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Ha 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF 

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES 

April 8, 2009 

MEMORANDUM

SUBJECT: Science and Ethics Review of AHETF Scenario Design and Protocol 

AHE120 for Exposure Monitoring of Workers during Mixing and Loading 

of Pesticide Products in Water Soluble Packets in Five Regions of the 

United States (submitted to EPA on January 16, 2009) 

FROM: Jeff Evans 

 Health Effects Division 

Kelly Sherman 

 Human Research Ethics Reviewer 

TO: Steve Knizner, Associate Director 

 Health Effects Division 

REF: Bruce, E. (2009) Determination of Dermal and Inhalation Exposure to 

Workers during Mixing/Loading of Pesticide Products in Water Soluble 

Packets in the United States. Unpublished protocol dated December 11, 

2008, prepared for the Agricultural Handlers Exposure Task Force under 

Sponsor ID AHE120, 552 p. 

We have reviewed the referenced proposal from both scientific and ethics 

perspectives. Scientific aspects of the proposed research are assessed in terms of the 

recommendations of the EPA Guidelines Series 875 and of the EPA Human Studies 

Review Board. Ethical aspects of the proposed research are assessed in terms of the 

standards defined by 40 CFR 26 subparts K and L and the recommendations of the EPA 

Human Studies Review Board. Below is a summary of the conclusions reached in our 

science and ethics reviews. 
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Science Review

• The protocol addresses the technical aspects of applicable exposure monitoring 

guidelines and is likely to produce scientifically valid and useful data. 

Ethics Review

• The protocol meets the applicable ethical requirements of 40 CFR part 26, 

subparts K and L. 

• Before the research is conducted, the protocol 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 Principal Analytical Investigator must be 

identified in the protocol. 

 The page headings on the English Language Research Participant Bill of 

Rights should be changed from Spanish to English. 

• In addition, please provide the following information to the Agency. If a protocol 

revision is necessary to address these comments (or for any other reason), please 

also re-submit for review by the approving IRB: 

 Collect information on growers who do not respond or who decline to 

participate, such that the representativeness of participating growers can 

be evaluated. 

 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. 

 Verify the appropriateness 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 Spanishspeaking subjects. 

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. 

The following two documents comprise the protocol submission and were 

considered in EPA’s review: 

• Water Soluble Packet Mixer/Loader Scenario Submission (January 16, 2009) (552 

pages); and 

• Supplemental Submission of Final Versions of 12 SOPs (February 24, 2009) (78 

pages). 
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The monitoring unit selection and scenario construction plan appear on pages 10-

47.1 The rationale for the proposed sample size and cluster configuration is presented on 

pages 15-21. The IRB-approved protocol and supporting documents (consent forms, 

product-specific risk statements, and recruitment flyers) appear on pages 85-147 

(English) and pages 148-163 (Spanish). Documentation of all interactions between the 

investigators and the Independent Investigational Review Board, Inc., of Plantation FL 

appears on pages 177-552. 

The following documents are included in the submission: 

• Monitoring Unit Selection and Construction Plan for Scenario (pp. 10-47) 

• Background Information from Experts (pp. 48-79) 

• IIRB Approval Letter and Approved Supporting Documents (pp. 80-176) 

• IIRB Approval Letter (pp. 81-84) 

• IIRB-approved Protocol (pp. 85-125) 

• Study Documents in English approved by IIRB: 

o Informed Consent Form (pp. 126-136) 

o Product Risk Statements (pp. 137-143) 

o Recruiting Flyer (pp. 144-145) 

o Research Participant Bill of Rights (pp. 146-147) 

• Spanish translations of study documents approved by IIRB: 

o Informed Consent Form (pp. 148-160) 

o Product Risk Statements (pp. 164-173) 

o Recruiting Flyer (pp. 174-176) 

o Research Participant Bill of Rights (pp. 161-163) 

• SOPs Referenced in the protocol (pp. 395-538) 

• Records of IRB Review (pp. 177-552) 

The SOPs listed below are cited in the scenario and protocols. The eight SOPs 

marked by a single asterisk have been revised since the October 2008 HSRB meeting to 

address EPA and HSRB comments. The four SOPs marked by a double asterisk are new 

SOPs written since the October 2008 HSRB meeting to address EPA and HSRB 

comments. Final versions of the twelve new or revised SOPs are provided in the 78-page 

supplemental submission that was provided to EPA by the AHETF on February 24, 2009. 

Final versions of the SOPs that are unchanged since the October 2008 HSRB 

meeting, plus draft versions of the twelve new or revised SOPs, are provided on pages 

395-538 of the main submission, as part of the materials submitted for IRB review.2 

 

1 Unless otherwise noted, all page references in this review are to “p. N of 552” of the main submission. If 

pages within the supplemental submission of the twelve new and revised SOPs are referenced, the page 

reference will indicate “SOP Supplemental Submission, p. N of 78.” 

2 When the protocol was submitted for IRB review in December 2008, the twelve new or revised SOPs 

were still in draft form. Since that time, the twelve SOPs have been finalized, and the final versions of the 

twelve SOPs are contained in the 78-page Supplemental Submission of SOPs (dated February 24, 2009). 
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AHETF-1.B.4* Personnel Responsibilities 

AHETF-1.F.0 Potential Referable Findings 

AHETF-1.H.0** Procedure for Recruiting Study Participants 

AHETF-2.C.2 Protocol Design and Preparation 

AHETF-6.B.1 Access to Archived Data 

AHETF-6.D.0 Access to Confidential Worker Info 

AHETF-8.A.3 Whole Body Sampling – Inner Dosimeters 

AHETF-8.B.4 Hand Wash Samples 

AHETF-8.C.6* Dermal Face/Neck Wipe Samples 

AHETF-8.D.4* Collection of Air Samples Using OVS Tubes 

AHETF-8.E.5* Fortification of Matrix Samples 

AHETF-8.F.5 Sample Identification 

AHETF-8.G.2 Worker Clothing Acceptability Criteria 

AHETF-8.K.0 Sample Quality 

AHETF-9.J.0 Analytical Quality Control and Statistics 

AHETF-10.C.4 Worker and Study Observations 

AHETF-10.E.2 Worker Sample Collection Sequence 

AHETF-10.G.1 Personal Air Sampling Pump Calibration 

AHETF-11.A.1 Ethical Requirements for AHETF Studies 

AHETF-11.B.4* Recruiting Study Volunteers 

AHETF-11.C.1 Worker Health Status 

AHETF-11.D.1 Pregnancy Testing 

AHETF-11.E.1 Pesticide Safety Instructions 

AHETF-11.F.1 Adverse Events Reporting for Institutional Review Boards 

AHETF-11.G.1 Identification and Control of Heat Stress 

AHETF-11.H.2* Emergency Procedures for Human Subjects 

AHETF-11.I.1* Language Requirements and Considerations for Study 

Volunteers 

AHETF-11.J.1* Seeking Informed Consent from Study Volunteers 

AHETF-11.K.0** Compiling Lists of Potential Growers 

AHETF-11.L.0** Compiling Lists of Potential Commercial Applicators 

AHETF-11.M.0** Recruiting Potentially Eligible Growers and Commercial 

Applicators 

B. Summary Assessment of the Scenario Design3

1. Scenario Design: This proposal addresses the handler exposure scenario 

involving mixing/loading of pesticides enclosed 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 Protection Standard (WPS) 

at 40 CFR 170.240(d)(4) states that WSP products, when used correctly, qualify 

as a closed mixing/loading system. 

 

3 Supporting details are in Attachment 1. 
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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 mixing/loading, then the respirator must 

be provided and worn also in case of emergency. 

 

The AHE120 protocol calls for mixing/loading one of two surrogate pesticides 

into a variety of tanks containing water in a variety of agricultural spraying 

operations. A total of 25 Monitoring Units (MUs) are proposed for this scenario; 

when the scenario is complete, the 25MUs will be added to the AHED database. 

