Document ID: EPA-HQ-ORD-2006-0798-0030
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-01-24T05:00Z

January 21, 2007

EPA-HSRB-06-04

George Gray, Ph.D.

Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject:  October 18-19, 2006 EPA Human Studies Review Board Meeting
Report

Dear Dr. Gray:

The United States Environmental Protection Agency (EPA or Agency)
requested the Human Studies Review Board (HSRB) to review scientific and
ethical issues addressing: (1) a  completed human toxicity study
evaluating the allergic contact dermatitis response in individuals with
known sensitivity to hexavalent chromium to repeated exposure to a wood
treatment solution containing hexavalent chromium (chromium repeat open
application test); (2) two revised research protocols to evaluate the
efficacy of new formulations of the repellent IR3535 against ticks and
mosquitoes; and (3) draft EPA guidance to the public concerning
submission of proposed and completed human research to EPA for review by
the HSRB.  In addition, at the Board’s request, EPA provided
background information regarding the handling of material claimed to be
confidential business information (CBI) for HSRB consideration.  

The enclosed HSRB report addresses the Board’s response to EPA charge
questions for the Board’s consideration discussed by the Board at its
October 18-19, 2006 meeting.  In addition, the Board welcomed the
Agency’s discussion in two areas: (1) draft EPA guidance to the public
concerning submission of proposed and completed human research to EPA
for review by the HSRB and EPA and (2) handling of material claimed to
be confidential business information (CBI) for HSRB consideration.  The
Board provided comments on these two topics as part of its review.    

A summary of the Board’s conclusions is provided below.

Chromium Repeat Open Application Test 

Scientific Consideration 

The HSRB concluded that the Repeated Open Application Test for Allergic
Contact Dermatitis due to Hexavalent Chromium as Coppershield® study
contained information sufficient for assessing human risk resulting from
potential dermal exposure to wood treated with acid copper chromate
(ACC). 

The HSRB also concluded that this study was sufficiently sound, from a
scientific perspective, to be used to estimate a safe level of repeated
dermal exposure to residues of ACC on treated wood. 

However, the HSRB rejected the differential classification of irritant
and allergic responses in the sensitized population because the study
dermatologist was not blinded to the status of the sensitized and
control groups, nor to the skin dose levels, and because of a
substantial discrepancy in the assignment of irritant and allergic
classifications for responses across the two groups. The HSRB
recommended that EPA consider all responses recorded in the study to be
allergic for the purpose of calculating the MET10. 

The HSRB also rejected the adjustment of study results through use of
the North American Contact Dermatitis Group database. The HSRB
recommended that the Agency use the empirical data from the study in its
calculation of the MET10.

Ethical Considerations

The Board concurred with the Agency’s assessment that there was no
clear and convincing evidence that the conduct of the studies was
fundamentally unethical in that the deficiencies did not result in
serious harm, nor seriously impair the informed consent of the research
subjects. 

The Board determined that there was no clear and convincing evidence
that the conduct of the study was significantly deficient relative to
the ethical standards prevailing when these two studies were conducted. 

IR3535 Insect Repellent Efficacy Protocols

Study EMD-003 from Carroll-Loye Biological Research

	Scientific Considerations

The HSRB noted that representatives from Carroll-Loye Biological
Research had responded to the numerous concerns raised by the Board in
its original review of the protocol.  The HSRB concluded that the
proposed research as described appears likely to generate
scientifically-reliable data that would be useful for assessing the
efficacy of a test substance for repelling ticks.

Ethical Considerations

The Board concurred with the initial assessment of the Agency that the
revised protocol, EMD-003, submitted for review by the Board meets the
applicable requirements of §40CFR26, subparts K and L. 

Study EMD-004 from Carroll-Loye Biological Research

Scientific Considerations

The revised protocol contains considerably greater detail than the
original and it answers all the scientific questions that were posed by
the HSRB in its original review.  The PI has been extremely responsive
to the original review comments. The revised protocol should generate
scientifically valid results of efficacy in repelling mosquitoes.

Ethical Considerations 

The Board concurred with the initial assessment of the Agency that the
revised protocol, EMD-004, submitted for review by the Board meets the
applicable requirements of §40CFR26, subparts K and L. 

In conclusion, the EPA HSRB appreciated the opportunity to advise the
Agency on the scientific and ethical aspects of human studies research
and looks forward to future opportunities to continue advising the
Agency in this endeavor. 

Sincerely,

Celia Fisher, Ph.D. Chair

EPA Human Studies Review BoardNOTICE

This report has been written as part of the activities of the EPA Human
Studies Review Board, a Federal advisory committee providing advice,
information and recommendations on issues related to scientific and
ethical aspects of human subjects research.  This report has not been
reviewed for approval by the Agency and, hence, the contents of this
report do not necessarily represent the view and policies of the
Environmental Protection Agency, nor of other agencies in the Executive
Branch of the Federal government, nor does the mention of trade names or
commercial products constitute a recommendation for use.  Further
information about the EPA Human Studies Review Board can be obtained
from its website at http://www.epa.gov/osa/hsrb/.  Interested persons
are invited to contact Paul Lewis, Designated Federal Officer, via
e-mail at lewis.paul@epa.gov.

	In preparing this document, the Board 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.

United States Environmental Protection Agency Human Studies Review
Board

Chair

Celia B. Fisher, Ph.D., Marie Ward Doty Professor of Psychology,
Director, Center for Ethics Education, Fordham University, Department of
Psychology, Bronx, NY 

Vice Chair

William S. Brimijoin, Ph.D., Chair and Professor, Molecular Pharmacology
and Experimental Therapeutics, Mayo Foundation, Rochester, MN    

Members 

David C. Bellinger, Ph.D., Professor of Neurology, Harvard Medical
School, Professor in the Department of Environmental Health, Harvard
School of Public Health

Children's Hospital, Boston, MA  

Alicia Carriquiry, Ph.D., Professor, Department of Statistics, Iowa
State University, Ames, IA *

Gary L. Chadwick, PharmD, MPH, CIP, Associate Provost, Director, Office
for Human Subjects Protection, University of Rochester, Rochester, NY 

Janice Chambers, Ph.D., D.A.B.T., William L. Giles Distinguished
Professor, Director, Center for Environmental Health Sciences, College
of Veterinary Medicine, Mississippi State University, Mississippi State,
MS 

Richard Fenske, Ph.D., MPH, Professor, Department of Environmental and
Occupational Health Sciences, University of Washington, Seattle WA 

Susan S. Fish, PharmD, MPH, Professor, Biostatistics & Epidemiology,
Boston University School of Public Health, Co-Director, MA in Clinical
Investigation, Boston University School of Medicine, Boston, MA 

Suzanne C. Fitzpatrick, Ph.D., DABT, Senior Science Policy Analyst,
Office of the Commissioner, Office of Science and Health Coordination,
U.S. Food and Drug Administration, Rockville, MD 

Kannan Krishnan, Ph.D., Professor, Département de santé
environnementale et santé au travail, Faculté de medicine, Université
de Montréal, Montréal, Canada

KyungMann Kim, Ph.D., CCRP, Professor & Associate Chair, Department of
Biostatistics & Medical Informatics, School of Medicine and Public
Health, University of Wisconsin-Madison, Madison, WI  

Michael D. Lebowitz, Ph.D., FCCP, Professor Emeritus of Medicine.
University of Arizona, Tucson, AZ 

Lois D. Lehman-Mckeeman, Ph.D., Distinguished Research Fellow, Discovery
Toxicology, Bristol-Myers Squibb Company, Princeton, NJ  

Jerry A. Menikoff, M.D., Associate Professor of Law, Ethics & Medicine,
Director of the Institute for Bioethics, Law and Public Policy,
University of Kansas Medical Center, 

Kansas City, KS 

Sean Philpott, Ph.D., MS Bioethics, Associate Director of the Alden
March Bioethics Institute, Associate Professor of Medicine, Albany
Medical Center, Albany, NY  

