
Predicted
Changes
in
Vmax
7
L~
J
100.0
I
Ratios
of
Dose
Metrics
in
Female
vs.
Male
Mice:
Corn
Oil
Gavage
0
100
200
300
400
Daily
do~
ot
1,1,2­
ICE
via
corn
oil
gavage
(mglkg/
d)

If
similar
effects
are
found
in
male
and
female
mice
given
a
high
dose
by
corn
oil
gavage,
metabolism
is
likely
to
be
a
more
appropriate
dose
metric
than
parent
blood
concentration
Route­
to­
Route
Extrapolation
based
on
Amount
Metabolized
in
Mice
(1­
Week
Exposure)

0
100
200
300
400
Do~
in
drinking
water
(mglkg/
d)

If
amount
metabolism
is
the
relevant
dose
metric
the
difference
between
males
and
females
is
small,
even
at
higher
doses
8
Pharmacokinetics
in
Mice:
Summary
°
Periodicity
achieved
°
At
sufficient
doses,
metabolism
in
female
mice
is
believed
to
be
inhibited
by
enzyme
destruction
by
a
bound,
reactive
intermediate
°
Constants
optimized
°
Ka
(water)
4.4/
hr
°
Ka
(corn
oil)
=
0.18/
hr
°
VmaxC
=
16.8
mg/
hr­
kg°
7
°
KM
0.222
mg/
L
°
KDBI
(enzyme
inactivation
rate)
=

0.1034/
hr
Pharmacokinetics
in
Mice:
Summary
(cont'd)

°
Models
validated
against
inhalation
data
°
Example
provided
for
application
of
model
to
dose
metric
selection
°
Route­
to­
route
extrapolation
demonstrated
Sensitivity
analysis
indicates
that
data
sets
were
appropriate
for
the
parameters
to
be
optimized
U
9
Comparison
of
Subchronic
Studies
°
Subchronic
drinking
water
study
in
mice
(White
et
aL,
1985).
°
Females:
decreased
cytochrome
P­
450
at
44
mg/
kg/
d
°
Subchronic
inhalation
study
in
rats
(WIL
Research,
2002)
°
Hepatocellular
vacuolization
noted
Studies
are
hard
to
compare
because
species
and
endpoints
are
different
Comparison
of
Subchronic
Studies
AMNL
mgIL
AUCV
h­
mg/
L
Liver
effect
Female
rat
inhalation
15
ppm
28,145
165
3/
10
40
ppm
75,010
442
3/
10
(NOAEL)

100
ppm
186,875
1147
10/
10
Female
mouse
DW
3.9
mg/
kg
6621
1.54
NOEL
44
mg/
kg
72,747
21.3
NOAEL
(~
P450)
U
I
10
Comparison
of
Subchronic
Studies
°
Assuming
a
common
mode
of
action
in
rats
and
mice,
amount
metabolized/
liver
volume
(AM/
VL)
appears
to
be
more
appropriate
metric
°
Reasonable
consistency
of
dose
vs.
degree
of
response
is
found
between
the
studies
Next
SteDs:
Tier
II
activities
°
Route­
to­
route
extrapolation
of
existing
carcinogenicity
study
(NCI,
1978)
(3
months)
°
Route­
to­
route
extrapolation
of
existing
immunotoxicity
study
(Sanders
et
al.,
1
985)
(6
months)
°
Conduct
and
route­
to­
route
extrapolation
of
oral
acute
neurotoxicity,
subchronic
neurotoxicity,
developmental,
and
reproductive
toxicity
studies
(1
to
2.5
years)
.4_

I11
