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 St udies Review Board Meeting Report

Dear Dr. Teichman:

The United States Environmental Protecti on Agency (EPA or Agency) requested the
Human Studies Review Bo ard (HSRB) to review three comp leted studies involving intentional human exposure to the organophosphate pesticide ch lorpyrifos. The Agency proposes to rely on these three studies, conducted prior to public ation 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 issu es regarding how the st udies 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 provi de scientific and et hical 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 pack ing mixing and loading scenar io and protocol (AHE-120).

The enclosed report provides the Board’s res ponse to EPA charge questions presented at the June 24-25, 2009 meeting.

Assessment of Completed Research Study MRID 124144: Nolan et al. (1982) Chlorpyrifos:
Pharmacokinetics in Human Volunteers Fo llowing Single Oral and Dermal Doses.

Science

• The Board concluded that data measuring chlo rpyrifos at the limit of detection in blood
and urine are not useful. The measurements of 3,5,6-trichloro-2-pyrid inol (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 variab ility of the erythrocyte cholinesterase activity data and the lack of a control group, but conc luded that measurements of cholinesterase activity/inhibition from Nolan et al. (1982) were likely to be reliable.

Page 1 of 40• The Board concluded that the data are reliabl e but suggested that the Agency be cautious in its use of the erythrocyte cholinestera se 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 a ssessment that there was neither clear and convincing evidence that the study was f undamentally unethical, nor clear and convincing evidence that the st udy was significantly deficien t relative to the ethical standards prevailing at the time the Nolan et al. (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 chlorpyrifos 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 chlorpyrifos exposure not bei ng 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 concer ns about their utility. Some of the Board’s concerns included: 1) the lack of an untr eated control; 2) the reliance on a single postexposure time point; 3) the small sample size; and 4) the dose received by the subjects varied and was only estimate d from dermal dosimetry.

Ethics

• The Board concurred with the Agency’s a ssessment that there neither was clear and convincing evidence that the study was f undamentally unethical, nor clear and convincing evidence that the st udy was significantly deficien t relative to the ethical standards prevailing at the time the Honeyc utt and DeGeare (1993) study was conducted.

Assessment of Completed Research Study MRID 44811002: Kisicki et al. (1999) A Rising Dose Toxicology Study to Determine the No-Observable Effect -Levels (NOEL) For Erythrocytes Acetylcholinesterase (AChE) In hibition and Cholinergic Signs and Symptoms of Chlorpyrifos at Three Dose Levels.

Page 2 of 40Science

• 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 chlorpyrifos 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 res ponder at the highest dose level.

• The Board cautioned against rely ing 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 expos ure 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 erythr ocyte data in light of the variability and analytical concerns raised.

Ethics

• The Board concluded that there neither was cl ear and convincing evidence that the study was fundamentally unethical, nor clear a nd convincing evidence that the study was significantly deficient relative to the ethical standards prevailing at the time the Kisicki et al. (1999) study was conducted.

Assessment of Completed Research Study MRID 47732701: ICR, Inc. Study A382 – Evaluation of the Efficacy of KBR 3023 (Pic aridin; Icaridin) - Ba sed Personal Insect Repellents (20% Cream and 20% Spray) Against Stable Flies in the Laboratory.

Science

• The Board concurred with the Agency’s assessm ent that this study pr ovides scientifically valid results to assess the repellent efficacy ag ainst stable flies of th e 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 e rror, not the planned standard error. The report should also be co rrected to indicate that the data presented are for product failure times and not complete protection times.

Ethics

Page 3 of 40• The Board concurred with the Agency’s a ssessment that the study submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 26.

Assessment of Proposed Carroll-Loye Biological Research Study LNX-002: Efficacy Test of KBR 3023 (Picaridin; Icaridin) - Based Person al Insect Repellent s (20% Cream and 20% Spray) with Biting Flie s Under Field Conditions.

Science

• The Board concurred with the Agency’s asse ssment 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 insuffi ciently high to yield va lid results and could lead to inappropriately rightcensored 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 explai ned or justified; 3) the varied behaviors and aggressiveness of four di fferent species of biting flie s 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 a nd conducted accordingly, is likely to meet the applicable requirements of 40 CFR 26, subparts K and L.

Assessment of Proposed AHETF Scenario a nd Protocol AHE-120: Water-Soluble Packing Mixing and Loading.

Science

• Given the lack of existent reliable and sound da ta in this area, the Board concurred with the Agency’s assessment that this protocol will generate data that ar e scientifically valid. These data may be useful for assessing th e exposure of handlers who mix and load soluble or wettable powder pesticid es in water-soluble packaging.

• The Board cautioned that these data are likely to be useful for cr eating distributions of worker exposure only if worker exposure is found to be proportio nal to the amount of active ingredient handled (AaiH).

Page 4 of 40The Board recommended that the AHETF and th e Agency acknowledge the limitations of the study design and add appropriate st atistical 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 us ed 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 a nd conducted accordingly, is likely to meet the applicable requirements of 40 CFR 26, s ubparts K and L. In particular, the Board recommended that the AHETF implement th e proposed protocol changes designed to address issues of representativeness langua ge in the informed consent and related
documents.

• The Board recommended that the AHETF rel ease 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,

Sean Philpott, PhD, MSBioethics
Chair
EPA Human Studies Review Board

Page 5 of 40NOTICE

This report has been written as part of th e 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 a nd, hence, the contents of this report do not necessarily represent the view a nd policies of the Environmental Protection Agency, nor of other agencies in the Executive Branch of the Fede ral government, nor does the mention of trade names or commercial products constitute a reco mmendation for use. Further information about
the EPA Human Studies Review Board can be obtained from its website at http://www.epa.gov/osa/hsrb/. 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 caref ully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. This document addresses the information provide d and presented within the structure of the charge by the Agency.

