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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

December 27, 2010 

MEMORANDUM

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

AHE80 for Exposure Monitoring of Workers during Open Pour Mixing 

and Loading of Wettable Powders in the United States 

FROM: Jeff Evans, Senior Scientist 

 Health Effects Division 

 Office of Pesticide Programs 

Laura Parsons, Human Research Ethics Reviewer 

Kelly Sherman, Human Research Ethics Reviewer 

Office of the Director 

 Office of Pesticide Programs 

TO: Steve Knizner, Associate Director 

 Health Effects Division 

 Office of Pesticide Programs 

REF: Collier, R. (2010) Wettable Powder Mixer/Loader Scenario Submission. 

Unpublished protocol dated October 18, 2010, prepared for the 

Agricultural Handler Exposure Task Force under Sponsor ID AHE80, 

403 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 (HSRB). 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 

HSRB. 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: 

 SOP AHETF-11-B.5 should be revised to specify that potential study 

participants will be asked about what they normally wear when handling 

pesticides in a way that does not direct them to a particular answer or lead 

them to agree to wear less PPE than they normally would out of a desire to 

participate in the research 

 The language in the consent form about refusing medical treatment should 

be revised to read as follows: 

• “You may refuse medical treatment unless the medical 

professional decides you are too sick to make a rational decision 

about getting medical treatment.” 

 The AHETF should revise its plan for providing exposure information to 

subjects to address subjects who might not speak English and/or are 

illiterate, and also to incorporate any future guidance from the HSRB’s 

working group on this issue. 

• The AHETF should clarify the discrepancy about whether hand wash samples are 

to be collected prior to water breaks. 

 Supplement 1 of the AHE80 protocol states the subjects will: Have their 

hands washed again, (with the assistance of a researcher), in mild 

surfactant and water, before they smoke or eat anything, any time they 

would normally wash their hands (such as before using the toilet), and at 

the end of the day. The water from these hand washes will be saved for 

analysis. 

 SOP AHETF-11.G-2 states: “Urge workers to drink liquid during the 

monitoring period....NOTE: Hand washes will not be taken during water 

breaks unless specifically required by the label or requested by the 

worker.” 

Requiring hand washes before water breaks may result in additional exposures to 

the surfactants and subjects may be reluctant to consume needed water in order to 

avoid the additional hand washes. However, not requiring hand washes before 

water breaks may result in hand-to-mouth exposure from the pesticide during 

water consumption and may confound results if some subjects request hand 

washes for water breaks while other subjects do not request hand washes. 
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• In addition, future AHETF protocols or SOPs should incorporate the following 

(the information has previously been provided in protocol supplements): 

 information about how subjects are presented with individual exposure 

information, including how this process will handled for subjects who do 

not speak English or are illiterate; and 

 an explanation of the process that the AHETF follows to improve and 

verify the accuracy of the Spanish translations 

A. Responsiveness to Previous EPA and HSRB Comments 

Previous EPA Comments (from Reviews of the 

Rights of Way Protocol and Mixer/Loader 

Water Soluble Package Protocols at the 

October 2010 HSRB Meeting) 

Is this comment addressed in this Protocol 

(Mixing/Loading Wettable Powder; submitted for 

review at the January 2011 HSRB Meeting)? 

1. The Local Site Coordinator, the Principal 

Field Investigator, the Analytical Facility, 

and the Principal Analytical Investigator 

must be identified in the protocol 

Yes. The Principal Field Investigator, three analytical 

facilities and three Principal Analytical Investigators 

are identified in Supplement 1. Local Site 

Coordinators are not being used in this protocol. 

2. Provide more information about how 

individual level exposure data will be 

presented to subjects upon request. In 

particular, please explain how the data will 

be framed and how the AHETF will work to 

prevent workers from changing future 

behavior to their own detriment if their 

individual risk levels are lower than the 

average of all workers. 

Yes. The AHETF provided detailed information about 

how subjects are to be presented with individual 

exposure information as Supplement 2 for the 

AHE120 Protocol (reviewed by the HSRB in October 

2010). In addition, the AHETF will incorporate any 

future guidance from the HSRB’s working group on 

this issue. 

The AHETF should incorporate this information 

into future protocols and/or an SOP. 

3. 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 Spanish speaking 

subjects 

Yes. Supplement 3 for the AHE120 Protocol 

(reviewed by the HSRB in October 2010) explained 

the process that the AHETF has followed to improve 

and verify the accuracy of the Spanish translations 

The AHETF should incorporate this information 

into future protocols and/or an SOP. 

Previous HSRB Comments (from the Report 

of the October 2010 Meeting; report dated 

12/13/10) 

Is this comment addressed in this Protocol 

(Mixing/Loading Wettable Powder; submitted for 

review at the January 2011 HSRB Meeting)? 

1. The AHETF should implement the proposed 

protocol changes designed to address issues 

of representativeness. 

Yes. See Section 4.5 in the revised protocol (p. 139 of 

392) 

2. The AHETF should release individual 

exposure data to participants only once the 

study is complete, except in those instances 

where data collected from individuals suggest 

an unusually high level of exposure and thus 

a clear need to mitigate exposure risks. 

Yes. Supplement 2 for the AHE120 Protocol 

(reviewed by the HSRB in October 2010) provides 

detailed information about how subjects are presented 

with individual exposure information. 

The AHETF should incorporate this information 

into future protocols and/or an SOP. 
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Previous HSRB Comments (from the Report 

of the October 2010 Meeting; report dated 

12/13/10) 

Is this comment addressed in this Protocol 

(Mixing/Loading Wettable Powder; submitted for 

review at the January 2011 HSRB Meeting)? 

3. Exposure to the surrogate chemicals should 

be listed as a potential risk of study 

participation in the protocol and the informed 

consent form 

Yes. Supplement 1states that the final protocol and 

consent forms will list exposure to the surrogate 

chemical as a potential risk of study participation. 

4. The protocol excludes participants who 

normally wear additional personal protective 

equipment (such as chemical-resistant 

clothing) that is not required by the chemical 

label and that might impact the objectives of 

the study. The Board recommended that this 

assessment be done in a non-directive way, 

so as not to encourage participants to wear 

less PPE than they would normally in order 

to participate in the study.

Yes. The AHETF’s practice is to ask potential study 

participants what they normally wear when handling 

pesticides so as not to direct potential participants to 

any particular answer. 

The AHETF should incorporate this concept in 

SOP AHETF-11-B.5. 

5. Hand washes should be required before any 

smoking break to reduce risk of exposure.

Yes. Supplement 1 lists changes to the protocol and 

consent form to require hand washing before smoking. 

6. The protocol and informed consent document 

should be more explicit as to who will make 

the determination that a participant is too sick 

to refuse medical treatment

Yes. Supplement 1 indicates that the protocol will be 

revised to state that the medical professional on site in 

the field will make the determination. The language 

proposed by the AHETF is as follows: 

“The revised statement on the consent form is “You 

may refuse medical treatment unless you get sick from 

too much exposure to pesticides or from getting too 

hot, or if the medical professional decides you are too 

sick to make a rational decision about getting medical 

treatment.” 

The statement proposed in Supplement 1 should be 

revised to read as follows: 

“You may refuse medical treatment unless 

you get sick from too much exposure to 

pesticides or from getting too hot, or if the 

medical professional decides you are too sick 

to make a rational decision about getting 

medical treatment.” 

7. The protocol must address how the Task 

Force plans to release individual exposure 

data to individual study participants who 

request this information, but who might not 

speak English and/or are illiterate. 

No. The AHETF provided detailed information about 

how subjects are to be presented with individual 

exposure information as Supplement 2 for the 

AHE120 Protocol (reviewed by the HSRB in October 

2010). This plan does not, however, address how the 

exposure information will be provided to subjects who 

might not speak English and/or are illiterate. 

 

The AHETF should revise its plan for providing 

exposure information to subjects to address 

subjects who might not speak English and/or are 

illiterate, and also to incorporate any future 

guidance from the HSRB’s working group on this 

issue. 

