Page 1 of 57 Ha
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF

CHEMICAL SAFETY AND POLLUTION

PREVENTION

December 30, 2011

MEMORANDUM

SUBJECT: Science and Ethics Review of AHETF Scenario Design and Protocol AHE600 for Exposure Monitoring of Workers during Mixing, Loading and Application of Pesticides in Managed Horticultu ral Facilities using Powered Handgun Equipment

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: Steve Knizner, Associate Director

Health Effects Division Office of Pesticide Programs

REF: Collier, R. (2011) Mixing, Loading and Application of Pesticides in Managed Horticultural Facilities using Powered Handgun Equipment. Unpublished protocol dated October 24, 2011, prepared for the Agricultural Handler Exposure Task Fo rce under Sponsor ID AHE600, 474 p.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 57 Science Review

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

• Please make the following revision to the prot ocol before proceedi ng with the research:

o EPA anticipates that wettable powder form ulations may result in higher inhalation exposures. As such, EPA requests that a wettable powder formulation (e.g., permethrin or sulfur) be used by one part icipant in each of the clusters for this

scenario. SR5 and the formulation sub bulle t for SR6 should be revised accordingly.

Ethics Review

• The protocol meets the applicable ethical re quirements of 40 CFR part 26, subparts K and L.

• Please make the following revisions in future protocol submissions:

o In the protocol, please revise the discussion of the “psychol ogical risks” to identify the risk of a breach of confidentiality a ssociated with photographs or video as a potential psychological risk of study participation. Please also clarify that the most significant psychological risk associated w ith pregnancy testing is the unwanted disclosure of test results, rather than em barrassment associated with administration of

the test.

o In the consent form, please list the risks of breach of confidentiality (related to unwanted disclosure of pregnancy test resu lts, photographs, and videos) in the section

titled “Risks and Discomforts.”

o In the protocol, please desc ribe the types of locations where recruitment discussions between researchers and potential subjects w ill take place. Specifically, please clarify whether these discussions will take place at the work site or at locations that are away from the work site. It is preferable for th ese discussions to take place away from the work site, to minimize the potential for coercion.

o As recommended in the HSRB’s report dated March 17, 2011, please revise SOP

AHETF-11.H.3 to include criteria for decision-making capacity as guidance for medical professionals who will perform this function in AHETF research.

A. Completeness and Contents of Protocol Submission

The submitted protocol was reviewed for completeness against the required elements listed in 40 CFR §26.1125. All required elements are present. EPA’s checklist is appended to

this review as Attachment 6.Page 3 of 57 B. Summary Assessment of the Scenario Design 1

1. Scenario Design: Protocol AHE600 is designed to a ddress the dermal and inhalation exposure of handlers using powered (gasolin e or electric) handgun/handwand equipment in greenhouses and nurseries. Participants will use the equipment to treat ornamentals and nonbearing fruit trees in nurseries. Part icipants may also treat ornamentals and vegetables grown in greenhouses. The spra y pattern shall include downward, outward and upward directions. The scenario will also include the task of mixing and loading liquid and solid formulations. Aside from th e mixing loading component, this scenario is similar to the handgun component of Protocol AHE400 (Rights of Way) reviewed by the Board in October 2010. That is, handlers will ap ply surrogate pesticides to the foliage of crops in a variety of directions using ha ndguns connected to long hoses. Conceptually, the difference between the two scenarios, w ith respect to potential impact on exposure (during application) may be due to the organized structure of plants grown in greenhouses and nurseries compared to the uno rganized structure of plants growing in Rights of Ways. Another key difference is th e degree of openness and enclosure. This

scenario will include treatments made in greenhouses and open and quasi-enclosed environments (e.g., shade or lath houses) in nursery settings.

The handler attire for this scenario is exp ected to consist of lo ng-sleeved shirts, long pants, shoes plus socks. The minimum am ount of PPE worn by participants will be chemical resistant gloves. However, addi tional PPE may be needed depending on end use product labeling directions for mixing/lo ading which may require chemical-resistant aprons. Chemical-resistant headgear will be worn when participants make overhead treatments. Patches placed inside and out side of the headgear will be employed to estimate dermal exposure of the protected portions of the body covered by these garments. Some surrogate pesticide labels ma y require chemical-resistant aprons to be worn by participants during mi xing and loading. Since the ma jority of dermal exposure will result from the application component of this scenario, we do not believe this will adversely impact the results.

This scenario will consist of all new data because there are no existing data that meet the AHETF’s criteria for inclusion in the Agricult ural Handlers Exposure Database (AHED). Due to the diversity of application sites, it is expected that ha ndler exposure for this scenario will be highly variable. Therefor e, to estimate number of monitoring units (MUs) required, a geometric standard deviati on (GSD) of 5 was used rather than a GSD of 4 when running simulations to determine th e sample size. The AHETF has selected a ten by three study design (clu ster by MUs, respectively) for a total of 30 MUs.

The definition of the clusters (i.e., monitoring areas) for this scenario can be contiguous counties in portions of states such as southe rn Florida or contiguous counties in adjoining states such as the proposed Ohio-Penns ylvania monitoring area or non-contiguous

1 Supporting details are in Attachment 1.Page 4 of 57 counties having greenhouses and nurseries in a given geographic region (e.g., eastern Texas and Louisiana). The cl usters are shown in Figure 1.

Figure 1: Clusters/Mon itoring Areas for AHE600

EPA intends to use these data to estimate daily dermal and inhalation exposures of pesticide handlers mixing/loading and applying sp rayable pesticides formulated as liquids or solids using powered hand gun equipment. It is EPA’s view that dermal exposure will be dominated by the application of the pe sticide and that the contribution of the mixing/loading component will be minimal. Thus, the occasional donning of aprons by participants for this task is not likely to impact the dermal exposure measures. However, for the inhalation route, it is possible that the use of the wettable powder formulation may result in increased inhalation exposure. Th erefore, the similarity restrictions should account for the use of a wettable powder by at least one participan t per monitoring area (i.e., cluster).

EPA anticipates that wettable powder form ulations may result in higher inhalation exposures. As such, EPA requests that a we ttable powder formulation (e.g., permethrin or sulfur) be used by one participant in each of the clusters for this scenario.

2. Sampling Design:

Ten new clusters (monitoring areas) each havi ng 3 monitoring units (MUs) have been proposed for this scenario. Each monitoring ar ea consists of a distinct group of counties representing a wide variety of geographica l and climactic conditions. The monitoring areas were selected by consid ering the following sources:Page 5 of 57 • An AHETF-conducted site visit of nu rseries and greenhouses (including interviews)

• An AHETF-conducted survey of growers operating ornamental greenhouses and nurseries in six states repres enting distinct growing areas

• An AHETF-conducted survey of grower s operating vegetable greenhouses in important growing areas of US and Canada

• The USDA National Agricultural Statis tics Service (NASS): 2007 Census of Agriculture and the Agricultural Chemi cal Usage 2009, Nursery and Floriculture Summary

The AHETF has purposively selected the follo wing monitoring areas. Specific counties in each region on a state by state basis are presented in Attachment 1 of AHETF’s protocol submission.

Proposed Study Monitoring Areas Region/Climatic Description 1 Lower New England NY, MA, CT and RI/Maritime with warm to cool,

humid summers and mild to cold winters 2 Mid-Atlantic PA, NJ, DE a nd MD/Warm and humid summers,

mild winters

3 North Carolina – South

Carolina - Tennessee Western NC, northwestern SC and eastern

TN/warm humid summers and mild winters. Cooler summers and cold winters at higher

elevations

4 Northern Florida Northern 2/3 r d of the state/warm and humid

summers and mild winters

5 Southern Florida Southern 1/3 r d of the state/moist tropical conditions 6 Ohio – Pennsylvania Eastern OH a nd western PA/warm to cool, humid summers, mild to cold winters 7 Indiana - Michigan Southern MI and northern ID/warm to cool, humid

summers and mild to cold winters

8 Illinois – Wisconsin Northern IL a nd southern WI/warm to cool, humid

summers and mild to cold winters

9 Louisiana – Texas Eastern TX a nd western LA/warm humid summers

and mild winters 10 Oregon – Washington Western areas of both OR and WA/Maritime with warm, humid summers and mild winters

EPA agrees that these monitoring areas are likel y to provide a wide range of climates and a wide variety of plant material s to be treated. Having such broad areas also increases the likelihood of identifying partic ipants and meeting the AHETF s similarity restrictions. This scenario addresses the exposures of both mixing/loading and making pesticide applications.

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)Page 6 of 57 that could be handled in a minimum two hour monitoring period. As discussed at the October 2011 HSRB meeting, th ere is generally no upper limit on the amount AaiH handled by a study participant. While the lowe r limit is imposed to ensure detectable residues, the upper limit should generally be considered as a guide and as a way to determine sample size and estimate participant exposure. Individuals handling more than 15 pounds would not be excluded from the study. However, for two surrogate chemicals (carbaryl and chlorothalonil), the upper AaiH limit is 4.8 pounds, in the middle stratum, and should not be exceeded based on risk (Mar gin Of Exposure) estimates. Three AaiH bands (strata) ranging from 0.5 to 15 pounds are proposed. They are as follows:

• 0.5 to 1.6 lbs AaiH

• Greater than 1.6 to 4.8 lbs AaiH

• Greater than 4.8 to 15 lbs AaiH

The next stage of sample sele ction results in identifying th e growers whose crops will be treated and the workers whose exposure will be monitored. As with other agricultural pesticide scenarios, growers who agree to coope rate with the research and to have their ornamentals or vegetables treated with any of surrogate pesticides must be identified before study participan ts can be recruited.

