Document ID: EPA-HQ-OPPT-2002-0056-0043
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-09-24T04:00Z

**
e
P.
O.
Box
331,
Millwood,
VA
22646
(540)
837­
1602
Task
Force
June
7,2002
Document
Control
Office
(7407)
Office
of
Pollution
Prevention
and
Toxics
Room
G­
099
c$

Environmental
Protection
Agency
401
M
Street,
S.
W.
Washington,
D.
C.
20460
Re:
Testing
Consent
Order
for
1,1,2­
Trichloroethane;
Final
Reports
of
Subchronic
Inhalation
Toxicity
and
Pharmacokinetic
Model
Development
Studies
Docket
No.
OPPTS­
42
198C)

Dear
Sirs:

Pursuant
to
Table
1
of
the
Enforceable
Consent
Agreement
for
1,1,2­
Trichloroethane,
the
HAP
Task
Force
submits
the
enclosed
final
reports:

­
"A
90­
Day
Inhalation
Study
of
1,1,2­
Trichloroethane
(I,
1,2­
TCE)
in
Rats
(With
Satellite
Groups
for
Pharmacokinetic
Evaluations
in
Rats
and
Mice)"
by
WTL
Research
Laboratories,
Inc.

"Physiologically
Based
Pharmacokinetic
Model
Develop
and
Sensitivity
Analysis
€or
Repeated
Exposure
to
1,1,2­
Trichloroethane''
by
The
Sapphire
Group
c
Six
copies
of
each
report
are
enclosed.
Please
do
not
hesitate
to
there
are
any
questions.

48828808839
Enclosures
C
.
Auer
(w/
out
enclosures)
R.
Leukroth
(w/
out
enclosures)
J.
Schaeffer
W.
C.
Norman,
Esq.
Manager
/

..
w
cr
..
,.
..(_
The
Sapphire
GroupTM
6
June
2002
Peter
E.
Voytek,
Ph.
D.
Manager,
HAP
Task
Force
P.
O.
Box
331
Millwood,
VA
22646
RE:
Report
on
Physiologically
Based
Pharmacokinetic
Modeling
of
1,1,2­
Trichloroethane
(1,1,2­
TCE)

Dear
Peter,

Please
find
attached
our
final
report
"Physiologically
Based
Pharmacokinetic
Model
Development,
Simulations,
and
Sensitivity
Analysis
for
Repeated
Exposure
to
1
,
1,2­
Trichloroethane."
This
report
is
intended
to
fulfill
the
HAP
Task
Force's
requirement
to
submit
a
report
on
the
development
and
validation
of
a
PBPK
mode
for
use
in
route­
to­
route
extrapolation
of
toxicity
studies
conducted
by
the
oral
route,
under
the
Enforceable
Consent
Agreement
(ECA).

Please
let
us
know
as
soon
as
possible
if
you
have
any
questions
concerning
this
report.

Sincerely
,

,.

*fp'

Michael
L.
Gargas,
Ph.
D.
Managing
Principal
Ref:
G:\
ProjectVFAPs­
TCE\
master\
reports\
pbpkreportcoverfinal.
wpd
FINAL
Physiologic
ally
Bas
ed
Pharmacokinetic
Mo
del
D
evelop
m
en
t
,
Simulations,
and
Sensitivity
Analysis
for
Repeated
Exposure
to
1,1,2­
Trichloroethane
Prepared
by
The
Sapphire
Group,
Dayton,
Ohio
Submitted
to
HAP
Task
Force,
Millwood,
Virginia
6
June
2002
FINAL
ABSTRACT
A
quantitative
understanding
of
the
inhalation
hazards
of
1
,
lY2­
trichloroethane
(1
,
lY2­
TCE)
is
desirable
for
assessing
risks
to
environmentally
or
occupationally
exposed
individuals.
The
objective
of
a
combination
of
experimental
studies
and
modeling
was
to
develop
a
model
that
would
allow
route­
to­
route
extrapolation
from
existing
and
future
data
on
hazards
of
oral
1
,
lY2­
TCE
exposure
to
assess
inhalation
hazards.

The
aims
of
the
pharmacokinetics
experiments
were
to
compare
time
courses
for
repeat
exposure
to
1
,
lY2­
TCE
and
provide
data
for
the
validation
of
physiologically­
based
pharmacokinetic
(PBPK)
models
to
describe
the
disposition
of
1
,
lY2­
TCE
in
female
rats
and
mice.
Female
rats
and
mice
were
exposed
to
100
ppm
1,1,2­
TCE
for
six
hours/
day,
five
days/
week
for
four
weeks,
with
blood
sampling
on
days
one,
three,
and
five
of
week
four.
Female
rats
and
mice
received
daily
doses
of
1
,
lY2­
TCE
by
gavage
(water
or
corn
oil
vehicle)
for
five
days,
with
blood
sampling
on
days
one,
three,
and
five.
Target
doses
for
mice
were
10
and
390
mgkg
in
water
and
corn
oil,
respectively,
and
1.7
mgkg
in
water
and
92
mgkg
in
corn
oil
for
rats.
These
target
doses
were
selected
based
on
doses
used
in
existing
toxicology
studies
for
which
PBPK
modeling
may
be
used
to
estimate
equivalent
inhalation
exposures.
A
lack
of
significant
differences
were
noted
between
day
three
and
day
five
blood
concentrations
of
1
,
lY2­
TCE
was
demonstrated
in
both
mice
and
rats
for
all
data
sets­
corn
oil
and
water
gavage
and
inhalation­
indicating
the
periodicity
was
achieved.
Additionally,
for
rats,
there
were
a
few
statistically
significant
differences
between
1
,
lY2­
TCE
blood
concentrations
on
day
one
and
concentrations
on
day
three
or
five,
but
the
actual
concentration
differences
were
generally
small
(factor
of
<2).
Therefore,
for
PBPK
modeling
analysis
of
the
rat
data,
all
three
days
(days
one,
three,
and
five)
were
combined.
Model
parameters
(maximum
biotransformation
rate,
enzyme
affinity,
and
absorption
rate
from
aqueous
or
corn
oil
vehicle)
were
determined
to
provide
adequate
fit
to
all
rat
data
sets
(inhalation,
aqueous
gavage,
and
corn
oil
gavage
on
days
one,
three,
and
five).

For
mice
exposed
to
1,1,2­
TCE
by
inhalation
or
corn
oil
gavage,
blood
concentrations
of
1,1,2­
TCE
were
significantly
higher
on
days
three
and
five
than
on
day
one.
The
model
structure
was
modified
to
incorporate
a
suicide
enzyme
inactivation
pathway.
The
modified
model
was
then
able
to
predict
peak
blood
concentrations
and
prolonged
elimination
time
on
days
three
and
five
(compared
to
day
one).
Examples
of
how
the'models
can
be
used
to
inform
the
selection
of
the
appropriate
dose
metric
and
to
conduct
a
route­
to­
route
extrapolation
are
provided,
demonstrating
the
utility
of
the
model
in
risk
assessment.

2
INTRODUCTION
1,1,2­
Trichloroethane
(1,1,2­
TCEY
CAS
No.
79­
00­
5)
is
used
as
an
intermediate
in
the
production
of
vinylidene
chloride,
as
a
solvent,
in
adhesives
and
lacquers,
and
in
the
production
of
Teflon@.
In
long­
term
carcinogenicity
studies,
1
,
1,2­
TCE
administered
by
gavage
resulted
in
hepatic
carcinomas
and
adrenal
gland
tumors
in
both
male
and
female
B6C3F1
mice.
No
incidences
of
neoplasms
were
detected
in
Osborne
Mendel
rats
administered
1
,
lY2­
TCE
by
corn
oil
gavage
(NTP,
1978).
Under
Section
4
of
the
Toxic
Substances
Control
Act
(TSCA),
the
U.
S.
EPA
issued
a
testing
consent
order
to
perform
toxicity
testing
and
mechanistic
and
pharmacokinetic
studies
to
satisfy
EPA's
dataneeds
for
1
,
1,2­
TCE
(U.
S.
EPA,
2000).
As
such,
a
need
has
been
identified
for
a
quantitative
understanding
of
the
hazards
of
1,1,2­
TCE
exposure
by
the
inhalation
route.
The
aims
of
the
pharmacokinetics
experiments
(Poet
et
al.,
2001)
were
to
compare
time
courses
for
repeat
exposure
to
1,
lY2­
TCE
and
provide
data
for
the
validation
of
physiologically­
based
pharmacokinetic
(PBPK)
models
to
describe
the
disposition
of
1
,
lY2­
TCE
in
female
rats
and
mice.
Examples
of
how
the
models
can
be
used
to
inform
the
selection
of
the
appropriate
dose
metric
and
to
conduct
a
route­
to­
route
extrapolation
demonstrate
their
utility
in
risk
assessment.

METHODS
Test
Materials
and
Chemicals.
1,1,2­
Trichloroethane
was
obtained
from
Dow
Chemical
Co.
(Midland,
MI).
Test
material
was
greater
than
99.5%
pure
as
reported
by
the
supplier.
All
other
compounds
and
solvents
were
reagent
grade
or
better.

TestAnimals.
Adult
(six
to
eight
week
old)
female
F344
rats
or
B6C3F1
~c
e
were
purchased
from
Charles
River
Laboratories,
Raleigh,
NC,
and
Portage,
MI,
by
Battelle
and
WIL
Research
Laboratories.
Deionized
water
(reverse
osmosis)
and
PMI
Nutrition
International,
Inc.
Certified
Rodent
Chow
#5002
(Purina
Mills,
Inc.,
St.
Louis,
MO)
were
provided
ad
libitum.
Female
animals
were
used
in
anticipation
of
reproductive
toxicity
studies
for
1
,
lY2­
TCE
that
may
be
conducted
by
the
oral
route
(U.
S.
EPA,
2000).
The
rooms
in
which
the
animals
were
housed
were
on
a
12­
hr
light
cycle
and
designed
to
maintain
adequate
temperatures,
relative
humidity,
and
airflows
for
the
species
under
study.
At
Battelle
(Poet
et
al.
,
200
l),
the
animals
were
housed
in
suspended
plastic
cages
with
chipped
bedding
and
acclimated
to
the
laboratory
for
at
least
five
days
prior
to
dosing
with
1
,
1,2­
TCE.
During
the
acclimation
period,
animals
were
uniquely
marked
with
a
tail
tattoo,
weighed,
and
randomly
assigned
to
subgroups
based
upon
targeted
sacrifice
times.
Animal
weights
were
recorded
on
each
day
of
exposure.
At
WIL
(WIL
Research
Laboratories,
2002),
animals
were
acclimated
for
at
least
16
days
and
individually
housed
in
clean,
wire
mesh
cages
suspended
above
cage
board.
During
acclimation,
rats
were
uniquely
identified
by
Monel@
metal
ear
tags,
and
mice
by
a
tail
tattoo.

3
FINAL,

Individual
body
weights
were
recorded
and
detailed
physical
examinations
were
performed
four
times
prior
to
initiation
of
exposure.

Inhalation
Study.
In
conjunction
with
a
subchronic
inhalation
study
(WIL
Research
Laboratories,
2002),
female
rats
and
mice
were
exposed
to
100
ppm
1,1,2­
TCE
by
inhalation
six
hrs/
day,
five
days/
week
for
three
weeks
before
blood
sampling
occurred.
During
week
four,
daily
exposures
continued
and
blood
samples
were
taken
during
and
after
exposures
on
days
one,
three,
and
five
of
that
week
(three
animals
per
species
per
time
point).
With
the
exception
of
blood
collection
days,
exposures
were
conducted
in
2
m3
stainless
steel
and
glass
whole­
body
exposure
chambers.
Chambers
were
operated
under
dynamic
conditions
fiom
a
HEPA
and
charcoal­
filtered
air
source.
Air
flow
rate
through
the
chamber
was
such
that
there
were
at
least
10
air
changes
per
hour.
Vapors
of
1,1,2­
TCE
were
generated
using
a
glass­
bead
vaporization
system,
consisting
of
a
glass
tube
filled
with
glass
beads,
heated
by
heating
tapes
operated
by
Omega
CN370
temperature
controls.
1,1,2­
TCE
vapor
was
mixed
with
chamber
ventilation
air
at
the
chamber
inlet.
On
blood
collection
days,
rats
in
the
pharmacokinetic
group
were
exposed
to
100
pprn
1,1,2­
TCE
in
a
500­
L
NYU­
type
whole­
body
chamber.
Rat
exposure
was
started
30
minutes
before
or
after
mouse
exposure
to
facilitate
prompt
blood
collection
from
both
rats
and
mice
at
designated
time
points.
.

Groups
of
three
female
F344
rats
or
three
female
B6C3F1
mice
per
sample
time
(36
animals/
species)
were
sacrificed
and
blood
collected
by
WIL
laboratories
at
target
times
of
four,
six,
6.25
and
eight
hrs
after
the
start
of
the
six­
hr
exposures
days
one,
three
and
five
of
the
4th
week
of
the
study.
The
lag
between
removing
animals
from
the
exposure
system
and
taking
blood
samples
was
carefully
noted,
so
that
it
could
be
incorporated
into
the
modeling.
On
day
one,
target
exposure
time
and
blood
sample
collection
were
all
delayed
one
hr
such
that
target
times
were
five,
seven,
7.25,
and
nine
hr.
Animals
were
anesthetized
as
quickly
as
possible
and
blood
was
collected
via
the
vena
cava
into
heparinized
syringes.
Aliquots
of
100
pl
of
blood
were
placed
in
headspace
vials
which
were
tightly
sealed
and
the
weight
of
the
blood
recorded.
After
weighing,
the
vials
were
placed
on
dry
ice.
Travel
and
storage
quality
control
spikes
containing
known
amounts
of
1,1,2­
TCE
in
each
sample
matrix
were
prepared
by
WIL
Research
Laboratories
to
be
included
in
the
analysis.
These
blood
samples
were
analyzed
at
Battelle's
Pacific
Northwest
Laboratory
(Richland,
WA),
where
the
remaining
pharmacokinetic
studies
(Poet
et
al.,
200
1)
were
conducted.

Gavage
Studies.
Study
Design.
A
total
of
four
gavage
studies
were
conducted
(Poet
et
al.,
200
1).
Group
1
mice
were
administered
1,1,2­
TCE
for
one
to
five
days
by
gavage
at
a
target
dose
of
390
mg/
kg/
day
in
corn
oil.
Group
2
mice
were
administered
1,1,2­
TCE
for
one
to
five
days
by
gavage
at
a
target
dose
of
9.5
mg/
kg/
day
in
water.
Group
1
rats
were
administered
1,1,2­
TCE
4
FINAL.

for
1
to
5
days
by
gavage
at
a
target
dose
of
92
mg/
kg/
day
in
corn
oil.
Group
2
rats
were
administered
1
,
172­
TCE
for
one
to
five
days
by
gavage
at
target
dose
of
1.7
mg/
kg/
day
in
water.
Two
extra
animals/
study
were
administered
1
,
172­
TCE
as
potential
replacements
in
the
event
that
any
problems
were
encountered
during
dosing
or
sacrifice.

Dose
Solutions
and
Administration.
Corn
oil
solutions
of
1
,
172­
TCE
were
prepared
late
on
the
Friday
before
administration
on
the
following
Monday,
and
stored
at
­8O'C.
Aliquots
of
dosing
solution
were
stored
for
concentration
check
analysis
by
gas
chromatography.
For
the
390
mg/
kg/
day
target
dose
(mice),
a
target
concentration
of
39
mg/
ml
was
prepared.
For
the
92
mg/
ml/
day
dose
(rats),
a
target
concentration
of
46
mg/
ml
was
prepared.
These
target
doses
were
chosen
to
match
the
highest
dose
administered
in
the
NTP
chronic
bioassay
(NTP,
1978).

Due
to
the
relatively
low
water
solubility
of
1
,
1
,2­
TCE,
water
target
concentrations
were
less
than
1
mg/
ml.
The
stated
water
solubility
for
1
,
172­
TCE
is
0.45%
(a
solubility
check
confirmed
this
as
the
maximum).
Repeated
checks
of
homogeneity
determined
that
1
mg/
d
was
the
maximum
concentration
of
1
,
1,2­
TCE
that
was
consistently
homogenous.

Samples
of
each
dose
solution
were
taken
for
analysis
on
the
day
of
dosing
to
confirm
targeted
concenbations.
Each
mouse
was
weighed
and
administered
dose
solutions
by
gavage
at
a
rate
of
­10
mlikg
body
weight
to
achieve
the
targeted
dose
levels.
Each
rat
was
weighed
and
administered
dose
solutions
by
gavage
at
a
rate
of
­2
mvkg
body
weight
to
achieve
the
target
dose
levels.
The
dosing
syringe
was
weighed
before
and
after
dosing
to
determine
the
actual
volume
delivered
to
each
animal.