This information should be incorporated into 
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Previous HSRB Comments (from the Report 

of the October 2010 Meeting; report dated 

12/13/10) 

Is this comment addressed in this Protocol 

(Mixing/Loading Wettable Powder; submitted for 

review at the January 2011 HSRB Meeting)? 

future protocols and/or an SOP.

8. The Board also recommended that the 

request for individual study results be 

included as a check box on the informed 

consent document. 

Yes. Supplement 1 lists this statement to be added to 

the consent form: “Did Subject request personal study 

results (on separate form)? □ Yes □ No” 

Rather than the statement proposed in Supplement 1, 

the following should be added to the consent form, 

under the subject signature line: 

“Do you want to receive your study results? □ Yes □

No” 

9. The consent form should explain that the 

pregnancy test will be provided by the 

researchers, and explain when it will take 

place. 

Yes. Supplement 1 indicates that the consent form will 

be revised to state: 

“...If you are female, you must take an over-thecounter urine pregnancy test less than 24 hours before 

your participation in the study begins. Researchers 

will provide the materials for the pregnancy test at no 

cost to you. More than one pregnancy test may be 

required. This test will be supervised by a female 

researcher and a private toilet area will be 

provided...” 

10. Clarify whether individuals must be trained 

in safe pesticide handling practices in order 

to be eligible to participate, or whether 

individuals who are not required to be trained 

under the Worker Protection Standard are 

also eligible to become subjects 

Yes. The eligibility criterion states: 

“[Study participants must] 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.” 

B. 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: 

• Wettable Powder Mixer/Loader Scenario Submission (October 18, 2010) (403 

pages); and 

• Supplement 1: AHETF Study AHE80 Changes Based on Comments in the 

October 27-28, 2010 EPA Human Studies Review Board Meeting Final 

Report. (5 pages). 

The monitoring unit selection and scenario construction plan appear on pages 8-

51 of 403. The rationale for the proposed sample size and cluster configuration is 

presented on pages 23-27 of 403. The IRB-approved protocol and supporting documents 
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(consent forms and recruitment flyers) appear on pages 93-174 of 403. Documentation of 

all interactions between the investigators and the Independent Investigational Review 

Board, Inc., of Plantation FL appears on pages 323-403 of 403. 

C. Summary Assessment of the Scenario Design1

1. Scenario Design: AHETF protocol AHE80 is designed to address exposures of 

individuals involved in the open mixing/loading of pesticide end use products 

formulated as wettable powders (WP). Wettable powders are a very simple type 

of pesticide formulation consisting of the pesticide manufacturer’s technical 

material added to inert diluents such as talc or clay. Wetting agents are also 

added to facilitate the WP’s ability to form suspensions when mixed with water. 

 

The mixing/loading activities involved in this scenario include the transferring of 

formulated product into a variety of tanks or buckets containing water which will 

ultimately be transferred to the tanks of various types of pesticide application 

equipment (e.g., ground boom or airblast sprayers). The AHETF have identified 

three mixing/loading activities as “categories or equipment and associated 

procedures used with WPs.” These are: 

• Direct pour: the mixer/loader pours the WP directly into the spray tank 

used for the application 

• Pre-Mix: the mixer/loader pours the WP into a holding tank. The 

concentration of the dilution in the holding tank has the same 

concentration that will be used in the application. The mixer/loader will 

later transfer this dilution to the tank associated with the equipment used 

to make the application 

• Slurry: the handler pours the WP into a holding tank or bucket with the 

resulting slurry having a higher concentration than will be used in the 

application. This concentrated slurry will be further diluted after it is 

transferred to the tank associated with the equipment used to make the 

application 

The open mix/load WP scenario is further defined as one where the mixer/loader 

wears a long-sleeved shirt, long pants, shoes plus socks and chemical resistant 

gloves. This scenario is likely to result in higher exposures than the AHETF 

study presented to the HSRB in October 2010: AHE120 mixing/loading water 

soluble packets. In scenario AHE120, dermal and inhalation exposure is expected 

to be mitigated by the WP being enclosed in a water soluble packet. 

 

Protocol AHE80 will involve the open mixing/loading of one of four surrogate 

pesticides; copper, DCPA (dacthal), sulfur and thiophanate-methyl. A total of 25 

Monitoring Units (MUs) are proposed for this scenario consisting of five distinct 

 

1 Supporting details are in Attachment 1. 
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geographic locations (i.e., clusters) with each cluster having five MUs. 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 formulated as WPs for a variety of 

mixing and loading scenarios associated with various types of application 

equipment (e.g., airblast and groundboom). One cluster is completed and is based 

on the results of a preexisting, pre-rule study. This study is identified by the 

AHETF as AHE39. In AHE39, the pesticide diazinon was used as a surrogate. 

2. Sampling Design: The remaining four clusters addressed in this protocol are 

purposively selected to reflect a diverse range of agronomic practices, geographic 

regions and likelihood of use of one of four surrogate pesticides. The previously 

conducted study AHE39 was conducted in Idaho, located in EPA Growing 

Region XI. 

The AHETF diversified the four new clusters for this scenario by surrogate 

pesticide usage and geographic/climatic regions through a purposive five-step 

process: 

• Identifying geographic areas associated with the use of WPs 

• Stratifying WP 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 remaining four 

states for the proposed monitoring sites: 

• New York (EPA Growing Region I) 

• Florida (EPA Growing Region III) 

• Michigan (EPA Growing Region V) 

• California (central/southern portion of EPA Growing Region X) 

These growing regions are appropriate choices and are likely to address regional 

and agronomic variations in addition to being likely areas of use for WP 

formulations of copper, DCPA, sulfur and thiophanate-methyl. This scenario 

addresses the exposures of individuals involved with mixing/loading WPs into a 

variety of tanks including those connected to the application equipment. The 

scenario does not address the exposures of the operators of the various application 

equipment types used in the above mentioned EPA Growing Regions. Those 

exposures will be addressed in other AHETF scenarios. 
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The four purposively selected clusters are described below: 

• New York represents a cool climate. Example crops include apples, 

grapes and snap beans. 

• Florida represents a hot and humid climate where the selected 

surrogate pesticides are applied to crops such as citrus, tomatoes and 

strawberries. 

• Michigan represents a cool climate in the upper Midwest where a wide 

variety of orchard, small fruit (e.g., blueberries) and vegetable crops 

are grown. 

• California (central/southern portion) represents a hot and dry climate 

in the western U.S. where a wide variety of tree fruits/nuts, grapes and 

field crops are grown. Sulfur is widely used in California. 

The next stage of the diversity selection process involves dividing the practical 

range of amount of active ingredient handled (AaiH) for the open WP mix/load 

scenario into five bands (strata) ranging from 5 to 2000 pounds AaiH. Past 

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

associated with differences in equipment and mixing/loading and spraying 

practices. AHETF has set a lower limit of 5 lbs, to minimize non-detects on the 

dosimeters. The upper range of the strata is also likely to be achieved based on 

the application rates of AHETF membership product labels as well as EPA 

standard values typically used to estimate AaiH when conducting agricultural 

scenario risk assessments. The AaiH strata for the WP, Open Mix/Load scenario 

are as follows: 

• 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 2000 lbs AI handled 

These AaiH strata are proposed for the four new clusters. However, the AaiH 

applied in the existing cluster (AHE39) was limited to 59 to 138 (the middle 

stratum). Perhaps because the range of AaiH is low, the resulting GSD for dermal 

(2.46) and inhalation (1.70) is smaller than the true within cluster GSD (3.19) 

described in the governing document. The AHETF asserts this narrow range of 

AaiH will have little impact on the overall results of this scenario because the 20 

new MUs in the remaining four clusters will be based on the above mentioned 

strata. EPA reminds the AHETF a wide range of AaiH is a particularly important 

element of the study design with respect to the ability to test for proportionality – 

the AHETF’s secondary study objective. Therefore, the AHETF must ensure 

that all strata be used in each of the four remaining clusters. 
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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 scenarios, growers who agree to cooperate with the research 

and to have their crop treated with one of the four surrogate pesticides must be 

identified before study participants 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 WPs 

• 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 (copper, DCPA, 

sulfur and thiophanate-methyl) 

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

accepted this approach. 