Richard Sharp, Ph.D., Assistant Professor of Medicine, Center for
Medical Ethics and Health Policy, Baylor College of Medicine, Houston,
TX

Human Studies Review Board Staff

Paul I. Lewis, Ph.D., Designated Federal Officer, United States
Environmental Protection Agency, Washington, DC 

* Not in attendance at October 18-19, 2006 Public MeetingTABLE OF
CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc153355391"  INTRODUCTION	 
PAGEREF _Toc153355391 \h  8  

  HYPERLINK \l "_Toc153355392"  REVIEW PROCESS	  PAGEREF _Toc153355392
\h  9  

  HYPERLINK \l "_Toc153355393"  CHARGE TO THE BOARD AND BOARD RESPONSE	 
PAGEREF _Toc153355393 \h  10  

  HYPERLINK \l "_Toc153355394"  Chromium Repeat Open Application Test	 
PAGEREF _Toc153355394 \h  10  

  HYPERLINK \l "_Toc153355404"  Study EMD-003 from Carroll-Loye
Biological Research	  PAGEREF _Toc153355404 \h  18  

  HYPERLINK \l "_Toc153355405"  Study EMD-004 from Carroll-Loye
Biological Research	  PAGEREF _Toc153355405 \h  22  

  HYPERLINK \l "_Toc153355406"  Review format	  PAGEREF _Toc153355406 \h
 26  

  HYPERLINK \l "_Toc153355407"  Draft EPA guidance to the public
concerning submission of proposed and completed human research to EPA
for review by the HSRB and EPA	  PAGEREF _Toc153355407 \h  27  

  HYPERLINK \l "_Toc153355408"  Confidential Business Information 	 
PAGEREF _Toc153355408 \h  29  

  HYPERLINK \l "_Toc153355409"  REFERENCES	  PAGEREF _Toc153355409 \h 
30  

 

INTRODUCTION

On October 18-19, 2006, the United States Environmental Protection
Agency’s (EPA or Agency) Human Studies Review Board (HSRB) met to
address scientific and ethical issues concerning three topics:  

(1) a completed human toxicity study, evaluating the allergic contact
dermatitis response in individuals with known sensitivity to hexavalent
chromium to repeated exposure to a wood treatment solution containing
hexavalent chromium (chromium repeat open application test [ROAT]).

The Agency received a report on a study involving repeated open dermal
application of a wood treatment solution containing hexavalent chromium
to human subjects with known sensitivity to hexavalent chromium.  This
study was initiated prior to the effective date of EPA regulation in 40
CFR Part 26, subparts K – Q, but submitted after the effective date of
subpart M, which requires documentation of ethical conduct.  The Agency
reviewed the study and supplemental materials concerning its ethical
conduct, determined that the study met the applicable provisions of the
EPA regulations, and deemed the study ethically acceptable.  EPA  also
concluded the report provides scientifically sound information that can
be used to estimate a level of exposure to hexavalent chromium (together
with confidence limits), below which exposure would be unlikely to
elicit an allergenic response in a specified percentage of individuals
with a preexisting sensitivity to hexavalent chromium.  The Agency’s
regulation, 40 CFR § 26.1602, requires EPA to seek HSRB review of
EPA’s decision to rely on the results of this study.  The hexavalent
chromium study was submitted in connection with a pending application to
register a wood preservative product that contains Acid Copper Chromate
(ACC).  

 

(2) two revised research protocols to evaluate the efficacy of new
formulations of the repellent IR3535 against ticks and mosquitoes (the
Board reviewed and commented on earlier versions of these revised
protocols at its June 2006 meeting).

EPA requires data from efficacy studies using appropriate insect species
to support an application for registration of a new product making
insect repellency claims.  An applicant for registration typically
conducts such research prior to submitting an application.  If such a
study is to be initiated after April 7, 2006, the Agency’s regulation,
40 CFR § 261125, requires the sponsor or investigator to submit to EPA,
before conducting the study, materials describing the proposed human
research in order to allow EPA to conduct scientific and ethics reviews.
 In addition, EPA’s regulation, 40 CFR § 26.1601, requires EPA to
seek HSRB review of the research proposal.  

In its June 2006 meeting, the HSRB reviewed and commented on materials
relating to two proposed insect repellent efficacy protocols from
Carroll-Loye Biological Research, submitted by Dr. Scott Carroll.  The
two protocols described research to evaluate the efficacy of new
formulations of repellent products containing the active ingredient, IR
3535.  One study would be conducted under laboratory conditions to
measure the efficacy of the test formulations against ticks.  The second
study would measure the efficacy of the test formulations against
mosquitoes under field conditions.  The HSRB offered extensive comments
on the two protocols.  Following the June 2006 meeting, Dr. Carroll
revised the protocols to address comments from the HSRB.  EPA reviewed
Dr. Carroll’s revised protocols and concluded that they appeared
likely to generate scientifically sound, useful information and to meet
the applicable provisions of the EPA regulations in 40 CFR part 26,
subparts K and L.  Because of the extent of the revisions to Dr.
Carroll’s earlier protocols, the Agency asked the HSRB to review the
protocols again.

(3) draft EPA guidance to the public concerning submission of proposed
and completed human research to EPA for review by the HSRB 

As noted above, the Agency’s regulation at 40 CFR §26.1125, requires
a sponsor or investigator to submit specified materials to allow EPA and
the HSRB to review the scientific and ethical aspects of the conduct of
certain types of proposed human research before the research is
initiated.  Based on its experience with early submissions of protocols
and associated materials since this provision took effect, EPA believes
the public would benefit from guidance explaining what materials should
be presented, how they would be most effectively organized, how EPA
would approach the review of a submission, and how long EPA would expect
to take to complete its review of the material and to prepare the
materials for submission to the HSRB.  Accordingly, EPA has drafted a
guidance document, referred to as a PR Notice, containing
recommendations for researchers who might submit materials under 40 CFR
§26.1125.

	EPA believes the most efficient process for review of proposals for
covered human research would be for submitters to transmit to EPA a
complete package which could be sent to the HSRB, without EPA having to
make any changes to the organization of the materials.  Because such an
approach would mean that the Board would usually be reviewing materials
in the form they were originally submitted, EPA asked the Board whether
the guidance for form and content of protocol submissions suggested in
the draft guidance represents an acceptable way of presenting
researchers’ materials for HSRB review.  (Of course, in addition to
the materials as submitted, EPA would provide to the Board its own
reviews of submitted protocols). While not required to undergo HSRB
review, EPA regards this draft guidance as an important step toward
improved quality and completeness of protocol submissions and toward
increased efficiency of both EPA and HSRB reviews of proposed new
research.  

In addition, the Board discussed handling of material claimed to be
confidential business information (CBI) for HSRB consideration.  This
report transmits the HSRB’s comments and recommendations from its
October 18-19, 2006 meeting.        

REVIEW PROCESS

On October 18-19, 2006 the Board had a public face-to-face meeting in
Arlington, Virginia.  Advance notice of the meeting was published in the
Federal Register “Human Studies Review Board: Notice of Public Meeting
(71 Federal Register 56527 and 71 Federal Register 56528).  At the
public meeting, following welcoming remarks from Agency officials, Celia
B. Fisher, HRSB Chair, proposed a set of scientific and ethics criteria
consistent with the language of 71 Federal Register 6137 to guide Board
evaluation of completed studies.  The Chair’s scientific criteria
asked the Board to consider the following two questions: (1) did the
research design and implementation meet scientific standards and (2) did
the data generated by the study have implications for the Agency’s
Weight of the Evidence (WOE) review and, when applicable, aspects of the
risk assessment?  The Chair also reviewed the Chair’s science criteria
and the Board’s criteria for scientific standards for human dosing
studies . The Chair’s ethics criteria asked the Board to consider
three questions: (1) did the study fail to fully meet specific ethical
standards prevalent at the time the research was conducted; (2) was the
conduct of the study fundamentally unethical (i.e., specifically was
there clear and convincing evidence that the research was intended to
seriously harm participants or failed to obtain informed consent); and
(3) was the conduct of the study significantly deficient relative to the
ethical standards prevailing at the time (i.e., was there clear and
convincing evidence that deficiencies identified could have resulted in
serious harm based on knowledge available at the time the study was
conducted or the information provided to participants could seriously
impair informed consent). 

