October 26, 2009
EPA-HSRB-09-02
Kevin P. Teichman, PhD
Acting Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: June 24-25, 2009 EPA Human Studies Review Board Meeting Report
Dear Dr. Teichman:
The United States Environmental Protection Agency (EPA or Agency) requested the
Human Studies Review Board (HSRB) to review three completed studies involving intentional
human exposure to the organophosphate pesticide chlorpyrifos. The Agency proposes 'to rely on
these three studies, conducted prior to publication of the EPA's expanded final rule for
protection of subjects in human research (40 CFR 26) on February 6, 2006 (71 Federal Register
24, 6137), in actions under the pesticide laws. The Agency asked the HSRB to advise the
Agency on a range of scientific and ethics issues regarding how the studies should be assessed
against the provisions in 40 CFR sections 26.1701 - 26.1704 of the final human studies rule.
The Agency also requested the HSRB to provide scientific and ethical reviews of one
completed and two proposed human studies: a completed ICR, Inc., (ICR) insect repellent
efficacy study (ICR A382); a proposed Carroll-Loye Biological Research, Inc. (CLBR) insect
repellent efficacy study (LNX-002); and a proposed Agricultural Handler Exposure Task Force,
LLC (AHETF) water-soluble packing mixing and loading scenario and protocol (AHE-120).
The enclosed report provides the Board's response to EPA charge questions presented at
the June 24-25, 2009 meeting.
Assessment of Completed Research Study MRID 124144: Nolan et al. (1982) Chlorovrifos:
Pharmacokinetics in Human Volunteers Following Single Oral and Dermal Doses.
Science
The Board concluded that data measuring chlorpyrifos at the limit of detection in blood
and urine are not useful. The measurements of 3,5,6-trichloro-2-pyridinol (TCP) in urine
are generally reliable. It is unclear if the measurement of TCP in blood is useful because
of concerns about the ability of the methods used to detect the appropriate TCP
conjugate.
The Board expressed concern over the variability of the erythrocyte cholinesterase
activity data and the lack of a control group, but concluded that measurements of
cholinesterase activity/inhibition from Nolan et al. (1982) were likely to be reliable.
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• The Board concluded that the data are reliable but suggested that the Agency be cautious
in its use of the erythrocyte cholinesterase data. Since only a single dose level was
evaluated, for example, no dose-response data are available from this study.
Ethics
• The Board concurred with the Agency’s assessment that there was neither clear and
convincing evidence that the study was fundamentally unethical, nor clear and
convincing evidence that the study was significantly deficient relative to the ethical
standards prevailing at the time the Nolan eta!. (1982) study was conducted.
Assessment of Completed Research Study MRID 42062701: Honeycutt and DeGeare ( 1993)
Worker Reentry Exposure to Chlorpyrifos in Citrus Treated with Lorsban* 4E Insecticide.
Science
• The Board concluded that the blood and urine measurements of chiorpyrifos and/or TCP
from Honeycutt and DeGeare (1993) are likely reliable but of limited value. Board
members expressed concerns about: 1) the small sample size; 2) the background
chiorpyrifos exposure not being properly accounted for; 3) the likely incompleteness of
urine collection; and 4) the high degree of variation seen in the daily measurements.
• The Board concluded that the measurements of cholinesterase activity/inhibition are
likely accurate and reliable but raised concerns about their utility. Some of the Board’s
concerns included: 1) the lack of an untreated control; 2) the reliance on a single post-
exposure time point; 3) the small sample size; and 4) the dose received by the subjects
varied and was only estimated from dermal dosimetry.
Ethics
• The Board concurred with the Agency’s assessment that there neither was clear and
convincing evidence that the study was fundamentally unethical, nor clear and
convincing evidence that the study was significantly deficient relative to the ethical
standards prevailing at the time the Honeycutt and DeGeare (1993) study was conducted.
Assessment of Completed Research Study MRID 44811002: Kisicki eta!. (1999 A Rising
Dose Toxicology Study to Determine the No-Observable Effect-Levels (NOEL) For
Ervthrocvtes Acetyicholinesterase (AChE) Inhibition and Choliner ic Signs and Symptoms
of Chiorpyrifos at Three Dose Levels .
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Science
• The Board raised concerns about the analytic procedures’ potential inability to control for
the glucuronide-conjugated TCP, and apparent discrepancies in the absorption data when
compared with the data from Nolan et al. (1982). Thus, the Board questioned the
reliability and utility of the blood and urine measurements of chiorpyrifos and/or TCP
from Kisicki et al. (1999) for risk assessment purposes.
• The Board concluded that these measurements of cholinesterase activity/inhibition likely
represent a reliable set of data, but cautioned the Agency about relying on data from the
incomplete profile for the one responder at the highest dose level.
• The Board cautioned against relying on the statistical analyses as presented in the report,
recommending that these analyses be replicated prior to applying these results to any risk
assessment or model development.
• The Board concluded that, in the absence of additional information about the analytic
methods used and the accuracy of the TCP measurements, the TCP data is of
questionable reliability. If the level of exposure cannot be confirmed as reliable, then by
default the erythrocyte data should not be used. The Board thus suggested that the
Agency be cautious in its use of the erythrocyte data in light of the variability and
analytical concerns raised.
Ethics
• The Board concluded that there neither was clear and convincing evidence that the study
was fundamentally unethical, nor clear and convincing evidence that the study was
significantly deficient relative to the ethical standards prevailing at the time the Kisicki et
a!. (1999) study was conducted.
Assessment of Completed Research Study MRID 47732701: ICR Inc. Study A382 —
Evaluation of the Efficacy of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect
Repellents (20% Cream and 20% S rav) Against Stable Flies in the Laboratory.
Science
• The Board concurred with the Agency’s assessment that this study provides scientifically
valid results to assess the repellent efficacy against stable flies of the formulations tested.
• The Board recommended correcting several of the statistical analyses present in the
report. For example, the standard error for mean protection time and resulting confidence
interval needs to be corrected to use the estimated standard error, not the planned
standard error. The report should also be corrected to indicate that the data presented are
for product failure times and not complete protection times.
Ethics
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• 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 Proposed Carroll-Love Biolo2ical Research Study LNX-002: Efficacy Test of
KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and 20%
S rav) with Bitin2 Flies Under Field Conditions.
Science
• The Board concurred with the Agency’s assessment that this protocol, if modified
according to HSRB recommendations and conducted accordingly, will provide
scientifically valid results on the efficacy of these two picaridin-based insect repellent
formulations against biting flies.
• The Board recommended that the protocol be revised to address the following concerns:
1) the standard of biting used may be insufficiently high to yield valid results and could
lead to inappropriately right censored data; 2) the change from the previously-used
paradigm of one minute exposure of treated limbs out of each 15 minute period to five
minutes in each 30 minute period was not explained or justified; 3) the varied behaviors
and aggressiveness of four different species of biting flies to be examined; and 4)
accurate calculation of mean complete protection time.
Ethics
• The Board concluded that the protocol submitted for review, if modified in accordance
with Agency and HSRB recommendations and conducted accordingly, is likely to meet
the applicable requirements of 40 CFR 26, subparts K and L.
Assessment of Proposed AHETF Scenario and Protocol AHE-120: Water-Soluble Packin2
Mixing and Loadin2.
Science
• Given the lack of existent reliable and sound data in this area, the Board concurred with
the Agency’s assessment that this protocol will generate data that are scientifically valid.
These data may be useful for assessing the exposure of handlers who mix and load
soluble or wettable powder pesticides in water-soluble packaging.
• The Board cautioned that these data are likely to be useful for creating distributions of
worker exposure only if worker exposure is found to be proportional to the amount of
active ingredient handled (AaiH).
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The Board recommended that the AHETF and the Agency acknowledge the limitations of the
study design and add appropriate statistical methods or data management approaches to ensure
that, once these data are inside the AHED database, the limitations of the original study design
are not forgotten and the data used inappropriately by end-users to generate typical statistical
distributions.
Ethics
• The Board concluded that the protocol submitted for review, if modified in accordance
with Agency and HSRB recommendations and conducted accordingly, is likely to meet
the applicable requirements of 40 CFR 26, subparts K and L. In particular, the Board
recommended that the AHETF implement the proposed protocol changes designed to
address issues of representativeness language in the informed consent and related
documents.
• The Board recommended that the AHETF release individual exposure data only once the
study is complete, except in those instances where data collected from individuals
suggest an unusually high level of exposure and thus a clear need to mitigate exposure
risks.