When selecting MUs, these 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 

• When mixing/loading procedures in a given area involve participants 

either pouring directly into the application tank, using pre-mix tanks 

(holding dilute sprays), or slurry tanks or buckets (holding concentrate 

sprays), then the MUs may not all be associated with the same equipment 
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and procedure category (Note: in AHE39, all participants used slurry 

buckets). 

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 copper, DCPA (Dacthal), thiophanate-methyl and sulfur formulated 

as WPs. The AHETF are relying on analytical methods developed by the outdoor 

residential exposure task force (ORETF) for the surrogate DCPA. EPA has 

reviewed the ORETF data and found them to be acceptable and believes DCPA is 

a reliable surrogate. Acceptable criteria for surrogate compounds include, low 

volatility, environmental stability, good field recovery, low limits of 

quantification (LOQ), etc. For sulfur and thiophanate-methyl, the AHETF have 

also developed acceptable methods for all matrices. For copper, the hand rinses, 

face/neck wipes and OVS tubes are developed and acceptable. However, for the 

Whole Body Dosimeters (WBD), the AHETF are currently attempting to lower 

LOQs which are currently at 30 μg per section. Generally the AHETF prefer an 

LOQ of 1μg per dermal matrix. However, due to the high application rates of 

copper (up to 8 lbs ai/acre) and because the open pour mix/load scenario is 

considered a high exposure potential, this level may be adequate to minimize the 

potential for non-detect measurements for inner dosimeter sections. 

C. Summary Assessment of the Scientific Aspects of the Study Design2

1. Statistical design: This protocol describes collecting 20 Monitoring Units (MUs) 

in addition to the five existing MUs reflecting the exposure of subjects 

mixing/loading WP formulations to support a variety of applications to field, 

orchard or trellis crops. These MUs will be collected in four additional 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 WPs are in the scenario design. No 

characteristics of this scenario have been identified which would justify a 

departure from the 5 x 5 configuration. However, of concern to EPA is the lack 

 

2 Supporting details are in Attachment 2. 
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of diversity with respect to AaiH strata and mix/load category (slurry bucket only) 

for the existing study AHE39. The study design of the existing study also 

includes having more than 1 MU per farm/grower. EPA will require additional 

MUs if the AHETF does not have the ability to test for proportionality. 

2. Proposed pattern of exposure: The proposed minimum exposure duration for 

each MU was described as being at least 4 hours in duration involving the 

mixing/loading of at least 3 tank-loads. The HSRB has noted that imposing a 

minimum duration may adversely impact the results by potentially “introducing 

unintended and undesired variability.” This protocol was submitted prior to the 

October 2010 meeting and does not incorporate this recommendation. In 

subsequent discussions with AHETF study personnel, this recommendation is 

viewed as acceptable. 

It should be noted that the 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 mix/load the 

surrogate active ingredient in one of the following five strata of AaiH: 

• 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 2000 pounds AI handled 

There are four designated surrogate pesticide active ingredients formulated as 

WPs. A cooperating grower may choose to use any of them for a specific MU. 

The WPs will be mixed with water and/or loaded into the various sprays tanks in 

one of three possible ways: 

• Pouring WPs directly into the tank associated with the application 

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

• Loading WPs into holding or nurse tanks before the finished spray 

solution/suspension is transferred to the application equipment tank (e.g., 

fixed wing aircraft). The concentration in the holding or nurse tank has 

the same concentration that will be used by the spray equipment 

• Loading individual WPs into slurry tanks or other tanks resulting 

concentrated solutions/suspensions that must be further diluted with water 

before spraying/applying 

The AHETF will attempt to ensure that at least one MU in each cluster will reflect 

each of the mixing/loading situations described above if it is determined that all 

three categories are possible in a given study area (i.e., cluster). 

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 
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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 as WPs. 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 
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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, 

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 WPs 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 confidenceinterval-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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EPA notes the following requirements for approval of the protocol: 

• Remove the minimum duration requirement for each MU 

• AHETF is to ensure all AaiH strata are applied at each cluster 

• AHETF is to strive to include all three mix/load categories at each cluster 

• Additional MUs will be required if AHETF are unable to test for 

proportionality due to the limitations of the existing study AHE39 

• Test for within same field correlations for existing study AHE39 

E. Summary Assessment of Ethical Aspects of the Proposed Research3

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 wettable 

powder formulations using open pouring techniques in four regions of the United 

States. 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 formulated as wettable powders, 

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

study (sulfur, copper, thiophanate-methyl or dacthal (DCPA)), 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 wettable powders by open pouring 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 

formulated as wettable powders. 

Subjects will be recruited according to the standard procedures set forth in SOP 

AHETF-11.B. 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 

 

3 Supporting details are in Attachment 2. 
Page 15 of 58 

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 are 

appropriate. 

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 

and Supplement 1, along with specific steps proposed to minimize them: 

• The risk of heat-related illness 

• The risk associated with scripting of field activities 

• Psychological risk 

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

• The risk of exposure to surrogate chemicals 

In this study, risks to subjects are classified as ‘greater than minimal’, primarily 

since agricultural work is considered a high risk occupation where the likelihood 

of harm or discomfort is greater than what is encountered in ordinary daily life. 

In particular, the risk of heat-related illness (resulting from wearing an extra layer 

of clothing to trap chemical) will be increased due to study participation. AHETF 

has adopted an extensive program to minimize these risks. 

Appropriate provision is made for safety and medical monitoring. 

4. Benefits: This research offers no direct benefits to the subjects. But subjects 

may request a summary of their personal results from the study. The results will 

include the distribution of chemical exposure among the various body parts and a 

comparison to the results for other workers performing the same task. Thus, a 

potential indirect benefit for subjects is knowledge about how their exposure 

compares to that of others doing similar work. 

The principal benefit of this research is likely to be reliable data about the dermal 

and inhalation exposure of workers mixing/loading pesticides formulated as 

wettable powders, usable by EPA and other regulatory agencies to support 

exposure assessments for a wide variety of pesticides with similar use patterns. 
Page 16 of 58 

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 record of correspondence 

between the investigators and IIRB, Inc. 

7. Informed Consent: Informed consent will be obtained from each prospective 

subject and appropriately documented. If participating in the study in California, 

subjects will also receive the California Research Participant Bill of Rights. 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 English or 

Spanish. 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 kept strictly 

confidential. 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. 

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. 

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. 
Page 17 of 58 

 If conducted according to the protocol, this research should meet the ethical 

standards of FIFRA §12(a)(2)(P) and 40 CFR 26 subparts K and L. 

Attachments: 

1. EPA Scenario Review: AHETF Mixing/Loading of Wettable Powder (AHE80) 

2. EPA Protocol Review: AHETF Mixing/Loading of Wettable Powder (AHE 80) 

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
Attachment 1 

Page 18 of 58 

EPA Scenario Review: AHETF Mixing/Loading of Open Pour 

Wettable Powder Products (AHE80) 

Title: Monitoring Unit Selection and Construction Plan for Scenario: Open 

Pour Mixing/Loading of Wettable Powders 

Date: September 30, 2010 

Sponsor: Agricultural Handler Exposure Task Force 

 

1. Scope of Scenario Design 

“This is a mixing/loading scenario defined by the formulation type and the lack of engineering 

controls, i.e., WPs that are open-poured into various types of farm equipment and are diluted with 

water for future application as liquid sprays. This is accomplished by mixing/loading the WP 

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 tank used for the actual application. (pp. 113 and 114 of 403) 

“it is felt that the following states proposed for this scenario will ultimately provide 

monitoring areas with the desired diversity in geography and likely use of one or more 

surrogates: the following states are proposed for this scenario to provide the desired diversity 

in geography and likely use of one or more surrogates: 

o California (Region X) 

o Florida (Region III) 

o Michigan (Region V) 

o New York (Region I)” 

The existing study (AHE39) was conducted in Idaho (EPA Region XI) using Diazinon 50W® 

Insecticide. Thus, the exposure data obtained for the WP mixing/loading scenario for all five 

monitoring areas will span five different EPA Growing Regions. (pp. 14 of 403) 

(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 WP 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 formulated as loose wettable powders. 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, turf etc.). 

