Page 1 of 52 Ha
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

September 30, 2010

MEMORANDUM

SUBJECT: Science and Ethics Review of AH E400: A new scenario design and associated protocol from the Agricu ltural Handler Exposure Task Force (AHETF) describing proposed research to measure dermal and inhalation exposure to applicators who use bac kpack or hand gun sprayers to apply pesticides in utility rights-of-way

FROM: Jeff Evans, Senior Scientist

Health Effects Division Office of Pesticide Programs

Kelly Sherman, Human Research Ethics Reviewer

Office of the Director Office of Pesticide Programs

TO: Steve Knizner, Associate Director

Health Effects Division Office of Pesticide Programs

REF: Bruce, E. (2010) Backpack and Handgun Application of Liquid Sprays in Utilities Rights-of-Way. Unpublishe d protocol dated June 18, 2010, prepared for the Agricultural Handlers Exposure Task Force under Sponsor ID AHE400, 558 p.

We have reviewed the referenced propos al from both scientific and ethics perspectives. Scientific asp ects of the proposed research are assessed in terms of the

recommendations of the EPA Guidelines Se ries 875 and of the EPA Human Studies Review Board. Ethical aspects of the propos ed research are assessed in terms of the standards defined by 40 CFR 26 subparts K and L and the recommendations of the EPAPage 2 of 52 Human Studies Review Board. Below is a summary of the conclusions reached in our

science and ethics reviews.

Science Review

• The protocol addresses the technical as pects of applicable exposure monitoring guidelines and is likely to produce scie ntifically valid and useful data.

• No revisions are requested by EPA at this time.

Ethics Review

• The protocol meets the applicable et hical requirements of 40 CFR part 26, subparts K and L.

• Before the research is conducted, the prot ocol should be revised as follows and resubmitted for review by the approving IRB:

 The Local Site Coordinator, the Principal Field Investigator, the Analytical Facility, and the Principa l Analytical Investigator must be identified in the protocol.

• In future AHETF protocols, please incor porate into the protocol or an SOP the following information (this information was provided separately to EPA – see Supplements 2 and 3):

 information about how subjects are pr esented with individual exposure information; and

 an explanation of the process that the AHETF follows to improve and verify the accuracy of the Spanish translations.

A. Completeness and Contents of Protocol Submission

The submitted protocol was reviewed for completeness against the required elements listed in 40 CFR §26.1125. All required elements are present. EPA’s checklist is appended to this review as Attachment 6.

The following four documents comprise the protocol submission and were

considered in EPA’s review:

• Backpack and Handgun Application of Li quid Sprays in Utilities Rights-ofWay Scenario Submission (June 18, 2010) (558 pages);

• Supplement 1: SOPs Cited in Backpack and Handgun Application of Liquid Sprays in Utilities Rights-of-Way Scenario Submission (142 pages);

• Supplement 2: Details about method for informing subjects about their individual exposure re sults (8 pages); and

• Supplement 3: Details about work unde rtaken by AHETF to improve Spanish translations (1 page).Page 3 of 52 The monitoring unit selection and scenario construction plan appear on pages 11-

58 of 558 1 . The rationale for the proposed samp le size and cluster configuration is presented on pages 19-27 of 558. The IRB- approved protocol and supporting documents (consent forms and recruitment flyers) appe ar on pages 266-345 of 558. Documentation

of all interactions between th e investigators and the Indepe ndent Investiga tional Review Board, Inc., of Plantation FL a ppears on pages 259-558 of 558.

B. Summary Assessment of the Scenario Designs 2

1. Scenario Designs: This protocol addresses two distinct handler scenarios to address the use of hand-held equipment fo r treating utility rights-of-way (ROW); backpack sprayers and hand gun spraye rs. Although the two scenarios are distinct, the AHETF intends to collect monitoring units (MUs) for each scenario in the same geographic locations. Th is may result in the AHETF monitoring participants using either equipment types on any given day. However, the

recruitment will be structured so that any participant will be monitored using either one of the equipment types but not both. Separate individuals will be recruited for each equipment type. The AHETF will conduct both studies at electric utility ROWs to develop data fo r these two scenarios. This is largely based Kline & Co. survey data inform ation suggesting that approximately 80 percent of utility ROWs are treated with herbicides compared to pipeline rights of

way.

The backpack sprayer, as the name im plies, is a small 3 to 5 gallon tank carried on the back of a handler. The sprayer has a hand pump to provide pressure for the spray and small lengths of hose connected to a hand wand. Backpack sprayers

are best suited for ROW treatments in areas where vehicle access is difficult or impossible. Unlike other backpack scen arios, there will be no mixing activities performed for this scenario. However, some participants may load their backpacks with dilute spray from a nurse tank if that is part of their normal work practice.

1 Unless otherwise noted, referenced pages may be found in the main scenario submission document (containing 558 pages).

2 Supporting details are in Attachment 1.Page 4 of 52 By contrast, the handgun sprayer consists of a trigger nozzle (handgun) connected to a length of hose which is attached to a vehicle mounted tank. The application of pesticides with this system requires th e handler to either treat vegetation from Backpack sprayer

There are a wide variety of backpack sprayers

availablePage 5 of 52 the truck or drag the hose from the spray vehicle to the treatment area. The length of the hose can range from 500 to 2000 feet and the handgun has an effective spraying distance of 15 to 30 feet.

The ROW scenarios are not covered by EPA’s Worker Protection Standard (WPS) at 40 CFR 170. The WPS only a ddresses agricultura l uses on farms, forests, nurseries and greenhouses. Re gardless, the study designed for the two scenarios, is based on participants wearing a long-sleeved shirt, long pants, shoes, socks, and chemical-resistant gloves. Other clothing items that may be worn by participants include vests, hats and g oggles. ROW applicators that normally wear chemical-resistant headgear will not participate. There is no specific mixing component for either of these two ROW scenarios (common for hand-held equipment scenarios). Therefore, these da ta will be used specifically to address occupational handler exposu re for ROW treatments.

The AHE400 protocol calls for applying one of four surrogate pesticides for the two ROW scenarios. The surrogate pest icides selected by the AHETF are the widely used herbicides fosamine, gyphos ate, imazapyr and 2,4-D. Although fosamine and imazapyr are new surrogates for the AHETF, these pesticides have been successfully used in other oc cupational and non-oc cupational exposure monitoring studies, including those in th e Pesticide Handlers Exposure Database (PHED). The Agency asserts that confir mation of method analysis, as outlined in the governing document, is required prior to study initiation.

A total of 21 Monitoring Units (MUs ) are proposed for both the backpack scenario and the handgun scenario. Thr ee MUs for each site w ill be collected in Hand gun sprayingPage 6 of 52 7 geographically distinctive EPA growi ng regions. Once the studies are reviewed and the AHETF primary and secondary objectives (i.e., relative accuracy and proportionality respectively) are substantiated, the two scenarios

will be added to the AHED database. EPA intends to use these data to estimate daily dermal and inhalation exposures of pesticide handlers using backpack and handgun equipment for pesticides register ed or to be registered for ROW

treatments.

2. Sampling Designs: Normally the AHETF (task force) select clusters purposively to reflect a diverse range of crops, ag ronomic practices, geographic regions and likelihood of finding participants that use the AHETF’s surrogate pesticides. For

the two ROW scenarios addressed in this protocol, the task force needed to identify regions having high ROW pesticid e use commensurate with areas having high electric transmission line densities. Furthermore, considerations such as number of utility companies in a given region and its impact on recruitment and the establishment of distinct study sites needed to be addressed. To accomplish this, the AHTEF designed both scenario cl uster configurations as having more study sites and fewer MUs per site (7 x 3 design instead of the 5 x 5 design seen in previous protocols presente d to the HSRB). That is, seven clusters (i.e., sites) with each site having three handlers (i.e., MUs) per ROW scenario. These

diversified clusters were identified through a two stage diversity selection

process:

• Identifying diverse geographic areas based on climate and areas of high pesticide use for ROW treatments (p redominantly the north central and south regions of the United States)

• Configuring three diverse MUs per ge ographic area within those regions

The result of executing these steps was the purposive choice of the following seven monitoring sites which may be stat es or portions of states purposively selected from six EPA growing regions:

• West Virginia (EPA Region I with some overlap into EPA Region II)

• North Carolina (EPA Region II)

• Florida (EPA Region III)

• Arkansas (EPA Region IV)

• Indiana (EPA Region V)

• Minnesota (EPA Region V)

• Eastern Texas (EPA Region VI)

There were a number of site selec tion considerations acknowledged by the AHETF with respect to util ity line density, number of utility companies and EPA growing regions. EPA agr ees that the site choices made by the task force are well reasoned and appear to strike a bala nce between maintaining site diversity and likely success of finding a sufficient pool of participants for the two proposed

ROW scenarios.Page 7 of 52 In the next stage of the diversity selection process, the AHETF identified the practical range of amount of active ingredient handled (AaiH) for the two ROW scenarios. For the backpack ROW scenario the range of amount active ingredient handled (AaiH) per day is 0.5 to 50 pounds per day. For the Handgun ROW scenario, the AaiH is 1 to 125 pounds per da y. The strata are designed to ensure that the range of AaiH per scenario is at least an order of magnitude. This will help the task force achieve is secondary objective, pr oportionality. The scenario specific ai strata are as follows:

Backpack ROW strata

• From 0.5 to less than 1.5 pounds active ingredient

• From 1.5 to less than 15 pounds active ingredient

• From 15 to 50 pounds active ingredient

Handgun ROW strata

• From 1 to less than 3.5 pounds active ingredient

• From 3.5 to less than 35 pounds active ingredient

• From 35 to 125 pounds active ingredient

Generally, the AHETF ensure that no 2 part icipants be in the same AaiH stratum per monitoring site in the same scenario. However, do to recruitment concerns, the AHETF are concerned that this may not always be possible and have modified the protocol to state that “it is preferable that no 2 MUs be in the same stratum in a monitoring area.” It is likely that the ra nge of AiaH at a given site would be at least an order of magn itude if this situation presents itself.