Specimen
Collection.
Scheduled
sacrifice
times
were
0.5,
1,
2,
and
8
hr
for
the
corn
oil
gavage
studies
and
0.1,
0.25,
0.5,
and
1
hr
for
the
water
gavage
studies.
At
each
scheduled
sacrifice
time,
animals
were
anesthetized
in
an
80%
COz
atmosphere
and
blood
samples
were
collected
by
closed­
chest
cardiac
puncture.
To
avoid
volatilization
loss
of
1
,
1
,2­
TCEY
blood
samples
were
quickly
aliquoted
into
duplicate
samples
of
100
pl
each
into
headspace
vials
that
were
immediately
sealed.
The
headspace
vials
were
weighed
and
immediately
frozen
on
dry
ice.
In
some
cases
for
mice,
only
a
single
100
1­
11
sample
was
available.
Any
remaining
blood
was
placed
into
chilled
heparinized
VacutainersB
in
the
event
that
additional
sample
might
be
needed.
The
time
of
death
was
recorded
at
blood
draw
and
all
animals
were
rapidly
dissected
to
remove,
trim
extraneous
tissues,
and
weigh
the
kidneys,
spleen,
liver,
lung,
and
brain.
The
time
at
which
the
final
tissue
(brain)
was
removed
was
also
recorded.
The
tissues
were
flash­
frozen
and
stored
along
with
the
blood
samples
at
­80°
C.

Exhaled
Breath
Studies.
Groups
of
mice
were
exposed
to
constant
concentrations
of
1
,
1,2­
TCE
(250,
500,
or
1000
ppm)
for
four
to
six
hrs,
and
then
placed
in
an
off­
gassing
chamber
5
FINAL
and
1,1,2­
TCE
concentrations
were
measured
for
up
to
nine
hours
by
direct
sampling
of
the
chamber
air.
Of
the
five
mice
exposed
to
1000
ppm,
one
animal
died
approximately
four
hours
post
exposure,
and
the
surviving
animals
were
still
lethargic
or
unconscious
six
hours
post
exposure.
The
mice
exposed
to
500
ppm
also
experienced
notable
anesthesia.
No
overt
effects
were
observed
in
mice
exposed
to
250
ppm
1
lY2­
TCE
(Poet
et
al.,
2001).
Preliminary
modeling
indicated
that
the
250
ppm
exposure
may
also
have
had
subtle
effects
on
the
mice
(e.
g.,
reduced
alveolar
ventilation
rate),
so
these
data
were
not
used
in
modeling.

Blood
Analysis.
Samples
of
heparinized
whole
blood
were
analyzed
for
1,1,2­
TCE
by
headspace
gas
chromatography.
Chloroform
was
used
as
an
internal
standard.
Blood
was
collected
from
control
(untreated)
female
rats
or
mice
and
standard
curves
were
generated
in
a
blood
matrix.
The
standard
curve
was
linear
up
to
58.9
pg/
m1
and
the
limit
of
detection
was
0.01
pg/
ml.
Aliquots
of
each
blood
sample
(­
0.
lg)
were
added
to
a
20
ml
headspace
vial.
The
20
ml
headspace
vials
were
incubated
in
a
100°
C
oven
for
five
minutes
before
GC
analysis.

.
Analyses
were
performed
on
a
Hewlett
Packard
6890
Series
gas
chromatograph
equipped
with
an
electron
capture
detector
(GC­
ECD).
Separations
were
achieved
with
a
J&
W
(cat.#
125­
1334)
DB­
624
fused
silica
capillary
column
(30
m
x
0.53
mmid,
3
pm
film
thickness;
J&
W,
Folsom,
CA).
Injections
were
splitless
using
a
4
mmid
Carbo­
Frit
liner.

Statistical
Analysis
of
Pharmacokinetic
Data
for
Repeat
Exposures.
For
each
data
set
(corn
oil
gavage,
drinking
water
gavage,
and
inhalation
by
both
mice
and
rats)
at
each
time
point,
the
blood
concentrations
on
days
one,
three,
and
five
were
compared
using
the
two­
tail,
two
sample
t­
test
(assuming
unequal
variances).
When
significant
differences
were
found
between
day
one
blood
concentrations
and
day
three
or
five
blood
concentrations,
the
data
were
reviewed,
and
a
decision
was
made
as
to
whether
the
differences
were
large
enough
to
warrant
analysis
of
subsets
of
the
data
(i.
e.
,
day
one
alone
vs.
combined
data
from
days
three
and
five)
using
PBPK
modeling,
Blood
concentrations
on
days
3
and
5
were
compared
using
two­
factor
analysis
of
variance
(ANOVA)
(alpha
=
0.05)
to
test
for
periodicity.

Partition
coefficient
determination.
Liquid:
air
and
tissue:
air
partition
coefficients
were
determined
for
mouse
blood
and
rat
brain
and
spleen
using
the
vial
equilibration
technique
of
Gargas
et
al.
(1989)
at
Battelle's
Pacific
Northwest
Laboratory
(Poet
et
al.,
2001).
Tissues
were
obtained
from
five
individual
rats
and
six
individual
mice,
and
blood
was
pooled
from
four
additional
mice.
Tissues
collected
from
the
rats
were
rinsed
in
phosphate
buffered
saline
(PBS),
and
homogenized
in
3
x
v/
w
PBS.
Blood
was
collected
in
heparinized
syringes.
Tissue
homogenate
(1
rnl)
was
incubated
with
shaking
for
one
hr
and
the
headspace
sampled
for
1
1,2­
TCE.
Due
to
the
low
volume
of
mouse
blood
obtained,
0.5
ml
of
whole
blood
was
incubated
for
one
hr.
Headspace
1
,
lY2­
TCE
concentrations
were
compared
to
vials
containing
1
lY2­
TCE
6
vapor
only
for
blood
or
vials
containing
0.75
ml
saline
for
the
tissues.
A
pilot
study
with
rat
blood
was
used
to
veri@
that
one
hr
incubations
with
0.5
ml
of
blood
were
sufficient
to
reach
steady
state.

PBPKModeZing
ofl,
l,
2­
TCE
disposition.
The
model
structure
(Figure
1)
was
selected
based
on
the
current
understanding
of
the
disposition,
mode
of
action,
and
endpoints
of
interest
for
1,1,2­
TCE.
Physiological
parameters
for
rats
and
mice
(e.
g.,
tissue
weights,
blood
flows,
and
alveolar
ventilation)
were
generally
taken
from
Brown
et
al.
(1
997)
and
are
listed
in
Table
1.
B1ood:
air
and
tissue:
blood
partition
coefficients
were
taken
from
the
literature
(Gargas
et
al.
,
1989)
or
measured
at
Battelle's
Pacific
Northwest
Laboratory
(Poet
et
al.,
2001)
and
are
listed
in
Table
2.
Kinetic
parameters
for
the
metabolism
of
lY1,2­
TCE
(Table
3)
were
determined
via
PBPK
modeling
as
a
part
of
this
effort.
Starting
values
for
VmaxC
and
Km,
optimized
for
male
F344
rats,
(7.7
mgA~­
kg'.~
and
0.75
mgL)
were
taken
from
Gargas
and
Andersen,
1989)
and
1
.O
h
was
selected
as
an
initial
value
for
the
absorption
rate
from
corn
oil,
based
on
the
rate
used
by
Clewell
et
al.
(2000)
to
model
the
disposition
of
trichloroethylene.
PBPK
model
simulations
were
conducted
using
ACSL
Sim
1
1.8
and
ACSL
Optimize
2.5.4
(AEgis
Technologies,
Inc.,
Austin,
TX)
on
a
Dell
Inspiron
7500
computer.
Model
equations
(in
standard
mathematical
form)
are
provided
in
Appendix
A;
and
ACSL
model
code
is
provided
in
Appendix
B.
Optimizations
were
performed
by
using
the
visual
best
fit
to
provide
starting
values
for
ACSL
Optimize.
ACSL
Optimize
determines
best
fit
parameters
through
maximization
of
the
Log
Likelihood
Function
(LLF),
selecting
possible
parameter
values
using
either
the
Generalized
Reduced
Gradient
(GRG)
or
the
Nelder­
Mead
Simplex
method
(MGA,
1997).

The
initial
model
description
did
not
adequately
describe
the
pharmacokinetics
of
1,
l72­
TCE
in
female
mice
that
had
been
exposed
to
1
,
lY2­
TCE
earlier
in
the
week.
Because
of
an
earlier
report
in
the
literature
that
subchronic
exposure
to
1
,
1,2­
TCE
decreases
total
cytochrome
P­
450
content
and
cytochrome
P­
450
2E1
activity
in
female
(but
not
male)
mice
(White
et
al.,
1985),
we
hypothesized
a
suicide
inhibition
mechanism
for
the
decrease
in
Vmax
in
female
mice
during
inhalation
and
corn
oil
gavage
studies.
Four
possible
inhibition
mechanisms,
as
described
by
Lilly
et
al.
(1998),
were
incorporated
into
the
model
for
hypothesis
testing.
The
mechanisms
demonstrate
inhibition
may
occur
because
(
1)
reactive
intermediate
reacts
with
the
enzyme­
substrate
complex,
(2)
reactive
intermediate
reacts
with
total
enzyme
present
,
(3)
reactive
metabolite
reacts
with
free
enzyme,
or
(4)
bound
intermediate
inactivates
enzyme
through
a
first
order
process.

For
modeling
of
male
mice,
it
was
assumed
that
the
oral
absorption
rate
(Ka),
Km,
and
the
baseline
value
of
Vmax
were
the
same
as
for
female
mice,
but
that
there
was
no
inactivation
of
cytochrome
P450,
as
indicated
in
White
et
al.
(1985).

7
Sensitivity
Analysis
of
PBPK
Model.
Sensitivity
analysis
was
conducted
by
increasing
a
parameter
value
by
1%
and
noting
the
change
in
the
model
predictions
of
interest
(peak
blood
concentration,
area
under
the
blood
concentration
vs.
time
curve,
and
total
1,1,2­
TCE
metabolized
divided
by
liver
volume).
The
fractional
increase
in
the
prediction
divided
by
the
fractional
increase
in
the
parameter
was
defined
as
the
normalized
sensitivity
coefficient.

Sensitivity
analyses
were
conducted
for
the
scenarios
used
in
the
pharmacokinetic
studies.
That
is,
five
days
of
exposure
(gavage
or
six
hrs
inhalation)
followed
by
two
days
unexposed
at
the
target
doses
and
concentrations
for
the
studies.
Sensitivity
analyses
were
conducted
using
the
optimized
parameters
for
female
rats
and
mice.

Application
of
the
Model.
To
demonstrate
a
potential
use
of
the
model
in
selecting
an
appropriate
dose
metric
for
extrapolation
of
a
toxicity
study,
a
case
study
was
performed.
The
model
was
used
to
calculate
three
potentially
relevant
dose
metrics
(same
endpoints
used
for
sensitivity
analysis)
in
both
female
mice
and
male
mice
administered
1
,
1,2­
TCE
corn
oil
by
gavage
five
consecutive
days,
and
dose
metric
predictions
for
the
two
sexes
were
compared.

Another
potential
application
of
the
model
is
extrapolation
of
a
drinking
water
study
to
exposure
by
the
inhalation
route.
Total
amount
metabolized
by
male
and
female
was
calculated
for
a
scenario
where
the
mice
ingested
the
water
as
six
boluses,
occurring
at
7
a.
m.
(23.3
%
of
total
dose),
11
a.
m.
(10
%),
3
p.
m.
(10
%),
7
p.
m.
(10
%),
11
p.
m.
(23.3
%),
and
3
a.
m.
(23.4
%).
This
scenario,
developed
by
Reitz
et
al.
(1997)
reflects
the
discontinuous
nature
of
drinking
water
ingestion
and
the
nocturnal
nature
of
rodents..

RESULTS
Statistical
Analysis
of
Pharmacokinetic
Data
for
Repeat
Exposures
Results
of
the
statistical
analysis
are
summarized
below,
and
are
also
presented
graphically
along
with
PBPK
model
predictions
(Figures
2­
7).

Pharmacokinetics
of
I
,
I,
2­
TCE
in
Rats
For
rats
exposed
to
100
ppm
1,1,2­
TCE
by
inhalation,
the
"four­
hour''
time
point
is
similar
to
a
post­
exposure
time
point
because
the
exposure
system
required
animals
to
be
removed
from
the
inhalation
chamber
before
blood
collection.
There
were
no
statistically
significant
differences
between
day
three
and
day
five
concentrations
(two­
factor
ANOVA
p
>
0.05
for
day
3
vs.
day
5
),
indicating
that
periodicity
was
achieved
in
the
inhalation
study
(Figure
2).
Blood
concentrations
during
exposure
were
higher
on
day
one
than
on
days
three
and
five,
and
the
differences
were
generally
statistically
significant,
but
the
average
concentrations
differed
by
no
more
than
50
percent
(e.
g.,
1,1,2­
TCE
blood
concentrations
of
2.3
on
day
1
vs.
1.6
on
8
FINAL/

day
5
at
the
end
of
exposure).
Also,
the
blood
concentrations
in
the
inhalation
exposures
were
I
lower
than
those
observed
in
the
corn
oil
gavage
(94.2
mgkg)
experiments
where
a
single
statistically
significant
difference
was
found
(blood
concentration
at
t
=
2
hours
on
day
one
vs.
day
three)
(Figure
3).
Thus
it
was
considered
unnecessary
to
divide
the
rat
inhalation
data
into
subsets
for
day
one
vs.
days
three
and
five
for
modeling
purposes.
No
statistically
significant
differences
(p<
0.05)
among
the
blood
concentrations
of
1,
l72­
TCE
measured
on
days
one,
three,
and
five
were
found
for
rats
given
1.66
mg
1
,
172­
TCEkg
by
gavage
in
water
(Figure
4).
These
results
indicate
that
periodicity
was
achieved
in
the
gavage
studies.

Pharmacokinetics
of
I
,
I,
2­
TCE
in
Female
Mice
For
female
mice
exposed
to
100
ppm
1
,
172­
TCE
by
inhalation,
a
single
statistically
significant
difference
was
found
among
the
blood
concentrations
of
1
,
1,2­
TCE
measured
on
days
three
and
five
(blood
concentration
at
t
=
8
hours)
(Figure
5).
Since
the
difference
does
not
affect
the
key
features
of
the
kinetic
profile
(the
steady­
state
concentration
and
the
completeness
of
elimination
on
a
single
day)
and
ANOVA
indicated
no
significant
overall
difference
between
days
3
and
5
(p
>
0.05),
we
interpret
this
data
as
demonstrating
that
the
kinetics
are
essentially
the
same
on
days
three
and
five,
and
periodicity
was
achieved.
Blood
concentrations
during
exposure
were
lower
on
day
one
than
on
days
three
and
five.
The
differences
were
generally
statistically
significant
and
difference
are
up
to
three­
fold.
The
blood
concentrations
in
the
inhalation
exposures
were
lower
than
those
observed
in
the
corn
oil
gavage
experiments
where
dramatic
differences
in
blood
concentrations
for
day
one
vs.
days
three
and
five
were
observed.
We
hypothesized
a
change
in
metabolism
of
inhaled
1,
ly2­
TCE
that
was
qualitatively
similar
to
(but
quantitatively
less
than)
that
observed
in
female
mice
treated
by
corn
oil
gavage
where
higher
blood
concentrations
of
1,1,2­
TCE
were
attained
on
all
sampling
days,
as
compared
to
the
inhalation
exposures.

For
corn
oil
gavage
dosing
(­
355
mgkg),
a
single
statistically
significant
difference
was
found
among
the
blood
concentrations
of
lY1,2­
TCE
measured
on
days
three
and
five
(blood
concentration
at
t
=
2
hours)
in
female
mice
(Figure
6).
The
absolute
difference
was
small
(19.11
mg/
L
on
day
three
vs.
23.5
on
day
five)
and
ANOVA
indicated
no
significant
overall
difference
between
days
3
and
5
(p
>
0.05)
,
so
it
is
our
interpretation
that
differences
between
days
three
and
five
were
minor
in
this
study,
and
periodicity
was
achieved.
Blood
concentrations
in
mice
on
day
one,
however,
are
significantly
lower
than
those
on
days
three
and
five,
including
a
60­
fold
difference
in
the
t
=
8
hr
time
point
between
days
one
and
five.
Clearly,
these
blood
concentrations
represent
a
change
in
the
disposition
of
1
,
1,2­
TCE
in
mice
that
needed
to
be
considered
in
the
PBPK
modeling
analysis.

