EPA-HSRB-11-01

Paul Anastas, PhD

EPA Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject: January 26, 2011 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 one new protocol for a study involving intentional
exposure of human subjects to pesticides: a proposed Agricultural
Handler Exposure Task Force, LLC (AHETF) scenario measuring dermal and
inhalation exposure of professional agricultural workers who perform
open mixing and loading of pesticides formulated as wettable powders. 

	The Agency also requested that the HSRB review five completed,
interrelated studies of dermal and inhalation exposure of professional
agricultural handlers who spray pesticides with closed-cab airblast
equipment, conducted by the AHETF. These studies (AHE55, AHE56, AHE57,
AHE58 and AHE59) were 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). These studies
were conducted under a single scenario monograph (MRID 48314201), which
incorporates the data from these five studies into a single dataset.
This dataset will be posted to the Agricultural Handlers Exposure
Database (AHED®), and used generically to estimate daily dermal and
inhalation exposures of workers who treat agricultural crops with
conventional pesticides using closed-cab airblast equipment. 

	 The enclosed report provides the Board’s response to EPA charge
questions presented at the January 26, 2011 meeting.

Assessment of Proposed AHETF Research Study AHE80: Determination of
Dermal and Inhalation Exposure to Workers During Mixing/Loading Wettable
Powders in the United States.

Science

	The Board concluded that the proposed AHETF scenario and field study
proposal AHE80, if revised as suggested and performed as described, is
likely to generate scientifically reliable data, useful for assessing
the exposure of handlers who perform open mixing and loading of
pesticide end use products formulated as wettable powders.

Ethics

The Board concluded that the proposed AHETF scenario and field study
proposal submitted for review, if revised as suggested and performed as
described, is likely to meet the applicable requirements of 40 CFR 26,
subparts K and L.

Assessment of Completed AHETF Research Studies AHE55, AHE56, AHE57,
AHE58 and AHE59: Determination of Dermal and Inhalation Exposure to
Workers During Airblast Applications of Liquid Sprays Using Closed Cab
Equipment (MRID 48280601, 48289602, 48303501, 48289604 and 48303502).

Science

	The Board concluded that the research reported in the completed
monograph, associated field study reports, 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 the
AHETF. 

	The Board also concluded that the Agency has adequately, but not
completely, considered the limitations on these data that should be
considered when using the data in estimating the dermal and inhalation
exposure of those who apply conventional pesticides with closed-cab
airblast equipment. Additional limitations and concerns have been
identified by the Board, and the conclusion as to the generalizability
of these data requires further consideration and analysis.

Ethics

The Board concluded that the study was conducted in substantial
compliance with subparts K and L 40 CFR 26.

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

* Not in attendance at January 26, 2011 Public Meeting

INTRODUCTION 

	On January 26, 2011, the United States Environmental Protection
Agency’s (EPA or Agency) Human Studies Review Board (HSRB) met to
address scientific and ethical issues concerning one new protocol for
research involving human participants: one new study measuring levels of
exposure received by agricultural handlers when mixing and loading
pesticides formulated as wettable powders under various conditions. In
accordance with 40 CFR 26.1601, EPA sought HSRB review of this proposed
protocol. The protocol is discussed more fully below.

	In addition, the Agency has data from five completed, interrelated
studies measuring levels of dermal and inhalation exposure received by
pesticide applicators who spray pesticides with closed-cab airblast
equipment. These studies were conducted under a single scenario
monograph (MRID 48314201), which incorporates the data from these five
studies into a single dataset. In accordance with 40 CFR 26.1602, EPA
sought HSRB review of these five completed studies. The completed
studies are discussed more fully below.

REVIEW PROCESS

On January 26, 2011, 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” (76 Federal Register 8, 2107).

	Following welcoming remarks from Agency officials, the Board heard
presentations from EPA on the following topics: one new study measuring
levels of exposure received by agricultural handlers when mixing and
loading pesticides formulated as wettable powders under various
conditions, and five completed studies measuring dermal and inhalation
exposure received by pesticide applicators who spray pesticides with
closed-cab airblast equipment.

	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 (AHETF)

Public oral comments were provided by: 

	Dr. Victor Cañez, Technical Chair, AHETF

	One written public comment was submitted by Ms. Barbara Sachau of
Florham Park, NJ (writing under the pseudonym Ms. Jean Public). That
comment did not specifically address any of the completed studies or
proposed protocols under review at the January 26, 2011 meeting.

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   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov . 

CHARGE TO THE BOARD AND BOARD RESPONSE

Assessment of Proposed AHETF Research Study AHE80: Determination of
Dermal and Inhalation Exposure to Workers During Mixing/Loading Wettable
Powders in the United States.

