Final Report Dated December 13, 2010

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EPA-HSRB-10-02

Paul Anastas, PhD

EPA Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject: October 27-28, 2010 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 two new and one 

revised protocols for studies involving intentional exposure of human subjects to pesticides: a 

proposed Carroll-Loye Biological Research, Inc. (CLBR) insect repellent efficacy study (No 

Mas-003); a proposed Agricultural Handler Exposure Task Force, LLC (AHETF) scenario 

measuring dermal and inhalation exposure by pesticide applicators who use backpack sprayers or 

hand gun sprayers in utility rights-of-way (AHE-400); and a revised AHETF water-soluble 

packaging mixing and loading scenario and protocol (AHE-120) previously reviewed by the 

HSRB in June 2009.

The Agency also requested that the HSRB review a completed study of dermal and 

inhalation exposure of professional janitorial workers who clean floors with an antimicrobial 

pesticide product using a mop and bucket, conducted by the Antimicrobial Exposure Assessment 

Task Force II (AEATF II). This study (AEA-03) was 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). The data will be posted to the Biocide Handlers Exposure 

Database (BHED®), and used generically to estimate daily dermal and inhalation exposures of 

those who clean floors with antimicrobial pesticides using a mop and pail. 

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

the October 27-28, 2010 meeting.

Assessment of Proposed Carroll-Loye Biological Research Study No Mas-003: Field Efficacy 

Test of 16% Para-menthane-3,8-diol (PMD) and 2% Lemongrass Oil Based Repellent ‘No Mas’ 

Against Mosquitoes.

Science

• The Board concluded that the protocol for the proposed field repellency study, if 

modified in accordance with Agency and HSRB recommendations and conducted 

accordingly, is likely to generate scientifically reliable data, useful for assessing the 

efficacy of the tested material in repelling mosquitoes.
Final Report Dated December 13, 2010

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Ethics

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

with Agency and HSRB recommendations and conducted accordingly, is likely to meet 

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

Assessment of Proposed AHETF Scenario and Protocol AHE-400: Backpack and Handgun 

Application of Liquid Sprays in Utility Rights-of-Way.

Science

• The Board concluded the proposed backpack and handgun application scenario, if revised 

as suggested and performed as described, is likely to generate scientifically reliable data 

that may be useful for assessing the exposure of workers who apply pesticides in utility 

rights-of-way using backpack or handgun sprayers.

Ethics

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

with Agency and HSRB recommendations and conducted accordingly, is likely to meet 

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

Assessment of Revised AHETF Scenario and Protocol AHE-120: Water-Soluble Packaging 

Mixing and Loading.

Science

• The Board concluded the submitted protocol, if revised as suggested and performed as 

described, is likely to generate scientifically reliable data that may be useful for assessing 

the exposure of workers who mix and load pesticides in water-soluble packaging.

Ethics

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

with Agency and HSRB recommendations and conducted accordingly, is likely to meet 

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

Assessment of Completed AEATF II Research Study AEA-03: A Study for Measurement of 

Potential Dermal and Inhalation Exposure during Application of a Liquid Antimicrobial Pesticide 

Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces (MRID 48210201, 

MRID 48231201, MRID 48231901).

Science

• The Board concurred with the Agency’s assessment that the research reported in the 

completed AEA-03 study report and associated supplemental documents was conducted 
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in a manner that was reasonably faithful to the design and objectives of the protocol and 

governing documents of AEATF-II. 

• The Board concluded that the Agency has adequately, if not completely, considered the 

limitations on these data that should be considered when using the data in estimating 

exposure of those who apply antimicrobial floor-cleaning products with mop and bucket.

Ethics

• The Board concurred with the Agency’s assessment that the study submitted for review 

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

• In response to a request from the study sponsor for guidance on how to provide 

individual exposure data to participants once the study is complete, the Board elected to 

establish a working group that could draft proposed guidance for the Agency and 

sponsors, which would be reviewed by the full Board during a future HSRB meeting. 

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 email 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.
Final Report Dated December 13, 2010

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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), 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
Final Report Dated December 13, 2010

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INTRODUCTION

On October 27-28, 2010, the United States Environmental Protection Agency’s (EPA or 

Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues 

concerning two new protocols and one revised protocol for research involving human 

participants: one new study measuring the efficacy of an insect repellent containing paramenthane-3,8-diol (PMD) and lemongrass oil against mosquitoes under field conditions; one 

new study measuring levels of exposure received by agricultural handlers when applying 

commercially-available pesticides using backpack sprayers or hand gun sprayers in utility rightsof-way, and a revised study measuring levels of exposure received by agricultural handlers when 

mixing and loading pesticides using water-soluble packaging under various conditions. In 

accordance with 40 CFR 26.1601, EPA sought HSRB review of these three proposed protocols. 

Each of these protocols is discussed more fully below.

In addition, the Agency has data from one completed study measuring levels of exposure 

received by janitorial workers when applying a commercially-available antimicrobial pesticide 

using a mop and bucket. In accordance with 40 CFR 26.1602, EPA sought HSRB review of this 

completed study. This completed study is discussed more fully below.

REVIEW PROCESS

On October 27-28, 2010, 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” (75 Federal Register 193, 61748).

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

EPA on the following topics: one new study protocol to measure the efficacy of an insect 

repellent containing PMD and lemongrass oil against mosquitoes under field conditions; one new 

study protocol for measuring levels of exposure received by agricultural handlers when applying 

commercially available pesticides using backpack sprayers or hand gun sprayers in utility rightsof-way, and a revised study protocol measuring levels of exposure received by agricultural 

handlers when mixing and loading pesticides using water-soluble packaging under various 

conditions. In addition, a completed study for the measurement of potential dermal and 

inhalation exposure during application of a liquid antimicrobial pesticide product using a bucket 

and mop was reviewed.

The Board asked clarifying questions of several individuals attending the meeting, 

including:

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

Dr. Scott Carroll, Study Director, Carroll-Loye Biological Research

Mr. Shawn King, Director of Operations, Carroll-Loye Biological Research

Mr. Robert Roogow, Chief Operations Officer, Independent Institutional Review Board, 

Inc. 

Dr. Sami Selim, Study Director, Selim & Associates
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Public comments were provided by: 

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

Dr. Scott Carroll, Principal, Carroll-Loye Biological Research

Dr. Hasmukh Shah, Manager, AEATF

No written public comments were submitted.

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. 

