DATE:	August 31, 2004

MEMORANDUM

SUBJECT:	Hexavalent Chromium - Finalization of Issues related to
Quantitation of Dermal Risk from exposure to treated wood containing
hexavalent chromium

FROM:	Timothy F. McMahon, Ph.D.

Chair, Antimicrobials Division Toxicity Endpoint Selection Committee

Antimicrobials  Division (7510C)

THROUGH:     Jess Rowland

 Stephen Dapson, Ph.D.

 Pv Shah

 Roger Gardner

 Michelle Centra

Timothy Leighton

Jonathan Chen, Ph.D.

Deborah Smegal

John Redden

PC Code: 021101, 068302, 068304

On November 12th , 2003, the Antimicrobials Division’s Toxicology
Endpoint Selection Committee (ADTC) in conjunction with the chair of the
Health Effects Division Hazard Identification Assessment Review
Committee (HIARC) met to discuss risk issues associated with dermal
exposure to hexavalent chromium (CrVI). On August 17, 2004, the ADTC
along with scientists from the Health Effects Division met again to
discuss the additional information and decisions made regarding dermal
exposure to CrVI and to finalize a level of concern for dermal exposure
to this chemical.  The results of these discussions are included in this
memorandum.

 Committee Members in Attendance

Present at the meeting were the following scientists from the noted
respective divisions within OPP: From the Health Effects Division: Jess
Rowland,  Stephen Dapson, Pv Shah; from the Biopesticides and Pollution
Prevention Division: Roger Gardner; from the Antimicrobials Division:
Timothy McMahon (chair), Michelle Centra, Timothy Leighton, Jonathan
Chen,  Deborah Smegal; from the Registration Division, John Redden.

Data evaluation prepared by: Timothy F. McMahon, Ph.D.

I. Background

On November 12, 2003, an internal workgroup composed of scientists
within the Office of Pesticide Programs met to discuss dermal risk
issues associated with exposure to chromium +6 (CrVI) as present in Acid
Copper Chromate (ACC)-treated wood. Present at the meeting were the
following scientists from the noted respective divisions within OPP:
From the Health Effects Division: Jess Rowland,  Stephen Dapson, PV
Shah, Yung Yang; from the Biopesticides and Pollution Prevention
Division: Roger Gardner; from the Antimicrobials Division: Timothy
McMahon (chair), Michelle Centra, Timothy Leighton, Jonathan Chen,
Sanyvette Williams, Melba Morrow, Deborah Smegal.

As a brief background, this standing workgroup in the Office of
Pesticide Programs deliberated on  an application pending before the
Antimicrobials Division for the use of ACC-treated wood as a replacement
for CCA-treated wood. The Division had expressed concerns for dermal
risks from exposure to ACC-treated wood, as there are potentially higher
levels of CrVI in ACC-treated wood vs. CCA-treated wood (approximately
1.5 times higher CrVI content), and the “fixation” time, or time in
which CrVI is reduced to the less toxic chromium +3, can be
significantly longer for ACC-treated wood. These factors can result in a
  potential for residential dermal exposure to CrVI as well as the
potential for children’s  incidental oral exposure from contaminated
soil as the result of leaching of ACC from treated wood.

Along with other issues (discussed in the previous memorandum), the
committee considered the following issue with respect to CrVI itself:

Can an appropriate dermal endpoint for exposure to chromium +6 be
selected based on the available data?  What are the appropriate
uncertainty considerations to address if such an endpoint is selected?

The results of the committee’s initial deliberation on this issue was
the following, in summary:

As an interim working measure, in November of 2003, the workgroup
determined that the study of Nethercott (1994) provides some
dose-response data on dermal sensitization to CrVI.  In this study, a
value of 0.018 µg/cm2 (lowest dose tested) was reported to elicit a
sensitization response. This value with an attendant total uncertainty
factor of 10x was selected by the committee. A factor of 3x was applied
for selection of an LOAEL to extrapolate to a NOAEL, and a factor of 3x
was applied to account for the relatively small study population and
attendant variability therein.