Page 6 of 40US ENVIRONMENTAL PROTECTION AGENCY
HUMAN STUDIES REVIEW BOARD

Chair

Sean Philpott, PhD, MS Bioethics, Scie nce and Ethics Officer, Global Campaign for Microbiocides, PATH, Washington, DC

Vice Chair

Rebecca Parkin, PhD, MPH, Associate Dean for Re search and Public Health Practice, School of Public Health and Human Services, The Geor ge Washington Universi ty, Washington, DC

Members

Janice Chambers, PhD, DABT, William L. Giles Di stinguished Professor, Director, Center for Environmental Health Sciences, College of Vete rinary Medicine, Mississ ippi 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 a nd Drug Administration, Rockville, MD *

Dallas E. Johnson, PhD, Professor Emeritus, Depart ment 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, Distinguish ed 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 Chance llor 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 Fl orida, Gainesville, FL

Consultants to the Human Studies Review Board

Sidney Green, Jr., PhD, Fellow, ATS, Profe ssor, Department of Pharmacology, Howard University College of Me dicine, Washington, DC

Page 7 of 40Alan Meisel, JD, Dickie, McCamey and Chilcote Pr ofessor of Bioethics, Professor of Law and Psychiatry, University of Pitts burgh 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, Depa rtment of Biology, Utah State University, Logan, UT

Lianne (Elizabeth A.) Sheppard, PhD, Professor, Department of Biostatistics, University of Washington, Seattle, WA

Human Studies Revi ew Board Staff

Paul I. Lewis, PhD, Executive Director, Huma n Studies Review Board Staff, Office of the Science Advisor, United States Environm ental Protection Agency, Washington, DC

* Not in attendance at June 24-25, 2009 Public Meeting

Page 8 of 40INTRODUCTION

From June 24-25, 2009, the United States Environmental Protection Agency’s (EPA or Agency) Human Studies Review Board (HSRB) me t to address scientific and ethical issues concerning: three completed human toxicity studie s involving one pesticide active ingredient – chlorpyrifos – conducted prior to publication of the EPA’s expande d final rule for protection of subjects in human research; and one complete d study involving one insect repellent active ingredient – picaridin – conduc ted 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 fully below.

In addition, the Agency submitted two prot ocols for conducting new research involving human participants: one study measuring the effi cacy of two registered insect repellents containing picaridin against biting flies under field conditions; and one study measuring levels of exposure received by agricultural handlers wh en mixing and loading pesticides using watersoluble 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 f ace-to-face meeting in Arlington, Virginia. Advance notice of the meeting was published in the Federal Regist er as “Human Studies Review Board; Notice of Public Meeting” (74 Federal Register 106, 26861).

During the public meeting, following welcomi ng remarks from Agency officials, the Board heard presentations from the Agency on the following topics: three completed studies involving intentional human exposur e to the organophosphate pesticide chlorpyrifos (Nolan et al. (1982), Honeycutt and DeGeare (1993), and Kisicki et al. (1999)); a completed ICR, Inc., (ICR) insect repellent efficacy study (ICR A382); a pro posed Carroll-Loye Biological Research, Inc. (CLBR) insect repellent efficacy study (L NX-002); and a proposed Agricultural Handler Exposure Task Force, LLC (AHETF) water-solu ble packing mixing and loading scenario and protocol (AHE-120).

The Board also asked clarifying questions of several study sponsors and/or research investigators, including:

Dr. Craig Barrow, Consultant to Dow AgroSciences Dr. Victor Canez, Technical Chair, Ag ricultural Handler Exposure Task Force Dr. Scott Carroll, Principal, Ca rroll-Loye Biological Research Dr. Richard H. Collier, Admi nistrative 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

Page 9 of 40Dr. Ken Racke, Regulatory Specialist, Dow AgroSciences Dr. Ghona Sangha, Toxicology and Regul atory Consultant, LANXESS Corp.

Oral comments were provided by:

Dr. Ghona Sangha, Toxicology and Regul atory 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 document s (e.g., published literature, sponsor and investigator research reports, study protocols, data evaluation r ecords, and Agency science and ethics reviews of proposed protocols and comp leted studies). A comprehensive list of background documents is available online at http://www.regulations.gov.

CHARGE TO THE BOARD AND BOARD RESPONSE

Assessment of Completed Research Study MRID 124144: Nolan et al. (1982) Chlorpyrifos:
Pharmacokinetics in Human Volunteers Fo llowing Single Oral and Dermal Doses.

Overview of the Study

The HSRB reviewed Nolan et al. (1982) as part of a packag e of three stud ies involving human volunteers exposed to chlorp yrifos that were proposed for use by EPA to characterize and help interpret epidemiolo gical and bio-monitoring data for this pesticide. In addition, the data from human participan ts might be used fo r setting bounding estimates and developing physiologically based pharmacokinetic (PBPK) models for chlorpyrifos.

Nolan et al. (1982) summarize the results of a si ngle dose level study that was designed to compare the fate of chlorpyrifos when ad ministered orally or dermally to humans. Chlorpyrifos is a highly li pophilic compound that is rapidly metabolized to 3,5,6-trichloro-2­ pyridinol (TCP) and diethylthiophosphate. TCP is excreted in urine predominantly as a glucuronide conjugate. Blood and urine levels of chlorpyrifos and TCP (unconjugated) were determined after oral (0.5 mg/kg) or dermal (5 mg/kg) administration of chlorpyrifos.

