June 25, 2008

EPA-HSRB-08-02

George Gray, Ph.D.

Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460

Subject: April 9-10, 2008 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)

EPA Review of Antimicrobial Exposure Assessment Task Force Mop and Wipe
scenario protocols; (2) ICR Protocol: A382 and (3) Carroll-Loye
Biological Research Completed Studies: SCI 001.4 and SCI 001.5.  The
enclosed HSRB report provides the Board’s response to EPA charge
questions presented at the April 9-10, 2008 meeting.  The Board also
appreciates the Agency providing an update of the EPA/ORD document
“Scientific and Ethical Approaches for Observational Exposure
Studies.”  The Board agrees with the Agency that the document will
serve as a valuable resource for EPA and other researchers to rely on as
they develop and conduct observational human exposure studies. In
addition to the recommendations for specific protocols and completed
studies summarized below, the Board provided comments on review and
format of AEATF and AHETF protocols.

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

EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of
the mop and wipe scenarios, both exposure scenarios were reviewed
together)

	Science

The Board considered the AEATF-II study protocols to successfully
address many design challenges. The Board appreciated particularly the
clarity of the protocols, the attention to detail, and the thorough
description of quality assurance and quality control procedures. The
Board concurred with the Agency that existing data on handler exposures
to antimicrobials are inadequate and that the development of more
accurate information is an appropriate goal.  The Board also concurred
with the Agency that there are only minimal risks associated with the
application of a dilute solution of didecyl dimethyl ammonium chloride
as described in the study protocols.

While the Board concluded that the research could produce scientifically
reliable data, the Board identified several contextual factors that may
limit the generalizability of the findings.  The Board therefore
recommended that the Agency reconsider the design of the study, or
develop an explicit statement of the limitations on the use of data that
will be collected under the proposed design. Specifically the Board
noted that any generalizations to moppers and wipers in other parts of
the country and in other kinds of buildings would be based on expert
opinion, and that such generalizations would not be statistical
generalizations. The Board cautioned the Agency regarding the 3x6 design
in the protocols, suggesting future scenario designs for the AEATF- II
program would likely have three clusters and six time durations, with
the justification being the Board’s recommendation of these protocols.
The Board also concluded that the task duration time frame was not
adequate to characterize daily exposure. The Board recommended that the
work time frame be expanded to exceed the 95th percentile of the
International Sanitary Supply Association survey findings. The Board
noted that if, instead of time, the number of Ai units handled were the
measure that defined each person’s participation, the data would more
likely lend themselves to a proper assessment of the assumption of
proportionality.

Finally, the Board encourages modifications of future related protocols
based on the lessons learned from this initial submission.  Such
adjustments are anticipated to improve the study design and subsequent
results, leading to a more accurate characterization of pesticide
handler exposure.

Ethics

The Board concurred with the initial assessment of the Agency that if
the proposed mop and wipe scenario design, protocol, and supporting
documentation is revised as suggested in EPA’s review, the research
would meet the applicable requirements of 40 CFR part 26, subparts K and
L.

ICR Protocol: A 382

Science

If amended in a manner consistent with the Board’s concerns and
recommendations, and with particular modification to subject ethnicity,
the Board concluded that the protocol ICR A382 studying the efficacy of
two formulations of picaridin for repelling stable flies would be
sufficiently sound, from a scientific perspective, to be used to assess
the repellent efficacy of these formulations against stable flies.

Ethics

The Board concurred with the initial assessment of the Agency that, if
the protocol is revised as suggested by EPA and the HSRB, the study
submitted for review by the Board would meet the applicable requirements
of 40 CFR 26, subparts K and L.

Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI
001.5

Science

The Board concluded that the study on the efficacy of LipoDEET 320 and
Coulson’s Duranon shows efficacy of both products in repelling
mosquitoes, and agreed with the Agency that the study was sufficiently
sound, from a scientific perspective, to be used to accurately calculate
the complete protection time for repelling mosquitoes.

Ethics

The Board concurred with the initial assessment of the Agency that the
study submitted for review by the Board meets the applicable
requirements of §40CFR26, subparts K and L.  However, the Board
expressed concern regarding a pattern of deviations from IRB approved
protocols apparent in this study and previous submissions by the
investigator. Implications of this concern are noted below.

Over several meetings, including the April 2008 meeting, the Board has
expressed concern with EPA submission for HSRB review of completed
studies in which planned protocol deviations were conducted prior to IRB
review and following HSRB review of the originally approved protocol.
Such actions are in violation of 40 CFR 26, Subpart K Sec. §26.1108 IRB
functions and operations.

Subpart K Sec. §26.1108 IRB functions and operations.

“In order to fulfill the requirements of this subpart, each IRB shall:

(a) Follow written procedures:

    	(1) For conducting its initial and continuing review of research
and for reporting its findings and actions to the investigator and the
institution;

(2) For determining which projects require review more often than
annually and which projects need verification from sources other than
the investigator that no material changes have occurred since previous
IRB review;

    	(3) For ensuring prompt reporting to the IRB of proposed changes in
research activity; and

    	(4) For ensuring that changes in approved research, during the
period for which IRB approval has already been given, may not be
initiated without IRB review and approval except where necessary to
eliminate apparent immediate hazards to the human subjects.”

The Board reached consensus regarding its future review procedures under
such conditions:

Any study executed prior to IRB approval of the Informed Consent Form
and the protocol, or changed in ways that were not approved by the IRB
will be judged by the Board as failing to meet the applicable
requirements of §40 CFR 26, subparts K.

If the EPA submits to the Board for review a completed protocol with
scientific deviations from the original protocol reviewed by the Board,
the EPA review of the completed protocol should provide the Board with
EPA's opinion regarding why the deviation did not meet the requirement
for re-review and why the protocol still meets the applicable
regulations.

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<EMAIL_ADDRESS>
	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.

U. S. ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD
MEMBERS

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

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

Snedecor Hall, 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, 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., D.A.B.T, Senior Science Policy Analyst,
Office of the Commissioner, Office of Science and Health Coordination,
U.S. Food and Drug Administration, Rockville, MD

Dallas E. Johnson, Ph.D., Professor Emeritus, Department of Statistics,
Kansas State University, Manhattan, KS

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

Michael D. Lebowitz, Ph.D., FCCP, Professor of Public Health & 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., Director, Office of Human Subjects Research,
Office of the Director, National Institutes of Health, Bethesda, MD

Rebecca Parkin, Ph.D., MPH, Associate Dean for Research and Public
Health Practice, School of Public Health and Human Services, The George
Washington University, Washington, DC

Sean Philpott, Ph.D., MS Bioethics, Science and Ethics Director, Global
Campaign for

Microbicides, Program for Appropriate Technology in Health, Washington,
DC

Ernest D. Prentice, Ph.D., Associate Vice Chancellor for Academic
Affairs, University of Nebraska Medical Center, Omaha, NE*

Richard Sharp, Ph.D., Director of Bioethics Research, Department of
Bioethics, Cleveland Clinic, Cleveland, OH

Linda J. Young, Ph.D., Professor, Department of Statistics, Institute of
Food and Agricultural Sciences, University of Florida, Gainesville, FL

Consultants to the Board

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

Human Studies Review Board Staff

Paul I. Lewis, Ph.D., Executive Director, Human Studies Review Board
Staff, Office of the Science Advisor, United States Environmental
Protection Agency, Washington, DC

* Not in attendance at April 9-10, 2008 Public Meeting

  TOC \o "1-3" \h \z \u   INTRODUCTION

On April 9-10, 2008, the United States Environmental Protection
Agency’s (EPA or Agency) Human Studies Review Board (HSRB) met to
address scientific and ethical issues concerning:  Sampling strategies
in proposed pesticide handler research, Antimicrobial Exposure
Assessment Task Force (AEATF) Governing Document, EPA Review of AEATF-II
Mop and Wipe Scenarios, ICR Protocol: A382, and Carroll-Loye Biological
Research Completed Studies: SCI 001.4 and SCI 001.5  Each of these
topics is discussed more fully below.  In addition, EPA’s Office of
Pesticide Programs provided a follow-up on pesticide specific HSRB
recommendations.  Finally, EPA’s Office of Research and Development
provided an update on revisions to its document “Scientific and
Ethical Approaches for Observational Exposure Studies.”  Each of these
topics is discussed more fully below.

1.  Proposed AEATF Research on Exposure of Subjects Using an
Antimicrobial Pesticide in Mopping and Wiping Activities

The HSRB has previously considered issues related to the design and
conduct of research to measure the levels of exposure received by people
when handling (i.e., mixing, loading, or applying) pesticides.  Two
industry Task Forces, the Antimicrobials Exposure Assessment Task Force
II (AEATF) and the Agricultural Handlers Exposure Task Force (AHETF),
have previously submitted materials for HSRB review.  Based on the
issues raised by the Board at its meeting in June 2006, EPA asked its
FIFRA Scientific Advisory Panel (SAP), an advisory committee of
independent expert scientific peer reviewers providing technical advice
to EPA on pesticide and pesticide-related issues, to address a number of
scientific issues at its January 2007 meeting.  Drawing on the advice of
the SAP, the Office of Pesticide Programs (OPP) presented additional
issues relating to the proposed handler research again at the April and
June 2007 HSRB meetings.  In response to those reviews the Task Forces
have extensively reworked their research proposals.

