Final Report Dated December 13, 2010
EPA-HSRB-10-02
Paul Anastas, PhD
EPA Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: October 27-28, 2010 EPA Human Studies Review Board Meeting Report
Dear Dr. Anastas,
The United States Environmental Protection Agency (EPA or Agency) requested that the
Human Studies Review Board (HSRB) provide scientific and ethics reviews of two new and one
revised protocols for studies involving intentional exposure of human subjects to pesticides: a
proposed Carroll-Loye Biological Research, Inc. (CLBR) insect repellent efficacy study (No
Mas-003); a proposed Agricultural Handler Exposure Task Force, LLC (AHETF) scenario
measuring dermal and inhalation exposure by pesticide applicators who use backpack sprayers or
hand gun sprayers in utility rights-of-way (AHE-400); and a revised AHETF water-soluble
packaging mixing and loading scenario and protocol (AHE-120) previously reviewed by the
HSRB in June 2009.
The Agency also requested that the HSRB review a completed study of dermal and
inhalation exposure of professional janitorial workers who clean floors with an antimicrobial
pesticide product using a mop and bucket, conducted by the Antimicrobial Exposure Assessment
Task Force II (AEATF II). This study (AEA-03) was conducted after publication of the EPA's
expanded final rule for protection of subjects in human research (40 CFR 26) on February 6,
2006 (71 Federal Register 24, 6137). The data will be posted to the Biocide Handlers Exposure
Database (BHED®), and used genetically to estimate daily dermal and inhalation exposures of
those who clean floors with antimicrobial pesticides using a mop and pail.
The enclosed report provides the Board's response to EPA charge questions presented at
the October 27-28, 2010 meeting.
Assessment of Proposed Carroll-Loye Biological Research Study No Mas-003: Field Efficacy
Test of 16% Para-menthane-3.8-diol fPMD^ and 2% Lemonerass Oil Based Repellent 'No Mas'
Against Mosquitoes.
Science
The Board concluded that the protocol for the proposed field repellency study, if
modified in accordance with Agency and HSRB recommendations and conducted
accordingly, is likely to generate scientifically reliable data, useful for assessing the
efficacy of the tested material in repelling mosquitoes.
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Final Report Dated December 13, 2010
Ethics
• The Board concluded that the protocol submitted for review, if modified in accordance
with Agency and HSRB recommendations and conducted accordingly, is likely to meet
the applicable requirements of 40 CFR 26, subparts K and L.
Assessment of Pronosed AHETF Scenario and Protocol AHE-400: Backpack and Handgun
Application of Liquid Sprays in Utility Rights-of-Way.
Science
• The Board concluded the proposed backpack and handgun application scenario, if revised
as suggested and performed as described, is likely to generate scientifically reliable data
that may be useful for assessing the exposure of workers who apply pesticides in utility
rights-of-way using backpack or handgun sprayers.
Ethics
• The Board concluded that the protocol submitted for review, if modified in accordance
with Agency and HSRB recommendations and conducted accordingly, is likely to meet
the applicable requirements of 40 CFR 26, subparts K and L.
Assessment of Revised AHETF Scenario and Protocol AHE-120: Water-Soluble Packaging
Mixing and Loading.
Science
• The Board concluded the submitted protocol, if revised as suggested and performed as
described, is likely to generate scientifically reliable data that may be useful for assessing
the exposure of workers who mix and load pesticides in water-soluble packaging.
Ethics
• The Board concluded that the protocol submitted for review, if modified in accordance
with Agency and HSRB recommendations and conducted accordingly, is likely to meet
the applicable requirements of 40 CFR 26, subparts K and L.
Assessment of Completed AEATF II Research Study AEA-03: 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 (MRID 48210201.
MRID 48231201. MRID 48231901).
Science
• The Board concurred with the Agency’s assessment that the research reported in the
completed AEA-03 study report and associated supplemental documents was conducted
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Final Report Dated December 13, 2010
in a manner that was reasonably faithful to the design and objectives of the protocol and
governing documents of AEATF-II.
• The Board concluded that the Agency has adequately, if not completely, considered the
limitations on these data that should be considered when using the data in estimating
exposure of those who apply antimicrobial floor-cleaning products with mop and bucket.
Ethics
• The Board concurred with the Agency’s assessment that the study submitted for review
was conducted in substantial compliance with subparts K and L of 40 CFR 26.
• In response to a request from the study sponsor for guidance on how to provide
individual exposure data to participants once the study is complete, the Board elected to
establish a working group that could draft proposed guidance for the Agency and
sponsors, which would be reviewed by the full Board during a future HSRB meeting.
Sincerely,
ç s
Sean Philpott, PhD, MSBioethics
Chair
EPA Human Studies Review Board
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Final Report Dated December 13, 2010
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. You may obtain further
information about the EPA Human Studies Review Board from its website at
http://www.epa.gov/osalhsrb . You may also contact the HSRB Designated Federal Officer, via e-
mail at ord-osa-hsrb@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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Final Report Dated December 13, 2010
US ENVIRONMENTAL PROTECTION AGENCY
HUMAN STUDIES REVIEW BOARD
Chair
Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union
Graduate College and the Mount Sinai School of Medicine, Schenectady, NY
Vice Chair
Janice Chambers, PhD, DABT, Fellow ATS, William L. Giles Distinguished Professor, Director,
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State
University, Mississippi State, MS
Members
George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada-
Reno Center for Research Design and Analysis, University ofNevada-Reno, Reno, NV
Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor
of Health Policy and American Studies, The George Washington University, Washington, DC
Sidney Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharmacology, Howard
University College of Medicine, Washington, DC
Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University,
Manhattan, KS
Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of
Arizona, Tucson, AZ
Jose E. Manautou, PhD, Associate Professor of Toxicology, Department of Pharmaceutical
Science, University of Connecticut School of Pharmacy, Storrs, CT
Jerry A. Menikoff, MD, JD, Director, Office for Human Subjects Research, Office of the
Secretary, Department of Health and Human Services, Rockville, MD
Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH), School of Public Health and Human
Services, The George Washington University, Washington, DC
William Popendorf, PhD, MPH, Professor Emeritus, Department of Biology, Utah State
University, Logan, UT
Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care,
Veterans Health Administration, Washington, DC
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Final Report Dated December 13, 2010
Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural
Sciences, University of Florida, Gainesville, FL
Human Studies Review Board Staff
Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science
Advisor, United States Environmental Protection Agency, Washington, DC
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Final Report Dated December 13, 2010
INTRODUCTION
On October 27-28, 2010, the United States Environmental Protection Agency’s (EPA or
Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues
concerning two new protocols and one revised protocol for research involving human
participants: one new study measuring the efficacy of an insect repellent containing para-
menthane-3,8-diol (PMD) and lemongrass oil against mosquitoes under field conditions; one
new study measuring levels of exposure received by agricultural handlers when applying
commercially-available pesticides using backpack sprayers or hand gun sprayers in utility rights-
of-way, and a revised study measuring levels of exposure received by agricultural handlers when
mixing and loading pesticides using water-soluble packaging under various conditions. In
accordance with 40 CFR 26.1601, EPA sought HSRB review of these three proposed protocols.
