# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 1 of 24 EPA

- HSRB

- 11

- 01 Paul Anastas, PhD EPA Science Advisor Office of the Science Advisor 1200 Pennsylvania Avenue, NW Washington, DC 20460 Subject: January

26, 2011 EPA Human Studies Review Board Meeting Report Dear Dr. Anastas, The United States Environme ntal Protection Agency (EPA or Agency) requested that the Human Studies Review Board (HSRB) provide scientific and ethics reviews of one new protocol for a study involving intentional exposure of human subjects to pesticides: a proposed Agricu ltural Handle r Exposure Task Force, LLC (AHETF) scenario measuring dermal and inhalation exposure of professional agricultural workers who perform open mixing and loading of pest icides formulated as wettable powders. The Agency

also requested that the HSRB review fi ve completed, interrelated studies of dermal and inhalation exposure of professional agricultural handlers who spray pesticides with closed

- cab airblast equipment, conducted b y the AHETF. These studies (AHE55, AHE56, AHE57, AHE58 and AHE59) were conducted after publication of the EPA’s expanded final rule for protection of subjects in human research (40 CFR 26) on February 6, 2006 (71 Federal Regi ster 24, 6137). These studies were conducted under a single scenario monograph (MRID 48314201), which incorporat es the data from these five studies into a single dataset. This dataset will be posted to the Agricultural Handlers Exposure Database (AHED®), and used genericall y to estimate daily

dermal and inhalation exposures of workers who treat agricultural crops wi th conventional pesticides using closed

- cab airblast equipment. The enclosed report provides the Board’s response to EPA charge questions presented at the January

26, 2011 meeting. Assessment of Proposed AHETF Research Study AHE80: Determination of De rmal and Inhal ation Exposure to Workers During Mixing/Loading Wettable Powders in the United States

. Science The Board concluded that the proposed AHETF scenario and field study proposal AHE80, if revised as suggested and performed as described, is like ly to generate scientificall y reliable data, useful for assessing the exposure of handlers who perform open mixing and loading of pesticide end use products formulated as wettable powders.Final Draft Document Dated March 1 1, 201 1

Page 2 of 24 Ethics The Board concluded that the proposed AHETF scenario and f ield study proposal submi tted for review, if revised as suggested and performed as described, is likely to meet the applic able requirements of 40 CFR 26, subparts K and L. Assessment of Completed AHETF Research Studies AHE55, AHE56, AHE57, AHE58 and AHE59 : Determination of Dermal and Inhalation Exposure to Workers During Airblast Applic ations of L iquid Spray s Using Closed Cab Equipment (MRID 48280601, 48289602, 48303501, 48289604 and 48303502)

. Science The Board concluded that the research reported in the completed monograph, associated field study

reports, and associated supplemental documents was conducted in a manner that was reasonabl y faithful to the design and objectives of the protocol and governing documents of the AHETF. The Board also conclu ded that the Agency has adequatel y, but not completely, cons idered the limitations on these data that should be considered when using the data in estimating the dermal and inhalation exposure of those who apply conventional pesticides with closed

- cab airbl ast equipment. Additional limitations and concerns have been identified by the Board, and the conclusion as to the generalizability of these data requires further consideration and anal ys is. Ethics The Board concluded that the study was conducted in subs tantial compliance with subparts K and L 40 CFR 26. Sincerel y,

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

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 3 of 24 NOTICE This report has been written as part of the activities of the EPA Human Studies Re view Board, a Federal advisory committee providing advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research. This report has not been reviewed for approval by the Agency

and, hence, the content s of this report do not nece ssarily represent the view and policies of the Environmental Protection Agency , nor of other agencies in the Executive Branch of the Federal government, nor does the mention of trade names or commercial products constitute a rec ommendation for use. You may obtain further information about the EPA Human Studies Review Board from its website at http://www.epa.gov/osa/hsrb

. You may also contact the HSRB Designated Federal Officer, via e - mail at ord

- osa - hsrb@epa.gov In preparing this document, the Board carefull y considered all information provided and presented b y the Agency presenters, as well as information presented b y public commenters. This document addresses the information provided and presented within the structure of the charge b y the Agency

.Final Draft Document Dated March 1 1, 201 1

Page 4 of 24 US ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD Chair Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bio ethics Program of Union Graduate College and the Mount Sinai School of Medicine, Schenectady, NY Vice Chair Janice Chambers, PhD, DABT, Fellow ATS, William L . Giles Distinguished Professor, Director, Center for Environmental Health Sciences, College of V eterinary Medicine, Mississippi State University , Mississippi State, MS Members George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada

Reno Center for Research Design and Anal ys is, University of Nevada

- Reno, Reno, NV Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor of Health Policy

and American Studies, The George Washington University , Washington, DC Sidney Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharma cology , Howard University

College of Medicine, Washington, DC Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University , Manhattan, KS Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, Univ ersit y of Arizona, Tucson, AZ Jose E. Manautou, PhD, Associate Professor of Toxicology , Department of Pharmaceutical Science, University

of Connecticut School of Pharmacy , Storrs, CT Jerry A. Menikoff, MD, JD, Director, Office for Human Subjects Researc h, Office of the Secretary , Department of Health and Human Services, Rockville, MD *Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH) Human Risk Assessment, School of Public Health and Human Services, The George Washington University , Washington, DC William Popendorf, PhD, MPH, Professor Emeritus, Department of Biology, Utah State Unive rsity , L ogan, UT Virginia Ashby

Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, Vete rans Health Administration, Washington, DC

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 5 of 24 Linda J. Yo ung, PhD, Professor, Department of Statistics, Institute of Food and Agricultural Sciences, University

of Florida, Gainesville, FL Human Studies Review Board Staff Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science Advisor, United States Environmental Protection Agency , Washington, DC * Not in attendance at January 26, 2011 Public MeetingFinal Draft Document Dated March 1 1, 201 1

Page 6 of 24 INTRODUCTION On January

26, 2011, the United States Environmental Protection Agency ’s (EPA or Agency) Human Studies Review B oard (HSRB) met to address scientific and ethical issues co ncerning one new protocol for research involving human participants: one new study measuring levels of exposure received by agricultural handlers when mixing and loading pesticides formulated as we ttable powders under various conditions. In accordance with 40 CFR 26.1601, EPA sought HSRB review of this proposed protocol. The protocol is discussed more fully below. In addition, the Agency

has data from five completed, interrelated studies measuring l evels of dermal and inhalation exposure received by pesticide applicators who spray pesticides with closed

