MEETING
SUMMARY
Title:
Technical
Consultation
Meeting
on
the
TCE
ECA
Date:
March
12,
2003
Time:
4:
30
PM
­
6:
30
PM
Location:
Society
ofToxicology
42w'
Annual
Meeting,
Sail
Lake
City
Convention
Center,
Room
252B.
Salt
Lake
City,
Utah.

Attendees:
For
EPA:
Richard
Leukroth
(
OPPT/
CCD),
Michel
Stevens
(
ORD/
NCEA),
Rob
Dewoskin
(
ORD/
NCEA),
Hugh
Barton
(
ORD/
NHEERL).

For
HAP
Task
Force:
Michael
Gargas,
Lisa
Sweeney
(
Sapphire
Group)

The
meeting
began
about
4:
30
p.
m.
A
copy
ofthe
Agenda
and
EPA
handout
is
attached.

Following
introductions,
Michael
Gargas
(
MG)
indicated
that
Peter
Voytek
(
PV)
was
not
able
to
attend
the
meeting.
PV
designated
MG
as
the
lead
representative
for
the
HAP
Task
Force
for
the
meeting.
He
explained
that
it
was
his
role
to
answer,
as
best
as
possible,
technical
questions
raised
by
EPA.
MG
indicated
that
any
policy
decision
would
need
to
be
relayed
back
to
PV
to
be
addressed
by
the
HAP
Task
Force.
Rich
Leukorth
(
RL)
summarized
accomplishments
to
date
under
the
enforceable
consent
agreement
for
1,1
,2­
trichloroethane
(
TCE
ECA)
and
reviewed
the
purpose
ofthe
EPA
Tier
I
Program
Review
as
described
in
the
ECA.
He
explained
that
this
technical
consultation
is
to
preview
EPA's
Tier
I
Program
Review
activity
preliminary
findings
for
the
HAP
Task
Force,
engage
in
scientist­
to­
scientist
discussions
on
clarifying
questions,
and
to
discuss
the
nature
and
scope
of
Tier
II
testing
to
be
conducted
under
the
TCE
ECA.

Pointing
to
the
first
paragraph
of
the
EPA
handout,
RL
acknowledged
HAP
Task
Force
accomplishments
under
the
TCE
ECA
for
Tier
I
Testing
and
Tier
I
Program
Review
Testing.
He
noted
that
the
preliminary
findings
for
the
EPA
Program
Review
conclude
that:
1)
the
PK/
MECH
data
report
and
Tier
I
toxicity
studies
appear
to
have
been
conducted
in
accordance
with
the
protocols
and
specifications
as
described
in
Appendix
C
of
the
ECA,
2)
the
available
study
records
are
sufficient
to
allow
an
evaluation
of
the
quality
of
the
studies
performed
and
the
data,
3)
the
TCE
PBPK
model
is
chemical­
specific,
and
based
on
the
current
understanding
ofthe
kinetics
of
TCE,
4)
the
species,
dose
level,
exposure
regimens,
and
vehicles
used
are
relevant
for
the
toxicity
data
that
are
the
object
ofthe
Tier
H
extrapolations,
and
5)
the
Tier
I
Program
Review
1
OPPT­
2002­
0056­
0063
RECEIVED
OPPT
NCIC
2003
JUN23
2:
46PM
PK/
MECH
data
demonstrated
that
periodicity
was
achieved
in
the
studies
that
support
the
model.
In
this
respect,
the
HAP
Task
Force
has
accomplished
the
goals
and
objectives
set
out
under
Tier
I
of
the
TCE
ECA.

RL
informed
the
HAP
Task
Force
that
EPA
is
preparing
a
Tier
I
Program
Review
Report
summarizing
this
activity.
In
the
process
of
preparing
the
Tier
I
Program
Review
Report
several
questions
arose
which
are
the
discussion
topics
listed
in
the
handout.
He
pointed
out
that
these
discussion
topics
fall
into
two
categories:
(
a)
items
that
need
to
be
addressed
as
a
clean­
up
of
Tier
I
reporting
activities
and
(
b)
items
that
need
to
be
reflected
in
protocol
development
under
Tier
II
Testing.
Discussion
began
with
handout
Discussion
Topic
#
2.