9
FINAL
No
statistically
significant
differences
among
the
blood
concentrations
of
1
,
lY2­
TCE
measured
on
days
three
and
five
were
found
for
mice
given
9.7
mg
1
,
lY2­
TCE/
kg
by
gavage
in
water
(Figure
7).
Significantly
lower
concentrations
on
day
one
compared
to
days
three
and
five
were
found
for
the
intermediate
time
points
(t
=
0.25
and
t
=
0.5
hr).
Since
the
differences
do
not
affect
the
key
features
of
the
elimination
profile
(the
peak
concentration
and
the
completeness
of
elimination
on
a
single
day),
we
elected
to
combine
the
data
of
all
three
days
for
PBPK
modeling.

PBPK
Modeling
of
191,2­
TCE
Disposition
in
Rats
and
Mice
Figures
2,3,
and
4
show
experimental
data
(Poet
et
al.,
200
1)
and
model
predictions
of
1
,
1,2­
TCE
concentrations
in
the
blood
of
female
F344
rats
exposed
to
1,1,2­
TCE
by
inhalation
(Figure
2)
and
gavage
(Figures
3
and
4).
VmaxC
and
KM
for
rats
were
determined
by
optimization
(Table
3)
of
the
fit
to
the
mean
blood
concentrations
in
the
inhalation
exposure,
averaged
across
the
three
days
on
which
concentrations
were
measured.
It
should
be
noted
that
blood
concentrations
decrease
rapidly
upon
removal
from
the
exposure
tower
(Figure
2).
The
interval
between
cessation
of
exposure
and
blood
sampling
is
included
in
the
modeling.
For
the
corn
oil
gavage
study
(Figure
3),
the
model
predicts
that
the
peak
blood
concentration
is
reached
22
minutes
after
dosing,
then
declines
rapidly
until
about
two
hours
after
dosing,
after
which
the
elimination
slows.
Modeling
of
the
water
gavage
study
(Figure
4)
suggests
that
maximum
blood
concentrations
are
rapidly
achieved
(approximately
five
minutes
after
dosing).
KA
for
absorption
of
1
,
lY2­
TCE
from
corn
oil
and
water
were
determined
by
optimization
of
the
fit
to
mean
blood
concentrations
measured
in
these
studies,
with
VmaxC
and
KM
fixed
at
the
values
determined
from
the
inhalation
study
(Table
3).

Figures
5
,6
,
and
7
show
experimental
data
(Poet
et
al.,
2001)
and
model
predictions
of
1,1,2­
TCE
concentrations
in
the
blood
of
female
B6C3F1
mice
exposed
to
1,
ly2­
TCE
by
inhalation
(Figure
5)
and
gavage
(Figures
6
and
7).
It
should
be
noted
that,
as
in
rats,
blood
concentrations
decrease
rapidly
upon
removal
from
the
exposure
tower
(Figure
5).
The
preliminary
model,
with
constant
Vmax,
was
not
adequate
to
fit
the
data,
and
was
modified
to
incorporate
possible
mechanisms
for
suicide
inhibition,
as
described
under
"Methods".
The
model
fit
to
the
corn
oil
data
was
optimized
to
all
four
possible
mechanisms,
and
allowing
VmaxC
and
KA
to
vary
as
well.
KM
was
not
varied
in
this
optimization
because
of
the
relative
insensitivity
of
these
model
predictions
to
the
value
of
KM,
as
blood
concentrations
were
well
above
the
anticipated
KM.
The
model
was
fit
to
the
measured
mean
blood
concentrations
and
to
cumulative
blood
AUC
estimated
by
the
trapezoidal
rule,
assuming
the
Day
two
AUC
was
the
average
of
Day
one
and
three
AUCs
and
the
Day
four
AUC
was
the
average
of
the
Day
three
and
five
AUCs.
The
inhibition
by
enzymatic
inactivation
through
binding
of
reactive
intermediate
to
enzyme
was
the
mechanism
found
to
provide
the
best
fit.
Model
predictions
10
FINAL
for
the
corn
oil
gavage
study
with
the
optimized
values
for
mechanism
BI
are
shown
with
the
experimental
data
in
Figure
6.
KA
for
absorption
from
water
and
KM
were
then
determined
by
optimization
of
the
fit
to
the
mean
blood
concentrations
measured
in
the
drinking
water
(Figure
6).
Parameter
optimization
from
the
corn
oil
gavage
study
was
repeated
using
the
KM
determined
from
the
drinking
water
study,
and
optimal
parameter
values
changed
by
less
than
one
percent.
Using
the
values
of
VmaxC
and
KM
determined
from
optimization
of
corn
oil
gavage
and
water
gavage
data,
blood
concentrations
during
and
after
inhalation
exposure
(1
00
ppm)
were
predicted
by
the
model,
and
compared
well
to
the
measured
experimental
data
with
no
further
parameter
adjustment
(Figure
5).

Model
predictions
of
the
changing
value
of
Vmax
in
female
mice
during
the
inhalation
and
gavage
exposures
are
shown
in
Figures
8
and
9,
respectively.
Both
figures
suggest
that
recovery
of
metabolic
capacity
over
two
exposure­
free
days
would
be
nearly
complete.

Sensitivity
Analysis
of
the
PEPK
Model
Predictions
Sensitivity
analyses
were
conducted
to
identify
parameters
that
determined
the
fit
of
the
model
to
the
experimental
data
(blood
concentrations,
as
AUC
or
peak
concentration),
and
the
sensitivity
of
an
additional
dose
metric
of
interest,
the
amount
of
1,
ly2­
TCE
metabolized
per
kg
of
liver,
during
one
week
of
five
days
of
repeated
exposure
followed
by
two
days
unexposed.
Results
of
sensitivity
analyses
of
the
female
mouse
and
female
rat
models
are
presented
in
Figures
10
and
1
1.
Parameters
were
included
on
the
figure
only
if
the
absolute
value
of
the
normalized
sensitivity
coefficient
(SC)
was
greater
than
0.1
for
at
least
one
dose
metric,
for
that
exposure
scenario.
SC
are
not
presented
for
total
metabolized
for
gavage
in
water
for
mice
or
rats,
because
predictions
were
sensitive
to
only
two
parameters,
dose
(in
mgkg),
with
a
normalized
SC
of
one,
and
fractional
volume
of
weight
as
liver,
with
a
normalized
SC
of
­
0.99
for
both
rats
and
mice.
Similarly,
the
predicted
amount
metabolized
in
rats
administered
1,1,2­
TCE
in
corn
oil
(92
mg/
kg/
d)
was
sensitive
only
to
dose
(SC
=
0.90),
liver
volume
(­
0.99),
and
slightly
sensitive
to
VmaxC
(0.1
1).
In
general,
the
amount
metabolizedkg
liver
was
determined
by
the
amount
to
which
the
animal
was
exposed
and
physiological
parameters,
rather
than
metabolic
rate
constants.
The
blood
concentrations,
however,
are
sensitive
to
the
metabolic
rate
constants
and
oral
absorption
rate
constants,
indicating
the
estimation
procedure
is
valid
for
determining
the
values
of
these
particular
parameters.

Application
of
the
PEPK
Model
Two
applications
of
the
PBPK
model
that
are
potentially
relevant
to
risk
assessment
are
(1)
selection
of
the
most
appropriate
dose
metric
and
(2)
determination
of
an
inhalation
exposure
11
FINAL
concentration
that
is
equivalent
(in
terms
of
an
internal
dose
metric)
to
an
oral
dose
used
in
toxicity
testing
(e.
g.,
NOAEL
or
LOAEL).

Figure
12
shows
how
three
measures
of
internal
dose
are
expected
to
differ
between
female
and
male
mice
exposed
to
daily
doses
of
1,1,2­
TCE
by
corn
oil
gavage,
based
on
PBPK
modeling
simulations.
If,
in
toxicity
testing,
no
significant
differences
in
susceptibility
were
noted
in
male
vs.
female
mice
dosed
with
150­
400
mg
l71,2­
TCE/
kg­
day
in
corn
oil,
one
would
deduce
that
the
effects
are
more
likely
to
be
mediated
by
total
metabolite
production
rather
than
peak
blood
concentration
or
blood
AUC
for
1
,
1,2­
TCE.
Total
metabolism
in
males
and
females
is
predicted
to
be
similar,
despite
a
slower
elimination
of
1
,
lY2­
TCE
in
female
mice.

The
potential
use
of
the
model
in
route­
to­
route
extrapolation
is
demonstrated
in
Figure
13.
For
various
daily
doses
in
mice
exposed
to
1,1,2­
TCE
in
drinking
water
(consumed
in
six
boluses
throughout
the
day
and
night,
as
described
under
"Methods"),
the
amount
metabolized
over
a
one
week
period
was
computed
using
PBPK
modeling.
Assuming
continuous
(24­
hour/
day)
exposure
for
one
week,
inhalation
exposures
resulting
in
the
same
amount
of
total
metabolism
were
determined.
As
depicted
in
Figure
13,
for
drinking
water
exposures
under
­120
mgkg­
d,
equivalent
continuous
inhalation
exposures
are
predicted
to
be
the
same
in
male
and
female
mice.
For
exposure
to
390
mg/
kg/
d,
the
equivalent
exposure
for
a
male
mouse
is
expected
to
be
54
ppm,
as
compared
to
42
for
a
female
mouse.
For
regulatory
purposes,
if
effects
are
similar
in
male
and
female
rats,
an
equivalent
inhalation
exposure
of
42
ppm
would
be
selected,
in
the
interest
of
health
protection.

DISCUSSION
The
pharmacokinetic
data
for
female
F344
rats
repeatedly
exposed
to
100
ppm
1
,
1,2­
TCE
by
inhalation,
94
mgkg/
d
in
corn
oil,
and
1.7
mg/
kg/
d
in
water
are
consistent
on
days
one,
three,
and
five.
The
current
data
suggest
a
higher
capacity
(roughly
three­
times
higher)
and
lower
affinity
(approximately
50
percent
lower)
for
saturable
metabolism
than
previous
work
with
male
F344
rats
(Gargas
and
Andersen,
1989).
The
exhaled
breath
methods
used
in
Gargas
and
Andersen
(1
989)
generally
provide
an
upper
bound
on
KM
estimation,
so
a
two­
fold
difference
in
Km
estimates
may
be
attributed
to
greater
sensitivity
of
the
current
experimental
design
to
the
value
of
KM.
Discrepancies
in
Vmax
may
be
due
to
gender
differences
or
the
>10
years
separation
in
the
studies.
The
model
is
considered
complete
and
validated
for
male
and
female
rats
for
inhalation,
water
ingestion,
and
corn
oil
gavage.

In
both
the
inhalation
(1
00
ppm
for
6
hours)
and
corn
oil
gavage
(3
66
mg/
kg/
day)
studies
in
B6C3F
1
mice,
higher
blood
concentrations
of
1
,
1,2­
TCE
were
observed
on
days
three
and
five,

12
FINAL
compared
to
day
one.
The
day
three
and
five
concentrations
in
these
studies
were
similar.
It
should
be
noted
that
the
inhalation
study
was
conducted
after
the
mice
had
already
been
exposed
for
three
weeks
(five
daydweek),
suggesting
that
there
may
be
recovery
over
the
two­
day
unexposed
period,
a
theory
supported
by
the
model
predictions
of
Vmax,
which
showed
this
recovery
is
likely.
Hepatic
aniline
hydroxylase
activity,
a
marker
for
P450
2E1
activity,
and
cytochrome
P450
content
showed
dose­
dependent
decreases
in
female
(but
not
male)
CD­
1
mice
consuming
44
or
384
mgkg/
d
1
,1,2­
TCE
in
drinking
water
for
90
days
(White
et
al.,
1985).
Cytochrome
P­
450
2E1
has
been
implicated
as
the
primary
isozyme
responsible
for
the
metabolism
of
many
low
molecular
weight
hydrocarbons
and
halogenated
hydrocarbons
(Nakajima,
1997).
At
the
higher
dose,
aniline
hydroxylase
activity
was
approximately
50
percent
of
that
in
control
mice
(White
et
al.,
1985).
Our
preliminary
modeling
indicates
that
at
approximately
the
same
daily
dose
(366
mg/
kg/
d)
in
corn
oil
female
B6C3F1
mice
show
a
slightly
greater
decrease
in
cytochrome
P450­
mediated
metabolism
(Vmax
­33%
of
initial
value
after
3­
5
days
of
dosing).

The
"day
1
'I
pharmacokinetics
of
1
,
lY2­
TCE
in
female
mice
exposed
via
inhalation,
corn
oil
gavage
and
water
gavage
can
all
be
described
by
the
PBPK
model.
The
fact
that
the
inhalation
data
for
exposure
day
one
of
week
four
are
consistent
with
the
pharmacokinetics
in
mice
in
the
gavage
studies
with
no
previous
1
,
lY2­
TCE
exposure
indicates
that,
at
this
level
of
1
,
lY2­
TCE
exposure,
the
metabolic
capacity
of
the
mice
can
recover
over
the
exposure­
free
weekend.
At
the
doses
that
can
be
achieved
with
gavage
in
a
water
vehicle,
there
are
no
evident
effects
of
previous
exposure
on
disposition
of
subsequent
doses
of
1
,
lY2­
TCE.
Because
of
apparently
slower
elimination,
the
data
for
days
three
and
five
of
the
corn
oil
gavage
studies
do
not
provide
very
much
information
on
the
elimination
phase
(i.
e.
,
the
0.5,
one,
and
two­
hour
values
are
essentially
the
same,
so
only
the
eight­
hr
point
describes
the
elimination
phase),
but
the
model
does
describe
the
eight­
hr
corn
oil
gavage
time
point,
and
describes
the
post­
exposure
inhalation
data
and
water
gavage
data
at
lower
blood
concentrations
of
1,1,2­
TCE.

The
impact
of
the
apparent
difference
in
CYP
2El­
mediated
metabolism
in
male
vs.
female
mice
on
route­
to­
route
extrapolation
is
pertinent
to
the
selection
of
the
critical
dose
measure.
Most
1,1,2­
TCE
is
eliminated
by
metabolism
(8
%
of
a
100­
200
mgkg
ip
dose
to
female
albino
mice
was
eliminated
as
1,1,2­
TCE
in
exhaled
breath,
Yllner
et
al.,
1971),
so
the
decrease
in
Vmax,
while
it
leaves
1,
ly2­
TCE
concentrations
elevated
for
a
greater
period
of
time,
does
not
significantly
impact
the
total
amount
of
orally
administered
1,
ly2­
TCE
that
mice
metabolized
over
a
24­
hour
period.
Thus
female
and
male
mice
will
have
roughly
equivalent
total
metabolism,
but
female
mice
will
have
a
greater
average
internal
exposure
to
1
,
1,2­
TCE
at
higher
doses
(blood
or
tissue
AUC).
As
demonstrated
in
Figure
12,
the
gender
differences
in
mice,
or
lack
there
of,
as
well
as
other
available
data
on­
mode
of
action,
should
13
FINAL
be
employed
in
the
selection
of
dose
metrics
for
extrapolation
of
toxicity
results
for
1,1,2­
TCE.

Male­
female
differences
in
mice
may
also
impact
the
determination
of
an
inhalation
exposure
equivalent
to
an
oral
exposure
used
in
a
toxicity
test.
However,
as
seen
in
the
water
gavage
results
(Figure
7)
and
route­
to­
route
exposure
example
for
total
amount
metabolized
(Figure
13),
these
differences
disappear
at
lower
doses.

In
conclusion,
data
collected
during
repeated
exposure
ofrats
andmice
to
1,1,2­
TCE
have
been
used
to
develop
PBPK
to
describe
disposition
by
inhalation
and
oral
exposure.
These
models
can
be
used
to
reduce
animal
experimentation
by
eliminating
the
need
for
toxicity
testing
by
both
oral
and
inhalation
routes
of
exposure
and
to
improve
risk
assessments
by
aiding
in
the
selection
of
the
most
appropriate
internal
dose
metrics.

14
APPENDIX
A
MODEL
EQUATIONS
Model
equations
presented
below
are
consistent
with
the
abbreviations
defined
in
Tables
1
­
3.

Alveolar
ventilation
QP
=
QPC
x
BW0.70
(Lhr)

Cardiac
output
QC
=
QCC
x
BW0.70
(LAW)

Tissue
blood
flows
QJ
=
QiC
x
QC
(LAX)
where
j=
L
(liver),
F
(fat),
S
(slowly
perfused
tissue),
SN
(spleen),
BR
(brain)
QR
=
QC
­
(QL
+
QF
+
QS
+
QBR
+
QSN)
(Lh)
(mass
balance
used
to
calculate
flow
to
richly
perfised
tissues
(R))

Tissue
volumes
Vj
=
VjC
x
BW
(L)
where
j
=
same
tissues
as
for
blood
flows.

