Page
1
of
28
July
1,
2004
MEMORANDUM
SUBJECT:
Transmittal
of
Minutes
of
the
FIFRA
Scientific
Advisory
Panel
Meeting
Held
May
4­
6,
2004:
A
Consultation
On
Dermal
Sensitization
Issues
For
Exposures
To
Pesticides
TO:
James
J.
Jones,
Director
Office
of
Pesticide
Programs
FROM:
Paul
I.
Lewis,
Designated
Federal
Official
FIFRA
Scientific
Advisory
Panel
Office
of
Science
Coordination
and
Policy
THRU:
Larry
C.
Dorsey,
Executive
Secretary
FIFRA
Scientific
Advisory
Panel
Office
of
Science
Coordination
and
Policy
Joseph
J.
Merenda,
Jr.,
Director
Office
of
Science
Coordination
and
Policy
Please
find
attached
the
minutes
of
the
FIFRA
Scientific
Advisory
Panel
open
meeting
held
in
Arlington,
Virginia
from
May
4­
6,
2004.
These
meeting
minutes
address
a
set
of
scientific
issues
being
considered
by
the
Environmental
Protection
Agency
regarding
a
consultation
on
dermal
sensitization
issues
for
exposures
to
pesticides.

Attachment
Page
2
of
28
cc:

Susan
Hazen
Adam
Sharp
Anne
Lindsay
Janet
Andersen
Debbie
Edwards
Steven
Bradbury
William
Diamond
Arnold
Layne
Tina
Levine
Lois
Rossi
Frank
Sanders
Margaret
Stasikowski
William
Jordan
Douglas
Parsons
Dayton
Eckerson
David
Deegan
Vanessa
Vu
(
SAB)
Jack
Housenger
Timothy
McMahon
Jonathan
Chen
Barbara
Hostage
David
Cooper
Elizabeth
Hofmann
Michele
Burgess
OPP
Docket
Attachment
Page
3
of
28
FIFRA
Scientific
Advisory
Panel
Members
Dr.
Steven
Heeringa
Dr.
Stuart
Handwerger
Dr.
Gary
Isom
Dr.
Mary
Anna
Thrall
Dr.
Paul
Bailey
Dr.
Gary
Burleson
Dr.
Ih
Chu
Dr.
Iain
Foulds
Dr.
A.
Wallace
Hayes
Dr.
Abigail
Jacobs
Dr.
Jean
Meade
Dr.
Torkil
Menne
Dr.
Nancy
Monteiro­
Riviere
Dr.
Richard
Pleus
Dr.
Paul
David
Siegel
Page
4
of
28
SAP
Report
No.
2004­
02
MEETING
MINUTES
FIFRA
Scientific
Advisory
Panel
Meeting,
May
4­
6,
2004
held
at
the
Holiday
Inn
Rosslyn
Hotel
at
Key
Bridge
Hotel
Arlington,
Virginia
A
Set
of
Scientific
Issues
Being
Considered
by
the
Environmental
Protection
Agency
Regarding:

Consultation
on
Dermal
Sensitization
Issues
for
Exposures
to
Pesticides
Page
5
of
28
NOTICE
These
meeting
minutes
have
been
written
as
part
of
the
activities
of
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA),
Scientific
Advisory
Panel
(
SAP).
These
minutes
have
not
been
reviewed
for
approval
by
the
United
States
Environmental
Protection
Agency
(
Agency)
and,
hence,
their
contents
do
not
necessarily
represent
the
views
and
policies
of
the
Agency,
nor
of
other
agencies
in
the
Executive
Branch
of
the
Federal
government,
nor
does
mention
of
trade
names
or
commercial
products
constitute
a
recommendation
for
use.

The
FIFRA
SAP
was
established
under
the
provisions
of
FIFRA,
as
amended
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996,
to
provide
advice,
information,
and
recommendations
to
the
Agency
Administrator
on
pesticides
and
pesticide­
related
issues
regarding
the
impact
of
regulatory
actions
on
health
and
the
environment.
The
Panel
serves
as
the
primary
scientific
peer
review
mechanism
of
the
EPA,
Office
of
Pesticide
Programs
(
OPP)
and
is
structured
to
provide
balanced
expert
assessment
of
pesticide
and
pesticide­
related
matters
facing
the
Agency.
Food
Quality
Protection
Act
Science
Review
Board
members
serve
the
FIFRA
SAP
on
an
ad­
hoc
basis
to
assist
in
reviews
conducted
by
the
FIFRA
SAP.
Further
information
about
FIFRA
SAP
meeting
minutes
and
activities
can
be
obtained
from
its
website
at
http://
www.
epa.
gov/
scipoly/
sap/
or
the
OPP
Docket
at
(
703)
305­
5805.
Interested
persons
are
invited
to
contact
Paul
Lewis,
Designated
Federal
Official,
via
e­
mail
at
lewis.
paul@
epa.
gov.
Page
6
of
28
SAP
Report
No.
2004­
02
MEETING
MINUTES:
FIFRA
Scientific
Advisory
Panel
Meeting,
May
4­
6,
2004,
held
at
the
Holiday
Inn
Rosslyn
Hotel
at
Key
Bridge
Hotel
Arlington,
Virginia
A
Set
of
Scientific
Issues
Being
Considered
by
the
Environmental
Protection
Agency
Regarding:

Consultation
on
Dermal
Sensitization
Issues
for
Exposures
to
Pesticides
Mr.
Paul
Lewis
Steven
Heeringa,
Ph.
D.
Designated
Federal
Official
FIFRA
SAP
Session
Chair
FIFRA
Scientific
Advisory
Panel
FIFRA
Scientific
Advisory
Panel
Date:
July
1,
2004
Date:
July
1,
2004
Page
7
of
28
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
Scientific
Advisory
Panel
Meeting
May
4­
6,
2004
Consultation
on
Dermal
Sensitization
Issues
for
Exposures
to
Pesticides
PARTICIPANTS
FIFRA
SAP
Session
Chair
Steven
Heeringa,
Ph.
D.,
Research
Scientist
&
Director
for
Statistical
Design,
Institute
for
Social
Research,
University
of
Michigan,
Ann
Arbor,
MI
FIFRA
Scientific
Advisory
Panel
Members
Stuart
Handwerger,
M.
D.,
Director,
Division
of
Endocrinology,
Cincinnati
Children's
Hospital
Medical
Center,
University
of
Cincinnati,
Cincinnati,
OH
Gary
E.
Isom,
Ph.
D.,
Professor
of
Toxicology,
Purdue
University,
School
of
Pharmacy
&
Pharmacal
Sciences,
West
Lafayette,
IN
Mary
Anna
Thrall,
D.
V.
M.,
Professor,
Microbiology,
Immunology
&
Pathology,
Colorado
State
University,
College
of
Veterinary
Medicine
and
Biomedical
Sciences,
Fort
Collins,
CO
FQPA
Science
Review
Board
Members
Paul
Bailey,
Ph.
D.,
Senior
Scientific
Associate,
Toxicology
and
Environmental
Sciences
Division,
Intermediates
and
Synthetics
Section,
ExxonMobil
Biomedical
Sciences,
Inc.,
Annandale,
NJ
Gary
Burleson,
Ph.
D.,
President,
BRT­
Burleson
Research
Technologies,
Inc.,
Raleigh,
NC
Ih
Chu,
Ph.
D.,
Head,
Systemic
Toxicology
and
Pharmacokinetics,
Environmental
Science
Bureau,
Health
Canada,
Ottawa,
ON,
Canada
Iain
Foulds,
F.
R.
C.
P.,
F.
F.
O.
M.
Senior
Lecturer
in
Occupational
and
Environmental
Dermatology,.
The
Birmingham
Skin
Centre,
Sandwell
and
West
Birmingham
NHS
Trust,
United
Kingdom
A.
Wallace
Hayes,
PhD.,
DABT,
FATS,
FIBiol,
FACFE,
ERT,
Visiting
Scientist,
Department
of
Environmental
Health,
Harvard
School
of
Public
Health,
Harvard
University,
Boston,
MA
Abigail
Jacobs,
Ph.
D.,
Associate
Director
for
Pharmacology
and
Toxicology,
Offices
of
Drug
Evaluation
4
and
5,
CDER,
FDA,
Rockville,
MD
Jean
Meade,
D.
V.
M.,
Ph.
D.,
Toxicologist,
Office
of
the
Director,
NIOSH,
Morgantown,
WV
Page
8
of
28
Torkil
Menne,
M.
D.,
Chair,
Department
of
Dermatology,
Gentofte
Hospital,
University
of
Copenhagen,
Hellerup,
Denmark
Nancy
Monteiro­
Riviere,
Ph.
D.,
Professor
of
Investigative
Dermatology
and
Toxicology,
Center
for
Chemical
Toxicology
Research
and
Pharmacokinetics,
North
Carolina
State
University,
Raleigh,
NC
Richard
Pleus,
Ph.
D.,
Director
and
Toxicologist,
Intertox,
Seattle,
WA;
Adjunct
Associate
Professor
of
Pharmacology
University
of
Nebraska
Medical
Center;
Faculty
member
of
the
Center
for
Environmental
Toxicology,
University
of
Nebraska
Paul
Siegel,
Ph.
D.,
M.
S.
P.
H.,
Team
Leader­
Bioorganic
Chemistry/
Director
Scientist,
Analytical
Services
Branch,
Health
Effects
Laboratory
Division,
NIOSH,
Morgantown,
WV
PUBLIC
COMMENTERS
Oral
statements
were
made
by:

