March 28, 2012

EPA-HSRB-12-01

Lek Kadeli, Acting Assistant Administrator

Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject: January 26, 2012 EPA Human Studies Review Board Meeting Report

Dear Mr. Kadeli,

	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 workers who perform mixing, loading and
application of pesticides using powered (gasoline or electric)
handgun/hand wand equipment in greenhouses and nurseries (AHE-600).

	The Agency also requested that the HSRB review a completed study of
dermal and inhalation exposure of professional janitorial workers who
clean indoor surfaces with an antimicrobial pesticide product using
hand-held pressurized aerosol canisters, conducted by the Antimicrobial
Exposure Assessment Task Force II (AEATF II). This study (AEA-04) was
conducted after publication of the EPA’s expanded final rule for
protection of subjects in human research. 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 wipe indoor
surfaces with antimicrobial pesticides.

	The enclosed report provides the Board’s response to EPA charge
questions presented at the January 26, 2012 meeting.

Assessment of Proposed AHETF Research Study AHE-600: Mixing, Loading,
and Applying Liquid Pesticides in Managed Horticultural Facilities Using
Powered Handgun Equipment.

Science

The Board concluded that the protocol submitted for review, if modified
in accordance with EPA (Evans, Sarkar and Sherman 2011) and HSRB
recommendations, is likely to generate high quality, reliable and useful
data for assessing worker’s pesticide exposures in horticultural
settings.  

The Board provided several additional comments or suggestions with
respect to the use of personal protective equipment (PPE), the potential
effect of unanticipated incidental exposures and other variables on
proportionality, and the utility of existing European Crop Protection
Association (ECPA) data.

Ethics

The Board concluded that the protocol submitted for review, if modified
in accordance with EPA and HSRB recommendations, is likely to meet the
applicable requirements of 40 CFR 26, subparts K and L.

Assessment of Completed AEATF II Research Study AEA-04: Measurement of
Potential Dermal and Inhalation Exposure During Application of a Liquid
Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for
Indoor Surface Disinfecting.

Science

The Board concurred with the Agency’s assessment that this study
provides scientifically valid results for estimating the dermal and
inhalation exposure of those who apply liquid antimicrobial pesticide
products for indoor surface disinfecting using a pressurized aerosol
can, but noted several issues, limitations and concerns with the data
and proposed analyses.

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.

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

Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH), School of Public
Health and Human Services, The George Washington University, Washington,
DC

Members

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

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

Jewell H. Halanych, MD, Assistant Professor, Department of Preventative
Medicine, University of Alabama at Birmingham, Birmingham, AL

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 

José 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

William Popendorf, PhD, MPH, Professor Emeritus, Department of Biology,
Utah State University, Logan, UT 

Leonard Ritter*, PhD, Professor Emeritus, School of Environmental
Sciences, University of Guelph, Guelph, ON, Canada

 

Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics
in Health Care, Veterans Health Administration, Washington, DC

Bernard A. Schwetz*, DVM, PhD, Director (Retired), Office of Human
Research Protections, Department of Health and Human Services, Cadott,
WI

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 present on January 26, 2012.

† Participated in the January 26, 2012 meeting via telepresence.

INTRODUCTION 

On January 26, 2012, 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: a study measuring dermal and
inhalation exposures associated with the mixing, loading and application
of pesticides using powered (gasoline or electric) handgun/hand wand
equipment in greenhouses and nurseries. In accordance with 40 CFR
26.1601, EPA sought HSRB review of this proposed study. This study is
discussed more fully below.

	In addition, the Agency has data from one completed study measuring
dermal and inhalation exposure of professional janitorial workers who
clean indoor surfaces with an antimicrobial pesticide product using
hand-held pressurized aerosol canisters. In accordance with 40 CFR
26.1602, EPA sought HSRB review of this completed study. This study is
discussed more fully below.

REVIEW PROCESS

On January 26, 2012, 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 248, 80938).

Following welcoming remarks from Agency officials, the Board heard
presentations from EPA on the following topics: one new study protocol
to measure dermal and inhalation exposures associated with the mixing,
loading and application of pesticides using powered (gasoline or
electric) handgun/hand wand equipment in greenhouses and nurseries, and
one completed study measuring dermal and inhalation exposure of
professional janitorial workers who clean indoor surfaces with an
antimicrobial pesticide product using hand-held pressurized aerosol
canisters. 

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

Ms. Megan Boatwright, Analytical Coordinator, Golden Pacific
Laboratories.