There were a total of six participants in the Nolan et al. (1982) study, with one participant (“subject A’) included in the evaluation of the fate of chlorpyrifos after oral dosing. However, this participant received dermal dosages of chlorpyrifos at 0.5 mg/kg in a preliminary evaluation and was not used in the final analyses of the derm al 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 chlorpyrifos was absorbed, whereas less than 3% of the dose was absorbed after dermal application.

Science

Page 10 of 40Although presented separately, the same scientific criteria were used to assess the reliability of the data from all three chlorpyrifos studies. These criteria are:

1. Verification that the administ ered dose of chlorpyrifos was confirmed in the study;

2. Assurance that sample collection (blood and urine) was reliable and complete;

3. Validation and appropriateness of the anal ytical methods for quantification of chlorpyrifos and TCP in blood and urine; and

4. Evaluation of the cholinesterase inhibiti on data (plasma and/or RBC cholinesterase) for sensitivity, accuracy, re producibility, 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 presente d, met these general criteria along with other relevant study issues are summarized in respons es 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 chlo rpyrifos at the limit of detection in blood
and urine are not useful. The measurements of TCP in urine are generally reli able. It is unclear if
the measurement of TCP in blood is useful because of concerns a bout the ability of the methods used to detect the appropriate TCP conjugate.

HSRB Detailed Recommendations and Rationale

Since blood and urinary concentrations of ch lorpyrifos were essent ially non-detectable,
there is little confidence in these data. Howe ver, urinary levels of TCP, determined after hydrolysis of the glucuronide conjugate, were well above the limit of de tection. Additionally, the data suggest relatively high absorption of chlor pyrifos from oral dosi ng and considerably less exposure from the dermal route, a pattern that is biologically plausi ble. It is not clear whether
the blood levels of TCP are accura te because the extent to whic h the glucuronide conjugate of
TCP circulates in the blood and the extent to wh ich 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 bl ood concentrations of TCP.

Charge to the Board

Page 11 of 40Are the measurements of cholinestera se activity/inhibition from the Nolan et al. (1982)
oral and dermal studies reliable?

Board Response to the Charge

HSRB Recommendation

The HSRB expressed some concern over the vari ability 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.

HSRB Detailed Recommendations and Rationale

A major issue with determination of cholin esterase activity is the inter-day and interassay variability (typically 10-15%) that may be observed. In the Nolan et al. (1982) study, plasma cholinesterase showed marked inhi bition (up to approximately 85%) after oral administration of chlorpyrifos, whereas less pl asma cholinesterase i nhibition was noted after dermal application (up to about 25%). In cont rast, no inhibition of eryt hrocyte cholinesterase
was observed with either r oute of administration.

The HSRB considered the following limitati ons or weaknesses of the cholinesterase
measurements in Nolan et al . (1982):

1. There was no untreated group to control for inter-day laborato ry 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 limiti ng 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 evalua ted, 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 absorpti on of chlorpyrifos following oral dosing.

Ethics

Charge to the Board

Is there clear and convincing eviden ce that the conduct of the Nolan et al. (1982) study was fundamentally unethical, or significantly de ficient relative to th e standards of ethical research conduct prevailing when it was conducted?

Page 12 of 40Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s a ssessment (Carley 2009a) that there neither was clear and convincing eviden ce that the study was fundament ally 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 a nd 1982, the Board concurred with the Agency’s assessment that the applicab le 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 c onsent form that gave few deta ils about the study but affirmed that they had read the study pr otocol (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 Investig ation 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 th is study met all applicable ethica l requirements for such research involving human participants, in accord ance with the following criteria:

a. Not fundamentally unethical . With regard to determining whether or not a study is fundamentally unethical, the Boar d’s standard is to decide if the research was intended to seriously harm participants, or if it faile d 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 reas ons it might have been fundamentally unethical, the Board concludes that it was not fundamentally unethical.

b. Not significantly deficient . With regard to determining whether a study was significantly
deficient relative to the ethical standard s prevailing at the time the research was conducted, the Board’s standard is to determin e whether or not any ethical deficiencies
identified could have resulted in seri ous 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 avai lable 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.

Page 13 of 40• The Board did not have a copy of the prot ocol 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 pa rticipants could seriously impair informed consent. With regard to studies that were conducted prior to the effective date of the Agency’s regulati ons, 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 de sirable for the Board to have had access to the actual study protocol.

Assessment of Completed Research Study MRID 42062701: Honeycutt and DeGeare (1993) Worker Reentry Exposure to Chlorpyrifos 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 chlorpyrifos in i ndividuals who reenter a citrus grove after agricultural use of ch lorpyrifos. There were 15 participants in the study, representing five citrus pickers and ten citrus pruners (five each in wet and dry conditions, respecti vely). Pickers entered the test site 43 days af ter 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 whol e body dosimeters, air sa mpling, leaf punches and quantification of urinar y excretion of TCP. The results from Nolan et al. (1982) justify monitoring urinary TCP to estimate chlorpyrifos exposure. The report included considerable emphasis on the handling of all samples in th e field and a comprehensive summary of all analytical conditions and methods used in dete rmining chlorpyrifos in all study matrices.

Both chlorpyrifos and TCP were analyzed with negative ion-ch emical ionization gas chromatography with mass select ive detection (GC/MS) and urin ary TCP was quantified after acid hydrolysis employing concentrated hydrochloric acid with heating for 1-2 hr followed by derivitization with N-methyl-(N-tertbutyldimethylsilyl)-trifloroacetamide. Analytical recoveries were reported, and the limit of detection was defi ned as three-times higher than the signal to noise ratio. No limit of qua ntitation (LOQ) was provided.

Science

Charge to the Board

Are the blood and urine measurements of ch lorpyrifos and/or TCP from the Honeycutt and DeGeare (1993) worker biomonitoring study reliable?