Each of these protocols is discussed more fully below.
In addition, the Agency has data from one completed study measuring levels of exposure
received by janitorial workers when applying a commercially-available antimicrobial pesticide
using a mop and bucket. In accordance with 40 CFR 26.1602, EPA sought HSRB review of this
completed study. This completed study is discussed more fully below.
REVIEW PROCESS
On October 27-28, 2010, the Board conducted a public face-to-face meeting in Arlington,
Virginia. Advance notice of the meeting was published in the Federal Register as “Human
Studies Review Board; Notice of Public Meeting” (75 Federal Register 193, 61748).
Following welcoming remarks from Agency officials, the Board heard presentations from
EPA on the following topics: one new study protocol to measure the efficacy of an insect
repellent containing PMD and lemongrass oil against mosquitoes under field conditions; one new
study protocol for measuring levels of exposure received by agricultural handlers when applying
commercially available pesticides using backpack sprayers or hand gun sprayers in utility rights-
of-way, and a revised study protocol measuring levels of exposure received by agricultural
handlers when mixing and loading pesticides using water-soluble packaging under various
conditions. In addition, a completed study for the measurement of potential dermal and
inhalation exposure during application of a liquid antimicrobial pesticide product using a bucket
and mop was reviewed.
The Board asked clarifying questions of several individuals attending the meeting,
including:
Dr. Victor Cafiez, Technical Chair, Agricultural Handler Exposure Task Force
Dr. Scott Carroll, Study Director, Carroll-Loye Biological Research
Mr. Shawn King, Director of Operations, Carroll-Loye Biological Research
Mr. Robert Roogow, Chief Operations Officer, Independent Institutional Review Board,
Inc.
Dr. Sami Selim, Study Director, Selim & Associates
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Final Report Dated December 13, 2010
Public comments were provided by:
Dr. Victor Cafiez, Technical Chair, Agricultural Handler Exposure Task Force
Dr. Scott Carroll, Principal, Carroll-Loye Biological Research
Dr. Hasmukh Shah, Manager, AEATF
No written public comments were submitted.
For their deliberations, the Board considered the materials presented at the meeting, oral
comments, and Agency background documents (e.g., published literature, sponsor and
investigator research reports, study protocols, data evaluation records, and Agency science and
ethics reviews ofproposed protocols and completed studies). A comprehensive list of
background documents is available online at http://www.regulations.gov.
CHARGE TO THE BOARD AND BOARD RESPONSE
Assessment of Proposed Carroll-Love Biological Research Study No Mas-003: Field
Efficacy Test of 16% Para-menthane-3.8-diol (PMD) and 2% Lemongrass Oil Based
Repellent ‘No Mas’ Against MosQuitoes .
Overview of the Study
This protocol describes a study to test the repellent efficacy of a lotion formulation
containing 16% PM]) and 2% lemongrass oil (‘No Mas’) against three species of mosquitoes in
the field. As submitted to the EPA, the proposed study consists of two interdependent analyses:
1) a dosimetry study designed to determine the amount of lotion that typical users would
typically apply; and 2) an efficacy study designed to measure the effectiveness of the compound
as a repellent for those species of mosquitoes likely to be vectors for West Nile Virus (WNV) in
the United States.
Dosimetry will be determined by direct measurement of compound application. The
efficacy of the formulation as a mosquito repellent will be determined by measuring the ability of
the formulations to prevent mosquito landings under field conditions at test sites in California’s
Central Valley. The efficacy study endpoint will be the “Landing with Intent to Bite” (LIBe), and
the criterion for data to calculate complete protection time will be the first confirmed LIBe.
Science
Charge to the Board
If the proposed field repellency study protocol No Mas-003 is revised as suggested in
EPA’s review and if the research is performed as described, is the research likely to generate
scientifically reliable data, useful for assessing the efficacy of the tested material in repelling
mosquitoes?
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Final Report Dated December 13, 2010
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment that the proposed field repellency
study protocol No Mas-003, if revised as suggested in EPA’s review (Fuentes and Sherman 2010)
and performed as described, is likely to generate scientifically reliable data, useful for assessing
the efficacy of the tested material in repelling mosquitoes.
HSRB Detailed Recommendations and Rationale
Protocol No Mas-003 from Carroll-Loye Biological Research (Carroll 2010) will be
conducted using methods similar to those presented to and commented on by the Board in the
past. Apart from the new test material, the proposal is generally similar to previous Carroll-Loye
field studies reviewed by the Board.
The study protocol was relatively clear and addressed adequately a number of key
scientific issues, including: scientific justification, objectives, and data collection and
compilation methods. The Board concurred with the Agency’s assessment that the proposed field
repellency study protocol No Mas-003 is likely to generate scientifically reliable data, useful for
assessing the efficacy of the tested material in repelling mosquitoes. In addition, the Board
recommended two minor changes to the protocol and associated study documents. First, the
protocol should be amended to remove erroneous reference to spray repellents (e.g. the first
sentence on page 79, under “Rationale”; Carroll 2010, 79). Second, the Board agreed with the
Agency that reference to sample size standards is now irrelevant in lighi of recently released
repellency testing guidelines. Rather than refer to a historical standard of 6 study participants, the
proposed sample size should be large enough to be likely to yield a defmitive answer to the
research question and its size justified statistically in the protocol.
Ethics
Charge to the Board
If the proposed field repellency study protocol No Mas-003 is revised as suggested in
EPA’s review and if the research is performed as described, is the research likely to meet the
applicable requirements of 40 CFR part 26, subparts K and L?
Board Response to the Charge
HSRB Recommendation
The Board concluded that the protocol submitted for review, if modified in accordance
with EPA (Fuentes and Sherman 2010) and HSRB recommendations, is likely to meet the
applicable requirements of 40 CFR 26, subparts K and L.
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Final Report Dated December 13, 2010
HSRB Detailed Recommendation and Rationale
The submitted documents assert that the study will be conducted in accordance with the
ethical and regulatory standards of 40 CFR 26, Subparts K and L, as well as the requirements the
US EPA’s Good Laboratory Practice (GLP) Standards described at 40 CFR 160, and the
California State EPA Department of Pesticide Regulation study monitoring (California Code of
Regulations Title 3, Section 6710) (Carroll 2010). Requirements of FIFRA §12(a)(2)(P) also
apply. The protocol was reviewed and approved by an independent human subjects review
committee, Independent Institutional Review Board (HRB), Inc. of Plantation, FL prior to
submission. IIRB, Inc. is filly accredited by the Association for the Accreditation of Human
Research Protection Programs (AAHRPP). IIRB is also listed as an active Institutional Review
Board (IRB) on the Office of Human Research Protection (0HRP) website (Reg.
#10R00002954). Minutes of IIRB, Inc. meetings (Carroll 2010) and a copy of IIRB, Inc.
policies and procedures were provided to the Agency. These documents indicate that IIRB, Inc.
reviewed this protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart
A).
