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January 11, 2012

EPA-HSRB-11-03

Paul Anastas, PhD

EPA Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460 

Subject: October 19-20, 2011 EPA Human Studies Review Board Meeting Report

Dear Dr. Anastas,

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

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

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

Antimicrobial Exposure Assessment Task Force II (AEATF) scenario to determine dermal and 

inhalation exposures associated with the manual pouring of liquid antimicrobial products (AEA05); and a proposed Agricultural Handler Exposure Task Force, LLC (AHETF) scenario 

measuring dermal and inhalation exposure of workers who perform closed system loading of 

liquid pesticides in non-returnable and returnable containers.

The Agency also requested that the HSRB review a completed study of insect repellent 

efficacy conducted by Carroll-Loye Biological Research, Inc. (CLBR). This study (No Mas-003) 

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, and was reviewed favorably at the HSRB’s 

October 2010 meeting.

Finally, the Agency asked the Board to review a published study involving intentional 

human exposure study measuring dermal absorption of nanosilver (Moiemen et al. 2011). The 

Agency proposes to rely on this study, conducted after publication of the EPA’s expanded final 

rule for protection of subjects in human research, for regulatory actions.

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

the October 19-20, 2011 meeting.

Assessment of Proposed AEATF Research Study AEA05: A Study for Measurement of 

Potential Dermal and Inhalation Exposure During Manual Pouring of a Liquid Containing 

an Antimicrobial.

Science

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

with EPA (Leighton, Sherman and Cohen 2011) and HSRB recommendations, is likely to 
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generate scientifically reliable data, useful for assessing the exposure of individuals who 

manually pour liquid antimicrobial products. 

• In addition to providing several additional comments or suggestions, the Board also pointed 

out two limitations not identified either within the protocol or by the Agency: 1) the wider 

range of exposures that could occur while pouring products outdoors than only indoors as 

proposed; and, 2) the unknown impact of potential differences in exposures between 

consumers and professionals. 

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 Proposed AHETF Research Study AHE500: Exposure Monitoring of 

Workers During Closed System Loading of Returnable and Non-Returnable Containers in 

the United States.

Science

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

field study proposal AHE500, if revised as suggested in EPA’s review and performed as 

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

of workers using closed systems to load liquid pesticide products from returnable or 

nonreturnable containers. 

• The Board provided an additional set of recommendations for the Agency and study

sponsors to consider when collecting and analyzing data concerning the exposure of 

workers using such closed load systems.

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

valid results to assess the repellent efficacy against mosquitoes for the formulation tested. 
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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.

Assessment of Published Research Study MRID 48607501: Moiemen et al. (2011) Acticoat 

Dressings and Major Burns: Systemic Silver Absorption.

Science

• Despite several deficiencies identified with the study design, the small number of subjects, 

and the interpretation of the data, the Board agreed with the Agency’s assessment that the 

Moiemen et al. (2011) study provides some potentially useful baseline information on the 

dermal absorption of silver from nanosilver-containing wound dressings. 

• The Board concluded that the Moiemen et al. (2011) study could be used to support the 

Agency’s conclusion that the dermal absorption of silver is less than 0.1% as part of the 

overall weight of evidence, but recommended that: 1) the Agency clarify its assumptions in 

estimating the dermal absorption of silver from nanosilver; and 2) that the Agency consider 

alternatives for estimating dermal absorption based on this study.

Ethics

• The Board concurred with the Agency’s assessment that there was sufficient information 

regarding value of the research to society, subject selection, risks and benefits, independent 

ethics review, informed consent, respect for potential and enrolled subjects to conclude that 

the study was conducted in substantial compliance with procedures at least as protective as 

those in subparts A - L of EPA’s regulation at 40 CFR Part 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 (Acting)

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

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

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

Veterans Health Administration, Washington, DC
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Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 

Sciences, University of Florida, Gainesville, FL

Human Studies Review Board Staff

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

Advisor, United States Environmental Protection Agency, Washington, DC

* Not present on October 19, 2011.

† Participated in the October 19-20, 2011 meeting via telepresence.

§ Not present on October 20, 2011.
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INTRODUCTION 

On October 19-20, 2011, 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 for research involving human participants: one new study

measuring dermal and inhalation exposures associated with the manual pouring of liquid 

antimicrobial products, and one new study measuring dermal and inhalation exposure of workers 

who perform closed system loading of liquid pesticides in non-returnable and returnable 

containers. In accordance with 40 CFR 26.1601, EPA sought HSRB review of these two 

proposed studies. Each of these studies is discussed more fully below.

In addition, the Agency has data from one completed study measuring the efficacy of an 

insect repellent containing para-menthane-3,8-diol (PMD) and lemongrass oil against mosquitoes 

under field conditions. In accordance with 40 CFR 26.1602, EPA sought HSRB review of this 

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

Finally, the Agency sought HSRB review of one published study of dermal absorption of 

silver (Ag) from silver nanoparticle-impregnated wound dressings used to treat major burns. This 

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

human research, was identified by Agency scientists from the peer reviewed literature. This 

study, which the Agency proposes to rely upon for regulatory actions, is discussed in detail 

below.

REVIEW PROCESS

On October 19-20, 2011, the Board conducted a public face-to-face meeting in Arlington, 

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

Studies Review Board; Notice of Public Meeting” (76 Federal Register 187, 59697).

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 manual pouring of liquid antimicrobial products, and one new study protocol 

to measure dermal and inhalation exposure of workers who perform closed system loading of 

liquid pesticides in non-returnable and returnable containers. A completed study measuring the 

efficacy of an insect repellent containing PMD and lemongrass oil against mosquitoes under field 

conditions was also reviewed, as was one published study measuring dermal absorption of silver 

(Ag) from silver nanoparticle-containing wound dressings applied to severely burnt human skin.

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

investigators, including:

Dr. Michael Bartels, Scientist, Dow Chemical Company (representing the Antimicrobial 

Exposure Assessment Task Force II)

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

Dr. Scott Carroll, Study Director, Carroll-Loye Biological Research
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Dr. Richard Collier, Administrative Committee Chair, Agricultural Handler Exposure 

Task Force

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

Ms. Leah Rosenheck, President, LR Risk Consulting, Inc. (representing the 

Antimicrobial Exposure Assessment Task Force II)

Public oral comments were provided by:

Dr. Michael Bartels, Scientist, Dow Chemical Company

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

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

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 AEATF Research Study AEA05: A Study for Measurement of 

Potential Dermal and Inhalation Exposure During Manual Pouring of a Liquid Containing 

an Antimicrobial.

Overview of the Study

AEATF II liquid pour protocol (AEA05) is designed to measure a typical occupational 

handler’s daily exposure to various antimicrobial products whose use and application requires 

the pouring of a liquid product (e.g., an antimicrobial concentrate that may be measured and 

diluted with water prior to use). This proposal presents two different occupational exposure 

scenarios: one involving pouring of liquids from conventional containers and one involving the 

use of containers designed to reduce splashing. 

