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April 11, 2012

EPA-HSRB-12-01

Lek Kadeli, Acting Assistant Administrator

Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject: January 26, 2012 EPA Human Studies Review Board Meeting Report

Dear Mr. Kadeli,

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

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

for a study involving intentional exposure of human subjects to pesticides: a proposed 

Agricultural Handler Exposure Task Force, LLC (AHETF) scenario measuring dermal and 

inhalation exposure of workers who perform mixing, loading and application of pesticides using 

powered (gasoline or electric) handgun/hand wand equipment in greenhouses and nurseries 

(AHE-600).

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

inhalation exposure of professional janitorial workers who clean indoor surfaces with an 

antimicrobial pesticide product using hand-held pressurized aerosol canisters, conducted by the 

Antimicrobial Exposure Assessment Task Force II (AEATF II). This study (AEA-04) was 

conducted after publication of the EPA’s expanded final rule for protection of subjects in human 

research. The data will be posted to the Biocide Handlers Exposure Database (BHED®), and used 

generically to estimate daily dermal and inhalation exposures of those who wipe indoor surfaces 

with antimicrobial pesticides.

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

the January 26, 2012 meeting.

Assessment of Proposed AHETF Research Study AHE-600: Mixing, Loading, and Applying 

Liquid Pesticides in Managed Horticultural Facilities Using Powered Handgun Equipment.

Science

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

with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to 

generate high quality, reliable and useful data for assessing worker’s pesticide exposures in 

horticultural settings. 

• The Board provided several additional comments or suggestions with respect to the use of 

personal protective equipment (PPE), the potential effect of unanticipated incidental 
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exposures and other variables on proportionality, and the utility of existing European Crop 

Protection Association (ECPA) data.

Ethics

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

with EPA and HSRB recommendations, is likely to meet the applicable requirements of 40 

CFR 26, subparts K and L.

Assessment of Completed AEATF II Research Study AEA-04: Measurement of Potential 

Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide 

Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting.

Science

• The Board concurred with the Agency’s assessment that this study provides scientifically

valid results for estimating the dermal and inhalation exposure of those who apply liquid 

antimicrobial pesticide products for indoor surface disinfecting using a pressurized aerosol 

can, but noted several issues, limitations and concerns with the data and proposed analyses.

Ethics

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

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

Sincerely,

Sean Philpott, PhD, MSBioethics

Chair

EPA Human Studies Review Board
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NOTICE

This report has been written as part of the activities of the EPA Human Studies Review 

Board, a Federal advisory committee providing advice, information and recommendations on 

issues related to scientific and ethical aspects of human subjects research. This report has not 

been reviewed for approval by the Agency and, hence, the contents of this report do not 

necessarily represent the view and policies of the Environmental Protection Agency, nor of other 

agencies in the Executive Branch of the Federal government, nor does the mention of trade 

names or commercial products constitute a recommendation for use. You may obtain further 

information about the EPA Human Studies Review Board from its website at 

http://www.epa.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.
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US ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD

Chair

Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union 

Graduate College and the Mount Sinai School of Medicine, Schenectady, NY

Vice Chair

Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH), School of Public Health and Human 

Services, The George Washington University, Washington, DC

Members

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

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

University, Mississippi State, MS

George Fernandez, PhD, Professor of Applied Statistics, Director of the University of 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

Jewell H. Halanych, MD, Assistant Professor, Department of Preventive Medicine, University of 

Alabama at Birmingham, Birmingham, AL

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

Manhattan, KS

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

of Arizona, Tucson, AZ 

José 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

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

University, Logan, UT
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Leonard Ritter*, PhD, Professor Emeritus, School of Environmental Sciences, University of 

Guelph, Guelph, ON, Canada

Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, 

Veterans Health Administration, Washington, DC

Bernard A. Schwetz*, DVM, PhD, Director (Retired), Office of Human Research Protections, 

Department of Health and Human Services, Cadott, WI

Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 

Sciences, University of Florida, Gainesville, FL

Human Studies Review Board Staff

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

Advisor, United States Environmental Protection Agency, Washington, DC

* Not present on January 26, 2012.

† Participated in the January 26, 2012 meeting via telepresence.
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INTRODUCTION 

On January 26, 2012, the United States Environmental Protection Agency’s (EPA or 

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

concerning one new protocol for research involving human participants: a study measuring 

dermal and inhalation exposures associated with the mixing, loading and application of 

pesticides using powered (gasoline or electric) handgun/hand wand equipment in greenhouses 

and nurseries. In accordance with 40 CFR 26.1601, EPA sought HSRB review of this proposed 

study. This study is discussed more fully below.

In addition, the Agency has data from one completed study measuring dermal and 

inhalation exposure of professional janitorial workers who clean indoor surfaces with an

antimicrobial pesticide product using hand-held pressurized aerosol canisters. In accordance with 

40 CFR 26.1602, EPA sought HSRB review of this completed study. This study is discussed 

more fully below.

REVIEW PROCESS

On January 26, 2012, the Board conducted a public face-to-face meeting in Arlington, 

Virginia. Advance notice of the meeting was published in the Federal Register as “Human 

Studies Review Board; Notice of Public Meeting” (76 Federal Register 248, 80938).

