Page 1 of 52 Ha
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

October 1, 2010

MEMORANDUM

SUBJECT: Science and Ethics Review of Revised AHETF Scenario Design and Protocol AHE120 for Exposure Monitori ng of Workers during Mixing and Loading of Pesticide Products in Wate r Soluble Packets in Five Regions

of the United States (August 2010)

FROM: Jeff Evans, Senior Scientist

Health Effects Division Office of Pesticide Programs

Kelly Sherman, Human Research Ethics Reviewer

Office of the Director Office of Pesticide Programs

TO: Steve Knizner, Associate Director

Health Effects Division Office of Pesticide Programs

REF: Bruce, E. (2010) Determination of Dermal and Inhalation Exposure to Workers during Mixing/Loading of Pe sticide Products in Water Soluble

Packets in the United States. U npublished protocol dated August 12, 2010, prepared for the Agricultural Ha ndler Exposure Task Force under Sponsor ID AHE120, 392 p.

We have reviewed the referenced propos al from both scientific and ethics perspectives. Scientific asp ects of the proposed research are assessed in terms of the

recommendations of the EPA Guidelines Se ries 875 and of the EPA Human Studies Review Board. Ethical aspects of the propos ed research are assessed in terms of the standards defined by 40 CFR 26 subparts K and L and the recommendations of the EPAPage 2 of 52 Human Studies Review Board (H SRB). Below is a summary of the conclusions reached

in our science and ethics reviews.

Why is the WSP Protocol Being Revised?

In June 2009, EPA and the HSRB favorably reviewed the protocol for the WSP study with carbaryl and acephate as the surrogates.

In November 2009, it became apparent that the surrogates originally selected for this protocol (carbaryl and acephate) were not optimum choices. The AHETF learned that carbaryl was no longer being sold in WSP packaging and that the existing acephate WSP products were being phased out of pr oduction. As a result, the AHETF began exploring alternative surroga tes for the WSP scenario.

In December 2009, the AHETF surveyed it s membership to determine (a) the importance of exposure data for WSP; and (b ) identification of ot her active ingredients currently packaged in WSP. The membership confirmed the need for data and identified products that might be suitable as surrogates.

In February 2010, the AHETF committed to identifying products that are packaged in WSP and to consider expandi ng the targeted area to include nursery, greenhouse, and turf uses/products.

In May 2010, the AHETF identified three additional surrogate active ingredients: dithiopyr, imidacloprid, and thiophanate-met hyl. AHETF only had analytical methods for dithiopyr, so laboratories were select ed for developing methods for the other two active ingredients. An in-depth investiga tion of products, uses, and use locations was undertaken for use in revising the MU Selection Plan.

In August 2010, the AHETF approved a re vised MU Selection Plan using the three additional surrogates listed above, plus acephate. This plan involves some different uses and monitoring areas based on the new su rrogates and a lower range for the amount of active ingredient handled.

On August 12, 2010, the AHETF submitted the revised protocol, informed consent form, recruitment flyer, and Californi a Bill of Rights to the IIRB. These revised documents reflected the following:

• Comments on the original protocol ma de by EPA, California Department of Pesticide Regulation, and the HSRB in 2009

• The new surrogate compounds

• Revised monitoring areas for the new surrogates

• Refinement of several procedures based on its experi ences in 2009 (most notably the elimination of Product Risk Statements and related changes to the risk discussion)Page 3 of 52 On August 16, 2010, IIRB approved the E nglish versions of the revised documents. On August 18, 2010: IIRB approved the Spanish versions of the revised

documents.

Previous Reviews by EPA and the HSRB

EPA and the HSRB originally reviewed this protocol in 2009. EPA’s written review was dated April 8, 2009, and the protoc ol was reviewed favorably at the June 2009 meeting of the HSRB. The tables below list the previous EPA and HSRB comments on this protocol and indicate wh ether the comments are addressed in the revised (August 2010) versi on of the WSP protocol.

Comments from Previous EPA Revi ew (Evans and Sherman, 4-8-09) :

EPA Comment Was comment addressed in the Revised WSP Protocol (August 2010)?

1. The Local Site Coordinator, the Principal Field Investigator, the Analytical Facility, and the Principal Analytical Investigator must be identified in the protocol No; will be addressed before study initiation

2. The page headings on the English Language Research Participant Bill of Rights should be changed from Spanish to English Yes; corrected

3. Collect information on growers who do not respond or who decline to participate, such that the representativeness of participating growers can be evaluated Yes; See Section 4.5 in the revised protocol (p. 139 of

392 1 )

4. Provide more information about how individual level exposure data will be presented to subjects upon request. In particular, please explain how the data will

be framed and how the AHETF will work to prevent workers from changing future

behavior to their own detriment if their

individual risk levels are lower than the average of all workers Yes; see Supplement 2 with detailed information about how subjects are presented with individual exposure information.

The AHETF should incorp orate this information into future protocols and/or an SOP.

5. Verify the appropriat eness of, or make necessary improvements to, the Spanish translations of the consent form, product risk statements, and recruitment materials. Spanish translations should be written in common, simple Spanish, appropriate to the reading ability of potential Spanish speaking subjects Yes; See Supplement 3 (email from D. Johnson to K. Sherman) explaining the process that the AHETF has followed to improve and veri fy the accuracy of their Spanish translations

The AHETF should incorp orate this information into future protocols and/or an SOP.

1 Unless otherwise noted, referenced pages may be found in the main scenario submission document (containing 392 pages).Page 4 of 52 Comments from HSRB Report of the J une 2009 Meeting (report dated 10-26-09) :

HSRB Comment Was comment addressed in the Revised WSP Protocol (August 2010)?

1. The AHETF should implement the proposed protocol changes designed to address issues of representativeness. Yes; See Section 4.5 in the revised protocol (p. 139 of 392)

2. The AHETF should release individual exposure data to participants 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. Yes; see Supplement 2 with detailed information about how subjects are presented with individual exposure information.

The AHETF should incorp orate this information into future protocols and/or an SOP.

3. The Board cautioned that these data are likely to be useful for creating distributions of worker exposure only if worker exposure is found to be proportional to the amount of active ingredient handled (AaiH). When the study is completed, EPA will examine the

data to determine whether the data are consistent with a conclusion that worker exposure is proportional to the amount of active ingredient handled. EPA will consider the Board’s comments in evaluating how to

use the data.

Results of EPA’s Current Revi ew of Revised WSP Protocol

Science Review of Revise d WSP Scenario (August 2010)

• The protocol addresses the technical as pects of applicable exposure monitoring guidelines and is likely to produce scie ntifically valid and useful data.

Ethics Review of Revise d WSP Scenario (August 2010)

• The protocol meets the applicable et hical requirements of 40 CFR part 26, subparts K and L.

• Before the research is conducted, the prot ocol should be revised as follows and resubmitted for review by the approving IRB:

 The Local Site Coordinator, the Principal Field Investigator, the Analytical Facility, and the Principa l Analytical Investigator must be identified in the protocol.

• In addition, in future AHETF protoc ols please incorporate the following information into the protocol or an SOP:

 information about how subjects are pr esented with individual exposure information; and

 an explanation of the process that the AHETF follows to improve and verify the accuracy of the Spanish translations.

A. Completeness and Contents of Protocol Submission

The submitted protocol was reviewed for completeness against the required elements listed in 40 CFR §26.1125. All required elements are present. EPA’s checklist is appended to this review as Attachment 6.Page 5 of 52 The following four documents comprise the protocol submission and were

considered in EPA’s review:

• Revised Water Soluble Packet Mixer/ Loader Scenario Submission (August 19, 2010) (392 pages);

• Supplement 1: SOPs Cited in Revised Water Soluble Packet Mixer/Loader Scenario Submission (149 pages);

• Supplement 2: Details about method for informing subjects about their individual exposure re sults (8 pages); and

• Supplement 3: Details about work unde rtaken by AHETF to improve Spanish translations (1 page).

The monitoring unit selection and scenario construction plan appear on pages 7- 109 of 392. The rationale for the proposed sa mple size and cluster configuration is presented on pages 16-23 of 392. The IRB- approved protocol and supporting documents (consent forms and recruitment flyers) appe ar on pages 114-198 of 392. Documentation

of all interactions between th e investigators and the Indepe ndent Investiga tional Review Board, Inc., of Plantation FL since June 2009 (when this protocol was previously presented to the HSRB) appears on pages 303-390 of 392.

B. Summary Assessment of the Scenario Design 2

1. Scenario Design: This revised proposal addres ses the handler exposure scenario involving mixing/loading of pesticides encl osed in water soluble packets (WSP). The mixing/loading activities will involve a variety of application equipment such as ground boom and airblast sprayers. EPA’s Worker Protec tion Standard (WPS) at 40 CFR 170.240(d)(4) states that WSP products, when used correctly, qualify as a closed mixing/loading system.

Mixers and loaders using water-soluble packets must:

• Wear a long-sleeved shirt, long pants, shoes, socks, chemical-resistant gloves and a chemical-resistant apron.

• Be provided with chemical -resistant footwear, immediately available in an emergency (such as a broken package, spill or equipment breakdown), and wear it in such an emergency.

• If a respirator is required for open mixi ng/loading, then the respirator must be provided and worn also in case of emergency.

The revised AHE120 protocol calls for mixing/loading one of two surrogate pesticides into a variety of tanks contai ning water in a variety of agricultural spraying operations. A total of 25 Mon itoring Units (MUs) are proposed for this scenario; when the scenario is complete, the 25MUs will be added to the AHED

2 Supporting details are in Attachment 1.Page 6 of 52 database. EPA intends to use these data to estimate daily dermal and inhalation exposures of pesticide handlers mixing/load ing pesticides in wa ter soluble packets (WSPs) for a variety of mixing and loading scenarios.

2. Sampling Design: The proposed mixing/loading of water soluble packets scenario will involve five clusters purpos ively selected to reflect a diverse range of agronomic practices, geographic regions and likelihood of us e of one of four surrogate pesticides (acepha te, dithiopyr, imidacloprid and thiophanate-methyl).

Each cluster is referred to as a monitori ng ‘site;’ at each site five workers will be

monitored.

The AHETF diversified the five clusters for this scenario by surrogate pesticide usage and geographic region throug h a purposive five-step process:

• Identifying geographic areas associat ed with the use of water soluble packets

• Stratifying WSP use areas by EPA growing regions

• Identifying the predominant surrogate pesticide-using states in the EPA growing regions

• Selecting one major producing state for each major crop, with no more than one state per region

• Selecting a site—a county or group of adjacent counties— in which to conduct each field study, likely to su pport an efficient study and to have an ample supply of handlers

The result of executing these steps was th e purposive choice of the following five states for the five proposed monitoring sites:

• New York (EPA Region I)

• Louisiana (EPA Region IV)

• Florida (EPA Region III)

• California (southern por tion of EPA Region X)

• North Dakota (western portion of EPA Region VII)

These choices are appropriate to cover th e most important regional and agronomic

variations and likelihoo d of use of WSP contai ning acephate, dithiopyr, imidacloprid or thi ophanate-methyl.

New York (Region I) represents a cool climate having a wide variety of orchard, trellis and field crops. The AHETF will focus on the western lake region where a large number of a pple orchards and snap bean farms are located. Apples and snap beans are two crops having high usage of thiophanate-methyl.Page 7 of 52 Louisiana (Region IV) represents a hot and humid climate where higher acreages of cotton and soybeans are available that are treated with acephate formulated in WSPs.

Florida (Region III) also represents a hot and humid climate where a variety of food crops and turfgrass ar e grown with commensurate uses of the proposed surrogate pesticides.

North Dakota (western portion of Region VII) represents a warm climate in the upper Midwest wher e canola and dry beans are grown. These crops are likely to be treated with thiopha nate-methyl, in particular, thiophanatemethyl formulated in WSPs.

California (central/souther n portion of Region X) re presents a hot and dry

climate in the western U.S. where a wide variety of orchard, trellis and field crops are grown. Acephate and thiophanate-methyl are both reportedly used on crops such as lettuce, pistachios, strawberries and grapes. Imidacloprid and dithiopyr are also reportedly used on turf grown

in California.