Overview of the Study

	This proposal presents an agricultural handler exposure scenario
involving pesticides formulated as wettable powders. The activities to
be monitored in this scenario include a variety of mixing and loading
activities, including pouring the wettable powder into a spray tank,
preparing the pesticide in a separate holding tank and then transferring
the formulated product into the pesticide application equipment, and
mixing and transferring a concentrated slurry of the pesticide. The
protocol calls for study participants to mix and load one of four
surrogate pesticides: copper, DCPA (dacthal), sulfur or
thiophanate-methyl. A total of 25 participants (described in the
protocol as “Monitoring Units” [MUs]) will be observed for each
scenario; five volunteers each from five 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 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 Agricultural Handlers
Exposure Database (AHED®), 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 mixing and loading pesticides formulated as wettable powders
under a variety of scenarios.

Science

Charge to the Board

	If the proposed AHETF scenario and field study proposal AHE80 is
revised as suggested in the 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 perform open mixing and loading of pesticide end use
products formulated as wettable powders?	

Board Response to the Charge

HSRB Recommendation 

	The Board concurred with the Agency’s assessment that the proposed
AHETF scenario and field study proposal AHE80, if revised as suggested
in EPA’s review (Evans et al. 2010) and performed as described, is
likely to generate scientifically reliable data, useful for assessing
the exposure of handlers who perform open mixing and loading of
pesticide end use products formulated as wettable powders.

HSRB Detailed Recommendations and Rationale

	The Board concluded that the research is likely to generate
scientifically reliable data, useful for assessing the exposure of
handlers who perform open mixing and loading of pesticide end use
products formulated as wettable powders. However, one significant
concern was raised about how the new MUs should be distributed among the
proposed strata particularly to achieve the second stated goal of the
research. Several other less pressing questions were raised concerning
information that was not presented clearly within the protocol.

	A significant concern was expressed about how the new MUs should be
distributed across the strata of amount of active ingredient handled
(AaiH). On page 8 of 58 (and in essence again on page 14) in the
Agency’s Review, the Agency states its desire that “the AHETF must
ensure that all strata be used in each of the four remaining clusters”
(Evans et al. 2010, 8). That desire may or may not be a conflict with an
extrapolation of a statement on page 27 and 33 of that same document
states a conclusion from the AHETF computer simulation runs that:

 

	the primary benchmark will still be satisfied providing:

	• The total number of new MUs is at least 20; and

		• No new cluster has more than five MUs.

This rule implies that if a new cluster has fewer than 5 MUs then more
than 4 new clusters will be necessary (Evans et al. 2010, 27).  

While this conclusion was based on the distribution of MUs among
clusters, it may also apply to the distribution of MUs among strata. 

	If the five MUs in each new cluster include all five of the strata,
there will be four new MUs at each stratum. When these four MUs are
added to the five MUs that were already completed within the middle
stratum, the final distribution of MUs across the five strata will be:
4, 4, 9, 4, and 4. Such a distribution is not optimal to achieve the
secondary objective of 80% power to test for proportionality between
dermal exposure and AaiH. Power is increased when more observations are
made at extreme values of AaiH, whereas the middle set of values will be
over sampled here. The Board recommended using further simulations to
explore the effect of the distribution of MUs among AaiH strata on the
power associated with Objective 2, viz. the proposed distribution ,
making allocations so that the number of MUs is the same within all
strata, or having an allocated distribution intermediate to these two
extremes. 

	The primary objective is to estimate the geometric mean, the arithmetic
mean, and the 95th percentile of exposure within 3-fold with 95%
confidence. To be meaningful, the population for which these quantities
are being estimated must be clearly defined. By design, five different
regions, involving different crops were chosen, and the mean exposure
could change with region. Further, within a region, AaiH is purposively
different for each monitoring unit. The mean exposure for each
region-AaiH combination is likely to be different. Thus, it is unclear
what the sample mean (the mean of the 25 region-AaiH combinations) is
estimating. Because the sample mean depends heavily on the design, the
validity of this Objective is questionable.

	A second concern is whether the last of four “restrictions” listed
on page 9 of the Agency’s assessment, to be employed when selecting
MUs, is adequate to both include all three possible ways to mix and load
wettable powders into the various spray tanks.  This restriction is
states that, 

When mixing/loading procedures in a given area involve participants
either pouring directly into the application tank, using pre-mix tanks
(holding dilute sprays), or slurry tanks or buckets (holding concentrate
sprays), then the MUs may not all be associated with the same equipment
and procedure category (Evans et al. 2010, 9).

Although the Board agreed with the desire of the Agency as stated in the
meeting that all three sub-scenarios should be included in each new
cluster, such a statement was not found within either the proposal or
the Agency’s Review. The exact nature of the agreed upon restriction
should be clarified. 