Maximal
oxidative
metabolism
VMAX
=
VMAXC
x
BW7
(mgh)

Tissue:
blood
partition
coefficients
Pj
=
PjARB,
where
j
=
same
tissues
as
listed
for
blood
flows.

CI
=
inhaled
concentration
CI
=
CONC
x
MW/
24450
or
0
(mg/
L).

CA
=
Concentration
in
arterial
blood
(mg/
l)
'
CA
=
(QC
x
CV
+
QP
x
CI)/(
QC
+
(QP/
PB))
(mg/
L)

Aj
=
Amount
in
non­
metabolizing
tissue
"j"
(all
tissues
except.
1iver)
d
Aj/
dt
=
QJ
x
(CA
­
Cj)
(mg/
hr)
CVj
=Aj/(
Vj
x
Pj)
(mgk)
Cj
=
Aj/
Vj
(mg/
L)

VMT
=
time­
dependent
maximal
capacity
of
metabolism,
initial
value
of
VMax
15
FINAL
d
VMT/
dt
=
(VMAX
­
VMT)
x
KDET
­
KDBI
X
RAM
Rate
of
oxidative
metabolism
RAM
=
(VMT
x
CVL)/(
KM
+
CVL)
(rngh)

Amount
metabolized
(mg)

AM
=
SRAM
dt
(mg)

Amount
in
stomach
(AS
)
and
amount
absorbed
from
the
stomach
(AAS)
Total
Dose
=
Daily
Dose
x
BW
x
number
of
doses
administered
(mg)
AS
=
Total
Dose
­
AAS
(mg)
d
AAS/
dt
=
KA
x
AS
Liver
mass
balance,
and
venous
blood
and
tissue
concentrations
d
AL/
dt
=
QL
x
(CA­
CVL)
­
RAM
+
KA
x
AS
(mghr)

CL
=
ALNL
(mg/
L)
CVL
=
AL/(
VL*
PL)
(mg/
L)

Mixed
venous
blood
concentration
CV
=
(QF
x
CVF
+
QL
x
CVL
+
QS
x
CVS
+
QR
x
CVR+
QBR
x
CVBR+
QSN
x
CVSN)/
QC
(mg/
L)

16
FINAL
APPENDIX
B
ACSL
MODEL
CODE
exhsir.
crnd
SET
TITLE
=
'EXHALED
BREATH
MODEL'

PREPAR
T,
CCH,
CV,
PPMOUT,
AUCV,
DM1
SET
TJNITG
=
1.0
$'Threshold
for
Jacobian
Error
Messages'
SET
TSMITG
=
.T.
$'Two
sided
matrix
evaluation
for
increased
accur.
'

SET
NSTP
=
1000
SET
WESItG=.
F.
$'Allow
the
integrator
to
take
very
small
steps'

PROCED
CCL2CCL
$'1,1,2­
TRICHLOROETHA"
SET
TCHNG=
G.,
TSTOP=
8.,
N=
5
SET
MW=
133.41
SET
FCH=
10.8,
vmch=
2.2,
POINTS=
24OO,
PLT=
6
SET
KFC=
O.
O,
ABGO=
O.
O,
KBG=
O.
O
END
proced
minhlOOO
mouse
ccl2ccl
set
conc=
985.2,
tchng=
6,
tstop=
15,
N=
5
set
bw=
0.0194
end
proced
minh500
mouse
ccl2ccl
set
conc=
492.6,
TCHNG=
4,
N=
5
set
bw=
0.0205
end
proced
minh250
mouse
ccl2ccl
set
conc=
248.3,
tchng=
6,
tstop=
ll,
N=
5
set
bw=
0.0196
end
PROCED
MlOO
CCL2
CCL
MOUSE
SET
CONC=
100,
N=
O,
BW=
0.0228,
VMCH=
22OO,
FCH=
10800
SET
TEXPOS=
6,
TCHNG=
170,
TSTOP=
168
17
FINAL
END
DATA
MlOO
(T,
CV)
4.07
0.608
6.1
0.951
6.3
0.960
8
0.022
52.07
1.84
54.07
1.73
54.3
0.43
56
0.007
100.07
1.98
102.07
2.16
102.3
0.592
104
0.055
END
PROCED
rat
$'revised
by
LMS
5/
1/
01,
041702'
'note
addition
of
brain,
spleen,
and
Vmaxrc'
'values
from
brown
et
al.,
1997'
SET
TITLE
=
'
1,1,2­
TCE
RAT'
SET
VMAXC=
20.7,
VMAXRC=
O,
KM=
O.
412,
KFC=
O.
O,
kdte=
O
SET
QLC=
0.183,
QFC=
0.07,
qbrc=
0.02,
qsc=
0.336,
QSNC=
0.011
SET
VLGO.
0366,
VFC=
0.0896,
vbrc=
0.0057,
vsc=
O.
5946,
VRC=.
2215
SET
BW=
0.25,
QPC=
20.9,
QCC=
l7.5
SET
VSNC=
0.002
SET
PB=
58.,
PFA=
1438,
PLA=
73,
PRb60.7,
PSA=
23,
PB~=
56.1
SET
PSNA=
53
END
$lof
proced
rat1
PROCED
RlOO
CCLZCCL
RAT
SET
CONC=
100,
N=
l,
BW=
0.160,
VMCH=
2200,
FCH=
10800
END
DATA
RlOODATA
(T,
CV)
4.08
1.73
6.06
1.88
6.3
0.78
8.0
0.15
END
PROCED
MOUSE
S'PHYSIOL
FROM
BROWN
ET
AL
1997
last
rev
050902'
SET
TITLE
=
1,1,2­
TCE
FEMALE
MOUSE'
SET
MW=
133.41,
PB=
71.1,
PFA=
1438,
PLA=
73,
P~=
60.7,
PSA=
23,
PBRA=
56.1
SET
PSNA=
53
FINAL
SET
VMAXC=
16.8,
VMAXRC=
OlKM=
O.
222,
KFC=
0.
O
SET
BW=
0.025,
QPC=
16.5,
QCC=
23.1
SET
QLC=
0.161,
QBRC=
0.033,
QFC=
0.07,
QSC=
0.217,
QSNC=
O.
Oll
SET
VLC=
0.0549,
VBRC=
0.0165,
VFC=
O.
O7,
VRC=
O.
l958,
VSC=
O.
5493
SET
VSNC=
0.0035
SET
KDET=
0.025,
KDbi=
0.1034
END
$'of
proced
mouse'

PROCED
MMOUSE
S'PHYSIOL
FROM
BROWN
ET
AL
1997
l
a
s
t
rev
050902'
SET
TITLE
=
'
1,1,2­
TCE
MALE
MOUSE'
SET
MW=
133.41,
PB=
71.1,
PFA=
1438,
PLA=
73,
PRA=
60.7,
PSA=
23,
PBRA=
56.1
SET
PSNA=
53
SET
VMAXC=
16.8,
VMAXRC=
O,
KM=
O.
222,
KFC=
O.
O
SET
BW=
0.025,
QPC=
16.5,
QCC=
23.1
SET
QLC=
0.161,
QBRC=
0.033,
QFC=
O.
07,
QSC=
O.
217,
QSNC=
O.
O11
SET
VLC=
0.0549,
VBRC=
0.0165,
VFC=
0.07,
VRC=
0.1958,
VSC=
0.5493
SET
VSNC=
0.0035
SET
KDET=
0.025,
KDBI=
O.
O
END
$'of
proced
Mmouse'

PROCED
r
a
t
SET
TITLE
=
'
1,1,2­
TCE
RAT'
SET
MW=
133.41,
PB=
58.,
PFA=
1438,
PLA=
73,
PRA=
60.7,
PSA=
23,
PB~=
56.1
SET
PSNA=
53
SET
VMAXC=
20.7,
VMAXRC=
O,
KM=
O.
412,
KFC=
O.
O
SET
BW=
0.25,
QPC=
20.9,
QCC=
l7.5
SET
QLC=
0.183,
QBRC=
0.02,
QFC=
0.07,
QSC=
0.336,
QSNC=
0.011
SET
VLC=
0.0366,
VBRC=
0.0057,
VFC=
O.
O896,~
C=
O.
2215,
VSC=
O.
5946
SET
VSNC=
0.002
SET
KDET=
0.025,
KDBI=
O.
END
$'of
proced
r
a
t
'

PROCED
FMSAl
MOUSE
$START
$
D
AUCV,
DM1
SET
PB=
71.811
$START
$
D
AUCV,
DM1
$MOUSE
SET
PFA=
1452.38
$START
$
D
AUCV,
DM1
$MOUSE
SET
PLA=
73.73
$START
$
D
AUCV,
DM1
$MOUSE
SET
PRA=
61.307
$START
$
D
AUCV,
DM1
$MOUSE
SET
PSA=
23.23
$START
$
D
AUCV,
DM1
$MOUSE
SET
PBRA=
56.661
$START
$
D
AUCV,
DM1
$MOUSE
SET
PSNA=
53.53
$START
$
D
AUCV,
DM1
$MOUSE
SET
VMAXC=
16.968
$START
$
D
AUCV,
DM1
$MOUSE
SET
KM=
0.22422
$START
$
D
AUCV,
DM1
$MOUSE
SET
BW=
0.02525
$START
$
D
AUCV,
DM1
$MOUSE
SET
QPC=
16.665
$START
$
D
AUCV,
DM1
$MOUSE
SET
QCC=
23.331
$START
$
D
AUCV,
DM1
$MOUSE
SET
QLC=
O.
16261
$START
$
D
AUCV,
DM1
$MOUSE
SET
N=
O
19
FINAL
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
QBRC=
0.03333
$START
$
D
AUCV,
DM1
$MOUSE
QFC=
0.0707
$START
$
D
AUCV,
DM1
$MOUSE
QSC=
O.
21917
$START
$
D
AUCV,
DM1
$MOUSE
QSNC=
O.
O1111
$START
$
D
AUCV,
DM1
$MOUSE
VLC=
O.
O55449
$START
$
D
AUCV,
DM1
$MOUSE
VBRC=
0.016665
$START
$
D
AUCV,
DM1
$MOUSE
VFC=
0.0707
$START
$
D
AUCV,
DM1
$MOUSE
VRC=
0.197758
$START
$
D
AUCV,
DM1
$MOUSE
VSC=
O.
554793
$START
$
D
AUCV,
DM1
$MOUSE
VSNC=
0.003535
$START
$
D
AUCV,
DM1
$MOUSE
KDET=
O.
02525
$START
$
D
AUCV,
DM1
$MOUSE
KDBI=
O.
104434
$START
$
D
AUCV,
DM1
$MOUSE
PROCED
FMSA2
MOUSE
$START
$
range
cv
SET
N=
O
SET
SET
.
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
PB=
71.811
$START
$
range
cv
$MOUSE
PFA=
1452.38
$START
$
range
cv
$MOUSE
PRA=
61.307
$START
$
range
cv
$MOUSE
PSA=
23.23
$START
$
range
cv
$MOUSE
PBRA=
56.661
$START
$
range
cv
$MOUSE
PSNA=
53.53
$START
$
range
cv
$MOUSE
vMAxC=
16.968
$START
$
range
cv
$MOUSE
KM=
0.22422
$START
$
range
cv
$MOUSE
BW=
0.02525
$START
$
range
cv
$MOUSE
QPC=
16.665
$START
$
range
cv
$MOUSE
QCC=
23.331
$START
$
range
cv
$MOUSE
QLC=
O.
16261
$START
$
range
cv
$MOUSE
QBRC=
0.03333
$START
$
range
cv
$MOUSE
QFC=
0.0707
$START
$
range
cv
$MOUSE
QSC=
0.21917
$START
$
range
cv
$MOUSE
QSNC=
O.
O1111
$START
$
range
cv
$MOUSE
VLC=
0.055449
$START
$
range
cv
$MOUSE
VBRC=
0.016665
$START
$
range
cv
$MOUSE
VFC=
0.0707
$START*$
range
cv
$MOUSE
VRC=
0.197758
$START
$
range
cv
$MOUSE
VSC=
O.
554793
$START
$
range
cv
$MOUSE
VSNC=
0.003535
$START
$
range
cv
$MOUSE
KDET=
0.02525
$START
$
range
cv
$MOUSE
KDBI=
0.104434
$START
$
range
cv
$MOUSE
PLA=
73.73
$START
$
range
CV
$MOUSE
proced
FEMmusSA
set
hvdprn=.
f
.
CCLZCCL
SET
VMCH=
2200,
FCH=
10800
SET
TEXPOS=
6,
TCHNG=
170,
TSTOP=
168
20
FINAL
set
CONC=
100
fmsal
SET
CONC=
101
$START
$
D
AUCV,
DM1
$set
CONC=
100
$START
$
D
AUCV,
DM1
fmsa2
SET
conc=
l01
$START
$
range
cv
$set
CONC=
100
$START
$
range
cv
END
SET
SET
SET
SET
SET
SET
.
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
PROCED
MMSAl
SET
N=
O
MMOUSE
$START
$
D
AUCV,
DM1
SET
PB=
71.811
$START
$
D
AUCV,
DM1
SMMOUSE
PFA=
1452.38
$START
$
D
AUCV,
DM1
SMMOUSE
PLA=
73.73
$START
$
D
AUCV,
DM1
SMMOUSE
PRA=
61.307
$START
$
D
AUCV,
PSA=
23.23
$START
$
D
AUCV,
DM1
SMMOUSE
PBRA=
56.661
$START
$
D
AUCV,
DM1
SMMOUSE
PSNA=
53.53
$START
$
D
AUCV,
DM1
SMMOUSE
VMAXC=
16.968
$START
$
D
AUCV,
DM1
SMMOUSE
KM=
0.22422
$START
$
D
AUCV,
DM1
$MMOUSE
BW=
0.02525
$START
$
D
AUCV,
DM1
SMMOUSE
QPC=
16.665
$START
$
D
AUCV,
DM1
SMMOUSE
QCC=
23.331
$START
$
D
AUCV,
DM1
SMMOUSE
QLC=
0.16261
$START
$
D
AUCV,
DM1
SMMOUSE
QBRC=
0.03333
$START
$
D
AUCV,
DM1
SMMOUSE
QFC=
0.0707
$START
$
D
AUCV,
DM1
$MMOUSE
QSC=
O.
21917
$START
$
D
AUCV,
DM1
SMMOUSE
QSNC=
O.
O1111
$START
$
D
AUCV,
DM1
SMMOUSE
VLC=
O.
O55449
$START
$
D
AUCV,
DM1
SMMOUSE
VBRC=
0.016665
$START
$
D
AUCV,
DM1
SMMOUSE
VFC=
0.0707
$START
$
D
AUCV,
DM1
SMMOUSE
VRC=
0.197758
$START
$
D
AUCV,
DM1
SMMOUSE
VSC=
O.
554793
$START
$
D
AUCV,
DM1
SMMOUSE
VSNC=
0.003535
$START
$
D
AUCV,
DM1
SMMOUSE
KDET=
0.02525
$START
$
D
AUCV,
DMI
SMMOUSE
DM1
$MMOUSE
PROCED
MMSA2
SET
N=
O
MMOUSE
$START
$
range
cv
SET
PB=
71.811
$START
$
range
cv
SMMOUSE
SET
PFA=
1452.38
$START
$
range
cv
SMMOUSE
SET
PLA=
73.73
$START
$
range
cv
SMMOUSE
SET
PRA=
61.307
$START
$
range
cv
SMMOUSE
SET
PSA=
23.23
$START
$
range
cv
SMMOUSE
SET
PBRA=
56.661
$START
$
range
cv
SMMOUSE
SET
PSNA=
53.53
$START
$
range
cv
SMMOUSE
SET
VMAXC=
16.968
$START
$
range
cv
SMMOUSE
21
FINAL
SET
KM=
0.22422
$START
$
range
cv
SMMOUSE
SET
BW=
0.02525
$START
$
range
cv
SMMOUSE
SET
QPC=
16.665
$START
$
range
cv
SMMOUSE
SET
QCC=
23.331
$START
$
range
cv
$MMOUSE
SET
QLC=
0.16261
$START
$
range
cv
SMMOUSE
SET
QBRC=
0.03333
$START
$
range
cv
SMMOUSE
SET
QSC=
O.
21917
$START
$
range
cv
SMMOUSE
SET
QSNC=
O.
O1111
$START
$
range
cv
SMMOUSE
SET
v~
c=
o.
O55449
$START
$
range
cv
SMMOUSE
SET
VBRC=
0.016665
$START
$
range
cv
SMMOUSE
SET
VFC=
0.0707
$START
$
range
cv
SMMOUSE
SET
VRC=
0.197758
$START
$
range
cv
SMMOUSE
SET
VSC=
O.
554793
$START
$
range
cv
SMMOUSE,
SET
VSNC=
0.003535
$START
$
range
cv
SMMOUSE
SET
KDET=
O.
02525
$START
$
range
cv
SMMOUSE
END
SET
QFC=
0.0707
$START
$
range
CV
$MMOUSE
proced
MALEmusSA
set
hvdprn=.
f.
CCL2CCL
SET
VMCH=
2200,
FCH=
10800
SET
TEXPOS=
6,
TCHNG=
170,
TSTOP=
168
set
CONC=
100
Mrnsal
SET
CONC=
101
$START
$
D
AUCV,
DM1
$set
CONC=
100
$START
$
D
AUCV,
DM1
Mmsa2
SET
CONC=
101
$START
$
range
cv
$set
CONC=
100
$START
$
range
cv
END
PROCED
RSAl
SET
RAT
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
N=
0
$START
$
D
AUCV,
DM1
PB=
58.58
$START
$
D
AUCV,
DM1
$RAT
PFA=
1452.38
$START
$
D
AUCV,
DM1
$RAT
PLA=
73.73
$START
$
D
AUCV,
DM1
$RAT
PRA=
61.307
$START
$
D
AUCV,
DM1
$RAT
PSA=
23.23
$START
$
D
AUCV,
DM1
$RAT
PBRA=
56.661
$START
$
D
AUCV,
DM1
$RAT
PSNA=
53.53
$START
$
D
AUCV,
DM1
$RAT
VMAXC=
20.907
$START
$
D
AUCV,
DM1
$RAT
KM=
0.41.612
$START
$
D
AUCV,
DM1
$RAT
BW=
0.2525
$START
$
D
AUCV,
DM1
$RAT
QPC=
21.109
$START
$
D
AUCV,
DM1
$RAT
QCC=
17.675
$START
$
D
AUCV,
DM1
$RAT
QLC=
0.18483
$START
$
D
AUCV,
DM1
$RAT
QBRC=
0.0202
$START
$
D
AUCV,
DM1
$RAT
22
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
QFC=
0.0707
$START
$
D
AUCV,
DM1
$RAT
QSC=
O.
33936
$START
$
D
AUCV,
DM1
$RAT
QSNC=
O.
O1111
$START
$
D
AUCV,
DM1
$RAT
VLC=
O.
O36966
$START
$
D
AUCV,
DM1
$RAT
VBRC=
0.005757
$START
$
D
AUCV,
DM1
$RAT
VFC=
0.090496
$START
$
D
AUCV,
DM1
$RAT
VRC=
0.223715
$START
$
D
AUCV,
DM1
$RAT
VSC=
O.
600546
$START
$
D
AUCV,
DM1
$RAT
VSNC=
0.00202
$START
$
D
AUCV,
DM1
$RAT
KDET=
0.02525
$START
$
D
AUCV,
DM1
$RAT
PROCED
RSA2
SET
RAT
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
N=
0
$START
$
range
cv
PB=
58.58
$START
$
range
cv
$RAT
PFA=
1452.38
$START
$
range
cv
$RAT
PLA=
73.73
$START
$
range
cv
$RAT
PRA=
61.307
$START
$
range
cv
$RAT
PSA=
23.23
$START
$
range
cv
$RAT
PBRA=
56.661
$START
$
range
cv
$RAT
PSNA=
53.53
$START
$
range
cv
$RAT
VMAXC=
20.907
$START
$
range
cv
$RAT
KM=
0.41612
$START
$
range
cv
$RAT
BW=
0.2525
$START
$
range
cv
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26
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27
FINAL
exhsir.
csl
PROGRAM:
PHYSIOLOGICAL
PHARMACOKINETIC
MODEL
­­
WITH
DATA
(EXH.
CSL)
'Model
to
examine
gas
phase
elimination
rate
data'
'M.
L.
Gargas
16
OCT
1987
........................