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

EPA on the following topics: one new study protocol to measure dermal and inhalation exposures 

associated with the mixing, loading and application of pesticides using powered (gasoline or 

electric) handgun/hand wand equipment in greenhouses and nurseries, and one completed study

measuring dermal and inhalation exposure of professional janitorial workers who clean indoor 

surfaces with an antimicrobial pesticide product using hand-held pressurized aerosol canisters. 

The Board also asked clarifying questions of several study sponsors and/or research 

investigators, including:

Ms. Megan Boatwright, Analytical Coordinator, Golden Pacific Laboratories.

Dr. Victor Cañez, Risk Assessment Solutions, Technical consultant to the Agricultural 

Handler Exposure Task Force.

Dr. Richard Collier, Administrative Committee Chair, Agricultural Handler Exposure 

Task Force.

Mr. William McCormick III, Clorox, on behalf of the Antimicrobial Exposure 

Assessment Task Force II.

Mr. Robert Testman, Vice-President, Golden Pacific Laboratories.
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Public oral comments were provided by:

Dr. Victor Cañez, Risk Assessment Solutions, Technical consultant to the Agricultural 

Handler Exposure Task Force

Dr. Richard Collier, Administrative Committee Chair, Agricultural Handler Exposure 

Task Force.

Mr. Robert Testman, Vice-President, Golden Pacific Laboratories.

One written public comment from a New Jersey resident was submitted, but the substance 

of that comment was not directly related to the two studies under review by the HSRB at the 

January 26, 2012 meeting. 

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

comments, and Agency background documents (e.g., published literature, sponsor and 

investigator research reports, study protocols, data evaluation records, and Agency science and 

ethics reviews of proposed protocols and completed studies). A comprehensive list of 

background documents is available online at http://www.regulations.gov. 

CHARGE TO THE BOARD AND BOARD RESPONSE

Assessment of Proposed AHETF Research Study AHE-600: Mixing, Loading, and Applying 

Liquid Pesticides in Managed Horticultural Facilities Using Powered Handgun Equipment.

Overview of the Study

This proposal presents an agricultural handler exposure scenario involving mixing, 

loading and application of pesticides using powered (gasoline or electric) handgun/hand wand 

equipment in greenhouses and nurseries. Pesticides can be formulated as either liquids or as 

wettable powders.

A total of 30 participants (described in the protocol as “Monitoring Units” [MUs]) will be 

observed; three volunteers from each of ten geographically distinct growing regions will be 

enrolled using a purposive sampling method (with some elements of random selection). For each 

monitoring area, volunteers will be randomized to mix and load a defined amount of active 

ingredient within one of three strata: 0.5 to 1.6 pounds, 1.6 to 4.8 pounds of active ingredient, or 

4.8 to 15 pounds of active ingredient. After mixing and loading the pesticide, participants will 

use powered equipment to treat ornamentals and nonbearing fruit trees in nurseries, or 

ornamentals and vegetables grown in greenhouses, using spray patterns that include downward, 

outward and upward directions.

For this protocol, all participants will wear long sleeved shirts, long pants, and shoes plus 

socks. In addition, all participants will wear chemical resistant gloves. Additional personal 

protective equipment (PPE) may be required depending on product labeling directions, including 

the use of chemical-resistant aprons when mixing and loading the pesticide, and chemicalresistant headgear when making overhead applications. 
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Dermal exposure will be measured by a whole body dosimeter worn beneath the subject’s 

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

after completion of pesticide loading and mixing procedures. For study participants wearing 

chemical-resistant headgear, patches placed inside and outside of the headgear will be employed 

to estimate dermal exposure of the protected portions of the body covered by these garments. 

Airborne concentrations of the surrogate will be monitored in the participant’s breathing 

zone using an OSHA Versatile Sampler (OVS) tube connected to a personal sampling pump. 

Additional measures will also record environmental conditions at the time of monitoring, and 

observers will make field notes, photographs and videos of participant activity throughout the 

monitoring event. 

The results of sample analysis under the powered handgun scenario will be posted to the 

Agricultural Handlers Exposure Database (AHED®), where they will be available to the EPA and 

other regulatory agencies for statistical analysis. The proposed documentation will report a 

confidence interval-based approach to determine the relative accuracy for the geometric mean, 

arithmetic mean and 95th percentile of unit exposures. The Agency proposes to use these data to 

estimate daily dermal and inhalation exposures of agricultural handlers who mix, load and apply

pesticides using powered handgun equipment.

Science

Charge to the Board

If the AHETF proposal is revised as suggested in EPA’s review and if the research is 

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

assessing the exposure of workers mixing, loading and applying pesticides in managed 

horticultural facilities using powered handgun equipment?

Board Response to the Charge

HSRB Recommendation

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

with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to generate 

high quality, reliable and useful data for assessing worker’s pesticide exposures in horticultural 

settings. 