	A somewhat related suggestion was made (without a particular
recommendation) that the proposal makes no attempt to assess the limited
breadth of equipment or/and processes that will be assessed in the
context of possibly wider range used in the field. A particular
challenge (and possible concern) is to ensure that the exposures that
are assessed in a given study do not underestimate the exposures to
those applicators who use equipment or processes that are specialized
for or relegated to small loads or/and small acreages (some of these
were discussed on page 30-31 of the Meeting Minutes of the FIFRA
Scientific Advisory Panel Meeting held January, 2007 on the Review of
Worker Exposure Assessment Methods [FIFRA Scientific Advisory Panel.
2007]; see also page 14 and 42-43 of the same Meeting Report). In this
regard, it may not be sufficient in such a proposal (or future reports)
to ask experts just “how the selected employers and equipment compare
to the local population of similar employers” (i.e., are the equipment
or/and processes typical?). They should also be asked about the extent
to which the selection process excluded any specialized equipment or
processes, e.g., those specialized for use in small loads. Such
information could be used to inform the Agency of limitations to the end
result.

	A question was raised regarding the appropriateness of the proposed
range of AaiH values, in particular the feasibility of achieving the
upper two strata (viz., 183 to 603 and 604 to 2000 lb a.i. handled).
This question was raised because the highest stratum proposed for the
OPM/L scenario is up to 20 times larger than the range of AaiH studied
in AHE80 study of closed-cab airblast (CCAB) applications.  However
information pointed to on page 36-37 of 403 of the Wettable Powder
Mixer/Loader Scenario Submission showed that it is feasible to apply up
to 350 acres per day via aircraft, and examples of product labels
obtained later from the web show that wettable sulfur can be applied to
grapes at rates of up to 20 lb./acre (Collier 2010a, 36-7). Based on the
label’s maximum rate of application of sulfur on grapes (a pair of
scenarios included within the proposal), then mixing/loading up to 7000
lb. in a day is feasible, well above the proposed upper limit. 

	

	Three points of clarification were raised concerning the proposal. 
First, the last sentence in the first paragraph of page 19 of 403 of the
Wettable Powder Mixer/Loader Scenario Submission seems to indicate that
a large overhead is better when it comes to cost (Collier 2010a, 19). A
large overhead would not make the study less expensive, but more
expensive, and thus less cost effective. For a given outcome the less
expensive option is more cost effective, the more expensive one is less
cost effective. The latter is the case with a high overhead.  Second, if
one examines the table on page 31 of 403 of the Wettable Powder
Mixer/Loader Scenario Submission, the numbers for total a.i. usage are
all in decreasing order until the items of strawberries and cherries
(Collier 2010a, 31).  This appears to be an error, but should be
clarified. Finally, the first paragraph page 273 of 403 of the Wettable
Powder Mixer/Loader Scenario Submission discusses “drugs and
devices” (Collier 2010a, 273). However, there are no drugs or devices
that are a part of this scenario. Perhaps this verbiage was copied from
the referenced document that came from the Department of Health and
Human Services and in all likelihood pertained to the FDA, and either
“pesticides” or “chemicals” should be stated.

Ethics

Charge to the Board

	If the proposed AHETF scenario and field study proposal AHE80 is
revised as suggested in the EPA’s review and if the research is
performed as described, is the research likely to meet the applicable
requirements of 40 CFR 26, subparts K and L?

Board Response to the Charge

The Board concluded that the protocol submitted for review, if modified
in accordance with EPA (Parsons and Sherman 2011) 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 of the US EPA’s Good
Laboratory Practice (GLP) Standards described at 40 CFR 160, and, for
research conducted in California, the California State EPA Department of
Pesticide Regulation study monitoring (California Code of Regulations
Title 3, Section 6710) (Ref 2010). Requirements of FIFRA §12(a)(2)(P)
also apply. Researchers who participate in the study and interact with
study participants will be required to undergo ethics training.  The
training will include the successful completion of the course from the
National Institutes of Health (Protecting Human Research Participants)
and/or the Basic Collaborative IRB Training Initiative Course. 

	The protocol was reviewed and approved by an independent human subjects
review committee, Independent Institutional Review Board, Inc. (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, Inc. 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 and a copy of IIRB, Inc. policies and procedures were provided
to the Agency (IIRB, Inc. 2010). 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 (Parsons and Sherman
2011). 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 fourfold: 

1)	The risk of heat-related illness. The study will likely involve an
increased risk of heat-related illness due to study participation. All
participants in the study will be wearing an extra layer of clothing
that they would not normally wear when mixing and loading wettable
powder formulations into a pre-mix or application tank and diluting it
under such conditions. In addition, mixing/loading activities might
occur indoors or outdoors and some locations and dates are likely to
result in hot and/or humid conditions.

2)	The risk associated with scripting of field activities. In order to
ensure all monitoring units (MUs) involve handling at least three loads,
AHETF may ask some workers to use a smaller tank size than they would
normally select or dilute the product more than usual. This might lead
to a slightly longer work period for those workers which may increase
the risks of acute toxicity to the surrogate chemical and of
heat-related illness. 

