April 11, 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
genetically 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
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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 C omøleted AE AT F II Research Study AE A-04: Measurement of Potential
Dermal and Inhalation ExposureDurinq 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
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NOTICE
This report has been written as part of the activities of the EPA Human Studies Review
Board, a Federal advisory committee providing advice, information and recommendations on
issues related to scientific and ethical aspects of human subjects research. This report has not
been reviewed for approval by the Agency and, hence, the contents of this report do not
necessarily represent the view and policies of the Environmental Protection Agency, nor of other
agencies in the Executive Branch of the Federal government, nor does the mention of trade
names or commercial products constitute a recommendation for use. You may obtain further
information about the EPA Human Studies Review Board from its website at
http://www.epa. ov/osa/hsrb . You may also contact the HSRB Designated Federal Officer, via e-
mail at ord-osa-hsrb epa.gov
In preparing this document, the Board carefully considered all information provided and
presented by the Agency presenters, as well as information presented by public commenters.
This document addresses the information provided and presented within the structure of the
charge by the Agency.
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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 Preventive Medicine, University of
Alabama at Birmingham, Birmingham, AL
Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University,
Manhattan, KS
Michael D. Lebowitzt, PhD, FCCP, Retired Professor of Public Health & Medicine, University
of Arizona, Tucson, AZ
José E. ManautouS, 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
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Leonard Ritter t , 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.
in the January 26, 2012 meeting via telepresence.
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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 Cafiez, Risk Assessment Solutions, Technical consultant to the 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.
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Public oral comments were provided by:
Dr. Victor Cafiez, Risk Assessment Solutions, Technical consultant to the 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 http:I/www.regulations.gov .
CHARGE TOTHE BOARDAND BOARD RESPONSE
Assessment of P ro osed A H El F R esea r ch Study A H E - 600: M ixi na. Loading. and Applying
Liquid Pesticides in Managed Horticultural Facilities Using Powered Handaun 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
monitoring area, 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.
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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 geometric mean,
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 B oard
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 theCharge
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.
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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 primary objective is to estimate the geometric mean, arithmetic mean and the 95th
percentile of normalized dermal exposure for agricultural workers who mix, load and apply
pesticides in nurseries or greenhouses using a hand-held sprayer or gun. A secondary 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 unanticipated exposures (e.g., accidentally touching a treated plant or
contaminated part of spray equipment), 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 exposures like these 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. 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
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density of deposition (j.tg/cm 2 ) 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 the Agency’s review of the
protocol. After the conclusion of the January 2012 meeting, however, it was pointed out to the
Board that the AHETF’s standard operating procedure (SOP) 9.K.0 provides information about
how measured skin exposure to the face will be adjusted upward in proportion to the area of the
face/neck covered by a respirator.
Several Board members noted that there are many sources of diversity in this scenario.
As a result, it may be difficult for the Agency to identify statistically significant differences.
Variables which may influence the proposed exposure data include:
1. The predominant direction of spray (downward, outward, or upward);
2. Whether the MU is walking or riding a motorized vehicle;
3. Whether or not the MU does “minor clean-up”;
4. Whether the MU uses a handgun or a hand wand;
5. Whether the MU applies the pesticide indoors or outdoors;
6. 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;
7. The formulation type mixed (liquid or solid/wettable powder); and
8. 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. Not knowing the number of MUs
who would handle the powder versus liquid formation, for example, raises statistical and
analytical questions that cannot be 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. 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 AI-IETF 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
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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 B oard
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 theCharge
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 § 1 2(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. #1OR00002954). 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).
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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
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-l 1 .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.
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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 chemical) will be increased due
to study participation. AFIETF 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 pesticide
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
pesticide 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 A1-IETF, and the Board recommends that such information be
included on the consent form.
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• Introduction and Purpose:
“ If you do I n 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 AE AT F II Research Study AEA-04: Measurement of Potential
Dermal and I nhalation 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., I to 1.5 cans, 1.5 to 2 cans, and so on up to 3.5 to 4 cans). These are
described in the completed study and associated documents as “Monitoring Events” (MEs).
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Participants all wore long pants and long sleeved shirts with shoes plus socks. The
clothing was analyzed in pieces to allow estimation of the expected exposure of people wearing
other clothing combinations, such as shorts or short-sleeved shirts. 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.
