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Ha 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF 

CHEMICAL SAFETY AND POLLUTION 

PREVENTION 

October 8, 2014 

MEMORANDUM

SUBJECT: Science and Ethics Review of AHETF Scenario Design and Protocol AHE170 for 

 Exposure Monitoring of Workers during Open Pour Loading of Granules 

FROM: Jeff Evans, Senior Scientist 

 Bayazid Sarkar, Mathematical Statistician 

 Health Effects Division 

 Office of Pesticide Programs 

Kelly Sherman, Human Research Ethics Review Officer 

Office of the Director 

 Office of Pesticide Programs 

TO: Dana Vogel, Acting Director 

 Health Effects Division 

 Office of Pesticide Programs 

REF: Collier, R. (2014) Determination of Dermal and Inhalation Exposure to Workers 

during Open Pour Loading of Granules, unpublished protocol dated July 25, 2014, 

prepared for the Agricultural Handler Exposure Task Force under Sponsor ID 

AHE170, 659 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. 

 EPA has no recommendations for revisions. 

Ethics Review 

 The protocol meets the applicable ethical requirements of 40 CFR part 26, subparts K and L. 

 EPA has no recommendations for revisions. 

A. Completeness and Contents of Protocol Submission 

The submitted protocol was reviewed for completeness against the required elements 

listed in 40 CFR §26.1125. All required elements are present. EPA’s checklist is appended to 

this review as Attachment 6. 

B. Summary Assessment of the Scenario Design1

1. Scenario Design: Protocol AHE170 is designed to address the dermal and inhalation 

exposure of handlers performing open pour loading of conventional granule formulations 

of pesticides from non-bulk containers into a variety of agricultural application 

equipment (e.g., planting equipment). Conventional granules are defined for this 

scenario as those utilizing generally greater than 90 percent of inert carriers (e.g., corn 

cobs, clay, limestone, and sand) and can pass through a 4 mesh sieve but not through an 

80 mesh sieve. Mesh refers to the number of wires per inch. These granular 

formulations are applied dry and are not mixed with water. They are considered 

conventional formulations that is they are not engineered to reduce dustiness by using 

polymers and/or Biodact®. Engineered, reduced dust, granular formulations would be 

considered a potential mitigation risk assessment option and would be a different handler 

scenario than the one currently being proposed by the AHETF. 

Participants will perform a variety of tasks involving the transfer of granule formulations 

from bags (weighing up to 50 pounds) into application equipment such as planters or 

broadcast spreaders (by aircraft or ground equipment). Other containers that may be 

similar to bags may be used provided they are easy to handle by the participant. Large 

bulk container will not be used. Other activities such as stacking bags and associated 

loading and unloading bags may also be performed in addition to any equipment clean-up 

after the applications have been made. This scenario does not include any application 

activities. This scenario does not involve open pouring into hand equipment such as push 

type granule spreaders. 

 

1 Supporting details are in Attachment 1. 
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The handler attire for this scenario is a “single layer” consisting of long-sleeved shirt, 

long pants, shoes plus socks (unless otherwise specified on the label or what would 

normally be worn by the participant). The minimum amount of PPE worn by participants 

will be chemical resistant gloves. Hats (including baseball type), eyewear (glasses, 

sunglasses, safety glasses or goggles) are permitted to be worn by participants for this 

scenario if they choose to do so. Particulate filtering face-piece, or elastomeric half-mask 

respirators may also be worn. In these cases, the measured face/neck wipes collected by 

AHETH will be corrected by extrapolating to the rest of the head. Likewise for any areas 

covered by eyewear or hats. 

During the study, the participant’s will wear long sleeved and long legged underwear 

beneath the single layer. This serves as dosimeter to collect the “to the skin 

measurements” for the respective areas of the body. For the subjects in this study, from 

and exposure perspective, this is essentially a double layer of clothing. In other words, 

the combination of the dosimeter and the single layer are considered the same as a double 

layer, therefore this study design can accommodate pesticide products requiring either a 

single layer or a double layer. There is one surrogate chemical (chlorpyrifos) which 

requires a double layer. For participants handling this surrogate, the long underwear 

mentioned above will serve as that second layer. 

There are no existing data available for this scenario that meet the AHETF’s criteria for 

inclusion in its database. Therefore, this scenario will consist of all new data. 

In accordance with the AHETF Governing Document, the estimated number of 

monitoring units (MUs) required shall be based on a geometric standard deviation (GSD) 

of 4 and an intra-cluster correlation of 0.3. The governing document also outlines the 

various potential combinations of number of study locations and corresponding number 

of participants to meet the primary objective of the study. For this study, the AHETF 

has selected a seven by three study design (cluster by MUs, respectively) for a total of 21 

MUs. 

The definition of the clusters (i.e., monitoring areas) for this scenario can be contiguous 

states or portion of states or individual states. The monitoring areas selected for this 

study and corresponding crops are shown in the following table. 

Monitoring Area Crops 

New York, Pennsylvania Corn, Sweet Corn 

Virginia, North Carolina, South Carolina, 

Georgia, Alabama 

Peanut, Sweet Corn, Onions, Sod 

Florida Peanut, Sweet Corn, Citrus, Sod 

Indiana, Ohio Corn, Sweet Corn 

Iowa, Illinois Corn, Sweet Corn 

Minnesota, North Dakota, South Dakota Sugar Beets, Dry Beans and Dry Peas, 

Corn, Sweet Corn, Sunflowers 

Idaho, Eastern Washington, Eastern Onion, Sweet Corn, Dry Beans and Dry 
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Monitoring Area Crops 

Oregon Peas, Sugar Beets 

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

pesticide handlers open pour loading pesticides formulated as granulars into various 

application equipment. 

2. Sampling Design: 

 

AHETF has a two stage selection process to diversify the Monitoring Units collected for 

a given scenario. One is to select distinct monitoring areas or regions of the country and 

two, to configure diverse monitoring units within the monitoring area. Seven new 

clusters (monitoring areas) each having 3 monitoring units (MUs) have been proposed for 

this scenario representing a wide variety of geographical and climactic conditions where 

granule formulations of pesticides are applied. Although two monitoring areas represent 

contiguous major corn growing states (IN/OH and IA/IL), the AHETF decided the area 

would be too large to be represented by only 3 MU. EPA agrees with this decision. The 

monitoring areas were selected by considering the high acre growing areas where the 

AHETFs suite of surrogate granular formulations are applied - coupled with the 

consideration of acreage data collected by the National Agricultural Statistics Service 

(NASS – 2007). 

In order to optimize the likelihood that one of the surrogate granular formulations would 

be used, the AHETF selected the following monitoring areas: 

Proposed Study Monitoring Areas 

EPA Growing Region/Climatic Description 

1 New York and 

Pennsylvania 

1/Warm to cool, humid summers and mild to cold 

winters 

2 Virginia, North Carolina, 

south Carolina, Georgia 

and Alabama 

2/Warm and humid summers, mild winters 

3 Florida 3/Northern 2/3rd of the state/warm and humid 

summers and mild winters. In the northern 1⁄2, 

peanuts is the major crop. In the southern 1/3rd of 

the state/moist tropical conditions. In the southern 

1⁄2 citrus, sod and sweet corn are likely crops. 

4 Indiana and Ohio 5/Warm and humid summers and mild to cold 

winters 

5 Iowa and Illinois 5/Warm and humid summers and mild to cold 

winters 

6 Minnesota, North Dakota 

and South Dakota 

5 and 7/Warm to cool, humid summers, mild to 

cold winters 

7 Idaho, Eastern 

Washington and Eastern 

Oregon 

11/Warm to cool summers and cold dry winters 
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EPA agrees that these monitoring areas are likely to provide a wide range of climates and 

high acre crops where the use of granular formulations of pesticides is likely. In addition, 

they are areas with a high likelihood of identifying participants and sites meeting the 

AHETFs similarity restrictions. Noticeably absent from the proposed study locations are 

potential monitoring areas in the southwestern United States. AHETF determined that 

there was relatively little expected granular in the region and thus expect a low likelihood 

of finding study participants. 

After the monitoring areas are identified, the next stage of the diversity selection process 

involves delineating the practical range of amount of active ingredient handled (AaiH) 

that could be handled in a minimum four hour monitoring period. The AaiH is stratified 

with the upper and lower strata having a three-fold difference and the middle an order of 

magnitude. As discussed at the October 2011 HSRB meeting, it was agreed there is 

generally no upper limit on the amount AaiH handled by a study participant. While the 

lower limit is imposed to ensure detectable residues, the upper limit should generally be 

considered as a guide and as a way to determine sample size and estimate participant 

exposure. Individuals handling more than 400 pounds would not be excluded from the 

study. Three AaiH bands (strata) ranging from 5 to 400 pounds are proposed. The high 

end is based on EPA’s assumption of treating 200 acres per day and an application rate of 

2 pounds active ingredient applied per acre. The AaiH strata are as follows: 

 5 to 15 lbs AaiH 

 Greater than 15 to 150 lbs AaiH 

 Greater than 150 to 400 lbs AaiH 

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

treated and the handlers whose exposure will be monitored. As with other AHETF 

studies, growers agreeing to cooperate with the research and to have their crops treated 

with any of surrogate pesticides must be identified before study participants can be 

recruited. 