3)	Exposure to surfactants. A very dilute surfactant solution (0.01% v/v
Aerosol® OT in water) is used as a surfactant for face/neck wipes and
hand washes for all MUs. This surfactant is in a very dilute solution
and its use represents a very short exposure period, but the undiluted
surfactant causes mild to moderate skin and eye irritation in animals.

4)	Psychological risks. Participating in AHETF exposure monitoring
studies involves activities that are unusual and might cause subjects
psychological distress. These include performing an over-the-counter
pregnancy test prior to participation (females only) and allowing a
researcher to assist with the removal of the whole body dosimeter.
Participating in AHETF exposure monitoring studies involves activities
that are unusual and might cause subjects psychological distress. 

AHETF has proposed several procedures to minimize these risks:

1)	Monitoring and stopping procedures will be instituted. The AHETF will
monitor ambient conditions to determine the heat index near the
mixing/loading station and base monitoring decisions on the current heat
index. Exposure monitoring will be discontinued if the heat index cutoff
of 105 F (adjusted for direct sun, if applicable) is reached or
exceeded. The Study Director or other researcher shall stop the
monitoring and/or move the worker to a cooler environment until
monitoring can be resumed. If necessary, some monitoring will take place
at night or early in the morning to avoid excessively hot and humid
conditions. 

2)	Clear inclusion/exclusion criteria have been established. Only
experienced pesticides handlers who consider themselves in good health
will be included in the study.  Experience with the mixing/loading
equipment to be used in the study and with the mixing/loading wettable
powder products will be required of all participants. Participants must
also understand Spanish or English.

3)	Workers will be reminded of safe chemical handing practices and
research staff will practice the face wipe and hand wash procedures with
each participant before pesticide handling begins.

4)	Appropriate medical management procedures are in place.  Eye rinse
stations will be on hand in case of an accidental exposure. Medical
treatment facilities will be identified in case of an emergency. A
medical professional will be on site to observe study participants and
provide urgent care.

5)	Minors and pregnant or lactating women are excluded from
participation, with pregnancy status confirmed by over-the-counter
pregnancy testing within 24 hours prior to study participation.  All
female volunteers will be notified that an additional pregnancy test may
be required if there are any delays in the planned start of the study.
Only non-pregnant volunteers will be allowed to participate.

6)	Procedures have been instituted to decrease psychological risks. 
Pregnancy tests will be conducted in a private place and information
regarding pregnancy test will be kept confidential.  Private dressing
areas will be provided and researchers of the same gender will be
available to assist study participants. 

These risks are minimized appropriately and are justified by the
potential societal benefits associated with gathering data to determine
the potential exposure for workers who mix and load wettable powder
formulations using open pouring techniques for workers four regions of
the United States.

b. Voluntary and informed consent of all participants.

1)	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.

2)	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.

3)	Monetary compensation is not so high as to unduly influence
participants.

c. Equitable selection of study participants.

1)	AHETF will first determine a pool of growers and/or commercial
pesticide application companies who are eligible to participate in this
study. Agricultural workers who work for these eligible businesses will
be recruited as study participants. Employers will be required in
writing to affirm that they will not influence their employees’
decisions about whether to participate in this study.   AHETF has
developed complete and appropriate inclusion/exclusion criteria. 

2. 	The Board recommended that the study protocol be modified to address
the concerns noted in the EPA’s Ethics Review (Evans et al. 2010). In
addition, the Board raised additional concerns:

a.	The Board concurred with the Agency’s recommendation (Evans et al.
2010, 5) that the protocol standard operating procedure (SOP)
AHETF-11-B.5 should be revised to specify that potential study
participants will be asked about what they normally wear when handling
pesticides in a way that does not direct them to a particular answer or
lead them to agree to wear less personal protective equipment (PPE) than
they normally would out of a desire to participate in the research.

b.	The Board concurred with the Agency’s recommendation that the
language in the consent form about refusing medical treatment should be
revised.  However, the board did not concur with the suggested
revisions.  The Agency recommends that the language be revised to read
as follows: “You may refuse medical treatment unless the medical
professional decides you are too sick to make a rational decision about
getting medical treatment.” The Board recommended that the language be
revised as follows: “You may refuse medical treatment unless the
medical professional decides (based on established criteria) that you
are too sick to make a decision about getting medical treatment.” In
addition, it recommended that in an appropriate SOP, the criteria for
decision-making capacity are provided as guidance for medical
professionals who perform this function in AHETF research. The criteria
for decision-making capacity can be found in the clinical and clinical
ethics literature (e.g., Appelbaum 2007) and generally include all the
following: The patient a) can appreciate the situation and its
consequences; b) can understand the relevant information; c) can reason
about the treatment decision; and d) can communicate a choice.