- cab airblast equipment. These studies were conducted under a single scenario mon ograph (MRID 48314201), which incorporates the data from these five studies into a single dat aset. In accordance with 40 CFR 26.1602, EPA sought HSRB review of these five completed studies. The completed studies are discussed more fully below.
REVIEW PROCESS On January

26, 2011, the Board conducted a public face

- to

- face meeting in Arlington, Virginia. Advance notice of the meeting was published in the Federal Register as “Human Studies Review Board; Notice of Public Meeting” (76 Federal Register 8, 2107). Following welcoming remarks from Agency officials, the Board heard presentations from EPA on the following topics: one new study measuring levels of exposure received b y agricu ltural handlers when mixing and loading pesticides formulated as wettable powders under various conditions, and five completed studies measuring dermal and inhalation exposure received b y pesticide applicators who spray pesticides with closed

- cab airblast equipment. The Board also asked clarifying questions of several study sponsors and/or research i nvestigators, including: Dr. Victor Cañez, Te chnical Chair, Agricultural Handler Exposure Task Force (AHETF) Public oral comments were provided b y: Dr. Victor Cañez, Technical Chair, AHETF One written public comment was submitted by Ms. Barbara Sachau of Florham Park, NJ (writing under the pseu dony m Ms. Jean Public). That comment did not specificall y address an y of the completed studies or proposed protocols under review at the January 26, 2011 meeting. For their deliberations, the Board considered the materials presented at the meeting, oral c omments, and Agency

background documents (e.g., published literature, sponsor and investig ator research reports, study protocols, data evaluation records, and Agency science and ethics r eviews of proposed protocols and completed studies). A comprehensive l ist of background doc uments is available online at http://www.regulations.gov

.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 7 of 24 CHARGE TO THE BOARD AND BOARD RESPONSE Assessment of Proposed AHETF Research Study AHE80: Determination of Dermal and Inhalation Ex posure to Workers During Mixing/Loading Wettable Powders in the United States . Overview of the Study This proposal presents an agricultural handler exposure scenario involving pesticides formulated as wettable powders. The activities to be monitored in this scenario include a variet y of mixing and loading activities, including pouring the wettable powder into a spray tank, preparing the pesticide in a separate holding tank and then transferri n g the formulated product into the pesticide application equipm ent, and mixing and transferring a concentrated slurry of the pest icide. The protocol calls for study participants to mix and load one of four surrogate pesticides: copper, DCPA (dacthal), sulfur or thi o phanate

- methyl. A total of 25 participants (described in the protocol as “Monitoring Units” [MUs]) will be observed for each scenario; five volunteers each from five geographically distinct growing regions will be enrolled using a purposive sampling method (with some elements of random selection). Dermal e xposure will be measured by a whole body

dosimeter worn beneath the subject’s outer clothing. Hand wash and face/neck wipe samples will also be collected prior to, during, and after completion of pesticide loading and mixing procedures. Airborne concentrations of the surrogate will be monitored in the participant’s breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector connected to a personal sampling pump. Additional measures will also record environmental conditions at the time of moni toring, and observers will make field notes, photographs and videos of participant activity throughout the monitoring event. The results of sample analy sis under the backpack and handgun application scenario will be posted to the Agricultural Handlers Exposure Database (AHED®), where they will be avail able to the EPA and other regulatory agencies for statistical anal ys is. The proposed documentation will report a confidence

- interval

- based approach to determine the relative accuracy for the arithmetic mean and 95th percentile of unit exposures. The Agency proposes to use these data to e stimate daily

dermal and inhalation exposures of agricultural handlers who are mixing and loa ding pesticides formulated as wettable powders under a variety of scenarios.
Scie nce Charge to the Board If the proposed AHETF scenario and field study proposal AHE80 is revised as suggested in the EPA’s review and if the research is performed as described, is the research likel y to gene rate scientificall y reliable data, useful for assessing the exposure of handlers who perform open mixing and loading of pesticide end use products formulated as wettable powders?Final Draft Document Dated March 1 1, 201 1

Page 8 of 24 Board Response to the Charge HSRB Recommendation The Board concurred with the Agency ’s assessment that the proposed A HETF scenario and field study

proposal AHE80, if revised as suggested in EPA’s review (Evans et al. 2010) and performed as described, is likely to generate scientifically reliable data, useful for assessing the exposure of handlers who perform open mixing and loading of pesticide end use products formulated as wettable powders.
HSRB Detailed Recommendations and Rationale The Board concluded that the research is likel y to generate scientifically reliable data, useful for assessing the exposure of handlers who perform open mixing and loading of pesticide end use products formulated as wettable powders. However, one significant concern was raised about how the new MUs should be distributed among the proposed strata particularl y to achieve the second stated g oal of the research. Several other less pressing questions were raised concerning information that was not presented clearl y within the protocol. A significant concern was expressed about how the new MUs should be distributed across the strata of amount of active ingredient handled (AaiH). On page 8 of 58 (and in essence again on page 14) in the Agency ’s Review, the Agency states its desire that “the AHETF must ensure that all strata be used in each of the four remaining clusters” (Evans et al. 2010, 8). That desire may

or may not be a conflict with an extrapolation of a statement on page 27 and 33 of that same document states a conclusion from the AHETF computer simulation runs that: the primary

benchmark will still be satisfied providing: • The tota l number of new MUs is at least 20; and • No new cluster has more than five MUs. This rule implies that if a new cluster has fewer than 5 MUs then more than 4 new clu sters will be necessary

(Evans et al. 2010, 27). While this conclusion was based on the distribution of MUs among clusters, it may also appl y to the distribution of MUs among strata. If the five MUs in each new cluster include all five of the strata, there will be four new MUs at each stratum. When these four MUs are added to the five MUs that were already co mpleted within the middle stratum, the final distribution of MUs across the five strata will be: 4, 4, 9, 4, and 4. Such a distribution is not optimal to achieve the secondary objective of 80% power to test for proportionality

betwe en dermal exposure and AaiH. Power is increased when more o bservations are made at extreme values of AaiH, whereas the middle set of values will be over sampled here. The Board recommended using further simulations to explore the effect of the di stribution of MUs among AaiH strata on the power associated with Objective 2, viz. the proposed distribution , making allocations so that the number of MUs is the same within all strata, or having an allocated distribution intermediate to these two extremes.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 9 of 24 The primary

objective is to estimate the geometric mean, the arithmetic mean, and the 95th percentile of exposure within 3