EPA intends to use these data to estimate daily dermal and inhalation exposures 

of pesticide handlers mixing/loading pesticides in water 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 purposively selected to reflect a diverse range 

of agronomic practices, geographic regions and likelihood of use of one or both 

surrogate pesticides (acephate and carbaryl). Each cluster is referred to as a 

monitoring ‘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 through a purposive five-step process: 

• Identifying geographic areas associated 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 support an efficient study and to have 

an ample supply of handlers 

The result of executing these steps was the purposive choice of the following five 

states for the five proposed monitoring sites: 

• New York (EPA Region I) 

• Louisiana (EPA Region IV) 

• Michigan (EPA Region V) 

• California (southern portion of EPA Region X) 

• Washington (eastern portion of EPA Region XI) 
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These choices are appropriate to cover the most important regional and agronomic 

variations and likelihood of use of WSP containing either acephate or carbaryl. 

New York (Region I) represents a cool climate having a wide variety of 

orchard, trellis and field crops. According to the annual use data from the 

National Agricultural Statistical Service (NASS), approximately 29,000 

pounds of carbaryl active ingredient (AI) were reportedly used on apples 

and 26,000 pounds AI being used on grapes. 

Louisiana (Region IV) represents a hot and humid climate where higher 

acreages of cotton and soybeans are available that are treated with 

acephate. According to the annual use data from NASS, approximately 

one million and 400,000 pounds of acephate AI were applied to cotton and 

soybeans respectively. 

Michigan (Region V) represents a cool climate in the upper Midwest 

having a wide variety of orchard crops such as cherries apples and 

peaches. Trellis and field crops are also represented in this state. 

According to the annual use data from NASS, approximately 67,000 

pounds AI of carbaryl and 11,000 pounds AI of acephate were applied to a 

variety of crops. 

California (central/southern portion of Region X) represents a region 

having high usage of both carbaryl and acephate on a wide variety of 

orchard, trellis and field crops. According to the annual use data from 

NASS, approximately 74,000 pounds AI of carbaryl and 68,000 pounds 

AI of acephate were applied to a variety of crops. California also 

represents a hot and dry climate in the western U.S. 

Washington (eastern portion of Region XI) also represents a hot and dry 

climate but situated in the northwest U.S. According to the annual use 

data from NASS, approximately 1.6 million and 53,000 pounds of 

carbaryl AI were applied to apples and cherries respectively. 

 

In the next stage of the diversity selection process, the practical range of amount 

of active ingredient handled (AaiH) for the water-soluble packet scenario is 

divided into five bands ranging from 5 to 2000 pounds AaiH. Past studies have 

shown that AaiH is strongly associated with exposure and is a meta-factor 

associated with differences in equipment and spraying practices. The AHETF 

selected the 2000 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 5 lbs, to minimize non-detects. AHETF has 

partitioned the practical AaiH range into five strata: 
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• 5 to 17 lbs AI handled 

• 18 to 55 lbs AI handled 

• 56 to 182 lbs AI handled 

• 183 to 603 lbs AI handled 

• 604 to 2,000 lbs AI handled 

This is a reasonable approach to stratification, and it should be possible to fill all 

strata in all five region field studies defined for this scenario within the range of 

standard agronomic practices. 

The next stage of sample selection results in identifying the growers whose crops 

will be treated and the workers whose exposure 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 growers 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 least one of the surrogates (acephate or 

carbaryl) 

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

accepted this approach. 
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When constructing MUs, three additional restrictions 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 obtained from one grower or commercial 

pesticide applicator company 

The growers and/or commercial pesticide applicator companies in the chosen 

configuration provide the pool of handlers from which handlers 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 complete a revised efficient configuration, 

the working pool can be expanded by approaching 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 carbaryl and acephate, formulated in water soluble packets as one of 

three registered products: Acephate 90 WSP, Acephate 75 WSP, or Sevin® 80 

Solupak. These pesticide active ingredients have been successfully used as 

surrogates in previous worker/handler exposure monitoring studies and have well 

established and reliable analytical methods. These are generally appropriate 

choices for this research. However, due to risk estimates for acephate, we 

recommend that no more than 700 pounds AI be handled by any worker on any 

given day. 

C. Summary Assessment of the Scientific Aspects of the Study Design4

1. Statistical design: This protocol describes collecting 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 climate. 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 revised AHETF Governing Document; details 

specific to the mixing/loading of water soluble packets scenario are in the 

scenario design. No characteristics of this scenario have been identified which 

would justify a departure from the 5 x 5 configuration. 

 

4 Supporting details are in Attachment 2. 
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2. Proposed pattern of exposure: The proposed minimum exposure duration for 

each MU will be at least 4 hours, involving 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 following five strata of AaiH: 

• 5 to 17 pounds AI handled 

• 17 to 55 pounds AI handled 

• 56 to 182 pounds AI handled 

• 183 to 603 pounds AI handled 

• 604 to 2000 pounds AI handled 

Three registered products containing one of the two designated surrogate pesticide 

active ingredients have been identified, and a cooperating grower may choose to 

use any of them for a specific MU. All of these products will be mixed with 

water and loaded into the various sprays tanks in one of three possible ways: 

• Loading individual WSPs directly into the tank associated with the 

application equipment (e.g., groundboom or airblast sprayers) 

• Loading individual WSPs into holding or nurse tanks before the finished 

spray solution/suspensions are transferred to the application equipment 

tanks (e.g., fixed wing aircraft). The pesticide 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 simply 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. 

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 
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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: the 

front torso (above the waist); rear torso (above the waist); right and left upper 

arms (shoulder to elbow); right and left lower arms (elbow to cuff); right and left 

upper legs (waist to knee) and the right and left lower legs (knee to cuff). 

Before beginning work, subjects will wash 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 requested 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 contamination not associated with the monitoring 

event. This wipe sample will be discarded. 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 retained for analysis. As required by AHETF 

SOP 10.C.4, the study team will record what type of personal protective 

equipment (PPE), including respirators, 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 will be operated for the total monitoring 

period including any breaks. 

Additional measures will record environmental conditions at the time of 

monitoring. Observers will make field notes 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 contractor 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, field fortification and control samples, 
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laboratory fortification and control samples, and guidelines on the use of 

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

Field fortifications will be conducted in the 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 field 

samples. Samples collected from the subjects will be corrected based on the 

results of the recovery of the 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 later statistical analysis. The documentation 

will report a confidence-interval-based approach to determine the relative 

accuracy for the arithmetic mean and 95th percentile of unit exposures. The 

AHETF will not otherwise statistically analyze the monitoring data. 

D. Compliance with Applicable Scientific Standards 

This protocol itself adequately 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 samples for laboratory, field, and storage 

stability samples 

Additionally, the proposal has addressed the technical aspects provided in the 

applicable exposure monitoring guidelines (i.e. Series 875 Group A and OECD 

Applicator Guidelines) as well as Good Laboratory Practices (GLPs). 
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E. Summary Assessment of Ethical Aspects of the Proposed Research5

1. Societal Value of Proposed Research: The objective of this study is to develop 

data to determine the potential exposure for workers who mix and load solid 

pesticide products packaged in water soluble packets. This mixing/loading 

method is widely used and applicable to a large variety of commercially important 

crops, and the existing exposure data are inadequate. EPA will use the results of 

this study to estimate the dermal and inhalation exposure likely for a wide range 

of agricultural pesticides applied under this exposure scenario. 

2. Subject Selection: Subjects will be recruited among the employees of 

commercial growers who utilize solid pesticides packaged in water soluble 

packets, who are willing to use at least one of the surrogate active ingredients for 

this study (acephate and carbaryl), and who meet AHETF criteria for 

participation. Eligible 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 eligible growers), with experience within the past year mixing and 

loading water soluble packets using the particular equipment to be used in the 

study, and who meet the eligibility requirements of the study. If more employees 

are available and interested than are needed, qualified participants will be selected 

randomly. Although the design is purposive, and thus participants are not 

representative 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.4 (SOP Supplemental Submission, pp. 29-34 of 78). 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’s facility, the Study Director or 

researcher may contact employees using an informational recruitment flyer posted 

in a common work area. 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 interest in participation. Such recruitment meetings will always 

occur without the grower or supervisors being present. The Study Director or 

researcher will describe the AHETF Exposure Monitoring Program, the goals of 

this specific study, the procedures to be used in exposure monitoring, and the 

risks and benefits to participants. 

The subject eligibility factors listed in the consent form and SOP AHETF-11.B.4 

are appropriate. However, the page headings on the English Language Research 

Participant Bill of Rights (p. 147) should be changed from Spanish to English. 

 

5 Supporting details are in Attachment 2. 
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Candidates who attend an individual interview will be paid $20 whether or not 

they agree to participate; enrolled subjects who put on the whole-body dosimeter 

will be paid $80 in addition to their usual pay, whether or not they complete 

participation. 

