Page 1 of 52 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 duri ng 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Collier, R. (2014) Determination of Derm al and Inhalation Exposure to Workers during Open Pour Loading of Granules , unpublished protocol dated July 25, 2014, prepared for the Agricultural Handler Exposure Task Force under Sponsor ID AHE170, 659 p.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 Hu man 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.Page 2 of 52 Science Review

 The protocol addresses the technical aspects of applicable exposure monitoring guidelines and is likely to produce scientif ically valid and useful data.

 EPA has no recommendations for revisions.

Ethics Review

 The protocol meets the applicable ethical re quirements 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 Design 1

1. Scenario Design: Protocol AHE170 is designed to a ddress the dermal and inhalation exposure of handlers performing open pour load ing of conventional granule formulations of pesticides from non-bulk containers in to a variety of agri cultural application equipment (e.g., planting equipment). C onventional granules are defined for this

scenario as those uti lizing generally greater than 90 percent of iner t carriers (e.g., corn cobs, clay, limestone, and sand) and can pa ss through a 4 mesh siev e but not through an

80 mesh sieve. Mesh refers to the nu mber of wires per in ch. These granular formulations are applied dry and are not mixed with water. They are considered conventional formulations that is they ar e not engineered to reduce dustiness by using polymers and/or Biodact ® . Engineered, reduced dust, granular formulations would be considered a potential mitigation risk assessm ent 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 app lication equipment such as planters or broadcast spreaders (by aircra ft or ground equipment). Othe r containers that may be similar to bags may be used provided they ar e easy to handle by the participant. Large

bulk container will not be used. Other activi ties such as stacking bags and associated loading and unloading bags may also be perf ormed 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.Page 3 of 52 The handler attire for this scenario is a “s ingle layer” consisting of long-sleeved shirt, long pants, shoes plus socks (unless otherw ise specified on the la bel or what would normally be worn by the participant). The mi nimum amount of PPE worn by participants will be chemical resistant gloves. Hats (including baseball type), eyewear (glasses, sunglasses, safety glasses or goggles) are perm itted 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 w ear long sleeved and long legged underwear beneath the single layer. Th is serves as dosimeter to collect the “to the skin measurements” for the respectiv e 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 sing le layer are considered the same as a double layer, therefore this study design can accomm odate 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 Governi ng Document, the estimated number of monitoring units (MUs) required shall be base d on a geometric standard deviation (GSD)

of 4 and an intra-cluster correlation of 0.3. The governing document also outlines the various potential combinati ons of number of study locat ions and corresponding number of participants to meet th e primary objective of the study. For this study, the AHETF has selected a seven by three study design (clust er by MUs, respectivel y) 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 monito ring 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 S ugar Beets, Dry Beans and Dry Peas, Corn, Sweet Corn, Sunflowers Idaho, Eastern Washington, Eastern On ion, Sweet Corn, Dry Beans and DryPage 4 of 52 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 regi ons of the country and two, to configure diverse monitoring units within the monitoring area. Seven new clusters (monitoring areas) each having 3 mon itoring units (MUs) have been proposed for this scenario representing a wide variety of geographical and clim actic conditions where granule formulations of pestic ides are applied. Although tw o monitoring areas represent contiguous major corn growing states (IN/ OH and IA/IL), the AHETF decided the area would be too large to be repr esented by only 3 MU. EPA agr ees with this decision. The monitoring areas were selected by consider ing the high acre growing areas where the AHETFs suite of surrogate granular formul ations 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 2/3 rd of the state/warm and humid summers and mild winters. In the northern 1⁄2, peanuts is the major crop. In the southern 1/3 rd 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 wintersPage 5 of 52 EPA agrees that these monitoring areas are likel y to provide a wide range of climates and high acre crops where the use of granular formul ations of pesticides is likely. In addition, they are areas with a high likelihood of iden tifying participants and sites meeting the AHETFs similarity restrictions . Noticeably absent from the proposed study locations are potential monitoring areas in the southweste rn 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 ne xt stage of the divers ity 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 thre e-fold difference and the middle an order of magnitude. As discussed at the Octobe r 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 dete rmine 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 20 0 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 sele ction results in identifying th e growers whose crops will be

treated and the handlers whos e exposure will be monitore d. As with other AHETF studies, growers agreeing to cooperate with th e 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 handl er participants recruited fr om farming operations using granular formulations include s 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 Sp ecials (LAS) such as county extension agents and employer refe rrals to the AHETF

 Secondary Sources: Growers and farm operato rs identified in publically available sources obtained via profe ssional call center personnel

Once a sufficient number of grow ers are identified, the AHETF:

 Put the list of growers into random orderPage 6 of 52  Contact a random subsample fr om the list, one at a time, in the sequence of the randomized list, to determine whether the grower is ‘eligibl e’ to participate

 Placing eligible employers into a “working pool”

Screening of employers for eligibility will co ntinue 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 worki ng pool, the following range of information will be compiled:

 The employer is willing to cooperate with the AHETF

 The employer will perform or has empl oyees 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 su ch that the minimum AaiH can be

mixed/loaded and treated

 The employer can fill a desired AaiH stratu m and is willing to use at least one of the surrogates

EPA believes this process of identif ying cooperating growers is acceptable.

When selecting MUs, the AHETF have devel oped 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 monito ring 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 eligib le entities. If there are too few handlers available in the pool to comp lete a revised efficient conf iguration, the working pool can be expanded by approaching more growers from the original randomized list. If the original randomized list is exhausted w ithout finding enough inte rested handlers to complete the field study design, another list will be generated. A lternatively, the AHETF may consider monitoring as soon as there is an eligible participan t 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 in secticides 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 appli cation rates to help obtain three AaiH strata needed for each monitoring area.Page 7 of 52 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 Scientif ic Aspects of the Study Design 2

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 th ree 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 th en 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 N C new monitoring areas and N M new MUs per area. The total number of new MUs in a scenario is, therefore, N= N C ×N M

.