'Revised
4/
16/
01
by
Lisa
M.
Sweeney,
adding
brain,
qsc,
vsc'
'9pc
and
qcc
scaling
changed
to
0.7'
'suicide
enzyme
inhib
and
resynthesis
added
12/
14/
01
LMS'

I
NI
TI
AL
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
liver
CONSTANT
CONSTANT
CONSTANT
CONSTANT
CONSTANT
Constant
Constant
Constant
CONSTANT
CONSTANT
CONSTANT
QPC
=
14.
$'Alveolar
ventilation
rate
(l/
hr)
I
QCC
=
14.
$'Cardiac
output
(l/
hr)
'
QLC
=
0.25
$'Fractional
blood
flow
to
liver'
QFC
=
0.09
$'Fractional
blood
flow
to
fat'
QSC
=
0.336
$'Fractional
blood
flow
to
slowly
perf'
QSNC
=
0.011
$'Fractional
blood
flow
to
spleen'
Qbrc
=
0.02
$'Fractional
blood
flow
to
brain'
BW
=
0.22
$'Body
weight
(kg)
'
VLC
=
0.04
$'Fraction
liver
tissue'
VFC
=
0.07
$'Fraction
fat
tissue'
VSC
=
0.5946
$'Fraction
of
slowly
perfused
tissue'
VSNC
=
0.0035
$'Fraction
of
spleen'
VBRC
=
0.0057
$'Fraction
of
brain
tissue'
VRC
=
0.2235
$'Fraction
of
richly
perfused
tissue'
PLA
=
3.46
$'Liver/
air
partition
coefficient'
PFA
=
86.5
$'Fat/
air
partition
coefficient'
PSA
=
1.16
$'Slowly
perfused
tissue/
air
partition'
PRA
=
3.46
$'Richly
perfused
tissue/
air
partition'
PSNA
=
1
$'Spleen/
air
partition'
PBRA
=
3.46
$'brain/
air
partition'
PB
=
40.2
$'Blood/
air
partition
coefficient'
MW
=
133.14
$'Molecular
weight
(g/
mol)
'
VMAXC
=
8.36
$'Maximum
velocity
of
metabolism
(mg/
hr­
lkg)
in
VMAXRC
=
0
$'Maximum
velocity
of
metabolism
(mg/
hr­
lkg)
in
rpt'
KM
=
0.36
$'Michaelis­
Menten
constant
(mg/
l)
I
KFC
=
0.
$'First
order
metabolism
rate
constant
(/
hr­
lkg)
'
Kdet=
0.025
$Irate
of
enzyme
turnover
(/
hr)
I
.
Kdes=
O
$'rate
of
enzyme
activity
loss
thru
inhibition
by
ES
mech'
kdte=
O
$Irate
of
enzyme
activity
loss
thru
inhibition
by
TE
mech'
kdfe=
O
$Irate
of
enzyme
activity
loss
thru
inhibition
by
FE
mechl
kdbi=
O
$'rate
of
enzyme
activity
loss
thru
inhibition
by
BI
mech'

CONC
=
1000.
$'Inhaled
concentration
(ppm)
VMCH
=
2.2
$'VOLUME
OF
METABOLISM
CHAMBER
(L)
'
FCH
=
1
0
.7
$'FLOW
THROUGH
METABOLISM
CHAMBER
(L/
HR)
1
28
FINAL
CONSTANT
N
=
1.
$'NUMBER
OF
RATS
IN
METABOLISM
CHAMBER'
CONSTANT
ABGO=
10.0
$'TOTAL
BACKGROUND
AMT
FROM
FUR
(MG)
'
CONSTANT
KBG
=
0.0
$'RATE
OF
FUR
OFF­
GASING
(/
HR)
'

'Timing
commands'

CONSTANT
TSTOP
=
24.
$'Length
of
experiment
(hrs)
'
CONSTANT
TEXPOS
=
6
$'Length
of
open
chamber
exposure'
CONSTANT
WEEK=
120.
$'exposure
only
on
week
days'
CONSTANT
TCHNG
=
168.
$'Length
of
inhalation
exposure
(hrs)
'
CONSTANT
POINTS
=
24.
$'Number
of
points
in
plot'
CINT
=
texpos/
POINTS
$'Communication
interval'
CHNG
=
TCHNG
­
0.00001
VMC
=
VMCH
­
N*
BW
$'NET
METABOLISM
CHAMBER
VOLUME
(L)
'

'Scaled
parameters'

QC
=
QCC*
BW**
0.70
QP
=
QPC*
BW**
0.70
QL
=
QLC*
QC
QF
=
QFC*
QC
QS
=
qsc*
QC
qsn
=
qsnc*
qc
QBR
=
qbrc*
QC
8
QR
=
QC­
(QL+
QF+
QS+
QBR+
QSN)
VL
=
VLC*
BW
VF
=
VFC*
BW
VS
=
VSC*
BW
vsn
=
vsnc*
bw
VR
=
vrc*
BW
VBR
=
VBRCXBW
VMAX
=
VMAXC*
BW**
0.7
VMAXR=
VMAXRC*
BW**
O.
7
KF
=
KFC/
BW**
O
.3
PF
=
PFA/
PB
$PL
=PLA/
PB
$PR=
PRA/
PB
$PS=
PSA/
PB
$
PBR=
PBRA/
PB
$
PSN=
PSNA/
PB
CII
=
0.0
END
$'End
of
initial'

DYNAMIC
..

ALGORITHM
IALG
=
2
$'Gear
method
for
stiff
systems'

DERIVATIVE
CI
=
PULSE(
O.,
24.,
TEXPOS)*
PULSE(
0.,
168.,
WEEK)*
CONC*
MW/
24450
'Amount
inhaled'

29
FINAL
RAI
=
QP*
CI
AI
=
INTEG(
RA1,
O.)

'CA
=
Concentration
in
arterial
blood
(mg/
l)
'
CA
=
(QC*
CV+
QP*
(CI+
CII*
CCH)
)
/
(QC+
(QP/
PB)
)

AUCB
=
INTEG(
CA,
O.)

'AX
=
Amount
exhaled
(mg)
I
cx
=
CA/
PB
CXPPM
=
(0.7*
CX+
0.3*
CI)*
2445O./
MW
RAX
=
QP*
CX
AX
=
INTEG(
RAX,
0.)

'ACH
=
AMOUNT
IN
METABOLISM
CHAMBER
(MG/
L)
'
RACH
=
N
*
CII*
QP
*
(CX­
CCH)
­
CII*
FCH*
CCH
­
RABG
ACH
=
INTEG(
RACH,
O.)
CCH
=
ACH/
VMC
PPMOUT
=
CCH*
24450./
MW
RATE1
=
FCH*
CCH
TOTAL
=
INTEG(
RATE1,
O.
O)

'ABG
=
AMT
OF
BACKGROUND
CONC
FROM
FUR"
RABG
=
­KBG*
ABG*
STEP
(TCHNG)
ABG
=
INTEG(
RABG,
ABGO)

'AS
=
Amount
in
slowly
perfused
tissues
(mg)
'
RAS
=
QS*(
CA­
CVS)
AS
=
INTEG(
RAS,
O.)

CS
=
AS/
VS
CVS
=
AS/(
VS*
PS)

'ASN
=
Amount
in
spleen
(mg)
RASN
=
QSN*
(CA­
CVSN)
ASN
=
INTEG
(RASN,
0.
)

CSN
=
ASN/
VSN
CVSN
=
ASN/
(VSN*
PSN)

AUCSN
=
INTEG(
CSN,
O.)

'AR
=
Amount
in
rapidly
perfused
tissues
(mg)
'
RAR
=
QR*
(CA­
CVR)
­
RAMR
AR
=
INTEG(
RAR,
O.)
CVR
=
AR/
(VR*
PR)
CR
=
AR/
VR
'ABR
=
Amount
in
bra
ABR
=
INTEG(
RABR,
O.
CVBR
=
ABR/
(VBR*
PBR)
CBR
=
ABR/
VBR
RABR
=
QBR"
(CA­
CVBR)

30
FINAL
'AF
=
Amount
in
fat
tissue
(mg)
'
RAF
=
QF*(
CA­
CVF)
AF
=
INTEG(
RAF,
O.)

CF
=
AF/
VF
CVF
=
AF/(
VF*
PF)

'AL
=
Amount
in
liver
tissue
(mg)
'
RAL
=
QL*(
CA­
CVL)
­
RAML
AL
=
INTEG(
RAL,
O.)
CVL
=
AL/(
VL*
PL)
CL
=
AL/
VL
AUCL
=
INTEG(
CL,
O.)

'VMT
=
maximal
rate
of
metabolism'
RVMT
=
(VMAX­
VMT)*
KDET­
KDES*
RAML*
RAML­
KDTE*
RAML*
VMT
...
­KDFE*
RAML*
VMT*
KM/
(KM+
CVL)
­KDBI*
RAML
VMT
=
INTEG(
RVMT,
VMAX)

'AM
=
Amount
metabolized
(mg)
I
RAML
=
(VMT*
CVL)/(
KM+
CVL)
+
KF*
CVL*
VL
RAMR
=
(VMAXR*
CVR)
/
(KM+
CVR)
RAM
=
RAML
+
RAMR
AM
=
INTEG(
RAM,
0.)
AML
=
INTEG(
RAML,
O)
DM~=
AML/
VL
'CV
=
Mixed
venous
blood
concentration
(mg/
l)
'
CV
=
(QF*
CVF
+
QL*
CVL
+
QS*
CVS
+
QR*
CVR
+
QBRXCVBR
+QSN*
CVSN)/
QC
AUCV
=
INTEG(
CV,
O.)

ITMASS
=
mass
balance
(mg)
'
TMASS
=
AF+
AL+
AS+
AR+
AM+
ABR+
ASN+
AX
'DOSEX
=
Net
amount
absorbed
(mg)
'
DOSEX
=
AI+=

TERMT
(T
.
GE
.
TSTOP)

END
$'End
of
derivative'

IF
(T.
GE.
CHNG)
CI=
O.
IF
(T
.GE.
CHNG)
CII=
l.
O
END
$'End
of
dynamic'

END
$'End
of
program'

31
FINAL
32
FINAL
GIsir2
.cmd
'File
Name
is
GI.
cmd,
Rev
1/
19/
90
at
9:
30
am'
'rev
5/
1/
01,
8/
31/
01
lms
for
112tce
only'
'rev
4/
16­
17/
02
for
sensitivity
analysis,
optimized
values'
'rev
05/
09/
02
for
reoptimized
values'

SET
TJNITG
=
1.0
$'Threshold
for
Jacoljian
Error
Messages'
SET
TSMITG
=
.T.
$'Two
sided
matrix
evaluation
for
increased
accur.
'
SET
NSTP
=
1000
$'Allow
the
integrator
to
take
very
small
steps'
'SET
PRN=
7
I
$'Save
output
in
SIMUSOLV.
LOG
file'

PREPAR
TI
PPMOUT,
CA,
CV,
CL,
CVL,
AUCL,
DM,
AM,
AUCB,
AML,
DM1
PROCED
MANY
$
S
NRWITG=.
T.,
FTSPLT=.
T.
$
END
PROCED
ONE
$
S
NRWITG=.
F.
$
END
PROCED
CCL2CCL
$~
1,1,2­
TRICHLOROETHANE,
X
MG/
KG
gavage
dose'
SET
N=
5
SET
Flow=
10700,~~
h~=
2200,
POINTS=
240
SET
KAz2.0,
KAI=
O.
,
KSI=
O
.
SET
DOSE=
O.,
TSTOP=
2.
END
proced
bolus
set
drpct=
l.
O,
0,
0,
0,
0,
0
set
drtime=
O,
4,
8,
12,
16,
20
set
tchng=
120
end
proced
perdwr
set
drpct=
0.233,
0.1,
0.1,
0.1,
0.233,
0.234
set
drtime=
O,
4,
8,
12,
16,
20
set
tchng=
99999
end
proced
begin
ccl2ccl
mouse
set
n=
l,
points=
30000,
tstop=
168
set
ka=
0.18
end
PROCED
MOUSE
S'PHYSIOL
FROM
BROWN
ET
AL
1997'
SET
TITLE
=
'
1,1,2­
TCE
FEMALE
MOUSE'
SET
MW=
133.41,
PB=
71.1,
PFA=
1438,
PLA=
73,
P~=
60.7,
PSA=
23,
PB~=
56.1
33
FINAL
SET
PSNA=
53
SET
VMAXC=
16.8,
VMAXRC=
O,
KM=
O.
222,
KFC=
O.
O
SET
BW=
0.025,
QPC=
16.5,
QCC=
23.1
SET
QLC=
0.161,
QBRC=
0.033,
QFC=
0.07,
QSC=
0.217,
QSNC=
O.
O11
SET
VLC=
0.0549,
VBRC=
0.0165,
VFC=
O.
O7,
VRC=
O.
l958,
VSC=
O.
5493
SET
VSNC=
0.0035
SET
KDET=
0.025,
KDbi=
0.1034
END
$'of
proced
mouse'