The AHETF plan to identify handler participants recruited from farming operations using 

granular formulations includes the following primary and secondary sources. The task 

force has procedures for randomizing and combining primary and secondary source 

names for reducing selection bias for all of its field studies. The primary and secondary 

sources are as follows: 

 Primary Sources: Local Agricultural Specials (LAS) such as county extension 

agents and employer referrals to the AHETF 

 Secondary Sources: Growers and farm operators identified in publically available 

sources obtained via professional call center personnel 

Once a sufficient number of growers are identified, the AHETF: 

 Put the list of growers into random order 
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 Contact a random subsample from the list, one at a time, in the sequence of the 

randomized list, to determine whether the grower is ‘eligible’ to participate 

 Placing eligible employers into a “working pool” 

Screening of employers for eligibility will continue until the pool contains somewhat 

more employers with somewhat more handlers than are needed to fill three MUs in each 

cluster. From each employer in the working pool, the following range of information will 

be compiled: 

 The employer is willing to cooperate with the AHETF 

 The employer will perform or has employees with experience open loading of 

granular formulations and when the applications will take place 

 The employer will permit AHETF to recruit their employee(s) 

 The employer has sufficient acreage such that the minimum AaiH can be 

mixed/loaded and treated 

 The employer can fill a desired AaiH stratum and is willing to use at least one of 

the surrogates 

EPA believes this process of identifying cooperating growers is acceptable. 

When selecting MUs, the AHETF have developed the following similarity restrictions 

(SR) to increase diversity within the cluster. 

 SR1. AHETF prefers that no two MUs in the same monitoring area handle AaiH 

from the same stratum 

 SR2. No two MUs can be the same participant 

 SR3. No two MUs in the same monitoring area can have the same employer 

 

The growers in the chosen configuration provide the pool of handlers from which 

handlers will be recruited to fill each of the three 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 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 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. Alternatively, the AHETF 

may consider monitoring as soon as there is an eligible participant if the traditional 

recruitment proves to be difficult. 

3. Choice of Surrogate Materials: The surrogate pesticides to be used in this study are 

fungicides, herbicides and insecticides that have been used in previous exposure 

monitoring studies and are known to be stable and have established analytical methods. 

These pesticides have a wide range of application rates to help obtain three AaiH strata 

needed for each monitoring area. 
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Surrogate Pesticide Type of Pesticide 

Carbaryl Insecticide 

Chlorpyrifos Insecticide 

Dithiopyr Herbicide 

Ethalfuralin Herbicide 

Imidacloprid Insecticide 

Mefenoxam Fungicide 

Pendimethalin Herbicide 

Permethrin Insecticide 

Tefluthrin Insecticide 

Thiophanate-methyl Fungicide 

 

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

1. Statistical design and sample size determination: 

There are no acceptable existing data for this scenario. The AHETF will collect 21 MUs 

based on a seven cluster by three MU per cluster design. 

Reference Distribution: 

Sample sizes are determined by using a random sampling reference model which is 

reasonably close to the actual diversity selection process. Sample sizes that would be 

appropriate under the reference model are then assumed to be reasonable for the study.

The AHETF reference model assumes that: 

• Normalized exposure is log-normally distributed with a known geometric 

standard deviation (GSD). This also means that the logarithm of normalized 

exposure is normally distributed with a known standard deviation SD=Log(GSD). 

• There will be NC new monitoring areas and NM new MUs per area. The total 

number of new MUs in a scenario is, therefore, N= NC×NM. 

• There may be correlation between the (logarithm of) normalized exposures of 

MUs if they have been efficiently configured to form a single cluster in a 

monitoring area. This is referred to as intra-cluster correlation, or simply ICC. 

Based on analyses of exposure from a number of available monitoring studies, Appendix 

C of the AHETF Governing Document derived a default relative variation structure 

consisting of a geometric standard deviation (GSD) of 4 and an intra-cluster correlation 

(ICC) of 0.3. 

 The Number and Configuration of New MUs: 

 

2 Supporting details are in Attachment 2. 
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According to the AHETF it is less costly to keep the number of monitoring areas as small 

as possible and have a large number of MUs per area. However, designs with a smaller 

number of MUs per monitoring area are more likely to be attainable for all the areas 

selected. Therefore, the configuration size is restricted to NM=3 for all new MUs. 

Appendix C of the Governing Document describes the simulation methodology needed to 

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

lognormal distribution. These simulations determine accuracy or power given the 

number and configuration of MUs that can 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 

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

sampling model applies. 

2. Secondary Objective: If the reference model was true, and AaiH is assumed to be 

the normalizing factor of interest for each scenario, there should be at least 80% 

statistical power to distinguish complete proportionality from complete independence 

between dermal exposure and AaiH. 

The AHETF suggest that “for the secondary objective the power to detect proportionality 

between exposure and AaiH also depends on the particular values of AaiH used.” For 

this scenario the practical AaiH range (5 to 400 lb ai/day) was partitioned into the 

following three strata: 

• From 0.5 to 15 AaiH 

• Greater than 15 to 150 AaiH 

• Greater than 150 to 400 AaiH 

There is a 3-fold difference between the upper and lower bound having roughly equal 

widths on a log scale (for AaiH). Based on the AHETF’s simulations for a 10 by 3 

cluster/MU configuration, assuming proportionality as well as the assumed variation 

structure, the primary objective was met. Based on those assumptions and values, the 

secondary objective is expected to be met as well. 

EPA is interested in the secondary objective of having enough power to be able to 

distinguish between independence and proportionality of exposure to AaiH. By 

incorporating this component of AaiH into AHETFs study designs, AHETF is 

acknowledging EPA’s (and other regulatory agencies) preference to use AaiH as a 

normalizing factor. Regardless of whether proportionality can be detected in a given 

study, stratifying AaiH is certainly useful as a meta-factor for diversity selection of MUs. 

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

was described as being half a work day or 4 hours in duration involving open pouring 

granular formulations of at least 3 loads. The hourly minimum is considered by the 

AHETF as a guideline rather than a requirement. 
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Participants will conduct open pour loading of granules which will require opening the 

granular bags (up to 50 pounds) and pouring the granules into the application equipment. 

The participants must have experience with the application equipment into which the 

granules will be loaded within the past 3 years. 

There are 10 surrogate pesticide active ingredients available for this scenario. A 

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

3. Endpoints and Measures: The study will measure dermal and inhalation exposure for 

each MU that can in turn contribute to development of unit exposures (exposure per unit 

of pesticide active ingredient applied) or other exposure metrics. Ultimately, the 

exposure data measured in this study will be used to estimate dermal and inhalation 

exposure to other pesticides for workers open pour loading granular formulation of 

pesticides. 

Dermal exposure will be measured by using a whole body dosimeter (WBD) which is to 

be worn beneath the subject’s outer clothing. After the monitoring event, the inner 

dosimeter will be removed from the subject and sectioned into two sections: upper (waist 

up) and lower (waist down). 

Before beginning work, subjects will wash their hands in 500 mL of 0.01% Aerosol® OT75 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 any breaks and again at the end of the exposure period; all 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 operating at 2L per minute. The unit will be calibrated prior to 

the monitoring event using a rotameter. Depending on the surrogate, the absorbant may 

be Chromosorb® or XAD-2. The OVS tube will be clipped to the subject’s shirt collar 

with the intake facing downward. The air sampling pump will be connected to the OVS 

tube and will be operated for the total monitoring period including any breaks. 

Additional measures will record environmental conditions at the time of monitoring. 

Observers will make field notes of subject activity throughout the monitoring event, and 

photographs or videos may be taken selectively to illustrate events while ensuring privacy 
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of the subject. EPA believes that the proposed measures are appropriate and sound for the 

study design. 

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 AHE170, and will be posted to the AHED® database, where they will be 

available to regulatory agencies. The documentation will report a confidence-intervalbased 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 

EPA agrees that the AHETF should collect MUs for this scenario based on participants 

open pour loading of granules into varying types of application equipment. The protocol 

adequately addresses the following elements according to applicable scientific standards: 

 Scientific objective 

 Experimental design for achieving objectives 

 Quantification of the test materials 

 Data collection, compilation and summary of test results 

 Justification for selection of test substances 

 Justification for sample size 

 Fortification levels and number of samples for laboratory, field, and storage 

stability samples 

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

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

Guidelines) as well as Good Laboratory Practices (GLPs). 
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E. Summary Assessment of Ethical Aspects of the Proposed Research3

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

determine the potential exposure of workers who manually open containers of granular 

products and open pour the granules into suitable application equipment using their 

normal practices. This loading method is 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 loaded under this exposure scenario. 

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

growers who are likely to perform open pour loading of granular pesticide products 

within the monitoring area during the timeframe of the. Eligible growers will be 

identified from a complete list of growers in the target area, processed in random 

sequence. Subjects will be recruited from employees of eligible employers who have 

experience within the past three years in manually opening bags containing a granular 

product and pouring the granules into application equipment that is similar to that which 

will be used in 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 open and load granular pesticide products. 