One issue, the design of the sampling strategies to be used by the Task
Forces, has drawn particular attention.  To resolve this question OPP
has consulted with experts both within and outside EPA, and has
carefully considered information presented by the Task Forces.  Based on
these interactions, OPP has decided to accept data developed through
“hybrid” sampling strategies, i.e., strategies that use a basic
purposive diversity sampling design but which incorporate random
elements whenever feasible.  OPP provided background documents on these
interactions on December 5, 2007 to the HSRB for subsequent
consideration.  Those same background documents are provided again in
this transmittal for the Board’s convenience in preparing for the
April 2008 HSRB meeting.

The AEATF has submitted two proposals.  Each includes both a
scenario-specific design document and the associated field study
protocol, along with supporting documentation, for EPA and HSRB review.
One proposal would measure inhalation and dermal exposure of subjects
applying an antimicrobial pesticide by mopping floors.  The other would
measure exposure of subjects who apply an antimicrobial pesticide by
wiping vertical and horizontal hard surfaces in two distinct
scenarios—one using a spray-and-wipe technique, and the other using
ready-to-use impregnated wipes.

EPA’s regulation, 40 CFR §26.1125, requires the sponsor or
investigator to submit to EPA, before conducting a study involving
intentional exposure of human subjects, 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.  Because the
research proposed by the AEATF involves scripted exposure, it meets the
regulatory definition of “research involving intentional exposure of a
human subject”, and thus these cited provisions of regulation apply to
it.

EPA has reviewed the AEATF proposals and has concluded that, with a
number of required revisions, they appear 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.
EPA has also concluded that the proposed hybrid sampling designs for all
three proposed exposure scenarios effectively incorporate elements of
randomization, consistent with EPA’s guidance to the AEATF.  Because
the sponsor wishes to initiate testing pursuant to these protocols as
soon as possible to meet regulatory requirements in other countries, and
since EPA finds the protocols can meet applicable scientific and ethical
standards, EPA presented this protocol for review at the Board’s April
2008 meeting.

EPA provided the following materials concerning the AEATF Exposure
Monitoring Program to the HSRB:

3.  AEATF Exposure Monitoring Program

a.	General Documents

(1)  Volume 5 AEATF Governing Document (Revised 2/13/08)

(2)  AEATF Governing Document (Revised 2/13/08; track changes)

(3)  Summary of Changes to Governing Document of 2/13/08

(4)  Volume 6 AEATF SOPs (Revised 2/25/08)

b.   Documents specific to the Mop Scenario

(1)  Volume 1 AEATF Mop Scenario Design/Protocol: Primary Documentation
(Revised 2/25/08)

(2)  Volume 2 AEATF Mop Scenario Design/Protocol: Secondary
Documentation (Revised 2/25/08)

(3)  EPA Science and Ethics Review: AEATF Mop Scenario (3/10/08)

c.    Documents specific to the Wipe Scenarios

(1)  Volume 3 AEATF Wipe Scenario Design/Protocol: Primary Documentation
(Revised 2/25/08)

(2)  Volume 4 AEATF Wipe Scenario Design/Protocol: Secondary
Documentation (Revised 2/25/08)

(3)   EPA Science and Ethics Review: AEATF Wipe Scenarios (3/10/08)

d.	Background documents on the Sampling Strategy Issue distributed to
the HSRB on December 5, 2007

(1)  Memorandum from William Jordan to Dr. Celia Fisher Re: “Design of
Sampling Strategies in Proposed Handler Research”

(2)  AHETF Study Design, Logistics, and Conduct (10-17-07) Power Point
presentation by David Barnekow and Victor Cañez

(3)  AEATF Introduction and Background (10-17-07) Power Point
presentation by Hasmukh Shah

(4)  AHETF Membership Benefits and Incentives (10-17-07) Power Point
presentation by Victor Cañez and David Barnekow

(5)  AHETF and AEATF Concepts, Objectives, and Sampling Issues
(10-17-07) Power Point presentation by Larry Holden

(6)  Report of Dr. Tapabrata Maiti, Associate Professor of Statistics at
Iowa State University, to EPA concerning sampling design issues in
proposed handler exposure research (11-30-07)

(7)  Letter from Debra Edwards, OPP director, to Hasmukh Shah, manager
of the American Chemistry Council’s Biocides Panel, concerning issues
involving the AEATF’s proposed handler research. (11-28-07)

(8)  Summary of EPA/OPP Teleconferences with AHETF (11-28-07)

2.   Proposed ICR Stable Fly Repellent Efficacy Study (A 382)

EPA requires submission of data from efficacy studies when a pesticide
product is directed against organisms classified as public health pests.
 EPA’s regulation, 40 CFR §26.1125, requires a sponsor or
investigator to submit to EPA, before conducting a study involving
intentional exposure of human subjects, materials describing the
proposed human research in order to allow EPA to conduct science and
ethics reviews.  In addition, EPA’s regulation, 40 CFR §26.1601,
requires EPA to seek HSRB review of the research proposal.

Insect Control & Research, Inc. (ICR) has submitted a proposal for new
research to evaluate the efficacy of two conditionally registered
products containing picaridin, to be conducted by Dr. William Gaynor.
ICR protocol number G4330108001A382 (A382) describes a laboratory study
of the efficacy of the test formulations against stable flies, a species
classified as a public health pest.

EPA has reviewed ICR’s protocol and has concluded that, with several
required revisions, it appears 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.  The sponsor wishes to
submit the data to EPA later this year in support of an application to
amend the registration of these picaridin products in order to claim
specifically that the products are effective at repelling stable flies.
In the interest of providing a thorough and timely decision on such
applications, and since EPA finds the protocol can meet applicable
scientific and ethical standards, EPA is presenting this protocol for
review at the Board’s April 2008 meeting.

EPA provided the following materials on the ICR repellent efficacy
protocol A382 to the HSRB:

2. 	ICR Repellent Efficacy Protocol A382

a.	ICR Stable Fly Protocol A382 (Rvsd 2/1/08)

b.	EPA Science & Ethics Review (3/7/08)

3.   Completed Insect Repellent Efficacy Studies (SCI-001.4 and
SCI-001.5) of DEET Formulations

In its January 2007 meeting the HSRB reviewed protocol SCI-001 from
Carroll-Loye Biological Research, submitted by Dr. Scott Carroll, to
test mosquito repellent efficacy of three controlled-release
formulations of DEET in the field.  The study was designed to measure
the efficacy of the three test formulations and one “comparison
article”—the US military standard repellent.  The HSRB offered
comments on the protocol at its January 2007 meeting.

Following that meeting, Dr. Carroll amended the protocol to address a
comment from the HSRB and to substitute a new, unregistered repellent
formulation for one of those proposed in the protocol.  Dr. Carroll then
proceeded to conduct the research according to the amended protocol in
July 2007, and submitted the results to EPA for review.  At its October
2007 meeting, the HSRB reviewed the results of the research, determined
that there were both scientific and ethical issues with the conduct of
the research, and advised EPA not to rely on the data.  Dr. Carroll
further amended the protocol, obtained IRB approval for both the
original and subsequent amendments, and re-executed the research in
November 2007, testing only two of the originally proposed test
repellents and omitting the comparison positive control formulation.
Reports of this testing have been submitted to EPA by the study sponsor,
Scientific Coordination, Inc., under study numbers SCI-001.4 and
SCI-001.5.  EPA is presenting the results of the re-execution of
protocol SCI-001 to the HSRB for review at this meeting.

The Agency’s regulation, 40 CFR §26.1602, requires EPA to seek HSRB
review of an EPA decision to rely on the results of these studies.  The
sponsor has submitted data in support of applications for amended
registration for the two test materials.  In order to facilitate review
of these applications within the time allowed by statute, EPA has
reviewed the research, applying the standard in 40 CFR §26.1705.  That
provision states:

§26.1705 Prohibition on reliance on unethical research with
non-pregnant, non-nursing adults conducted after April 7, 2006

Except as provided in §26.1706, in actions within the scope of
§26.1701, EPA shall not rely on data from any research initiated after
April 7, 2006, unless EPA has adequate information to determine that the
research was conducted in substantial compliance with subparts A through
L of this part . . . This prohibition is in addition to the prohibition
in §26.1703.

	OPP has determined that the data are scientifically sound and that the
research meets the standard in §26.1705.  Therefore OPP proposes to
rely on the results in considering the pending applications.

EPA provided the following materials on the completed insect repellent
efficacy studies SCI-001.4 and SCI-001.5 to the HSRB:

1.	Insect Repellent Efficacy Studies SCI-001.4 and SCI-001.5

MRID 47322501 SCI-001.4: Test of DermAegis LipoDEET 302

MRID 47322401 SCI-001.5: Test of Coulston’s Duranon

dence IIRB↔CLBR 3/5/08

EPA Science and Ethics Review (Protocol) SCI-001 (12/20/06)

Changes in consent form version of 11-6-07

EPA Ethics Review: SCI-001.4 and SCI-001.5 (3/7/08)

EPA Science Review: SCI-001.4 and SCI-001.5 (3/7/08)

  This report transmits the HSRB’s comments and recommendations from
its April 9-10, 2008 meeting.