- fold with 95% confidence. To be meaningful, the popul ation for which these quantities are being estimated must be clearl y defined. By des ign, five di fferent regions, involving different crops were chosen, and the mean exposure could change with region. Further, within a region, AaiH is purposively different for each monitoring unit. The mean exposure for each region

- AaiH combination is like ly to be different. Thus, it is unclear what the sample mean (the mean of the 25 region

- AaiH combinations) is estimating. Because the sample mean depends heavily on the design, the validity of this Objective is questionable. A second concern is whether the last of four “restrictions” listed on page 9 of the Age ncy ’s assessment, to be employed when selecting MUs, is adequate to both include all three pos sible way s to mix and load wettable powders into the various spray tanks. This restriction is states th at, When mixing/loading procedures in a given area involve participants either pouring directl y into the application tank, using pre

- mix tanks (holding dilute spray s), or slurry tanks or buckets (holding concentrate spray s), then the MUs may not all be a ssociated with the same equipment and procedure category (Evans et al. 2010, 9). Although the Board agreed with the desire of the Agency a s stated in the meeting that all three sub

- scenarios should be included in each new cluster, such a statement was not found within e ither the proposal or the Agency ’s Review. The exact nature of the agreed upon restriction should be clarified. A somewhat related suggestion was made (without a particular recommendation) that the proposal makes no attempt to assess the limited breadth of equipment or/and processes that will be assessed in the context of possibly w ider range used in the field. A particular challenge (and possible concern) is to ensure that the exposures that are assessed in a given study d o not und erestim ate the exposures to those applicators who use equipment or processes that are specialized for or relegated to small loads or/and small acreages (some of these were discussed on page 30

- 31 of the Meeting Minutes of the FIFRA Scientific Advisory P anel Meeti ng held January , 2007 on the Review of Worker Exposure Assessment Methods [FIFRA Scientific Advisory P anel. 2007]; see also page 14 and 42

- 43 of the same Meeting Report). In this regard, it may not be su fficient in such a proposal (or future reports) to as k experts just “how the selected employers and equipment compare to the local population of similar employers” (i.e., are the equipment or/and processes ty

pical?). They should also be asked about the extent to which the selection process excluded an y speci alized equipment or processes, e.g., those specialized for use in small loads. Such information could be used to inform the Agency of limitations to the end result.
A question was raised regarding the appropriateness of the proposed range of AaiH va lues, in particular the feasibility o f achieving the upper two strata (viz., 183 to 603 and 604 to 2000 lb a.i. handled). This question was raised because the highest stratum proposed for the OPM/Ls cenario is up to 20 times larger than the range of AaiH studie d in AHE80 study o f closed

- cab airblast (CCAB) applications. H owever information pointed to on page 36

- 37 of 403 of the Wettable Powder Mixer/L oader Scenario Submission showed that it is feasible to appl y up to 350 acres per day

v ia aircraft, and examples of product labels obtained later from the webFinal Draft Document Dated March 1 1, 201 1

Page 10 of 24 show that wettable sulfur can be applied to grapes at rates of up to 20 lb./acre (Collier 2010a, 36

- 7). Based on the label’s maximum rate of application of sulfur on grapes (a pair of scenarios i ncluded within the proposal), then mixing/loading up to 7000 lb. in a day i s feasible, well above the proposed upper limit. Three points of clarification were raised concerning the proposal. First, the last sentence in the first paragraph of page 19 of 403 of the W ettable Powder Mixer/L oader Scenario Submi ssion seems to indicate that a large overhead is better when it comes to cost (Collier 2010a, 19). A large overhead would not make the study less expensive, but more expensive, and thus less cost effective. For a g iven outcome the less expensive option is more cost effective, the more expe nsive one is less cost effective. The latter is the case with a high overhead. Second, if one e xamines the table on page 31 of 403 of the Wettable Powder Mixer/L oader Scenario Sub mission, the numbers for total a.i. usage are all in decreasing order until the items of strawberries and cherries (Collier 2010a, 31). This appears to be an error, but should be clarified. Finall y, the first paragraph page 273 of 403 of the Wettable Powd er Mixer/L oader Scenario Submission discusses “drugs and devices” (Collier 2010a, 273). However, there are no drugs or devices that are a part of this scenario. Perhaps this verbiage was copied from the referenced document that came from the Department of Health and Human Services and in all likelihood pertained to the FDA, and either “pesticides” or “chemicals” should be stated.
Ethics Charge to the Board If the proposed AHETF scenario and field study proposal AHE80 is revised as suggested in the EPA’s review and if the research is performed as described, is the research likel y to meet the applicable requirements of 40 CFR 26, subparts K and L ? Board Response to the Charge The Board concluded that the protocol submitted for review, if modified in acco rdance with EPA (Parsons and Sherman 2011) and HSRB recommendations, is likely to meet the appl icable requirements of 40 CFR 26, subparts K and L. HSRB Detailed Recommendation and Rationale The submitted documents assert that the study will be conducted in accordance with the ethical and regulatory

standards of 40 CFR 26, Subparts K and L, as well as the requirements of the US EPA’s Good Laboratory

Practice (GLP) Standards described at 40 CFR 160, and, for research conducted in California, the California State EPA Department of Pesticide Regulation study monitoring (California Code of Regulations Title 3, Section 6710) (Ref 2010). Requirements of FIFRA §12(a)(2)(P) also apply . Researchers who participate in the study and interact with study participants w ill be required to undergo ethics training. The training will include the successful completion of the course from the National Institutes of Health (Protecting Human Research Participants) and/or the Basic Collaborative IRB Training Initiative Course.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 11 of 24 The protocol was reviewed and approved b y an independent human subjects review committee, Independent Institutional Review Board, Inc. (IIRB, Inc.) of Plantation, FL prior to submission. IIRB, Inc. is fully accredited by

the Association for the Accreditat ion of Human R esearch Protection Programs (AAHRPP). IIRB, Inc. is also listed as an active Institutional Review Board (IRB) on the Office of Human Research Protection (OHRP) website (Reg. #I ORG0002954). Minutes of IIRB, Inc. meetings and a cop y of IIRB, In c. policies and proc edures were provided to the Agency (IIRB, Inc. 2010). These documents indicate that IIRB, Inc. reviewed this protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A). 1. Except as noted below, the Board concurred with the conclusions and factual observations of the ethical strengths and weaknesses of the study, as detailed in the EPA’s Ethics Review (Parsons and Sherman 2011). The proposed study is likely to meet the applicable ethical r equirements for researc h involving human subjects, in accordance with the following criteria:

a. Acceptable risk

- benefit ratio . The risks as noted in the study protocol are fourfold: 1) The risk of heat

