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 (AEA-
05); 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 AH ET F R esearch Study A HE 500: E xposure 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 AIHETF 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 C om leted Carroll-L oye Biological R esearch Study No M as-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 MRI D 48607501: Moiemen etal. (2011) Acticoat
Dressings and Major Burns: Systemic Silver Absorøtion.
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/osalhsrb . You may also contact the HSRB Designated Federal Officer, via e-
mail at ord-osa-hsrb@epa.gov
In preparing this document, the Board carefully considered all information provided and
presented by the Agency presenters, as well as information presented by public commenters.
This document addresses the information provided and presented within the structure of the
charge by the Agency.
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US ENVIRONMENTAL PROTECTION AGENCY
HUMAN STUDIES REVIEW BOARD
Chair
Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union
Graduate College and the Mount Sinai School of Medicine, Schenectady, NY
Vice Chair (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 Nevada-
Reno Center for Research Design and Analysis, University of Nevada-Reno, Reno, NV
Vanessa Northington Gambles, 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. Lebowitzt, 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
present on October 19, 2011.
t 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 Caflez, 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 Cafiez, 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 httD://www.regulations.gov .
CHARGE TO THE BOARD AND BOARD RESPONSE
Assessment of Proposed AEATF Research Study AEAO5: A Study for Measurement of
Potential Dermal and Inhalation ExDosureDuringManual Pourinciofa Liquid Containing
an Antimicrobial .
Overview of the Study
AEATF II liquid pour protocol (AEAO5) 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” [ MIEs]) 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 theCharge
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-ll 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 I (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 pit-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 900) 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 (AFIETF 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 poois, 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 ResponsetotheCharge
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 LRB 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. #10RG0002954). Copies of all correspondence with
IIRB, Inc. (Shah 201 ib, 2011c) and a copy of IIRB, Inc. policies and membership roster were
provided (IIRB, Inc. 201 Ia; 201 Ib). These documents indicate that IIRB, Inc. reviewed this
protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A).
I. 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. Infonned 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 quatemary 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 I n 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 A EAT F 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
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• 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 201 ib).
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.”
• Ouestions 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 AH ETF Research Study AH E 500: Exposure Monitoring of
Workers During Closed System Loadingof Returnableand Non-ReturnableContainers 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
pesticides’ using 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.”
Possible surrogate pesticides include carbaryl, chiorothalonil, Dacthal (DCPA), fosamine, glyphosate, imazapyr,
imidacloprid, Malathion, simazine, sulfur, thiophanate-methyl, 2,4-Dichiorophenoxyacetic 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.
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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
C harge 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?
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Board Response to theCharge
HSRB Recommendation
The Board concurred with the Agency’s assessment that the proposed A1-IETF 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 AH5O1 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 AFIED
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 201 la). 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 AI-IETF 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
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would be observed from random selection (e.g., Figure B2 in the AFIEFT 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 pooi 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 AHE8O
open pour wettable powder mixer/loader protocol (EPA HSRB 201 Ia).
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 theCharge
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.
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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, I1RB, 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; 201 ib).
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 acth,ities. 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 (0.0 1% v/v sodium dioctyl
sulfosuccinate in water) is used as a surfactant for face/neck wipes and hand washes
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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) Riskofexposureto 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 105° F (adjusted for direct sun, if applicable)
is reached or exceeded. The Study Director or other researcher shall stop the
monitoring and/or move the worker to a cooler environment until monitoring can be
resumed. If necessary, some monitoring will take place at night or early in the
morning to avoid excessively hot and humid conditions.
2) Clear inclusion/exclusion criteria have been established. Only experienced pesticides
handlers who consider themselves in good health will be included in the study.
Experience with the mixing/loading equipment to be used in the study 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.
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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 pooi 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 stud results, the Board
felt that it was still unclear whether or not this was indeed the case. Thus, the Board
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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 201 ib]) for an example of how such information might be
provided.