The next stage of sample se lection results in identifyi ng the employers of handlers who make ROW treatments. This process requires securing the permission of the utility companies as well as employers of contract ROW application companies. The AHETF established a process for iden tifying handler subjects that could be recruited directly from utility companies th at make their own applications or from utility companies that rely on contract appl ication companies. In either case, the AHETF will need to gain the permission of the utility company to participate in the study. The first step in this proce ss in to list and scr een all application companies (which may include the utility company). The procedure is as

follows:

• Assemble a comprehensive list of all possible application companies. Eliminate all duplicates where possible.

• On a scenario basis, contact all employers on the list to determine if they are qualified and willing to participat e. Those willing and qualified will be put on a potentially eligible list.Page 8 of 52 • In order to establish an efficient configuration for the eventual field studies, the number of available employees from each application company that is eligible as well as the timing of their ROW applications

will be identified.

The second step involves identifying partic ipants for the three MUs per scenario. The second step will be conducted indepe ndently for each scenario. This second step includes:

• Establishing a set of el igible employers willing to cooperate with the

AHETF

• Conducting recruiting activities

• Selecting volunteers meeting the scenario conditions.

This process of identifying cooperating employers is basically sound. EPA has accepted this approach.

When constructing MUs, three additional re strictions will be enforced to increase diversity within the cluster:

• No handler may be used more than once

• On a site basis, each handler must come from a different employer

The employers in the chosen configurat ion provide the pool of handlers from

which handlers will be recruited to fill each of the three MU sl ots. If selected employers or handlers drop out as th e time of the field study approaches, additional handlers appropriate to fill out the MU desi gn may be recruitable from among those employed by other eligible application companies.

3. Choice of Surrogate Materials: The surrogate chemicals proposed for these scenarios are fosamine, gyphosate, imazapyr and 2,4-D, formulated as liquids. There are a few wettable powder formulations of 2,4-D, however it is important to

note that these two scenarios involv e applying sprays without a mixing component. Although two of these surroga tes are new to the AHETF, they have been successfully used in other monitoring studies including thos e in the Pesticide Handlers Exposure Database (PHED). Th e Agency asserts that confirmation of method analysis is required prior to study in itiation. Given this final verification the Agency agrees that these surrogates ar e generally appropriate choices for this research. Preliminary risk estimates fo r the surrogates having toxicity endpoints of concern (2,4-D and imazapyr), indicate th e estimated exposures of participants in the proposed studies are not of concern.Page 9 of 52 C. Summary Assessment of the Scientif ic Aspects of the Study Design 3

1. Statistical design: This protocol describes co llecting 21 Monitoring Units (MUs)

for the BP/ROW and HG/ROW reflecti ng the exposure of subjects applying sprays containing fosamine, gyphosate, imazapyr and 2,4-D. These MUs will be collected in seven separate clusters diverse in geogra phic location and climate. Each cluster or study site will include three MUs. The AHETF recently designed

handler scenarios based on a 5 site x 5 MU configurati on, largely for agricultural scenarios. The general rationale for the 7 x 3 cluster configur ation is primarily based on concerns of being able to identif y more than 3 partic ipants per scenario at any given site. Thus, the AHETF se lected a configuration weighted towards having more sites and fewer MUs per site. The overall rational for efficient study designs is presented in Appendix C of the revised AHETF Go verning Document.

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

each MU will be at least 4 hours. The activ ities performed by the participants will be primarily spraying however some loadi ng of dilute spray from tanks situated on trucks may be possible for the backpack scenario. Each participant will spray at least 3 tank-loads. The mixing will be done by others not participating in the study. At each site, during the monitori ng period, each subject will apply the surrogate active ingred ient in one of the following th ree strata of amount of active ingredient handled (AaiH):

Backpack ROW strata

• From 0.5 to less than 1.5 pounds active ingredient

• From 1.5 to less than 15 pounds active ingredient

• From 15 to 50 pounds active ingredient

Handgun ROW strata

• From 1 to less than 3.5 pounds active ingredient

• From 3.5 to less than 35 pounds active ingredient

• From 35 to 125 pounds active ingredient

The AHETF acknowledges that some scripting may be needed for subjects assigned to the lower AI strata. This is to ensure that at least 3 mixing/loading

events are measured for each worker a nd that a minimum 4 hour work monitoring period is achieved.

3. Endpoints and Measures: The study is designed to measure dermal and inhalation exposure for each MU. These da ta will contribute to development of

3 Supporting details are in Attachment 2.Page 10 of 52 Unit Exposures (exposure per unit of pesticid e active ingredient applied) or other exposure metrics that will be used to es timate dermal and inhalation exposure to other pesticides for handlers making RO W applications using backpack or handgun sprayers. EPA believes that the proposed measures are appropriate and sound for the study design.

Dermal exposure will be measured by a whole body dosimeter (WBD) worn beneath the subject’s outer clothing. After the monitoring event, the inner dosimeter will be removed from the subject and sectioned into six pieces: the front torso (above the waist); rear tors o (above the waist); right and left upper arms (shoulder to elbow); right and left lo wer arms (elbow to cuff); right and left upper legs (waist to knee) a nd the right and left lower legs (knee to cuff).

Before beginning work, subjects will wa sh their hands in 500 mL of 0.01%

Aerosol ® OT-75 solution (AOT solution) to remove any source of contamination and to practice the method of hand-washing. These samples will be discarded. Hand wash samples will be collected before toilet and lunch breaks, before water breaks if required by the label or reques ted by the subject, and at the end of each exposure period.

Before beginning work, each subject’s face and neck will be wiped with a cotton gauze swab to remove any contaminati on not associated with the monitoring event. This wipe sample will be di scarded. 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 retain ed for analysis. As required by AHETF SOP 10.C.4, the study team will record what type of personal protective equipment (PPE), including respirator s, was worn at any time during the monitoring event.

Airborne concentrations of the surrogate will be monitored in the subject’s breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector connected to a personal sampling pump. The unit will be calibrated prior to the monitoring event using a rotameter. The OVS tube will be clipped to the subject’s shirt collar with the intake facing downward. The air sampling pump

will be connected to the OVS tube and w ill be operated for the total monitoring period including any breaks. Inhalation measures will need to be based on moderate breathing levels due to the higher activity level of appl ying pesticides in heavy terrain rather than lower activity levels expected of individuals making groundboom applications.

Additional measures will record envi ronmental conditions at the time of monitoring. Observers will make field not es of subject activity throughout the monitoring event, and photographs or videos may be taken selectively to illustrate

events.

4. QA/QC Plan: The study will be monitored by three different quality assurance units: one from the exposure monitoring contr actor that conducts the study in thePage 11 of 52 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, fi eld fortification and control samples, laboratory fortification and control sa mples, and guidelines on the use of

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

Field fortifications will be conducted in th e field under the same conditions as the field samples. They will be transported and stored in a similar manner as the field samples, and will be analyzed in the laboratory concurrently with the field samples. Samples collected from the s ubjects will be corrected based on the results of the recovery of th e field fortified samples.

5. Statistical Analysis Plan: The results of physical sample analysis will be provided in the final report of this field study and in the scenario monograph covering all monitoring conducted under the mixing/loading of water soluble packets scenario, and will be posted to the AHED ® database, where they will be available to regulatory agencies for late r statistical analysis. The documentation will report a confidence-interval-based approach to determine the relative accuracy for the arithmetic mean and 95 th percentile of un it exposures. The AHETF will not otherwise statistically analyze the monitoring data.

D. Compliance with Applicable Scientific Standards

This protocol itself adequately addresses the following elements according to applicable scientific standards:

• Scientific objective

• Experimental design for achieving objectives

• Quantification of the test materials

• Data collection, compilation and summary of test results

• Justification for selection of test substances

• Justification for sample size

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

Additionally, the proposal has addressed the technical aspects provided in the applicable exposure monitoring guidelin es (i.e. Series 875 Group A and OECD Applicator Guidelines) as well as Good Laboratory Practices (GLPs).Page 12 of 52 E. Summary Assessment of Ethical As pects of the Proposed Research 4

1. Societal Value of Proposed Research: The objective of this study is to develop data to determine the potential exposur e for workers who use backpack and handgun sprayers to apply liquid sprays in utilities ROW. This application method is widely used in utilities ROW to maintain vegetatio n control, and “is

critical to the deliverance of electrici ty, natural gas, and petroleum across the country. Access to utility lines must be available for maintenance and repair purposes, and is accomplished by controlli ng line-threatening vegetation.” (p. 15 of 558) The existing exposure data for this exposure scenario are inadequate. EPA will use the results of this study to estimate the dermal and inhalation exposure likely for a wide range of ag ricultural pesticides applied under this exposure scenario.

2. Subject Selection: Subjects will be recru ited among the employees of application companies that apply pesticide sprays for vegetation control to utilities ROW using backpack or handgun sprayers, w ho are willing to us e at least one of the surrogate active ingredients for this study (glyphosate, fosamine, imazapyr, and 2,4-D), and who meet AHETF criter ia for participation. Application companies (either those utility companies that make their own applications or contract application companies hired by utility companies) will be eligible to participate in the study. AH ETF must obtain employer c ooperation before it can recruit workers. This includes willingne ss of the utility company to have its ROW treated as well as willingness of the application company (either the utility company or its contractor applicator) to volunteer their application equipment and

allow AHETF to recruit their workers. E ligible employers will be identified from a complete list of ROW application compan ies (i.e. either those utility companies that make their own applications or c ontract application companies hired by utility companies) in the target area, pr ocessed in random sequence. Subjects will be recruited who are employees of eligib le employers, have experience within the past year with applying liquids with BP (BP/ROW scenario) or HG spray equipment (HG/ROW scenario) in utilitie s ROW (including the type of equipment to be used), , and who meet the eligibili ty requirements of the study. If more employees are available and interested than are needed, qualified participants will be selected randomly. Although the design is purposive, and thus participants are not representative in a statis tical sense, they are expect ed to be typical of those who apply liquids with BP or HS spray equipment in utilities ROW.