• There may be correlation between the (logarithm of) normali zed 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 derive d a default relative variation structure consisting of a geometric standard deviation (GSD) of 4 and an in tra-cluster correlation (ICC) of 0.3.

The Number and Configuration of New MUs:

2 Supporting details are in Attachment 2.Page 8 of 52 According to the AHETF it is less costly to k eep the number of monitoring areas as small as possible and have a large number of MUs pe r 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 configur ation size is restricted to N M =3 for all new MUs.

Appendix C of the Governing Document desc ribes the simulation methodology needed to calculate sample sizes when the referen ce 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

95 th percentile of normalized dermal exposure ge nerally need to be accurate to within approximately 3-fold of their actual p opulation 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 th e particular values of AaiH used.” For this scenario the practical AaiH range (5 to 400 lb ai/d ay) 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 th e upper and lower bound having roughly equal widths on a log scale (for AaiH). Base d on the AHETF’s simulations for a 10 by 3 cluster/MU configuration, assuming proportiona lity 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 object ive of having enough power to be able to distinguish between independence and propor tionality of exposure to AaiH. By incorporating this component of AaiH into AHETFs study designs, AHETF is acknowledging EPA’s (and other regulatory ag encies) 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 divers ity selection of MUs.

2. Proposed pattern of exposure: The proposed minimum exposur e duration for each MU was described as being half a work day or 4 hours in duratio n 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.Page 9 of 52 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 ingr edients 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 deve lopment of unit exposures (exposure per unit of pesticide active i ngredient applied) or other e xposure 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 clothi ng. After the monitoring event, the inner dosimeter will be removed from the subject a nd 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 s ource 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, befo re 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 a nd neck will be wiped with a cotton gauze swab to remove any contamination not associat ed 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 expos ure period; all samples will be retained for analysis. As required by AHETF SOP 10.C.4, th e study team will reco rd what type of personal protective equipment (PPE), including respirators, was worn at any time during the monitoring event.

Airborne concentrations of th e surrogate will be monitore d 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 minut e. 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 c lipped 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 selectivel y to illustrate events while ensuring privacyPage 10 of 52 of the subject. EPA believes that the proposed measures are appropr iate 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 st udy 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 c onditions 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 fiel d study and in the scenario m onograph covering all monitoring conducted under AHE170, and will be posted to the AHED ® database, where they will be available to regulatory agenci es. The documentation will report a confidence-intervalbased approach to determine the relativ e accuracy for the arithmetic mean and 95 th
percentile of unit exposures. The AHETF w ill not otherwise statis tically analyze the monitoring data.

D. Compliance with Applicable Scientific Standards

EPA agrees that the AHETF should collect MU s for this scenario based on participants open pour loading of granules in to varying types of applicatio n equipment. The protocol adequately addresses the followi ng elements according to applicab le scientific standards:

 Scientific objective

 Experimental design for achieving objectives

 Quantification of the test materials

 Data collection, compilation a nd summary of test results

 Justification for selection of test substances

 Justification for sample size

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

Additionally, the proposal has ad dressed the technical aspects provided in the applicable exposure monitoring guidelines (i.e. Se ries 875 Group A and OECD Applicator Guidelines) as well as Good Laboratory Practices (GLPs).Page 11 of 52 E. Summary Assessment of Ethical As pects of the Proposed Research 3

1. Societal Value of Proposed Research: The objective of this st udy is to develop data to determine the potential exposure of workers who manually open containers of granular products and open pour the granules into su itable application equipment using their normal practices. This loading method is appl icable to a large va riety of commercially important crops and the existing exposure data are inadequate. EPA will use the results of this study to estimate the dermal and inhala tion exposure likely for a wide range of agricultural pesticides loaded under this exposure scenario.

2. Subject Selection: Subjects will be recruited am ong the employees of commercial growers who are likely to perform open pour loading of granular pesticide products within the monitoring area during the timefra me of the. Eligible growers will be identified from a complete list of grower s 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 applicatio n 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 th e 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 acco rding to the standard procedures set forth in SOP AHETF11.B.7. (p. 228-233 of 659) The Study Director or designated rese archer will seek permission from an eligible employer to appr oach his/her employees to recruit workers for the study. Depending on the number of empl oyees and size of the grower’s facility, the Study Director or researcher may c ontact employees using an informational recruitment flyer posted in a common work ar ea. Alternatively, or s ubsequent to the use of a flyer, the Study Director or researcher will arrange a meeting with the employer’s employees who express interest in participa tion. Such recruitment meetings will always occur without supervisors being present. The Study Director or researcher will describe the AHETF Exposure Monitoring Program, th e goals of the research study, the procedures used in exposure monitoring, a nd the risks and benefits to subjects. The subject eligibility factors listed in th e consent form and SOP AHETF-11.B.6 are appropriate.

Candidates who attend an individu al interview will be paid $2 0 whether or not they agree to participate; enrolle d subjects who put on the whole-body do simeter 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 ordi nary daily life. In particular, the risk of heat -related illness (resulting from wearing an extra layer of clothing to trap chemical) will be increas ed due to study participation. AHETF has adopted an extensive program to minimize thes e 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 assessme nts 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 li kely benefits to society from new data supporting more accurate handler e xposure 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 i nvestigators and SAIRB.

