EPA-HSRB-19-2
Dr. Jennifer Orme-Zavaleta
EPA Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: April 24th, 2019 EPA Human Studies Review Board Meeting Report
Dear Dr. Orme-Zavaleta,
The United States Environmental Protection Agency requested that the Human
Studies Review Board provide scientific and ethics review of a completed human study
sponsored by the Agricultural Handler Exposure Task Forces, LLC (AHETF). The AHETF
Study Report and Monograph (AHE600 and AHE1023) summarize completed research that has
monitored the potential dermal and inhalation exposure for workers who perform open pour
mixing, loading and application activities, and where appropriate associated equipment clean-up
activities, using powered handgun equipment to make foliar applications in managed
horticultural facilities (nurseries and greenhouses).
The Board's responses to the charge questions presented at the April 24, 2019 meeting along
with detailed rationale and recommendations for their conclusions on this study are provided in
the enclosed final meeting report.
Jennifer Cavallari, ScD, CIH
Chair
EPA Human Studies Review Board
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INTRODUCTION
On April 24th, 2019, The United States Environmental Protection Agency (EPA or Agency)
Human Studies Review Board (HSRB or Board) met to address the scientific and ethical charge
questions related to a completed study involving human participants measuring dermal and
inhalation exposure for workers who perform open pour mixing, loading and application
activities, and, where appropriate, associated equipment clean-up activities such as using
powered handgun equipment to make foliar applications in managed horticultural facilities
(nurseries and greenhouses). In accordance with 40 CFR 26.1601, EPA sought HSRB review of
this completed study. The study is discussed more fully below.
REVIEW PROCESS
The Board conducted a public meeting via virtual meeting on April 24Ih, 2019, Advance notice
of the meeting was published in the Federal Register as "Human Studies Review Board;
Notification of a Public Meeting" (EPA, FRL-9991-24-ORD) This Final Report of the meeting
describes the HSRB's discussion, recommendations, rationale and consensus in response to the
charge questions on ethical and scientific aspects of the Agricultural Handler Exposure Task
Forces, LLC (AHETF) completed research, Dermal and Inhalation Exposure to Workers during
Mixing, Loading and Application of Pesticides in Managed Horticultural Facilities using
Powered Handgun Equipment as presented in the study report (AHE600) and monograph
(AHE1023).
Agency staff presented their review of scientific and ethical aspects of the study, with each
presentation followed by clarifying questions from the Board. The HSRB solicited public
comments and then took up the charge questions under consideration. The Board discussed the
science and ethics charge questions and developed a consensus response to each question in turn.
For each of the charge questions, the Chair called for the Board to vote to confirm concurrence
on a summary statement reflecting the Board's response.
For their evaluation and discussion, the Board considered presentations given by EPA staff at the
meeting, oral comments from Agency staff and the investigators during the meeting discussions,
as well as the information contained within the following documents: AHETF AHE600 Study
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Report, AHETF AHE600IRB Correspondence Report, AHETF AHE1023 Monograph; EPA's
science and ethics review memos, and AHE600 monograph data tables; the January 26, 2012
Board Meeting report all of which were provided to the Board prior to the meeting..
Charge to the Board- Science:
Is the research presented in AHE600 and the associated documents scientifically sound,
providing reliable data useful for assessing the exposure of those who manually open, pour and
mix pesticide products in spray solution tanks and apply the solutions using powered handgun
equipment in managed horticultural facilities such as greenhouse and nurseries?
Response to the charge question:
The HSRB concluded that the research presented in AHE600 and the associated documents are
scientifically sound, and provide reliable data useful for assessing the exposure of those who
manually open, pour and mix pesticide products in spray solution tanks and apply the solutions
using powered handgun equipment in managed horticultural facilities such as greenhouse and
nurseries.
The Board also has specific recommendations and additional minor points which are described
the discussion below.