1. Except as noted below, the Board concurred with the conclusions and factual observations of
the ethical strengths and weaknesses of the study, as detailed in the EPA’s Ethics Review
(Fuentes and Sherman 2010). The proposed study is likely to meet the applicable ethical
requirements for research involving human subjects, in accordance with the following
criteria:
a. Acceptable risk-benefit ratio. The risks as noted in the study protocol are fivefold: 1)
allergic reaction to test materials themselves; 2) exposure to biting arthropods; 3) possible
exposure to arthropod-borne diseases; 4) physical stress from the test conditions; and 5)
psychological stress and/or breach of confidentiality for pregnancy test results. These
risks are minimized appropriately and are justified by the potential societal benefits
associated with data on the efficacy of the active ingredients, PMD and lemongrass oil, as
mosquito repellents.
• Based on toxicological data currently available for PMD and lemongrass oil,
coupled with appropriate exclusion criteria, study participantsare unlikely to be at
risk of adverse side effects with exposure.
• The study is designed to minimize the likelihood of mosquito bites, through the use
of: LIBes rather than actual confirmed bites as a study endpoint; bite removal and
joint observation; clear stopping rules; and limited periods of exposure to
mosquitoes. Study participants will be trained in proper insect observation and
handling techniques.
• Mosquito bites, should they occur, are usually mild and easily treated with over-the-
counter steroidal creams. The study will also exclude participants who have a’
history of severe skin reactions to such bites.
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• Possible exposure to vectors of arthropod-borne diseases is minimized through the
use of certified disease-free laboratory-reared insect populations, selection of field
sites in low virus areas, and limited skin exposure.
• The potential risks to participants from environmental stress are minimized by the
provision of a climate controlled rest area, food, water and medical supplies, and by
careful monitoring for signs of dehydration, heat stress and hypothermia.
Appropriate stopping rules and medical management procedures are in place.
• Minor and pregnant or lactating women are excluded from participation, with
pregnancy either confirmed by over-the-counter pregnancy testing on the day of
study or by opt-out. Only volunteers scored as non-pregnant will be allowed to
participate. Information regarding pregnancy test results will be kept confidential.
b. Voluntary and informed consent of all participants
• There is the possibility that the participants in this study might represent particularly
vulnerable populations, susceptible to coercion and undue influence. The study
protocol, however, includes several mechanisms designed to minimize coercive
recruitment and enrollment.
• The informed consent materials, if changed as recommended by the HSRB below, will
adequately inform the subjects of the Eisks, discomforts and benefits from participation,
and of their right to withdraw.
• Monetary compensation is not so high as to unduly influence participants.
c. Equitable selection of study participants
• The majority of research participants will be recruited from the University of California
at Davis student population. Study participants are likely to represent the appropriate
ethnic and racial diversity of individuals in and around the University, but the use of
this convenience sample may limit the broad applicability of the study results to the
general population. The investigators have noted this fact in the protocol (Carroll 2010).
2. The Board recommended that the study protocol be modified to address the concerns noted in
the EPA’s Ethics Review (Fuentes and Sherman 2010). In addition, the Board also raised the
following concerns:
• The Board concurred with the Agency’s recommendation that the protocol be revised to
exclude as participants employees of the study sponsor. The Board added the
recommendation that this exclusion also be extended to dependents of the study sponsor or
sponsor employees.
• The consent form and protocol should be modified as follows:
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Final Report Dated December 13, 2010
1) Carroll-Loye should add “child/minor” to the list of exclusion criteria.
2) The term “treatment” is used ambiguously throughout the protocol and informed
consent form to describe both the application of the test materials and treatment for
research-related injuries. For example, on page 23 the protocol states that
“application of a test material is considered a treatment” (Carroll 2010, 23).
Elsewhere, however, the protocol states that “candidates are again encouraged to
ask any questions they have about the study, which may include understanding
treatment and compensation for injury more fully” (Carroll 2010, 17, 238). This
ambiguity should be resolved with the use of a different term to describe the
application of test materials.
3) On page 16, the protocol states that “. . .dosimetry subjects may be consented before
repellency subjects. Untreated control subjects for the repellency phase (field study)
are consented before the treated subjects for that phase...” (Carroll 2010, 16). The
verb “to consent” is an intransitive verb; from a grammatical point of view,
someone cannot “be consented.” From an ethical perspective, this infelicitous use of
the verb also employs the passive voice, which is not best practice when the issue is
to affirm that researchers will be accountable for obtaining informed consent. It is
recommended that the protocol be modified to use alternate phrasing such as
“Researchers may obtain informed consent from dosimetry subjects before
repellency subjects . . .“
4) Carroll-Loye should spell out the acronym “PMD” when it is first used in the
protocol and consent form.
5) On page 2 of the consent form, the phrase “You have been offered an opportunity to
participate in this research study because ...“ (Carroll 2010, 199, 209, 219) be
modified by Carroll-Loye to minimize the impression that participation in this
intentional exposure study is somehow a beneficial or favorable occasion. A neutral
alternative might be: “We are asking you to participate in this research study
because...”
6) A description of the symptoms of heat stress and equine encephalitis should also be
included in the consent form. Currently, only the symptoms of West Nile Virus are
listed.
Assessment of ProDosed AHETF Scenario and Protocol AHE-400: Backpack and Handgun
ADDlication of Liguid SDrays in Utility Rights-of-Way .
Overview of the Study
This proposal presents an agricultural handler exposure scenario involving backpack and
handgun application of liquid pesticides along utility rights-of-way. The protocol calls for study
participants to apply (and potentially load) four surrogate pesticides (fosamine, glyphosate,
imazapyr and 2,4-D). A total of2l participants (described in the protocol as “Monitoring Units”
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Final Report Dated December 13, 2010
[ MUs]) will be observed for each scenario; three volunteers each from seven geographically
distinct growing regions will be enrolled using a purposive sampling method (with some
elements of random selection).
Dermal exposure will be measured by a whole body dosimeter (WBD) worn beneath the
subject’s outer clothing. Hand wash and face/neck wipe samples will also be collected prior to,
during, and after completion of pesticide loading and mixing procedures. Airborne
concentrations of the surrogate will be monitored in the participant’s breathing zone using an
OSHA Versatile Sampler (OVS) tube sample collector connected to a personal sampling pump.
Additional measures will also record environmental conditions at the time of monitoring, and
observers will make field notes, photographs and videos of participant activity throughout the
monitoring event.
The results of sample analysis under the backpack and handgun application scenario will
be posted to the AHED® database, where they will be available to the EPA and other regulatory
agencies for statistical analysis. The proposed documentation will report a confidence-interval-
based approach to determine the relative accuracy for the arithmetic mean and 95 th percentile of
unit exposures. The Agency proposes to use these data to estimate daily dermal and inhalation
exposures of agricultural handlers who are applying pesticides using backpack and/or handgun
applicators under a variety of scenarios.