Therefore, it is necessary to have data in AHED for the mixing/loading technique 

described by this scenario... 
Attachment 1 

Page 19 of 58 

“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 open pour WP mixing/loading studies; 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 WPs comprise PHED Scenario 4 – Wettable Powder, Open Mixing 

and Loading (MLOD). ...The “Single Layer, Gloves clothing scenario data were graded 

as Medium Confidence”. The inhalation data were also graded as “Medium 

Confidence”... 

“Finally, EPA examined data from existing WP 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 (verbal communication 

from EPA and JRC meeting, September, 2008).” (pp. 15-16 of 403) 

AHETF generated data for this scenario in a 2006 study (AHE39; Klonne, 2007) conducted 

in Idaho (EPA Growing Region XI) in which five MUs were collected. The surrogate product 

used in that study was Diazinon 50W® Insecticide. Table 2 summarizes several important 

characteristics of the MUs obtained from this study. 

Table 2. Design Characteristics of the Five Mixing/loading Monitoring Units 

Obtained from Study AHE39 

Date Worker Field 

Site(s) 

Pre-Mix 

Bucket 

Size 

(gal) 

Appl. 

Tank 

Size 

(gal) 

Number 

of 

Loads 

Mixed 

Total 

Amt. a.i. 

Handled 

(lbs) 

6/1/2006 M3 1 5 55 3 59 

6/2/2006 M2 2,3 5 150 3 59 

6/2/2006 M4 4 30 150 5 98 

6/3/2006 M1 5,2 5 150 7 138 

6/4/2006 M5 4 30 150 5 98 

“Although this study was conducted prior to adoption of the current MU selection methods 

(see Section 4.2 below), Table 2 shows that the five MUs are reasonably diverse. The MUs 

used different workers and their mixing/loading activities spanned multiple dates and field 

sites. The current practice of capturing the entire practical range of AaiH within each 

monitoring area was not followed in this study. As a result, the AaiH range in AHE39 is 

rather narrow compared to what is being proposed for new monitoring areas in this scenario. 

AHE39 provides a reasonably diverse set of MUs that can be considered an independent 

cluster of five MUs and can be combined with the new clusters of MUs...” (pp 16-17 of 

403) 
Attachment 1 

Page 20 of 58 

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 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 as how the WP is loaded (e.g., open 

poured directly into water in a tank which is then used for application, or added to a 

tank to make a concentrated solution that must be further diluted and transferred to 

another tank for application.) whether or not diluted product is transferred to another 

tank.” (p 38 of 403) 

 

“Experts identified three general categories of equipment and associated procedures used 

with WPs (Honeycutt, 2008): 

• Direct Pour: Pouring into tanks that are used directly for the application (e.g., 

groundboom, airblast, chemigation tanks) 

• Pre-Mix: Pouring of the WP 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) 

• Slurry: Pouring of the WP into 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... 

Consequently, additional diversity will be added by imposing the restriction that the 

MUs in the same efficient configuration in a monitoring area cannot all use the same 

equipment and procedure category. This similarity restriction will only apply if the 

Study Director determines that more than one category is applicable in an efficient 

configuration in the monitoring area.” (p 39 of 403) 

“Geographic Stratification: . . . the use of WPs can be found throughout the United 

States and can involve a wide variety of equipment types and use sites, including field 

crops, trellis crops, orchard crops, turf, ornamentals, and pest control. Geographic 

diversity between clusters of monitoring units is expected to provide some variability in 

agronomic conditions and of other factors, such as equipment type, work practices, 

weather, etc. That is, it is viewed as a 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. 

... Growing Region XIII consists of Hawaii and Puerto Rico and is not being considered 
Attachment 1 

Page 21 of 58 

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. 28 of 403) 

“Predominant Surrogate Use: Although WPs may be used in all 12 EPA Growing 

Regions, not all regions are expected to have wide use of all four AHETF surrogate 

active ingredients (sulfur, copper, thiophanate-methyl, and DCPA). Thus, for practical 

reasons, the distribution of surrogate use will be considered when selecting the four 

monitoring areas... (pp. 29 of 403) 

Table 3 summarizes this surrogate distribution with chemical usage data for all four 

surrogates combined (NASS 2000 through 2007). Since NASS data is only compiled for 

certain chemicals and crops, but not on a yearly schedule, the data span a number of 

years. The table shows the highest usage of the four WP surrogates for the top ten states 

of the 48 contiguous United States. (pp. 30 of 403) 

“Selection of a Geographically Diverse Set of Monitoring Areas: Four new 

monitoring areas need to be selected so that all five areas (i.e., including AHE39) are 

geographically diverse. Such a diverse configuration can be obtained by simply locating 

each site in a different EPA Growing Region. Because of an existing cluster of MUs 

(i.e., AHE39) was already obtained from Growing Region XI (Idaho), only 11 growing 

regions remain in placement of the four new monitoring areas. In theory, four growing 

regions could be selected at random from among the 11 regions that stratify the 

continental U.S. A state (or, perhaps adjacent states) could be randomly or purposively 

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

would be quite inefficient...Locating monitoring areas in crop areas where the surrogates 

are currently in 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 areas.” (pp. 32 of 403) 

1. New York (Region I) 

New York is a state with high combined usage of the four surrogates. The primary crops 

where the surrogates are used include apples (an orchard crop), grapes (a trellis crop), and 

snap beans (a field crop). This state reflects a cool climate in the northeastern U.S. 

2. Florida (Region III) 

Florida is a state with high combined usage of the four surrogates. The primary crops 

where the surrogates are used include citrus (an orchard crop), tomatoes and strawberries 

(field crops). Thiophanate-methyl is also used in Florida on a variety of crops including 

snap beans, melons, strawberries, and tomatoes. This state reflects a hot and humid 

climate in the southeastern U.S. 
Attachment 1 

Page 22 of 58 

3. Michigan (Region V) 

Michigan is as state with high combined usage of the four surrogates. The primary crops 

where the surrogates are used include sweet and tart cherries, apples, and peaches 

(orchard crops). Although the primary crops for the surrogates are orchard crops, a 

significant variety of crops (i.e., cucumbers, blueberries, squash, and potatoes) where the 

surrogates may be used are also grown nearby. This state reflects a cool climate in the 

Midwestern U.S. 

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

This state involves by far the highest usage of sulfur, usage of all four surrogate 

chemicals, and a wide variety of crops. The crops include rice, vegetables, grapes, and 

orchards, which should provide the opportunity for a range of application equipment 

when constructing MUs. The central and southern portions of California generally reflect 

a hot and dry climate in the western U.S.” (pp. 32-33 of 403) 

“Reduction of Monitoring Areas: The final step for selecting monitoring areas is to 

choose a specific area within each selected state identified above where growers and 

workers can be recruited to conduct the exposure monitoring in a reasonable amount of 

time. This involves further limiting each monitoring area geographically so that MU 

identification and selection operations can be conducted efficiently. This will facilitate 

the logistics of the field research team and keep the costs of study conduct reasonable so 

a sufficient number of MUs can be obtained in the AHETF monitoring program. (As 

described in Section 5.2.4, a monitoring area can also be increased in size under some 

conditions). 

“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 

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

are minimized. 

“Therefore, a smaller portion of each initial monitoring area, a particular area (e.g., a 

state or a large portion of a state) will be selected and identified in the study protocol and 

the monitoring area reduced accordingly. The final monitoring area will be determined 

based on the locations of crops predominantly associated with surrogate use and will 

likely involve identifying several counties where mixer/loaders are most likely to utilize 

the surrogate WP product and that have sufficient growers, and equipment, and workers 

to allow an efficient design.” (pp. 34-35 of 403) 

(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.
Attachment 1 

Page 23 of 58 

“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 monitoring area. Random 

selection of growers is preferable, when feasible, to reduce the possibility of selection 

bias that might arise from researchers purposively choosing specific growers to contact. 