Dr. Victor Cañez, Technical Chair, Agricultural Handler Exposure Task
Force.

Dr. Richard Collier, Administrative Committee Chair, Agricultural
Handler Exposure Task Force.

Mr. William McCormick III, Clorox, on behalf of the Antimicrobial
Exposure Assessment Task Force II.

Mr. Robert Testman, Vice-President, Golden Pacific Laboratories.

Public oral comments were provided by: 

Dr. Victor Cañez, Technical Chair, Agricultural Handler Exposure Task
Force

Dr. Richard Collier, Administrative Committee Chair, Agricultural
Handler Exposure Task Force.

Mr. Robert Testman, Vice-President, Golden Pacific Laboratories.

One written public comment from a New Jersey resident was submitted, but
the substance of that comment was not directly related to the two
studies under review by the HSRB at the January 26, 2012 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 AHE-600: Mixing, Loading,
and Applying Liquid Pesticides in Managed Horticultural Facilities Using
Powered Handgun Equipment.

Overview of the Study

	This proposal presents an agricultural handler exposure scenario
involving mixing, loading and application of pesticides using powered
(gasoline or electric) handgun/hand wand equipment in greenhouses and
nurseries. Pesticides can be formulated as either liquids or as wettable
powders.

	A total of 30 participants (described in the protocol as “Monitoring
Units” [MUs]) will be observed; three volunteers from each of ten
geographically distinct growing regions will be enrolled using a
purposive sampling method (with some elements of random selection). For
each scenario, volunteers will be randomized to mix and load a defined
amount of active ingredient within one of three strata: 0.5 to 1.6
pounds, 1.6 to 4.8 pounds of active ingredient, or 4.8 to 15 pounds of
active ingredient. After mixing and loading the pesticide, participants
will use powered equipment to treat ornamentals and nonbearing fruit
trees in nurseries, or ornamentals and vegetables grown in greenhouses,
using spray patterns that include downward, outward and upward
directions.

	For this protocol, all participants will wear long sleeved shirts, long
pants, and shoes plus socks. In addition, all participants will wear
chemical resistant gloves. Additional personal protective equipment
(PPE) may be required depending on product labeling directions,
including the use of chemical-resistant aprons when mixing and loading
the pesticide, and chemical-resistant headgear when making overhead
applications. 

	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. For study participants wearing
chemical-resistant headgear, patches placed inside and outside of the
headgear will be employed to estimate dermal exposure of the protected
portions of the body covered by these garments. 

	Airborne concentrations of the surrogate will be monitored in the
participant’s breathing zone using an OSHA Versatile Sampler (OVS)
tube 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 powered handgun 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 mix, load and apply
pesticides using powered handgun equipment.

Science

Charge to the Board

	If the AHETF proposal 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 mixing, loading and applying pesticides in managed
horticultural facilities using powered handgun equipment?

Board Response to the Charge

HSRB Recommendation 

	The Board concluded that the protocol submitted for review, if modified
in accordance with EPA (Evans, Sarkar and Sherman 2011) and HSRB
recommendations, is likely to generate high quality, reliable and useful
data for assessing worker’s pesticide exposures in horticultural
settings.  

	Several comments or suggestions were made by the Board with respect to
the use of PPE, the potential effect of unanticipated incidental
exposures and other variables on proportionality, and the utility of
existing European Crop Protection Association (ECPA) data. 

HSRB Detailed Recommendations and Rationale

This protocol, a study designed to measure dermal and inhalation
exposure of agricultural workers who mix, load and apply pesticides in
nurseries or greenhouses using a hand-held sprayer or gun, was well
thought out and well designed.  The study sponsors (Collier 2011) found
no suitable existing information that could constitute some of the MUs
for this particular scenario; consequently, the entire scenario has to
be conducted. The design requires ten (10) regions with three (3) MUs
per region, for a total of 30 MUs. The rationale for this design is that
there are relatively few nurseries and greenhouses that would be
suitable for this scenario in most, if not all, regions of the United
States. Similarity restrictions will be imposed to assure diversity. The
investigators consulted several information sources to identify
locations with suitable nurseries or greenhouses that could be venues
for the conduct of this scenario. The areas of the country selected
represent a variety of climatic and geographic conditions, likely
providing the representativeness and diversity sought for the scenario.
Given these factors and considerations, the Board determined that the
proposed study design is reasonable. 