REVIEW PROCESS

On April 9-10, 2008, 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
(73 Federal Register 46, 12413).  At the public meeting, following
welcoming remarks from Agency officials the Board then heard
presentations from the Agency on the following topics:

Update On Revisions To The EPA Document “Scientific And Ethical
Approaches For Observational Exposure Studies

EPA Follow-up on Pesticide Specific HSRB Recommendations

Overview of EPA’s Assessment of Proposed Pesticide Handler Research

		Sampling Strategies in Proposed Pesticide Handler Research

Antimicrobial Exposure Assessment Task Force (AEATF) Governing Document

		EPA Review of AEATF-II Mop and Wipe Scenarios

ICR Protocol: A382

Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI
001.5

Oral comments

The following oral comments were presented at the meeting:

AEATF-II Mop and Wipe Scenarios

Jeff Driver, Ph.D. of infoscientific.com on behalf of the AEATF-II

Larry Holden of Sielken and Associates, Inc. on behalf of the AEATF-II

ICR Protocol: A382

William Gaynor, Ph.D. on behalf of ICR, Inc.

Robin Todd, Ph.D. on behalf of ICR, Inc.

Ralph Piedmont, Ph.D. of Loyola College on behalf of ICR, Inc.

Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI
001.5

Scott Carroll, Ph.D. and Mr. Shawn King on behalf of Carroll-Loye
Biological Research

Written comments

Written comments were received by:

General

Stephen A. McFadden, Independent Scientific Research Advocates

AEATF-II Mop and Wipe Scenarios

American Chemistry Council on behalf of the AEATF-II

	For their deliberations, the Board considered the materials presented
at the meeting, written public comments and Agency background documents
(e.g., the published literature, Agency data evaluation record, weight
of evidence review, ethics review, pesticide human study protocols and
Agency evaluation of the protocol or study).   For a comprehensive list
of background documents visit the   HYPERLINK
"http://www.regulations.gov"  www.regulations.gov , Docket ID No.
EPA-HQ-ORD-2007-0942, or EPA’s HSRB website at   HYPERLINK
"http://www.epa.gov/osa/hsrb/oct-24-26-2007-public-meeting.htm"
http://www.epa.gov/osa/hsrb/oct-24-26-2007-public-meeting.htm .

CHARGE TO THE BOARD AND BOARD RESPONSE

Update On Revisions To The EPA Document “Scientific And Ethical
Approaches For Observational Exposure Studies

No Charge to the Board

EPA Follow-up on Pesticide Specific HSRB Recommendations

No Charge to the Board

Overview of EPA’s Assessment of Proposed Pesticide Handler Research

	Sampling Strategies in Proposed Pesticide Handler Research

	No Charge to the Board

Antimicrobial Exposure Assessment Task Force (AEATF-II) Governing
Document

	No Charge to the Board

Board Recommendations on Review and Format of AEATF and AHETF Protocols

Overall recommendations

1.    Random sampling designs are preferred.

2.    When random sampling is not possible, a purposive diversity
sampling (PDS) protocol must nonetheless have a well-developed sampling
frame based on knowledge of the range of active ingredient
concentrations and distribution of methods used in the field.

3.    Each protocol should be individually assessed for the feasibility
of random assignment. When random sampling is not possible, each
protocol should be individually assessed for the adequacy of the PDS
sampling frame.

Format of protocols for subsequent HSRB review

1.    A detailed description of the methods and rationale for data
collection (e.g., neck wipes).

2.    If random sampling is not used, a detailed description of efforts
made to incorporate random elements in each scenario-specific design and
why it was not feasible (in terms of availability of information, costs,
and time) to obtain a random sample.

3.    For both random and PDS designs, a detailed description, rationale
and justification for the scenario, selection of clusters, and what will
be done within each cluster and why.

4.    For all protocols, a detailed explanation of how data will be
analyzed and interpreted by AHETF & AEATF.

5.    For all protocols, a detailed explanation of how the data is
anticipated to be analyzed by EPA and how it will be useful for EPA risk
assessments.

Format of Agency presentations, specifically OPP presentations to the
Board

1.    OPP should develop a written glossary of terms (e.g., cluster,
scenario) for HSRB and public reference. This glossary should be
distributed but not summarized during OPP presentations.

2.    For each protocol OPP should provide a brief (1 page if possible)
abstract in terms appropriate for a lay audience describing the nature
and purpose of the study and how EPA intends to use the data.

3.   OPP’s oral presentation should not focus on details. The Board
believes that such detailed presentations distract from focusing
attention on those aspects of the protocol for which OPP is eliciting
Board feedback.

4.    OPP’s oral presentation on the science should not be a summary
of the protocol, but a focused discussion of OPP’s evaluation of why
they think the study has sufficient scientific validity; the
presentation should include questions regarding scientific validity that
OPP wishes the Board to address.

5.    OPP’s oral presentation should also include a description of how
the Agency plans to analyze and use the data.

6.    Similarly, OPP’s oral presentation should not focus on the
details regarding the protection of human subjects as such details are
described in the written materials. Rather, a brief oral presentation
should identify those aspects of the design that OPP believes raise
human subjects

concerns.

AHETF and AEATF Comments at HSRB meetings:

1.    Since the HSRB makes its recommendations to EPA and not directly
to sponsors, it is the responsibility of the Agency to present the
protocol to HSRB, along with EPA’s critique and conclusions.

2.    Sponsors have the opportunity to express their perspectives and
clarify information during the public comment periods.

3.    During Board discussion of protocols, sponsors should be available
for additional clarifications that may be needed.

4.    In addition, if sponsors believe that a specific point has not
been adequately addressed they should have the opportunity to alert OPP
to their concerns during the time allotted to the protocol; OPP in
consultation with the Chair and DFO may recommend to the Board that the
sponsor provide additional clarification on the issue(s).

EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of
the mop and wipe scenarios, both exposure scenarios were reviewed
together)

	Science

Charge to the Board

If the proposed research described in AEATF’s proposed mop scenario
design, protocol, and supporting documentation is revised as suggested
in EPA’s review, does the research appear likely to generate
scientifically reliable data, useful for assessing the exposure of
handlers who apply an antimicrobial pesticide by mopping?

If the proposed research described in AEATF’s proposed wipe scenario
designs, protocol, and supporting documentation is revised as suggested
in EPA’s review, does the research appear likely to generate
scientifically reliable data, useful for assessing the exposure of
handlers who apply an antimicrobial pesticide by wiping?

Board Response to the Charge

The two proposed human studies focus on handlers during floor mopping or
surface wiping with a liquid antimicrobial pesticide product to
determine potential dermal and inhalation exposures. The studies are (1)
AEA03, “A Study for Measurement of Potential Dermal and Inhalation
Exposure During Application of a Liquid Antimicrobial Pesticide Product
Using Bucket and Mop Equipment for Cleaning Indoor Surfaces,” and (2)
AEA02, “A Study for Measurement of Potential Dermal and Inhalation
Exposure During Application of a Liquid Antimicrobial Pesticide Product
using Trigger Spray and Wipe or Ready to Use Wipes for Cleaning Indoor
Surfaces.” The protocols associated with these studies have many
similarities. The Board’s comments were therefore very similar for the
two studies. All comments below can be applied to both studies, unless
otherwise noted.

	Study Objective

	AEATF II stated that the primary purpose of the handler studies is to
develop more accurate information on worker exposures to antimicrobials.
AEATF II also presented information to indicate that existing human
exposure data are inadequate. The Board concurred that existing data are
inadequate and that the development of more accurate information is an
appropriate goal.

Benefits and Risks

The Board concurred with the Agency that the generation of new data for
mop and wipe activities would be of value in the assessment of risks for
antimicrobial products. The Board concurred with the Agency that there
are only minimal risks associated with the application of a dilute
solution of didecyl dimethyl ammonium chloride (DDAC) as described in
the study protocols.

Study Design Criteria

The Board was pleased by the amount of randomization included in the
design of these studies.  The investigators and the Agency have
indicated that they are interested in knowing the statistical
distribution of the exposure level, with an acceptable bound for the
relative accuracy of the estimated mean and 95 percentile. In both AEA03
(mop) and AES02 (wipe) studies, the same set of three sites will be used
as clusters, each representing a random sample of one for three
different types of buildings. In order to understand the spectrum of
exposure, six volunteers will be randomly selected to fill each of six
consecutive time durations. This configuration of three clusters of six
handlers for each cluster is based on a simulation study under two-stage
cluster sampling with an intra-class correlation coefficient of 0.3 and
a geometric standard deviation (GSD) of 2.86. The sample size
justification depends on these design parameters.