3. Risks to Subjects: Five kinds of risks to subjects are discussed in the protocol, 

along with specific steps proposed to minimize them: 

• The risk of heat-related illness 

• The risk of exposure to surrogate chemicals 

• The risk associated with scripting of field activities 

• Psychological risk 

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

The surrogate chemicals used will be acephate or carbaryl; both are fully tested 

and well understood. Individual growers will choose from three registered 

products (two containing acephate as the active ingredient and one containing 

carbaryl as the active ingredient), for each of which a product-specific supplement 

to the consent form describes the specific risks identified on the approved label. 

Margins of Exposure (MOEs) calculated for the highest levels of exposure 

proposed in the protocol meet or exceed EPA’s target MOEs, and therefore the 

exposures are not of concern to EPA. 

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 benefits to the subjects, but subjects may 

request their individual results. If they are told only their own results, little 

benefit would result, but if they are told how their exposure compared to that of 

others, it could be of potential indirect benefit to them. The principal benefit of 

this research is likely to be reliable data about the dermal and inhalation exposure 

of workers mixing/loading water soluble packets of pesticide formulations, usable 

by EPA and 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 reasonable in light of the likely benefits to 

society from new data supporting more accurate 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 Investigational Review Board, Inc., (IIRB, Inc.) of 

Plantation, Florida. The submitted materials include a full record of 

correspondence between the investigators and the IIRB.
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7. Informed Consent: Informed consent will be obtained from each prospective 

subject and appropriately documented. Subjects will sign both the consent form 

and the product-specific supplement describing the surrogate material chosen by 

the grower. If participating in the study in California, subjects will also receive 

the California Research Participant Bill of Rights. Oral fluency in English or 

Spanish is a criterion for inclusion, but literacy is not required. The reading level 

of the English language consent form is appropriate. Adequate provision is made 

to meet the needs of subjects who do not read either language. EPA assessments 

of compliance with the requirements of 40 CFR §26.1116 and §26.1117 appear in 

Attachments 4 and 5 to this review. 

8. Respect for Subjects: Subject identifying information will be recorded only 

once; all subsequent data records and reports will refer to individual subjects only 

by a code. Provision is made for discrete handling of pregnancy testing, required 

of all female subjects on the day of testing. 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 research involving intentional exposure of 

human subjects to a pesticide, with the intention of submitting the resulting data to EPA 

under the pesticide laws. Thus the primary ethical standards applicable to this proposal 

are 40 CFR 26, Subparts K and L. In addition, the requirements of FIFRA §12(a)(2)(P) 

for fully informed, fully voluntary consent of subjects apply. 

A detailed evaluation of how this proposal addresses applicable standards of 

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

The following specific deficiencies in the protocol should be addressed before the 

research is initiated: 

• The Local Site Coordinator, the Principal Field Investigator, the Analytical 

Facility, and the Principal Analytical Investigator must be identified in the 

protocol. 

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 any research involving intentional 

exposure of any human subject who is a pregnant woman (and therefore 

her fetus), a nursing woman, or a child. 
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The protocol requires that subjects be at least 18 years old and excludes female subjects 

who are pregnant or lactating. Thus §26.1703 would not forbid EPA to rely on a study 

executed according to this protocol. 

 If the deficiencies noted above are addressed and the amended protocol is 

approved by the overseeing IRB, 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/Loading of Wettable Powder in Water 

Soluble Packets (AHE120)

2. EPA Protocol Review: AHETF Mixing/Loading of Wettable Powder in Water 

Soluble Packet (AHE 120)

3. §26.1111 Criteria for IRB approval of research 

4. §26.1116 General requirements for informed consent 

5. §26.1117 Documentation of informed consent 

6. §26.1125 Criteria for Completeness of Proposals for Human Research 

7. Responsiveness to Recommendations in the Final Report of the October 2008 

HSRB Meeting
Attachment 1 

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EPA Scenario Review: AHETF Mixing/Loading of Wettable Powder in Water Soluble 

Packets (AHE120) 

Title: Monitoring Unit Selection and Construction Plan for Scenario: 

Mixing/Loading of Water Soluble Packets 

Date: December 4, 2008 

Sponsor: Agricultural Handlers 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 future application as liquid sprays. This is 

accomplished by mixing/loading the packets directly into the tank to be used for the 

application or into a pre-mix tank where the contents will later be transferred to the spray 

tank used for the actual application.” (p. 12) 

“...the following states are proposed for this scenario to provide 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)” (p. 152) 

(a) Is the scenario adequately defined? 

The scenario is clearly and 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 within 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 crops (e.g., orchards, row crops, grains, field 

crops, trellis crops, greenhouse and nursery plants, forestry, 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 measurements in existing studies (mostly 

not included in PHED) to identify those that satisfy current acceptability criteria and 
Attachment 1 

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qualify for inclusion in a generic database. For this particular scenario, the JRC reviewed 

three studies (AH508, AH520, andAH608) involving mixing/loading only with water 

soluble packets; however, none of these studies were deemed appropriate for a generic 

database.

“AHETF also conducted a detailed 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 packets comprise PHED Scenario 5 – Wettable 

Powder, Water Soluble Bags (MLOD). Data within that scenario were graded by EPA as 

“Low Confidence” for the “No Clothes”, “Single Layer, No Gloves” and “Single Layer, 

Gloves” clothing scenarios. The inhalation exposure data are also graded as “Low 

Confidence”. The low confidence ratings were primarily due to low numbers of 

measurements... 

“Finally, EPA examined data from existing water soluble packet mixing/loading 

exposure studies or exposure assessments that were not available to the AHETF and 

concluded that none of the exposure data should be included in the AHETF database 

(meeting, November 3, 2008).” (pp. 16-17) 

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 identified equipment type as a potentially 

important parameter that might impact exposure. 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 chest 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 such a whether or not diluted product is 

transferred to another tank. Therefore, equipment type will be informally diversified 

within clusters of MUs. 

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

that are identified below (Honeycutt, 2008): 

• Direct mixing WSPs into tanks that are used directly for application (e.g., 

groundboom, airblast, chemigation, etc., tanks) 

• Mixing WSPs into tanks not directly used for the application but which serve as 

holding tanks and contain the spray mix solution 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 final tank used for the application... 
Attachment 1 

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Consequently, it is proposed that the possible equipment types used for this scenario 

be grouped into the following 3 general categories: 

1. Mixing of WSPs directly into the 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 & transferred to the final application tank,” (pp. 

38-40) 

“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, and orchard crops. 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 meta-factor that is associated 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 Region XIII consists of Hawaii and Puerto Rico 

and is not being considered for this scenario. These Growing Regions provide a 

convenient basis for geographic stratification. These Regions have been used when 

planning and conducting pesticide residue trials for various crop types. The regions were 

based on natural geography and climatic boundaries (ACPA, 1992) and are therefore 

useful for indicating when locations selected for exposure monitoring are geographically 

diverse. . . .” (pp. 24-25) 

“Predominant Surrogate Use: Although water soluble packets may be used in all 12 

EPA Growing Regions, not all are expected to have wide use of the two AHETF 

surrogate active ingredients (acephate and carbaryl). Thus, for practical reasons, the 

distribution of surrogate use will be considered when selecting the five monitoring sites. 

Table 2 illustrates this surrogate distribution with chemical usage data obtained from 

USDA on (NASS 2003 and 2006). The total usage for acephate and carbaryl (in 

thousands of lbs per year) are shown for the top seven crops for each chemical. For 

acephate, these seven crops account for more than 99% of acephate usage reported by 

NASS. For carbaryl, the top seven crops account for 77% of reported usage. ...The set 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.” (p. 26) 

“Selection of a Geographically Diverse Set of Clusters: Five new monitoring sites 

need to be selected that are geographically diverse. Such a diverse configuration can be 

obtained by simply locating each site in a different EPA Growing Region. In theory, five 

growing regions could be selected at random from among the 12 regions that stratify the 
Attachment 1 

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continental U.S. A state (or portion of a state) could be randomly or purposively chosen 

from within the selected Region. . . . However, such undirected selection of states would 

be quite inefficient...Locating sites near crop areas where the surrogates have wide use 

over 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 sites. 

