Document ID: EPA-HQ-OPP-2004-0099-0020
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-05-06T04:00Z

QUESTIONS
TO
SAP
ON:

PROPOSED
HAZARD
IDENTIFICATION
METHODOLOGY
FOR
ASSESSMENT
OF
DERMAL
SENSITIZATION
RISK
Timothy
F.
McMahon,
Ph.
D
Jonathan
Chen,
Ph.
D.

Office
of
Pesticide
Programs
U.
S.
EPA,
Washington
D.
C.

FIFRA
Scientific
Advisory
Panel
(
SAP)

Consultation
On
Dermal
Sensitization
Issues
for
Exposures
to
Pesticides
May
4­
6,
2003
May
4­
6,
2004
2
Question
For
SAP
ISSUE
1:
Quantitative
Risk
Assessment
for
the
Induction
Phase
of
ACD
May
4­
6,
2004
3
Issue
1
 
Background
Approaches
for
determination
of
quantitative
assessment
of
sensitization
induction
thresholds
have
been
proposed
in
the
scientific
literature
using
the
results
of
murine
LLNA
data
and/
or
data
from
human
patch
testing
(
Gerberick
2000,
2001;
Griem
et
al.,
2003).
May
4­
6,
2004
4
Issue
1
(
Cont.)

Gerberick
(
2000,
2001)
proposed
a
methodology
for
determination
of
a
`
sensitization
reference
dose'
for
sensitizers
in
consumer
products.
The
lower
boundary
of
the
potency
category
for
a
sensitizing
chemical
is
used
as
the
starting
point,

with
application
of
uncertainty
factors
for
interindividual
variability,
product
matrix
effects,

and
use
pattern.
May
4­
6,
2004
5
Issue
1
(
Cont.)

Griem
et
al
(
2003)
proposed
a
quantitative
approach
in
which
identification
of
known
human
sensitizing
chemicals
used
both
an
EC3
value
(
defined
as
the
concentration
of
a
sensitizer
required
to
generate
a
threefold
stimulation
of
proliferation
in
draining
lymph
nodes)
from
an
LLNA
test
and
a
NOAEL
or
LOAEL
from
human
repeat
insult
patch
tests
(
HRIPT)
or
human
maximization
tests
(
HMT).
From
this
analysis
it
was
concluded
that
the
EC3
value
could
be
used
as
a
surrogate
value
for
a
NOAEL
that
can
be
used
as
a
starting
point
in
quantitative
risk
assessment
(
Griem
et
al.,

2003).
May
4­
6,
2004
6
Issue
1
(
Cont.)

Uncertainty
factors
for:

interspecies
variation

intraspecies
variation

product
matrix
effects,
and

conditions
of
exposure
(
including
repeated
exposures)
have
been
proposed
for
use
in
conduct
of
dermal
risk
assessments.
May
4­
6,
2004
7
Question
For
SAP
 
Question
1
What
are
the
strengths
and
weaknesses
of
the
proposed
quantitative
approach
for
determination
of
induction
thresholds
to
dermal
sensitizing
chemicals?

What
other
approaches
does
the
Panel
recommend
EPA
consider?
Which
uncertainty
factors
does
the
Panel
feel
are
the
most
appropriate
for
application
to
quantitative
methods
of
induction
threshold
determination?
What
factors
should
be
included
in
the
determination
of
the
magnitude
of
each
uncertainty
factor?
May
4­
6,
2004
8
Question
For
SAP
ISSUE
2:
Quantitative
Risk
Assessment
for
the
Elicitation
Phase
of
ACD
May
4­
6,
2004
9
Question
For
SAP
Issue
2
(
Background)

The
Minimum
Elicitation
Threshold
(
MET)
concept
has
been
discussed
in
previous
publications
(
Nethercott
et
al.,

1994;
Zewdie,
1998;
NJDEP,
1998;
Basketter
et
al.,
2003)

specifically
with
respect
to
hexavalent
chromium.
The
concept
behind
the
MET
is
that
there
is
an
`
elicitation
threshold'
below
which
no
sensitization
reaction
is
expected
(
Horowitz
and
Finley,
1994).

The
setting
of
an
MET
is
usually
performed
as
a
result
of
tests
in
previously
sensitized
individuals;
thus,
the
MET
is
considered
protective
of
elicitation
reactions.