Sincerely,
ç s
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. Further information about
the EPA Human Studies Review Board can be obtained from its website at
http://www.epa.gov/osalhsrb/. Interested persons are invited to contact Paul Lewis, Designated
Federal Officer, via e-mail at lewis.paul 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, MS Bioethics, Science and Ethics Officer, Global Campaign for
Microbiocides, PATH, Washington, DC
Vice Chair
Rebecca Parkin, PhD, MPH, Associate Dean for Research and Public Health Practice, School of
Public Health and Human Services, The George Washington University, Washington, DC
Members
Janice Chambers, PhD, DABT, William L. Giles Distinguished Professor, Director, Center for
Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University,
Mississippi State, MS
Suzanne C. Fitzpatrick, PhD, DABT, Senior Science Policy Analyst, Office of the
Commissioner, Office of Science and Health Coordination, US Food and Drug Administration,
Rockville, MD *
Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University,
Manhattan, KS
Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of
Arizona, Tucson, AZ
Lois D. Lehman-Mckeeman, PhD, Distinguished Research Fellow, Discovery Toxicology,
Bristol-Myers Squibb Company, Princeton, NJ
Jerry A. Menikoff, MD, JD, Director, Office of Human Subjects Research, Office of the
Director, National Institutes of Health, Bethesda, MD
Ernest D. Prentice, PhD, Associate Vice Chancellor for Academic Affairs, University of
Nebraska Medical Center, Omaha, NE *
Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural
Sciences, University of Florida, Gainesville, FL
Consultants to the Human Studies Review Board
Sidney Green, Jr., PhD, Fellow, ATS, Professor, Department of Pharmacology, Howard
University College of Medicine, Washington, DC
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Alan Meisel, JD, Dickie, McCamey and Chilcote Professor of Bioethics, Professor of Law and
Psychiatry, University of Pittsburgh School of Law, Pittsburgh, PA
Martin A. Philbert, PhD, Director, Center for Risk Science and Communications, University of
Michigan School of Public Health, Ann Arbor, MI
William Popendorf, PhD,MPH, Professor, Department of Biology, Utah State University,
Logan, UT
Lianne (Elizabeth A.) Sheppard, PhD, Professor, Department of Biostatistics, University of
Washington, Seattle, WA
Human Studies Review Board Staff
Paul I. Lewis, PhD, Executive Director, Human Studies Review Board Staff, Office of the
Science Advisor, United States Environmental Protection Agency, Washington, DC
* Not in attendance at June 24-25, 2009 Public Meeting
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INTRODUCTION
From June 24-25, 2009, the United States Environmental Protection Agency’s (EPA or
Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues
concerning: three completed human toxicity studies involving one pesticide active ingredient —
chiorpyrifos — conducted prior to publication of the EPA’s expanded final rule for protection of
subjects in human research; and one completed study involving one insect repellent active
ingredient — picaridin — conducted after promulgation of the EPA’s expanded final human
studies rule. In accordance with 40 CFR 26.1602, EPA sought HSRB review of these completed
studies. Each of these studies is discussed more frilly below.
In addition, the Agency submitted two protocols for conducting new research involving
human participants: one study measuring the efficacy of two registered insect repellents
containing picaridin against biting flies under field conditions; and one study measuring levels of
exposure received by agricultural handlers when mixing and loading pesticides using water-
soluble packing under various conditions. In accordance with 40 CFR 26.1601, EPA sought
HSRB review of these proposed protocols. Each of these studies are also is discussed more fully
below.
REVIEW PROCESS
On June 24-25, 2009, the Board had 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” (74 Federal Register 106, 26861).
During the public meeting, following welcoming remarks from Agency officials, the
Board heard presentations from the Agency on the following topics: three completed studies
involving intentional human exposure to the organophosphate pesticide chiorpyrifos (Nolan et al.
(1982), Honeycutt and DeGeare (1993), and Kisicki eta!. (1999)); a completed ICR, Inc., (ICR)
insect repellent efficacy study (ICR A382); a proposed Carroll-Loye Biological Research, Inc.
(CLBR) insect repellent efficacy study (LNX-002); and a proposed Agricultural Handler
Exposure Task Force, LLC (AHETF) water-soluble packing mixing and loading scenario and
protocol (AHE- 120).
The Board also asked clarifying questions of several study sponsors andlor research
investigators, including:
Dr. Craig Barrow, Consultant to Dow AgroSciences
Dr. Victor Canez, Technical Chair, Agricultural Handler Exposure Task Force
Dr. Scott Carroll, Principal, Carroll-Loye Biological Research
Dr. Richard H. Collier, Administrative Committee Chair, Agricultural Handler Exposure
Task Force
Mr. Bill Gaynor, Staff Member, ICR
Mr. Shawn King, Director of Operations, Carroll-Loye Biological Research
Dr. Ralph Piedmont, Consultant to ICR
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Dr. Ken Racke, Regulatory Specialist, Dow AgroSciences
Dr. Ghona Sangha, Toxicology and Regulatory Consultant, LANXESS Corp.
Oral comments were provided by:
Dr. Ghona Sangha, Toxicology and Regulatory Consultant, LANXESS Corp.
No written public comments were provided.
For their deliberations, the Board considered the materials presented at the meeting, oral
comments, and Agency background documents (e.g., published literature, sponsor and
investigator research reports, study protocols, data evaluation records, and Agency science and
ethics reviews of proposed protocols and completed studies). A comprehensive list of
background documents is available online at http://www.regulations.gov.
CHARGE TO TILE BOARD AND BOARD RESPONSE
Assessment of Completed Research Study MRID 124144: Nolan et al. (1982’ Chiorpyrifos:
Pharmacokinetics in Human Volunteers Followina Sin2le Oral and Dermal Doses .
Overview of the Study
The HSRB reviewed Nolan et al. (1982) as part of a package of three studies involving
human volunteers exposed to chlorpyrifos that were proposed for use by EPA to characterize and
help interpret epidemiological and bio-monitoring data for this pesticide. In addition, the data
from human participants might be used for setting bounding estimates and developing
physiologically based pharmacokinetic (PBPK) models for chiorpyrifos.
Nolan eta!. (1982) summarize the results of a single dose level study that was designed
to compare the fate of chlorpyrifos when administered orally or dermally to humans.
Chiorpyrifos is a highly lipophilic compound that is rapidly metabolized to 3,5,6-trichloro-2-
pyridinol (TCP) and diethyithiophosphate. TCP is excreted in urine predominantly as a
glucuronide conjugate. Blood and urine levels of chiorpyrifos and TCP (unconjugated) were
determined after oral (0.5 mg/kg) or dermal (5 mg/kg) administration of chiorpyrifos.
There were a total of six participants in the Nolan eta!. (1982) study, with one participant
(“subject A’) included in the evaluation of the fate of chiorpyrifos after oral dosing. However,
this participant received dernial dosages of chlorpyrifos at 0.5 mg/kg in a preliminary evaluation
and was not used in the final analyses of the dermal fate of chlorpyrifos (n =5 for the dermal
study). Based on the urinary excretion of TCP, it was estimated that approximately 70% of the
orally administered dose of chiorpyrifos was absorbed, whereas less than 3% of the dose was
absorbed after dermal application.
Science
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Although presented separately, the same scientific criteria were used to assess the
reliability of the data from all three chiorpyrifos studies. These criteria are:
1. Verification that the administered dose of chiorpyrifos was confirmed in the study;
2. Assurance that sample collection (blood and urine) was reliable and complete;
3. Validation and appropriateness of the analytical methods for quantification of
chlorpyrifos and TCP in blood and urine; and
4. Evaluation of the cholinesterase inhibition data (plasma and/or RBC cholinesterase)
for sensitivity, accuracy, reproducibility, timing of sample collection and proper
sample handling for analysis.
Along with other relevant study issues, an assessment of how the Nolan et al. (1982), as well
as the other two chlorpyrifos studies presented, met these general criteria along with other
relevant study issues are summarized in responses to the Agency’s charge questions below.
Charge to the Board
Are the blood and urine measurements of chlorpyrifos and/or TCP from the Nolan et al.
(1982) oral and dermal studies reliable?
Board Response to the Charge
HSRB Recommendation
The Board concluded that data measuring chlorpyrifos at the limit of detection in blood
and urine are not useful. The measurements of TCP in urine are generally reliable. It is unclear if
the measurement of TCP in blood is useful because of concerns about the ability of the methods
used to detect the appropriate TCP conjugate.
HSRB Detailed Recommendations and Rationale
Since blood and urinary concentrations of chlorpyrifos were essentially non-detectable,
there is little confidence in these data. However, urinary levels of TCP, determined after
hydrolysis of the glucuronide conjugate, were well above the limit of detection. Additionally, the
data suggest relatively high absorption of chlorpyrifos from oral dosing and considerably less
exposure from the dermal route, a pattern that is biologically plausible. It is not clear whether
the blood levels of TCP are accurate because the extent to which the glucuronide conjugate of
TCP circulates in the blood and the extent to which the glucuronide conjugate may be detected in
blood. Confirmation of how the blood samples were handled for analysis may help to increase
the confidence in the reported blood concentrations of TCP.
Charge to the Board
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Are the measurements of cholinesterase activity/inhibition from the Nolan eta!. (1982)
oral and dermal studies reliable?
Board Response to the Charge
HSRB Recommendation
The HSRB expressed some concern over the variability of the erythrocyte cholinesterase
activity data and the lack of a control group, but concluded that measurements of cholinesterase
activity/inhibition from Nolan eta!. (1982) were likely to be reliable.