The Board then heard presentations from the Agency on the following
topics: (1) a chromium repeat application test; (2) protocols for
conducting two insect repellent efficacy studies; (3) draft guidance to
the public concerning submission of proposed and completed human
research to EPA for review by the HSRB and; (4) handling of material
claimed to be confidential business information (CBI) for HSRB
consideration. 

The Board received written public comments from Dr. Scott Carroll
representing Carroll- Loye Biological Research, Laura Hepting
representing Beyond Pesticides, William J. Gaynor representing Insect
Control & Research, Inc. and Paul Bogart representing The Healthy
Building Network.

For their deliberations, the Board considered the materials presented at
the meeting, written public comments and Agency background documents
(e.g. pesticide human study, Agency data evaluation record (DER) of the
pesticide human study, weight of evidence review, ethics review,
pesticide human study protocols and Agency evaluation of the protocol). 

CHARGE TO THE BOARD AND BOARD RESPONSE

Chromium Repeat Open Application Test 

Charge to the Board

Hexavalent chromium is a component of a pesticide product intended to be
used as a wood preservative.  Members of the general public may
experience dermal exposure to residues of hexavalent chromium remaining
on wood treated with a wood preservative.  Because chromium has caused
allergic contact dermatitis (ACD) in occupational settings, EPA has
determined that it should assess the potential for ACD in the general
public resulting from exposure to hexavalent chromium on wood treated
with acid copper chromate (ACC).

Scientific considerations  

The Agency has concluded that the study contained information sufficient
for assessing human risk resulting from potential dermal exposure to
wood treated with ACC, containing hexavalent chromium.    

Please comment on whether this study is sufficiently sound, from a
scientific perspective, to be used to estimate a safe level of repeated
dermal exposure to residues of ACC on treated wood.

Board Response to the Charge

Critique of Study

A Repeat Open Application Test (ROAT) was performed on 60 human study
subjects who had been confirmed allergic to hexavalent chromium [Cr(VI)]
through closed-patch testing.  The purpose of this study was to develop
a 10% minimum elicitation threshold value (MET10) for elicitation of
allergic contact dermatitis for hexavalent chromium (as contained within
the CopperShield® wood preservative treatment solution).  The study
design involved the application of five concentrations of hexavalent
chromium (as contained within the CopperShield® wood preservative
treatment solution) to the right forearm of the test subjects, and
application of five concentrations of potassium dichromate to the left
forearm of the same subjects.  

Test subjects received application of both CopperShield® treatment
solution and potassium dichromate once per day for 10 days.  Duration of
each exposure was 6 hours after which the forearms were washed using
soap provided to them.  Prior to the next application, participants were
evaluated for occurrence of any skin responses, including erythema,
papules, pruruitis, scaling, and vesicles.  Results were evaluated by
the study’s dermatologist, who interpreted them as either allergic or
irritant in nature, and graded each response.  Seventy-two hours
following the last testing day, participants were evaluated by the
dermatologist to determine if an allergic contact dermatitis response
had occurred.  Results from the ROAT phase of the study were modeled
using Benchmark Dose Software (BMDS) to fit the dose-response data and
calculate the MET10.   

Results of closed-patch testing with potassium dichromate using 12mm
Finn Chambers showed that all participants for the ROAT phase of the
study were confirmed to have sensitivity to hexavalent chromium.  

The study investigators compared these results to data from the North
American Contact Dermatitis Group (NACDG) database (1998-2002). The
number of participants in the ROAT phase of the study who exhibited a
high grade of ACD response (+3) was disproportionate to the NACDG
database for this grade of reaction. The study investigators considered
the NACDG database to be representative of the hexavalent
chromium-sensitized population in the United States, and therefore
adjusted the study results based on the NACDG database.

In addition to normalization of the study data, two scenarios were
modeled from the CopperShield® results.  Scenario 1 included only
responses determined to be allergic in nature.  Under this scenario it
was assumed that if a participant reacted to a lower dose, they were
allergic to all higher doses even if they did not actually react to the
higher dose.  Scenario 2 included both irritant and allergic responses
in calculation of a 10% response level. The purpose of this scenario was
to determine the effect on the MET10 if all of the irritant responses
were allergic in nature. 

The study investigators concluded that the unconstrained log-probit
model provided the best fit for the dose-response data.   For
CopperShield®, the MET10 values for Scenarios 1 and 2 of the
untransformed dose-response data were 270 and 91.8 ng Cr(VI)/cm2
respectively. The MET10 values for the patch-test normalized data were
349 and 166 ng Cr(VI)/cm2 respectively.

General Scientific Criteria

This study was managed by scientists at Exponent, and was a
collaboration with Dermatology Specialists, PSC. Dermatology Specialists
is the private medical practice of Dr. Joseph Fowler. Dr. Fowler’s
research staff conducted activities that involved study participants.

The study was not blinded. All of the sensitized participants were
patients of the study dermatologist, and nearly all of the control
participants were employees of the study dermatologist. Skin dosing was
conducted in a systematic pattern known to the study dermatologist.

Study Design Criteria 

Purpose/objectives

The purpose of the study was clearly stated. The objective was to
estimate the MET10 minimum elicitation threshold in a population known
to be allergic (pre-sensitized) to hexavalent chromium. 

Sample size

The sample size appeared to be based on the sample size used by
Nethercott et al. 1994. It was the judgment of the investigators that a
similar number of subjects would have sufficient statistical power. No
power calculation was included in the report. Nonetheless, the data
collected appeared to be sufficient to allow calculation of the MET10 .

Dose levels

Repeat open application testing provides a more realistic evaluation of
human exposures than does patch testing. The use of mass per unit area,
rather than concentration, is the appropriate metric for dermal exposure
studies.  Dose levels were thoughtfully constructed. They included a
control (0 ng CrVI/cm2) level. The lowest dose level was similar to that
used in the Nethercott et al. (1994) study. The highest dose was based
on an estimate of the maximum exposure that could occur from contacting
Coppershield-treated wood.

Participation Criteria 

Controls were recruited from the employees of Dermatology Specialists. A
negative response to a patch test was required to be eligible for
participation in the study.

Recruitment of pre-sensitized individuals involved contacting
potentially eligible patients of Dr. Fowler via telephone by research
nurses of Dr. Fowler’s staff. Individuals whose records showed more
recent positive patch tests and strong patch-test responses were
contacted first. Of the 148 individuals contacted, 88 were found to be
eligible, showed interest, and agreed to come in for an initial visit.
Inclusion and exclusion criteria were clearly stated in the report, but
the details of excluding 60 individuals were not presented. Of the 88
individuals who made the initial visit, 58 were enrolled in the study.
Two additional participants were enrolled from the control group pool
because they tested positive to the patch test.

All controls were female. The sensitized group was 42% (25) male and 58%
(35) female. The report did not make clear why a control group of only
one gender was recruited for the study, nor did the report discuss
possible confounding that this discrepancy might introduce.

Measurement Criteria 

A standard patch testing method was used to determine eligibility for
both sensitized and control participants.  The load of potassium
dichromate applied to the skin during the patch test was not reported,
but was estimated by Agency scientists to be in the range of 25-50
micrograms applied to the 1 cm2 area of the skin. All evaluations were
conducted by a single observer. An advantage of this approach was that
it avoided inter-observer variability. Disadvantages of a single
observer approach were that it left open the possibility of systematic
bias, and did not allow for an independent review of the evaluations.
All irritant patch test cases were excluded from the study population;
all cases in doubt were also excluded. 

There was a clear gender discrepancy regarding the severity of patch
test responses: for the 1+ responses, 33% occurred in males (11/33), and
67% in females (22/33); whereas, for the 2+ or 3+ responses, 52%
occurred in males (14/27), and 48% in females (13/27). This gender
discrepancy was not discussed in the study report.