Subjects will be recruited according to the standard procedures set forth in SOP AHETF-11.B. The Study Director or desi gnated researcher will seek permission from an eligible employer to approach hi s/her employees to recruit subjects for the study. Depending on the number of employees and size of the application company, the Study Director or researcher may cont act employees using an informational recruitment flyer posted in a common work area. Alternatively, or

4 Supporting details are in Attachment 2.Page 13 of 52 subsequent to the use of a flyer, the St udy Director or researcher will arrange a meeting with the employees who expre ss interest in participation. Such recruitment meetings will always occur without the employer or supervisors being present. The Study Director or resear cher will describe the AHETF Exposure Monitoring Program, the goals of this specif ic study, the procedures to be used in exposure monitoring, and the risks and benefits to participants.

The subject eligibility fa ctors listed in the consen t form and SOP AHETF-11.B are appropriate.

Candidates who attend an individual inte rview will be paid $20 whether or not they agree to participate; enrolled su bjects who put on the whole-body dosimeter will be paid $80 in addition to their us ual pay, whether or not they complete participation.

3. Risks to Subjects: Four kinds of risks to subject s 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 risks

• The risk of exposure to surfactants

In this study risks to subjects are classifi ed as ‘greater than minimal’, primarily since agricultural work is considered a high risk occupation where the likelihood of harm or discomfort is greater than what is encountered in or dinary daily life. In particular, the risk of heat-related illn ess (resulting from wearing an extra layer of clothing to trap chemical) will be in creased due to study pa rticipation. AHETF has adopted an extensive program to minimize these risks.

Appropriate provision is made for safety and medical monitoring. At the end of the test day, subjects will be reminded that they have a copy of the consent form with phone numbers to call if they think they have any adverse effects resulting from participation.

4. Benefits: This research offers no direct be nefits to the subjects. But subjects may request a summary of their personal re sults from the stu dy. The results will

include the distribution of chemical exposure among the various body parts and a comparison to the results for other workers performing the same task. Thus, a potential indirect benefit for subject s is knowledge about how their exposure compares to that of others doing similar work.

The principal benefit of this research is likely to be reli able data about the dermal and inhalation exposure of workers applying liquid sprays to utilities ROW with BP or HG spray equipment, usable by EPA and other regulatory agencies toPage 14 of 52 support exposure assessments for a wide va riety 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 reas onable in light of the likely benefits to society from new data supporting more accu rate applicator exposure assessments for a wide range of agricultural pesticides.

6. Independent Ethics Review: The proposed research has been reviewed and approved by the Independent Investigati onal Review Board, Inc., (IIRB, Inc.) of Plantation, Florida. The submitted ma terials include a full record of correspondence between the i nvestigators and the IIRB.

7. Informed Consent: Informed consent will be obtained from each prospective subject and appropriately documented. Oral fluency in English or Spanish is a criterion for inclusion, but literacy is not required. The r eading level of the English language consent form is appropr iate. Adequate provision is made to meet the needs of subjects who do not read either language. EPA assessments of compliance with the requirements of 40 CFR §26.1116 and §26.1117 appear in

Attachments 4 and 5 to this review.

8. Respect for Subjects: Subject identifying information will be recorded only once; all subsequent data records and repor ts will refer to i ndividual subjects only by a code. Provision is made for discrete handling of pregnancy testing, required of all female subjects on the day of te sting. Candidates and subjects will be repeatedly reminded that they are free to decline to participate or to withdraw at any time for any reason, without penalty.

F. Compliance with Applicable Ethical Standards

This is a protocol for third-party rese arch involving inte ntional exposure of human subjects to a pesticide, with the inte ntion of submitting the resulting data to EPA under the pesticide laws. Thus the primary et hical standards applicab le to this proposal are 40 CFR 26, Subparts K and L. In addi tion, the requirements of FIFRA §12(a)(2)(P) for fully informed, fully voluntary consent of subjects apply.

A detailed evaluation of how this propos al addresses appli cable standards of

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

40 CFR 26 Subpart L, at §26.1703, as amended effective August 22, 2006, provides in pertinent part:

EPA shall not rely on data from a ny research involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a child.Page 15 of 52 The protocol requires that s ubjects be at least 18 years ol d and excludes female subjects who are pregnant or lacta ting. Thus §26.1703 would not forbid EPA to rely on a study executed according to this protocol.

If conducted according to the protocol, this research should meet the ethical standards of FIFRA §12(a)(2)(P) and 40 CFR 26 subparts K and L.

Attachments:

1. EPA Scenario Review: AHETF Applicati ons in Utilities Rights-of-Way Scenario (AHE400) 2. EPA Protocol Review: AHETF Applicati ons in Utilities Rights-of-Way Scenario (AHE400) 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 52 EPA Scenario Review: AHETF Applications in Utilities Rights-of- Way Scenario (AHE400)

Title: MU (Monitoring Unit) Selection Plan: Backpack and Handgun Application of Liquid Sprays in Utilities ROW

Date: June 4, 2010

Sponsor: Agricultural Handler Exposure Task Force

1. Scope of Scenario Design

“Both rights-of-way applicati on scenarios are defined by the form of diluted product, application equipment and use site (i.e., ROW) as follows:

• Backpack application of liqui ds in utilities ROW (BP/ROW)

Backpacks provide a low volume, low pressu re directed spray me thod of application for controlling undesirable utility line-thr eatening species of vegetation such as weeds, brush and vines. Although there ar e different brands of backpack sprayers,

and there is some variation in nozzle/wand configurations and ta nk capacity, they are all operated in more or less the same way. That is, the backpack is carried on the back of a worker; and spray pressure is accomplished by manual pumping to pressurize the tank and squeezing a trigger to release spray via the nozzle/wand. In contrast the HG/ROW scenario, backpack application can be use when vehicle access is not possible or difficult.

• Handgun application of liquids in utilities ROW (HG/ROW)

Handgun spray equipment provides a high volume targeted spray method of application for controlling undesirable uti lity line-threatening species of vegetation such as weeds, brush and vines. The a pplication system itself is comprised of a handgun which is attached to a hose, which is in turn attached, through a pump, to the spray tank. The spray tank and pump system are mounted on a vehicle such as a truck, so this application technique require s the target vegetation to be accessible by

service roads. The worker is often required to drag hose fr om the spray vehicle to the treatment area where the applicati on is then made. (pp. 14 of 558)

“...Although it is possible that backpacks and handguns are used in utilities ROW in all of the EPA Growing Regions listed in Table 3, not all are expected to have significant use. In particular, the drier climate associated with th e western portions of states in Regions VII and VII is not expected to be conductive to the type of vege tation growth that would present utility line-threatening conditions (Standart, 2010). This woul d result in a minimal amount of backpack and handgun use, especially when co mpared to such in less dry climates in the east. Therefore, portions of the two Kline marketing areas that intersect EPA GrowingAttachment 1

Page 17 of 52 Regions VII and VII will be excluded from the Scenario Target Area. Table 4 lists those EPA Growing Regions that are still likely to have significant backpack and handgun use in

utilities. This table documents the final restricted Scenario Target Area and the geographic/climatic stra tification of the Area.

Table 4: Final Geographic and Climatic Stra tification of the Scenario Target Area based on EPA Growing Regions

EPA Growing Region States (or portions of stat es) in the Scenario Target Area that are in EPA Growing Regions I Eastern OH, Northern WV, Northern MD, DE II Southern WV, Southern MD, VA, NC, SC, GA, AL, Eastern TN,

Eastern KY III Florida, boot heel of AL
IV Western TN, MS, AR, LA
V MI, Western OH, IN, Western KY, IL, MO, IA, WI, MN, Eastern ND, Eastern SD, Eastern NE, Eastern KS
VI Eastern OK, Eastern TX

(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 both the BP/R OW and the HG/ROW scenarios as being within the scope of the task force goals and one for which da ta are lacking. A number of AHETF member products are labe led for these use patterns. These products are important because maintaining vegetation control in util ities ROW is critical to the deliverance of electricity, natural gas and petroleum across th e country. Access to utility lines must be available for maintenance and repair purpos es, and is accomplished by controlling linethreatening vegetation. For these reasons, it is necessary to have data in AHED for the application method described by bo th scenarios.” (pp. 15 of 558)

BP/ROW Scenario

“AHETF (in conjunction with EPA, PMRA, and CDPR, collectively the Joint Regulatory Committee (JRC)) reviewed handler exposure m easurements in existing studies (mostly not included in PHED) to identify those that satisfy current acceptability criteria and qualify for inclusion in a generic database. For this particular scenario, the JRC reviewed four studies (AH309, AH313, and AH605, AH613) involving either application only or mixing/loading/applying of liqui d formulations with backpack sprayers. None of these studies were deemed appropriate for a generic database.Attachment 1

Page 18 of 52 “The AHETF purchased a liquid formulati on backpack mixer/loader/applicator study (AH605-MLA) that was conducted in a gr eenhouse using a typical low pressure backpack with a handwand. Applications we re made to plants on benches and, in some cases hanging overhead baskets. Thus, low volume equipment and general directions are comparable in greenhouse and ROW. However, this study was not deemed appropriate for extrapolation to this scenario becaus e there are differences in other important exposure conditions. For example, conditions encountered in ROW application include walking in rough, uneven terrain while target ing a mixture of brush/vine/weed heights and densities, and contending with outdoor environmental conditions...” (pp. 16 of 558)

The AHETF also conducted a detailed review of the data in two potential relevant PHED (EPA, 1998a) backpack applica tion scenarios to determine if any of the data were suitable for a modern generic database. These PHED scenarios were:

• Scenario 20 – Backpack Application (APPL ). This PHED scenario contains exposure data for monitoring units making only backpack applications

• Scenario 34 – Liquid/Open Pour/Backp ack (MLAP). This PHED scenario

contains data for MUs involved in mixing, loading, and applying liquid formulations with backpacks.