The AHETF process for identifying handler subjects recruited from ornamental and greenhouse (ornamental and vegetable) growers includes five steps:

• Contacting commercial list providers: Meister Media Worldwide, Moose River

Media and Dun and Bradstreet

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

• Putting the list of growers into random order

• 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 has at least one handler with experience with handgun equipment

• 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 an AaiH stratum a nd is willing to use at least one of the

surrogatesPage 7 of 57 This process of identifying cooperating gr owers is basically sound. EPA has accepted this approach.

When selecting MUs, the following the AHETF have developed similarity restrictions (SR) to increase diversity within the cluste r. Some SRs are intended to be enforced, others, while desirable, won’ t be strictly enforced.

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

from the same stratum

• SR2 . No two MUs obtained for the same scenario can monitor the same worker

• SR3 . No two MUs in the same monitori ng area can have the same employer

• SR4 . Since this scenario includes both greenhouses and nurseries, no two MUs can be based the same conditions in terms of openness or enclosure for each monitoring

area.

• SR5 . AHETF prefers that all three MUs in a gi ven cluster not use the same formulation type (liquid or solid) *

• SR6 . AHETF has the following list of SRs that each pair of MU in a monitoring area must differ by at least one of the following by:

o The facility type such as ornamental greenhouse, vegetable greenhouse or nursery

o Mixing either directly into the spray tank or pre-mix then transfer to the spray

tank.

o Type of hose attachment (handgun or ha ndwand). [AHETF recognizes that the term ‘handgun’ can vary but in genera l distinguishes th e term handgun from handwand as follows: A handgun is spray device consisting of single or multiple nozzles in which the operator squeezes a ‘trigger’. The handwand, while similar, has a long lightweight extension from the hose ending with a nozzle or cluster of

nozzles that can be turned on with a tri gger or a valve. In sum, they differ primarily by length]

o The formulation type mixed (i.e., liquid or solid) *

o The predominant direction of spray dur ing the monitoring period (downwards, outwards, or upwards)

o The size of the surrogate pesticide product container

o Whether or not equipment clean-up was performed after the application

* The AHETF assert that existing data suggest that mixing/loading a dry/solid formulation like a wettable powder or dry fl owable may result in higher inhalation exposures. EPA agrees with the AHETF however our view is that th is is particularly true with wettable powder formulations. EPA recommends that wettable powder formulation (e.g., permethrin and sulfur) be used by one participant in each of the clusters

selected for this scenario. SR5 and the fo rmulation sub bullet for SR6 should be revised accordingly.

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 byPage 8 of 57 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 recruitment proves

to be difficult.

3. Choice of Surrogate Materials: The surrogate pesticides to be used in this study are fungicides and insecticides si nce the study design is of ha ndlers treating the foliage of desirable crops and not weed control. These pesticides have a wide range of application rates that should help obtain the thre e AaiH strata in each monitoring area.

Surrogate Pesticide Type of Pesticide Restrictions on AaiH handled Azoxystrobin Insecticide No Carbaryl Insecticide Apply no more than 4.8 pounds per day Chlorothalonil Fungicide Appl y no more than 4.8 pounds per day Fosetyl-al Fungicide No Imidacloprid Insecticide No

Malathion Insecticide No

Permethrin Insecticide No Sulfur Fungicide/Miticide No Thiophanate-Methyl Fungicide No

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 30 MUs based on a 10 cluster by three MU 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).

2 Supporting details are in Attachment 2.Page 9 of 57 • 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. AHETF increased the GSD from 4 to 5 based on the expected variability of the handler activities in these highly varied application sites. EPA agrees with this change.

The Number and Configuration of New MUs:

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 (0.5 to 15 lb ai/d ay) was partitioned into the following three strata:

• From 0.5 to 1.6 AaiH

• Greater than 1.6 to 4.8 AaiH

• Greater than 4.8 to 15 AaiH

There is approximately a 3.1 fold differ ence between the upper and lower bound having roughly equal widths on a log scale (for AaiH ). Based on the AHETF’s simulations for aPage 10 of 57 10 by 3 cluster/MU configuration, assuming proportionality as well as the assumed variation structure, 100 percent power was found for meeting the primary objective. Based on those assumptions and values, the seco ndary 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 at least 2 hours in duration involving mixi ng/loading and applying a maximum of 3 tank-loads. The 2 hour minimum is considered by the AHETF as a guideline rather than a requirement.

Participants will conduct open mixing of surroga tes either directly into the tank to be used for spraying or into a premix tank prior to pouring the premix into the tank to be used for spraying. The tank may be stationary or mobile (in some cases may be mounted on a vehicle). The handguns or handwands w ill generally be connected by long hoses to the tanks containing the finished spray. It is also possible that some participants will make the applications from a vehicle. The sp ray orientation for each MU will be directed to the foliage in predominantly downwar d, outward or upward patterns. Hose management will also be performed by the participant. Minor clean-up consisting of draining, flushing and rinsing the equipment (a s well as containers) may be performed if it is the participant’s norma l work practice to do so.

There are nine surrogate pest icide active ingredients available for this scenario. A cooperating grower may choose to use any of them for a specific MU. However, only two are reportedly available as wettable pow ders. EPA recommends that at least one MU use a wettable powder in each of the 10 clusters.

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

each MU. These data will contribute to development of Unit Exposures (exposure per unit of pesticide active ingredie nt applied) or other exposure metrics, and to estimates of dermal and inhalation exposure to other pest icides for workers mixing and loading and applying pesticides using handguns and handw ands in nurseries and greenhouses.

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 and sectioned into six sections: right and left upper arms (shoulder to elbow); right and left lower arms (elbow to cuff); front torso (above the waist); rear torso (a bove the waist); right and left upper legs (waist to knee) and the right and left lower legs (knee to cuff). Inner and outer head patches (100 cm 2

and 50 cm 2 respectively) affixed to the inside and outside of chemical resistant headgearPage 11 of 57 when worn by participants making overhead sprays. The head patches will be made

from the inner dosimeters. Sock dosimeter s worn beneath the participant’s socks will also be part of the dermal exposure measurements.

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 the break and again at the end of the exposure period; both these samples will be retained for analysis. As required by AHETF SOP 10.C.4, the st udy team will record what type of personal protective equipment ( PPE), including respirator s, was worn at any time during the monitoring event.

Sectioning WBDs, and measuring the remaini ng body regions separately will help inform exposure patterns for this scenario. By unde rstanding the exposure patterns (e.g., percent of exposure to lower legs) EPA may be ab le to develop mitiga tion strategies (e.g., chemical resistant headgear or chemical re sistant footwear) during the risk assessment

process.

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. The unit will be calib rated prior to the monitoring event using a rotameter. The OVS tube will be clipped to the subject’s shirt collar with the intake facing downward. The air sampling pump will be connected to the OVS tube and will be operated for the total monitoring period including any breaks.

Additional measures will record environmental conditions at the time of monitoring. Observers will make field notes of subject activity throughout the monitoring event, and photographs or videos may be taken selectivel y to illustrate events. EPA believes that the proposed measures are appropriate and sound for the study design

4. QA/QC Plan: The study will be monitored by three different quality assurance units: one from the exposure monitoring contractor that conducts the 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.Page 12 of 57 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 AHE600, and will be posted to the AHED ® database, where they will be available to regulatory agencies for later statistical analysis. The documentation will report a confidence-interval-ba sed approach to determine the relative accuracy for the

arithmetic mean and 95 th percentile of unit exposures. The AHETF will not otherwise statistically analyze th e monitoring data.

D. Compliance with Applicable Scientific Standards

EPA agrees that the AHETF collect MUs for this scenario based on participants using handguns or handwands under a wide range of nursery and greenhouse conditions provided the AHETF adjust its similarity re strictions and monitor at leas t one MU using a wettable powder formulation per cluster.

Otherwise the protocol adequately addr esses the following elements according to applicable 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 sample s 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. Series 875 Group A and OECD Applicator Guidelines) as well as Good Laboratory Practices (GLPs).

E. Summary Assessment of Ethical As pects of the Proposed Research 3

1. Societal Value of Proposed Research: The objective of this st udy is to develop data to determine the potential exposure for workers who mix, load, and apply liquid pesticides

3 Supporting details are in Attachment 2.Page 13 of 57 using powered handgun equipment in managed horticultural facilities in the United States. This mixing/loading/ applying method is applicab le to a large variety of commercially important crops associated w ith the nursery and gr eenhouse industry across the U.S. and Canada, and the existing exposure data are inadequate. EPA will use the results of this study to estimate the dermal and inhalation exposure likely for a wide range of agricultural pesticides mixed, loaded, and applied under this exposure scenario.

2. Subject Selection: Subjects will be recruited am ong the employees of commercial growers who mix, load, and apply liquid pest icides using powered handgun equipment, who are willing to use at leas t one of the surrogate active ingredients for this study, and who meet AHETF criteria for participation. Eligible growers will be identified from a complete list of growers in the target area, processed in random sequence. Subjects will be recruited who are employees of eligible growers (or of pesticid e application service companies used by eligible growers), with expe rience within the past year using the piece of hand held application equipment that will be used in the study. If more employees are available and interested than are needed, qualif ied participants will be selected randomly. Although the design is purposive, and thus pa rticipants are not re presentative in a statistical sense, they are exp ected to be typical of those who mix, load, and apply liquid pesticides with powered handgun equipment.