The study dermatologist provided a detailed description of each
response, and the reasons for classifying each response as either
irritant or allergic. The findings indicated that positive responses
were likely to be classified as irritant responses in the sensitized
group when compared to the control group: 13/60 (22%) for Coppershield
® and for Potassium dichromate in the sensitized group; 0/10 for
Coppershield ® and 1/10 (10%) for potassium dichromate in the control
group. The study investigators did not provide an explanation as to the
higher rates of irritation in the sensitized group.  It was not clear
from the information provided that the difference between an irritant
and allergic response was clear-cut, leaving open the possibility of
misclassification. Given these uncertainties, it seems most appropriate
for the Agency to treat all responses classified as either irritant or
allergic as allergic responses.

Statistical Analysis Criteria 

The use of the NACDG database for adjustment of the study results seems
inappropriate for several reasons. First, it was not clear from the
information provided that the database is a representative sample of the
U.S. population. Second, it was not clear that the classification of
irritant vs. allergic response was consistent across all dermatologists
who contributed data to the database. Third, it was not clear whether
some of the patients who participated in the study were also included in
the database. Fourth, EPA scientists have not examined the database, and
therefore are not able to confirm the accuracy of the calculations
reported in the study. Given these uncertainties, it seems most
appropriate for the Agency to use the unadjusted data from the study in
its determination of a minimum elicitation threshold.

Laboratory Conditions

The lack of blinded evaluation of irritant and allergic responses among
the sensitized and control groups diminished the overall quality of this
study.

HSRB Consensus and Rationale

The HSRB concluded that the Repeated Open Application Test for Allergic
Contact Dermatitis due to Hexavalent Chromium as Coppershield ® study
contained information sufficient for assessing human risk resulting from
potential dermal exposure to wood treated with ACC. The HSRB also
concluded that this study was sufficiently sound, from a scientific
perspective, to be used to estimate a safe level of repeated dermal
exposure to residues of ACC on treated wood. However, the HSRB rejected
the differential classification of irritant and allergic responses in
the sensitized population because the study dermatologist was not
blinded to the status of the sensitized and control groups, nor to the
skin dose levels, and because of a substantial discrepancy in the
assignment of irritant and allergic classifications for responses across
the two groups. The HSRB recommended that EPA consider all responses
recorded in the study to be allergic for the purpose of calculating the
MET10. The HSRB also rejected the adjustment of study results through
use of the NACGD database for the reasons cited above. The HSRB
recommended that the Agency use the empirical data from the study in its
calculation of the MET10.

Charge to the Board

Ethical considerations  

The Agency requested that the Board provide comment on the following:

Is there clear and convincing evidence that the conduct of the
hexavalent chromium ROAT study was fundamentally unethical?

Is there clear and convincing evidence that the conduct of the study was
significantly deficient relative to the ethical standards prevailing at
the time the research was conducted?

Board Response to the Charge

Brief Overview of the Study

Two previously unpublished studies involving dermal exposure of 70
healthy volunteers to increasing doses of hexavalent chromium were
evaluated (Proctor et al. 2006a; 2006b; 2006c). The stated goal of each
study was to determine the MET10, defined as the concentration of
chromium that would induce allergic contact dermatitis in 10% of
chromium-sensitized individuals following repeat dermal exposure to
hexavalent chromium  as CopperShield  ® and aqueous potassium
dichromate, respectively.  Both studies were conducted concurrently
using the same group of study participants.

Forest Products Research Laboratory, LLC, sponsored the studies.
Exponent, Inc., an engineering and scientific consulting firm based in
Irvine, CA, conducted these studies in late 2005. The majority of study
participants (58/70) were recruited from the patient population of a
private medical practice in Louisville, KY (Dermatology Specialists,
PSC). An additional 12 study participants were recruited from employees,
former employees, or relatives of employees of Dermatology Specialists,
PSC. The physician-owner of Dermatology Specialists, Dr. Joseph Fowler,
is recognized as an expert in the area of allergy and dermal
sensitivity. Dr. Fowler and his company were paid to work with study
coordinators from Exponent, Inc. to recruit patients and conduct all
experimental phases of these two studies. 

The studies were conducted after the promulgation of federal protections
for the protection of human participants in research (45 CFR Part 46;
adopted by the EPA in 1991 and published at 40 CFR Part 26) and each
study affirms compliance with 40 CFR Part 26, so the regulatory
requirements of the Common Rule are applicable. In addition to
asserting compliance with 40 CFR Part 26, each study affirms compliance
with Section 12(a)2(P) of the Federal Insecticide, Fungicide and
Rodenticide Act, the 2004 recommendations of the National Academy of
Science’s National Research Council regarding intentional human dosing
studies, the 2004 revision of the Declaration of Helsinki, and the
Nuremberg Code (Proctor et al. 2006a, 5; 2006c, 5).

Critique of Study

The Board concurred with the factual observations of the strengths and
weaknesses of these studies, as detailed in the EPA’s “Initial
Ethics Review of Cr(VI) Human Study,” (Carley 2006a).  However,
further comments are regarding: 1) whether the repeated multi-dose
dermal-exposure protocols used were designed to minimize risks to study
participants; and 2) whether the documentation and process of study
subject enrollment was sufficient to meet prevailing standards of
voluntary informed consent.

1)	Minimization of Risks to Study Participants

The Proctor et al. (2006a; 2006b; 2006c) studies employed a repeated
multi-dose dermal-exposure protocol. Pregnant women, individuals
receiving immunosuppressive or steroid medications, and patients with
recent or concurrent dermatological conditions were excluded from study
participation. One hundred forty-eight individuals, patients of Dr.
Fowler’s dermatology practice who tested positive for chromium
sensitivity previously, were invited to participate. These individuals
initially were contacted by telephone by a research nurse employed by
Dermatology Specialists, PSC.

One hundred subjects agreed to participate and met the initial inclusion
criteria, including completion of chromium sensitization testing. An
additional twelve study participants – employees, former employees, or
the relatives of employees Dermatology Specialists, PSC – were also
recruited to serve as chromium insensitive controls.  These one hundred
twelve volunteers were then screened for hexavalent chromium sensitivity
by dermal exposure using a 12mm Finn chamber and a chromium
concentration estimated to be 45 (g Cr(VI)/cm2; this is equivalent to
approximately 10-times the standard dose used in patch testing for skin
allergies in the Nethercott et al. (1994) studies (e.g., 4.4 (g
Cr(VI)/cm2 ), but only 1.8-times the estimated dose using the standard
8mm Finn chamber commonly employed in clinical dermal sensitivity tests.

Eighty-eight chromium-sensitive subjects (including two “control”
subjects) were identified by using Finn chamber sensitivity testing; 60
of these individuals elected to participate in the repeated open
application experiment. All ten chromium-insensitive controls also
elected to participate in repeated open application testing. Each study
participant then received multiple simultaneous doses of hexavalent
chromium. Doses equivalent to 0, 90, 250, 750, and 2,500 ng/cm2  Cr(VI)
as CopperShield ® and aqueous potassium dichromate were applied to the
right and left forearms of each subject, respectively. Although these
exposure levels were significantly greater than those used in the
previous Nethercott et al. (1994) study, which used occluded patch
testing - a method known to predispose the skin to allergic reactions --
the concentrations chosen for the Proctor et al. (2006a; 2006b; 2006c)
studies appear reasonable based on investigator review of previous
repeat open application and dermal hexavalent chromium sensitivity
studies. The doses chosen also are equivalent to or significantly
smaller than those routinely employed for allergy testing.

Exposures lasted approximately six hours, after which unsupervised
subjects were instructed to wash their arms with hypoallergenic soap.
Ten exposures to hexavalent chromium occurred over a two-week period
(once per day, Monday through Friday). Subjects were monitored for
evidence of allergic contact dermatitis during each weekday visit, and
72 hours after the final application. Topical steroids were offered to
any subject who exhibited contact dermatitis. Continued challenge with a
particular dose was discontinued in the event of a confirmed allergic
response, although it was a bit surprising that exposure was only
discontinued for the specific dose and not higher hexavalent chromium
doses.