HSRB Detailed Recommendations and Rationale
A major issue with determination of cholinesterase activity is the inter-day and inter-
assay variability (typically 10-15%) that may be observed. In the Nolan eta!. (1982) study,
plasma cholinesterase showed marked inhibition (up to approximately 85%) after oral
administration of chlorpyrifos, whereas less plasma cholinesterase inhibition was noted after
dermal application (up to about 25%). In contrast, no inhibition of erythrocyte cholinesterase
was observed with either route of administration.
The HSRB considered the following limitations or weaknesses of the cholinesterase
measurements in Nolan et al. (1982):
1. There was no untreated group to control for inter-day laboratory variations; the
subject’s response was based only on a change from their own pretest samples.
2. The inter-day variability for each subject was high, particularly for the erythrocyte
cholinesterase activity, thereby limiting the interpretation of the results.
3. Although the method used to measure cholinesterase activity (the micro-Michel
method) is an older method, it was probably the most reliable at the time.
4. Since only a single dose level was evaluated, no dose-response data are available
from this study.
Nevertheless, the results demonstrated that oral administration of chlorpyrifos caused
greater inhibition of plasma cholinesterase than that observed after dermal application, a result
that is consistent with higher absorption of chlorpyrifos following oral dosing.
Ethics
Charge to the Board
Is there clear and convincing evidence that the conduct of the Nolan eta!. (1982) study
was ftrndamentally unethical, or significantly deficient relative to the standards of ethical
research conduct prevailing when it was conducted?
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Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Carley 2009a) that there neither
was clear and convincing evidence that the study was fundamentally unethical, nor clear and
convincing evidence that the study was significantly deficient relative to the ethical standards
prevailing at the time the research was conducted.
HSRB Detailed Recommendations and Rationale
Given that the Nolan et al. study was conducted in 1981 and 1982, the Board concurred
with the Agency’s assessment that the applicable regulatory standard at that time was FIFRA
§12(a)(2)(P). In response to questions from the Agency, the study sponsor indicated that
participants signed a one-page consent form that gave few details about the study but affirmed
that they had read the study protocol (Dow AgroSciences 2009a). There had been two ethical
reviews of this protocol, one by the Dow Human Health Research Committee, and a second by
the University of Michigan Ethical Review Committee (The Committee to Review Grants for
Clinical Research and Investigation Involving Human Beings).
1. The Board concurred with the conclusions and factual observations of the ethical strengths
and weaknesses of the study, as detailed in the Agency’s Ethics Review (Carley 2009a).
2. The Board concluded that this study met all applicable ethical requirements for such research
involving human participants, in accordance with the following criteria:
a. Not fundamentally unethical. With regard to determining whether or not a study is
fundamentally unethical, the Board’s standard is to decide if the research was intended to
seriously harm participants, or if it failed to obtain informed consent, or if it was
fundamentally unethical for other reasons.
The study was not intended to seriously harm participants. Voluntary informed
consent of participants was obtained. Given that there does not appear to be clear and
convincing evidence that for any other reasons it might have been fundamentally
unethical, the Board concludes that it was not fundamentally unethical.
b. Not sign flcantly deficient. With regard to determining whether a study was significantly
deficient relative to the ethical standards prevailing at the time the research was
conducted, the Board’s standard is to determine whether or not any ethical deficiencies
identified could have resulted in serious harm based on knowledge available to
researchers at the time the study was conducted, or whether the information provided to
study participants could seriously impair informed consent.
• Based on toxicological data that was available at the time for chlorpyrifos, study
participants were unlikely to be at risk for serious side effects given the exposure dose
used in this study.
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• The Board did not have a copy of the protocol that was given to the prospective
participants when obtaining their informed consent, so the HSRB did not know
exactly what information the participants received. Given that the study was reviewed
by two ethics review boards, however, the Board concluded that there was no clear
and convincing evidence that the information provided to participants could seriously
impair informed consent. With regard to studies that were conducted prior to the
effective date of the Agency’s regulations, the Board does wish to convey to the
Agency the importance of obtaining as much information about such studies as is
reasonably possible. It would have been desirable for the Board to have had access to
the actual study protocol.
Assessment of Completed Research Study MilD 42062701: Honeycutt and DeGeare ( 1993)
Worker Reentry Exposure to Chiorpyrifos in Citrus Treated with Lorsban* 4E Insecticide .
Overview of the Study
The study reported by Honeycutt and DeGeare (1993) was a biological monitoring study
to determine potential exposure to chiorpyrifos in individuals who reenter a citrus grove after
agricultural use of chlorpyrifos. There were 15 participants in the study, representing five citrus
pickers and ten citrus pruners (five each in wet and dry conditions, respectively). Pickers entered
the test site 43 days after application of chlorpyrifos, whereas pruners re-entered two days after
the application of chlorpyrifos. The exposure period was 5-6 hours, and the assessment of
chlorpyrifos exposure was achieved with whole body dosimeters, air sampling, leaf punches and
quantification of urinary excretion of TCP. The results from Nolan et all (1982) justify
monitoring urinary TCP to estimate chlorpyrifos exposure. The report included considerable
emphasis on the handling of all samples in the field and a comprehensive summary of all
analytical conditions and methods used in determining ch lorpyrifos in all study matrices.
Both chiorpyrifos and TCP were analyzed with negative ion-chemical ionization gas
chromatography with mass selective detection (GCIMS) and urinary TCP was quantified after
acid hydrolysis employing concentrated hydrochloric acid with heating for 1-2 hr followed by
derivitization with N-methy1-(N-tertbutyldimethyL ilyl)-trifloroacetamide. Analytical recoveries
were reported, and the limit of detection was defined as three-times higher than the signal to
noise ratio. No limit of quantitation (LOQ) was provided.
Science
Charge to the Board
Are the blood and urine measurements of chiorpyrifos and/or TCP from the Honeycutt
and DeGeare (1993) worker biomonitoring study reliable?
Board Response to the Charge
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HSRB Recommendation
The Board concluded that the data from Honeycutt and DeGeare (1993) are likely
reliable but of limited value. Board members expressed concerns about: 1) the small sample
size; 2) the background chiorpyrifos exposure not being properly accounted for; 3) the likely
incompleteness of urine collection; and 4) the high degree of variation seen in the daily
measurements.
HSRB Detailed Recommendations and Rationale
Relevant weaknesses or limitations concerning study conduct and data reported by
Honeycutt and DeGeare (1993) were assessed as follows:
1. The strength of this study is that it provides data on real-world exposures to
chiorpyrifos. However, the critical element regarding confirmation of the dosage was
not achieved in this study because the purpose of this study was to actually determine
the dosage.
2. Urine samples were collected for 24 hrs prior to reentry and across 12-hr time
intervals for up to five days after completion of the 5-6 hr work period. However,
there is evidence to suggest that urine collections were not complete. This conclusion
was based on variability in total urinary creatinine excretion along with several
instances in which incomplete sample collection was noted. In total, five of 15
participants had total urinary creatinine levels that were significantly below normal
daily reference range for creatinine excretion. In addition, for nine of 15 study
participants the coefficient of variability exceeded reported urinary creatinine levels
by up to four-fold, suggesting that urine collection was inconsistent at best. In light of
these discrepancies, efforts were made to normalize urinary excretion data to a
population average for creatinine excretion, but the accuracy and validity of this
calculation is unknown, as discussed further below.
3. The control of the participants both prior to and after completion of the exposure was
inadequate. One worker (Pruner 9) showed maximum urinary TCP levels on day
three of the study suggesting additional exposure to chiorpyrifos after the test
exposure period. More importantly, several workers showed detectable levels of
urinary TCP in pretest samples, which was suggested to represent a steady state level
of TCP resulting from occupational exposure. However, the validity of this
conclusion is unknown, and the possibility that the observed levels may have resulted
from a more recent exposure to chlorpyrifos was not considered.
4. In light of the uncertainties regarding urine sample collection and subject control,
urinary TCP, and hence exposure to chiorpyrifos, were determined using six different
methods including no corrections, correction for background TCP excretion,
correction for creatinine excretion and combinations of corrections for background
and creatinine levels. Across the six different methods used, the range of urinary
TCP concentrations was about two-fold for pickers and four-fold for pruners. In
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addition to the range of urinary TCP concentrations and the uncertainty regarding
which method is most accurate, the small sample size (n = 5 participants per scenario)
decreases the confidence of the final reported values.
Thus, although this study provides the potential for assessing chiorpyrifos exposure from
a relevant occupational exposure, the uncertainty resulting from incomplete urine sample
collection, background exposure to chiorpyrifos, the small sample size, inter-individual and
inter-day variability and the use of six different calculations to estimate chiorpyrifos exposure
undermine confidence in the reliability of the data.
Charge to the Board
Are the measurements of cholinesterase activity/inhibition from the Honeycutt and
DeGeare (1993) worker biomonitoring study reliable?
Board Response to the Charge
HSRB Recommendation
The Board concluded that the laboratory data are likely accurate and reliable but raised
concerns about their utility. Some of the Board’s concerns included: 1) the lack of an untreated
control group; 2) the reliance on a single post-exposure time point; 3) the small sample size; and
4) the dose received by the subjects varied and was only estimated from dermal dosimetry.