- related illness. The study will likely

involve an increased risk of heat

- related illness due to study participation. All participants in the study will be wearing an extra layer of clothing that they would not normally

wear when mixing and loading wettable powder formulations into a pre

- mix or application tank and d iluting it under such conditions. In addition, mixing/loading activities might occur i ndoors or outdoors and some locations and dates are likely to result in hot and/or humid conditions. 2) The risk associated with scripting of field activities. Inorder to ensure all monitoring units (MUs) involve handling at least three loads, AHETF may ask some workers to use a smaller tank size than they would normall y s elect or dilute the product more than usual. This might lead to a slightl y longer work period for those worker s which may increase the risks of acute toxicity to the surrogate chemical and of heat

- related illness. 3) Exposure to surfactants. A very dilute surfactant solution (0.01% v/v Aerosol® OT in water) is used as a surfactant for face/neck wipes and hand wa shes for all MUs. This surfactant is in a very

dilute solution and its use represents a very short exposure p eriod, but the undiluted surfactant causes mild to moderate skin and eye irritation in animals. 4) Psychological risks. Participating in AHETF exp osure monitoring studies involves activities that are unusual and might cause subjects psychological distress. These i nclude performing an over

- the

- counter pregnancy test prior to participation (females only) and allowing a researcher to assist with the re moval of the whole body dosim eter. Participating in AHETF exposure monitoring studies involves activities that are unusual and might cause subjects psychological distress.Final Draft Document Dated March 1 1, 201 1

Page 12 of 24 AHETF has proposed several procedures to minimize these risks: 1) Monitoring and stopping procedures will be instituted. The AHETF will monitor ambient conditions to determine the heat index near the mixing/loading station and base monitoring decisions on the current heat index. Exposure monitoring will be disco ntinued if the heat inde x cutoff of 105 F (adjusted for direct sun, if applicable) is reached or exceeded. The Study Director or other researcher shall stop the monitoring and/or move the worker to a cooler environment until monitoring can be resumed. If necessary , some monitorin g will take place at night or earl y in the morning to avoid excessively

hot and humid conditions. 2) Clear inclusion/exclusion criteria have been established. Only experienced pesticides handlers who consider themselves in good health will be included in the study . Exp erience with the mixing/loading equipment to be used in the study and with the mi xing/loading wettable powder products will be required of all participants. Participants must also understand Spanish or English. 3) Workers will be reminded of safe chemical handing practices and research staff will practice the face wipe and hand wash procedures with each participant before pesticide handling begins. 4) Appropriate medical management procedures are in place. Eye rinse stations will be on hand in case of an accidental exposure. Medical treatment facilities will be identified in case of an emergency . A medical professional will be on site to observe study participants and provide urgent care. 5) Minors and pregnant or lactating women are excl uded from participation, with pre gnancy status confirmed by

over - the

- counter pregnancy testing within 24 hours prior to study participation. All female volunteers will be notified that an additional pre gnancy test may be required if there are any delay s i n the planned start of the study

. Only non - pregnant volunteers will be allowed to participate. 6) Procedures have been instituted to decrease psychological risks. Pregnancy tests will be conducted in a private place and information regarding pregnancy te st will be kept confidential. Private dressing areas will be provided and researchers of the same gender will be available to assist study participants. These risks are minimized appropriatel y and are justified by the potential societal benefits associated with gathering data to determine the potential exposure for workers who mix and load wettable powder formulations using open pouring techniques for workers four regions of the United States. b. Voluntary

and informed consent of all participants

. 1) T here is the possibility that the participants in this study might represent particularly vulnerable populations, susceptible to coercion and undue influence. The study prot o-

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 13 of 24

col, however, includes several mechanisms designed to minimize coercive recrui tment and enrollment. 2) The informed consent materials, if changed as recommended by the HSRB below, will adequatel y inform the subjects of the risks, discomforts and benefits from parti cipation, and of their right to withdraw. 3) Monetary

compensation is no t so high as to unduly influence participants.

c. Equitable selection of study participants. 1) AHETF will first determine a pool of growers and/or commercial pesticide applic ation companies who are eligible to participate in this study . Agricultural wor kers who work for these eligible businesses will be recruited as study participants. Employers will be required in writing to affirm that they will not influence their employees’ d ecisions about whether to participate in this study . AHETF has developed c omplete and appropriate inclusion/exclusion criteria. 2. The Board recommended that the study protocol be modified to address the concerns noted in the EPA’s Ethics Review (Evans et al. 2010). In addition, the Board raised additional co ncerns:

a. The B oard concurred with the Agency ’s recommendation (Evans et al. 2010, 5) that the protocol standard operating procedure (SOP) AHETF

- 11

- B.5 should be revised to specify that potential study

participants will be asked about what they normally wear when handlin g pesticides in a way

that does not direct them to a particular answer or lead them to agree to wear less personal protective equipment (PPE) than they normall y would out of a desire to participate in the research. b. The Board concurred with the Agency ’s recommendation that the language in the consent form about refusing medical treatment should be revised. However, the board did not concur with the suggested revisions. The Agency recommends that the language be r evised to read as follows: “You may refu se medical treatment unless the medical profe ssional decides you are too sick to make a rational decision about getting medical treatment.” The Board recommended that the language be revised as follows: “You may refuse medical treatment unless the medical professional decides (based on established criteria) that you are too sick to make a decision about getting medical treatment.” In a ddition, it recommended that in an appropriate SOP, the criteria for decision

- making c apacity are provided as guidance for m edical professionals who perform this function in AHETF research. The criteria for decision

- making capacity can be found in the clin ical and clinical ethics literature (e.g., Appelbaum 2007) and generall y include all the fo llowing: The patient a) can appre ciate the situation and its consequences; b) can unde rstand the relevant information; c) can reason about the treatment decision; and d) can communicate a choice.

c. The Board partly

concurred with the Agency recommendation that the AHETF should revise it s plan for providing exposure information to subjects to address subjects whoFinal Draft Document Dated March 1 1, 201 1