Michele
Burgess,
Ph.
D.,
United
States
Environmental
Protection
Agency,
Office
of
Solid
Waste
and
Emergency
Response
Mr.
James
Aidala,
The
Acta
Group,
L.
L.
C.,
representing
Forest
Products
Research
Laboratory
Howard
Maibach,
MD.,
University
of
California
at
San
Francisco,
representing
Forest
Products
Research
Laboratory
Susan
Hunter
Youngren,
Ph.
D.,
The
Acta
Group,
L.
L.
C.
representing
Forest
Products
Research
Laboratory
Mr.
Dennis
J.
Morgan,
representing
Forest
Products
Research
Laboratory
Paul
A.
Cooper,
Ph.
D.,
University
of
Toronto,
representing
Osmose,
Inc.

Mr.
John
Horton,
representing
Osmose,
Inc.

Ms.
Deborah
Proctor,
Exponent,
Inc.,
representing
Tierra
Solutions,
Inc.

Joel
Barnhart,
Ph.
D.,
representing
Elementis
Chromium
Mr.
Warren
Stickle,
representing
the
Chemical
Producers
and
Distributors
Association
Jane
Vergenes,
Ph.
D.,
International
Specialty
Products,
representing
the
ACC
Biocides
Panel
Mr.
Richard
Wiles,
representing
the
Environmental
Working
Group
Page
9
of
28
Written
statements
were
received
from:

The
ACTA
Group,
LLC
Beyond
Pesticides
and
The
Healthy
Building
Network
Joel
Barnhart,
Ph.
D.,
Elementis
Chromium,
LLP
Michele
Burgess,
Ph.
D.,
United
States
Environmental
Protection
Agency,
Office
of
Solid
Waste
and
Emergency
Response
Forest
Products
Research
Laboratory
Dr.
Peter
Griem,
Clariant
GmbH
INTRODUCTION
The
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA),
Scientific
Advisory
Panel
(
SAP)
has
completed
its
review
of
the
set
of
scientific
issues
being
considered
by
the
Agency
pertaining
to
its
review
of
dermal
sensitization
issues
for
exposures
to
pesticides.
Advance
notice
of
the
meeting
was
published
in
the
Federal
Register
on
April
16,
2004.
The
review
was
conducted
in
an
open
Panel
meeting
held
in
Arlington,
Virginia,
from
May
4­
6,
2004.
The
meeting
was
chaired
by
Steven
Heeringa,
Ph.
D.
Mr.
Paul
Lewis
served
as
the
Designated
Federal
Official.
Mr.
Joseph
J.
Merenda,
Jr.
(
Director,
Office
of
Science
Coordination
and
Policy,.
EPA)
and
Mr.
Jim
Jones
(
Director,
Office
of
Pesticide
Programs,
EPA)
provided
opening
remarks
at
the
meeting.
Timothy
McMahon,
Ph.
D.
(
Office
of
Pesticide
Programs,
EPA)
discussed
the
proposed
hazard
identification
methodology
for
assessment
of
dermal
sensitization
risk,
and
Jonathan
Chen,
Ph.
D.
(
Office
of
Pesticide
Programs,
EPA)
reviewed
the
proposed
hazard
identification
methodology
for
assessment
of
dermal
sensitization
risk
 
a
case
study
of
Cr(
VI)
in
wood
preservatives.
In
preparing
these
meeting
minutes,
the
Panel
carefully
considered
all
information
provided
and
presented
by
the
Agency
presenters,
as
well
as
information
presented
by
public
commenters.
This
document
addresses
the
information
provided
and
presented
within
the
structure
of
the
charge
by
the
Agency.
Page
10
of
28
CHARGE
Dermal
sensitization,
also
known
as
allergic
contact
dermatitis
(
ACD)
is
typically
characterized
by
two
phases,
termed
induction
and
elicitation.
In
the
induction
phase,
the
allergen
is
transported
to
regional
draining
lymph
nodes
where
clonal
expansion
of
allergenspecific
T
lymphocytes
results.
The
elicitation
phase
results
from
a
subsequent
exposure
to
the
allergen,
in
which
the
allergen­
specific
T­
lymphocytes
provoke
a
cutaneous
immune
response.
Although
several
approaches
have
been
proposed
to
assess
threshold
concentrations
for
induction
and
elicitation
of
ACD
and
risk
determination
for
these
concentrations,
there
is
no
established
scientific
approach
within
the
Agency
to
do
a
quantitative
risk
assessment
associated
with
ACD.

There
are
several
accepted
methods
for
hazard
identification
of
dermal
sensitization,
including
the
Buehler
occluded
patch
test,
the
guinea
pig
maximization
test,
and
the
murine
local
lymph
node
assay
(
LLNA).
The
guinea
pig
maximization
test
as
well
as
the
Buehler
test,
while
providing
reliable
information
on
skin
sensitization,
are
best
suited
for
hazard
identification.
Several
proposals
have
been
published
regarding
quantitative
determination
of
sensitization
induction
and
elicitation
thresholds.

ISSUE
1:
Quantitative
Risk
Assessment
for
the
Induction
Phase
of
ACD
The
Mouse
Local
Lymph
Node
Assay
(
LLNA)
is
a
test
method
for
assessing
the
allergic
contact
dermatitis
(
skin
sensitization)
potential
of
chemicals,
specifically
the
induction
phase
of
sensitization.
Using
the
incorporation
of
radiolabeled
thymidine
or
iododeoxyuridine
into
DNA,
the
LLNA
measures
lymphocyte
proliferation
in
the
draining
lymph
nodes
of
mice
topically
exposed
to
the
test
article.
The
stimulation
index
(
ratio
of
lymphocyte
proliferation
in
treated
mice
compared
to
controls)
is
used
as
the
indicator
of
potential
sensitization.
In
1998,
following
review
by
the
FIFRA
SAP,
the
LLNA
was
incorporated
as
a
screening
test
in
OPPTS
Test
Guideline
870.2600
Skin
Sensitization.
In
1999,
the
Interagency
Coordinating
Committee
on
the
Validation
of
Alternative
Methods
(
ICCVAM)
Immunotoxicity
Working
Group
(
IWG)
endorsed
the
LLNA
as
an
acceptable
alternative
to
currently
accepted
guinea
pig
test
methods
for
hazard
identification
of
chemicals
with
potential
to
produce
contact
hypersensitivity.
Following
additional
studies
to
validate
the
method,
the
LLNA
was
endorsed
by
the
SAP
in
December
2001
as
a
full
stand­
alone
assay.
The
OPPTS
guideline
870.2600
(
Skin
Sensitization)
has
been
revised
to
include
the
LLNA
as
a
stand­
alone
assay
for
appropriate
applications.
The
OPPTS
guideline
has
also
been
harmonized
with
OECD's
Guideline
429
for
LLNA,
which
was
adopted
in
April
2002.
Although
the
LLNA
has
not
been
validated
for
determination
of
sensitization
potency,
approaches
for
determination
of
quantitative
assessment
of
sensitization
induction
thresholds
have
been
proposed
in
the
scientific
literature
(
Gerberick
2000,
2001;
Griem
et
al.,
2003).