HSRB Detailed Recommendations and Rationale
Plasma and blood cholinesterase activities were determined pre-exposure (typically 2
occasions prior to exposure) and 24 hr after working in the citrus grove. The modified Eliman
procedure was used to determine cholinesterase activities. Overall, no significant changes in
plasma or erythrocyte cholinesterase activities were observed. The following limitations
concerning plasma and erythrocyte cholinesterase activities reported by Honeycutt and DeGeare
(1993) were identified:
1. Only one post-exposure sample was collected for analysis (24 hr). Additional
sampling would have been helpful, as it is not clear whether the 24 hr time point was
most appropriate for analysis.
2. Considerable variability was noted across the samples. In six of the workers, the two
pre-dose measurements were not within 15% of each other, thereby confounding the
accuracy of the baseline activities, and in three of the pruners, post-exposure
erythrocyte cholinesterase levels were actually increased by more than 20% over
baseline values. Collectively, there is considerable uncertainty in the baseline data.
3. No data from an unexposed group of control subjects was used to control for inter-
day variability in the assay. It was noted that the practice of including laboratory
controls for intra-assay variability is published, standard practice for this assay.
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4. The small group size further confounds the interpretation of the highly variable
results.
Thus, the HSRB concluded that the experimental evidence suggesting that plasma and
erythrocyte cholinesterase activities were not significantly altered in the pickers and pruners
exposed to chiorpyrifos in this study were likely to be accurate. However, the Board also
cautioned that the reliability of the data was limited because of the issues noted above including
analysis at only a single time point after exposure, the small sample size, the high degree of
intra- and inter-subject variability and the lack of an untreated control.
Ethics
Charge to the Board
is there clear and convincing evidence that the conduct of the Honeycutt and DeGeare
(1993) study was fundamentally unethical, or significantly deficient relative to the standards of
ethical research conduct prevailing when it was conducted?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Carley 2009b) that there neither
was clear and convincing evidence that the study was fundamentally unethical, nor clear and
convincing evidence that the study was significantly deficient relative to the ethical standards
prevailing at the time the research was conducted.
HSRB Detailed Recommendations and Rationale
This study was initiated in 1991 in California. As a result, it was subject to the
California Code of Regulations, Title 3, Section 6710, as amended September 26, 1988, which
required pre-approval of the study by the Director of the California Department of Pesticide
Registration, and by an Institutional Review Board approved by the US Department of Health
and Human Services. It was also subject to FIFRA § 12(a)(2)(P). The study was reviewed and
approved by the Committee on Human Subjects Research at the University of California, San
Francisco.
1. The Board concurred with the conclusions and factual observations of the ethical strengths
and weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley 2009b).
2. The Board concluded that this study met all applicable ethical requirements for such research
involving human participants, in accordance to the following criteria:
a. Not fundamentally unethical. With regard to determining whether or not a study is
fundamentally unethical, the Board’s standard is to decide if the research was intended to
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seriously harm participants, or if it failed to obtain informed consent, or if it was
fundamentally unethical for other reasons.
The study was not intended to seriously harm participants. Voluntary informed
consent of participants was obtained. Given that there does not appear to be clear and
convincing evidence that for any other reasons it might have been fundamentally
unethical, the Board concludes that it was not fundamentally unethical.
b. Not sign j/Icantly deficient. With regard to determining whether a study was significantly
deficient relative to the ethical standards prevailing at the time the research was
conducted, the Board’s standard is to determine whether or not any ethical deficiencies
identified could have resulted in serious harm based on knowledge available to
researchers at the time the study was conducted, or whether the information provided to
study participants could seriously impair informed consent.
• Based on toxicological data that was available at the time for chlorpyrifos, study
participants were unlikely to be at risk for serious side effects given the exposure dose
used in this study.
• Exposure took place while participants were performing activities that were the same
as those they regularly performed as part of their usual employment as citrus workers.
Accordingly, it does not appear that there were ethical deficiencies that could have
resulted in serious harm.
• The volunteers were briefed about the design of the study and the risks relating to
participation, and they signed consent forms containing that information. As the
Agency noted (Carley 2009b), there was misleading information in some of the
forms, such as comments that the residue from the spraying of the pesticide would
have disappeared by the time they entered the groves. That misinformation was
certainly inappropriate but does not, in and of itself, provide clear and convincing
evidence that the informed consent process was seriously impaired.
• The study participants were employed by Mr. Gary Austin of Leffingwell Ag Sales
Co., and he recruited them himself. It is unclear to what extent these participants
might therefore have been vulnerable to his influence in deciding to enter the study.
Nonetheless, this type of arrangement does not appear to be unusual at that time.
• The privacy of participants was compromised by the fact that their full names and
Social Security numbers were included in an appendix to the study report. This is
inappropriate, but would not appear to constitute clear and convincing evidence of an
ethical deficiency that resulted in serious harm to these participants.
Assessment of Comr,leted Research Study MRID 44811002: Kisicki Ct a!. (1999) A Rising
Dose Toxicolo2v Study to Determine the No-Observable Effect-Levels (NOEL) For
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Erythrocytes Acetvlcholinesterase ( AChE) Inhibition and Cholineraic Signs and Symptoms
of Chiorpyrifos at Three Dose Levels .
Overview of the Study
This study was a double blind, randomized and placebo-controlled rising dose study
designed to determine the no-observable effect level (NOEL) for inhibition of erythrocyte
acetyicholinesterase in human volunteers. The dosages used in the study were 0.5, 1 and 2
mg/kg, with the starting dose of 0.5 mg/kg based on the results of Nolan eta!. (1982) discussed
previously. In addition to assessing cholinesterase activity, blood and urine were collected and
analyzed for chlorpyrifos and TCP to help define the pharmacokinetic properties in humans.
Finally, paraoxonase status of each subject was determined (but will not be discussed here).
Chlorpyrifos was administered orally in a gelatin capsule with 0 (lactose), 0.5 and I mg
chlorpyrifos/kg administered in Phase I of the study followed by a second phase that include 0
(control) and 2 mg/kg dosages. There were six male and six female participants for each dose
level. Subjects were confined to the testing facility overnight prior to treatment through the first
48 hr after dosing. Additional samples were collected thereafter at 24 hr intervals through 168 hr
(one week) post dosing. Blood, collected pre-dose (-10 and 0 hr) and at 2, 4, 8, 24, 36, 48, 72,
96, 120, 144 and 168 hr post treatment, was used for determining erythrocyte
acetyicholinesterase activity and chiorpyrifos and TCP levels. Voided urine was collected at 12
hr intervals starting 48 hr prior to dosing and through the 168 hr dosing period (with the
exception that immediately after dosing urine was collected at 0-6 and 6-12 hr).
Science
Charge to the Board
Are the blood and urine measurements of chiorpyrifos and/or TCP from the Kisicki eta!.
(1999) oral study reliable and appropriate for use in characterizing the results of epidemiological
studies with chiorpyrifos?
Board Response to the Charge
HSRB Recommendation
Because of concerns about the analytic procedures’ potential inability to control for the
glucuronide-conjugated TCP, and apparent discrepancies in the absorption data when compared
with the data from Nolan eta!. (1982), the Board questioned the reliability and utility of the
blood and urine measurements of chlorpyrifos and/or TCP from Kisicki eta!. (1999) for risk
assessment purposes.
HSRB Detailed Recommendations and Rationale
With respect to the general elements considered in the evaluation of the scientific
reliability of the chiorpyrifos exposure data, this study provided clear documentation of the
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administered dose. Chiorpyrifos was added to a gelatin capsule normalized with lactose powder
and the weight of the filled capsule was determined. There was one noted discrepancy that one
participants in the 2 mg/kg dose group may have received a lower dose (1.63 mg/kg) based on
conflicting data on body weight and administered dose data, but overall the documentation of the
administered dose was satisfactory.
There was also generally good reliability with respect to sample collections. Participants
remained in the testing facility for the first 48 hrs after dosing and 48 of the 60 subjects provided
all periodic urine samples. - Urine collections were judged to be complete based on creatinine
excretion for 19 of the 60 subjects. One participant in the 2-mg/kg-dose group failed to return for
sample collection and clinical monitoring after the initial 48 hr post-dosing period.
Chlorpyrifos and TCP were measured in blood and urine with GCIMS detection, and
TCP was derivatized with N-methyl-(N-tertbutyldimethylsilyl)-trifloroacetamide. In general,
these methods were similar to those described by Honeycutt and DeGeare with the exception that
stable labels of chiorpyrifos and TCP (13C and/or 15N-labeled) were used as internal standards
in the present analyses.
In reviewing this study, the HSRB identified several limitations or issues that may impact
the overall reliability of the data. These included:
1. The amount of chiorpyrifos absorbed after oral administration in the present study
was markedly lower than that reported by Nolan et al. (1982). A dose of 0.5 mg/kg
was common to both studies, with Nolan et al. reporting approximately 70%, and
Kisicki et a!. reporting approximately 35% absorbed. The rationale provided by the
authors for this large difference was that chlorpyrifos was administered using lactose
tablets and gelatin capsules in the Nolan et al. and Kisicki et a!. studies, respectively.