The AHETF is interested in only those PH ED MUs corresponding to a single layer of clothing with chemical-resistant gloves. In the detailed AHETF review of these PHED data, no MUs were found that met the acceptance criteria established by AHETF (Klonne, 2010a; Klonne 2010b). For Scenario 20 the dermal data are graded as “Low Confidence” due to insufficient dosimetry, a lthough the inhalation data are graded as ‘High Confidence”. For Scenario 34 the derm al and inhalation data are graded as “Low Confidence”, primarily due to low numbers of measurements. Thus, there are no data currently in PHED for this scenario that are useful for a modern generic database.

“Finally, EPA examined data from exis ting water soluble p acket mixing/loading exposure studies or exposure assessments th at were not available to the AHETF and concluded that none of the exposure data s hould be included in the AHETF database (meeting, November 3, 2008).” (pp. 17 of 558)

HG/ROW Scenario

“For the HG/ROW scenario the JRC reviewed on study (AH315-A) involving application of liquid sprays with a handgun sprayer from a truck. This study was ultimately determined not to be appropriate for a gene ric database due to a variety of clothing combinations and the use of two layers of clothing.

The AHETF review of the ha ndgun application data in PHED focused on data for a single layer of clothing (w ith gloves) in the following seven PHED scenarios:

• Scenario 18 – Low Pressure Handwand Application (APPL). This PHED scenario contains exposure data for m onitoring units making applications only.Attachment 1

Page 19 of 52 • Scenario 19 – High Pressure Handwand Application (APPL). This PHED scenario contains exposure data for m onitoring units making applications to indoor (poultry houses) and outdoor (weeds and brush) environments.

• Scenario 21 – Hand Gun (Lawn) Sprayer (APPL ). This PHED scenario contains exposure data for monitoring units ma king handgun applications to lawns.

• Scenario 24 – Right-of-Way Sprayer Applic ation (APPL). This PHED scenario contains exposure data for monito ring units making actual ROW handgun applications in brush.

• Scenario 32 – Wettable Powder/ Open P our/ Low Pressure Handwand (MLAP) – This PHED scenario contains exposure data for mixing/loading and application

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/ Hi gh Pressure Handwand (MLAP) – This PHED scenario contains exposure data for mixing/loading and application

activities.

“For scenario 18 the dermal data are graded as “Low Confidence” due to an inadequate

number of dermal and hand measurements. Inhalation data ar e graded as “Low Confidence” due to an inadequate number of measurements. For Scenario 19 the dermal data are graded as “Low Confidence” due to an inadequate number of dermal and hand measurements and to poor grade quality. Inhalation data ar e graded as “Low

Confidence” due to low number of measurem ents and to poor grade quality. For

scenario 21 the dermal and inhalation data are graded as “Low Confidence”. For Scenario 24 the dermal data are graded as “Low Confidence” due to lack of dermal and hand measurements, but the inhalation data are graded as “High Confidence”. For Scenario 32 the dermal data are graded as “Low Confidence” due to an inadequate number of dermal and hand replicates. Inhalation data are graded as “Medium

Confidence”. For Scenario 33 the dermal and inhalation data are graded as “Medium

Confidence”. For Scenario 35 the dermal and inhalation data are graded as “Low Confidence” due to an inadequate number of measurements.” (pp. 17 – 18 of 558)

EPA asserts that rejecting data in PHED based on low numbers of samples is not sufficient justification for not considering PHED data for inclusion in the new database. The more important reasons, as is the case fo r these data, include issues such as study design (patches, AaiH strata) and that the activ ities measured are not specific to the ROW scenarios the AHETF are addressing in this protocol (e.g., studies conducted in greenhouses, poultry houses and lawn care settings).Attachment 1

Page 20 of 52 “Lastly, EPA examined data from existi ng handgun applicator studies or exposure

assessments that were not available to th e AHETF and concluded that none of the exposure data should be incl uded in the AHETF database (Meeting of Joint Regulatory Committee with AHETF, May 05, 2009).” (pp. 19 of 558)

2. Rationale for Scenario Sampling Design

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

“... the Target Area for both scenarios is iden tical and has been restricted to two of the four major marketing regions defined by Klin e & Co. covering 28 stat es (or portions of states) in the mid-west, south and eastern por tions of the US. Thes e two regions account for about 90% of chemicals used in vegeta tion management in utilities ROW. Although

other areas of the U.S. not contained in these two regions may utilize backpacks or handgun in utilities, applicati on conditions are not expected to differ significantly from those in the Target Area. This is beca use regardless of location, each scenario’s application equipment (i.e., backpack or handgu n) is typically used under certain growth conditions such as height and density of brus h, and can involve terrai n ranging from flat

to mountainous.

Both of these scenarios focus on treating foliage of the target vegetation because it is the most efficient, and therefore most commonl y used, method of application. However, some vegetation situations ma y require a non-folia r treatment such as frilling (hack and squirt) to be used in conjunction with foliar ap plication. If a non-fo liar technique is used in conjunction with foliar application, it wi ll be included in the monitoring; however, MUs will not be monitored solely for non- foliar application.” (pp 6 – 7 of 558)

“The selection of monitoring sites within each stratum was purposive and considered several factors including size of the monitoring site (e.g. stat e or portion of state) and utility transmission line density. The follo wing monitoring sites ar e proposed for both scenarios to provide the desired diversity in geography and climate within each scenario.

• West Virginia (in EPA Growing Regi on I, extending slightly into II)

• North Carolina (in EPA Growing Region II)

• Florida (in EPA Growing Region III)

• Arkansas (in EPA Growing Region IV)

• Indiana (in EPA Growing Region V)

• Minnesota (in EPA Growing Region V)

• Eastern Texas (in EPA Growing Region VI)” (pp. 5 or 558)

(b) How have random elements been incorpor ated into the scenar io sampling design?

For both scenarios, all choices in the pr oposed diversity sele ction process, and stratification by AaiH are purposive choices.Attachment 1

Page 21 of 52 “Both backpack and handgun fo liar application to utilities ROW can occur over a wide geographic area and at different times. Lo cating a potential worker and handling-day

condition from which to construct an MU is a complicated process. No comprehensive list of future applicator locations and dates is available. As a resu lt, potential application

conditions have to be selected (and/or constructed in stages).

In essence, this selection pro cess for a particular scenario can be envisioned as occurring in two successive stages. The first stage consists of selecti ng moderately-sized geographic areas from which the monitoring units will be obtained. Each such area is termed a ‘monitoring site’ and will typically co nsist of a convenient political entity, such as a state (or portion of a state). Applica tion companies within each monitoring site are screened to indentify qualified employers willing to participate in the monitoring program. The second stage of this proce ss identifies potential worker volunteers and application conditions from among the identified employers and uses this information to

construct a diverse set of monito ring units. When feasible, it is preferable that this final set of MUs be arranged in an efficient confi guration. That is, all else being equal, the configuration of locations and monitoring date s of the MUs should be as cost-effective as possible. An efficient configuration is expe cted to result in a singl e cluster of MUs that are slightly correlated with respect to exposure. Consequently, for scenario design purposes only, it will be assume d, conservatively, that there is only a single cluster per monitoring site. In practice, less cost-effective configur ation of MUs consisting of multiple clusters might arise.” (pp 11-12 of 558)

“...the basic conditions necessary to construc t MUs for either the BP/ROW scenario or the HG/ROW scenario are obtained by a two-stag e diversity selection process. These

two stages are:

1. Selection of seven monitoring sites that are diverse with respect to geography and climate. (Section 5.2)

2. Selection and construction of a configuration of three diverse monitoring units within each monitoring site. (Section 5.3)

At both stages, diversity among selection units (monitoring sites of MUs) is formally induced by first grouping the available units to be selected into comb inations called strata (Section 5.1). Then, similarity restrictions and preference s are imposed on the selection units making use of these strata and other characteristics. For practical reasons, selection of units will usually be purposive. Howeve r, whenever feasible, random selection of monitoring units will be used to re duce selection bias. (pp 19 of 558)

“...diversity among MUs is aided by grouping se lectable units into ‘strata’ defined by one or more key characteristics of the scenari o. These strata are then utilized at both the first and second stages of selection. At the first stage, the relevant strata are geographic/climatic partitions of the Scenario Target Area. The Scenario Target Area for both scenarios is the geographic extent cons idered for MUs and encompasses that portionAttachment 1

Page 22 of 52 of the U.S. where both backpack and handgun application in util ities ROW are most likely to occur.

The second stage of selection makes use of a stratification of the amount of active ingredient handled (AaiH) to diversify MUs. A practical AaiH range is first defined for each scenario. The practical range encompasses AaiH levels that can be readily found in practice and are expected to produce detectable exposure resu lts. The practical range is

then stratified so that an MU can be sele cted from each AaiH stratum. (pp 20 of 558)

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

have been overlooked?

By constructing an “efficient configuration” of MUs such that more handlers are in the recruiting pool in a given geographical area, it is likely that the opportunity will often arise to select randomly from among interested workers.

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

“...the workers will be allowed to follow thei r normal procedures as long as they fit the

scenario definition. The duration of the work activity will be partially determined by the

amount of AaiH but will invol ve the application of at l east three loads (BP/ROW only)

and a minimum duration of f our hours (both scenarios).

Work activity characteristics that are s cenario specific include the following:

• BP/ROW Scenario

A parameter that might impact exposure is returning to the filling station and re-filling the backpack. According to experts, ROW backpack application workers typically fill their own sprayer. The filling process can range from using completely closed systems to us ing a nozzle to a mixing tank to pump liquid into the backpack tank opening, which could result in direct contact with the liquid in cases of overfilling of splashing. In addition, the worker could increase dermal exposure by contacting contaminated surfaces such as the support vehicle or mixing tank. For th is scenario, whethe r or not a subject loads his own backpack will be determined by the standard practice of the particular application company.