In the next stage of the diversity selec tion process, the practical range of amount of active ingredient handled (AaiH) for the water-soluble packet scenario is

divided into five bands ranging from 4 to 400 pounds AaiH. Past studies have shown that AaiH is strongly associated with exposure and is a meta-factor associated with differences in equipm ent and spraying practices. The AHETF selected the 400 pound AaiH value as the practical upper limit based on experience in other mixer/loader studies. This limit was also selected to reduce the burden on subjects in the studies, and to avoid long monitoring periods. AHETF has set a lower limit at 3 lbs, to minimize non-detects. AHETF has partitioned the practical AaiH range into five strata:

• 3 to 7 lbs AI handled

• 8 to 21 lbs AI handled

• 22 to 56 lbs AI handled

• 57 to 150 lbs AI handled

• 151 to 400 lbs AI handled

This is a reasonable approach for the AaiH stratification. However, it may not be possible to fill all strata in all five field study regions (i.e., clusters) designed for this scenario. For exampl e, Florida was selected because it is an area where low rates of imidacloprid and dithiopyr are likely to be used making it easier to identify participants for the lower strata. In other areas such as North Dakota, the lowest strata may not be feasible due to the higher application rates of the surrogate chemicals acephate and thiophanate-methyl c oupled with high acreage crops such as canola. EPA understands the logistical challenges to fulfilling this scenario. We also note the Monte Carlo simulations performed by the AHETFPage 8 of 52 suggest this modification will still re sult in the ability to distinguish proportionality from independence. Howeve r, we agree to this approach with reservations recognizing other MUs may be needed if both AHTEF benchmark goals are not achieved (i.e., propor tionality and a K of 3).

The next stage of sample se lection results in identify ing the growers whose crops will be treated and the workers whose expos ure will be monitored. As with other agricultural pesticide application scenarios, growers who agree to cooperate with the research and to spray their crop must be identified before workers can be

recruited.

The AHETF process for identifying handler subjects recruited from growers or commercial pesticide application firms includes five steps:

• Contacting local resources to identify gr owers of the crops of interest

• Assembling a list of growers from all resources contacted and suppressing duplicates

• Putting the list of growers into random order

• Contacting growers, one at a time, in the sequence of the randomized list, to determine whether the grower is ‘eligible’ to participate

• Placing eligible growers into a “working pool”

Screening of growers for eligibility will continue until the pool contains somewhat more growers with somewhat more workers than are needed to fill five MUs in each cluster. From each grower in the working pool, the following range of information will be compiled:

• The grower is willing to cooperate with the AHETF

• The grower has the necessary mixing/loading equipment

• The grower has at least one worker with experience in the mixing/loading of water soluble packets

• The grower has sufficient acreage that the minimum AaiH can be

mixed/loaded

• The grower is willing to use a leas t one of the surrogates (acephate or carbaryl)

This process of identifying cooperating growers is basically sound. EPA has accepted this approach.

When constructing MUs, three additional re strictions will be enforced to increase diversity within the cluster:

• No handler may be used more than once

• No piece of equipment may be utilized more than once

• No more than one MU may be obtai ned from one grower or commercial pesticide applicator companyPage 9 of 52 The growers and/or commercial pesticide applicator companies in the chosen configuration provide the pool of handlers from which ha ndlers will be recruited to fill each of the five MU slots. If selected growers or handlers drop out as the time of the field study approaches, additional handlers appropriate to fill out the MU design may be recruitable from among those employed by growers and commercial firms already in the working pool of eligible entities. If there are too few handlers available in the pool to comp lete a revised efficient configuration, the working pool can be expanded by a pproaching more growers or commercial firms from the original randomized list. If the original randomized list is exhausted without finding enough interested handlers to complete the field study design, another list will be generated.

3. Choice of Surrogate Materials: The surrogate chemicals proposed for this scenario are acephate, dithiopyr, imidacl oprid and thiophanate-methyl which are also available water soluble packets. A cephate has been successfully used as a surrogate in a previous AHETF handler exposure monitoring study. Dithiopyr and imidacloprid have been used suc cessfully in post application reentry monitoring studies that measured fiel d residues and inhalation and dermal exposure using identical passive dosimet ry techniques. These are generally appropriate choices for this research. However, confirmation of method results for the thiophanate-methyl is required prio r to the initiation of the field phase of

this scenario.

C. Summary Assessment of the Scientif ic Aspects of the Study Design 3

1. Statistical design: This protocol describes co llecting 25 Monitoring Units (MUs) reflecting the exposure of subjects mixing /loading formulations of acephate or carbaryl enclosed in water soluble packets, to support a variety of applications to field, orchard or trellis crops. These MUs will be collected in five separate clusters diverse in geographic location and c limate. Each cluster or study site will include five MUs. The general rationale for the 5 x 5 cluster configuration is presented in Appendix C of the revise d AHETF Governing Document; details specific to the mixing/loading of water soluble packets scen ario are in the scenario design. No characteristics of th is scenario have been identified which would justify a departure from the 5 x 5 configuration.

2. Proposed pattern of exposure: The proposed minimum exposure duration for each MU will be at least 4 hours, involvi ng the mixing/loading of at least 3 tankloads. Subjects will only mix and load the surrogate pesticide; applying the finished spray solution/suspension will be done by others not participating in the study. Over the course of a day each subject will apply the surrogate active ingredient in one of the fo llowing five strata of AaiH:

3 Supporting details are in Attachment 2.Page 10 of 52 • 3 to 7 pounds AI handled

• 8 to 21 pounds AI handled

• 22 to 56 pounds AI handled

• 57 to 150 pounds AI handled

• 151 to 400 pounds AI handled

There are four designated su rrogate pesticide active in gredients. A cooperating grower may choose to use any of them fo r a specific MU. All of these surrogate pesticides will be enclosed in water soluble packets (WSP), mixed with water and/or loaded into the various sprays tanks in one of three possible ways:

• Loading individual WSPs directly in to the tank associated with the application equipment (e.g., ground boom or airblast sprayers)

• Loading individual WSPs into holding or nurse tanks before the finished spray solution/suspensions are transf erred to the application equipment tanks (e.g., fixed wing aircraft). The pe sticide concentrate in this situation

is the same concentration that will be applied using the spray equipment to

which it will be transferred

• Loading individual WSPs into slurry tanks or other tanks to make more concentrated solutions/suspensions that must be diluted with water before being transferred to the final spray tank

The AHETF will ensure that at least one MU in each cluster will reflect each of the mixing/loading situations described above.

For this scenario the duration of the monitoring period is expected to vary considerably because of the wide range of AI to be handled by the different subjects. Furthermore, some subjects may perform other tasks between episodes of mixing and loading, and others may si mply wait at the mixing site between episodes. The AHETF acknowledges that some scripting may be needed for subjects assigned to the lower AI strata to ensure at least 3 mixing/loading events are measured for each worker. However, in some cases application of the lowest strata may not be feasible.

3. Endpoints and Measures: The study will measure dermal and inhalation exposure for each MU. These data will contribute to development of Unit Exposures (exposure per unit of pesticide active ingredient applied) or other exposure metrics, and to estimates of dermal and inhalation exposure to other pesticides for workers mixing and loading pesticides formulated in water soluble packets. EPA believes that the proposed measures are appropriate and sound for the study design.

Dermal exposure will be measured by a whole body dosimeter (WBD) worn beneath the subject’s outer clothing. After the monitoring event, the inner dosimeter will be removed from the subject and sectioned into six pieces: thePage 11 of 52 front torso (above the waist); rear tors o (above the waist); right and left upper arms (shoulder to elbow); right and left lo wer arms (elbow to cuff); right and left upper legs (waist to knee) a nd the right and left lower legs (knee to cuff).

Before beginning work, subjects will wa sh their hands in 500 mL of 0.01%

Aerosol ® OT-75 solution (AOT solution) to remove any source of contamination and to practice the method of hand-washing. These samples will be discarded. Hand wash samples will be collected before toilet and lunch breaks, before water breaks if required by the label or reques ted by the subject, and at the end of each exposure period.

Before beginning work, each subject’s face and neck will be wiped with a cotton gauze swab to remove any contaminati on not associated with the monitoring event. This wipe sample will be di scarded. Subjects will undergo another face/neck wipe sampling prior to the break and again at the end of the exposure period; both these samples will be retain ed for analysis. As required by AHETF SOP 10.C.4, the study team will record what type of personal protective equipment (PPE), including respirator s, was worn at any time during the monitoring event.

Airborne concentrations of the surrogate will be monitored in the subject’s breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector connected to a personal sampling pump. The unit will be calibrated prior to the monitoring event using a rotameter. The OVS tube will be clipped to the subject’s shirt collar with the intake facing downward. The air sampling pump

will be connected to the OVS tube and w ill be operated for the total monitoring period including any breaks.

Additional measures will record envi ronmental conditions at the time of monitoring. Observers will make field not es of subject activity throughout the monitoring event, and photographs or videos may be taken selectively to illustrate

events.

4. QA/QC Plan: The study will be monitored by three different quality assurance units: one from the exposure monitoring contr actor that conducts the study in the field, one from the analytical laboratory that determines the level of pesticide residues in field samples, and one contracted directly by AHETF.

Analytical and field sampling quality control procedures include complete validation of all analytical methods, fi eld fortification and control samples, laboratory fortification and control sa mples, and guidelines on the use of

calibration curves to determine chemical residues found on all sample matrices.

Field fortifications will be conducted in th e field under the same conditions as the field samples. They will be transported and stored in a similar manner as the field samples, and will be analyzed in the laboratory concurrently with the fieldPage 12 of 52 samples. Samples collected from the s ubjects will be corrected based on the results of the recovery of th e field fortified samples.

5. Statistical Analysis Plan: The results of physical sample analysis will be provided in the final report of this field study and in the scenario monograph covering all monitoring conducted under the mixing/loading of water soluble packets scenario, and will be posted to the AHED ® database, where they will be available to regulatory agencies for late r statistical analysis. The documentation will report a confidence-interval-based approach to determine the relative accuracy for the arithmetic mean and 95 th percentile of un it exposures. The AHETF will not otherwise statistically analyze the monitoring data.

D. Compliance with Applicable Scientific Standards

This protocol itself adequa tely addresses the following elements according to applicable scientific standards:

• Scientific objective

• Experimental design for achieving objectives

• Quantification of the test materials

• Data collection, compilation and summary of test results

• Justification for selection of test substances

• Justification for sample size

• Fortification levels and number of sa mples for laboratory, field, and storage stability samples

Additionally, the proposal has addressed the technical aspects provided in the applicable exposure monitoring guidelin es (i.e. Series 875 Group A and OECD Applicator Guidelines) as well as Good Laboratory Practices (GLPs).

E. Summary Assessment of Ethical As pects of the Proposed Research 4

1. Societal Value of Proposed Research: The objective of this study is to develop data to determine the potential exposur e for workers who mix and load solid pesticide products packaged in water so luble packets. This mixing/loading method is widely used and applicable to a large variety of commercially important crops, and the existing exposure data are in adequate. EPA will use the results of this study to estimate the dermal and inha lation exposure likely for a wide range of agricultural pesticides app lied under this exposure scenario.

4 Supporting details are in Attachment 2.Page 13 of 52 2. Subject Selection: Subjects will be recru ited among the employees of commercial growers who util ize solid pesticides packaged in water soluble packets, who are willing to use at least one of the surrogate active ingredients for this study (acephate, dithiopyr, imidaclopr id, and thiophanate-methyl), and who meet AHETF criteria for participation. E ligible growers will be identified from a complete list of growers in the target area, processed in random sequence. Subjects will be recruited who are employees of eligible growers (or of pesticide application service companies used by e ligible growers), with experience within the past year mixing and loading water soluble packets using the particular equipment to be used in the study, and w ho meet the eligibil ity requirements of the study. If more employees are availa ble and interested than are needed, qualified participants will be sel ected randomly. A lthough the design is purposive, and thus participants are not re presentative in a statistical sense, they are expected to be typical of those who mix and load pesticide products packaged in water soluble packages.

Subjects will be recruited according to the standard procedures set forth in SOP AHETF-11.B. The Study Director or desi gnated researcher will seek permission from the eligible grower to approach hi s/her employees to recruit volunteers for the study. Depending on the number of employees and size of the grower’s facility, the Study Director or resear cher may contact employees using an informational recruitment flyer posted in a common work area. Alternatively, or subsequent to the use of a flyer, the St udy Director or researcher will arrange a meeting with the grower’s employees who e xpress interest in participation. Such recruitment meetings will always occur without the grower or supervisors being present. The Study Director or resear cher will describe the AHETF Exposure Monitoring Program, the goals of this specif ic study, the procedures to be used in exposure monitoring, and the risks and bene fits to participants. The subject eligibility factor s listed in the consent fo rm and SOP AHETF-11.B are appropriate.

Candidates who attend an individual inte rview will be paid $20 whether or not they agree to participate; enrolled su bjects who put on the whole-body dosimeter will be paid $80 in addition to their us ual pay, whether or not they complete participation.