7. Informed Consent: Informed consent will be obtained from each prospective subject and appropriately documented. Adequate provisi on is made to meet the needs of subjects who do not read either English or Spanis h. 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 a nd 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 resear ch involving intentio nal exposure of human subjects to a pesticide, with the intention of submitting the resulting data to EPA under thePage 13 of 52 pesticide laws. Thus the primar y 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 amende d effective August 22, 2006, provides in pertinent part:

EPA shall not rely on data from any rese arch involving intent ional exposure of any human subject who is a pregnant wo man (and therefore her fetus), a nursing woman, or a child.

The protocol requires that subj ects 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 re search 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 Sele ction 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 ResearchAttachment 1

Page 14 of 52 EPA Scenario Review: AHE170

Title: Determination of Dermal and Inhala tion 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 formul ated 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 pro ducts to include those products composed of a high percentage (generally greater than 90%) of granular inert carrie r(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., stat es 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, Sout h 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 s od. 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 expe cted to yield MUs in this state include sweet corn, citrus and sod, concentrated in the lower half of the stat e, and peanuts in the northern

half of the state.

4. Indiana and Ohio Corn is the crop most likely to utilize gra nular products. These two Midwestern states, situated in EPA Region 5 are major corn produc ers, 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 Mi dwest 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 ar ea representing portions of EPA Regions 5 and 7.

7. Idaho, Eastern Washington and Eastern Oregon Crops expected to yield MUs for this monito ring 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 a nd appropriately defined.

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

“ AHETF has identified the Open Pour Loadi ng 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 b ecause 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 loadin g methods described by this scenario .” (p. 15 of 659)

“AHETF in conjunction with the JRC, revi ewed handler exposure measurement in existing studies (mostly not included in PHED ) to identify those that satisfy current acceptability criteria and qualify for inclusi on in a generic database. For this OPLG scenario, one study involving ‘open pout only’ of granular products potentially ap plicable 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 fo r a generic database (AHETF, 2003), however, because it involved a polymer-coated engi neered 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 potenti ally 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 PH ED MUs corresponding to a single layer of clothing with chemical-resistant gloves. The review found that there were two potentially useful studies in that scenari o. PHED studies 1004 and 1011. Those studies were summarized and then reviewed by the AH ETF 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 re peated 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 pres umed to be in high-acre growing areas of main crops listed on re presentative granular product labels of the surrogate AIs. Such crops include corn, pe anuts, 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 porti on of the U.S. is likely to pr ovide an adequate number of MUs, but would encompass very little geogra phic 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 se lection 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 acr oss 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 pestic ides is anticipated.

If these four states were combined into a single monitoring area , it would not only be large but the entire area woul d be underrepresented with ju st 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-methylAttachment 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. Finall y, 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 stabil ity under field study conditions .” (p. 38 of 659)

Selection of a Geographically Di verse 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, So uth Carolina, Georgia, and Alabama

These five southeastern states are situat ed 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, concentrat ed 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 ut ilize granular products. These two Midwestern states, situated in EPA Re gion 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 monitori ng area because of their expected high granule use.

6. Minnesota, North Da kota and South Dakota

Crops expected to yield MUs for this upper Midwest monitoring area are dry beans and peas, sugar beets, sweet cor n, 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 Washing ton, and Eastern OregonAttachment 1

Page 18 of 52 Crops expected to yield MUs for this m onitoring area are sweet corn, onions, sugar beets, and dry beans and peas. Th e 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 pestic ides is anticipated.

If these four states were combined into a single monitoring area , it would not only be large but the entire area woul d be underrepresented with ju st three MUs instead of the planned six.

Acreages of the crops men tioned 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, an y crop may be associated with an MU as long as it is labeled for the granular surroga te 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 concen trated in the Target Area. For this scenario, the best opportunities for MUs are pres umed to be in high acre growing areas of main crops listed on representative granular pr oduct labels of the surrogate AIs. Such crops include corn, peanuts, citrus, sugar be ets, 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 provi de 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 porti on of the U.S.) would be quite impractical since they would be un likely 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 incorpor ated into the scenar io sampling design?

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

“ Not all qualified employers wi ll be eligible or willing to participate in the study. AHETF must obtain employer coop eration before it can recru it workers. This includesAttachment 1

Page 19 of 52 willingness of the grower to volunteer his f acility and applicati on equipment and allow

AHETF to recruit his workers.

For this reason, qualified employers are contacted to verify their qua lified status and to determine if they are also w illing 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 el igible’ 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 influenc ing their participation.” (pp. 32 - 33 of 659)

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

have been overlooked?

If more handlers and growers ar e in the recrui ting 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 gene ral involves a worker that opens the granular product container and manually empties the contents into the application equipment; however, associated activities can vary. For exampl e, loading could take place near a product storage area where the worker might work o ff 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 tr ansferring containers from st orage onto a vehicle and then driving to the application site. In all cas es, 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 surr ogate AIs will be pack aged in paper bags containing up to 50 pounds of formulated pr oduct. After the cont ainers have been emptied, the worker may begin the disposal process in his/her usual manner. This might include loading onto a truck orstacking and storing in a sh ed 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 cl eanout will only involve the ap plication equipment loaded by the participants after the a pplications 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 th ey 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 fi lters. 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 stab ility under field study conditions. ” (p. 36 of 659)

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

“Appendix C of the Governing Document desc ribes the simulation methodology to calculate sample sizes when the reference model us ed is cluster sampling from a lognormal

distribution. These simulations determine e ither accuracy or power given the number and configuration of MUs. The num ber and structure of the propos ed MUs should be adequate to satisfy the following benchmark objec tives discussed in Section 4.4:

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

the 95 th percentile of normalized dermal exposur e generally need to be accurate to within 3-fold of their actual populati on value assuming the reference random sampling model applies.