Subjects will be recruited according to the standard procedures set forth in SOP AHETF11.B.7. (p. 228-233 of 659) The Study Director or designated researcher will seek 

permission from an eligible employer to approach his/her employees to recruit workers 

for the study. Depending on the number of employees and size of the grower’s facility, 

the Study Director or researcher may contact employees using an informational 

recruitment flyer posted in a common work area. Alternatively, or subsequent to the use 

of a flyer, the Study Director or researcher will arrange a meeting with the employer’s 

employees who express interest in participation. Such recruitment meetings will always 

occur without supervisors being present. The Study Director or researcher will describe 

the AHETF Exposure Monitoring Program, the goals of the research study, the 

procedures used in exposure monitoring, and the risks and benefits to subjects. The 

subject eligibility factors listed in the consent form and SOP AHETF-11.B.6 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, along 

with specific steps proposed to minimize them: 

 

3 Supporting details are in Attachment 2. 
Page 12 of 52 

 The risk of heat-related illness 

 The risk associated with scripting of field activities 

 Psychological risks 

 The risk of exposure to surfactants 

 The risk of exposure to surrogate chemicals 

In this study, risks to subjects are classified as ‘greater than minimal’ since 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. The principal benefit of 

this research is likely to be new data about the dermal and inhalation exposure of workers 

who perform open pour loading of granular pesticides, for use by EPA and other 

regulatory agencies to support exposure assessments for a wide variety of pesticides with 

similar use patterns. 

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

research. The low residual risk is reasonable in light of the likely benefits to society from 

new data supporting more accurate handler exposure assessments for a wide range of 

agricultural pesticides. 

6. Independent Ethics Review: The proposed research has been reviewed and approved 

by the Schulman Associates IRB (SAIRB). The submitted materials include a record of 

correspondence between the investigators and SAIRB. 

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

and appropriately documented. 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 
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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. 

 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: Monitoring Unit Selection and Construction Plan for Scenario: 

Open Pour Loading of Granules (AHE170) 

2. EPA Protocol Review: Determination of Dermal and Inhalation Exposure to Workers 

during Open Pour Loading of Granules (AHE170) 

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 14 of 52 

EPA Scenario Review: AHE170 

Title: Determination of Dermal and Inhalation Exposure to Workers During Open 

Pour Loading of Granules 

Date: July 25, 2014 

Sponsor: Agricultural Handler Exposure Task Force 

 

1. Scope of Scenario Design 

“This scenario involves pesticide products formulated and applied as granules. They can be 

used across the U.S. and applied to virtually any type of crop. The Environmental Protection 

Agency (EPA) “considers granular pesticide products to include those products composed of 

a high percentage (generally greater than 90%) of granular inert carrier(s) (corn cobs, clay, 

limestone, sand, food: 40CFR 180.910 and 180.950) and a minimal amount of sticker/binder 

(generally 5% or less of the formulation.” (p. 13 of 659) 

“The following seven monitoring areas (i.e., states and portions of states) were purposively 

selected from within the U.S. Target Area: 

1. New York and Pennsylvania 

These two northeastern state are situated in EPA Region 1 (ACPA, 1992). Crops expected to 

yield MUs include mostly field and sweet corn. 

2. Virginia, North Carolina, South Carolina, Georgia, and Alabama 

These five southeastern states are situated in EPA Region 2. Crops expected to yield MUs 

are peanuts, onions, corn, sweet corn and sod. Limited use information suggests that 

granules are used mainly on crops that tend to be scattered across these five states. 

3. Florida 

Florida is situated in EPA Region 3. Crops expected to yield MUs in this state include sweet 

corn, citrus and sod, concentrated in the lower half of the state, and peanuts in the northern 

half of the state. 

4. Indiana and Ohio 

Corn is the crop most likely to utilize granular products. These two Midwestern states, 

situated in EPA Region 5 are major corn producers, and are therefore expected to provide 

MUs. 

5. Iowa and Illinois 

The two Midwestern States are also major corn producers in EPA Region 5 and were 

selected as a monitoring area because of their expected high granule use. 
Attachment 1 

Page 15 of 52 

6. Minnesota, North Dakota and South Dakota 

Crops expected to yield MUs for this upper Midwest monitoring area are dry beans and peas, 

sugar beets, sweet corn and sunflowers. Since actual granular use information on these crops 

is limited this area covers a fairly wide area representing portions of EPA Regions 5 and 7. 

7. Idaho, Eastern Washington and Eastern Oregon 

Crops expected to yield MUs for this monitoring area are sweet corn, onions, sugar beets, 

and dry beans and peas. The monitoring area is somewhat large because it appears that these 

crops are scattered in localized areas across these states. These northwestern states are 

located in EPA region 11.” (pp. 26 – 27 of 659)

(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 Open Pour Loading of Granules (OPLG) scenario as being 

within the scope of the task force goals and one for which data of sufficient quality for a 

generic database are lacking. A number of AHETF member products are labeled for this 

use pattern. These products are critical because they help support and maintain 

commercially important crops across the U.S and Canada by providing the user an 

additional formulation option to meet his/her individual needs. Therefore, it is necessary 

to have data in AHED for the loading methods described by this scenario.” (p. 15 of 659)

“AHETF in conjunction with the JRC, reviewed handler exposure measurement 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 OPLG 

scenario, one study involving ‘open pout only’ of granular products potentially applicable 

to this scenario was reviewed by the JRC. 

“Study AH519 involved open pouring of a granular product into a planter. It was initially 

determined to be potentially acceptable for a generic database (AHETF, 2003), however, 

because it involved a polymer-coated engineered formulation and workers wore 

chemical-resistant aprons, this study does not fall within the current OPLG scenario 

definition and is therefore unacceptable... 

“....AHETF reviewed the data in the potentially relevant PHED (EPA, 1998) granular 

loading scenario (Scenario 2 – Granular, Open Mixing and Loading [MLOD] to 

determine if any of the data was suitable for a modern generic database. 

“The AHETF is interested in only those PHED MUs corresponding to a single layer of 

clothing with chemical-resistant gloves. The review found that there were two 

potentially useful studies in that scenario. PHED studies 1004 and 1011. Those studies 

were summarized and then reviewed by the AHETF to determine if they met the criteria 

for a generic database established by AHETF and approved by the JRC (Klonne, 2014). 
Attachment 1 

Page 16 of 52 

“It was determined that these studies did not meet the criteria for a generic database, as 

Study 1004 employed two layers of clothing over the whole body dosimeters and Study 

1011 (formerly reviewed by AHETF as AH827) had very short monitoring times 

(maximum of 20 minutes), a limited number of unique workers, and a single load 

handled. Additionally, both studies used repeated measures of a small number of 

workers, which limits the utility of the data by today’s standards.” (p. 17 of 659)

2. Rationale for Scenario Sampling Design 

(a) Are the variables in the scenario design likely to capture diverse exposures at the 

high-end? 

“For this scenario, the best opportunities for MUs are presumed to be in high-acre 

growing areas of main crops listed on representative granular product labels of the 

surrogate AIs. Such crops include corn, peanuts, citrus, sugar beets, dry beans and 

peas, onions, sod, sweet corn, and sunflowers. Based on acreage data from the National 

Agricultural Statistics Service (NASS, 2007), the acres of potential granule use on these 

important crops are highly concentrated in the Midwest Corn Belt. Locating most of the 

monitoring areas in this portion of the U.S. is likely to provide an adequate number of 

MUs, but would encompass very little geographic diversity. Conversely, monitoring 

units located in areas with very little expected granular use (e.g., the Southwestern 

portion of the U.S.) would be quite impractical since they would be unlikely to provide 

the necessary MUs. As a compromise, the selection of monitoring areas was biased 

towards increased geographic diversity even though it meant including some areas with 

lower potential granule use.” (p. 26 of 659) 

 

“These seven monitoring areas are widely distributed across the U.S., including the 

Northeast, Southeast, South, lower and upper Midwest and the Northwest. They 

incorporate six separate EPA Growing Regions. Although Indiana, Ohio, Iowa, and 

Illinois are in the same EPA region, they are split into separate monitoring areas because 

they are major corn producing states where high use of granular pesticides is anticipated. 

If these four states were combined into a single monitoring area, it would not only be 

large but the entire area would be underrepresented with just three MUs instead of the 

planned six.” (p. 27 of 659) 

The following active ingredients will be considered for use in this scenario. 

• Carbaryl 

• Chlorpyrifos 

• Dithiopyr 

• Ethalfluralin 

• Imidacloprid 

• Mefenoxam 

• Pendimethalin 

• Permethrin 

• Tefluthrin 

• Thiophanate-methyl 
Attachment 1 

Page 17 of 52 

“Granular labels of these AIs indicate that they would provide a range of use rates that 

will enable measurements across the desired range of AaiH per day. Prior to sample 

analysis, analytical methods for each surrogate AI will have been developed and 

validated for each matrix used in this study. Matrices include: inner dosimeter, hand 

rinse, face/neck wipe, and OVS tubes. Finally, these active ingredients will be or have 

been either tested for stability or used as surrogates in previous studies and are known to 

have the required stability under field study conditions.” (p. 38 of 659) 

Selection of a Geographically Diverse Set of Monitoring Areas: 

“The following seven monitoring areas (i.e., states and portions of states) were 

purposively selected from within the U.S. Target Area: 

1. New York and Pennsylvania

These two northeastern states are situated in EPA Region 1 (ACPA, 

1992). Crops expected to yield MUs include mostly field and sweet corn. 