Several comments or suggestions were made by the Board with respect to the use of PPE, 

the potential effect of unanticipated incidental exposures and other variables on proportionality, 

and the utility of existing European Crop Protection Association (ECPA) data.
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HSRB Detailed Recommendations and Rationale

This protocol, a study designed to measure dermal and inhalation exposure of agricultural 

workers who mix, load and apply pesticides in nurseries or greenhouses using a hand-held 

sprayer or gun, was well thought out and well designed. The study sponsors (Collier 2011) 

found no suitable existing information that could constitute some of the MUs for this particular 

scenario; consequently, the entire scenario has to be conducted. The design requires ten (10) 

regions with three (3) MUs per region, for a total of 30 MUs. The rationale for this design is that 

there are relatively few nurseries and greenhouses that would be suitable for this scenario in 

most, if not all, regions of the United States. Similarity restrictions will be imposed to assure 

diversity. The investigators consulted several information sources to identify locations with 

suitable nurseries or greenhouses that could be venues for the conduct of this scenario. The areas 

of the country selected represent a variety of climatic and geographic conditions, likely providing 

the representativeness and diversity sought for the scenario. Given these factors and 

considerations, the Board determined that the proposed study design is reasonable. 

The scenario will include several tasks: mixing/loading of the pesticide product, open 

pouring of the formulated product, application of the product to the plants, and potentially some 

cleaning. The primary objective is to estimate the geometric mean, arithmetic mean and the 95th 

percentile of normalized dermal exposure for agricultural workers who mix, load and apply

pesticides in nurseries or greenhouses using a hand-held sprayer or gun. A secondary objective is 

to demonstrate proportionality between the amount of active ingredient handled (AaiH) and 

exposure level. One concern that was raised by the Board was that proportionality may not be 

observed due to unanticipated exposures (e.g., accidentally touching a treated plant or 

contaminated part of spray equipment), and these sources may contribute substantially to 

participants’ exposure levels. Because workers may be close to some of the sprayed plants in a 

setting such as a nursery, it seems likely that unintended contact of workers with these plants 

might easily occur. In scenarios where unanticipated exposures like these are likely to occur, it 

will be important for researchers to observe and document all unintentional contacts with treated 

plants or other events that might contribute to the exposure levels. However, even if 

proportionality is not seen -- particularly if the results are attributable to observed unanticipated 

exposures -- this scenario will still provide valid information about worker exposure when using 

a powered handgun or hand wand in a horticultural setting.

The Board provided additional recommendations and advice to the Agency about 

personal protective equipment (e.g., chemical-resistant headgear), respirators, the many sources 

of diversity, and analysis of data. For example, the Agency was reminded that, should chemicalresistant headgear be worn, the use of patches inside the headgear should yield valid estimates of 

exposure for those participants wearing such a hat. However, this method may underestimate 

exposures if attempts were made to extrapolate these data to those not wearing such headgear. 

Such extrapolation may not be an explicit intent, but the Agency states its plans to use the head 

exposure data to develop mitigation strategies (e.g. Evans, Sarkar and Sherman 2011, 11). The 

effect of the protection afforded by the brim of the chemical-resistant headgear would negatively 

affect that use. Thus, the Board suggested that the sponsors consider: 1) having study participants 

use chemical-resistant headgear without a brim (but only if this is allowed by the Worker 

Protection Standards); or 2) add a third patch dosimeter against the head below the brim, as the 
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density of deposition (μg/cm2) onto this patch could be compared to the deposition onto the rest 

of the face to estimate the magnitude of protection afforded by such a brim.

The Board also discussed the use of respirators and half-masks in the scenario, and how 

to handle the impact that use of such PPE might have on dermal exposure levels. For example, 

the Board raised concerns about whether the measured skin exposure to the face would be 

adjusted upward in proportion to the area of the face/neck covered by a respirator. Although the 

Agency responded affirmatively, this adjustment was not stated the Agency’s review of the 

protocol. After the conclusion of the January 2012 meeting, however, it was pointed out to the 

Board that the AHETF’s standard operating procedure (SOP) 9.K.0 provides information about 

how measured skin exposure to the face will be adjusted upward in proportion to the area of the 

face/neck covered by a respirator. 

Several Board members noted that there are many sources of diversity in this scenario. 

As a result, it may be difficult for the Agency to identify statistically significant differences. 

Variables which may influence the proposed exposure data include:

1. The predominant direction of spray (downward, outward, or upward);

2. Whether the MU is walking or riding a motorized vehicle; 

3. Whether or not the MU does “minor clean-up”; 

4. Whether the MU uses a handgun or a hand wand;

5. Whether the MU applies the pesticide indoors or outdoors; 

6. The width of the path through which the applicator must pass, as determined by

facility type (i.e., ornamental greenhouse, vegetable greenhouse, nursery), which may

or may not be a surrogate for the proximity of foliage;

7. The formulation type mixed (liquid or solid/wettable powder); and 

8. The mixing sequence (pre-mix or tank mix). 

The Board also considered issues related to the Agency’s recommendation to include 

wettable powder by at least one participant in each cluster (Evans, Sarkar and Sherman 2011, 4). 

In particular, concerns were raised about the use of two formulation types (wettable powder and 

liquid) in the scenario; this could be seen as akin to conducting two studies. The lack of clarity as 

to how many participants would use the wettable powder in each cluster is problematic for 

assessing the recommended study design and field conduct. Not knowing the number of MUs 

who would handle the powder versus liquid formation, for example, raises statistical and 

analytical questions that cannot be answered. If both formulations are to be used, the Board 

recommended that the Agency conduct a separate analysis of each type before combining all of 

the data for analysis. The sponsor could have 15 MUs use the powder formulation and 15 MUs 

use the liquid formulation. Alternatively, all MUs could use the wettable powder, as that 

formulation type is more likely to generate more conservative exposure data. 