A total of 18 participants (described in the protocol as “Monitoring Events” [MEs]) will 

be observed. Each volunteer will pour antimicrobial products from both conventional and 

“reduced splash” containers at a laboratory site in Concord, OH. Didecyl dimethyl ammonium 

chloride (DDAC; Maquat WP) and N-alkyl dimethyl benzyl ammonium chloride (ADBAC; 

Maquat DS 1412-10%) will be the antimicrobial materials used for the conventional pour and 

reduced splash scenarios, respectively. These two commonly used products can be distinguished 

analytically, thus allowing researchers to use a single participant to monitor dermal and 

inhalation exposure to antimicrobial agents under both a conventional pour and reduced splash 

scenario. For each scenario, the study participants will be randomized to pour different amounts 

of liquid; 40 ounces to 20 gallons in the conventional pour scenario, and 60 ounces to 30 gallons 
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in the reduced splash scenario. A variety of source and receiving containers will also be used, 

including 32 ounce spray bottles, 2 and 4 gallon buckets, and 10 gallon basins.

Participants will wear long sleeved shirts and long pants (provided by the researchers), 

and shoes plus socks (provided by the subject). The low toxicity and low concentration of the 

surrogate compounds used eliminates the need to have participants wear additional protective 

equipment, such as chemical resistant gloves or aprons. 

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 the liquid pour 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 collect field notes, take 

photographs, and record video of participant activity throughout the monitoring event. 

These data will be used by the Agency generically to estimate dermal and inhalation 

exposures and risks for other antimicrobial ingredients where the product is packaged as a liquid 

concentrate in conventional or reduced splash containers. 

Science

Charge to the Board

If the AEATF liquid pour study 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 individuals who manually pour liquid antimicrobial 

products?

Board Response to the Charge

HSRB Recommendation

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

with EPA (Leighton, Sherman and Cohen 2011) and HSRB recommendations, is likely to 

generate scientifically reliable data, useful for assessing the exposure of individuals who 

manually pour liquid antimicrobial products. 

Several comments or suggestions were made by the Board with respect to the Agency’s 

proposed revisions to the protocol, the Task Force’s proposal to use a single participant and a 

single dosimeter to assess dermal and inhalation exposure in two scenarios, and the lack of 

information provided within the protocol on the source containers to be used. 

The Board also pointed out two limitations not identified either within the protocol or by 

the Agency: 1) the wider range of exposures that could occur while pouring products outdoors 
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than only indoors as proposed; and, 2) the unknown impact of potential differences in exposures 

between consumers and professionals. These limitations are described in detail below.

HSRB Detailed Recommendations and Rationale

The AEATF-II liquid pour protocol is complicated and highly scripted, but seems to be a 

feasible way to generate scientifically reliable exposure assessment data that includes the effects 

of source container size, size and type of receiving container, use of measuring cups or not, and 

height of pouring. The Board had several recommendations, however, as to how the study might 

be improved.

1. Proposed Revisions to the Protocol.

First, the Agency has proposed that the protocol be revised to randomize the use of a 

measuring cup by participants in monitoring Group 2 (Leighton, Sherman and Cohen 2011, 

17). The Board has no substantive insight into the impact on dermal and inhalation exposures 

if Group 2 does or does not use a measuring cup. Indeed, the inclusion of the measuring cup 

appears to be more of a policy decision based on perceived future uses of the data than a 

question of science. Nonetheless, the Board made the following observations. Because

using a 4 ounce measuring cup twice for each of 10 pours into a bucket means that only 80 

ounces (~ 2⁄3 of a gallon) will comprise only 5-10% of the total of 7.5 to 14 gallons expected 

to be handled by each ME in Group 2, the effect of this difference on exposures may be 

slight in either direction. The ability to detect a slight difference within two subgroups of 3 

MEs each is very small. Given this, two alternatives for assessing the effect of using a 

measuring cup were suggested by the Board. The first alternative is to consider having half 

of the participants in Group 2 use a measuring cup to transfer all of their assigned source 

volume into the receiving container, and the other half to not use the cup. Another 

alternative is for no one in Group 2 to use a measuring cup, but instead to test for a difference 

in the unit exposure values between Group 1 (all of whom use a measuring cup) and Group 2 

(all of whom do not use a measuring cup).

The second revision proposed by the Agency would be to allow study participants to “fill the 

spray bottles from the source container and with water in the order they would normally do as 

opposed to the researchers directing them to fill with water after pouring the concentrate 

from the measuring cup” (Leighton, Sherman and Cohen 2011, 17). This is probably a good 

revision. However, the Agency should also ensure that the protocol directs the handlers to 

follow the label instructions. The label information provided within this protocol was not 

complete, and the lack of more specific instruction should be confirmed among all applicable 

labels. Based on the information available, however, the Board concurs with this proposed 

revision. A related but separate comment was made that since the bactericidal solution to be 

used in the study has been pre-diluted by the study director(s), none of the labeling 

instructions that would normally be present on the original container will be present in the 

pouring containers within this study. The protocol thus should be amended to specify what 

label information will be made available to study participants.
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Regarding the third revision proposed by the Agency -- to “provide a description of how the 

different size source containers will be randomly assigned to each ME” (Leighton, Sherman 

and Cohen 2011, 17) -- the Board suggested adding statistical constraints to the 

randomization process used to assign the different size source containers to each ME. Since 

the array of conditions is already scripted, it seems reasonable to avoid creating statistical 

outliers that might result from a completely random distribution. For example, the study 

director could generate the random array of size distributions beforehand and screen it to 

assure that all distributions fall within the “to-be defined” probability limits. 

The Board concurs with the Agency’s fourth proposed revision, namely to request that the 

Task Force “provide details about how the airflow in the laboratory room will be measured 

and what the target airflow will be (e.g., will the airflow be minimized?)” (Leighton, 

Sherman and Cohen 2011, 17). However, the focus of interest in ventilation should be on the 

local air flow between the pouring operation (the purported source of exposure) and the 

handler. Analyses of the pattern of exposures to applicators in the AEATF-II completed 

mopping protocol showed that the amount of room ventilation seemed to have virtually no 

effect on exposures (EPA HSRB 2010). Mopping is a mobile task, and moving throughout a 

room can balance the effects of localized air currents between the source of exposure and the 

handler. In contrast, someone pouring a liquid is likely to be relatively stationary. Thus, a 

consistent local air flow (its speed and especially its direction between the pouring operation 

and the handler) is likely to bias the measured exposures. Because air flow patterns 

generated by a Heating, Ventilation and Air Conditioning (HVAC) system are likely to be 

consistent, at the very least, that pattern should be measured before and/or after exposures 

and the orientation between the source and each handler should be documented for each ME. 

Alternatively, the room’s setup and the orientation between the source and handler could be 

varied (e.g., rotated 90°) either within or among MEs; this approach may increase the 

variability in the resulting exposure data and is more likely to include the higher downwind 

exposures than having only one orientation for all MEs. Increasing the variability

independent of the amount of the active ingredient handled (AaiH) may adversely affect the 

ability to detect proportionality, akin to the effect discussed herein regarding the Agricultural 

Handlers Exposure Task Force’s Closed System Load Liquid (AHETF CSLL) study. In 

addition, it was pointed out that the airflow through laboratories is generally more than what 

would be expected in many other work rooms in which such pouring would take place; 

therefore, some steps to minimize the air flow should be considered. One possible, simple 

way to reduce the airflow through the room is to close the laboratory fume hood’s sash door, 

although some fume hoods have a bypass that prevents the sash’s position from affecting the 

HVAC airflow. 

