Ha
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

September 23, 2008

MEMORANDUM

SUBJECT: Science and Ethics Review of AHET F Scenario Design and Protocol for Exposure Monitoring in California Trellis Crops

FROM: Jeff Evans

Health Effects Division

Kelly Sherman

Human Research Ethics Reviewer

TO: Jack Housenger, Associate Director

Health Effects Division

REF: Smith, L. (2008) Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of Liquid Sprays Using Closed Cab Equipment in California Trellis Crops. Unpublished protocol dated July 24, 2008, prepared for the Agricultur al Handlers Exposure Task Force under Sponsor ID AHE58, 383 p., plus 343 p. scenario design and supporting documents.

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 EPA

Human Studies Review Board.

Page 1 of 51A. 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 scenario design for the closed-cab airb last scenario appears in Volume 1 of the AHETF submission of August 14, 2008 (V1:7-51) 1 . The IRB-approved protocol and supporting documents (consent forms, product-sp ecific risk statements, and recruitment flyers in both English and Spanish) app ear in Volume 3 of the AHETF submission (V3:14-126). Documentation of all interac tions between the investigators and the Independent Investigational Review Board, Inc ., of Plantation FL also appears in Volume 3 of the AHETF submission (V3:127-383).

In addition to the final protocol (V3:14-55), Volume 3 includes the following supporting documents:

• Study documents in English approved by IIRB:

o Informed Consent Form approved 7/29/08 (pp. 59-66)

o Product-specific risk statemen ts approved 7/29/08 (pp. 67-81)

o Recruiting flyer approved 8/04/08 (p. 82-83)

o California Subjects Bill of Right s approved 7/29/08 (p. 123-124)

• Spanish translations of st udy documents approved by IIRB:

o Informed Consent Form approved 7/29/08 (pp. 98-119)

o Product-specific risk statements approved 7/29/08 (pp.98-119)

o Recruiting flyer approved 8/04/08 (pp. 120-122)

o California Subjects Bill of Right s approved 7/29/08 (p. 123-124)

• Correspondence between the investig ator and IIRB (pp. 11-13, 128-142, 249-252, 321, 322-325)

• Protocol and supporting documents as in itially submitted to IIRB on 7/24/08 (pp. 126-246)

• Revised SOP AHETF 11.B.2 dated 7/24/ 08 and submitted to IIRB on 7/24/08 (pp. 228-244)

• IIRB response to 7/24/0 8 submission (pp. 286-288)

• Recruiting flyers as submitted to IIRB on 7/31/08 (pp. 310-3190

• IIRB approval letters of 8/01/08 (pp. 11-13)

1 This convention will be used for all page number refe rences in this review and its attachments. For example, “V1” refers to Volume 1 of the AHETF subm ission, which contains the “General Information and Scenario Sampling Plan” for the Closed-Cab Airblast scenario. “V3” indicates Volume 3 of the AHETF submission. Volume 1 and Volume 3 together documen t the protocol for California trellis crops. Many pages in the two volumes bear more than one page number. All page references in this review to Volume 1 are to “page N of 343”, and page referenc es to Volume 3 are to “page N of 383.”

Page 2 of 51• IIRB approval letter of 8/04/08 for E nglish and Spanish language recruiting flyers (pp. 320-322)

• Minutes of 7/29/08 IIRB Meeting (pp. 253-263)

The rationale for the proposed sample size and cluster configurat ion is presented in Volume 1 (pp. 15-21).

The following SOPs are cited in the protocol. Those marked by an asterisk have been revised since the HSRB meeting of June 2008 to address EPA and HSRB comments.

AHETF-1.B.3* Personnel Responsibilities AHETF-1.F.0 Potential Referable Findings

AHETF-2.C.2 Protocol Design and Preparation

AHETF-6.B.1 Access to Archived Data

AHETF-6.D.0 Access to Confidential Worker Info AHETF-8.A.3 Whole Body Sampling – Inner Dosimeters AHETF-8.B.4 Hand Wash Samples AHETF-8.C.4 Dermal Face/Neck Wipe Samples AHETF-8.D.2 Collection of Air Samples Using OVS Tubes AHETF-8.E.4 Fortification of Matrix Samples AHETF-8.F.5* Sample Identification

AHETF-8.G.2 Worker Clothi ng Acceptability Criteria AHETF-8.H.2 Head Patch Samples AHETF-8.K.0 Sample Quality

AHETF-10.C.4* Worker a nd Study Observations AHETF-10.D.0 Application Equi pment Operation Verification AHETF-10.G.1 Personal Air Sampling Pump Calibration AHETF-11.B.3* Recruitment of Study Vo lunteers and Informed Consent

AHETF-11.C.1* Worker Health Status AHETF-11.D.1* Pregnancy Testing AHETF-11.F.1* Adverse Events Reporting for IRBs

AHETF-11.G.1* Identification a nd Control of Heat Stress

Reports of interviews with e xperts knowledgeable about the use of airblast application equipment in orchard and tr ellis crops are pr ovided in Volume 1, pp. 52-80.

B. Summary Assessment of the Scenario Design 2

1. Scenario Design: This protocol addresses the handler exposure scenario involving application of li quid pesticides to orchar d and trellis crops using conventional airblast sprayers drawn by closed-cab vehicles. EPA’s Worker Protection Standard (WPS) at 40 CFR 170.240(d)(5) requires enclosed cabs to completely surround occupants with a nonpor ous barrier that prevents contact

2 Supporting details are in Attachment 1.

Page 3 of 51with pesticides outside the cab. Limita tion to use with an enclosed cab is arisk/exposure mitigation option EPA may exercise in its regulatory decisionmaking.

