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EPA-HSRB-11-01

Paul Anastas, PhD

EPA Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject: January 26, 2011 EPA Human Studies Review Board Meeting Report

Dear Dr. Anastas,

The United States Environmental Protection Agency (EPA or Agency) requested that the 

Human Studies Review Board (HSRB) provide scientific and ethics reviews of one new protocol 

for a study involving intentional exposure of human subjects to pesticides: a proposed Agricultural Handler Exposure Task Force, LLC (AHETF) scenario measuring dermal and inhalation 

exposure of professional agricultural workers who perform open mixing and loading of pesticides formulated as wettable powders. 

The Agency also requested that the HSRB review five completed, interrelated studies of 

dermal and inhalation exposure of professional agricultural handlers who spray pesticides with 

closed-cab airblast equipment, conducted by the AHETF. These studies (AHE55, AHE56, 

AHE57, AHE58 and AHE59) were conducted after publication of the EPA’s expanded final rule 

for protection of subjects in human research (40 CFR 26) on February 6, 2006 (71 Federal Register 24, 6137). These studies were conducted under a single scenario monograph (MRID 

48314201), which incorporates the data from these five studies into a single dataset. This dataset 

will be posted to the Agricultural Handlers Exposure Database (AHED®), and used generically 

to estimate daily dermal and inhalation exposures of workers who treat agricultural crops with 

conventional pesticides using closed-cab airblast equipment. 

The enclosed report provides the Board’s response to EPA charge questions presented at 

the January 26, 2011 meeting.

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

Science

The Board concluded that the proposed AHETF scenario and field study proposal 

AHE80, if revised as suggested and performed as described, is likely to generate scientifically 

reliable data, useful for assessing the exposure of handlers who perform open mixing and loading 

of pesticide end use products formulated as wettable powders.
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Ethics

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

Assessment of Completed AHETF Research Studies AHE55, AHE56, AHE57, AHE58 and 

AHE59: Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of Liquid Sprays Using Closed Cab Equipment (MRID 48280601, 48289602, 48303501, 

48289604 and 48303502).

Science

The Board concluded that the research reported in the completed monograph, associated 

field study reports, and associated supplemental documents was conducted in a manner that was 

reasonably faithful to the design and objectives of the protocol and governing documents of the 

AHETF. 

The Board also concluded that the Agency has adequately, but not completely, considered the limitations on these data that should be considered when using the data in estimating 

the dermal and inhalation exposure of those who apply conventional pesticides with closed-cab 

airblast equipment. Additional limitations and concerns have been identified by the Board, and 

the conclusion as to the generalizability of these data requires further consideration and analysis.

Ethics

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

Sincerely,

Sean Philpott, PhD, MSBioethics

Chair

EPA Human Studies Review Board
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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.gov/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

Janice Chambers, PhD, DABT, Fellow ATS, William L. Giles Distinguished Professor, Director, 

Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State 

University, Mississippi State, MS

Members

George Fernandez, PhD, Professor of Applied Statistics, Director of the University of NevadaReno Center for Research Design and Analysis, University of Nevada-Reno, Reno, NV

Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor 

of Health Policy and American Studies, The George Washington University, Washington, DC

Sidney Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharmacology, Howard 

University College of Medicine, Washington, DC

Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University, 

Manhattan, KS

Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of 

Arizona, Tucson, AZ 

Jose E. Manautou, PhD, Associate Professor of Toxicology, Department of Pharmaceutical 

Science, University of Connecticut School of Pharmacy, Storrs, CT

Jerry A. Menikoff, MD, JD, Director, Office for Human Subjects Research, Office of the

Secretary, Department of Health and Human Services, Rockville, MD

*Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH) Human Risk Assessment, School of 

Public Health and Human Services, The George Washington University, Washington, DC

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

Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, Veterans Health Administration, Washington, DC
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Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 

Sciences, University of Florida, Gainesville, FL 

Human Studies Review Board Staff

Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science 

Advisor, United States Environmental Protection Agency, Washington, DC

* Not in attendance at January 26, 2011 Public Meeting
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INTRODUCTION

On January 26, 2011, the United States Environmental Protection Agency’s (EPA or 

Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues concerning one new protocol for research involving human participants: one new study measuring 

levels of exposure received by agricultural handlers when mixing and loading pesticides formulated as wettable powders under various conditions. In accordance with 40 CFR 26.1601, EPA 

sought HSRB review of this proposed protocol. The protocol is discussed more fully below.

In addition, the Agency has data from five completed, interrelated studies measuring levels of dermal and inhalation exposure received by pesticide applicators who spray pesticides 

with closed-cab airblast equipment. These studies were conducted under a single scenario monograph (MRID 48314201), which incorporates the data from these five studies into a single dataset. In accordance with 40 CFR 26.1602, EPA sought HSRB review of these five completed studies. The completed studies are discussed more fully below.

REVIEW PROCESS

On January 26, 2011, the Board conducted a public face-to-face meeting in Arlington, 

Virginia. Advance notice of the meeting was published in the Federal Register as “Human Studies Review Board; Notice of Public Meeting” (76 Federal Register 8, 2107).

Following welcoming remarks from Agency officials, the Board heard presentations from 

EPA on the following topics: one new study measuring levels of exposure received by agricultural handlers when mixing and loading pesticides formulated as wettable powders under various 

conditions, and five completed studies measuring dermal and inhalation exposure received by 

pesticide applicators who spray pesticides with closed-cab airblast equipment.