Page 14 of 24 might not speak English and/or are illiterate, and also to incorporate any future guidance from the HSRB’s working group on this issue. The Board concurred that the AHETF and the Agency

need to develop procedures to protect the needs of study participants who do not speak English or who have low levels of literacy . However the Board recommended that these procedures need to be rooted in the vocabulary and best practices of approp riate fields such as cultural competence and literacy . For example, the term illiterate is no longer used b y literacy

experts. The Agency

should consider seeking guidance on these issues from the report of the US Department of Health and Human Services, National A ction Plan to Improve Health L iteracy (2010) and reports from the Institute of Medicine, Health L iteracy : A Prescription to End Confusion (2004); Toward Health Equity and P atient

- Centeredness: Integrating Health Literacy , Disparities Reduction, and Quality Improvement, Workshop Summary (2009). The Board concurred that AHETF should inco rporate an y future guidance from the HSRB’s work group on return of results to partic ipants after it submits its reports. d. The Board concurs with the Agency that AHETF should clarify the discrepancy

about whether hand wash samples are to be collected prior to water breaks (Evans et al. 2010, 2).

e. The Board concurs with the Agency review that future AHETF protocols or SOPs should incorporate information about how subjects are presented with individual exposure i nformation, including how this process will be handled for research participants who do not speak English or have low levels of literacy ; and an explanation of the process that the AHETF follows to improve and verify the accuracy

of the Spanish translations (Evans et al. 2010, 2). The Board recommends that these future protocols be grounded best practices in literacy

and cultural competence and that the Spanish translations be in the appropriate dialect of the research participants. 3. The Board added these additional recommendations:

a. The requirement for additional pregnancy tests should be clarified throughout the doc uments. The Agency

review indicates without explanation that the consent form states that “more than 1 pregnancy

test may be required” (Evans et al. 2010, 5). However, on page 268 of the protocol it states that female volunteers “will be notified that an additional pregnancy

test may be required if there any

delay s in the planned start of the study” (Co llier 2011, 268). This explanation for wh y additional pregnancy tests may be required should be made explicit in the informed consent document. b. The Agency

review states that the return of individual exposure results may benefit r esearch s ubjects (Evans et al. 2010, 15). The Board recommended that this language be d e leted until the Board Working Group finishes its report and the Board reviews it.

c. The Board recommended that AHETF clarify how witnesses will be selected for workers who se lf

- identify as non - readers. According to the protocol they “may choose a witness, or a third

- party

witness will be identified by the Study

Director or designee and provided to the worker during the private consent meeting” (Collier 2010a, 292). It needs to be cl arified that these witnesses are not associated with the research project.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 15 of 24 d. The Board recommended that the risk of surrogate chemicals be included as one of the risks associated with participation in this study and be listed in the consent forms and in the protocol. It appears that the Task Force understood a prior Board recommendation that the phy sical risks associated with agricultural work should not be listed in the prot ocol and informed consent document to mean that exposure to the surrogate p esticides should likewise not be not be listed. The AHETF’s perspective on as reflected on page 109 of the protocol: AHETF generally

monitors exposure to professional workers that normally use one of the surrogate chemicals approved b y AHETF. Therefore, AHETF does not consider the risk of toxicity

from pesticide handling to be strictly due to study

participation (Collier 2010a, 109). Because the study involves scripted activities and may require use of a pesticide that workers wouldn't have applied that day if not for the study , however, the Board co ncluded that exposure to the surrogate compound should be listed in the protocol and co nsent document. When exposure to surrogate pesticides is re

- included as a risk of the study , several documents will need revisions, including SOP AHETF

- 11.J.2. with I C checklist; DSM Form 386; and the Governing Document. The AHETF also contends that the short duration of the study (generall y one day) limits the toxic risk of exposure to the surrogate chemicals to acute or short

- term effects. These effects are currentl y not listed in the consent forms or in the protocol, but the protocol states that the acute toxic effects from each surrogate product handled in this study will be discussed with the study participant before their participation begins (Collier 2010a, 109, 111). The Board concluded, however, that the discussion of these effects is consp icuously absent from the consent form and recommended that they either be listed expl icitly or, at a minimum, that the consent document be revised to include a statement like, The label for the [surrogate compound] will be reviewed with you before yo u take part in the study . This review will include how much of that product you might handle during the study, the symptoms and sh ort

- term health effects of accidental exp osure to the product, what clothing and personal protective equipment you must wear, the importance of washing your hands before eating, and other safety precautions that should be followed” (c.f. Collier 2010a, 146

- 7).

e. The Board recommended that the discussion of “greater than minimal risk” in the prot ocol be clarified. On page 44, the EPA review states, Inthis study

risks to subjects are classified as ‘greater than minimal’, primarily since agricultural work is considered a high risk occupation where the likelihood of harm or discomfort is greater than what is encountered in ordinary dail y life (Evans et al. 2010, 44).Final Draft Document Dated March 1 1, 201 1

Page 16 of 24 However, on page 106, the AHETF protocol states, In this study, risks to subjects are classified as “greater than minimal”, since the lik elihood of harm or discomfort is greater than what is encountered in ordinary daily life. In particular, the risk of heat

- related illness (resulting from wearing an extra layer of clothing to trap chemical ) will be increased due to study participation (Collier 2010a, 106). It is not clear whether “greater than minimal risk” refers to agricultural work or the risk of heat

- related illness associated with participation in the study or to both.

Assessment o f Completed AHETF Research Studies AHE55, AHE56, AHE57, AHE58 and AHE59: Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of Liquid Sprays Using Closed Cab Equipment . Overview of the Study Five separate field studi es were conducted, each monitoring dermal and inhalation exp osure of workers to comme r cially available pesticides while spraying tree or trellis crops in five different U.S. states where closed

- cab airblast equipment is commonly used in production agriculture. A total of 24 professional agricultural handlers were monitored as they applied pesticides using closed

- cab airblast equipment: five adult men applying pesticides to citrus trees in Florida (AHE55), five adult men applying pesticides to pecan trees in Georgia (AHE56), four adult men and one adult woman applying pesticides to cherry trees in Michigan (AHE 57), five adult men applying pesticides to grape vines in California (AHE58), and four adult men applying pesticides to apple trees in Washington stat e (AHE59). The scenario design, protocols for the five studies, SOPs and governing documents were reviewed favorably by the HSRB at its June 24

- 25, 2008 meeting (EPA HSRB 2008). Monitored on actual day s of work, study participants handled from 7 to 90 lb s of active ingredient (carbaryl, malathion, or chlorothalonil), spraying 4 to 30 acres in 2 to 9 hours. Dermal exposure was measured using hand washes, face/neck wipes, and whole body dosimeters (100% cotton union suits) for the remainder of the body (tor so, arms, and legs). Inhalation exposure was measured using personal air sampling pumps and OVS mounted on the shirt collar. Results represent dermal exposure while wearing a long