3. Risks to Subjects: Four kinds of risks to subject s are discussed in the protocol, along with specific steps proposed to minimize them:

• The risk of heat-related illness

• The risk associated with scripting of field activities

• Psychological risk

• The risk of exposure to surfactants used for hand washing and face wipes

In this study, risks to subjects are classifi ed as ‘greater than minimal’, primarily since agricultural work is considered a high risk occupation where the likelihoodPage 14 of 52 of harm or discomfort is greater than what is encountered in or dinary daily life. In particular, the risk of heat-related illn ess (resulting from wearing an extra layer of clothing to trap chemical) will be in creased due to study pa rticipation. AHETF has adopted an extensive program to minimize these risks.

Appropriate provision is made for safety and medical monitoring. At the end of the test day, subjects will be reminded that they have a copy of the consent form with phone numbers to call if they think they have any adverse effects resulting from participation.

4. Benefits: This research offers no direct be nefits to the subjects. But subjects may request a summary of their personal re sults from the stu dy. The results will

include the distribution of chemical exposure among the various body parts and a comparison to the results for other workers performing the same task. Thus, a potential indirect benefit for subject s is knowledge about how their exposure compares to that of others doing similar work.

The principal benefit of this research is likely to be reli able data about the dermal and inhalation exposure of workers mixi ng/loading water soluble packets of pesticide formulations, usable by EPA a nd other regulatory agencies to support exposure assessments for a wide variety of pesticides with similar use patterns.

5. Risk/Benefit Balance: Risks to subjects have been minimized in the design of

the research. The low residual risk is reas onable in light of the likely benefits to society from new data supporting more accu rate applicator exposure assessments for a wide range of agricultural pesticides.

6. Independent Ethics Review: The proposed research has been reviewed and approved by the Independent Investigati onal Review Board, Inc., (IIRB, Inc.) of Plantation, Florida. The submitted materi als include a record of correspondence between the investigators and IIRB, Inc. since the time of the HSRB review in

June 2009.

The proposed research was originally a pproved by IIRB, Inc. in December 2008. In August 2010, IIRB, Inc. approved the revised research proposal under an expedited procedure, as permitted under 40 CFR 26.1110(b)(1)(ii) for minor changes to previously approved research. II RB, Inc. did not explain its analysis in concluding that the proposed changes qua lify as minor changes. While EPA can understand an argument that the changes ar e minor, the Agency concluded, after consultation with the HSRB Chair and Vice Chair, that the proposed changes warranted a new review by EPA and the HSRB.

7. Informed Consent: Informed consent will be obtained from each prospective subject and appropriately documented. If participating in the study in California, subjects will also receive the California Re search Participant Bill of Rights. Oral fluency in English or Spanish is a crit erion for inclusion, but literacy is notPage 15 of 52 required. The reading level of the Englis h language consent form is appropriate. Adequate provision is made to meet the n eeds of subjects who do not read either language. EPA assessments of complianc e with the requirements of 40 CFR §26.1116 and §26.1117 appear in Attachment s 4 and 5 to this review.

8. Respect for Subjects: Subject identifying information will be recorded only once; all subsequent data records and repor ts will refer to i ndividual subjects only by a code. Provision is made for discrete handling of pregnancy testing, required of all female subjects on the day of te sting. Candidates and subjects will be repeatedly reminded that they are free to decline to participate or to withdraw at any time for any reason, without penalty.

F. Compliance with Applicable Ethical Standards

This is a protocol for third-party rese arch involving inte ntional exposure of human subjects to a pesticide, with the inte ntion of submitting the resulting data to EPA under the pesticide laws. Thus the primary et hical standards applicab le to this proposal are 40 CFR 26, Subparts K and L. In addi tion, the requirements of FIFRA §12(a)(2)(P) for fully informed, fully voluntary consent of subjects apply.

A detailed evaluation of how this propos al addresses appli cable standards of

ethical conduct is included in A ttachments 2-5 to this review.

40 CFR 26 Subpart L, at §26.1703, as amended effective August 22, 2006, provides in pertinent part:

EPA shall not rely on data from a ny research involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a child.

The protocol requires that s ubjects be at least 18 years ol d and excludes female subjects who are pregnant or lacta ting. Thus §26.1703 would not forbid EPA to rely on a study executed according to this protocol.

If conducted according to the protocol, this research should meet the ethical standards of FIFRA §12(a)(2)(P) and 40 CFR 26 subparts K and L.

Attachments:

1. EPA Scenario Review: AHETF Mixing/Lo ading of Wettable Powder in Water Soluble Packets (AHE120) (Revised version dated August 2010) 2. EPA Protocol Review: AHETF Mixing/Lo ading of Wettable Powder in Water Soluble Packet (AHE 120) (Revised version dated August 2010) 3. §26.1111 Criteria for IRB approval of research 4. §26.1116 General requirements for informed consentPage 16 of 52 5. §26.1117 Documentation of informed consent 6. §26.1125 Criteria for Completeness of Proposals for Human ResearchAttachment 1

Page 17 of 52 EPA Scenario Review: AHETF Mixing/Load ing of Wettable Powder in Water Soluble Packets (AHE120) (Revised version dated August 2010)

Title: Monitoring Unit Selection and Construction Plan for Scenario: Mixing/Loading of Water Soluble Packets

Date: August 12, 2010

Sponsor: Agricultural Handler Exposure Task Force

1. Scope of Scenario Design

“This scenario includes the mixing/loading of water soluble packets into various types of farm equipment and dilution with water for futu re application as liquid sprays. This is accomplished by mixing/loading the packets dire ctly into the tank to be used for the application or into a pre-mix tank where the co ntents will later be transferred to the spray tank used for the actual application.” (pp. 12 of 392)

“the following states are proposed for this scenario to provi de the desired diversity in geography and likely use of one or more surrogates:

o New York

o Louisiana

o Michigan

o California (the southern portion in EPA Region X)

o Washington (the eastern portion in EPA Region XI)” (pp. 14 of 392)

(a) Is the scenario adequately defined?

The scenario is clearly a nd appropriately defined.

(b) Is there a need for the data? Will it fill an important gap in understanding?

“AHETF has identified the WSP mixing/loading scenario as being with in the scope of the task force goals and one for which data are lacking. A number of AHETF member products are labeled for this use pattern. This mixing/loading scenario is applicable to a wide variety of commercially important cr ops (e.g., orchards, ro w crops, grains, field crops, trellis crops, greenhouse and nursery plants, forestry, turf etc.). Therefore, it is necessary to have data in AHED for the mixing/loading technique described by this

scenario...

“AHETF (in conjunction with EPA, PMRA, and CDPR, collectively the Joint Regulatory Committee (JRC)) reviewed handler exposure m easurements in existing studies (mostly not included in PHED) to identify those that satisfy current acceptability criteria andAttachment 1

Page 18 of 52 qualify for inclusion in a generic database. For this particular scenario, the JRC reviewed three studies (AH508, AH520, andAH608) i nvolving mixing/loading only with water soluble packets; however, none of these studi es were deemed appropriate for a generic

database.

“AHETF also conducted a detaile d review of the data in PHED (EPA, 1998a) for this scenario to determine if any of the data were suitable for a modern generic database. Data for mixing/loading of water soluble packet s comprise PHED Scenario 5 – Wettable Powder, Water Soluble Bags (MLOD). Data w ithin that scenario were graded by EPA as “Low Confidence” for the “No Clothes”, “Singl e Layer, No Gloves” and “Single Layer, Gloves” clothing scenarios. The inhalation exposure data are also graded as “Low Confidence”. The low confidence ratings we re primarily due to low numbers of

measurements...

“Finally, EPA examined data from exis ting water soluble p acket mixing/loading exposure studies or exposure assessments th at were not available to the AHETF and concluded that none of the exposure data s hould be included in the AHETF database (meeting, November 3, 2008).” (pp. 15-16 of 392)

2. Rationale for Scenario Sampling Design

(a) Are the variables in the scenario design likely to capture diverse exposures at the high-end?

“Exposure experts within the AHETF have iden tified equipment type as a potentially important parameter that might impact exposur e. Factors such as the design of the equipment affect the spatial relationship of the worker to the opening where loading occurs (e.g., a short tank at ch est height versus a taller tank where loading may be slightly overhead). Equipment design can also affect the amount of contact the worker has with

contaminated surfaces and other factors su ch a whether or not diluted product is transferred to another tank. Therefore, equi pment type will be informally diversified

within clusters of MUs.

Experts identified several general types of equipment and procedures used with WSPs

that are identified be low (Honeycutt, 2008):

• Direct mixing WSPs into tanks that are used directly for application (e.g., groundboom, airblast, ch emigation tanks)

• Mixing WSPs into tanks not directly used for the application but which serve as holding tanks and contain the spray mix so lution in the final concentration at which it will be applied (e.g., these tanks go by various names such as holding, nurse, pre-mix, etc. tanks)

• Mixing WSPs in tanks not directly used for the application (e.g., slurry tank or bucket) and which contain a concentrated spray mix solution that must be further

diluted and transferred to a fina l tank used for the application...Attachment 1

Page 19 of 52 Consequently, it is proposed that the possibl e equipment types used for this scenario be grouped into the following 3 general equipment type categories:

1. Mixing of WSPs directly into th e tank used for the application

2. Mixing of WSPs into a “pre-mix” tank in which the solution is at the same concentration as that applied to the crop

3. Mixing of WSPs into a tank (or other container) to make a concentrated

solution that must be diluted & transfe rred to the final a pplication tank,” (pp. 43-44 of 392)

“Geographic Stratification: . . . the use of water soluble packets can be found throughout the United States and can involve a wide variety of crops, including field crops, trellis crops, orchard cr ops, turf, ornamentals, and pest control. Geographic diversity between clusters of monitoring units is expected to provide some variability in agronomic conditions and of other factors, such as equipment type, work practices, weather, etc. That is, it is viewed as a me ta-factor that is associ ated with both known and unknown effects usually classified as simply ‘study effects’. . . .

EPA has established 13 U.S. Growing Regions. The 12 regions of the continental U.S. are shown below in Figure 1. Growing Regi on XIII consists of Hawaii and Puerto Rico and is not being considered for this s cenario. These Growing Regions provide a convenient basis for geographi c stratification. These Regi ons have been used when planning and conducting pesticide residue trials for various cr op types. The regions were based on natural geography and climatic boundaries (ACPA, 1992) and are therefore useful for indicating when locations select ed for exposure monitoring are geographically diverse. . . .” (pp. 24-25 of 392)

“Predominant Surrogate Use: Although water soluble packets may be used in all 12 EPA Growing Regions, wide use of the f our AHETF surrogate active ingredients (acephate, thiophanate-methyl, imid acloprid and dithiopyr) is not expected in all regions. Thus, for practical reasons, the distribution of surrogate use will be considered when selecting the five monitoring sites...

Table 2 summarizes chemical usage data fo r all formulations obt ained from USDA on (NASS 2003 and 2006) for two of the four surro gates that are used on agricultural crops. In a few cases (e.g., thiophanate-methyl uses on nuts and grapes), data from the CA Pesticide Use Report system are also in cluded since NASS does not survey these crop/chemical combinations and registrants in formed AHETF of significant sales in these areas. The estimated total usage for each surroga te active (in thousands of lbs per year) is shown for the top seven or eight crops for each chemical. For acephate, the top seven crops account for more than 99% of usage reported by NASS. For thiophanate-methyl, the top eight crops account for 81% of usage reported by NASS and CA. For each crop, the predominant states in which the surrogate s are used are also shown. The sets of predominant states accounts for at least 90% of the total surrogate usage in the listed crop, or are the only states listed in the USDA database for that crop. The majority ofAttachment 1

Page 20 of 52 usage for these two surrogate active ingred ients is concentrated in 20 of the 48 contiguous states.” (pp. 26-27 of 392)

“ Selection of a Geographically Dive rse Set of Monitoring Areas: Five new monitoring areas need to be selected that ar e geographically diverse. Such a diverse configuration can be obtained by simply loca ting each site in a different EPA Growing Region. In theory, five growing regions c ould be selected at random from among the 12 regions that stratify the contin ental U.S. A state (or portion of a state) could be randomly or purposively chosen from within the select ed Region. . . . However, such undirected

selection of states would be quite inefficient...Locating m onitoring areas in crop areas where the surrogates are currently in use ove r a wide variety of crops increases the likelihood that surrogates will be in use at the particular monitoring site ultimately chosen....the following states were purposively selected to contain the following five monitoring areas.