c.	The Board partly concurred with the Agency recommendation that the
AHETF should revise its plan for providing exposure information to
subjects to address subjects who might not speak English and/or are
illiterate, and also to incorporate any future guidance from the
HSRB’s working group on this issue. The Board concurred that the AHETF
and the Agency need to develop procedures to protect the needs of study
participants who do not speak English or who have low levels of
literacy.  However the Board recommended that these procedures need to
be rooted in the vocabulary and best practices of appropriate fields
such as cultural competence and literacy.  For example, the term
illiterate is no longer used by literacy experts.  The Agency should
consider seeking guidance on these issues from the report of the US
Department of Health and Human Services, National Action Plan to Improve
Health Literacy (2010) and reports from the Institute of Medicine,
Health Literacy: A Prescription to End Confusion (2004); Toward Health
Equity and Patient-Centeredness: Integrating Health Literacy,
Disparities Reduction, and Quality Improvement, Workshop Summary (2009).
The Board concurred that AHETF should incorporate any future guidance
from the HSRB’s work group on return of results to participants after
it submits its reports.

d.	The Board concurs with the Agency that AHETF should clarify the
discrepancy about whether hand wash samples are to be collected prior to
water breaks (Evans et al. 2010, 2).

e.	The Board concurs with the Agency review that future AHETF protocols
or SOPs should incorporate information about how subjects are presented
with individual exposure information, including how this process will be
handled for research participants who do not speak English or have low
levels of literacy; and an explanation of the process that the AHETF
follows to improve and verify the accuracy of the Spanish translations
(Evans et al. 2010, 2).  The Board recommends that these future
protocols be grounded best practices in literacy and cultural competence
and that the Spanish translations be in the appropriate dialect of the
research participants.

3.	The Board added these additional recommendations:

a.	The requirement for additional pregnancy tests should be clarified
throughout the documents. The Agency review indicates without
explanation that the consent form states that “more than 1 pregnancy
test may be required” (Evans et al. 2010, 5). However, on page 268 of
the protocol it states that female volunteers “will be notified that
an additional pregnancy test may be required if there any delays in the
planned start of the study” (Collier 2011, 268).  This explanation for
why additional pregnancy tests may be required should be made explicit
in the informed consent document.

b.	The Agency review states that the return of individual exposure
results may benefit research subjects (Evans et al. 2010, 15). The Board
recommended that this language be deleted until the Board Working Group
finishes its report and the Board reviews it. 

c.	The Board recommended that AHETF clarify how witnesses will be
selected for workers who self-identify as non-readers. According to the
protocol they “may choose a witness, or a third-party witness will be
identified by the Study Director or designee and provided to the worker
during the private consent meeting” (Collier 2010a, 292). It needs to
be clarified that these witnesses are not associated with the research
project.

d.	The Board recommended that the risk of surrogate chemicals be
included as one of the risks associated with participation in this study
and be listed in the consent forms and in the protocol. It appears that
the Task Force understood a prior Board recommendation that the physical
risks associated with agricultural work should not be listed in the
protocol and informed consent document to mean that exposure to the
surrogate pesticides should likewise not be not be listed. The AHETF’s
perspective on as reflected on page 109 of the protocol:  

AHETF generally monitors exposure to professional workers that normally
use one of the surrogate chemicals approved by AHETF. Therefore, AHETF
does not consider the risk of toxicity from pesticide handling to be
strictly due to study participation (Collier 2010a, 109).

	Because the study involves scripted activities and may require use of a
pesticide that workers wouldn't have applied that day if not for the
study, however, the Board concluded that exposure to the surrogate
compound should be listed in the protocol and consent document. When
exposure to surrogate pesticides is re-included as a risk of the study,
several documents will need revisions, including SOP AHETF-11.J.2. with
IC checklist; DSM Form 386; and the Governing Document.

	The AHETF also contends that the short duration of the study (generally
one day) limits the toxic risk of exposure to the surrogate chemicals to
acute or short-term effects. These effects are currently not listed in
the consent forms or in the protocol, but the protocol states that the
acute toxic effects from each surrogate product handled in this study
will be discussed with the study participant before their participation
begins (Collier 2010a, 109, 111). The Board concluded, however, that the
discussion of these effects is conspicuously absent from the consent
form and recommended that they either be listed explicitly or, at a
minimum, that the consent document be revised to include a statement
like, 

	The label for the [surrogate compound] will be reviewed with you before
you take part in the study. This review will include how much of that
product you might handle during the study, the symptoms and short-term
health effects of accidental exposure to the product, what clothing and
personal protective equipment you must wear, the importance of washing
your hands before eating, and other safety precautions that should be
followed” (c.f. Collier 2010a, 146-7).

e.	The Board recommended that the discussion of “greater than minimal
risk” in the protocol be clarified. On page 44, the EPA review states,

 In this study risks to subjects are classified as ‘greater than
minimal’, primarily since agricultural work is considered a high risk
occupation where the likelihood of harm or discomfort is greater than
what is encountered in ordinary daily life (Evans et al. 2010, 44).  