Assessment of Comøleted Carroll-Love Biological Research Study No Mas-003: Field
EfficacvTestof 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
paflic ant received an average of 1.20 p.1/cm 2 of product when ap 1 lied to the arms, and 1.04
p.1/cm when applied to the legs. This is equivalent to 1.14 mg/cm and 0.99 mg/cm 2 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 LD5O value for PMD at the limit
dose of greater than 5,000 mgfkg. For the arm s, 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 I (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 I were
treated approximately 3.2 hours before field exposure, whereas participants at Site 2 were treated
approximately 6 minutes prior to field exposure.
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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 theCharge
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.
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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 non-
parametric (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 SASI 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 product-
limit 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 R esponse to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Sherman 201 la) 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,
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Inc. 2011). IIRB, Inc. also reviewed and approved Amendment I 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 201 la). 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 201 la).
c. SuL stantial Compliance with Reporting Requirements (40 CF R 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
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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 M RID 48607501: Moiemen etal. (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
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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 theCharge
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.
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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 maincategories of wound thickness seemed
insufficient to study them separately.
2. I nter pretati on. The authors of the Moiemen et a I. (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 pgfL 2 . 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.
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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%.
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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 theCharge
HSRB Recommendation
The Board concurred with the EPA’s Ethics Review (Sherman 201 ib), 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 201 la). 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 201 ib), 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, non-
nursing 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
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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 201 ib), 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 patientlsubjects mayhave
been adversely affected because of this prohibition. Based on clinical information on silver-
based products in bum 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
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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.
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REFERENCES
Agricultural Handler Exposure Task Force (AHETF). 2010. Governing Documents for a Multi-
Year Pesticide Handler Worker Exposure Monitoring Program (Version 2). Dated August 12,
2010. Unpublished document prepared by the AHETF. l 56 p.
Antimicrobial Exposure Assessment Task Force II (AEATF II). 2011. Governing Document for a
Multi-Year Antimicrobial Chemical Exposure Monitoring Program (Version 3). Dated July 8,
2011. Unpublished document prepared by the AEATF. l29p.
Appelbaum, P.S. 2007. Clinical Practice. Assessment of Patients’ Competence to Consent to
Treatment. New England Journal of Medicine 357(18): 1834-40.
Carroll, S. 2011. Field Efficacy Test of a PMD and Lemongrass oil- Based Repellent ‘No Mas’
Against Mosquitoes. Dated August 14, 2011. Unpublished document prepared by Carroll-Loye
Biological Research. 4 lIp.
Collier, C.H., for the Agricultural Handler Exposure Task Force (AHETF). 2011. Closed System
Loading of Liquids in Returnable and Non-Returnable Containers (AHETF Study No. AHE500).
Dated August 2, 2011. Unpublished document prepared by the AHETF. 438p.
Coombs, C.J., A.T. Wan, J.P. Masterton, R.A. Conyers, J. Pedersen, and Y.T. Chia. 1992. Do
Burn Patients Have a Silver Lining? B urns 18(3): 179-84.
EPA Human Studies Review Board. 2010. October 27-28, 2010 Human Studies Review Board
Meeting Report. 3ip.
EPA Human Studies Review Board. 201 la. January 17, 2010 Human Studies Review Board
Meeting Report. 24p.
EPA Human Studies Review Board. 201 lb. April 13-14, 2010 Human Studies Review Board
Meeting Report. 3lp.
Evans, J., B. Sarkar, K. Sherman, and S. Knizer. 2011. Science and Ethics Review of AHETF
Scenario Design and Protocol AHE500 for Exposure Monitoring of Workers During Closed
System Loading of Returnable and Non-Returnable Containers in the United States. Dated
September 26, 2011. Unpublished document prepared by the Office of Pesticide Programs,
United States Environmental Protection Agency. 59p.
Fuentes, C. 2011. Science Review of Completed Carroll-Loye Mosquito Repellent Field Efficacy
Study No Mas 003. Dated September 29, 2011. Unpublished document prepared by the
Biopesticides & Pollution Prevention Division, Office of Pesticide Programs, United States
Environmental Protection Agency. 8p.
Fuentes, C., and K. Sherman. 2010. Science and Ethics Review of Protocol for Human Study of
Mosquito Repellent Performance: Proposed Carroll-Loye Field Efficacy Test of PMD and
Lemongrass Oil-Based Repellent ‘No Mas’ Against Mosquitoes. Dated October 1, 2010.