1. New York (Region I) 

New York involves usage of carbaryl on a variety of crops including orchard, trellis, and 

field crops. This state reflects a cool climate in the northwestern U.S. 

2. Louisiana (Region IV) 

Louisiana involves by far the highest usage of acephate, including cotton and soybeans. 

Louisiana reflects mostly a hot and humid climate in the southern U.S. 

3. Michigan (Region V) 

Michigan involves usage of acephate and carbaryl and a variety of crops including 

orchard, trellis, and field crops. This state reflects a cool climate in the upper Midwestern 

U.S. 

4. California (the central/southern portion in Region X) 

California involves significant usage of acephate and carbaryl and a variety of orchard, 

trellis, and field crops. The central and southern portions of California generally reflect a 

hot and dry climate in the western U.S. 

5. Washington (the eastern portion in Region XI) 

Washington involves the highest usage of carbaryl, primarily on apples and cherries, but 

also some on grapes. Eastern portions of Washington reflect a hot and dry climate in the 

northwestern U.S.” (pp. 28-30) 

“Selection of Specific Monitoring Sites for Each Study: The final step for selecting 

sites is to choose a specific area within each selected state(s) identified above where 

growers and workers can be recruited to conduct a study in a reasonable amount of time. 

This involves selecting the sites in a reasonably limited geographic area so that MU 

identification and selection operations can be conducted efficiently in one local area. This 

will facilitate the logistics of the field research team and keep the costs of study conduct 

reasonable so a sufficient number MUs can be obtained in the AHETF monitoring 

program. 

“Choosing a cost-effective configuration of MUs 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 
Attachment 1 

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the same visit so researcher salary, travel, food, lodging, and field fortification expenses 

are minimized. 

“Therefore, for each cluster, a particular area of each target state will be selected and 

identified in the study protocol. The actual site location within this general growing 

region will be determined by discussions with local resources to indicate counties that are 

most likely to apply the surrogate product and have sufficient growers, equipment, and 

workers to allow an efficient design.” (pp. 30-31) 

(b) How have random elements been incorporated into the scenario sampling design? 

All choices in the first stage of the proposed diversity selection process, 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 selection bias that might 

arise from the LSC (i.e., a local agricultural researcher) purposively choosing which 

growers to contact. Therefore, 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 that list, will be established in the protocol for that study. The 

general procedure 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 water soluble packets at the identified site (generally 

about one to three 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 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, including 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 AHETF to recruit his/her worker(s) 
Attachment 1 

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• 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 commercial pesticide application companies to 

mix/load their product will also be considered. Those growers will be asked to 

identify their preferred commercial companies and AHETF will contact them to 

screen them for willingness to cooperate ....The important consideration with this 

step is that the first the appropriate equipment is identified and the workers associated 

with that equipment are identified... 

4. “Each grower identified as eligible (sometimes along with an associated 

commercial pesticide application company) is placed into a working pool along 

with information on: 

• Specific location of mixing/loading sites 

• Description of equipment available (e.g., number, type, and size) 

• Surrogate chemical(s) that might be utilized 

• Approximate timing of surrogate applications 

• Number of workers available 

• AaiH those workers might be able to handle in a day. (pp. 35-36) 

(c) What feasible opportunities to incorporate 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 geographical area, it is likely that the opportunity will 

often arise to select randomly from among interested workers. 

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

“The workers will be allowed to follow their 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 partially determined by the amount 

of AaiH but will involve the mixing/loading 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 transferring diluted product from tank to tank and 

potential contact with contaminated surfaces (e.g., water soluble packets, tanks, hoses, 

etc.)...If other functions are also associated with the mixing/loading event (e.g., 

transferring from a slurry tank to an application tank) then these events are also included 

as part of the monitoring.” (p. 40) 
Attachment 1 

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(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. However WSPs are generally 

packaged in relatively small packets of 1 to 5 pound product. Therefore, in this instance, 

variability in packaging is not considered a parameter for purposive diversification. 

Other factors such as the crop being treated are no expected to directly affect exposure, 

but might lead to selection of various equipment set-ups that could impact exposure 

potential.” (p. 41) 

3. Are the proposed test materials appropriate surrogates? 

“The following active ingredients are available in water soluble packets and will be 

considered for use in this mixing/loading scenario. The commercial products of the active 

ingredients that might be used in particular will be listed in the study protocol. 

• Acephate 

• Carbaryl 

“These surrogate active ingredients also typically have high use rates for the potential crops 

of interest that enables measurements at the high end of AaiH per day. 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.” (p. 42) 

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

“Appendix C of the Governing Document describes the methodology to calculate sample 

sizes when the reference model used is cluster sampling from a lognormal distribution. For 

the purposes of determining sample sizes, the 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 the Joint Regulatory Committee agreed there is 

no evidence to suggest otherwise and no strong opinion to the contrary (meeting with 

AHETF, June 27, 2007). 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 (NC =5) with 5 MUs per cluster (NM=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/cluster 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 site) 

will be addressed by a separate study protocol. 

“Appendix C of the Governing Document also shows that when the benchmark accuracy 

requirement above is met there may also be sufficient power to permit users of the database 

to perform a limited examination of the relationship between the normalizing factor (e.g., 
Attachment 1 

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AaiH) and exposure. This is true provided: (1) the practical range of the normalizing factor 

is at least an order of magnitude and (2) there is adequate within-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% statistical power to distinguish complete proportionality 

from complete independence between exposure and the normalizing factor used in the 

primary benchmark. Since these conditions can be satisfied for the reference sampling 

design, then the purposive diversity design for the water soluble packet scenario should 

provide adequate power for the minor (i.e., secondary) objective: the ability to conduct 

limited examinations of the relationship between AaiH and exposure.” (p. 23) 
Attachment 2 

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EPA Protocol Review: AHE120: Water Soluble Packet Mixer/Loader Scenario 

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: December 11, 2008 

Study Director and Sub-Investigators: 

 Eric D. Bruce 

 Brian Lange6

 Tami Belcher5

 Aaron Rotondaro5 

Local Site Coordinator: TBD7

 

Field Facility: TBD6

 

Analytical Facility: TBD6 

 

Sponsor: Agricultural Handlers 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 products packaged in water soluble packets in 

five regions of the United States.” (p. 89) 

 

6 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. 

7 The Local Site Coordinator, Field Facility, Analytical Facility, and Principle Analytical Investigator must all be 

identified. 
Attachment 2 

Page 25 of 54 

(b) What research question does it address? Why is this question important? Would 

the research fill an important 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 pesticides formulated in water soluble packets. 

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

“AHETF (in conjunction with EPA, PMRA, and CDPR, collectively the Joint Regulatory 

Committee (JRC)) reviewed handler exposure measurements in existing studies (mostly 

not included in PHED to identify those that satisfy current acceptability criteria and 

qualify for inclusion in a generic database. For this particular scenario, the JRC reviewed 

three studies (AH508, AH520, and AH608) involving mixing/loading with water soluble 

packets; however, none of these studies were deemed appropriate for a generic database. 

“AHETF also conducted a detailed review of the data in PHED for this scenario to 

determine if any of the data were suitable for a modern generic database. . . . Thus there 

are no data currently in PHED for this scenario that are useful for a modern generic 

database. (p. 16) 

(e) Could the question be answered without newly exposing human subjects? If so 

how? If not, why not? 

There is no alternative to monitoring handlers as they mix/load pesticides for measuring 

their dermal and inhalation exposure. 

2. Study Design 

(a) What is the scientific objective of the study? 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 data which regulators and other potential users 

of the generic database can utilize to characterize a predicted distribution of future 

exposures and perform exposure assessments for this scenario.” (p. 44) 
Attachment 2 

Page 26 of 54 

“The primary benchmark objective for this scenario is that a sample from the 

hypothetical reference sampling distribution above be of adequate size to describe 

selected measures of the (normalized) exposure distribution with a pre-determined level 

of accuracy...The current consensus is that estimates of the geometric mean, the 

arithmetic mean, and the 95th percentile generally need to be accurate to within 

approximately 3-fold of the actual population value. AHETF and the Joint Regulatory 

Committee (EPA, California Dept. of Pesticide Registration, Pest Management 

Regulatory Agency [Canada], and the U.S. Department of Agriculture) agreed 3-fold 

accuracy is an appropriate benchmark for this scenario (meeting with AHETF, November 

3, 2008).” (p 21 of 552) 

No explicit hypothesis is stated, nor is the study explicitly 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 for the choice of sample size?