In an earlier mop study, conducted by the Chemical Manufacturers’
Association (CMA), the estimated GSD was 3.53. It therefore appeared to
the Board that the proposed AEA03 study design would not ensure
three-fold relative accuracy (K=3) for the resulting estimated mean and
the 95 percentile of the exposure distribution.  Furthermore, in an
earlier CMA wipe study the estimated GSD was 5.00, much larger than 2.86
assumed in the simulation study that was used to derive the sample size
justification. Again, it appeared unlikely to the Board that the AEA02
study design would produce a three-fold relative accuracy for the
resulting estimated mean and the 95 percentile of the exposure
distribution.

The Board also noted that the stratified nature of selecting a cluster
from each of three types of sites makes it impossible to assess the
variability of exposure distribution from site to site. Likewise,
because of the stratified nature of selecting one handler for each of
six mopping/wiping durations, one cannot estimate the exposure
distribution.  The experimental design can be viewed as consisting of 18
design points with 18 data points, resulting in no degrees of freedom
for estimation of variability as there are no replications at any design
point.

In light of these concerns, the Board recommended that the Agency
reconsider the design of the study, or develop an explicit statement of
the limitations on the use of data that will be collected under the
proposed design.

Site selection

The studies will take place in Fresno, California, in three buildings:
an office building, a retail building, and a building with large meeting
spaces. The way in which the clusters have been defined suggests that
they represent a fixed effect factor (i.e., building type) rather than a
random effect factor. The proposed study design will not replicate this
fixed effect by having more of than one building of each type. The Board
acknowledged the practical considerations that led to the decision to
have both studies in the same city, using the same buildings. However,
it must be realized that any generalizations to moppers and wipers in
other parts of the country and in other kinds of buildings would be
based on expert opinion, and that such generalizations would not be
statistical generalizations. Nevertheless, the Board concurred with the
Agency that some generalizations from these data would seem to be
reasonable at this point in time.

Sample size

The proposed sample size of 18 observations for each scenario did not
appear to have a statistical justification, as indicated above. The
Board was concerned about recommending this sample size and the 3x6
design (three sites, six workers per site) on which it is based. The
concern is that all that all future scenario designs for the AEATF- II
program are likely to have three clusters and six time durations, with
the justification being the Board’s recommending these protocols. The
Board has seen this happen with insect repellency studies repeatedly.
That is, a new protocol has justified its sample size by reference to a
previously submitted protocol.  The adequacy of the proposed sample size
for future studies will be informed by the data collection and analysis
of this first set of studies.  In general, the Board will not consider a
new protocol that has justified its sample size by reference to a
previously submitted protocol.

Task duration

AEATF-II’s protocol for mopping proposed that handlers mop for a
maximum of 90 minutes. This value was derived from a survey conducted by
the International Sanitary Supply Association (ISSA). AEATF-II
calculated an average mopping duration to 83 minutes from the ISSA study
data. The Board understood that this value was calculated in the
following manner:

ISSA data indicated that handlers spend, on average, 12 minutes to mop
1000 square feet.

It was assumed that a hospital room consists of a 240 square feet
(12x20) main room and a 36 square foot (6x6) bathroom for a total floor
area of 276 sq ft.

It was assumed that a worker would mop 25 such rooms for a total of
6,900 sq feet.

Thus, 6900 square feet x 12 minutes per 1000 square feet  = 82.8 minutes

A similar calculation was made for the wipe scenarios, resulting in an
estimated average wiping time of 212.75 minutes.

The Board concluded that the task duration time frame was not adequate
to characterize daily exposure. The Board recommended that the work time
frame be expanded to exceed the 95th percentile of the ISSA survey
findings.

The Board also noted that the lengths of mopping (or wiping) would be
consistently tested from the longest time period to the shortest time
period for each site. For this to be a valid approach, one must be
willing to assume that there is no “carry-over” effect from one
testing period to another. One factor that could lead to a carry-over
effect would be whether residues from earlier mopping (or wiping) could
affect the measurements on later study participants, especially
respiratory effects. The Board recommended that these concerns be
reflected in the protocols.

The Board found the explanation of potential analyses that the Agency
would conduct based on these studies to be very helpful.  A basic
assumption for these analyses is that the distribution of exposure/unit
handled is the same regardless of the number of active ingredient (Ai)
units handled or the time spent mopping (or wiping).  However, the mean
exposure/Ai unit and/or variance of the exposure/unit is likely to
increase with the number of units due to fatigue. This assumption could
be at least partially checked by plotting exposure/Ai unit by Ai unit,
though such an analysis might conflict with the second analysis
identified: the assessment of the assumption of proportionality. A
regression would likely be conducted for this second analysis. If the
distribution of exposure/unit handled were constant or increased with
the number of units handled and proportionality was demonstrated, then
both the mean and the variance would be expected to increase with the
number of units handled. In simple linear regression, the variance is
assumed to be constant for all values of x. Thus, a weighted regression,
not a simple linear regression would be needed.  Because the protocol
does not ensure that there will be replication of exposures for the same
number of units, whether a simple or weighted regression would be more
appropriate could not be fully evaluated. If, instead of time, the
number of Ai units handled were the measure that defined each person’s
participation, the data would more likely lend themselves to a proper
assessment of the assumption of proportionality.

Participation Criteria

AEATF plans to recruit subjects from among identifiable and willing
professional janitors. A rationale for this decision was provided. AEATF
also assumes that these professionals would have higher exposures than
consumers. One Board member expressed the view that professionals have
substantial experience and perhaps training in how to minimize exposure,
and that consumers might have higher exposures per Ai unit handled.
AEATF-II plans to recruit subjects through service providers. The Board
suggested that unions also be considered in the development of the
recruitment procedures.

Measurement Criteria

	The Board noted that inhalation exposure from vapors would likely be
low in these studies due to the relatively low volatility of the active
ingredient used in the scenarios. However, the extent to which liquid
aerosols generated in the mop protocol would contribute to aggregate
exposure is not known. It was not clear what particle size range was
expected to be generated in these studies, nor was it clear what
particle size range would be captured by the sampling method. The Board
suggested that a laboratory study that measured aerosol size under
varying environmental conditions would be helpful in clarifying these
uncertainties.

The following are key variables that will have an effect on inhalation
exposure:

Ventilation

Temperature

Total area treated

Duration

Volume of the enclosed space

	The protocols state as follows: “light level, air temperature, and
relative humidity of the work area for the duration of exposure
monitoring will be documented with automated instrumentation logging and
recording at intervals appropriate for the duration of the work period.
Monitoring equipment will be calibrated or standardized according to the
cooperating contractors’ SOPs. HVAC will be described in detail and
the air turnover rate will be measured or estimated.” The Board
recommended that the equipment and procedures used to characterize these
environmental factors be described in greater detail, either in the
protocols or in the SOPs. The Board also asked investigators to explain
how the effects of such factors as ventilation, temperature and the
volume of the enclosed space would be used to modify or interpret study
results.

AEATF-II proposed to use dermal exposure assessment methods similar to
those used by the Agricultural Handler Exposure Task Force studies;
i.e., cotton garments on most of the body, handwashing, and face/neck
wiping. As in its previous reports, the Board noted that these methods
have the potential to underestimate exposure. The Board supported the
use of a double layer of socks to capture potential exposure from spills
or splashes.

Laboratory and Field Conditions

The Board considered the quality assurance and quality control
procedures that accompanied these protocols to be of high quality. The
Board appreciated the attention to detail provided by the investigators.

The Board raised several concerns regarding field conditions.

 Sani-Care Lemon Quat™ as the chemical of interest. The Board agreed
that the choice of DDAC as the antimicrobial material for these studies
was appropriate, given its wide use, availability, and the existence of
a reliable and sensitive analytical method.

The Board encouraged the Agency and the investigators to ensure that
work activities be as realistic as possible. For example, a worker
should use a bucket of the disinfectant solution until it becomes dirty;
the worker should then empty the bucket and pick up a fresh bucket. All
of this could be done without the involvement of study staff. In
general, the Board viewed the activities of the study staff described in
the current protocols to be too disruptive of “usual practices”. The
Board recommended that the protocols be revised to provide a more
detailed description of what the workers will actually do, and that the
presence of staff during the exposure period be kept to a minimum.

The Board was also concerned with what is sometimes called the
“Hawthorne Effect”. That is, workers will change behavior
consciously or unconsciously when they are aware that they are being
observed. The current protocols indicate that there will be constant
surveillance of workers, including video recording. The Board urged the
Agency and the investigators to minimize these observations and to train
staff to be as unobtrusive as possible.

Finally, the Board requested that the protocol provide more specificity
as to where study subjects will be located while waiting to participate
in the study. There was a concern that observation of some study
subjects by other study subjects could alter behavior.

	HSRB Consensus and Rationale

The Board considered the AEATF-II study protocols to successfully
address many design challenges. The Board appreciated particularly the
clarity of the protocols, the attention to detail, and the thorough
description of quality assurance and quality control procedures. The
Board concurred with the Agency that existing data on handler exposures
to antimicrobials are inadequate and that the development of more
accurate information is an appropriate goal.  The Board also concurred
with the Agency that there are only minimal risks associated with the
application of a dilute solution of didecyl dimethyl ammonium chloride
as described in the study protocols.