Page 34 of 36
-------
Unpublished document prepared by the Office of Chemical Safety and Pollution Prevention,
United States Environmental Protection Agency. 30p.
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. l3lp.
ILRB, Inc., 2011. IRB Membership Roster. Dated September 12, 2011. Unpublished document
prepared by IIRB, Inc. Ip.
Lansdown, A.B.G 2010. A Pharmacological and Toxicological Profile of Silver as an
Antimicrobial Agent in Medical Devices. Advances in Pharmacological Sciences 2010: Article
ID 910686, l6 . doi: 10.1155/2010/910686.
Larese, F.F., F. D’Agostin, M. Crosera, (1 Adami, N. Renzi, M. Bovenzi, and C I Mama. 2009.
Human Skin Penetration of Silver Nanoparticles Through Intact and Damaged Skin. Toxicology
255(1-2): 33-7.
Leighton, T., K. Sherman, and J. Cohen. 2011. Science and Ethics Review of AEATF II Liquid
Pour Scenario Design and Protocol for Monitoring. Dated September 23, 2011. Unpublished
document prepared by the Office of Pesticide Programs, United States Environmental Protection
Agency. 54p.
Moiemen, N.S., E. Shale, K. J. Drysdale, et al. 2011. Acticoat Dressings and Major Bums:
Systemic Silver Absorption. Burns 37(1): 27-35. MRID 48607501.
Ryman, J. 2011. Data Evaluation Record: SILCRYST TM . Dated October 3, 2011. Unpublished
document prepared by the Health Effects Division, United States Environmental Protection
Agency. I6p.
Shah, H., for the AEATF II. 2011 a. A Study for Measurement of Potential Dermal and Inhalation
Exposure During Manual Pouring of a Liquid Containing an Antimicrobial. Volume 1 of 4:
Transmittal Letter; 40 CFR 26.1125 Checklist for Study AEAO5; Liquid Pour Study Design
Document. Dated July 28, 2011. Unpublished document prepared by the AEATF II. 33p.
Shah, H., for the AEATF II. 2011b. A Study for Measurement of Potential Dermal and Inhalation
Exposure During Manual Pouring of a Liquid Containing an Antimicrobial. Volume 2 of 4: Study
Protocol; IIRB Approval Letter and Supporting Documents. Dated July 28, 2011. Unpublished
document prepared by the AEATF II. l’77p.
Shah, H., for the AEATF II. 2011c. A Study for Measurement of Potential Dermal and Inhalation
Exposure During Manual Pouring of a Liquid Containing an Antimicrobial. Volume 3 of 4:
Records of IIRB Review of Study AEAO5. Dated July 28, 2011. Unpublished document prepared
by the AEATF II. 224p.
Shah, H., for the AEATF II. 20 lid. A Study for Measurement of Potential Dermal and Inhalation
Page 35 of 36
-------
Exposure During Manual Pouring of a Liquid Containing an Antimicrobial. Volume 4 of 4: CVs
and Ethics Training Records; SOPs Referenced in AEAO5 Protocol. Dated July 28, 2011.
Unpublished document prepared by the AEATF II. l’73p.
Sherman, K. 201 la. Ethics Review of Completed Carroll-Loye Mosquito Repellent Field
Efficacy Study No Mas 003. Dated September 29, 2011. Unpublished document prepared by the
Office of the Director, Office of Pesticide Programs, United States Environmental Protection
Agency. 7p.
Sherman, K. 2011 b. Ethics Review of Intentional Exposure Human Toxicity Study (Ref:
Moiemen, N.S., Shale, E., Drysdale, K.J., Smith, G., Wilson, Y.T., Rapini, R. Acticoat dressings
and major buns: Systemic silver absorption. The Midlands Burn Centre, University Hospitals
Birmingham Foundation Trust, United Kingdom. Burns, 37, 27-35 [ 2011J. [ MRID 48607501]).
Dated October 3, 2011. Unpublished document prepared by the Office of the Director, Office of
Pesticide Programs, United States Environmental Protection Agency. lop.
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