1. New York (Region I)

New York is a state with high usage of th iophanate-methyl on appl es (an orchard crop) and snap beans (a field crop), the two predomin ant crops for this surr ogate. This state

reflects a cool climate in the northeastern U.S.

2. Florida (Region III)

Florida has the most acres of sod farms in th e U.S. and has been identified as a primary usage state for imidacloprid. Because dithiopyr is registered for use on sod farms, it might also be possible to find locations wher e this product is being used. In addition, data from NASS indicate that acephate and th iophanate-methyl are used in Florida on a variety of crops indicating snap beans, mel ons, strawberries and to matoes. This state

reflects a hot and humid climate in the southeastern U.S.

3. Louisiana (Region IV) Louisiana represents by far the highest us age state for acephate, including cotton and soybeans. The southern U.S. was also indica ted as being on of the top usage states for the WSP formulation of acephate. Louisiana reflects mostly a hot and humid climate in

the southern U.S.

4. North Dakota (the western portion in Region VII)

North Dakota was selected because it was id entified as a top usage state for the WSP formulation of thiophanate-methyl. The prim ary crops treated with thiophanate-methyl in ND are dry beans and canola. During the summer growing season, this state reflects a warm climate in the upper Midwestern U.S.Attachment 1

Page 21 of 52 5. California (the central/southern portion in Region X)

Acephate and thiophanate-methyl are used in California on a variety of crops including lettuce, celery, bell pepper, melon, strawberr y, pistachio, grape, and almond. Information from the California Pesticide Use Reporting system indicates that the majority of thiophanate-methyl applications in 2008 we re made to pistachios followed by landscape

maintenance and strawberries. California is also a primary usage area for imidacloprid and perhaps dithiopyr, on turf. The central and southern portions of California generally reflect a hot and dry climate in the western U.S.” (pp. 31-33 of 392)

“ Selection of Specific Monitoring Areas: The final step for selecting monitoring areas is to choose a specific area with in each selected state(s) identified above where growers

and workers can be recruited to conduct th e exposure monitoring in a reasonable amount

of time. This involves sel ecting each monitoring area in a reasonably limited geographic

area so that MU identificati on and selection operations can be conducted efficiently in one local area. This will facilitate the logist ics of the field research team and keep the costs of study conduct reasonable so a suffi cient number MUs can be obtained in the AHETF monitoring program.

“Choosing a cost-effective configuration of MU s is necessary since costs escalate rapidly when a research team makes multiple visits to a location in order to monitor the desired five MUs. Cost-effectiveness is obviously maximized when all MUs are collected during the same visit so researcher salary, travel , food, lodging, and field fo rtification expenses

are minimized.

“Therefore, for each monitoring area, a particular area of each target state will be selected and identified in the study protocol. Th e actual monitoring area within each selected

state will be determined based on the locations of crops predominantly associated with surrogate use and will likely involve identify ing several counties where mixer/loaders are most likely to utilize the surrogate WSP product and that have sufficient growers, equipment, and workers to allow an efficient design.” (pp. 34-35 of 392)

(b) How have random elements been incorpor ated into the scenar io sampling design?

All choices in the first stage of the proposed diversity selection pro cess, and stratification by AaiH in the second stage, are purposive choices.

“AHETF has determined that a method of randomly choosing a working pool of growers is practical for this scenario. This pool of growers will provide the workers and mixing/loading conditions needed to construct MUs for the cluster. Random selection of growers is preferable, when feasible, to reduce the possibility of sel ection bias that might arise from researchers purposively choosing sp ecific growers to contact. Therefore, a procedure for generating a list of available gr owers for each cluster (i.e., associated with each local monitoring area), and selecting a pool of growers from that list, will beAttachment 1

Page 22 of 52 established in the protocol. The general pr ocedure to be followed is described in the following steps:

1. “Contact local resources from each of the following groups and ask for a list of growers that might utilize wa ter soluble packets at the id entified site (generally several counties):

• Farm Market ID

• Commercial list providers

• State and local government entities

• Grower associations

• Grower Publication subscription lists

2. “Assemble a reasonably sized and randomly se lected list of growers from all of

the resources contacted and eliminate any duplicates.

3. “Contact all the growers on th e list and determine whether the grower is ‘eligible’ to participate. Eligibility generally means all of the following are true:

• The grower is willing to cooperate with AHETF, incl uding the ethical aspects of the research

• The grower has the necessary mixing/loading equipment

• The grower has at least one worker with experience in the mixing/loading of water soluble packets

• The grower is willing to allow AH ETF to recruit his/her worker(s)

• The grower has sufficient acreage that the minimum AaiH can reasonably be handled by a worker in one day

• The grower is willing to use at least on of the surrogate active ingredients listed in this protocol

Growers who indicate they use commerci al pesticide application companies to mix/load their product will also be consid ered. Those growers will be asked to identify their preferred commercial companies and AHETF will contact them to screen them for willingness to coopera te by providing suitable mixing/loading equipment and workers. The actual workers involved could be the grower himself, a grower’s employee, or an owner or employ ee of a commercial pesticide application

company.

4. “Each grower identified as eligible (s ometimes along with an associated commercial pesticide application compa ny) is placed into a working pool along

with information on:

• Specific location of mixing/loading area • Description of equipment availa ble (e.g., number, type, and size) • Surrogate chemical(s) th at might be utilized • Approximate timing of surrogate applications

• Number of workers availableAttachment 1

Page 23 of 52 • AaiH those workers might be able to handle in a day.” (pp. 39-40 of 392)

(c) What feasible opportunities to incorp orate random elements in the design—if any—

have been overlooked?

By constructing an “efficient configuration” of MUs such that more handlers and growers are in the recruiting pool in a given geographi cal area, it is likely that the opportunity will often arise to select randomly fr om among interested workers.

(d) What typical patterns of exposure will likely be included by the sampling design?

“The workers will be allowed to follow thei r normal procedures as long as they fit the

scenario definition and do not conflict with EPA’s Worker Protection Standard (WPS) regulations. The duration of the work activity will be part ially determined by the amount of AaiH but will involve the mixing/loadi ng of at least three loads and a minimum

duration of four hours.

“A parameter that might impact exposure is the number of loads prepared since each mixing/loading event might require transfer ring diluted product from tank to tank and potential contact with contaminated surfaces (e.g., water soluble packets, tanks, hoses, etc.)...If other functions ar e also associated with th e mixing/loading event (e.g., transferring from a slurry tank to an application tank) then th ese events are also included as part of the monitoring.” (pp. 45 of 392)

(e) What typical patterns of exposure will likely be excluded by the sampling design?

“While other factors were considered that might potentially affect exposure potential, they will not be purposively diversified. For example, size of packets or concentration of the product in the packet might possibly impact exposure. For the four selected surrogate actives collectively, the following packet sizes are expected to be available: 1.6 ounces, 5 ounces, 1.0 pound, and 2.5 pounds. However, AHETF will not have control over which product or package size is available and desire d by each participating grower. Therefore, in this scenario, variability in packaging is not considered a parameter for purposive diversification, but rather some diversity in packaging size is e xpected by virtue of including various surrogate activ es. Other factors such as the crop being treated are not expected to directly affect e xposure, but might lead to selection of various equipment setups that could impact exposure potential.” (pp. 46 of 392)

3. Are the proposed test materials appropriate surrogates?

“The following active ingredients are availa ble in water soluble packets and will be considered for use in this mixing/loading scen ario. The commercial products of the active ingredients that might be used in particul ar will be listed in the study protocol.

• Acephate

• DithiopyrAttachment 1

Page 24 of 52 • Imidacloprid

• Thiophanate-methyl

Ideal surrogate active ingredients also have hi gh use rates for the poten tial crops of interest that enables measurements at the high end of Aa iH per day. This is the case for acephate and thiophanate-methyl where use rates are up to 1.0 lb./A or a bit higher, however, the other two surrogates are used at lower use rates, someti mes as low as 0.05 lb./A and up to a maximum of 0.5 lbs./A. Additionally, cooperating growers who will use these products are likely to be available. Finally, these active ingredients have been used as surrogates in other studies and are known to have the required stability under field study conditions.” (pp. 48 of 392)

4. What is the rationale for the prop osed cluster design and sample size?

“Appendix C of the Governing Document desc ribes the methodology to calculate sample

sizes when the reference model used is clus ter sampling from a lognormal distribution. For the purposes of determining sample sizes, th e default variation structure for normalized dermal exposure derived in Appendix C is also assumed applicable to the water soluble packet mixing/loading scenario. AHETF and th e Joint Regulatory Comm ittee agreed there is no evidence to suggest otherwise and no str ong opinion to the cont rary (meeting with AHETF, November 3, 2008). It is therefore appropriate to use the default relative variation structure consisting of a geometric standard deviation (GSD) of 4.0 and intra-cluster correlation (ICC) of 0.3.

Appendix C shows that under these conditions (and where no suitable MUs exist) a sample of 5 clusters (N C =5) with 5 MUs per cluster (N M =5) is the most cost effective design configuration that meets the 3-fo ld accuracy requirement. This accuracy is possible with a

variable number of MUs/cluste r as long as the total number of MUs is at least 25 and no

cluster has more than 5 MUs. Each cluster (i.e. monitoring area) will be addressed in the same study protocol.

“Appendix C of the Governing Document also shows that when the benchmark accuracy requirement above is met there may also be su fficient power to permit users of the database to perform a limited examination of the rela tionship between the nor malizing factor (e.g., AaiH) and exposure. This is true provided: (1 ) the practical range of the normalizing factor is at least an order of magnit ude and (2) there is adequate w ithin-cluster variation in the normalizing factor. When these conditions occur, the MU sample will be of sufficient size and diversity to provide at least 80% statisti cal power to distinguish complete proportionality from complete independence between exposur e and the normalizing factor used in the primary benchmark. Since these conditions can be satisfied for the reference sampling design, then the purposive divers ity design for the water soluble packet scenario should provide adequate power for the minor (i.e., secondary) objective: th e ability to conduct limited examinations of the relationship betw een AaiH and exposure.” (pp. 22- 23 of 392)Attachment 2

Page 25 of 52 EPA Protocol Review: AHE120: Water Solu ble Packet Mixer/Loader Scenario (Revised version dated August 2010)

Title: Determination of Dermal and Inhalation Exposure to Workers during Mixing/Loading of Pesticide Products in Water Soluble Packets in the United

States

Revision Date: August 12, 2010

Study Director and Sub-Investigators:

Eric D. Bruce Brian Lange 5

Tami Belcher 5

Aaron Rotondaro 5

Local Site Coordinator: TBD 6

Field Facility: TBD 6

Analytical Facility: TBD 6

Sponsor: Agricultural Handler Exposure Task Force, LLC c/o David R. Johnson, Ph.D. 1720 Prospect Drive

Macon MO 63552

Reviewing IRB: Independent Investigational Review Board, Inc.

6738 West Sunrise Blvd Suite 102

Plantation FL 33313

1. Societal Value of Proposed Research

(a) What is the stated purpose of the proposed research?

“The objective of this study is to develop data to determine the potential exposure for workers who mix and load solid pesticide produc ts packaged in water soluble packets in five regions of the United States.” (pp. 119 of 392)

5 One of these three will be the “Principal Field Investigator” for this study. When the choice is made it will be reflected in the protocol and consent document.

6 The Local Site Coordinator, Field Facility, Analytical Fac ility, and Principle Analytical Investigator must all be

identified.Attachment 2

Page 26 of 52 (b) What research question does it address? Why is this question important? Would the research fill an importan t gap in understanding?

This study will provide a partial answer to the question of what dermal and inhalation exposures are likely for workers who mix and load solid pesticide products packaged in water soluble packets. This is a widespread method of mixing and loading solid pesticide products, for which existing data are inadequate.

(c) How would the study be used by EPA?

EPA will use the results of this study to estimate the dermal and inhalation exposure likely for mixing and loading agricultural pestic ides formulated in water soluble packets.

(d) Could the research question be answered wi th existing data? If so, how?

“AHETF (in conjunction with EPA, PMRA, a nd CDPR, collectively referred to as the Joint Regulatory Committee (JRC)) reviewed handler exposure measurements in existing studies (mostly not included in PHED) to id entify those that satisfy current acceptability criteria and qualify for inclusi on in a generic database. For this particular scenario, the JRC reviewed three studies (AH508, AH520, and AH608) involving mixing/loading only with water soluble packets; however, none of these studies were deemed appropriate for a generic database.

“AHETF also conducted a detaile d review of the data in PH ED for this scenario to determine if any of the data were suitable fo r a modern generic database. . . . Thus there are no data currently in PHED for this scen ario that are useful for a modern generic database. (pp. 15-16 of 392)

(e) Could the question be answered without newly exposing human subjects? If so how? If not, why not?