Subjects will be recruited acco rding to the standard procedures set forth in SOP AHETF11.B.6. The Study Director or designated re searcher will seek permission from the eligible grower to approach his/her empl oyees to recruit volu nteers for the study. Depending on the number of employees and si ze of the grower’s facility, the Study Director or researcher may contact employees using an informational recruitment flyer posted in a common work area. Alternatively, or subsequent to the use of a flyer, the Study Director or researcher will arrange a meeting with the grower’s employees who express interest in participation. Such r ecruitment meetings will always occur without the grower or supervisors being present. The Study Director or researcher will describe the AHETF Exposure Monitoring Program, th e goals of this specific study, the procedures to be used in exposure monitoring, and the risks and benefits to participants. The subject eligibility factors listed in the consen t 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:

• The risk of heat-related illness

• The risk associated with scripting of field activities

• Psychological risk

• The risk of exposure to surfactants

• The risk of exposure to surrogate chemicalsPage 14 of 57 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 these risks. Appropriate provision is made for safety and medical monitoring.

4. Benefits: This research offers no direct benefits to the subjects. The principal benefit of this research is likely to be reliable data about the dermal and inhalation exposure of workers mixing/loading/applyi ng pesticides using powered handgun equipment, usable by EPA and other regulatory agencies to suppor t exposure assessments for a wide variety of pesticides with similar use patterns.

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

research. The low residual risk is reasonable in light of the likely benefits to society from new data supporting more accurate handler e xposure assessments for a wide range of agricultural pesticides.

6. Independent Ethics Review: The proposed research has been reviewed and approved by the Independent Investigational Review Board, Inc., (IIRB, Inc.) of Plantation, Florida. The submitted materials include a record of correspondence between the investigators and IIRB, Inc.

7. Informed Consent: Informed consent will be obtai ned from each prospective subject and appropriately documented. The reading level of the English language consent form is appropriate. Adequate provi sion is made to meet the need s of subjects who do not read either English or Spanish. EPA assessments of compliance with the requirements of 40 CFR §26.1116 and §26.1117 appear in Attach ments 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 the pesticide laws. Thus the primary ethical standa rds 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.Page 15 of 57 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 Mixing/Loading of Pesticides and Application of Liquid Sprays using Powered Handgun Equipment in Managed Horticultural Facilities (AHE600)

2. EPA Protocol Review: Determination of Dermal and Inhalation Exposure to Workers during Mixing, Loading and Application of Liquid Sprays using Powered Handgun Equipment in Managed Hortic ultural Facilit ies (AHE600) 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 16 of 57 EPA Scenario Review: AHE600

Title: Monitoring Unit Selection and Constructi on Plan for Scenario: Open Pour Mixing/Loading of Pesticides and A pplication of Liquid Sprays using Powered Handgun Equipment in Mana ged Horticultural Facilities

Date: September 27, 2011

Sponsor: Agricultural Handler Exposure Task Force

1. Scope of Scenario Design

“ This is a mixing/loading-appli cation (MLA) scenario defined by the activity, equipment, the form of formulated and diluted product, and ty pe of horticultural faci lity (i.e., nursery or greenhouse). More specifically, th is scenario involves the mixing of dry or liquid formulated product with water which can be accomplished by either preparing a pre-mix and transferring to a spray tank where the mixture is diluted w ith an appropriate amount of water, or the product can be transferred direc tly to the tank and diluted. App lication involves the use of powered handgun equipment in which the liquid sp ray is applied to th e foliage of plants typically grown in commercial horticultural facilities .” (p. 13 of 474)

“It is important to note that each of the 10 ‘regions’ shown on the map is merely a convenient boundary that visually circumscri bes the extent of a particular monitoring area. In reality, only those counties with 20 opera tions (i.e. those shaded in grey) actually belong to the monitoring area...

1. Lower New England Monitoring Area This monitoring area consists of 36 counties in southeastern Ne w York and virtually all of Massachusetts, Connecticut and Rhode Island. Th e climate is Maritime with warm-to-cool,

humid summers and mild-to-cold winters.

2. Mid-Atlantic Monitoring Area This monitoring area consists of 52 counties in southeastern Pe nnsylvania and virtually all of New Jersey, Maryland and Delaware. The clim ate is generally warm and humid in the

summer and has mild winters.

3. North Carolina-South Carolina-Tennessee Monitoring Area This monitoring area consists of 52 counties located in wester n North Carolina, northwestern

South Carolina and eastern Tennessee. The c limate generally has warm, humid summers and mild winters, with cooler summers a nd cold winters at higher elevations.

4. Northern Florida Monitoring Area This monitoring area consists of 30 counties located in roughly th e northern two-thirds of the state. The climate is generally warm and hum id in the summer and has mild winters.Attachment 1

Page 17 of 57 5. Southern Florida Monitoring Area This monitoring area consists of 6 counties in roughly the southern third of Florida. This area has a tropical, moist climate.

6. Ohio-Pennsylvania Monitoring Area This monitoring area consists of 37 counties in eastern Ohio and western Pennsylvania. The climate generally has warm-to-cool, humi d summers and mild-to-cold winters.

7. Indiana-Michigan Monitoring Area This monitoring area consists of 34 counties in the southern half of Michigan and the northern part of Indiana. The climate ranges from warm-to-cool, humid summers and mildto-cold winters.

8. Illinois-Wisconsin Monitoring Area This monitoring area consists of 47 counties in the northern part of Illinois and roughly the

southern half of Wisconsi n. The climate ranges from warm-to-cool, humid summers and

mild-to-cold winters.

9. Louisiana-Texas Monitoring Area This monitoring area consists of 22 counties in the eastern part of Texas and most of the western portion of Louisiana. The area genera lly reflects a climate that has warm, humid

summers and mild winters.

10. Oregon-Washington Monitoring Area This monitoring area consists of 30 counties in roughly the we stern third of both Washington and Oregon. The climate is Maritime with generally warm, humid summers and mild winters.” (pp. 32 – 33 of 474)

(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 Mixing /Loading of Pesticides and Application of Liquid Sprays Using Powered Handgun Equipmen t in Managed Horticultural Facilities (Powered Handgun Spraying in Horticultural Fa cilities) scenario as being within the scope of the task force goals and one for which data are lacking. A number of AHETF member products are labeled for this use pa ttern. These products are important because they help support and maintain commercially important crops associat ed with the nursery and greenhouse industry across the U.S and Canada . Therefore, it is necessary to have data in AHED for the mixing/loading and application methods described by this

scenario .” (p. 20 of 474)Attachment 1

Page 18 of 57 “ Regulatory Committee (JRC)) re viewed handler exposure measurements in existing studies (mostly not included in PHED) to id entify those that satisfy current acceptability criteria and qualify for inclusion in a generi c database. Seven studi es involving handheld spraying potentially applicable to this scenar io were reviewed by th e JRC, and are listed

below.

AHE04 – This is an AHETF-conducted study in which applicators made handheld applications in greenhouses. AH102 – This study involved herbicide a pplications made around almonds using a handheld spray gun attached to tractor-mounted tanks. AH401 – This study involved handheld applications made in greenhouses. AH520 – This study involved handheld applications made in greenhouses. AH705 – This is a mixer/loader-applicator study that involved handheld applications made in greenhouses. AH903 – This study involved handheld applications in greenhouses. AH315 – This study involved termiticide a pplications using truck-mounted handheld application equipment.

Based on these reviews, it was concluded that none of the studies listed above provided MUs that met the acceptance criteria estab lished by AHETF and approved by JRC (did not fit the scenario definition, used double laye rs of clothing or PPE). Thus, there are no available existing data for this scenario th at are useful for a m odern generic database . (p. 2 of 474)

2. Rationale for Scenario Sampling Design

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

“... feedback from nursery/greenhouse growers who were interviewed in 2009 (Standart, 2011) also indicated that workers who ma ke applications using handgun equipment usually perform the associated mixing/loading activities as well.

“Therefore, given that a single worker usi ng handgun equipment usually performs both mixing/loading and application activities, th is scenario will involve mixing/loading and application. Mixing/loading will be genera lly accomplished by mixing formulated product directly in the tank to be used for application or into a pre-mix tank where the

contents will later be transf erred to the actual application tank. Exposure monitoring for this scenario will only include open-pouri ng situations since open pouring is most common and is expected to represent a highe r exposure potential than the use of closed systems (which includes water-soluble p ackets). Application will be generally accomplished by manually operating the wand or gun and directing spray to foliage while walking along walkways or rows, or in some cases by spraying from a vehicle.

“AHETF also learned that workers often perf orm some clean-up activ ities at the end of spraying. Clean-up typically consists of drai ning and collecting any excess spray mixture;Attachment 1

Page 19 of 57 flushing the sprayer with soapy water and then rinsing with clean wate r; and triple rinsing

containers. These activities will be include d in the exposure monitoring whenever the subjects would normally perform them.” (pp. 13-14 of 474)

“[T]he ten monitoring areas for this scenario ar e widely distributed geographically across the U.S., including the Northeast, East, South, Southeast, Northwest, Midwest, and upper Midwest. The wide geographical distribution in turn represents climates ranging from maritime to tropical to mountainous, temperat ures ranging from cool/cold to warm/hot, and precipitation from wet or hum id to relatively dry conditions .” (pp. 33 of 474)

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

• Azoxystrobin

• Carbaryl

• Chlorothalonil

• Fosetyl-al

• Imidacloprid

• Malathion

• Permethrin

• Sulfur

• Thiophanate-methyl

“Results from the NASS chemical usage survey summary showed that one or more of these AIs are commonly used. They 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 w ill have been developed and validated for each matrix used in this study. Matrices include : inner dosimeter, hand rinse, face/neck wipe, socks, head patches, OVS tubes, and cassette filters. Finally, these active ingredients will

be or have been either tested for stability or used as surroga tes in previous studies and are known to have the required stab ility under field study conditions. ” (p. 43 of 474)

Selection of a Geographically Di verse Set of Monitoring Areas:

“ The Scenario Target Area is the potential geogr aphic extent of this scenario.