- sleeved shirt, pants, shoes/socks and chemical

resistant gloves, and inhalat ion exposure without respiratory protection. The Agency

proposes to use data from these five studies, posted to AHED®, to estimate generically

daily dermal and inhalation exposures of workers who treat agricultural crops with conventional pesticides usin g closed

- cab airblast equipment.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 17 of 24 Science Charge(s) to the Board 1) Was the research reported in the AHETF completed monograph report and associated field study

reports faithful to the design and objectives of the protocol, SOPs and governing do cuments ? 2) Has the Agency

adequately

characterized, from a scientific perspective, the limitations on these data that should be considered when using the data in estimating exposure of those who apply conventional pesticides with closed

- cab airblast equipment ? Board Response to the Charge(s) HSRB Recommendation The Board concurred in part with the Agency ’s assessment (Crowley 2011; Crowley

and Sarkar 2011). The research reported in the completed monograph, associated field study reports, and associated su

pplemental documents (Bruce 2010a, 2010b, 2010c, 2010d; Klonne and Holden 2010; Smith 2010a, 2010b, 2010c, 2010d, 2010e, 2010f) was conducted in a manner that was reasonabl y faithful, to the extent possible under field conditions, to the design and objecti ves of the protocol and governing documents of the AHETF. The Board also concluded that the Agency has not completely

considered the limitations on these data that should be considered before using the data to estimate the dermal and inhal ation exposure of those who apply conventional pesticides with closed

- cab airblast equipment. Additional limitations and concerns have been identified by the Board, and conclusions as to the generalizability

of these data require further consideration and anal ys is.
HSRB Detailed Recommendations and Rationale While any

field study

of the nature of these AHETF studies have unanticipated deviations from the protocol and SOPs, this completed study was reasonabl y faithful to the design and o bjectives of the protocol, SOPs and governing documents. Many of the reported protocol devi ations were minor, but some were not. However, it was unclear the effect these deviations would have, if an y, on the results; the effect of these deviations of the data has not yet been determined. With some exceptions, the quality assurance results appeared to be good. In terms of measured values below the limit of detection (LOD) or the limit of quantitation (LOQ)

-- 7/48 inner dosimeters, 21/24 total head exposures, 4/36 hand wash samples, mos t OVS inhalation tube back samples

-- the use of 1⁄2 LOD in such cases to extrapolate face/neck wipe exposure me asurements to un

- wiped portions of the face and head may have significantly

affected the reported anal ys es and results. It also is unclear wheth er temperature, humidity , wind speed, foliage density and/or the ty pe of equipment used had any effects on exposure and whether or not these variables should be included in further exposure modeling. Additional questions raised by the Board included: 1)Final Draft Document Dated March 1 1, 201 1

Page 18 of 24 wo ndering what was so different about the California grape study (AHE58; Bruce 2010a, 2011b) that the actual AaiH exceeded the upper limit in three of the five strata; and 2) questioning why the whole body dosimeter field fortification samples in the Califor nia grape study

also exceeded the appropriate range at times

. Despite these concerns and questions, the Board concluded that the data obtained from these completed studies are likely to be reasonabl y accurate from the standpoint of the collection and han dling of samples, and from chemical analysis. The data may not be an accurate reflection of the potential exposure to pesticides by agricultural workers using closed

- cab airblast pesticide application equipment, mainly because of the impact of the incidental exposures. However, a lthough the Board raised concerns regarding the utility of these data for predicting proportionalit y in a closed

- cab airblast scenario, this concern does not invalidate the scientific validity of the a ctual data. In its Scientif

ic Review of the AHETF Closed Cab Airblast Monograph (Klonne and Holden 2010), the Agency stated that, “the secondary objective to evaluate proportionality b etween dermal and inhalation exposure and the amount of active ingredient handled with 80% st atisti cal power

– a key

assumption in the use of exposure data as ‘unit exposures’

– was not met” (Crowley and Sarkar 2011, 2) such that the null hypothesis was not rejected. The Board agrees with this conclusion; the fact that the 95% confidence interval includ es one does not mean that the assumption of proportionality is correct. The EPA Scientific Review of the AHETF Closed Cab Airblast Monograph further states that, “additional anal ys es point to incidental exposure sources such as contacts with exterior surfaces having a more substantial impact on exposure” (Crowley and Sarkar 2011, 2). This is not unreasonable, specifically for dermal exposure. The fact that the reported data do not seem to reflect the proportionality of exposure to AaiH suggests that the engineering controls used here (i.e., a closed

- cab air

- conditioned vehicle) are likely to be effective in preventing exposure of the agricultural handler to the bulk of the pesticide being applied. The data also indicate that the protocol did not measure i ncidental exposures to pesticide, such as contaminations occurring outside the cab, in a manner that would have been helpful in exposure assessment. The prominence of incidental exposure in this scenario may not have been anticipated in advance of the study. As the surrogates selected are pesticides that are appropriate and registered for the crops of the sc enarios, they

would be expected to be used in the field on some occasions. Finally , the reported results also suggest that the number of MUs may be too small to assess the proportionality of e xposure to AaiH. Given these issues, the Board raised concerns that the assumption of proportionality could not be demonstrated for dermal exposure without accurately measuring and factoring in incidental exposure s and then recalculating the regression. Inhalation exposure estimates would be much less affected b y such incidental exposures, and the Board concluded that the assumption of proportionality

is not correct for such exposures as confirmed in Table 1 of the EPA Review (Crowley and Sarkar 2011, 2). The range of dermal and inhalation exposures was very great and, as predicted, skewed toward larger exposures even after normalizing the data. This range makes statistical estimation