While the Board concluded that the research could produce scientifically
reliable data, the Board identified several contextual factors that may
limit the generalizability of the findings.

The Board recommended that the Agency reconsider the design of the
study, or develop an explicit statement of the limitations on the use of
data that will be collected under the proposed design. The Board noted
that any generalizations to moppers and wipers in other parts of the
country and in other kinds of buildings would be based on expert
opinion, and that such generalizations would not be statistical
generalizations. The Board cautioned the Agency regarding the 3x6 design
in the protocols, suggesting future scenario designs for the AEATF- II
program would likely have three clusters and six time durations, with
the justification being the Board’s recommendation of these protocols.
The Board concluded that the task duration time frame was not adequate
to characterize daily exposure. The Board recommended that the work time
frame be expanded to exceed the 95th percentile of the International
Sanitary Supply Association survey findings. The Board noted that if,
instead of time, the number of Ai units handled were the measure that
defined each person’s participation, the data would more likely lend
themselves to a proper assessment of the assumption of proportionality.

In regard to inhalation exposure assessment, the Board suggested that a
laboratory study that measured aerosol size under varying environmental
conditions would helpful in clarifying uncertainties regarding particle
size and sampling methods. The Board raised several concerns regarding
the field conditions for these studies: ensure that any carry-over
effect in buildings is avoided; ensure that work activities be as
realistic as possible; revise protocols to provide a more detailed
description of what the workers will actually do; keep the presence of
staff and intrusive observation of workers during the exposure period to
a minimum; and, provide more specificity as to where study subjects will
be located while waiting to participate in the study..

Finally, the Board encourages modifications of future related protocols
based on the lessons learned from these initial submissions.  Such
adjustments are anticipated to improve the study design and subsequent
results, leading to a more accurate characterization of pesticide
handler exposure.

Ethics

	Charge to the Board

	If the proposed research described in AEATF’s proposed mop scenario
design, protocol, and supporting documentation is revised as suggested
in EPA’s review, does the research appear to meet the applicable
requirements of 40 CFR part 26, subparts K and L?

If the proposed research described in AEATF’s proposed wipe scenario
designs, protocol, and supporting documentation is revised as suggested
in EPA’s review, does the 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 Studies

Each of these scenarios (mop and wipe) has been designed to develop data
for a database of exposure monitoring information which will be used by
the EPA for making regulatory decisions about future exposures to a
variety of antimicrobial products and their active ingredients. The
sponsor of both scenarios is the Antimicrobial Exposure Assessment Task
Force II (AEATF-II) of the American Chemistry Council. The scenarios
will be conducted on behalf of that entity by Golden Pacific
Laboratories, LLC, of Fresno, California. For each of the scenarios,
there will be three field sites in Fresno, California.

According to the protocols, these studies are intended to comply with
the ethical standards contained in 40 CFR Part 26, subparts K and L, in
addition to the requirements of FIFRA § 12(a)(2)(P), and Title 3, §
6710 of the California Code of Regulations. Both scenarios were reviewed
and approved by a commercial IRB, the Independent Investigational Review
Board, Inc. (IIRB, Inc.) of Plantation, Florida.

For each scenario, the protocols include detailed explanations of how
the buildings in which the scenarios take place will be chosen, how the
subjects will be recruited, how the informed consent of those subjects
will be obtained, and what will take place during the conduct of the
scenarios.

Each of the protocols requires that the subjects be at least 18 years of
age, and they exclude female subjects who are pregnant or lactating.

The test substance that will be used in both scenarios is diluted
Sani-Care Lemon Quat. Its two active ingredients are didecyl dimethyl
ammonium chloride (DDAC) and n-Alkyl dimethyl benzyl ammonium chlorides
(ADBAC).

Critique of Studies

The Board concurred with the factual observations of the ethical
strengths and weaknesses of the studies, as detailed in the EPA’s
Science and Ethics Reviews (Carley 2008a and 2008b).

In general, the research described in these two protocols appears to
comport with the applicable requirements of 40 CFR Part 26, subparts K
and L. The risks to study participants, in general, will be minimal and
would appear to be justified by the likely societal benefits,
specifically the production of data that could be used by the EPA in
determining acceptable exposures to antimicrobial products used in
certain mopping and wiping activities.

The test compound contains two active ingredients, DDAC and ADBAC, both
of which have been extensively tested in animals. The subjects will only
be exposed to concentrations of the test compound at the label dilution
rates. At those dilutions, animal testing has shown the compound to have
low acute toxicity and a low chronic hazard profile. Both of the active
ingredients have already been approved by the EPA for use in many
formulations, and in many janitorial products. In addition, the test
compound itself, Sani-Care Lemon Quat, has been approved by the EPA, and
will only be used in the scenarios in conformity with its approved
labeling. All of the subjects will be professional janitors with
extensive experience in using these products, and thus unlikely to
misuse them in a way that might increase their likelihood of being
harmed.

Although the risks to subjects from exposure to the test compound appear
very low, it should be noted that in terms of the purposes of these
scenarios, it is not actually necessary that subjects be exposed to an
antimicrobial product. The scenarios are intended to measure only the
amount of skin, clothing and inhalation exposure when someone is engaged
in certain activities relating to applying an antimicrobicide. They are
not measuring the actual effects to the test subject from that exposure.
Thus, it might be possible to design scenarios in which instead of an
antimicrobicide, some less toxic tracer substance might be used. It
would be appropriate for protocols to discuss this possibility for
further minimizing risks, and to indicate why (if it is true) such an
option would not allow the needed information to be collected.

Another possible risk is that of heat-related illness, given that the
subjects will be required to wear two layers of clothing during the
scenario activities. That risk is being minimized by the fact that those
activities will take place indoors in temperature-controlled
environments. In addition, subjects will be given appropriate breaks.
The breaks will not only minimize the likelihood of heat-related
illness, but also reduce the likelihood of cardiovascular harms.

With regard to subject selection, EPA observed that “[n]o potential
subjects are from a vulnerable population” (Carley 2008a and 2008b).
In this regard, it should be noted that 45 CFR § 46.111(b) states that
“economically or educationally disadvantaged persons” may constitute
a vulnerable population. Accordingly, given that this study is
recruiting from a population of individuals who may not have substantial
education, who may be relatively disadvantaged from an economic
viewpoint, and many of whom may not speak or read English, it would be
appropriate not to dismiss the possibility that the subjects in this
study might be vulnerable to coercion and undue influence, but rather to
instead recognize that there are sufficient safeguards in the design of
the study to protect the subjects, even if they are vulnerable.

The study protocols included several mechanisms designed to minimize
coercive recruitment and enrollment, including the fact that subjects
were not recruited directly from their employers, but instead would
themselves respond to flyers that have been posted. Compensation was not
considered to be so high as to unduly influence participation, and
minors and pregnant or lactating women were explicitly excluded from
volunteering (pregnancy being confirmed by requiring all female
volunteers under the age of 50 to undergo a urine pregnancy test). The
potential stigmatization resulting from study exclusion was minimized by
the use of so-called ‘alternate’ participants, allowing for
volunteers to withdraw or be excluded from participating without unduly
compromising their confidentiality.

With regard to the eligibility criteria, the Board believes that the
requirement for females under the age of 50 to take a pregnancy test
could be refined. It would be possible to design criteria that created a
better fit between which female subjects might be able to get pregnant,
and which of them are being asked to take that test. By doing this, the
researchers would be showing greater respect for this group of subjects.

The protocol might provide a greater justification for why subjects
older than 65 are excluded.

Most of the issues raised by the Board relate to informed consent and
recruitment. With regard to the consent forms, as a general matter,
given the population from which subjects are being recruited, it would
be appropriate to make sure that the consent forms are at an appropriate
level of readability. In at least some places, there appears to be room
for further simplification.

The consent forms do not appear to describe adequately the procedures
discussed in the protocol relating to (a) still photography of the
subjects, (b) videotaping of the subjects, and (c) observation of the
subjects by members of the study team. All of these procedures pose
possible risks to the privacy and confidentiality of the subjects. The
fact that each of these procedures will be part of the protocols should
be adequately explained in the consent forms. That explanation should
include the details relating to who will be observing and who will be
taking the photographs (e.g., members of the study team, outside
contractors, other subjects). In addition, both the protocol and the
consent forms should explain what procedures will be in place to make
sure that the photographs and videos will be stored in a way that
adequately protects both the confidentiality and the privacy of the
subjects, and explains what harms to subjects might result if those
protections are not adequate. If subjects will be accorded the right to
opt out of being photographed, that should be explained in the consent
form.

In the Purpose section of the consent form, it should be explained that
the underlying purpose of the study will be to collect information that
will be provided to the EPA, and that the EPA would use that information
to determine the appropriate standards for allowable exposures to
products such as the test compound.

The consent form in one instance (the paragraph numbered 4 under Study
Procedures) uses the term “same-sex person.” That confusing term
should be replaced with the descriptions used elsewhere in the form,
such as “a researcher of your own sex.”