Horticultural facilities that use powered handguns are likely to be found to some extent or another in any portion of the country. Of the 3,109 counties in the Continental U.S., USDA’s National Agricultural Statistical Se rvice’s (NASS) 2007 Census of Agriculture reported that 2,636 had at least one operation involved with floriculture, nursery, or greenhouse vegetable production....” (p. 31 of 474)

“The NASS production statistics from the Census were placed on maps of U.S. counties using ESRI’s ArcMap 10.0 software. These ma ps aided in selecti ng groups of counties from the restricted Target Area that coul d provide a diverse se t of monitoring areas.

“The counties in the restricted Target Ar ea were then grouped into 10 monitoring areas based on their spatial distance to each other. These groupings of counties were examined for having a reasonable number of enclosed square feet and open production acres. ToAttachment 1

Page 20 of 57 assure geographic distinctness, a similarity restriction required mon itoring areas to be physically separated from each other. That is, counties from one monitoring area could not be interlaced with counties from another monitoring area. Taken together, the set of 10 monitoring areas were constructed to provi de diversity in geogr aphy and/or climate.

“The resulting set of 10 distinct monitoring areas are shown on the map in Figure 1 and summarized below. It is important to note th at each of the 10 ‘regions’ shown on the map is merely a convenient boundary that visually circumscribes the extent of a particular monitoring area. In reality, onl y those counties with 20 operations (i.e. those shaded in grey) actually belong to the monitoring area. Attachment 1 lists the individual counties in each of the 10 monitoring areas.” (p. 31-32 of 474)

“1. Lower New England Monitoring Area This monitoring area consists of 36 counties in s outheastern New York and virtually allof Massachusetts, Connecticut and Rhode Island. The climate is Maritime with warm-tocool, humid summers and mild-to-cold winters.

“2. Mid-Atlantic Monitoring Area This monitoring area consists of 52 counties in s outheastern Pennsylvania and virtually all of New Jersey, Maryland and Delaware. Th e climate is generally warm and humid in

the summer and has mild winters.

“3. North Carolina-South Carolina-Tennessee Monitoring Area This monitoring area consists of 52 coun ties located in western North Carolina,

Northwestern South Carolina and eastern Te nnessee. The climate generally has warm, humid summers and mild winters, with c ooler summers and cold winters at higher

elevations.

“4. Northern Florida Monitoring Area This monitoring area consists of 30 counties located in roughly the northern two-thirds of the state. The climate is generally warm and humid in the summer and has mild winters.

“5. Southern Florida Monitoring Area This monitoring area consists of 6 counties in roughly the southe rn third of Florida. This area has a tropical, moist climate.

“6. Ohio-Pennsylvania Monitoring Area This monitoring area consists of 37 counties in eastern Ohio and western Pennsylvania. The climate generally has warm-to-cool, hum id summers and mild-to-cold winters.

“7. Indiana-Michigan Monitoring Area This monitoring area consists of 34 counties in the southern half of Michigan and the northern part of Indiana. The climate ra nges from warm-to-cool, humid summers and

mild-to-cold winters.

“8. Illinois-Wisconsin Monitoring AreaAttachment 1

Page 21 of 57 This monitoring area consists of 47 counties in the northern part of Illinois and roughly

the southern half of Wisconsin. The climat e ranges from warm-t o-cool, humid summers

and mild-to-cold winters.

“9. Louisiana-Texas Monitoring Area This monitoring area consists of 22 counties in the eastern part of Texas and most of the western portion of Louisiana. The area genera lly reflects a climate that has warm, humid

summers and mild winters.

“10. Oregon-Washington Monitoring Area This monitoring area consists of 30 coun ties in roughly the we stern third of both Washington and Oregon. The climate is Mariti me with generally warm, humid summers and mild winters.” (pp. 32 – 33 of 474)

Reduction of Monitoring Areas:

“...T he Target Area is essentially the enti re U.S...However, for efficiency, AHETF normally restricts a scenario’s theoretical Targ et Area to areas likely to provide the best opportunities to obtain the needed MUs. For this scenario, th e Target Area was restricted to just those 667 counties that NASS repor ted had at least 20 operations. The 10 monitoring areas selected are simply large, geographically distin ct groups of these

counties.” (p. 31 of 474)

(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 growers will be eligible or willing to participate in the study. AHETF must obtain employer cooperation before it can recrui t workers. This includes willingness of the grower to volunteer his facility and application e quipment and allow AHETF to

recruit his workers.

“For this reason, growers that are both qualif ied and willing to participate need to be identified within each monitoring area. AHETF has determined that it is practical to list and screen the vast majority of growers w ithin each entire monitoring area for this information. The general procedure to be followed for each area is described in the steps below. A detailed procedure will be described in the study protocol:

1. “Assemble a list of all kn own nursery and greenhouse growers in the selected monitoring areas. This information will be obtained from multiple sources. The grower lists from all sources will be combined to provide a single list of possible nursery and greenhouse grower s. Any duplicate grower names will

be eliminated and the order of names on the list randomized. (Alternatively, if the list is very large, a randomly selected subset of the names may be used.)Attachment 1

Page 22 of 57 2. “Contact growers on the list and dete rmine whether the grower is both qualified and willing to participate. Growers found to be both qualified and willing to participate in the study in a manner consistent with AHETF’s technical and ethical guidelines are cons idered ‘potentially eligible’ for a scenario. For example, the potentially eligible grower will have the appropriate equipment and will allow hi s workers to be recruited without influencing their participation. Full details about identifying potentially eligible growers are provid ed in the study protocol.

3. “As an aid to eventual selection of MUs, each grower identified as ‘potentially eligible’ will also be asked to provide specific information such as the number of their available employees and when their applications are expected to occur. Specific information to be collected from potentially eligible employers is provided in the study protocol. The above screening process will be conducted by one or more task force contractors as specified in the study protocol. (pp. 38-39 of 474)

(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?

“ .... a single worker using handgun equipment usually performs bot h mixing/loading and application activities, this scenario w ill involve mixing/loading and application. Mixing/loading will be generally accomplished by mixing formulated product directly in the tank to be used for application or into a pre-mix tank where the contents will later be transferred to the actual app lication tank. Exposure monitoring for this scenario will only include open-pouring situations since open pour ing is most common and is expected to represent a higher exposure potential than th e use of closed systems (which includes water-soluble packets). Application w ill be generally accomplished by manually operating the wand or gun and directing spray to foliage while walking along walkways or rows, or in some cases by spraying from a vehicle. See ‘Powered Handgun Equipment’ below for more detail.

“AHETF also learned that workers often perf orm some clean-up activ ities at the end of spraying. Clean-up typically consists of drai ning and collecting any excess spray mixture; flushing the sprayer with soapy water and then rinsing with clean wate r; and triple rinsing

containers. These activities will be include d in the exposure monitoring whenever the subjects would normally perform them.

“This scenario involves power ed handgun prayers (HG). Thes e sprayers are commonly used in nurseries (N) and greenhouses (G) fo r the control of pests and diseases on aAttachment 1

Page 23 of 57 ‘scheduled’ (preventive) or ‘as needed’ (curative) basis. Handgun spray equipment is available in various configura tions. However, all handgun equipment is similar in that it is comprised of a ‘handgun’ (or ‘hand wand’) de vice which is attached to a hose, which is in turn attached, through a pump, to the spray tank.

“For mixing, the worker prepares the spray mix in a stationary (or fi xed spray tank) or in a mobile spray tank (e.g., on a cart or tractor) which can vary in size from a few gallons to several hundred gallons. The tank is usually partially filled with water and the agitator is started. The product is open poured into the tank and agitated until the tank is filled with water. In some situations, such as with wettable powders, the product can be premixed before being added to the spray tank (e.g., in a bucket or pre-mix tank). ” (pp. 14 of 474)

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

“... horticultural facilities range from complete ly open to completely closed, along with

‘in-between’ structure and/or production area situations. AH ETF furthermore recognizes

that the structure and/or production area environment in which a worker performs scenario-specific tasks might impact his expos ure; therefore, the scenario design will encourage some diversity in the amount of ope nness (or enclosure) in the set of MUs. In particular, workers that perform scenario activ ities in any of the types of production areas listed above will be acceptable. However, as specified in Section 5.2.2, all three MUs within the same monitoring area must have monitoring conditi ons with a different degree of openness or enclosure.” (p. 18 of 474)

3. Are the proposed test materials appropriate surrogates?

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

• Azoxystrobin

• Carbaryl

• Chlorothalonil

• Fosetyl-al

• Imidacloprid

• Malathion

• Permethrin

• Sulfur

• Thiophanate-methyl

“Results from the NASS chemical usage survey summary showed that one or more of these AIs are commonly used. They 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 a nd validated for each matrix used in this study. Matrices include: inner dosimeter, hand rinse, face/neck wipe, socks, head patches, OVS tubes, and cassette filters. Finally, these active in gredients will be or have been either testedAttachment 1

Page 24 of 57 for stability or used as surrogates in previ ous studies and are known to have the required stability under fiel d study conditions. ” (p. 43 of 474)

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).” (pp. 27 -28 of 474)

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 geometri c standard deviation (GSD) of 4 and an intracluster correlation (ICC) of 0.3. Unless ther e is other evidence or expert opinion to the contrary, sample sizes are dete rmined using these default values.