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

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

Public oral comments were provided by:

Dr. Victor Cañez, Technical Chair, AHETF

One written public comment was submitted by Ms. Barbara Sachau of Florham Park, NJ 

(writing under the pseudonym Ms. Jean Public). That comment did not specifically address any 

of the completed studies or proposed protocols under review at the January 26, 2011 meeting.

For their deliberations, the Board considered the materials presented at the meeting, oral 

comments, and Agency background documents (e.g., published literature, sponsor and investigator research reports, study protocols, data evaluation records, and Agency science and ethics reviews of proposed protocols and completed studies). A comprehensive list of background documents is available online at http://www.regulations.gov. 
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CHARGE TO THE BOARD AND BOARD RESPONSE

Assessment of Proposed AHETF Research Study AHE80: Determination of Dermal and 

Inhalation Exposure to Workers During Mixing/Loading Wettable Powders in the United 

States.

Overview of the Study

This proposal presents an agricultural handler exposure scenario involving pesticides 

formulated as wettable powders. The activities to be monitored in this scenario include a variety 

of mixing and loading activities, including pouring the wettable powder into a spray tank, preparing the pesticide in a separate holding tank and then transferring the formulated product into the 

pesticide application equipment, and mixing and transferring a concentrated slurry of the pesticide. The protocol calls for study participants to mix and load one of four surrogate pesticides: 

copper, DCPA (dacthal), sulfur or thiophanate-methyl. A total of 25 participants (described in 

the protocol as “Monitoring Units” [MUs]) will be observed for each scenario; five volunteers 

each from five geographically distinct growing regions will be enrolled using a purposive sampling method (with some elements of random selection).

Dermal exposure will be measured by a whole body dosimeter worn beneath the subject’s 

outer clothing. Hand wash and face/neck wipe samples will also be collected prior to, during, and 

after completion of pesticide loading and mixing procedures. Airborne concentrations of the surrogate will be monitored in the participant’s breathing zone using an OSHA Versatile Sampler 

(OVS) tube sample collector connected to a personal sampling pump. Additional measures will 

also record environmental conditions at the time of monitoring, and observers will make field 

notes, photographs and videos of participant activity throughout the monitoring event.

The results of sample analysis under the backpack and handgun application scenario will 

be posted to the Agricultural Handlers Exposure Database (AHED®), where they will be available to the EPA and other regulatory agencies for statistical analysis. The proposed documentation 

will report a confidence-interval-based approach to determine the relative accuracy for the arithmetic mean and 95th percentile of unit exposures. The Agency proposes to use these data to estimate daily dermal and inhalation exposures of agricultural handlers who are mixing and loading pesticides formulated as wettable powders under a variety of scenarios.

Science

Charge to the Board

If the proposed AHETF scenario and field study proposal AHE80 is revised as suggested 

in the EPA’s review and if the research is performed as described, is the research likely to generate scientifically reliable data, useful for assessing the exposure of handlers who perform open 

mixing and loading of pesticide end use products formulated as wettable powders?
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Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment that the proposed AHETF scenario 

and field study proposal AHE80, if revised as suggested in EPA’s review (Evans et al. 2010) and 

performed as described, is likely to generate scientifically reliable data, useful for assessing the 

exposure of handlers who perform open mixing and loading of pesticide end use products formulated as wettable powders.

HSRB Detailed Recommendations and Rationale

The Board concluded that the research is likely to generate scientifically reliable data, 

useful for assessing the exposure of handlers who perform open mixing and loading of pesticide 

end use products formulated as wettable powders. However, one significant concern was raised 

about how the new MUs should be distributed among the proposed strata particularly to achieve 

the second stated goal of the research. Several other less pressing questions were raised concerning information that was not presented clearly within the protocol.

A significant concern was expressed about how the new MUs should be distributed 

across the strata of amount of active ingredient handled (AaiH). On page 8 of 58 (and in essence 

again on page 14) in the Agency’s Review, the Agency states its desire that “the AHETF must 

ensure that all strata be used in each of the four remaining clusters” (Evans et al. 2010, 8). That 

desire may or may not be a conflict with an extrapolation of a statement on page 27 and 33 of 

that same document states a conclusion from the AHETF computer simulation runs that:

the primary benchmark will still be satisfied providing:

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

• No new cluster has more than five MUs.

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

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

the distribution of MUs among strata. 

If the five MUs in each new cluster include all five of the strata, there will be four new 

MUs at each stratum. When these four MUs are added to the five MUs that were already completed within the middle stratum, the final distribution of MUs across the five strata will be: 4, 4, 

9, 4, and 4. Such a distribution is not optimal to achieve the secondary objective of 80% power to 

test for proportionality between dermal exposure and AaiH. Power is increased when more observations are made at extreme values of AaiH, whereas the middle set of values will be over 

sampled here. The Board recommended using further simulations to explore the effect of the distribution of MUs among AaiH strata on the power associated with Objective 2, viz. the proposed 

distribution , making allocations so that the number of MUs is the same within all strata, or having an allocated distribution intermediate to these two extremes. 
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The primary objective is to estimate the geometric mean, the arithmetic mean, and the 

95th percentile of exposure within 3-fold with 95% confidence. To be meaningful, the population for which these quantities are being estimated must be clearly defined. By design, five different regions, involving different crops were chosen, and the mean exposure could change with 

region. Further, within a region, AaiH is purposively different for each monitoring unit. The 

mean exposure for each region-AaiH combination is likely to be different. Thus, it is unclear 

what the sample mean (the mean of the 25 region-AaiH combinations) is estimating. Because the 

sample mean depends heavily on the design, the validity of this Objective is questionable.