HSRB Detailed Review and Recommendations:
HSRB reviewed information provided in advance of the meeting, as well as the EPA scientific
and ethics presentations provided at the meeting. The Board noted and agreed with the EPA's
assessment including: the study followed the protocol with amendments and deviations
appropriately documented, and the analytical field and laboratory recovery results were
acceptable. Furthermore, the Board agreed with EPA's assessment that the study is acceptable
and appropriate for use in assessing exposure and risk for workers applying pesticides with
handgun equipment in facilities such as greenhouses and nurseries. The workers' activities
consisted of opening liquid or dry flowable pesticide products, manually mixing and/or loading
the product into a spray solution tank, then spraying the solution on ornamental
potted/hanging/bench plants or vegetables using gas-, electric-, or battery-powered handheld

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spray guns or wands. Dermal exposures were measured using hand washes, faee/neck wipes, and
whole-body dosimeters. Dermal exposures were extrapolated to areas covered by eye protection
and or respirators. Patches on top and beneath head chemical resistant hats were used to
represent exposure without head protection. In effect, exposure monitoring aims to represent a
worker wearing long-sleeved shirts, pants, shoes/socks and chemical resistant gloves.
Inhalation exposure was determined using personal air monitors air sampling pumps and OSHA
Versatile samples (OVS) mounted on the shirt collar. An inhalation rate of 16.7 L/min was
assumed for light activity. Environmental conditions of temperature, humidity, wind speed and
direction and rainfall were recorded. Small holes (3) in worker clothing were repaired prior to the
study monitoring. Researchers verified that clothing worn by subjects was clean.
The AHE600 protocol included specific restrictions (called similarity restrictions (SR)) to build
variability into the study. Within one study location, all three MEs must have different degrees
of openness or enclosure (SR 4) and each pair of MEs must have a difference in one of a number
of characteristics such as container size, formulation or hose attachment (SR 6). SR4 was not met
(protocol deviation made this allowed change), while SR 6 was met.
Although 30 monitoring events (MEs) were planned, 3 MEs were excluded due to deviations,
providing a final count of 27 MEs. A "10 x 3" configuration was planned to meet study
objectives (i.e., 3 subjects in each of 10 location). However, recruiting difficulties caused a
deviation from the original "10 x 3" configuration resulting in 17 monitoring locations with 1 to
4 subjects per location. Analytical field and laboratory recovery results mostly averaged between
70 and 120% recovery, with coefficients of variation less than 25% again for the majority of
results.
Within the final dataset including 27 unique workers, subjects ranged in age from 22 years to 60
years. There were 6 females and 21 males. Years of experience ranged from 1 year to 42. The
total product loaded over the ME varied from 0.152 oz. to 6 lbs. Exposure times ranged from 0.6
to 8.5 hours and the amount of active ingredient handled ranged from 0.0023 to 5.85 lbs.
Observation on subject activities/behaviors were recorded to potentially account for unusual
deviations in measurements.
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There were 9 protocol amendments and 3 protocol deviations. Protocol amendments occurred to
account for additional surrogate active ingredients and allow for varied recruitment strategies.
Protocol deviations resulted in the exclusion of 3 ME's (their data was invalidated).
The primary objective was not met. Estimates of arithmetic mean and the 95th percentile dermal
exposure were not within 3-fold accuracy with 95% confidence. EPA plans to incorporate a
multiplier to incorporate additional uncertainty beyond the 3-fold target level, which the Board
supports. Although in the data that there is a relationship (positive upward trend) evident
between pounds active ingredient and dermal/inhalation exposure, proportionality may be weak.
HRSB and EPA in 201.2 made a numbei of comments based on the review of the protocols in
2012. Most comments referred to human subject clarification on risks and additional notes to the
consent form, and were revised accordingly.
Recommendations
The Board recommends that EPA consider the following when using the data.
Accounting for hat residues: The chemical resistant hat was not analyzed. Ideally the residues
from the hat would be combined with the inner and outer patches. Since residues were found on
the inner patch, consider adding a safety factor on total head exposure to account for what is lost
on the hat.
Activity level for inhalation calculations: If subjects are lifting/pulling anything during the
application period, a moderate activity level can be assumed. EPA can consider using higher
inhalation rate in calculating inhalation exposures based on a moderate activity level.
Extrapolating hand exposures with respect to glove use: If some pesticide application labels do
not require the use of chemical-resistant gloves, dermal exposure estimates may be higher than
anticipated. EPA should consider extrapolating exposure to the hand when no glove is used.