Board Response to the Charge

Page 14 of 40HSRB Recommendation

The Board concluded that the data from Honeycutt and DeGeare (1993) are likely
reliable but of limited value. Board members e xpressed concerns about: 1) the small sample size; 2) the background chlorpyrif os 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 c oncerning 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 chlorpyrifos. However, the critical elem ent regarding confirmation of the dosage was not achieved in this study because the purpos e 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 comple tion of the 5-6 hr work period. However, there is evidence to suggest that urine collect ions were not complete. This conclusion was based on variability in total urinar y creatinine excretion along with several instances in which incomplete sample coll ection 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 a ddition, for nine of 15 study participants the coefficient of variability exceeded reported urinary creatinine levels by up to four-fold, suggesting that urine collect ion 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) s howed maximum urinary TCP levels on day three of the study suggesting additional e xposure to chlorpyrifos after the test exposure period. More importantly, several workers showed detectable levels of urinary TCP in pretest samples, which was s uggested to represent a steady state level of TCP resulting from occupational exposur e. 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 co llection and subject control, urinary TCP, and hence exposure to chlorpyr ifos, were determined using six different methods including no corrections, corre ction for background TCP excretion,
correction for creatinine excretion and co mbinations of corrections for background
and creatinine levels. Across the six diffe rent methods used, the range of urinary
TCP concentrations was about two-fold for pickers and four-fold for pruners. In

Page 15 of 40addition to the range of urinary TCP con centrations and the uncertainty regarding which method is most accurate, the small samp le size (n = 5 participants per scenario)
decreases the confidence of the final reported values.

Thus, although this study pr ovides the potential for assess ing chlorpyrifos exposure from a relevant occupational exposure, the uncertain ty resulting from incomplete urine sample collection, background exposure to chlorpyrifos, the small sample size, inter-individual and inter-day variability and the use of six different calculations to estimate chlorpyrifos 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 biom onitoring 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) th e lack of an untreated control group; 2) the re liance on a single post-exposure time poi nt; 3) the small sample size; and 4) the dose received by the subjects varied a nd 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 work ing in the citrus grove. The modified Ellman procedure was used to determine cholinesterase activities. Overall, no significant changes in plasma or erythrocyte cholin esterase activities were observed. The following limitations concerning plasma and erythrocyte cholinestera se activities reported by Honeycutt and DeGeare (1993) were identified:

1. Only one post-exposure sample was collect ed 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 not ed 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 ac tivities, and in three of the pruners, post-exposure erythrocyte cholinesterase levels were actually increased by more than 20% over baseline values. Collectively, there is cons iderable uncertainty in the baseline data.

3. No data from an unexposed group of contro l subjects was used to control for interday variability in the assay. It was note d that the practice of including laboratory controls for intra-assay variability is published, standard practice for this assay.

Page 16 of 404. The small group size further confounds the interpretation of th e highly variable
results.

Thus, the HSRB concluded that the experime ntal evidence suggesti ng that plasma and erythrocyte cholinesterase activi ties were not significantly alte red in the pickers and pruners exposed to chlorpyrifos in this study were lik ely to be accurate. However, the Board also cautioned that the reliability of the data was li mited because of the issues noted above including analysis at only a single time point after expos ure, the small sample size, the high degree of intra- and inter-subject variability an d the lack of an untreated control.

Ethics

Charge to the Board

Is there clear and convincing evidence that the conduct of the H oneycutt and DeGeare (1993) study was fundamentally unethical, or signif icantly 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 a ssessment (Carley 2009b) that there neither was clear and convincing eviden ce that the study was fundament ally 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 Californi a. As a result, it was subject to the California Code of Regulati ons, 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 Bo ard 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 Res earch 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 ap plicable ethical requirements for such research involving human participants, in acco rdance to the following criteria:

a. Not fundamentally unethical . With regard to determining whether or not a study is fundamentally unethical, the Boar d’s standard is to decide if the research was intended to

Page 17 of 40seriously harm participants, or if it faile d 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 reas ons it might have been fundamentally unethical, the Board concludes that it was not fundamentally unethical.

b. Not significantly deficient . With regard to determining whether a study was significantly
deficient relative to the ethical standard s prevailing at the time the research was conducted, the Board’s standard is to determin e whether or not any ethical deficiencies
identified could have resulted in seri ous 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 avai lable 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 desi gn of the study and the risks relating to participation, and they signed consent fo rms containing that information. As the Agency noted (Carley 2009b), there was mi sleading 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 entere d the groves. That misinformation was certainly inappropriate but does not, in a nd 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 compromi sed 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 cons titute clear and convincing evidence of an ethical deficiency that resulted in serious harm to these participants.

Assessment of Completed Research Study MRID 44811002: Kisicki et al. (1999) A Rising Dose Toxicology Study to Determine the No-Observable Effect -Levels (NOEL) For

Page 18 of 40Erythrocytes Acetylcholinesterase (AChE) In hibition and Cholinergic Signs and Symptoms of Chlorpyrifos 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 acetylcholinesterase in human volunteers. Th e 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 et al . (1982) discussed previously. In addition to asse ssing cholinesterase activity, bl ood and urine were collected and analyzed for chlorpyrifos and TCP to help de fine the pharmacokinetic properties in humans. Finally, paraoxonase status of each subject was de termined (but will not be discussed here).

Chlorpyrifos was administered orally in a gelatin capsule with 0 (lactose), 0.5 and 1 mg chlorpyrifos/kg administered in Phase I of the study followed by a second phase that include 0 (control) and 2 mg/kg dosages. Th ere were six male and six fema le 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 coll ected 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 acetylcholinesterase activity and chlorpyrifos 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 ur ine was collected at 0-6 and 6-12 hr).