2. Virginia, North Carolina, South Carolina, Georgia, and Alabama

These five southeastern states are situated in EPA Region 2. Crops expected to 

yield MUs are peanuts, onions, corn, sweet corn and sod. Limited use 

information suggests that granules are used mainly on crops that tend to be 

scattered across these five states. 

3. Florida

Florida is situated in EPA Region 3. Crops expected to yield MUs in this state 

include sweet corn, citrus and sod, concentrated in the lower half of the state, and 

peanuts in the northern half of the state. 

4. Indiana and Ohio

Corn is the crop most likely to utilize granular products. These two 

Midwestern states, situated in EPA Region 5, are major corn producers, and are 

therefore expected to provide MUs. 

5. Iowa and Illinois

These two Midwestern states are also major corn producers in EPA Region 5 and 

were selected as a monitoring area because of their expected high granule use. 

6. Minnesota, North Dakota and South Dakota

Crops expected to yield MUs for this upper Midwest monitoring area are dry 

beans and peas, sugar beets, sweet corn, and sunflowers. Since actual granular 

use information on these crops is limited, this monitoring area covers a fairly 

wide area representing portions of EPA Regions 5 and 7. 

7. Idaho, Eastern Washington, and Eastern Oregon
Attachment 1 

Page 18 of 52 

Crops expected to yield MUs for this monitoring area are sweet corn, onions, 

sugar beets, and dry beans and peas. The monitoring area is somewhat large 

because it appears that these crops are scattered in localized areas across these 

states. These northwestern states are located in EPA Region 11. 

These seven monitoring areas are widely distributed across the U.S., including the 

Northeast, Southeast, South, lower and upper Midwest and the Northwest. They 

incorporate six separate EPA Growing Regions. Although Indiana, Ohio, Iowa, and 

Illinois are in the same EPA region, they are split into separate monitoring areas because 

they are major corn producing states where high use of granular pesticides is anticipated. 

If these four states were combined into a single monitoring area, it would not only be 

large but the entire area would be underrepresented with just three MUs instead of the 

planned six. 

Acreages of the crops mentioned above were provided by the National Agricultural 

Statistics Service (NASS, 2007) and used as a basis for identifying monitoring 

areas. These crops will also be the basis for obtaining grower names from publically 

available sources. However, any crop may be associated with an MU as long as it is 

labeled for the granular surrogate used, the grower is qualified and willing to participate 

in the study, and all other conditions of the MU are met. (pp. 19 – 20 of 659) 

Reduction of Monitoring Areas: 

“OPLG MUs tend to be geographically concentrated in the Target Area. For this 

scenario, the best opportunities for MUs are presumed to be in high acre growing areas of 

main crops listed on representative granular product labels of the surrogate AIs. Such 

crops include corn, peanuts, citrus, sugar beets, dry beans and peas, onions, sod, sweet 

corn, and sunflowers. Based on acreage data from the National Agricultural Statistics 

Service (NASS, 2007), the acres of potential granule use on these important crops are 

highly concentrated in the Midwest Corn Belt. Locating most of the monitoring areas in 

this portion of the U.S. is likely to provide an adequate number of MUs, but would 

encompass very little geographic diversity. Conversely, monitoring units located in areas 

with very little expected granular use (e.g., the Southwestern portion of the U.S.) would 

be quite impractical since they would be unlikely to provide the necessary MUs. As a 

compromise, the selection of monitoring areas was biased towards increased geographic 

diversity even though it meant including some areas with lower potential granule use.” 

(p. 26 of 659) 

(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.

“Not all qualified employers will be eligible or willing to participate in the study. 

AHETF must obtain employer cooperation before it can recruit workers. This includes 
Attachment 1 

Page 19 of 52 

willingness of the grower to volunteer his facility and application equipment and allow 

AHETF to recruit his workers. 

For this reason, qualified employers are contacted to verify their qualified status and to 

determine if they are also willing to participate. Employers found to be both qualified 

and willing to participate in the study in a manner consistent with AHETF’s technical and 

ethical guidelines are considered ‘potentially eligible’ for this scenario. For example, the 

potentially eligible employer will perform, or have workers that perform, open pouring of 

granules into suitable application equipment, and if workers are used, the employer will 

allow them to be recruited without influencing their participation.” (pp. 32 - 33 of 659) 

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

have been overlooked? 

If more handlers and growers are in the recruiting pool in a given monitoring area, it is 

likely that the opportunity will arise to select randomly from among interested workers. 

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

“The loading activity in general involves a worker that opens the granular product 

container and manually empties the contents into the application equipment; however, 

associated activities can vary. For example, loading could take place near a product 

storage area where the worker might work off pallets, or it could occur close to the 

application site where the worker works off of a delivery vehicle. Situations could also 

involve the worker himself transferring containers from storage onto a vehicle and then 

driving to the application site. In all cases, however, the product packaging will include 

any type, size and weight that can be lifted by the worker. It is expected, however, that 

most granular products of the selected surrogate AIs will be packaged in paper bags 

containing up to 50 pounds of formulated product. After the containers have been 

emptied, the worker may begin the disposal process in his/her usual manner. This might 

include loading onto a truck or stacking and storing in a shed for subsequent disposal; 

however, the worker may not actually dispose of the containers since they will be 

retained for GLP purposes. Finally, this scenario does not include loading from minibulk or bulk containers such as super sacks, nor does it include loose bulk loading.” (p. 

14 of 659) 

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

Any application equipment cleanout will only involve the application equipment loaded 

by the participants after the applications have been made. This study is loading only and 

does not involve application. 

3. Are the proposed test materials appropriate surrogates? 

“The following active ingredients will be considered for use in this scenario. 
Attachment 1 

Page 20 of 52 

 Carbaryl 

 Chlorpyrifos 

 Dithiopyr 

 Ethalfluralin 

 Imidacloprid 

 Mefenoxam 

 Pendimethalin 

 Permethrin 

 Tefluthrin 

 Thiophanate-methyl 

Granular labels of these AIs indicate that they would provide a range of use rates that will 

enable measurements across the desired range of AaiH per day. Prior to sample analysis, 

analytical methods for each surrogate AI will have been developed and validated for each 

matrix used in this study. Matrices include: inner dosimeter, hand rinse, face/neck wipe, 

socks, head patches, OVS tubes, and cassette filters. Finally, these active ingredients will be 

or have been either tested for stability or used as surrogates in previous studies and are 

known to have the required stability under field study conditions.” (p. 36 of 659)

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

“Appendix C of the Governing Document describes the simulation 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. The number and structure of the proposed MUs should be adequate to 

satisfy the following benchmark objectives discussed in Section 4.4: 

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).” (p. 22 of 

659) 

4.5.1. GSD and ICC 

“To determine sample sizes, reasonable values for reference model variation parameters 

are needed. Based on analyses of exposure from a number of available monitoring 

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

variation structure consisting of a geometric standard deviation (GSD) of 4 and an intracluster correlation (ICC) of 0.3. Unless there is other evidence or expert opinion to the 

contrary, sample sizes are determined using these default values. 
Attachment 1 

Page 21 of 52 

The greater the differences between MUs in the same monitoring area, the closer the ICC 

should be to zero. Mixer/loader-applicators located in the same area, but working for 

different, widely dispersed nursery or greenhouse operations, are unlikely to show strong 

within-cluster correlations in exposure. However, although near zero within-cluster 

correlation is always the goal of diversity selection, it can never be completely counted 

upon. Thus, it seems reasonable to continue the conservative default assumption that ICC 

could be as large as 0.3. 

Because the AHETF and the Joint Regulatory Committee agreed there is no additional 

evidence to suggest otherwise and no other strong opinion to the contrary the default 

values of GSD=4 and ICC=0.3 will be used for determining sample size for the Open 

Pour Loading of Granules scenario....” (p. 23 of 659) 

 4.5.2. Required Number and Configuration of New MUs 

As discussed in Appendix C of the Governing Document, when the above default 

variation structure is used (and there are no suitable existing MUs) there are several 

equivalent configurations of number of monitoring areas (NC) and number of MUs per 

monitoring area (NM) that will meet the 3-fold relative accuracy requirement. These 

equivalent configurations are listed in Table 2. 

Table 2: Equivalent configurations of Number of Monitoring Areas and Number of 

MUs per Monitoring Area 

Number of Monitoring 

Areas NC

Number of MUs per 

Monitoring Area NM

Fixed/Variable Cost Ration 

where Optimal 

15 1 0 – 0.5 

9 2 0.5 – 1.5 

7 3 1.5 - 2 

5 5 2 - 7 

4 8 Over 7 

Although these five configurations are statistically equivalent, they can differ 

substantially in the cost or in the attainability. When the five configurations in Table 2 

are equally feasible, the choice among them usually depends upon the expected ratio of 

the overhead (or ‘fixed’) cost of obtaining and characterizing a monitoring area and the 

additional (or variable) cost per MU. For the most typical scenarios the AHETF 

estimates that this ration is between 4.5 and 6. That is, the overhead cost of a new 

monitoring area is about the same as the cost of adding 5 or six new MUs to an existing 

monitoring area. Given this cost ratio, a sample of five monitoring areas (NC=5) is 

usually the most cost effective design configuration that meets the 3-fold accuracy 

requirement. Configurations with more monitoring areas and fewer MUs per area 

provide greater statistical information per MU (the reason that fewer total MUs are 

needed) but they are also more costly due to the large overhead per additional monitoring 

area. 
Attachment 1 

Page 22 of 52 

For this scenario, AHETF cannot predict the magnitude of use of granular products that 

would be used, it is uncertain the extent to which the surrogates approved for this study 

would be among the. Even some surrogate products could be disqualified if, for 

example, they are not formulated with a common carrier such as clay, or the employer 

prefers to handle them via closed loading systems rather than open pouring. Therefore, 

although it is more costly. AHETF believes that a 7-area design configuration with three 

MUs per monitoring area will be more successful than the less costly 5-area 

configuration with five MUs per monitoring area. It should be emphasized, however, that 

these two configurations only differ in cost and feasibility. Both provide identical 

statistical power. 