Hand wand versus hand gun: For dermal exposures, there was a non-linear relationship between
amount of AaiH and log of total dermal exposure. The Board recommends analyzing the
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relationships between dermal exposure and AaiH separately for workers who used the hand
wand versus the hand gun during application. The application method (hand wand versus hand
gun) may be a large source of variability and modeling them separately may better elucidate the
relationship between dermal exposure and AaiH.
Exposure time and amount of solution sprayed: Due to the high variability in both amount of
solution sprayed and exposure time, the Board recommends evaluating the relationship between
exposure time and amount of solution sprayed or exposure time and the dermal or inhalation
measurements.
Statistical review. In general, the proposed statistical design and analysis of the protocol are
appropriate for EPA's intended use of the data. A detailed review follows.
Appropriate standard curves met AHETF accuracy requirements. Quality control samples were
successfully analyzed at routine intervals with each batch of field study samples. Standard curves
based on a set of standard concentrations versus the corresponding peak area responses were
utilized in order to determine concentrations of the analyte found during sample analysis from
the calculated regression line. Analytical data for the study samples were calculated and acquired
using automated software applications based on the appropriate regression equation for each
analytical set of samples.
For seven surrogates (i.e., acephate, azoxystrobin, ehlorothalonil, fosetyi-aluminum,
imidacloprid, mefenoxam, thiophanate-methyl), the response of the detectors used in the
analyses was linear over the range of residues in the samples. For seven surrogates (i.e.,
acephate, azoxystrobin, ehlorothalonil, fosetyi-aluminum, imidacloprid, mefenoxam,
thiophanate-methyl), concurrent recoveries were measured with each set of samples to verify
method performance. For acephate, fosetyi-aluminum, mefenoxam, and thiophanate-methyl,
interferences for concurrent laboratory controls were less than the LOD for all the samples
evaluated for each matrix.
For acephate, the correlation coefficients (r) were >= 0.993. For azoxystrobin, the correlation
coefficients (r) were >= 0.994. For ehlorothalonil, the correlation coefficients (r) were >= 0.985.
For fosetyi-aluminum, the correlation coefficients (r) were >= 0.990. For imidacloprid, the
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correlation coefficients (r) were >= 0.984. For mefenoxam, the correlation coefficients (r) were
>= 0.998. For thiophanate-methyl, the correlation coefficients (r) were >= 0.996.
For azoxystrobin, interferences for concurrent laboratory controls were less than the LOD for all
the samples evaluated for each matrix, except for 2 samples: 1 of 11 faee/neck wipe controls and
1 of 11 OVS tube controls. The residues found were slightly higher than the LOD except for one
of the hand wash controls that contained about 10-times the LOD. For chlorothalonil,
interferences for concurrent laboratory controls were less than the LOD for all the samples
evaluated for each matrix, except for: 3 of 6 inner dosimeter controls and 4 of 6 OVS tube
controls. For imidacloprid, interferences for concurrent laboratory controls were less than the
LOD for all the samples evaluated for each matrix except for 7 samples: 2 of 12 inner dosimeter
controls, 1 of 10 head patch controls, 3 of 12 sock controls, and 1 of 12 OVS tube controls. The
residues found were slightly higher than the LOD except for the OVS tube control that contained
about 10-times the LOD.
For almost all of the surrogates and matrices, LODs were successfully determined using a one-
tailed t-statistic on a minimum of seven fortification sample recoveries at the LOQ from the
method validation trial using a procedure recommended by EPA (EPA, 2000). However, a
theoretical LOD was calculated as a percentage of the LOQ for these surrogate/matrix
combinations. Several sample results were below the LOQ and/or LOD. The following
chromatography and detection methods used were used:
*	Acephate: GC coupled with flame photometric detection operating in the phosphorus
specific mode (GC-FPD).
*	Azoxystrobin, imidacloprid, mefenoxam, and thiophanate-methyl: HPLC coupled
with positive-ion electrospray tandem mass spectrometric detection (LC/MS/MS).
*	Chlorothalonil: gas chromatography coupled with electron capture detection
(GCECD).