There is no alternative to mon itoring handlers as they mix/load pesticides for measuring their dermal and inhalation exposure.

2. Study Design

(a) What is the scientific objective of the st udy? If there is an explicit hypothesis, what

is it?

“The goal of conducting a water soluble packet mixing/loading study is to develop a set of generic dermal and inhalation exposure da ta which regulators and other potential users of the generic database can utilize to characterize a pred icted distribution of future exposures and perform exposure assessments for this scenario.” (pp. 50 of 392)Attachment 2

Page 27 of 52 “The primary benchmark objective for this scenario is that a sample from the hypothetical reference sampling distribution a bove be of adequate size to describe selected measures of the (normalized) exposur e distribution with a pre-determined level of accuracy...The current consensus is that estimates of the geometric mean, the arithmetic mean, and the 95 th percentile generally need to be accurate to within approximately 3-fold of the actual populat ion value. AHETF and the Joint Regulatory Committee (EPA, California Dept. of Pes ticide Registration, Pest Management Regulatory Agency [Canada], and the U.S. De partment of Agriculture) agreed 3-fold accuracy is an appropriate benchmark for th is scenario (meeting with AHETF, November 3, 2008).” (pp. 21 of 392)

No explicit hypothesis is st ated, nor is the study explic itly designed to test one.

(b) Can the study as proposed achieve that objective or test this hypothesis?

It is likely that the objective can be achieved by the proposed study.

2.1 Statistical Design

(a) What is the rationale fo r the choice of sample size?

“Appendix C of the Governing Document describes the methodology to calculate sample sizes when the reference model us ed is cluster sampling from a lognormal distribution. For the purposes of determin ing sample sizes, the default variation structure for normalized dermal exposure derived in Appendix C is also assumed applicable to the water soluble packet mi xing/loading scenario. AHETF and the Joint Regulatory Committee agreed th ere is no evidence to suggest otherwise and no strong opinion to the contrary (meeting with AH ETF, November 3, 2008). It is therefore appropriate to use the default relative vari ation structure consisting of a geometric standard deviation (GSD) of 4.0 and in tra-cluster correlation (ICC) of 0.3.

“Appendix C shows that under these conditions (and where no suitable MUs exist) a sample of 5 clusters (N C =5) with 5 MUs per cluster (N M =5) is the most cost effective design configuration that meets the 3-fold accuracy requirement. This accuracy is possible with a variable number of MUs/clus ter as long as the total number of MUs is at least 25 and no cluster has more than 5 MUs.” (pp. 22 of 392)

(b) What negative and positive controls are proposed? Are proposed controls appropriate for the study design and statistical analysis plan?

No positive or negative controls are propos ed. This is appropriate for the study design and statistical analysis plan.Attachment 2

Page 28 of 52 (c) How is the study blinded?

The study is not blinded, nor could it be.

(d) What is the plan for allocating individuals to t reatment or control groups?

“After the randomly-selected pool of eligible growers is assembled, researchers (e.g., the Study Director) will examine the deta ils of potential MUs and identify a configuration of MUs (i.e., gr owers, chemicals, workers, AaiH, timing) that will result in an efficient cluster design.” (pp. 41 of 392)

“When constructing MUs, three restrictions will be enforced to ensure diversity

within the cluster of MUs:

• No worker may be used for more than one MU in the cluster. Worker-related

behaviors are also viewed as a meta-fact or since individual practices might be associated with exposure potential.

• No piece of equipment may be used mo re than once and each of the three general equipment types must be used at least once per cl uster (see section 6.1 below)

• No more than one MU may be obtai ned from any grower or commercial pesticide application company (so a grow er with several workers and several pieces of equipment can contribute one MU).” (pp. 41-42 of 392)

(e) Can the data be statistically analyzed?

“As has always been the case, any statistical conclusions based on such data imply the qualification: ‘to the extent that the da ta can be viewed as deriving from a true random sample.’” (pp. 51 of 392)

(f) What is the plan for statis tical analysis of the data?

“As detailed in the Governing Document, the data collected from the clusters for this scenario will only be statistically evaluate d with respect to the benchmark measures of adequacy. These two categories of data adequacy are:

1. The relative accuracy of selected stat istics characterizing the distribution of exposure normalized by amount of ac tive ingredient handled (AaiH).

2. How well the data can be expected to describe a relationship between exposure and AaiH, if one existed.” (pp. 50 of 392)

“The primary benchmark objective is that selected lognormal-based estimates of normalized dermal exposure distribution be accu rate to within 3-fold, at least 95% ofAttachment 2

Page 29 of 52 the time. The benchmark estimates speci fied are those for the geometric mean, arithmetic mean, and the 95 th percentile.

“To evaluate how well the collected data conform to this benchmark, the 95 percent bound on relative accuracy will be calculated from the confidence interval for each of the three parameters give n above.” (pp. 51 of 392)

“This secondary benchmark objective [Adequ acy of the Data for Distinguishing a Proportional from an Independent Relations hip between Exposure and AaiH] applies to the water soluble packet mixing/loading s cenario because the practical range in the amount of active ingredient ha ndled (AaiH) exceeds an orde r of magnitude. In this

case it is reasonable to consider the lin ear regression of log dermal exposure on log AaiH. Such a regression would use a mixed model formulation in order to incorporate random cluster effects.” (pp. 52 of 392)

(g) Are proposed statistical methods appr opriate to answer the research question?

Yes.

(h) Does the proposed design have adequate statistical power to definitively answer the research question?

Since the primary objective of the research is to characterize the distribution of exposure normalized by the amount of active ingredient handled (AaiH), statistical power does not relate to this objective. However, EPA believes the resulting data will reliably characterize the distribution of exposures for the individuals monitored during the mixing/loading using water solubl e packets in this study, and that these exposures can inform assessments of the li kely exposures for individuals in similar

future situations.

Regarding the secondary objective, distingu ishing a proportional from an independent relationship between exposure and Aa iH, statistical power is relevant.

“This secondary benchmark objective applies to the water soluble scenario because the practical range in the amount of activ e ingredient handled (AaiH) exceeds an order of magnitude. In this case it is reas onable to consider the linear regression of log dermal exposure on log AaiH. Such a regression would use a mixed model formulation in order to incorporate random cluster effects. As described in the Governing Document, in such a model the true slope, β , would be equal to one if dermal exposure were directly proportional to AaiH. If exposure were independent of AaiH, then β =0. This benchmark objective requires that the number of clusters and

the allocation of AaiH levels to MUs should be adequate to ensure that the regression analysis has at least 80% power to reject the hypothesis that β =0 when β is actually equal to one. By symmetry, the mixed mode l linear regression would also have the same power to reject the hypothesis that β =1 when β =0. This is the precise meaningAttachment 2

Page 30 of 52 of being able to ‘discriminate between pr oportionality and indepe ndence’.” (pp. 52 of 392)

2.2 How and to what will human subjects be exposed?

“The water soluble packet mixing/loading program will monitor in stances of worker exposure resulting from the mixing/loading th e packets of pesticide.” (pp. 16 of 392)

“The test substance active ingredients approve d for use in this study are listed in Section 2.3.5 above. The most appropriate end-use pesticide product, based largely on the preference of the grower, will be used at each of the individual MU site s. A different test substance may be used at each site and by each worker within a monitoring area if appropriate.” (pp. 112-113)

(a) What is the rationale for the choi ce of test material and formulation?

“The AHETF has developed several pesticide active ingredient compounds for use as surrogates . . . . Since the AHETF is developing a generic database that will be applicable to nearly all pesticide products and uses, any of the AHETF surrogates can be used for generating exposure data for th is scenario. The choice of surrogate at each location will depend largely upon the pref erence of the grower and pest pressure on his crop at that time...

“The following active ingredients are availabl e in water soluble packets and will be considered for use in this mixing/loading s cenario. The commercial products of these active ingredients that might be used in particular studies will be listed in study protocol.

• Acephate

• Dithiopyr

• Imidacloprid

• Thiophanate-methyl

“Ideal surrogate active ingredients also have high use rates for the potential crops of

interest that enables measurements at the hi gh end of AaiH per day. This is the case for acephate and thiophanate-methyl where use rates are up to 1.0 lb./A or a bit higher, however the other two surrogates are used at lower use rates, sometimes as low as 0.05 lb./A and up to a maximum of 0.5 lbs./A. Additionally, cooperating growers who will use these surrogate actives ar e likely to be available. Finally, these active ingredients have been used as surr ogates in other studies and are known to have the required stability under fi eld study conditions.” (pp. 47-48 of 392)Attachment 2

Page 31 of 52 (b) What is the rationale for the choice of dose/exposure levels and the staging of

dose administration?

“Since the number of pounds of active ingr edient handled is th e normalizing factor and indirectly influences many other hand ling conditions, efforts will be taken to generate data in as wide a range of AaiH as practical within ea ch cluster of MUs.

AaiH is selected since AHETF feels it is the most reasonable measure of active ingredient contact potentia l for this scenario. . . . In addition, EPA currently normalizes water soluble packet mixing/lo ading exposure by AaiH during pesticide product exposure assessments. No other normalizing factor has been identified as being more appropriate.

“In addition to its potentia l direct relationship to e xposure, the amount of active ingredient handled is also vi ewed as a meta-factor affecting parameters such as tank size, number of loads applied, etc. T hus, diversification of AaiH induces

diversification of such associated factors as well.

“AHETF has calculated a practical range in Aa iH for this scenario taking into account such factors as typical use rates of pr oducts, types of products available on the market, types of crops on which the products are used, number of acres that can be treated in a day, etc. AHETF has selected a range of 3 to 400 lbs active ingredient to be handled per day for this scenario.” (pp. 35-36 of 392)

“[I]t is important that the AaiH levels be well diversified within each monitoring area (i.e., cluster of MUs). This allows the data fo r this scenario to be used to discriminate a completely proportional relationship from a completely inde pendent relationship between exposure and AaiH (if one of thos e two relationships were true). Withincluster diversification of AaiH will be accomplished by following the standard approach of partitioning the practical AaiH range into five logarithmically-spaced

strata. These strata are:

• 3 to 7 pounds AI handled

• 8 to 21 pounds AI handled

• 22 to 56 pounds AI handled

• 57 to 150 pounds AI handled

• 151 to 400 pounds AI handled

“...[A]n attempt will be made within each cluster to obtain a single MU from each of

the five strata. ...

However, due to differences in the user rates of WSP formulations of the four surrogate chemicals it may not be possible to select or cons truct MUs in all five AaiH strata in every monitoring area....[T]wo monitoring areas (CA and FL) are selected primarily to target applicati ons to turf with imidacloprid and dithiopyr. These actives are used at lower use rates than acephate and thiophanate-methyl (0.19 – 0.5 lb ai/A for dithiopyr and 0.07 – 0.4 lb ai/A for imidacl oprid on turf. Theref ore, if only theseAttachment 2

Page 32 of 52 surrogates are utilized at a monitoring area it will not be possible to reach the higher levels of AaiH. To accommodate this po ssibility the following general procedure should be followed at each monitoring area:

1. Based on local information obtained pr ior to constructing MUs, the Study

Director will determine which of the five AaiH strata are feasible for the monitoring area.

2. The AaiH levels for the five MUs will then be allocated to the feasible

strata so that the distributions of MUs over strata will be as even as possible.” (p. 37-38 of 392)

(c) What duration of exposure is proposed?

“Duration of monitoring is another para meter that could vary between MUs, especially since the AaiH will be varied by more than two orders of magnitude. Mixer/loaders might spend several hours pe r day at the mixing area but can also spend long intervals performing other tasks (or just sitting ar ound) between actual mix/load events (i.e., while the applicator is making the application). So MUs will be monitored during their entire work day since many other unknown factors might contribute to exposure. All monitoring pe riods for this scenario must meet the general rule of being at leas t 4 hours. This is designed to overcome the criticism of early exposure studies where many of the sampling regimes monitored workers for only a few minutes. Avoiding very short mon itoring intervals will ensure that daily exposure estimates are not biased by unusual conditions during that short interval. If necessary, some minor scripting of worker ac tivities will be done to ensure the lowest

levels of AaiH are handled and/or a minimum of four hours are monitored. For example, a worker might be asked to use a smaller tank, make smaller loads, or increase the spray volume slightly in orde r to mix 3 loads in four hours.” (pp. 45-46 of 392)

2.3 Endpoints and Measures

(a) What endpoints will be measured? Are they appropriate to the question(s) being

asked?