“However, the Powered Handgun Spraying in Ho rticultural Facilities scenario is expected to be quite heterogeneous. Many oppor tunities for selecting MUs that differ in ways that might impact exposure are exp ected. Thus, AHETF suspects that diversity selection might result in normalized exposure va riation slightly larger than for a typical scenario. For this reason, for sample si ze determination purposes, a GSD of 5 is considered more likely than the usual value of 4.

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

ICC should be to zero. Mixe r/loader-applicators located in the same area, but working for different, widely dispersed nursery or greenhouse operations, ar e unlikely to show strong within-cluster correla tions in exposure. However, although near zero withincluster correlation is always the goal of diversity selecti on, it can never be completely counted upon. Thus, it seems reasonable to cont inue the conservative default assumption that ICC could be as large as 0.3.Attachment 1

Page 25 of 57 “Because the AHETF and the Joint Regulatory Committee agreed there is no additional evidence to suggest otherwise and no othe r strong ICC=0.3 opinion to the contrary (meeting, June, 2011) the values of GSD=5 and will be used for determining sample size for the Powered Handgun Spraying in Ho rticultural Facil ities scenario. (pp. 28 -29 of 474)

4.5.2. Required Number and Configuration of New MUs

“In addition to the benchmark obj ectives described above, a criti cal issue for this scenario

is the likelihood of obtai ning a sufficient number of eligible MUs in a monitoring area. In general it is less costly to keep the number of monitoring areas as small as possible and conduct more MUs per area. However, it is expected that designs with a smaller number of MUs per monitoring area are more likely to be attainable for all the areas selected. Therefore, for this scenario, the configurati on size is restricted to NM=3 for all MUs. This restriction will necessarily result in the need for a larger number of monitoring areas than would be typical if NM were larger . Although it might be more costly, AHETF believes that configurations with more mon itoring areas and fewer MUs per area will be more successful in obtaining the planned numbe r of MUs than configurations with more MUs per monitoring area.

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

simulation methods that can be used to dete rmine reasonable sample sizes for MUs. In brief, the simulation procedure for this s cenario consists of the following steps:

1. “Given candidate values for number of monitoring areas, NC, numbers of MUs per cluster, NM, and AaiH strata, simulate normalized exposures, AaiH levels, and exposures derived from AaiH levels assuming proportionality, from the twostage lognormal reference model. For this model, a GSD of 5 and an ICC of 0.3 is

assumed.

2. “From these simulated data, estimate the geometric mean, arithmetic mean, and 95th percentile of normalized exposure. Calculate the fold relative accuracy of these estimates compared to their true values.

3. “In addition, from these same simulated data, determine if the slope from a mixed model regression of log exposure on log AaiH is significantly di fferent from zero.

4. “Repeat steps 1 through 3 10,000 times and calculate the 95 th percentile of fold relative accuracy for each normalized expos ure statistic and determine if it satisfies the primary benchmark objective. Also compute the percentage of simulations yielding a statistically significan t slope. This percentage is the power needed to evaluate the secondary benchmark objective.

“Using this approach, it was found that the primary objective can be met with NC = 10 monitoring areas of NM = 3 MUs each. This would provide a total of 30 MUs.Attachment 1

Page 26 of 57 “For the secondary objective, the power to detect proportionality between exposure and AaiH also depends on the partic ular set of AaiH used. But as noted in step 1 above, AaiH levels must be simulated for the hypothesized MUs. As described in Section 5.2.1 below, diversity selection for new clusters will require that the AaiH levels for MUs extend over the complete practical range expected the scen ario. This practical ra nge is 0.5 to 15 lb AI handled per workday and covers two orders of magnitude. Diversity in AaiH levels is achieved by first partitioning the appropriate pr actical range into 3 strata. Then for each configuration, a single MU is obtained from within each Aa iH stratum. The AaiH strata are each designed to have approximately the same upper-to-lower bound ratio, slightly greater than 3-fold.

“An analogous procedure is followed in step 2 above when simulating AaiH levels for MUs: within each simulated new configuration, an AaiH level is simulated log-uniformly

from within each of the 3 strata. Th en exposure data are simulated assuming proportionality with the AaiH le vels and using the assumed vari ation structure. For each simulated set of data, a regression analysis is performed and the significance of the loglog slope determined (2-sided test). The power is the proportion of the time that the slope was found significant at p<0.05.

“When this simulation method is used assumi ng the 10 3-MU clusters needed to satisfy the primary benchmark, the power was found to be essentially 100%. In other words, the secondary power objective for this scenario is automatically met with the number and configuration of MUs required for the primary benchmark objective.” (pp. 29 - 30 of 474)Attachment 2

Page 27 of 57 EPA Protocol Review: AHE600

Title: Determination of Dermal and Inhalation Exposure to Workers during Mixing, Loading and Application of Pesticides in Managed Horticultural Facilities using Powered Handgun Equipment

Revision Date: September 28, 2011

Study Director and Sub-Investigators: Douglas Baugher

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: Independent Investigatio nal Review Board, Inc.

6738 West Sunrise Blvd Suite 102

Plantation FL 33313

1. Societal Value of Proposed Research

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

“The objective of this study is to develop da ta to characterize the potential exposure of workers who perform open pour mixing, loadin g and application activities using powered handgun equipment in managed horticultural fa cilities. Specifically, workers will use powered handgun equipment to make foliar appl ications to plants grown in commercial nurseries or greenhouses. Greenhouses can include both ornamental and vegetable greenhouses. In addition, equipment clean- up activities will be monitored in those situations in which the worker normally perfor ms such activities. Exposure monitoring will be conducted at ten monitoring areas representing a variety of geographical and climatic regions of the United States.” (pp. 331 of 474)

(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 28 of 57 This study will provide a partial answer to the question of what dermal and inhalation exposures are likely for workers who mix /load and apply pesticide products using handguns and handwands in nurse ries and greenhouses.

(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 using open mixing and load ing techniques and making applications with hand-held equipment (handguns and handwands).

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

“AHETF (in conjunction with EPA, PMRA and CDPR, collectively the Joint Regulatory Committee (JRC)) reviewed handler exposure meas urements in existing studies (mostly not included in PHED) to iden tify those that satisfy current acceptability criteria and qualify for inclusion in a generic database. Seven studi es involving handheld spraying potentially applicable to this scenario were revi ewed by the JRC, a nd are listed below.

• AHE04 – This is an AHETF-conducted study in which applicators made handheld applications in greenhouses.

• AH102 – This study involved herbicide a pplications made around almonds using a handheld spray gun attached to tractor-mounted tanks.

• AH401 – This study involved handheld applications made in greenhouses.

• AH520 – This study involved handheld applications made in greenhouses.

• AH705 – This is a mixer/loader-applicator study that involved handheld applications made in greenhouses.

• AH903 – This study involved handheld applications in greenhouses.

• AH315 – This study involved termiticide appl ications using truck-mounted handheld application equipment.

“Based on these reviews, it was concluded that none of the studies listed above provided MUs that met the acceptance criteria establis hed by AHETF and approved by JRC (did not fit the scenario definition, used double layers of clothing or PPE) . Thus, there are no available existing data for this scenario that are useful for a mode rn generic database.

“AHETF reviewed the data in potentiall y relevant PHED (EPA, 1998a) handgun (wand) application scenarios to determine if any of the data were suitable for a modern generic

database.

“The scenarios were:

• Scenario 18 – Low Pressure Handwand App lication (APPL). This PHED scenario contains exposure data for monitoring units making applications only.

• Scenario 19 - High Pressure Handwand App lication (APPL). This PHED scenario contains exposure data for monitoring un its making applications to indoor (poultry houses) and outdoor (weeds a nd brush) environments.Attachment 2

Page 29 of 57 • Scenario 21 – Hand Gun (Lawn) Sprayer (A PPL). This PHED scenario contains exposure data for monitoring units ma king handgun applications to lawns.

• Scenario 32 – Liquid / Open Pour / Low Pressure Handwand (MLAP). This PHED scenario contains exposure data for mi xing/loading and appl ication activities.

• Scenario 33 – Wettable Powder / Open P our / Low Pressure Handwand (MLAP) – This PHED scenario contains exposure data for mixing/loading and application

activities in crack and crevice situations.

• Scenario 35 – Liquid / Open Pour / High Pressure Handwand (MLAP) – This PHED scenario contains exposure data for mi xing/loading and appl ication activities.

“The AHETF is interested in only those PH ED MUs corresponding to a single layer of clothing with chemical-resistant gloves. The review found no MUs that met the acceptance criteria established by AHETF and appr oved by the JRC (incomplete dosimetry, unacceptable data quality). Thus, there are no data currently in PHED fo r this scenario that are useful for a modern generic database.

“AHETF also reviewed and evaluated several exposure monitoring studies sponsored by the European Crop Protection Associ ation (ECPA) and conducted in Europe within the past 10 years. Seven of those studies, consisting of 105 MUs, involved handheld applications in a variety of greenhouse situations with hose-end sprayers. Four other st udies, consisting of 76 MUs, involved handheld applicatio ns in orchard crops or vineya rds using hose-end sprayers. All eleven of these studies were applicable to this scenario. However, as discussed in the Scenario Definition, AHETF plans to generate da ta for this scenario that involve individual workers performing both mixing/loading and appl ication activities. Since all of the ECPA MUs evaluated involved application only, none of the ECPA studies are acceptable for the AHETF generic database.