PROCED
MMOUSE
S'PHYSIOL
FROM
BROWN
ET
AL
1997'
SET
TITLE
=
'
1,1,2­
TCE
MALE
MOUSE'
SET
MW=
133.41,
PB=
71.1,
PFA=
1438,
PLA=
73,
PRA=
60.7,
PSA=
23,
PBRA=
56.1
SET
PSNA=
53
SET
VMAXC=
16.8,
VMAXRC=
O,
KM=
O.
222,
KFC=
O.
O
SET
BW=
0.025,
QPC=
16.5,
QCC=
23.1
SET
QLC=
0.161,
QBRC=
0.033,
QFC=
O.
07,
QSC=
O.
217,
QSNC=
O.
Oll
SET
VLC=
0.0549,
VBRC=
0.0165,
VFC=
O.
O7,
VRC=
O.
l958,
VSC=
O.
5493
SET
VSNC=
0.0035
SET
KDET=
0.025,
KDBI=
O.
O
END
$'of
proced
Mmouse'

PROCED
r
a
t
SET
TITLE
=
'
1,1,2­
TCE
RAT'
SET
MW=
133.41,
PB=
58.,
PFA=
1438,
PLA=
73,
PRA=
60.7,
PSA=
23,
PBRA=
56.1
SET
PSNA=
53
SET
VMAXC=
20.7,
VMAXRC=
O,
KM=
0.412,
KFC=
O.
O
SET
BW=
0.25,
QPC=
20.9,
QCC=
l7.5
SET
QLC=
0'.
183,
QBRC=
0.02,
QFC=
0.07,
QSC=
0.336,
QSNC=
0.011
SET
VLC=
0.0366,
VBRC=
0.0057,
VFC=
O.
O896,~
C=
O.
2215,
VSC=
O.
5946
SET
VSNC=
0.002
SET
KDET=
0.025,
KDTE=
O.
END
$'of
proced
r
a
t
'

PROCED
FMSAl
SET
N=
l
MOUSE
$START
$
D
AUCV,
DM1
SET
PB=
71.811
$START
$
D
AUCV,
DM1
$MOUSE
SET
PFA=
1452.38
$START
$
D
AUCV,
DM1
$MOUSE
SET
PLA=
73.73
$START
$
D
AUCV,
DM1
$MOUSE
SET
PRA=
61.307
$START
$
D
AUCV,
DM1
$MOUSE
SET
PSA=
23.23
$START
$
D
AUCV,
DM1
$MOUSE
SET
PBRA=
56.661
$START
$
D
AUCV,
DM1
$MOUSE
SET
PSNA=
53.53
$START
$
D
AUCV,
DM1
$MOUSE
SET
VMAXC=
16.968
$START
$
D
AUCV,
DM1
$MOUSE.
SET
KM=
0.22422
$START
$
D
AUCV,
DM1
$MOUSE
SET
BW=
0.02525
$START
$
D
AUCV,
DM1
$MOUSE
SET
QPC=
16.665
$START
$
D
AUCV,
DM1
$MOUSE
SET
QCC=
23.331
$START
$
D
AUCV,
DM1
$MOUSE
34
FINAL
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
QLC=
O.
16261
$START
$
D
AUCV,
DM1
$MOUSE
QBRC=
0.03333
$START
$
D
AUCV,
DM1
$MOUSE
QFC=
0.0707
$START
$
D
AUCV,
DM1
$MOUSE
QSC=
0.21917
$START
$
D
AUCV,
DM1
$MOUSE
QSNC=
O.
O1111
$START
$
D
AUCV,
DM1
$MOUSE
VLC=
O.
O55449
$START
$
D
AUCV,
DM1
$MOUSE
VBRC=
0.016665
$START
$
D
AUCV,
DM1
$MOUSE
VFC=
0.0707
$START
$
D
AUCV,
DM1
$MOUSE
VRC=
0.197758
$START
$
D
AUCV,
DM1
$MOUSE
VSC=
O.
554793
$START
$
D
AUCV,
DM1
$MOUSE
VSNC=
0.003535
$START
$
D
AUCV,
DM1
$MOUSE
KDET=
O.
02525
$START
$
D
AUCV,
DM1
$MOUSE
KDBI=
0.104434
$START
$
D
AUCV,
DM1
$MOUSE
PROCED
FMSA2
SET
N=
l
MOUSE
$START
$
range
cv
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
PB=
71.811
$START
$
range
cv
$MOUSE
PFA=
1452.38
$START
$
range
CV
$MOUSE
PLA=
73.73
$START
$
range
Cv
$MOUSE
PRA=
61.307
$START
$
range
cv
$MOUSE
PSA=
23.23
$START
$
range
cv
$MOUSE
PBRA=
56.661
$START
$
range
cv
$MOUSE
PSNA=
53.53
$START
$
range
cv
$MOUSE
VMAXC=
16.968
$START
$
range
cv
$MOUSE
KM=
O.
22422
$START
$
range
cv
$MOUSE
BW=
0.02525
$START
$
range
cv
$MOUSE
QPC=
16.665
$START
$
range
cv
$MOUSE
QCC=
23.331
$START
$
range
cv
$MOUSE
QLC=
O.
16261
$START
$
range
CV
$MOUSE
QBRC=
0.03333
$START
$
range
cv
$MOUSE
QFC=
0.0707
$START
$
range
CV
$MOUSE
QSC=
0.21917
$START
$
range
cv
$MOUSE
QSNC=
O.
O1111
$START
$
range
cv
$MOUSE
VLC=
O.
O55449
$START
$
range
cv
$MOUSE
VBRC=
0.016665
$START
$
range
cv
$MOUSE
VFC=
0.0707
$START
$
range
cv
$MOUSE
VRC=
0.197758
$START
$
range
cv
$MOUSE
VSC=
O.
554793
$START
$
range
cv
$MOUSE
VSNC=
0.003535
$START
$
range
cv
$MOUSE
KDET=
O.
02525
$START
$
range
cv
$MOUSE
KDBI=
O.
104434
$START
$
range
cv
$MOUSE
proced
FEMmusSA
set
hvdprn=.
f.,
tstop=
168,
points=
30000
bolus
set
dose=
390,
ka=
O
.18
35
FINAL
fmsal
SET
dose=
393.9
$START
SET
ka=
0.1818
$START
$
$START
$
D
AUCV,
DM1
fmsa2
SET
dose=
393.9
$START
SET
ka=
0.1818
$START
$
$START
$
range
cv
$
D
AUCV,
DM1
$set
dose=
390
D
AUCV,
DM1
$set
ka=
0.18
$
range
cv
$set
dose=
390
range
cv
$set
ka=
0.18
set
dose=
10,
ka=
4.4,
tstop=
23.5
fmsal
SET
dose=
l0.1
$START
$
D
AUCV,
DM1
$set
dose=
lO
SET
ka=
4.444
$START
$
D
AUCV,
DM1
$set
ka=
4.4
$START
$
D
AUCV,
DM1
fmsa2
SET
dose=
l0.1
$START
$
range
cv
$set
dose=
lO
SET
ka=
4.444
$START
$
range
cv
$set
ka=
4.4
$START
$
range
cv
END
PROCED
MMSAl
SET
N=
l
MMOUSE
$START
$
D
AUCV,
DM1
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
SET
END
PB=
71.811
$START
$
D
AUCV,
DM1
SMMOUSE
PFA=
1452.38
$START
$
D
AUCV,
DM1
SMMOUSE
PLA=
73.73
$START
$
D
AUCV,
DM1
SMMOUSE
PRA=
61.307
$START
$
D
AUCV,
DM1
SMMOUSE
PSA=
23.23
$START
$
D
AUCV,
DM1
SMMOUSE
PBRA=
56.661
$START
$
D
AUCV,
DM1
SMMOUSE
PSNA=
53.53
$START
$
D
AUCV,
DM1
SMMOUSE
VMAXC=
16.968
$START
$
D
AUCV,
DM1
SMMOUSE
KM=
O.
22422
$START
$
D
AUCV,
DM1
SMMOUSE
BW=
0.02525
$START
$
D
AUCV,
DM1
SMMOUSE
QPC=
16.665
$START
$
D
AUCV,
'DM1
SMMOUSE
QCC=
23.331
$START
$
D
AUCV,
DM1
SMMOUSE
QLC=
0.16261
$START
$
D
AUCV,
DM1
SMMOUSE
QBRC=
0.03333
$START
$
D
AUCV,
DM1
SMMOUSE
QFC=
0.0707
$START
$
D
AUCV,
DM1
SMMOUSE
QSC=
O.
21917
$START
$
D
AUCV,
DM1
$MMOUSE
QSNC=
O.
O1111
$START
$
D
AUCV,
DM1
$MMOUSE
VLC=
O.
O55449
$START
$
D
AUCV,
DM1
SMMOUSE
VBRC=
0.016665
$START
$
D
AUCV,
DM1
SMMOUSE
VFC=
0.0707
$START
$
D
AUCV,
DM1
SMMOUSE
VRC=
0.197758
$START
$
D
AUCV,
DM1
SMMOUSE
VSC=
O.
554793
$START
$
D
AUCV,
DM1
SMMOUSE
VSNC=
0.003535
$START
$
D
AUCV,
DM1
SMMOUSE
KDET=
0.02525
$START
$
D
AUCV,
'
DM1
SMMOUSE
36
FINAL,

PROCED
MMSA2
SET
N=
l
MMOUSE
$START
$
range
cv
SET
PB=
71.811
$START
$
range
cv
SMMOUSE
SET
PFA=
1452.38
$START
$
range
cv
SMMOUSE
SET
PLA=
73.73
$START
$
range
cv
SMMOUSE
SET
PRA=
61.307
$START
$
range
cv
SMMOUSE
SET
PSA=
23.23
$START
$
range
cv
SMMOUSE
SET
PBRA=
56.661
$START
$
range
cv
SMMOUSE
SET
PSNA=
53.53
$START
$
range
cv
SMMOUSE
SET
VMAXC=
16.968
$START
$
range
cv
SMMOUSE
SET
KM=
0.22422
$START
$
range
cv
SMMOUSE
SET
BW=
0.02525
$START
$
range
cv
SMMOUSE
SET
QPC=
16.665
$START
$
range
cv
SMMOUSE
SET
QCC=
23.331
$START
$
range
cv
SMMOUSE
SET
QBRG0.03333
$START
$
range
cv
SMMOUSE
SET
QSC=
O.
21917
$START
$
range
cv
SMMOUSE
SET
QLC=
0.16261
$START
$
range
CV
SMMOUSE
SET
QFC=
0.0707
$START
$
range
Cv
SMMOUSE
SET
QSNC=
O.
O1111
$START
$
range
CV
SMMOUSE
SET
VLC=
O.
O55449
$START
$
range
CV
SMMOUSE
SET
VBRC=
0.016665
$START
$
range
CV
SMMOUSE
SET
VFC=
0.0707
$START
$
range
Cv
SMMOUSE
SET
VRC=
0.197758
$START
$
range
CV
$MMOUSE
SET
VSGO.
554793
$START
$
range
cv
SMMOUSE
SET
VSNC=
0.003535
$START
$
range
cv
SMMOUSE
END
SET
KDET=
O.
02525
$START
$
range
CV
$MMOUSE
proced
MALEmusSA
bolus
set
hvdprn=.
f.,
tstop=
168,
points=
30000
set
dose=
390,
ka=
O
.18
Mmsal
SET
dose=
393.9
$START
$
D
AUCV,
DM1
$set
doses390
SET
ka=
0.1818
$START
$
D
AUCV,
DM1
$set
ka=
0.18
$START
$
D
AUCV,
DM1
Mmsa2
SET
dose=
393.9
$START
$
range
cv
$set
dose=
390
SET
ka=
0.1818
$START
$
range
cv
$set
ka=
0.18
$START
$
range
cv
set
dose=
10,
ka=
4.4,
tstop=
23.5
Mmsal
SET
dose=
l0.1
$START
$
D
AUCV,
DM1
$set
dose=
lo
SET
ka=
4.444
$START
$
D
AUCV,
DM1
$set
ka=
4.4
$START
$
D
AUCV,
DM1
Mmsa2
SET
dose=
l0.1
$START
$
range
cv
$set
dose=
lO
SET
ka=
4.444
$START
$
range
cv
$set
ka=
4.4
37
FINAL
$START
$
range
CV
END
PROCED
RSAl
SET
N=
l
RAT
$START
$
D
AUCV,
DM1
SET
PB=
58.58
$START
$
D
AUCV,
DM1
$RAT
SET
PFA=
1452.38
$START
$
D
AUCV,
DM1
$RAT
SET
PLA=
73.73
$START
$
D
AUCV,
DM1
$RAT
SET
PRA=
61.307
$START
$
D
AUCV,
DM1
$RAT
SET
PSA=
23.23
$START
$
D
AUCV,
DM1
$RAT
SET
PBRA=
56.661
$START
$
D
AUCV,
DM1
$RAT
SET
PSNA=
53.53
$START
$
D
AUCV,
DM1
$RAT
SET
VMAXC=
20.907
$START
$
D
AUCV,
DM1
$RAT
SET
KM=
0.41612
$START
$
D
AUCV,
DM1
$RAT
SET
BW=
0.2525
$START
$
D
AUCV,
DM1
$RAT
SET
QPC=
21.109
$START
$
D
AUCV,
DM1
$RAT
SET
QCC=
17.675
$START
$
D
AUCV,
DM1
$RAT
SET
QLC=
0.18483
$START
$
D
AUCV,
DM1
$RAT
SET
QBRC=
0.0202
$START
$
D
AUCV,
DM1
$RAT
SET
QFC=
0.0707
$START
$
D
AUCV,
DM1
$RAT
SET
QSC=
0.33936
$START
$
D
AUCV,
DM1
$RAT
SET
QSNC=
O.
O1111
$START
$
D
AUCV,
DM1
$RAT
SET
VLC=
O.
O36966
$START
$
D
AUCV,
DM1
$RAT­
SET
VBRC=
0.005757
$START
$
D
AUCV,
DM1
$RAT
SET
VFC=
0.090496
$START
$
D
AUCV,
DM1
$RAT
SET
VRC=
0.223715
$START
$
D
AUCV,
DM1
$RAT
SET
VSC=
O.
600546
$START
$
D
AUCV,
DM1
$RAT
SET
VSNC=
0.00202
$START
$
D
AUCV,
DM1
$RAT
SET
KDET=
O.
02525
$START
$
D
AUCV,
DM1
$RAT
END
PROCED
RSA2
RAT
$START
$
range
cv
SET
PB=
58.58
$START
$
range
cv
$RAT
SET
PFA=
1452.38
$START
$
range
cv
$RAT
SET
PLA=
73.73
$START
$
range
cv
$RAT
SET
PRA=
61.307
$START
$
range
cv
$RAT
SET
PSA=
23.23
$START
$
range
cv
$RAT
SET
PBRA=
56.661
$START
$
range
cv
$RAT
SET
PSNA=
53.53
$START
$
range
cv
$RAT
SET
VMAXC=
20.907
$START
$
range
cv
$RAT
SET
KM=
0.41612
$START
$
range
cv
$RAT
SET
BW=
0.2525
$START
$
range
cv
$RAT
SET
QPC=
21.109
$START
$
range
cv
$RAT
SET
QCC=
17.675
$START
$
range
cv
$RAT
SET
QLC=
0.18483
$START
$
range
cv
$RAT
SET
QBRC=
0.0202
$START
$
range
cv
$RAT
SET
N=
l
38
FINAL
SET
QFC=
0.0707
$START
$
range
cv
$RAT
SET
QSG0.33936
$START
$
range
cv
$RAT
SET
QSNC=
O.
O1111
$START
$
range
cv
$RAT
SET
VLC=
0.036966
$START
$
range
cv
$RAT
SET
VBRC=
0.005757
$START
$
range
cv
$RAT
SET
VFC=
0.090496
$START
$
range
cv
$RAT
SET
VRC=
0.223715
$START
$
range
cv
$RAT
SET
VSC=
0.600546
$START
$
range
cv
$RAT
SET
VSNC=
0.00202
$START
$
range
cv
$RAT
SET
KDET=
O.
02525
$START
$
range
cv
$RAT
END
proced
RATSA
set
hvdprn=.
f.,
tstop=
l68,
points=
30000
bolus
set
dose=
92,
ka=
0.887
Rsal
SET
dose=
92.92
$START
$
D
AUCV,
DM1
$set
dose=
92
SET
ka=
0.89587
$START
$
D
AUCV,
DM1
$set
ka=
0.887
$START
$
D
AUCV,
DM1
Rsa2
SET
dose=
92.92
$START
$
range
cv
$set
dose=
92
SET
ka=
0.89587
$START
$
range
cv
$set
ka=
0.887
$START
$
range
cv
set
dose=
1.7,
ka=
5.07,
tstop=
23.5
Rsal
SET
dose=
1.717
$START
$
D
AUCV,
DM1
$set
dose=
1.7
SET
ka=
5.1207
$START
$
D
AUCV,
DM1
$set
ka=
5.07
$START
$
D
AUCV,
DMl
Rsa2
SET
dose=
1.717
$START
$
range
cv
$set
dose=
1.7
SET
ka=
5.1207
$START
$
range
cv
$set
ka=
5.07
$START
$
range
cv
END
PROCED
ROIL
CCL2CCL
RAT
bolus
SET
N=
l,
DOSE=
94.2,
BW=
0.147,
KA=
O.
887,
TSTOP=
8.02
.'
END
DATA
ROILDATA
(T,
CV)
0.52
12.13
1.01
8.45
2.01
4.04
8.02
0.16
39
FINAL
END
PROCED
RWAT
CCL2CCL
RAT
bolus
SET
N=
l,
DOSE=
1.66,
BW=
0.152,
KA=
5.07,
TSTOP=
l
END
DATA
RWATDATA
(T,
CV)
0.11
0.047
0.25
0.026
0.51
0.024
1.00
0.024
END
PROCED
MOIL
CCL2CCL
MOUSE
bolus
SET
N=
l,
DOSE=
365,
BW=
0.0194,
KA=
O.
18,
TSTOP=
168.0
END
DATA
MOILlDAT
(T,
CV)
0.52
11.1
0.98
7.8
2.0
4.0
8.0
0.21
END
PROCED
MWAT
CCL2CCL
MOUSE
bolus
SET
N=
l,
DOSE=
9.7,
BW=
0.0194,
KA=
4.4,
TSTOP=
l
END
DATA
MWATDATA
(T,
CV)
0.11
0.19
0.25
0.045
0.51
0.049
1.0
0.026
END
PROCED
MGAVEXH
CCL2CCL
MOUSE
SET
N=
5,
DOSE=
26.6,
BW=
0.0228,
KA=
2,
TSTOP=
2
SET
FLOW=
10.7,
VCHC=
2.2
40
FINAL
END
PROCED
SHOWIT
DISPLY
QPC,
QCC,
QFC,
QLC,
QRC,
QSC,
...
VFC,
VLC,
VRC,
VSC,
.
.
.
PFA,
PLA,
PRA,
PSA,
PB,
.
.
.
VMAXC,
KM,
BW,
MW,
ka,
ksi,
kai,
...
VCHC,
FLOW,
DOSE,
IALG,
TSTOP,
POINTS,
contdose,
N
END
$`
of
proced
proced
contmet
set
cont
do
s
e
=