2. Secondary Objective : There should be at leas t 80% statisti cal 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 exposur e from a number of available monitoring studies, Appendix C of the AHETF Governi ng 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 determ ined using these default values.Attachment 1

Page 21 of 52 The greater the differences between MUs in th e same monitoring area, the closer the ICC

should be to zero. Mixer/lo ader-applicators located in th e same area, but working for different, widely dispersed nursery or gree nhouse operations, are unlikely to show strong within-cluster correlations in exposure. However, although near zero within-cluster correlation is always the goal of diversity se lection, 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 Regulator y 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 Gove rning 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 (N C ) and number of MUs per monitoring area (N M ) that will meet the 3-fold rela tive accuracy requirement. These equivalent configurations are listed in Table 2.

Table 2: Equivalent configurations of Nu mber of Monitoring Areas and Number of MUs per Monitoring Area Number of Monitoring

Areas N C Number of MUs per Monitoring Area N M 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 st atistically equivalent, they can differ substantially in the cost or in the attainabil ity. When the five conf igurations in Table 2 are equally feasible, the choice among them us ually depends upon the expected ratio of the overhead (or ‘fixed’) cost of obtaining and characterizi ng 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 rati o, a sample of five monitoring areas (N C =5) is usually the most cost effective design c onfiguration 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 pe r additional monitoring

area.Attachment 1

Page 22 of 52 For this scenario, AHETF cannot predict the ma gnitude of use of gr anular 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 co mmon carrier such as clay, or the employer prefers to handle them via closed loading sy stems rather than open pouring. Therefore, although it is more costly. AHETF believes th at a 7-area design configuration with three MUs per monitoring area will be more su ccessful 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 examin ation of the relationship between the normalizing factor (e.g., AaiH) and exposure. This is true provide d: (1) the practical range of the normalizing factor is at least an order of magnit ude and (2) there is adequate within-monitoring-area variati on 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 proportiona lity 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 Inhala tion 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 da ta to characterize the potential exposure of workers who manually open containers of gran ular products and open pour the granules into suitable application equipment using th eir normal practices. Product containers will include any type, size and wei ght that can be lifted or car ried by the worker; however, it is expected that granular products of the se lected surrogate active ingredients (AIs) will most likely be packaged in paper bags contai ning up to 50 pounds of formulated product. Additional loading details about this load ing activity are provided in Section 6.6.

“Exposure monitoring will be conducted in se ven 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 importan t 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 form ulated as granulars.

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

“AHETF in conjunction with the JRC, revi ewed handler exposure measurement in existing studies (mostly not included in PHED ) to identify those that satisfy current acceptability criteria and qualify for inclusi on in a generic database. For this OPLG scenario, one study involving ‘open pout only’ of granular products potentially ap plicable 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 fo r a generic database (AHETF, 2003), however, because it involved a polymer-coated engi neered 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 potenti ally 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 PH ED MUs corresponding to a single layer of clothing with chemical-resistant gloves. The review found that there were two potentially useful studies in that scenari o. PHED studies 1004 and 1011. Those studies were summarized and then reviewed by the AH ETF 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 re peated 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 mon itoring handlers as they mix/load pesticides for measuring their potential dermal and inhalation exposure.

2. Study DesignAttachment 2

Page 25 of 52 (a) What is the scientific objective of the st udy? If there is an explicit hypothesis, what

is it?

“The goal of conducting MUs for th is scenario is to develop a set of generic dermal and inhalation exposure data which regulators and other potential us ers of the generic

database can utilize to char acterize the magnitude and likel y 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 ‘a nalysis’ of these data. Rather, the data collected for this scenario will only be statis tically evaluated with respect to specific ‘benchmark’ measures of adequacy. As disc ussed in the Governing Document, the two categories of benchmark data adequacy considered are:

1. The relative accuracy of select ed statistics characterizing the distribution of exposure normalized by amount of active ingredient handled (AaiH).

2. How well the data can be expected to desc ribe a relationship between exposure and AaiH, if one existed.” (p. 38 of 659)

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

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

It is likely that the objective can be achiev ed 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 exposur e from a number of available monitoring studies, Appendix C of the AHETF Governi ng 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 determ ined using these default values.

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

should be to zero. Mixer/lo ader-applicators located in th e same area, but working for different, widely dispersed nursery or gree nhouse operations, are unlikely to show strong within-cluster correlations in exposure. However, although near zero within-cluster correlation is always the goal of diversity se lection, 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 Regulator y Committee agreed there is no additional evidence to suggest otherwise and no other strong opinion to the contrary the defaultAttachment 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 Gove rning 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 (N C ) and number of MUs per monitoring area (N M ) that will meet the 3-fold rela tive accuracy requirement. These equivalent configurations are listed in Table 2.

Table 2: Equivalent configurations of Nu mber of Monitoring Areas and Number of MUs per Monitoring Area Number of Monitoring

Areas N C Number of MUs per Monitoring Area N M 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 st atistically equivalent, they can differ substantially in the cost or in the attainabil ity. When the five conf igurations in Table 2 are equally feasible, the choice among them us ually depends upon the expected ratio of the overhead (or ‘fixed’) cost of obtaining and characterizi ng 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 rati o, a sample of five monitoring areas (N C =5) is usually the most cost effective design c onfiguration 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 pe r additional monitoring

area.

For this scenario, AHETF cannot predict the ma gnitude of use of gr anular 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 co mmon carrier such as clay, or the employer prefers to handle them via closed loading sy stems rather than open pouring. Therefore, although it is more costly. AHETF believes th at a 7-area design configuration with three MUs per monitoring area will be more su ccessful 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 examin ation of the relationship between the normalizing factor (e.g., AaiH) and exposure. This is true provide d: (1) the practical range of the normalizing factor is at least an order of magnit ude and (2) there is adequate within-monitoring-area variati on 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 proportiona lity 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 propos ed. 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 t reatment 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 enti re log AaiH range when log exposure is regressed against log AaiH.