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.
This
approach
was
applied
to
the
fragrance
component
cinnamic
aldehyde
and
the
preservative
methylchloroisothiazolinone/
methylisothiazolinone
for
which
both
LLNA
and
human
Page
11
of
28
sensitization
potency
were
available
(
Griem
et
al.,
2003).

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).
The
reported
concentrations
were
converted
into
specific
and
molar
area
doses.
Comparison
of
the
area
doses
of
the
LLNA
and
human
test
results
indicated
that
sensitization
thresholds
were
similar
in
mice
and
humans
despite
the
fact
that
the
area
doses
for
different
chemicals
ranged
over
several
orders
of
magnitude
(
Griem
et
al.,
2003).
It
was
concluded
from
this
analysis
that
the
LLNA
EC3
value
is
a
useful
measure
of
sensitizing
potency
in
humans,
and
that
the
EC3
value
can
be
used
as
a
surrogate
value
for
the
human
NOAEL
that
can
be
used
as
a
starting
point
in
quantitative
risk
assessment.

Uncertainty
factors
to
account
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.
Griem
et
al.
(
2003)
have
discussed
the
application
and
magnitude
of
all
of
these
uncertainty
factors
with
respect
to
establishment
of
safe
area
doses
for
both
induction
and
elicitation,
while
Felter
et
al
(
2003)
have
proposed
the
use
of
only
the
intraspecies
variation
factor,
product
matrix
factor,
and
exposure
conditions
factor
for
determination
of
safe
area
doses
for
induction.
The
interspecies
uncertainty
factor
is
intended
to
account
for
differences
in
response
between
tests
in
animals
and
results
in
humans,
although
it
has
been
reported
(
Griem
et
al,
2003)
that
sensitizing
area
doses
are
very
similar
between
murine
and
human
data,
thus
supporting
a
potentially
reduced
uncertainty
factor
for
this
area.
The
intraspecies
uncertainty
factor
is
used
to
account
for
inherent
variability
in
the
human
population
based
on
age,
sex,
genetic
makeup,
or
health
status,
and
is
generally
agreed
that
a
factor
of
10
is
appropriate
for
this
uncertainty.
An
uncertainty
factor
may
also
be
included
for
vehicle
matrix
effects,
as
the
matrix
in
which
an
allergen
is
presented
to
the
skin
may
have
an
influence
on
the
potential
for
induction
of
ACD.
Most
experimental
data
are
generated
using
simple
vehicles,
while
actual
exposures
are
usually
to
more
complex
formulations
that
may
contain
irritants
or
penetration
enhancers.
A
factor
of
10
may
considered
in
such
a
case,
while
a
reduced
factor
may
be
considered
for
mild
formulations.
Finally,
an
uncertainty
factor
may
be
applied
to
account
for
exposure
variables
that
may
influence
the
potential
for
induction
of
ACD,
including
the
site
of
the
body
exposed,
the
integrity
of
the
skin,
and
the
potential
for
multiple
exposures.
Using
the
above
approaches,
a
maximum
uncertainty
factor
of
1000
or
3000
could
be
derived
depending
on
the
criteria
used.
By
contrast,
a
minimum
uncertainty
factor
of
10
could
be
derived
if
results
from
human
studies
are
used.

Thresholds
for
induction
of
ACD
can
occur
following
a
single
exposure
of
sufficient
magnitude,
after
contact
with
a
large
area
of
skin,
or
as
a
consequence
of
repeated
skin
applications
(
Marzulli
and
Maibach).
Griem
et
al.
(
2003)
suggested
a
possible
higher
sensitizing
potency
of
a
chemical
upon
repeated
exposures.
This
would
make
sense
in
the
case
of
hexavalent
chromium,
as
the
significant
irritancy
of
the
chemical
could
lend
itself
to
an
increased
sensitizing
potency
by
allowing
more
chemical
to
penetrate
the
stratum
corneum.

QUESTION
1:
What
are
the
strengths
and
weaknesses
of
the
proposed
quantitative
approach
for
Page
12
of
28
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?

ISSUE
2:
Quantitative
Risk
Assessment
for
the
Elicitation
Phase
of
ACD
Several
proposals
have
been
published
regarding
determination
of
elicitation
thresholds
in
sensitized
populations.
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;
thus,
the
MET
is
analogous
to
an
RfD
(
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.

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?

ISSUE
3:
Children
Sensitivity
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).
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.

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.
Page
13
of
28
ISSUE
4:
Case
Example
­
Cr(
VI)
in
treated
wood
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.
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.
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
ug/
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
ug/
cm2
respectively.

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?

SUMMARY
OF
PANEL
DISCUSSION
AND
RECOMMENDATIONS
 
The
Panel
did
not
endorse
any
particular
method
for
risk
assessment
related
to
the
identification
of
thresholds
for
induction
by
dermal
sensitizing
chemicals
but
acknowledged
the
importance
of
incorporating
all
relevant
data
into
the
weight
of
evidence.
 
Although
the
Panel
sees
promise
in
the
use
of
the
LLNA
as
a
quantitative
risk
assessment
tool,
further
development
and
validation
of
this
application
is
necessary.
 
The
Panel
proposed
the
following
uncertainty
factors
be
considered
for
the
induction
phase:
interspecies
variation
(
value
of
1­
10),
intraspecies
variation
(
value
of
1­
10),
matrix/
vehicle
(
value
of
less
than
1
to
10),
and
exposure
(
value
of
less
than
1
to
10).
 
Given
that
sensitization
responses
are
based
on
dose/
surface
area,
the
Panel
concluded
that
both
the
Minimum
Elicitation
Threshold
(
MET)
and
LLNA
exposure
methodologies
are
appropriate
for
collecting
sensitization
data.
 
The
Panel
identified
four
uncertainty
factors
(
UF)
for
application
to
quantitative
methods
of
elicitation
threshold
determination:
interspecies
variation,
intraspecies
variation,
exposure,
and
vehicle/
matrix.
 
The
Panel
agreed
with
the
Agency
that
there
is
no
evidence
of
a
significant
difference
in
the
sensitivity
of
children
versus
adults
to
the
induction/
or
elicitation
of
ACD.
 
Based
on
current
exposure
levels
of
hexavalent
chromium
in
the
environment,
sensitivity
in
children
is
very
rare.
Page
14
of
28
 
There
are
no
data
to
suggest
that
allergic
contact
dermatitis
occurs
more
frequently
in
children
with
atopic
dermatitis
compared
to
non­
atopic
children.
 
Due
to
the
availability
of
human
data,
there
is
no
need
at
this
stage
to
consider
LLNA
studies
for
the
derivation
of
the
`
safe'
area
dose
(
mass
per
unit
area)
for
chromate
exposure.
 
The
Panel
identified
the
critical
dose
(
lowest
observed
adverse
effect
level)
[
LOAEL]
from
the
Nethercott
et
al.
(
1994)
study
should
be
0.088ug/
cm2,
which
the
Panel
considered
to
still
be
a
conservative
safety
level.
 
Applying
a
matrix/
vehicle
(
value
0.1),
interspecies
variation
(
value
1),
intraspecies
variation
(
value
1),
and
exposure
(
value
3
to
10)
uncertainty
factors,
the
S­
RfD
calculated
as
specific
to
hexavalent
chromium
in
treated
wood
ranged
from
0.09
to
0.3
ug/
cm2
.
 
The
Panel's
estimate
of
an
S­
RfD
should
be
protective
against
elicitation
and
therefore
would
also
be
protective
of
induction.
 
Although
the
Panel
calculated
a
S­
RfD
for
hexavalent
chromium
in
ACC
treated
wood,
the
Panel
stressed
that
the
Agency
consider
all
data
as
part
of
a
weight
of
evidence
approach.