2. Proposal to Monitor Two Scenarios Using the Same Dosimeters.

The proposal for each ME to monitor two scenarios using the same set of dosimeters seems 

novel and efficient. There is no evidence to suggest that the plan as proposed will not work, 

and precedents for collecting and analyzing multiple active ingredients in the same 

environment were discussed. The Board suggested that consideration be given to ways of 

leveraging the data from two exposures to the same individual during the analysis of the 

results. However, the Board pointed out the potential for a portion of a dosimeter 
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(particularly an outer dosimeter) that becomes locally saturated by a significant spill or 

splash to behave differently from a fresh dosimeter in terms of its transmission and/or 

retention of the handled mixture. While such an event may not occur during the study, such 

wetting of the outer clothing is likely to be quite visible to the study observer. Thus, a 

suggestion was made to modify the protocol to allow the study observer to decide if 

someone’s dosimeters should be changed between the two scenarios to avoid such a 

foreseeable event from confounding the sample results of the second scenario. Discussion 

pointed out that this flexibility should be implemented in a way that does not cause the 

handler to change his or her behavior. Finally, no rationale was provided for using DDAC in 

the conventional pour scenario and ADBAC in the reduced-splash pour scenario versus 

randomizing the two antimicrobial agents between the conventional and reduced splash 

containers.

3. Source Containers.

The lack of information within the protocol about the source containers to be used was noted. 

Granted that the definition of reduced-splash non-refillable containers is performance based 

rather than product specific; however, neither the specific reduced-splash container(s) was to 

be used in this study not identified, nor were a list of candidate reduced-splash containers 

potentially to be used or a description of how the final container(s) will be chosen provided. 

A similar comment about the lack of candidates or specificity (other than size) applies to the 

refillable containers. It seems prudent to agree upon the selection process or final containers 

before beginning the study.

4. Additional Study Limitations.

The Board also pointed out two limitations not identified either within the protocol or by the 

Agency: 1) the wider range of exposures that could occur while pouring products outdoors 

than only indoors as proposed, and; 2) the unknown impact of potential differences in 

exposures between consumers and professionals. 

First, pouring operations are likely to occur outdoors within three of the eight ‘Use 

Categories’ identified by the Agency at which a majority of liquid pouring operations are 

likely to occur (i.e., Agricultural, Swimming pools, and Aquatic areas), and it may occur 

outdoors in a fourth (III Commercial / institutional / industrial premises and equipment) 

(Leighton, Sherman and Cohen 2011, 5-6). Air velocity outdoors is likely to be more variable 

(particularly on the high-end) than indoors. The Agency should review and determine the 

importance of the limitation of not assessing exposures outdoors.

Second, while pouring a liquid product from a container may not be a specialized task (see, 

e.g., Leighton, Sherman and Cohen 2011, 25), the experience of a user may reduce the 

incidence of high exposure events. This pattern leads to the hypothesis that a consumer (or 

less experienced handler) may have a higher exposure on any given pour than a professional 

(or more experienced handler). Despite this, the Board did not disagree with Agency’s 

conclusion that “because of greater quantities of antimicrobial, professional handler exposure 

is expected to be greater than that of consumers” [sic] (Leighton, Sherman and Cohen 2011, 
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8). Professionals seem to be the appropriate group upon which to later assess chronic risk, 

but having data only from highly experienced (and nominally more proficient) handlers may

underestimate the acute hazards experienced by consumers who have potentially higher but 

less frequent exposures.

Ethics

Charge to the Board

If the AEATF liquid pour study 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 (Leighton, Sherman and Cohen 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) (AEATF 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. (Shah 2011b, 2011c) and a copy of IIRB, Inc. policies and membership roster were 

provided (IIRB, Inc. 2011a; 2011b). These documents indicate that IIRB, Inc. reviewed this 

protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A). 

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, Sherman and 

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

research involving human subjects, in accordance with the following criteria: 
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a. Societal value of the proposed research. The clearly stated purpose of the proposed 

monitoring study is to determine potential dermal and inhalation exposures to 

occupational workers and consumers associated with the manual pouring of liquid 

antimicrobial products. Many consumers and workers pour antimicrobial products, so the 

research question is important and cannot be answered with confidence without new 

monitoring data meeting contemporary standards of quality and reliability. 

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

appropriate. Pregnant or nursing women are excluded from participation. Employees or 

relatives of employees of the investigators and of cleaning product manufacturers 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 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 AEATF 

identify the recruiting newspapers and specify “Spanish” rather than “second alternate 

language.” Subjects will be recruited through newspaper advertisements, which will 

minimize the potential for coercion or undue influence, and 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.

c. Risks to subjects. The proposed test materials are EPA-registered for the use proposed, 

are of low toxicity to mammals, 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 known to be sensitive to quaternary ammonium 

compounds or in poor health or with broken skin on hands, face, or neck; testing in a 

controlled-temperature environment; alerting subjects to signs and symptoms of heat 

stress; monitoring heat index with associated stopping rules; allowing subjects to rest 

whenever they want or need to; 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 Personal Protective Equipment (PPE). Provision is made for discrete 

handling of the pregnancy testing that is required of female subjects on the day of testing. 

The Board agreed with the Agency’s suggestion to clarify the steps that participants 

should take if participants have an adverse reaction within 24 hours.

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 pouring liquid antimicrobial products from conventional 

and reduced-splash containers. These data are intended to be used by EPA and other 

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

products and their uses. 
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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 

antimicrobial 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:

• Introduction: 

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

(Line 4).

• Purpose of this Study:

“This study is being funded by the American Chemistry Council’s Antimicrobial Exposure 

Assessment Task Force II (AEATF II) which. The AEATF II is a ...” (Line 1).

• Purpose of this Study:

The last sentence of this section currently reads: “If you cannot read or understand English, 

a Spanish speaking member of the research team will read the Spanish translation to you 

and answer your questions.” It is not clear what translated document(s) are being referred 

to here. The protocol indicates that the forms and supporting documents will be available in 

either English or Spanish and literacy is required, thus it is not clear why someone would 

need to read to the participant. The Board suggests clarifying this sentence.

• Study Procedures:

The numbered list under “Here’s exactly what will happen” sequences the pregnancy test 

prior to checking for cuts and scrapes on the hands. Some (though not all) Board members 

were concerned that this ordering might subject female participants to an unnecessary

pregnancy test and recommended that the sponsors consider conducting the skin check 

earlier than any pregnancy test since evidence of any exclusion factors here would make 

the pregnancy test unnecessary. 

• Benefits:

Regarding the section of the informed consent form that discusses return of results as a 

possible benefit of the study, the Board discussed:

• Whether this adequately covers the issue of return of research results to participants;

• Whether this topic deserves its own section in the informed consent form under 

“Receiving your Research Results”; 

• Whether it should be presumed that receiving the results would be a benefit; and
Page 16 of 36

• Whether the Board would recommend that the AEATF not offer to return research results 

to participants.

Based on this discussion, the Board determined that at this time there is neither a positive 

nor a negative duty to provide results to participants of this study as there is not a clear 

rationale or benefit to participants. The Board concluded that it would not be objectionable 

if the Sponsor and the Agency decided not to return individual research results and 

removed language relating to this from the Informed Consent form. Likewise, if the 

sponsor chooses to return individual research results to participants, the Board would offer 

guidance regarding language in the Informed Consent form and to provide the sample letter 

drafted and discussed during the May 2011 teleconference (EPA HSRB 2011b).

• Right to Withdraw:

The Board recommended revising language consistent to clarify that “If you withdraw from 

the study after the exposure monitoring begins, you will still be paid for your time.”