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

states that, 

When mixing/loading procedures in a given area involve participants either pouring directly into the application tank, using pre-mix tanks (holding dilute sprays), or slurry

tanks or buckets (holding concentrate sprays), then the MUs may not all be associated 

with the same equipment and procedure category (Evans et al. 2010, 9).

Although the Board agreed with the desire of the Agency as stated in the meeting that all three 

sub-scenarios should be included in each new cluster, such a statement was not found within either the proposal or the Agency’s Review. The exact nature of the agreed upon restriction should 

be clarified. 

A somewhat related suggestion was made (without a particular recommendation) that the 

proposal makes no attempt to assess the limited breadth of equipment or/and processes that will 

be assessed in the context of possibly wider range used in the field. A particular challenge (and 

possible concern) is to ensure that the exposures that are assessed in a given study do not underestimate the exposures to those applicators who use equipment or processes that are specialized 

for or relegated to small loads or/and small acreages (some of these were discussed on page 30-

31 of the Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting held January, 2007 

on the Review of Worker Exposure Assessment Methods [FIFRA Scientific Advisory Panel. 

2007]; see also page 14 and 42-43 of the same Meeting Report). In this regard, it may not be sufficient in such a proposal (or future reports) to ask experts just “how the selected employers and 

equipment compare to the local population of similar employers” (i.e., are the equipment or/and 

processes typical?). They should also be asked about the extent to which the selection process 

excluded any specialized equipment or processes, e.g., those specialized for use in small loads. 

Such information could be used to inform the Agency of limitations to the end result.

A question was raised regarding the appropriateness of the proposed range of AaiH values, in particular the feasibility of achieving the upper two strata (viz., 183 to 603 and 604 to 

2000 lb a.i. handled). This question was raised because the highest stratum proposed for the 

OPM/L scenario is up to 20 times larger than the range of AaiH studied in AHE80 study of 

closed-cab airblast (CCAB) applications. However information pointed to on page 36-37 of 403 

of the Wettable Powder Mixer/Loader Scenario Submission showed that it is feasible to apply up 

to 350 acres per day via aircraft, and examples of product labels obtained later from the web 
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show that wettable sulfur can be applied to grapes at rates of up to 20 lb./acre (Collier 2010a, 36-

7). Based on the label’s maximum rate of application of sulfur on grapes (a pair of scenarios included within the proposal), then mixing/loading up to 7000 lb. in a day is feasible, well above 

the proposed upper limit. 

Three points of clarification were raised concerning the proposal. First, the last sentence 

in the first paragraph of page 19 of 403 of the Wettable Powder Mixer/Loader Scenario Submission seems to indicate that a large overhead is better when it comes to cost (Collier 2010a, 19). A 

large overhead would not make the study less expensive, but more expensive, and thus less cost 

effective. For a given outcome the less expensive option is more cost effective, the more expensive one is less cost effective. The latter is the case with a high overhead. Second, if one examines the table on page 31 of 403 of the Wettable Powder Mixer/Loader Scenario Submission, 

the numbers for total a.i. usage are all in decreasing order until the items of strawberries and 

cherries (Collier 2010a, 31). This appears to be an error, but should be clarified. Finally, the first 

paragraph page 273 of 403 of the Wettable Powder Mixer/Loader Scenario Submission discusses 

“drugs and devices” (Collier 2010a, 273). However, there are no drugs or devices that are a part 

of this scenario. Perhaps this verbiage was copied from the referenced document that came from 

the Department of Health and Human Services and in all likelihood pertained to the FDA, and 

either “pesticides” or “chemicals” should be stated.

Ethics

Charge to the Board

If the proposed AHETF scenario and field study proposal AHE80 is revised as suggested 

in the EPA’s review and if the research is performed as described, is the research likely to meet 

the applicable requirements of 40 CFR 26, subparts K and L?

Board Response to the Charge

The Board concluded that the protocol submitted for review, if modified in accordance 

with EPA (Parsons and Sherman 2011) and HSRB recommendations, is likely to meet the applicable requirements of 40 CFR 26, subparts K and L. 

HSRB Detailed Recommendation and Rationale

The submitted documents assert that the study will be conducted in accordance with the ethical 

and regulatory standards of 40 CFR 26, Subparts K and L, as well as the requirements of the US 

EPA’s Good Laboratory Practice (GLP) Standards described at 40 CFR 160, and, for research 

conducted in California, the California State EPA Department of Pesticide Regulation study

monitoring (California Code of Regulations Title 3, Section 6710) (Ref 2010). Requirements of 

FIFRA §12(a)(2)(P) also apply. Researchers who participate in the study and interact with study

participants will be required to undergo ethics training. The training will include the successful 

completion of the course from the National Institutes of Health (Protecting Human Research Participants) and/or the Basic Collaborative IRB Training Initiative Course. 
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The protocol was reviewed and approved by an independent human subjects review 

committee, Independent Institutional Review Board, Inc. (IIRB, Inc.) of Plantation, FL prior to 

submission. IIRB, Inc. is fully accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP). IIRB, Inc. is also listed as an active Institutional Review 

Board (IRB) on the Office of Human Research Protection (OHRP) website (Reg. 