 

Forty-three chromium-sensitive subjects showed no reaction to
CopperShield  ® after ten days of repeat open application testing,
sixteen developed a mild or moderate response to at least one doses, and
one developed a strong response. Forty, eighteen and two
chromium-sensitive subjects developed no, mild, or strong responses to
aqueous potassium dichromate, respectively. None of the ten control
subjects exhibited allergic contact dermatitis after repeated exposure
to CopperShield ® and aqueous potassium dichromate.

 

In sensitized individuals, chromium exposure elicits an allergic contact
dermatitis similar to a poison oak or poison ivy rash. The result
typically is an itching, red rash with bumps or blisters; these
transient symptoms usually are mild and can be treated with calamine
lotion and hydrocortisone cream. Repeated open application exposure to
hexavalent chromium, even when it knowingly results in allergic contact
dermatitis, would meet the generally accepted definition of minimal risk
under the experimental conditions described in the Proctor et al.
(2006a; 2006b; 2006c) studies. The study exclusion criteria, initial
screening of subjects for chromium sensitivity followed by an additional
round of repeat open application testing using doses significantly
smaller than those routinely employed for allergy testing, and exclusion
of study participants from further exposure to reactive doses (although
not to higher Cr(VI) doses), likely minimized the risk of serious harm
to research participants. Although the use of a multi-step protocol
using exposure to escalating doses of Cr(VI) would have been ideal, it
would have been difficult to achieve logistically.  

Thus, the Board believed that there was no clear and convincing evidence
that these studies could have resulted in serious harm based on the
knowledge available to the investigators at the time.

2)	Voluntary Informed Consent

		The Common Rule provides a comprehensive framework for initial and
continuing review of research involving human subjects. In order to
ensure that studies like Proctor et al. (2006a; 2006b; 2006c) are
performed ethically, the Common Rule requires that: (1) people who
participate as subjects in research are selected equitably and give
informed and voluntary written consent; and 2) research involving human
subjects be reviewed and approved by an independent oversight group,
i.e., an Institutional Review Board (IRB). 

		The Proctor et al. (2006a; 2006b; 2006c) studies were reviewed and
approved by an appropriate Institutional Review Board. IRB minutes
demonstrate that the board carefully considered the benefits and risks
to study participants.

		Recruitment and compensation of patients was acceptable. Study
participants received $75.00 for patch testing and $90.00/day during the
open application experiment, for a total of $1,215.00, but this level of
compensation seemed appropriate given the repeated visits necessary for
clinical monitoring. Several HSRB members, however, did express concern
about the selection of study participants from patients and employees of
Dr. Fowler’s dermatology practice. For example, questions about
“therapeutic misconception” can be raised, although the study
protocol stated that “the role of Dr. Fowler as researcher not
physician was emphasized” (e.g., Proctor et al. 2006a, 40).
Furthermore, the recruitment of employees to serve as
chromium-insensitive controls was considered by some Board members to be
inappropriate; chromium-insensitive patients of Dr. Fowler’s practice,
recruited using the same procedures as for the chromium-sensitive
population, would have been a better subject pool. The reviewing IRB
recognized the potential coercive nature of enrolling employees as
subjects, requiring that they sign a “non-coercion” statement, but
such forms provide little protection in situations where true coercion
of subjects is likely to occur. 

		Of greatest concern was the multi-step recruitment process, in which
potential study participants were first recruited by telephone and then
underwent additional screening during a clinic visit. Written consent
for study participation and release of medical information was not
obtained until the clinic visit, yet potential participants were asked
confidential and potentially stigmatizing questions about their personal
health during the initial telephone interview. Verbal consent was
obtained for the telephone interview, but no documentation of such
consent was provided to the HSRB. Furthermore, there was no discussion
of the methods employed to maintain telephone interview confidentiality.
 

Nevertheless, the Board concluded there was no evidence that the consent
process used failed to meet the regulatory and ethical standards
applicable to research conducted in the United States in 2005, or that
the deficiencies noted above seriously impaired the voluntary informed
consent of the research subjects.

HSRB Consensus and Rationale

The Board concurred with the Agency’s assessment that there was no
clear and convincing evidence that the conduct of this study was
fundamentally unethical in that the deficiencies did not result in
serious harm, nor seriously impair the informed consent of the research
subjects. 

The Board determined that there was no clear and convincing evidence
that the conduct of the study was significantly deficient relative to
the ethical standards prevailing when these two studies were conducted. 

Study EMD-003 from Carroll-Loye Biological Research

Charge to the Board

Scientific Considerations

Does the proposed research described in Study EMD-003 from Carroll-Loye
Biological Research appear likely to generate scientifically reliable
data, useful for assessing the efficacy of a test substance for
repelling ticks? 

Board Response to the Charge

Protocol EMD-003 from Carroll-Loye Biological Research represents the
resubmission of a protocol to evaluate the efficacy of three
formulations of IR3535 that was previously reviewed by the HSRB (USEPA,
2006). The revised protocol outlined studies to evaluate the efficacy of
IR3535 as a tick repellent in human subjects.  The protocol described a
laboratory study in which the movement of the Western black-legged tick
(Ixodes pacificus) up the forearm will be determined.  Studies in humans
are required to assess the efficacy of such repellents because
laboratory animals differ in their attractiveness to the pest, and
therefore do not provide an accurate assessment of efficacy in humans.  

In its previous review, the HSRB recognized three major limitations to
the protocol as initially submitted.  These limitations included: (1)
the lack of a clear rationale underlying the conduct of the study; (2)
the lack of identification and characterization of the formulations to
be tested and (3) numerous concerns for the overall scientific design of
the study.  In the revised protocol, the investigators have carefully,
comprehensively and conscientiously addressed the concerns and
shortcomings of the original protocol.  The work outlined in the revised
protocol clearly identifies the purpose and objectives of the study, and
justifies that efficacy testing in human subjects is required.  Relevant
details regarding the formulations (aerosol spray, pump spray and
lotion) to be evaluated have been provided.  The study size has been
increased from 6 to 10 subjects per formulation, and each subject will
serve as his own untreated control, thereby enabling a direct comparison
between treated and non-treated arms.  The investigators have also
included information regarding how subjects would be trained to
accurately and consistently collect information regarding the number of
ticks crossing or repelled from the arm skin.  Finally, the
investigators have added a dosimetry component to the protocol that will
provide valid information on the applied dose of IR3535 per square
centimeter of skin in order to determine individual subject doses of the
formulation during the conduct of the repellency portion of the
protocol.  

IR3535 is commercially available, and there is a large amount of
toxicology data available demonstrating that it is a compound of low
toxic potential.  Therefore, human subjects are unlikely to be at risk
of experiencing adverse effects relative to exposure to the proposed
formulations.  However, reference to the available toxicology data was
not included in the protocol.  The HSRB recommended that information
concerning the no-adverse-effect levels (NOAELs) for toxicity studies
should be included in order to assure human safety during the conduct of
these studies.

In the revised protocol, the investigators raised the possibility that
because the pump and aerosol formulations were identical in composition
and differed only in the manner of application, they could be “tested
together on alternate limbs of the same subjects” in order to reduce
the number of human subjects required for this work.  The HSRB
recommended that the investigators should not test these formulations
together, concluding that they should be tested on separate groups of
subjects.

HSRB Consensus and Rationale

The HSRB noted that representatives from Carroll-Loye Biological
Research had responded to the numerous concerns raised by the Board in
its original review of this protocol.  

The HSRB concluded that the proposed research as described in Study
EMD-003 appears likely to generate scientifically-reliable data that
would be useful for assessing the efficacy of a test substance for
repelling ticks.

Charge to the Board

Ethical Considerations

Does the proposed research described in Study EMD-003 from Carroll-Loye
Biological Research appear to meet the applicable requirements of 40 CFR
part 26, subparts K and L?  