Science

Charge to the Board

Are the blood and urine measurements of chlorpyrifos and/or TCP from the Kisicki et al. (1999) oral study reliable and appropriate for use in characterizing the results of epidemiological studies with chlorpyrifos?

Board Response to the Charge

HSRB Recommendation

Because of concerns about the analytic proc edures' potential inability to control for the glucuronide-conjugated TCP, and a pparent discrepancies in the absorption data when compared
with the data from Nolan et al . (1982), the Board questioned the reliability and utility of the
blood and urine measurements of chlo rpyrifos and/or TCP from Kisicki et al. (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 chlorpyrifos exposure data , this study provided clear documentation of the

Page 19 of 40administered dose. Chlorpyrifos 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 ha ve received a lower dose (1.63 mg/kg) based on conflicting data on body weight a nd administered dose data, but overall the documentation of the administered dose was satisfactory.

There was also generally good reliability with respect to sample coll ections. Participants remained in the testing facility for the first 48 hrs after dosing and 48 of the 60 subjects provided all periodic urine samples. Ur ine 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 GC/MS detection, and
TCP was derivatized with N-met hyl-(N-tertbutyldimethyl silyl)-trifloroacetamide. In general, these methods were similar to those described by Honeycutt and DeGeare w ith the exception that stable labels of chlorpyrifos and TCP (13C and/or 15N-labeled) were used as internal standards in the present analyses.

In reviewing this study, the HSRB identified se veral limitations or issu es that may impact the overall reliability of the data. These included:

1. The amount of chlorpyrifos absorbed afte r 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 al. reporting approximately 35% absorb ed. The rationale provided by the authors for this large difference was that ch lorpyrifos was administered using lactose tablets and gelatin capsules in the Nolan et al. and Kisicki et al. studies, respectively.
Kisicki et al. suggested that oral absorption is sl owed 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 wa s some skepticism that the difference in dosage form would yield the large discrepanc y 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 s ubjected to acid hydrolysis required to liberate the glucuronide conjugate of TCP, which is the major urinary metabolite of chlorpyrifos. This is an impor tant distinction, as both Nolan et al. (1982) and Honeycutt and DeGeare (1993) indicated th at urine samples were treated with concentrated sulfuric or hydrochloric aci d and heated in order to hydrolyze the glucuronide conjugate and liberate TCP whic h is then derivatized (in the methods used by Honeycutt and DeGeare and Kisicki et al. ). In the analytic al portion of the
Kisicki et al. study (Brzak 2000), there is a clear designation th at 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

Page 20 of 40critical analytical step raises some doubt that it was done. If urine samples were not properly hydrolyzed prior to analysis, then th e validity and reliability of these data are uncertain. Furthermore, since urinary TCP is used to estimate oral absorption of chlorpyrifos, it is possible that differences in sample handling may explain or at least contribute to the lower percen t absorption reported by Kisicki et al

.

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 th e study and possibly clarify wh ether there was an issue with the TCP analysis conducted by Kisicki et al

.

4. There were several questions regardi ng 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 alte rnate participants we re not adequately provided.

Because of concerns about the analytic proc edures' potential inability to control for the glucuronide-conjugated TCP, and a pparent discrepancies in the ab sorption 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 chlo rpyrifos and/or TCP from Kisicki et al. (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 acetylcholinestera se 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 tr eatment 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 alo ng with the fact that peak inhibition would be

Page 21 of 40expected to occur before 96 hr, this result was no t 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 afte r treatment. However,
this volunteer did not return for blood collections afte r the initial 48 hr pe riod, resulting in an incomplete profile. This participan t 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 inhibiti on was considered to be 1 mg/kg.

In reviewing this study, the Board identified se veral 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 th e recognized inter-day and inter-assay variability associated with the Ellman 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 utilizati on of the unexposed control data to correct for day-to-day
or batch-to-batch variations in the mean la b results. This limitation is particularly important to detect or to quantify accur ately small changes within an exposed population.

2. The interpretation of the re sults is centered on the singl e individual who showed more than a 25% inhibition of erythr ocyte cholinesterase activity at the 2-mg/kg-dose level. The conclusions regarding both the durati on and magnitude of inhibition depend upon the inclusion of this partic ipant, and the lack of follo w-up in this participant beyond 48 hr thereby limits the interpretation of the results.

3. The reported statistical anal yses of these data are highly problematic, and the results in Appendix 3 were judged to be clearl y wrong. Specifically, it was noted that a univariate repeated measures ANOVA was performed (Kisicki et al . 1999, 25), and Appendix 3 summarizes the results of such analyses (Kisicki et al . 1999, 151-158, 184-188, 206-211). 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 al . 1999, 24). The report indicates that the Group Mean Square (Kisicki et al . 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 Individua l 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 al . 1999, 25) also indicates that mixed effects models were used where gende r and treatment were considered to be fixed factors, and that time was consider ed to be a random continuous covariate. According to the mixed model analyses repo rted in Appendix 3, time is treated as a continuous covariate, but not as a random c ontinuous 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.

Page 22 of 404. Plasma cholinesterase activity was not determined in the study. It is recognized that the erythrocyte cholinestera se activity is more biologi cally relevant for assessing potential adverse effect of chlorpyrifos, and as such, the lack of data on plasma
cholinesterase is not a serious limitati on. 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 measurem ents of erythrocyte acetylcholinesterase activities were generally reliab le. However, Board members cautioned that the incomplete profile obtained from the only subject who showed inhibition at the 2 m/kg dose level limited the utility of the data. Moreover, the Board recomm ended that, although the data might be reliable, the statistical analyses in genera l and particularly for the data in Appendix 3 should be replicated prior to applying these resu lts to any risk assessment or model development.