The scenario will include several tasks: mixing/loading of the pesticide
product, open pouring of the formulated product, application of the
product to the plants, and potentially some cleaning. The objective is
to demonstrate proportionality between the amount of active ingredient
handled (AaiH) and exposure level.  One concern that was raised by the
Board was that proportionality may not be observed due to the high
variability of unanticipated incidental exposures (e.g., accidentally
touching a treated plant or contaminated part of spray equipment in some
settings but not others), and these sources may contribute substantially
to participants’ exposure levels. Because workers may be close to some
of the sprayed plants in a setting such as a nursery, it seems likely
that unintended contact of workers with these plants might easily occur.
In scenarios where unanticipated incidental exposures are likely to
occur, it will be important for researchers to observe and document all
unintentional contacts with treated plants or other events that might
contribute to the exposure levels. However, even if proportionality is
not seen -- particularly if the results are attributable to observed
unanticipated exposures -- this scenario will still provide valid
information about worker exposure when using a powered handgun or hand
wand in a horticultural setting.

The Board provided additional recommendations and advice to the Agency
about personal protective equipment (e.g., chemical-resistant headgear),
respirators, the many sources of diversity, and analysis of data. For
example, the Agency was reminded that, should chemical-resistant
headgear be worn, the use of patches inside the headgear should yield
valid estimates of exposure for those participants wearing such a hat
(an issue previously raised at the April 2011 HSRB meeting [EPA HSRB
2011]).  However, this method may underestimate exposures if attempts
were made to extrapolate these data to those not wearing such headgear. 
Such extrapolation may not be an explicit intent, but the Agency states
its plans to use the head exposure data to develop mitigation strategies
(e.g. Evans, Sarkar and Sherman 2011, 11).  The effect of the protection
afforded by the brim of the chemical-resistant headgear would negatively
affect that use. Thus, the Board suggested that the sponsors consider:
1) having study participants use chemical-resistant headgear without a
brim (but only if this is allowed by the Worker Protection Standards);
or 2) add a third patch dosimeter against the head below the brim, as
the density of deposition (µg/cm2) onto this patch could be compared to
the deposition onto the rest of the face to estimate the magnitude of
protection afforded by such a brim.

The Board also discussed the use of respirators and half-masks in the
scenario, and how to handle the impact that use of such PPE might have
on dermal exposure levels.  For example, the Board raised concerns about
whether the measured skin exposure to the face would be adjusted upward
in proportion to the area of the face/neck covered by a respirator. 
Although the Agency responded affirmatively, this adjustment was not
stated in the protocol or the Agency’s review of the protocol.   

Several Board members noted that there are many sources of diversity in
this scenario.  As a result, it may be difficult to test the numerous
variables to the degree the Agency intends for identifying statistically
significant differences. Variables that may influence the proposed
exposure data include:

The predominant direction of spray (downward, outward, or upward); 

Whether or not the MU does “minor clean-up”; 

Whether the MU uses a handgun or a hand wand;

Whether the MU applies the pesticide indoors or outdoors; 

The width of the path through which the applicator must pass, as
determined by facility type (i.e., ornamental greenhouse, vegetable
greenhouse, nursery), which may or may not be a surrogate for the
proximity of foliage;

The formulation type mixed (liquid or solid/wettable powder); and 

The mixing sequence (pre-mix or tank mix).  

The Board also considered issues related to the Agency’s
recommendation to include wettable powder by at least one participant in
each cluster (Evans, Sarkar and Sherman 2011, 4).  In particular,
concerns were raised about the use of two formulation types (wettable
powder and liquid) in the scenario; this could be seen as akin to
conducting two studies. The lack of clarity as to how many participants
would use the wettable powder in each cluster is problematic for
assessing the recommended study design and field conduct. The number of
MUs who would handle the powder versus liquid formation is critical for
statistical and analytical questions to be fully answered. If both
formulations are to be used, the Board recommended that the Agency
conduct a separate analysis of each type before combining all of the
data for analysis. If the intent is to maximize the power of detecting a
difference attributable to this variable, then the sponsor could have 15
MUs use the powder formulation and 15 MUs use the liquid formulation.
Alternatively, all MUs could use the wettable powder, as that
formulation type is more likely to generate more conservative exposure
data. 

