August 25, 2016
EPA-HSRB-16-2
Thomas A. Burke, Ph.D., MPH
EPA Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: July 12-13, 2016 EPA Human Studies Review Board Meeting Report
Dear Dr. Burke,
The United States Environmental Protection Agency (EPA) requested that the Human Studies
Review Board (HSRB) provide scientific and ethics reviews of two completed studies from the
Agricultural Handler Exposure Task Force (AHETF). These two studies were reviewed at a
meeting of the Board on July 12-13, 2016:
•	The Completed Study and Monograph Report for Agricultural Handler Exposure
for Wettable Powders
•	The Completed Study and Monograph Report for Agricultural Handler Exposure
during Mixing/Loading of Pesticide Products in Water Soluble Packets
The Board's responses to the charge questions are detailed in the enclosed final report of the
meeting.
Signed,
Liza Dawson, PhD
Chair
EPA Human Studies Review Board
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INTRODUCTION
On July 12-13, 2016, the United States Environmental Protection Agency's (EPA or Agency)
Human Studies Review Board (HSRB or Board) met to address the scientific and ethical charge
questions related to two studies conducted by the Agricultural Handlers Exposure Task Force
(AHETF):
•	The Completed Study and Monograph Report for Agricultural Handler Exposure
for Wettable Powders (AHE80)
•	The Completed Study and Monograph Report for Agricultural Handler Exposure
during Mixing/Loading of Pesticide Products in Water Soluble Packets (AHE 120)
REVIEW PROCESS
The Board conducted a public meeting on July 13-14, 2016. Advance notice of the meeting was
published in the Federal Register as "Human Studies Review Board; Notification of a Public
Meeting" (FRL-9947-46-ORD).
This Final Report of the meeting describes the HSRB's discussion, recommendations, rationale
and consensus in response to each charge question for each of these items.
For each agenda item, Agency staff first presented their review of the science and the Board
asked the Agency presenters clarifying questions. The staff then described their review of the
ethical aspects and the Board asked clarifying questions with regard to the ethical review. The
HSRB solicited public comments and next proceeded to address the charge questions, first
discussing scientific review and then ethical review, for each study. The Chair called for a vote
to confirm concurrence on a summary statement in response to each charge question.
For their evaluation and discussion, the Board considered study reports, related materials and
documents such as standard operating procedures provided by the AHETF, the Agency's science
and ethics reviews of the studies, as well as oral responses from the AHETF and from EPA staff
at the meeting. A comprehensive list of background documents is available online at
http ://www. epa. gov/hsrb/.
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The HSRB review of the two AHETF studies is presented below. This report presents the
board's finding for each study in the order in which the studies were reviewed at the meeting.
Because some of the same scientific concerns were raised for the two studies, the report makes
note of the common issues raised but does not duplicate the discussion of issues when identical
concerns were raised in the two reviews.
HSRB review of the Completed Study and Monograph Report for Agricultural Handler
Exposure for Wettable Powders (AHE80 and AHE1015)
Science Review
Charge to the Board
1.	Was the research reported in the Agricultural Handler Exposure Task Force (AHETF)
completed monograph report and associated field study report for AHE80 faithful to the
design and objectives of the protocol?
2.	Did the research generate scientifically reliable data, useful for assessing the exposure of
individuals who mix and load conventional pesticides formulated as wettable powders?
Board Response
1.	The research reported in the Agricultural Handler Exposure Task Force (AHETF)
completed monograph report (AHE1015) and associated field study report (AHE80) were
faithful to the design and objectives of the protocol.
2.	The research generated scientifically reliable data, useful for assessing exposures related
to conventional pesticides formulated as wettable powders, subject to recognition of some
limitations in the data, as described below.
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HSRB Detailed Recommendations and Rationale
The Board commented that the study was well conducted and adherent to the protocol and
research plan. However, given recruitment challenges and limited diversity of scenarios
available for inclusion in the study, there are some limitations in the data that affect the
conclusions that can be drawn from this study. In spite of consistent effort on the part of the
study team to collect sufficient data to address study goals, there were three areas in which the
study results were less than optimal: a) limited diversity in scenarios; b) failure to confirm
proportionality of exposure with AaiH and c) uncertainty in estimates of inhalation exposures
due to high variability. Each of these will be discussed in more detail below.