Panel
Response
To
Question
1
General
Comments
Before
beginning
to
address
the
specific
questions,
the
Panel
offered
some
general
comments
relevant
to
the
overall
risk
assessment
process.
Firstly,
it
was
stated
that
there
has
been
no
established
scientific
approach
within
the
Agency
to
conduct
a
quantitative
risk
assessment
associated
with
allergic
contact
dermatitis
(
ACD)
(
Stern
et
al.,
2003)
and
although
several
methods
have
been
proposed
and
show
promise,
the
Panel
suggested
that
the
weight
of
evidence
approach
remains
appropriate
at
this
time.
The
mechanisms
of
the
induction
and
elicitation
phases
of
ACD
as
well
as
the
science
underlying
the
proposed
test
methods
will
be
discussed
before
evaluating
the
relevancy
and
validity
of
the
proposed
approaches.
Each
chemical
has
its
own
thresholds
for
induction
and
elicitation.
For
example,
thresholds
for
Cr
VI
cannot
be
extrapolated
to
Cr
III.
Thresholds
for
induction
of
ACD
can
occur
following
a
single
dermal
exposure
of
sufficient
magnitude,
after
contact
with
the
skin,
or
as
a
consequence
of
repeated
skin
applications
(
Marzulli
and
Maibach
1975).
Griem
et
al.
(
2003)
suggested
a
possible
higher
potential
for
inducing
sensitization
to
a
chemical
upon
repeated
exposures.

ACD
is
characterized
by
two
phases.
The
first
is
the
induction
phase
which
requires
exposure
of
a
susceptible
individual
to
an
allergen
in
sufficient
concentration
and
for
a
sufficient
duration
to
activate
specific
immune
mechanisms
that
result
in
the
acquisition
of
sensitization.
During
the
induction
phase,
the
allergen
must
penetrate
the
stratum
corneum
layers
and
be
taken
up
by
epidermal
Langerhans
cells
which
then
process
and
transport
the
allergen
to
regional
draining
lymph
nodes.
Presentation
of
allergen
results
in
clonal
expansion
of
allergen­
specific
T
lymphocytes
and
the
generation
of
effector
and
memory
T
cells.
The
second
phase
is
termed
elicitation
where
re­
exposure
to
the
allergen
(
challenge)
in
a
previously
sensitized
individual
results
in
the
elicitation
of
an
inflammatory
dermal
response
(
Stern
et
al.,
1993).
As
with
induction,
the
elicitation
phase
requires
penetration
of
the
allergen
through
the
stratum
corneum
and
presentation
by
antigen
presenting
cells.
Page
15
of
28
It
is
important
when
evaluating
data
derived
from
both
animal
and
human
studies
to
consider
elements
of
the
experimental
design.
Most
animal
assays
used
in
the
evaluation
of
ACD
were
originally
designed
for
hazard
identification.
Guinea
pig
assays
have
been
used
for
decades
to
predict
the
potential
of
chemicals
to
induce
ACD
in
humans.
The
most
frequently
used
tests
are
the
Guinea
Pig
Maximization
Test
(
GMT)
and
the
Buehler
test.
These
tests
rely
on
the
induction
of
sensitization
in
animals
with
the
read
out
being
the
elicitation
of
a
dermal
inflammatory
response
following
challenge.
As
the
name
would
imply,
the
GMT
provides
for
an
exaggerated
exposure
regimen
which
includes
intradermal
injection
of
the
allergen
along
with
the
use
of
an
adjuvant
and
topical
application
under
an
occluded
patch
to
maximize
the
potential
to
induce
sensitization.
In
the
Buhler
test,
animals
undergo
multiple
exposures
under
an
occluded
patch.
For
the
guinea
pig
assays,
the
end
point
is
subjective
and
semi­
quantitative.

More
recently,
a
murine
assay,
the
Local
Lymph
Node
Assay
(
LLNA),
has
been
developed
which
evaluates
the
induction/
sensitization
phase
of
ACD
and
provides
for
a
dose
response
evaluation.
Animals
in
this
assay
receive
three
consecutive
days
of
topical
exposure
to
intact,
non­
occluded
skin.
The
read
out
is
a
quantitative
measurement
of
3H­
thymidine
or
I125
­
deoxyuridine
incorporation
into
draining
lymph
node
cells
as
an
indication
of
cellular
proliferation.
The
LLNA
has
undergone
intra­
and
inter­
laboratory
validation
and
peer­
review
sponsored
by
the
ICCVAM
(
NIH
1999).
The
results
of
the
ICCVAM
review
supported
an
equivalent
percent
accuracy
for
the
LLNA
and
guinea
pig
assays
in
predicting
the
sensitizing
potential
of
chemicals
(~
73%).

The
Panel
cited
the
strengths
of
the
LLNA
as:

 
It
is
mechanistically­
based,
i.
e.
allergenic
substances
cause
proliferation
of
lymphocytes;
 
It
provides
an
objective
and
quantitative
endpoint;
 
It
permits
the
evaluation
of
ACD
potential
of
chemicals
that
are
too
toxic
to
be
tested
in
humans;
 
It
has
been
sufficiently
validated
for
a
hazard
assessment;
 
It
reduces
stress
in
animals
due
to
the
short
duration
of
the
assay,
the
open
application
of
test
material
and
the
lack
of
the
elicitation
of
the
inflammatory
response.

Deficiencies
of
the
LLNA
were
described
as:

 
The
irritant
properties
of
the
matrix
or
test
substance
may
contribute
to
the
local
lymph
node
proliferation
resulting
in
false
positives
for
strong
irritants;
 
The
method
has
not
been
sufficiently
evaluated
using
mixtures;
 
At
the
time
of
the
ICCVAM
review,
its
application
had
not
yet
been
validated
for
metals
or
aqueous
soluble
materials
(
however
since
that
time
investigators
have
shown
a
similar
predictive
accuracy
of
the
LLNA
for
metals
(
85%)
as
compared
to
low
molecular
weight
chemicals
(
88%)
(
Basketter
et
al.
1999)
and
alternative
vehicles
for
testing
aqueous
soluble
materials
have
been
investigated
(
Ryan
et
al.,
2002).

Like
the
guinea
pig
assays,
human
tests
to
evaluate
sensitization
potential
require
the
induction
of
sensitization
and
subsequent
evaluation
of
the
elicitation
response
following
Page
16
of
28
challenge.
Exposure
under
an
occluded
patch
is
used
for
induction
in
the
Human
Maximization
Test
(
HMT)
and
the
Human
Repeated
Insult
Test
(
HRIPT),
while
the
Open
Epicutaneous
Test
utilizes
topical
application
to
non­
occluded
skin.
The
data
from
these
tests
are
semi­
qualitative
and
based
on
subjective
scoring
using
macroscopic
observation
(
i.
e.,
+
1
to
+
4).
Although
ethical
issues
may
limit
future
human
testing,
the
Panel
felt
strongly
that
when
human
data
are
available
they
should
be
given
primary
consideration.

Panel
Conclusions/
Recommendations
in
Response
to
Question
1.

Proposed
quantitative
approaches
The
Panel
did
not
endorse
any
particular
method
for
risk
assessment
related
to
the
identification
of
thresholds
for
induction
by
dermal
sensitizing
chemicals
but
acknowledged
the
importance
of
incorporating
all
relevant
data
into
the
weight
of
evidence.
The
Panel
strongly
agreed
that
given
that
the
threshold
for
induction
is
considered
to
be
higher
than
that
required
for
elicitation
(
Friedman
1990),
that
establishing
a
safe
level
below
the
threshold
for
elicitation
would
also
be
protective
of
induction.
Therefore
it
was
anticipated
that
risk
assessment
for
the
induction
phase
of
sensitization
would
only
be
appropriate
for
chemicals
where
no
data
were
available
(
e.
g.
new
chemicals).
If
risk
assessment
is
based
on
induction
only,
exposure
limits
will
be
more
conservative.
If
people
are
protected
from
induction,
then
elicitation
should
not
be
an
issue
(
Gerberick
and
Robinson
2000).
While
there
is
basis
for
this
hypothesis,
there
may
be
unanticipated
exposure
scenarios
that
could
lead
to
a
sensitized
subpopulation.

In
1999,
ICCVAM
recommended
that
with
certain
protocol
modifications,
the
LLNA
was
sufficiently
validated
as
a
stand­
alone
test
for
the
identification
of
skin
sensitizing
chemicals
with
the
exception
of
metals,
mixtures,
and
the
use
of
aqueous
vehicles
(
National
Institutes
of
Health
1999)
.
Since
that
time
several
authors
have
proposed
the
use
of
the
LLNA
for
risk
assessment.
The
first
step
was
the
analysis
of
dose
response
data
to
calculate
an
EC3
value
(
the
concentration
of
chemical
required
to
elicit
a
3­
fold
increase
in
lymphocyte
proliferation
as
compared
to
vehicle)
as
an
estimation
of
the
concentration
of
a
chemical
required
to
induce
sensitization
(
Kimber
and
Basketter
1997).
EC3
values
of
chemicals
were
then
used
to
establish
relative
potencies.
Potency
data
generated
using
this
method
compared
favorably
with
the
corresponding
human
data
(
Basketter
et
al.
2000;
Gerberick
et
al.
2001).