#IORG0002954). Minutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures were provided to the Agency (IIRB, Inc. 2010). These documents indicate that IIRB, Inc. 

reviewed this protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart 

A). 

1. Except as noted below, the Board concurred with the conclusions and factual observations of 

the ethical strengths and weaknesses of the study, as detailed in the EPA’s Ethics Review 

(Parsons and Sherman 2011). The proposed study is likely to meet the applicable ethical requirements for research involving human subjects, in accordance with the following criteria: 

a. Acceptable risk-benefit ratio. The risks as noted in the study protocol are fourfold: 

1) The risk of heat-related illness. The study will likely involve an increased risk of 

heat-related illness due to study participation. All participants in the study will be 

wearing an extra layer of clothing that they would not normally wear when mixing 

and loading wettable powder formulations into a pre-mix or application tank and diluting it under such conditions. In addition, mixing/loading activities might occur indoors or outdoors and some locations and dates are likely to result in hot and/or humid conditions.

2) The risk associated with scripting of field activities. In order to ensure all monitoring 

units (MUs) involve handling at least three loads, AHETF may ask some workers to 

use a smaller tank size than they would normally select or dilute the product more 

than usual. This might lead to a slightly longer work period for those workers which 

may increase the risks of acute toxicity to the surrogate chemical and of heat-related 

illness. 

3) Exposure to surfactants. A very dilute surfactant solution (0.01% v/v Aerosol® OT in 

water) is used as a surfactant for face/neck wipes and hand washes for all MUs. This 

surfactant is in a very dilute solution and its use represents a very short exposure period, but the undiluted surfactant causes mild to moderate skin and eye irritation in 

animals.

4) Psychological risks. Participating in AHETF exposure monitoring studies involves 

activities that are unusual and might cause subjects psychological distress. These include performing an over-the-counter pregnancy test prior to participation (females 

only) and allowing a researcher to assist with the removal of the whole body dosimeter. Participating in AHETF exposure monitoring studies involves activities that are 

unusual and might cause subjects psychological distress. 
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AHETF has proposed several procedures to minimize these risks:

1) Monitoring and stopping procedures will be instituted. The AHETF will monitor ambient conditions to determine the heat index near the mixing/loading station and base 

monitoring decisions on the current heat index. Exposure monitoring will be discontinued if the heat index cutoff of 105 F (adjusted for direct sun, if applicable) is 

reached or exceeded. The Study Director or other researcher shall stop the monitoring 

and/or move the worker to a cooler environment until monitoring can be resumed. If 

necessary, some monitoring will take place at night or early in the morning to avoid 

excessively hot and humid conditions. 

2) Clear inclusion/exclusion criteria have been established. Only experienced pesticides 

handlers who consider themselves in good health will be included in the study. Experience with the mixing/loading equipment to be used in the study and with the mixing/loading wettable powder products will be required of all participants. Participants 

must also understand Spanish or English.

3) Workers will be reminded of safe chemical handing practices and research staff will 

practice the face wipe and hand wash procedures with each participant before pesticide handling begins.

4) Appropriate medical management procedures are in place. Eye rinse stations will be 

on hand in case of an accidental exposure. Medical treatment facilities will be identified in case of an emergency. A medical professional will be on site to observe study

participants and provide urgent care.

5) Minors and pregnant or lactating women are excluded from participation, with pregnancy status confirmed by over-the-counter pregnancy testing within 24 hours prior 

to study participation. All female volunteers will be notified that an additional pregnancy test may be required if there are any delays in the planned start of the study. 

Only non-pregnant volunteers will be allowed to participate.

6) Procedures have been instituted to decrease psychological risks. Pregnancy tests will 

be conducted in a private place and information regarding pregnancy test will be kept 

confidential. Private dressing areas will be provided and researchers of the same 

gender will be available to assist study participants. 

These risks are minimized appropriately and are justified by the potential societal benefits 

associated with gathering data to determine the potential exposure for workers who mix 

and load wettable powder formulations using open pouring techniques for workers four 

regions of the United States.

b. Voluntary and informed consent of all participants.

1) There is the possibility that the participants in this study might represent particularly

vulnerable populations, susceptible to coercion and undue influence. The study proto-
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col, however, includes several mechanisms designed to minimize coercive recruitment and enrollment.

2) The informed consent materials, if changed as recommended by the HSRB below, 

will adequately inform the subjects of the risks, discomforts and benefits from participation, and of their right to withdraw.

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

c. Equitable selection of study participants.

1) AHETF will first determine a pool of growers and/or commercial pesticide application companies who are eligible to participate in this study. Agricultural workers who 

work for these eligible businesses will be recruited as study participants. Employers 

will be required in writing to affirm that they will not influence their employees’ decisions about whether to participate in this study. AHETF has developed complete 

and appropriate inclusion/exclusion criteria. 