Finally, the Board cautioned the Agency and the sponsors that the
justification for the study may be weak.  In particular, the Board
raised a question about the utility of ECPA data.  The Agency’s
rationale for not using those data was that the proposed AHETF scenario
involves individual workers performing both mixing/loading and
application activities, whereas the ECPA exposure data was collected
from agricultural handlers involved only in the application of
pesticides.  The Board was not convinced, however, that this difference
precludes the use of existing ECPA data.  While there may be other
scenario or data quality issues with the ECPA data, the Board
recommended that the Agency consider the viability of combining the ECPA
application-only exposure data with the Task Force’s
mixing/loading-only exposure data to satisfy the Agency’s registration
needs without further human exposure studies. Despite this, the Board
noted that the amount of active ingredient handled might be very
different for the proposed scenario and the existing ECPA data set; if
true, then the existing data sets might not be useful in assessing
worker exposure in this horticultural scenario.

Ethics

Charge to the Board

	If the AHETF proposal 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, Sarkar and Sherman 2011) and HSRB
recommendations, is likely to meet the applicable requirements of 40 CFR
26, subparts K and L.

HSRB Detailed Recommendations 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) (Collier 2011). 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, 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). Copies of
all correspondence with IIRB, Inc. (Collier 2011) and a copy of IIRB,
Inc. policies and membership roster were provided (IIRB, Inc. 2010;
2011). These documents indicate that IIRB, Inc. reviewed this protocol
pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart
A). 

1.	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, Sarkar 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. 	Societal value of the proposed research. The clearly stated purpose
of the proposed monitoring study is to develop data to determine the
potential exposure for workers who mix, load, and apply liquid
pesticides using powered handgun equipment in managed horticultural
facilities in the United States. This mixing/loading/applying method is
applicable to a large variety of commercially important crops associated
with the nursery and greenhouse industry across the US and Canada, and
the existing exposure data are likely inadequate. This study will
provide a partial answer to the question of what dermal and inhalation
exposures are likely for workers who mix/load and apply pesticide
products using handguns and hand wands in nurseries and greenhouses. EPA
will use the results of this study to estimate the dermal and inhalation
exposure likely for a wide range of agricultural pesticides mixed,
loaded, and applied under this exposure scenario.

b.	Subject selection and informed consent.  The inclusion/exclusion
criteria are complete and appropriate. Pregnant or nursing women are
excluded from participation. Pesticide company employees and contractors
to the AHETF are also excluded from participation. Protections are
adequate even if a subject were from a vulnerable population. Informed
consent will be obtained from each prospective subject and appropriately
documented in the language (Spanish or English) preferred by the
subject. Recruitment materials and interactions with potential subjects
will be conducted in English or Spanish, depending on subject
preference. The Board agrees with EPA’s suggestion that it is
preferable for recruitment discussions to take place away from the work
site, to minimize the potential for coercion and that the protocol
should describe the types of locations where recruitment discussions
between researchers and potential subjects will take place, clarifying
whether these discussions will take place at the work site or at
locations that are away from the work site. The proposed monetary
compensation is not so high as to unduly influence participation.
Candidates and subjects will be repeatedly informed that they are free
to decline to participate or to withdraw at any time for any reason,
without penalty.

	Depending on the number of employees and size of the grower’s
facility, the Study Director or researcher may contact employees using
an informational recruitment flyer posted in a common work area.
Alternatively, or subsequent to the use of a flyer, the Study Director
or researcher will arrange a meeting with the grower’s employees who
express interest in participation. Such recruitment meetings will always
occur without supervisors being present. The Study Director or
researcher will describe the AHETF Exposure Monitoring Program, the
goals of this specific study, the procedures to be used in exposure
monitoring, and the risks and benefits to participants. The subject
eligibility factors listed in the consent form and SOP AHETF-11.B.6 are
appropriate. Candidates who attend an individual interview will be paid
$20 whether or not they agree to participate; enrolled subjects who put
on the whole-body dosimeter will be paid $80 in addition to their usual
pay, whether or not they complete participation.

c.	Risks to subjects. The proposed test materials are EPA-registered
products registered for nursery and/or greenhouse use and the specific
application planned by the grower, and will be used in full compliance
with the approved labels. All identified risks are characterized as of
low probability, and risks are further minimized by exclusion of
candidates who self-report that they are in less than “good” health;
alerting subjects to signs and symptoms of heat stress; monitoring heat
index with associated stopping rules; close observation of subjects;
training of experienced technicians to minimize embarrassment;
incorporation of procedures to keep results of pregnancy testing private
and to permit discrete withdrawal; provision of appropriate work
clothing and PPE. Provision is made for discrete handling of the
pregnancy testing that is required of female subjects on the day of
testing.