In the description of risks to subjects from exposure to the test
compound, it is merely stated that the risks are low. If there is a
known risk from getting the compound in a person’s eyes, for example,
that risk should be explained.

The approved version of the consent form, under the Pregnancy Risks
heading, begins with “We don’t know the risks to the unborn from
exposure to SANI-CARE LEMON QUAT and may be hazardous . . .” There is
a word or words missing in this sentence, and it therefore needs to be
revised. More significantly, the “and may be hazardous” language
differs from the language that appears in the versions of the consent
forms submitted to the IRB by the researchers. The Board was not able to
determine how this change in language took place. There is not
documentation that the IRB asked for the change, or that the change was
initiated by the researchers themselves, and that they submitted a copy
of the consent form with this change to the IRB. This circumstance
raises some concerns regarding whether the EPA was provided with the
full documentation of what went on during the IRB approval process. The
Board believes it would be appropriate for the EPA to determine how this
change occurred. In addition, some members were concerned that this lack
of documentation might relate to the operation of IIRB, Inc., which
might reinforce prior Board concerns about the operation of that IRB.

With regard to the recruitment brochure, it would appear appropriate for
that document to mention that the product which will be used in the
study is Sani-Care Lemon Quat. At the beginning of that document, it
fails to mention that the study will look not only at how much of the
product “gets on” the workers, but also how much of it they inhale.
Under the eligibility criteria, it states that subjects must be “Male
or non pregnant, non or nursing female.” This language needs to be
corrected. And in the last sentence, the brochure incorrectly states
that the EPA will use this information to reduce risks to workers. The
statement should be revised to more accurately state the EPA will use
the information to determine how much of the product workers will be
exposed to; it is not true that it will necessarily lead to a reduction
in risks to workers.

The phone texts that are used for calls to employers, and for calls to
workers making inquiries, fail to mention that the study will be looking
at inhalation risks in addition to risks relating to getting the
compound on the worker’s skin and clothing.

With regard to recruiting and obtaining the informed consent of
Spanish-speaking persons, the Board agrees with the changes recommended
by the EPA (Carley 2008a and 2008b). It would also be appropriate for
the protocol to include a more detailed discussion of how the
researchers will obtain appropriate community involvement (such as, for
example, discussions with unions representing janitorial workers).

With regard to the translations into Spanish of the various documents,
the Board believes that it is important to make sure that the
appropriate dialect of Spanish is being used in he translations. The
translation of the consent form, for example, was provided by someone
from Miami, Florida, yet the study will be taking place in California.
The Spanish-speaking communities in Miami and California might well use
significantly different dialects of Spanish. It was also not clear from
the documents who was producing the Spanish-language version of some of
the materials, such as the recruitment brochure.

HSRB Consensus and Rationale

The Board concurred with the initial assessment of the Agency that if
the proposed mop and wipe scenario design, protocol, and supporting
documentation is revised as suggested in EPA’s review, the research
does appear to meet the applicable requirements of 40 CFR part 26,
subparts K and L.

ICR Protocol: A382

Science

Charge to the Board

If the proposed research described in ICR’s proposed picaridin
protocol is revised as suggested in EPA’s review, does the research
appear likely to generate scientifically reliable data, useful for
assessing the efficacy of the test substances for repelling stable
flies?

Board Response

Protocol A382 outlined a laboratory test to evaluate the efficacy of
picaridin against stableflies when applied dermally as a 20% cream or
spray product.  The purpose of the study was clearly defined (i.e.,
efficacy testing), and the use of human subjects was adequately
justified.  Briefly, the proposed study will involve a total of 13
subjects, 12 of whom are designated for treatment with the picaridin
spray and cream, with one additional subject designated as the negative
control.  The negative control will be selected at random and serves to
establish the aggressiveness of each cage of stable flies to be used in
the test.  The first phase of the planned study will determine the
average dose applied under normal use conditions, but will not exceed 4
mg/cm2.  The second phase of the study is the repellency test in which
subjects’ arms will be treated with measured amounts of both products
(one product on each forearm), after which they will expose their
treated forearms to stableflies for a 5 minute period every half hour
for up to 10 hours.  The submitted protocol proposed to use the time to
first confirmed bite on both arms (both products) as the quantitative
measure of repellent efficacy.  The Sponsor provided a thorough
statistical justification for the protocol design, including the
determination that a minimum of 7 subjects would be required to achieve
a 95% confidence interval for assessing protection up to 8 hours with a
( 2-hour confidence limit.

There was general consensus that the protocol was well written and a
sound scientific rationale was provided.  There were several minor
issues that were identified during the course of the HSRB discussion,
representing issues that can easily be addressed in a revised protocol.
These included: (1) clarifying the protocol to specify that there are 13
subjects, representing 1 negative control and 12 treated individuals;
(2) providing some information as to what activities are permitted
during the 25 minute intervals when subjects are not actively on test
and specifying what activities are precluded by being involved in the
test; (3) ensuring the accuracy of the margin of exposure (MOE) assuming
a maximum application rate of 4 mg/cm2 ; and (4) recommending that the
Sponsor design the test to randomize the treatment modalities (spray or
cream) on the left and right arms and to ensure that the professional
staff involved in the conduct of the study are blinded to the
treatments.  The HSRB recommends that these modifications should be made
to the protocol and study conduct.

There were however, three additional matters concerning the protocol
design for which there was additional board discussion and more
significant changes recommended to the proposed study.  These issues
were as follows:

It was noted during the Board’s discussion that the Sponsor specified
that the subject pool was exclusively Caucasian.  There was concern as
to whether the results obtained from such a constrained population could
be generalized to other races, and there was a minority, but strongly
voiced opinion that the protocol was not scientifically sound given this
limitation.  The HSRB recommended that the subjects used in this study
should not be homogeneous, but rather, that there should be diversity
across the subjects used for the test.  The Board did not provide a
specific recommendation on how diverse the test population should be,
but suggested that, at a minimum, it should reflect the diversity of the
region from which the possible subjects are drawn.  The Board agreed
that the Sponsor must address this scientific issue prior to executing
the study.

OPP staff recommended that a positive control be used in this study,
suggesting that it would improve the overall scientific validity of the
test.  In its discussion, the HSRB concluded that the inclusion of a
positive control was not essential to the protocol, and the Board
recommended against requiring a positive control in the study.

The protocol was designed to evaluate repellent efficacy using the
accepted paradigm of time to first confirmed bite for each treatment
(cream or spray product).  As such, this design would result in a total
of 4 bites per subject upon loss of repellency (first bite to be
followed by a confirming bite for each treatment).  In consideration of
the biology of stable flies, there was general consensus among the HSRB
that the study would be scientifically valid if the time to first bite,
requiring only one bite per treatment, was used as the endpoint for
evaluating the efficacy of the repellent.

HSRB Consensus and Rationale

If amended in a manner consistent with the Board’s concerns and
recommendations, and with particular modification to subject ethnicity,
the protocol ICR A382 studying the efficacy of two formulations of
picaridin for repelling stable flies would be sufficiently sound, from a
scientific perspective, to be used to assess the repellent efficacy of
these formulations against stable flies.

Ethics

Charge to the Board

If the proposed research described in ICR’s proposed picaridin
protocol is revised as suggested in EPA’s review, does the research
appear to meet the applicable requirements of 40 CFR part 26, subparts K
and L?

Board Response

The Board concurred with the factual observations of the ethical
strengths and weaknesses of the proposed study, as detailed in the
EPA’s Science and Ethics Review (Carley and Sweeney 2008).

Overall, this is a well written protocol, consent document, and
application, answering many of the questions that HSRB has asked when
reviewing in other studies. The risks to study participants were minimal
and were justified by the likely societal benefits, including data on
the efficacy of these new formulations as repellents against stable
flies.

The 20% concentration of picaridin in the products to be used in this
study is “higher than the marketed and EPA-registered formulation.”
Based on toxicological data currently available, however, picaridin has
low acute toxicity. The potential risks include irritation or allergic
response to the product. Individuals known to be sensitive to insect
repellents or skin care products are excluded from the study. In
addition, subjects will be monitored for signs of reaction to the
products during the dosimetry portion of the study as well as during the
repellent phase of the study.

While stable fly bites are acutely painful, the flies are not known to
transmit any diseases to humans. Individuals known to be sensitive to
stable fly bites are excluded from the study.  Topical lotions and
rubbing alcohol will be available to subjects to help relieve the
itching from the bites.

The study protocol also included several mechanisms designed to minimize
coercive recruitment and enrollment, compensation ($11/hour,
time-and-a-half over 9 hours) was not considered to be so high as to
unduly influence participation, and minors and pregnant or lactating
women were explicitly excluded from enrolling (pregnancy being confirmed
by requiring all female volunteers to undergo a self-administered
over-the-counter pregnancy test “shortly before any treatment with a
test article”). The potential stigmatization resulting from study
exclusion was minimized by the use of ‘alternate’ participants,
allowing for volunteers to withdraw or be excluded from participating
without unduly compromising their confidentiality.