CHARGE TO THE BOARD AND BOARD RESPONSE

Assessment of Proposed Carroll-Loye Biological Research Study No Mas-003: Field 

Efficacy Test of 16% Para-menthane-3,8-diol (PMD) and 2% Lemongrass Oil Based 

Repellent ‘No Mas’ Against Mosquitoes.

Overview of the Study

This protocol describes a study to test the repellent efficacy of a lotion formulation 

containing 16% PMD and 2% lemongrass oil (‘No Mas’) against three species of mosquitoes in 

the field. As submitted to the EPA, the proposed study consists of two interdependent analyses: 

1) a dosimetry study designed to determine the amount of lotion that typical users would 

typically apply; and 2) an efficacy study designed to measure the effectiveness of the compound 

as a repellent for those species of mosquitoes likely to be vectors for West Nile Virus (WNV) in 

the United States.

Dosimetry will be determined by direct measurement of compound application. The 

efficacy of the formulation as a mosquito repellent will be determined by measuring the ability of 

the formulations to prevent mosquito landings under field conditions at test sites in California’s 

Central Valley. The efficacy study endpoint will be the “Landing with Intent to Bite” (LIBe), and 

the criterion for data to calculate complete protection time will be the first confirmed LIBe.

Science

Charge to the Board

If the proposed field repellency study protocol No Mas-003 is revised as suggested in 

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

scientifically reliable data, useful for assessing the efficacy of the tested material in repelling 

mosquitoes?
Final Report Dated December 13, 2010

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Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment that the proposed field repellency 

study protocol No Mas-003, if revised as suggested in EPA’s review (Fuentes and Sherman 2010) 

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

the efficacy of the tested material in repelling mosquitoes.

HSRB Detailed Recommendations and Rationale

Protocol No Mas-003 from Carroll-Loye Biological Research (Carroll 2010) will be 

conducted using methods similar to those presented to and commented on by the Board in the 

past. Apart from the new test material, the proposal is generally similar to previous Carroll-Loye 

field studies reviewed by the Board.

The study protocol was relatively clear and addressed adequately a number of key 

scientific issues, including: scientific justification, objectives, and data collection and 

compilation methods. The Board concurred with the Agency’s assessment that the proposed field 

repellency study protocol No Mas-003 is likely to generate scientifically reliable data, useful for 

assessing the efficacy of the tested material in repelling mosquitoes. In addition, the Board 

recommended two minor changes to the protocol and associated study documents. First, the 

protocol should be amended to remove erroneous reference to spray repellents (e.g. the first 

sentence on page 79, under “Rationale”; Carroll 2010, 79). Second, the Board agreed with the 

Agency that reference to sample size standards is now irrelevant in light of recently released 

repellency testing guidelines. Rather than refer to a historical standard of 6 study participants, the 

proposed sample size should be large enough to be likely to yield a definitive answer to the 

research question and its size justified statistically in the protocol. 

Ethics

Charge to the Board

If the proposed field repellency study protocol No Mas-003 is revised as suggested in 

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

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

Board Response to the Charge

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

with EPA (Fuentes and Sherman 2010) and HSRB recommendations, is likely to meet the 

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

HSRB Recommendation
Final Report Dated December 13, 2010

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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 the 

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

California State EPA Department of Pesticide Regulation study monitoring (California Code of 

Regulations Title 3, Section 6710) (Carroll 2010). Requirements of FIFRA §12(a)(2)(P) also 

apply. The protocol was reviewed and approved by an independent human subjects review 

committee, Independent Institutional Review Board (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 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 (Carroll 2010) and a copy of IIRB, Inc. 

policies and procedures were provided to the Agency. These documents indicate that IIRB, Inc. 

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

A).

HSRB Detailed Recommendation and Rationale

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 

(Fuentes and Sherman 2010). 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 fivefold: 1) 

allergic reaction to test materials themselves; 2) exposure to biting arthropods; 3) possible 

exposure to arthropod-borne diseases; 4) physical stress from the test conditions; and 5) 

psychological stress and/or breach of confidentiality for pregnancy test results. These 

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

associated with data on the efficacy of the active ingredients, PMD and lemongrass oil, as 

mosquito repellents.

• Based on toxicological data currently available for PMD and lemongrass oil, 

coupled with appropriate exclusion criteria, study participants are unlikely to be at 

risk of adverse side effects with exposure.

• The study is designed to minimize the likelihood of mosquito bites, through the use 

of: LIBes rather than actual confirmed bites as a study endpoint; bite removal and 

joint observation; clear stopping rules; and limited periods of exposure to 

mosquitoes. Study participants will be trained in proper insect observation and 

handling techniques.

• Mosquito bites, should they occur, are usually mild and easily treated with over-thecounter steroidal creams. The study will also exclude participants who have a 

history of severe skin reactions to such bites.
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• Possible exposure to vectors of arthropod-borne diseases is minimized through the 

use of certified disease-free laboratory-reared insect populations, selection of field 

sites in low virus areas, and limited skin exposure.

• The potential risks to participants from environmental stress are minimized by the 

provision of a climate controlled rest area, food, water and medical supplies, and by 

careful monitoring for signs of dehydration, heat stress and hypothermia. 

Appropriate stopping rules and medical management procedures are in place.

• Minor and pregnant or lactating women are excluded from participation, with 

pregnancy either confirmed by over-the-counter pregnancy testing on the day of 

study or by opt-out. Only volunteers scored as non-pregnant will be allowed to 

participate. Information regarding pregnancy test results will be kept confidential.

b. Voluntary and informed consent of all participants 

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

vulnerable populations, susceptible to coercion and undue influence. The study 

protocol, however, includes several mechanisms designed to minimize coercive 

recruitment and enrollment.

• 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.

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

c. Equitable selection of study participants

• The majority of research participants will be recruited from the University of California 

at Davis student population. Study participants are likely to represent the appropriate 

ethnic and racial diversity of individuals in and around the University, but the use of 

this convenience sample may limit the broad applicability of the study results to the 

general population. The investigators have noted this fact in the protocol (Carroll 2010).

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

the EPA’s Ethics Review (Fuentes and Sherman 2010). In addition, the Board also raised the 

following concerns:

• The Board concurred with the Agency’s recommendation that the protocol be revised to 

exclude as participants employees of the study sponsor. The Board added the 

recommendation that this exclusion also be extended to dependents of the study sponsor or 

sponsor employees.