	Five kinds of risks to subjects are discussed in the protocol, along
with specific steps proposed to minimize them: the risk of heat-related
illness; the risk associated with scripting of field activities;
psychological risk; the risk of exposure to surfactants, and; the risk
of exposure to surrogate chemicals.  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 the chemical) will be
increased due to study participation. AHETF has adopted an extensive
program to minimize these risks. Appropriate provision is made for
safety and medical monitoring. The protocol also incorporates procedures
to keep results of pregnancy testing private and to permit discrete
withdrawal of a study subject.  Finally, the protocol incorporates
procedures to ensure that no photographs or videos will be taken in
which a worker can be readily identified. 

d. 	Benefits to participants. This research offers no direct benefits to
the subjects. The principal benefit of this research is likely to be
reliable data about the dermal and inhalation exposure of people mixing,
loading and application of pesticides using powered handgun equipment.
These data are intended to be used by EPA and other regulatory agencies
to support exposure assessments for a wide variety of antimicrobial
products and their uses. 

e.	Risk/benefit balance. Risks to subjects have been thoughtfully and
thoroughly minimized in the design of the research. The low residual
risk is reasonable, in light of the likely benefits to society from new
data supporting more accurate exposure assessments for antimicrobial
products. 

2.	In addition to this analysis, the Board recommended a few edits to
improve the clarity of the Informed Consent Form. These are listed
below, organized according to the section within the Informed Consent
Form in which they appear. In particular, in the past the Agency and the
Board have suggested that protocols and consent forms clarify the steps
that participants should take if participants have an adverse reaction
within 24 hours. This was not included in the materials provided by the
AHETF, and the Board recommends that such information be included on the
consent form.

Introduction and Purpose: 

“If you do In order to take part in this study, you must read and sign
this consent form” (Line 4).

Procedures Before the Start of the Study:

Modify the language per the protocol (p. 248/SOP II.D.2) to clarify that
the pregnancy test will be taken prior to the start of the study:

8. If you are female, within 24 hours of prior to starting the study you
will perform an over-the-counter pregnancy test. If there is a delay in
the start of the study of more than 24 hours, another pregnancy test may
be needed. The negative results of your pregnancy test will be verified
by a female member of the study.

Injury to Participants:

Add a line indicating the name and contact information of the Study
Director or other individual to be contacted if the participant
experiences an adverse event within 24 hours.

3.	The Board agreed with the Agency that information about potential
psychological and social harms related to unwanted disclosure of test
results and breach of confidentiality associated with photographs or
video may be included in the protocol (Evans, Sarkar and Sherman 2011). 
However, the Board recommended that this information not be included in
the informed consent form as it might give participants the erroneous
impression that these risks are particularly significant or that
appropriate steps have not been taken to mitigate them. 

Assessment of Completed AEATF II Research Study AEA-04: Measurement of
Potential Dermal and Inhalation Exposure During Application of a Liquid
Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for
Indoor Surface Disinfecting.

Overview of the Study

	AEATF II aerosol spraying scenario was designed to measure a typical
occupational handler’s daily exposure to an antimicrobial spray
(containing C14 alkyl dimethyl benzyl ammonium chloride [ADBAC])
packaged in a commercially-available pressurized aerosol spray can. 

	Eighteen (18) professional janitors were enrolled in the study, and
applied (but did not wipe) the product on surfaces at one of three
motels in the Fresno, CA area. Study participants were randomized to
apply different amounts of product, from one (1) to four (4) cans of
product in 1/2-can increments (i.e., 1 to 1.5 cans, 1.5 to 2 cans, and
so on up to 3.5 to 4 cans).

	Participants wore a variety of clothing combinations, ranging from
short pants and short sleeved shirts with shoes plus socks, to long
pants and long sleeved shirts with shoes plus socks. No participant wore
gloves, but participants were given the option of wearing a respirator
during product application; all 18 subjects elected to wear respirators
during monitoring. All participants wore inner and outer sets of
whole-body dosimeters that were sectioned and analyzed separately.

	Dermal exposures were measured using whole-body dosimeters (inner and
outer), and hand and face washes.  Dermal unit exposures (reported in
mg/lb AaiH) were calculated by dividing the summed total exposure by
AaiH. The study sponsor report normalized the dermal exposures by
milligrams (mg) of active ingredient applied, but these exposure data
were recalculated by the Agency and expressed as mg/lb of active
ingredient applied.