Science
Charge to the Board
If the proposed AHETF Right-of-Way application scenario and field study proposal
AHE400 is revised as suggested in EPA’s review and if the research is performed as described, is
the research likely to generate scientifically reliable data, useful for assessing the exposure of
workers who apply pesticides in utility rights-of-way using backpack or handgun sprayers?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment that the proposed AHETF Right-of-
Way application scenario and field study proposal AFIE400, if revised as suggested in EPA’s
review (Evans and Sherman 2010a) and performed as described, may generate scientifically
reliable data useful for assessing the exposure of workers who apply pesticides in utility rights-
of-way using backpack or handgun sprayers.
HSRB Detailed Recommendations and Rationale
Given the lack of existing reliable and sound data in this area, the Board concurred with
the Agency’s assessment (Evans and Sherman 2010a) that this protocol will likely generate data
that may be useful for assessing the exposure of handlers who apply pesticides using backpack or
handgun sprayers.
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The study, if conducted as described, will provide newer exposure information on dermal
arid inhalation exposures of pesticide handlers using backpack sprayers and handgun sprayers
treating utility rights-of-way in appropriate and distinct geographic locations; some study partic-
ipants will be exposed during loading $ckpacks or tanks as well. The Board agreed with the
Agency’s assessment that the protocol adequately addresses a number of scientific questions, in-
cluding having clear scientific objectives, a reasonable experimental design for achieving these
objectives: appropriate quantification of test materials, adequate procedures for collecting, com-
piling and summarizing test results, appropriate justification for selection of test substances,
sample size, and study site selection, and acceptable QA/QC procedures.
However, the Board noted a few weaknesses in the proposed study design. In particular,
the variability in individual dermal and inhalation exposure levels may be extremely high be-
cause of the diversity of terrains and locations selected for the study and the opportunity for large
(but potentially categorical) personal differences in application practices. As such, results may
not be reproducible should the study be repeated. The proposal to impose a minimum exposure
duration of at least 4 hours will also create opportunities for the applicator’s exposures to be in-
fluenced by variables that by theft nature are likely to be unrelated to the amount of active ingre-
dient handled (AaiH). Should this diversity yield high variability in the data sets, then the pro-
portionality of exposure with AaiH may not be apparent. If the 4-hour minimum is not removed,
the Task Force may want to ensure that field notes are adequate to report time-on-task as a frac-
tion of the total monitored time for use in later data analysis and usage within Al-LED. The ratio-
nale for having and using this “fraction” is discussed more fully in the Board’s discussion of pro-
tocol AFIEI2O below. Even if the proportionality hypothesis is not supported by the resultant da-
ta sets, these data are likely to still be useful and relevant to assessing the levels of exposure to
workers applying pesticides to utility rights-of-way.
Ethics
Charge to the Board
If the proposed AHETF Right-of-Way application scenario and field study proposal
AHE400 is revised as suggested in EPA’s review and if the research is performed as described, is
the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L?
Board Response to the Charge
HSRB Recommendation
The Board concluded that the protocol submitted for review, if modified in accordance
with EPA (Evans and Sherman 2010a) and HSRB recommendations, is likely to meet the
applicable requirements of 40 CFR 26, subparts K and L.
HSRB Detailed Recommendation and Rationale
The submitted documents assert that the revised study will be conducted in accordance
with the ethical and regulatory standards of 40 CFR 26, Subparts K and L, as well as the
requirements the US EPA’s GLP Standards described at 40 CFR 160 (AHETF 2010a; Collier
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Final Report Dated December 13, 2010
2010a). FIFRA §12(a)(2)(P) also applies. The protocol was reviewed and approved by an
independent human subjects review committee, IIRB, Inc. of Plantation, FL prior to submission.
Minutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures were provided.
This IRB is fully accredited by AAHRPP and listed by OHRP (see details above).
1. Except as noted below, the Board concurred with the conclusions and factual observations of
the ethical strengths and weaknesses of the study, as detailed in the EPA’s Ethics Review
(Evans and Sherman 2010a). The proposed study is likely to meet the applicable ethical
requirements for research involving human subjects, in accordance with the following
criteria:
a. Acceptable risk-benefit ratio. Risks as noted in the study protocol are four-fold: 1) heat-
related illness; 2) injury associated with scripted field activities; 3) allergic reaction to
surfactants used for hand washing; and 4) psychological stress and/or breach of
confidentiality for pregnancy test results. These risks are minimized appropriately and are
justified by the potential societal benefits, particularly data for new exposure assessments
for occupational risks associated with spraying pesticides to rights-of-way using
backpack and handgun sprayers.
• Only experienced pesticide handlers, with specific experience with the type of
application equipment to be used, and who consider themselves to be in good
health, will be enrolled.
• Risk of heat-related illness is minimized appropriately. Heat index will be
monitored with an associated stopping rule. A medical professional will be on site
to observe the workers and provide urgent care. Nearby medical facilities have been
identified in case of emergency, and transportation to medical treatment will be
provided, if needed.
• Subjects will be reminded about safe chemical handling practices and procedures,
wearing appropriate personal protective equipment (PPE), and will be monitored for
any accidental or unintended product exposure.
• Minors and pregnant or lactating women are excluded from participation, with
pregnancy either confirmed by over-the-counter pregnancy testing on the day of
study or by opt-out. The potential stigma resulting from study exclusion due to
pregnancy is appropriately minimized.
The Board disagreed with the AHETF conclusion, however, that “the risk of toxicity from
pesticide handling [ is not] strictly due to study participation [ and therefore], the risk of
surrogate toxicity will not be listed in consent forms or this protocol” (Collier 2010a,
309). This study is subject to 40 CFR 26 subparts K and L precisely because it is
considered to be a study in which the subjects are “intentionally exposed,” for research
purposes, to pesticides. Given its scripted nature, the AHETF protocol influences the
behavior of workers and their employers in a number of ways. That a particular
agricultural worker will be applying a particular pesticide on a particular day is due, to a
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Final Report Dated December 13, 2010
large extent, to the fact that the study is being conducted. Accordingly, the risk from
exposure to the pesticides being applied should clearly be categorized as a risk of study
participation.
The Board does agree, however, that the risk from exposure to those pesticides is a
reasonable one, and that it has been appropriately minimized. The products being used in
this study are ones already registered by EPA for vegetation control in rights-of-way, and
will be applied in accordance with label requirements.
b. Voluntary and informed consent of all participants
• There is the possibility that the participants in this study might represent particularly
vulnerable populations, susceptible to coercion and undue influence. The study
protocol, however, includes several mechanisms designed to minimize coercive
recruitment and enrollment.
• The informed consent materials, if changed as recommended by the HSRB below, will
adequately inform the subjects of the risks, discomforts and benefits from participation,
and of their right to withdraw.
• Monetary compensation is not so high as to unduly influence participants.
• Spanish translations of the informed consent documents, informational packets, and
recruitment flyers were provided. Researchers will be working with local Spanish-
speaking community members to ensure that the appropriate regional dialect of Spanish
is used (AHETF 20 lOb).
c. Equitable selection of study participants
• The study is designed to recruit an appropriately diverse population of participants who
represent skilled workers in the study locations.