Finally, the Board cautioned the Agency and the sponsors that the justification for the 

study may be weak. In particular, the Board raised a question about the utility of ECPA data. 

The Agency’s rationale for not using those data was that the proposed AHETF scenario involves 

individual workers performing both mixing/loading and application activities, whereas the ECPA 

exposure data was collected from agricultural handlers involved only in the application of 
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pesticides. The Board was not convinced, however, that this difference precludes the use of 

existing ECPA data. While there may be other scenario or data quality issues with the ECPA 

data, the Board recommended that the Agency consider the viability of combining the ECPA 

application-only exposure data with the Task Force’s mixing/loading-only exposure data to 

satisfy the Agency’s registration needs without further human exposure studies. Despite this, the 

Board noted that the amount of active ingredient handled might be very different for the 

proposed scenario and the existing ECPA data set; if true, then the existing data sets might not be 

useful in assessing worker exposure in this horticultural scenario.

Ethics

Charge to the Board

If the AHETF proposal is revised as suggested in EPA’s review and if the research is 

performed as described, is the research likely to meet the applicable requirements of 40 CFR part 

26, subparts K and L?

Board Response to the Charge

HSRB Recommendation

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

with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to meet the 

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

HSRB Detailed Recommendations and Rationale

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

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

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

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

study monitoring (California Code of Regulations Title 3, Section 6710) (Collier 2011). 

Requirements of FIFRA §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. 

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

committee, IIRB, Inc. of Plantation, FL, prior to submission. IIRB, Inc. is fully accredited by the 

Association for the Accreditation of Human Research Protection Programs (AAHRPP). IIRB, 

Inc. is also listed as an active Institutional Review Board (IRB) on the Office of Human 

Research Protection (OHRP) website (Reg. #IORG0002954). Copies of all correspondence with 

IIRB, Inc. (Collier 2011) and a copy of IIRB, Inc. policies and membership roster were provided 

(IIRB, Inc. 2010; 2011). These documents indicate that IIRB, Inc. reviewed this protocol 

pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A). 
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1. The Board concurred with the conclusions and factual observations of the ethical strengths 

and weaknesses of the study, as detailed in the EPA’s Ethics Review (Evans, Sarkar and 

Sherman 2011). The proposed study is likely to meet the applicable ethical requirements for 

research involving human subjects, in accordance with the following criteria: 

a. Societal value of the proposed research. The clearly stated purpose of the proposed 

monitoring study is to develop data to determine the potential exposure for workers who 

mix, load, and apply liquid pesticides using powered handgun equipment in managed 

horticultural facilities in the United States. This mixing/loading/applying method is 

applicable to a large variety of commercially important crops associated with the nursery

and greenhouse industry across the US and Canada, and the existing exposure data are 

inadequate. This study will provide a partial answer to the question of what dermal and 

inhalation exposures are likely for workers who mix/load and apply pesticide products 

using handguns and hand wands in nurseries and greenhouses. EPA will use the results of 

this study to estimate the dermal and inhalation exposure likely for a wide range of 

agricultural pesticides mixed, loaded, and applied under this exposure scenario.

b. Subject selection and informed consent. The inclusion/exclusion criteria are complete 

and appropriate. Pregnant or nursing women are excluded from participation. Pesticide 

company employees and contractors to the AHETF are also excluded from participation. 

Protections are adequate even if a subject were from a vulnerable population. Informed 

consent will be obtained from each prospective subject and appropriately documented in 

the language (Spanish or English) preferred by the subject. Recruitment materials and 

interactions with potential subjects will be conducted in English or Spanish, depending 

on subject preference; the Board agrees with EPA’s suggestion that it is preferable for 

recruitment discussions to take place away from the work site, to minimize the potential 

for coercion and that the protocol should describe the types of locations where 

recruitment discussions between researchers and potential subjects will take place, 

clarifying whether these discussions will take place at the work site or at locations that 

are away from the work site. The proposed monetary compensation is not so high as to 

unduly influence participation. Candidates and subjects will be repeatedly informed that 

they are free to decline to participate or to withdraw at any time for any reason, without 

penalty.

Depending on the number of employees and size of the grower’s facility, the Study 

Director or researcher may contact employees using an informational recruitment flyer 

posted in a common work area. Alternatively, or subsequent to the use of a flyer, the 

Study Director or researcher will arrange a meeting with the grower’s employees who 

express interest in participation. Such recruitment meetings will always occur without 

supervisors being present. The Study Director or researcher will describe the AHETF 

Exposure Monitoring Program, the goals of this specific study, the procedures to be used 

in exposure monitoring, and the risks and benefits to participants. The subject eligibility

factors listed in the consent form and SOP AHETF-11.B.6 are appropriate. Candidates 

who attend an individual interview will be paid $20 whether or not they agree to 

participate; enrolled subjects who put on the whole-body dosimeter will be paid $80 in 

addition to their usual pay, whether or not they complete participation.
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c. Risks to subjects. The proposed test materials are EPA-registered products registered for 

nursery and/or greenhouse use and the specific application planned by the grower, and 

will be used in full compliance with the approved labels. All identified risks are 

characterized as of low probability, and risks are further minimized by exclusion of 

candidates who self-report that they are in less than “good” health; alerting subjects to 

signs and symptoms of heat stress; monitoring heat index with associated stopping rules; 

close observation of subjects; training of experienced technicians to minimize 

embarrassment; incorporation of procedures to keep results of pregnancy testing private 

and to permit discrete withdrawal; provision of appropriate work clothing and PPE. 