Given the limited use of wettable powder in current agricultural practice, in addition to ongoing
challenges of locating enough companies interested in participating, there were challenges in
recruiting sufficient numbers of monitoring units (MUs) for the study. In addition, the lowest
AaiH stratum was not populated and therefore the range of AaiH was not as broad as desired to
achieve better statistical power. The EPA scientific review acknowledged these limitations1 but
accepted them as unavoidable given current practices in the field and difficulties in recruiting.
The HSRB agreed with this assessment.
Sufficient diversity was not achieved with regard to the type of mixing tank used.2 This reflects
the original concern from the HSRB review3 about breadth and representativeness of scenarios
but again, EPA reviewers provided a rationale for accepting this deficiency, given that the
wettable powders are not commonly used, so it is difficult to recruit sufficient diversity in
equipment. The HSRB also agreed with this conclusion.
Furthermore, the data collected are neither fully observational nor random (representative) but
EPA recognizes and accepts this limitation and maintains that the new data is clearly an
1	Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division. Review of Agricultural
Handler Exposure Task Force (AHETF) Monograph: "Open Pour Mixing/Loading of Wettable Powders"
(AHE1015), page 9.
2	Baugher, Douglas and Rosenheck, Leah. (2016) Determination of Dermal and Inhalation Exposure to Workers
during Mixing/Loading Wettable Powders in the United States. Study Number AHE80, 796 p. January 27, 2016
(MRID 49841201)
3	Philpott, S. October 27-28, 2010 EPA Human Studies Review Board Final Report, EPA-HSRB-10-02, (December
13,2010).
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improvement over the earlier (PHED) data.4 Limitations of existing database and need for new
data are explained and need for new data clearly justified in the AHE1015 report,5 and the HSRB
concurs.
A key assumption for the validity of the study is that the exposure measurements are independent
of the type of active ingredient handled—and that therefore results from this study should be
suitable for extrapolation to other active ingredients used in the field. The AHE report states
"Exposure is not determined by the properties of the active ingredient in a product but rather by
physical factors ... ,"6 This may not be true in all cases, although in the case of the wettable
powder mixing/loading scenario as tested in AEH80 and AEH39 the statement is likely true, but
this should not be generalized to all exposure scenarios. A second critical assumption is
proportionality of exposure to AaiH. The latter assumption of proportionality was not
demonstrated in the study, but in part this may be due to the limited AaiH and small number of
MUs.
Two observations may also be helpful for understanding the data: 1) most of the workers wash
gloves with water then remove gloves between loadings and 2) some of the subjects actually got
wet during the loading (likely to impact dissolution and transfer of S through outer clothes).
In terms of statistical soundness, the study met the primary criterion of estimating exposure to
within three-fold accuracy for dermal exposure. For dermal exposure, it was notable that Subject
M13 is a potential outlier because of unusually small exposure value. The data from M13 was
included in the analysis. For geometric and arithmetic means and 95th upper confidence limit, all
estimates were within three-fold accuracy.
4	Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division. Review of Agricultural
Handler Exposure Task Force (AHETF) Monograph: "Open Pour Mixing/Loading of Wettable Powders"
(AHE1015)
5	Baugher, Douglas and Rosenheck, Leah. (2016) Determination of Dermal and Inhalation Exposure to Workers
during Mixing/Loading Wettable Powders in the United States. Study Number AHE80, 796 p. January 27, 2016
(MRID 49841201) page 25
6	Baugher, Douglas and Rosenheck, Leah. (2016) Determination of Dermal and Inhalation Exposure to Workers
during Mixing/Loading Wettable Powders in the United States. Study Number AHE80, 796 p. January 27, 2016
(MRID 49841201) Page 26
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In contrast, inhalation exposure was not a priority for the three-fold accuracy requirement as part
of the study, based on EPA's statement of objectives.7 Subject M13's inhalation exposure value
was within the range of the data from the remaining subjects and hence, not a potential outlier.
Most of the exposure statistics estimates were not within three fold accuracy.
The secondary statistical objective was to test for a proportional relationship between exposure
and amount of active ingredient handled versus independence (no linear relationship) with at
least 80% power. Assuming a straight line model for exposure as a function of amount of active
ingredient handled (with or without accounting for the correlation structure generated by the
design), testing the hypotheses
Ho: slope = 1 (proportionality)
Hi: slope = 0 (independence)
is equivalent to checking for one or zero in the 95% confidence interval for the slope.