• The study will first involve identifying and contacting the employers involved in right-
of-way application of pesticides. Only employees of these employers are eligible to be
recruited. The recruitment process has been carefully designed to assure that employees
will not be coerced into participating: recruitment will take place using brochures and
meetings with employees at which the employer and supervisors will not be present.
2. The Board recommended that the study protocol be modified to address the concerns noted in
the EPA’s Ethics Review (Evans and Sherman 201 Oa). In addition, the Board also raised the
following concerns:
• As noted above, the Board concluded that the risk of toxicity from pesticide handling is
indeed a risk of participating in the study, and accordingly it should be described as such,
and discussed appropriately, in the consent form.
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• The consent form should explain that the pregnancy test will be provided by the
researchers, and explain when it will take place.
• There appears to be a discrepancy between the exclusion criteria stated in the EPA review
(Evans and Sherman 2010a, 36), which refer to training in handling pesticides, and the
AHETF-provided consent form (AHETF 2010a, 267), which notes that the subject might
need only to confirm that “you are not required to take this training.” This discrepancy
should be clarified.
• Study participants will undergo hand washes prior to eating anything, which will reduce
their risk of accidental ingestion of the surrogate compounds. As many of the adults in the
US still smoke, however, hand washes should also occur before any smoking break to
further reduce participant’s risk of accidental pesticide ingestion.
Assessment of Completed AEATF II Research Study AEA-03: AStudv for Measurement of
Potential Dermal and Inhalation Exposure during Application of a Liquid Antimicrobial
Pesticide Product Using Bucket and Mo Equipment for Cleaning Indoor Surfaces (MRID
48210201. MRID 48231201. MRID 4823190fl .
Overview of the Study
The objective of this study was to measure individual exposures to a surrogate
antimicrobicidal pesticide (didecyl dimethyl ammonium chloride; DDAC) while mopping floors
and emptying mop buckets. Eighteen volunteers participated in the study, mopping floors in one
of three building types (an office building, a Rite Aid pharmacy building, or a retired teacher’s
memorial building in Fresno, CA) for one of six pre-determined mopping times (30-40, 40-50,
50-60, 60-70, 70-80 and 80-90 minutes total mopping time, respectively).
Dermal and inhalation exposure monitoring was conducted while study participants
mopped floors and emptied the mop buckets; all participants wore long-sleeved shirts, long
pants, shoes, socks, and no gloves. Dermal exposure was measured by inner and outer body
dosimeters. Airborne concentrations of the surrogate compound were monitored in the
participant’s breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector
connected to a personal sampling pump. Environmental conditions were also recorded at the time
of monitoring, and observers made notes, photographs and videos of participant activity
throughout the mopping period.
These exposure data will be used to populate a database representing inhalation and
dermal exposure during a number of antimicrobial handler scenarios. A scenario is defmed as a
pesticide handling task based on activity (e.g., application) and equipment type (e.g., mop &
bucket, ready-to-use wipes, pressure treatment of wood facilities, painting). These data will be
used by the Agency to estimate dermal and inhalation exposures of antimicrobial handlers who
are applying pesticides using a mop and bucket under a variety of scenarios.
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Science
Charges to the Board
1) Was the research reported in the Antimicrobial Exposure Assessment Task Force II (AEATF—
II) completed study report AEA-03 and associated supplemental reports faithful to the design
and objectives of the protocol and governing documents ofAEATF-II?
2) Has the Agency adequately characterized, from a scientific perspective, the limitations on
these data that should be considered when using the data in estimating exposure of those who
apply antimicrobial floor-cleaning products with mop and bucket?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Leighton 2010) that the research
reported in the completed AEA-03 study report and associated supplemental documents (Selim
and Taylor 2010a, 20 lOb, 2010c) was conducted in a manner that was reasonably faithful to the
design and objectives of the protocol and governing documents of AEATF-H. The Board also
concluded that the Agency has adequately, if not completely, considered the limitations on these
data that should be considered when using the data in estimating exposure of those who apply
antimicrobial floor-cleaning products with mop and bucket.
HSRB Detailed Recommendations and Rationale
The study was conducted in a manner that was reasonably faithful to the design of the
protocol and governing documents. The study report (Scum and Taylor 201 Oa) contains sections
that adequately describe the test substance, recruitment procedures, field procedures, sample
collection and handling, sample analysis, and data analysis. Previous Board recommendations
(EPA HSRB 2008) for the use of a double layer of socks and provision of more detail about staff
activities during the observation period were adopted. Appropriate rationale for changes in key
elements of the study design, including justification for the purposive sampling of monitoring
events (MEs) and the sample size of 18, was also provided. Finally, assuming that only one
participant was present in the cluster when an ME was conducted, it also appears that no
participant observed another participant’s activities during the study, as previously
recommended. However, some of the issues raised by the Board in its initial review of the mop
and bucket scenario (EPA HSRB 2008) were not addressed, including: the bases for the 90-
minute maximum mopping period choice, the possibility (or not) of “carry-over effects” between
MEs, and the interaction between aerosolized particles, heating, ventilation and air conditioning
(HVAC) systems, and inhalation exposure estimates. Although the importance of measuring the
impact of HVAC systems on inhalation exposures was mentioned in the protocol (Selim and
Taylor 2010a, 28), it was not given appropriate attention nor were HVAC operations consistently
documented during the conduct of the study.
The study was also conducted in a manner that was reasonably faithful to the objectives
of the protocol and governing documents. As stated in the fmal report, the study was conducted
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primarily to “determine potential dermal and inhalation exposures to professional janitorial
workers when mopping indoor surfaces with a liquid antimicrobial pesticide product containing
didecyl dimethyl ammonium chloride (DDAC)” (Selim and Taylor 2010a, 28). Dermal exposures
were reported, with estimates based on total collected residue from all matrices (face and hand
wipes, socks, and all parts of the inner dosimeter). Dermal exposures were expressed as
micrograms of active ingredient (Al) handled per subject and as milligrams of A! per
subject/pound of Al applied. Inhalation exposure was also presented as units of concentration.
However, sufficient data is available (i.e., the duration of each exposure) to express those results
in the same units as dermal exposures if an average respiratory minute volume for the applicators
is also applied to the calculation.
The overall study objective was listed differently in the Agency’s scientific review than in
the protocol, stating it as: “the study objective is to monitor inhalation and dermal exposures to
be used as inputs in exposure algorithms to predict future exposures to persons mopping floors.”
(Leighton 2010, 5). The Agency added two sub-objectives not found in the protocol: “to be 95%
confident that key statistics of normalized dermal exposure are accurate within 3-fold” and “to
evaluate the presumption of proportionality between exposure and amount of active ingredient
handled,” respectively. The Agency provided a thorough assessment of their first sub-objective
supporting the sample size and analyses used to achieve the 3-fold accuracy goal. However,
although the presumption of proportionality was demonstrated for dermal exposure and the
amount of A! handled, the rationale supporting the presumption of proportionality for inhalation
exposure needs to be recalculated to include duration of exposure.