Provision is made for discrete handling of the pregnancy testing that is required of female 

subjects on the day of testing.

Five kinds of risks to subjects are discussed in the protocol, along with specific steps 

proposed to minimize them: the risk of heat-related illness; the risk associated with 

scripting of field activities; psychological risk; the risk of exposure to surfactants, and; 

the risk of exposure to surrogate chemicals. In this study, risks to subjects are classified 

as ‘greater than minimal’ since the likelihood of harm or discomfort is greater than what 

is encountered in ordinary daily life. In particular, the risk of heat-related illness 

(resulting from wearing an extra layer of clothing to trap chemical) will be increased due 

to study participation. AHETF has adopted an extensive program to minimize these risks. 

Appropriate provision is made for safety and medical monitoring. The protocol also 

incorporates procedures to keep results of pregnancy testing private and to permit discrete 

withdrawal of a study subject. Finally, the protocol incorporates procedures to ensure 

that no photographs or videos will be taken in which a worker can be readily identified. 

d. Benefits to participants. This research offers no direct benefits to the subjects. The 

principal benefit of this research is likely to be reliable data about the dermal and 

inhalation exposure of people mixing, loading and application of pesticides using

powered handgun equipment. These data are intended to be used by EPA and other 

regulatory agencies to support exposure assessments for a wide variety of pesticide 

products and their uses. 

e. Risk/benefit balance. Risks to subjects have been thoughtfully and thoroughly minimized 

in the design of the research. The low residual risk is reasonable, in light of the likely

benefits to society from new data supporting more accurate exposure assessments for 

pesticide products. 

2. In addition to this analysis, the Board recommended a few edits to improve the clarity of the 

Informed Consent Form. These are listed below, organized according to the section within 

the Informed Consent Form in which they appear. In particular, in the past the Agency and 

the Board have suggested that protocols and consent forms clarify the steps that participants 

should take if participants have an adverse reaction within 24 hours. This was not included in 

the materials provided by the AHETF, and the Board recommends that such information be 

included on the consent form.
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• Introduction and Purpose: 

“If you do In order to take part in this study, you must read and sign this consent form” 

(Line 4).

• Procedures Before the Start of the Study:

Modify the language per the protocol (p. 248/SOP II.D.2) to clarify that the pregnancy test 

will be taken prior to the start of the study:

8. If you are female, within 24 hours of prior to starting the study you will perform an

over-the-counter pregnancy test. If there is a delay in the start of the study of

more than 24 hours, another pregnancy test may be needed. The negative

results of your pregnancy test will be verified by a female member of the study.

• Injury to Participants:

Add a line indicating the name and contact information of the Study Director or other 

individual to be contacted if the participant experiences an adverse event within 24 hours.

3. The Board agreed with the Agency that information about potential psychological and social 

harms related to unwanted disclosure of test results and breach of confidentiality associated 

with photographs or video may be included in the protocol (Evans, Sarkar and Sherman 

2011). However, the Board recommended that this information not be included in the 

informed consent form as it might give participants the erroneous impression that these risks 

are particularly significant or that appropriate steps have not been taken to mitigate them. 

Assessment of Completed AEATF II Research Study AEA-04: Measurement of Potential 

Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide 

Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting.

Overview of the Study

AEATF II aerosol spraying scenario was designed to measure a typical occupational 

handler’s daily exposure to an antimicrobial spray (containing C14 alkyl dimethyl benzyl

ammonium chloride [ADBAC]) packaged in a commercially-available pressurized aerosol spray

can. 

Eighteen (18) professional janitors were enrolled in the study, and applied (but did not 

wipe) the product on surfaces at one of three motels in the Fresno, CA area. Study participants 

were randomized to apply different amounts of product, from one (1) to four (4) cans of product 

in 1/2-can increments (i.e., 1 to 1.5 cans, 1.5 to 2 cans, and so on up to 3.5 to 4 cans). These are 

described in the completed study and associated documents as “Monitoring Events” (MEs).
Page 15 of 22

Participants all wore long pants and long sleeved shirts with shoes plus socks. The 

clothing was analyzed in pieces to allow estimation of the expected exposure of people wearing 

other clothing combinations, such as shorts or short-sleeved shirts. No participant wore gloves, 

but participants were given the option of wearing a respirator during product application; all 18 

subjects elected to wear respirators during monitoring.

Dermal exposures were measured using whole-body dosimeters (inner and outer), and 

hand and face washes. Dermal unit exposures (reported in mg/lb AaiH) were calculated by 

dividing the summed total exposure by AaiH. The study sponsor report normalized the dermal 

exposures by milligrams (mg) of active ingredient applied, but these exposure data were 

recalculated by the Agency and expressed as mg/lb of active ingredient applied.

Inhalation exposures were measured using a personal air sampling pump and OVS tubes 

plus a separate pump used to run a RespiCon Particle Sampler. This allows for collection and 

analysis of inhalation exposure monitoring results as total particles, as inhalable particles (<100 

μm), as thoracic particles (<10 μm), and as respirable particles (<2.5 μm). Inhalation unit 

exposures (reported in mg/m3/lb AaiH) were calculated by dividing the air concentrations by

AaiH.