Board Response to the Charge

Brief Overview of the Study

This protocol was originally reviewed at the June 2006 meeting of the
HSRB, at which time the Board concluded that the study failed to meet
the requirements established in the Environmental Protection Agency’s
final human studies rule (40 CFR Part 26). In particular, the study did
not comport with the applicable requirements of 40 CFR Part 26, subpart
K. The Board also raised questions about: (1) equitable study subject
selection and recruitment; and (2) whether or not the documentation and
process of study subject enrollment was sufficient to meet prevailing
standards of voluntary informed consent.

A revised, IRB-approved protocol was submitted for review (Carroll
2006a). The research is to be conducted by Carroll-Loye Biological
Research, a private laboratory in Davis, California by using healthy
volunteers and a controlled environment. The revised research protocol
submitted consisted of two interdependent studies: 1) a dosimetry study
designed to determine the amount of an insect-repelling compound, known
as IR3535, that normal subjects would typically apply when provided with
one of three compound formulations (lotion, pump or aerosol); and 2) an
efficacy study designed to measure the efficacy of IR3535 as a tick
repellent. Dosimetry would be determined either by passive dosimetry
using self-adhesive roll-gauze (spray and aerosol formulations) or by
direct measurement of compound application (lotion formulation). The
efficacy of IR3535 as a tick repellent would be determined by placing
Western black-legged ticks (Ixodes pacificus) on IR3535-treated and
untreated forearms and measuring the speed and distance that moving
insects would penetrate into the treated area. 

The dosimetry study, conducted in conjunction with the dosimetry
analyses described in protocol EMD-004, would enroll 12 subjects per
test formulation, for a total of 36 subjects. The efficacy study will
enroll 10 subjects per test formulation, for a total of 30 subjects.
Each subject would serve as their own control. Subjects may participate
in either or both studies, making the total number of volunteers
enrolled no less than 36 but no greater than 66. In addition, three
alternate subjects would be enrolled to: 1) replace any subject who
withdraws from participating; and 2) protect the confidentiality of any
subject excluded from the study as a result of pregnancy or a
potentially stigmatizing condition, as described below.

Critique of Study

The Board concurred with the factual observations of the strengths and
weaknesses of the study, as detailed in the EPA’s Science and Ethics
Review (Carley and Fuentes 2006). With the provision of detailed IRB
minutes and the exclusion of children and pregnant women, the proposed
research described in Protocol EMD-003 comports with the applicable
requirements of 40 CFR Part 26, subparts K and L. 

In brief, the risks to study participants are minimal and justified by
the likely societal benefits, including data on the efficacy of IR3535
as a tick repellent. As IR3535 is commercially available and has been
used as a repellent in Europe for years with no evidence of toxic
effects, the subjects enrolled in this study are unlikely to be at
increased risk of experiencing adverse side effects upon exposure. The
ticks used for the study are bred and raised in a laboratory environment
and are considered to be pathogen-free, minimizing the risk of
vector-borne disease. Clear stopping rules also have been developed, as
have plans for the medical management of any side effects or adverse
events. The Board recommended, however, that the nature and likelihood
of any side effects or adverse events be clearly described in the
informed consent documents. Carroll-Loye Biological Research also may
wish to designate a specific physician to be contacted in the event that
any adverse side effects are seen.

At the June 2006 meeting, the Board expressed concern about the
potentially coercive nature of study subject recruitment. Although the
study is to be conducted by Carroll-Loye Biological Research, a private
research laboratory in Davis, California, the Principal Investigator of
the study and Co-Owner of the research laboratory, Dr. Scott P. Carroll,
also is an adjunct faculty member of the Department of Entomology at the
University of California, Davis. As the majority of research
participants would be recruited from the University’s student
population, including from Dr. Carroll’s own department, the Board
previously recommended that the protocol and consent documents be
altered to define clearly the mechanisms in place to prevent coercion.
The revised protocol included several such mechanisms, including the
exclusion of any student or employee of the Study Director, a
substantial waiting period between recruitment and study enrollment, and
an interview by Dr. Carroll, designed to minimize coercive subject
recruitment and enrollment.

In accordance with the newly promulgated provisions in the EPA’s final
human studies rule (40 CFR §§ 26.1701-1704), children and pregnant
women are explicitly excluded from participation, the latter being
confirmed by requiring all female volunteers to undergo a
self-administered over-the-counter pregnancy test on the day of the
study. Previously, the Board raised concerns about the potentially
stigmatizing nature of a positive test, and recommended that
Carroll-Loye develop additional protections to ensure that the results
of over-the-counter pregnancy tests would be kept private. The use of
so-called “alternate” subjects is one such safeguard; that study
participants may be designated as alternate subjects and automatically
excluded from participation allows for potentially pregnant volunteers
to withdraw without compromising their confidentiality.

HSRB Consensus and Rationale

The Board concurred with the initial assessment of the Agency that the
revised protocol, EMD-003, submitted for review by the Board meets the
applicable requirements of §40CFR26, subparts K and L. 

Study EMD-004 from Carroll-Loye Biological Research

Charge to the Board

Scientific Considerations

Does the proposed research described in Study EMD-004 from Carroll-Loye
Biological Research appear likely to generate scientifically reliable
data, useful for assessing the efficacy of a test substance for
repelling mosquitoes? 

Board Response to the Charge

Protocol EMD-004 is now revised and contains considerably more detail
than the original protocol. Overall the revised protocol is greatly
improved from the original and in many respects may be considered
exemplary. The protocol describes a test of the efficacy of
3-[N-butyl-N-acetyl]-aminopropionic acid, ethyl ester (IR3535) to repel
mosquitoes in field experiments.  It describes the use of three
formulations (pump spray, aerosol and lotion), and the number of
replications (10 for each formulation). The components of the three
formulations are stated.  There will now be two untreated controls, both
of whom are experienced in the field,  and no positive controls.  Two
habitats are proposed for use, in or adjacent to the Central Valley in
California and/or in the Florida Keys. The compound has a very low
toxicity profile in animal tests. The compound has been used in Europe
for over 20 years as a repellent without reports of adverse effects in
humans. The new protocol also includes a dosimetry experiment. 

General HSRB Scientific Criteria

The scientific question was stated (i.e., to test the efficacy of IR3535
in repelling mosquitoes).

Existing data were not adequate to answer the question of efficacy of
these new formulations.

Because existing data were not adequate to answer the question of
efficacy, new studies involving human subjects are necessary.

The potential benefits of the study were clear, i.e., that an effective
repellent would be available that would have either greater efficacy
and/or fewer drawbacks than what was currently approved.

It is likely that the benefits would be realized (i.e., efficacy as a
repellent) because there was a long positive history of efficacious use
with this compound from its European use.

The risks have been more extensively described, as have the strategies
to minimize risk.

The most likely relevant risk would be disease transmitted by the
mosquitoes, if the mosquitoes carried pathogens, and some mosquito-borne
diseases (e.g., West Nile virus-mediated disease) are very serious. The
revised protocol does indicate that the likelihood is low of the
mosquitoes in the two test areas to be carriers of disease organisms
that could be transmitted to humans.  However, using the fewest number
of untreated controls (now indicated to be two persons experienced in
removing the mosquitoes before they bite) would provide minimal risk of
disease to the participants. The protocol now indicates that all the
inert ingredients in the formulations lack toxicity at the exposure
levels anticipated.

Study Design Criteria

The purpose of the study was clearly defined (i.e., efficacy testing).

There were specific objectives/hypotheses (i.e., that IR3535 in the
proposed formulations is an effective repellent) and the study as
described can test this hypothesis.

The sample size is now a definite 10 individuals (with 2 extra recruits
in case a subject drops out or fails to attend the test session) with 2
negative controls and no positive controls. The same number of subjects
would be tested in both locations (if both locations are tested). The
basis for the dose levels and formulations had not been provided;
however, there is now a dosimetry experiment prior to the field
experiment that would  quantify the amount of repellent being used.
There were no controls with just the formulation matrix without the
repellent; the PI has provided an adequate explanation for this.