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

requirement above is met the design can also provide sufficient power to permit users of 

the database to perform a limited examination of the relationship between the 

normalizing factor (e.g., AaiH) and exposure. This is true provided: (1) the practical 

range of the normalizing factor is at least an order of magnitude and (2) there is adequate 

within-monitoring-area variation in the normalizing factor. When these conditions occur, 

the MU sample will be of sufficient size and diversity to provide at least 80% statistical 

power to distinguish complete proportionality from complete independence between 

exposure and the normalizing factor used in the primary benchmark. Since these 

conditions can be satisfied for the reference sampling design, then the purposive diversity 

design for the Open Pour Loading of Granules scenario should provide adequate power 

for the secondary objective: the ability to conduct limited examinations of the 

relationship between AaiH and exposure.” (pp. 24 - 25 of 659) 
Attachment 2 

Page 23 of 52 

EPA Protocol Review: AHE170 

Title: Determination of Dermal and Inhalation Exposure to Workers during Open 

Pour Loading Granules 

Submitted Date: July 25, 2014 

Study Director and Sub-Investigators: 

 Eric Bruce 

Aaron Rotondaro 

 Brian Lange 

Field Facility: Multiple outdoor agricultural locations; each principal field investigator 

utilizes a mobile laboratory 

 

Analytical Facility: TBD

 

Sponsor: Agricultural Handler Exposure Task Force, LLC 

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

1720 Prospect Drive 

Macon, MO 63552 

 

Reviewing IRB: Schulman Associates IRB 

 Sawgrass Plaza, Suite 1120 

 1550 Sawgrass Corporate Parkway 

 Ft. Lauderdale, FL 33323 

 

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 characterize the potential exposure of 

workers who manually open containers of granular products and open pour the granules 

into suitable application equipment using their normal practices. Product containers will 

include any type, size and weight that can be lifted or carried by the worker; however, it 

is expected that granular products of the selected surrogate active ingredients (AIs) will 

most likely be packaged in paper bags containing up to 50 pounds of formulated product. 

Additional loading details about this loading activity are provided in Section 6.6. 

“Exposure monitoring will be conducted in seven monitoring areas representing a variety 

of geographical and climatic regions of the United States.” (p. 409 of 659) 

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

the research fill an important gap in understanding? 
Attachment 2 

Page 24 of 52 

This study will provide a partial answer to the question of what dermal and inhalation 

exposures are likely for workers who open pour load pesticide products formulated as 

granulars. 

(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 handlers who open pour load pesticide products formulated as granulars. 

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

“AHETF in conjunction with the JRC, reviewed handler exposure measurement 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 OPLG 

scenario, one study involving ‘open pout only’ of granular products potentially applicable 

to this scenario was reviewed by the JRC. 

“Study AH519 involved open pouring of a granular product into a planter. It was initially 

determined to be potentially acceptable for a generic database (AHETF, 2003), however, 

because it involved a polymer-coated engineered formulation and workers wore 

chemical-resistant aprons, this study does not fall within the current OPLG scenario 

definition and is therefore unacceptable... 

“....AHETF reviewed the data in the potentially relevant PHED (EPA, 1998) granular 

loading scenario (Scenario 2 – Granular, Open Mixing and Loading [MLOD] to 

determine if any of the data was suitable for a modern generic database. 

“The AHETF is interested in only those PHED MUs corresponding to a single layer of 

clothing with chemical-resistant gloves. The review found that there were two 

potentially useful studies in that scenario. PHED studies 1004 and 1011. Those studies 

were summarized and then reviewed by the AHETF to determine if they met the criteria 

for a generic database established by AHETF and approved by the JRC (Klonne, 2014). 

It was determined that these studies did not meet the criteria for a generic database, as 

Study 1004 employed two layers of clothing over the whole body dosimeters and Study 

1011 (formerly reviewed by AHETF as AH827) had very short monitoring times 

(maximum of 20 minutes), a limited number of unique workers, and a single load 

handled. Additionally, both studies used repeated measures of a small number of 

workers, which limits the utility of the data by today’s standards.” (p. 17 of 659)

(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 potential dermal and inhalation exposure. 

2. Study Design 
Attachment 2 

Page 25 of 52 

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

is it? 

“The goal of conducting MUs for this scenario 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 the magnitude and likely range of future exposures, 

and to perform exposure assessments for this scenario. Because the number and types of 

such analyses will depend on the specific objectives of each future user, there will be no 

attempt to conduct a comprehensive universal ‘analysis’ of these data. Rather, the data 

collected for this scenario will only be statistically evaluated with respect to specific 

‘benchmark’ measures of adequacy. As discussed in the Governing Document, the two 

categories of benchmark data adequacy considered are: 

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

normalized by amount of active ingredient handled (AaiH). 

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

AaiH, if one existed.” (p. 38 of 659)

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? 

“To determine sample sizes, reasonable values for reference model variation parameters 

are needed. Based on analyses of exposure from a number of available monitoring 

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

variation structure consisting of a geometric standard deviation (GSD) of 4 and an intracluster correlation (ICC) of 0.3. Unless there is other evidence or expert opinion to the 

contrary, sample sizes are determined using these default values. 

The greater the differences between MUs in the same monitoring area, the closer the ICC 

should be to zero. Mixer/loader-applicators located in the same area, but working for 

different, widely dispersed nursery or greenhouse operations, are unlikely to show strong 

within-cluster correlations in exposure. However, although near zero within-cluster 

correlation is always the goal of diversity selection, it can never be completely counted 

upon. Thus, it seems reasonable to continue the conservative default assumption that ICC 

could be as large as 0.3. 

Because the AHETF and the Joint Regulatory Committee agreed there is no additional 

evidence to suggest otherwise and no other strong opinion to the contrary the default 
Attachment 2 

Page 26 of 52 

values of GSD=4 and ICC=0.3 will be used for determining sample size for the Open 

Pour Loading of Granules scenario....” (p. 23 of 659) 

4.5.2. Required Number and Configuration of New MUs 

As discussed in Appendix C of the Governing Document, when the above default 

variation structure is used (and there are no suitable existing MUs) there are several 

equivalent configurations of number of monitoring areas (NC) and number of MUs per 

monitoring area (NM) that will meet the 3-fold relative accuracy requirement. These 

equivalent configurations are listed in Table 2. 

Table 2: Equivalent configurations of Number of Monitoring Areas and Number of 

MUs per Monitoring Area 

Number of Monitoring 

Areas NC

Number of MUs per 

Monitoring Area NM

Fixed/Variable Cost Ration 

where Optimal 

15 1 0 – 0.5 

9 2 0.5 – 1.5 

7 3 1.5 - 2 

5 5 2 - 7 

4 8 Over 7 

Although these five configurations are statistically equivalent, they can differ 

substantially in the cost or in the attainability. When the five configurations in Table 2 

are equally feasible, the choice among them usually depends upon the expected ratio of 

the overhead (or ‘fixed’) cost of obtaining and characterizing a monitoring area and the 

additional (or variable) cost per MU. For the most typical scenarios the AHETF 

estimates that this ration is between 4.5 and 6. That is, the overhead cost of a new 

monitoring area is about the same as the cost of adding 5 or six new MUs to an existing 

monitoring area. Given this cost ratio, a sample of five monitoring areas (NC=5) is 

usually the most cost effective design configuration that meets the 3-fold accuracy 

requirement. Configurations with more monitoring areas and fewer MUs per area 

provide greater statistical information per MU (the reason that fewer total MUs are 

needed) but they are also more costly due to the large overhead per additional monitoring 

area. 

For this scenario, AHETF cannot predict the magnitude of use of granular products that 

would be used, it is uncertain the extent to which the surrogates approved for this study 

would be among the. Even some surrogate products could be disqualified if, for 

example, they are not formulated with a common carrier such as clay, or the employer 

prefers to handle them via closed loading systems rather than open pouring. Therefore, 

although it is more costly. AHETF believes that a 7-area design configuration with three 

MUs per monitoring area will be more successful than the less costly 5-area 

configuration with five MUs per monitoring area. It should be emphasized, however, that 

these two configurations only differ in cost and feasibility. Both provide identical 

statistical power. 
Attachment 2 

Page 27 of 52 

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

requirement above is met the design can also provide sufficient power to permit users of 

the database to perform a limited examination of the relationship between the 

normalizing factor (e.g., AaiH) and exposure. This is true provided: (1) the practical 

range of the normalizing factor is at least an order of magnitude and (2) there is adequate 

within-monitoring-area variation in the normalizing factor. When these conditions occur, 

the MU sample will be of sufficient size and diversity to provide at least 80% statistical 

power to distinguish complete proportionality from complete independence between 

exposure and the normalizing factor used in the primary benchmark. Since these 

conditions can be satisfied for the reference sampling design, then the purposive diversity 

design for the Open Pour Loading of Granules scenario should provide adequate power 

for the secondary objective: the ability to conduct limited examinations of the 

relationship between AaiH and exposure.” (pp. 24 - 25 of 659) 

(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. 