Therefore, a procedure for generating a list of available growers for each monitoring area, 

and 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 from each of the following groups and ask for a list of 

growers that might utilize open pour WP mixing/loading at the identified 

monitoring area (generally several counties): 

• Farm Market ID 

• Commercial list providers 

• State and local government entities 

• Grower associations 

• Grower Publication subscription lists 

2. Assemble a reasonably sized and randomly selected list of growers from all of the 

resources contacted and eliminate any duplicates. 

3. Contact all the growers on the list 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 WPs 

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

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

be handled by a worker in one day 

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

listed in this protocol 

Growers who indicate they use 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 by providing suitable mixing/loading 

equipment and workers. The actual workers involved could be the grower himself, a 

grower’s employee, or an owner or employee of a commercial pesticide application 

company. 

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: 
Attachment 1 

Page 24 of 58 

• Specific location of mixing/loading area 

• 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. 39-41 of 403) 

(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.” (pp. 43 of 403) 

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

“Many other possible MU characteristics might potentially affect exposure potential. For 

example, measuring WP from a container, i.e., when less than a whole container is 

required, may influence exposure potential. Other factors such as the crop being treated 

are not expected to directly affect exposure, but might lead to selection of various 

equipment set-ups that could impact exposure potential. All such characteristics are 

expected to vary naturally or indirectly as a result of other differences between MUs.” 

(pp. 44 of 403) 

3. Are the proposed test materials appropriate surrogates? 

“The following active ingredients are available as wettable powders and will be 

considered for use in this wettable powder open mixing/loading scenario. 

• Sulfur 
Attachment 1 

Page 25 of 58 

• Copper 

• Thiophanate-methyl 

• DCPA (dacthal) 

These surrogate active ingredients, except thiophanate-methyl, 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.” (pp. 45 of 403) 

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. 

These simulations determine either accuracy or power given the number and configuration of 

MUs. When there are no existing data, the simulations only consider new MU 

configurations. However, for this scenario, the simulations require that the structure of the 

existing MUs be held constant and only the number of new MUs is varied. Regardless, it is 

still the combination of existing and new MUs that must satisfy the benchmark objectives: 

1. Primary Objective: Estimates of the geometric mean, the arithmetic mean, and 

the 95th percentile of normalized dermal exposure generally need to be accurate to 

within 3-fold of their actual population value assuming the reference random 

sampling model applies. 

2. Secondary Objective: There should be at least 80% statistical power to 

distinguish complete proportionality from complete independence between 

dermal exposure and AaiH (the normalizing factor for this scenario). 

4.5.1. GSD and ICC 

Reasonable values of the geometric standard deviation (GSD) and the intra-cluster 

correlation (ICC) are needed. Based on analysis of exposure from a number of available 

monitoring studies, Appendix C of the AHETF Governing Document derived a default 

relative variation structure consisting of GSD=4 and ICC=03. Unless there is other 

evidence or expert opinion to the contrary, sample sizes are determined for all scenarios 

using these default values. It is reasonable to as however, whether the existing MU data 

provide evidence that this scenario will be inconsistent with the default assumptions for 

the GSD and ICC. 

As noted above, the existing data consist only of five MUs from study AHE39. Because this 

study represents only a single cluster just within-cluster variation can be examined. Based on 

these five MUs, the observed within-study GSD for normalized dermal exposure is 2.46. The 

analogous value obtained for normalized inhalation exposure is 1.70. If the true GSD and 

ICC were 4 and 0.3, respectively, then the true within-cluster GSD is: 

GSD√1-ICC = 3.19 

 

If the normalized exposures of the five MUs are lognormally distributed then the 4· quantity 
Attachment 1 

Page 26 of 58 

2

4· loge Observed Within – Cluster GSD

 log e True Within – Cluster GSD 

 

has a chi-square distribution with 4 degrees of freedom. Therefore, if the true GSD=3.19 

then, 95% of the time, an observed GSD should vary between the values of 1.50 and 

6.93. Since both 2.46 (dermal) and 1.70 (inhalation) lie between these two bounds, they 

are consistent with a within-cluster GSD of 3.19. Consequently, the single cluster of 

MUs from study AHE39 is also consistent with a true total GSD of 4 and a true ICC of 

0.3. Because the AHETF default values will be used for determining sample size for the 

WP mixer/loader scenario. 

4.5.2. Required Number and Configuration of New MUs 

As noted above, Appendix C of the AHETF Governing Document describes several 

simulation methods that can be used to determine reasonable sample sizes for new 

clusters of MUs. In principle, these methods are easily extended to accommodate 

existing MUs as well. In brief, the simulation procedure consists of the following steps: 

1. Using the structure of the existing data (e.g., number of clusters, number 

of MUs per cluster, AaiH levels for each MU, etc.) simulate normalized 

exposures, and exposures derived from AaiH levels assuming 

proportionality, from the multistage lognormal reference model. 

2. Given candidate values for numbers of new clusters, numbers of MUs per 

cluster, and AaiH levels, simulate normalized exposure, and exposures 

derived from AaiH levels assuming proportionality, from the two-stage 

lognormal reference model 

3. Combine the existing and new simulated data together and estimate the 

geometric mean, arithmetic mean, and 95th percentile of normalized 

exposure. Calculate the fold relative accuracy of these estimates 

compared to their true values. 

4. In addition, from the combined new and existing exposure data, determine 

if the slope from a mixed model regression of log exposure of AaiH is 

significantly different from zero. 

5. Repeat steps 1 through 4 10,000 times and calculate the 95th percentile of 

fold relative accuracy for each normalized exposure statistic and 

determine if it satisfies the primary benchmark objective. Also compute 

the percentage of simulations yielding a statistically significant slope. The 

percentage is the power needed to evaluate the secondary benchmark 

objective. 

For this particular scenario, new simulations to examine the fold-accuracy of 

the geometric mean, arithmetic mean, and 95th percentiles (i.e., the primary 

objective) are unnecessary. Appendix C of the AHETF Governing contains 

the results of such simulations when GSD=4 and ICC=03 are assumed. In 
Attachment 1 

Page 27 of 58 

this case, the configuration that satisfies the primary objective is a set of N=4 

clusters and Mc=5 MUs per cluster. Since the existing study AHE39 already 

contributes one cluster of five MUs, only four additional 5-MU clusters need 

to be obtained. 

However, assessing the secondary objective is more complicated since the 

power to detect proportionality between exposure and AaiH also depends on 

the particular set of AaiH used. The AaiH levels are known for existing MUs 

(Table 2), but must be generated for the hypothesized new clusters of MUs in 

the simulations described in step 4 above. Appendix C of the AHETF 

Governing Document shows that under the default GSD and ICC, the 

configuration of MUs satisfying the primary objective will also satisfy the 

secondary objective if (1) the AaiH levels for the scenario range over an order 

of magnitude or more and (2) there is adequate within-cluster variation in 

AaiH levels. 

As described in Section 5.2.1 below, diversity selection for new clusters will 

require that the AaiH levels for MUs extend over the complete practical range 

expected for the WP mixer/loader scenario. This practical range is 5 to 2000 

lbs ai handler per workday and extends over several orders of magnitude (i.e., 

400x). For each new cluster, diversity in AaiH levels is achieved by first 

partitioning this practical range into Mc strata and then obtaining a single MU 

from within each AaiH stratum. The within-cluster strata are logarithmically 

spaced within the practical range. 

An analogous procedure is followed when obtaining AaiH levels for new 

MUs in the simulations: within each simulated new cluster, an AaiH level is 

simulated log-uniformly from within each of the Mc strata. The exposure data 

are simulated for both existing and new clusters assuming proportionality with 

the AaiH levels and using the default variation structure. For each simulated 

set of data, a regression analysis is performed and the significance of the loglog slope determined (2-sided test). The power is the proportion of the time 

that the slope was significant at p<0.05. 