However, on page 106, the AHETF protocol states, 

In this study, risks to subjects are classified as “greater than
minimal”, since the likelihood of harm or discomfort is greater than
what is encountered in ordinary daily life. In particular, the risk of
heat-related illness (resulting from wearing an extra layer of clothing
to trap chemical) will be increased due to study participation (Collier
2010a, 106). 

It is not clear whether “greater than minimal risk” refers to
agricultural work or the risk of heat-related illness associated with
participation in the study or to both.

Assessment of Completed AHETF Research Studies AHE55, AHE56, AHE57,
AHE58 and AHE59: Determination of Dermal and Inhalation Exposure to
Workers During Airblast Applications of Liquid Sprays Using Closed Cab
Equipment.

Overview of the Study

	Five separate field studies were conducted, each monitoring dermal and
inhalation exposure of workers to commercially available pesticides
while spraying tree or trellis crops in five different U.S. states where
closed-cab airblast equipment is commonly used in production
agriculture. A total of 24 professional agricultural handlers were
monitored as they applied pesticides using closed-cab airblast
equipment: five adult men applying pesticides to citrus trees in Florida
(AHE55), five adult men applying pesticides to pecan trees in Georgia
(AHE56), four adult men and one adult woman applying pesticides to
cherry trees in Michigan (AHE 57), five adult men applying pesticides to
grape vines in California (AHE58), and four adult men applying
pesticides to apple trees in Washington state (AHE59). The scenario
design, protocols for the five studies, SOPs and governing documents
were reviewed favorably by the HSRB at its June 24-25, 2008 meeting (EPA
HSRB 2008).

	Monitored on actual days of work, study participants handled from 7 to
90 lbs of active ingredient (carbaryl, malathion, or chlorothalonil),
spraying 4 to 30 acres in 2 to 9 hours. Dermal exposure was measured
using hand washes, face/neck wipes, and whole body dosimeters (100%
cotton union suits) for the remainder of the body (torso, arms, and
legs). Inhalation exposure was measured using personal air sampling
pumps and OVS mounted on the shirt collar. Results represent dermal
exposure while wearing a long-sleeved shirt, pants, shoes/socks and
chemical-resistant gloves, and inhalation exposure without respiratory
protection.

	The Agency proposes to use data from these five studies, posted to
AHED®, to estimate generically daily dermal and inhalation exposures of
workers who treat agricultural crops with conventional pesticides using
closed-cab airblast equipment. 

Science

Charge(s) to the Board

	1) Was the research reported in the AHETF completed monograph report
and associated field study reports faithful to the design and objectives
of the protocol, SOPs and governing documents?

	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
conventional pesticides with closed-cab airblast equipment?

Board Response to the Charge(s)

HSRB Recommendation 

	The Board concurred in part with the Agency’s assessment (Crowley
2011; Crowley and Sarkar 2011). The research reported in the completed
monograph, associated field study reports, and associated supplemental
documents (Bruce 2010a, 2010b, 2010c, 2010d; Klonne and Holden 2010;
Smith 2010a, 2010b, 2010c, 2010d, 2010e, 2010f) was conducted in a
manner that was reasonably faithful, to the extent possible under field
conditions, to the design and objectives of the protocol and governing
documents of the AHETF. 

	The Board also concluded that the Agency has not completely considered
the limitations on these data that should be considered before using the
data to estimate the dermal and inhalation exposure of those who apply
conventional pesticides with closed-cab airblast equipment. Additional
limitations and concerns have been identified by the Board, and
conclusions as to the generalizability of these data require further
consideration and analysis.

HSRB Detailed Recommendations and Rationale

	While any field study of the nature of these AHETF studies have
unanticipated deviations from the protocol and SOPs, this completed
study was reasonably faithful to the design and objectives of the
protocol, SOPs and governing documents. Many of the reported protocol
deviations were minor, but some were not. However, it was unclear the
effect these deviations would have, if any, on the results; the effect
of these deviations of the data has not yet been determined. 

	With some exceptions, the quality assurance results appeared to be
good. In terms of measured values below the limit of detection (LOD) or
the limit of quantitation (LOQ) -- 7/48 inner dosimeters, 21/24 total
head exposures, 4/36 hand wash samples, most OVS inhalation tube back
samples -- the use of ½ LOD in such cases to extrapolate face/neck wipe
exposure measurements to un-wiped portions of the face and head may have
significantly affected the reported analyses and results.

	It also is unclear whether temperature, humidity, wind speed, foliage
density and/or the type of equipment used had any effects on exposure
and whether or not these variables should be included in further
exposure modeling. Additional questions raised by the Board included: 1)
wondering what was so different about the California grape study (AHE58;
Bruce 2010a, 2011b) that the actual AaiH exceeded the upper limit in
three of the five strata; and 2) questioning why the whole body
dosimeter field fortification samples in the California grape study also
exceeded the appropriate range at times.