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

“...the within-monitoring-area AaiH diversity for new MUs is imposed by specifying 

that: 

SR1. It is preferable that no two MUs obtained in the same monitoring area be in 

the same AaiH stratum 

When achievable this similarity restriction results in AaiH levels for all MUs being 

approximately uniformly located over the entire log AaiH range when log exposure is 

regressed against log AaiH. 

In addition to the similarity restriction on AaiH (i.e., SR1 above), diversity among 

MUs is also enhanced by imposing the following mandatory similarity restrictions on 

each set of three MUs in the same monitoring area: 

SR2. No two MUs are permitted to utilize the same worker 

SR3. No two workers are permitted to have the same employer (i.e., grower or 

commercial applicator) 
Attachment 2 

Page 28 of 52 

(e) Is the proposed research designed in accordance with current scientific 

standards and practices to include representative study populations for the 

endpoint in question? 

The study design exceeds current guideline requirements. This is not a study to 

investigate exposure to a given pesticide. Rather it is designed to generate surrogate 

data that is generalizable for use in all Agency risk assessments involving the loading 

of granular formulations of pesticides. 

(f) 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. 

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

As discussed in the Governing Document, the two categories of benchmark data 

adequacy considered are: 

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

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

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

and AaiH, if one existed. 

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. 

This secondary benchmark objective Adequacy of the Data for Distinguishing a 

Proportional from an Independent Relationship between Exposure and AaiH applies 

to the open pour loading of granular formulations scenarios 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. 

(h) Are proposed statistical methods appropriate to answer the research question? 

 Yes. 
Attachment 2 

Page 29 of 52 

(i) 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 open pour loading of granulars 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. 

As described in the Governing Document, in such a model the true slope, β, would be 

equal to one if dermal exposure were directly proportional to AaiH. If exposure were 

independent of AaiH, then β=0. This benchmark objective requires that the number 

of clusters and the allocation of AaiH levels to MUs should be adequate to ensure that 

the regression analysis has at least 80% power to reject the hypothesis that β=0 when 

β is actually equal to one. By symmetry, the mixed model linear regression would 

also have the same power to reject the hypothesis that β=1 when β=0. This is the 

precise meaning of being able to ‘discriminate between proportionality and 

independence. 

(j) Does the investigator propose to conduct the research in accordance with 

recognized good research practices, including, when appropriate, good clinical 

practice guidelines and monitoring for the safety of subjects? 

This study is proposed to be conducted in accordance with recognized good research 

practices. This is not a clinical study and therefore good clinical practice guidelines are 

not applicable. 

2.2 How and to what will human subjects be exposed? 

AHETF will monitor worker exposure resulting from the open pour loading of 

granular formulations into various application equipment. The following active ingredients 

will be considered for use in this scenario. 

 Carbaryl 

 Chlorpyrifos 

 Dithiopyr 

 Ethalfluralin 

 Imidacloprid 

 Mefenoxam 

 Pendimethalin 

 Permethrin 
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 Tefluthrin 

 Thiophanate-methyl 

(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.” (p. 35 of 659) 

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

dose administration? 

“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 

number of bags loaded. Thus, diversification of AaiH induces diversification of such 

associated factors as well. Therefore, in addition to having a wide range, the MUs 

within the same monitoring area should not have similar AaiH levels. 

A practical AaiH range is first defined for the entire scenario. It encompasses AaiH 

levels that can be readily found in practice and are expected to produce detectable 

exposure results. This practical range is then partitioned into three strata. For each 

monitoring area, there is an attempt to restrict the MUs to no more than one MU per 

AaiH stratum. This similarity restriction imposes AaiH diversity on the MUs and 

ensures a wide range of AaiH levels within each monitoring area. 

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

such factors as the typical use rates of products, types of products available on the 

market, area that can be treated in a day, etc. The practical range for amount of active 

ingredient handled per day is 5 to 400 lb per day. The lower practical limit of five 

pounds of active ingredient per day is selected to avoid an inordinate number of 

non-quantifiable residues on worker exposure matrices and to allow for at least four 

hours of work performing loading activities.”

“...within-monitoring-area diversification of the AaiH will be accomplished by 

partitioning this practical AaiH range into three strata. These strata are: 

 Stratum 1 – From 5 lb to 15 lb 

 Stratum 2 – Greater than 15 lb to 150 lb 

 Stratum 3 – Greater than 150 lb to 400 lb” (pp. 28 – 30 of 659) 

(c) What duration of exposure is proposed? 

“Work Duration 
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Monitoring duration will be largely driven by the amount of AaiH. However, AHETF 

strives to monitor workers that represent a full workday with a desired minimum 

monitoring duration of half the workday or four hours. This helps to ensure that daily 

exposure estimates are not biased by unusual conditions during short intervals. 

Number of Loads Handled 

The number of loading cycles performed could have an impact on exposure. 

AHETF’s standard guideline is that each MU will handle at least three load/apply 

cycles. This ensures the generic database will contain exposure data generated from 

work periods that represent a full day and from repeated application cycles that 

increase the opportunity for exposure (and therefore will not underestimate exposure 

potential). However, performing three load/apply cycles may, in some cases, not be 

practical to achieve. For instance, if a surrogate having a relatively big application 

rate is used in an MU involving the low AaiH stratum, the desired AI may be reached 

before three load/apply cycles are performed. However, scripting (such as reducing 

the load size to increase the number of loads) will be done if needed and practical 

under the application conditions for the particular operation in order to meet this 

desired minimum.” (p. 35 of 659) 

2.3 Endpoints and Measures 

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

asked? 

“Full details of procedures for dermal exposure sampling and for sample removal are 

specified in the most recent versions of SOPs AHETF-8.A, 8.B and 8.C. 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), the hand washes, then face/neck wipes, and finally inner dosimeters as 

described in SOP AHETF-10.E. Samples will be identified as described in SOP 

AHETF-8.F. For this study, inner dosimeters will be cut into two sections after 

collection. 

Full details for sampling air with OSHA Versitile Sampler (OVS) tubes and personal 

air sampling pumps are given in the most recent versions of SOP AHETF-8.D and 

10.G. The pumps and calibration equipment will be uniquely labeled and this 

information recorded in the raw data records. Each pump will be calibrated to a 

nominal sample flow rate of 2 L/min. OVS tubes will contain and appropriate 

adsorbed for the surrogate involved (e.g., Chromosorb® 102 or XAD-2).” (pp. 438 - 

439 of 659) 
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(b) What steps are proposed to ensure measurements are accurate and reliable? 

“Full details regarding field recovery evaluation procedures for all sampling media 

are given in the most recent version of SOP AHETF-8.E. The SOP instructions for 

the “by vial and ampoule” spiking using active ingredient (ai) in an organic solvent 

will be followed for all matrices except OVS tubes. The OVS tubes will be spiked at 

the laboratory with the proper amount of analytical standard using an appropriate 

solvent.” (p. 439 of 659) 

(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]). Field portions of the Study 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 Study Report will contain a Quality Assurance Statement from the QAU of each 

contributing facility conducting QA audits, and from the QAU specified in Section 

1.14.” (p. 446 of 659) 

(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, transit and storage 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. If more than one active 

ingredient is utilize in a particular monitoring area, at least on day of field 

fortifications will be conducted for each active ingredient.” 

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.” All field fortification and untreated control 

samples will be identified as described in SOP AHETF-8.F. (p. 445 - 446 of 659) 

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 
Attachment 2 

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

dosimeter matrix. If the recovery from that matrix was 80%, the reported 

measurement for that sample would be 300 ug/80% = 375 ug. 

3. Subject Selection 

3.1 Representativeness of Sample 

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

“AHETF will monitor worker exposure resulting from the open pour loading of a 

granular pesticide product. Each instance of exposure monitoring is termed a 

monitoring unit (MU). Each MU consists of a set of mixing/loading-application 

conditions (including the particular worker) that are intended to represent the scenario 

activities for a single workday. Therefore each MU is an experimental realization of 

a ‘handler-day’ from the scenario population of all possible handler-days. In many 

cases monitoring units will be selected from ‘naturally occurring’ MLA-days. 

However, the selected handling conditions are sometimes modified or scripted 

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

scenario population. It is important to emphasize that MU conditions are not 

necessarily associated with the particular active ingredient used. The key assumption 

underlying the AHETF monitoring program is that exposures are generic: they do not 

depend upon the chemical identity of any particular active ingredient although they 

may sometimes depend upon the way in which that active ingredient is handled. As a 

result, some MUs could be selected for conditions that are less typical for the active 

ingredient being monitored providing these conditions are expected for other active 

ingredients. For example, assume three AIs can be ground applied to field crops. 