The data will be posted to the Biocide Handlers Exposure Database (BHED®). The 

Agency plans to use these data generically to estimate dermal and inhalation exposures and risks 

for other antimicrobial ingredients where the applied product is packaged in a pressurized 

aerosol spray can. Although the scenario as performed did not include the subsequent wiping of 

the aerosol spray solution, the Agency believes that dermal and inhalation exposure that results 

from the subsequent wiping of sprayed antimicrobial solutions can be determined by combining 

the results of this study with the results of the previously AEATF II conducted ready-to-use 

(RTU) wipe study (favorably reviewed at the April 2011 HSRB meeting; EPA HSRB 2011).

Science

Charges to the Board

Was the research reported in the AEATF II completed aerosol study report faithful to the 

design and objectives of the protocol and governing documents of the AEATF? 

Has EPA adequately characterized, from a scientific perspective, the limitations on these 

data that should be considered when using the data in estimating the exposure of professional 

janitorial workers who apply liquid antimicrobial pesticide products to indoor surfaces using 

pressurized aerosol cans? 

Board Response to the Charge

HSRB Recommendation

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

field study reports, and associated supplemental documents was conducted in a manner that was 
Page 16 of 22

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

AEATF. 

The Board also concluded that the Agency has adequately, but not completely, 

considered the limitations in this study when using the data in estimating the dermal and 

inhalation exposure of those who apply liquid antimicrobial pesticide products for indoor surface 

disinfecting using a pressurized aerosol can. In particular, the Board noted several issues, 

limitations and concerns with the data and analyses. These are described in greater detail below.

HSRB Detailed Recommendations and Rationale

The Board concluded that the study (Testman and Boatwright 2011) was done 

thoroughly, yielding detailed and helpful data which appear to be reliable. Some data trends 

were not explained in the accompanying Agency analysis, but overall the diversity of subjects 

and settings were strengths of the study. 

The Board agreed with the Agency that the number of participants was adequate to 

achieve the primary benchmark accuracy goal. The Board also agreed that the modest diversity

of application settings was a reasonable attempt to offset the practical limitation of recruiting and 

assessing all exposures within one geographic area. The documented diversity in application 

behaviors indicates the robust nature of the resulting exposure data. 

The Agency's analyses of protocol deviations and of the blank, fortified field, and lab 

samples were acceptable. In addition to the deviations noted in the final report (Testman and 

Boatwright 2011, 1033-104) or by the Agency (Leighton 2012, 9), however, the Board identified 

a few more. For example, subject AE4 was apparently observed to be applying the product to 

surfaces at much heavier rates than usual. About 20% of the way into the sampling time, the 

study director instructed this subject to “lighten up” in their application (Testman and Boatwright 

2011, 488). This intervention comprises an unknown limitation that may have had a large effect 

on reducing a potentially high exposure. Alternatively, it may have had no significant effect and 

was unjustified in terms of protecting the subject. No specific prohibition against such 

interventions was found in the protocol, such instructions regarding applicator behavior were 

counter to the intent of the protocol (i.e., that the study participants “spray surfaces as they would 

normally do” [Testman and Boatwright 2011, 18]). Thus, it is unclear whether this event actually

qualifies as a protocol deviation. However, the lack of an explicit prohibition of study director 

intervention raised issues in this study’s analysis and interpretation. Guidance about how to 

handle interventions should be incorporated into future protocols and SOPs. 

Subject AE18 (in cluster #1) was a borderline outlier without any indication in the note of 

intervention by the researchers. The Board did not disagree completely with the Agency’s 

conclusion that AE18’s data was not an outlier (Leighton 2012, 15), but believed that one 

particular combination of these data -- application rate -- reflects the characteristics of an outlier. 

However, the Board did not advocate excluding this data point from subsequent analyses. Rather, 

these sometimes statistically significant differences provide additional support for the diverse 

and therefore broadly representative nature of the subjects and the qualitatively robust nature of 

the study results. 
Page 17 of 22

The Board also discussed outliers in laboratory recovery data. These data were not used 

by the Agency to correct field samples; the Board agreed with the EPA’s approach. However, 

the lack of explicit procedures for handling outliers raised questions among Board members. 

Explicit discussions about when data should or should not be excluded should be incorporated 

into future protocols and SOPs.

The Board raised concerns that the 20% higher flow rates (or discharge rates) from the 

batch of aerosol cans used in the first four MEs, as compared with the flow rates from those cans 

used in the last 14 MEs, could cause an appreciable difference in exposure (Leighton 2012, 9). 

Typically, a faster discharge rate through a given nebulizer produces smaller droplets. An 

analysis of variance for data in this study found a statistically significant difference between the 

average fraction of the a.i. <10 μm in the first four RespiCon samples and the last 14 samples 

(44% versus 55%, respectively; p < 0.00001). This difference is consistent with the expectation 

that the first batch of canisters may have produced particles with a mass median aerodynamic 

diameter just over 10 μm and the last batch particles with a mass median aerodynamic diameter 

just under 10 μm. The difference in particle size is more likely to have been due to the reported 

difference between flow rates than the difference in ADBAC concentration in the product. 