*	Fosetyl-aluminum: HPLC coupled with negative-ion electrospray tandem mass
spectrometric detection (LC/MS/MS).
The amount of active ingredient in the test substances handled by subjects was successfully
determined based on a sample of each lot of test substance. The results of these analyses were
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used to determine the actual amount of active ingredient handled (AaiH) by each study
participant. Each of the 27 valid MUs in this scenario handled a single lot of test substance, so a
total of 27 different lots were analyzed. All 27 lots assayed within ±3% of the nominal
concentration shown on the product label, except for the test substance sample for MU 01 which
was 13% above the nominal concentration.
Secondary benchmark was successfully met. Analysis shows results are consistent with study
design of at least 80% power. These statistical procedures were deemed appropriate. The
research presented in AHE600 and the associated documents is scientifically sound, providing
reliable data useful for assessing the exposure of those who manually open, pour and mix
pesticide products in spray solution tanks and apply the solutions using powered handgun
equipment in managed horticultural facilities such as greenhouses and nurseries.
CHARGE TO THE BOARD - ETHICS
Does the available information support a determination that the study was conducted in
substantial compliance with the applicable requirements of 40 CFR part 26?
Response to the charge question:
The Board believes that this study was conducted in substantial compliance with the applicable
requirements of 40 CFR part 26.
HSRB detailed recommendations and rationale:
The Agency's rules at 40 CFR part 26 subpart Q that are applicable to this review include the
following: §26.1703: Except as provided in §26.1706, EPA must not rely on data from any
research subject to this subpart involving intentional exposure of any human subject who is a
pregnant woman (and therefore her fetus), a nursing woman, or a child. And §26.1705: Except as
provided in §26.1706, EPA must not rely on data from any research subject to this section unless
EPA determines that the research was conducted in substantial compliance with all applicable
provisions of subparts A through L of this part.
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The Final Report and supporting materials submitted by AEATFII for EPA review indicate that
all planned recruitment procedures were followed in the conduct of the study. Thirty-four
potential participants signed an informed consent document and 30 subjects were monitored.
For the 6 female subjects who completed study assessments, pregnancy testing was performed on
the day of the monitoring procedures to ensure that pregnant women were not included in the
study. Nursing women were excluded by the eligibility criteria.
The informed consent process was performed in an appropriate way, with privacy provided for
the consent discussion with potential participants. A Spanish translation of the consent document
was provided and a Spanish-speaking research team member was present for both the consent
discussion and the research procedures day, for participants who asked to communicate in
Spanish. Modifications to the consent process including reading the consent document out loud
were in place for potential participants who were not literate.
Compensation for study participation included $20 for the consent discussion, and $80 for
participation in the study monitoring. Payment was provided in cash at the end of each activity.
The amount of compensation is reasonable and unlikely to cause undue influence on the decision
to participate in the study.
Risks of the study participation were minimized by compliance with the protocol. Risks that
were considered were related to surrogate chemical exposure and surfactants in the skin wipes
used. The researchers incorporated all comments from the EPA HSRB in the initial protocol
review, to reduce study risks. Subjects were also monitored for heat-induced illness during the
monitoring period of the study, with a plan for action and care of heat illness should this be
necessary. No adverse events were reported in the clinical study report.
Privacy of participants was respected by providing a private location for them to change clothing
on the monitoring days, and if assistance was needed to change into the garments for the study, a
same-gender researcher was available to assist. Confidentiality of pregnancy testing results was
identified as a potential risk, and appropriate measures were taken to ensure that testing was
conducted and the results communicated in a confidential manner.
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The initial protocol, nine protocol amendments, annual continuing reports, and all ancillary
materials including recruitment materials were reviewed and approved by an AAHRPP-
accredited independent institutional review board (IRB). The IRB performing the initial approval
was Independent Institutional Review Board, which was acquired by Schulman Associates
Institutional Review Board, which then became Advarra Institutional Review Board, The events
of protocol non-compliance were reported to the IRB, none were considered serious or
continuing. Two protocol deviations were reported to the IRB. None of the reported events had
any impact on the safety, welfare or rights of study participants.
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