More
recent
studies
(
Gerberick
and
Robinson
2000;
Gerberick
et
al.
2001;
and
Griem
et
al.
2003)
have
incorporated
LLNA
derived
EC3
values
into
quantitative
risk
assessment
protocols.
Gerberick
et
al.
(
2000,
2001)
proposed
a
methodology
for
determining
the
`
sensitization
reference
dose'
for
sensitizers
in
consumer
products.
The
lower
boundary
of
the
potency
category
for
a
sensitizing
chemical
was
used
as
the
starting
point,
with
the
application
of
uncertainty
factors
for
interindividual
variability,
product
matrix
effects,
and
use
pattern.
This
approach
was
applied
to
the
fragrance
component
cinnamic
aldehyde
and
the
preservative
methyl­
chloroisothiazolinone/
methylisothiazolinone
for
which
both
LLNA
and
human
sensitization
potency
were
available
(
Griem
et
al.,
2003).

Griem
et
al.
(
2003)
proposed
a
quantitative
approach
using
both
an
EC3
value
from
the
LLNA
and
a
NOAEL
or
LOAEL
from
HRIPT
or
HMT.
The
reported
concentrations
were
Page
17
of
28
converted
into
specific
and
molar
area
doses.
The
authors
concluded
from
their
analysis
that
the
LLNA
EC3
value
was
a
useful
measure
of
sensitizing
potency
in
humans,
and
that
the
EC3
value
can
be
used
as
a
surrogate
value
for
the
human
NOAEL
and
as
a
starting
point
in
quantitative
risk
assessment.

Although
the
Panel
sees
promise
in
the
use
of
the
LLNA
as
a
quantitative
risk
assessment
tool,
further
development
and
validation
of
this
application
is
necessary.
Validation
should
include
different
classes
of
chemicals
including
metals.
Academia,
industry,
and
contract
laboratories
should
participate
in
the
validation
process.

Uncertainty
Factors
Uncertainty
factors
to
account
for
interspecies
variation,
intraspecies
variation,
product
matrix
effects,
and
conditions
of
exposure
(
including
repeated
exposures)
have
been
proposed
for
the
conduct
of
dermal
risk
assessments.
Griem
et
al.
(
2003)
discussed
the
application
and
magnitude
of
all
of
these
uncertainty
factors
with
respect
to
establishment
of
safe
area
doses
for
both
induction
and
elicitation,
while
Felter
et
al.
(
2003)
discussed
the
use
of
only
the
intraspecies
variation
factor,
product
matrix
factor,
and
exposure
conditions
factor
for
determination
of
safe
area
doses
for
induction.
Uncertainty
factors
are
generally
assigned
a
value
between
1
and
10.
The
interspecies
uncertainty
factor
is
intended
to
account
for
differences
in
response
between
tests
in
animals
and
results
in
humans.
The
intraspecies
uncertainty
factor
is
used
to
account
for
inherent
variability
in
the
human
population
based
on
age,
sex,
genetic
makeup,
or
health
status,
and
is
generally
agreed
that
a
factor
of
10
is
appropriate
for
this
uncertainty.
An
uncertainty
factor
may
also
be
included
for
vehicle
matrix
effects,
as
the
matrix
in
which
an
allergen
is
presented
to
the
skin
may
have
an
influence
on
the
potential
for
induction
of
ACD.
Most
experimental
data
are
generated
using
simple
vehicles,
while
actual
exposures
are
usually
to
more
complex
formulations
that
may
contain
irritants
or
penetration
enhancers.
An
uncertainty
factor
may
be
applied
to
account
for
exposure
variables
that
may
influence
the
potential
for
induction
of
ACD,
including
the
site
of
the
body
exposed,
the
integrity
of
the
skin,
and
the
potential
for
multiple
exposures.
Using
the
above
approaches,
a
maximum
uncertainty
factor
of
1000
or
3000
could
be
derived
depending
on
the
criteria
used.
By
contrast,
a
minimum
uncertainty
factor
of
less
than
1
could
be
derived
if
proper
human
studies
are
conducted
and
used.

The
Panel
proposed
the
following
uncertainty
factors
be
considered
for
the
induction
phase:
interspecies
variation,
intraspecies
variation,
matrix/
vehicle,
and
exposure
as
described
below.
Uncertainty
factors
must
be
assigned
on
a
case
by
case
basis
dependent
in
part
on
the
experimental
design
from
which
the
data
were
generated
and
the
use
of
the
chemical
and
product
matrix.

Intraspecies
variation
­
the
Panel
recommended
a
value
for
intraspecies
variation
of
1­
10.
The
values
depend
on
the
experimental
design
of
the
study
in
question
including
factors
such
as
the
sample
size,
age,
gender
and
ethnic
composition
of
the
sample
population.

Interspecies
variation
­
the
Panel
recommended
values
from
1
to
10.
The
values
depend
on
the
experimental
design
of
the
study
in
question.
Rodent
skin
is
much
more
permeable
than
Page
18
of
28
human
skin
for
most
compounds,
potentially
allowing
enhanced
penetration
of
the
chemical
and
greater
bioavailability
(
Tregear
et
al.
1975;
Bartek
et
al.
1972).
In
addition,
Griem
et
al.
(
2003)
reported
that
sensitizing
area
doses
are
similar
between
murine
and
human
data,
thus
suggesting
a
potentially
reduced
uncertainty
factor
for
this
area.
Thus,
this
could
result
in
an
interspecies
variation
closer
to
1.

Matrix/
vehicle
­
this
uncertainty
factor
is
dependent
upon
the
matrix
used
during
testing
as
well
as
the
anticipated
matrix
during
use.
Exposures
during
testing
may
have
been
exaggerated
as
compared
to
normal
use.
For
example,
exposure
during
patch
testing
may
have
been
occluded
for
48
hours.
Additionally,
DMSO,
an
irritant
and
skin
penetration
enhancer,
is
frequently
used
in
the
LLNA.
Conversely,
if
mixtures
were
tested
where
the
matrix
included
agents
which
may
interfere
with
dermal
penetration
of
the
test
article
such
as
barrier
creams
or
agents
that
may
interfere
with
physiological
responses
such
as
vasoconstrictors
or
anti
inflammatory
agents,
an
uncertainty
factor
of
greater
than
1
would
be
expected.
Therefore
once
the
matrix
used
during
testing
and
the
anticipated
matrix
of
exposure
have
been
considered,
the
matrix/
vehicle
value
assigned
may
range
from
less
than
1
(
e.
g.,
DMSO)
to
10
(
e.
g.,
dexamethasone).

Exposure
­
there
is
a
need
to
consider
the
total
dose
when
establishing
an
uncertainty
factor
for
exposure.
This
may
be
dependent
on
the
body
site
where
exposure
occurs
as
dermal
penetration
has
been
shown
to
vary
between
anatomical
locations.
The
potential
for
repeat
exposure
and
exposure
to
damaged
skin
must
also
be
taken
into
consideration.
Thus,
the
Panel
recommended
values
from
less
than
1
to
10.

Panel
Response
To
Question
2
Given
that
sensitization
responses
are
based
on
dose/
surface
area,
the
Panel
concluded
that
both
the
Minimum
Elicitation
Threshold
(
MET)
and
LLNA
exposure
methodologies
are
appropriate
for
collecting
sensitization
data
(
however,
the
LLNA
does
not
measure
elicitation).
The
use
of
the
MET
approach
eliminates
the
need
to
extrapolate
from
animal
data
to
humans.
Variability
with
using
this
approach
relates
to
the
reliability
of
the
patch
test
data
(
i.
e.
variability
in
defining
threshold,
the
concentration
of
the
patch
test
material,
vehicle
used,
proper
occlusion,
consistency
between
readers,
irritant
responses,
skin
condition
at
patch
site,
patch
time
and
the
sample
size).
The
issue
related
to
sample
size
could
be
addressed
by
using
95%
confidence
limits.
The
10%
MET
may
not
be
an
acceptable
approach
for
new
chemicals,
however,
since
a
sensitized
population
would
not
be
available
for
testing,
and
ethical
issues
may
prohibit
the
use
of
the
HRIPT.