The interim endpoint selected by the ADTC differed from a proposal by
the registrant made prior to the ADTC meeting.   In the  registrant’s
proposal (pages 41-42 of the submitted document “Meeting with U.S.
Environmental Protection Agency Antimicrobials Division and Forest
Products Research Laboratory, LLC October 30, 2003: Documents Submitted
to EPA as of October 30, 2003, Volume I of II) two values were suggested
as levels of concern:   the LOAEL of 0.018  µg/cm2 from the Nethercott
et al.  study using only a  factor of 3x   to account for the use of a
LOAEL, or the 10% minimum elicitation threshold value of 0.088 µg/cm2
with again a 3x uncertainty factor.  This results in two proposed values
of 0.006 or 0.03 µg/cm2.   As stated in the submission, ‘This would
suggest that any exposures to Cr(VI) concentration in treated wood of
less than 0.006 µg/cm2 (or 0.03 µg/cm2 if using the minimum
elicitation threshold) would be safe...”

II. Update of Hexavalent Chromium Dermal Risk Issue

Following the selection of the level of concern for hexavalent chromium
by the ADTC,  scientific issues related to the use of a quantitative RfD
 approach for assessment of dermal sensitization risk were raised by the
registrant of the treated wood product.  It was recognized that within
the Agency, quantitation of such risk had never been performed although
the issue had been raised within the Office of Pesticide Programs with
regard to certain agricultural pesticides.  Thus, the issue was
presented before the FIFRA Scientific Advisory Panel (SAP) as part of a
set of issues on May 4-6, 2004.  The SAP issued their final report in
July of 2004.

With respect to the question of sensitization potential from exposure to
hexavalent chromium in treated wood and what level of concern should be
established, the SAP recognized that allergic contact dermatitis from
exposure to CrVI may sometimes be very severe with a major impact on the
quality of life for some sensitized individuals. The condition can be
reversed when exposure is removed. There is currently no published
literature to suggest that allergic contact dermatitis results from
exposure to chromate in treated wood (although no such studies have been
conducted specifically, and no such data exist for the treated wood
product registration currently before the Agency-comment added).

Considering all of the data made available, the SAP identified the same
study as that chosen by the ADTC (Nethercott et al., 1994) as the best
available regarding quantitation of a  level of CrVI causing dermal
sensitization using a sensitized human study population.  The Panel
identified the “critical dose (lowest observed adverse effect level
[LOAEL]) from the Nethercott et al. (1994) study should be 0.088
µg/cm2, which the Panel considered to be a conservative safety
level.”    This represented the 10% minumum elicitation threshold, or
MET, in that study.

Uncertainty considerations in the selection of the endpoint included
inter- and intra-species variability,  and exposure matrix uncertainty
(i.e. differences between the exposures in the critical study which was
an acute exposure with the treated area occluded and anticipated product
exposures, which are expected to be repeated and not involve occlusion).

As a result of the Panel’s recommendation, the estimated RfD was
determined to encompass a range of   0.09-0.3 µg/cm2 based on the use
of the following  factors, as taken from the SAP report:

                  Condition

              SAP Recommended Uncertainty Factor

Matrix/vehicle factor

0.1

Interspecies variation (uncertainty)

1

Intraspecies variation (uncertainty)

1

Exposure factor

3-10

The actual calculation is illustrated, from the SAP report:

 S-RfD =          0.088 µg/cm2   =   0.09 - 0.3 µg/cm2

        (1)(1)(0.1)(3 to10)

The Panel concluded that this estimate of a RfD should be protective
against elicitation (i.e. reactions in already sensitized persons) and
therefore would also be protective against induction (i.e. reaction in
non-sensitized persons). However, the Panel also stressed that the
Agency “consider all data as part of a weight of evidence approach.”

Subsequent Agency Considerations

The Agency recognized that defining a RfD for dermal sensitization was a
new approach. Moreover, there was a need to better characterize
uncertainty to account for differences in exposure between the critical
study and the anticipated exposures.  These issues were presented to the
Agency’s Science Policy Council Steering Committee (SPC SC) on August
11, 2004 for further discussion.

The SPC SC considered these two areas and provided comments: The SPC SC
agreed that dermal sensitization can be used in an approach to determine
a RfD.  Secondly, the UFs for matrix/vehicle and exposure as recommended
by the SAP are not recognized UFs by the Agency (cf., Agency RfD/RfC
technical report document, EPA/630/P-02/002F, 2002).  Further,  factors
of less than 1 are typically not applied. The SPC SC stated that, as a
policy issue, it does not recommend setting UFs of less than 1 without
actual data to indicate it is appropriate to do so (there are no data on
these issues for Cr(VI)).