“Appendix C of the Governing Document describes the methodology to calculate 

sample sizes when the reference model used is cluster sampling from a lognormal 

distribution. For the purposes of determining sample sizes, the 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 the Joint 

Regulatory Committee agreed there is no evidence to suggest otherwise and no strong 

opinion to the contrary (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 (NC=5) with 5 MUs per cluster (NM=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/cluster as long as the total number of MUs is 

at least 25 and no cluster has more than 5 MUs.” (pp. 22-23) 

(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 proposed. This is appropriate for the study 

design and statistical analysis plan. 
Attachment 2 

Page 27 of 54 

(c) How is the study blinded? 

The study is not blinded, nor could it be.

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

“After the randomly-selected pool of eligible growers is assembled, researchers (e.g., 

LSC and Study Director) will examine the details of potential MUs and identify a 

configuration of MUs (i.e., growers, chemicals, workers, AaiH, timing) that will 

result in an efficient cluster design.” (p. 36)

“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-factor since individual practices might be 

associated with exposure potential. 

• No piece of equipment may be used more than once and each of the three 

general equipment types must be used at least once per cluster (see section 6.1 

below) 

• No more than 1 MU may be obtained from any grower or commercial 

pesticide application company (so a grower with several workers and several 

pieces of equipment can contribute one MU).” (p. 37) 

(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 data can be viewed as deriving from a true 

random sample.’” (p. 44) 

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

“As detailed in the Governing Document, the data collected from the studies for this 

scenario will only be statistically evaluated with respect to the benchmark measures 

of adequacy. These two categories of data adequacy are: 

1. The relative accuracy of selected statistics characterizing the distribution of 

exposure normalized by amount of active ingredient handled (AaiH). 

2. How well the data can be expected to describe a relationship between exposure 

and AaiH, if one existed.” (p. 44) 

“The primary benchmark objective is that selected lognormal-based estimates of 

normalized dermal exposure distribution be accurate to within 3-fold, at least 95% of 
Attachment 2 

Page 28 of 54 

the time. The benchmark estimates specified are those for the geometric mean, 

arithmetic mean, and the 95th 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 given above.” (p. 45) 

“This secondary benchmark objective [Adequacy of the Data for Distinguishing a 

Proportional from an Independent Relationship between Exposure and AaiH] applies 

to the water soluble packet mixing/loading scenario because the practical range in the 

amount of active ingredient handled (AaiH) exceeds an order of magnitude. In this 

case it is reasonable 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.” (p. 45) 

(g) Are proposed statistical methods appropriate 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 soluble packets in this study, and that these 

exposures can inform assessments of the likely exposures for individuals in similar 

future situations. 

Regarding the secondary objective, distinguishing a proportional from an independent 

relationship between exposure and AaiH, statistical power is relevant. 

“This secondary benchmark objective applies to the water soluble scenario because 

the practical range in the amount of active ingredient handled (AaiH) exceeds an 

order of magnitude. In this case it is reasonable 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 model linear regression would also have the 

same power to reject the hypothesis that β=1 when β=0. This is the precise meaning 

of being able to ‘discriminate between proportionality and independence’.” (p. 45) 
Attachment 2 

Page 29 of 54 

2.2 How and to what will human subjects be exposed? 

“The water soluble packet mixing/loading program will monitor instances of worker 

exposure resulting from the mixing/loading the packets of pesticide.” (p. 17) 

“The test substances approved for use in this study are listed in Section 2.3.2 above. The 

most appropriate test substance, based largely on the preference of the grower, will be 

used at each of the individual sites. A different test substance may be used at each site 

and by each worker within a site if appropriate.” (pp. 112-113)

(a) What is the rationale for the choice 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 this scenario. The choice of surrogate at 

each location will depend largely upon the preference of the grower and pest pressure 

on his crop at that time... 

“The following active ingredients are available in water soluble packets and will be 

considered for use in this mixing/loading scenario. The commercial products of these 

active ingredients that might be used in particular studies will be listed in study 

protocol. 

• Acephate 

• Carbaryl 

“These surrogate active ingredients also typically have high use rates for the potential 

crops of interest that enables measurements at the high end of AaiH per day. 

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. 41-42) 

(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 ingredient handled is the normalizing factor 

and indirectly influences many other handling conditions, efforts will be taken to 

generate data in as wide a range of AaiH as practical within each cluster of MUs. 

AaiH is selected since AHETF feels it is the most reasonable measure of active 

ingredient contact potential for this scenario. . . . In addition, EPA currently 

normalizes water soluble packet mixing/loading exposure by AaiH during pesticide 

product exposure assessments and there is no other factor identified as being more 

appropriate. 
Attachment 2 

Page 30 of 54 

“In addition to its potential direct relationship to exposure, the amount of active 

ingredient handled is also viewed as a meta-factor affecting parameters such as tank 

size, number of loads applied, etc. Thus, diversification of AaiH induces 

diversification of such associated factors as well. 

“AHETF has calculated a practical range in AaiH for this scenario taking into account 

such factors as typical use rates of products, 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 5 to 2,000 lbs active ingredient 

to be handled per day for this scenario.” (pp. 31-32) 

“[I]t is important that the AaiH levels be well diversified within each cluster. This 

allows the data for this scenario to be used to discriminate a completely proportional 

relationship from a completely independent relationship between exposure and AaiH 

(if one of those two relationships were true). Within-cluster 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: 

• 5 to 17 pounds AI handled 

• 18 to 55 pounds AI handled 

• 56 to 182 pounds AI handled 

• 183 to 603 pounds AI handled 

• 604 to 2,000 pounds AI handled

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

the five strata.” (p. 34)

(c) What duration of exposure is proposed? 

“Duration of monitoring is another parameter 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 per day at the staging site but can also spend 

long intervals performing other tasks (or just sitting around) 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 periods for this scenario must meet the 

general rule of being at least 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 monitoring intervals will ensure that daily 

exposure estimates are not biased by unusual conditions during that short interval. If 

necessary, some minor scripting of worker activities 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 order to mix 3 loads in four hours.” (pp. 40-41) 
Attachment 2 

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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 contamination: inhalation samples (discussed in the 

next section), then hand washes, then face/neck wipes, and finally inner dosimeters as 

described in SOP AHETF-10.E.2 (pp. 465-466) and SOP AHETF-8.A.3 (pp. 422-

426). 

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

Full details of the personal air-sampling method, attachment of pumps, monitoring of 

workers, and pump calibration are presented in AHETF-8.D.4 (SOP Supplemental 

Submission, pp. 11-14). 

(b) What steps are proposed to ensure measurements are accurate and reliable? 

Please see SOP AHETF-8.E.5, Fortification of Matrix Samples (SOP Supplemental 

Submission pp. 15-23). 

“This SOP describes the methods by which agricultural worker exposure monitoring 

matrices, (i.e., inner dosimeters, hand washes, face/neck wipes, inner socks, outer 

head patches, inner head patches [inner socks and inner and outer head patches are 

not monitored in this study] and OVS tubes) are to be spiked. 

“Field fortification samples are exposure matrix samples that are fortified (or spiked), 

generally in the field, with known amounts of active ingredient and subsequently 

analyzed to determine the amount of active ingredient recovered. Field fortification 

samples are subjected to the same environmental, handling, shipping and storage 

conditions as worker samples. Because these conditions are similar, and because 

field fortification samples are analyzed along with worker samples, recovery values 

calculated from analysis of fortification samples are applicable to worker exposure 

samples. Field fortification recoveries are therefore used to adjust residue levels 

found in worker samples for residue losses that might have occurred during 

collection, handling, shipping and storage.” (p. 438) 

(c) What QA methods are proposed? 

“AHETF intends that all regulatory studies are conducted in accordance with the 

FIFRA GLP Standards (40 CFR part 160). Field and analytical aspects of this study 

will be monitored by the relevant quality assurance units(s) (QAU) while this study is 

in progress to ensure compliance with the FIFRA GLP regulation and adherence to 

this protocol and relevant SOPs. The QAU(s) will submit copies of its/their 
Attachment 2 

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inspection reports to the Study Director and 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 contents of the report accurately 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 

1.15.” (p. 123) 

(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 transit conditions in or on the sampling materials (inner 

dosimeters, hand wash solutions, face/neck wipes, and air sampling matrices) will be 

conducted on a minimum of one day of exposure monitoring at each location, or more 

days as appropriate for environmental conditions. . . . On each fortification day, two 

untreated control samples of each matrix will be processed similar to the field 

fortification 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. 116-117) 

In general, field measurements are adjusted based on the recovery from the 

fortification sample. For example, a field measurement for an inner dosimeter of 300 

ug would be adjusted based on the applicable fortification sample for the inner 

dosimeter matrix. If the recovery from 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 concern? How was it identified? 