“Finally, EPA examined data from existi ng handgun MLA exposure studies or exposure

assessments that were not available to the AHE TF and concluded that none of the exposure

data should be included in the AHETF database (Meeting of Joint Regulatory Committee with AHETF, June, 2011). Since no existing data were found that might provide acceptable MUs for this scenario, this sel ection plan proposes to collect all the MUs necessary to meet the benchmark objectives....” (pp. 20-22 of 474)

(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, and apply pesticides for measuring their potential derm al and inhalation exposure.

2. Study Design

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

is it?Attachment 2

Page 30 of 57 “ 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. 49 of 474)

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 geometri c standard deviation (GSD) of 4 and an intracluster correlation (ICC) of 0.3. Unless ther e is other evidence or expert opinion to the contrary, sample sizes are dete rmined using these default values.

“However, the Powered Handgun Spraying in Ho rticultural Facilities scenario is expected to be quite heterogeneous. Many oppor tunities for selecting MUs that differ in ways that might impact exposure are exp ected. Thus, AHETF suspects that diversity selection might result in normalized exposure va riation slightly larger than for a typical scenario. For this reason, for sample size determination purposes, a GSD of 5 is considered more likely than the usual value of 4.

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

ICC should be to zero. Mixer/lo ader-applicators located in the 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.Attachment 2

Page 31 of 57 Because the AHETF and the Joint Regulator y Committee agreed there is no additional evidence to suggest otherwise and no other st rong opinion to the contrary (meeting, June, 2011) the values of GSD=5 and ICC=0.3 will be used for determining sample size for the Powered Handgun Spraying in Horticultural Facilities scenario. ” (pp. 28-29 of 474)

4.5.2. Required Number and Configuration of New MUs

“ ... Appendix C of the AHETF Governing Do cument describes several simulation

methods that can be used to determine reason able sample sizes for MUs. In brief, the simulation procedure for this scenario consists of the following steps:

1. Given candidate values for number of m onitoring areas, NC, numbers of MUs per cluster, NM, and AaiH strata, simulate normalized exposures, AaiH levels, and exposures derived from AaiH levels a ssuming proportionality, from the two-stage lognormal reference model. For this model, a GSD of 5 and an ICC of 0.3 is assumed.

2. From these simulated data, estimate the geometric mean, arithmetic mean, and 95th percentile of normalized exposure. Calcul ate the fold relativ e accuracy of these estimates compared to their true values.

3. In addition, from these same simulated da ta, determine if the slope from a mixed model regression of log exposure on log AaiH is significantly di fferent from zero.

4. Repeat steps 1 through 3 10,000 times and calculate the 95 th percentile of fold relative accuracy for each normalized exposure statis tic and determine if it satisfies the primary benchmark objective. Also compute the percentage of simulations yielding a statistically significant slope. This percenta ge is the power needed to evaluate the secondary benchmark objective.

“Using this approach, it was found that the primary objective can be met with NC = 10 monitoring areas of NM = 3 MUs each. Th is would provide a total of 30 MUs.

“For the secondary objective, the power to detect proportionality between exposure and AaiH also depends on the partic ular set of AaiH used. But as noted in step 1 above, AaiH levels must be simulated for the hypothesized MUs. As described in Section 5.2.1 below, diversity selection for new clusters will require that the AaiH levels for MUs extend over the complete practical range expected the scen ario. This practical ra nge is 0.5 to 15 lb AI handled per workday and covers two orders of magnitude. Diversity in AaiH levels is achieved by first partitioning the appropriate pr actical range into 3 strata. Then for each configuration, a single MU is obtained from within each Aa iH stratum. The AaiH strata are each designed to have approximately the same upper-to-lower bound ratio, slightly greater than 3-fold.

“An analogous procedure is followed in step 2 above when simulating AaiH levels for MUs: within each simulated new configuration, an AaiH level is simulated log-uniformly

from within each of the 3 strata. Th en exposure data are simulated assumingAttachment 2

Page 32 of 57 proportionality with the AaiH levels and usi ng the assumed variation structure. For each simulated set of data, a regression analysis is performed and the significance of the loglog slope determined (2-sided test). The power is the proportion of the time that the slope was found significant at p<0.05.

“When this simulation method is used assumi ng the 10 3-MU clusters needed to satisfy the primary benchmark, the power was found to be essentially 100%. In other words, the secondary power objective for this scenario is automatically met with the number and configuration of MUs required fo r the primary benchmark objective .” (pp. 29-30 of 474)

(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, nor could it be.

(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 obt ained in the same monitoring area be in

the same AaiH stratum

“This similarity restriction results in Aa iH levels for all MUs being approximately uniformly located over the entire log AaiH range when log exposure is regressed against log AaiH.

“In addition to the similarity restricti on on AaiH (i.e., SR1 above), diversity among MUs is also enhanced by imposing the fo llowing mandatory and preferred similarity

restrictions on each se t 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)

“SR4. All three MUs must have monitoring conditions with a di fferent degree of openness or enclosure

“SR5. When possible, all th ree MUs should not have th e same formulation type (i.e., liquid or solid)Attachment 2

Page 33 of 57 “SR6. Each pair of MUs must differ in at least one of the following

characteristics:

• Facility type/sub-type (i.e., N, OGH, or VGH)

• Method of mixing product (example: directly into spray tank or pre-mixed and then added to spray tank)

• Hose attachment (example: ha ndgun-type or hand wand type)

• Predominant spray orientation during monitoring period (i.e., downward, outward, upward, or some combination)

• Formulation type (i.e., liquid or solid)

• Product container size

• Performing equipment clean-up (i.e., yes or no) ” (p. 37 of 474)

(e) Can the data be statistically analyzed?

“As has always been the case, any statistical conclusions based on such data imply the qualification: ‘to the extent that the da ta can be viewed as deriving from a true random sample.’” (p. 49 of 474)

(f) 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 sta tistics 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 re lationship between exposure and AaiH, if one existed.” (p. 49 of 474)

“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.”Attachment 2

Page 34 of 57 “This secondary benchmark objective [Adequ acy of the Data for Distinguishing a Proportional from an Independent Relations hip between Exposure and AaiH] applies to each of the closed loading of liquids s cenarios because the practical range in the amount of active ingredient ha ndled (AaiH) exceeds an orde r of magnitude. In this

case it is reasonable to consider the lin ear regression of log dermal exposure on log AaiH. Such a regression would use a mixed model formulation in order to incorporate random cluster e ffects.” (pp. 49 - 50 of 474)

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

Yes.

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

Since the primary objective of the research is to characterize the distribution of exposure normalized by the amount of active ingredient handled (AaiH), statistical power does not relate to this objective. However, EPA believes the resulting data will reliably characterize the distribution of exposures for the individuals monitored during closed system liquid loading in this study, and that these exposures can inform assessments of the likely exposures for i ndividuals 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 directly proportional to AaiH. If exposure were independent of AaiH, then β =0. This benchmark objective requires that the

number of clusters and the allocation of AaiH levels to MUs should be adequate to ensure that the regression analysis has at least 80% power to reje ct the hypothesis that β =0 when β is actually equal to one. By symm etry, the mixed model linear regression would also have the same power to reject the hypothesis that β =1 when β =0. This is the precise meaning of being able to ‘discriminate between proportionality and independence’.” (p. 50 of 438)

2.2 How and to what will human subjects be exposed?

“ AHETF will monitor worker exposure resultin g from the mixing/loading and application of a pesticide product usi ng powered handgun equipment in nurseries and greenhouses

. ” (p. 23 of 474)

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

• Azoxystrobin

• Carbaryl

• ChlorothalonilAttachment 2

Page 35 of 57 • Fosetyl-al

• Imidacloprid

• Malathion

• Permethrin

• Sulfur

• Thiophanate-methyl” (p. 43 of 474)

(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 ti me.” (pp. 41-42 of 474)

(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 spray volume, number of loads sprayed, etc. Thus, diversification of AaiH induces

diversification of such associated factors as well. Therefore, in addition to having a wide range, the MUs within the same mon itoring area should not have similar AaiH

levels.

“A practical AaiH range is fi rst 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 then partitioned into three strata of approximately equal width on a logarithmic scale. Then, for each monitoring area, there is an attempt to restrict the MUs to no more than one per AaiH stratum. This similarity restriction imposes AaiH divers ity on the MUs and ensures a wide range of AaiH levels within each monitoring area.

“AHETF has developed a practical range in AaiH for this scenario taking into account such factors as the typical use rate s of products, types of products available on the market, area that can be treated in a day, etc. The practical range for amount of active ingredient handled per day is 0.5 to 15 lb per day. The lower practical limit of 0.5 pounds of active ingredient per day is sele cted to avoid an i nordinate number of non-quantifiable residues on worker exposure matrices and to a llow for at least 2 hours of work time with the high output handgun equipment being used in this

scenario .” (p. 35 of 474)

“This practical AaiH range was partitioned into the following three strata:

• Stratum 1 – From 0.5 lb to 1.6 lb

• Stratum 2 – Greater than 1.6 lb to 4.8 lbAttachment 2

Page 36 of 57 • Stratum 3 – Greater than 4.8 lb to 15 lb” (pp. 36 of 474)

(c) What duration of exposure is proposed?

“Work Duration

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

AHETF strives to monitor workers that represent a full workday with a desired minimum monitoring duration of half the wo rkday. This helps to insure that daily exposure estimates are not biased by unusual conditions during short intervals. However, the typical workday for this scen ario is generally sh orter than in other scenarios studied by AHETF. That is, surv ey results indicate that, depending on equipment and facility type, roughly 55 to 90% of workers make th eir applications in less than four hours. Therefore, for pur poses of this scenario design, a typical workday is assumed to be 4 hours, which wi ll result in a desired minimum duration of two hours. Minor scripting may be invol ved in order to achieve the desired monitoring duration such as spraying from pa rtially filled tanks resulting in more tank fillings than normal.