In addition to the similarity restrictio n on AaiH (i.e., SR1 above), diversity among MUs is also enhanced by imposing the follo wing 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 rep resentative 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. Ra ther it is designed to generate surrogate data that is generalizable for use in all Agency risk assessments involving the loading of granular formula tions of pesticides.

(f) Can the data be statistically analyzed?

As has always been the case, any statistica l 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 statis tical 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 stat istics characterizing the distribution of exposure normalized by amount of ac tive ingredient handled (AaiH).

2. How well the data can be expected to describe a relationship between exposure and AaiH, if one existed.

The primary benchmark objective is that selected lognormal-based estimates of normalized dermal exposure distribution be accu rate to within 3-fold, at least 95% of the time. The benchmark estimates speci fied are those for the geometric mean, arithmetic mean, and the 95 th percentile.

To evaluate how well the collected data conform to this benchmark, the 95 percent bound on relative accuracy will be calculated fr om the confidence interval for each of the three parameters given above.

This secondary benchmark objective Adequ acy of the Data for Distinguishing a Proportional from an Independent Relations hip between Exposure and AaiH applies to the open pour loading of granular form ulations 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 ra ndom cluster effects.

(h) Are proposed statistical methods appr opriate 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 th is study, and that these exposures can inform assessments of the likely exposures for individuals in similar future situations.

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

As described in the Governing Document, in such a model the true slope, β , would be equal to one if dermal exposure were direc tly 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 symmetr y, 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 ‘dis criminate between proportionality and independence.

(j) Does the investigator propose to conduct the research in accordance with recognized good research practices, includi ng, when appropriate, good clinical practice guidelines and monitori ng for the safety of subjects?

This study is proposed to be conducted in accordance with recognized good research practices. This is not a clin ical study and therefore good c linical practice guidelines are not applicable.

2.2 How and to what will human subjects be exposed?

AHETF will monitor worker exposure re sulting from the open pour loading of granular formulations into va rious application equipment. Th e following active ingredients

will be considered for use in this scenario.

 Carbaryl

 Chlorpyrifos

 Dithiopyr

 Ethalfluralin

 Imidacloprid

 Mefenoxam

 Pendimethalin

 PermethrinAttachment 2

Page 30 of 52  Tefluthrin

 Thiophanate-methyl

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

“The AHETF has developed several pesticide active ingredient compounds for use as surrogates...Since the AHETF is developing a generic database that will be applicable to nearly all pesticide products and uses, any of the AHETF surrogates can be used for generating exposure data for th is scenario. The choice of surrogate at each location will depend largely upon the pref erence of the grower and pest pressure on his crop at that time.” (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 rela tionship 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 induc es diversification of such associated factors as well. Therefore, in addition to having a wide range, the MUs within the same monitoring area shou ld not have similar AaiH levels.

A practical AaiH range is firs t defined for the entire scenario. It encompasses AaiH levels that can be readily found in practi ce and are expected to produce detectable exposure results. This practical range is th en 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 restric tion imposes AaiH diversity on the MUs and ensures a wide range of AaiH leve ls within each monitoring area.

AHETF has developed a practical range in Aa iH 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, et c. 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 pe r day is selected to avoi d an inordinate number of non-quantifiable residues on worker exposure ma trices and to allow for at least four hours of work performing loading activities .”

“...within-monitoring-area diversificati on of the AaiH will be accomplished by partitioning this practical AaiH range in to 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 DurationAttachment 2

Page 31 of 52 Monitoring duration will be largely driven by the amount of AaiH. However, AHETF strives to monitor workers that represen t a full workday with a desired minimum monitoring duration of half the workday or f our 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 performe d 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 wi ll contain exposure data generated from work periods that represent a full day and from repeated application cycles that increase the opportunity for exposure (and th erefore will not underestimate exposure potential). However, performing three lo ad/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 invol ving the low AaiH stratum, th e desired AI may be reached before three load/apply cycles are performe d. However, scripting (such as reducing

the load size to increase the number of load s) will be done if needed and practical under the application conditions for the par ticular 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 e xposure 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: i nhalation 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 w ill 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 equipmen t 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)Attachment 2

Page 32 of 52 (b) What steps are proposed to ensure measurements are accurate and reliable?

“Full details regarding fiel d recovery evaluation proce dures for all sampling media are given in the most recent version of SOP AHETF-8.E. The SOP instructions for the “by vial and ampoule” spiking using active ingredient (ai) in an organic solvent will be followed for all matrices except OVS t ubes. The OVS tubes will be spiked at the laboratory with the proper amount of an alytical standard using an appropriate solvent.” (p. 439 of 659)

(c) What QA methods are proposed?

“AHETF intends that all regulatory studies are conducted in a ccordance with the FIFRA GLP Standards (40 CFR part 160). Fi eld and analytical aspects of this study will be monitored by the relevant quality a ssurance units(s) (QAU) while this study is in progress to ensure compliance with th e FIFRA GLP regulation and adherence to this protocol and relevant SOPs. Th e QAU(s) will submit copies of its/their inspection reports to the Study Director a nd AHETF Sponsor Representative (40 CFR part 160.35[4]). Field portions of th e Study Report will be audited by the QAU specified in Section 1.15 to en sure that the conten ts of the report accurately describe the conduct and findings of the study.