“The water soluble packet mixing/loading scenario program will monitor instances of 

worker exposure resulting from the mixing/loading the packets of pesticides. Each 

instance is termed a monitoring unit (MU). Each MU consists of a set of 

mixing/loading conditions (including the particular worker) that are intended to 

represent the scenario activities for a single workday. In many cases monitoring units 

will be selected from ‘naturally occurring’ water soluble packet mixer/loader-days. 

However, the selected application conditions are sometimes modified or scripted 

slightly to ensure that the sample of MUs reflects the expected diversity in the entire 

population of future water soluble mixer/loader-days. . . .Thus, MUs are technically 
Attachment 2 

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not ‘sampled’ from a population. More correctly, they should be viewed as synthetic 

water soluble mixing/loading-days derived from both selected and constructed 

conditions.” (pp. 17-18) 

(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.” (p. 37) 

(c) Are expected participants representative 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 that 

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 obtain a list of growers 

that might utilize water soluble packets at the identified site (generally about 

one to three counties) 

• Farm Market ID 

• Commercial list providers 

• State an 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 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, including 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 AHETF 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 
Attachment 2 

Page 34 of 54 

• The grower is willing to use at least one of the surrogate active 

ingredients listed in the study protocol.” (pp. 35-36) 

“The growers and/or commercial pesticide application companies in the chosen 

configuration provide the pool of workers from which cluster participants will be 

recruited. (p. 37) 

(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: 

• Have experience within the past year with the work activity being monitored 

in the study (including the particular equipment to be used during 

mixing/loading or application) 

• Handle pesticides as part of their job 

• Be trained in safe pesticide handling practices 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 years 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.1 for health status determination) 

• Not be pregnant or nursing (See SOP AHETF-11.D.1, pp. 481-483) 

• Confirm they do not normally wear personal 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 researcher to review and discuss the consent 

form 

• Understand English or Spanish (See SOP AHETF-11.I.1 for a detailed 

discussion of this topic) 

• Understand and sign the consent form, Product Risk Statement, and if in 

California, the California Experimental Research Subject’s Bill of Rights” 

(SOP AHETF-11.B.4) 
Attachment 2 

Page 35 of 54 

“For this mixing/loading of water soluble packets study, the following inclusion 

criteria also apply: 

• Have experience within the past year with mixing/loading water soluble 

packets (including the particular equipment to be used) (p. 92) 

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

None 

(c) If any potential subjects are from a vulnerable population, what is the 

justification for including them? 

Potential subjects are of necessity agricultural 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 writing not to influence their employee’s 

decisions. 

(d) What process is proposed for recruiting and informing potential subjects? 

“For each selected site, AHETF will follow standard procedures (see SOP AHETF11.B.4) to recruit potential participants for this water soluble packet mixing/loading 

study. Individual workers will be recruited during an initial site inspection or 

subsequent visit(s) to a potentially eligible grower 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 briefly 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 previously 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.4). 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 they desire additional 

information about the study or are interested in participating in the study. All 

presentation materials, such as handouts or visual aids, shall be reviewed and 

approved by an IRB prior to use in recruiting subjects.” (pp. 109-110) 
Attachment 2 

Page 36 of 54 

(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.4, the individual growers will be asked to 

sign a non-coercion statement (Employer Cooperation Statement) affirming to their 

workers and AHETF that they will not coerce 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. 109) 

3.3 Remuneration of Subjects 

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

“During recruitment, workers will be offered an opportunity to take part in a 

recruitment meeting with the Study Director or other designated member of the study 

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

No remuneration is offered for this introductory meeting. Workers who are still 

interested in participating in the study will attend a private consent meeting with a 

researcher who will obtain the informed consent of the worker. Workers will be paid 

$20 for their attendance right after the consent 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 weather or other unexpected occurrences. The 

additional $80 is provided in cash at the end of the monitoring period or at the time the 

volunteer withdraws from the study. All workers who participate will receive the 

payment, even if they withdraw or their participation is terminated by the study team.” 

(pp. 208-209) 

(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 after their participation 
Attachment 2 

Page 37 of 54 

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 registered with EPA, are well understood, and 

have been fully tested. 

This study could involve either of two active ingredients: acephate or carbaryl. “The 

pesticide products containing these active ingredients and potentially used in this 

study are currently registered for agricultural use. AHETF will only monitor workers 

making applications in accordance with all label and Worker Protection Standard 

(WPS) requirements.” (p. 94) 

For both of the active ingredients that may be used in this study, the calculated MOEs 

meet or exceed the required MOE for both the individual dermal and inhalation routes 

of exposure, as well as for the combined exposure, and their use is acceptable for this 

scenario. 

 

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

“Five kinds of risks are associated with the conduct of the current exposure 

monitoring study. These are: 

• The risk of heat-related illness 

• The risk of exposure to surrogate chemicals 

• The risk associated with scripting of field activities 

• Psychological risks 

• The risk of exposure to detergents 

“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, 

this study involves the use of chemicals (pesticides, fertilizers, additives, etc.) that 

present a risk of adverse health effects. In addition, AHETF believes the risk of heatrelated illness (resulting from wearing an extra layer of clothing to trap chemical) will 

be increased due to study participation.” (p. 93) 

Each of these five kinds of risk is discussed in the protocol (pp. 93-100) and the 

consent form (p. 131). 
Attachment 2 

Page 38 of 54 

(c) What is the probability of each risk associated 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, designed to minimize these risks and respond to injuries, 

will be followed during this study: 

• Selecting only experienced pesticide handlers who consider themselves to be 

in good health 

• Requiring experience with the mixing/loading equipment to be used 

• 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 treatment and covering the costs of 

treatment 

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

urgent care 

• Observing study participants throughout the monitoring period

• Ensuring that all tank mix products are used according to approved label(s) 

and do not require any additional PPE that could adversely affect the study 

objectives (for example, chemical-resistant coveralls).” (pp. 98-99) 

Risk reduction actions specific to each of the six identified kinds of risk are 

discussed in the protocol (pp. 93-99). 

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

for the test materials? 

For both of the active ingredients that may be used in this scenario, the Margins of 

Exposure (MOEs) calculated for the highest level of exposure in this protocol “meet 

or exceed the minimum required MOE, or level of concern, for the individual dermal 

and inhalation routes of exposure, as well as for the combined exposure.” (p. 95)

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

“AHETF will monitor ambient conditions outside 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 discontinued if the heat index cutoff of 120o

 F 
Attachment 2 

Page 39 of 54 

(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. 94) 

(d) How does the protocol provide for medical 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 observe you for signs of illness. They will 

provide medical attention as needed.” (p. 131) 

SOP AHETF-11.H.2 (SOP Supplemental Submission, pp. 35-38) defines procedures 

to be followed if a subject in an AHETF study requires emergency medical attention. 

(e) How does the protocol provide for safety monitoring? 

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

• SOP AHETF-11.E.1 (pp. 484-486) 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. 

• SOP AHETF-11.G.1 (pp. 489-503) calls for the Study 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.2 (SOP Supplemental Submission, pp. 35-38) defines 

procedures to be followed if a subject in an AHETF study requires emergency 

medical attention. 

(f) How does the protocol provide for post-exposure monitoring or follow-up? Is it 

of long enough duration to discover adverse events which might occur? 

“During the consenting process each volunteer will be provided the opportunity to 

request a summary of their personal results from the study. This will require the 

worker to provide a name and address (mail 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. Results are typically available six 

to nine months after monitoring occurs. The personal information related to this 

follow-up will be retained as described in SOP AHETF-6.D.0. 

“Just prior to the completion of the worker’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 signed consent form with phone numbers for 

reporting any health changes they think might be related to participation in the study. 
Attachment 2 

Page 40 of 54 

Post-study inquiries will be forwarded to the Study Director who will deal with the 

situation as appropriate and notify AHETF management (SOP AHETF-11.B.4).” (p. 