Another parameter that might impact e xposure is the number of loads handled, primarily because it involves re-fil ling the backpack tank. AHETF has a standard practice that each MU will apply a minimum of three tank loads. This ensures the generic database will contain exposure da ta generated from work periods that represen t a full day (i.e., generally four hours or more), and from repeated filling and application cy cles that increases the chance for exposure (and therefore will not underes timate exposure potential). Some diversity in the number of loads w ill naturally occur since AaiH andAttachment 1

Page 23 of 52 equipment tank size will vary, as will MU site conditions such as distance from mix tank to target vegetation, th ickness of vegetation and roughness of terrain.” (pp 37 of 558)

• “HG/ROW Scenario

A parameter that might impact exposure is returning to the vehicle. A worker

could return to the vehicle to take brea ks, wait for a new load of spray mix, or get into the vehicle to move to the ne xt treatment area. In any of these situations, dermal exposure could be increased by contacting contaminated surfaces of the vehicle or contacting treate d foliage that is in the path of the worker walking out of the treatment area to the vehicle.

Duration of monitoring is another parameter that could vary between MUs of either scenario, especially since the AaiH will pr obably vary by more than an order of magnitude. Experts indicate that ROW backpack and handgun applicators spend several hours per day making applications (including walking to and from the treatment site). All monitoring periods for this scenario must meet the general rule of being at least 4 hours. This is designed to overcome the criticism of early exposure studies where many of the sampling regi mes monitored workers for only a few minutes. Avoiding very short monitoring in tervals will ensure that daily exposure estimates are not biased by unusual conditions during the short interval. If necessary, some minor scripting of worker activities will be done to en sure the lowest levels of

AaiH are handled and/or a minimum of four hours are monitored. For example, in the BP/ROW scenario, a worker may be aske d to use a smaller ta nk, or decrease load size, etc., in order to apply 3 loads in f our hours. Or, an HG/ROW scenario worker may be asked to adjust the spray concentrati on in order to achieve the lowest levels of AaiH.” (pp 46 of 558)

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

“Because of the diversity obtained for AaiH and the variability of vegetation conditions which may be encountered in this study, equi pment will likely differ among MUs as each applicator utilizes the appropr iate spray volume, pressure, nozzle configuration, etc.” (p. 39 of 558)

“...some workers might wear non label-require d items such as leggings or chaps over their regular clothing. However, such addi tional attire would in terfere with AHETF’s preference to collect data using baseline clothi ng (i.e., long pants and long sleeved shirt). Therefore only workers who do not wear items su ch as leggings or chaps will be used in this study.

...chemical-resistant headgear is not require d by any product labels reviewed to date; however, since applications can involve sprayi ng into vegetation that can reach about 10 feet (BP/ROW) or 20 feet (HG/ ROW) in height, it is possibl e that a worker might chooseAttachment 1

Page 24 of 52 to wear some type of chemical-resistant h eadgear. Nonetheless, only workers who do not wear chemical-resistant headgear will be used in this study.

...not all products that might be used in these two scenarios require the use of chemicalresistant gloves. However, AHETF has learne d that some companies interviewed require their use as company policy, and that other products frequently used in tank mixes do require the use of gloves. For this reason, and to ensure consistency of data collection for hand residues, it will be the practice of AHETF to only monitor workers wearing chemical-resistant gloves.” (pp 48 of 558)

3. Are the prop osed test materials appropriate surrogates?

“The following active ingredients will be considered for use in both the BP/ROW and HG/ROW application scenarios.

• Glyphosate

• Fosamine

• Imazapyr

• 2,4-D

These AHETF survey confirmed that one or mo re of these AIs are commonly used in all seven of the monitoring sites. They provide a range of use rates, including one with a relatively high rate which will enable measurem ents at the high end of the AaiH per day. Prior to study conduct analytical methods fo r each surrogate AI will be developed and validated for each matrix used in this study. Matrices include: inner dosimeter, hand rinse, face/neck wipe, socks and OVS tubes. Finally, these active ingredients will be or have been either tested for stability or have been used as surrogates in other studies and are known to have the required stability under fi eld study conditions.” (pp. 48-49 of 558)

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

“Appendix C of the Governing Document desc ribes the methodology to calculate sample

sizes when the reference model used is clus ter sampling from a lognormal distribution. For the purposes of determining sample sizes, th e default variation structure for normalized dermal exposure derived in Appendix C from an an alysis of multiple studies. This default, a geometric standard deviation (GSD) of 4.0 is also assumed applicable to both the BP/ROW

and HG/ROW scenarios. AHETF and the Jo int Regulatory Committee agreed there is no evidence to suggest that dermal exposure variatio n is substantially different from this default value and had no strong opinion to the c ontrary (meeting with AHETF, May 27, 2010).

The analogous default intra- cluster correlation (ICC) deve loped in Appendix C of the Governing Document is 0.3. For both of these ROW application scenarios, it is conceivable

that the ICC could be less than 0.03. ...since there are no data available for estimating a different ICC value to use and since overestimating the ICC results in larger total sample sizes, the use of ICC=0.3 is still consid ered reasonable, al beit conservative.Attachment 1

Page 25 of 52 As discussed in Appendix C, when this defau lt variation structure is used (and there are no suitable existing MUs) there are several equivale nt configurations of number of monitoring sites (N C ) and number of MUs per monitoring site (N M ) that will meet the 3-fold accuracy requirement. These equivalent c onfigurations are listed in Table 2.

Table 2: Equivalent Configurations of Nu mber of Monitoring Sites and Number of MUs per Monitoring Site

Number of Monitoring Sites,

N C Number of MUs per Monitoring Site, N M Fixed/Variable Cost Ratio where Optimal

15 1 0 - 05

9 2 0.5 - 1.5

7 3 1.5 - 2

5 5 2 - 7

4 8 Over 7

Although these five configurations are statistically equivalent, they can differ substantially in cost or in their attainability. When the 5 conf igurations an Table Two are equal feasible, the choice among them depends upon the expected rati on of the overhead (o r ‘fixed’) cost of obtaining and characterizing a monitoring site an d the additional (or variable) cost per MU. For most typical scenarios the AHETF estimates th at this ratio is betw een 4.5 and 6. That is,

the overhead cost of a new monito ring site is about the same as the cost of adding 5 or 6 new MUs to an existing monitoring site. Given this cost ratio, a sample of 5 monitoring sites (N C =5) with 5 MUs per site (N M =5) is usual the most cost eff ective design configuration that meets the 3-fold accuracy requirement. Configur ations with more moni toring sites and fewer MUs per site provide greater statistical inform ation per MU (the reason that fewer total MUs are needed) but they are also more costly due to the large overhead per additional monitoring

site.

“Appendix C of the Governing Document also shows that when the benchmark accuracy requirement above is met there may also be su fficient power to permit users of the database to perform a limited examination of the rela tionship between the nor malizing factor (e.g., AaiH) and exposure. This is true provided: (1 ) the practical range of the normalizing factor is at least an order of magnit ude and (2) there is adequate w ithin-cluster variation in the normalizing factor. When these conditions occur, the MU sample will be of sufficient size and diversity to provide at least 80% statisti cal power to distinguish complete proportionality from complete independence between exposur e and the normalizing factor used in the primary benchmark. Since these conditions can be satisfied for the reference sampling design, then the purposive dive rsity design for both the BP/ROW scenario and the HG/ROW scenario should provide adequate power for th e minor (i.e., secondary) objective: the ability

to conduct limited examinations of the relations hip between AaiH and exposure.” (pp. 17-19 of 558)Attachment 2

Page 26 of 52 EPA Protocol Review: AHETF Applications in Utilities Rights-of-Way Scenario (AHE400)

Title: Determination of Dermal and Inhalation Exposure to Workers during Backpack and Handgun Application of Li quid Sprays in Utilities Rights-ofWay

Revision Date: June 4, 2010

Study Director and Principal Investigator:

Eric D. Bruce

Principal Field Director:

Aaron Rotondaro

Local Site Coordinator: TBD

Field Facility: “ The study...will be conducted in a variety of utilities ROW locations in an outdoor environment. The Principal Fi eld Investigator utilizes a mobile laboratory (a large truck or trailer) th at provides the necessary private and clean environment for dressing worker s, undressing workers, and collecting exposure samples from workers. Si nce there is no field facility per se where the study is conducted, no addr ess is provided.” (p. 303)

Analytical Facility: TBD 5

Sponsor: Agricultural Handlers Exposure Task Force, LLC c/o David R. Johnson, Ph.D. 1720 Prospect Drive

Macon MO 63552

Reviewing IRB: Independent Investigational Review Board, Inc.

6738 West Sunrise Blvd Suite 102

Plantation FL 33313

1. Societal Value of Proposed Research

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

“The objective of this study is to develop data to determine the potential exposure for workers making backpack (PB) and handgun (HG) liquid applications in utilities rights-

5 The analytical laboratory selected will depend on which active ingredients are actually used in the study. This study may involve multiple active ingredients so multiple analytical investigators and analytical facilities may be involved. The final report will document which laboratories and Principal Analytical Investigators are involved with analysis of samples from this study. (p. 304)Attachment 2

Page 27 of 52 of-Way (ROW) at seven monito ring sites spanning six geogr aphical/climatic regions of the United States.” (p. 301)

(b) What research question does it address? Why is this question important? Would the research fill an importan t gap in understanding?

This study will provide a partial answer to the question of what dermal and inhalation exposures are likely for handlers making BP/R OW and HG/ROW applications. This is an important pesticide handling scenario for which existing data are inadequate.

(c) How would the study be used by EPA?

EPA will use the results of this study to estimate the dermal and inhalation exposure likely for handlers making BP/R OW and HG/ROW applications.

(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 m easurements in existing studies (mostly not included in PHED) to identify those that satisfy current acceptability criteria and qualify for inclusion in a generic database. For the BP/ROW scenario, the JRC reviewed four studies (AH309, AH313, AH6 05 and AH613) involving eith er application only or mixing/loading/applying of liqui d formulations with backpack sprayers. None of these studies except AH605 was found to be appropriate for a generic database.