“At the completion of the monitoring period, exposure samples will be taken in the following order to minimize cross contaminatio n: inhalation samples (discussed in the next section), then hand washes, then face/n eck wipes, and finally inner dosimeters as

described in SOP AHETF- 10.E.2.” (pp. 148 of 392)

For this study, inner dosimeters will be cut into six sections.

“Full details for sampling air with OSHA Versatile Sampler (OVS) tubes and personal air-sampling pumps are given in the most recent versions of SOP AHETF8.D and 10.G.” (pp. 149 of 392)Attachment 2

Page 33 of 52 (b) What steps are proposed to ensure measurements are accurate and reliable?

Field fortification samples are exposure matrix samples that are fo rtified (or spiked), generally in the field, with known amounts of active ingredient and subsequently analyzed to determine the am ount of active ingredient rec overed. Field fortification samples are subjected to the same envi ronmental, handling, shipping and storage conditions as worker samples. Because these conditions are similar, and because field fortification samples are analyzed al ong with worker samples, recovery values calculated from analysis of fo rtification samples are app licable to worker exposure samples. Field fortification recoveries ar e therefore used to adjust residue levels found in worker samples for residue lo sses that might have occurred during collection, handling, shipping and storage.

“Full details regarding fiel d recovery evaluation proce dures for all sampling media are given in the most recent version of SOP AHETF-8.E. The SOP instructions for the ‘by vial’ spiking using active ingredient (ai) in an organic solvent will be followed for all matrices except OVS tubes. The tubes will be spiked at the laboratory with the proper amount of analytical standard.” (pp. 150 of 392)

(c) What QA methods are proposed?

“AHETF intends that all regulatory studies are conducted in a ccordance with the FIFRA GLP Standards (40 CFR part 160). Fi eld and analytical aspects of this study will be monitored by the relevant quality a ssurance units(s) (QAU) while this study is in progress to ensure compliance with th e FIFRA GLP regulation and adherence to this protocol and relevant SOPs. Th e QAU(s) will submit copies of its/their inspection reports to the Study Director a nd AHETF Sponsor Representative (40 CFR part 160.35(4)). The final report will be audited by the QAU specified in Section

1.15 to ensure that the cont ents of the report accuratel y describe the conduct and findings of the study.

“The final report will contain a Quality Assurance Statement from the QAU of each contributing laboratory conducting QA audits , and from the QAU specified in section 1.14.” (pp. 156 of 392)

(d) How will uncertainty be addressed? Will reported point values be accompanied by measures of uncertainty?

Uncertainty in field measurements will be addressed via fortification samples.

“Sample matrix fortifications designed to assess the stability of the active ingredient during field, storage and tran sit conditions in or on the sampling materials (inner dosimeters, hand wash solutions, face/neck wipes, and air sampli ng matrices) will be conducted on a minimum of one day of exposure monitoring at each monitoring area, or more days as appropriate for environmental conditions. . . .Attachment 2

Page 34 of 52 For each fortification event, two untreated control samples of each matrix will be processed similar to the field fortifica tion samples (i.e., some are weathered). Packaging, storage and shipment of the field fortification samples will be the same as for the worker exposure samples.” (pp. 150 of 392)

In general, field measurements are ad justed based on the recovery from the fortification sample. For example, a fiel d measurement for an inner dosimeter of 300 ug would be adjusted based on the applicab le fortification sample for the inner dosimeter matrix. If the recovery fr om that matrix was 80%, the reported measurement for that sample would be 300 ug/80% = 375 ug.

3. Subject Selection

3.1 Representativeness of Sample

(a) What is the population of conc ern? How was it identified?

“The water soluble packet mixing/loading scenario program will monitor instances of worker exposure resulting fr om the mixing/loading of p ackets of pesticides. Each instance is termed a monitoring unit (M U). Each MU consists of a set of mixing/loading conditions (including the par ticular worker) that are intended to represent the scenario activities for a singl e workday. In many cases monitoring units will be selected from ‘naturally occurring’ water soluble packet mixer/loader-days. However, the selected application conditi ons are sometimes modified or scripted slightly to ensure that the sample of MUs reflects the expected di versity in the entire population of future water soluble mixer/lo ader-days. . . .Thus, MUs are technically not ‘sampled’ from a population. More corr ectly, they should be viewed as synthetic water soluble mixing/loading-days derive d from both selected and constructed conditions.” (pp. 16-17 of 392)

(b) From what populations will subjects be recruited?

“The growers and/or commercial pesticide application companies in the chosen configuration provide the pool of workers from which cluster participants will be recruited.” (pp. 41 of 392)

(c) Are expected participants representativ e of the population of concern? If not, why not?

“AHETF has determined that a method of randomly choosing a working pool of growers is practical for this scenario. This pool of growers will provide the workers and mixing/loading conditions needed to construct MUs for the cluster. . . .a procedure for generating a list of available growers for each cluster (i.e., associated with each local monitoring site), and randomly selecting a pool of growers from thatAttachment 2

Page 35 of 52 list will be established in the protocol. The general procedure to be followed is described in the following steps:

1. “Contact local resources such as those listed below to obtai n a list of growers that might utilize water soluble packets at the identified site (generally several counties)

• Farm Market ID

• Commercial list providers

• State and local government entities

• Grower associations

• Grower Publication subscription lists

2. “Assemble a reasonably sized and randomly selected list of growers from all of the resources contacted and eliminate any duplicates

3. “Contact all the growers on the list a nd determine whether the grower is ‘eligible’ to participate. Eligibility generally m eans all of the following are

true:

• The grower is willing to cooperate with AHETF, incl uding the ethical aspects of the research

• The grower has the necessary mixing/loading equipment

• The grower has at least one wo rker with experience in the mixing/loading of water soluble packets

• The grower is willing to allow AH ETF to recruit his/her worker(s)

• The grower has sufficient acreage that the minimum AaiH can be reasonably be handled by a worker in one day

• The grower is willing to use at least one of the surrogate active ingredients listed in the study protocol.” (pp. 39-40 of 392)

“The growers and/or commerc ial pesticide application companies in the chosen configuration provide the pool of workers from which cluster pa rticipants will be recruited. (pp. 41 of 392)

(d) Can the findings from the proposed study be generalized beyond the study sample?

Yes, within the limits imposed by the purposive design of the study.

3.2 Equitable Selection of Subjects

(a) What are the inclusion/exclusion criteria? Are they complete and appropriate?

“[A]ll AHETF Study participants must meet these inclusion criteria:Attachment 2

Page 36 of 52 • Have experience within the past year with the work activity being monitored in the study (including the particul ar equipment to be used during mixing/loading or application)

• Handle pesticides as part of their job

• Be trained in safe pesticide handling pr actices in accordance with the Worker Protection Standard (WPS) or equivalent Canadian regulations, or be exempt from such training

• Provide proof of being at least 18 ye ars old with a government-issued photo

ID

• Confirm they do not work for a pesticide company or a contractor of the

AHETF

• Consider their general health status to be good and tell researchers they have

no medical conditions that affect their ability to participate in the study (See

SOP AHETF-11.C for health status determination)

• Not be pregnant or nursing (See SOP AHETF-11.D)

• Confirm they do not normally wear pers onal protective equipment that is not required by the label and that might impact the objectives of the study, such as chemical-resistant clothing. Confirm they will follow label directions.

• Have a private meeting with a research er to review and discuss the consent

form

• Understand English or Spanish (S ee SOP AHETF-11.I for a detailed discussion of this topic)

• Understand and sign the consent form, a nd if in California, the California Experimental Research Subject’s Bill of Rights” (SOP AHETF-11.B.5)

“For this mixing/loading of water sol uble packets study, the following inclusion criteria also apply:

• Have experience within the past year with mixing/loading water soluble packets (including the particular equi pment to be used) (p. 209 of 392)

(b) What, if any, is the relationship be tween the investigator and the subjects?

None

(c) If any potential subjects are likely to be especially vulnerable to coercion or undue influence, what is the ju stification for including them?

Potential subjects are of necessity agricu ltural workers, and could potentially be subjected to undue influence either to participate or not to participate by their employers. This possibility is minimized through methods of recruiting growers and by requiring growers to promise in wr iting not to influence their employee’s

decisions.Attachment 2

Page 37 of 52 (d) What process is proposed for recru iting and informing potential subjects?

“For each monitoring area, AHETF will follow standard procedures (see SOP AHETF-11.B) to recruit poten tial participants for this water soluble packet mixing/loading study. Individual workers will be recruited duri ng an initial site inspection or subsequent visi t(s) to a potentially eligib le grower and/or commercial applicator facility.

“The Study Director or designated researcher will seek permission from the eligible grower to approach his/her employees to recruit volunteers for the study. Depending on the number of employees and size of the grower facility the Study Director or researcher may contact employees using an informational recruitment flyer posted in a common work area. Such a flyer will br iefly describe the research study and provide a toll-free phone number for employees to express an interest in participating in the study. The flyer shall have been prev iously reviewed and approved by an IRB.

“Alternatively, or subsequent to the use of a flyer, the Study Director or researcher will arrange a meeting with the grower’s employees who express an interest in participation. Such recruitment meetings will always occur without the grower or supervisors being present (SOP AHETF-11.B). The Study Director or researcher shall make a presentation describing the AHETF Exposure Monitoring Program, the goals of the research study, the procedures used in exposure monitoring, and the risks and benefits to participants. A toll-free phone number will be provided, and individuals will be encouraged to contact AHETF if th ey desire additional information about the study or are interested in part icipating in the study. All presentation materials, such as handouts or visual aids, sha ll be reviewed and approved by an IRB prior to use in recruiting subjects.” (pp. 140-141 of 392)

(e) If any subjects are potentially subject to coercion or undue influence, what specific safeguards are proposed to protect their rights and welfare?

“In accordance with SOP AHETF-11.B, the individual growers will be asked to sign a non-coercion statement (Employer Coopera tion Statement) affirming to their workers and AHETF that they will not co erce or unduly influence their workers to either participate or not participate in the study. Growers must also certify that alternate work will be provided on study days for workers who choose not to volunteer; and that the employee’s decision to participate or not will have no impact on their employment.” (p. 140 of 392)

3.3 Remuneration of Subjects

(a) What remuneration, if any, is proposed for the subjects?

“During recruitment, workers will be o ffered an opportunity to take part in a recruitment meeting with the Study Director or other designated member of the studyAttachment 2

Page 38 of 52 team (but without the workers’ supervisors) to learn about participating in this study.

No remuneration is offered for this in troductory meeting. Workers who are still interested in participating in the study w ill attend a private consent meeting with a

researcher who will obtain the informed cons ent of the worker. Workers will be paid $20 for their attendance right after the consen t meeting, whether or not they decide to participate in the study. Workers who decide to participate in the study will be paid an additional $80 each time they suit up (i.e., put on the long underwear) to participate in the study. Usually, workers will participate in the study on only one day unless their participation is terminated due to weat her or other unexpected occurrences. The additional $80 is provided in cash at the end of the monitoring period or at the time the subject withdraws from the study. All wo rkers who participat e will receive the payment, even if they withdraw or their pa rticipation is terminated by the study team.” (pp. 123 of 392)

(b) Is proposed remuneration so high as to be an undue inducement? No.

(c) Is proposed remuneration so low that it will only be attractive to economically disadvantaged subjects? No.

(d) How and when would subjects be paid?

In cash, immediately afte r their participation.

4. Risks to Subjects

4.1 Risk Characterization

(a) Have all appropriate prerequisite studies been performed? What do they show

about the hazards of the test materials?

The potential surrogate materials are regi stered with EPA, are well understood, and have been fully tested.

This study could involve any of four ac tive ingredients: acephate, dithiopyr, imidacloprid, and thiophanate-methyl. “T he pesticide products containing these active ingredients and potentially used in this study are curren tly registered for agricultural use. AHETF will only mon itor workers making applications in accordance with all label, Worker Prot ection Standard (WPS), and state (e.g., California) regulatory requi rements.” (p. 127 of 392)

For the active ingredients that may be used in this study, the calculated MOEs meet or exceed the required Margin of Exposure (M OE) or Aggregate Risk Index (ARI) for

both the individual dermal and inhalation ro utes of exposure, as well as for the combined exposure, and their use is acceptable for this scenario. (See p. 127 of 392)Attachment 2

Page 39 of 52 (b) What is the nature of the risks to subjects of the proposed research?