	Inhalation exposures were measured using a personal air sampling pump
and OVS tubes plus a separate pump used to run a RespiCon™ Particle
Sampler. This allows for collection and analysis of inhalation exposure
monitoring results as total particles, as inhalable particles (<100
μm), as thoracic particles (<10 μm), and as respirable particles (<2.5
μm). Inhalation unit exposures (reported in mg/m3/lb AaiH) were
calculated by dividing the air concentrations by AaiH.

	The data will be posted to the Biocide Handlers Exposure Database
(BHED®). The Agency plans to use these data generically to estimate
dermal and inhalation exposures and risks for other antimicrobial
ingredients where the applied product is packaged in a pressurized
aerosol spray can. Although the scenario as performed did not include
the subsequent wiping of the aerosol spray solution, the Agency believes
that dermal and inhalation exposure that results from the subsequent
wiping of sprayed antimicrobial solutions can be determined by combining
the results of this study with the results of the previously AEATF II
conducted ready-to-use (RTU) wipe study (favorably reviewed at the April
2011 HSRB meeting; EPA HSRB 2011).

Science

Charges to the Board

	Was the research reported in the AEATF II completed aerosol study
report faithful to the design and objectives of the protocol and
governing documents of the AEATF? 

	Has EPA adequately characterized, from a scientific perspective, the
limitations on these data that should be considered when using the data
in estimating the exposure of professional janitorial workers who apply
liquid antimicrobial pesticide products to indoor surfaces using
pressurized aerosol cans? 

Board Response to the Charge

HSRB Recommendation 

	 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
AEATF.  

The Board also concluded that the Agency has adequately, but not
completely, considered the limitations in this study when using the data
in estimating the dermal and inhalation exposure of those who apply
liquid antimicrobial pesticide products for indoor surface disinfecting
using a pressurized aerosol can.  In particular, the Board noted several
issues, limitations and concerns with the data and analyses. These are
described in greater detail below.

HSRB Detailed Recommendations and Rationale

The Board concluded that the study (Testman and Boatwright 2011) was
done thoroughly, yielding detailed and helpful data that appear to be
reliable.  Some data trends were not explained in the accompanying
Agency analysis, but overall the diversity of subjects and settings were
strengths of the study.  

The Board agreed with the Agency that the number of participants was
adequate to achieve the primary benchmark accuracy goal.  The Board also
agreed that the modest diversity of application settings was a
reasonable attempt to offset the practical limitation of recruiting and
assessing all exposures within one geographic area. The documented
diversity in application behaviors indicates the robust nature of the
resulting exposure data.  

The Agency's analyses of protocol deviations and of the blank, fortified
field, and lab samples were acceptable.  In addition to the deviations
noted in the final report (Testman and Boatwright 2011, 1033-104) or by
the Agency (Leighton 2012, 9), however, the Board identified a few more.
For example, subject AE4 was apparently observed to be applying the
product to surfaces at much heavier rates than usual. About 20% of the
way into the sampling time, the study director instructed this subject
to “lighten up” in their application (Testman and Boatwright 2011,
488).  This intervention comprises an unknown limitation that may have
had a large effect on reducing a potentially high exposure.
Alternatively, it may have had no significant effect and was unjustified
in terms of protecting the subject.  Although no specific prohibition
against such interventions was found in the protocol, such instructions
regarding applicator behavior were counter to the intent of the protocol
(i.e., that the study participants “spray surfaces as they would
normally do” [Testman and Boatwright 2011, 18]). Thus, it is unclear
whether this event actually qualifies as a protocol deviation. However,
the lack of an explicit prohibition of study director intervention
raised issues in this study’s analysis and interpretation. Guidance
about how to handle interventions should be incorporated into future
protocols and standard operating procedures (SOPs).  

Subject AE18 (in cluster #1) was a borderline outlier without any
indication in the field notes of intervention by the researchers.  The
Board did not disagree completely with the Agency’s conclusion that
AE18’s data was not an outlier (Leighton 2012, 15), but believed that
one particular combination of these data -- application rate -- reflects
the characteristics of an outlier.  However, the Board did not advocate
excluding this data point from subsequent analyses. Rather, these
sometimes substantial differences provide additional support for the
diverse and therefore broadly representative nature of the subjects and
the qualitatively robust nature of the study results. 

