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).
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• 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 MET 10 .
• 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 MET 10 .
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.
1R3535 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.
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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 P1
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
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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/osalhsrb/. Interested persons are invited to contact Paul Lewis, Designated
Federal Officer, via e-mail at 1ewis.pau1 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.
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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 sante environnementale et sante 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
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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
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TABLE OF CONTENTS
iNTRODUCTION 8
REVIEW PROCESS 9
CHARGE TO THE BOARD AND BOARD RESPONSE 10
Chromium Repeat Open Application Test 10
Study EMD-003 from Carroll-Loye Biological Research 18
Study EMD-004 from Carroll-Loye Biological Research 22
Review format 26
Draft EPA guidance to the public concerning submission of proposed and completed human
research to EPA for review by the HSRB and EPA 27
Confidential Business Information 29
REFERENCES 30
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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
1R3535 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.
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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
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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 si.gn4flcantly 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.
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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
Criticiue 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 (MET 10 )
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 MET 10 .
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 detennined 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
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of this scenario was to determine the effect on the MIET 10 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 MET 10 values for Scenarios 1 and 2
of the untransformed dose-response data were 270 and 91.8 ng Cr(VI)/cm 2 respectively. The
MET 10 values for the patch-test normalized data were 349 and 166 ng Cr(VI)/cm 2 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 MET 10
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 MET 10 .
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/cm 2 ) 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.
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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 cm 2 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.
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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 MET 10 . 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 MET 10 .
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?
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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 MET 10 , 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 (5 8/70) 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).
Criticiue 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
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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 p.g Cr(VI)/cm 2 ; 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 p.g Cr(VI)/cm 2 ), 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/cm 2 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 a!. (1994) study, which used occluded patch testing - a method
known to predispose the skin to allergic reactions -- the concentrations chosen for the
Proctor et a!. (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
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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 dennatology 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
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of Dr. Fowler’s practice, recruited using the same procedures as for the chromium-
sensitive population, would have been a better subject pooi. 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 1R3535 that was previously
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reviewed by the HSRB (USEPA, 2006). The revised protocol outlined studies to evaluate the
efficacy of 1R3535 as a tick repellent in human subjects. The protocol described a laboratory
study in which the movement of the Western black-legged tick (Ixodes pac /icus) 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 careflully, 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 trainçd 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 1R3535 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.
1R3535 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
(NOAEL5) 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.
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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 1R3535, 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 1R3535 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 1R3535 as a tick repellent would be determined by placing Western
black-legged ticks (1xodespac /Icus) on 1R3535-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. -
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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 1R3535 as a tick repellent. As 1R3535 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
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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 (1R3535) 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 1R3535 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
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(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 1R3535 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 P1 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
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• 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 P1 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 1R3 535, 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 1R3535 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 1R3535 as a mosquito repellent would be determined by
measuring the ability of the three formulations to prevent mosquito landings (defined as “Lite
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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
1R3535’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 1R3535 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 1R3535 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.
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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 oi 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
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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 1R3535 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
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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.
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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.
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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 prepared by Carroll-Loye Biological Research.
Carroll, S. (2006b) Efficacy Test Protocol EM1D-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 chromium induced allergic
contact dermatitis with 54 volunteers: implications for environmental risk assessment. Occup.
Environ. Med. 51: 371-380.
Proctor, D.; Gujral, S.; Fowler, J. (2006a) Repeated Open Application Test for Allergic Contact
Dermatitis due to Hexavalent Chromium [ Cr(VI)] as CopperShield®: Risk Assessment for
Dermal Contact with Cr(VI). Unpublished study conducted by Dermatology Specialists, PSC,
and Exponent under Project No. FPRL #0 12506. 324 p. (MRID 46884001)
Proctor, D.; Gujral, S.; Fowler, J. (2006b) Supplemental Information to the Final Report Titled
“Repeated Open Application Test for Allergic Contact Dermatitis due to Hexavalent Chromium
[ Cr(VI)] as CopperShield®: Risk Assessment for Dermal Contact with Cr(VI).” Unpublished
document dated August 24, 2006. Project No. FPRL #0 12506. 347 p. (MRID 46922901)
Proctor, D.; Gujral, S.; Su, S.; Fowler, J. (2006c) Repeated Open Application Test for Allergic
Contact Dermatitis due to Hexavalent Chromium [ Cr(VI)] as Potassium Dichromate: Risk
Assessment for Dermal Contact with Cr(VI). Unpublished study conducted by Dermatology
Specialists, PSC, and Exponent under Project No. FPRL #0 12406. Includes Supplemental
Information documenting ethical conduct of the research. 664 p. (MRID 46930701).
USEPA. 2006. June 27-30, 2006 EPA Human Studies Review Board Meeting Report. 68 pp.
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