When this simulation method is used with the single existing cluster (i.e., 

AHE39) and four new 5-MU clusters the power was essentially 100%. That is 

the AaiH diversity in four new clusters is more than sufficient to compensate 

for the narrow AaiH range in AHE39. Consequently, by obtaining four new 

clusters of five MUs each, both the primary accuracy objective and the 

secondary power objective should be satisfied. 

Although four new clusters with five MU/cluster is the scenario target, 

Appendix C of the AHETF Governing Document also shows that some 

variation in this configuration can be tolerated in the event that five MUs 

cannot be obtained in every cluster. In particular, the primary benchmark will 

still be satisfied providing: 

• The total number of new MUs is at least 20, and 

• No new cluster has more than five MUs 
Attachment 1 

Page 28 of 58 

Obviously, this rule implies that if a new cluster has fewer than 5 MUs then more 

than 4 new clusters will be necessary. (pp. 23- 26 of 403) 
Attachment 2 

Page 29 of 58 

EPA Protocol Review: Wettable Powder Open Pour Mixer/Loader Scenario (AHE80) 

Title: Determination of Dermal and Inhalation Exposure to Workers during 

Mixing/Loading Wettable Powders in the United States 

Revision Date: October 5, 2010 

Study Director and Sub-Investigators: 

 Larry Smith 

 Brian Lange4

 Tami Belcher5

 Aaron Rotondaro5 

Field Facility: TBD6

 

Analytical Facility: TBD6 

 

Sponsor: Agricultural Handler Exposure Task Force, LLC 

c/o David R. Johnson, Ph.D. 

1720 Prospect Drive 

Macon MO 63552 

 

Reviewing IRB: Independent Investigational Review Board, Inc. 

 6738 West Sunrise Blvd Suite 102 

 Plantation FL 33313 

 

1. Societal Value of Proposed Research 

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

“The objective of this study is to develop data to determine the potential exposure for 

workers who mix and load wettable powder formulations using open pouring techniques 

in four regions of the United States.” (pp. 102 of 403) 

(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 pesticide products formulated as 

wettable powders. This is a widespread method of mixing and loading solid pesticide 

products, for which existing data are inadequate. 

 

4 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. 
Attachment 2 

Page 30 of 58 

(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 as wettable powders 

(WP). 

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

“AHETF (in conjunction with EPA, PMRA, and CDPR, collectively referred to as 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 open pour studies WP mixing/loading studies; 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. 

AHETF generated data for this scenario in a 2006 study (AHE39; Klonne, 2007) 

conducted in Idaho (EPA Growing Region XI) in which five MUs were collected. The 

surrogate product used in that study was Diazinon 50W® Insecticide. Table 2 

summarizes several important characteristics of the MUs obtained from this study (pp. 

15-16 of 403) 

(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 WP 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.” (pp. 48 of 403) 

1. Primary Objective: Estimates of the geometric mean, the arithmetic mean, and the 95th 

percentile of normalized dermal exposure generally need to be accurate to within 

approximately 3-fold of their actual population value assuming the reference random 

sampling model applies. 
Attachment 2 

Page 31 of 58 

2. Secondary Objective: There should be at least 80% statistical power to distinguish 

complete proportionality from complete independence between dermal exposure and AaiH 

(the normalizing factor for this scenario).” (pp. 23 of 403) 

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. These simulations determine either accuracy or power given the 

number and configuration of MUs. When there are no existing data, the simulations 

only consider new MU configurations. However, for this scenario, the simulations 

require that the structure of the existing MUs be held constant and only the number of 

new MUs is varied. 

Reasonable values of the geometric standard deviation (GSD) and the intra-cluster 

correlation (ICC) are needed. Based on analysis of exposure from a number of available 

monitoring studies, Appendix C of the AHETF Governing Document derived a default 

relative variation structure consisting of GSD=4 and ICC=03. Unless there is other 

evidence or expert opinion to the contrary, sample sizes are determined for all scenarios 

using these default values. It is reasonable to as however, whether the existing MU data 

provide evidence that this scenario will be inconsistent with the default assumptions for 

the GSD and ICC. 

As noted above, the existing data consist only of five MUs from study AHE39. Because 

this study represents only a single cluster just within-cluster variation can be examined. 

Based on these five MUs, the observed within-study GSD for normalized dermal 

exposure is 2.46. The analogous value obtained for normalized inhalation exposure is 

1.70. If the true GSD and ICC were 4 and 0.3, respectively, then the true within-cluster 

GSD is: 

GSD√1-ICC = 3.19 

 

If the normalized exposures of the five MUs are lognormally distributed then the 4· 

quantity 

 2 

4· loge Observed Within – Cluster GSD

 log e True Within – Cluster GSD 

 
Attachment 2 

Page 32 of 58 

has a chi-square distribution with 4 degrees of freedom. Therefore, if the true GSD=3.19 

then, 95% of the time, an observed GSD should vary between the values of 1.50 and 

6.93. Since both 2.46 (dermal) and 1.70 (inhalation) lie between these two bounds, they 

are consistent with a within-cluster GSD of 3.19. Consequently, the single cluster of 

MUs from study AHE39 is also consistent with a true total GSD of 4 and a true ICC of 

0.3. Because the AHETF default values will be used for determining sample size for the 

WP mixer/loader scenario. 

4.5.2. Required Number and Configuration of New MUs 

As noted above, Appendix C of the AHETF Governing Document describes several 

simulation methods that can be used to determine reasonable sample sizes for new 

clusters of MUs. In principle, these methods are easily extended to accommodate 

existing MUs as well. In brief, the simulation procedure consists of the following steps: 

6. Using the structure of the existing data (e.g., number of clusters, number 

of MUs per cluster, AaiH levels for each MU, etc.) simulate normalized 

exposures, and exposures derived from AaiH levels assuming 

proportionality, from the multistage lognormal reference model. 

7. Given candidate values for numbers of new clusters, numbers of MUs per 

cluster, and AaiH levels, simulate normalized exposure, and exposures 

derived from AaiH levels assuming proportionality, from the two-stage 

lognormal reference model 

8. Combine the existing and new simulated data together and estimate the 

geometric mean, arithmetic mean, and 95th percentile of normalized 

exposure. Calculate the fold relative accuracy of these estimates 

compared to their true values. 

9. In addition, from the combined new and existing exposure data, determine 

if the slope from a mixed model regression of log exposure of AaiH is 

significantly different from zero. 

10. Repeat steps 1 through 4 10,000 times and calculate the 95th percentile of 

fold relative accuracy for each normalized exposure statistic and 

determine if it satisfies the primary benchmark objective. Also compute 

the percentage of simulations yielding a statistically significant slope. The 

percentage is the power needed to evaluate the secondary benchmark 

objective. 

For this particular scenario, new simulations to examine the fold-accuracy of 

the geometric mean, arithmetic mean, and 95th percentiles (i.e., the primary 

objective) are unnecessary. Appendix C of the AHETF Governing contains 

the results of such simulations when GSD=4 and ICC=03 are assumed. In 

this case, the configuration that satisfies the primary objective is a set of N=4 

clusters and Mc=5 MUs per cluster. Since the existing study AHE39 already 

contributes one cluster of five MUs, only four additional 5-MU clusters need 

to be obtained. 
Attachment 2 

Page 33 of 58 

However, assessing the secondary objective is more complicated since the 

power to detect proportionality between exposure and AaiH also depends on 

the particular set of AaiH used. The AaiH levels are known for existing MUs 

(Table 2), but must be generated for the hypothesized new clusters of MUs in 

the simulations described in step 4 above. Appendix C of the AHETF 

Governing Document shows that under the default GSD and ICC, the 

configuration of MUs satisfying the primary objective will also satisfy the 

secondary objective if (1) the AaiH levels for the scenario range over an order 

of magnitude or more and (2) there is adequate within-cluster variation in 

AaiH levels. 

As described in Section 5.2.1 below, diversity selection for new clusters will 

require that the AaiH levels for MUs extend over the complete practical range 

expected for the WP mixer/loader scenario. This practical range is 5 to 2000 

lbs ai handler per workday and extends over several orders of magnitude (i.e., 

400x). For each new cluster, diversity in AaiH levels is achieved by first 

partitioning this practical range into Mc strata and then obtaining a single MU 

from within each AaiH stratum. The within-cluster strata are logarithmically 

spaced within the practical range. 