set
contdose=
set
contdose=
set
c
ont
do
s
e=
set
contdose=
set
contdose=
set
cont
dos
e
=

set
contdose=
set
cont
do
s
e
=
set
cont
dose=
set
contdose=
set
contdose=
set
cont
dose=

set
contdose=
set
contdose=
set
cont
dose
=

set
contdose=
set
cont
do
s
e=
set
cont
dose=
set
contdose=
set
contdose=
set
cont
dos
e
=

set
cont
do
s
e=
set
cont
do
s
e=
set
contdose=
set
contdose=

end
proced
contoral
CCLZCCL
s
h
o
w
i
t
2
4
10
30
50
80
100
12
0
190
240
290
340
390
2
4
10
30
50
80
100
120
190
240
290
34
0
390
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
contdose,
contdose,
contdose,
contdose,
contdose
I
contdose,
contdose,
contdose,
contdose,
contdose
I
contdose,
contdose,
contdose,

$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
aucv
,
aucv
,
aucv
,
aucv
,
aucv
I
aucv
,
aucv
,
aucv
,
aucv
,
aucv
,
aucv,
aucv
,
aucv,
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
SET
tdur=
12,
TSTOP=
168
set
n=
O
,
ka=
4.4,
dose=
O
mouse
contmet
mmouse
'
contmet
41
FINAL
end
proced
gavmet
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=

set
d~
se=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=
set
dose=

end
2
4
10
30
50
80
1
0
0
12
0
190
240
290
340
390
2
4
10
30
50
80
1
0
0
12
0
190
240
290
340
390
PROCED
PERORAL
CCL2CCL
PERDWR
set
TSTOP=
168
set
n=
O,
ka=
4.4,
mouse
gavmet
mmouse
gavmet
end
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
$start
contdose=
O
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,
$d
dose,
aucv,

$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
$range
cv
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
dml
proced
OIL
set
hvdprn=.
f.
CCLZCCL
bolus
Set
TSTOP=
168
42
FINAL
set
n=
O,
ka=
0.18,
contdose=
O
mouse
gavmet
mmouse
gavmet
end
SET
WESITG=.
F.,
GRDCPL=.
F.,
XINCPL=
6.0,
YINCPL=
4.0
SET
DEVPLT=
l,
CJVITG=.
F.,
HVDPRN=.
T.

43
FINAL
GISIR2.
CSL
PROGRAM:
GIsir.
CSL
'Modified
to
describe
off­
gasing
so
we
can
refine
gavage
parms'
'Has
provision
for
two/
one
compartment
stomach
comparisons.
'M.
L.
Gargas
I
'Revised
4/
16/
2001
and
8/
31/
01
by
LM
Sweeney'
'revised
12/
17/
2001,
add
suicide
inhib
rel.
to
tot
enz'
INITIAL
1..
FORMAT(/,
'
GI.
CSL,
Rev.
1/
19/
90
at
9:
OO
am
I
,/)

WRITE(
0,
l)
$
WRITE(
7,
l)

CONSTANT
BW
=
0.029
$'Body
weight
(kg)
for
MICE'
CONSTANT
QPC
=
15.
$'Alveolar
ventilation
rate
(l/
hr)
I
CONSTANT
QCC
=
15.
$'Cardiac
output
(l/
hr)
'

'Flows
to
Tissue
Compartments'
CONSTANT
QLC
=
0.24
$'Fractional
CONSTANT
QSC
=
0.18
$'Fractional
CONSTANT
QFC
=
0.02
$'Fractional
CONSTANT
QSNC
=
0.011
$'Fractional
CONSTANT
QBRC
=
0.02
$'Fractional
QRC
=
1.0
­
(QFC
+
QSC
+
'Volumes
of
Tissue
Compartments'
blood
flow
to
liver'
blood
flow
to
fat'
blood
flow
to
slow'
blood
flow
to
spleen'
blood
flow
to
brain'
QLC
i­
QBRC
+
QSNC)

CONSTANT
VLC
=
0.04
$'Fraction
liver
tissue'
CONSTANT
VFC
=
0.04
$'Fraction
fat
tissue'
CONSTANT
VRC
=
0.05
$'Fraction
Rapidly
Perf
tissue'
CONSTANT
VBRC
=
0.0057
$'Fraction
of
brain'
CONSTANT
VSC
=
0.5946
$'Fraction
spt'
CONSTANT
VSNC
=
0.0035
$'Fraction
spleen'

'Partition
Coefficients'
CONSTANT
PLA
=
8.60
$'Liver/
air
partition
coefficient'
CONSTANT
PFA
=
263.0
$'Fat/
air
partition
coefficient'
CONSTANT
PSA
=
3.15
$'Muscle/
air
(Slow
Perf)
partition'
CONSTANT
PSNA
=
53
$'spleen/
air
partition'
CONSTANT
PRA
=
8.60
$'Richly
perfused
tissue/
air
partition'
CONSTANT
PBRA
=
8.60
$'brain/
air
partition'
CONSTANT
PB
=
10.8
$'Blood/
air
partition
coefficient'

'Other
Compound
Specific
Parameters'
CONSTANT
MW
=
133.5
$'Molecular
weight
(g/
mol)
CONSTANT
VMAXC
=
0.419
$'Maximum
Velocity
of
Metabol.
'
CONSTANT
VMAXRC
=
0.419
$'Maximum
Velocity
of
Metabol.
in
rpt'
CONSTANT
KM
=
5.75
$'Michaelis
Menten
Constant'
CONSTANT
KFC
=
0.0
$'First
order
rate
constant'
CONSTANT
DOSE
=
0.0
$'BOLUS
GAVAGE
dose
(mg/
kg/
day)
'
CONSTANT
ka
=
0.6
$'Stomach
Absorption
Rate
constant'

44
FINAL
CONSTANT
kai
=
0.0
$'Intestine
Absorption
Rate
constant'
CONSTANT
ksi
=
0.0
$'Stomach/
Intestine
Xfer
Rate
Constant'

CONSTANT
TSTOP
='
6.
$
'Length
of
experiment
(hrs)
'Timing
commands'

CONSTANT
POINTS
=
72.
$'Number
of
points
in
plot'

constant
contdose=
O
$'continuous
oral
dose
(mg/
kg/
d)
Constant
tdur
=24
$'duration
of
continuous
ingestion
(hr)
CONSTANT
TCHNG=
120
$'allows
exposure
free
weekends
(hr)
array
drt
ime
(
6
$'splits
DW
bolus
into
6
boluses'
array
drpct
(6
)
$'pet
of
dw
ingestion
at
each
bolus'
constant
drtime=
6*
0.0,
drpct=
6*
0.0
CINT
=
TSTOP/
POINTS
'Constants
associated
with
Off­
Gasing
Chamber'
CONSTANT
VCHC
=
2.54
$'Volume
of
Chamber
(liters)
'
CONSTANT
FLOW
=
7.2
$'Flow
thru
Chamber
(liters/
hr)
CONSTANT
N'=
1
$'Number
of
animals
in
chamber'

'Scaled
parameters
calculated
in
this
sectkon
of
Program'
QC=
QCC*
BW**
0.7
$
QP=
QPC*
BW**
0.7
QL=
QLC*
QC
$
QF=
QFC*
QC
$
QS=
QSC*
QC
$
QR=
QRC*
QC
$QBR=
QBRC*
QC
$QSN=
QSNC*
QC
VL=
VLC*
BW
$
VF=
VFC*
BW
$
VS=
VSC*
BW
$
VR=
VRC*
BW
$
VBR=
VBRC*
BW
$VSN=
VSNC*
BW
PL=
PLA/
PB
$
PR=
PRA/
PB
$
PS=
PSA/
PB
$
PF=
PFA/
PB
$pbr=
pbra/
pb
$PSN=
PSNA/
PB
NEWDAY
=
0
INTEGER
I
1=
1
VMAX
=
VMAXC*
BW**
O.
7
$
DOSE2=
O
$
KF=
KFC/
BW**
0.3
VMAXR
=VMAXRC*
BW**
0.7
VCH
=
VCHC­
BW*
N
IF(
VCH
.LE.
0.0)
WRITE(
0,2)
2..
FORMAT(//,
IChamber
Volume
Less
than
ZERO!!!
',//)

'parameters
associated
with
suicide
inact
of
enz
and
resynthesis'
CONSTANT
Kdes=
O
$'rate
of
enzyme
activity
loss
thru
inhibition
by
ES
mechl
Constant
kdte=
O
$'rate
of
enzyme
activity
loss
thru
inhibition
by
TE
mech'
Constant
kdfe=
O
$'rate
of
enzyme
activity
loss
thru
inhibition
by
FE
mech'
Constant
kdbi=
O
$'rate
o
f
enzyme
activity
loss
thru
inhibition
by
BI
mech'
CONSTANT
Kdet=
0.025
$'normal
turnover
of
enzyme'

END
$'End
of
initial'

DYNAMIC
ALGORITHM
IALG
=
2
$'Gear
method
for
stiff
systems'
TERMT
(T.
GE.
TSTOP)
CR
=
AR/
VR
$
CS
=
AS/
VS
$
CF
=
AF/
VF
$
CL
=
AL/
VL
$
CBR
=
ABR/
VBR
CSN
=
ASN/
VSN
BODY
=
AL
+
AR
­I­
AS
+
AF
+
ABR
+
ASN
+
STOM
+
INT
FINAL
BURDEN
=

DERIVATIVE
'ACH
=

RACH
=

ACH
=
CI
=

RLOST
=

LOST
=

PPMOUT
=
AM
+
BODY
Amount
in
Off
Gasing
Chamber
(mg)
'

INTEG
(
RACH
,

CIXFLOW
INTEG
(RLOST
I
CI*
24450./
MW
N*
QP*(
CX
­
CI)
­
CI*
FLOW
0
)
ACH/
VCH
0
.
0
)

PROCEDURAL
IF(
T
.LT.
(drtime(
1)
+
NEWDAY)
)
GO
TO
SKIP2
DOSE2
=
dose2
+
dose*
bw*
drpct(
I)*
PULSE(
O.
O,
l68.
O,
tchng)
I
=I
+1
IF(
1
.LT.
7
)
GO
TO
SKIP2
I
=I
­6
NEWDAY
=
NEWDAY
+
24.0
SKIP2..
CONTINUE
END
$'of
PROCEDURAL'

'Mass
Balance
for
the
Stomach'

STOM
=
INTEG(
RSTOM,
O)+
dose2
RSTOM
=
­ka*
STOM
­ksi*
STOM
+contdose*
bw/
tdur*
PULSE(
O.
O,
24.
O,
TDUR)

'Mass
Balance
for
the
Intestine'
RINT
=
+ksi*
STOM
­kai*
INT
INT
=
INTEG(
RINT,
0.0)

'CA
=
Concentration
in
arterial
blood
(mg/
l)
'
CA
=
(QC*
CV+
QP*
CI)
/
(QC+
(QP/
PB)
)

AUCB
=
INTEG(
CA,
O.)
cx
=
CA/
PB
'AS
=
Amount
in
slowly
perfused
tissues
(mg)
'
RAS
=
QS*(
CA­
CVS)
AS
=
INTEG(
RAS,
O.)
CVS
=
AS/(
VS*
PS)

'ASN
=
Amount
in
spleen
(mg)
RASN
=
QSN*
(CA­
CVSN)
ASN
=
INTEG(
RASN,
O.)
CSN
=
ASN/
VSN
CVSN
=
CSN/
PSN
aucsn=
integ
(CSN,
0.
)

'AR
=
Amount
in
rapidly
perfused
tissues
(mg)
'
RAR
=
QR*(
CA­
CVR)
­
RAMR
46
FINAL
AR
=
INTEG(
RAR,
O.)
CVR
=
AR/(
VR*
PR)

END
END
EM)
'ABR
=
Amount
in
rapidly
perfused
tissues
(mg)
'
RABR
=
QBR*
(CA­
CVBR)
ABR
=
INTEG(
RABR,
O.)
CVBR
=
ABR/
(VBR*
PBR)

'AF
=
Amount
in
fat
tissue
(mg)
'
RAF
=
QF*(
CA­
CVF)
AF
=
INTEG(
RAF,
O.)
CVF
=
AF/(
VF*
PF)

'VMT
=
maximal
rate
of
metabolism'
RVMT
=
(VMAX­
VMT)*
KDET­
KDES*
RAML*
RAML­
KDTE*
RAMLT
..
­KDFE*
RAML*
VMT*
KM/(
KM+
CVL)­
KDBI*
RAML
VMT
=
INTEG(
RVMT,
VMAX)

'
A
M
=
Amount
metabolized
(mg)
'
RAML
=
(VMT*
CVL)/(
KM+
CVL)
+
KF*
CVL*
VL
RAM
=
RAML
+
RAMR
RAMR
=
(VMAXR*
CVR)
/
(KM+
CVR)

AM
=
INTEG(
RAM,
0.)
AML
=
INTEG(
RAML,
O)

'AL
=
Amount
in
liver
tissue
(mg)
'
RAL
=
QL*(
CA­
CVL)
­
RAML
+
ka*
STOM
+
kai*
INT
AL
=
INTEG(
RAL,
O.)
CL
=
AL/
VL
AUCL
=
INTEG(
CL,
O.)
CVL
=
AL/(
vL*
PL)

DM1
=
AML/
VL
DM
=
DM1*
1000/
MW
'CV
=
Mixed
venous
blood
concentration
(mg/
l)

aucv=
integ(
cv,
0
.)
CV
=
(QF*
CVF
+
QL*
CVL
+
QS*
CVS
+
QR*
CVR
+
QBR*
CVBR
+QSN*
CVSN)/
QC
$'End
of
derivative'
$'End
of
dynamic'
$'End
of
program'

47
FINAL
REFEmNCES
Brown,
R.
P.,
Delp,
M.
D.,
Lindstedt,
S.
L.,
Rhomberg,
L.
R.,
Beliles,
R.
P.
(1997).
Physiological
parameter
values
for
physiologically
based
pharmacokinetic
models.
Toxicol
Ind
Health
13,407­
484
Clewell,
H.
J.,
111,
Gentry,
P.
R.,
Covington,
T.
R.,
Gearhart,
J.
M..
(2000).
Development
of
a
physiologically
based
pharmacokinetic
model
of
tichloroethylene
and
its
metabolites
for
use
in
risk
assessment.
Environ
Health
Perspect
108(
Suppl.
2),
283­
305.