The Agency’s scientific review (Leighton 2010) discussed the limitations of the dermal
and inhalation exposure data. The Agency also presented alternative models for estimating
dermal and inhalation exposures, evaluated the impacts of non-detects and of assigning low
limits of quantification (LOQs) at 3 different values (0, V 2 and full LOQ). The Agency concluded
that dermal exposures and pounds of active ingredient are related in a proportional manner, while
accounting for sampling efficiency and normalizing the data in terms of milligrams/pounds of
active ingredient applied. The Agency also discussed the dermal exposure estimates in
relationship to its sub-objectives of the study (accuracy within 3-fold and proportionality). Their
assessment acknowledged that some estimates included a high level of uncertainty and some
bias. The Board concluded that the Agency adequately, if not completely, considered limitations
in its interpretation and subsequent estimates of dermal exposure data. The Agency should
carefully examine the handwash data, however, to ensure that it does not overcorrect for face and
neck residue estimates. Additionally, the model may not always support the conclusion of
proportionality for all clothing configurations.
With respect to limitations of the inhalation exposure data due to study deviations, some
(but not all) of the limitations that need to be considered when estimating inhalation exposure
were discussed. In its initial 2008 review (EPA HSRB 2008), the Board noted several factors that
could influence these estimates, including: ventilation, room temperature, total area mopped,
duration of mopping, and volume of the enclosed space and respiration rate of the study
participants. Although the fmal study report provides some of these data for the facilities in
which mopping activities were conducted (Selim and Taylor 2010a, 105-7), neither ventilation
data nor a discussion of these factors were provided, thus limiting the Board’s and Agency’s
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ability to interpret fully the reported environmental data. Furthermore, the rationale for the
Agency’s conclusion that air changes per hour was not a significant factor influencing inhalation
exposure estimates, based on the low vapor pressure of DDAC and the LOQs observed, does not
recognize fully how HVAC parameters could have affected reported air concentrations from
mopping activities. The Agency also failed to consider whether the limited areas available for
mopping in Clusters 1 and 3 could have compromised the study design or affected inhalation
exposure estimates. Similarly, although surface areas of the floors mopped were noted, the
ceiling heights were not reported. The Agency’s review also fails to consider the impact that
ceiling height and room volume may have had on the reported air concentration data. The
respiration rates of study participants were not discussed by the Task Force researchers or the
Agency; ignoring this factor could introduce important uncertainties into exposure estimates.
Finally, the Board’s previous recommendation to consider particle size (e.g.,whether DDAC is
aerosolized) and its potential impact on inhalation exposures were not addressed by the Agency.
Although not discussed in detail by the Board at the October 2010 meeting, several of these
factors are discussed in a separate report (submitted independently by an HSRB member to the
Agency).
Ethics
Charge to the Board
Does available information support a determination that the study was conducted in
substantial compliance with subparts K and L of 40 CFR Part 26?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Carley 2010) that the study was
conducted in substantial compliance with subparts K and L 40 CFR 26.
HSRB Detailed Recommendation and Rationale
The documents provided by Golden Pacific Laboratories, LLC, under Project No. AEA-
03, state that the study was conducted in compliance with the requirements of 40 CFR 26
subparts K, L and M; FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3,
Section 6710 (Selim and Taylor, 2010a, 2010b, 2010c). The protocol was reviewed and approved
by an independent human subjects review committee, IIRB, Inc. of Plantation, FL prior to
submission. Minutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures
were provided. This IRB is fully accredited by AAI-LRPP and listed by OFIRP (see details above).
1. The Board concurred with the conclusions and factual observations relating to the study, as
detailed in the EPA’s Ethics Review (Carley 2010) and summarized briefly below.
a. Prior HSRB and Agency Review. Because this study was initiated after 7 April 2006,
prior submission of the protocol and supporting materials to EPA was required by 40
CFR §26.1125. The requirements of 40 CFR §26.1125 for prior submission of the
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protocol to EPA and of §26.1601 for HSRB review of the protocol were satisfied. The
scenario design and study were approved by IIRB, Inc. and submitted to the EPA in
February 2008. The HSRB discussed the protocol at its April 2008 meeting, concurring
with the Agency’s assessment that the proposed mop and wipe scenario, if revised as
suggested by the Agency and the HSRB, would meet the applicable requirements of 40
CFR part 26, subparts K and L.
b. Responsiveness to HSRB and Agency Recommendations.
The Agency’s initial ethics review noted two deficiencies to be corrected before the study
was initiated. The first focused on measures to improve the informed consent process for
Spanish-speaking candidates. The Agency called for the candidate interviews for Spanish
speakers to be conducted by a member of the research team fluent in Spanish, rather than
an independent translator. The second deficiency focused on references in the informed
consent forms to “normal business hours”. The Agency asked that the researchers revise
the consent form to show hours for calling in local (Pacific) time.
In the revisions submitted to IIRB, Inc. in February 2009, the researchers addressed these
ethical concerns. Because the study was conducted in California, the approval of the
California Department of Pesticide Regulation (CDPR) was also required. CDPR granted
final approval of the amended protocol and supporting documents in April 2009.
c. Responsiveness to HSRB and Agency Reviews. The Agency’s and HSRB’s comments
were satisfactorily addressed in the revisions approved by the IIRB in March 2009 (Selim
and Taylor 2010a).
At its April 2008 meeting, the HSRB made several specific recommendations for
refinements of the study. As noted in Amendment 4 of the Agency’s ethics review
(Carley 2010), the investigators addressed fully most of these recommendations,
addressed partially some of these recommendations, and did not address two of these
recommendations. The Board agreed with the Agency conclusion, however, that the
investigators’ failure to address all of the recommendations did not violate applicable
ethical standards for the protection of human participants of research.
d. Substantial Compliance with Reporting Requirements (40 CFR §26 subpart M).
The study sponsor initially did not provide adequate documentation to demonstrate that
they had satisfied the requirements of §26.1303. The initial report (Selim and Taylor,
2010a) contained several reporting deficiencies, including: inadequate documentation of
interaction between the investigators and the overseeing IRB, incomplete study
chronology, and a lack of tracked consent forms showing how they were revised to
address Agency and HSRB concerns. These deficiencies were corrected by the
submission of supplemental documents (Selim and Taylor, 2010b, 2010c).
IRB minutes documenting discussion and review of these revised documents were not
provided for review. All IIRB, Inc. reviews subsequent to the HSRB’s April 2008
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Final Report Dated December 13, 2010
meeting were conducted using an expedited procedure and did not require a full meeting
of the IRB. Neither the IRB roster nor the operational procedures were submitted as part
of the study documents.
The HSRB agreed with the Agency that these deficiencies in the conduct and the
documentation of the research did not compromise the ethical conduct of the study, and
concluded that the requirements of 40 CFR §26.1303 were satisfactorily addressed. The
HSRB did recommend, however, that the Agency require the submission of reports for all
research that undergoes expedited IRB review in the future.