“Number of Loads Handled

“The number of loads handled could have an impact on exposure. AHETF’s standard guideline is that each MU will handle a minimum of three tank loads (i.e., mixing/loading and application). This ensu res the generic database will contain exposure data generated from work peri ods that represent a full day and from repeated application cycles that increase the opportunity for exposure (and therefore will not underestimate exposure potential). However, handling three loads may, in some cases, not be practical to achieve b ecause of the large spray tank sizes, the overall relatively low amounts of AaiH i nvolved, and the potentially short monitoring periods. However, scripting will be done if needed and practical under the application conditions of the particular operation in order to meet this desired

minimum. ” (p. 41 of 403)

2.3 Endpoints and Measures

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

asked?

“At the completion of the monitoring period, exposure samples will be taken in the following order to minimize cross contaminatio n: inhalation samples (discussed in the next section), then inner head patches af ter worker removes the chemical-resistant headgear, then inner socks, then hand wash es, then face/neck wipes, and finally inner

dosimeters as described in SOP AHETF- 10.E.2. Outer head patches are removed after the worker removes his headgear. Samples will be identified as described in SOP AHETF-8.F. For this study, inner dosimeter s will be cut into six sections after

collection.Attachment 2

Page 37 of 57 “Full details for sampling air with OSHA Versatile Sampler (OVS) tubes and personal air-sampling pumps are given in th e most recent versions of SOP AHETF8.D and 10.G.” (p. 364 of 474)

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

“Field fortification samples ar e exposure matrix samples that are fortified (or spiked), generally in the field, with known amounts of active ingredient and subsequently analyzed to determine the am ount of active ingredient rec overed. Field fortification samples are subjected to the same envi ronmental, handling, shipping and storage conditions as worker samples. Because these conditions are similar, and because field fortification samples are analyzed al ong with worker samples, recovery values calculated from analysis of fo rtification samples are app licable to worker exposure samples. Field fortification recoveries ar e therefore used to adjust residue levels found in worker samples for residue lo sses that might have occurred during collection, handling, shipping and storage. ” (SOP AHETF-8.E.6; p. 190 of 474)

(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 contai n a Quality Assurance Statement from the QAU of each contributing facility conducting QA audits, and from the QAU specified in Section 1.14.” (p. 374 of 474)

(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 e nvironmental conditions.” (p. 365 of 474)Attachment 2

Page 38 of 57 “For each fortification event, two untreate d 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.” (p. 366 of 474)

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

3. Subject Selection

3.1 Representativeness of Sample

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

“ AHETF will monitor worker exposure re sulting from the mixing/loading and application of a pe sticide product using powered handgun equipment in nurseries and greenhouses. Each instance of exposure m onitoring is termed a monitoring unit (MU). Each MU consists of a set of mi xing/loading-application conditions (including the particular worker) that are intended to represent the scenario activities for a single workday. Therefore each MU is an experimental realization of a ‘mixer/loader/applicator-day’ (or MLA-day) from the scenario population of all possible MLA-days. In many cases monitoring un its will be selected from ‘naturally occurring’ MLA-days. However, the select ed mixing/loading-a pplication conditions are sometimes modified or scripted slightly to ensure that the complete sample of MUs reflects the diversity in the entire scenario popul ation. It is important to emphasize that MU conditions are not necessa rily associated with the particular active ingredient used. The key assu mption underlying the AHETF monitoring program is that exposures are generic: th ey do not depend upon the chemical identity of any particular active ingredient although they may sometimes depend upon the way in which that active ingredient is handled. As a result, some MUs could be selected for conditions that are less typical for the active ingredient being monitored providing these conditions are expected for other active ingredients. Thus, MUs are technically not ‘sampled’ from an existing population as would be the case, say, with a statistical survey. More correctly, they should be vi ewed as synthetic handgun MLA-days derived from both sele cted and constructed conditions .” (p. 23 of 474)

(b) From what populations will subjects be recruited?

“The first step typically i nvolves contacting and selecti ng growers and/or commercial application companies that can provide the necessary crop/site, equipment and workers, and are willing to use an AHETF surrogate. This will be done by calling from a randomized list of growers in a local area (See SOP AHETF-11.M). GrowersAttachment 2

Page 39 of 57 that meet the criteria listed above will be pl aced in a pool of eligible growers. At this time, growers (employers) will be asked for permission to recruit their workers for the research study. Written assurance will be obtained from the employer that the workers will not suffer any consequence if they decide either to pa rticipate or not to participate in the study and that there will be no coercion of the workers (see Attachment 11-B-1).” (SOP AHETF-11.B.6; p. 240 of 474)

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

“A comprehensive list of growers will be created for each monitoring area listed in

Section 3 and will be referred to as the Gr ower Universe List (GUL). Growers on the GUL (or a random subset of the GUL) will undergo various qualifying screenings and interviews (described in later sections) that will identify growers that operate nurseries and/or greenhouses (including ornamental and ve getable greenhouses), that use powered handgun spray equipment, and that are potentially el igible to provide monitoring units (MUs) in the monitoring area. The list of growers for each monitoring area will be obtai ned from commercial list providers. They include:

• Meister Media Worldwide (publis her of the trade magazine Greenhouse

Grower )

• Moose River Media (publishe r of the trade magazine American Nurseryman )

• Dun & Bradstreet

“Names obtained from these list providers will be combined and their order randomized to provide a single list of grow ers that might operate nurseries and/or greenhouses and use powered handgun spray equipment. Any duplicate names will be removed from this grower list.

“The MGL is that portion of the GUL that will be subjected to the qualifying and eligibility determination process.

“All of the employers on the GUL may be placed on the MGL. However, if the number of growers on the GUL is expected to be larger than needed to provide an adequate set of potentially e ligible growers, the Study Dire ctor may choose to select a

random subset of the GUL to use for the MGL. The size of this subset is at the discretion of the Study Director. The rema ining growers on the GUL (or additional random subsets of remaining growers) can be added to the MGL at a later time as

needed.

“Missing or duplicate phone numbers on the MGL will be reconciled and/or corrected

as needed.

“The MGL will be screened to identify qualifying growers. A professional call center will contact each grower listed on the MGL and conduct screening interviews. Growers that can be screened comple tely and that meet minimum qualifyingAttachment 2

Page 40 of 57 requirements of the study will be identified as ‘qualified growers’ and added to a qualified grower list (QGL).

“The call center will attempt to contact and administer th e screening questionnaire to every grower on the MGL unless notified by the Study Director that additional qualified growers are no longer needed. Th e call center will make 15-20 attempts to reach each grower; if the grower is not reac hed after these attempts, then that grower

is eliminated.

“The screening questions will be used to identify growers that meet the minimum requirements for the study. As a minimum, a qualifying grower must:

• Make pesticide applications in nurseries or greenhouses within the monitoring

area

• Use powered handgun spray equipment

• Have at least one worker within th e operation that typically performs mixing/loading and application activi ties (and equipment cleanup if normally performed) at least 2 hours in a day.

“Additional qualifying questions may be includ ed as appropriate. For qualified growers,

the Call Center will also:

• Inform the grower that he will receive an introductory letter from the AHETF and be contacted by an AHETF represen tative to obtain additional information

• Determine the best time of day to cal l for follow-up questions (pp. 351-352 of 474)

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

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

3.2 Equitable Selection of Subjects

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

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

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

• Handle pesticides as part of their jobAttachment 2

Page 41 of 57 • Be trained in safe pesticide handling pr actices in accordance with the Worker Protection Standard (WPS) or equivalent Canadian regulations, or be exempt from such training

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

ID

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

AHETF

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

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

SOP AHETF-11.C for health status determination)

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

• Confirm they do normally wear personal protective equipment that is required by the label. If the worker indicates that they may wear additional PPE not required by the product label, and that additional PPE might impact the 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 will follow label dir ections. 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 (S ee SOP AHETF-11.I for a detailed discussion of this topic)

• Understand and sign the consent form, a nd if in California, the California Experimental Research Subject’s Bi ll of Rights” (SOP AHETF-11.B.6; pp. 242-3 of 474)

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

• Have experience within the past year with open pour mixing and loading of solid or liquid formulations, and with spraying the diluted product using a powered handgun in nurseries or gr eenhouses, including the type of equipment to be used.

• Agree to wear chemical-resistant gloves even if the label does not require

them.

• Agree to wear chemical-resistant he adgear during applications involving either ‘overhead only’ spray situatio ns or a mix of ‘overhead’ and ‘nonoverhead’ spray situations, even if th e label does not requ ire it.” (p. 335 of 474)

(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?Attachment 2

Page 42 of 57 Potential subjects are of necessity agricu ltural workers, and could potentially be subjected to undue influence either to participate or not to participate by their employers. This possibility is minimized through methods of recruiting growers and by requiring growers to promise in wr iting not to influence their employee’s

decisions.

(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.6; pp. 239-244 of 474) to recr uit potential partic ipants for this study. Individual workers will be recruited dur ing an initial interview with (or visit to) a potentially eligible employer once eligibility has been established. Alternatively, recruitment can occur on subsequent interviews with or visit(s) to an eligible employer.

“The Study Director or designated researcher will seek permission from the eligible grower to approach his/her employees to recruit workers for the study. Depending on the number of employees and size of the employer’s facility the Study Director or researcher may contact employees using an informational recruitment flyer posted in a common work area. Such a flyer will 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. 357 of 474)

(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. 240 of 474) A copy of the “Employer Cooperation Statement” is provided on p. 244 of 474.