The Board also discussed outliers in laboratory recovery data.  These
data were not used by the Agency to correct field samples; the Board
agreed with the EPA’s approach.  However, the lack of explicit
procedures for handling outliers raised questions among Board members.
Explicit discussions about when data should or should not be excluded
should be incorporated into future protocols and SOPs.

The Board raised concerns that the 20% higher flow rates (or discharge
rates) from the batch of aerosol cans used in the first four MEs, as
compared with the flow rates from those cans used in the last 14 MEs,
could cause an appreciable difference in exposure (Leighton 2012, 9). 
Typically, a faster discharge rate through a given nebulizer produces
smaller droplets.  An analysis of variance for data in this study found
a statistically significant difference between the average fraction of
the a.i. <10 µm in the first four RespiCon™ samples and the last 14
samples (44% versus 55%, respectively; p < 0.00001).  This difference is
consistent with the expectation that the first batch of canisters may
have produced particles with a mass median aerodynamic diameter just
over 10 μm and the last batch particles with a mass median aerodynamic
diameter just under 10 μm. The difference in particle size is more
likely to have been due to the reported difference between flow rates
than the difference in ADBAC concentration in the product.  Notably, the
impact of this probable shift to slightly smaller droplets is small in
comparison to the much wider variation in flow rates and particle sizes
among the many other products these studies are intended to represent.

The Board also raised concerns that the ventilation data presented were
unclear, inadequately recorded, and inadequately interpreted (Testman
and Boatwright 2011, 119-20).  For example, “fresh air” was
presented using different metrics (e.g., %, total fan cubic feet per
minute [CFM], and CFM fresh air).  Furthermore, the reported air changes
per hour seem to differ from separately calculated values by factors of
1.5- to 3-fold. Analyses by one Board member suggest that the overall
effect of the deficiencies may have been small; the amount of time that
participants spent in each room was so short that airborne ABDAC was
just beginning to accumulate by the time the subjects left the space,
limiting the effect of ventilation on overall rates of exposure. 
However, the Board recommended that the Agency consider the potential
limitations associated with the heating, ventilation and air
conditioning systems in the test facilities.

The Agency requested the Board’s advice on the use of RespiCon™
versus OVS results. The major advantage of the RespiCon™ air samples
is their ability to look at the data by size ranges. A disadvantage of
collecting RespiCon™ samples is the challenge of confronting the
difference inherent in the entrance losses of any two air samplers. 
Such losses are a characteristic primarily of entrance diameters and
flow rates, but also of the shape of those entrances and their
orientation, and the air velocity and particle diameters in any given
setting.  These characteristics affect both the RespiCon™ and OVS
samples.  Unfortunately, it appears that no tests could be found in the
literature comparing the OVS with the RespiCon™ sampler (e.g.,
Leighton 2012, 35-7).  Thus, there is no reliable basis upon which to
correct the RespiCon™ to the OVS data. For the purposes of calculating
dose via inhalation, however, the Board recommends that the <10
micron-size results from RespiCon™ monitors be used because this size
range represents the fraction that enters the respiratory tract and thus
provides a more conservative estimate of inhalation exposure. 

The Board suggested that the dermal and inhalation exposure data be
combined to obtain total exposure results. The Board also questioned
whether a slope of 1.5, with a confidence interval (CI) including one
(1), should be considered as evidence of proportionality. Furthermore, a
CI that does not include one may not provide adequate protection. The
Board thus recommended that the Agency always clarify coefficients over
one. Finally, the Board recommended that the Agency and the Task Force
refrain from using the word ‘proportional’ without preceding it by
an adjective such as 1:1 proportional or 1:2 proportional.  

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 (Sherman 2012) that
the study submitted for review was conducted in substantial compliance
with subparts K and L of 40 CFR Part 26. 

HSRB Detailed Recommendation and Rationale

The documents prepared by Golden Pacific Laboratories, LLC, and
submitted by American Chemistry Council Antimicrobial Exposure
Assessment Task Force II under Project No. AEA-04, state that the study
was conducted in compliance with the requirements of the EPA’s Good
Laboratory Practice (GLP) Standards; FIFRA §12(a)(2)(P); and the
applicable subparts of 40 CFR 26 (Testman and Boatwright 2011). 

 

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
registered with OHRP (see details above). Documentation provided to the
EPA indicated that IIRB, Inc. reviewed this study pursuant to the
standards of the Common Rule (45 CFR Part 46, Subpart A) and found it in
compliance (IIRB, Inc. 2010; 2011).