Notably, the impact of this probable shift to slightly smaller droplets is small in comparison to 

the much wider variation in flow rates and particle sizes among the many other products these 

studies are intended to represent.

The Board also raised concerns that the ventilation data presented were unclear, 

inadequately recorded, and inadequately interpreted (Testman and Boatwright 2011, 119-20). 

For example, “fresh air” was presented using different metrics (e.g., %, total fan cubic feet per 

minute [CFM], and CFM fresh air). Furthermore, the reported air changes per hour seem to 

differ from separately calculated values by factors of 1.5- to 3-fold. Although the deficiencies 

noted could have seriously affected the sampling results, analyses by one Board member suggest 

that the overall effect may have been small; the amount of time that participants spent in each 

room was so short that airborne ABDAC was just beginning to accumulate by the time the 

subjects left the space, limiting the effect of ventilation on overall rates of exposure. However, 

the Board recommended that the Agency consider the potential limitations associated with the 

heating, ventilation and air conditioning systems in the test facilities.

The Agency requested the Board's advice on the use of RespiCon versus OVS results. 

The major advantage of the RespiCon air samples is the ability to look at the data by size ranges. 

A disadvantage of collecting RespiCon samples is the challenge of confronting the difference 

inherent in the entrance losses of any two air samplers. Such losses are a characteristic primarily 

of entrance diameters and flow rates, but also of the shape of those entrances and their 

orientation, and the air velocity and particle diameters in any given setting. These characteristics 

affect both the RespiCon and OVS samples. 

There is no reliable basis available for comparing the two types of samplers (see, e.g., the 

articles cited by Leighton 2012, 35-7). For the purposes of calculating dose via inhalation, the 

Board thus recommended that the <10 micron-size results from RespiCon monitors be used 

because this size range represents the fraction that enters the lower respiratory tract and thus was 
Page 18 of 22

believed to provide a more accurate estimate of respiratory exposure. The Agency’s Office of 

Pesticide Programs has recommended OVS sampling results of <100 microns be used in 

estimation of risk because most of the information they have collected has been with OVS 

monitors and there is some benefit to having continuity in their estimation of risk. This would 

provide a more conservative estimate of particles.

The Board suggested that the dermal and inhalation exposure data be combined to obtain 

total exposure results. The Board also questioned whether a slope of 1.5, with a confidence 

interval (CI) including one (1), should be considered as evidence of 1:1 proportionality. The 

Board thus recommended that the Agency always address how estimates of coefficients will be 

used. Finally, the Board recommended that the Agency and the Task Force refrain from using the 

word ‘proportional’ without preceding it by an adjective such as 1:1 proportional or 1:2 

proportional. 

Ethics

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 (Sherman 2012) that the study

submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 

Part 26. 

HSRB Detailed Recommendation and Rationale

The documents prepared by Golden Pacific Laboratories, LLC, and submitted by

American Chemistry Council Antimicrobial Exposure Assessment Task Force II under Project 

No. AEA-04, state that the study was conducted in compliance with the requirements of the 

EPA’s Good Laboratory Practice (GLP) Standards; FIFRA §12(a)(2)(P); and the applicable 

subparts of 40 CFR 26 (Testman and Boatwright 2011). 

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

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

a copy of IIRB, Inc. policies and procedures were provided. This IRB is fully accredited by 

AAHRPP and registered with OHRP (see details above). Documentation provided to the EPA 

indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule (45 

CFR Part 46, Subpart A) and found it in compliance (IIRB, Inc. 2010; 2011).

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

detailed in the EPA’s Ethics Review (Sherman 2012). Specifically:
Page 19 of 22

a. Prior HSRB and Agency Review. The requirements of 40 CFR §26.1125 for prior 

submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol 

were satisfied. The study (Testman and Boatwright 2011) was conducted in accordance 

with the protocol previously reviewed by the Agency (Leighton, Walls and Sherman 

2009) and by the HSRB (EPA HSRB 2009). Neither the Agency’s nor the HSRB’s ethics 

reviews identified any significant deficiencies requiring correction relative to 40 CFR 26, 

subparts K and L, or to FIFRA § 12(a)(2)(P) (Leighton, Walls and Sherman 2009). 

Because the study was conducted in California, the approval of the California 

Department of Pesticide Regulation (CDPR) was also required before the study could be 

initiated. CDPR granted final approval of the amended protocol and supporting 

documents on April 19, 2010.

b. Responsiveness to HSRB and Agency Reviews. Following HSRB review, the protocol and 

consent form were modified to incorporate changes responsive to the all of the comments 

of EPA (Leighton, Walls and Sherman 2009) and the HSRB (EPA HSRB 2009). 

Additional corrections and amendments were also requested by CDPR. IIRB, Inc. granted 

approval to the amended protocol and supporting documents on April 6 and April 7-9, 

2010, respectively (Testman and Boatwright 2011; Sherman 2012). 

c. Substantial Compliance with Reporting Requirements (40 CFR Part 26 subpart M). The 

AEATF II’s submission (Testman and Boatwright 2011), along with the separately 

submitted documents describing the procedures and roster of the IRB (IIRB, Inc. 2010; 

2011), fully meet the requirements of 40 CFR §26.1303 to document the ethical conduct 

of the research.