• The consent form and protocol should be modified as follows:
Final Report Dated December 13, 2010

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1) Carroll-Loye should add “child/minor” to the list of exclusion criteria.

2) The term “treatment” is used ambiguously throughout the protocol and informed 

consent form to describe both the application of the test materials and treatment for 

research-related injuries. For example, on page 23 the protocol states that 

“application of a test material is considered a treatment” (Carroll 2010, 23). 

Elsewhere, however, the protocol states that “candidates are again encouraged to 

ask any questions they have about the study, which may include understanding ... 

treatment and compensation for injury more fully” (Carroll 2010, 17, 238). This 

ambiguity should be resolved with the use of a different term to describe the 

application of test materials.

3) On page 16, the protocol states that “...dosimetry subjects may be consented before 

repellency subjects. Untreated control subjects for the repellency phase (field study) 

are consented before the treated subjects for that phase...” (Carroll 2010, 16). The 

verb “to consent” is an intransitive verb; from a grammatical point of view, 

someone cannot “be consented.” From an ethical perspective, this infelicitous use of 

the verb also employs the passive voice, which is not best practice when the issue is 

to affirm that researchers will be accountable for obtaining informed consent. It is 

recommended that the protocol be modified to use alternate phrasing such as 

“Researchers may obtain informed consent from dosimetry subjects before 

repellency subjects ...”

4) Carroll-Loye should spell out the acronym “PMD” when it is first used in the 

protocol and consent form.

5) On page 2 of the consent form, the phrase “You have been offered an opportunity to 

participate in this research study because ...” (Carroll 2010, 199, 209, 219) be 

modified by Carroll-Loye to minimize the impression that participation in this 

intentional exposure study is somehow a beneficial or favorable occasion. A neutral 

alternative might be: “We are asking you to participate in this research study 

because...”

6) A description of the symptoms of heat stress and equine encephalitis should also be 

included in the consent form. Currently, only the symptoms of West Nile Virus are 

listed. 

Assessment of Proposed AHETF Scenario and Protocol AHE-400: Backpack and Handgun 

Application of Liquid Sprays in Utility Rights-of-Way.

Overview of the Study

This proposal presents an agricultural handler exposure scenario involving backpack and 

handgun application of liquid pesticides along utility rights-of-way. The protocol calls for study 

participants to apply (and potentially load) four surrogate pesticides (fosamine, glyphosate, 

imazapyr and 2,4-D). A total of 21 participants (described in the protocol as “Monitoring Units” 
Final Report Dated December 13, 2010

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[MUs]) will be observed for each scenario; three volunteers each from seven 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 (WBD) 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 AHED® database, where they will be available to the EPA and other regulatory 

agencies for statistical analysis. The proposed documentation will report a confidence-intervalbased 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 applying pesticides using backpack and/or handgun 

applicators under a variety of scenarios.

Science

Charge to the Board

If the proposed AHETF Right-of-Way application scenario and field study proposal 

AHE400 is revised as suggested in EPA’s review and if the research is performed as described, is 

the research likely to generate scientifically reliable data, useful for assessing the exposure of 

workers who apply pesticides in utility rights-of-way using backpack or handgun sprayers? 

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment that the proposed AHETF Right-ofWay application scenario and field study proposal AHE400, if revised as suggested in EPA’s 

review (Evans and Sherman 2010a) and performed as described, may generate scientifically 

reliable data useful for assessing the exposure of workers who apply pesticides in utility rightsof-way using backpack or handgun sprayers.

HSRB Detailed Recommendations and Rationale

Given the lack of existing reliable and sound data in this area, the Board concurred with 

the Agency’s assessment (Evans and Sherman 2010a) that this protocol will likely generate data 

that may be useful for assessing the exposure of handlers who apply pesticides using backpack or 

handgun sprayers. 
Final Report Dated December 13, 2010

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The study, if conducted as described, will provide newer exposure information on dermal 

and inhalation exposures of pesticide handlers using backpack sprayers and handgun sprayers 

treating utility rights-of-way in appropriate and distinct geographic locations; some study participants will be exposed during loading backpacks or tanks as well. The Board agreed with the 

Agency’s assessment that the protocol adequately addresses a number of scientific questions, including having clear scientific objectives, a reasonable experimental design for achieving these 

objectives: appropriate quantification of test materials, adequate procedures for collecting, compiling and summarizing test results, appropriate justification for selection of test substances, 

sample size, and study site selection, and acceptable QA/QC procedures.

However, the Board noted a few weaknesses in the proposed study design. In particular, 

the variability in individual dermal and inhalation exposure levels may be extremely high because of the diversity of terrains and locations selected for the study and the opportunity for large 

(but potentially categorical) personal differences in application practices. As such, results may 

not be reproducible should the study be repeated. The proposal to impose a minimum exposure 

duration of at least 4 hours will also create opportunities for the applicator’s exposures to be influenced by variables that by their nature are likely to be unrelated to the amount of active ingredient handled (AaiH). Should this diversity yield high variability in the data sets, then the proportionality of exposure with AaiH may not be apparent. If the 4-hour minimum is not removed, 

the Task Force may want to ensure that field notes are adequate to report time-on-task as a fraction of the total monitored time for use in later data analysis and usage within AHED. The rationale for having and using this “fraction” is discussed more fully in the Board’s discussion of protocol AHE120 below. Even if the proportionality hypothesis is not supported by the resultant data sets, these data are likely to still be useful and relevant to assessing the levels of exposure to 

workers applying pesticides to utility rights-of-way. 

Ethics

Charge to the Board

If the proposed AHETF Right-of-Way application scenario and field study proposal 

AHE400 is revised as suggested in EPA’s review and if the research is performed as described, is 

the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L? 

Board Response to the Charge

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

with EPA (Evans and Sherman 2010a) and HSRB recommendations, is likely to meet the 

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

HSRB Recommendation

The submitted documents assert that the revised 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 the US EPA’s GLP Standards described at 40 CFR 160 (AHETF 2010a; Collier 

HSRB Detailed Recommendation and Rationale
Final Report Dated December 13, 2010

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2010a). FIFRA §12(a)(2)(P) also applies. The protocol was reviewed and approved by an 

independent human subjects review committee, IIRB, Inc. of Plantation, FL prior to submission. 

Minutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures were provided. 

This IRB is fully accredited by AAHRPP and listed by OHRP (see details above).