... [This purchased study will, however be considered in another scenario that represents backpack applications in greenhouses and nurseries.]

The AHETF also conducted a detailed review of the data in two potentially relevant PHED (EPA 1998a) backpack appl ication scenarios to determin e if any of the data were suitable for a modern generic database . . . T hus there are no data currently in PHED for

this scenario that are useful for a mo dern generic database.” (pp. 16-17 of 558)

For the HG/ROW scenario, the JRC revi ewed one study (AH315-A) involving application of liquid sprays with a ha ndgun sprayer from a truck. This study was ultimately determined not to be appropriate for a generic database due to a variety of clothing combinations and the us e of two layers of clothing.

“AHETF also conducted a detaile d review of the data in PH ED for this scenario to determine if any of the data were suitable fo r a modern generic database. . . . Thus there are no data currently in PHED for this scen ario that are useful for a modern generic database.” (pp. 17 of 558)Attachment 2

Page 28 of 52 (e) Could the question be answered without newly exposing human subjects? If so how? If not, why not?

There is no alternative to monitoring ha ndlers as they apply ROW pesticides for measuring their dermal 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?

“The goal of conducting MUs for the BP/ROW and HG/ROW scenarios is to develop a set of generic dermal and inhalation exposure data which regulators and other potential users of the generic database can utilize to characterize the magnitude and likely range of future exposures, and to perform exposure asse ssments for these two related scenarios. . .

. . the data collected for these two scenar ios will only be statistically evaluated with respect to specific ‘benchmark’ measures of adequacy. As discussed in the Governing Document, the two categories of benchm ark data adequacy considered are:

1. the relative accuracy of se lected statistics characte rizing the distribution of exposure normalized by amount of ac tive ingredient handled (AaiH).

2. How well the data can be expected to de scribe a relationship between exposure and AaiH, if one existed (pp. 54 of 558)

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 achieved by the proposed study.

2.1 Statistical Design

(a) What is the rationale fo r the choice of sample size?

“Appendix C of the Governing Document desc ribes the methodology to calculate sample

sizes when the reference model used is clus ter sampling from a lognormal distribution. For the purposes of determining sample sizes, th e default variation structure for normalized dermal exposure derived in Appendix C from an an alysis of multiple studies. This default, a geometric standard deviation (GSD) of 4.0 is also assumed applicable to both the BP/ROW

and HG/ROW scenarios. AHETF and the Jo int Regulatory Committee agreed there is no evidence to suggest that dermal exposure variatio n is substantially different from this default value and had no strong opinion to the c ontrary (meeting with AHETF, May 27, 2010).Attachment 2

Page 29 of 52 The analogous default intra- cluster correlation (ICC) developed in Appendix C of the Governing Document is 0.3. For both of these ROW application scenarios, it is conceivable

that the ICC could be less than 0.03. ...since there are no data available for estimating a different ICC value to use and since overestimating the ICC results in larger total sample sizes, the use of ICC=0.3 is stil l considered reasonable, albeit conservative.” (pp. 17 of 558)

(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?

“A configuration of three MUs is obtained from among the potential volunteers and their possible monitoring conditions. It is desirable that the set of potential MUs be large enough to permit some random selec tion of equivalent volunteers and to account for situations in which companies of participants are not av ailable at the last minute for the scheduled monitoring. Gene rally, this means an attempt to identify conditions that might provi de about twice the number of MUs actually needed.

... The three MUs in any monitoring site mu st also satisfy the following similarity

restrictions:

• No two MUs obtained for the same scen ario can utilize the same worker

• No two workers in the same monitoring site used for the same scenario can have the same employer

In addition, whenever feasible, it is pr eferable, but not mandatory, that the configuration of MUs in a monitoring site also satisfy the following two similarity

restrictions:

• It is preferable that no two MUs obtained for the same scenario in the same monitoring site be in the same AaiH stratum

• If an employer has previously cont ributed a worker to an MU in a different monitoring site for the same scenario, then it is preferable that this same employer not contribute a nother worker. (pp. 43 to 44 of 558)Attachment 2

Page 30 of 52 “The study director will determine the mean ing of sufficient set of potential MUs’ that should apply to a scenario or to an individual monitoring ar ea. In general, however, it is desirable that the set of potential MUs be large enough to permit some random selection of equivalent volunteers and to account for situations in which companies or participants are not availa ble at the last minute for the scheduled monitoring. Therefore, for each monitori ng area every effort should be made to obtain (for each scenario):

• At least 6 workers who may poten tially volunteer for the study

• At least 2 of these workers available for each of the AaiH strata” (pp. 406 of 558)

(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.’” (pp. 54 of 588)

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

“... the data collected for thes e two scenarios will only be statistically evaluated with respect to specific ‘benchmark’ measures of adequacy. As discussed in the Governing Document, the two categories of benchmark data adequacy considered

are:

1. The relative accuracy of selected stat istics characterizing the distribution of exposure normalized by amount of ac tive ingredient handled (AaiH).

2. How well the data can be expected to describe a relationship between exposure and AaiH, if one existed.” (pp. 54 of 558)

“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 give n above.” (pp. 55 of 558)

“This secondary benchmark objective [Adequ acy of the Data for Distinguishing a Proportional from an Independent Relations hip between Exposure and AaiH] applies

to both the BP/ROW and the HG/ROW scenar ios because the practical range in the

amount of the AaiH exceeds an order of magnitude in both cases. In this case it is reasonable to consider the linear regressi on of log dermal exposure on log AaiH. Such a regression would use a mixed mode l formulation in order to incorporate random cluster effects.” (pp. 55 of 558)Attachment 2

Page 31 of 52 (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 the BP/ROW and HG/ROWstudies, a nd 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.

“This secondary benchmark objective a pplies to both the BP/ROW and HG/ROW scenarios because the practical range in the AaiH exceeds an order of magnitude in

both cases. In this case it is reasonable to c onsider the linear regr ession of log dermal exposure on log AaiH. Such a regression would use a mixed model formulation in order to incorporate random cluster effects. As describe d 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 expos ure 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 an alysis has at least 80% power to reject the hypothesis that β =0 when β is actually equal to one. By symmetry, the mixed model linear regressi on would also have the same power to reject the hy pothesis that β =1 when β =0. This is the precise m eaning of being able to ‘discriminate between proportionality and independence’.” (pp. 55 of 558)

2.2 How and to what will human subjects be exposed?

“ The following active ingredients will be consid ered for use in both the BP/ROW and the HG/ROW application scenarios.

• Glyphosate

• Fosamine

• Imazapyr

• 2,4-D” (pp. 48 of 558)

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

“The AHETF survey confirmed that one or more of these AIs are commonly used in all seven of the monitoring sites. They pr ovide a range of use rates, including oneAttachment 2

Page 32 of 52 with a relatively high rate which will enab le measurements at the high end of the AaiH per day.” (pp. 40 of 558 )

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

dose administration?

“Since the number of pounds of active ingr edient handled is th e normalizing factor and indirectly influences many other hand ling conditions, efforts will be taken to generate data in as wide a range of AaiH as practical within each monitoring site. AaiH is selected as the normalizing f actor since AHETF feels it is the most reasonable measure of active ingredient contact potential for both of these scenarios. . . . In addition, EPA currently normalizes both backpack and handgun application exposure by AaiH during pesticide produc t exposure assessments. No other normalizing factor identified as being more appropriate.

In addition to its potential direct relati onship 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.

AHETF has developed practical ranges in Aa iH for both scenarios taking into account such factors as the typical use rates of products, types of products available on the market, area that can be treated in a day, etc. These practical ranges for amounts of active ingredient ha ndled per day are:

• BP/ROW scenario: 0.5 to 50 lbs per day

• HG/ROW Scenario: 1 to 125 lbs per day

The lower practical limits of 0.5 pounds (BP/ROW) and 1 pound (HG/ROW) of active ingredient per day ar e selected to avoid an i nordinate number of nonquantifiable residues on worker expo sure matrices. (pp. 23-33 of 558)

(c) What duration of exposure is proposed?

“Duration of monitoring is another para meter that could vary between MUs, especially since the AaiH will be varied by more than an order of magnitude. Experts indicate that ROW backpack and handgun a pplicators spend several hours per day making applications (including walking to and from the treatment site). All monitoring periods for this scenario must m eet the general rule of being at least 4 hours. This is designed to overcome the criticism of early exposure studies where many of the sampling regimes monitored wo rkers for only a few minutes. Avoiding very short monitoring interv als will ensure that daily exposure estimates are not biased by unusual conditions during that s hort interval. If necessary, some minor scripting of worker ac tivities will be done to ensure the lowest levels of AaiH are

handled and/or a minimum of four hours are monitored. For example, a worker mightAttachment 2

Page 33 of 52 be asked to adjust the spray concentration in order to ach ieve the lowest levels of AaiH.” (pp. 46 of 558)

2.3 Endpoints and Measures

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

asked?

“Full details of procedures for dermal and inhalation exposure sampling and for sample removal are specified in the most recent versions of SOPs AHETF-8.A, 8.B, 8.C and 8.I. At the completion of the monitoring period, exposure samples will be taken in the following order to minimize cr oss contamination: inhalation samples

... , then inner socks, then hand washes, th en face/neck wipes, and finally inner dosimeters as described in SOP AHETF-10.E....For this study, inner dosimeters will

be cut into six sections after collection.

“Full details for sampling air with OSHA Versatile Sampler (OVS) tubes and personal air-sampling pumps are given in th e most recent versions of AHETF-8.D and 10.G (pp. 334-335 of 558).”

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

“Full details regarding fiel d recovery evaluation proce dures for all sampling media are given in the most recent version of SOP AHETF-8.E...

“ In addition for each fortification event, duplicate samples of the inner dosimeters fortified in the field at the highest leve l, and duplicate OVS tubes fortified in the laboratory at the next-to-highest fortificati on level, will be processed in the field for immediate frozen storage and used as travel spikes. These travel spikes will be analyzed on if deemed necessary be th e Study Director, for example to help

determine the cause of unusua lly low field fortification re covery results.” (pp. 336 of 558).