Rob
Dewoskin
(
RD)
led
the
discussion
on
the
need
for
quality
review
of
the
PK
and
PBPK
reports.
He
identified
examples
ofreporting
errors
and
inconsistencies
in
these
reports.
RL
explained
that
reporting
problems
concern
EPA,
especially
in
light
of
EPA's
Information
Quality
Guidelines'
(
IQGs)
and
resepct
to
the
receipt
of
data
and
information
that
the
Agency
will
rely
on
for
decision
making.
RL
emphasized
the
need
for
reports
to
be
fully
transparent
in
describing
experimental
procedures
and
the
assumptions
used
in
reporting
experimental
results.
MG
questioned
whether
the
IQGs
apply
to
ECAs.
RL
cited
a
section
of
the
IQG
indicating
that
IQGs
may
be
invoked
as
part
ofnegotiated
agreements
such
as
memorandum
ofunderstandings
(
i.
e.,
ECAs).
RD
pointed
out
that
neither
report
included
GLP
requirements
for
quality
assurance
audits
and
compliance
statements.
He
indicated
that
it
should
be
possible
for
the
contracted
laboratories
to
conduct
audits
of
laboratory
notebooks
and
reports
and
to
develop
a
compliance
I
non­
compliance
statement
that
could
satisfy
this
reporting
requirement
need.
MG
and
Lisa
Sweeney
(
LS)
indicated
that
one
of
the
laboratories
probably
had
a
quality
assurance
unit
that
could
respond
appropriately
and
that
standard
operating
procedures
were
probably
available
for
much
ofthe
PK
work.
RL
suggested
that
these
required
corrections
of
reporting
problems
and
omissions
could
be
made
either
as
an
addendum
to
the
reports
or
as
a
submission
ofrevised
reports.
He
indicated
that
EPA
will
initiate
a
letter
to
the
HAP
Task
Force
indicating
the
problem
and
suggesting
a
resolution.

Handout
discussion
Topic
#
1:
Characterizing
variability
and
uncertainty
in
the
kinetic
data
and
the
model
simulations
RD
questioned
the
adequacy
of
the
HAP
Task
Force
PBPK
report
discussion
for
the
variability
in
the
kinetic
data
used
to
develop
the
model,
and
the
variability
and
uncertainty
in
the
model
with
respect
to
the
"
fit"
of
the
simulations
to
the
kinetic
data.
He
explained
how
a
more
thorough
discussion
could
further
support
scientifically
defensible
arguments
for
use
ofthe
PBPK
model
in
each
ofthe
proposed
route­
to­
route
extrapolations
and
indicated
that
examples
of
criteria
for
characterizing
"
fit"
might
include
percent
match
for
AUC,
or
simulation
curves
that
fall
within
±
"
x"
number
of
standard
deviations
of
the
mean.
HB
indicated
that
this
was
among
the
criteria
for
evaluating
a
models
"
goodness
of
fit"
that
his
group
had
included
in
a
poster
`
Available
from
http:
Ilwww
.
epa.
gov!
oei/
qualityguidelines/
index.
html
2
presented
at
the
SOT.
MG
and
LS
acknowledged
these
considerations
and
indicated
that
the
HAP
Task
Force
applied
a
factor
of
2­
fold
to
determine
a
reasonable
agreement
of
the
model
with
the
experimental
data.
They
pointed
out
that
this
criteria
was
listed
in
the
ECA
as
acceptable.
EPA
agreed
that
applying
a
factor
of
2­
fold
is
acceptable
under
this
ECA
and
indicated
that
including
objective
measures
of
variance
to
compare
residual
variance
would
strengthen
the
report
and
improve
transparency
for
interpretation
ofthe
results.
RL
indicated
that
the
HAP
Task
Force
may
want
to
consider
including
an
additional
discussion
of
this
point
in
an
addendum
to
the
report.

Handout
discussion
Topic
#
3:
Choice
of
dose
metrics
and
dosing
regimens
HB
indicated
that
the
real
tests
for
applying
the
PBPK
model
fall
into
Tier
H
activities.
As
presently
written
the
HAP
Task
Force
reports
are
not
transparent
in
regard
to
which
dose
metric
will
be
applied
to
specific
route­
to­
route
extrapolations
called
for
in
Tier
H.
Furthermore,
the
data
developed
in
Tier
I
provides
new
information
that
might
change
some
of
the
assumptions
for
best
approach
to
Tier
H
activities.
This
makes
it
difficult
to
review
how
the
model
will
perform
for
the
specific
studies
and
dose
metrics
called
for
in
Tier
H
since
the
utility
of
the
model
for
each
application
depends,
in
part,
on
the
choice
ofthe
dose
metric
and
the
dose
regimen
used
in
the
simulation.
MG
and
LS
indicated
that
the
model
is
designed
to
consider
multiple
dose
metric
scenarios
and
the
selection
of
the
most
appropriate
dose
metric
is
a
matter
of
scientific
judgement
and
details
related
to
the
endpoint
of
concern.
HB
indicated
that,
as
an
example,
it
may
be
appropriate
for
the
immunotoxicity
route­
to­
route
extrapolation
to
include
consideration
for
both
parent
and
amount
metabolized.
He
noted
that
similar
considerations
would
also
be
appropriate
for
the
neurotoxicity,
developmental,
and
reproductive
effects
studies
and
that
determining
the
Vmax
for
the
rat
would
also
be
informative
before
conducting
Tier
H
testing.
There
was
general
agreement
that
these
additional
considerations
should
be
included
as
a
component
ofprotocol
development
for
Tier
H
activities.