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

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

been stated in the Board’s prior review of this study protocol (EPA HSRB 2009):

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

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

dermal and inhalation exposure of professional janitorial workers to antimicrobial 

compounds as they sprayed indoor surfaces with aerosolized pesticides. These data could 

be used to develop mechanisms to protect future users of these antimicrobial pesticides.

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

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

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

minimized. 

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

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

• The study was designed to minimize the risks of exposure to the test compounds.
Page 20 of 22

b. Voluntary and informed consent of all participants.

• The study protocol included several mechanisms designed to minimize coercive 

recruitment and enrollment. 

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

and pregnant or lactating women were excluded from participation, with pregnancy

confirmed by over-the-counter pregnancy testing on the day of study or by opt-out. The 

potential of stigma resulting from study exclusion was also appropriately minimized. 

3. Although the first study participants were enrolled in April 2010 and monitoring began in 

June 2010, shortly thereafter the study was placed on ‘hold’ as the result of an issue raised 

by CDPR. In response to a request from some participants to wear a respirator while 

engaged in study related tasks, the AEATF II decided to offer all study subjects the option 

of wearing a half-mask respirator fitted with organic vapor cartridges. This decision was 

made after consulting with the Agency and with the IRB, and the amended protocol and 

informed consent forms were reviewed and approved by the IRB. Upon receipt of the 

approved protocol amendment, CDPR requested that the study be halted temporarily until 

Golden Pacific Laboratories could conduct an additional review of its procedures for 

respirator use. CDPR granted approval for the amended protocol on May 11, 2011.

This hold is unlikely to have affected the integrity of the research or the safety of 

participants. In fact, by allowing subjects to wear a respirator, the researchers further 

minimized potential risks to study participants. All 18 monitored subjects used a respirator, 

which was fitted by a trained study investigator and worn under the supervision of a 

registered study nurse.

4. There were several minor deviations from GLP were reported by the study sponsors 

(Testman and Boatwright 2011, 3) but these were unlikely to have affected the integrity of 

the research or the safety of participants. Only one of these deviations bears further 

discussion, namely the enrollment of a participant who self-reported that his health was 

only “fair,” despite the requirement that all participants be in “good health” (Testman and 

Boatwright 2011, 227). This same issue was discussed by the HSRB during its October 

2010 and April 2011 meetings (EPA HSRB 2010; 2011), at which time the Board 

recommended that the study sponsors clarify the criteria used to establish participants’

health status prior to enrollment. Enrollment of this particular participant, however, 

happened prior to those two Board meetings. Furthermore, although formally enrolled in 

the study, this participant was not one of the 18 subjects monitored. Thus, the Board 

concluded that this deviation did not put the participant at increased risk.
Page 21 of 22

REFERENCES

Collier, R. for the Agricultural Handler Exposure Task Force (AHETF). 2011. Mixing, Loading 

and Application of Pesticides in Managed Horticultural Facilities using Powered Handgun 

Equipment (AHETF Study No. AHE600). Dated October 24, 2011. Unpublished document 

prepared for the AHETF, 474 p.

EPA Human Studies Review Board. 2009. October 21-22, 2009 Human Studies Review Board 

Meeting Report. 26p.

EPA Human Studies Review Board. 2010. October 27-28, 2010 Human Studies Review Board 

Meeting Report. 31p.

EPA Human Studies Review Board. 2011. April 13-14, 2011 Human Studies Review Board 

Meeting Report. 31p.

Evans, J., B. Sarkar, and K. Sherman. 2011. Science and Ethics Review of AHETF Scenario 

Design and Protocol AHE600 for Exposure Monitoring of Workers during Mixing, Loading and 

Application of Pesticides in Managed Horticultural Facilities using Powered Handgun 

Equipment. Dated December 30, 2011. Unpublished document prepared by the Office of 

Pesticide Programs, United States Environmental Protection Agency. 57p. 

Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Human Research Protection 

Program Plan (HRPP Plan). Dated November 3, 2010. Unpublished document prepared by IIRB, 

Inc. 131p.

IIRB, Inc., 2011. IRB Membership Roster. Dated September 12, 2011. Unpublished document 

prepared by IIRB, Inc. 1p.

Leighton, T., C. Walls and K. Sherman. 2009. Science and Ethics Review of AEATF II Aerosol 

Scenario Design and Protocol for Exposure Monitoring. Dated September 21, 2009. 

Unpublished document prepared by Office of Pesticide Programs, United States Environmental 

Protection Agency. 52p.

Leighton, T. 2012. Science Review of the AEATF II Aerosol Human Exposure Monitoring 

Study. Dated January 3, 2012. Unpublished document prepared by Office of Pesticide Programs, 

United States Environmental Protection Agency. 38p.

Sherman, K. 2012. Ethics Review of Completed AEATF II Aerosol Scenario Worker Exposure

Monitoring Study. Dated January 4, 2012. Unpublished document prepared by the Office of the 

Director, Office of Pesticide Programs, United States Environmental Protection Agency. 20p.

Testman, R.J. and M.T. Boatwright, for the AEATF II. 2011. A Study for Measurement of 

Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial 

Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting. Dated 
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November 14, 2011. Unpublished document prepared by the Golden Pacific Laboratories, LLC, 

for the AEATF II. 1851p. MRID 48659001.