Field fortification samples are exposure matrix samples that are fo rtified (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.Attachment 2

Page 34 of 52 (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 1.14 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 laboratory conducting QA audits , and from the QAU specified in section 1.14.” (pp. 343 of 558)

(d) How will uncertainty be addressed? Will reported point values be accompanied by measures of uncertainty?

Uncertainty in field measurements will be addressed via fortification samples.

“Sample matrix fortifications designed to assess the stability of the active ingredient during field, storage and tran sit 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 location, or more days as appropriate for environmental conditi ons. . . . For each fortification event, two untreated control samples of each matrix will be processed similar to the field fortification samples (i.e., some are weathe red). Packaging, storage and shipment of the field fortification samples will be the same as for the worker exposure samples.” (pp. 335-336 of 558)

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 result ing from the filling (if applicable) and applying liquid sprays of pesticide to target foliage under both the BP/ROW andAttachment 2

Page 35 of 52 HG/ROW scenarios. Each instance is term ed a monitoring unit (MU). Every MU consists of a set of application conditions (including the particular worker) that are intended to represent the scenario activ ities for a single workday. In many cases monitoring units will be selected from ‘naturally occurring’ applicator-days. However, the selected application conditi ons are sometimes modified or scripted slightly to ensure that the complete sample of MUs reflects the e xpected diversity in the entire population of futu re applicator-days. . . .T hus, MUs are technically not ‘sampled’ from a population. More correctl y, they should be viewed as synthetic applicator-days derived from both selected and construc ted conditions.” (pp. 19 of 558)

(b) From what populations will subjects be recruited?

“Not all application companies (i.e. either those utility companies that make their own applications or contract application comp anies hired by utility companies) will be eligible or be willing to participate in the study. AHETF must obtain employer cooperation before it can recruit workers. This includes willingness of the utility company to have its ROW treated as well as willingness of the application company (either the utility company or its contractor applicator) to volunteer their application equipment and allow AHETF to recruit their workers.

For this reason, employers that are both quali fied for a particular scenario and willing to participate need to be identified wi thin each monitoring site. AHETF has determined that it is practical to list and screen the vast majority of application companies within each entire monitoring si te for this information.” (pp. 40-41 of 558)

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

“Subject recruiting activities can be conducted for any eligible employer, giving preference to those with more time-critical a pplication schedules, more likely to fill a desired AaiH stratum, or expected to pr ovide needed diversity in other important conditions. Specific recruitment procedures will be detailed in the protocol and appropriate SOPs. Workers desiring to vol unteer are evaluated to determine if they, and their expected handling conditions, are consistent wi th the three MUs needed.

The recruitment activities and the evalua tion of volunteers continue as long as potential MUs are needed or until no furthe r recruitment is possible.” (p. 43 of 558)

“Study participants will always use equipment that is typical for a particular scenario and that they have recently operated (with in the last year). Recent experience is required to ensure that the activity performe d by each worker is on that they typically perform.” (pp. 46 of 558)Attachment 2

Page 36 of 52 (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?

“Participants in this study must m eet the following inclusion criteria:

• Have experience within the past year with applying liquids with BP (BP/ROW scenario) or HG spray equipment ( HG/ROW scenario) in utilities ROW (including the type of equipment to be used)

• Handle pesticides as part of their job

• Be trained in safe pesticide handling procedures

• 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.1 for health status determination]

• Not be pregnant or nursi ng [See SOP AHETF-11.D.1]

• Confirm they do not normally wear pers onal protective equipment that is not required by the label and that might impact the objectives of the study, such as chemical-resistant clothing. NOTE: Vol unteers may not participate in this study if they indicate they always w ear extra clothing such as chaps or leggings to protect against physical hazards. However, if application

conditions are such that the volunteer would not normally wear this type of additional clothing, then the vol unteer is eligible to pa rticipate in the study if

all other inclusion criteria are met.

• Confirm they will follow label directions.

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

them.

• 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.2 for a detailed discussion of this topic]

• Understand and sign the consent form [SOP AHETF-11.B.5]” (pp. 304-305 of 558]

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

NoneAttachment 2

Page 37 of 52 (c) If any potential subjects are likely to be especially vulnerable to coercion or undue influence, what is the justification for including them?

Potential subjects are of necessity 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 employers and by requiring employers 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 company selected, AH ETF will follow standard procedures (see SOP AHETF-11.B) to recruit pot ential participants for th is study. Individual workers will be recruited during an initial interview with (or visit to) a potentially eligible employer once eligibility has been establis hed. Alternatively, recruitment can occur on subsequent interviews with or vi sit(s) to an eligible employer.

“The Study Director or designated researcher will seek permission from the eligible employer to approach his/her employees to recruit workers for the study. Depending on the number of employees and size of the company’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 company’s employees who express an interest in participation. Such recruitment meetings will always occur without supervisors being present (SOP AHETF-11.B). The Study Dir ector or researcher shall make a presentation describing the AHETF Exposur e Monitoring Program, the goals of the research study, the procedures used in e xposure monitoring, and the risks and benefits to participants. A toll-fre e phone number will be provided, and individuals will be encouraged to contact AHETF if they desi re additional information about the study or are interested in particip ating in the study. All presen tation materials, such as handouts or visual aids, sha ll be reviewed and approved by an IRB prior to use in recruiting subjects.” (p. 327 of 558)

(e) If any subjects are potentially subject to coercion or undue influence, what specific safeguards are proposed to protect their rights and welfare?

“In accordance with SOP AHETF-11.B[.5], the individual employers will be asked to sign a noncoercion statement (Employer Coope ration Statement) affirming to their workers and AHETF that they will not co erce or unduly influence their workers to either participate or not participate in the study. Employers must also certify that alternate work will be provided on study days for workers who choose not toAttachment 2

Page 38 of 52 volunteer; and that the employee’s decision to participate or not will have no impact on their employment.” (p. 326 of 558)

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 consent meeting

with a researcher who will obtain the informed consent of the worker (Section 2.7). Workers will be paid $20 for their attenda nce right after the c onsent meeting, whether or not they decide to partic ipate in the study. Workers who d ecide 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. Usuall y, workers will participate in the study on only one day unless their partic ipation is terminated due to weather or other unexpected occurrences. The additional $80 is provided in cash at the end of the monitoring period

or at the time the volunteer withdraws fr om the study. All worker s who participate will receive the payment, even if they withdraw or their participation is terminated by the study team.” (pp. 305-306 of 558)

(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.

For both the BP/ROW and HG/ROW scenarios, the study could involve any of four active ingredients: imazapyr, 2,4-D, fosa mine, and glyphosate. “The pesticide products containing these active ingredients and potentially used in this study areAttachment 2

Page 39 of 52 currently registered for vegetation cont rol in utilities RO W. AHETF will only monitor workers making applications in acco rdance with all label requirements.” (p. 308 of 558)

For imazapyr and 2,4-D, the calculated MOEs meet or exceed the required MOE for

both the individual dermal and inhalation ro utes of exposure, as well as for the combined exposure, and their use is acceptable for this scenario. For fosamine and glyphosate, MOEs cannot be calculated becau se no adverse effects were reported at the highest dose tested in any of the ac ute toxicity studies. Their use is also acceptable.

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

“Four kinds of risks are associated w ith the conduct of the current exposure monitoring study. These are:

• The risk of heat-related illness

• The risk associated with scripting of field activities

• Psychological risks

• The risk of exposure to surfactants

“In this study risks to subjects are classified as ‘greater than minimal’, primarily since agricultural work is considered a high risk occupation where the likelihood of harm or discomfort is greater than what is encountered in ordinary daily life. In particular, the

risk of heat-related illness (resulting from wearing an extr a layer of clothing to trap chemical) will be increased due to study participation. AHETF has adopted an extensive program to minimize these risks.” (p. 306 of 558)

Each of these four kinds of risk is disc ussed in the protocol (pp. 306-312 of 558) and the consent form (pp. 429-430 of 558).

(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 40 of 52 • Requiring experience with th e type of 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 stopping the study if conditions warrant

• Providing transportation to medical tr eatment and covering the costs of treatment, if needed

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

urgent care

• Observing study participants th roughout the monitoring period

• Ensuring that all tank mix products are used according to approved label(s) and do not require any additional PPE that could adversely affect the study objectives (for example, chemical-resi stant coveralls).” (pp. 311-312 of 558)

Risk reduction actions specific to each of the four identified kinds of risk are discussed in the protoc ol (pp. 306-312 of 558).

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

for the test materials?

For imazapyr and 2,4-D, the calculated MOEs meet or exceed the required MOE for

both the individual dermal and inhalation ro utes of exposure, as well as for the combined exposure, and their use is acceptable for this scenario. For fosamine and glyphosate, MOEs cannot be calculated becau se no adverse effects were reported at the highest dose tested in any of the ac ute toxicity studies. Their use is also acceptable.

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

“AHETF will monitor ambient conditions outs ide the cab to determine the heat index near the mixing/filling station. Exposure monitoring will be discontinued if the heat

index cutoff of 105 o F (adjusted for direct sun, if a pplicable) is reached or exceeded. The Study Director or other researcher sh all stop the monitoring and/or move the

worker to a cooler environment until m onitoring can be resumed.” (p. 307 of 558)

(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 paramedic, physician’ s assistant, nurse, or emergency medical technician. This professional will also watch you for signs of illness. They will provide medical attention as needed.” (p. 429 of 558)

SOP AHETF-11.H.2 defines procedures to be followed if a subj ect in an AHETF study requires emergency medical attention.Attachment 2

Page 41 of 52 (e) How does the protocol provi de for safety monitoring?

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

• SOP AHETF-11.E.2 calls for researchers to monitor worker compliance with

label and Worker Protection Standard requirements, and permits the Study Director to remove from the study a worker who engages in unsafe work practices.