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 

(Evans and Sherman 2010a). 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. Risks as noted in the study protocol are four-fold: 1) heatrelated illness; 2) injury associated with scripted field activities; 3) allergic reaction to 

surfactants used for hand washing; and 4) psychological stress and/or breach of 

confidentiality for pregnancy test results. These risks are minimized appropriately and are 

justified by the potential societal benefits, particularly data for new exposure assessments 

for occupational risks associated with spraying pesticides to rights-of-way using 

backpack and handgun sprayers.

• Only experienced pesticide handlers, with specific experience with the type of 

application equipment to be used, and who consider themselves to be in good 

health, will be enrolled. 

• Risk of heat-related illness is minimized appropriately. Heat index will be 

monitored with an associated stopping rule. A medical professional will be on site 

to observe the workers and provide urgent care. Nearby medical facilities have been 

identified in case of emergency, and transportation to medical treatment will be 

provided, if needed. 

• Subjects will be reminded about safe chemical handling practices and procedures, 

wearing appropriate personal protective equipment (PPE), and will be monitored for 

any accidental or unintended product exposure. 

• Minors and pregnant or lactating women are excluded from participation, with 

pregnancy either confirmed by over-the-counter pregnancy testing on the day of 

study or by opt-out. The potential stigma resulting from study exclusion due to 

pregnancy is appropriately minimized. 

The Board disagreed with the AHETF conclusion, however, that “the risk of toxicity from 

pesticide handling [is not] strictly due to study participation [and therefore], the risk of 

surrogate toxicity will not be listed in consent forms or this protocol” (Collier 2010a, 

309). This study is subject to 40 CFR 26 subparts K and L precisely because it is 

considered to be a study in which the subjects are “intentionally exposed,” for research 

purposes, to pesticides. Given its scripted nature, the AHETF protocol influences the 

behavior of workers and their employers in a number of ways. That a particular 

agricultural worker will be applying a particular pesticide on a particular day is due, to a 
Final Report Dated December 13, 2010

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large extent, to the fact that the study is being conducted. Accordingly, the risk from 

exposure to the pesticides being applied should clearly be categorized as a risk of study 

participation.

The Board does agree, however, that the risk from exposure to those pesticides is a 

reasonable one, and that it has been appropriately minimized. The products being used in 

this study are ones already registered by EPA for vegetation control in rights-of-way, and 

will be applied in accordance with label requirements. 

b. Voluntary and informed consent of all participants 

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

vulnerable populations, susceptible to coercion and undue influence. The study 

protocol, however, includes several mechanisms designed to minimize coercive 

recruitment and enrollment.

• 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.

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

• Spanish translations of the informed consent documents, informational packets, and 

recruitment flyers were provided. Researchers will be working with local Spanishspeaking community members to ensure that the appropriate regional dialect of Spanish 

is used (AHETF 2010b).

c. Equitable selection of study participants

• The study is designed to recruit an appropriately diverse population of participants who 

represent skilled workers in the study locations.

• The study will first involve identifying and contacting the employers involved in rightof-way application of pesticides. Only employees of these employers are eligible to be 

recruited. The recruitment process has been carefully designed to assure that employees 

will not be coerced into participating: recruitment will take place using brochures and 

meetings with employees at which the employer and supervisors will not be present.

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

the EPA’s Ethics Review (Evans and Sherman 2010a). In addition, the Board also raised the 

following concerns:

• As noted above, the Board concluded that the risk of toxicity from pesticide handling is 

indeed a risk of participating in the study, and accordingly it should be described as such, 

and discussed appropriately, in the consent form.
Final Report Dated December 13, 2010

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• The consent form should explain that the pregnancy test will be provided by the 

researchers, and explain when it will take place.

• There appears to be a discrepancy between the exclusion criteria stated in the EPA review 

(Evans and Sherman 2010a, 36), which refer to training in handling pesticides, and the 

AHETF-provided consent form (AHETF 2010a, 267), which notes that the subject might 

need only to confirm that “you are not required to take this training.” This discrepancy 

should be clarified.

• Study participants will undergo hand washes prior to eating anything, which will reduce 

their risk of accidental ingestion of the surrogate compounds. As many of the adults in the 

US still smoke, however, hand washes should also occur before any smoking break to 

further reduce participant’s risk of accidental pesticide ingestion.

Assessment of Completed AEATF II Research Study AEA-03: A Study for Measurement of 

Potential Dermal and Inhalation Exposure during Application of a Liquid Antimicrobial 

Pesticide Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces (MRID 

48210201, MRID 48231201, MRID 48231901).

Overview of the Study

The objective of this study was to measure individual exposures to a surrogate 

antimicrobicidal pesticide (didecyl dimethyl ammonium chloride; DDAC) while mopping floors 

and emptying mop buckets. Eighteen volunteers participated in the study, mopping floors in one 

of three building types (an office building, a Rite Aid pharmacy building, or a retired teacher’s 

memorial building in Fresno, CA) for one of six pre-determined mopping times (30-40, 40-50, 

50-60, 60-70, 70-80 and 80-90 minutes total mopping time, respectively).

Dermal and inhalation exposure monitoring was conducted while study participants 

mopped floors and emptied the mop buckets; all participants wore long-sleeved shirts, long 

pants, shoes, socks, and no gloves. Dermal exposure was measured by inner and outer body 

dosimeters. Airborne concentrations of the surrogate compound were monitored in the 

participant’s breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector 

connected to a personal sampling pump. Environmental conditions were also recorded at the time 

of monitoring, and observers made notes, photographs and videos of participant activity 

throughout the mopping period.

These exposure data will be used to populate a database representing inhalation and 

dermal exposure during a number of antimicrobial handler scenarios. A scenario is defined as a 

pesticide handling task based on activity (e.g., application) and equipment type (e.g., mop & 

bucket, ready-to-use wipes, pressure treatment of wood facilities, painting). These data will be 

used by the Agency to estimate dermal and inhalation exposures of antimicrobial handlers who 

are applying pesticides using a mop and bucket under a variety of scenarios. 
Final Report Dated December 13, 2010

Page 18 of 31

Science

Charges to the Board

1) Was the research reported in the Antimicrobial Exposure Assessment Task Force II (AEATF–

II) completed study report AEA-03 and associated supplemental reports faithful to the design 

and objectives of the protocol and governing documents of AEATF-II? 

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 antimicrobial floor-cleaning products with mop and bucket? 