103) 

(g) How and by whom will medical care for research-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 transportation 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 includes deductible costs and any out-ofpocket expenses, including co-payments, you might have. The Study Director, in 

consultation with the on-site medical professional, will decide if you have an illness 

or injury that is due to your participation in this study.” (p. 132) 

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. 99) 

Although there are no direct benefits to study participants, a potential indirect benefit is 

knowledge about how their exposure compares to that of others doing similar work; this 

is not addressed in the protocol. 

(b) What benefits to society are anticipated 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 mixing/loading water soluble packets, society 

will likely benefit from data generated by this study through the improved risk 

assessments by EPA and other regulatory agencies.” (p. 99)

“Data from the AHETF exposure monitoring program has the potential to improve the 

ability of EPA and other regulatory agencies to accurately assess occupational risks 

associated with mixing/loading pesticides packaged in water soluble packets. Water 

soluble packets are considered an engineering control designed to reduce exposure 

potential for mixer/loaders. The knowledge likely to be obtained from this study is 
Attachment 2 

Page 41 of 54 

generalizable and will contribute to assessments of the risks of both new and existing 

pesticides.” (p. 99) 

 (c) How would societal benefits be distributed? Who would 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 will likely realize a benefit by addressing 

regulatory data requirements generically, 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 identified societal benefits would be realized? 

Identified societal benefits are likely to be realized. 

6. Risk/Benefit Balance: How do the risks to subjects weigh against the anticipated 

benefits of the research, to subjects or to society? 

“By monitoring exposure to professional agricultural 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 warranted based on environmental conditions. 

“The likely benefit to agricultural workers as a whole 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 packaged in water soluble packets are becoming 

more common for many agricultural uses across 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 the margins of exposure are acceptable for the 

products proposed for use in this research study, subjects are very unlikely to experience 

acute toxic effects, and because extensive procedures will be in place to minimize these and 

other risks to participants, the likelihood of serious adverse effects is very small. In 

summary, AHETF believes the risks to study participants from participating in this study are 

reasonable in light of the likely benefit to society of the knowledge to be gained.” (p. 100) 
Attachment 2 

Page 42 of 54 

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 investigators 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. 

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

“This study will be conducted in accordance with 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.1). The protocol, informed consent form(s), California 

Experimental Research Subject’s Bill of Rights, and other required documentation for 

this study will be approved by an institutional 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 Investigational Review 

Board Inc. (IIRB) of Plantation, Florida. Complete 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.4). The training shall include successful 

completion of the course from the National Institutes of Health (Protecting Human 

Research Participants (PHRP)) and/or the Basic Collaborative IRB Training Initiative 

Course (CITI; The Protection of Human Research 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 AHETF and all contract facilities.)” (p. 92)
Attachment 2 

Page 43 of 54 

8. Informed Consent 

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

(b) Will informed consent be appropriately 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 the risks and discomforts to subjects from 

participation in the research, the potential benefits 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 provision is made for informing English or 

Spanish-speaking candidates who cannot read the consent form. 

(e) What measures are proposed to overcome language differences, if any, between 

investigators and subjects? 

See SOP AHETF-11.I.1 (SOP Supplemental Submission, pp. 39-44) 

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

discomforts? 

“In all situations, the SD (or designee) will not sign the Consent Form unless he/she 

believes the candidate fully understands the information presented. This will be 

ascertained by providing repeated opportunities 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 Attachment 11.J.1 will be used to ascertain general understanding.” 

(SOP AHETF-11.J.1 §3.10, SOP Supplemental Submission, p. 47) 

(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 participation in the study. Any materials used during the consent 

 meeting will be approved by the IRB before use. 

“Informed consent discussions will be conducted by the person obtaining consent in 

private with each worker. The worker may have a friend, family member, or advisor with 

them during the meeting. Witnesses may also be present as described in SOP AHETF11.I.1. 
Attachment 2 

Page 44 of 54 

“The person obtaining consent will inform the worker that he/she will receive $20 for 

participation in the consent meeting, or the amount specified in the protocol, even if 

he/she decides not to participate in the study. 

“During the private consent meeting the person obtaining consent will provide each 

worker with a full explanation 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 for any reason without jeopardizing their normal 

position with their employers or their daily wages. Workers will be told they will receive 

an additional $80, or the amount specified in the protocol, if they decide to participate 

(don the dosimeters) even if they withdraw before the end of 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 as an attachment to the Consent Form (referred to as 

Product Risk Statement {PRS}). WPS requirements, especially proper use of clothing, 

personal protective equipment, etc., will be discussed. Refer to SOP AHETF-11.E.1 for 

details. 

“Information will be provided about the risk of heat stress, including signs and 

symptoms, and ways to prevent it. Information will also be provided about the 

availability of medical attention during the study. Details on heat stress and its 

presentation are outlined in SOP AHETF-11.G.1, while details on emergency medical 

procedures are outlined in SOP AHETF-11.H.2. 

“During the discussions between potential participants and the person obtaining consent, 

ample time will be provided for questions and the person obtaining consent will provide 

any additional information or clarification that is requested. 

“The IRB-approved Consent Form (and all supporting documents) 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 the 

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. 

“An additional IRB-approved document, “Product Risk Statement”, will be attached to 

the Consent Form. If the study is conducted in California, the IRB-approved “California 

Experimental Research Subject’s Bill of Rights” will also be attached. These documents 

(in the appropriate language) will be reviewed, signed and dated by the worker, and 

copies will be provided. 

“In all situations, the person obtaining consent will not sign the Consent Form unless 

he/she believes the candidate fully understands the information presented. This will 

be ascertained by providing repeated opportunities to ask questions and by asking 
Attachment 2 

Page 45 of 54 

questions of the potential workers that would require a response that indicates 

understanding of key issues. The form in Attachment 11-J-1 will be used to ascertain 

general understanding. 

“The person obtaining consent will 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 consent form.” (SOP AHETF-11.J.1 §3.2-3.11, SOP 

Supplemental Submission, pp. 46-47) 

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

coercion or undue influence? 

“In accordance with SOP AHETF-11.B.4 the individual growers will be asked to sign a 

non-coercion statement (Employer Cooperation Statement) affirming to their workers and 

AHETF that they will not coerce 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. 109) 

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 protect 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.1, 6.D.0, 11.B.4, 11.D.1, and 11-J.1.” (p. 100) 

“Your name will only appear on the consent 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 your 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 Environmental 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 confidentiality. There may be a need to give information 

to some organizations or to parties in legal actions, as required by law. Records which 

identify you may be looked at or copied by the AHETF and any consultants working with 
Attachment 2 

Page 46 of 54 

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. 132-133) 

(b) How will subjects be informed of their freedom 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. Prospective and enrolled subjects will be informed of their 

right to withdraw without consequence prior to and during the conduct of the research. 

“Any volunteer expressing a need or desire to withdraw from the research 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 collected 

with the worker’s consent. The Study Director will decide whether these samples will be 

analyzed (SOP AHETF-8.K.0).” (pp. 100-101) 

“Your employer has agreed to let us do the research and has confirmed that he/she does 

not care whether you take part in this study or not. Your decision 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 study after it starts, will have no effect on your 

job or pay or include any penalty or loss of benefits you are owed.” (p. 133) 

(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 include 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 researchers 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. 
Attachment 2 

Page 47 of 54 

“No one can force you to take part in this study. Taking part is totally voluntary. If you 

choose not to take part in this study you will perform your ordinary activities on the day 

of the study. Your alternative is to not take part.” (pp. 133-134)
Attachment 3 

Page 48 of 54 

§ 26.1111 Criteria for IRB approval of research 

AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets 

Criterion Y/N Comment/Page Reference 

(a)(1)(i) Risks to subjects are minimized by using 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 reasonable in relation to anticipated benefits, if any, to 

subjects, and the importance of the knowledge 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 research (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 applying knowledge gained in the research (for 

example, the possible effects of the research 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 involving 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 protect the privacy of 

subjects and to maintain the 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. 