However,
there
has
not
been
an
extensive
discussion
of
the
criteria
for
employing
this
concept
for
purposes
of
risk
assessment.
May
4­
6,
2004
10
Question
For
SAP
 
Question
2
What
are
the
strengths
and
weaknesses
of
the
proposed
quantitative
approaches
for
determination
of
elicitation
thresholds
to
dermal
sensitizing
chemicals?
What
other
approaches
does
the
Panel
recommend
that
EPA
consider?
Which
uncertainty
factors
does
the
Panel
feel
are
the
most
appropriate
for
application
to
quantitative
methods
of
elicitation
threshold
determination?
What
factors
should
be
included
in
the
determination
of
the
magnitude
of
each
uncertainty
factor?
May
4­
6,
2004
11
Question
For
SAP
ISSUE
3:
Children
Sensitivity
May
4­
6,
2004
12
Background
For
SAP
Issue
3
Paustenbach
et
al.
(
1992)
and
Felter
et
al.
(
2002)
have
discussed
the
issue
of
whether
children
are
more
or
less
at
risk
for
development
of
ACD.

Paustenbach
et
al.
addressed
this
issue
specifically
for
hexavalent
chromium,
and
this
paper
concluded
that
risk
to
children
ages
3
to
8
is
not
likely
to
be
greater
than
adults
as
there
is
no
evidence
that
repeated
exposures
to
hexavalent
chromium
places
a
person
at
greater
risk
of
sensitization.

Felter
et
al.
suggested
that
infants
and
children
may
actually
be
at
lower
risk
for
development
of
ACD
based
on
data
gathered
from
dinitrochlorobenzene
and
pentadecylcatechol
(
poison
ivy
allergen).
May
4­
6,
2004
13
Background
For
SAP
Issue
3
(
Continue)

However,
it
is
also
understood
that
young
children
may
not
have
been
exposed
to
different
allergens
as
compared
to
adults.
In
addition,
increased
frequency
of
exposure
in
children
may
increase
the
chance
of
induction
to
different
allergens.
May
4­
6,
2004
14
Question
For
SAP
 
Question
3
Does
the
Panel
agree
that
the
available
scientific
data
suggest
no
significant
difference
in
the
relative
sensitivity
of
children
vs.
adults
to
the
induction
and/
or
elicitation
of
ACD?
If
so,
please
provide
scientific
justification
for
this
position.
If
the
Panel
disagrees,
please
provide
scientific
justification,
including
supporting
data
and/
or
uncertainties
in
the
explanation.
May
4­
6,
2004
15
Question
For
SAP
ISSUE
4:
Case
Study
­
Cr(
VI)
in
treated
wood
May
4­
6,
2004
16
Background
For
SAP
Issue
4
Data
from
murine
LLNA
tests
as
well
as
from
human
patch
testing
studies
using
hexavalent
chromium
are
available
in
the
scientific
literature.

Results
of
LLNA
testing
show
EC3
values
that
indicate
area
doses
that
result
in
the
induction
of
sensitization
in
the
mouse,
while
the
results
of
patch
test
studies
in
humans
show
area
doses
that
result
in
elicitation
of
sensitization
in
already
sensitized
individuals.
May
4­
6,
2004
17
Background
For
SAP
Issue
4
(
Continue)

In
the
Agency's
initial
assessment
seeking
to
assess
dermal
sensitization
risk
from
hexavalent
chromium,

the
lowest
dose
tested
(
0.018
ug/
cm2)
from
the
human
patch
test
study
of
Nethercott
et
al
(
1994)

was
selected
for
determination
of
dermal
risk
from
hexavalent
chromium.
A
10x
uncertainty
factor
(
3x
for
use
of
the
lowest
dose
tested
[
LOAEL]
in
this
study,
and
3x
to
account
for
the
small
size
of
the
study
population
in
the
Nethercott
study)
was
applied,
resulting
in
a
`
safe
area'
dose
of
0.0018
ug/
cm2.
May
4­
6,
2004
18
Background
For
SAP
Issue
4
(
Continue)

Use
of
the
test
data
of
Basketter
et
al.
(
2001)
and
Hansen
et.
al
(
2003)
also
result
in
derivation
of
similar
`
safe'
area
doses
of
0.001
and
0.003
µ
g/
cm2
respectively.
Use
of
the
murine
LLNA
test
data
and
application
of
an
uncertainty
factor
of
either
1000
or
3000
calculated
`
safe'
area
doses
of
0.01
or
0.003
µ
g/
cm2
respectively.
May
4­
6,
2004
19
Question
For
SAP
 
Question
4
Please
comment
on
the
methods
used
for
derivation
of
`
safe'
area
doses
using
the
available
LLNA
data
and
the
human
patch
test
data,
including
the
magnitude
of
the
applied
uncertainty
factors,
and
include
a
scientific
rationale
in
support
of
your
position.
Please
comment
on
whether
it
is
scientifically
supportable
to
derive
separate
`
safe'
area
doses
for
protection
against
induction
of
dermal
sensitization
as
well
as
elicitation
in
sensitized
individuals
by
hexavalent
chromium?
May
4­
6,
2004
20
END