	Despite these concerns and questions, the Board concluded that the data
obtained from these completed studies are likely to be reasonably
accurate from the standpoint of the collection and handling of samples,
and from chemical analysis.  The data may not be an accurate reflection
of the potential exposure to pesticides by agricultural workers using
closed-cab airblast pesticide application equipment, mainly because of
the impact of the incidental exposures. However, although the Board
raised concerns regarding the utility of these data for predicting
proportionality in a closed-cab airblast scenario, this concern does not
invalidate the scientific validity of the actual data. 

	In its Scientific Review of the AHETF Closed Cab Airblast Monograph
(Klonne and Holden 2010), the Agency stated that, “the secondary
objective to evaluate proportionality between dermal and inhalation
exposure and the amount of active ingredient handled with 80%
statistical power – a key assumption in the use of exposure data as
‘unit exposures’ – was not met” (Crowley and Sarkar 2011, 2)
such that the null hypothesis was not rejected. The Board agrees with
this conclusion; the fact that the 95% confidence interval includes one
does not mean that the assumption of proportionality is correct. 

	The EPA Scientific Review of the AHETF Closed Cab Airblast Monograph
further states that, “additional analyses point to incidental exposure
sources such as contacts with exterior surfaces having a more
substantial impact on exposure” (Crowley and Sarkar 2011, 2). This is
not unreasonable, specifically for dermal exposure. The fact that the
reported data do not seem to reflect the proportionality of exposure to
AaiH suggests that the engineering controls used here (i.e., a
closed-cab air-conditioned vehicle) are likely to be effective in
preventing exposure of the agricultural handler to the bulk of the
pesticide being applied. The data also indicate that the protocol did
not measure incidental exposures to pesticide, such as contaminations
occurring outside the cab, in a manner that would have been helpful in
exposure assessment. The prominence of incidental exposure in this
scenario may not have been anticipated in advance of the study. As the
surrogates selected are pesticides that are appropriate and registered
for the crops of the scenarios, they would be expected to be used in the
field on some occasions.  Finally, the reported results also suggest
that the number of MUs may be too small to assess the proportionality of
exposure to AaiH.

	Given these issues, the Board raised concerns that the assumption of
proportionality could not be demonstrated for dermal exposure without
accurately measuring and factoring in incidental exposures and then
recalculating the regression. Inhalation exposure estimates would be
much less affected by such incidental exposures, and the Board concluded
that the assumption of proportionality is not correct for such exposures
as confirmed in Table 1 of the EPA Review (Crowley and Sarkar 2011, 2).

	The range of dermal and inhalation exposures was very great and, as
predicted, skewed toward larger exposures even after normalizing the
data. This range makes statistical estimation of exposure difficult, and
the Board recommended that a different type of probability density
function should be used in statistical analyses.

	The Board also raised concern that the method efficiency adjusted (MEA)
correction factor used in estimating dermal exposures was not as
accurate as it should be. This suggests that additional lab work is
required to develop more accurate ways of obtaining exposure estimates
for the various dermal exposures. The secondary analyses performed
utilizing observations on clothing and on number of times exiting and
entering the cab were very illuminating, indicating a different type of
statistical regression model might be used if either field measurements
or lab data could be combined.  (It is questionable, however, given the
limited number of observations whether sensitivity analyses could or
should be performed.)  Even considering alternative uses of these
existing data, additional exposure ‘models’ should be investigated
before final conclusions are made as to the use of the results in
AHED®.  The Agency should be careful, however, not to make any
inferences from discoveries that the closed cab airblast scenario was
not designed to address; they should not conclude, for example, that
incidental exposures are the primary source of dermal exposure to
pesticides as these five studies were not designed to measure the
contribution of these sources of contamination to overall handler
exposure estimates.

	Finally, the Board agrees with the Agency’s conclusion in its
Scientific Review of the AHETF Closed Cab Airblast Studies that, given
that some field control samples for the air samplers were found to have
detectable residues, this finding “may impact field fortification
recovery estimates, which in turn could alter actual field sample
measurements” (Crowley 2011, 6). It was assumed by AHETF that, as the
amounts of such residues in the field control samples were small, they
could be ignored. Adjusting the data to account for the presence of
detectable residues in the field control samples would have been more
appropriate.  

Ethics

Charge to the Board

	Does the available information support a determination that the studies
were 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 (Sherman 2011) that
the study was conducted in substantial compliance with subparts K and L
40 CFR 26.

HSRB Detailed Recommendation and Rationale

	The documents provided include reports of each of five field studies
conducted on behalf of the Agricultural Handler Exposure Task Force
(AHETF) (Bruce 2010a, 2010b, 2010c, 2010d; Klonne and Holden, 2010;
Smith 2010a, 2010b, 2010c, 2010d, 2010e, 2010f). The five protocols were
each 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, as described above in the Board’s review of proposed AHETF
research study AHE80: Determination of Dermal and Inhalation Exposure to
Workers During Mixing/Loading Wettable Powders in the United States.