Kisicki et al. suggested that oral absorption is slowed by the dissolution of the gelatin
capsule with a concurrent reduction in the total amount absorbed. Although the
Board agreed that absorption of chlorpyrifos from the gelatin capsule might be slower
than that from a lactose tablet, there was some skepticism that the difference in
dosage form would yield the large discrepancy in total percent absorbed in the two
studies.
2. In the methodological details provided for the analysis of urinary levels of TCP, there
was no indication that urine samples were subjected to acid hydrolysis required to
liberate the glucuronide conjugate of TCP, which is the major urinary metabolite of
chlorpyrifos. This is an important distinction, as both Nolan et al. (1982) and
Honeycutt and DeGeare (1993) indicated that urine samples were treated with
concentrated sulfuric or hydrochloric acid and heated in order to hydrolyze the
glucuronide conjugate and liberate TCP which is then derivatized (in the methods
used by Honeycutt and DeGeare and Kisicki et a!.). In the analytical portion of the
Kisicki et a!. study (Brzak 2000), there is a clear designation that blood samples were
treated with concentrated hydrochloric acid prior to extraction, but no similar details
are provided for the analysis of the urine samples. Although it seems unlikely that
this important (and necessary) step was omitted, the lack of explicit indication of this
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critical analytical step raises some doubt that it was done. If urine samples were not
properly hydrolyzed prior to analysis, then the validity and reliability of these data are
uncertain. Furthermore, since urinary TCP is used to estimate oral absorption of
chloipyrifos, it is possible that differences in sample handling may explain or at least
contribute to the lower percent absorption reported by Kisicki et a!.
3. The total mass balance (total recovery of the administered chlorpyrifos) was not
determined. Inclusion of total recovery could increase the confidence in the estimated
percent of absorption in the study and possibly clarify whether there was an issue
with the TCP analysis conducted by Kisicki et a!.
4. There were several questions regarding the designation and use of alternate
participants in the study. The basis for participant replacement and verification of
body weight and dose administered to the alternate participants were not adequately
provided.
Because of concerns about the analytic procedures’ potential inability to control for the
glucuronide-conjugated TCP, and apparent discrepancies in the absorption data when compared
with the data from Nolan et al. (1982), the Board thus questioned the reliability and utility of the
blood and urine measurements of chlorpyrifos and/or TCP from Kisicki eta!. (1999) for risk
assessment purposes.
Charge to the Board
Are the measurements of cholinesterase activity/inhibition from the Kisicki et al. (1999)
oral study reliable?
Board Response to the Charge
HSRB Recommendation
The Board concluded that these measurements likely represent a reliable set of data, but
cautioned the Agency about relying on data from the incomplete profile for the one responder at
the highest dose level. The Board also cautioned against relying on the statistical analyses as
presented in the report.
HSRB Detailed Recommendations and Rationale
In this study, erythrocyte acetylcholinesterase activities were determined pre-dose (2
samples) and 2,4, 8, 12, 24, 36, 48, 72, 96, 120, 144 and 168 after dosing (Ellman method).
Plasma cholinesterase activity was not measured. The results showed a relatively high degree of
variability, and samples collected at 96 hr (Phase I; 0, 0.5 and 1 mg/kg) were judged to be low
relative to all other treatment times. One participant in the 1-mg/kg dose group showed a 24.5%
decrease in activity at the 96 hr time point. However, given the decreased activity observed in
the entire group of samples collected at 96 hr along with the fact that peak inhibition would be
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expected to occur before 96 hr, this result was not considered to be a real finding. Only one
participant in the 2-mg/kg-dose group showed a reduction in erythrocyte cholinesterase activity
in the study, with a nadir (72% of her baseline level) observed 12 hr after treatment. However,
this volunteer did not return for blood collections after the initial 48 hr period, resulting in an
incomplete profile. This participant did not appear to show adverse clinical signs associated with
cholinesterase inhibition. Based on the reduction in erythrocyte cholinesterase activity in this
subject, the NOEL for enzyme inhibition was considered to be 1 mg/kg.
In reviewing this study, the Board identified several limitations or issues that may impact
the overall reliability of the data. These included:
1. There was generally poor documentation provided for the grouping or batch
processing of the blood samples. Given the recognized inter-day and inter-assay
variability associated with the Eliman method, this is a critical weakness. The study
records were noted to be insufficient to confirm that samples were batched correctly
to allow the proper utilization of the unexposed control data to correct for day-to-day
or batch-to-batch variations in the mean lab results. This limitation is particularly
important to detect or to quantify accurately small changes within an exposed
population.
2. The interpretation of the results is centered on the single individual who showed more
than a 25% inhibition of erythrocyte cholinesterase activity at the 2-mg/kg-dose level.
The conclusions regarding both the duration and magnitude of inhibition depend upon
the inclusion of this participant, and the lack of follow-up in this participant beyond
48 hr thereby limits the interpretation of the results.
3. The reported statistical analyses of these data are highly problematic, and the results
in Appendix 3 were judged to be clearly wrong. Specifically, it was noted that a
univariate repeated measures ANOVA was performed (Kisicki eta!. 1999, 25), and
Appendix 3 summarizes the results of such analyses (Kisicki et a!. 1999, 151-158,
184-188, 206-2 1 1). Although it is not possible to replicate these analyses, the report
suggests that the variable being analyzed is the Normalized Percent of Baseline
(Kisicki et a!. 1999, 24). The report indicates that the Group Mean Square (Kisicki et
a!. 1999, 157) is 19.1207 while the Error Mean Square is 52,835,395,914.644. It is
virtually impossible that these two values can be this different for real data.
Furthermore, the corresponding Individual Hour Error Mean Squares from the
corresponding mixed model analysis range from about 14.39 to 48.26. These are
much more reasonable values. The report (Kisicki et a!. 1999, 25) also indicates that
mixed effects models were used where gender and treatment were considered to be
fixed factors, and that time was considered to be a random continuous covariate.
According to the mixed model analyses reported in Appendix 3, time is treated as a
continuous covariate, but not as a random continuous covariate. Overall, the Board
concluded that the statistical analyses are likely incorrect, and there should be some
effort to perform correct analyses before relying on these data.
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4. Plasma cholinesterase activity was not determined in the study. It is recognized that
the erythrocyte cholinesterase activity is more biologically relevant for assessing
potential adverse effect of chiorpyrifos, and as such, the lack of data on plasma
cholinesterase is not a serious limitation. However, given the issues raised
concerning sample handling, batch processing and statistical evaluations, inclusion of
plasma cholinesterase may have helped to assess the overall reliability of the data.
The Board thus concluded that the measurements of erythrocyte acetylcholinesterase
activities were generally reliable. However, Board members cautioned that the incomplete
profile obtained from the only subject who showed inhibition at the 2 rn/kg dose level limited the
utility of the data. Moreover, the Board recommended that, although the data might be reliable,
the statistical analyses in general and particularly for the data in Appendix 3 should be replicated
prior to applying these results to any risk assessment or model development.
Ethics
Charge to the Board
Is there clear and convincing evidence that the conduct of the Kisicki eta!. (1999) study
was fundamentally unethical, or significantly deficient relative to the standards of ethical
research conduct prevailing when it was conducted?
Board Response to the Charge
HSRB Recommendation
The Board concluded that there neither was clear and convincing evidence that the
study was fundamentally unethical, nor clear and convincing evidence that the study was
significantly deficient relative to the ethical standards prevailing at the time the research was
conducted.
HSRB Detailed Recommendations and Rationale
According to documents supplied by the sponsor (Juberg and Mattsson 2009a, Juberg
and Mattsson 2009b), the study was conducted in accordance with US Food and Drug
Administration rules relating to the protection of human subjects, as codified at 21 CFR parts 50
and 56, and in accordance with the International Guidelines for Human Testing promulgated in
the Declaration of Helsinki (as amended in 1996). In addition, the study was subject to FIFRA
§ 12(a)(2)(P). The protocol and related study documents were reviewed and approved by the
MDS Harris Institutional Review Board. The consent of all participants was obtained and
documented through the use of a consent form approved by that IRB.
1. The Board concurred with most of the conclusions and factual observations of the ethical
strengths and weaknesses of the study, as detailed in the EPA’s initial Ethics Review (Carley
2009c). The Board disagreed, however, with the Agency’s initial conclusion that the study
was significantly deficient relative to the ethical standards prevailing at the time the research
was conducted. After considering additional supplementary information provided to the
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Agency on June 23, 2009 and described in detail below (Kisicki 2009), the Board found no
clear and convincing evidence that the study was fundamentally unethical or significantly
deficient in its design and conduct. Following the public meeting, additional supplementary
material (including copies of MDS Harris Laboratories screening and consent logs) was
submitted to the Agency for review. Although the Board shares the Agency’s concerns that
these supplementary documents still raise concerns about the recruitment and consent
process (Carley 2009e), the information contained therein do not meet the evidentiary
standard of clear and convincing evidence that the study was fundamentally unethical or
significantly deficient relative to the ethical standards prevailing at the time. It is possible, for
example, that the deficiencies noted in the logs are the result of sloppy record keeping rather
than a serious impaired participant recruitment, consent and screening process.