Several ethical issues were raised, and can be categorized as they
relate to the Belmont Principles of Respect for Persons, Beneficence and
Justice. The Board concluded that all of the issues could be addressed
with additional explanations or minor protocol modifications. Concerns
were raised relating to the Justice principle. Subjects greater than 70
years of age are excluded without adequate justification. Subjects who
cannot “read, speak, and understand English” are also excluded,
without a description of how that will be assessed or a justification of
why reading English is required for this study. The recruitment pool of
potential subjects is overwhelmingly Caucasian. While ICR will “look
for recruits from the Afro-American community,” there are no plans
presented to assure racial/ethnic diversity of the study population,
which would be more appropriate given that these products, if marketed,
will be marketed to the general diverse population.

Issues related to the Respect for Persons principle include the
requirement that women not of child-bearing potential, such as women who
have had a hysterectomy or who are post-menopausal, are nevertheless
required to undergo a pregnancy test. Some HSRB members found this
disrespectful, but a minority of other members did not.

While most issues related to the Beneficence principle were addressed,
the question of whether or not the stable flies to be used in this study
would be given bovine blood at any time prior to the study remained
unanswered. Because bovine blood carries with it a potential risk to
humans of Creutzfeld-Jacob disease or exposure to bovine leukemia virus,
the Board recommended that this question of whether or not the stable
flies would receive bovine blood prior to their opportunity to bite
human volunteers and the attendant risks be addressed.  In addition, the
scientific issue of using unblinded ICR staff to measure the outcome
variable (stable fly bites) may jeopardize the scientific validity of
the study, and thus alter the risk-benefit assessment. The HSRB
recommended randomizing which product is applied to which arm, and using
a blinded evaluator to measure the outcome variable.

HSRB Consensus and Rationale

The Board concurred with the initial assessment of the Agency that, if
the protocol is revised as suggested by EPA and the HSRB, the study
submitted for review by the Board meets the applicable requirements of
40 CFR 26, subparts K and L.

Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI
001.5

Science

Charge to the Board

Are these studies sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy of the formulations tested
against mosquitoes?

Board Response

The active ingredient DEET in two lotion formulations was tested for its
ability to repel mosquitoes from the arms of volunteers by the protocol
presented and modified by Carroll-Loye in two separately described
studies which were conducted simultaneously using common sites and
negative controls. This was a repeat of two products previously tested
but not accepted for ethical reasons at the October, 2007, HSRB meeting.
The protocol had been modified based on the suggestions and input of EPA
and HSRB.  The results were reported in SCI.001.4, DermaAegis LipoDEET
302, and SCI.001.5 Coulston’s Duranon. The results on these two
products were not compared to a positive control substance nor to one
another. Because of the common elements between the two studies, they
are discussed together in this report. All experiments were conducted
using Good Laboratory Practices. Margins of exposure were high.

The dosimetry for the two products was done in the laboratory on
November 7-9, 2007.  The field tests were conducted on November 10,
2007, at Site 1 in Glenn County, a forest habitat, and on November 11,
2007, at Site 2 in Butte County, a grassland habitat, both in
California.  Slightly different mosquito species composition occurred at
the two sites, but overall the species composition of the two sites was
similar. Ten subjects were used for the dosimetry tests.  Ten subjects
were used for each of the two products. The subjects were required to be
above 18 years of age and no more than 55 years of age, and active in
rural outdoor settings. Only arms were tested in this study. There were
two experienced persons serving as negative controls (i.e., without any
repellent product) to confirm mosquito landing pressure (and landing
pressure was maintained throughout the period of the study, defined as
at least one Landing with Intent to Bite, LIBe, per min during the
period of exposure). LIBe’s were monitored in experimental subjects
during a one min interval each 15 min, until the First Confirmed LIBe
(FCLIBe) could be determined. Stopping rules were employed. No evidence
of West Nile Virus was present in either test site from sentinels prior
to conduct of the study. Mosquitoes landing were taken to the laboratory
for later identification, and for screening for West Nile, Western
Equine Encephalitis, and St. Louis Encephalitis viruses, and all
mosquitoes were negative.  All subjects wore Tyvek coverall, head nets
and surgical gloves.  Observation was initiated 150-180 minutes post
application.  Complete protection time (CPT) was measured, defined as
the time to the FCLIBe.  The data were presented as mean ± standard
deviations.  Because of the low number of repellency failures observed,
a Kaplan-Meier analysis (suggested at previous HSRB meetings) was not
conducted.

LipoDEET 302 is 30% DEET on lipid spheres designed to improve the
durability and to improve the cosmetic properties. It yielded a CPT of
11.25 ± 0.0 hr in Site 1 (no repellency failures) and 11.28 ± 0.79 hr
in Site 2.

Coulson’s Duranon is 20% DEET in microscopic protein spheres to
reduced skin absorption of DEET, improve cosmetic properties and inhibit
evaporation. It yielded a CPT of 11.25 ± 0.0 (no failures) in Site 1
and 10.78 ± 1.3 hr in Site 2.

The report was clearly written. The study was justified in that
additional insect repellents that are more efficacious and/or more
acceptable cosmetically to the public would be an advantage from both
the standpoint of health (to reduce the chances of contracting a
mosquito-borne disease) and of comfort. The information should be
generalizable to the public, although the exclusions, which were highly
appropriate, excluded some subpopulations that would likely use insect
repellents. The experiment was necessary to determine the field efficacy
of these test formulations, and the experiments were set up to meet the
study objective.  Measurements taken were appropriate for the objective
and quality assurance considerations were in place.

The experiment was conducted according to the approved protocol with
some deviations, none of which negatively impacted the scientific
validity. Discussion was related to a lack of positive control (this was
not considered a flaw and did not impact the usefulness of the data);
the deviation of a lag time between application of the repellants and
the initiation of monitoring (this was probably related to the short day
length available for testing in November and the necessity of applying
the repellant early to assure a sufficiently long observation period
before dark); and the allowance of an application of repellant on the
day before the study (it was clarified in the previous HSRB meeting that
the repellant was washed off after dosimetry or testing, and the target
skin was washed again prior to a new study, thereby insuring that there
was no carry-over to compromise data).

HSRB Consensus and Rationale

The Board concluded that the study on the efficacy of LipoDEET 320 and
Coulson’s Duranon shows efficacy of both products in repelling
mosquitoes, and agreed with the Agency that the study was sufficiently
sound, from a scientific perspective, to be used to accurately calculate
the CPT for repelling mosquitoes.

Ethics

Charge to the Board

Does available information support a determination that this study was
conducted in substantial compliance with subparts K and L of EPA
regulations at 40 CFR part 26?

Board Response

Brief Overview of the Study

The basic protocol for these studies (SCI-001) was initially reviewed at
the January 2007 HSRB meeting, at which time the Board concluded that
the study would meet the requirements established in the Environmental
Protection Agency’s final human studies rule (40 CFR Part 26) pending
minor revision. Most, although not all, of these suggestions were
incorporated into a revised protocol, submitted to the IRB of record
(Institutional Review Board, Inc., [IIRB, Inc.] of Plantation, FL) for
re-review, and approved (Carley 2008; Carroll 2008).

Using the revised protocol and consent documents for SCI-001,
Carroll-Loye Biological Research conducted dosimetry and field trials of
three compounds in July 2007: DermAegis LipoDEET 302, DermAegis LipoDEET
3434, and Coulston’s Duranon Personal Insect Repellent. At the October
2007 meeting of the HSRB, the Board recommended that the data obtained
in July under protocol SCI-001 not be accepted for regulatory
decision-making purposes (EPA HSRB 2007). The Board concluded that the
use of a previously unapproved pesticide formulation  (DermAegis
LipoDEET 3434) violated the applicable requirements of 40 CFR Part 26.

The data presented to the Board in April 2008 represents the results of
new dosimetry and field trials of two compounds in November 2007:
DermAegis LipoDEET 302 and Coulston’s Duranon Personal Insect
Repellent. The documents provided by Carroll-Loye (Carroll 2007a;
Carroll 2007b) specifically state that each study was conducted in
compliance the requirements of the U.S. EPA Good Laboratory Practice
Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K
and L; FIFRA § 12(a)(2)(P); and the California State EPA Department of
Pesticide Regulations for study monitoring (California Code of
Regulations Title 3, Section 6710). Each study was also reviewed and
approved by a commercial human subjects review committee, IIRB, Inc.
Documentation provided to the EPA by IIRB, Inc. indicates that it
reviewed these studies pursuant to the standards of the Common Rule (45
C.F.R. Part 46, Subpart A) and determined them to be in compliance with
that Rule.