There was a plan allocating individuals to treatments.

It is anticipated that the findings from this study can probably be
generalized beyond the study sample.

Participation Criteria

There was more extensive justification for the selection of the target
population.

The participants were representative of some of the population of
concern; however, there are others in the population unlike these
participants who are likely to use these products, but it would either
be unethical to test them or would be less appropriate to test them. 
The participating population is considered appropriate and reasonable.

The inclusion/exclusion criteria were appropriate.

The sample was not a vulnerable group.

Measurement Criteria

The measurements were expected to be accurate and reliable.

The measurements were appropriate to the question being asked.

Quality assurances issues are now more appropriately addressed.

Statistical Analysis Criteria

The data should be able to be analyzed statistically if the efficacy
with time was the subject of the analysis and the comparisons are made
across time. It is not the intent of the protocol to compare treated to
untreated statistically.  The purpose of the two untreated control
subjects is to monitor the biting pressure.

The statistical method seems to be appropriate.

Measures of uncertainty were now addressed.

Laboratory and Field Conditions

No laboratory experiments were proposed in this protocol, probably
because of the data already available due to the compound’s long
previous use.

The field conditions were representative of the intended use.

The protocol now includes a stop rule plan, medical management plan, and
a safety monitor.

HSRB Consensus and Rationale

The revised protocol, EMD-004, contains considerably greater detail than
the original and it answers all the scientific questions that were posed
by the HSRB in its original review.  The PI has been extremely
responsive to the original review comments. The revised protocol should
generate scientifically valid results of efficacy in repelling
mosquitoes.

Ethical Considerations

Charge to the Board

Does the proposed research described in Study EMD-004 from Carroll-Loye
Biological Research appear to meet the applicable requirements of 40 CFR
part 26, subparts K and L?  

Board Response to the Charge

Overview of Study

This protocol was originally reviewed at the June 2006 meeting of the
HSRB, at which time the Board concluded that the study failed to meet
the requirements established in the Environmental Protection Agency’s
final human studies rule (40 CFR Part 26). In particular, the study did
not comport with the applicable requirements of 40 CFR Part 26, subpart
K. The Board also recommended that the protocol be revised to include:
(1) a more accurate discussion of subject assignment; (2) a more
extensive discussion of the risks (with specific information about the
risk of vector borne diseases); (3) clarification of proposed
compensation for research-related injuries; (4) a clarification of the
lack of direct benefit to research subjects; and (5) the inclusion of
specific mechanisms to prevent coercive enrollment and to protect
subject confidentiality.

A revised, IRB-approved protocol was submitted for review (Carroll
2006b). The research is to be conducted by Carroll-Loye Biological
Research, a private laboratory in Davis, California by using healthy
volunteers. The revised research protocol submitted consists of two
interdependent studies: 1) a dosimetry study, performed under controlled
laboratory conditions, designed to determine the amount of an
insect-repelling compound, known as IR3535, that normal subjects would
typically apply when provided with one of three compound formulations
(lotion, pump or aerosol); and 2) an efficacy study, performed at field
sites in Northern California and/or Southern Florida, designed to
measure the efficacy of IR3535 as a mosquito repellent. Dosimetry will
be determined either by passive dosimetry using self-adhesive roll-gauze
(spray and aerosol formulations) or by direct measurement of compound
application (lotion formulation). The efficacy of IR3535 as a mosquito
repellent would be determined by measuring the ability of the three
formulations to prevent mosquito landings (defined as “Lite with
Intent to Bite”; LIBe) under field conditions. Mosquitoes will be
aspirated mechanically prior to biting.  Prior to initiation of the
efficacy study, all volunteers will be trained both to recognize a
mosquito landing with the intent to bite (LIBe) and to remove such
mosquitoes with an aspirator using laboratory-raised, pathogen-free
mosquitoes in a controlled laboratory setting. 

The dosimetry study, conducted in conjunction with the dosimetry
analyses described in protocol EMD-003, would enroll 12 subjects per
test formulation, for a total of 36 subjects. The efficacy study would
enroll 10 subjects per test formulation, for a total of 30 subjects. Two
additional untreated control subjects (experienced field-workers) would
be enrolled to determine ambient LIBe pressure under field conditions;
such measurements are necessary to determine IR3535’s efficacy as a
mosquito repellent. Each untreated subject would be attended by two
assistants who would aspirate mosquitoes prior to biting, thus
minimizing risk of exposure to vector-borne illnesses. Subjects may
participate in either or both studies, making the total number of
volunteers enrolled no less than 38 but no greater than 68. In addition,
three alternate subjects would be enrolled to: 1) replace any subject
who withdraws from participating; and 2) protect the confidentiality of
any subject excluded from the study as a result of pregnancy or a 
potentially stigmatizing condition, as described below.

Critique of Study

The Board concurred with the factual observations of the strengths and
weaknesses of the study, as detailed in the EPA’s Science and Ethics
Review (Carley and Fuentes 2006b). With the provision of detailed IRB
minutes and the exclusion of children and pregnant women, the proposed
research described in Protocol EMD-004 comports with the applicable
requirements of 40 CFR Part 26, subparts K and L. 

In brief, the risks to study participants are minimal and justified by
the likely societal benefits, including data on the efficacy of IR3535
as a mosquito repellent. The nature and likelihood of any side effects
or adverse events are described clearly in the informed consent
documents. Specifically, the risks to study participants are three-fold:
1) allergic reaction to test materials themselves; 2) exposure to biting
arthropods; and 3) possible exposure to arthropod-borne diseases. Plans
for the medical management of any side effects or adverse events have
been developed, but Carroll-Loye Biological Research also may wish to
designate a specific physician to be contacted in the event that any
adverse side effects are seen.

As IR3535 is commercially available and has been used as a repellent in
Europe for years with no evidence of toxic effects, the subjects
enrolled in this study are unlikely to be at increased risk of
experiencing adverse side effects upon exposure to the test materials.
Reactions to mosquito bites are usually mild and easily treated with
over-the-counter steroidal creams. Excluding subjects who have a history
of such severe skin reactions will minimize the risk of a subject
experiencing a severe physical reaction to a mosquito bite. In addition,
the study protocol is designed specifically to minimize the likelihood
that a mosquito will bite, through the use of clear stopping rules,
limited exposure periods, and joint observation. Finally, to minimize
the risk that study subjects would be exposed to diseases like West Nile
Virus, field tests of repellent efficacy would be conducted only in
areas where known vector-borne diseases have not been detected by county
and state health or vector/mosquito control agencies for at least one
month. 

At the June 2006 meeting, the Board expressed concern about the
potentially coercive nature of study subject recruitment. Although the
study is to be conducted by Carroll-Loye Biological Research, a private
research laboratory in Davis, California, the Principal Investigator of
the study and Co-Owner of the research laboratory, Dr. Scott P. Carroll,
also is an adjunct faculty member of the Department of Entomology at the
University of California, Davis. As the majority of research
participants will be recruited from the University’s student
population, including from Dr. Carroll’s own department, the Board
previously recommended that the protocol and consent documents be
altered to define clearly the mechanisms in place to prevent coercion.
The revised protocol includes several such mechanisms, including the
exclusion of any student or employee of the Study Director, a
substantial waiting period between recruitment and study enrollment, and
an interview by Dr. Carroll, designed to minimize coercive subject
recruitment and enrollment. Several HSRB members, however, expressed
concern that offering to send subjects recruited in California to a
field site in Florida might unduly influence individuals to engage in
research activities for which they would not otherwise volunteer;
Carroll-Loye Biological Research may wish to restrict recruitment of
participants to specific localities or, alternatively, discuss
opportunities for out-of-state travel only after subjects have enrolled
in the research study.  