“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 AHETFAttachment 2

Page 43 of 57 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.” (pp. 356-7 of 474)

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). Workers 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 each time they suit up (i.e ., put on the long underwear) to participate in the study. Usually, workers wi ll participate in the study on only one day unless their participation is terminated due to weather or other unexpected occurrences. The additional $80 is provided in cash at the end of the monitoring pe riod or at the time the worker withdraws from the study. All workers who participate will receive the payment, even if they withdraw or their pa rticipation is terminated by the study team.” (p. 335 of 474)

(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.Attachment 2

Page 44 of 57 This study could involve any of nine ac tive ingredients: Azoxystrobin, Carbaryl, Chlorothalonil, Fosetyl-al, Imidacloprid, Ma lathion, Permethrin, Sulfur, ThiophanateMethyl.

“The pesticide products that contain these active ingredients and potentially used in this study will be products registered fo r nursery and/or greenhouse use and the specific application planned by the gr ower. AHETF will only monitor workers mixing/loading and applying products in acco rdance with all labe l requirements.” (p. 339 of 474)

For all nine 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 activities

• 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.” (p. 336 of 474)

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

Quantitative probabilities are not estimated.

4.2 Risk Minimization

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

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

• Selecting only experienced pesticide ha ndlers who consider themselves to be in good healthAttachment 2

Page 45 of 57 • Requiring experience with the type of powered handgun mixing/loading and application equipment to be used

• Reminding workers of safe chemical handling practices

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

• Identifying nearby medical treatment facilities in case of emergency

• Monitoring the heat index and stoppi ng the study if conditions warrant

• 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 th roughout the monitoring period

• Ensuring that all tank mix products are used according to approved label(s) and state regulations, and do not requ ire any additional PPE that could adversely affect the study objectives (for example, chemical-resistant coveralls).” (p. 344 of 474)

Risk reduction actions specific to the identi fied kinds of risk are discussed in the protocol (pp. 336-344 of 474).

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

for the test materials?

For all nine 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?

“AHETF will monitor environm ental conditions to determin e the heat index near the mixing/loading or application activities. Exposure monitoring will be discontinued if

the heat index cutoff of 105 o F (adjusted for direct sun, if applicable) is reached or exceeded. The Study Director or other rese archer shall stop the monitoring and/or

move the worker to a cooler environmen t until monitoring can be resumed.” (p. 336 of 474)

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

“As a safety measure, AHETF will have a medical professional on site during the study. This may be a 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. 416 of 474)Attachment 2

Page 46 of 57 SOP AHETF-11.H.3 (pp. 267-270 of 474) 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.3 (pp. 250-251 of 474) 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.3 (pp. 254-266 of 474) 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.3 (pp. 267-270 of 474) 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 AH ETF management (SOP AHETF-11.J).” (pp. 349 of 474)

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

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

Page 47 of 57 “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. 417 of 474)

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. 344 of 474)

(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 mixing/loading and applic ation of pesticides using powered handgun equipment in managed horticultural facilities . The knowledge likely to be obtained from this study is generalizable and will contribute to assessments of the risks of both new and existing pesticides.

“Since there are insufficient existing data suita ble for use in a generic database describing the exposure to workers who mix/load and apply pesticides from powered handgun equipment in managed horticultural faciliti es, society will likely benefit from data generated by this study through the impr oved risk assessments by EPA and other regulatory agencies.” (p. 345 of 403)

“Growers (employers) who allow the study to be conducted using their equipment, facilities, crops and workers will be reimbur sed for the pesticides used for the study. While this is beneficial to the grower, it is considered a minor benefit when compared to the costs of running their business.” (p. 344-5 of 474)

(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 traps chemical that penetrates the work clothing), this study presents a greater than minimal risk toAttachment 2

Page 48 of 57 participants. Participating in this study increases the risk of heat-related illness, but this risk is mitigated by a medical management program which emphasizes prevention measures and guidelines for stopping participation when warrant ed based on environmental conditions.

“The likely benefit to agricultural workers as a w hole and to society in general, in the form of more accurate measurements of potential exposure to pesticides, must be weighed against the risks to participants. Experts consulte d by AHETF reported that the use of handgun equipment is a common method of pesticide application in nurseries and greenhouses. Therefore, exposure data for these scenarios meeting contemporary standards of reliability and quality will likely provide a significant be nefit to society. Because margins of exposure are acceptable for the products proposed for us e in this research study, subjects are very unlikely to experience acute toxic effects, and because extensive procedures will be in place to minimize these and other risks to participants , the likelihood of seri ous adverse effects is very small. In summary, AHETF believes the risks to study participants from participating in this study are reasonable in light of the likel y benefit to society of the knowledge to be gained.” (p. 345 of 474)

7. Independent Ethics Review

(a) What IRB reviewed the proposed research?

Independent Investigational Review Board, Inc., of Plantation FL

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

(c) Is this IRB registered with OHRP? Yes

(d) Is this IRB accredited?

IIRB, Inc. earned “Full Accreditation” fr om the Association fo r the Accreditation of Human Research Protection Programs, Inc. (AAHRPP) in December of 2009.

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

Yes.

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

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

conduct.Attachment 2

Page 49 of 57 “The IRB for the proposed research shall be the Independent Inve stigational Review Board Inc. (IIRB) of Plantation, Florida. Comp lete records of the IIRB review as required by 40 CFR 26.1125 will be submitted to EPA for review along with this protocol and

other documents.

“Researchers that participate in the study and interact with study participants must undergo ethics training (SOP AHETF-1.B). The training shall include successful completion of the course from the Nationa l Institutes of Health (Protecting Human Research Participants (PHRP)) and/or the Basic Collaborative IRB Training Initiative Course (CITI; The Protection of Human Resear ch Subjects). Copies of the certificates of completion for the ethics courses will be submitted to the IRB and stored in the respective personnel files (maintained by the AH ETF and all contract facilities.)” (p. 334 of 474)

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 notaddressed 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. 271-276 of 474)

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

See SOP AHETF-11.I.3 (pp. 271-276 of 474)

(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 50 of 57 issues. The form in Attachment 11-J-1 will be used to ascertain general understanding.” (SOP AHETF-11.J.1 §3.10.a; p. 279 of 474)

(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, 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 51 of 57 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. 278-9 of 474)

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

coercion or undue influence?

“In accordance with SOP AHETF-11.B, grower s 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 volunteer; and that th e employee’s decision to participate or not will have no impact on their empl oyment.” (p. 356-7 of 474)

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. 346 of 474)

“Your name will only appear on the consent form, an optional form for you to request your personal study results. In all other pa rts of the study you will be identified by a code. Records with your name will be stor ed in a secure place with limited access.Attachment 2

Page 52 of 57 “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 agencies, and by the Independent Investigational Review Board, Inc., (IIRB). IIRB is a group of people who review and

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

“You may ask the Study Director for a copy of your personal results from this study. You will need to provide your name and a mail or e-mail address.” (p. 417-8 of 474)

(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 an d face/neck samples will be collected with the worker’s consent. The Study Director will decide whether these samples will be analyzed (SOP AHETF-8.K).” (p. 346 of 474)

“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. 419 of 474)

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

dealt with?

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

are owed.Attachment 2

Page 53 of 57 “If you withdraw or if your part in this st udy is stopped at any time by the researchers or the AHETF, the long underwear, inner socks, chemical-resistant ha t with outer patch, inner head patch and air sampling pump will be removed. The handwash and face/neck samples may be collected if you agree.

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

“No one can force you to take pa rt in this study. Taking part is totally voluntary. If you choose not to take part in this study you w ill perform your ordinary activities on the day of the study. Your alte rnative is to not take part.” (pp. 419 of 474)Attachment 3

Page 54 of 57 § 26.1111 Criteria for IRB approval of research AHETF Protocol: M/L/A in Managed Horticultural Facilities w/ Powered Handgun Equipment (AHE600)

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 55 of 57 §26.1116 General requirements for informed consent AHETF Protocol: M/L/A in Managed Horticultural Facilities w/ Powered Handgun Equipment (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 56 of 57 §26.1117 Documentation of informed consent AHETF Protocol: M/L/A in Managed Horticultural Facilities w/ Powered Handgun Equipment (AHE600)

Criterion Y/N Comment/Page Reference

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

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

(b)(2) The consent form may be a short form written consent document stating that the elements of informed consent required by §26 .1116 have been presented orally to the subject or the subject’s legally authorized r epresentative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subjec t or the representative. Only the short form itself is to be signed by the subject or t he representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A co py of the summary shall be given to the subject or the representative, in add ition to a copy of the short form. n/aAttachment 6

Page 57 of 57 40 CFR 26.1125 Prior submission of proposed human research for EPA review AHETF Protocol: M/L/A in Managed Horticultural Facilities w/ Powered Handgun Equipment (AHE600)

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. 335-344

None

pp. 411-422, 456-469

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. 303-474 (5) ● A list of IRB members identified by name; earned degrees; representative capacity; indications of experience su ch as board certifications, licenses, etc., sufficient to describe each mem ber’s chief anticipated contributions to IRB deliberations;

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

with EPA

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). Y Separately submitted to EPA under confidentiality claim (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. 335-344 (2) The measures proposed to minimize risks to the human subjects; Y pp. 335-344 (3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y pp. 344-5

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y pp. 20-22

(5) The balance of risks and benefits of the proposed research. Y p. 345 §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. 384, 438 Approved pp. 411, 456

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y pp. 39-40, 335, 350-355, 409,

454 §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. 346-9

§1125(e): All correspondence between the IRB and the investi gators or sponsors. Y pp. 308, 400-406, 437, 452-453,

470-471 §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. 405, 453