An analogous procedure is followed when obtaining AaiH levels for new 

MUs in the simulations: within each simulated new cluster, an AaiH level is 

simulated log-uniformly from within each of the Mc strata. The exposure data 

are simulated for both existing and new clusters assuming proportionality with 

the AaiH levels and using the default variation structure. For each simulated 

set of data, a regression analysis is performed and the significance of the loglog slope determined (2-sided test). The power is the proportion of the time 

that the slope was significant at p<0.05. 

When this simulation method is used with the single existing cluster (i.e., 

AHE39) and four new 5-MU clusters the power was essentially 100%. That is 

the AaiH diversity in four new clusters is more than sufficient to compensate 

for the narrow AaiH range in AHE39. Consequently, by obtaining four new 

clusters of five MUs each, both the primary accuracy objective and the 

secondary power objective should be satisfied. 

Although four new clusters with five MU/cluster is the scenario target, 

Appendix C of the AHETF Governing Document also shows that some 

variation in this configuration can be tolerated in the event that five MUs 

cannot be obtained in every cluster. In particular, the primary benchmark will 

still be satisfied providing: 

• The total number of new MUs is at least 20, and 

• No new cluster has more than five MUs 

Obviously, this rule implies that if a new cluster has fewer than 5 MUs then more 

than 4 new clusters will be necessary. (pp. 23- 26 of 403) 
Attachment 2 

Page 34 of 58 

(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. 

(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., 

the 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.” (pp. 41of 403)

“When constructing MUs within each monitoring area, the following similarity 

restrictions and preferences will be used to ensure diversity: 

 

• No worker may be used for more than one MU. 

• No more than one 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). 

• Whenever possible, each MU should use an AaiH level from a different 

stratum (see Section 5.2.1) 

• When more than one piece of equipment and procedure category is applicable 

in the efficient configuration, the MUs cannot all be associated with the same 

category (see Section 5.2.2). 

• No single piece of equipment may be used for more than one MU. (pp. 42 of 

403) 

(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.’” (pp. 48 of 403) 

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

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

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

of adequacy. These two categories of data adequacy are: 
Attachment 2 

Page 35 of 58 

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.” (pp. 48 of 403) 

“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 

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.” (pp. 48 of 403) 

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

Proportional from an Independent Relationship between Exposure and AaiH] applies 

to the WP 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.” (pp. 49 of 403) 

(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 wettable powders 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 wettable powder 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. As 
Attachment 2 

Page 36 of 58 

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’.” (pp. 49 of 403) 

2.2 How and to what will human subjects be exposed? 

“Collectively, the complete WP mixing/loading scenario will include instances of worker 

exposure resulting from the open pouring mixing/loading of wettable powder pesticide 

formulations.” (pp. 17 of 403) 

“The test substance active ingredients approved for use in this study are listed in Section 

2.3.5 above. The most appropriate end-use pesticide product, based largely on the 

preference of the grower, will be used at each of the individual MU sites. A different test 

substance may be used at each site and by each worker within a monitoring area if 

appropriate.” (pp. 127 of 403)

(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 as wettable powders and will be 

considered for use in this mixing/loading scenario. 

• Sulfur 

• Copper 

• Thiophanate-methyl 

• DCPA (dacthal) 

“These surrogate active ingredients, except thiophanate-methyl, 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 use these products are 

likely to be available.” (pp. 44-45 of 403) 
Attachment 2 

Page 37 of 58 

(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 WP mixing/loading exposure by AaiH during pesticide product exposure 

assessments. No other normalizing factor has been identified as being more 

appropriate. 

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 5to 2000 lbs active ingredient to 

be handled per day for this scenario.” (pp. 36 of 403) 

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

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). Diversification of 

AaiH within each monitoring area 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

“...AaiH diversity between MUs in the same monitoring area will be obtained by 

attempting to restrict each of the five MUs in each monitoring area to a different 

AaiH stratum.” (p. 37-38 of 403)

(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 mixing area but can also 
Attachment 2 

Page 38 of 58 

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. 43-44 

of 403) 

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. 130 - 131 of 403) 

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

“Full details for sampling air with OSHA Versatile Sampler (OVS) tubes and 

personal air-sampling pumps are given in the most recent versions of SOP AHETF8.D and 10.G.” (pp. 131 of 403) 

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

“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.” (pp. 223 of 403) 
Attachment 2 

Page 39 of 58 

(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 

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 

1.14.” (pp. 138-139 of 403) 

(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 monitoring area, 

or more days as appropriate for environmental conditions. . . . 

For each fortification event, 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. 131-132 of 403) 

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. 
Attachment 2 

Page 40 of 58 

3. Subject Selection 

3.1 Representativeness of Sample 

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

“Collectively, the complete WP mixing/loading scenario data set will include 

instances of worker exposure resulting from the mixing/loading of 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’ WP mixing/loading-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 WP mixer/loader-days. . . .Thus, MUs are technically not ‘sampled’ from a 

population. More correctly, they should be viewed as synthetic WP mixing/loadingdays derived from both selected and constructed conditions.” (pp. 17 of 403) 

(b) From what populations will subjects be recruited? 

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

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

recruited.” (pp. 42 of 403) 

(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 open pour WP mixing/loading at the identified site 

(generally several counties): 

• Farm Market ID 

• Commercial list providers 

• State and local government entities 

• Grower associations 

• Grower Publication subscription lists 
Attachment 2 

Page 41 of 58 

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 WPs 

• 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 

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

ingredients listed in the study protocol.” (pp. 39-40 of 403) 

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

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

recruited. (pp. 42 of 403) 

(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 
Attachment 2 

Page 42 of 58 

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

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

SOP AHETF-11.C for health status determination) 

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

• Confirm they do not normally wear 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 for a detailed 

discussion of this topic) 

• Understand and sign the consent form, and if in California, the California 

Experimental Research Subject’s Bill of Rights” (SOP AHETF-11.B.5) 

“For this mixing/loading of wettable powders study, the following inclusion criteria 

also apply: 

• Have experience within the past year with mixing/loading wettable powders 

by open pouring (including the particular equipment to be used) (p. 106 of 

403) 

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

None 

(c) If any potential subjects are likely to be especially vulnerable to coercion or 

undue influence, what is the 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 monitoring area, AHETF will follow standard procedures (see SOP 

AHETF-11.B) to recruit potential participants for this wettable powder packet 

mixing/loading study. Individual workers will be recruited during an initial site 

inspection or subsequent visit(s) to a potentially eligible grower and/or commercial 

applicator facility. 

“The Study Director or designated researcher will seek permission from the eligible 

grower to approach his/her employees to recruit volunteers for the study. Depending 

on the number of employees and size of the grower facility the Study Director or 

researcher may contact employees using an informational recruitment flyer posted in 
Attachment 2 

Page 43 of 58 

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). 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. 123 of 403) 

(e) If any subjects are potentially subject to coercion or undue influence, what 

specific safeguards are proposed to protect their rights and welfare? 

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

a non-coercion statement (Employer 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. 122 of 403) 

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. 

(Section 6.2) 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 (Section 2.7). 

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 subject withdraws from the study. All workers who participate will 
Attachment 2 

Page 44 of 58 

receive the payment, even if they withdraw or their participation is terminated by the 

study team.” (p 106 of 403) 

(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. 

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 any of four active ingredients: copper, DCPA (dacthal), 

sulfur and thiophanate-methyl. “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, Worker Protection Standard (WPS), and state (e.g., California) regulatory 

requirements.” (p. 110 of 403) 

For sulfur, copper and dacthal, 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 (generally 100), for the individual dermal and inhalation 

routes of exposure, as well as for the combined exposure. For thiophanate methyl, 

however, the protocol does not permit application of more than 100 lbs AaiH in order 

to keep MOEs below the level of concern. This means that thiophanate methyl may 

only be used in the lower two strata (5-17 lbs AaiH or 18-55 lbs AaiH).