• Questions about this Study:

The Board recommends adding information to clarify what the IIRB is and does (e.g., “The 

organization that reviewed and approved this study meets requirements for the protection 

of research subjects”).

3. The Board recommended that EPA and the sponsors consider breach of confidentiality

associated with photographs taken or video recorded as a potential risk associated with study

participation. For future studies, this risk should be listed on the informed consent form and 

should be considered by the Agency in its ethics review.

Assessment of Proposed AHETF Research Study AHE500: Exposure Monitoring of 

Workers During Closed System Loading of Returnable and Non-Returnable Containers in 

the United States.

Overview of the Study

This proposal presents two agricultural handler exposure scenarios involving loading of 

liquid pesticides packaged in non-returnable containers and returnable containers respectively. 

The scenario calls for study participants to mix and load one of thirteen possible surrogate 

pesticides1using closed systems, which are defined by the Agency’s Worker Protection Standard 

(WPS; 40 CFR 170) as mixing and loading systems that are “designed by the manufacturer to 

enclose the pesticide to prevent it from contacting handlers or other people while it is being 

handled.”

 

1

Possible surrogate pesticides include carbaryl, chlorothalonil, Dacthal (DCPA), fosamine, glyphosate, imazapyr, 

imidacloprid, Malathion, simazine, sulfur, thiophanate-methyl, 2,4-Dichlorophenoxyacetic acid, and 4-(2,4-

dichlorophenoxy)butyric acid. The choice of surrogate pesticide will be determined by the preference of the 

grower involved in the study and the pest pressure on the crop at the time of monitoring.
Page 17 of 36

A total of 21 participants (described in the protocol as “Monitoring Units” [MUs]) will be 

observed for the non-returnable container scenario; three volunteers from each of seven 

geographically distinct growing regions will be enrolled using a purposive sampling method 

(with some elements of random selection). For the returnable container scenario, a total of 15 

participants (three volunteers from each of five geographically distinct growing regions) will be 

observed; these data will be combined with existing exposure data from two pre-Rule studies 

involving two participants in California and seven participants in Texas (see Collier 2011, 23-

25). For each scenario, volunteers will be randomized to mix and load a defined amount of active 

ingredient within one of three strata. For the non-returnable container scenario, these strata are: 

12 to 30 pounds, 31 to 310 pounds, or 311 to 800 pounds of active ingredient, respectively. For 

the returnable container scenario, these strata are: 60 to 119 pounds, 120 to 1200 pounds, or 1201 

to 2400 pounds of active ingredient.

Although the use of closed mixing loading systems permits handlers to wear less PPE 

than required by pesticide labeling for open mixing/loading, including not wearing chemical 

resistant gloves in some cases, for this protocol all participants will wear long sleeved shirts, 

long pants, and shoes plus socks. Chemical resistant gloves and protective eyewear will also be 

required when the study participants are using closed systems that operate under pressure.

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

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

after completion of pesticide loading and mixing procedures. Airborne concentrations of the 

surrogate will be monitored in the participant’s breathing zone using an OVS tube connected to a 

personal sampling pump. Additional measures will also record environmental conditions at the 

time of monitoring, and observers will collect field notes, take photographs, and record video of 

participant activity throughout the monitoring event.

The results of sample analysis under the closed system scenario will be posted to the 

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

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

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

and 95th percentile of unit exposures. The Agency proposes to use these data to estimate daily

dermal and inhalation exposures of agricultural handlers who are mixing and loading pesticides 

using closed systems. 

Science

Charge to the Board

If the AHETF closed system loading study 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 using closed systems to 

load liquid pesticide products from returnable or nonreturnable containers?
Page 18 of 36

Board Response to the Charge

HSRB Recommendation

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

and field study proposal AHE500, if revised as suggested in EPA’s review (Evans et al. 2011) 

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

the exposure of workers using closed systems to load liquid pesticide products from returnable or 

nonreturnable containers. The Board raised a number of additional concerns, however, for the 

Agency and study sponsors to consider when collecting and analyzing the exposure data.

HSRB Detailed Recommendations and Rationale

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

useful for assessing the exposure of handlers who using closed systems to load liquid pesticide 

products from returnable or nonreturnable containers. However, five additional concerns were 

raised by the Board.

First, the Board was concerned that the pre-Rule exposure study conducted in 1991 

(referred to as AH501 in the AHETF submission [Collier 2011, 23-25]) might not have been 

conducted with similar attention to detail (e.g., careful observation and recording data about the 

workers, work practices and equipment) as the proposed studies. The quality of the older data 

might therefore not match the quality of the data collected in the proposed studies. The Board 

thus urged the Agency and sponsors to be cautious about including these older data in the AHED 

exposure data, particularly if they are substantially different from the data collected using the 

proposed design and protocols.

Second, there is some concern that the proportionality premise regarding levels of 

residues and amount of active ingredient handled might not hold for these scenarios. These 

scenarios are somewhat reminiscent of the completed study of the closed cab scenario that the 

HSRB reviewed at its January 2011 meeting (EPA HSRB 2011a). In the closed cab scenario, the 

pesticide residues detected on the study participants’ hands and clothing appeared to be more 

related to incidental exposures than to the amount of active ingredient handled. If, as designed, 

the engineering controls of the closed systems used in this proposal are effective in restricting 

worker exposure to pesticides, it would not be surprising if similar results were obtained here. 

Therefore, the HSRB strongly supports the EPA’s recommendation (Evans et al. 2011) that 

detailed observations should occur during the conduct of the exposure so that any incidental 

worker contacts with contaminated surfaces are noted. Furthermore, the Board suggested that the 

sponsors and Agency consider the value of measuring surface contamination at the start of the 

study; if there were a background residue present prior to the conduct of the study, this existing 

residue would contribute to the total exposure and should be quantified. Because the 

proportionality objective (objective 2) is crucial to the proposed analysis, as described in Section 

C12 of the AHETF Governing Document (AHETF 2010, 150), exposure and normalized 

exposure is interpretable only when the proportionality constants are zero and one. The effect of 

assuming the proportionality constant is one (or zero), when in fact it may not be, should be also 

considered. Diversity selection will lead to exposures being more uniformly spread than what 
Page 19 of 36

would be observed from random selection (e.g., Figure B2 in the AHEFT governing document 

[AHETF 2010, 119]). However, under the assumed model, it is not evident that the normalized 

exposures would also have a more uniform spread. 

Third, Board members raised some concerns about the necessity for and the 

appropriateness of upper limits to the AaiH for those handlers to be included in these studies. 

While the rationale for the proposed upper limit on study participants using closed systems to 

load liquid pesticide products from returnable containers seemed sound (particularly since 

existing data from the two pre-Rule studies was collected from participants with very high AaiH 

values), it was suggested that no upper limit be imposed on the AaiH of participants using closed 

systems to load liquid pesticide products from nonreturnable containers. Expanding their range 

will increase the potential pool of acceptable participants, expand the power of demonstrating 

proportionality, and also have the potential to yield a better match in the AaiH from this portion 

of the study with the data coming both from this study and from the previously reviewed AHE80 

open pour wettable powder mixer/loader protocol (EPA HSRB 2011a).