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment (Leighton 2010) that the research 

reported in the completed AEA-03 study report and associated supplemental documents (Selim 

and Taylor 2010a, 2010b, 2010c) was conducted in a manner that was reasonably faithful to the 

design and objectives of the protocol and governing documents of AEATF-II. The Board also 

concluded that the Agency has adequately, if not completely, considered the limitations on these 

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

antimicrobial floor-cleaning products with mop and bucket.

HSRB Detailed Recommendations and Rationale

The study was conducted in a manner that was reasonably faithful to the design of the 

protocol and governing documents. The study report (Selim and Taylor 2010a) contains sections 

that adequately describe the test substance, recruitment procedures, field procedures, sample 

collection and handling, sample analysis, and data analysis. Previous Board recommendations 

(EPA HSRB 2008) for the use of a double layer of socks and provision of more detail about staff 

activities during the observation period were adopted. Appropriate rationale for changes in key 

elements of the study design, including justification for the purposive sampling of monitoring 

events (MEs) and the sample size of 18, was also provided. Finally, assuming that only one 

participant was present in the cluster when an ME was conducted, it also appears that no 

participant observed another participant’s activities during the study, as previously 

recommended. However, some of the issues raised by the Board in its initial review of the mop 

and bucket scenario (EPA HSRB 2008) were not addressed, including: the bases for the 90-

minute maximum mopping period choice, the possibility (or not) of “carry-over effects” between 

MEs, and the interaction between aerosolized particles, heating, ventilation and air conditioning 

(HVAC) systems, and inhalation exposure estimates. Although the importance of measuring the 

impact of HVAC systems on inhalation exposures was mentioned in the protocol (Selim and 

Taylor 2010a, 28), it was not given appropriate attention nor were HVAC operations consistently 

documented during the conduct of the study. 

The study was also conducted in a manner that was reasonably faithful to the objectives 

of the protocol and governing documents. As stated in the final report, the study was conducted 
Final Report Dated December 13, 2010

Page 19 of 31

primarily to “determine potential dermal and inhalation exposures to professional janitorial 

workers when mopping indoor surfaces with a liquid antimicrobial pesticide product containing 

didecyl dimethyl ammonium chloride (DDAC)” (Selim and Taylor 2010a, 28). Dermal exposures 

were reported, with estimates based on total collected residue from all matrices (face and hand 

wipes, socks, and all parts of the inner dosimeter). Dermal exposures were expressed as 

micrograms of active ingredient (AI) handled per subject and as milligrams of AI per 

subject/pound of AI applied. Inhalation exposure was also presented as units of concentration. 

However, sufficient data is available (i.e., the duration of each exposure) to express those results 

in the same units as dermal exposures if an average respiratory minute volume for the applicators 

is also applied to the calculation.

The overall study objective was listed differently in the Agency’s scientific review than in 

the protocol, stating it as: “the study objective is to monitor inhalation and dermal exposures to 

be used as inputs in exposure algorithms to predict future exposures to persons mopping floors.” 

(Leighton 2010, 5). The Agency added two sub-objectives not found in the protocol: “to be 95% 

confident that key statistics of normalized dermal exposure are accurate within 3-fold” and “to 

evaluate the presumption of proportionality between exposure and amount of active ingredient 

handled,” respectively. The Agency provided a thorough assessment of their first sub-objective 

supporting the sample size and analyses used to achieve the 3-fold accuracy goal. However, 

although the presumption of proportionality was demonstrated for dermal exposure and the 

amount of AI handled, the rationale supporting the presumption of proportionality for inhalation 

exposure needs to be recalculated to include duration of exposure. 

The Agency’s scientific review (Leighton 2010) discussed the limitations of the dermal 

and inhalation exposure data. The Agency also presented alternative models for estimating 

dermal and inhalation exposures, evaluated the impacts of non-detects and of assigning low 

limits of quantification (LOQs) at 3 different values (0, 1⁄2 and full LOQ). The Agency concluded 

that dermal exposures and pounds of active ingredient are related in a proportional manner, while 

accounting for sampling efficiency and normalizing the data in terms of milligrams/pounds of 

active ingredient applied. The Agency also discussed the dermal exposure estimates in 

relationship to its sub-objectives of the study (accuracy within 3-fold and proportionality). Their 

assessment acknowledged that some estimates included a high level of uncertainty and some 

bias. The Board concluded that the Agency adequately, if not completely, considered limitations 

in its interpretation and subsequent estimates of dermal exposure data. The Agency should 

carefully examine the handwash data, however, to ensure that it does not overcorrect for face and 

neck residue estimates. Additionally, the model may not always support the conclusion of 

proportionality for all clothing configurations.

With respect to limitations of the inhalation exposure data due to study deviations, some 

(but not all) of the limitations that need to be considered when estimating inhalation exposure 

were discussed. In its initial 2008 review (EPA HSRB 2008), the Board noted several factors that 

could influence these estimates, including: ventilation, room temperature, total area mopped, 

duration of mopping, and volume of the enclosed space and respiration rate of the study 

participants. Although the final study report provides some of these data for the facilities in 

which mopping activities were conducted (Selim and Taylor 2010a, 105-7), neither ventilation 

data nor a discussion of these factors were provided, thus limiting the Board’s and Agency’s 
Final Report Dated December 13, 2010

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ability to interpret fully the reported environmental data. Furthermore, the rationale for the 

Agency’s conclusion that air changes per hour was not a significant factor influencing inhalation 

exposure estimates, based on the low vapor pressure of DDAC and the LOQs observed, does not 

recognize fully how HVAC parameters could have affected reported air concentrations from 

mopping activities. The Agency also failed to consider whether the limited areas available for 

mopping in Clusters 1 and 3 could have compromised the study design or affected inhalation 

exposure estimates. Similarly, although surface areas of the floors mopped were noted, the 

ceiling heights were not reported. The Agency’s review also fails to consider the impact that 

ceiling height and room volume may have had on the reported air concentration data. The 

respiration rates of study participants were not discussed by the Task Force researchers or the 

Agency; ignoring this factor could introduce important uncertainties into exposure estimates. 

Finally, the Board’s previous recommendation to consider particle size (e.g., whether DDAC is 

aerosolized) and its potential impact on inhalation exposures were not addressed by the Agency. 

Although not discussed in detail by the Board at the October 2010 meeting, several of these 

factors are discussed in a separate report (submitted independently by an HSRB member to the 

Agency).