Ethics

Charge to the Board

Is there clear and convincing eviden ce that the conduct of the Kisicki et al. (1999) study was fundamentally unethical, or significantly de ficient relative to th e standards of ethical research conduct prevailing when it was conducted?

Board Response to the Charge

HSRB Recommendation

The Board concluded that there neither wa s 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 st andards prevailing at the time the research was
conducted.

HSRB Detailed Recommendations and Rationale

According to documents supplied by the s ponsor (Juberg and Mattsson 2009a, Juberg and Mattsson 2009b), the study was conducted in accordance with US Food and Drug Administration rules relating to th e 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 review ed and approved by the
MDS Harris Institutional Review Board. The co nsent of all participants was obtained and documented through the use of a cons ent form approved by that IRB.

1. The Board concurred with most of the conc lusions 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

Page 23 of 40Agency on June 23, 2009 and described in deta il below (Kisicki 2009), the Board found no clear and convincing evidence that the study wa s fundamentally unethi cal or significantly deficient in its design and conduct. Following the public meeting, additional supplementary material (including copies of MDS Harris La boratories 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 cont ained therein do not meet the evidentiary
standard of clear and convinc ing evidence that the study was fundamentally unethical or significantly deficient relative to the ethical standa rds 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 recr uitment, consent and screening process.

2. The Board concluded that th is study met all applicable ethica l requirements for such research involving human participants, in acco rdance to the following criteria:

a. Not fundamentally unethical . With regard to determining whether or not a study is fundamentally unethical, the Boar d’s standard is to decide if the research was intended to seriously harm participants, or if it faile d 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 reas ons it might have been fundamentally unethical, the Board concludes that it was not fundamentally unethical.

b. Not significantly deficient . With regard to determining whether a study was significantly
deficient relative to the ethical standard s prevailing at the time the research was conducted, the Board’s standard is to determin e whether or not any ethical deficiencies
identified could have resulted in seri ous 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 avai lable 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 test s (urine and blood sampling) prior to signing the written consent fo rm. According to materials provided to the EPA and made public on the day of the Board’s di scussion of this study (Kisicki 2009), volunteers were given a copy of the approve d consent form and required to listen to an audiotape about the study before they ag reed 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 scr eening. Although the failure to have potential participants and alternates sign an informed consent form pr ior to screening could be a violation of

Page 24 of 40applicable FDA regulations, given these ci rcumstances 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 a ddition, portions of that fo rm were written at an inappropriately high reading level. Taken as a whole, however, the informed consent document does appear to have provided pr ospective subjects with an accurate and understandable picture of the likely risks fr om 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 (Pic aridin; Icaridin) - Ba sed Personal Insect Repellents (20% Cream and 20% Spray) 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-rear ed 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 init ial study had to be
aborted because the stable flies did not show suffic ient biting pressure for a valid repellency test. Adjustments were subsequently made in the husb andry of the flies to insure that they were sufficiently hungry to bite the test subjects in the testing perio d, 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 perspectiv e, to be used to assess the repellent efficacy of the tested formula tions 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 th e repellent efficacy agains t stable flies of the formulations tested. However, some of the data presenta tion requires revision.

Page 25 of 40HSRB Detailed Recommendations and Rationale

ICR was responsive to Board concerns a nd recommendations of the previous Board review (EPA HSRB 2008). These responses in cluded the use of a dosimetry phase for dose
determination and the inclusion of individuals from racial minor ities in the test population. The study also used the time to first bite as the cr iterion, 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). On e female participant served as an untreated control to verify landing pressure . The total number of study partic ipants is higher than the EPA guidelines recommend. Study doc uments (Gaynor 2009, Gaynor et al. 2009) indicated that, according to ICR’s database, landings underestimat e bites. Thus, bites were selected as the endpoint despite earlier Board recommendations concerning participan t safety (EPA HSRB 2008). Nevertheless, in order to obta in scientifically valid data us eful 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 participan ts from the potential toxicity of the repellent.

Statistical analyses were generally appropr iate. 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 ha ve 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 determ ination 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 substantia l 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 a pplicable. The study was reviewed and approved

Page 26 of 40by 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 benef its, 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-count er pregnancy testi ng on the day of study or by opt-out. The potential stigma resulti ng from study exclusion due to pregnancy was also appropriately minimized.

• Based on toxicological data currently av ailable 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. St able fly bites, however, usually cause only minor symptoms and are readily treated w ith over-the-counter antipruritic lotions.

• The study was conducted with laboratory-rai sed flies free of known pathogens. This latter point, in particular, resulted in th e one notable change to the protocol. At its initial review, the HSRB reco mmended that the stable flie s be raised on 10% sucrose rather than bovine blood meals, thus minimi zing 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 entomol ogist, ICR researchers concluded that the stable flies “[overfed] on the 10% sucrose so lution, 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 regime n to dry sugar cubes; 2) increasing the numbers of stable flies used per cage; a nd 3) increasing the length of participant exposure to stable flies to determine attr activeness. These changes were submitted to EIRB, Inc. as protocol amendments a nd approved prior to implementation. This protocol change was unlikely to have incr eased the risk of study participants or compromised the informed consent process.

b. Voluntary and informed c onsent of all participants

Page 27 of 40• The study protocol included several mech anisms 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 recru itment 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 IRB 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 mee ting minutes that offer a desc ription of IRB deliberations and debate of intentional exposure protocols. It is unlikely that th ese deficiencies placed study participants at risk or compromised the informed consent process, but they do represent a deviation from th e expectations of 40 CFR 26.

b. The sponsor and IRB of record should en sure that all telephone scripts and other recruitment materials, and informed cons ent documents be reviewed prior to study
initiation to ensure that the information cont ained 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 durati on 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 surgic ally sterilized) to opt-out of over-the-counter pregnancy testi ng. This deviation, however, was unlikely to have compromised the informed consent pr ocess as potential study participants were informed of these protocol changes later when formally consented at the ICR facility.