Y 
Attachment 4 

Page 49 of 54 

§26.1116 General requirements for informed consent 

AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets 

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 the legally effective informed consent of the 

subject or the subject’s legally authorized representative 

OK 

An investigator shall seek such consent only under circumstances that provide the 

prospective subject or the representative sufficient 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 appears to release the investigator, the sponsor, 

the institution or its agents from 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 procedures to be followed, and identification 

of any procedures which are experimental 

OK 

(2) A description of any reasonably foreseeable 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 alternative 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 Although research doesn’t involve 

more than minimal risk, compensation and treatment of injuries are 

provided for 

(7) An explanation of whom to contact for answers to pertinent questions 

about the research and research subjects’ rights, and whom to contact in the 

event of a research-related injury to the subject 

OK 

(a) In seeking informed consent the following information 

shall be provided to each subject 

(8) A statement that participation is voluntary, refusal to participate will involve 

no penalty or loss of benefits to which the subject is otherwise entitled, and the 

subject may discontinue participation at any time without penalty or loss of 

benefits to which the subject is otherwise entitled 

OK 

(1) A statement that the particular treatment or procedure may involve risks to 

the subject (or to the embryo or fetus, if the subject may become pregnant) 

which are currently unforeseeable 

OK 

(2) Anticipated circumstances under which the subject’s participation may be 

terminated by the investigator without regard to the subject’s consent 

OK 

(3) Any additional costs to the subject that 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 or 

more of the following elements 

of information shall also be 

provided 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. 

OK 
Attachment 5 

Page 50 of 54 

§26.1117 Documentation of informed consent 

AHETF Protocol AHE120: Mixing/Loading of Wettable Powder in Water Soluble Packets 

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 given to the person signing the form. 

OK 

(b)(1) The consent form may be a written 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 authorized 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 representative. 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 subject or the representative. Only the short form 

itself is to be signed by the subject or the 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 copy of the summary shall be given to the 

subject or the representative, in addition to a copy of the short form. 

n/a 
Attachment 6 

Page 51 of 54 

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 

Any person or institution who intends to conduct or sponsor human 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 additional 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 investigators, and reports of injuries 

to subjects. 

Y 

n/a 

Y 

n/a 

pp. 180-538 

pp. 127-136, 149-158 

(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. 

Y 

Y 

Y 

N 

n/a 

pp. 550-552 

The only required changes 

were minor typographical 

changes to the ICF 

No controverted issues 

(3) Records of continuing review activities. n/a 

(4) Copies of all correspondence between the IRB and the investigators. Y pp. 80-84, 180, 182-183, 541, 

543, 545, 548 

(5) ● A list of IRB members identified by name; earned degrees; representative 

capacity; indications of experience such as board certifications, licenses, 

etc., sufficient to describe each member’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 claim 

All 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. 93-99 

(2) The measures proposed to minimize risks to the human 

subjects; 

Y pp. 93-99 

(3) The nature and magnitude of all expected benefits of such 

research, and to whom they would accrue 

Y p. 99 

(4) Alternative means of obtaining information comparable to what 

would be collected through the proposed research; and 

Y pp. 16-17 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. 100 

§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. 243-252 

Approved pp. 127-136 

§1125(c): Information about how subjects will be recruited, including any 

advertisements proposed to be used. 

Y pp. 34-38, 92-93, 105-111, 

145, 175 

§1125(d): A description of the circumstances and methods proposed for 

presenting information to potential human subjects for the purpose of 

obtaining their informed consent. 

Y pp. 100-103 

§1125(e): All correspondence between the IRB and the investigators or 

sponsors. 

Y pp. 80-84, 180, 182-183, 541, 

543, 545, 548 

The following Information, to the 

extent not already included: 

§1125(f): Official notification to the sponsor or investigator...that research 

involving human subjects has been reviewed and approved by an IRB. 

Y pp. 82-84 
Page 52 of 54 

Responsiveness to Recommendations in the Final Report of the October 2008 HSRB 

Recommendations in the Oct. 2008 HSRB Final Report about the AHETF 

Closed Cab and Open Cab Airblast Protocols 

Addressed in the 

M/L WSP 

Proposal? 

How/Whe

1 5 monitoring units in each cluster, each from a different farm, is needed to ensure that the design and analyses are scientifically sound. YES 2 

Information should be collected about growers who do not respond or 

who decline to participate, such that the representativeness of participating growers can be evaluated. 

NO 

3 

The Local Site Coordinator, the Principal Field Investigator, the Field Facility, the Analytical Facility, and the Principal Analytical Investigator 

must be identified in the protocol 

NO, but will be 

addressed prior to 

study initiation 

4 

Any key members of the research team who will have contact with the 

research subjects or their identifiable data must receive and document their recent (not expired) training in human subjects’ protection 

YES Revised SOP AHET

Supplemental Subm

5 Revise subject recruitment plan to specifically address the probability that subjects may also be growers. YES Revised SOP AHET

and (c) (SOP Suppl31) 

6 Remove risks of agricultural work from the listing of risks related to the research. YES Section removed fro

protocol 

7 Identify risks of pesticide products that are due to scripting. YES p. 97 8 Revise the IRB application to indicate expected ethnic/racial distribution specific to the location in which the study will be conducted. YES p. 194 9 Complete a Data and Safety Monitoring Plan YES pp. 196-197 

10 

Revise the description of the consent process to indicate how bilingual 

witnesses are going to be recruited and the amount of remuneration, as referenced in the recruitment standard operating procedures. 

YES 

Revised SOP AHET2.4 (SOP Suppleme41) 

11 Revise the section of the recruitment SOP that relates to recruitment and enrollment of illiterate or low literacy subjects. YES Revised SOP AHET

2.4, 2.5 (SOP Supppp. 40-43) 

8 HSRB recommendations that are specific to the closed cab and open cab airblast protocols reviewed in October, but which are not app

protocol being reviewed herein, are not included in the table. 
Page 53 of 54 

Recommendations in the Oct. 2008 HSRB Final Report about the AHETF 

Closed Cab and Open Cab Airblast Protocols 

Addressed in the 

M/L WSP 

Proposal? 

How/Whe

12 Describe how individual level data will be presented to the subject upon request. YES Revised SOP AHET

(SOP Supplementa

13 

Explain 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. 

NO 

14 Harmonize enrollment criteria (inclusion, exclusion) between the protocol and consent form. YES pp. 92, 128; Revise

Sec. 5.0 (SOP Supppp. 32-33) 

15 In the consent form, replace “regular working hours” with the specific hours for the time zone in which the research will take place. YES p. 134 16 

Revise the consent form with the underlined word: “you may refuse medical treatment. However, you cannot refuse medical treatment if you 

get sick from too much exposure to pesticides.....” 

YES p. 132 

17 

Verify the appropriateness of, or make necessary improvements to, the 

Spanish translations of the consent form, product risk statements, and recruitment materials. 

NO 

18 Revise the consent form to identify who makes the determination that an injury is study-related. YES p. 132 19 Revise attestation statement for witness on consent form to eliminate subject’s understanding or accuracy of the consent process. YES p. 136 20 

Revise consent form’s attestation statement of person obtaining consent 

to “I conducted the private consent meeting with the worker named above and confirm that consent was given voluntarily after the 

participant was fully informed of all of the information stated above, 

including the procedures, risks, and benefits of the research.”

YES p. 136 

21 Confirm and clarify in informed consent that compensation for research- related injury includes any co-pay. YES p. 132 22 

Consider revising Product Risk Statements to indicate which sign and symptoms are due to use that follows the product label, and which are due to overdose or massive spills or excessive exposure beyond what is 

expected to occur in the research. 

YES pp. 139, 141, 143 
Page 54 of 54 

Recommendations in the Oct. 2008 HSRB Final Report about the AHETF 

Closed Cab and Open Cab Airblast Protocols 

Addressed in the 

M/L WSP 

Proposal? 

How/Whe

23 Define the term “sufficient” when used in the inclusion criterion “sufficient experience”. YES 

Inclusion criteria noparticipants must “Hpesticide products psoluble packets, an

mixing/loading equistudy, within the las

24 

Revise wording of eligibility criterion that states “Confirm that you normally wear the personal protective equipment (PPE) listed on the 

Product Risk Statement. Confirm that you will follow label directions.” 

YES p. 128 

25 

Add to the protocol some provisions for counting and reporting the number of potentially eligible workers linked to each grower, the number of potential subjects attending initial group meetings, number attending individual consent interviews, number consenting to participation, number subsequently withdrawing or being withdrawn (with the reason for withdrawal) and number completing the study. 

YES pp. 107, 110