Finally, in accordance with the newly promulgated provisions in the
EPA’s final human studies rule (40 CFR §§ 26.1701-1704), children
and pregnant women are explicitly excluded from participation, the
latter being confirmed by requiring all female volunteers to undergo a
self-administered over-the-counter pregnancy test on the day of the
study. Previously, the Board raised concerns about the potentially
stigmatizing nature of a positive test, and recommended that
Carroll-Loye develop additional protections to ensure that the results
of over-the-counter pregnancy tests would be kept private. The use of
so-called “alternate” subjects is one such safeguard; that study
participants may be designated as alternate subjects and automatically
excluded from participation allows for potentially pregnant volunteers
to withdraw without compromising their confidentiality.

HSRB Consensus and Rationale

The Board concurred with the initial assessment of the Agency that the
revised protocol, EMD-004, submitted for review by the Board meets the
applicable requirements of §40CFR26, subparts K and L. 

Review format

Charge to the Board

Please comment on the format used for EPA’s science and ethics reviews
of Dr. Carroll’s protocols in terms of: 

a. whether future use of this format is likely to produce reviews that
adequately explain the basis for EPA’s position regarding the ethical
and scientific acceptability of the proposed research; and 

b. whether presentation of future EPA reviews in such a format will
assist the Board’s review of proposed protocols. 

					and

Draft EPA guidance to the public concerning submission of proposed and
completed human research to EPA for review by the HSRB and EPA 

Charge to the Board

Please comment on the approach, as described in the Agency’s draft PR
Notice, to organizing materials submitted under 40 CFR § 26.1125 for
EPA and HSRB review.  In particular, please address whether this
approach is appropriate for anticipated types of studies involving
intentional exposure of human subjects, and whether EPA should provide
different guidance for various types of research.

Board Response to the Charge

The Board discussed its response to review format of IR3535 and the
Agency’s guidance document together, as noted below.  

The Board is of the view that the EPA’s approach to the submission of
materials is very appropriate, and that the draft guidance takes an
approach that will be extremely helpful to the Board in its review of
future submissions. The following comments represent some specific
changes in parts of the draft guidance that the Board would suggest, but
should in no way be viewed as criticism of the overall excellence of the
draft guidance. Unless otherwise noted, the comments refer to Appendix
B.

1. It would appear desirable, given its importance in Board
deliberations, to have a separate numbered heading for Risk
Minimization, under which the Agency might consolidate the questions
that currently appear under other headings (such as 2(d), 2(e), 5(c),
5(d), and 5(e), with perhaps the addition of some additional questions).

2. Item 5(g), relating to remuneration of subjects, should generally not
be treated as a benefit of participation.  This item might fit better
under section 4, Subject Selection, because the appropriateness of
amounts paid to subjects raises issues relating to undue influence,
which currently is addressed under section 4.

3. In some of the items, questions are posed that require merely a
“yes” or “no” answer (such as, for example, items a-c under
section 7, and the items under section 8). The Board believed that in
general, such questions should be rewritten in a manner that encourages
the submitter to provide an explanation of how the specific requirement
is being satisfied. For example, item 8(a) might be rewritten to ask,
“How will information about prospective and enrolled subjects be
managed so as to ensure their privacy?” (The Board acknowledged that
many of the “yes/no” questions currently in Appendix B are in that
format because the EPA was using the format for those questions that the
Board itself had previously proposed.)

4. In appropriate places in Appendix B, there should be questions that
ask the submitter to address the limitations of the study.

5. To the extent that there are special items of information that are
required (or desired) for specific types of studies (such as human
dosing studies, or single dose studies, or insect repellant studies),
those special requirements should be noted somewhere in the guidance
document.

6. A question should be added to Section relating to the dose of the
compound being tested: (1) a question should be added to Section 3 that
asks, where appropriate, about how the selection of the dose being
tested relates to known information about the NOAEL or LOAEL for that
compound and (2) the draft guidance should include recommendations
adopted by EPA as a result of prior deliberations by this Board, such
as, for example, studies that test only one dose of a compound will
usually be considered inadequate.

7. To the extent that the EPA can make it easier for submitters to put
together or submit this information, perhaps by creating electronic
templates that can easily be filled in, such formatting should be
pursued.  

8. Item 6(c), which currently asks whether an IRB is registered with HHS
Office of Human Research Protections (OHRP), should be rewritten or
expanded. The goal of this question is presumably to collect information
about the quality of the review that is being performed by the IRB.  IRB
registration with OHRP is a purely clerical act that gives little or no
information about the quality of the IRB.  The Board suggested several
options for the Agency to consider about the quality of the IRB.  These
include:

(a) Federalwide Assurance by OHRP of the IRB

(b) Accreditation by Association for the Accreditation of Human Research
Protection Programs, Inc. 

(c) Submission of IRB policy and procedures.  

9. Items 7(d) and 7(e), relating to the relationship between the
investigator and the subjects, and to measures designed to avoid
coercion and undue influence, might be more appropriately included under
section 8, Respect for Subjects.

10. The guidance document should make it clear to a submitter that
addressing all of the questions included in the Appendix B document,
plus providing appropriate documentation about where the answers to
specific questions appear in the submitted documents, are steps that
would be of great help to this Board in performing its review of a
submission, and in avoiding subsequent delays in its review.  However,
the Agency should unequivocally state that following the guidance is not
an assurance that a study or protocol would be accepted by the HSRB or
the Agency.  

11. The Board expects that when the EPA presents its review of future
studies to the Board, those reviews should include significantly more
discussion of deficiencies that the EPA has found (of whatever nature)
in its review of the submitted documents. The EPA should also provide
this Board with its conclusions relating to the completeness and
comprehensiveness of a submission.

Handling of Material Claimed to be Confidential Business Information for
HSRB Consideration

The Board welcomed the Agency’s discussion of possible submission of
proposed or completed intentional dosing studies claimed as CBI. Many
members regarded openness and transparency as the Board’s top
priority. Therefore, the Board made the following recommendations:

(1) EPA should conduct due diligence to determine the legitimacy of CBI
claims and then explain the basis of their decision to the Board.

(2) When providing redacted documents to the Board, the EPA should
provide information about the type of information being withheld.

(3) EPA should be prepared to answer questions, within legal limits, as
to the material being provided

(4) If a submitter chooses to withhold the identity of an active
ingredient whose toxicity will be the subject of Board determinations,
EPA should provide the Board with a critical scientific summary of the
available information within the data evaluation record.  

(5) Submitters should be informed in advance that providing as much open
information as possible will increase the Board’s ability to make
recommendations in a timely fashion.

REFERENCES

Carley, J.M. (2006) Ethics Review of Cr(VI) Human Study. United States
Environmental Protection Agency Office of Prevention, Pesticides and
Toxic Substances. Unpublished memorandum. September 12, 2006.

Carley, J.M., and C. Fuentes. (2006a) Science and Ethics Review of
Protocol for Human Study of Tick Repellent Performance. Unpublished
memorandum. September 15, 2006.

Carley, J.M., and C. Fuentes. (2006b) Science and Ethics Review of
Protocol for Human Study of Mosquito Repellent Performance. Unpublished
memorandum. September 15, 2006.

Carroll, S. (2006a). Efficacy Test Protocol EMD-003: Test of Personal
Insect Repellents, dated September 8, 2006.  Unpublished document
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Carroll, S. (2006b) Efficacy Test Protocol EMD-004: Test of Personal
Insect Repellents, dated September 8, 2006.  Unpublished document
prepared by Carroll-Loye Biological Research.

Nethercott, J.; Paustenbach, D.; Adams, R. et al. (1994). A study of
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Proctor, D.; Gujral, S.; Fowler, J. (2006a) Repeated Open Application
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Unpublished study conducted by Dermatology Specialists, PSC, and
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Proctor, D.; Gujral, S.; Fowler, J. (2006b) Supplemental Information to
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Unpublished document dated August 24, 2006. Project No. FPRL #012506.
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Proctor, D.; Gujral, S.; Su, S.; Fowler, J. (2006c) Repeated Open
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Chromium [Cr(VI)] as Potassium Dichromate: Risk Assessment for Dermal
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USEPA.  2006.  June 27-30, 2006 EPA Human Studies Review Board Meeting
Report.  68 pp. 

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