Assessment of Proposed Carroll-Loye Biological Research Study LNX-002: Efficacy Test of KBR 3023 (Picaridin; Icaridin) - Based Person al Insect Repellent s (20% Cream and 20% Spray) with Biting Flie s Under Field Conditions.

Overview of the Study

The protocol describes a study to test the effi cacy of two formulations (lotion and spray) of 20% picaridin in the field ag ainst at least one of 4 species of biting flies. Dosimetry data recently accumulated in a previous study (LNX- 001) 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.

Page 28 of 40Repellent-treated skin would be exposed for 5 mi nutes in each 30-minute in terval until repellent failure. The endpoint would be the “Lite with Intent to Bite” (LIB e), and the criterion for data to calculate complete protection time would be first confirmed LIBe.

Science

Charge to the Board

If the proposed field repelle ncy study protocol LNX-002 is re vised as suggested in EPA’s review and if the research is performed as de scribed: Is the resear ch 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 asse ssment (Carley and Sweeney 2009) that this protocol will provide scientific ally valid results on the efficac y of two picaridin formulations against biting flies, with modification as noted be low. 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 cl arity. The study protocol and asso ciated 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 insuffici ently 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 just ified (Carley and Sweeney 2009). The Board concurred with both of these concerns, and reco mmended that they be addressed in the revised protocol as possible.

Additional Board recommendations concerned two issues: 1) the pa rticular species on which data would be accumulated; and 2) the calculation of complete protection time.

With respect to the species tested, although f our 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, th e Agency indicated that it already had some useful data on some species of biting flies – su ch as stable flies – accumulated in the laboratory.

Page 29 of 40The 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, othe r types of biting flies should not be considered acceptable substitutes.

Echoing earlier concerns about the types of calculations and st atistical 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 type s of statistical analyses. Mean pr otection time versus the duration of the study should be clarified, part icularly as it affects the prev alence of censored data. The study’s duration should be sufficientl y long to ensure that the repe llent will fail for a substantial portion of study participants, thereby limiting the o ccurrence of right-censored data. The protocol should also be revised to clarify how the analys is will proceed in the presence of censored data (using Maximum-likelihood or Kaplan-Meier methods).

In the context of this and other insect re pellency 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 repelle ncy study protocol LNX-002 is re vised as suggested in EPA’s review and if the research is performed as describe d: 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 st udy 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 mon itoring (California Code of Re gulations Title 3, Section 6710) (Carroll 2009). The requirements of FIFRA §12(a)(2)(P) also apply. The protocol was reviewed

Page 30 of 40and approved by an independent human subjects re view committee, Indepe ndent 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 requi rements for research involving human participants, in accord ance with the following criteria:

a. Acceptable risk-benefit ratio . The risks as noted in the st udy protocol are five-fold: 1) allergic reaction to test materials themselves ; 2) exposure to biting arthropods; 3) possible exposure to arthropod-borne diseases; 4) physic al stress from the test conditions; and 5) psychological stress and/or breach of confid entiality for pregnancy test results. These risks are minimized appropriately and are ju stified by the potential societal benefits, particularly data on the efficacy of these ne w formations as personal insect repellents.

• Based on toxicological data currently av ailable 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 like lihood of biting fly and mosquito bites, through the use of: LIBes rath er than actual confirmed b ites as a study endpoint; prebite removal and joint obse rvation; clear stopping rule s; limited exposure periods. Study participants will be trained in proper insect observation and handling techniques.

• Biting fly and mosquito bites, should they occur, are us ually mild and easily treated
with over-the-counter steroi dal creams. The study will also exclude participants who have a history of severe skin reactions to such bites.

• To minimize the risk that study participan ts will be exposed to pathogens like West Nile Virus – not transmitted by the biting f lies in question but via other arthropods that may be present at the field sites – th e study will be conducted only in areas where
known vector-borne diseases have not been detected by county a nd state health or vector/mosquito control agencies for at leas t 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-borne pathogens ar e 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-bor ne pathogens—including West Nile Virus, Western Equine Encephalitis Virus, and St. Louis Encephalitis Virus—with clear plans to contact study participants a nd alert them if a transmissible pathogen is detected.

• The potential risks to participants from environmental stress are minimized by the provision of a climate contro lled 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.

Page 31 of 40• Minor and pregnant or lactating women are excluded from participation, with pregnancy either confirmed by over-the-count er pregnancy testi ng 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 c onsent of all participants

• The study protocol includes several mech anisms 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 pa rticipants 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 invest igators 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 (Carle y and Sweeney 2009). In addition, the Board
recommended that the inves tigators clarify of what “3 rd party” medical coverage means, as
listed in the current informed consent document.

Assessment of Proposed AHETF Scenario a nd Protocol AHE-120: Water-Soluble Packing Mixing and Loading.

Overview of the Study

This proposal presents an agricultu ral handler exposure scenario involving mixing/loading of pesticides enclosed in wate r-soluble packets (WSP). The protocol calls for study participants to mix and load one of two WSP-enclosed surr ogate 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 differe nt 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 wi pe samples will also be collected prior to, during, and after completion of pesticide loading and mixing procedures. Airborne concentrations of the surrogate will be monitore d in the participant’s breathing zone using an OSHA Versatile Sampler (OVS) tube sample co llector connected to a personal sampling pump.
Additional measures will also record environmen tal conditions at the time of monitoring, and observers will make field notes, photographs and vi deos of participant ac tivity throughout the

Page 32 of 40monitoring event.