 

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

The protocol and consent form currently lists four kinds of risks: 

• The risk of heat-related illness 

• The risk associated with scripting of field activities 

• Psychological risks 

• The risk of exposure to surfactants 
Attachment 2 

Page 45 of 58 

“In this study risks to subjects are classified as ‘greater than minimal’, primarily since 

agricultural work is considered a high risk occupation where the likelihood of harm or 

discomfort is greater than what is encountered in ordinary daily life. In particular, the 

risk of heat-related illness (resulting from wearing an extra layer of clothing to trap 

chemical) will be increased due to study participation. AHETF has adopted an 

extensive program to minimize these risks.” (p. 106 of 403) 

In response to the comments from the HSRB in its report of the October 2010 

meeting, Supplement 1 indicates that the protocol and consent form will be revised to 

include the risk of potential exposure to the surrogate chemicals as a risk of study 

participation. Specifically, the AHETF is proposing to add the following statement to 

the Consent Form: 

“Handling a pesticide as part of the research may cause sickness, eye or skin 

irritation, allergic skin reactions, or temporarily affect the nervous system. 

These kinds of risks occur when you handle many types of pesticides, but 

might be higher if you are asked to handle more pesticide or work longer than 

usual. A researcher will show you the label for the product you will be using 

and discuss the risks of that product with you.” 

(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 (see AHETF SOPS 11.C, 11.E, 11.G and 11.H): 

• Selecting only experienced pesticide handlers who consider themselves to be 

in good health 

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

study and with mixing/loading products in wettable powder products 

• 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 
Attachment 2 

Page 46 of 58 

• Observing study participants throughout the monitoring period

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

and state regulations, and do not require any additional PPE that could 

adversely affect the study objectives (for example, chemical-resistant 

coveralls or aprons).” (pp. 111-112 of 403) 

Risk reduction actions specific to the identified kinds of risk are discussed in the 

protocol (pp. 108-111 of 403). 

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

for the test materials? 

For sulfur, copper and dacthal, 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 (generally 100), for the individual dermal and inhalation 

routes of exposure, as well as for the combined exposure. For thiophanate methyl, 

however, the protocol does not permit application of more than 100 lbs AaiH in order 

to keep MOEs below the level of concern. This means that thiophanate methyl may 

only be used in the lower two strata (5-17 pounds ai handled or 18-55 lbs ai handled).

(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 105o

 F 

(adjusted for direct sun, if applicable) is reached or exceeded. The Study Director or 

other researcher shall stop the monitoring and/or move the worker to a cooler 

environment until monitoring can be resumed.” (p. 107 of 403) 

(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. 147 of 403) 

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

requires emergency medical attention. 

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

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

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

label and Worker Protection Standard requirements and labeling, and permits 
Attachment 2 

Page 47 of 58 

the Study Director to remove from the study a worker who engages in unsafe 

work practices. 

• SOP AHETF-11.G 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 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. This follow-up procedure is 

described in SOP AHETF-11.J and the personal information related to this follow-up 

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

 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 a toll free phone number 

for reporting any health changes they think might be related to participation in the 

study. 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.J).” (p. 

116 of 403) 

(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 to have you taken to receive medical attention.” (p 

148 of 403) “You may refuse medical treatment unless you get sick from too much 

exposure to pesticides or from getting too hot, or if the medical professional decides you 

are too sick to make a rational decision about getting medical treatment.” (p 5 of 

Supplement 1) 

“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. 148 of 403) 
Attachment 2 

Page 48 of 58 

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. 112 of 403) 

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? 

“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 wettable powder pesticides. The knowledge likely to be 

obtained from this study is generalizable and will contribute to assessments of the risks of 

both new and existing pesticides.” (p. 112 of 403) 

“Since there are not sufficient existing data suitable for use in a generic database 

describing the exposure to workers from mixing/loading wettable powders, society will 

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

EPA and other regulatory agencies.” (p. 112 of 403)

(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. 112 of 

403)

 

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

Identified societal benefits are likely to be realized. 
Attachment 2 

Page 49 of 58 

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. Wettable powder products are 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 

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 113 of 403) 

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? Yes. 

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

Yes. 

(f) 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). 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 
Attachment 2 

Page 50 of 58 

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). 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. 105 

of 403)

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. According to documents submitted to IRB, appropriate 

provision is made for informing English or Spanish-speaking candidates who cannot read 

the consent form. (p 340 of 403) 

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

investigators and subjects? 

See SOP AHETF-11.I 

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

discomforts? 
Attachment 2 

Page 51 of 58 

“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 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) (p 299 of 403) 

(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 will be sought in an individual meeting 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 AHETF-11.I. 

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

another amount specified in the protocol) for participation in the consent meeting, or the 

amount specified in the protocol, even if he/she decides not to participate in the research. 

“During the private consent meeting the person conducting the consent meeting 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 another amount specified in the protocol) if they decide to 

participate and put on the dosimeters, whether or not they complete the monitoring 

period. 

“The person obtaining consent will provide information about the risk of the surrogate 

chemical in the study, including signs and symptoms of acute overexposure. This 

information will be presented in the product label and/or the MSDS. Refer to SOP 

AHETF-11.E 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, while details on emergency medical 

procedures are outlined in SOP AHETF-11.H. 

“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. 
Attachment 2 

Page 52 of 58 

“The IRB-approved Consent Form (and all supporting documents, except the product 

labels and MSDS forms) will be presented in the preferred language (English or Spanish) 

of the worker. All sections of the Consent Form will be explained in detail. When the 

person obtaining consent is satisfied that 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. 

“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 

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) 

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

coercion or undue influence? 

“In accordance with SOP AHETF-11.B the 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. 122 of 403) 

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, 6.D, 11.B, 11.D, and 11-J.” (p. 113 of 403) 
Attachment 2 

Page 53 of 58 

“Your name will only appear on the consent form, 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 

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. 148-149 of 403) 

(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 subject 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 subject 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). (p. 113 of 403) 

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

not mind if you do or do not take part in this study. 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 not affect your job or 

pay or include any penalty or loss of benefits you are owed.” (p. 149 of 403) 
Attachment 2 

Page 54 of 58 

(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. 

“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. 149-150 of 403)
Attachment 3 

Page 55 of 58 

§ 26.1111 Criteria for IRB approval of research 

AHETF Protocol: Mixing/Loading of Wettable Powders (AHE80) 

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 56 of 58 

§26.1116 General requirements for informed consent 

AHETF Protocol: Mixing/Loading of Wettable Powders (AHE80) 

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 

(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 57 of 58 

§26.1117 Documentation of informed consent 

AHETF Protocol: Mixing/Loading of Wettable Powders (AHE80) 

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 58 of 58 

40 CFR 26.1125 Prior submission of proposed human research for EPA review

AHETF Protocol: Mixing/Loading of Wettable Powders (AHE80) 

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 325-390 

pp. 143-171 

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

• attendance at the meetings; 

• actions taken by the IRB; 

• the vote on these actions including the number of members voting for, 

against, and abstaining; 

• the basis for requiring changes in or disapproving research; 

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

resolution. 

n/a 

n/a 

Pp 397-399 

Protocol approved without 

changes. 

No controverted issues 

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

(4) Copies of all correspondence between the IRB and the investigators. Y pp. 91-95 and 324-403, 

(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 106-112 of 403 and p 2 of 

Supplement 1 

(2) The measures proposed to minimize risks to the human subjects; Y pp. 106-112 of 403 and p 2 of 

Supplement 1 

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

and to whom they would accrue 

Y p. 112-113 

(4) Alternative means of obtaining information comparable to what would 

be collected through the proposed research; and 

Y pp.15-17 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. 112-113 

§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 submission pp 349-359 

and 375-388 

Approved pp. 143-171 

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

advertisements proposed to be used. 

Y pp. 39-41, 106, 118-126, 155, 

173 

§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. 113-116 

§1125(e): All correspondence between the IRB and the investigators or sponsors. Y pp. 95-96, 324-403 

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. 95-96