The Study Report will contain a Quality Assu rance 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 st orage conditions in or on the sampling materials (inner dosimeters, hand wash solutions, face/neck wipes, and air sampli ng matrices) will be conducted on a minimum of one day of exposure monitoring at each monitoring area, or more days as appropriate for environm ental conditions. If more than one active ingredient is utilize in a particular m onitoring 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 fortifica tion samples (i.e., some are weathered). Packaging, storage and shipment of the field fortification samples will be the same as for the worker exposure samples.” All fi eld 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 ad justed based on the recovery from the fortification sample. For example, a fiel d measurement for an inner dosimeter of 300Attachment 2

Page 33 of 52 ug would be adjusted based on the applicab le fortification sample for the inner dosimeter matrix. If the recovery fr om that matrix was 80%, the reported measurement for that sample would be 300 ug/80% = 375 ug.

3. Subject Selection

3.1 Representativeness of Sample

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

“ AHETF will monitor worker exposure resu lting 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 partic ular worker) that are intende d to represent the scenario activities for a single workday. Therefore each MU is an experime ntal realization of a ‘handler-day’ from the scenario populat ion 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 di versity in the entire scenario population. It is important to emphasize that MU conditions are not necessarily associated with the particular active ingredie nt used. The key assumption underlying the AHETF monitoring program is th at exposures are generic: they do not depend upon the chemical identity of any pa rticular active ingred ient although they may sometimes depend upon the way in which th at active ingredient is handled. As a result, some MUs could be selected for condi tions that are less typical for the active ingredient being monitored providing thes e 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 repres ent 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 co rrectly, 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 pub lically available sources (e.g., commercial databases, surveys) or who have given perm ission for their identity to be provided to AHETF. To be considered qualified, su ch 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 likel y to make these pesticide applications). (pp. 423-424 of 659)Attachment 2

Page 34 of 52 (c) Are expected participants representativ e 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 fo r MUs seven sets of states and portion of states with in 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 ar e qualified to participate Screen qualified employers to identify those who are willing to participate in the study Select employers, recruit pa rticipants, and construct a configuration of three MU s in each monitoring area using similarity restrictions on AaiH strata, employers, workers, and other monito ring 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, referre d to as primary sources, may include but

are not limited to:

 Contract research organizations

 Crop consultants

 Agricultural chemical marketing, sale s, or technical services personnel

 Technical and sales repres entatives from AHETF

 Agricultural extension personnel

These local specialists will be asked to c ontact employers that they believe perform manual open pour loading of granular produc ts into application equipment.” (p. 414 of 659)

“Secondary source employers are growers obtai ned from large lists or databases from public, institutional, and commercial sources that are expected to contain some growers that might qualify for the study. Ho wever, 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 screeningAttachment 2

Page 35 of 52 interviews (described in 4.2.1-4.2.3. below) th at 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 cr ops in each monitoring area provided by

sources such as Farm Market ID and Meiste r 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 criteri a? 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 pr actices in accordance with the Worker Protection Standard (WPS) or equivalent Canadian regulations, or be exempt from such training

 Provide proof of being at least 18 year s old (or 19 if monitoring occurs in Alabama or Nebraska) with a governme nt-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 pesticid e 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 theAttachment 2

Page 36 of 52 objectives of the study, such as chemi cal-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 dire ctions. 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 research er to review and discuss the consent

form

 Understand English or Spanish (see SO P AHETF-11.I for detailed discussion of this topic)

 Understand and sign the consent form, a nd if in California, the California Experimental Research Subject’s Bi ll of Rights” (SOP AHETF-11.B.7; p. 231-232 of 659)

“For this study, the following incl usion criteria also apply:

 Have experience within the past th ree years in manually opening bags containing a granular product and pour ing 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 be tween the investigator and the subjects?

None

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

Potential subjects are of necessity agricu ltural workers, and could potentially be subjected to undue influence either to participate or not to participate by their employers. This possibility is minimized thr ough 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 recru iting and informing potential subjects?

“For each eligible employer identified, AH ETF will follow standard procedures (see SOP AHETF-11.B; pp. 228-233 of 659) to recruit pot ential participants for this study. Individual workers will be recruited during an initial interview with (or visit to) a potentially eligible employer once eligibil ity has been established. Alternatively,

recruitment can occur on subs equent interviews with or visit(s) to an eligible employer.

The Study Director or designate d researcher will seek pe rmission from the eligible grower to approach his/her employees to recruit workers for the study. Depending onAttachment 2

Page 37 of 52 the number of employees and size of the em ployer’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 br iefly describe the research study and provide a toll-free phone number for employees to express an interest in participating in the study. The flyer shall have been prev iously reviewed and approved by an IRB.

“Alternatively, or subsequent to the use of a flyer, the Study Director or researcher will arrange a meeting with the 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 th ey desire additional information about the study or are interested in part icipating in the study. All presentation materials, such as handouts or visual aids, sha ll be reviewed and approved by an IRB prior to use in recruiting subjects.” (pp. 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 Stat ement” is provided on p. 233 of 659.

“In accordance with SOP AHETF-11.B, grower s 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 altern ate work will be provided on study days for workers who c hoose 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 indi viduals, 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 o ffered 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 part icipating in the study will at tend a private meeting with a

researcher who will obtain the informed cons ent of the worker (Section 2.7). WorkersAttachment 2

Page 38 of 52 will be paid $20 for their attendance right after the consent meeting, whether or not they decide to participate in the study. Wo rkers who decide to participate in the study will be paid an additional $80 if they put on the long underw ear 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 st udy. All workers who part icipate will receive the payment, even if they withdraw or th eir 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 afte r their participation.

4. Risks to Subjects

4.1 Risk Characterization –

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

about the hazards of the test materials?