One is a surrogate but not commonly used in this situation while the other two are 

widely used but not surrogates; however, because exposures are generic, the 

commonly used AI can be used to represent the other two AIs. Thus, MUs are 

technically not ‘sampled’ from an existing population as would be the case, say, with 

a statistical survey. More correctly, they should be viewed as synthetic handler-days 

derived from both selected and constructed conditions.” (pp. 17 -18 of 659)

(b) From what populations will subjects be recruited? 

“The first step in identifying potentially eligible employers is to determine if an 

employer is qualified to participate in the study. AHETF only considers employers 

whose identities were obtained from publically available sources (e.g., commercial 

databases, surveys) or who have given permission for their identity to be provided to 

AHETF. To be considered qualified, such employers must be likely to make 

granular pesticide applications within the monitoring area during the timeframe of 

this study (or have at least one worker likely to make these pesticide applications). 

(pp. 423-424 of 659) 
Attachment 2 

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(c) Are expected participants representative of the population of concern? If not, 

why not? 

Summary of Tasks in the MU selection and Construction Plan for Open Pout 

Loading of Granules Monitoring Units 

Task Basic Steps Involved 

Select Monitoring Areas Define the Scenario Target Area 

Select as monitoring areas for MUs seven sets of states 

and portion of states within the Target Area that 

balances both geographical diversity and the likelihood 

of granular pesticide use 

Select and Construct 

Monitoring Units 

Using multiple sources for each monitoring area, 

identify employers that are qualified to participate 

Screen qualified employers to identify those who are 

willing to participate in the study 

Select employers, recruit participants, and construct a 

configuration of three MUs in each monitoring area 

using similarity restrictions on AaiH strata, employers, 

workers, and other monitoring conditions to obtain 

diversity 

“Two primary sources of pre-qualified employers will be used: 1) Local agricultural 

specialists who identify qualified growers or commercial ground or aerial applicators 

and 2) qualified employers referred to the AHETF from other employers. Because 

these qualified employers will not have been obtained from publically available lists 

they must have also given permission for their name, address, and phone number to 

be released to AHETF. 

...The locally knowledgeable sources, referred to as primary sources, may include but 

are not limited to: 

 Contract research organizations 

 Crop consultants 

 Agricultural chemical marketing, sales, or technical services personnel 

 Technical and sales representatives from AHETF 

 Agricultural extension personnel 

These local specialists will be asked to contact employers that they believe perform 

manual open pour loading of granular products into application equipment.” (p. 414 

of 659) 

“Secondary source employers are growers obtained from large lists or databases from 

public, institutional, and commercial sources that are expected to contain some 

growers that might qualify for the study. However, only a small portion of such listed 

growers will actually use granular pesticides in the monitoring area. Consequently, 

such listed growers (or a random subset of them) must first undergo screening 
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interviews (described in 4.2.1-4.2.3. below) that will identify those qualified for this 

study...Note that secondary source employers are growers only. However, as noted 

in 4.1.2, a grower whose name is obtained from a secondary source might ultimately 

refer a qualified commercial applicator company. 

A list of growers will be created for each monitoring area listed in Section 3 and 

referred to as the Employer Universe List (UEL). If needed, employers on the EUL 

(or random subset of the EUL) will undergo various qualifying screenings and 

interviews (described in later sections) that will identify employers that use granular 

pesticides and are potentially eligible to provide monitoring units (MUs) in the 

monitoring area. 

The list consist of growers for certain crops in each monitoring area provided by 

sources such as Farm Market ID and Meister Media Worldwide. Only lists that have 

grower names and associated phone numbers will be purchased....A professional call 

center will attempt to contact each employer....” (pp. 424 – 426) 

(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: 

 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 (or 19 if monitoring occurs in 

Alabama or Nebraska) with a government-issued photo ID. If other more 

restrictive age of consent requirements are identified (for example other states 

or provinces with age of consent above 18 years) they will be enforced by 

AHETF. 

 Confirm they do not work for a pesticide company (that is, a manufacturer or 

pesticide registrant or a contractor of the AHETF 

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

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

SOP AHETF-11.C for health status determination) 

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

 Confirm they do normally wear personal protective equipment that is required 

by the label. If the worker indicates that they may wear additional PPE not 

required by the product label, and that additional PPE might impact the 
Attachment 2 

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objectives of the study, such as chemical-resistant clothing, then the Study 

Director should be notified to determine if the worker shall be included in the 

study. 

 Confirm they intend to follow label directions. The research staff shall not 

influence nor ask in a manner to influence the worker to wear less PPE than 

they normally wear. 

 Have a private meeting with a researcher to review and discuss the consent 

form 

 Understand English or Spanish (see SOP AHETF-11.I for 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.7; p. 

231-232 of 659) 

“For this study, the following inclusion criteria also apply: 

 

 Have experience within the past three years in manually opening bags 

containing a granular product and pouring the granules into application 

equipment that is similar to that used in the study.” (p. 61 of 659)

The inclusion/exclusion criteria are complete and appropriate.

(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 language in the consent form and by 

requiring employers to promise in writing not to influence their employee’s decisions. 

See p. 233 of 659 for the Employer Cooperation Statement. 

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

“For each eligible employer identified, AHETF will follow standard procedures (see 

SOP AHETF-11.B; pp. 228-233 of 659) to recruit potential participants for this study. 

Individual workers will be recruited during an initial interview with (or visit to) a 

potentially eligible employer once eligibility has been established. Alternatively, 

recruitment can occur on subsequent interviews with or visit(s) to an eligible 

employer. 

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

grower to approach his/her employees to recruit workers for the study. Depending on 
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the number of employees and size of the employer’s facility, the Study Director or 

researcher may contact employees using an informational recruitment flyer posted in 

a common work area. Such a flyer will briefly describe the research study and 

provide a toll-free phone number for employees to express an interest in participating 

in the study. The flyer shall have been previously reviewed and approved by an IRB. 

“Alternatively, or subsequent to the use of a flyer, the Study Director or researcher 

will arrange a meeting with the employer’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. 80 of 659) 

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

specific safeguards are proposed to protect their rights and welfare? 

“Written assurance will be obtained from the employer that the workers will not 

suffer any consequence if they decide either to participate or not to participate in the 

study and that there will be no coercion of the workers.” (p. 229 of 659) 

A copy of the “Employer Cooperation Statement” is provided on p. 233 of 659. 

“In accordance with SOP AHETF-11.B, 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. 

For ‘employers’ that are self-employed individuals, this non-coercion statement is not 

applicable and will not be used.” (pp. 80 of 659) 

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 5.2) No remuneration is offered for this introductory meeting. Workers who 

are still interested in participating in the study will attend a private meeting with a 

researcher who will obtain the informed consent of the worker (Section 2.7). Workers 
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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 if they put on the long underwear to participate in the 

study. The additional $80 is provided in cash at the end of the monitoring period or at 

the time the worker withdraws from the study. All workers who participate will receive 

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

team.” (p. 62 of 659) 

(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 ten pesticide active ingredients: carbaryl, 

chlorpyrifos, dithiopyr, ethalfluralin, imidacloprid, mefenoxam, pendimethalin, 

permethrin, tefluthrin, thiophanate-methyl. 

“The pesticide products that contain these active ingredients and potentially used in 

this study will be products registered for agricultural or non-crop use and the specific 

application planned by the employer.” (p. 65 of 659) 

For all ten of the possible active ingredients for this study, 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. 

 

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

The protocol and consent form currently list five kinds of risks: 

 The risk of heat-related illness 

 The risk associated with scripting of field activities 
Attachment 2 

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 Psychological risks 

 The risk of exposure to surfactants 

 The risk of exposure to surrogate chemicals 

“In this study risks to subjects are classified as ‘greater than minimal’ since 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. All of the risk 

minimization procedures described in the AHETF SOPs will be followed during the 

conduct of this study.” (p. 62 of 659) 

(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 10.C, 11.C, 11.E, 11.G 11.H, 

and 11.N): 

 Selecting only experienced pesticide handlers who consider themselves to be 

in good health 

 Requiring experience with opening and pouring granular products into the 

type of equipment to be used in the study 

 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 environmental conditions using either the heat index or WBGT 

index for purposes of minimizing the risk of heat illness 

 Providing transportation to medical treatment and covering the costs of 

treatment, if needed 

 Having a medical professional at each MU site to observe the worker, provide 

urgent care, and decide whether the subject is too sick to make a decision 

about refusing medical treatment 

 Observing study participants throughout the monitoring period, taking care to 

avoid photos or videos potentially identifying the subject

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

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

objectives (for example, chemical-resistant coveralls).” (p. 67 of 659) 
Attachment 2 

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

protocol (pp. 62-67 of 659). 

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

for the test materials? 

For all ten of the possible active ingredients for this study, 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. 

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

Detailed information about stopping rules related to environmental conditions and the 

risk of heat-related illness is provided in SOP 11.G.5 (p. 243-256 of 659) and SOP 

11.N.0 (pp. 284-317 of 659). 

“At the discretion of the Study Director, AHETF will employ one of two procedures 

to minimize the risk of heat illness. One procedure is to monitor environmental 

conditions at the loading area to determine the 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. If this occurs, the Study Director or other 

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

until monitoring can be resumed (see SOP AHETF 11.G). 