Ethics

Charge to the Board

Does available information support a determination that the study was conducted in 

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

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment (Carley 2010) that the study was 

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

HSRB Detailed Recommendation and Rationale

The documents provided by Golden Pacific Laboratories, LLC, under Project No. AEA03, state that the study was conducted in compliance with the requirements of 40 CFR 26 

subparts K, L and M; FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3, 

Section 6710 (Selim and Taylor, 2010a, 2010b, 2010c). The protocol was reviewed and approved 

by an independent human subjects review committee, IIRB, Inc. of Plantation, FL prior to 

submission. Minutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures 

were provided. This IRB is fully accredited by AAHRPP and listed by OHRP (see details above).

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

detailed in the EPA’s Ethics Review (Carley 2010) and summarized briefly below. 

a. Prior HSRB and Agency Review. Because this study 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 
Final Report Dated December 13, 2010

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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. and submitted to the EPA in 

February 2008. The HSRB discussed the protocol at its April 2008 meeting, concurring 

with the Agency’s assessment that the proposed mop and wipe scenario, 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 Agency’s initial ethics review noted two deficiencies to be corrected before the study 

was initiated. The first focused on measures to improve the informed consent process for 

Spanish-speaking candidates. The Agency called for the candidate interviews for Spanish 

speakers to be conducted by a member of the research team fluent in Spanish, rather than 

an independent translator. The second deficiency focused on references in the informed 

consent forms to “normal business hours”. The Agency asked that the researchers revise 

the consent form to show hours for calling in local (Pacific) time. 

In the revisions submitted to IIRB, Inc. in February 2009, the researchers addressed these 

ethical concerns. Because the study was conducted in California, the approval of the 

California Department of Pesticide Regulation (CDPR) was also required. CDPR granted 

final approval of the amended protocol and supporting documents in April 2009.

c. Responsiveness to HSRB and Agency Reviews. The Agency’s and HSRB’s comments 

were satisfactorily addressed in the revisions approved by the IIRB in March 2009 (Selim 

and Taylor 2010a). 

At its April 2008 meeting, the HSRB made several specific recommendations for 

refinements of the study. As noted in Amendment 4 of the Agency’s ethics review 

(Carley 2010), the investigators addressed fully most of these recommendations, 

addressed partially some of these recommendations, and did not address two of these 

recommendations. The Board agreed with the Agency conclusion, however, that the 

investigators’ failure to address all of the recommendations did not violate applicable 

ethical standards for the protection of human participants of research.

d. Substantial Compliance with Reporting Requirements (40 CFR §26 subpart M). 

The study sponsor initially did not provide adequate documentation to demonstrate that 

they had satisfied the requirements of §26.1303. The initial report (Selim and Taylor, 

2010a) contained several reporting deficiencies, including: inadequate documentation of 

interaction between the investigators and the overseeing IRB, incomplete study 

chronology, and a lack of tracked consent forms showing how they were revised to 

address Agency and HSRB concerns. These deficiencies were corrected by the 

submission of supplemental documents (Selim and Taylor, 2010b, 2010c). 

IRB minutes documenting discussion and review of these revised documents were not 

provided for review. All IIRB, Inc. reviews subsequent to the HSRB’s April 2008 
Final Report Dated December 13, 2010

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meeting were conducted using an expedited procedure and did not require a full meeting 

of the IRB. Neither the IRB roster nor the operational procedures were submitted as part 

of the study documents. 

The HSRB agreed with the Agency that these deficiencies in the conduct and the 

documentation of the research did not compromise the ethical conduct of the study, and 

concluded that the requirements of 40 CFR §26.1303 were satisfactorily addressed. The 

HSRB did recommend, however, that the Agency require the submission of reports for all 

research that undergoes expedited IRB review in the future. 

2. The Board concluded that this study, as conducted, met all applicable ethical requirements for 

research involving human participants, in accordance with the following criteria that had 

been stated in the Board’s prior review of this protocol (EPA HSRB 2008).

a. Acceptable risk-benefit ratio. The risks to study participants were minimized 

appropriately and were justified by the potential societal benefits, particularly data on the 

dermal and inhalation exposure of professional janitorial workers to antimicrobial 

pesticides as they mopped indoor floors and disposed of spent mop water. These data 

could be used to develop mechanisms to protect future users of these antimicrobial 

pesticides.

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

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

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

minimized. 

• Clear stopping rules and medical management procedures were in place, and no adverse 

events or other incidents of concern related to product exposure were reported.

• The study was designed to minimize the risks of exposure to the test compounds.

b. Voluntary and informed consent of all participants

• The study protocol included several mechanisms designed to minimize coercive 

recruitment and enrollment. 

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

3. Three minor protocol deviations were reported. These included: 1) most study participants 

declining to take rest breaks or taking less than the 10 minutes provided for in the protocol; 

2) full facial photographs taken of participants at one monitoring site; and 3) enrollment of 

participants who self-reported that their health was only “fair,” despite the requirement that 

all participants be in “good health” (Selim and Taylor, 2010b, 31). The Board concluded, 

however, that these minor deviations did not affect the integrity of the research or the safety 

of participants. The Board did recommend, however, that sponsors clarify the criteria used to 

establish participants’ health status prior to study enrollment.
Final Report Dated December 13, 2010

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Assessment of Revised AHETF Scenario and Protocol AHE-120: Water-Soluble Packaging 

Mixing and Loading.

Overview of the Study

This revised proposal presents an agricultural handler exposure scenario involving 

mixing/loading of pesticides enclosed in water-soluble packets (WSP). The original protocol, 

which was favorably reviewed by the Board at its June 2009 meeting (EPA HSRB 2009), called 

for study participants to mix and load one of two WSP-enclosed surrogate pesticides (acephate 

and carbaryl) into a variety of tanks containing water in a variety of agricultural spraying 

operations. Carbaryl in water-soluble packaging is no longer being produced by pesticide 

manufacturers; however, the AHETF proposed substituting three additional surrogate compounds 

for carbaryl: dithiopyr, imidacloprid, and thiophanate-methyl. Because of use patterns of these 

surrogate compounds, the AHETF also identified additional study sites. The previously reviewed 

study was to be conducted at three cool dry sites in Michigan, New York, and Washington State, 

one hot humid site in Louisiana, and one hot dry site in California. The revised protocol will also 

be conducted at five sites, including two cool dry sites in New York and North Dakota, two hot 

humid sites in Florida and Louisiana, and one hot dry site in California.