The results of sample analysis under th e 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 an alysis. The proposed documentation will report a confidence-interval-based approach to determin e the relative accuracy for the arithmetic mean
and 95 th percentile of unit exposures. The Agency pr oposes to use these data to estimate daily dermal and inhalation exposures of agricultural handlers who are mixing/lo ading 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 pr otocol AHE120 is revised as suggested in EPA’s review and if the research is performed as described: Is the res earch likely to generate scientifically reliable data, useful for asse ssing 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 da ta in this area, the Board concurred with the Agency’s assessment (Evans and Sherman 2009) th at this protocol will generate data that are scientifically valid and that may be useful for assessing the e xposure 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 e xposure only if worker exposure is found to be proportional to the am ount of active ingredie nt handled (AaiH).

The Board also recommended a number of prot ocol modifications, as listed below.
Additional Board review of th e protocol is not required prior to study implementation.

HSRB Detailed Recommendations and Rationale

The Board concluded that the proposed m onitoring and quality assurance and control methods appear adequate, particularly in th e supplemental SOPs provided by the AHETF in response to the Agency’s initia l science and ethics review (C ollier 2009b; Evans and Sherman 2009). The protocol and supplemental SOPs ade quately address a number of key scientific issues, including: the scientific objective, the quantification of the test materials, the data collection and compilation methods a nd summary of test results, the justification for selection of the test substances, and the QA/QC requirement s. The Board also commended the AHETF 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 relate d protocols. The protocol presented to the Board was well thought out and written as a result.

Page 33 of 40The 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 ina ppropriate statistical analyses. The Board raised many of these issues previous ly when it reviewed earlier AHETF protocols. Both the AHETF and the Agency will need to acknowledge the limitations of the study design that occur in the AHETF 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 wide r regulatory purposes that these data will be used for. Some Board members expressed the co ncern, for example, once these data are inside
the AHED ® database, some users may overlook the lim itations of the original study design and use the data to generate the typical statistical distribut ions in error.

Illustrating this point, the Bo ard raised concerns about the types of statis tical analyses proposed for the water-soluble packing scenario presented here. The proposed study will rely on a purposive sampling strategy, for example, but th e 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. Ther e is no statistical th eory that can be applied to non-random samples of this type. Th us, 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 work er exposure and AaiH. In particular, the Board disagreed with the Agency’s assessment that “p ast 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 exp ect 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 AHETF to the Agency’s FIFRA Sc ientific 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 exposur e and AaiH, including ecological, engineering,
and statistical factors. As subm itted, 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 ecologica l variables that may influence worker exposure, including: environm ental 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 ac tive ingredient being monitored. Myriad sources of na tural variation are likely to have a marked impact on worker exposure. Given the relatively small sample si ze of each monitoring cluster in this exposure scenario, these sources of natural variation will li kely introduce considerable estimation bias into
the final data.

Finally, current consensus is that estimate s 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 valida te the actual population data and determine whether the resulting estimates fall within this necessary range.

Page 34 of 40Ethics

Charge to the Board

If the proposed mix/load WSP field study pr otocol AHE120 is revised as suggested in EPA’s review and if the research is performed as described: Is the res earch likely to meet the applicable requirements of 40 CF R 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 st udy 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 §12(a)(2)(P) and, where applicable, the California State EPA Depart ment 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 requi rements for research involving human participants, in accord ance with the following criteria:

a. Acceptable risk-benefit ratio . The risks as noted in the st udy 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 st ress and/or breach of confid entiality for pregnancy test results. These risks are minimized appropriately and are justified by th e potential societal benefits, particularly data on occupational expo sure of agricultural workers to pesticides during mixing and loading activities.

• The greatest risk to participants is that of heat-related illn ess, given that the participants will be required to wear tw o layers of clothing during the scenario
activities. This risk is lessened but not el iminated by the applic ation of appropriate stopping rules (including cessation of all m onitoring activities when the ambient heatindex exceeds 105 ° F) and frequent monitoring of pa rticipants. Participants will be

Page 35 of 40given 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 procedur es are also in place.

• The surrogate materials consist of two co mmon pesticides, acephate and carbaryl, both of which have been extensively teste d. The participants will only be exposed to concentrations of the surrogate comp ound at accepted exposure thresholds.

• Participants will be selected from vol unteers with experience handling these or similar compounds in WSP mixing and loading s cenarios. Thus, all of the participants will have extensive experience in using thes e or similar products, and thus unlikely to misuse them in a way that might increa se their likelihood of being accidentally exposed.

• Participants will be reminded about safe handling practices and procedures, wear appropriate PPE, and will be monitored fo r 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-count er pregnancy testi ng 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 c onsent of all participants

• There is the possibility that the participants in this study might re present particularly vulnerable populations, susceptible to coercion and undue influence. The study protocol, however, includes several m echanisms designed to minimize coercive
recruitment and enrollment.

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

• Spanish translations of the informed cons ent documents, informational packets, andrecruitment flyers were provided. Researchers will be working with local Spanishspeaking community members to ensure th at the appropriate regional dialect of Spanish is used.

c. Equitable selection of study participants

• The study is designed to recru it an appropriately diverse population of participants who represent skilled agricultural workers in the 5 study locations.

Page 36 of 40• 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 a nd Sherman 2009). In addition, the Board also
addressed three concerns of the Agency and the sponsors (C ollier 2009c) with respect to representativeness, language, and re lease of individual exposure data.

• The Board recommended that the AHETF im plement 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 in formed consent and related documents are likely to yield translations that are writt en in the appropriate regional dialect of Spanish.

• The Board commended the Task Force for wanting to release individual exposure data to participants promptly but recomme nded that these data only be released once the study is complete, except in those instan ces 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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