As submitted to the EPA, each completed study consists of two
interdependent analyses: 1) a dosimetry study designed to determine the
amount of an insect-repelling compound (30% DEET in liposomal capsules
or 20% DEET in protein capsules) that typical users would typically
apply when provided with a lotion formulations; and 2) an efficacy study
designed to measure the effectiveness of each compound as a mosquito
repellent. The two studies, SCI-001.4 and SCI-001.5, were performed
simultaneously at a laboratory site in Davis, California, and at field
sites in Butte and Glenn Counties, California, by researchers at
Carroll-Loye Biological Research. The study sponsor was Scientific
Coordination, Inc., of Rockville, Maryland. The studies were conducted
using products from two manufacturers: LipoDEET 302 was manufactured and
supplied by DermAegis, Inc. of Rockford, Illinois; Duranon was
manufactured and supplied by Sawyer Products of Safety Harbor, Florida.

Dosimetry was determined by direct measurement of compound application.
The efficacy of each as a mosquito repellent was determined by measuring
the ability of the formulations to prevent mosquito landings (defined as
“Lite with Intent to Bite”; LIBe) under field conditions. Mosquitoes
were 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 and to remove such mosquitoes
with an aspirator using laboratory-raised, pathogen-free mosquitoes in a
controlled laboratory setting. During the field studies, participants
worked in pairs to facilitate identification and aspiration of LIBing
mosquitoes during brief exposure periods. The strengths and weaknesses
of each study design are described above.

The dosimetry study enrolled a total of 10 individuals, each of whom
tested both formulations. Each efficacy study enrolled 10 subjects for
each formulation at each of the two field sites. Many volunteers
participated in multiple analytic phases, both dosimetric and effective.
In total, 29 volunteers participated in at least one analytic phase of
SCI-001.4 and SCI-001.5. In addition, three alternate participants were
enrolled to: 1) replace any individual who withdrew; and 2) protect the
confidentiality of any participant excluded from the study as a result
of pregnancy or other potentially stigmatizing condition, as described
below.

Critique of Study

The Board concurred with the factual observations of the ethical
strengths and weaknesses of the study, as detailed in the EPA’s
Science and Ethics Review (Carley 2008).

In general, the research described in SCI-001.4 and SCI-001.5 comported
with the applicable requirements of 40 CFR Part 26, subparts K and L.
The risks to study participants, in general, were minimal and were
justified by the likely societal benefits, including data on the
efficacy of these new formulations (30% DEET in liposomal capsules and
20% DEET in protein capsules) as personal insect repellents.

Based on toxicological data currently available for DermAegis LipoDEET
302 and Coulston’s Duranon Personal Insect Repellent, compounds
registered with the EPA, the subjects enrolled in this study were
unlikely to be at increased risk of experiencing adverse side effects
upon exposure. Higher concentrations of DEET are commercially available
and have been used as repellents for years.

Reactions to mosquito bites are usually mild and easily treated with
over-the-counter steroidal creams. The study also excluded individuals
who have a history of severe skin reactions to further minimize the risk
of a participant experiencing a severe physical reaction to a mosquito
bite. In addition, the study protocol was designed specifically to
minimize the likelihood that a mosquito will bite, through the use of
clear stopping rules, limited exposure periods, and paired observation;
no side effects or adverse events were reported.

To minimize the risk that study participants will be exposed to
illnesses like West Nile Virus, the study protocol called for field
tests of repellent efficacy to 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. Mosquitoes
collected during the field studies also were subjected to serologic or
molecular analyses to confirm that they were free of known pathogens.

The study protocol also included several mechanisms designed to minimize
coercive recruitment and enrollment, compensation was not considered to
be so high as to unduly influence participation, and minors and pregnant
or lactating women were explicitly excluded from volunteering (pregnancy
being confirmed by requiring all female volunteers to undergo a
self-administered over-the-counter pregnancy test on the “day of the
study”). The potential stigmatization resulting from study exclusion
was minimized by the use of so-called ‘alternate’ participants,
allowing for volunteers to withdraw or be excluded from participating
without  compromising their confidentiality. There was some question as
to the appropriate timing of such testing (Carley 2008), but no female
participant was exposed to product without first undergoing pregnancy
testing. Future trials conducted by Carroll-Loye Biological Research,
however, should use protocols and informed consent documents that
explicitly outline the nature and timing of pregnancy testing for female
participants.

Several Board members raised ethical and procedural concerns about the
numerous protocol changes present in the documents submitted to the EPA
(Carroll 2007a, 2007b) but which were not presented to the Board prior
to the conduct of the study. For example, in its initial review of
Protocol SCI-001 in January 2007, the HSRB approved a protocol that
involved the experimental administration of four compounds (three
sponsor-submitted test compounds and one comparator [3M Ultrathon;
34.34% polymerized DEET]). The study, as completed, used only two test
compounds and no comparator. Many HSRB members considered this to be a
major change in study design, a change to which the Board was unaware
until the study was completed and the data submitted for review. In
light of these concerns, the Board recommended that the EPA review
existing regulations and establish clear guidelines as to when modified
protocols should be submitted to the Board for re-review.

Finally, several Board members also voiced concerns about the type and
nature of the protocol deviations reported by Dr. Carroll to IIRB, Inc.
Many of these same deviations have occurred in completed studies
previously submitted to the Agency and the Board for review, raising
questions about the unanticipated nature of these protocol changes. It
is clearly stated in Federal regulations for research involving human
subjects that the only protocol changes that can be made without prior
IRB approval are those that are unanticipated and which are necessary to
protect the safety of trial participants. No protocol changes, reported
or not, are allowed for reasons of expedience, as appeared to be the
case here.

HSRB Consensus and Rationale

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

Board Decision Regarding Future Review of Protocols with Planned
Deviations from Prior IRB Review

Over several meetings, including the April 2008 meeting, the Board has
expressed concern with EPA submission for HSRB review of completed
studies in which planned protocol deviations were conducted prior to IRB
review and following HSRB review of the originally approved protocol.
Such actions are in violation of 40 CFR 26, Subpart K Sec. §26.1108 IRB
functions and operations.

Subpart K Sec. §26.1108 IRB functions and operations.

“In order to fulfill the requirements of this subpart, each IRB shall:

(a) Follow written procedures:

    	(1) For conducting its initial and continuing review of research
and for reporting its findings and actions to the investigator and the
institution;

(2) For determining which projects require review more often than
annually and which projects need verification from sources other than
the investigator that no material changes have occurred since previous
IRB review;

    	(3) For ensuring prompt reporting to the IRB of proposed changes in
research activity; and

    	(4) For ensuring that changes in approved research, during the
period for which IRB approval has already been given, may not be
initiated without IRB review and approval except where necessary to
eliminate apparent immediate hazards to the human subjects.”

The Board reached consensus regarding its future review procedures under
such conditions:

1. Any study executed prior to IRB approval of the Informed Consent Form
and the protocol, or changed in ways that were not approved by the IRB
will be judged by the Board as failing to meet the applicable
requirements of §40 CFR 26, subparts K.

2. If the EPA submits to the Board for review a completed protocol with
scientific deviations from the original protocol reviewed by the Board,
the EPA review of the completed protocol should provide the Board with
EPA's opinion regarding why the deviation did not meet the requirement
for re-review and why the protocol still meets the applicable
regulations.

REFERENCES

Carley, J.M., Leighton T., Walls C. 2008a. Science and Ethics Review of
AEATF Mop Scenario Design and Protocol for Exposure Monitoring. Dated
March 10, 2008.  Unpublished document prepared by Office of Pesticide
Programs, United States Environmental Protection Agency.

Carley, J.M., Leighton T., Walls C. 2008b. Science and Ethics Review of
AEATF Scenario Design and Protocol for Exposure Monitoring in Wipe
Scenarios. Dated March 10, 2008.  Unpublished document prepared by
Office of Pesticide Programs, United States Environmental Protection
Agency.

Carley, J.M. 2008. Ethics Review of Reports of Completed Carroll-Loye
Field Mosquito Repellent Efficacy Studies SCI-001.4 and SCI-001.5. Dated
March 7, 2008.  Unpublished document prepared by Office of Pesticide
Programs, United States Environmental Protection Agency.

Carley, JM and Sweeney K. 2008. Science and Ethics Review of Protocol
for Human Study of Stable Fly Repellent Performance. Unpublished
document prepared by Office of Pesticide Programs, United States
Environmental Protection Agency.

Carroll, S. 2007a. SCI-001.4: Test of DermAegis LipoDEET 302 Personal
Insect Repellent (EPA Reg. #82810-1). MRID 47322501. Dated November 27,
2007. Unpublished study report prepared by Carroll-Loye Biological
Research.

Carroll, S. 2007b. SCI-001.5: Test of Coulston’s Duranon Personal
Insect Repellent (EPA Reg. #50404-8). MRID 47322401.Dated November 27,
2007. Unpublished study report prepared by Carroll-Loye Biological
Research.

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y transmitting supplemental correspondence between Carroll-Loye
Biological Research and Independent Investigations Review Board, Inc.,
concerning SCI-001, with enclosures. Dated March 5, 2008. Unpublished
letter prepared by Carroll-Loye Biological Research.

EPA HSRB. 2007. October 24-26, 2007 EPA Human Studies Review Board
Meeting Report.

National Commission for the Protection of Human Subjects of Biomedical
and Behavioral Research. The Belmont Report:

Ethical Principles and Guidelines for the Protection of Human

Subjects of Research.  1979.
http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm

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