A total of 25 participants (described in the protocol as “Monitoring Units” [MUs]) will be 

observed; five volunteers each from five different growing regions will be enrolled using a 

purposive sampling method. Dermal exposure will be measured by a whole body dosimeter 

(WBD) 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 mixing/loading of water-soluble packets 

scenario, and will be posted to the AHED® database, where they will be available to the EPA 

and other regulatory agencies for statistical analysis. The Agency proposes to use these data to 

estimate daily dermal and inhalation exposures of agricultural handlers who are mixing/loading 

pesticides in water-soluble packets under a variety of mixing and loading scenarios.

Science

Charge to the Board

If the revised AHETF scenario and field study proposal AHE120 is revised as suggested 

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

scientifically reliable data, useful for assessing the exposure of handlers who mix and load 

pesticides in water-soluble packaging? 
Final Report Dated December 13, 2010

Page 24 of 31

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment (Evans and Sherman 2010b) that this 

protocol will generate data that are scientifically valid and that may be useful for assessing the 

exposure of handlers who mix and load soluble or wettable powder pesticides in water-soluble 

packaging. The Board cautioned, however, that these data might not be useful for creating 

distributions of worker exposure that are scientifically accurate or that are precise.

HSRB Detailed Recommendations and Rationale

The protocol is largely the same as when it was first reviewed by the HSRB in June 2009 

(EPA HSRB 2009). The major changes are that one of the surrogate active ingredients (carbaryl) 

was deleted and three other active ingredients (dithiopyr, imidacloprid, and thiophanate-methyl) 

were added. This change necessitated revising the geographical regions in which the study could 

be conducted and a slight lowering of each of the five strata in the amounts of active ingredient 

handled. 

Each of these changes seems justified. Assuming that the AHETF can provide adequate 

evidence of the validity of the analytical methods for each of the new compounds, the revised 

study protocol still allows a good probability of the study successfully obtaining its primary and 

secondary objectives (i.e., “that selected lognormal-based estimates of normalized dermal exposure distribution be accurate to within 3-fold, at least 95% of the time,” and the ability to distinguish “a proportional from an independent relationship between exposure and AaiH,” respectively [Evans and Sherman 2010b, 28-9]).

However, the Board pointed out that many of the same concerns it raised in June 2009 

remain for the revised protocol. Of particular note is the conflict between the non-random, purposive study design and the statistical methods proposed to analyze the exposure data. Moreover, 

the protocol does not control for ecological, engineering, and statistical factors that may obscure 

a linear relationship between AaiH and worker exposure. Previously the Board said that “there is 

no statistical theory that can be applied to non-random samples of this type. Thus, the statistical 

analyses proposed, including mixed model approaches, are not valid” (EPA HSRB 2009, 34). In 

contrast to the prior version, this protocol indicates that AHETF will not statistically analyze the 

monitoring data; that begs the question as to what statistical methods are appropriate to use on 

these data. 

The Board also raised one new concern regarding the potentially adverse impact of the 

protocol’s exposure duration of at least 4 hours for all of the MUs. This constraint seems unnecessary and may introduce unintended and undesired variability into the results. The Board 

noted that scripting activities to include more time than would otherwise be required to apply the 

amount of active ingredient in the designated stratum is likely to change the applicator’s exposures by introducing variables that by their nature are unrelated to the AaiH. In particular, other 

tasks within those hours are likely to result in the transfer of active ingredient either to or from 

other surfaces from or onto the subject. For this study, the fraction of the total monitored time 
Final Report Dated December 13, 2010

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that is time on-task is likely to be highly variable, probably among strata (particularly if the artificial constraint on the minimum time monitored affects the low AaiH preferentially) and potentially even within strata. While omitting this time constraint would avoid these random variables, 

the Board recommended that all field notes for this study report the time on-task as a fraction of 

the total monitored time, and that the total monitored time and the fraction of the total time ontask be tabulated for this study. This fraction can be used later by the Agency, sponsors and 

AHED users to reliably extrapolate from the time-weighted average concentrations or rates of 

exposure measured by the existing protocols to task-specific concentrations or rates of dermal 

and inhalation exposure per AaiH.

Ethics

Charge to the Board

If the revised AHETF scenario and field study proposal AHE120 is revised as suggested 

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

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

Board Response to the Charge

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

with EPA (Evans and Sherman 2010b) and HSRB recommendations, is likely to meet the 

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

HSRB Recommendation

The submitted documents assert that the revised 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 the US EPA’s GLP Standards described at 40 CFR 160 (AHETF 2010c; Collier 

2010b). FIFRA §12(a)(2)(P) and the California State EPA Department of Pesticide Regulation’s 

study monitoring requirements (California Code of Regulations Title 3, Section 6710) also apply. 

The protocol was reviewed and approved by an independent human subjects review committee, 

IIRB, Inc. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and a copy of 

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

listed by OHRP (see details above).

HSRB Detailed Recommendation and Rationale

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

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

Review (Evans and Sherman 2010b). The proposed study is likely to meet the applicable 

ethical requirements for research involving human participants, in accordance with the 

following criteria:

a. Acceptable risk-benefit ratio. Risks as noted in the study protocol are four-fold: 1) heatrelated illness; 2) injury associated with scripted field activities; 3) allergic reaction to 

surfactants used for hand washing; and 4) psychological stress and/or breach of 

confidentiality for pregnancy test results. These risks are minimized appropriately and are 
Final Report Dated December 13, 2010

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justified by the potential societal benefits, particularly data on occupational exposure of 

agricultural workers to pesticides during mixing and loading activities.

• The greatest risk to participants is that of heat-related illness, given that the 

participants will be required to wear two layers of clothing during the scenario 

activities. This risk is lessened but not eliminated by the application of appropriate 

stopping rules (including cessation of all monitoring activities when the ambient 

heat-index exceeds 105°F) and frequent monitoring of participants. Participants will 

be given frequent breaks, access to ample amounts of water or sports drinks, and 

educated about the dangers and symptoms of heat-related illness. Appropriate

medical management procedures are also in place.

• The surrogate materials consist of four common pesticides: acephate, dithiopyr, 

imidacloprid, and thiophanate-methyl. The participants will only be exposed to 

concentrations of the surrogate compound at accepted exposure thresholds. 