  In this particular instance, the SPC SC recommended that to address
the SAP's concerns about occlusion and repeated exposure are to be
addressed, they should be characterized as dose adjustment factors to
apply to this particular situation of exposure to hexavalent chromium in
treated wood and not as a general policy at this time. Dose adjustment
can be thought of in terms of what concentration of chemical would cause
a sensitization response under occluded vs. non-occluded conditions, and
how repeated exposures over time might cause sensitization reactions in
the human population, given the inherent variability of the human
population.   It has been suggested that, given the same area dose to
the skin, occluded conditions would lead to a sensitization reaction
that might not otherwise occur under non-occluded conditions. However,
this statement, particularly with regard to hexavalent chromium, has
never been systematically investigated. Thus there are no data to
suggest  what the actual magnitude of this factor would be; it is likely
a chemical-specific phenomenon and could vary , based on the potency of
the sensitizing agent.      The SPC SC noted that further study is
necessary to examine the comparative dose between occluded and
non-occluded exposures to  hexavalent chromium exposure.

The use of a factor to account for repeated exposures an individual may
receive from contacting ACC-treated wood was supported by the SPC SC,
but the factor was felt to be more indicative in this case as one to
account for variations in response to repeated exposure among the human
population (i.e., intraspecies variation UF) . Even among sensitized
individuals, variations in response may occur due to age, gender,
previous history of sensitization, skin condition, etc. and the response
over time to repeated exposures may also show variability.  There was no
specific recommendation of the SPC SC regarding the magnitude of this
factor.

Based on the discussions with the SPC SC, the ADTC was convened again on
August 17, 2004 to consider all of the updated information and peer
reviews since issuance of the first memorandum of November 2003 and to
decide on a level of concern regarding the concentration of hexavalent
chromium on the surface of ACC-treated wood that would be protective
against development of ACD.

Conclusions of Second ADTC Meeting

The ADTC, in light of all the information made available since
addressing the issue of dermal sensitization and risk assessment
(including open literature, the SAP recommendations, and the SPC SC
comments), concluded the following:

1) The ADTC agreed with the SAP recommendation of the use of the 10% MET
value of 0.088 µg/cm2 from the Nethercott et al. (1994) study instead
of the previously selected value of 0.018 µg/cm2 from that same study.

2) The ADTC agreed with the SPC’s SC comment that a dose adjustment
factor of 0.1 for matrix effects was not supported and would not be
applied at this time for determination of a level of concern for
hexavalent chromium.  More data to address this specific issue are
necessary as noted above.

3) The ADTC concluded that, for addressing the human variability
regarding sensitization from repeated dermal exposures expected with
ACC-treated wood,  a factor of 10x is appropriate at this time. A
different factor is not warranted at this time, as (a) there is no
definitive data on levels of hexavalent chromium on the surface of
freshly-treated wood using the ACC treatment solution, nor is there
definitive data on the time course for the conversion of this surface
level to  chromium III (Cr III); and (b) there is expected to be
variation in the response to repeated exposures to surface residues of
hexavalent chromium in humans but there is no data to suggest a
different factor.  As data become available regarding human variability
and levels of Cr(VI) on wood, the ADTC can revisit the RfD for Cr(VI)
treated wood.

Recommendation/Conclusion:

 The derivation of the level of concern by the ADTC  for hexavalent
chromium, based on peer review by the FIFRA SAP and comment from  the
Agency’s SPC SC, is summarized below.  At this time, it is  concluded
that an UF that applies here is a factor of 10 for intraspecies
variation.  This factor is applied at this time based on the lack of
definitive data on levels of hexavalent chromium on the surface of
freshly-treated wood using the ACC treatment solution, the lack of
definitive data on the time course for the conversion of the surface
level to chromium III (Cr III), and the lack of definitive data on
variation in the response to repeated exposures to surface residues of
hexavalent chromium in humans. As more data become available, the 10x
factor can be reconsidered.

The derivation of the sensitization RfD, based on this conclusion, is
thus:

S-RfD =          0.088 µg/cm2   =   0.009  µg/cm2

           (10)

 .

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