For dermal exposure, when subject Ml3 was included, the confidence interval for the slope
contained both 1 and 0 indicating that both proportionality and independence are feasible. Hence,
the results should be considered as inconclusive. When subject Ml3 was not included, the
confidence interval for the slope contained 1 but did not contain 0 indicating consistency with a
proportionality assumption. However, based on the confidence interval width, the 80% power
requirement was not met.
For inhalation exposure, when subject M13 was included, the confidence interval for the slope
contained 1 but did not contain 0, indicating consistency with a proportionality assumption.
However, based on the confidence interval width, the 80% power requirement was not met.
In conclusion, the principal criterion of three-fold accuracy was met for dermal exposure in the
study; the other statistical criteria (three fold accuracy for inhalation and 80% power to
determine proportionality for either dermal or inhalation) were not met. Given the limited
diversity and small sample size, these results are not surprising.
7 Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division. Review of Agricultural
Handler Exposure Task Force (AHETF) Monograph: "Open Pour Mixing/Loading of Wettable Powders"
(AHE1015), page 10
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Ethics Review
Charge to the Board: Does the available information support a determination that the studies
were conducted in substantial compliance with subparts K and L of 40 CFR Part 26?
Board Response to the Charge: The Board concurred with the EPA assessment that available
information supports a determination that the studies were conducted in substantial compliance
with 40 CFR 26 subparts K and L.
HSRB Detailed Recommendations and Rationale
The protocol was reviewed and approved by an independent human subject review committee,
Independent Institutional Review Board, Inc. (IIRB, Inc.) of Plantation, FL (initial submission
9/30/10) and Schulman Associates IRB, Inc. (SAIRB) of Cincinnati, OH/Ft. Lauderdale, FL
prior to submission and as the study progressed [note: during the conduct of this study, IIRB was
acquired by Schulman Associates IRB on 10/24/12](AHE80 - IRB Correspondence Report 3-23-
16). Both IRBs are fully accredited by the Association for the Accreditation of Human Research
Protection Programs (AAHRPP). Minutes of IRB meetings and copies of all correspondence
were provided to the Agency. These documents indicate that the IRBs reviewed this protocol,
amendments and reports in accord with the standards of the Common Rule (40 CFR Part 26,
Subpart A).
The informed consent materials (AHE80 - IRB Correspondence Report 3-23-16, pp. 44-58; 143-
154; 225-234; 248-259; 297-318; 338-350; and 351-364[Spanish]) contained adequate
information for the subjects (n=21) about the risks, discomforts and benefits of participation, and
of their right to withdraw (n=2). The risk-benefit ratio was determined to be acceptable and risks
were minimized appropriately and were justified by the potential societal benefits associated
with gathering data to determine the potential exposure for workers who mix and load wettable
powder formulations using open pouring techniques. The selection of study participants (English
or Spanish speaking) appeared to be equitable and no children or pregnant women were enrolled.
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The submitted documents (AHE80 - Field Study Report Final 01-27-16, Heat Index from Field
Notebooks for AHE80, and AHE1015 Monograph for Wettable Powder Mixer Loader - Final 4-
7-16 [especially section 4.0]) indicate that the study was 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 Good Laboratory Practice (GLP) Standards described at 40 CFR 160. For the
research conducted in California ("Area 84" of study AHE80), the requirements of the California
State EPA Department of Pesticide Regulation study monitoring (California Code of Regulations
Title 3, Section 6710) (Ref 2010) applied. Requirements of FIFRA §12(a)(2)(P) also applied.
Researchers who participated in the study and interacted with study participants were required to
complete ethics training.
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HSRB review of the Completed Study and Monograph Report for Agricultural Handler
Exposure during Mixing/Loading of Pesticide Products in Water Soluble Packets (AHE
120 and AHE 1014)
Science Review
Charge to the Board
•	Was the research reported in the Agricultural Handler Exposure Task Force (AHETF)
completed monograph reports and associated field study report for AHE120 faithful to
the design and objectives of the protocol?
•	Did the research generate scientifically reliable data, useful for assessing the exposure of
individuals who mix and load conventional pesticides formulated in water soluble
packets?
Board Response
•	The research reported in the AHETF completed monograph reports and the associated
field study report for AHE120 was faithful to the design and objectives of the protocol.