• Participants will be selected from volunteers with experience handling these or 

similar compounds in WSP mixing and loading scenarios. Thus, all of the 

participants will have extensive experience in using these or similar products, and 

thus will be unlikely to misuse them in a way that might increase their likelihood of 

being accidentally exposed.

• Participants will be reminded about safe handling practices and procedures, about 

wearing appropriate PPE, and will be monitored for any accidental or unintended 

product exposure.

• Allergic reactions to the surfactants used in hand washing are usually mild and 

easily treated with over-the-counter steroidal creams. The study will exclude 

participants who have a history of severe skin reactions to such detergents.

• Minors and pregnant or lactating women are excluded from participation, with 

pregnancy either confirmed by over-the-counter pregnancy testing on the day of 

study or by opt-out. The potential stigma resulting from study exclusion due to 

pregnancy is also appropriately minimized.

Several members noted, however, that exposure to the surrogate chemicals is no longer 

listed as a potential risk to study participants in either the protocol or in the informed 

consent documents. Study volunteers, it was argued, are likely to handle these chemicals 

as part of their daily activities and the possibility of exposure is thus a risk of 

employment and not a risk of study participation. However, because of the nature of the 

study (including scripted handling of specific amounts of chemical), the Board felt that 

exposure to the surrogate chemicals was a potential risk of study participation and 

recommended that the sponsor explicitly list this risk in the protocol and informed 

consent documents. 
Final Report Dated December 13, 2010

Page 27 of 31

b. Voluntary and informed consent of all participants

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

vulnerable populations, susceptible to coercion and undue influence. The study 

protocol, however, includes several mechanisms designed to minimize coercive 

recruitment and enrollment.

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

• Spanish translations of the informed consent documents, informational packets, and 

recruitment flyers were provided. Researchers will be working with local Spanishspeaking community members to ensure that the appropriate regional dialect of Spanish 

is used (AHETF 2010d).

c. Equitable selection of study participants

• The study is designed to recruit an appropriately diverse population of participants who 

represent skilled agricultural workers in the five study locations.

• Community representatives and advocates are appropriately involved in the recruitment 

and enrollment of study participants.

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

the EPA’s Ethics Review (Evans and Sherman 2010b). In addition, the Board also raised the 

following concerns:

• The Board raised concerns that the revised water-soluble packaging protocol was reviewed 

by IIRB, Inc. using an expedited procedure. Future protocol revisions that involve major 

changes like substitution of surrogate compounds and/or change in study site should be 

reviewed under full-board procedures and reflected properly in the IRB minutes.

• As noted above, the Board recommended that accidental exposure to the surrogate 

chemicals be listed in the protocol and that the informed consent form also list surrogate 

exposure as a potential risk of study participation.

• The protocol excludes participants who normally wear additional personal protective 

equipment (such as chemical-resistant clothing) that is not required by the chemical label 

and that might impact the objectives of the study. The Board recommended that this 

assessment be done in a non-directive way, so as not to encourage participants to wear less 

PPE than they would normally in order to participate in the study.

• Study participants will undergo hand washes prior to eating anything, which will reduce 

their risk of accidental ingestion of the surrogate compounds. As many of the adults in the 

U.S. still smoke, however, the Board recommended that hand washes also occur before any 

smoking break to further reduce their risk of accidental pesticide ingestion.
Final Report Dated December 13, 2010

Page 28 of 31

• The informed consent document states that “you may refuse medical treatment unless you 

get sick from too much exposure to pesticides or from getting too hot, or if we believe you 

are too sick to make a rational decision about getting medical treatment” (Collier 2010b, 

emphasis added). It was unclear how this determination of rationality will be made, 

however. The protocol and informed consent document should be more explicit as to who 

will make this determination, and what criteria would be used.

• The Board raised some concerns about how the Task Force plans to release individual 

exposure data to individual study participants who request this information. For example, 

the Board encouraged the sponsor to consider how this information might be provided to 

participants who do not speak English and/or are illiterate. The Board also recommended 

that the request for individual study results be included as a check box on the informed 

consent document. The HSRB will be establishing a small working group to develop some 

guidance for the Agency and sponsors regarding the release of individual exposure data to 

study participants.
Final Report Dated December 13, 2010

Page 29 of 31

REFERENCES

Agricultural Handler Exposure Task Force (AHETF). 2010a. Supplemental 1 to the Backpack 

and Handgun Application of Liquid Sprays in Utilities Rights-of-Way Scenario Submission 

(AHE-400): SOPs Cited in AHE-400 ROW Submission. Undated and unpublished document 

prepared by the AHETF.

AHETF. 2010b. Supplemental 2 to the Backpack and Handgun Application of Liquid Sprays in 

Utilities Rights-of-Way Scenario Submission (AHE-400): Providing Individual Exposure 

Information to Subjects. Undated and unpublished document prepared by the AHETF.

AHETF. 2010c. Supplemental 1 to the Revised Water Soluble Packet Mixer/Loader Scenario 

Submission (AHE-120): SOPs Cited in AHE-120 ROW Submission. Undated and unpublished 

document prepared by the AHETF.

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Carley, J.M. 2010. Ethics Review of Completed AEATF II Mop Scenario Worker Exposure 

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EPA Human Studies Review Board. 2008. April 9-10, 2008 Human Studies Review Board 

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Evans, J., and K. Sherman. 2010a. Science and Ethics Review of AHE400: A New Scenario 

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Use Backpack or Hand Gun Sprayers to Apply Pesticides in Utility Rights-of-Way. Dated 
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Evans, J., and K. Sherman. 2010b. Science and Ethics Review of Revised AHETF Scenario 

Design and Protocol AHE120 for Exposure Monitoring of Workers during Mixing and Loading 

of Pesticide Products in Water Soluble Packets in Five Regions of the United States (August 

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Johnson, D., for the Agricultural Handler Exposure Task Force (AHETF). 2010a. Supplemental 3 

to the Revised Water Soluble Packet Mixer/Loader Scenario Submission (AHE-120): 

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Leighton, T. 2010. Science Review of the AEATF II Mop Human Exposure Monitoring Study 

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II). 2010a. A Study for Measurement of Potential Dermal and Inhalation Exposure during 

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Cleaning Indoor Surfaces. Dated August 2, 2010. Unpublished document prepared by the 

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Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment Task Force II (AEATF 

II). 2010b. Supplement 1 to A Study for Measurement of Potential Dermal and Inhalation 

Exposure during Application of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop 

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