HB
also
indicated
that
the
HAP
Task
Force
report
was
not
transparent
in
regard
to
the
assumptions
that
would
be
applied
to
drinking
water
consumption
I
dose
exposure.
LS
explained
that
the
Sapphire
Group
has
experience
working
with
a
model
for
rat
drinking
water
consumption
that
assumes
most
of
the
water
consumption
occurs
at
night.
In
addition,
she
pointed
to
a
recent
UN
paper
on
the
subject
that
improves
the
state­
of­
the­
art
for
these
modeling
considerations.
All
agreed
that
this
should
be
fully
elaborated
in
the
Tier
II
protocols.

Handout
discussion
Topic
#
4:
Support
for
inclusion
of
suicide
inhibition
in
the
model
Discussion
on
this
topic
focused
on
research
opportunities
that
clearly
were
outside
the
scope
of
the
TCE
ECA.
MG
and
LS
indicated
that
the
HAP
Task
Force
report
cited
the
White
et
al.
(
1985)
2
publication
that
reported
decreases
in
total
cytochrome
P­
450
content
and
cyp
2E1
2
White,
K.
L.,
Sanders,
V.
M.,
Barnes,
D.
W.,
Shopp,
G.
M.,
Jr.,
Munson,
A.
E.
(
1985).

Toxicology
of
1,1,2­
trichioroethane
in
the
mouse.
Drug
Chem.
Toxicol.
8,
333­
355.

3
activity
in
female
mice.
Furthermore,
Tier
I
study
observations
showed
that
the
amount
ofparent
compound
increased
over
the
course
of
weekly
dosing
but
returned
to
predicted
values
following
weekend
periods
when
no
dosing
occurred.
This
pattern
is
indicative
of
loss
of
enzyme
activity
which
recovers
when
dosing
is
withdrawn
over
the
weekend.
The
inclusion
of
a
suicide
inhibition
parameter
appropriately
models
this
phenomena
for
modeling
purposes.

Handout
discussion
Topic
#
5:
Route
specific
considerations
for
nasal
toxicity.

EPA
noted
that
the
HAP
Task
Force
PBPK
modeling
report
did
not
include
a
discussion
of
the
potential
impact
ofthe
nasal
toxicity
effects
observed
in
the
TierI
Testing
inhalation
studies.
Concern
was
expressed
that
modeled
dosimetry
data
from
an
oral
toxicity
study
may
not
adequately
reflect
for
the
response
seen
from
inhalation
exposure.
The
HAP
Task
Force
commented
that
a
study
conducted
by
the
oral
route
would
potentially
identify
true
neurotoxicity
effect
and
rule
out
the
impact
of
nasal
irritation
on
functional
observations.
RL
suggested
that
a
discussion
of
this
point
should
be
included
as
justification
for
the
selection
of
the
oral
route
in
the
Tier
H
neurotoxicity
protocol.
Similar
considerations
could
also
be
provided
to
address
for
route
specific
effects
on
the
kinetics
including
first
pass
effects
and
delivery
ofparent
compound
to
the
brain
compartment
as
well
as
modeled
comparison
ofbioavailability
for
different
exposure
routes.

RL
closed
the
meeting
by
thanking
everyone
for
their
contributions.
He
explained
that
the
next
steps
will
include
the
following:
1)
EPA
will
send
the
HAP
Task
Force
a
letter
indicating
conditional
acceptance
of
the
PKIMECH
and
PBPK
modeling
reports
and
describing
reporting
problems
and
omissions
that
must
be
corrected,
2)
EPA
will
complete
a
Tier
I
Program
Review
Report
and
announce
the
report
in
a
Federal
Register
Notice
that
will
also
reset
the
clock
for
Tier
H
Testing
(
tentatively
scheduled
for
mid­
May),
and
3)
EPA
will
convey
by
letter
to
the
HAP
Task
Force
the
final
conclusions
from
the
Tier
I
Program
Review
and
indicate
that
Tier
H
Testing
can
proceed.

The
meeting
adjourned
at
about
6:
30
PM.

Prepared
by:
Richard
Leukroth
cc:
e­
docket
OPPT­
2002­
0056
4
Technical
Consultation
Meeting
on
1,1,2­
Trichloroethane
(
TCE)
EPA
Tier
I
Program
Review
Update
DATE
I
TIME:
March
12,
2003
4:
30
p.
m.
­
6:
00
p.
m.