2. The Board recommended that the study protocol be modified to address the concerns noted in 

the EPA’s Ethics Review (Evans et al. 2010). In addition, the Board raised additional concerns:

a. The Board concurred with the Agency’s recommendation (Evans et al. 2010, 5) that the 

protocol standard operating procedure (SOP) AHETF-11-B.5 should be revised to specify

that potential study participants will be asked about what they normally wear when handling pesticides in a way that does not direct them to a particular answer or lead them to 

agree to wear less personal protective equipment (PPE) than they normally would out of a 

desire to participate in the research.

b. The Board concurred with the Agency’s recommendation that the language in the consent 

form about refusing medical treatment should be revised. However, the board did not 

concur with the suggested revisions. The Agency recommends that the language be revised to read as follows: “You may refuse medical treatment unless the medical professional decides you are too sick to make a rational decision about getting medical treatment.” The Board recommended that the language be revised as follows: “You may 

refuse medical treatment unless the medical professional decides (based on established 

criteria) that you are too sick to make a decision about getting medical treatment.” In addition, it recommended that in an appropriate SOP, the criteria for decision-making capacity are provided as guidance for medical professionals who perform this function in 

AHETF research. The criteria for decision-making capacity can be found in the clinical and clinical ethics literature (e.g., Appelbaum 2007) and generally include all the following: The patient a) can appreciate the situation and its consequences; b) can understand the relevant information; c) can reason about the treatment decision; and d) can 

communicate a choice.

c. The Board partly concurred with the Agency recommendation that the AHETF should 

revise its plan for providing exposure information to subjects to address subjects who 
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might not speak English and/or are illiterate, and also to incorporate any future guidance 

from the HSRB’s working group on this issue. The Board concurred that the AHETF and 

the Agency need to develop procedures to protect the needs of study participants who do 

not speak English or who have low levels of literacy. However the Board recommended 

that these procedures need to be rooted in the vocabulary and best practices of appropriate fields such as cultural competence and literacy. For example, the term illiterate is no 

longer used by literacy experts. The Agency should consider seeking guidance on these 

issues from the report of the US Department of Health and Human Services, National Action Plan to Improve Health Literacy (2010) and reports from the Institute of Medicine, 

Health Literacy: A Prescription to End Confusion (2004); Toward Health Equity and Patient-Centeredness: Integrating Health Literacy, Disparities Reduction, and Quality Improvement, Workshop Summary (2009). The Board concurred that AHETF should incorporate any future guidance from the HSRB’s work group on return of results to participants after it submits its reports.

d. The Board concurs with the Agency that AHETF should clarify the discrepancy about 

whether hand wash samples are to be collected prior to water breaks (Evans et al. 2010, 

2).

e. The Board concurs with the Agency review that future AHETF protocols or SOPs should 

incorporate information about how subjects are presented with individual exposure information, including how this process will be handled for research participants who do 

not speak English or have low levels of literacy; and an explanation of the process that 

the AHETF follows to improve and verify the accuracy of the Spanish translations 

(Evans et al. 2010, 2). The Board recommends that these future protocols be grounded 

best practices in literacy and cultural competence and that the Spanish translations be in 

the appropriate dialect of the research participants.

3. The Board added these additional recommendations:

a. The requirement for additional pregnancy tests should be clarified throughout the documents. The Agency review indicates without explanation that the consent form states that 

“more than 1 pregnancy test may be required” (Evans et al. 2010, 5). However, on page 

268 of the protocol it states that female volunteers “will be notified that an additional 

pregnancy test may be required if there any delays in the planned start of the study” (Collier 2011, 268). This explanation for why additional pregnancy tests may be required 

should be made explicit in the informed consent document.

b. The Agency review states that the return of individual exposure results may benefit research subjects (Evans et al. 2010, 15). The Board recommended that this language be 

deleted until the Board Working Group finishes its report and the Board reviews it. 

c. The Board recommended that AHETF clarify how witnesses will be selected for workers 

who self-identify as non-readers. According to the protocol they “may choose a witness, 

or a third-party witness will be identified by the Study Director or designee and provided 

to the worker during the private consent meeting” (Collier 2010a, 292). It needs to be clarified that these witnesses are not associated with the research project.
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d. The Board recommended that the risk of surrogate chemicals be included as one of the 

risks associated with participation in this study and be listed in the consent forms and in 

the protocol. It appears that the Task Force understood a prior Board recommendation 

that the physical risks associated with agricultural work should not be listed in the protocol and informed consent document to mean that exposure to the surrogate pesticides 

should likewise not be not be listed. The AHETF’s perspective on as reflected on page 

109 of the protocol: 

AHETF generally monitors exposure to professional workers that normally use one of 

the surrogate chemicals approved by AHETF. Therefore, AHETF does not consider 

the risk of toxicity from pesticide handling to be strictly due to study participation 

(Collier 2010a, 109).

Because the study involves scripted activities and may require use of a pesticide that 

workers wouldn't have applied that day if not for the study, however, the Board concluded that exposure to the surrogate compound should be listed in the protocol and consent document. When exposure to surrogate pesticides is re-included as a risk of the 

study, several documents will need revisions, including SOP AHETF-11.J.2. with IC 

checklist; DSM Form 386; and the Governing Document.

The AHETF also contends that the short duration of the study (generally one day) limits 

the toxic risk of exposure to the surrogate chemicals to acute or short-term effects. These 

effects are currently not listed in the consent forms or in the protocol, but the protocol 

states that the acute toxic effects from each surrogate product handled in this study will 

be discussed with the study participant before their participation begins (Collier 2010a, 

109, 111). The Board concluded, however, that the discussion of these effects is conspicuously absent from the consent form and recommended that they either be listed explicitly or, at a minimum, that the consent document be revised to include a statement like, 

The label for the [surrogate compound] will be reviewed with you before you take 

part in the study. This review will include how much of that product you might handle during the study, the symptoms and short-term health effects of accidental exposure to the product, what clothing and personal protective equipment you must wear, 

the importance of washing your hands before eating, and other safety precautions that 

should be followed” (c.f. Collier 2010a, 146-7).