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

This study could involve any of ten pe sticide active ingredients: carbaryl, chlorpyrifos, dithiopyr, ethalflurali n, imidacloprid, mefenoxam, pendimethalin, permethrin, tefluthri n, thiophanate-methyl.

“The pesticide products that contain these active ingredients and potentially used in this study will be products registered for ag ricultural or non-crop use and the specific application planned by the employer.” (p. 65 of 659)

For all ten of the possible active ingredie nts 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 c oncern (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 curre ntly list five kinds of risks:

 The risk of heat-related illness

 The risk associated with scripting of field activitiesAttachment 2

Page 39 of 52  Psychological risks

 The risk of exposure to surfactants

 The risk of exposure to surrogate chemicals

“In this study risks to subjects are classifi ed as ‘greater than minimal’ since the likelihood of harm or discomfort is greater th an what is encountered in ordinary daily life. In particular, the risk of heat-rela ted 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 asso ciated with the research? How was this probability estimated?

Quantitative probabilities are not estimated.

4.2 Risk Minimization

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

“The following practices, desi gned to minimize these risk s and respond to injuries, will be followed during this study (see AHETF SOPS 10.C, 11.C, 11.E, 11.G 11.H, and 11.N):

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

 Requiring experience with opening and pour ing 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 usi ng either the heat index or WBGT index for purposes of minimizing the risk of heat illness

 Providing transportation to medical tr eatment 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 subj ect 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 potent ially 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-re sistant coveralls). ” (p. 67 of 659)Attachment 2

Page 40 of 52 Risk reduction actions specific to the identi fied 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 ingredie nts 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 c oncern (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 re lated to environmental conditions and the

risk of heat-related illn ess 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. On e procedure is to monitor environmental conditions at the loading area to determin e the heat index. Exposure monitoring will

be discontinued if the heat index cutoff of 105 o F (adjusted for direct sun, if applicable) is reached or exceeded. If this occurs, th e 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 procedur e 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 associat ed 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 (s ee 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 ex ample metabolic heat value in the SOP may be revised based on the Study Director’s observati on 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 encourag e this if it is a common pr actice for the cooperator. (p. 63 of 659)

(d) How does the protocol provide for medica l management of potential illness or injury to subjects?Attachment 2

Page 41 of 52 “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 prof essional 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) define s procedures to be followed if a subject in an AHETF study require s 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) cal ls for researchers to monitor worker compliance with label and Work er Protection Standard requirements and labeling, and permits the Study Di rector to remove from the study a worker who engages in unsafe work practices.

 SOP AHETF-11.G.5 (pp. 243-255 of 659) ca lls 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) defi nes procedures to be followed if a subject in an AHETF study requ ires emergency medical attention.

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

“During the consenting process each volunt eer will be provided the opportunity to request a summary of their pe rsonal results from the study

. This will require the worker to provide a name and address (m ail or e-mail). The results will include a distribution of chemical exposure among th e various body parts and a comparison of results from other workers performing the sa me task. Results are typically available 9-12 months after all monitoring is comple ted. 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 participatio n 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 sign ed consent form with phone numbers for reporting any health changes they think might be related to participation in the study. Post-study inquiries will be forwarded to th e Study Director who will deal with the situation as appropriate and notify AHETF management (SOP AHETF-11.J).” (p. 365 of 659)

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

“If you are injured or get sick because of your participation in this study, medical treatment will be available at your workplace and at a nearby health care facility. IfAttachment 2

Page 42 of 52 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 in cludes deductible costs and any out-ofpocket expenses, including co-payments, you might have. The Study Director, in consultation with the on-site medical profe ssional, will decide if you have an illness or injury that is due to your partic ipation in this study.” (p. 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 pr ogram has the potential to improve the ability of EPA and other regulatory agencies to accurately asse ss occupational risks associated with open pour loading of gra nules into various kinds of application equipment. The knowledge likely to be obtaine d 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 suita ble 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 fr om data generated by this study through the improved risk assessments by EPA and othe r regulatory agencies.” (p. 68 of 659)

“Employers (i.e. growers or commercial applic ators, if applicable) who allow the study to be conducted using their equipment will be re imbursed 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 runni ng their businesses.” (p. 68 of 659)

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

Identified societal benefits are likely to be realized.

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

“By monitoring exposure to professional agri cultural handlers who follow their normal practices, but wear an additional layer of clothing (as an inner dosimeter which trapsAttachment 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 incr eases the risk of heat-related illness.

“The likely benefit to pesticide ha ndlers as a whole and to societ y in general, in the form of more accurate measurements of potential exposure to pesticides, must be weighed against the risks to participants. The availa bility of pesticide products form ulated as granules provides growers and other users additi onal options for meeting their individual needs. Therefore, exposure data for this study meeting contempor ary standards of reliab ility 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 st udy, subjects are very unlikely to experience acute toxic effects, and because extensive proc edures will be in place to minimize these and other risks to participants, th e likelihood of serious adverse effects is very small. In summary, AHETF believes the risks to study partic ipants from participating in this study are reasonable in light of the likely benefit to soci ety 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 investi gators and sponsors of the research? Yes

(c) Is this IRB registered with OHRP? Yes

(d) Is this IRB accredited?

Schulman Associates IRB earned Full Accred itation from the Association for the

Accreditation of Human Res earch 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 Pr otection of Human Subjects of

Biomedical and Behavioral Research, April 18, 1979 (http://www.hhs.gov/ohrp/humansubj ects/guidance/belmont.htm). [Note: this document is not an o fficial policy or a code of ethicalAttachment 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 work ing 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 complete d are described in SO P 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 appropriatel y documented, consistent with the requirements of 40 CFR §26.1117? Yes

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

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

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 ensu re subject comprehension of risks and

discomforts?