Although
the
LLNA
method
shows
promise
and
data
are
being
accumulated
related
to
the
use
of
the
assay
in
risk
assessment,
the
Panel
does
not
feel
that
the
method's
suitability
is
yet
adequately
demonstrated.
Validated
methods
for
estimating
elicitation
thresholds
do
not
currently
exist.
The
Panel
encourages
the
Agency
to
support
research
in
methods
development
for
use
in
risk
assessment.

The
Panel
identified
four
uncertainty
factors
(
UF)
for
application
to
quantitative
methods
of
elicitation
threshold
determination:
interspecies
variation,
intraspecies
variation,
Page
19
of
28
vehicle/
matrix
and
exposure.
For
all
uncertainty
factors,
determination
of
the
magnitude
should
be
assessed
on
a
case
by
case
basis.
When
animal
models
are
used,
it
will
be
necessary
to
assign
interspecies
uncertainty
factors.
For
mouse
models,
this
UF
should
be
on
the
low
end
of
the
1­
10
scale.
Sensitization
is
based
on
dose
per
surface
area
and
not
on
a
mg/
kg
basis
as
with
other
toxicological
effects
and
data
have
demonstrated
a
similarity
in
doses
required
to
sensitize
humans
and
mice
(
Gerberick
et
al.
2001).
Additionally,
dermal
penetration
is
an
important
factor
in
the
initiation
of
sensitization
and,
as
stated
previously,
mouse
skin
is
more
permeable
than
human.

Intraspecies
factors
will
be
dependent
on
whether
animal
or
human
data
are
used
for
evaluation.
When
the
extrapolation
is
from
animal
data
to
human,
in
addition
to
the
interspecies
factor,
an
intraspecies
factor
of
10
is
generally
used
to
account
for
differences
in
age,
gender,
ethnic
background,
genetic
polymorphisms
and
skin
condition.
When
human
data
are
used,
intraspecies
uncertainty
factors
should
take
into
account
the
study
design
and
quality
of
the
data,
bearing
in
mind
that
the
study
population
may
consist
of
a
sensitive
subpopulation.
The
uncertainty
factor
should
be
dependent
upon
the
number
of
people
patch
tested
in
relation
to
the
percentage
of
individuals
sensitized
and
the
quality
of
the
patch
test
data.
The
quality
of
the
patch
test
data
will
depend
on
the
expertise
of
the
readers
and
consistency
within
and
between
centers.
The
determination
of
the
threshold
for
interpreting
a
positive
patch
test
reaction
is
variable.
Additionally,
an
individual's
irritant
threshold,
genetic
factors,
polymorphisms
related
to
dermal
metabolism,
skin
condition,
and
ultraviolet
exposure
may
all
influence
their
reaction.

Exposure
factors
must
take
into
account
repeat
exposures,
dermal
integrity,
potential
for
occlusion
and
anatomical
site
of
exposure.
The
vehicle/
matrix
factors
should
take
into
account
the
matrix
in
which
the
chemical
was
tested
as
well
as
the
vehicle/
matrix
anticipated
during
environmental
exposure.
This
should
include
factors
such
as
the
irritant
nature
of
the
matrix,
the
presence
of
penetration
enhancers
or
retardants
and
the
bioavailability
of
chemical
from
the
matrix.

Panel
Response
To
Question
3
Background
and
Panel
Recommendations
On
Clinical
Aspects
of
ACD
in
Children
Compared
to
adults,
ACD
in
children
is
rare.
However
this
may
be
due
to
decreased
exposure
and
not
a
difference
in
their
immunologic
response.
The
Panel
agreed
with
the
Agency
that
there
is
no
evidence
of
a
significant
difference
in
the
sensitivity
of
children
versus
adults
to
the
induction/
or
elicitation
of
ACD.
The
Panel
recommended
the
Agency
review
the
article
on
this
subject
by
Hjorth
(
1981).
Historically,
most
cases
of
ACD
in
children
have
been
caused
by
nickel,
cobalt,
fragrance,
rubber
additives
and
occasionally
potassium
dichromate.
Most
clinical
cases
in
children
are
acute
contact
dermatitis
settling
rapidly
with
withdrawal
from
the
allergen.
Chronic
dermatitis
in
children
as
a
result
of
allergic
contact
factors
is
the
exception.
In
recent
years
p­
phenylenediamine
has
become
a
more
frequent
contact
allergen
in
children
as
a
result
of
temporary
`
Henna'
Tattoos.
A
single
exposure
to
p­
phenylenediamine
from
Henna
tattoos
can
induce
sensitization
within
10
days,
resulting
in
severe
reactions
at
the
site
of
exposure
(
Brancaccio
et
al
2002;
Sidbury
and
Storrs
2000).
The
dermatitis
experienced
by
children
is
equivalent
to
that
experienced
by
adults.
It
involves
any
site
exposed
to
an
allergen
and
can
Page
20
of
28
cause
severe
discomfort
including
itching,
weeping,
and
pain.
Significant
morbidity
can
result.

Primary
Sensitization
In
Children
Like
adults,
children
can
be
sensitized
with
only
one
exposure
to
an
allergen.
Pphenylenediamine
is
one
such
example.
Epstein
et
al
(
1961)
demonstrated
positive
reactions
to
pentadecyl
catechol
(
poison
ivy)
could
be
expressed
in
children
of
different
age
groups.
This
study
suggested
that
not
only
can
children
be
sensitized
but
that
the
rate
of
sensitization
increases
with
increasing
age.
The
rate
of
demonstrable
sensitization
rose
from
30%
in
children
under
1
year
to
50%
between
1
and
3
years.
From
ages
3
to
8
the
rate
rose
further
to
76%.
However,
the
older
children
may
have
had
increased
environmental
exposure
to
this
common
allergen
with
increasing
age
resulting
in
increased
reaction
rates.
Thus,
this
study
does
not
indicate
that
very
young
children
are
less
likely
to
become
sensitized.

Thimerosal
reactions
are
common
in
young
adults.
Up
to
15%
of
Swedish
army
recruits
demonstrated
this
sensitivity
(
Hansonn
and
Moller
1971).
This
sensitivity
is
acquired
from
vaccinations
preserved
with
thimerosal
given
in
the
early
years
of
life.

Population
Based
Patch
Test
Studies
One
cohort
study
has
recently
been
performed
by
Mortz
et
al
(
2002).
The
study
was
designed
to
investigate
both
atopic
disease
and
delayed
type
hypersensitivity.
The
cohort
examined
1000
children
aged
10
to
14
years
old
who
were
patch
tested
using
the
T.
R.
U.
E
test.
15.2%
revealed
patch
test
positive
reactions.
This
figure
was
similar
to
that
of
an
adult
population
(
Neilsen
and
Menne
1992).
The
most
common
positive
allergens
were
nickel,
fragrances
and
thimerosal.

A
study
by
Wohrl
et
al.
(
2003)
reported
2776
consecutive
patch
tests
given
to
a
variety
of
age
ranges.
In
the
under
10­
year­
old
age
range,
62%
gave
positive
reactions.
In
the
over
70­
year­
old
age
range,
a
lower
figure
of
34.9%
gave
positive
reactions.
The
study
suggested
that
children
may
be
more
easily
sensitized.
However,
this
study
makes
no
allowance
for
the
selection
of
patients
for
patch
testing
in
the
first
instance.
There
is
often
reluctance
to
patch
test
small
children
because
of
the
discomfort
of
the
testing,
the
small
skin
area
available
for
testing
and
the
cause
of
the
ACD
which
is
usually
detectable
from
patient
history.
The
patch
test
tends
to
be
used
in
children
to
support
a
suspicion
of
sensitivity
when
confirmation
is
required
and
therefore
when
a
child
is
tested
it
is
more
likely
to
be
positive.
In
adults
with
persistent
dermatitis,
patch
testing
is
more
likely
to
be
conducted
in
the
hope
of
identifying
a
relevant
allergen.
Hence
the
incidence
of
positive
patch
test
reactions
in
adults
can
be
expected
to
be
considerably
lower.