2. The Board concluded that this study met all applicable ethical requirements for such research
involving human participants, in accordance to the following criteria:
a. Not fundamentally unethical. With regard to determining whether or not a study is
fundamentally unethical, the Board’s standard is to decide if the research was intended to
seriously harm participants, or if it failed’to obtain informed consent, or if it was
fundamentally unethical for other reasons.
The study was not intended to seriously harm participants. Voluntary informed
consent of participants was obtained. Given that there does not appear to be clear and
convincing evidence that for any other reasons it might have been fundamentally
unethical, the Board concludes that it was not fundamentally unethical.
b. Not sign j/Icantly deficient. With regard to determining whether a study was significantly
deficient relative to the ethical standards prevailing at the time the research was -
conducted, the Board’s standard is to determine whether or not any ethical deficiencies
identified could have resulted in serious harm based on knowledge available to
researchers at the time the study was conducted, or whether the information provided to
study participants could seriously impair informed consent.
• Based on toxicological data that was available at the time for chlorpyrifos, study
participants were unlikely to be at risk for serious side effects given the exposure dose
used in this study.
• Participants underwent some screening tests (urine and blood sampling) prior to
signing the written consent form. According to materials provided to the EPA and
made public on the day of the Board’s discussion of this study (Kisicki 2009),
volunteers were given a copy of the approved consent form and required to listen to
an audiotape about the study before they agreed to undergo the screening procedures.
Later documents submitted to the Agency (Radke 2009), however, raise questions as
to whether all potential study participants or alternates underwent voluntary informed
consent prior to screening. Although the failure to have potential participants and
alternates sign an informed consent form prior to screening could be a violation of
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applicable FDA regulations, given these circumstances it does not appear that the
informed consent process was serious impaired.
• There were various sentences in the informed consent form that appear inappropriate,
such as characterizing the study compound as one that improves performance on tests
of mental functioning. In addition, portions of that form were written at an
inappropriately high reading level. Taken as a whole, however, the informed consent
document does appear to have provided prospective subjects with an accurate and
understandable picture of the likely risks from participation — which were very low.
Thus, it does not appear that the form, as written, seriously impaired the informed
consent process.
Assessment of Completed Research Study MRID 47732701: ICR . Inc. Study A382 —
Evaluation of the Efficacy of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect
Repellents (20% Cream and 20% S rav) Against Stable Flies in the Laboratory .
Overview of the Study
A382 was a laboratory study conducted by ICR to assess the efficacy of two formulations
containing the repellent picaridin against laboratory-reared stable flies. The study followed the
protocol previously reviewed by the HSRB and recommended for acceptance with some
suggested modifications.
The study used a dosimetry phase for dose determination. The initial study had to be
aborted because the stable flies did not show sufficient biting pressure for a valid repellency test.
Adjustments were subsequently made in the husbandry of the flies to insure that they were
sufficiently hungry to bite the test subjects in the testing period, and the data from the second
test, along with the dosimetry results, were presented. Complete protection times were
calculated.
Science
Charge to the Board
Is the ICR study A382 sufficiently sound, from a scientific perspective, to be used to
assess the repellent efficacy of the tested formulations against stable flies in the laboratory?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Sweeney 2009) that this study
provides scientifically valid results to assess the repellent efficacy against stable flies of the
formulations tested. However, some of the data presentation requires revision.
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HSRB Detailed Recommendations and Rationale
ICR was responsive to Board concerns and recommendations of the previous Board
review (EPA HSRB 2008). These responses included the use of a dosimetry phase for dose
determination and the inclusion of individuals from racial minorities in the test population. The
study also used the time to first bite as the criterion, and not the time to first confirmed bite,
which was also a Board recommendation for participant protection. The study included 12
participants (seven females and five males). One female participant served as an untreated
control to verify landing pressure. The total number of study participants is higher than the EPA
guidelines recommend. Study documents (Gaynor 2009, Gaynor et al. 2009) indicated that,
according to ICR’s database, landings underestimate bites. Thus, bites were selected as the
endpoint despite earlier Board recommendations concerning participant safety (EPA HSRB
2008). Nevertheless, in order to obtain scientifically valid data useful for regulatory purposes, the
use of first bite, unconfirmed by a subsequent bite, is acceptable. The Margins of Exposure
(MoEs) were adequate for protection of participants from the potential toxicity of the repellent.
Statistical analyses were generally appropriate. However, the standard error for mean
protection time and resulting confidence interval need to be corrected to use the estimated
standard error, not the planned standard error. It would also be helpful to present the range of
values observed in the data. For study planning, basing sample size calculations on an estimated
standard deviation from stable fly data would have been more appropriate than using a published
estimate from mosquito data. Lastly, Table 4 in the submitted report should be corrected to
indicate that the data presented are for product failure times and not complete protection times.
Ethics
Charge to the Board
Does available information support a determination that study ICR A382 was conducted
in substantial compliance with subparts K and L 40 CFR Part 26?
Board response to the Charge
HSRB recommendation
The Board concurred with the Agency’s assessment (Carley 2009d) that the study
submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR
26.
HSRB Detailed Recommendations and Rationale
The documents provided by ICR (Gaynor 2009, Gaynor et al. 2009) state that each study
was conducted in compliance the requirements of the US EPA Good Laboratory Practice (GLP)
Regulations for Pesticide Programs (40 CFR 160). Additional regulations —40 CFR 26 subparts
K and L; and FIFRA § 12(a)(2)(P — are also applicable. The study was reviewed and approved
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by a commercial human subjects review committee, Essex Institutional Review Board, Inc.
(EIRB, Inc.) of Lebanon, NJ.
1. The Board concurred with the conclusions and factual observations of the ethical strengths
and weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley 2009d). The
completed study met all applicable ethical requirements for research involving human
participants, in accordance with the following criteria as developed by the Board:
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 formations as personal insect repellents.
• Minor and pregnant or lactating women were excluded from participation, with
pregnancy either confirmed by over-the-counter pregnancy testing on the day of study
or by opt-out. The potential stigma resulting from study exclusion due to pregnancy
was also appropriately minimized.
• Based on toxicological data currently available for picaridin, 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, with no
adverse events related to product exposure reported.
• The study uses first bite as an endpoint. Stable fly bites, however, usually cause only
minor symptoms and are readily treated with over-the-counter antipruritic lotions.
• The study was conducted with laboratory-raised flies free of known pathogens. This
latter point, in particular, resulted in the one notable change to the protocol. At its
initial review, the HSRB recommended that the stable flies be raised on 10% sucrose
rather than bovine blood meals, thus minimizing the risk of potential zoonoses (EPA
HSRB 2008). As a result, the first planned test of picaridin as a repellent for stable
flies failed. Specifically, the trial had to be aborted due to insufficient landing
pressure. Upon consulting with an entomologist, ICR researchers concluded that the
stable flies “ [ overfed] on the 10% sucrose solution, which then interfered with their
normal inclination to land and take a blood meal” (Gaynor et al. 2009). This was
addressed by: 1) changing the feeding regimen to dry sugar cubes; 2) increasing the
numbers of stable flies used per cage; and 3) increasing the length of participant
exposure to stable flies to determine attractiveness. These changes were submitted to
EIRB, Inc. as protocol amendments and approved prior to implementation. This
protocol change was unlikely to have increased the risk of study participants or
compromised the informed consent process.
b. Voluntary and informed consent of all participants
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• The study protocol included several mechanisms designed to minimized coercive
recruitment and enrollment.
• Monetary compensation was not so high as to unduly influence participants.
c. Equitable study participant selection and recruitment
• In response to HSRB concerns, ICR modified their recruitment strategy to identify
study participants more representative of the racial and ethnic distribution of likely
repellent users.
2. The Board also recommended that, for future intentional dosing studies, the sponsor work
with the 1RB of record to address some of the gaps of submitted information noted in the
EPA ’s Ethics Review (Carley 2009d).
a. Several Board members raised concerns about the quality of IRB review and the
qualifications of IRB members to review insect repellent protocols, given the failure of
EIRB, Inc. to provide the sponsor or the Agency with a description of IRB member
qualifications and detailed meeting minutes that offer a description of IRB deliberations
and debate of intentional exposure protocols. It is unlikely that these deficiencies placed
study participants at risk or compromised The informed consent process, but they do
represent a deviation from the expectations of 40 CFR 26.
b. The sponsor and IRB of record should ensure that all telephone scripts and other
recruitment materials, and informed consent documents be reviewed prior to study
initiation to ensure that the information contained in each is accurate. For example, the
telephone script submitted to the IRB for review and approval failed to note two
significant changes to the study design: the change on the duration of attractiveness
testing; and the change to pregnancy screening protocol that allowed women who are
physically incapable of having children (i.e., post-menopausal or surgically sterilized) to
opt-out of over-the-counter pregnancy testing. This deviation, however, was unlikely to
have compromised the informed consent process as potential study participants were
informed of these protocol changes later when formally consented at the ICR facility.
Assessment of Proposed Carroll-Love Biological Research Study LNX-002: Efficacy Test of
KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and 20%
Spray) with Biting Flies Under Field Conditions .