Fourth, the Board recommended that criteria be developed before the conduct of the 

study to ensure that the closed systems included within these studies comply with the provision 

within the Agency’s WPS that such systems must be functioning properly. These criteria should 

describe how ‘proper function’ will be (or were) determined and by whom. Such criteria are 

expected to be a part of scientifically reliable data collection process and to ensure compliance 

with the WPS. 

Finally, a suggestion was made to consider the addition of cotton gloves, to be worn over 

the handlers’ chemical protective gloves. While the Board did not question the rationale to place 

the focus of these studies on hand exposures inside chemical protective gloves, it felt that being 

able to measure both unprotected and protected hand exposures would greatly increase the value 

of this study. In this case, such cotton gloves would need to be tested to see if they would fit 

over the chemical protective gloves and not interfere with the work tasks. 

Ethics

Charge to the Board

If the proposed AHETF scenario and field study proposal AHE500 is revised as 

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

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

Board Response to the Charge

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

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

applicable requirements of 40 CFR 26, subparts K and L. 
Page 20 of 36

HSRB Detailed Recommendation and Rationale

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

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

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

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

study monitoring (California Code of Regulations Title 3, Section 6710) (AHETF 2010; Collier 

2011). Requirements of FIFRA §12(a)(2)(P) also apply. Researchers who participate in the study

and interact with study participants have or will undergo appropriate ethics training.

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

committee, IIRB, Inc. of Plantation, FL, prior to submission. As described previously, IIRB, Inc. 

is fully accredited by AAHRPP, listed as an active IRB on the OHRP website, and reviewed this 

protocol and associated documents pursuant to the standards of the Common Rule (45 CFR Part 

46, Subpart A. Copies of all correspondence with IIRB, Inc. (Collier 2011) and a copy of IIRB, 

Inc. policies and membership roster were provided (IIRB, Inc. 2011a; 2011b). 

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, 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. Acceptable risk-benefit ratio. The risks as described in the study protocol are fivefold: 

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

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

wearing an extra layer of clothing that they would not normally wear using closed 

systems to load liquid pesticide products from returnable or nonreturnable containers. 

In addition, loading activities might occur indoors or outdoors and some locations and 

dates are likely to result in hot and/or humid conditions.

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

units (MUs) fall within one of the AaiH strata, AHETF may ask some workers to load 

more or less product than usual. For some, this might lead to a slightly longer work 

period for those workers which may increase the risks of acute toxicity associated 

with exposure to the surrogate chemical or of heat-related illness. 

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

activities that are unusual and might cause subjects psychological distress. These 

include performing an over-the-counter pregnancy test prior to participation (females 

only) and allowing a researcher to assist with the removal of the whole body

dosimeter. 

4) Exposure to surfactants. A very dilute surfactant solution (0.01% v/v sodium dioctyl 

sulfosuccinate in water) is used as a surfactant for face/neck wipes and hand washes 
Page 21 of 36

for all MUs. This surfactant is in a very dilute solution and its use represents a very

short exposure period, but the undiluted surfactant causes mild to moderate skin and 

eye irritation in animals.

5) Risk of exposure to surrogate chemicals.

AHETF has proposed several procedures to minimize these risks:

1) Monitoring and stopping procedures will be instituted. The AHETF will monitor 

ambient conditions to determine the heat index near the mixing/loading station and 

base monitoring decisions on the current heat index. Exposure monitoring will be 

discontinued if the heat index cutoff of 105o F (adjusted for direct sun, if applicable) 

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

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

resumed. If necessary, some monitoring will take place at night or early in the 

morning to avoid excessively hot and humid conditions. 

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

handlers who consider themselves in good health will be included in the study. 

Experience with the mixing/loading equipment to be used in the study will be 

required of all participants. Participants must also understand Spanish or English, and 

appropriate provisions have been made for participants who have low levels of 

literacy.

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

practice the face wipe and hand wash procedures with each participant before 

pesticide handling begins. The use of PPE is required of all participants, and in some 

cases will exceed the minimum requirements established by the WPS. 

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

on hand in case of an accidental exposure. Medical treatment facilities will be 

identified in case of an emergency. A medical professional will be on site to observe 

study participants and provide urgent care.

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

pregnancy status confirmed by over-the-counter pregnancy testing within 24 hours 

prior to study participation. All female volunteers will be notified that an additional 

pregnancy test may be required if there are any delays in the planned start of the 

study. Only non-pregnant volunteers will be allowed to participate.

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

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

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

gender will be available to assist study participants. 
Page 22 of 36

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

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

and load liquid pesticides using closed systems in five regions of the United States.

b. Voluntary and informed consent of all participants:

1) There is the possibility that the participants in this study might be vulnerable (i.e., 

susceptible to coercion and undue influence). The study protocol, however, includes 

several mechanisms designed to minimize coercive recruitment and enrollment.

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

will adequately inform the subjects of the risks, discomforts and benefits from 

participation, and of their right to withdraw.

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

c. Equitable selection of study participants:

1) AHETF will first determine a pool of growers and/or commercial pesticide 

application companies who are eligible to participate in this study. Agricultural 

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

Employers will be required in writing to affirm that they will not influence their 

employees’ decisions about whether to participate in this study. AHETF has 

developed complete and appropriate inclusion/exclusion criteria. 

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

the EPA’s Ethics Review (Evans et al. 2011). In addition, the Board raised additional 

concerns:

a. The Board concurred with the Agency’s recommendation (Evans et al. 2011) that a 

standard operating procedure (SOP) needs to be developed which specifies the criteria by 

which study investigators will decide that a participant is “too sick to make a decision 

about getting medical treatment” (Collier 2011, 378). As mentioned in previous HSRB 

reviews of similar AHETF protocols (e.g., EPA HSRB 2011a), appropriate criteria for 

determining decision-making capacity can be found in the clinical and clinical ethics 

literature (e.g., Appelbaum 2007) and generally include all the following: The patient a) 

can appreciate the situation and its consequences; b) can understand the relevant 

information; c) can reason about the treatment decision; and d) can communicate a 

choice.

b. With regard to the return of exposure results to study participants, the Board reiterated its 

opinion that there is neither a clear positive nor a clear negative duty to provide results to 

participants at this time. Although the Agency and sponsors have argued that the return of 

individual exposure results may benefit research participants, based on current debate 

within the bioethics community regarding the return of individual study results, the Board 

felt that it was still unclear whether or not this was indeed the case. Thus, the Board 
Page 23 of 36

currently neither recommends nor discourages the return of individual study results. The 

Board remarked that it would not be objectionable should the study sponsors chose to 

return individual exposure results to study participants, nor would it be objectionable 

should they chose not to do so. However, if the sponsor did elect to return individual 

exposure results to study participants, the Board recommended that they look to the letter 

developed by an HSRB working group (as discussed during the Board’s May 2011 

teleconference [EPA HSRB 2011b]) for an example of how such information might be 

provided.

Assessment of Completed 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

No Mas-003 was a field-based study to measure the effectiveness of a lotion containing 

16% PMD and 2% lemongrass oil (‘No Mas’) as a repellent against three genera of mosquitoes 

(Culex, Anopheles and Aedes). It 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, and was 

reviewed favorably at the HSRB’s October 2010 meeting (EPA HSRB 2010).