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 19 of 24 of exposure difficult, and th e Board recommended that a different ty pe of probability

densit y function should be used in statistical analy ses. The Board also raised concern that the method efficiency adjusted (MEA) correction fa ctor used in estimating dermal exposures was not as acc urate as it should be. This suggests that additional lab work is required to develop more accurate way s of obtaining exposure estimates for the various dermal exposures. The secondary analy ses performed utilizing observations on clothing and on number of t imes exiting and entering the cab were very illuminating, indicating a different t ype of statistical regression model might be used if either field measurements or lab data could be combined. (It is questionable, however, given the limited number of obser vations whether sensitivity

anal yses could or should be performed.) Even considering alternative uses of these existing data, additional exposure ‘models’ should be investigated before final conclusions are made as to the use of the results in AHED®. The Agency should be careful, however, not to make an y inferences from discoveries that the closed cab airblast scenario was not designed to address; they

should not conclude, for example, that incidental exposures are the primary source of dermal exposure to pesticides as these five studies were not designed to measure the contrib ution of these sources of contamination to overall handler exposure estimates. Finally , the Board agrees with the Agency ’s conclusion in its Scientific Review of the AHETF Closed C ab Airblast Studies that, given that some field control samples for the air samplers were found to have detectable residues, this finding “may impact field fortification reco very estimates, which in turn could alter actual field sample measurements” (Crowl ey 2011, 6). It was assumed b y AHETF that, as the amounts of such residues in the field control samples were small, they

could be ignored. Adjusting the data to account for the presence of detectable res idues in the field control samples would have been mo re appropriate.
Ethics Charge to the Board Does the available information support a determination that the studies were conducted in substantial compliance with subparts K and L of 40 CFR Part 26? Board Response to the Charge HSRB Recommendation The Board concurred with the Agency ’s assessment (Sherman 2011) that the study was conducted in substantial compliance with subparts K and L 40 CFR 26.
HSRB Detailed Recommendation and Rationale The documents provided include reports of each of five fi eld studies conducted on behalf of the Agricultural Handler Exposure Task Force (AHETF) (Bruce 2010a, 2010b, 2010c, 2010d; Klonne and Holden, 2010; Smith 2010a, 2010b, 2010c, 2010d, 2010e, 2010f). The five protocols were each reviewed and approved b y an in dependent human subjects review committee, IIRB, In c. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and a cop y of IIRB,Final Draft Document Dated March 1 1, 201 1

Page 20 of 24 In c. policies and procedures were provided. This IRB is fully accredited by AAHRPP and listed by OHRP, as descri bed above in the Board’s review of proposed AHETF research study AHE80: Determination of Dermal and Inhalation Exposure to Workers During Mixing/Loading Wettable Powders in the United States. 1. The Board concurred with the conclusions and factual observations relating to the study , as detailed in the EPA’s Ethics Review (Sherman 2011) and summarized briefly below.

a. Prior HSRB and Agency Review. Because each of these five studies was initiated after 7 April 2006, prior submission of the protocol and s upporting materials to EPA was r equired by 40 CFR §26.1125. The requirements of 40 CFR §26.1125 for prior submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol were satisfied. The scenario design and study were approved b y IIRB , Inc. in March 2008 (for protocols AHE55 and AHE56) and in August 2008 (for protocols AHE57, AHE58, and AHE 59). The HSRB discussed protocols AHE55 and AHE56 at its June 2008 meeting, and AHE57, AHE58, and AHE59 at its October 2008 meeting, in each instan ce concurring with the Agency ’s assessment (Sherman 2011) that these five proposed closed

- cab ai rblast field study

protocols, if revised as suggested by the Agency

and the HSRB, would meet the applicable requirements of 40 CFR part 26, subparts K and L. b

. Responsiveness to HSRB and Agency Recommendations. The initial ethics review b y the Agency and b y the HSRB provided 26 recommendations with regard to these five prot ocols. All of those recommendations, and the responses made with regard to them, are d eta iled in Attachment 4, on pages 42 and 43, of the Agency ’s Review (Sherman 2011, 42

- 3). The HSRB agrees with the Agency that the comments by

the Agency

and HSRB were satisfactoril y addressed. 2. The Board also concluded that this study , as conducted, me t all applicable ethical requir ements for research involving human participants, in accordance with the following criteria.

a. Acceptable risk

- benefit ratio. 1) The risks to study

participants were minimized appropriatel y and were justified by the pote ntial societal benefits, particularl y data on the dermal and inhalation exposure of professional pesticide applicators to the liquid pesticides they apply to orchard and trellis crops using an airblast sprayer drawn by a vehicle with an enclosed cab. These data could be used to develop mechanisms to protect future persons who apply these liquid pesticides. 2) Minors and pregnant or lactating women were excluded from participation, with pregnancy

confirmed by

over - the

- counter pregnancy testing on the day

of study or b y opt

- out. The potential of stigma resulting from study exclusion was also appropriatel y minimized. 3) Clear stopping rules and medical management procedures were in place, and no a dverse events or other incidents of concern related to product exposure were reported, except as described in section 3, below.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 21 of 24 4) The study

was designed to minimize the risks of exposure to the test compounds, subject to being able to accomplish the purposes of the study

. b. Voluntary

and informed consent of all p articipants. 1) The study

protocol included several mechanisms designed to minimize coercive r ecruitment and enrollment. 2) Monetary

compensation was not so high as to unduly influence participation. 3. Twenty

- two minor protocol deviations were reported by the sponsor. The Agency ’s Ethics Review also notes thirteen minor protocol deviations that were unreported. All of these are documented in some detail in Table 2 of the Ethics Review (Sherman 2011, 18). The Board agrees with the Agency ’s evaluation of these deviations, and the fact that they do not require any changes in the Board’s determinations described above. However, one category

of protocol deviation is given special attention in the EPA Ethics R eview and merits discussion here. These deviatio ns involved the fact, on multiple occasions in three of the five CCAB studies, subjects failed to wear gloves while touching a contaminated surface, usuall y part of the airblast cab or attached machinery. As the Agency

notes, according to the protocols, since these protocol violations involved a safet y issue (exposure to the pesticide). In each instance the person who observed these v iol ations of safet y standards should have reminded the workers to wear their gloves and reported the behavior to the study director. There is no record that these steps took place. Ho wever, given the nature of these exposures to the pesticides, and the pesticides that were ch osen for use in these protocols, the actual increased risk to the subjects appears minimal. We agree w ith the Agency ’s determination in that regard (Sherman 2011, 29). Be yond these completed studies, however, these deviations raise an issue that the Agency and sponsors may

wish to consider with regard to the design of future protocols. That 25% of the s ubjects in these five studies engaged in this behavior suggests that it is probably not uncommon. Although experienced pesticide applicators are told of the need to wear gloves b efore touching certain pieces of equipment, it appears that they commonl y fail to do so. I f i ndeed this is a common behavior, and EPA wants to collect data from such exposures, then Agency and the sponsors may

want to consider an approach that specifies safet y standards in the informed consent form but indicates that observers will not necessaril y remind partic ipants of the standard each time they are observed violating these standards. In addition to or as an alternative to this approach, it may be desirable to write an SOP that is referenced in future protocols. The purpose of the SOP would be to clarify for study observers the safet y - related interve ntions, if any , that observers should make when participant’s engage in behaviors that are i nconsistent with either the protocol or the label. In such an SOP, it would be necessary to clearl y spell out which safety