1.	The Board concurred with the conclusions and factual observations
relating to the study, as detailed in the EPA’s Ethics Review (Sherman
2012). Specifically:

a. 	Prior HSRB and Agency Review. 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 study (Testman and Boatwright
2011) was conducted in accordance with the protocol previously reviewed
by the Agency (Leighton, Walls and Sherman 2009) and by the HSRB (EPA
HSRB 2009). Neither the Agency’s nor the HSRB’s ethics reviews
identified any significant deficiencies requiring correction relative to
40 CFR 26, subparts K and L, or to FIFRA § 12(a)(2)(P) (Leighton, Walls
and Sherman 2009). Because the study was conducted in California, the
approval of the California Department of Pesticide Regulation (CDPR) was
also required before the study could be initiated. CDPR granted final
approval of the amended protocol and supporting documents on April 19,
2010.

b.	Responsiveness to HSRB and Agency Reviews. Following HSRB review, the
protocol and consent form were modified to incorporate changes
responsive to the all of the comments of EPA (Leighton, Walls and
Sherman 2009) and the HSRB (EPA HSRB 2009). Additional corrections and
amendments were also requested by CDPR. IIRB, Inc. granted approval to
the amended protocol and supporting documents on April 6 and April 7-9,
2010, respectively (Testman and Boatwright 2011; Sherman 2012). 

c.	Substantial Compliance with Reporting Requirements (40 CFR Part 26
subpart M). The AEATF II’s submission (Testman and Boatwright 2011),
along with the separately submitted documents describing the procedures
and roster of the IRB (IIRB, Inc. 2010; 2011), fully meet the
requirements of 40 CFR §26.1303 to document the ethical conduct of the
research.

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 study protocol (EPA HSRB 2009):

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 compounds as they
sprayed indoor surfaces with aerosolized pesticides. 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. 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. 

Although the first study participants were enrolled in April 2010 and
monitoring began in June 2010, shortly thereafter the study was placed
on ‘hold’ as the result of an issue raised by CDPR. In response to a
request from some participants to wear a respirator while engaged in
study related tasks, the AEATF II decided to offer all study subjects
the option of wearing a half-mask respirator fitted with organic vapor
cartridges. This decision was made after consulting with the Agency and
with the IRB, and the amended protocol and informed consent forms were
reviewed and approved by the IRB. Upon receipt of the approved protocol
amendment, CDPR requested that the study be halted temporarily until
Golden Pacific Laboratories could conduct an additional review of its
procedures for respirator use. CDPR granted approval for the amended
protocol on May 11, 2011.

This hold is unlikely to have affected the integrity of the research or
the safety of participants. In fact, by allowing subjects to wear a
respirator, the researchers further minimized potential risks to study
participants. All 18 monitored subjects used a respirator, which was
fitted by a trained study investigator and worn under the supervision of
a registered study nurse.

Several minor deviations from GLP were reported by the study sponsors
(Testman and Boatwright 2011, 3), but these were unlikely to have
affected the integrity of the research or the safety of participants.
Only one of these deviations bears further discussion, namely the
enrollment of a participant who self-reported that his health was only
“fair,” despite the requirement that all participants be in “good
health” (Testman and Boatwright 2011, 227). This same issue was
discussed by the HSRB during its October 2010 and April 2011 meetings
(EPA HSRB 2010; 2011), at which time the Board recommended that the
study sponsors clarify the criteria used to establish participants’
health status prior to enrollment. Enrollment of this particular
participant, however, happened prior to those two Board meetings.
Furthermore, although formally enrolled in the study, this participant
was not one of the 18 subjects monitored. Thus, the Board concluded that
this deviation did not put the participant at increased risk.

REFERENCES

Collier, R. for the Agricultural Handler Exposure Task Force (AHETF).
2011.
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湡条摥䠠牯楴畣瑬牵污䘠捡汩瑩敩⁳獵湩⁧潐敷敲⁤慈
摮畧⁮煅極浰湥⁴䄨䕈䙔匠畴祤丠⹯䄠䕈〶⤰‮慄整⁤
捏潴敢⁲㐲‬〲ㄱ‮湕異汢獩敨⁤潤畣敭瑮瀠敲慰敲⁤
潦⁲桴⁥䡁呅ⱆ㐠㐷瀠മ

A

B

Ý

Þ

&

&

&

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