•	The research did generate scientifically reliable data, useful for assessing the exposure of
individuals who mix and load conventional pesticides formulated in water soluble
packets, subject to some limitations in the data, as discussed below.
HSRB Detailed Recommendations and Rationale
Much of the discussion of the AHE 120 study was similar to that for the previous study of
wettable powders. There was a small number of MUs and limited diversity in the sample, again
due to recruitment difficulties. Barring unresolved concerns raised in the previous review
regarding conflicts between the non-random, purposive study design and conventional statistical
methodology, the study generated scientifically reliable data that may be useful for assessing
exposure of individuals who mix and load conventional pesticides formulated in water-soluble
packets.
In a previous review the HSRB had commented that time on task might be an appropriate
measure to help capture variability in exposures for a given AaiH. It does not appear that the
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ratio of time on task to the total monitored time was calculated. Regarding study design it should
be noted that only 16 of the 25 sets of monitoring unit samples were used in the analysis given
that nine MUs were invalidated due to equipment use or practices that were deemed
inappropriate for the scenario; therefore the final sample size was smaller than planned. A total
of 15 Amendments with no protocol deviations were reported and the amendments were
considered to be scientifically appropriate. Of minor concern is the lack of an executive
summary to capture the salient findings of the study.
Regarding the statistical aspects of the study, the primary benchmark objective is for select
statistics (the geometric mean (GM), the arithmetic mean (AM), and the 95th percentile (P95)) to
be accurate within 3- fold with 95% confidence. The primary benchmark of 3-fold accuracy for
select statistics was met for both dermal but not for inhalation exposure data. The AHETF
demonstrated both dermal and inhalation unit exposures were shown to fit lognormal
distributions reasonably well.
The secondary objective of the study design is to be able to distinguish complete proportionality
from complete independence between dermal exposure and amount of active ingredient handled
with an 80% statistical power. The AHETF performed regression analysis of ln(exposure) and
ln(AaiH) to determine if the slope is 1 (which provides support for a proportional relationship) or
0 (which provides support for an independent relationship). Simple linear regression and mixed-
effects regression (that accounts for within-cluster correlation) were performed to evaluate the
relationship between exposure and AaiH. A confidence interval of 1.4 (or less) indicates at least
80%) statistical power. Based on the AHETF analysis, this benchmark was met and analyses for
both dermal and inhalation exposure had 80%> power to detect proportionality or independence.
The 95% confidence interval slope of the mixed-effects regression suggested a proportional
relationship is more plausible than an independent one based on data.
Ethics review
Charge to the Board:
Does the available information support a determination that the research was conducted in
substantial compliance with 40 CFR part 26, subparts K and L?
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Board Response:
The available information supports a determination that the research was conducted in
substantial compliance with 40 CFR part 26, subparts K and L.
HSRB Detailed Recommendations and Rationale:
This protocol (AHE 120) was reviewed by the HSRB at its October 2010 meeting8 and
subsequently reviewed and approved by the Independent Institutional Review Board (IIRB), Inc.
of Plantation, Florida in December 2010. According to the HSRB's December 13, 2010 Final
Report, IIRB was fully accredited by the Association for the Accreditation of Human Research
Protection Programs (AAHRPP) and listed as an active IRB by the Office for Human Research
Protections (OHRP) at the time of IRB review. IIRB was later purchased by Schulman
Associates IRB (SAIRB), though that transaction had no adverse impact on the IRB review
process for this protocol. SAIRB is also fully accredited by AAHRPP and listed as an active IRB
by OHRP. The July 31, 2015 IRB Correspondence Report for Study AHE120 indicate that the
IRB of oversight reviewed the protocol and its 15 subsequent amendments in accordance with
their responsibilities under subpart K. Amendments were not implemented until after receiving
IRB approval.
The greatest risk to participants in this study was the potential for heat-related illness because
they were required to wear two layers of clothing. However, the study protocol contained
oversight by an on-site medical professional and appropriate stopping measures (including
cessation of monitoring activities when the ambient heat index exceeded 105°F). There were no
heat-related adverse events reported in the AHE 120 Study Report of IRB Correspondence
Report.
8 Philpott, S. October 27-28, 2010 EPA Human Studies Review Board Final Report, EPA-
HSRB-10-02, (December 13, 2010).