Children's
Exposure
To
Hexavalent
Chromium
And
ACD
Based
on
current
exposure
levels
of
hexavalent
chromium
in
the
environment,
sensitivity
in
children
is
very
rare.
Children
around
the
world
have
for
years
been
exposed
to
chromate
in
treated
woods
(
CCA
and
ACC)
and
there
are
no
reports
in
the
literature
of
either
sensitization
occurring
from
this
exposure
or
the
elicitation
of
dermatitis
in
a
sensitized
child.
Panel
members
Page
21
of
28
had
collectively
more
than
50
years
of
patch
testing
experience,
yet
could
not
recall
a
single
case
of
sensitization
to
hexavalent
chromium
being
attributable
to
treated
wood
exposure
either
in
children
or
in
adults.
Nor
could
they
recall
a
single
case
of
elicitation
of
ACD
in
hexavalent
chromium
sensitized
children.
One
case
was
reported
of
an
adult
who
had
been
previously
sensitized
to
hexavalent
chromium
in
the
construction
industry.
This
patient
subsequently
returned
to
work
at
a
wood
treatment
plant,
directly
handled
freshly
treated
wet
wood
and
subsequently
developed
an
elicitation
reaction
from
this
exposure.
This
resulted
in
removal
of
the
patient
from
the
source.

There
are
no
data
to
suggest
that
allergic
contact
dermatitis
occurs
more
frequently
in
children
with
atopic
dermatitis
compared
to
non­
atopic
children.
Some
studies
actually
suggest
that
the
incidence
of
delayed
type
hypersensitivity
is
reduced
in
atopic
children
(
Agner
and
Menne
2001).
Therefore,
children
with
active
atopic
skin
disease
should
not
be
at
any
increased
risk
of
ACD
from
hexavalent
chromium
in
treated
woods.
This
conclusion
also
applies
when
exposure
might
be
expected
to
occur
on
actively
inflamed
skin.

Panel
Response
To
Question
4
Introduction
ACD
to
hexavalent
chromium
may
sometimes
be
very
severe,
with
a
major
impact
on
the
quality
of
life
for
some
sensitized
individuals.
ACD
can
be
a
reversible
condition
if
exposure
is
removed.
In
chromate
dermatitis,
the
condition
can
persist
when
exposure
is
apparently
removed
(
Wall
1980;
Freeman
2000).
As
stated
previously,
there
is
no
published
literature
to
suggest
that
there
is
any
primary
sensitization
or
elicitation
of
ACD
as
a
result
of
chromate
exposure
from
treated
woods.

LLNA
Data
There
were
five
studies
cited
by
the
Agency
on
the
use
of
the
LLNA
and
induction
of
chromate
sensitivity
(
Griem
2003).
However,
as
noted
previously
by
the
Panel,
the
LLNA
has
not
been
formally
evaluated
for
use
in
risk
assessment
and
issues
still
remain
regarding
the
use
of
the
LLNA
in
assessing
metals.
There
are
a
number
of
well
designed
human
studies
in
chromate
sensitized
individuals.
Thus,
due
to
the
availability
of
human
data,
there
is
no
need
at
this
stage
to
consider
LLNA
studies
for
the
derivation
of
the
`
safe'
area
dose
(
mass
per
unit
area)
for
chromate
exposure.

Exposure
Scenario
for
Chrome
VI
Case
Study
A
major
concern
in
conducting
a
risk
assessment
on
hexavalent
chromium
in
treated
wood
is
the
paucity
of
exposure
data.
The
Panel
suggested
that
if
exposure
scenarios
are
to
be
considered,
the
following
situations
be
considered:
 
Wood
treated
with
ACC
(
aged
versus
newly
treated
wood).
 
Contact
of
treated
wood
used
in
the
construction
of
structural
components
of
outdoor
play
sets.
 
Wood
used
in
home
patios,
porches,
decks,
docks,
etc.
Page
22
of
28
 
Woods
treated
with
deck
cleaners
and
bleaches.

Chromate
Human
Threshold
Studies
The
critical
human
chromate
study
conducted
by
Nethercott
et
al.
(
1994)
was
an
elicitation
study
of
an
identified
chromate
sensitized
population.
This
therefore
represents
a
specialized
subpopulation
of
the
general
population.
Although
there
are
no
methods
available
to
predict
which
individuals
have
a
particular
propensity
for
developing
ACD
to
chromate,
Nethercott
et
al.
(
1994)
identified
their
subpopulation
from
a
group
of
6000
patients
who
had
been
patch
tested.
Of
this
group,
102
were
re­
patch
tested
to
hexavalent
chromate
and
54
were
confirmed
to
be
chromate
sensitive.
This
is
therefore
a
significantly
large
population
of
sensitized
individuals.
The
study
had
a
good
experimental
design
with
several
rounds
of
testing
to
not
only
reconfirm
sensitivity
but
also
to
establish
a
dose­
response
relationship
for
elicitation.
The
hexavalent
chromium
sensitized
subpopulation
was
identified
using
the
T.
R.
U.
E.
test,
a
sensitive
patch
test
system
for
metals.
The
Nethercott
et
al.
(
1994)
study
was
conducted
under
occlusion
and
can
be
considered
to
be
conservative.

The
Panel
also
reviewed
other
chromium
studies.
The
Hansen
et
al.
(
2002;
2003)
study
was
supportive
but
not
large
enough
to
be
considered
by
itself
as
there
was
a
smaller
subpopulation
of
17
hexavalent
chromium
sensitized
individuals
compared
to
the
Nethercott
et
al.
(
1994)
study.
The
study
by
Fowler
et
al.
(
1999)
did
not
have
a
good
experimental
design
and
therefore
cannot
be
considered
as
a
critical
study.
Other
studies
cited
were
reviewed
(
e.
g.
Hansen
et
al.
2002)
and
these
are
also
supportive
but
have
larger
thresholds
for
elicitation
of
reactions.
If
designed
for
risk
assessment
purposes,
a
more
appropriate
study
should
have
been
undertaken
over
a
period
of
at
least
four
weeks,
performed
as
an
Open
Test
with
repeated
daily
exposures.

The
Critical
Dose
(
LOAEL)

The
Panel
identified
the
critical
dose
(
lowest
observed
adverse
effect
level)
[
LOAEL]
from
the
Nethercott
et
al.
(
1994)
study
should
be
0.088ug/
cm2,
which
the
Panel
considered
to
still
be
a
conservative
safety
level.
This
dose
was
in
contrast
to
the
0.018ug/
cm2
suggested
by
the
Agency.
At
0.088ug/
cm2
reactions
occurred
in
4
out
of
54
subjects
tested,
representing
about
10%
of
the
hexavalent
chromium
sensitized
subpopulation
and
equivalent
to
a
MET
10.

Uncertainty
Factors
Considerations
Areas
of
uncertainty
are
considered
when
extrapolating
the
result
of
the
critical
dose
to
conditions
relevant
to
the
human
exposure
of
interest.
In
this
case,
the
Panel
assessed
human
exposure
to
wood
treated
with
hexavalent
chromium.
As
presented
previously
by
the
Panel,
the
areas
of
uncertainty
that
have
been
identified
for
dermal
risk
assessment
are:
(
1)
interspecies
variation;
(
2)
intraspecies
variation;
(
3)
vehicle
or
product
matrix
effects;
and
(
4)
exposure
considerations
(
i.
e.,
area
of
the
body
exposed,
repeated
exposures).
For
each
of
these
four
areas,
a
range
of
values
less
than
1
to
as
high
as
10
were
chosen.
A
summary
of
the
values
chosen
for
each
UF
is
presented
in
Table
1.
Page
23
of
28
Given
that
the
Nethercott
et
al.
study
(
1994)
was
conducted
in
humans
and
there
was
no
need
for
an
UF
for
interspecies
variation,
a
value
of
1
was
assigned.
As
the
subjects
in
Nethercott
et
al.
(
1994)
were
sensitized
to
hexavalent
chromium,
these
individuals
represent
a
subpopulation
of
the
normal
population,
which
would
have
a
reaction
to
hexavalent
chromium.
This
subpopulation
is
more
sensitive
to
induction
and
subsequent
elicitation
to
hexavalent
chromium.
Thus
for
intraspecies
UF,
a
value
of
1
was
chosen
as
a
conservative
estimate.