A total of 32 participants (selected from a pool of 92 volunteers diverse in age and 

ethnicity) participated in this study. There were 10 participants (5 female and 5 male) in the 

dosimetry phase. Twenty treated volunteers, 4 untreated experienced volunteers, and 6 alternates 

participated in the field-based efficacy test. One female and 2 male volunteers participated in 

both the dosimetry phase and the field-based efficacy test. The two untreated experienced 

volunteers from Site 1 also participated as treated subjects at Site 2. Finally, one of the female 

alternates for the field-based efficacy test also participated in the dosimetry phase of the study.

Dosimetry data was collected from 10 participants (5 female and 5 male). Each 

participant received an average of 1.20 μl/cm2of product when applied to the arms, and 1.04 

μl/cm2 when applied to the legs. This is equivalent to 1.14 mg/cm2 and 0.99 mg/cm2 of active 

ingredient for the arms and the legs, respectively. Margin of Exposure (MOE) calculations were 

based on an assumed 70 kg participant and an acute dermal LD50 value for PMD at the limit 

dose of greater than 5,000 mg/kg. For the arms, the MOE was greater than 583 and for the legs 

the MOE was greater than 287, both exceeding a target MOE of 100. 

The effectiveness of ‘No Mas’ as a mosquito repellent was determined in a study

conducted at two diverse field sites in the Central Valley of California. Site 1 (Glenn County) 

was mature floodplain forest surrounding some marshy areas with standing water; only Aedes 

spp. of mosquitoes were detected at this site. Site 2 (Butte County) was a relatively open 

landscape with hedgerows of willows growing along an active stream; all three genera of 

mosquitoes were detected at this site, with Aedes spp. predominant. Participants at Site 1 were 

treated approximately 3.2 hours before field exposure, whereas participants at Site 2 were treated 

approximately 6 minutes prior to field exposure.
Page 24 of 36

Prior to the field-based efficacy tests, each study participant received training in proper 

observation and aspiration of mosquitoes using pathogen-free laboratory-raised insects. During 

the field-based test, 10 participants (5 female and 5 male) at each site exposed a treated limb to 

mosquitoes for one minute every 15 minutes. Two additional experienced volunteers (1 male and 

1 female) served as untreated controls to measure mosquito biting pressure. Participants were 

partnered in groups of two and each partner monitored the front of their own exposed limb and 

the back of their partner’s exposed limb. Mosquitoes landing with intent to bite (LIBe) were 

recorded, aspirated into containers, and identified in the laboratory. Participants remained in the 

test until the repellent failed as determined by the first confirmed LIBe, or until the end of the 

test period, whichever came first. The time at which the repellent failed equaled the Complete 

Protection Time (CPT) for each subject. 

All 10 of the treated volunteers at Site 1 experienced a confirmed LIBe, versus 4 of the 

treated volunteers at Site 2. Weibull mean CPT values were not significantly different at the two 

sites, with mean CPT calculated at 9.8 hours (h) (lower and upper 95% = 9.0 h and 10.6 h) at Site 

1 and 10.2 h (lower and upper 95% = 8.2 h and 12.5 h) at Site 2. The normal mean CPT values 

were 9.2 h (lower and upper 95% = 8.1 h and 10.2) and 8.5 h (lower and upper 95% = 7.8 h and 

9.2 h) at Sites 1 and 2, respectively. Kaplan-Meier median CPT was 9.6 h (lower and upper 95% 

= 6.4 h and 10.5 h) at Site 1. Neither the Kaplan-Meier median CPT nor the upper 95% 

confidence limit could be determined for Site 2, but the lower 95% confidence limit was 

estimated to be 6.8 h.

Science

Charge to the Board

Is the CLBR completed study No Mas-003 sufficiently sound, from a scientific 

perspective, to be used to estimate the duration of complete protection against mosquitoes 

provided by the tested repellent?

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment (Fuentes 2011) that this study

provides scientifically valid results to assess the repellent efficacy against mosquitoes for the 

formulation tested. 

HSRB Detailed Recommendations and Rationale

The Board agreed in full with the Agency’s assessment (Fuentes 2011) of the completed 

CLBR study No Mas-003. The study was conducted consistently with the protocol and produced 

results which are sufficiently sound, from a scientific perspective, to be used to estimate the 

duration of complete protection provided by the tested repellent against three genera of 

mosquitoes. 
Page 25 of 36

During the meeting, the Agency also asked the Board to consider the question of which 

of statistical methods -- parametric (with Weibull distribution or normal distribution) or nonparametric (Kaplan-Meier) -- would be appropriate to calculate the CPT for the No Mas 

repellent. The Board considered the fact that parametric methods based on a normal distribution

are not suitable to estimate the CPT due to right-censored and heavily skewed data. Because of 

this, the HSRB previously recommended the use of survival analysis methods to estimate the 

mean CPT and its confidence intervals (CI) (see, e.g., EPA HSRB 2010). 

The Board concluded that Parametric Survival Analysis based on a Weibull distribution 

is one form of survival analysis methods and is suitable for predicting right-censored CPT if the 

Weibull distribution assumption is validated before estimating the mean CPT and its confidence 

intervals. This type of parametric analysis can be performed using SAS/STAT LIFEREG or 

SAS/QC PROC Reliability procedures. However, if the Weibull distributional assumption is not 

confirmed, a Non-Parametric right-censored Survival Analysis method based on the productlimit method (also called the Kaplan-Meier method) should be used to estimate the CPT median 

and percentiles and the 95% CI, with relatively smaller samples (10 subjects/group or stratum). 

Furthermore, a separate survivor function can be estimated for each stratum, and tests of the 

homogeneity among the groups can be conducted using this method. This type of non-parametric 

analysis can be performed using SAS/STAT LIFETEST procedures.

Ethics

Charge to the Board

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

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

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s assessment (Sherman 2011a) that the studies 

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 provided by Carroll-Loye Biological Research (Carroll 2011) state that 

the study was conducted in compliance with the requirements of the US EPA Good Laboratory

Practice Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; 

FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710. The study

was reviewed and approved by a commercial human subjects review committee, Independent 

Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL. 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 (Carroll 2011; IIRB, Inc. 2010; IIRB, 
Page 26 of 36

Inc. 2011). IIRB, Inc. also reviewed and approved Amendment 1 of November 15, 2010 (Carroll 

2011; Sherman 2011a).

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

detailed in the EPA’s Ethics Review (Sherman 2011a). Specifically:

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 (Carroll 2011) was conducted in accordance with the protocol 

previously reviewed by the Agency (Fuentes and Sherman 2010) and by the HSRB (EPA 

HSRB 2010). Neither the Agency’s nor the HSRB’s ethics reviews identified significant 

deficiencies requiring correction relative to 40 CFR 26, subparts K and L, or to FIFRA § 

12(a)(2)(P) (Carley 2010a). 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 March 21, 2011.

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

and consent form were modified through Amendment 1 of November 15, 2010 (Carley

2010a; Carroll 2010c). This amendment incorporated changes responsive to the 

comments of EPA, the HSRB, and CDPR, as well as additional corrections initiated by

the investigators. Only two Agency and HSRB suggestions were not incorporated into the 

revised protocol: the addition of “child/minor” to the list of exclusion criteria and the 

definition of the acronym ‘PMD’ in the protocol and informed consent document. Failure 

to incorporate these suggestions into study protocol and informed consent documents, 

however, is unlikely to compromise the informed consent process or place the study

participants at risk. IIRB, Inc. granted approval to Amendment 1 and supporting 

documents on November 16, 2010 (Carroll 2011; Sherman 2011a). 