• SOP AHETF-11.G.2 calls for the Study Director, the on-site medical professional, and all researchers and observers to monitor subjects for any

indication of heat-related illness.

• SOP AHETF-11.H.2 defines procedures to be followed if a subject in an AHETF study requires emer gency 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 personal resu lts from the study. This will require the worker to provide a name and address (ma il or e-mail). The results will include the distribution of chemical exposure among th e various body parts and a comparison to the results for other workers performing the same task. Results are typically available 9-12 months after monitoring occurs. The pers onal information related to this followup will be retained as de scribed in SOP AHETF-6.D.

“Just prior to the completion of the worke r’s participation in the study, a researcher will remind the participant he/she should bathe or shower as soon as practical and that they have received a copy of the sign ed consent form with phone numbers for reporting any health changes they think might be related to participation in the study. Post-study inquiries will be forwarded to th e Study Director who will deal with the situation as appropriate and notify AHETF management (SOP AHETF-11.J).” (p. 316 of 558)

(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 transportati on for you to receive medical attention. You may refuse medical treatment unless you get sick from too much exposure to pesticides or from getting too hot, or if we believe you are too sick to make a rational decision about getting medical treatment.

“AHETF will cover the cost of reasonable and appropriate medical attention for a study-related injury or illness that is not covered by your own insurance or insuranceAttachment 2

Page 42 of 52 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. 430 of 558)

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. 390 of 558)

Although there are no direct benefits to study pa rticipants, a potential indirect benefit is knowledge about how their exposure compares to that of others doi ng similar work; this is not addressed in the protocol.

(b) What benefits to society are anticipate d from the information likely to be gained through the research?

“Since there are not sufficient existing data suitable for use in a generic database describing the exposure to workers from BP and HG application in rights-of-way, society will likely benefit from data generated by this study through the improved risk assessments by EPA and other regul atory agencies.” (p. 390 of 558)

“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 spraying pesticides to ri ghts-of-ways using backpack sprayers and handgun sprayers. The knowledge likely to be ob tained from this study is generalizable and will contribute to assessments of the risks of both new and existing pesticides.” (p. 390 of 558)

(c) How would societal benefi ts be distributed? Who woul d benefit from the proposed

research?

“Utility companies (or their contract applicator) who a llow the study to be conducted using their equipment will be reimbursed for th e pesticides used for the study. While this is beneficial to the application company, it is considered a minor benefit when compared to the costs of running their businesses. The AHETF member companies will likely realize a benefit by addressing regulatory data requirements generically, at lower cost (and using fewer human subjects), than if they conducted similar studies for individual pesticide ingredients.” (p. 390 of 558)

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

Identified societal benefits are likely to be realized.Attachment 2

Page 43 of 52 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 to participants. Participating in this study increases the risk of heat-related illness, but this risk is mitigated by a medical management program which emphasizes prevention measures and guidelines for stopping participation when warrant ed based on environmental conditions.

“The likely benefit to utility workers as a whol e 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. BP and HG applications are often essential components of an overall vegetation management program for maintaining utilities ROW. Therefore, exposure data for these scenarios meeting contemporary standa rds of reliability and quality will likely provide a significant benefit to society. Because the margins of exposure are acceptable for the products proposed for use in this research st udy, subjects are very unlikely to experience acute toxic effects, and because extensive proc edures will be in place to minimize these and other risks to participants, th e likelihood of serious adverse effects is very small. In summary, AHETF believes the risks to study partic ipants from participating in this study are reasonable in light of the likely benefit to soci ety of the knowledge to be gained.” (p. 391 of 558)

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? No.

(e) Does this IRB hold a Federal-Wide Assurance from OHRP? No.

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

Yes.

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

“This study will be conducted in accordance with EPA’s final regulation published atAttachment 2

Page 44 of 52 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.

“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/or contract facilities).” (p. 304 of 558)

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?

Not addressed in protocol. Appropriate pr ovision is made for informing English or Spanish-speaking candidates who cannot read the consent form.

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

See SOP AHETF-11.I.1Attachment 2

Page 45 of 52 (f) What measures are proposed to ensu re subject comprehension of risks and

discomforts?

“In all situations, the SD (or designee) wi ll not sign the Consent Form unless he/she believes the candidate fully understands th e 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 key

issues. The form in Attachment 11.J.1 will be used to ascertain general understanding.” (SOP AHETF-11.J.2 §3.10)

(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 obtaining consent will inform th e worker that he/she will receive $20 (or another amount specified in th e protocol) for participation in the consent meeting, or the amount specified in the protocol, even if he/she decides not to particip ate in the research.

“During the private consent meeting the pe rson obtaining consent 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 and fo r any reason without jeopa rdizing their normal position with their employers or their daily wage s. Workers will be to ld they will receive an additional $80 (or another amount specifie d 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.Attachment 2

Page 46 of 52 “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 and risks of the study, and if the worker still wants to participate, he/she will be asked to sign and date the Consent Form and the person obtaining consent will provide a copy of the signed form to the worker.

“If the study is conducted in California, the IRB-approved “California Experimental Research Subject’s Bill of Rights” will 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 cons ent form.” (SOP AHETF-11.J.1 §3.2-3.11)

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

coercion or undue influence?

“In accordance with SOP AHETF-11.B, the individual employers will be asked to sign a non-coercion statement (Employer Cooperation St atement) affirming to their workers and AHETF that they will not coerce or unduly infl uence their workers to either participate or not participate in the study. Employers must also certify that alternate work will be provided on study days for workers who choose not to volunteer; and that the employee’s decision to participate or not will have no impact on their employment.” (p. 326 of 558)

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 alsoAttachment 2

Page 47 of 52 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. 313 of 558)

“Your name will only appear on the consent fo rm and an optional form for you to request your personal study results. In all other 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.

“Information about you taking part in this study will not be given to your employer.

“A study report will be written by AHETF and will be available to member companies.

It will be sent to the US 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 promise you total conf identiality. 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.” (pp. 430-431 of 558)

(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 volunteer expressing a need or desire to withdraw from the re search after exposure monitoring begins will be paid $80 and allowed to return to their normal work duties for their employer. If a participant withdraws while being monitored, the long underwear, inner socks and air sampling pump will be removed, and the hand, and face/neck samples

will be collected with the work er’s consent. The Study Direct or will decide whether these samples will be analyzed (SOP AHETF-8.K).” (pp. 313-314 of 558)

“Your employer has agreed to let us do the re search and has confir med that it does not care whether you take part in this study or not . Your decision to be in this study is voluntary. This decision is entirely up to you. If you decide to take part, you may change your mind and drop out of the study at any time and for any reason. A decision not to take part, or to withdraw from the st udy after it starts, will have no effect on your job or pay or include any penalty or loss of benefits you are owed.” (p. 431 of 558)Attachment 2

Page 48 of 52 (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.

“If you withdraw, the long underwear, socks, and air sampling pump will be removed. The hand and face/neck samples ma y be collected if you agree.

“Your part in this study may be stopped at any time by the resear chers or the AHETF. The long underwear, socks, and air samp ling pump will be removed. The hand and face/neck samples may be co llected if you agree.

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

work activities.

“No one can force you to take 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. 431-432 of 558)Attachment 3

Page 49 of 52 § 26.1111 Criteria for IRB approval of research AHETF Backpack and Handgun Applications in Utilities Rights-of-Way (Protocol AHE400)

Criterion Y/N Comment/Page Reference

(a)(1)(i) Risks to subjects are minimized by us ing procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk. Y

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

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

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

persons. Y

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

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

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

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

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

Page 50 of 52 §26.1116 General requirements for informed consent AHETF Backpack and Handgun Applications in Utilities Rights-of-Way (Protocol AHE400)

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

(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(a) In seeking informed consent the following informationshall be provided to each subject

(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 subj ect is otherwise entitled OK

(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(b) When appropriate, one ormore of the following elementsof information shall also beprovided to each subject

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

function. OKAttachment 5

Page 51 of 52 §26.1117 Documentation of informed consent AHETF Backpack and Handgun Applications in Utilities Rights-of-Way (Protocol AHE400)

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 52 of 52 40 CFR 26.1125 Prior submission of proposed human research for EPA review AHETF Backpack and Handgun Applications in Ut ilities Rights-of-Way (Protocol AHE400)

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 Refs
(1) Copies of

• all research proposals reviewed by the IRB,

• scientific evaluations, if any, that accompanied the proposals reviewed by the IRB,

• approved sample consent documents,

• progress reports submitted by investi gators, and reports of injuries to subjects. Y
n/a

Y

n/a p. 352

pp. 266, 282

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

• attendance at the meetings;

• actions taken by the IRB;

• the vote on these actions including the number of members voting for, against, and abstaining;

• the basis for requiring changes in or disapproving research;

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

resolution. Y

Y

Y

N

n/a pp. 555-557

The only required changes were minor typographical changes to

the ICF

No controverted issues

(3) Records of continuing review activities. n/a (4) Copies of all correspondence between the IRB and the investigators. Y pp. 261, 2 62, 264, 265, 281, 296, 347, 349, 352, 453, 454, 463-469, 481, 494, 496, 547, 549-551,

553-554 (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 p. 558

(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 claimAll information relevant to the proposed research specified by § 26.1115(a)

(7) Statements of significant new findings provided to subjects, as required by §26.1116(b)(5). n/a

(1) The potential risks to human subjects Y p. 306 (approved protocol) (2) The measures proposed to minimize risks to the human subjects; Y p. 306 (approved protocol) (3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y p. 312 (approved protocol)

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y p. 15§1125(a)a discussion of:

(5) The balance of risks and benefits of the proposed research. Y p. 313 §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. 425-445 Approved pp. 266-276, 282-294

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y pp. 40, 305, 218-330, 277-8

§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. 313-316

§1125(e): All correspondence between the IRB and the investigat ors or sponsors. Y pp. 261, 262, 264, 265, 281, 296, 347, 349, 352, 453, 454, 463-469, 481, 494, 496, 547, 549-551,

553-554The following Information, to theextent not already included:

§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. 264-265