Document ID: EPA-HQ-ORD-2010-0919-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-12-13T05:00Z

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 generically 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 (PMD) and 2%
Lemongrass 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.

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 Proposed 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 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,

Sean Philpott, PhD, MSBioethics

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.  You may obtain
further information about the EPA Human Studies Review Board from its
website at   HYPERLINK "http://www.epa.gov/osa/hsrb" 
http://www.epa.gov/osa/hsrb .  You may also contact the HSRB Designated
Federal Officer, via e-mail at   HYPERLINK "mailto:ord-osa-hsrb@epa.gov"
 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.

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 of Nevada-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) Human Risk
Assessment, 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

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

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 also asked clarifying questions of several study sponsors
and/or research investigators, including:

Dr. Victor Cañez, 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

Public oral comments were provided by: 

Dr. Victor Cañez, 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 of proposed 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-Loye 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% PMD 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?	

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
light 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 definitive
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.

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 (IIRB), Inc. of Plantation, FL
prior to submission. IIRB, Inc. is fully 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 ( OHRP) website (Reg. #IORG0002954).
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 participants are
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.

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 risks, 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:

	

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 Proposed AHETF Scenario and Protocol AHE-400: Backpack and
Handgun Application of Liquid Sprays 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 of 21 participants (described
in the protocol as “Monitoring Units” [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 95th 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 AHE400,
if revised as suggested in EPA’s review (Evans and Sherman 2010a) and
performed as described, is 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.

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. 

	The study, if conducted as described, will provide newer exposure
information on dermal and inhalation exposures of pesticide handlers
using backpack sprayers and handgun sprayers treating utility
rights-of-way in appropriate and distinct geographic locations; some
study participants will be exposed during loading backpacks or tanks as
well. The Board agreed with the Agency’s assessment that the protocol
adequately addresses a number of scientific questions, including having
clear scientific objectives, a reasonable experimental design for
achieving these objectives: appropriate quantification of test
materials, adequate procedures for collecting, compiling 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 because of the diversity of
terrains and locations selected for the study and the opportunity for
large (but potentially categorical) personal differences in application
practices. The proposal to impose a minimum exposure duration of at
least 4 hours will also create opportunities for the applicator’s
exposures to be influenced by variables that by their nature are likely
to be unrelated to the amount of active ingredient handled (AaiH).
Should this diversity yield high variability in the data sets, then the
proportionality 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 fraction of the total
monitored time for use in later data analysis and usage within AHED. he
rationale for having and using this “fraction” is discussed more
fully in the Board’s discussion of protocol AHE120 below. Even if the
proportionality hypothesis is not supported by the resultant data 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 2010a). FIFRA
§12(a)(2)(P) also applys. 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 using 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
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 2010b).

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
2010a). 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.

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: 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).

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 defined 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. 

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 of AEATF-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, 2010b, 2010c)
was conducted in a manner that was reasonably faithful to the design and
objectives of the protocol and governing documents of AEATF-II. 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 (Selim
and Taylor 2010a) 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. While this lack of information places potentially
important limitations on how the inhalation data should be interpreted,
in the professional opinion of at least one Board member the impact of
differences among the test sites are likely to be within a factor of
about two and thus not substantively change the overall mean exposure
levels.	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 final report, the study was conducted 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 (AI) handled per subject and as milligrams of AI per
subject/pound of AI 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
appicators 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 AI handled, the
rationale supporting the presumption of proportionality for inhalation
exposure needs to be recalculated but based on current data may not be
as clear and consistent as for the dermal 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, ½ 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. One
Board member observed, however, that the Agency’s reliance on hand
wash data may have over-corrected face and neck residue estimates. 
Another Board member questioned whether the model actually supports the
conclusion of proportionality for some of the dermal 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 final 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 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 Appendix 1 below (written as a separate report
by HSRB member Dr. William Popendorf).

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 AAHRPP and listed by OHRP (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 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.

b. 	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.

c. 	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 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.

Assessment of Revised AHETF Scenario and Protocol AHE-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 AHETF 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 AHETF scenario and field study proposal AHE120 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? 

Board Response to the Charge

HSRB Recommendation 

	The Board concurred with the Agency’s assessment (Evans and Sherman
2010b) 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 exposure distribution be accurate to within 3-fold,
at least 95% of the time,” and the ability to distinguish “a
proportional from an independent relationship between exposure and
AaiH,” respectively (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, purposive 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 AaiH 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 call for an exposure duration of at least 4
hours for all of the MUs.  This constraint seems unnecessary 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 exposures 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 that is time on-task is likely to be highly variable, probably
among strata (particularly if the artificial constraint on the minimum
time monitored affects the low AaiH preferentially) and potentially 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 AHETF scenario and field study proposal AHE120 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 2010b) 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 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
revised study, as detailed in the EPA’s Ethics Review (Evans and
Sherman 2010b). 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 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. 

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.

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 we 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.

REFERENCES

Agricultural Handler Exposure Task Force (AHETF). 2010a. Supplemental 1
to the Backpack and Handgun Application of Liquid Sprays in Utilities
Rights-of-Way Scenario Submission (AHE-400): SOPs Cited in AHE-400 ROW
Submission. Undated and unpublished document prepared by the AHETF.