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

CLBR’s submission (Carroll 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 were 

fully satisfied.

2. The Board concluded that this study 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:

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 

efficacy of these new formulations as personal insect repellents.

• 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 
Page 27 of 36

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

minimized. 

• Based on toxicological data currently available for ‘No Mas’, coupled with appropriate 

exclusion criteria, study participants were unlikely to be at risk of adverse side effects 

with exposure. 

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

events related to product exposure were reported.

• The study was designed to minimize the likelihood of mosquito bites.

• The field-based trials were conducted only in areas where known vector-borne diseases 

like West Nile Virus had not been detected by county and state health or 

vector/mosquito control agencies for at least two weeks. Mosquitoes collected during 

the field studies also were subjected to molecular analyses to confirm that they were 

free of known pathogens.

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. There was one minor protocol deviation reported: use of a reformatted lotion dosimetry

data form without prior IRB review. The Board concluded, however, that this deviation did 

not affect the integrity of the research or the safety of participants.

Assessment of Published Research Study MRID 48607501: Moiemen et al. (2011) Acticoat 

Dressings and Major Burns: Systemic Silver Absorption.

Overview of the Study

In the Moiemen et al. (2011) study, 6 human volunteers being treated for severe burns 

(defined as burns covering greater than 20% of the total body surface area) were exposed to 

antimicrobial wound dressings containing silver in nanocrystalline form. The study was 

conducted at the Selly Oak Hospital Burns Unit (also known as the Midlands Burn Center) in 

Birmingham, United Kingdom (UK), between May 2006 and May 2007. One female subject and 

five male subjects, ranging from 22 to 56 years of age, were enrolled. As part of their treatment, 

participants’ burns were dressed with either Acticoat® antimicrobial barrier dressings and/or 

Acticoat® Absorbent; this represents standard of care for patients with severe burns. 

Acticoat dressings consist of an absorbent inner core of rayon and polyester fabric 

sandwiched between two layers of silver-coated, low adherent polyethylene mesh. Acticoat 

Absorbent is a silver-coated calcium alginate fabric. Both products release silver slowly over 
Page 28 of 36

several days. Silver nanoparticles are an effective microbiocide, and Acticoat and Acticoat 

Absorbent have established antimicrobial efficacy and are licensed for use as wound dressings.

Serum levels of silver were determined prior to enrollment in the study, during treatment 

with wound dressings, and after treatment discontinuation. Hematology, clinical chemistry, and 

clinical observations were also performed in order to identify any adverse effects of treatment 

with the wound dressing. No treatment related adverse effects on hematology, clinical chemistry, 

wound healing, or clinical signs of toxicity were observed. 

Serum levels of silver increased during the wound dressing treatment periods, but there 

was no apparent relationship between the Total Body Surface Area (TBSA) of the wound and the 

amount of silver absorbed. Serum levels of silver also remained elevated after discontinuation of 

wound dressing treatment, suggesting continued systemic absorption of skin-associated silver 

and/or slow clearance of circulating serum silver. The study authors calculated a median half-life 

of 46.4 days for elimination of serum silver, which was extrapolated to give a median reduction 

of 1.5% per day. 

Using the data reported in the Moiemen et al. (2011) study, in conjunction with in vitro

data from the Larese et al. (2009) study, EPA scientists have estimated that the maximum amount 

of silver absorbed from nanosilver on human skin is approximately 0.1% per day. The Agency

proposes to use this estimated 0.1% absorption factor as part of the overall weight of evidence to 

estimate dermal exposure for pesticide formulations that contain nanosilver.

Science

Charge(s) to the Board

1) Is the Moiemen et al. (2011) study scientifically sound, providing reliable data?

2) If so, can the Moiemen et al. (2011) study be used to support the Agency’s conclusion 

that the dermal absorption factor for silver from nanosilver on human skin is less than 0.1%?

Board Response to the Charge

HSRB Recommendation

Despite several deficiencies identified with the study design, the small number of 

subjects, and the interpretation of the data, the Board agreed with the Agency’s assessment that 

the Moiemen et al. (2011) study provides some potentially useful baseline information on the 

dermal absorption of silver from nanosilver-containing wound dressings. 

The Board noted that the calculated values for the dermal absorption of silver from 

nanosilver in the Moiemen et al. (2011) study were higher than values previously reported by 

another study using in vitro intact and abraded skin (Larese et al. 2009). Despite this, the Board 

concluded that the Moiemen et al. study could be used to support the Agency’s conclusion that 

the dermal absorption of silver is less than 0.1% as part of the overall weight of evidence. 
Page 29 of 36

The Board recommended, however, that the Agency clarify its assumptions in estimating 

the dermal absorption of silver from nanosilver. The Board also suggested that the Agency 

consider alternatives for estimating dermal absorption based on the Moiemen et al. (2011) study, 

such as using the less-conservative approach suggested by one Board member and which will be 

detailed in a separate memorandum to the Agency.

HSRB Detailed Recommendations and Rationale

The estimates for dermal absorption of silver from nanosilver-containing wound 

dressings in patients with various degrees of skin burns reported in the Moiemen et al. (2011) are 

within the range of values previously reported in some articles but higher than that seen in others 

(see, e.g., Larese et al. 2009). This may be due to limitations in the design and execution of the 

study, as well as the interpretation of the results, as described in detail below:

1. Study design and execution. The authors did not include hematologic and blood chemistry

data in their article, so it was difficult to assess whether or not changes in normal organ 

physiological and biochemical functions (e.g., liver or kidney) may have influenced plasma 

values of silver for each patient. Although the Agency had access to this information, it was 

not at liberty to share it with the Board. However, based on their review of these data, the 

Agency believed that no treatment related adverse effects on hematology, clinical chemistry, 

wound healing or clinical signs of toxicity were observed. 

The Board noted that the clustering of patients with partial thickness and full thickness 

wounds might have masked any potential dose-response relationship. Unfortunately, the 

number of patients in each of these two main categories of wound thickness seemed 

insufficient to study them separately.

2. Interpretation. The authors of the Moiemen et al. (2011) study calculated a plasma half-life 

for silver of 46.4 days and a median elimination rate of 1.5% per day upon cessation of 

Acticoat treatment; in other words, after treatment was stopped, the daily reduction rate of 

serum silver levels was estimated to be at 1.5% of the total amount measured in blood. In its 

discussion of these estimated half-life and median elimination rates, however, the Board 

viewed the lack of urinary excretion measures as a shortcoming. Urine data are needed to 

obtain an accurate measurement of the total amount of chemical actually absorbed by the 

worker via all routes (see, e.g., AEATF 2011, 52). Any estimation of dermal absorption from 

blood serum samples would be more reliable if urinary excretion data are available. 

The pattern of silver elimination from plasma for most patients was described as biphasic. 

The study investigators concluded that this apparent biphasic elimination involved biliary

excretion at low serum silver levels and urinary excretion levels greater than 100 μg/L2. The 

Agency considered the possibility that this biphasic response may reflect competing 

processes of systemic absorption of any skin-associated silver present after the wound 

 

2 This value is the same as that originally reported by Coombs et al. (1992) in a prospective clinical study that 

determined the absorption and effects of the silver ion from sliver sulfadiazine in the context to hepatic and 

renal function.
Page 30 of 36

dressings were removed. The Board argued that, for this biphasic response to be valid, 

saturation of biliary excretion pathways should occur under the conditions reported in the 

study. As this is unlikely when considering the maximal plasma levels of silver achieved and 

that the fraction of silver eliminated daily was ~1.5% of what was present in blood, the Board 

suggested two alternative interpretations. 