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
tm), as thoracic particles (<10 tm), and as respirable particles (<2.5 tm). Inhalation unit
exposures (reported in mg/m 3 /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
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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 which 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 fmal 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. 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 SOPs.
Subject AE1 8 (in cluster #1) was a borderline outlier without any indication in the note 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 statistically significant differences provide additional support for the diverse
and therefore broadly representative nature of the subjects and the qualitatively robust nature of
the study results.
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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 MiEs, 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 tm 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 j .i.n1 and the last batch particles with a mass median aerodynamic diameter
just under 10 tim. 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. Although the deficiencies
noted could have seriously affected the sampling results, analyses by one Board member suggest
that the overall effect 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 the 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.
There is no reliable basis available for comparing the two types of samplers (see, e.g., the
articles cited by Leighton 2012, 3 5-7). For the purposes of calculating dose via inhalation, the
Board thus recommended that the <10 micron-size results from RespiCon monitors be used
because this size range represents the fraction that enters the lower respiratory tract and thus was
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believed to provide a more accurate estimate of respiratory exposure. The Agency’s Office of
Pesticide Programs has recommended OVS sampling results of <100 microns be used in
estimation of risk because most of the information they have collected has been with OVS
monitors and there is some benefit to having continuity in their estimation of risk. This would
provide a more conservative estimate of particles.
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 1:1 proportionality. The
Board thus recommended that the Agency always address how estimates of coefficients will be
used. 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
C harge 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 theCharge
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 IRE 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:
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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,
201 0 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 IIRB (IIRB, Inc. 2010;
2011), fi.illy 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.
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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.
3. 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.
4. There were 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.
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REFERENCES
Collier, R. for the Agricultural Handler Exposure Task Force (AHIETF). 2011. Mixing, Loading
and Application of Pesticides in Managed Horticultural Facilities using Powered Handgun
Equipment (AFIETF Study No. AHE600). Dated October 24, 2011. Unpublished document
prepared for the AHETF, 474 p.
EPA Human Studies Review Board. 2009. October 2 1-22, 2009 Human Studies Review Board
Meeting Report. 26p.
EPA Human Studies Review Board. 2010. October 27-28, 2010 Human Studies Review Board
Meeting Report. 31 p.
EPA Human Studies Review Board. 2011. Apri 113-14, 2011 Human Studies Review Board
Meeting Report. 3lp.
Evans, J., B. Sarkar, and K. Sherman. 2011. Science and Ethics Review of AHETF Scenario
Design and Protocol AHE600 for Exposure Monitoring of Workers during Mixing, Loading and
Application of Pesticides in Managed Horticultural Facilities using Powered Handgun
Equipment. Dated December 30, 2011. Unpublished document prepared by the Office of
Pesticide Programs, United States Environmental Protection Agency. 57p.
Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Human Research Protection
Program Plan (FIRPP Plan). Dated November 3, 2010. Unpublished document prepared by IIRB,
Inc. l3lp.
IIRB, Inc., 2011. IRB Membership Roster. Dated September 12, 2011. Unpublished document
prepared by IIRB, Inc. ip.
Leighton, T., C. Walls and K. Sherman. 2009. Science and Ethics Review of AEATF II Aerosol
Scenario Design and Protocol for Exposure Monitoring. Dated September 21, 2009.
Unpublished document prepared by Office of Pesticide Programs, United States Environmental
Protection Agency. 52p.
Leighton, T. 2012. Science Review of the AEATF II Aerosol Human Exposure Monitoring
Study. Dated January 3, 2012. Unpublished document prepared by Office of Pesticide Programs,
United States Environmental Protection Agency. 38p.
Sherman, K. 2012. Ethics Review of Completed AEATF II Aerosol Scenario Worker Exposure
Monitoring Study. Dated January 4, 2012. Unpublished document prepared by the Office of the
Director, Office of Pesticide Programs, United States Environmental Protection Agency. 2Op.
Testman, R.J. and M.T. Boatwright, for the AEATF II. 2011. A Study for Measurement of
Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial
Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting. Dated
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November 14, 2011. Unpublished document prepared by the Golden Pacific Laboratories, LLC,
fortheAEATF II. l85lp. MRID 48659001.
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