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

In this study risks to subjects are classified as ‘greater than minimal’, primarily since 

agricultural work is considered a high risk occupation where the likelihood of harm or 

discomfort is greater than what is encountered in ordinary daily life (Evans et al. 

2010, 44). 
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However, on page 106, the AHETF protocol states, 

In this study, risks to subjects are classified as “greater than minimal”, since the likelihood of harm or discomfort is greater than what is encountered in ordinary daily

life. In particular, the risk of heat-related illness (resulting from wearing an extra 

layer of clothing to trap chemical) will be increased due to study participation (Collier 

2010a, 106). 

It is not clear whether “greater than minimal risk” refers to agricultural work or the risk 

of heat-related illness associated with participation in the study or to both.

Assessment of Completed AHETF Research Studies AHE55, AHE56, AHE57, AHE58 and 

AHE59: Determination of Dermal and Inhalation Exposure to Workers During Airblast 

Applications of Liquid Sprays Using Closed Cab Equipment.

Overview of the Study

Five separate field studies were conducted, each monitoring dermal and inhalation exposure of workers to commercially available pesticides while spraying tree or trellis crops in five 

different U.S. states where closed-cab airblast equipment is commonly used in production agriculture. A total of 24 professional agricultural handlers were monitored as they applied pesticides 

using closed-cab airblast equipment: five adult men applying pesticides to citrus trees in Florida 

(AHE55), five adult men applying pesticides to pecan trees in Georgia (AHE56), four adult men 

and one adult woman applying pesticides to cherry trees in Michigan (AHE 57), five adult men 

applying pesticides to grape vines in California (AHE58), and four adult men applying pesticides 

to apple trees in Washington state (AHE59). The scenario design, protocols for the five studies, 

SOPs and governing documents were reviewed favorably by the HSRB at its June 24-25, 2008 

meeting (EPA HSRB 2008).

Monitored on actual days of work, study participants handled from 7 to 90 lbs of active 

ingredient (carbaryl, malathion, or chlorothalonil), spraying 4 to 30 acres in 2 to 9 hours. Dermal 

exposure was measured using hand washes, face/neck wipes, and whole body dosimeters (100% 

cotton union suits) for the remainder of the body (torso, arms, and legs). Inhalation exposure was 

measured using personal air sampling pumps and OVS mounted on the shirt collar. Results 

represent dermal exposure while wearing a long-sleeved shirt, pants, shoes/socks and chemicalresistant gloves, and inhalation exposure without respiratory protection.

The Agency proposes to use data from these five studies, posted to AHED®, to estimate 

generically daily dermal and inhalation exposures of workers who treat agricultural crops with 

conventional pesticides using closed-cab airblast equipment. 
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Science

Charge(s) to the Board

1) Was the research reported in the AHETF completed monograph report and associated 

field study reports faithful to the design and objectives of the protocol, SOPs and governing documents?

2) Has the Agency adequately characterized, from a scientific perspective, the limitations 

on these data that should be considered when using the data in estimating exposure of those who 

apply conventional pesticides with closed-cab airblast equipment?

Board Response to the Charge(s)

HSRB Recommendation

The Board concurred in part with the Agency’s assessment (Crowley 2011; Crowley and 

Sarkar 2011). The research reported in the completed monograph, associated field study reports, 

and associated supplemental documents (Bruce 2010a, 2010b, 2010c, 2010d; Klonne and Holden 

2010; Smith 2010a, 2010b, 2010c, 2010d, 2010e, 2010f) was conducted in a manner that was 

reasonably faithful, to the extent possible under field conditions, to the design and objectives of 

the protocol and governing documents of the AHETF. 

The Board also concluded that the Agency has not completely considered the limitations 

on these data that should be considered before using the data to estimate the dermal and inhalation exposure of those who apply conventional pesticides with closed-cab airblast equipment. 

Additional limitations and concerns have been identified by the Board, and conclusions as to the 

generalizability of these data require further consideration and analysis.

HSRB Detailed Recommendations and Rationale

While any field study of the nature of these AHETF studies have unanticipated deviations 

from the protocol and SOPs, this completed study was reasonably faithful to the design and objectives of the protocol, SOPs and governing documents. Many of the reported protocol deviations were minor, but some were not. However, it was unclear the effect these deviations would 

have, if any, on the results; the effect of these deviations of the data has not yet been determined.

With some exceptions, the quality assurance results appeared to be good. In terms of 

measured values below the limit of detection (LOD) or the limit of quantitation (LOQ) -- 7/48 

inner dosimeters, 21/24 total head exposures, 4/36 hand wash samples, most OVS inhalation tube 

back samples -- the use of 1⁄2 LOD in such cases to extrapolate face/neck wipe exposure measurements to un-wiped portions of the face and head may have significantly affected the reported 

analyses and results.

It also is unclear whether temperature, humidity, wind speed, foliage density and/or the 

type of equipment used had any effects on exposure and whether or not these variables should be 

included in further exposure modeling. Additional questions raised by the Board included: 1) 
Final Draft Document Dated March 11, 2011

Page 18 of 24

wondering what was so different about the California grape study (AHE58; Bruce 2010a, 2011b) 

that the actual AaiH exceeded the upper limit in three of the five strata; and 2) questioning why 

the whole body dosimeter field fortification samples in the California grape study also exceeded 

the appropriate range at times.