Another
major
area
for
data
extrapolation
involves
the
matrix
in
which
the
chemical
is
present
and
how
the
individual
was
exposed
(
Felter
et
al.
2002).
The
product
matrix
may
affect
the
permeability
of
the
skin
such
that
there
may
be
an
enhancement
or
inhibition
of
the
chemical
penetration
into
the
skin.
This
includes
such
things
as
irritants,
penetration
enhancers
or
inhibitors
etc.
The
subjects
in
the
Nethercott
et
al.
(
1994)
study
were
tested
to
hexavalent
chromium
in
occluded
patches
for
a
continuous
48
hour
period.
Patch
testing
with
occlusion
is
designed
to
maximize
penetration
of
the
test
substance.
Thus
for
the
matrix
UF,
a
value
of
0.1
was
chosen
to
account
for
the
more
artificial
situation
in
the
Nethercott
et
al.
(
1994)
study
relative
to
actual
exposures
to
wood
treated
with
hexavalent
chromium.
A
value
of
less
than
1
was
considered
appropriate
where
the
test
matrix
is
likely
to
induce
enhanced
penetration
and
or
augment
the
induction/
elicitation
process
relative
to
the
matrix
of
environmental
concern.
As
the
Panel
has
presented
in
response
to
this
and
previous
questions,
uncertainty
factors
range
from
1
to
10
(
Dourson
et
al.
1996).
The
Panel
is
cognizant
their
selection
of
an
uncertainty
factor
less
than
1
deviates
from
traditional
uncertainty
factor
analyses.
However,
based
on
the
conditions
presented
by
the
Panel,
the
Panel
believed
that
an
uncertainty
factor
less
than
1
was
appropriate
for
the
matrix
effect.

The
Nethercott
et
al.
(
1994)
exposure
assessment
provides
for
an
estimate
of
the
dermal
exposure
to
the
test
substance
in
units
of
ug/
cm2.
Such
factors
as
site
of
body
exposed,
effect
of
occlusion,
dermal
integrity
and
certain
environmental
conditions
were
included
in
the
Panel's
determination
of
an
exposure
UF.
The
real
world
exposure
to
hexavalent
chromium
would
consist
of
short­
term
repeated
dermal
exposures.
Typically,
most
potential
dermal
exposures
would
be
prevented
by
barriers
people
would
have
as
a
part
of
their
normal
life,
such
as
clothing,
shoes,
and
towels.
However,
it
is
likely
that
hands
and
feet
can
come
into
short
term
and
repeated
contact
to
treated
wood.
On
decks
with
built
in
furniture,
people
would
have
dermal
exposure
on
the
legs
(
e.
g.
back
of
the
thighs
and
calves)
if
they
are
wearing
short
pants.
Furthermore
the
exposure
to
hexavalent
chromium
could
be
enhanced
from
routine
cleaning
of
decking
with
alkaline­
based
deck­
cleaning
products.
The
Panel's
determination
of
an
exposure
UF
accounts
for
the
differences
between
conditions
in
the
Nethercott
et
al.
(
1994)
study
and
those
conditions
likely
to
be
encountered
for
ACC
hexavalent
chromium
treated
wood
products.
Thus,
for
the
exposure
UF
a
value
ranging
from
3
to
10
was
chosen
to
account
for
real
world
repeated
exposures
that
would
occur
to
wood
treated
with
hexavalent
chromium.
Page
24
of
28
Table
1.
Summary
of
Uncertainty
Factors
Condition
Uncertainty
Factor
Matrix/
vehicle
0.1
Interspecies
variation
1
Intraspecies
variation
1
Exposure
3
to
10
Estimated
S­
RfD
S­
RfD
is
a
conservative
estimate,
with
associated
uncertainty,
of
a
dermal
exposure
(
in
units
of
ug/
cm2
)
that
would
not
be
expected
to
result
in
the
induction
of
sensitization
in
the
general
population,
including
more
responsive
subpopulations
(
Felter
et
al
2003).
The
minimum
elicitation
threshold
(
MET
10%)
is
the
concentration
that
would
elicit
an
allergenic
reaction
in
10%
of
a
sensitized
population.
As
described
previously,
the
Panel
selected
a
MET
10
of
0.088
ug/
cm2
from
the
Nethercott
et
al.
(
1994)
study
for
use
in
calculating
a
S­
RfD.
Applying
the
uncertainty
factors
presented
in
Table
1
(
uncertainty
factors
ranged
from
0.3
to
1),
the
S­
RfD
calculated
as
specific
to
hexavalent
chromium
in
treated
wood
ranged
from
0.09
to
0.3
ug/
cm2
.
This
calculation
is
presented
in
Figure
1.

Figure
1.
Calculation
of
S­
RfD
0.088
ug/
cm2
=
0.3
to
0.09
ug/
cm2
(.
1)
(
1)
(
3
to
10)
[.
3
to
1]

The
Panel's
estimate
of
an
S­
RfD
should
be
protective
against
elicitation
and
therefore
would
also
be
protective
of
induction,
as
thresholds
for
induction
are
generally
higher
than
those
for
elicitation
(
Kimber
et
al.,
2003).
Although
the
Panel
calculated
a
S­
RfD
for
hexavalent
chromium
in
ACC
treated
wood,
the
Panel
stressed
that
the
Agency
consider
all
data
as
part
of
a
weight
of
evidence
approach.

Panel
Consideration
Of
Relationship
Of
Environmental
Media
And
The
Acceptable
Area
Dermal
Dose
During
the
public
comments
section
of
this
FIFRA
SAP
meeting,
the
EPA,
Office
of
Solid
Waste
and
Emergency
Response,
presented
comments
on
the
relationship
of
environmental
media
(
e.
g.
soil,
wood
or
water)
and
acceptable
area
dermal
dose.
While
the
Panel
was
not
explicitly
charged
with
responding
to
the
issues
presented
by
EPA
OSWER,
they
decided
that
such
issues
require
consideration
by
the
FIFRA
SAP.
EPA
OSWER's
questions
to
the
Panel
and
the
Panel's
response
are
presented
below.

EPA
OSWER
Questions
(
1)
Does
the
Panel
agree
that
environmental
matrix
variables
will
influence
the
acceptable
area
dermal
dose
to
induce/
elicit
contact
dermal
sensitization
in
an
individual
when
exposed
to
a
Page
25
of
28
chemical
incorporated
in
an
environmental
media?

(
2)
Please
describe
how
media­
specific
characteristics
have
or
do
not
have
a
substantial
impact
on
determining
an
environmental
acceptable
dermal
dose
for
a
chemical
incorporated
in
soil,
wood,
and
water
matrices.

Panel
Response
The
FIFRA
SAP
agreed
that
matrix
(
wood,
soil,
water)
variables
can
influence
the
amount
of
compound
available
for
penetration
through
the
stratum
corneum
bilipid
layers
to
have
an
effect.
Thus,
the
use
of
uncertainty
factors
are
applied
to
account
for
this
variation.
For
example,
wet
cement
is
different
from
cement
powder.
Aqueous
solutions
can
hydrate
the
stratum
corneum,
thereby
increasing
the
rate
of
penetration
of
a
compound
through
the
skin.
The
pH
of
the
matrix
can
also
influence
the
penetration
of
a
compound
and
change
the
charge
of
a
compound.
Fixation
of
a
compound
in
an
environmental
medium
can
lower
the
bioavailability
of
that
compound.

Media­
specific
characteristics
can
play
an
important
role
in
assessing
the
bioavailability
of
a
compound.
The
physical/
chemical
characteristics,
including
potential
for
the
matrix
to
cause
dermal
irritation,
may
contribute
to
or
decrease
a
compound's
ability
to
cause
dermal
induction/
elicitation.
Metal
speciation
of
the
compound
in
the
matrix
is
also
important,
for
example
Cr
(
VI)
is
more
toxic
than
Cr
(
III)
and
therefore
poses
a
greater
hazard.
It
is
not
important
how
much
of
a
chemical
is
in
the
matrix
but
how
much
is
leached
out
of
it
and
available
for
exposure.
All
of
these
factors
can
influence
how
much
material/
compound
would
be
available
to
have
an
effect.
Page
26
of
28
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