July 1, 2004

[MEMORANDUM]{.underline}

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

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]{.underline}

[FIFRA Scientific Advisory Panel Members]{.underline}

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

**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**

**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/]{.underline} 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.

**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**

Number range CHAPTER

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

**Federal Insecticide, Fungicide, and Rodenticide Act**

**Scientific Advisory Panel Meeting**

**May 4-6, 2004**

**Consultation on Dermal Sensitization Issues for**

**Exposures to Pesticides**

**PARTICIPANTS**

Number range CHAPTER

**[FIFRA SAP Session Chair]{.underline}**

**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]{.underline}**

Number range CHAPTER**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]{.underline}**

**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

**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

**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.
Number range CHAPTERAdvance 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. Number range CHAPTERMr. 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.

**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 allergen-specific 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 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 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.

**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/cm^2^) 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/cm^2^. 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/cm^2^ 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.

-   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/cm^2^, 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/cm^2^ .

-   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.

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
^3^H-thymidine or I^125^ -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 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.]{.underline}

[Proposed quantitative approaches]{.underline}

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 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]{.underline}

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 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, 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]{.underline}

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 cause severe discomfort including
itching, weeping, and pain. Significant morbidity can result.

[Primary Sensitization In Children]{.underline}

Like adults, children can be sensitized with only one exposure to an
allergen. P-phenylenediamine 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]{.underline}

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]{.underline}

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 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]{.underline}

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]{.underline}

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]{.underline}

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.

-   Woods treated with deck cleaners and bleaches.

[Chromate Human Threshold Studies]{.underline}

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)]{.underline}

The Panel identified the critical dose (lowest observed adverse effect
level) \[LOAEL\] from the Nethercott et al. (1994) study should be
0.088ug/cm^2^, which the Panel considered to still be a conservative
safety level. This dose was in contrast to the 0.018ug/cm^2^ suggested
by the Agency. At 0.088ug/cm^2^ 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]{.underline}

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.

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/cm^2^. 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.

**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]{.underline}

S-RfD is a conservative estimate, with associated uncertainty, of a
dermal exposure (in units of ug/cm^2^ ) 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/cm^2^ 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/cm^2^ .
This calculation is presented in Figure 1.

**Figure 1. Calculation of S-RfD**

[0.088 ug/cm^2^]{.underline} = 0.3 to 0.09 ug/cm^2^

(.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** Number range CHAPTER**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**

\(1\) Number range CHAPTERDoes 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 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.

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