“Four kinds of risks are associated w ith the conduct of the current exposure monitoring study. These are:

• The risk of heat-related illness

• The risk associated with scripting of field activities

• Psychological risks

• The risk of exposure to surfactants

“In this 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 daily life. In particular, the

risk of heat-related illness (resulting from wearing an extr a layer of clothing to trap chemical) will be increased due to study participation. AHETF has adopted an extensive program to minimize these risks.” (p. 123 of 392)

Each of these four kinds of risk is disc ussed in the protocol (pp. 123-129 of 392) and the consent form (p. 169 of 392).

(c) What is the probability of each risk asso ciated with the research? How was this probability estimated?

Quantitative probabilities are not estimated.

4.2 Risk Minimization

(a) What specific steps are proposed to minimize risks to subjects?

“The following practices, desi gned to minimize these risk s and respond to injuries, will be followed during this study (see AHETF SOPS 11.C, 11.E, 11.G and 11.H):

• Selecting only experienced pesticide ha ndlers who consider themselves to be in good health

• Requiring experience with the mixing/load ing equipment to be used in the study and with mixing/loading produ cts in water so luble packets

• Reminding workers of safe chemical handling practices

• Practicing the face wipe and hand wash procedures with each participant before pesticide handling begins

• Identifying nearby medical treatment facilities in case of emergency

• Monitoring the heat index and stopping the study if conditions warrant

• Providing transportation to medical tr eatment and covering the costs of

treatment

• Having a medical professional on site to observe the workers and provide

urgent careAttachment 2

Page 40 of 52 • Observing study participants th roughout the monitoring period

• Ensuring that all tank mix products are used according to approved label(s) and state regulations, and do not requ ire any additional PPE that could adversely affect the study objectives (for example, chemical-resistant coveralls or aprons).” (pp. 128-129 of 392)

Risk reduction actions specific to each of the six identified kinds of risk are discussed in the pr otocol (pp. 123-129).

(b) How do proposed dose/exposure levels compare to established NOELs/NOAELs

for the test materials?

For the active ingredients that may be used in this scenario, the Margins of Exposure (MOEs) calculated for the highest level of e xposure in this protocol “meet or exceed the minimum required MOE, or level of c oncern (generally 100), for the individual dermal and inhalation routes of exposure, as well as for the combined exposure.” (p. 127 of 392)

(c) What stopping rules are proposed in the protocol?

“AHETF will monitor ambient conditions outs ide the cab to determine the heat index near the mixing/loading station and base monitoring decisions on the current heat index. Exposure monitoring will be disc ontinued if the heat index cutoff of 105 o 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.” (p. 124 of 392)

(d) How does the protocol provide for medica l management of potential illness or injury to subjects?

“As a safety measure, AHETF will have a medical professional on site during the study. This may be a paramedic, physician’ s assistant, nurse, or emergency medical technician. This professional will also obs erve you for signs of illness. They will provide medical attention as needed.” (p. 169 of 392)

SOP AHETF-11.H defines procedures to be followed if a subject in an AHETF study requires emergency medical attention.

(e) How does the protocol provi de for safety monitoring?

The protocol refers to various SOPs which define procedures for safety monitoring:

• SOP AHETF-11.E calls for researchers to monitor worker compliance with

label and Worker Protection Standard requirements, and permits the Study Director to remove from the study a worker who engages in unsafe work practices.Attachment 2

Page 41 of 52 • SOP AHETF-11.G calls for the Stud y Director, the on-site medical professional, and all researchers and observers to monitor subjects for any

indication of heat-related illness.

• SOP AHETF-11.H defines procedures to be followed if a subject in an AHETF study requires emer gency medical attention.

(f) How does the protocol provide for post-e xposure monitoring or follow-up? Is it of long enough duration to discover adverse events which might occur?

“During the consenting process each volunt eer will be provided the opportunity to request a summary of their personal resu lts from the study. This will require the worker to provide a name and address (ma il or e-mail). The results will include the distribution of chemical exposure among the various body areas measured so the

worker can be aware of where most dermal exposure occurs and a comparison to the results for other workers performing the same task. This follow-up procedure is described in SOP AHETF-11.J and the persona l information related to this follow-up

will be retained as described in SOP AHETF-6.D.” (p. 133 of 392)

Detailed information about how subject s who have requested their exposure information will be provided with it is provided in Supplement 2.

“Just prior to the completion of the worke r’s participation in the study, a researcher will remind the participant he/she should bathe or shower as soon as practical and that they have received a copy of the sign ed consent form with phone numbers for reporting any health changes they think might be related to participation in the study. Post-study inquiries will be forwarded to th e Study Director who will deal with the situation as appropriate and notify AH ETF management (SOP AHETF-11.B).” (p. 133 of 392)

(g) How and by whom will medical care for rese arch-related injuries to subjects be paid for?

“If you are injured or get sick because of your participation in this study, medical treatment will be available at your workplace and at a nearby health care facility. If necessary, AHETF will arrange transportati on for you to receive medical attention. You may refuse medical treatment unless you get sick from too much exposure to pesticides or from getting too hot, or if we believe you are too sick to make a rational decision about getting medical treatment.

“AHETF will cover the cost of reasonable and appropriate medical attention for a study-related injury or illness that is not covered by your own insurance or insurance provided through your employer. This in cludes deductible costs and any out-ofpocket expenses, including co-payments, you might have. The Study Director, in consultation with the on-site medical profe ssional, will decide if you have an illness or injury that is due to your partic ipation in this study.” (p. 170 of 392)Attachment 2

Page 42 of 52 5. Benefits

(a) What benefits of the proposed research, if any, would accrue to individual subjects?

“There are no personal benefits to the study participants.” (p. 129 of 392)

Although there are no direct benefits to study pa rticipants, a potential indirect benefit is knowledge about how their exposure compares to that of others doi ng similar work; this is not addressed in the protocol.

(b) What benefits to society are anticipate d from the information likely to be gained through the research?

“Since there are not sufficient existing data suitable for use in a generic database describing the exposure to workers from mixi ng/loading water soluble packets, society will likely benefit from data generated by this study through the improved risk assessments by EPA and other regul atory agencies.” (p. 129 of 392)

“Data from the AHETF exposure monitoring pr ogram has the potential to improve the ability of EPA and other regulatory agencies to accurately asse ss occupational risks associated with mixing/loading pesticides pa ckaged in water soluble packets. Water soluble packets are considered an engin eering control designed to reduce exposure potential for mixer/loaders. The knowledge likely to be obtained from this study is generalizable and will contribute to assessm ents of the risks of both new and existing pesticides.” (p. 129 of 392)

(c) How would societal benefi ts be distributed? Who woul d benefit from the proposed

research?

“Growers who allow the study to be conducted using their equipment, crops and facilities will be reimbursed for the pesticides used for the study. While this is beneficial to the grower, it is considered a minor benefit when compared to the costs of running their businesses. The AHETF member companies wi ll likely realize a benefit by addressing regulatory data requirements ge nerically, at lower cost (and using fewer human subjects), than if they conducted similar studies for individual pesticide ingredients.” (p. 99)

(d) What is the likelihood that each identi fied societal benefits would be realized?

Identified societal benefits are likely to be realized.Attachment 2

Page 43 of 52 6. Risk/Benefit Balance: How do the risk s to subjects weigh against the anticipated benefits of the research, to subjects or to society?

“By monitoring exposure to professional agri cultural handlers who follow their normal practices, but wear an additional layer of clothing (as an inner dosimeter which traps chemical that penetrates the work clothing), this study presents a greater than minimal risk to participants. Participating in this study increases the risk of heat-related illness, but this risk is mitigated by a medical management program which emphasizes prevention measures and guidelines for stopping participation when warrant ed based on environmental conditions.

“The likely benefit to agricultural workers as a w hole and to society in general, in the form of more accurate measurements of potential exposure to pesticides, must be weighed against the risks to participants. Pesticide products p ackaged in water soluble packets are becoming more common for many agricultural uses acr oss the country and a variety of experts consulted by AHETF reported their use occurs widely throughout the country. Exposure data for this scenario meeting contemporary standards of reliability and quality will likely provide a significant benefit to society. Because th e margins of exposure are acceptable for the products proposed for use in this research study, subjects are very unl ikely to experience acute toxic effects, and because extensive proc edures will be in place to minimize these and other risks to participants, th e likelihood of serious adverse effects is very small. In summary, AHETF believes the risks to study partic ipants from participating in this study are reasonable in light of the likely benefit to so ciety of the knowledge to be gained.” (pp. 129- 130 of 392)

7. Independent Ethics Review

(a) What IRB reviewed the proposed research?

Independent Investigational Review Board, Inc., of Plantation FL

(b) Is this IRB independent of the investi gators and sponsors of the research? Yes

(c) Is this IRB registered with OHRP? Yes

(d) Is this IRB accredited? No.

(e) Does this IRB hold a Federal-Wide Assurance from OHRP? No.

(f) Are complete records of the IRB review provided as required by 40 CFR 26.1125?

Yes.Attachment 2

Page 44 of 52 (g) What standard(s) of ethical conduct would govern the work?

“This study will be conducted in accordance w ith EPA’s final regulation published at 40 CFR Part 26 that establishes requirements for the protection of subjects in human research (see SOP AHETF-11.A). The protoc ol, informed consent form(s), California Experimental Research Subject’s Bill of Ri ghts, and other required documentation for this study will be approved by an instituti onal review board (IRB) and the California Department of Pesticide Regulation, and submitted to the EPA as required by 40 CFR 26.1125. The report of the completed research is subject to 40 CFR 26.1303 requirements

to document its ethical conduct.

“The IRB for the proposed research shall be the Independent Inve stigational Review Board Inc. (IIRB) of Plantation, Florida. Comp lete records of the IIRB review as required by 40 CFR 26.1125 will be submitted to EPA for review along with this protocol and

other documents.

“Researchers that participate in the study and interact with study participants must undergo ethics training (SOP AHETF-1.B). The training shall include successful completion of the course from the Nationa l Institutes of Health (Protecting Human Research Participants (PHRP)) and/or the Basic Collaborative IRB Training Initiative Course (CITI; The Protection of Human Resear ch Subjects). Copies of the certificates of completion for the ethics courses will be submitted to the IRB and stored in the respective personnel files (maintained by the AH ETF and all contract facilities.)” (p. 122 of 392)

8. Informed Consent

(a) Will informed consent be obtained from each prospective subject? Yes

(b) Will informed consent be appropriatel y documented, consistent with the requirements of 40 CFR §26.1117? Yes

(c) Do the informed consent materials meet the requirements of 40 CFR §26.1116, including adequate characterization of th e risks and discomforts to subjects from participation in the research, the potential be nefits to the subject or others, and the right to withdraw from the research? Yes

(d) What is the literacy rate in English or other languages among the intended research subjects?

Not addressed in protocol. Appropriate pr ovision is made for informing English or Spanish-speaking candidates who cannot read the consent form.Attachment 2

Page 45 of 52 (e) What measures are proposed to overcome language differences, if any, between investigators and subjects?

See SOP AHETF-11.I

(f) What measures are proposed to ensu re subject comprehension of risks and

discomforts?

“In all situations, the SD (or designee) wi ll not sign the Consent Form unless he/she believes the candidate fully understands th e information presented. This will be ascertained by providing repeat ed opportunities to ask quest ions and by asking questions of the potential workers that would require a response that indicates understanding of key

issues. The form in Attachment 11.J will be used to ascertain general understanding.” (SOP AHETF-11.J.1 §3.10)

(g) What specific procedure will be followed to inform prospective subjects and to seek

and obtain their consent?

“The SD (or designee) will be responsible for obtaining informed consent from all study workers prior to their partic ipation in the study. Any materials used during the consent meeting will be approved by the IRB before use.

“Informed consent will be sought in an indivi dual meeting with each worker. The worker may have a friend, family member, or adviso r with them during the meeting. Witnesses may also be present as de scribed in SOP AHETF-11.I.

“The person obtaining consent will inform th e worker that he/she will receive $20 (or another amount specified in th e protocol) for participation in the consent meeting, or the amount specified in the protocol, even if he/she decides not to particip ate in the research.

“During the private consent meeting the pe rson obtaining consent will provide each worker with a full explanati on of the study, its requirements, any potential risks, its benefits, alternatives to participation, etc . Workers will be advised of their right to withdraw from the study at any time and fo r any reason without jeopa rdizing their normal position with their employers or their daily wage s. Workers will be to ld they will receive an additional $80 (or another amount specifie d in the protocol) if they decide to participate and put on the dosimeters, whet her or not they complete the monitoring period.

“The person obtaining consent will provide information about the risk of the surrogate chemical in the study, including signs and symptoms of acute overexposure. This information will be presented in the produc t label and/or the MSDS. Refer to SOP

AHETF-11.E for details.