LOCATION:

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

I.
Introductions
TENTATIVE
AGENDA
Rich
Leukroth
I
Peter
Voytek
H.
Overview
ofthe
ORD
Program
Review
Activity
III.
EPA
Discussion
Topics
IV.
Other
Comments
V.
Summary
and
Next
Steps
Rob
Dewoskin
(
see
attachment)

5
Meeting
Handout
March
12,
2003
Technical
Consultation
Meeting
for
1,1,2­
Trichioroethane
Tier
I
Program
Review
Overview
ofORD
Preliminary
Findings
EPA's
Tier
I
Programl
Review
for
1,1,2­
trichloroethane
(
TCE)
is
focused
on
four
reports
submitted
by
the
HAP
Task
Force
in
accordance
with
the
Enforceable
Consent
Agreement
(
ECA)
for
TCE.
The
on­
going
Program
Review
notes
that
the
PK/
MECH
data
and
Tier
I
toxicity
studies
appear
to
have
been
conducted
in
accordance
with
the
protocols
and
specifications
as
described
in
the
ECA.
The
available
study
records
are
sufficient
to
allow
an
evaluation
ofthe
quality
ofthe
studies
and
the
data.
The
TCE
PBPK
model
is
chemical­
specific,
and
is
based
on
the
current
understanding
of
the
kinetics
of
TCE.
The
species,
dose
level,
exposure
regimens,
and
vehicles
used
are
relevant
for
the
toxicity
data
that
are
the
object
of
the
Tier
H
extrapolations.
The
Tier
I
Program
Review
PKJMECH
data
demonstrated
that
periodicity
was
achieved
in
the
studies
that
support
the
model.
The
EPA
preliminary
review
identified
five
topics
for
discussion
at
a
technical
consultation
meeting
with
the
HAP
Task
Force.

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

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

6
Meeting
Handout
March
12,
2003
2)
Quality
review
of
the
pharmacokinetic
and
PBPK
data
and
reports.

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

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

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

3a)
Choice
of
dose
metrics
and
dosing
regimens
EPA
Preliminary
Finding:
The
PBPK
model
report
provides
a
good
example
of
the
potential
use
of
the
model
for
a
route­
to­
route
extrapolation,
in
this
case,
for
a
drinking
water
exposure
to
an
inhalation
exposure
using
amount
metabolized
as
the
dose
metric.
EPA
views
that
additional
examples
of
study
specific
route­
to­
route
extrapolation
curves
are
needed
to
adequately
review
how
the
PBPK
model
will
perform
for
the
specific
studies
and
dose
metrics
called
for
in
the
Tier
II
route­
to­
route
extrapolations.
The
utility
of
the
model
for
each
application
depends,
in
part,
on
the
choice
ofthe
dose
metric
and
the
dose
regimen
used
in
the
simulation
(
e.
g.,
the
dose
pattern
used
to
simulate
a
drinking
water
exposure).
Such
route­
toroute
extrapolation
curves
could
readily
be
developed
specific
to
each
ofthe
extant
Tier
H
studies
for
which
extant
data
is
available
(
immunotoxicity
and
carcinogenicity).
These
curves
will
provide
comparisons
among
different
dose
metrics
and
exposure
patterns,
and
will
support
a
more
scientifically
defensible
evaluation
ofthe
utility
ofthe
PBPK
model
for
each
application.

7
Meeting
Handout
March
12,
2003
3a)
Continued
Preliminary
Recommendation:
The
HAP
Task
Force
is
encouraged
to
proceed
with
these
reporting
activities
as
a
means
to
further
support
the
TCE
model
even
though
they
are
listed
as
Tier
II
ECA
activities.

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

Preliminary
Recommendation:
(
discussion
at
the
technical
consultation
meeting)

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

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

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

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

Preliminary
Recommendation:
(
discussion
at
the
technical
consultation
meeting)

8
Meeting
Handout
March
12,
2003
Sb)
Route
specific
considerations
of
the
nasal
toxicity
observed
in
the
inhalation
studies
on
the
kinetics.
EPA
Preliminary
Finding:
The
nasal
toxicity
may
not
be
adequately
addressed
for
route
specific
effects
on
the
kinetics
including
first
pass
effects
and
delivery
of
parent
compound
to
the
brain
compartment
(
i.
e.,
peak
concentrations
or
time
above
a
given
concentration).
First
pass
effects
can
be
evaluated
using
the
model
(
i.
e.,
comparison
of
bioavailability
for
different
exposure
routes).

Preliminary
Recommendation:
(
discussion
at
the
technical
consultation
meeting)

9