2. The Board concluded that this study, as conducted, met all applicable ethical requirements for
research involving human participants, in accordance with the following criteria that had
been stated in the Board’s prior review of this protocol (EPA HSRB 2008).
a. Acceptable risk-benefit ratio. The risks to study participants were minimized
appropriately and were justified by the potential societal benefits, particularly data on the
dermal and inhalation exposure of professional janitorial workers to antimicrobial
pesticides as they mopped indoor floors and disposed of spent mop water. These data
could be used to develop mechanisms to protect future users of these antimicrobial
pesticides.
• Minors and pregnant or lactating women were excluded from participation, with
pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by
opt-out. The potential of stigma resulting from study exclusion was also appropriately
minimized.
• Clear stopping rules and medical management procedures were in place, and no adverse
events or other incidents of concern related to product exposure were reported.
• The study was designed to minimize the risks of exposure to the test compounds.
b. Voluntary and informed consent of all participants
• The study protocol included several mechanisms designed to minimize coercive
recruitment and enrollment.
• Monetary compensation was not so high as to unduly influence participation.
3. Three minor protocol deviations were reported. These included: 1) most study participants
declining to take rest breaks or taking less than the 10 minutes provided for in the protocol;
2) full facial photographs taken of participants at one monitoring site; and 3) enrollment of
participants who self-reported that their health was only “fair,” despite the requirement that
all participants be in “good health” (Selim and Taylor, 2010b, 31). The Board concluded,
however, that these minor deviations did not affect the integrity of the research or the safety
of participants. The Board did recommend, however, that sponsors clarify the criteria used to
establish participants’ health status prior to study enrollment.
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Assessment of Revised AHETF Scenario and ProtocolAHE-120: Water-Soluble Packaging
Mixing and Loading .
Overview of the Study
This revised proposal presents an agricultural handler exposure scenario involving
mixing/loading of pesticides enclosed in water-soluble packets (WSP). The original protocol,
which was favorably reviewed by the Board at its June 2009 meeting (EPA HSRB 2009), called
for study participants to mix and load one of two WSP-enclosed surrogate pesticides (acephate
and carbaryl) into a variety of tanks containing water in a variety of agricultural spraying
operations. Carbaryl in water-soluble packaging is no longer being produced by pesticide
manufacturers; however, the AHETF proposed substituting three additional surrogate compounds
for carbaryl: dithiopyr, imidacloprid, and thiophanate-methyl. Because of use patterns of these
surrogate compounds, the AI-IETF also identified additional study sites. The previously reviewed
study was to be conducted at three cool dry sites in Michigan, New York, and Washington State,
one hot humid site in Louisiana, and one hot dry site in California. The revised protocol will also
be conducted at five sites, including two cool dry sites in New York and North Dakota, two hot
humid sites in Florida and Louisiana, and one hot dry site in California.
A total of 25 participants (described in the protocol as “Monitoring Units” [ MUs]) will be
observed; five volunteers each from five different growing regions will be enrolled using a
purposive sampling method. Dermal exposure will be measured by a whole body dosimeter
(WBD) worn beneath the subject’s outer clothing. Hand wash and face/neck wipe samples will
also be collected prior to, during, and after completion of pesticide loading and mixing
procedures. Airborne concentrations of the surrogate will be monitored in the participant’s
breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector connected to a
personal sampling pump. Additional measures will also record environmental conditions at the
time of monitoring, and observers will make field notes, photographs and videos of participant
activity throughout the monitoring event.
The results of sample analysis under the mixing/loading of water-soluble packets
scenario, and will be posted to the AHED® database, where they will be available to the EPA
and other regulatory agencies for statistical analysis. The Agency proposes to use these data to
estimate daily dermal and inhalation exposures of agricultural handlers who are mixing/loading
pesticides in water-soluble packets under a variety of mixing and loading scenarios.
Science
Charge to the Board
If the revised AHIETF scenario and field study proposal ARE 120 is revised as suggested
in EPA’s review and if the research is performed as described, is the research likely to generate
scientifically reliable data, useful for assessing the exposure of handlers who mix and load
pesticides in water-soluble packaging?
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Final Report Dated December 13, 2010
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Evans and Sherman 20 lOb) that this
protocol will generate data that are scientifically valid and that may be useful for assessing the
exposure of handlers who mix and load soluble or wettable powder pesticides in water-soluble
packaging. The Board cautioned, however, that these data might not be useful for creating
distributions of worker exposure that are scientifically accurate or that are precise.
HSRB Detailed Recommendations and Rationale
The protocol is largely the same as when it was first reviewed by the HSRB in June 2009
(EPA HSRB 2009). The major changes are that one of the surrogate active ingredients (carbaryl)
was deleted and three other active ingredients (dithiopyr, imidacloprid, and thiophanate-methyl)
were added. This change necessitated revising the geographical regions in which the study could
be conducted and a slight lowering of each of the five strata in the amounts of active ingredient
handled.
Each of these changes seems justified. Assuming that the AHETF can provide adequate
evidence of the validity of the analytical methods for each of the new compounds, the revised
study protocol still allows a good probability of the study successfully obtaining its primary and
secondary objectives (i.e., “that selected lognormal-based estimates of normalized dermal expo-
sure distribution be accurate to within 3-fold, at least 95% of the time,” and the ability to distin-
guish “a proportional from an independent relationship between exposure and AaiH,” respective-
ly [ Evans and Sherman 2010b, 28-9]).
However, the Board pointed out that many of the same concerns it raised in June 2009
remain for the revised protocol. Of particular note is the conflict between the non-random, pur-
posive study design and the statistical methods proposed to analyze the exposure data. Moreover,
the protocol does not control for ecological, engineering, and statistical factors that may obscure
a linear relationship between AaiFI and worker exposure. Previously the Board said that “there is
no statistical theory that can be applied to non-random samples of this type. Thus, the statistical
analyses proposed, including mixed model approaches, are not valid” (EPA HSRB 2009, 34). In
contrast to the prior version, this protocol indicates that AHETF will not statistically analyze the
monitoring data; that begs the question as to what statistical methods are appropriate to use on
these data.
The Board also raised one new concern regarding the potentially adverse impact of the
protocol’s exposure duration of at least 4 hours for all of the MUs. This constraint seems unne-
cessary and may introduce unintended and undesired variability into the results. The Board
noted that scripting activities to include more time than would otherwise be required to apply the
amount of active ingredient in the designated stratum is likely to change the applicator’s expo-
sures by introducing variables that by their nature are unrelated to the AaiH. In particular, other
tasks within those hours are likely to result in the transfer of active ingredient either to or from
other surfaces from or onto the subject. For this study, the fraction of the total monitored time
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Final Report Dated December 13, 2010
that is time on-task is likely to be highly variable, probably among strata (particularly if the ar-
tificial constraint on the minimum time monitored affects the low Aa1H preferentially) and poten-
tially even within strata. While omitting this time constraint would avoid these random variables,
the Board recommended that all field notes for this study report the time on-task as a fraction of
the total monitored time, and that the total monitored time and the fraction of the total time on-
task be tabulated for this study. This fraction can be used later by the Agency, sponsors and
AHED users to reliably extrapolate from the time-weighted average concentrations or rates of
exposure measured by the existing protocols to task-specific concentrations or rates of dermal
and inhalation exposure per AaiH.