- related deviations are “acceptable” (meaning they would not require an intervention such as a reminder to the subject to alter their behavior each time thatFinal Draft Document Dated March 1 1, 201 1

Page 22 of 24 behavior is observed), and which are not (meaning they would require an intervention, such as a reminder or warning). Acceptable deviations should only be those that involve very low risks to subjects. Observers should receive guidance on safet y violations that would merit reminders or warnings to subjects, reports to the study director, and immediate interventions to correct inappropriate behavior, including the most common examples of behaviors that are and are not acceptable. In addition to potentially reducing participant risk, this guidance would also help to stand ardize observation by removing variation introduced when observers are required to make their own subjective evaluations of risk in determining when and how to intervene.

# DRAFT

Final Draft Document Dated March 1 1, 201 1

Page 23 of 24 REFERENCES Appelbaum, P.S. 2007. Clinical Practice. Assessment of Patients' Compe tence to Consent to Treatment. New England Journal of Medicine 357(18): 1834

- 40. Bruce, E.D., for the Agricultural Handler Exposure Task Force (AHETF). 2010a. Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of L iqui d Spray s Using Closed Cab Equipment in California Trellis Crops. Study Number AHE58. Dated Nove mber 3, 2010. Unpublished document prepared b y the AHETF. MRID 48289604. Bruce, E.D., for the AHETF. 2010b. IIRB Correspondence Report for Cluster Report AHE58. Dated November 4, 2010. Unpublished document prepared b y the AHETF. MRID 48289609. Bruce, E.D., for the AHETF. 2010c. Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of L iquid Spray s Using Closed Cab Equipment in W ashington Pome Fruit. Study

Number AHE59. Dated November 3, 2010. Unpublished document prepared by the AHETF. MRID 48303502. Bruce, E.D., for the AHETF. 2010d. IIRB Correspondence Report for Cluster Report AHE59. Dated November 4, 2010. Unpublished docume nt prepared b y the AHETF. MRID 48289610. Collier, C.H., for the AHETF. 2010a. Wettable Powder Mixer/L oader Scenario Submission (AHE80). Dated October 19, 2010. Unpublished document prepared b y the AHETF. Collier, C.H., for the AHETF. 2010b. Supplement t o Protocol and Informed Consent Form for AHETF Stud y AHE80, Determinations of Dermal and Inhalation Exposure to Workers During Open Pour Mixing/L oading Wettable Powders in the United States. Dated December 22, 2010. Unpublished document prepared b y the AHE TF. Crowley , M. 2011. Review of Agricultural Handler Exposure Task Force (AHETF) Closed Cab Airblast Applicator Exposure Monitoring Studies: AHE55, AHE 56, AHE 57, AHE 58, AHE 59. Dated January

7, 2011. Unpublished document prepared b y the Chemistry and E xposure Branch, Health Effects Division, United States Environmental Protection Agency

. Crowley , M., and B. Sarkar. 2011. Review of Agricultural Handler Exposure Task Force (AHETF) Monograph: Closed Cab Airblast Application of Liquid Spray s. Dated January 7, 2011. Unpublished document prepared b y the Chemistry and Exposure Branch, Health Effects Division, United States Environmental Protection Agency

. EPA Human Studies Review Board. 2008. June 24

- 25, 2008 Human Studies Review Board Meeting Report.
Evans , J., L . Parsons, and K. Sherman. Science and Ethics Review of AHETF Scenario Design and Protocol AHE80 for Exposure Monitoring of Workers during Open Pour Mixing and L oa ding of Wettable Powders in the United States. Dated December 27, 2010. Unpublished do cument prepared b y the Office of Chemical Safet y and Pollution Prevention, United States Environme ntal Protection Agency

.Final Draft Document Dated March 1 1, 201 1

Page 24 of 24 FIFRA Scientific Advisory Panel. 2007. Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting Held January 9

- 12, 2007 on the Review of Worker Exposure Assessment M ethods. Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Roster and Procedures. Unpublished materials prepared by IIRB. Institute of Medicine of the National Academies. 2004. Health L iteracy : A Presc ription to End Confusion. Washington, DC: National Academies Press. Institute of Medicine of the National Academies. 2009. Toward Health Equity and Patient

Centeredness: Integrating Health L iteracy , Disparities Reduction, and Quality Improvement, Workshop Summary . Washington, DC: National Academies Press. Klonne, D.R., and L.R. Holden for the AHETF. 2010. Agricultural Handler Exposure Scenario Monograph: Closed Cab Airblast Application of Liquid Spray s. Dated December 2, 2010. Unpublished document prepar ed b y the AHETF. MRID 48314201. Smith, L .D., for the AHETF. 2010a. Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of L iquid Spray s Using Closed Cab Equipment in Florida C itrus. Study

Number AHE55. Dated November 3, 2010. Unpublished document prepared b y the AHETF. MRID 48289601. Smith, L .D., for the AHETF. 2010b. IIRB Correspondence Report for Cluster Report AHE55. 2 Dated November 4, 2010. Unpublished document prepared b y the AHETF. MRID 48303503. Smith, L .D., fo r the AHETF. 2010c. Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of L iquid Spray s Using Closed Cab Equipment in Georgia P ecans. Study

Number AHE56. Dated November 3, 2010. Unpublished document prepared by the AHET F. MRID 48289602. Smith, L .D., for the AHETF. 2010d. IIRB Correspondence Report for Cluster Report AHE56. Dated November 4, 2010. Unpublished document prepared b y the AHETF. MRID 48303504. Smith, L .D., for the AHETF. 2010e. Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of L iquid Spray s Using Closed Cab Equipment in Michigan Stone Fruit. Study

Number AHE57. Dated November 3, 2010. Unpublished document prepared by the AHETF. MRID 48303501. Smith, L .D., for the AHET F. 2010f. IIRB Correspondence Report for Cluster Report AHE57. Dated November 4, 2010. Unpublished document prepared b y the AHETF. MRID 48289608. US Department of Health and Human Services, Office of Disease Prevention and Health Prom otion. 2010. National Action Plan to Improve Health L iteracy . Washington, DC: US Department of Health and Human Services, Office of Disease Prevention and Health Promotion.