Overview of the Study
The protocol describes a study to test the efficacy of two formulations (lotion and spray)
of 20% picaridin in the field against at least one of 4 species of biting flies. Dosimetry data
recently accumulated in a previous study (LNX-00l) would be used for dose selection. One
habitat is proposed. Ten test subjects and two untreated controls would be tested in a suitable
environment that had adequate biting pressure of biting flies but relatively few mosquitoes.
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Repellent-treated skin would be exposed for 5 minutes in each 30-minute interval until repellent
failure. The endpoint would be the “Lite with Intent to Bite” (LIBe), and the criterion for data to
calculate complete protection time would be first confirmed LIBe.
Science
Charge to the Board
If the proposed field repellency study protocol LNX-002 is revised as suggested in EPA’s
review and if the research is performed as described: Is the research likely to generate
scientifically reliable data, useful for assessing the efficacy of the tested materials in repelling
biting flies in the field?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Carley and Sweeney 2009) that this
protocol will provide scientifically valid results on the efficacy of two picaridin formulations
against biting flies, with modification as noted below. Additional Board review of the protocol is
not required prior to study implementation.
HSRB Detailed Recommendations and Rationale
The protocol submitted for review had many similarities to previously reviewed CLBR
protocols and completed studies involving mosquitoes. The format of the protocol description
was revised to provide greater clarity. The study protocol and associated documents incorporated
many of the Board’s previous comments and recommendations. The endpoint was LIBe, which
the Board has previously expressed preference for because of the lesser risk to study participants
than bites.
Agency reviewers identified two concerns: 1) the standard of biting of one LIBe in five
minutes was not well justified and may be insufficiently high to yield valid results and could lead
to inappropriately right censored data; and 2) a change of the previously-used paradigm of one
minute exposure of treated limbs to insects out of each 15 minute period to five minutes in each
30 minute period was not explained or justified (Carley and Sweeney 2009). The Board
concurred with both of these concerns, and recommended that they be addressed in the revised
protocol as possible.
Additional Board recommendations concerned two issues: 1) the particular species on
which data would be accumulated; and 2) the calculation of complete protection time.
With respect to the species tested, although four types of biting flies were proposed as
possible insects to be monitored, it was pointed out that these four species display varied
behaviors and aggressiveness. When questioned, the Agency indicated that it already had some
useful data on some species of biting flies — such as stable flies — accumulated in the laboratory.
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The Agency thus expressed interest in obtaining data from other species that cannot be readily
studied in laboratory tests. The Board thus recommended that the study be conducted only if
black flies (preferably) and/or biting midges were present in sufficient numbers at the field site.
Accumulated data should be acquired on one or both of these species, as well as any other
species of biting flies that may also be present. If black flies or biting midges are not available in
sufficient numbers and with sufficient biting pressure at the field site, other types of biting flies
should not be considered acceptable substitutes.
Echoing earlier concerns about the types of calculations and statistical analyses that will
be conducted on these insect repellency data, the Board recommended that the protocol be
amended to explain better how mean complete protection time will be calculated accurately
using the appropriate types of statistical analyses. Mean protection time versus the duration of
the study should be clarified, particularly as it affects the prevalence of censored data. The
study’s duration should be sufficiently long to ensure that the repellent will fail for a substantial
portion of study participants, thereby limiting the occurrence of right-censored data. The protocol
should also be revised to clarify how the analysis will proceed in the presence of censored data
(using Maximum-likelihood or Kaplan-Meier methods).
In the context of this and other insect repellency studies, the Agency is again urged to
update its guidance to sponsors so that they can conduct tests and analyze the resultant data in a
useful and accurate manner.
Ethics
Charge to the Board
If the proposed field repellency study protocol LNX-002 is revised as suggested in EPA’s
review and if the research is performed as described: Is the research likely to meet the applicable
requirements of 40 CFR part 26, subparts K and L?
Board response to the Charge
HSRB recommendation
The Board concluded that the protocol submitted for review, if modified in accordance
with EPA (Carley and Sweeney 2009) 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 the
US EPA’s GLP Standards described at 40 CFR 160, and the California State EPA Department of
Pesticide Regulation study monitoring (California Code of Regulations Title 3, Section 6710)
(Carroll 2009). The requirements of FIFRA § I 2(a)(2)(P) also apply. The protocol was reviewed
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and approved by an independent human subjects review committee, Independent Investigational
Review Board, Inc. (IIRB, Inc.), of Plantation, FL prior to submission.
1. The Board concurred with the conclusions and factual observations of the ethical strengths
and weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley and Sweeney
2009). The proposed study is likely to meet the applicable ethical requirements for research
involving human participants, in accordance with the following criteria:
a. Acceptable risk-benefit ratio. The risks as noted in the study protocol are fiverfold: 1)
allergic reaction to test materials themselves; 2) exposure to biting artbropods; 3) possible
exposure to arthropod-bome diseases; 4) physical stress from the test conditions; and 5)
psychological stress and/or breach of confidentiality for pregnancy test results. These
risks are minimized appropriately and are justified by the potential societal benefits,
particularly data on the efficacy of these new formations as personal insect repellents.
• Based on toxicological data currently available for picaridin, coupled with
appropriate exclusion criteria, study participants are unlikely to be at risk of adverse
side effects with exposure.
• The study is designed to minimize the likelihood of biting fly and mosquito bites,
through the use of: LIBes rather than actual confirmed bites as a study endpoint; pre-
bite removal and joint observation; clear stopping rules; limited exposure periods.
Study participants will be trained in proper insect observation and handling
techniques.
• Biting fly and mosquito bites, should they occur, are usually mild and easily treated
with over-the-counter steroidal creams. The study will also exclude participants who
have a history of severe skin reactions to such bites.
• To minimize the risk that study participants will be exposed to pathogens like West
Nile Virus — not transmitted by the biting flies in question but via other arthropods
that may be present at the field sites — the study will be conducted only in areas where
known vector-borne diseases have not been detected by county and state health or
vector/mosquito control agencies for at least two weeks. The study is also planned for
a location where mosquitoes are not abundant and at a time of year in which most
arthropod-bome pathogens are not usually detected. Finally, mosquitoes that land
with the intent to bite will be collected and subjected to multiplex RT-PCR assays for
several known arthropod-bome pathogens—including West Nile Virus, Western
Equine Encephalitis Virus, and St. Louis Encephalitis Virus—with clear plans to
contact study participants and alert them if a transmissible pathogen is detected.
• The potential risks to participants from environmental stress are minimized by the
provision of a climate controlled rest area, food, water and medical supplies, and by
careful monitoring for signs of dehydration, heat stress and hypothermia. Appropriate
stopping rules and medical management procedures are in place.
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• Minor and pregnant or lactating women are excluded from participation, with
pregnancy either confirmed by over-the-counter pregnancy testing on the day of study
or by opt-out. The potential stigma resulting from study exclusion due to pregnancy is
also appropriately minimized.
b. Voluntary and informed consent of all participants
• The study protocol includes several mechanisms designed to minimize coercive
recruitment and enrollment.
• Monetary compensation is not so high as to unduly influence participants.
c. Equitable selection of study participants
• The majority of research participants will be recruited from the University of
California at Davis student population. Study participants are likely to represent the
appropriate ethnic and racial diversity of individuals in and around the University, but
the use of this convenience sample may limit the broad applicability of the study
results to the general population. The investigators in the protocol have noted this
fact.
2. The Board recommended that the study protocol be modified to address the few concerns
noted in the EPA’s Ethics Review (Carley and Sweene y 2009). In addition, the Board
recommended that the investigators clarif ’ of what 3 r party” medical coverage means, as
listed in the current informed consent document.
Assessment of Proposed AHETF Scenario and Protocol AHE-120: Water-Soluble Packing
Mixina and Loading .
Overview of the Study
This proposal presents an agricultural handler exposure scenario involving
mixing/loading of pesticides enclosed in water-soluble packets (WSP). The protocol calls for
study participants to mix and load one of two WSP-enclosed surrogate pesticides (acephate and
carbaryl) into a variety of tanks containing water in a variety of agricultural spraying operations.
A total of 25 participants (described in the protocol as “Monitoring Units” [ MUs]) will be
observed; 5 volunteers each from five different growing regions will be enrolled using a
purposive sampling method.
Dermal exposure will be measured by a whole body dosimeter (WBD) worn beneath the
subject’s outer clothing. Hand wash and face/neck wipe samples will also be collected prior to,
during, and after completion of pesticide loading and mixing procedures. Airborne
concentrations of the surrogate will be monitored in the participant’s breathing zone using an
051-IA Versatile Sampler (OVS) tube sample collector connected to a personal sampling pump.
Additional measures will also record environmental conditions at the time of monitoring, and
observers will make field notes, photographs and videos of participant activity throughout the
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monitoring event.
The results of sample analysis under the mixing/loading of water-soluble packets
scenario, will be posted to the AHED® database, where they will be available to the EPA and
other regulatory agencies for statistical analysis. The proposed documentation will report a
confidence-interval-based approach to determine the relative accuracy for the arithmetic mean
and 95 th percentile of unit exposures. The Agency proposes to use these data to estimate daily
dermal and inhalation exposures of agricultural handlers who are mixing/loading pesticides in
water-soluble packets under a variety of mixing and loading scenarios.