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Risks were further minimized by enrolling only participants who were experienced in the mixing
and loading by open pouring and by requiring training in safe pesticide handling procedures in
accordance with the Worker Protection Standard (WPS) or be exempt from such training.
The study followed an appropriate IRB-approved consent process. The informed consent
document was translated into Spanish and the consent process for four participants was led by a
bilingual researcher. Spanish language materials were IRB approved.
Recruitment procedures for this study followed AHETF Standard Operating Procedures (SOPs)
for recruitment. An HSRB ethicist reviewer expressed concern about the lack of women enrolled
in the study, but information provided in the EPA ethics review during the HSRB meeting
indicated that past experience strongly suggests that the general working population who engages
in mixing and loading activities is overwhelmingly male, hence the all-male study population.
This additional information assuaged the concerns of the HSRB ethicist reviewer.
AHETF SOPs, the AHE 120 protocol, and the AHE 120 informed consent document indicated
that personal exposure results would be provided to participants upon request. At the July 13,
2016 meeting, AHETF representatives confirmed that those personal results had been given to all
participants whose data were analyzed. For those two individuals who requested personal results
but for whom none were available, they were informed of the lack of personal results.
Concerning subpart L considerations, the AHE 120 protocol specifically excluded pregnant or
lactating women and minors from study participation. There was a pregnancy screening process
approved by the IRB and deemed acceptable by HSRB in its December 2010 Final Report.
However, no females enrolled in the study.
For these reasons, the HSRB concludes that the available information supports a determination
that the research was conducted in substantial compliance with 40 CFR part 26, subparts K and
L.
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References
Baugher, Douglas and Rosenheck, Leah. (2016) Determination of Dermal and Inhalation
Exposure to Workers during Mixing/Loading Wettable Powders in the United States. Study
Number AHE80, 796 p. January 27, 2016 (MRID 49841201)
Baugher, Douglas. (2016) IRB Correspondence Report for Study AHE80. Related Submissions.
Study Report AHE80 and Scenario Monograph Report No. AHE1015. 667 p. plus 337A. March
23, 2016. (MRID 49893002)
Baugher, Douglas. (2015) IRB Correspondence Report for Study AHE120. Related Submissions.
Study Report AHE120 and Scenario Monograph Report No. AHE1014. 951 p. July 31, 2015.
(MRID 49687701)
Canez, Victor and Baugher, Douglas. (2015) Determination of Dermal and Inhalation Exposure
to Workers during Mixing/Loading of Pesticide Products in Water Soluble Packets in the United
States. Study Number AHE120, 652 p. plus page 313A, July 21, 2015 (MRID 49680501)
Klonne, Dennis R. and Holden, Larry R. (2015) Scenario Monograph Report. Agricultural
Handler Exposure Scenario Monograph: Mixing/Loading of Pesticide Products in Water Soluble
Packets. Report Number AHE1014, 203 p., August 27, 2015 (MRID 49711901)
Klonne, Dennis R. and Holden, Larry R. (2016) Scenario Monograph Report. Agricultural
Handler Exposure Scenario Monograph: Open Pour Mixing/Loading of Wettable Powders.
Report Number AHE1015, 218 p., April 7, 2016 (MRID 49893001)
Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division.
Review of Agricultural Handler Exposure Task Force (AHETF) Monograph: "Mixing/Loading
of Pesticide Products in Water Soluble Packets" (AHE1014).
Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division.
Review of "Determination of Dermal and Inhalation Exposure to Workers During Mixing /
Loading of Pesticide Products in Water Soluble Packets in the United States" (AHE 120)
Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division.
Review of "Determination of Dermal and Inhalation Exposure to Workers During Mixing /
Loading Wettable Powders in the United States" (AHE80)
Crowley, Matthew (2016), EPA Chemistry and Exposure Branch Health Effects Division.
Review of Agricultural Handler Exposure Task Force (AHETF) Monograph: "Open Pour
Mixing/Loading of Wettable Powders" (AHE1015)
Lydon, Maureen, EPA Office of Pesticide Programs. (2016) Ethics Review of Completed
AHETF Study AHE80 on Worker Exposure during Mixing/Loading of Wettable Powders. June
21, 2016
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Lydon, Maureen, EPA Office of Pesticide Programs. (2016) Ethics Review of Completed
AHETF Study AHE120 on Worker Exposure during Mixing/Loading of Water Soluble Packets.
June 22, 2016
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