First, the biphasic mode of elimination suggests that two forms of silver -- silver 

nanoparticles and silver ions -- were being absorbed from the skin. The particles can be 

subjected to uptake and storage in a tissue compartment(s) from which these particles can be 

dissociated, leading to a slow release of silver ions into the blood, while the silver ions 

absorbed from the skin provide the more rapid phase of elimination. The authors did not 

report whether they considered the likelihood that two forms of silver were being absorbed 

from the wound dressing. 

Alternatively, deposition of ionic silver itself (not necessarily nanoparticles) in tissue 

reservoirs may explain the apparent biphasic elimination mode. A recent review article by

Lansdown (2010) describes how ionic silver that is absorbed into the body readily binds to 

intracellular proteins, such as serum albumin and macroglobulin, and to intracellular 

cysteine-rich proteins like metallothioneins. Bone is also described as a potentially relevant 

storage site for silver -- along with soft tissues such as the eye, brain, liver, kidney spleen, 

and bone marrow -- following systemic absorption. Slow release from these tissues/cellular 

reservoirs can contribute to the slow elimination phase of silver seen in the Moiemen et al.

(2011) study.

The dermal absorption analysis described in Appendix 1 of the Agency’s science review 

(Ryman 2011) was based on the conservative assumption that the blood serum silver levels on 

any given day are due to that day’s absorption. Implicit in that assumption is that each prior 

day’s serum silver is removed from the blood and sufficient new silver is absorbed to reach the 

next day’s level. As described above, such an assumption is not based on a realistic 

pharmacokinetic model and its results are inconsistent with the median of 9.5 days that it took 

for patients’ serum levels to reach their maximum level and with the estimated 46.4-day half-life 

serum levels after treatment was discontinued. 

Despite these limitations, this absorption factor calculated by the Agency appears to be 

greater than any of the absorption factors estimated by Board members using alternative 

approaches, or the absorption factors seen in other studies in the current literature. Use of such a 

conservative dermal absorption factor is likely to provide greater protections when used for 

regulatory decision-making purposes. Thus, the Board concluded that the Moiemen et al. (2010) 

study could be used as part of a weight-of-evidence approach to support the Agency’s conclusion 

that the dermal absorption factor for silver from nanosilver on human skin is equal to or less than 

0.1%. 
Page 31 of 36

Ethics

Charge to the Board

Is there adequate information to support a determination that the study was conducted in 

substantial compliance with procedures at least as protective as those at subparts A-L of 40 CFR 

Part 26?

Board Response to the Charge

HSRB Recommendation

The Board concurred with the EPA’s Ethics Review (Sherman 2011b), that there was 

sufficient information regarding value of the research to society, subject selection, risks and 

benefits, independent ethics review, informed consent, respect for potential and enrolled subjects 

to conclude that the Moiemen et al. (2011) study was conducted in substantial compliance with 

procedures at least as protective as those in subparts A-L of EPA’s regulation at 40 CFR Part 26. 

HSRB Detailed Recommendations and Rationale

This is the second time that the Agency has asked the HSRB to review a study that was 

located in the public literature and which was conducted after promulgation of the Final Human

Studies Rule in April 2006 (c.f. EPA HSRB 2011a). This study was conducted in Britain and 

was reviewed and approved by the Sandwell and West Birmingham Local Research Ethics 

Committee, in accordance with the policies and procedures of the British National Research 

Ethics Service.

1. Standards Applicable to EPA’s Reliance on the Research.

As noted in the EPA’s Ethics Review (Sherman 2011b), the Agency’s Final Human Studies 

Rule (40 CFR part 26 subpart Q) defines standards for EPA to apply in deciding whether to 

rely on research―like this study―involving intentional exposure of human subjects. The 

applicable acceptance standards are: 

§26.1703. Prohibition of reliance on research involving intentional exposure of human 

subjects who are pregnant women (and therefore their fetuses), nursing women, or 

children. Except as provided in §26.1706, in actions within the scope of §26.1701 EPA 

shall not rely on data from any research involving intentional exposure of any human 

subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a child. 

§26.1705 Prohibition of reliance on unethical human research with non-pregnant, nonnursing adults conducted after April 7, 2006. Except as provided in §26.1706, in actions 

within the scope of §26.1701, EPA shall not rely on data from any research initiated after 

April 7, 2006, unless EPA has adequate information to determine that the research was 

conducted in substantial compliance with subparts A through L of this part, or if 

conducted in a foreign country, under procedures at least as protective as those in 
Page 32 of 36

subparts A through L of this part. This prohibition is in addition to the prohibition in 

§26.1703.

2. Compliance with Applicable Standards.

As noted in the EPA’s Ethics Review (Sherman 2011b), this research did not involve 

intentional exposure of any pregnant or nursing female subjects or any children. Reliance on 

the research is therefore not prohibited by 40 CFR §26.1703. 

EPA is forbidden by 40 CFR §26.1705 to rely on data from research involving intentional 

exposure―such as this study― “unless EPA has adequate information to determine that the 

research was conducted in substantial compliance with subparts A through L of [40 CFR part 

26], or if conducted in a foreign country, under procedures at least as protective as those in 

subparts A through L of [40 CFR part 26].” This research was approved by an independent 

ethics review committee, the Sandwell and West Birmingham Local Research Ethics 

Committee and conducted in accordance with requirements under the UK Central Office for 

Research Ethics Committees and the Medicine for Human Use Clinical Trial Regulations. 

The Board observed that the protocol provides that the research “will be performed in 

accordance with the guidelines of the Declaration of Helsinki (1964) and subsequent 

revisions,” but noted that the Declaration of Helsinki is not regulatory in nature. Rather, the 

fact that the protocol was reviewed and performed in accordance with specific UK 

requirements for the conduct of ethical research ensures that the research was conducted 

under procedures as at least as protective as subparts A through L of the Agency’s Final 

Human Studies Rule.

EPA’s regulations governing third-party human research for pesticides at 40 CFR part 26 

subpart K permit consent for a subject’s participation in research to be given by the subject’s 

“legally authorized representative” when the subject lacks the capacity to consent for himself 

or herself. Subpart K is consistent with the Common Rule, which was drafted to protect 

subjects in a wide variety of research settings, including, for example, research into 

emergency procedures to save lives of unconscious patients.

3. Additional Board Comments and Concerns.

In order to ensure that quality of data regarding Acticoat absorption, the protocol prohibited 

the use of other silver-based products in these burn patients. One question that was raised 

concerned whether or not the quality of care provided to these patient/subjects may have 

been adversely affected because of this prohibition. Based on clinical information on silverbased products in burn care, and additional research by the Agency and Board members 

regarding standard-of-care for burn patients, the Board was satisfied that the silver-based 

wound dressing being tested would have been the only silver-based product used. All study

participants were thus treated using an appropriate standard of care.

Finally, one member of the Board observed that the reference in this study to obtaining 

“retrospective consent” is a misnomer. Informed consent is a prospective decision made by 
Page 33 of 36

and individual or surrogate to consent for treatment and/or study participant. It is not possible 

for a study participant or their surrogate to agree to something that happened in the past.
Page 34 of 36

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