Delp,
M.
D.,
Manning,
R.
O.,
Bruckner,
J.
V.,
Armstrong,
R.
B..
(1991).
Distribution
of
cardiac
output
during
diumal
changes
of
activity
in
rats.
Am
J
Physiol261,
H1487­
H1493.

Gargas,
M.
L.,
Burgess,
R.
J.,
Voisard,
D.
E.,
Cason,
G.
H.,
andhdersen,
M.
E.
(1989).
Partition
coefficients
for
low
molecular
weight
volatile
chemicals
in
various
liquids
and
tissues.
Toxicol.
Appl.
Pharmacol.
98,
87­
99.

Gargas,
M.
L.,
Andersen,
M.
E.(
1989).
Determining
kinetic
constants
of
chlorinated
ethane
metabolism
in
the
rat
from
rates
of
exhalation.
Toxicol
Appl
Pharmacol99,
344­
353.

Lilly,
P.
D.,
Thornton­
Manning,
J.
R.,
Gargas,
M.
L.,
Clewell,
H.
J.
Andersen,
M.
E.
(1997).
Kinetic
characterization
of
CYP2E1
inhibition
in
vivo
and
in
vitro
by
the
chloroethylenes.
Arch.
Toxicol.
72,
609­
62
1.

MGA
(1997).
ACSL
Optimize
User's
Guide.
Version
2.1.
MGA
Software,
Concord,
MA.

Nakajima,
T
(1
997).
Cytochrome
P450
isoforms
and
the
metabolism
of
volatile
hydrocarbons
of
low
relative
molecular
mass.
J.
Occup.
Health
39,
83­
9
1,

National
Toxicology
Program
(1
978).
Bioassay
of
1
,
lY2­
trichloroethane
for
possible
carcinogenicity.
CAS
No.
79­
00­
5.
NCI­
CG­
TR­
74.
U.
S.
Department
of
Health,
Education,
and
Welfare,
Public
Health
Service,
National
Institutes
of
Health.
DHEW
Pub.
No.
(NIH)
79­
1324.
Bethesda,
Maryland.

Poet,
TS;
Curry,
TL;
Luders,
TM,
Wu,
H;
Studniski,
KG;
Weitz,
KK;
and
Corley,
RA.
(200
1).
Pharmacokinetics
of
1,1,2­
Trichloroethane
in
Rats
and
Mice.
Battelle
Project
No.
41608.
Oct.
18,2001.
Final
Report.

48
FINAL
Reitz,
RH;
Hays,
SM;
Gargas,
ML.
(1997).
Addressing
priority
data
needs
for
methylene
chloride
with
physiologically
based
pharmacokinetic
modeling.
Prepared
for
the
Agency
for
Toxic
Substances
and
Disease
Registry
on
behalf
of
the
Halogenated
Solvents
Industry
Alliance
by
RHR
Consulting
Services
and
McLaredHart.
February
4,
1997.

U.
S.
EPA
(2000)
1
,
lY2­
Trichloroethane
(TCE);
Final
Enforceable
Consent
Agreement
and
Federal
Register
65,
No.
116,
pp
37550­
37553,
June
15,
Testing
Consent
Order.
2000.

West,
J.
B.
and
Wagner,
P.
D.
(1
99
1).
Chapter
5.3.4.
Ventilation­
Perfusion
Relationships.
In:
The
Lung:
Scientific
Foundations.
Edited
by
RG
Crystal
and
JB
West.
Raven
Press,
Ltd.,
New
York.
Pp.
1289­
1305.

White,
K.
L.,
Sanders,
V.
M.,
Barnes,
D.
W.,
Shopp,
G.
M.,
Jr.,
Munson,
A.
E..
(1985).
Toxicology
of
1,1,2­
trichloroethane
in
the
mouse.
Drug
Chem
Toxicol8,
333­
355.

WIL
Research
Laboratories
(2002).
A
90­
day
inhalation
toxicity
study
of
1,
1,
2­
trichloroethane
(1,
1,
2­
TCE)
in
rats
(with
satellite
groups
for
pharmacokinetic
evaluation
in
rats
and
mice.
WIL
study
number
WIL­
417002.
WIL
Research
Laboratories,
Ashland,
Ohio.
In
preparation;
anticipated
June
2002.

Yllner,
S.
(1
97
1).
Metabolism
of
1,1,2­
trichloroethane
­
1
,2­
I4C
in
the
mouse.
Acta
Pharmacol
Toxicol30,
248­
256.

49
FINAL
TABLES
50
FINAL
Source
TABLE
1
Physiological
parameters
for
preliminary
PBPK
models
of
1,1,2­
TCE
(B6C3F1
mice
and
F344
rats)

Comment
Value
Units
I
Parameter
Mouse
Rat
20.9
Alveolar
ventilation
rate
(Q
W
16.5
L
h
k
g
body
Brown
et
al.
(1997)
QP
=
QPC
*
BW0.7.
Value
for
mouse
is
the
low
end
of
the
average
range;
rat
value
is
the
mean.

1
output
23.1
17.5
Lihrkg
body
Brown
et
al.
(1997)
QC
=
QCC
*
B
W0.7
I
Fractional
blood
flow
to
liver
(Q
W
0.161
0.183
Brown
et
al.
(1997)
dimensionless
I
Fractional
blood
flow
to
brain
(Q
B
W
0.033
0.02
dimensionless
Brown
et
al.
(1997)

Fractional
blood
flow
to
richly
perfused
tissues
(QRC)
0.508
0.38
dimensionless
QR=
QC­
QL­
QF
­
QS
­QSN
Fractional
blood
flow
to
fat
(QFC)
0.07
0.07
dimensionless
Brown
et
al.
(1997)
Rat
value
also
used
for
mouse
Fractional
blood
perfused
tissues
flow
to
slowly
(QW
0.217
0.01
1
0.336
0.01
1
dimensionless
Brown
et
al.
(1997)
Skin
and
muscle
dimensionless
Fractional
blood
flow
to
spleen
(Q
S
W
Delp
et
al.
(1991)
Rat
value
also
used
for
mouse
51
FINAL
Units
Source
I
Parameter
Comment
!
Value
Mouse
Rat
0.0366
0.0.549
Brown
et
al.
(1997)
Fractional
weight
of
liver
(VLC)
dimensionless
0.0169
Brown
et
al.
(1997)
Fractional
weight
of
brain
(VBRC)
0.00.57
dimensionless
0.1958
dimensionless
Brown
et
al.
(1997)
Fractional
weight
of
richly
perfused
tissue
(V
W
0.22
15
1­(
bone
+
other
modeled
tissues)

I
0.07
Fractional
weight
of
fat
(VFC)
dimensionless
0.07
Brown
et
al.
(1997)

Brown
et
al.
(1997)
0.5493
0.5946
Fractional
weight
perfused
tissues
of
slowly
(V
W
dimensionless
Skin
and
muscle
I
0.0035
~

dimensionless
0.002
Fractional
weight
of
spleen
(VSPC)
Brown
et
al.
(1997)

Measured
body
weights
used
in
modeling
of
'1.11
experiments,
if
Default
body
weight
(BW)
0.025
0.25
52
FINAL
TABLE
2
Partition
Coefficients
F344
rat
Source
Comment
B6C3F1
Mouse
71
58
Rat:
Gargas
et
al.
(1989)
Mouse:
Poet
et
al.
(200
1)
B1ood:
air
PC
(PB)

Liver:
air
PC
(PLA)

Brain:
air
P
C
(P
B
W
73
Rat
tissue:
air
PC
from
Gargas
et
al.
(1
989).
Tissue:
blood
PCs
calculated
as
tissue:
air
PC/
b1ood:
air
PC.
Mouse
tissue:
air
PC
assumed
equal
to
rat
value.
73
56.1
Rat
tissue:
air
PC
from
Poet
et
al.
(200
1)
~

Same
as
described
for
liver.
56.1
60.7
60.7
Average
of
liver,
brain,
and
sp1een:
air
PCs.
Richly
perfused
tissue:
air
PC
(Pw
1438
1438
Rat
tissue:
air
PC
from
Gargas
et
al.
(1
989)
Same
as
described
for
liver.
Fat:
air
PC
(PFA)

Muscle
(slowly
perfused
tissue):
air
PC
(PSA)
23
23
Rat
tissue:
air
PC
From
Gargas
et
al.
[
1989)
Same
as
described
for
liver.

53
53
Rat
tissue:
air
PC
From
Poet
et
al.
:2001)
Same
as
described
for
liver.
'
Sp1een:
air
PC
(PSNA)

53
FINAL
Source
TABLE
3
Kine
tic/
'Up
take
Parameters
Comment
Maximum
capacity
of
saturable
metabolism
(VMAXC,
mg/
hrA~
gO.~)
This
study
This
study
~
~

Enzyme
affinity
for
saturable
metabolism
(m,
m
g
u
Determined
by
optimization
as
described
in
text.

Determined
by
optimization
as
described
in
text.

~
~~

Normal
enzyme
turnover
rate
(KDET,
1
h
)
Lilly
et
al.
(1
998)

Enzyme
destruction
by
suicide
inhibition
through
first
order
inactivation
by
bound,
reactive
intermediate
(KDBI,
l
h
)
Normal
enzyme
(cytochrome
P­
450
2E1)
half
life
of
29
hours
for
rat.

First
order
metabolism
(KFC)
This
study
Absorption
rate­
water
(KA,
l
h
)
Determined
by
optimization
of
fit
to
corn
oil
gavage
data.

Absorption
rate­
corn
oil
(KA,
l/
hr)
This
study
This
study
B6C3F1
Mouse
(female)

Determined
by
optimization
of
fit
to
gavage
data.

Determined
by
optimization
of
fit
to
gavage
data.
16.8
0.222
0.025
0.1034
0
4.4
0.18
F344
rat
(female)

20.7
0.412
Not
applicable
Not
applicable
0
5.07
0.887
54
1
i
Gargas
and
Ander­
sen
(1
989)
FINAL
FIGURE
LEGENDS
Figure
1.
Structure
of
physiologically
based
pharmacokinetic
models
of
1,1,2­
TCE
disposition
in
female
rats
and
mice.
Solid
lines:
Blood
flow.
Heavy
solid
line:
metabolism.
Dotted
line:
air
exchange.
Dashed
line:
gastrointestinal
absorption.

Figure
2.
Blood
concentrations
of
1,1,2­
TCE
in
female
F344
rats
(average
body
weight
=

0.160
kg)
exposed
to
100
ppm
1,1,2­
TCE
for
6
hours.
Blood
concentrations
were
measured
on
days
1
,
3,
and
5
of
the
fourth
week
of
exposure
(5
daydweek).
Day
1,
A
Day
3,
+
Day
5
experimental
data
of
Poet
et
al.
(200
1).
Error
bars:
standard
deviation
of
experimental
data
(n
=
3
animals).
Line:
model
simulations.
*,
**
=
significant
difference
(pCO.
05,
two­
tailed)
between
days
1
and
3
or
1
and
5,
respectively.

Figure
3.
Blood
concentrations
of
1,1,2­
TCE
in
female
F344
rats
(average
body
weight
=

0.147
kg)
administered
94.2
mgkg
1,1,2­
TCE
in
corn
oil
by
gavage,
once
daily.
Day
1,
A
Day
3,
Day
5
experimental
data
of
Poet
et
al.
(2001).
Error
bars:
standard
deviation
of
experimental
data
(n
=
3
animals).
Line:
model
simulation.
*
significant
difference
(p<
0.05,
two­
tailed)
between
days
1
and
3.

Figure
4.
Blood
concentrations
of
1,1,2­
TCE
in
female
F344
rats
(average
body
weight
=

0.152
kg)
administered
1.66
mgkg
1,
ly2­
TCE
in
water
by
gavage,
once
daily.
Day
1,
A
Day
3,
Day
5
experimental
data
of
Poet
et
nl.
(2001).
Error
bars:
standard
deviation
of
experimental
data
(n
=
3
animals).
Line:
model
simulation.

Figure
5.
Blood
concentrations
of
1,1,2­
TCE
in
female
B6C3F1
mice
(average
body
weight
=
0.0228
kg)
exposed
to
100
ppm
1,1,2­
TCE
for
6
hours.
Blood
concentrations
were
measured
on
days
1,3,
and
5
of
the
fourth
week
of
exposure
(5
daydweek).
Day
1,
A
Day
3,
+
Day
5
experimental
data
of
Poet
et
nl.
(2001).
Error
bars:
standard
deviation
of
experimental
data
(n
=
3
animals).
Lines:
model
simulations
with
suicide
inhibition.
Model
simulation
for
4
hour­
exposure
shown
only
for
Day
1.
*,
**,
***
=
significant
difference
(p<
0.05,
two­
tailed)
between
days
1
and
3,
1
and
5,
or
3
and
5
,
respectively.

Figure
6.
Blood
concentrations
of
1,
ly2­
TCE
in
female
B6C3F1
d
c
e
(average
body
weight
=
0.0194
kg)
administered
365
mgkg
1,1,2­
TCE
in
corn
oil
by
gavage,
once
daily.
Day
1,
A
Day
3,
+
Day
5
experimental
data
of
Poet
et
al.
(2001).
Error
bars:
standard
deviation
of
experimental
data
(n
=
3
animals).
Lines:
model
simulations
with
suicide
inhibition.
*,
**,
***
=
significant
difference
(p<
0.05,
two­
tailed)
between
days
1
and
3,
1
and
5,
or
3
and
5
,
respectively.

55
FINAL
Figure
7.
Blood
concentrations
of
1,1,2­
TCE
in
female
B6C3F
1
mice
(average
body
weight
=
0.0
194
kg)
administered
9.7
mgkg
1,1,2­
TCE
in
water
by
gavage,
once
daily.
Day
1,
A
Day
3,
Day
5
experimental
data
of
Poet
et
al.
(2001).
Error
bars:
standard
deviation
of
experimental
data
(n
=
3
animals).
Line:
model
simulation
with
suicide
inhibition.
*,
**
=

significant
difference
(px0.05,
two­
tailed)
between
days
1
and
3
or1
and
5,
respectively.

Figure
8.
Predicted
changes
in
Vmax
for
female
B6C3F1
mice
(average
body
weight
=
0.0228
kg)
exposed
to
100
ppm
1,1,2­
TCE
for
6
hours/
day
for
five
days.
Line:
model
simulation
with
suicide
inhibition.

Figure
9.
Predicted
changes
in
Vmax
for
female
B6C3F1
mice
(average
body
weight
=

0.0
194
kg)
administered
365
mg/
kg
1,1,2­
TCE
in
corn
oil
by
gavage,
once
daily
for
five
days.
Line:
model
simulation
with
suicide
inhibition.

Figure
10.
Normalized
sensitivity
coefficients,
from
analyses
of
the
female
mouse
PBPK
model
of
1,1,2­
TCE
disposition
under
different
5­
day
exposure
scenarios.(
A).
Gavage
dosing,
390
mg/
kg/
d
in
corn
oil.
(B).
Gavage
dosing,
10
mg/
kg/
d
in
water.
(C)
Inhalation
exposure,
100
ppm,
6
hours/
d.

Figure
11.
Normalized
sensitivity
coefficients,
from
analyses
of
the
female
rat
PBPK
model
of
1,
lY2­
TCE
disposition
under
different
5­
day
exposure
scenarios.(
A).
Gavage
dosing,
92
mg/
kg/
d
in
corn
oil.
(B).
Gavage
dosing,
1.7
mgkg/
d
in
water.
(C)
Inhalation
exposure,
100
ppm,
6
hours/
d.

Figure
12.
Ratio
of
model­
predicted
values
of
various
dose
metrics
in
female
vs.
male
B6C3F1
mice
(assumed
body
weight
=
0.025
kg)
administered
1,1,2­
TCE
in
corn
oil
by
gavage,
once
daily
for
five
days.
Dashed
line:
blood
AUC.
Solid
line:
peak
blood
concentration.
Heavy
solid
line:
total
amount
metabolized.

Figure
13.
Equivalent
exposures
determined
by
PBPK
modeling
for
continuous
inhalation
(24
hrs/
day
for
seven
days)
and
drinking
water
(divided
into
six
boluses/
day
for
seven
days)
drinking
water
consumption
by
mice.
Solid
line:
female
B6C3F1
mice.
Heavy
solid
line:
male
B6C3F1
mice.

56
Figure
1.

Final
06/
2002
Inhalation
4­
1
Exhalation
b
.........................
I...
.
..................
.
...............................
.
................

Lung
1
Slowly
1_
perfused
tissue
Other
well
perfused
tissue
Brain
I_
I
I
Spleen
i
Gavage
or
drinking
water
I
I
I
I
I
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L
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