“Information will be provided about the ri sk of heat stress, including signs and symptoms, and ways to prevent it. Info rmation will also be provided about theAttachment 2

Page 46 of 52 availability of medical a ttention during the study. De tails on heat stress and its presentation are outlined in SOP AHETF- 11.G, while details on emergency medical procedures are outlined in SOP AHETF-11.H.

“During the discussions between potential part icipants and the person obtaining consent, ample time will be provided for questions and the person obtaining consent will provide any additional information or clar ification that is requested.

“The IRB-approved Consent Form (and all supporting documents, except the product labels and MSDS forms) will be presented in the preferred language (English or Spanish)

of the worker. All sections of the Consent Form will be explained in detail. When the person obtaining consent is satisfied that th e worker understands the requirements and risks of the study, and if the worker still wants to participate, he/she will be asked to sign and date the Consent Form and the person obtaining consent will provide a copy of the signed form to the worker.

“If the study is conducted in California, the IRB-approved “California Experimental Research Subject’s Bill of Rights” will al so be attached. These documents (in the appropriate language) will be reviewed, signe d and dated by the worker, and copies will be provided.

“In all situations, the person obtaining c onsent will not sign the Consent Form unless he/she believes the candidate fully understands the information presented. This will be ascertained by providing repeated opport unities to ask questions and by asking questions of the potential workers that would require a response that indicates understanding of key issues. The form in A ttachment 11-J-1 will be used to ascertain general understanding.

“The person obtaining consent wi ll not sign the Consent Form unless he/she believes that the process has been free of any element of coercion or undue influence and the witness (when required) has signed the cons ent form.” (SOP AHETF-11.J.1 §3.2-3.11)

(h) What measures are proposed to ensure fully voluntary participation and to avoid

coercion or undue influence?

“In accordance with SOP AHETF-11.B the indi vidual growers will be asked to sign a non-coercion statement (Employer Cooperation St atement) affirming to their workers and AHETF that they will not coerce or unduly infl uence their workers to either participate or not participate in the study. Growers must also certify that alternate work will be provided on study days for workers who choose not to volunteer; and that the employee’s decision to participate or not will have no impact on their employment.” (p. 140 of 392)Attachment 2

Page 47 of 52 9. Respect for Subjects

(a) How will information about prospective and enrolled subjects be managed to ensure their privacy?

“The AHETF employs many procedures to prot ect subject privacy during recruitment, consent, study conduct, and maintenance of study records. The consent form also summarizes important confidentiality issues for subjects. These procedures are described in SOPs AHETF-6.B, 6.D, 11.B, 11.D, and 11-J.” (p. 130 of 392)

“Your name will only appear on the consen t form, the Product Risk Statement, an optional form for you to request your personal study results, and if in California the California Experimental Research Subject’s Bill of Rights. In all other parts of the study you will be identified by a code. Records with yo ur name will be stored in a secure place

with limited access.

“Information about you taking part in this study will not be given to your employer.

“A study report will be written by AHETF and will be available to member companies.

It will be sent to the US E nvironmental Protection Agency (EPA ). It may also be sent to state government agencies and to governments in other countries. Your name will not be in the study report.

“We cannot promise you total conf identiality. There may be a need to give information to some organizations or to parties in lega l actions, as required by law. Records which identify you may be looked at or copied by the AHETF and any consultants working with the AHETF, by EPA or other government agencies, and by the Independent Investigational Review Board, Inc., (IIRB). IIRB is a group of people who review and

monitor research to make sure the people who take part are protected.

“You may ask the Study Director for a copy of your personal results from this study. You will need to provide your name and a mail or e-mail address.” (pp. 170 of 392)

(b) How will subjects be informed of their fr eedom to withdraw from the research at any time without penalty?

“The absolute right for subjects to withdraw from the research is the cornerstone of protection of human subjects. Pr ospective and enrolled subjects will be informed of their right to withdraw w ithout consequence prior to and dur ing the conduct of the research.

“Any volunteer expressing a need or desire to withdraw from the re search after exposure monitoring begins will be paid $80 and allowed to return to their normal work duties for their employer. If a participant withdraws while being monitored, the long underwear and air sampling pump will be removed, and the hand and face/neck samples will be collectedAttachment 2

Page 48 of 52 with the worker’s consent. The Study Director will decide whether these samples will be analyzed (SOP AHETF-8.K).” (p. 130 of 392)

“Your employer has agreed to let us do the re search and has confirmed that he/she does not care whether you take part in this study or not. Your deci sion to be in this study is voluntary. This decision is entirely up to you. If you decide to take part, you may change your mind and drop out of the study at any time and for any reason. A decision not to take part, or to withdraw from the st udy after it starts, will have no effect on your job or pay or include any penalty or loss of benefits you are owed.” (p. 171 of 392)

(c) How will subjects who decline to participate or who withdraw from the research be

dealt with?

“If you decide to take part, you may change your mind and drop out of the study at any time and for any reason. A decision not to take part, or to withdraw from the study after it starts, will not affect your job or pay or in clude any penalty or any loss of benefits you

are owed.

“If you withdraw, the long underwear and air sampling pump will be removed. The hand and face/neck samples may be collected if you agree.

“Your part in this study may be stopped at any time by the resear chers or the AHETF. The long underwear and air sampling pump will be removed. The hand and face/neck samples may be collected if you agree.

“If you withdraw or are removed from the study, you can go back to your usual work activities. If the study does not last an entire workday, you can go back to your usual

work activities.

“No one can force you to take pa rt in this study. Taking part is totally voluntary. If you choose not to take part in this study you w ill perform your ordinary activities on the day of the study. Your alte rnative is to not take part.” (pp. 171-172 of 392)Attachment 3

Page 49 of 52 § 26.1111 Criteria for IRB approval of research
AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets (Revised version dated August 2010)

Criterion Y/N Comment/Page Reference

(a)(1)(i) Risks to subjects are minimized by us ing procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk. Y

(a)(1)(ii) Risks to subjects are minimized, whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. n/a

(a)(2) Risks to subjects are re asonable in relation to antici pated benefits, if any, to subjects, and the importance of the knowle dge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the resear ch (as distinguished from risks and benefits subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of appl ying knowledge gained in the research (for example, the possible effects of the re search on public policy) as among those research risks that fall within the purview of its responsibility. Y

(a)(3) Selection of subjects is equitable, taking into account the purposes of the research and the setting in which it will be conducted, and being particularly cognizant of the special problems of research in volving vulnerable populations, such as prisoners, mentally disabled persons, or economically or educationally disadvantaged

persons. Y

(a)(4) Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by §26.1116. Y

(a)(5) Informed consent will be appropriately documented, in accordance with, and to the extent required by §26.1117. Y

(a)(6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. Y

(a)(7) When appropriate, there are adequate provisions to prot ect the privacy of subjects and to maintain t he confidentiality of data. Y

(b) When some or all of the subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these subjects. YAttachment 4

Page 50 of 52 §26.1116 General requirements for informed consent AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets (Revised version dated August 2010)

Criterion Y/N Comment/Page Reference

No investigator may involve a human being as a subject in research covered by this subpart unless the investigator has obtained t he legally effective informed consent of the subject or the subject’s le gally authorized representative OK

An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative suffici ent opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence OK

The information that is given to the subject or the representative shall be in language understandable to the subject or the representative OK

No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or ap pears to release the investigator, the sponsor, the institution or its agents fr om liability for negligence OK

(1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the proced ures to be followed, and identification of any procedures which are experimental OK

(2) A description of any reasonably fo reseeable risks or discomforts to the subject OK

(3) A description of any benefits to the subject or to others which may reasonably be expected from the research OK

(4) A disclosure of appropriate alternativ e procedures or courses of treatment, if any, that might be advantageous to the subject n/a

(5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained OK

(6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained OK

(7) An explanation of whom to contact for answers to pertinent questions about the research and research subjec ts’ rights, and whom to contact in the event of a research-related injury to the subject OK(a) In seeking informed consent the following informationshall be provided to each subject

(8) A statement that participation is vol untary, refusal to participate will involve no penalty or loss of benefits to which t he subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subj ect is otherwise entitled OK

(1) A statement that the particular treatme nt or procedure may involve risks to the subject (or to the embryo or fetu s, if the subject may become pregnant) which are currently unforeseeable OK

(2) Anticipated circumstances under wh ich the subject’s participation may be terminated by the investigator with out regard to the subject’s consent OK

(3) Any additional costs to the subject t hat may result from participation in the

research OK

(4) The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject OK

(5) A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject n/a(b) When appropriate, one ormore of the following elementsof information shall also beprovided to each subject

(6) The approximate number of subjects involved in the study OK
(e) If the research involves intentional exposure of subjects to a pesticide, the subjects of the research must be informed of the identity of the pesticide and the nature of its pesticidal

function. OKAttachment 5

Page 51 of 52 §26.1117 Documentation of informed consent AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets (Revised version dated August 2010)

Criterion Y/N Comment/Page Reference

(a) Informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject’s legally authorized representative. A copy shall be gi ven to the person signing the form. OK

(b)(1) The consent form may be a writt en consent document that embodies the elements of informed consent required by §26.1116. This form may be read to the subject or the subject’s legally authoriz ed representative, but in any event, the investigator shall give either the subject or the representative adequate opportunity to read it before it is signed; or OK

(b)(2) The consent form may be a short form written consent document stating that the elements of informed consent required by §26 .1116 have been presented orally to the subject or the subject’s legally authorized r epresentative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subjec t or the representative. Only the short form itself is to be signed by the subject or t he representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A co py of the summary shall be given to the subject or the representative, in add ition to a copy of the short form. n/aAttachment 7

Page 52 of 52 40 CFR 26.1125 Prior submission of proposed human research for EPA review AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets (Revised version dated August 2010)

Any person or institution who intends to conduct or sponsor hu man research covered by §26.1101(a) shall, after receiving approval from all appropriate IRBs, submit to EPA prior to initiating such research all information relevant to the proposed research specified by §26.1115(a), and the following addition al information, to the extent not already included:

Requirement Y/N Comments/Page Refs
(1) Copies of

• all research proposals reviewed by the IRB,

• scientific evaluations, if any, that accompanied the proposals reviewed by the IRB,

• approved sample consent documents,

• progress reports submitted by investi gators, and reports of injuries to subjects. Y
n/a

Y

n/a pp. 8-198

pp. 110-176

(2) Minutes of IRB meetings . . . in sufficient detail to show

• attendance at the meetings;

• actions taken by the IRB;

• the vote on these actions including the number of members voting for, against, and abstaining;

• the basis for requiring changes in or disapproving research;

• a written summary of the discussion of controverted issues and their

resolution. n/a

n/a Revisions met the criteria for a minor change in previously approved research and was reviewed under expedited review procedures

No controverted issues

(3) Records of continuing review activities. n/a (4) Copies of all correspondence between th e IRB and the investigators. Y pp. 303-390 (5) ● A list of IRB members identified by name; earned degrees; representative capacity; indications of experience su ch as board certifications, licenses, etc., sufficient to describe each mem ber’s chief anticipated contributions to IRB deliberations;

• any employment or other relationship between each member and the institution, for example, full-time employee, a member of governing panel or board, stockholder, paid or unpaid consultant. Y IIRB roster and credentials on file

with EPA.

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). Y Separately submitted to EPA under confidentiality claimAll information relevant to the proposed research specified by § 26.1115(a)

(7) Statements of significant new findings provided to subjects, as required by §26.1116(b)(5). n/a

(1) The potential risks to human subjects Y pp. 123-129 (2) The measures proposed to minimize risks to the human subjects; Y pp. 123-129 (3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y p. 129

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y pp. 15-16 and AHETF Governing Document (reviewed at June 2008 HSRB meeting)§1125(a)a discussion of:

(5) The balance of risks and benefits of the proposed research. Y p. 129-130 §1125(b): All information for subjects and written informed consent agreements as originally provided to the IRB, and as approved by the IRB. Y Original pp. 315-317, 200-267,

320-360 Approved pp. 114-176, 371-382 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y pp. 140, 160, 196, 265, 334, 350

§1125(d): A description of the circumst ances and methods proposed for presenting information to potential human subjects fo r the purpose of obtaining their informed

consent. Y pp. 140-143

§1125(e): All correspondence between the IRB and t he investigators or sponsors. Y pp. 303-390The following Information, to theextent not already included:

§1125(f): Official notific ation to the sponsor or invest igator...that res earch involving human subjects has been reviewed and approved by an IRB. Y pp. 112-113