Despite these concerns and questions, the Board concluded that the data obtained from 

these completed studies are likely to be reasonably accurate from the standpoint of the collection 

and handling of samples, and from chemical analysis. The data may not be an accurate reflection 

of the potential exposure to pesticides by agricultural workers using closed-cab airblast pesticide 

application equipment, mainly because of the impact of the incidental exposures. However, although the Board raised concerns regarding the utility of these data for predicting proportionality 

in a closed-cab airblast scenario, this concern does not invalidate the scientific validity of the actual data. 

In its Scientific Review of the AHETF Closed Cab Airblast Monograph (Klonne and 

Holden 2010), the Agency stated that, “the secondary objective to evaluate proportionality between dermal and inhalation exposure and the amount of active ingredient handled with 80% statistical power – a key assumption in the use of exposure data as ‘unit exposures’ – was not met” 

(Crowley and Sarkar 2011, 2) such that the null hypothesis was not rejected. The Board agrees 

with this conclusion; the fact that the 95% confidence interval includes one does not mean that 

the assumption of proportionality is correct. 

The EPA Scientific Review of the AHETF Closed Cab Airblast Monograph further states 

that, “additional analyses point to incidental exposure sources such as contacts with exterior surfaces having a more substantial impact on exposure” (Crowley and Sarkar 2011, 2). This is not 

unreasonable, specifically for dermal exposure. The fact that the reported data do not seem to 

reflect the proportionality of exposure to AaiH suggests that the engineering controls used here 

(i.e., a closed-cab air-conditioned vehicle) are likely to be effective in preventing exposure of the 

agricultural handler to the bulk of the pesticide being applied. The data also indicate that the protocol did not measure incidental exposures to pesticide, such as contaminations occurring outside 

the cab, in a manner that would have been helpful in exposure assessment. The prominence of 

incidental exposure in this scenario may not have been anticipated in advance of the study. As 

the surrogates selected are pesticides that are appropriate and registered for the crops of the scenarios, they would be expected to be used in the field on some occasions. Finally, the reported 

results also suggest that the number of MUs may be too small to assess the proportionality of exposure to AaiH.

Given these issues, the Board raised concerns that the assumption of proportionality

could not be demonstrated for dermal exposure without accurately measuring and factoring in 

incidental exposures and then recalculating the regression. Inhalation exposure estimates would 

be much less affected by such incidental exposures, and the Board concluded that the assumption 

of proportionality is not correct for such exposures as confirmed in Table 1 of the EPA Review 

(Crowley and Sarkar 2011, 2).

The range of dermal and inhalation exposures was very great and, as predicted, skewed 

toward larger exposures even after normalizing the data. This range makes statistical estimation 
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of exposure difficult, and the Board recommended that a different type of probability density 

function should be used in statistical analyses.

The Board also raised concern that the method efficiency adjusted (MEA) correction factor used in estimating dermal exposures was not as accurate as it should be. This suggests that 

additional lab work is required to develop more accurate ways of obtaining exposure estimates 

for the various dermal exposures. The secondary analyses performed utilizing observations on 

clothing and on number of times exiting and entering the cab were very illuminating, indicating a 

different type of statistical regression model might be used if either field measurements or lab 

data could be combined. (It is questionable, however, given the limited number of observations 

whether sensitivity analyses could or should be performed.) Even considering alternative uses of 

these existing data, additional exposure ‘models’ should be investigated before final conclusions 

are made as to the use of the results in AHED®. The Agency should be careful, however, not to 

make any inferences from discoveries that the closed cab airblast scenario was not designed to 

address; they should not conclude, for example, that incidental exposures are the primary source 

of dermal exposure to pesticides as these five studies were not designed to measure the contribution of these sources of contamination to overall handler exposure estimates.

Finally, the Board agrees with the Agency’s conclusion in its Scientific Review of the 

AHETF Closed Cab Airblast Studies that, given that some field control samples for the air samplers were found to have detectable residues, this finding “may impact field fortification recovery estimates, which in turn could alter actual field sample measurements” (Crowley 2011, 6). It 

was assumed by AHETF that, as the amounts of such residues in the field control samples were 

small, they could be ignored. Adjusting the data to account for the presence of detectable residues in the field control samples would have been more appropriate. 

Ethics

Charge to the Board

Does the available information support a determination that the studies were conducted in 

substantial compliance with subparts K and L of 40 CFR Part 26? 

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment (Sherman 2011) that the study was 

conducted in substantial compliance with subparts K and L 40 CFR 26.

HSRB Detailed Recommendation and Rationale

The documents provided include reports of each of five field studies conducted on behalf 

of the Agricultural Handler Exposure Task Force (AHETF) (Bruce 2010a, 2010b, 2010c, 2010d; 

Klonne and Holden, 2010; Smith 2010a, 2010b, 2010c, 2010d, 2010e, 2010f). The five protocols 

were each reviewed and approved by an independent human subjects review committee, IIRB, 

Inc. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and a copy of IIRB, 
Final Draft Document Dated March 11, 2011

Page 20 of 24

Inc. policies and procedures were provided. This IRB is fully accredited by AAHRPP and listed 

by OHRP, as described above in the Board’s review of proposed AHETF research study AHE80: 

Determination of Dermal and Inhalation Exposure to Workers During Mixing/Loading Wettable 

Powders in the United States.