“A second heat stress management procedure may be used, especially if it is 

anticipated that the heat index cutoff might be reached or exceeded. This procedure 

involves the monitoring of environmental conditions and managing heat exposure by 

utilizing the metabolic heat value associated with loading granules in conjunction 

with the WBGT Index (wet-bulb, globe, and dry-bulb temperatures). When necessary, 

cycles of work and rest in the same environment will be implemented, or the worker 

will be placed in a cooler environment (see SOP AHETF 11.N) to assure that shortterm time-weighted heat exposures do not exceed the threshold limit values 

established by the American Conference of Governmental Industrial Hygienists 

(ACGIH). Note that the example metabolic heat value in the SOP may be revised 

based on the Study Director’s observation of the subject’s level of activity. 

“In addition to the procedures discussed above, it is possible that some monitoring 

will take place at night or early in the morning to avoid excessively hot and humid 

conditions. AHETF will encourage this if it is a common practice for the cooperator. 

(p. 63 of 659) 

(d) How does the protocol provide for medical management of potential illness or 

injury to subjects? 
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“As a safety measure, AHETF will have a medical professional on site during the 

study. This may be a certified first responder, paramedic, physician’s assistant, nurse, 

or emergency medical technician. This professional will also watch you for signs of 

illness. They will provide medical attention as needed.” (p. 102 of 659) 

SOP AHETF-11.H.4 (pp. 257-260 of 659) 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.4 (pp. 239-240 of 659) calls for researchers to monitor 

worker compliance with label and Worker Protection Standard requirements 

and labeling, and permits the Study Director to remove from the study a 

worker who engages in unsafe work practices. 

 SOP AHETF-11.G.5 (pp. 243-255 of 659) 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.4 (pp. 257-260 of 659) 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 a 

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

results from other workers performing the same task. Results are typically available 

9-12 months after all monitoring is completed. 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 volunteer’s participation in the study, a researcher 

will remind the volunteer he/she should bathe or shower as soon as practical and that 

they have received a copy of the signed consent form with phone numbers for 

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

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. 365 

of 659) 

(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 
Attachment 2 

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necessary, AHETF will arrange to have you taken to receive medical attention. You 

may refuse medical treatment unless the medical professional decides you are too sick to 

make a decision about getting medical treatment. 

AHETF will cover the cost of reasonable and appropriate medical attention for a 

study-related injury or illness that is not covered by your own insurance or insurance 

provided through your employer. This includes deductible costs and any out-ofpocket expenses, including co-payments, you might have. The Study Director, in 

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

or injury that is due to your participation in this study.” (p. 102-103 of 659) 

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. 68 of 659) 

(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 open pour loading of granules into various kinds of application 

equipment. 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. 

“Since there are insufficient existing data suitable for use in a generic database describing 

the exposure to workers who open pour granules into a variety of pesticide application 

equipment, society will likely benefit from data generated by this study through the 

improved risk assessments by EPA and other regulatory agencies.” (p. 68 of 659) 

“Employers (i.e. growers or commercial applicators, if applicable) who allow the study to 

be conducted using their equipment will be reimbursed for the pesticides used for the 

study. While this may be beneficial to the employer, it is considered a minor benefit 

when compared to the costs of running their businesses.” (p. 68 of 659)

 

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

Identified societal benefits are likely to be realized. 

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

benefits of the research, to subjects or to society? 

“By monitoring exposure to professional agricultural handlers who follow their normal 

practices, but wear an additional layer of clothing (as an inner dosimeter which traps 
Attachment 2 

Page 43 of 52 

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. 

“The likely benefit to pesticide handlers 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. The availability of pesticide products formulated as granules provides 

growers and other users additional options for meeting their individual needs. Therefore, 

exposure data for this study 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. 68 of 

659) 

7. Independent Ethics Review 

(a) What IRB reviewed the proposed research? 

Schulman Associates IRB 

(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? 

Schulman Associates IRB earned Full Accreditation from the Association for the 

Accreditation of Human Research Protection Programs, Inc. (AAHRPP) in June 2008. 

(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? 

“All AHETF field studies involving worker exposure monitoring are designed and 

conducted in accordance with scientific and ethical criteria set forth in the following 

ethical codes: 

 a. U.S. EPA 40 CFR Part 26, Subparts A through L 

b. The Belmont Report, Office of the Secretary, “Ethical Principles 

 and Guidelines for the Protection of Human Subjects of Research”, 

The National Commission for the Protection of Human Subjects of 

Biomedical and Behavioral Research, April 18, 1979 

(http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm). 

[Note: this document is not an official policy or a code of ethical 
Attachment 2 

Page 44 of 52 

conduct and is mentioned only as reference material.] 

“All protocols, informed consent forms, and any materials to be distributed to workers 

must undergo review and approval for ethical compliance by an IRB. The specific IRB 

used will be documented in the study file.” (p. 225 of 659) 

“The SD, the Principal Field Investigator (PFI), the Task Force Field Study Monitor, the 

worker observers, and other researchers working on behalf of the AHETF who interact 

with study participants, will have completed one or more training courses for protection 

of human subjects. Certificates of completion for the course(s) will be available prior to 

these individuals participating in the field phase study on behalf of the AHETF. 

Details on the courses that may be completed are described in SOP AHETF-1.B.” (p. 225 

of 659) 

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? 

The literacy rate of intended subjects is not addressed in the protocol. Procedures for 

accommodating English- or Spanish-speaking candidates of low or limited literacy are 

explained in SOP AHETF-11.I.3. (pp. 261-266 of 659) 

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

investigators and subjects? 

See SOP AHETF-11.I.3 (pp. 261-266 of 659) 

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

discomforts? 

“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 
Attachment 2 

Page 45 of 52 

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

(SOP AHETF-11.J.1 §3.10.a; p. 269 of 659) 

(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 conducting the consent meeting will inform the worker that he/she will 

receive $20 (or another amount specified in the protocol) for participation in the meeting, 

whether or not he/she volunteers 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 and AHETF-11.N, 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. 

“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 
Attachment 2 

Page 46 of 52 

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; pp. 268-9 

of 659) 

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

coercion or undue influence? 

“In accordance with SOP AHETF-11.B, employers 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. Employers 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. For ‘employers’ that are 

self-employed individuals, this non-coercion statement is not applicable and will not be 

used.” (p. 80 of 659) 

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. 68-9 of 659) 
Attachment 2 

Page 47 of 52 

“Your name will only appear on the consent form and an optional form for you to request 

your personal study results. 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 we collect while you take 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 guarantee 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 Schulman Associates IRB 

(SAIRB). SAIRB is a group of people who review and monitor research to help protect 

the people who take part in the research. An institutional review board (IRB) is an 

independent committee established to help protect the rights of research subjects. 

“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.” (p. 103 of 659) 

(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 wash and face/neck samples will only be 

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

samples will be analyzed (SOP AHETF-8.K).” (p. 69 of 659) 

“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. 104 of 659) 

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

dealt with? 
Attachment 2 

Page 48 of 52 

“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. 

“If you withdraw, the long underwear and air sampling pump will be removed. The hand 

wash and face/neck samples may be collected. 

“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. 104 of 659)
Attachment 3 

Page 49 of 52 

§ 26.1111 Criteria for IRB approval of research 

AHETF Protocol: Granular Open-Pour Loading (AHE170) 

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 50 of 52 

§26.1116 General requirements for informed consent 

AHETF Protocol: Granular Open-Pour Loading (AHE600) 

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 

(a) In seeking informed consent the following information 

shall be provided to each subject 

(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 

(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 

(b) When appropriate, one or 

more of the following elements 

of information shall also be 

provided to each subject 

(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 

(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 51 of 52 

§26.1117 Documentation of informed consent 

AHETF Protocol: Granular Open-Pour Loading (AHE170) 

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. 

OK 

SOP AHETF 11.I.3 
Attachment 6 

Page 52 of 52 

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

AHETF Protocol: Granular Open-Pour Loading (AHE170) 

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

All information relevant to the proposed research specified by § 26.1115(a) 

(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. 54-97 

None 

pp. 98-107 

None 

(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. 472 

No controverted issues 

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

(4) Copies of all correspondence between the IRB and the investigators. Y pp. 323-659 

(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 Provided to HSRB with 

background materials 

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) 

and §26.1108(b). 

Y Provided to HSRB with 

background materials 

(7) Statements of significant new findings provided to subjects, as required by 

§26.1116(b)(5). 

n/a 

The following Information, to the 

extent not already included: 

§1125(a) 

a discussion of: 

(1) The potential risks to human subjects Y pp. 62-67 

(2) The measures proposed to minimize risks to the human subjects; Y pp. 62-67 

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

and to whom they would accrue 

Y pp. 68 

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

be collected through the proposed research; and 

Y pp. 58 

(5) The balance of risks and benefits of the proposed research. Y p. 68 

§1125(b): All information for subjects and written informed consent agreements as 

originally provided to the IRB, and as approved by the IRB. 

Y Original pp. 338-347 

Approved pp. 98-107 

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

advertisements proposed to be used. 

Y pp. 62, 110, 111, 113, 130 

§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. 68-69 

§1125(e): All correspondence between the IRB and the investigators or sponsors. Y pp. 323-659 

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

human subjects has been reviewed and approved by an IRB. 

Y pp. 52, 53, 109, 112, 114, 116, 

129