AHETF. 2010b. Supplemental 2 to the Backpack and Handgun Application of
Liquid Sprays in Utilities Rights-of-Way Scenario Submission (AHE-400):
Providing Individual Exposure Information to Subjects. Undated and
unpublished document prepared by the AHETF.

AHETF. 2010c. Supplemental 1 to the Revised Water Soluble Packet
Mixer/Loader Scenario Submission (AHE-120): SOPs Cited in AHE-120 ROW
Submission. Undated and unpublished document prepared by the AHETF.

AHETF. 2010d. Supplemental 2 to the Revised Water Soluble Packet
Mixer/Loader Scenario Submission (AHE-120): Providing Individual
Exposure Information to Subjects. Undated and unpublished document
prepared by the AHETF.

Carley, J.M. 2010. Ethics Review of Completed AEATF II Mop Scenario
Worker Exposure Monitoring Study AEA-03. Dated October 4, 2010.
Unpublished document prepared by the Office of Chemical Safety and
Pollution Prevention, United States Environmental Protection Agency. 

Carroll, S. 2010. Efficacy Test Protocol: Field Efficacy Test of PMD and
Lemongrass Oil Based Repellent ‘No Mas’ Against Mosquitoes. Dated
July 15, 2010. Unpublished document prepared by Carroll-Loye Biological
Research.

Collier, C.H., for the Agricultural Handler Exposure Task Force (AHETF).
2010a. Backpack and Handgun Application of Liquid Sprays in Utilities
Rights-of-Way Scenario Submission (AHE-400). Dated June 18, 2010.
Unpublished document prepared by the AHETF.

Collier, C.H., for the Agricultural Handler Exposure Task Force (AHETF).
2010b. Revised Water Soluble Packet Mixer/Loader Scenario Submission
(AHE-120). Dated August 19, 2010. Unpublished document prepared by the
AHETF.

EPA Human Studies Review Board. 2008. April 9-10, 2008 Human Studies
Review Board Meeting Report.

EPA Human Studies Review Board. 2009. June 24-25, 2009 Human Studies
Review Board Meeting Report.

Evans, J., and K. Sherman. 2010a. Science and Ethics Review of AHE400: A
New Scenario Design and Associated Protocol from the Agricultural
Handler Exposure Task Force (AHETF) Describing Proposed Research to
Measure Dermal and Inhalation Exposure to Applicators Who Use Backpack
or Hand Gun Sprayers to Apply Pesticides in Utility Rights-of-Way. Dated
September 30, 2010. Unpublished document prepared by the Office of
Chemical Safety and Pollution Prevention, United States Environmental
Protection Agency.

Evans, J., and K. Sherman. 2010b. Science and Ethics Review of Revised
AHETF Scenario Design and Protocol AHE120 for Exposure Monitoring of
Workers during Mixing and Loading of Pesticide Products in Water Soluble
Packets in Five Regions of the United States (August 2010). Dated
October 1, 2010. Unpublished document prepared by the Office of Chemical
Safety and Pollution Prevention, United States Environmental Protection
Agency.

Fuentes, C., and K. Sherman. 2010. Science and Ethics Review of Protocol
for Human Study of Mosquito Repellent Performance: Proposed Carroll-Loye
Field Efficacy Test of PMD and Lemongrass Oil-Based Repellent ‘No
Mas’ Against Mosquitoes. Dated October 1, 2010. Unpublished document
prepared by the Office of Chemical Safety and Pollution Prevention,
United States Environmental Protection Agency. 

Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Roster
and Procedures. Unpublished materials prepared by IIRB.

Johnson, D., for the Agricultural Handler Exposure Task Force (AHETF).
2010a. Supplemental 3 to the Backpack and Handgun Application of Liquid
Sprays in Utilities Rights-of-Way Scenario Submission (AHE-400):
Explanation of AHETF Spanish Translation Project. Dated September 30,
2010. Unpublished document prepared by the AHETF.

Johnson, D., for the Agricultural Handler Exposure Task Force (AHETF).
2010a. Supplemental 3 to the Revised Water Soluble Packet Mixer/Loader
Scenario Submission (AHE-120): Explanation of AHETF Spanish Translation
Project. Dated September 30, 2010. Unpublished document prepared by the
AHETF.

Leighton, T. 2010. Science Review of the AEATF II Mop Human Exposure
Monitoring Study (AEA-03). MRID Numbers 48210201, 48231201, and 48231901
. Dated October 4, 2010. Unpublished document prepared by the Office of
Chemical Safety and Pollution Prevention, United States Environmental
Protection Agency.

Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment
Task Force II (AEATF II). 2010a. 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. Dated August 2, 2010. Unpublished document
prepared by the AEATF II. MRID 48210201.

Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment
Task Force II (AEATF II). 2010b. Supplement 1 to 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. Dated September 15, 2010. Unpublished
document prepared by the AEATF II. MRID 48231201.

Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment
Task Force II (AEATF II). 2010c. Supplement 2 to 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. Dated September 21, 2010. Unpublished
document prepared by the AEATF II. MRID 48231901.

Appendix 1

[to be added at a later date]

Final Draft Document Dated December 8, 2010

Page   PAGE  14  of   NUMPAGES  14 

Page   PAGE  15  of   NUMPAGES  15 

DRAFT