1. The Board concurred with the conclusions and factual observations relating to the study, as 

detailed in the EPA’s Ethics Review (Sherman 2011) and summarized briefly below. 

a. Prior HSRB and Agency Review. Because each of these five studies was initiated after 7 

April 2006, prior submission of the protocol and supporting materials to EPA was required by 40 CFR §26.1125. The requirements of 40 CFR §26.1125 for prior submission 

of the protocol to EPA and of §26.1601 for HSRB review of the protocol were satisfied. 

The scenario design and study were approved by IIRB, Inc. in March 2008 (for protocols 

AHE55 and AHE56) and in August 2008 (for protocols AHE57, AHE58, and AHE 59). 

The HSRB discussed protocols AHE55 and AHE56 at its June 2008 meeting, and 

AHE57, AHE58, and AHE59 at its October 2008 meeting, in each instance concurring 

with the Agency’s assessment (Sherman 2011) that these five proposed closed-cab airblast field study protocols, if revised as suggested by the Agency and the HSRB, would 

meet the applicable requirements of 40 CFR part 26, subparts K and L.

b. Responsiveness to HSRB and Agency Recommendations. The initial ethics review by the 

Agency and by the HSRB provided 26 recommendations with regard to these five protocols. All of those recommendations, and the responses made with regard to them, are detailed in Attachment 4, on pages 42 and 43, of the Agency’s Review (Sherman 2011, 42-

3). The HSRB agrees with the Agency that the comments by the Agency and HSRB were 

satisfactorily addressed. 

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

a. Acceptable risk-benefit ratio. 

1) The risks to study participants were minimized appropriately and were justified by the 

potential societal benefits, particularly data on the dermal and inhalation exposure of 

professional pesticide applicators to the liquid pesticides they apply to orchard and 

trellis crops using an airblast sprayer drawn by a vehicle with an enclosed cab. These

data could be used to develop mechanisms to protect future persons who apply these 

liquid pesticides.

2) Minors and pregnant or lactating women were excluded from participation, with 

pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by 

opt-out. The potential of stigma resulting from study exclusion was also appropriately 

minimized. 

3) Clear stopping rules and medical management procedures were in place, and no adverse events or other incidents of concern related to product exposure were reported, 

except as described in section 3, below.
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4) The study was designed to minimize the risks of exposure to the test compounds, subject to being able to accomplish the purposes of the study.

b. Voluntary and informed consent of all participants.

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

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

3. Twenty-two minor protocol deviations were reported by the sponsor. The Agency’s Ethics 

Review also notes thirteen minor protocol deviations that were unreported. All of these are 

documented in some detail in Table 2 of the Ethics Review (Sherman 2011, 18). The Board 

agrees with the Agency’s evaluation of these deviations, and the fact that they do not require 

any changes in the Board’s determinations described above. 

However, one category of protocol deviation is given special attention in the EPA Ethics Review and merits discussion here. These deviations involved the fact, on multiple occasions in 

three of the five CCAB studies, subjects failed to wear gloves while touching a contaminated 

surface, usually part of the airblast cab or attached machinery. 

As the Agency notes, according to the protocols, since these protocol violations involved a 

safety issue (exposure to the pesticide). In each instance the person who observed these violations of safety standards should have reminded the workers to wear their gloves and reported the behavior to the study director. There is no record that these steps took place. However, given the nature of these exposures to the pesticides, and the pesticides that were chosen for use in these protocols, the actual increased risk to the subjects appears minimal. We 

agree with the Agency’s determination in that regard (Sherman 2011, 29). 

Beyond these completed studies, however, these deviations raise an issue that the Agency 

and sponsors may wish to consider with regard to the design of future protocols. That 25% of 

the subjects in these five studies engaged in this behavior suggests that it is probably not uncommon. Although experienced pesticide applicators are told of the need to wear gloves before touching certain pieces of equipment, it appears that they commonly fail to do so. If indeed this is a common behavior, and EPA wants to collect data from such exposures, then 

Agency and the sponsors may want to consider an approach that specifies safety standards in 

the informed consent form but indicates that observers will not necessarily remind participants of the standard each time they are observed violating these standards. In addition to or 

as an alternative to this approach, it may be desirable to write an SOP that is referenced in future protocols. 

The purpose of the SOP would be to clarify for study observers the safety-related interventions, if any, that observers should make when participant’s engage in behaviors that are inconsistent with either the protocol or the label. In such an SOP, it would be necessary to 

clearly spell out which safety-related deviations are “acceptable” (meaning they would not 

require an intervention such as a reminder to the subject to alter their behavior each time that 
Final Draft Document Dated March 11, 2011

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behavior is observed), and which are not (meaning they would require an intervention, such 

as a reminder or warning). Acceptable deviations should only be those that involve very low 

risks to subjects. Observers should receive guidance on safety violations that would merit 

reminders or warnings to subjects, reports to the study director, and immediate interventions 

to correct inappropriate behavior, including the most common examples of behaviors that are 

and are not acceptable. In addition to potentially reducing participant risk, this guidance 

would also help to standardize observation by removing variation introduced when observers 

are required to make their own subjective evaluations of risk in determining when and how to 

intervene. 
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