Ethics
Charge to the Board
If the revised AFIETF scenario and field study proposal Al-IE 120 is revised as suggested
in EPA’s review and if the research is performed as described, is the research likely to meet the
applicable requirements of 40 CFR part 26, subparts K and L?
Board Response to the Charge
HSRB Recommendation
The Board concluded that the protocol submitted for review, if modified in accordance
with EPA (Evans and Sherman 20 lOb) and HSRB recommendations, is likely to meet the
applicable requirements of 40 CFR 26, subparts K and L.
HSRB Detailed Recommendation and Rationale
The submitted documents assert that the revised study will be conducted in accordance
with the ethical and regulatory standards of 40 CFR 26, Subparts K and L, as well as the
requirements the US EPA’s GLP Standards described at 40 CFR 160 (AHETF 2010c; Collier
2010b). FIFRA §12(a)(2)(P) and the California State EPA Department Of Pesticide Regulation’s
study monitoring requirements (California Code of Regulations Title 3, Section 6710) also apply.
The protocol was reviewed and approved by an independent human subjects review committee,
IIRB, Inc. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and a copy of
IIRB, Inc. policies and procedures were provided. This IRB is fully accredited by AAFIRPP and
listed by OI-IRP (see details above).
1. Except as noted below, the Board concurred with the conclusions and factual observations of
the ethical strengths and weaknesses of the revised study, as detailed in the EPA’s Ethics
Review (Evans and Sherman 201 Ob). The proposed study is likely to meet the applicable
ethical requirements for research involving human participants, in accordance with the
following criteria:
a. Acceptable risk-benefit ratio. Risks as noted in the study protocol are four-fold: 1) heat-
related illness; 2) injury associated with scripted field activities; 3) allergic reaction to
surfactants used for hand washing; and 4) psychological stress and/or breach of
confidentiality for pregnancy test results. These risks are minimized appropriately and are
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Final Report Dated December 13, 2010
justified by the potential societal benefits, particularly data on occupational exposure of
agricultural workers to pesticides during mixing and loading activities.
The greatest risk to participants is that of heat-related illness, given that the
participants will be required to wear two layers of clothing during the scenario
activities. This risk is lessened but not eliminated by the application of appropriate
stopping rules (including cessation of all monitoring activities when the ambient
heat-index exceeds 105°F) and frequent monitoring of participants. Participants will
be given frequent breaks, access to ample amounts of water or sports drinks, and
educated about the dangers and symptoms of heat-related illness. Appropriate
medical management procedures are also in place.
• The surrogate materials consist of four common pesticides: acephate, dithiopyr,
imidacloprid, and thiophanate-methyl. The participants will only be exposed to
concentrations of the surrogate compound at accepted exposure thresholds.
• Participants will be selected from volunteers with experience handling these or
similar compounds in WSP mixing and loading scenarios. Thus, all of the
participants will have extensive experience in using these or similar products, and
thus will be unlikely to misuse them in a way that might increase their likelihood of
being accidentally exposed.
• Participants will be reminded about safe handling practices and procedures, about
wearing appropriate PPE, and will be monitored for any accidental or unintended
product exposure.
• Allergic reactions to the surfactants used in hand washing are usually mild and
easily treated with over-the-counter steroidal creams. The study will exclude
participants who have a history of severe skin reactions to such detergents.
• Minors and pregnant or lactating women are excluded from participation, with
pregnancy either confirmed by over-the-counter pregnancy testing on the day of
study or by opt-out. The potential stigma resulting from study exclusion due to
pregnancy is also appropriately minimized.
Several members noted, however, that exposure to the surrogate chemicals is no longer
listed as a potential risk to study participants in either the protocol or in the informed
consent documents. Study volunteers, it was argued, are likely to handle these chemicals
as part of their daily activities and the possibility of exposure is thus a risk of
employment and not a risk of study participation. However, because of the nature of the
study (including scripted handling of specific amounts of chemical), the Board felt that
exposure to the surrogate chemicals was a potential risk of study participation and
recommended that the sponsor explicitly list this risk in the protocol and informed
consent documents.
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b. Voluntary and informed consent of all participants
There is the possibility that the participants in this study might represent particularly
vulnerable populations, susceptible to coercion and undue influence. The study
protocol, however, includes several mechanisms designed to minimize coercive
recruitment and enrollment.
• Monetary compensation is not so high as to unduly influence participants.
• Spanish translations of the informed consent documents, informational packets, and
recruitment flyers were provided. Researchers will be working with local Spanish-
speaking community members to ensure that the appropriate regional dialect of Spanish
is used (AHETF 2010d).
c. Equitable selection of study participants
• The study is designed to recruit an appropriately diverse population of participants who
represent skilled agricultural workers in the five study locations.
• Community representatives and advocates are appropriately involved in the recruitment
and enrollment of study participants.
2. The Board recommended that the study protocol be modified to address the concerns noted in
the EPA’s Ethics Review (Evans and Sherman 2010b). In addition, the Board also raised the
following concerns:
• The Board raised concerns that the revised water-soluble packaging protocol was reviewed
by IIRB, Inc. using an expedited procedure. Future protocol revisions that involve major
changes like substitution of surrogate compounds and/or change in study site should be
reviewed under full-board procedures and reflected properly in the IRB minutes.
• As noted above, the Board recommended that accidental exposure to the surrogate
chemicals be listed in the protocol and that the informed consent form also list surrogate
exposure as a potential risk of study participation.
• The protocol excludes participants who normally wear additional personal protective
equipment (such as chemical-resistant clothing) that is not required by the chemical label
and that might impact the objectives of the study. The Board recommended that this
assessment be done in a non-directive way, so as not to encourage participants to wear less
PPE than they would normally in order to participate in the study.
• Study participants will undergo hand washes prior to eating anything, which will reduce
their risk of accidental ingestion of the surrogate compounds. As many of the adults in the
U.S. still smoke, however, the Board recommended that hand washes also occur before any
smoking break to further reduce their risk of accidental pesticide ingestion.
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• The informed consent document states that “you may refuse medical treatment unless you
get sick from too much exposure to pesticides or from getting too hot, or if e believe you
are too sick to make a rational decision about getting medical treatment” (Collier 2010b,
emphasis added). It was unclear how this determination of rationality will be made,
however. The protocol and informed consent document should be more explicit as to who
will make this determination, and what criteria would be used.
• The Board raised some concerns about how the Task.Force plans to release individual
exposure data to individual study participants who request this information. For example,
the Board encouraged the sponsor to consider how this information might be provided to
participants who do not speak English and/or are illiterate. The Board also recommended
that the request for individual study results be included as a check box on the informed
consent document. The HSRB will be establishing a small working group to develop some
guidance for the Agency and sponsors regarding the release of individual exposure data to
study participants.
Page 28 of3l
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Final Report Dated December 13, 2010
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Final Report Dated December 13, 2010
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