1.	The Board concurred with the conclusions and factual observations
relating to the study, as detailed in the EPA’s Ethics Review (Sherman
2011) and summarized briefly below. 

a. 	Prior HSRB and Agency Review. Because each of these five studies 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. in March 2008 (for
protocols AHE55 and AHE56) and in August 2008 (for protocols AHE57,
AHE58, and AHE 59). The HSRB discussed protocols AHE55 and AHE56 at its
June 2008 meeting, and AHE57, AHE58, and AHE59 at its October 2008
meeting, in each instance concurring with the Agency’s assessment
(Sherman 2011) that these five proposed closed-cab airblast field study
protocols, 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 initial ethics
review by the Agency and by the HSRB provided 26 recommendations with
regard to these five protocols. All of those recommendations, and the
responses made with regard to them, are detailed in Attachment 4, on
pages 42 and 43, of the Agency’s Review (Sherman 2011, 42-3). The HSRB
agrees with the Agency that the comments by the Agency and HSRB were
satisfactorily addressed. 

2.  	The Board also concluded that this study, as conducted, met all
applicable ethical requirements for research involving human
participants, in accordance with the following criteria.

a.	Acceptable risk-benefit ratio. 

1) 	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 pesticide applicators
to the liquid pesticides they apply to orchard and trellis crops using
an airblast sprayer drawn by a vehicle with an enclosed cab. These data
could be used to develop mechanisms to protect future persons who apply
these liquid pesticides.

2)	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. 

3)	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, except as described in section 3, below.

4)	The study was designed to minimize the risks of exposure to the test
compounds, subject to being able to accomplish the purposes of the
study.

b.	Voluntary and informed consent of all participants.

1)	The study protocol included several mechanisms designed to minimize
coercive recruitment and enrollment.

2)	Monetary compensation was not so high as to unduly influence
participation.

3.	Twenty-two minor protocol deviations were reported by the sponsor.
The Agency’s Ethics Review also notes thirteen minor protocol
deviations that were unreported. All of these are documented in some
detail in Table 2 of the Ethics Review (Sherman 2011, 18). The Board
agrees with the Agency’s evaluation of these deviations, and the fact
that they do not require any changes in the Board’s determinations
described above. 

	However, one category of protocol deviation is given special attention
in the EPA Ethics Review and merits discussion here. These deviations
involved the fact, on multiple occasions in three of the five CCAB
studies, subjects failed to wear gloves while touching a contaminated
surface, usually part of the airblast cab or attached machinery. 

	As the Agency notes, according to the protocols, since these protocol
violations involved a safety issue (exposure to the pesticide). In each
instance the person who observed these violations of safety standards
should have reminded the workers to wear their gloves and reported the
behavior to the study director. There is no record that these steps took
place. However, given the nature of these exposures to the pesticides,
and the pesticides that were chosen for use in these protocols, the
actual increased risk to the subjects appears minimal. We agree with the
Agency’s determination in that regard (Sherman 2011, 29). 

	Beyond these completed studies, however, these deviations raise an
issue that the Agency and sponsors may wish to consider with regard to
the design of future protocols. That 25% of the subjects in these five
studies engaged in this behavior suggests that it is probably not
uncommon. Although experienced pesticide applicators are told of the
need to wear gloves before touching certain pieces of equipment, it
appears that they commonly fail to do so. If indeed this is a common
behavior, and EPA wants to collect data from such exposures, then Agency
and the sponsors may want to consider an approach that specifies safety
standards in the informed consent form but indicates that observers will
not necessarily remind participants of the standard each time they are
observed violating these standards.  In addition to or as an alternative
to this approach, it may be desirable to write an SOP that is referenced
in future protocols.  

	The purpose of the SOP would be to clarify for study observers the
safety-related interventions, if any, that observers should make when
participant’s engage in behaviors that are inconsistent with either
the protocol or the label.  In such an SOP, it would be necessary to
clearly spell out which safety-related deviations are “acceptable”
(meaning they would not require an intervention such as a reminder to
the subject to alter their behavior each time that behavior is
observed), and which are not (meaning they would require an
intervention, such as a reminder or warning). Acceptable deviations
should only be those that involve very low risks to subjects. Observers
should receive guidance on safety violations that would merit reminders
or warnings to subjects, reports to the study director, and immediate
interventions to correct inappropriate behavior, including the most
common examples of behaviors that are and are not acceptable. In
addition to potentially reducing participant risk, this guidance would
also help to standardize observation by removing variation introduced
when observers are required to make their own subjective evaluations of
risk in determining when and how to intervene. 

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Final Draft Document Dated March 11, 2011

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DRAFT