“In all situations, the person obtaining c onsent will not sign the Consent Form unless he/she believes the candidate fully understands the information presented. This will be ascertained by providing repeat ed opportunities to ask quest ions and by asking questions of the potential workers that would require a response that indicates understanding of keyAttachment 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 partic ipation in the study. Any materials used during the consent meeting will be approved by the IRB before use.

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

“The person conducting the consent meeting w ill 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 explanati on of the study, its requirements, any potential risks, its benefits, alternatives to participation, etc. Workers will be advised of their right to withdraw from the study at any time a nd for any reason without jeopardizing their normal position with their employers or their daily wages. Workers wi ll be told they will receive an additional $80 (or another amount speci fied in the protocol) if they decide to participate and put on the dosimeters, whet her or not they complete the monitoring period.

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

AHETF-11.E for details.

“Information will be provided about the ri sk of heat stress, including signs and symptoms, and ways to prevent it. Info rmation will also be provided about the availability of medical a ttention during the study. De tails 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 part icipants and the person obtaining consent, ample time will be provided for questions and the person obtaining consent will provide any additional information or clar ification that is requested.

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

of the worker. All sections of the Consent Form will be explained in detail. When the person obtaining consent is satisfied that th e worker understands the requirements andAttachment 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 al so be attached. These documents (in the appropriate language) will be reviewed, signe d and dated by the worker, and copies will be provided.

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

“The person obtaining consent wi ll not sign the Consent Form unless he/she believes that the process has been free of any element of coercion or undue influence and the witness (when required) has signed the 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) af firming to their workers and AHETF that they will not coerce or unduly influence th eir 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 vo lunteer and that the employee’s decision to participate or not will ha ve no impact on their employme nt. For ‘employers’ that are self-employed individuals, this non-coercion st atement 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 prot ect subject privacy during recruitment, consent, study conduct, and maintenance of study records. The consent form also summarizes important confidentiality issues for subjects. These procedures are described in SOPs AHETF-6.B, 6.D, 11.B, 11. D, and 11-J.” (p. 68-9 of 659)Attachment 2

Page 47 of 52 “Your name will only appear on the consent fo rm 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 E nvironmental Protection Agency (EPA ). It may also be sent to state government agencies and to governments in other countries. Your name will not be in the study report.

“We cannot guarantee you total c onfidentiality. There may be a need to give information to some organizations or to parties in lega l actions, as required by law. Records which identify you may be looked at or copied by the AHETF and any consultants working with the AHETF, by EPA or other government ag encies, 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 pr otect 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 fr eedom to withdraw from the research at any time without penalty?

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

Any 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. Th e Study Director will decide whether these samples will be analyzed (S OP AHETF-8.K).” (p. 69 of 659)

“Your employer has agreed to let us do the re search 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 st udy 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 in clude 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 st udy 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 st udy. Taking part is totally voluntary. If you choose not to take part in this study you w ill perform your ordinary activities on the day of the study. Your alte rnative is to not take part.” (pp. 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 us ing procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk. Y

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

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

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

persons. Y

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

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

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

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

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

Page 50 of 52 §26.1116 General requirements for informed consent AHETF Protocol: 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 t he legally effective informed consent of the subject or the subject’s le gally authorized representative OK

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

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

No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or ap pears to release the investigator, the sponsor, the institution or its agents fr om liability for negligence OK(a) In seeking informed consent the following informationshall 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 proced ures to be followed, and identification of any procedures which are experimental OK

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

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

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

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

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

(7) An explanation of whom to contact for answers to pertinent questions about the research and research subjec ts’ rights, and whom to contact in the event of a research-related injury to the subject OK

(8) A statement that participation is vol untary, refusal to participate will involve no penalty or loss of benefits to which t he subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled OK(b) When appropriate, one ormore of the following elementsof information shall also beprovided to each subject (1) A statement that the particular treatme nt or procedure may involve risks to the subject (or to the embryo or fetu s, if the subject may become pregnant) which are currently unforeseeable OK

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

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

research OK

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

(5) A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject n/a

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

function. OKAttachment 5

Page 51 of 52 §26.1117 Documentation of informed consent AHETF Protocol: 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 gi ven to the person signing the form. OK

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

(b)(2) The consent form may be a short form written consent document stating that the elements of informed consent required by §26 .1116 have been presented orally to the subject or the subject’s legally authorized r epresentative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subjec t or the representative. Only the short form itself is to be signed by the subject or t he representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A co py of the summary shall be given to the subject or the representative, in add ition to a copy of the short form. OK SOP AHETF 11.I.3Attachment 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 hu man research covered by §26.1101(a) shall, after receiving approval from all appropriate IRBs, submit to EPA prior to initiating such research all information relevant to the proposed research specified by §26.1115(a), and the following addition al information, to the extent not already included:
Requirement Y/N Comments/Page RefsAll 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 investi gators, 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 th e IRB and the investigators. Y pp. 323-659 (5) ● A list of IRB members identified by name; earned degrees; representative capacity; indications of experience su ch as board certifications, licenses, etc., sufficient to describe each mem ber’s chief anticipated contributions to IRB deliberations;

 any employment or other relationship between each member and the institution, for example, full-time employee, a member of governing panel or board, stockholder, paid or unpaid consultant. Y 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/aThe following Information, to theextent 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 circumst ances and methods proposed for presenting information to potential human subjects fo r the purpose of obtaining their informed

consent. Y pp. 68-69

§1125(e): All correspondence between the IRB and t he investigators or sponsors. Y pp. 323-659 §1125(f): Official notific ation to the sponsor or invest igator...that res earch involving human subjects has been reviewed and approved by an IRB. Y pp. 52, 53, 109, 112, 114, 116,

129