Science
Charge to the Board
If the proposed mix/load WSP field study protocol AIFIEI2O is revised as suggested in
EPA’ s review and if the research is performed as described: Is the research likely to generate
scientifically reliable data, useful for assessing the exposure of handlers who mix and load
soluble or wettable powder pesticides in water-soluble packaging?
Board Response to the Charge
HSRB Recommendation
Given the lack of existent reliable and sound data in this area, the Board concurred with
the Agency’s assessment (Evans and Sherman 2009) that this protocol will generate data that are
scientifically valid and that may be useful for assessing the exposure of handlers who mix and
load soluble or wettable powder pesticides in water-soluble packaging. The Board cautioned that
these data are likely to be useful for creating distributions of worker exposure only if worker
exposure is found to be proportional to the amount of active ingredient handled (AaiH).
The Board also recommended a number of protocol modifications, as listed below.
Additional Board review of the protocol is not required prior to study implementation.
HSRB Detailed Recommendations and Rationale
The Board concluded that the proposed monitoring and quality assurance and control
methods appear adequate, particularly in the supplemental SOPs provided by the AHETF in
response to the Agency’s initial science and ethics review (Collier 2009b; Evans and Sherman
2009). The protocol and supplemental SOPs adequately address a number of key scientific
issues, including: the scientific objective, the quantification of the test materials, the data
collection and compilation methods and summary of test results, the justification for selection of
the test substances, and the QAIQC requirements. The Board also commended the AI-IETF and
the Agency for taking the time to plan, test, and revise different scenarios and approaches, and
for pilot testing some aspects of these and related protocols. The protocol presented to the Board
was well thought out and written as a result.
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The Board did raise a number of concerns, however, about the perceived inadequacies in
the study design, including issues of sample size and the use of inappropriate statistical analyses.
The Board raised many of these issues previously when it reviewed earlier AHETF protocols.
Both the AFIETF and the Agency will need to acknowledge the limitations of the study design
that occur in the AI-IETF handling scenarios and either change their goals accordingly, or add
appropriate statistical methods or data management approaches to extrapolate from the data
obtained from these limited scenarios to the wider regulatory purposes that these data will be
used for. Some Board members expressed the concern, for example, once these data are inside
the AI-IED database, some users may overlook the limitations of the original study design and
use the data to generate the typical statistical distributions in error.
Illustrating this point, the Board raised concerns about the types of statistical analyses
proposed for the water-soluble packing scenario presented here. The proposed study will rely on
a purposive sampling strategy, for example, but the researchers propose to treat the monitoring
data as if “it were collected as a two-stage random sample from an infinite population” (Collier
2009a). The Board questioned the validity of this approach, noting that the data will be collected
from a non-random non-population based sample. There is no statistical theory that can be
applied to non-random samples of this type. Thus, the statistical analyses proposed, including
mixed model approaches, are not valid.
The Board also raised concerns about the key objective of the study — namely, to
determine the relationship between measured worker exposure and AaiH. In particular, the Board
disagreed with the Agency’s assessment that “past studies have shown that AaiH is strongly
associated with exposure and is a meta-factor associated with differences in equipment and
spraying practices” (Evans and Sherman 2009). To expect a linear relationship between AaiH
and worker exposure seems logical; one should expect that a consistently small fraction of the
amount of pesticide that a worker handles would be deposited onto their skin. Data previously
presented by the AFIETF to the Agency’s FIFRA Scientific Advisory Panel (SAP), however, did
not demonstrate a linear relationship between worker exposures of the amount of active
ingredient handled. There are a number of factors that may explain why there is not a clear linear
relationship between measured worker exposure and AaiH, including ecological, engineering,
and statistical factors. As submitted, the AHETF protocol will not be able to distinguish between
these different factors nor allow researchers to determine the true relationship between exposure
and AaiH. For example, there are a number of uncontrolled ecological variables that may
influence worker exposure, including: environmental conditions, the types of equipment used,
the types of crops treated, grower preferences, etc. Indeed, some workers will likely experience
mixing and loading conditions that are atypical for normal use of the active ingredient being
monitored. Myriad sources of natural variation are likely to have a marked impact on worker
exposure. Given the relatively small sample size of each monitoring cluster in this exposure
scenario, these sources of natural variation will likely introduce considerable estimation bias into
the final data.
- Finally, current consensus is that estimates of the geometric mean, the arithmetic mean,
and the 95th percentile need to be accurate within three-fold of the actual population value. The
current protocol includes no methods to validate the actual population data and determine
whether the resulting estimates fall within this necessary range.
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Ethics
Charge to the Board
If the proposed mixlload WSP field study protocol AHE 120 is revised as suggested in
EPA’s review and if the research is performed as described: Is the research likely to meet the
applicable requirements of 40 CFR part 26, subparts K and L?
Board response to the Charge
HSRB recommendation
The Board concluded that the protocol submitted for review, if modified in accordance
with EPA (Evans and Sherman 2009) 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 the
US EPA’s GLP Standards described at 40 CFR 160 (Collier 2009a). The requirements of FIFRA
§ 1 2(a)(2)(P) and, where applicable, the California State EPA Department of Pesticide Regulation
study monitoring (California Code of Regulations Title 3, Section 6710) also apply. The protocol
was reviewed and approved by an independent human subjects review committee, IIRB, Inc. of
Plantation, FL prior to submission.
1. The Board concurred with the conclusions and factual observations of the ethical strengths
and weaknesses of the study, as detailed in the EPA’s Ethics Review (Evans and Sherman
2009). The proposed study is likely to meet the applicable ethical requirements for research
involving human participants, in accordance with the following criteria:
a. Acceptable risk-benefit ratio. The risks as noted in the study protocol are five-fold: 1)
heat-related illness; 2) accidental exposure to the surrogate chemicals; 3) injury
associated with scripted field activities; 4) allergic reaction to surfactants using for hand
washing; and 5) psychological stress and/or breach of confidentiality for pregnancy test
results. These risks are minimized appropriately and are justified by the potential societal
benefits, particularly data on occupational exposure of agricultural workers to pesticides
during mixing and loading activities.
• The greatest risk to participants is that of heat-related illness, given that the
participants will be required to wear two layers of clothing during the scenario
activities. This risk is lessened but not eliminated by the application of appropriate
stopping rules (including cessation of all monitoring activities when the ambient heat-
index exceeds 105°F) and frequent monitoring of participants. Participants will be
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given frequent breaks, access to ample amounts of water or sports drinks, and
educated about the dangers and symptoms of heat-related illness. Appropriate
medical management procedures are also in place.
• The surrogate materials consist of two common pesticides, acephate and carbaryl,
both of which have been e tensively tested. The participants will only be exposed to
concentrations of the surrogate compound at accepted exposure thresholds.
• Participants will be selected from volunteers with experience handling these or
similar compounds in WSP mixing and loading scenarios. Thus, all of the participants
will have extensive experience in using these or similar products, and thus unlikely to
misuse them in a way that might increase their likelihood of being accidentally
exposed.
• Participants will be reminded about safe handling practices and procedures, wear
appropriate PPE, and will be monitored for any accidental or unintended product
exposure.
• Allergic reactions to the surfactants used in hand washing are usually mild and easily
treated with over-the-counter steroidal creams. The study will exclude participants
who have a history of severe skin reactions to such detergents.
• Minor and pregnant or lactating women are excluded from participation, with
pregnancy either confirmed by over-the-counter pregnancy testing on the day of study
or by opt-out. The potential stigma resulting from study exclusion due to pregnancy is
also appropriately minimized.
b. Voluntary and informed consent of all participants
• There is the possibility that the participants in this study might represent particularly
vulnerable populations, susceptible to coercion and undue influence. The study
protocol, however, includes several mechanisms designed to minimize coercive
recruitment and enrollment.
• Monetary compensation is not so high as to unduly influence participants.
• Spanish translations of the informed consent documents, informational packets, and
recruitment flyers were provided. Researchers will be working with local Spanish-
speaking community members to ensure that the appropriate regional dialect of
Spanish is used.
c. Equitable selection of study participants
• The study is designed to recruit an appropriately diverse population of participants
who represent skilled agricultural workers in the 5 study locations.
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• Community representatives and advocates are appropriately involved in the
recruitment and enrollment of study participants.
2. The Board recommended that the study protocol be modified to address the few concerns
noted in the EPA’s Ethics Review (Evans and Sherman 2009). In addition, the Board also
addressed three concerns of the Agency and the sponsors (Collier 2009c) with respect to
representativeness, language, and release of individual exposure data.
• The Board recommended that the AHETF implement the proposed protocol changes
designed to address issues of representativeness.
• As noted above, the Board concluded that the proposed protocol changes designed to
address concerns of language in the informed consent and related documents are
likely to yield translations that are written in the appropriate regional dialect of
Spanish.
• The Board commended the Task Force for wanting to release individual exposure
data to participants promptly but recommended that these data only be released once
the study is complete, except in those instances where data collected from individuals
suggest an unusually high level of exposure and thus a clear need to mitigate
exposure risks.
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