According to the WPS, in an enclosed cab that does not provide respiratory protection, handlers need not wear all th e PPE listed on the pesticide labeling, but

must wear at least:

• long-sleeved shirt and long pants,

• shoes and socks

• any respirator of a type listed on the label.

In an enclosed cab that does provide respiratory protec tion equivalent to that provided by respirators identified on the pes ticide label, handlers must still wear a long-sleeved shirt and long pant s, shoes and socks, but need not wear a respirator.

The AHE58 protocol calls for closed-cab airblast application of one of two surrogate insecticides to California trellis crops (e.g., grapes). A total of 25 Monitoring Units (MUs) are proposed for th e closed-cab airblast scenario; when the scenario is complete, the five (MUs) to be collected under this protocol will be

combined in the AHED database with tw enty more to be collected under other field study protocols. EPA intends to use these data to estimate daily dermal and inhalation exposures of pesticide applicat ors applying liquid pest icides to orchard and trellis crops using conventional ai rblast equipment drawn by closed-cab

vehicles.

2. Sampling Design: The closed-cab airblast scenario, as currently planned, will involve five clusters, each defined as a separate field study. Clusters have been purposively selected to create a diverse ra nge of orchard/tre llis crops, agronomic practices, and geographic regions. Each cluster is referred to as a monitoring

‘site.’

The AHETF diversified the five clusters for this scenario by crop and geographic region through a five-step purposive process:

• Identifying the principle crop types a ssociated with airblast application, based on consultation with experts

• Identifying the states where each principle crop is grown from NASS

statistics

• Grouping the states by EPA’s growing regions

• Selecting one of the major producing states for each major crop, but no more than one state/crop pair per region

• Selecting a county or counties for each state/crop pair in which to conduct each field study

Page 4 of 51The result of executing the first four step s of this first stage of the diversity selection process was the purposive c hoice of the following five crop/state combinations for the five proposed monitoring sites:

• Citrus crops in Florida (oranges)

• Nut crops in Georgia (pecans)

• Pome fruit in Washington (apples)

• Stone fruit in Michigan (cherries)

• Trellis crops in California (grapes)

These choices are appropriate to cover th e most important regional and agronomic variations in the use of airblast equipm ent. A review of protocols addressing citrus crops in Florida (AHE55) and nut crops in Georgia (AHE56) were presented to the Board during the June 2008 HSRB meeting. Of specific relevance to this protocol (AHE57), Califor nia is a major producing state of trellis crops such as grapes and caneberries and represents a logical choice for a cluster representing trellis crops grown in the EPA Growing Region X.

The specific ‘site’ selected in which to conduct the trellis crop study is Fresno County with options to consider nearby Maderia, Merced, Monterey and Tulare

Counties. These counties are located in the Central Valley of California. There are approximately 220,000 acres of bearing vineyards produced in Fresno County on approximately 2800 farms. The other counties have approximately 200,000 acres of bearing vineyards. According to USDA’s Agricultural Chemical Usage 2005 Fruit Summary, there are limited applic ations of malathi on and carbaryl. However, in 2007, approximately 50,000 acres were treated with these two

chemicals. OPP believes the likelihood of finding a sufficient pool of volunteers is high.

In the next stage of the diversity selecti on process the practical range of amount of active ingredient handled (Aai H) for the airblast scenario is divided into five bands, of equal width on the log AaiH scal e. Past studies have shown that AaiH is strongly associated with exposure and is a meta-factor associated with differences in equipment and spraying practices. Although the AHETF calculates the maximum amount an applicator may handle as 200 lbs AI/day, a more practical upper bound is 100 lbs AI/day. AHE TF has set a lower limit at 5 lbs, to minimize non-detects. AHETF has partitioned the practical AaiH range from 5 to 100 lbs AI/day into five strata:

• 5 to 9 lbs AI handled

• 10 to 17 lbs AI handled

• 18 to 30 lbs AI handled

• 31 to 55 lbs AI handled

• 56 to 100 lbs AI handled

Page 5 of 51This is a reasonable approach to stratifi cation, and it should be possible to fill all strata in all five crop/regi on field studies defined for this scenario within the range of standard agronomic practices.

The next stage of sample se lection results in identify ing the growers whose crops will be treated and the workers whose expos ure will be monitored. As with other agricultural pesticide application scenarios, growers who agree to cooperate with the research and to spray their crop must be identified before workers can be

recruited.

The AHETF process for identifyi ng growers includes five steps:

• Contacting local resources to identif y growers of the crop of interest

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

• Putting the list of growers into random order

• Contacting growers, one at a time, in the sequence of the randomized list, to determine whether the grower is ‘eligible’ to participate

• Placing eligible growers into a “working pool”

Screening of growers for eligibility will continue until the pool contains somewhat more growers with somewhat more workers than are needed to fill five MUs. From each grower in the worki ng pool, the following range of information will be compiled:

• Crop and acreage that might be treated

• Specific location of crop(s) that might be treated

• Number, type, and size of ai rblast sprayers available

• Surrogate chemical(s) that might be used

• Estimated timing of applications

• Number of experienced workers available

• Range of AaiH those workers might be able to handle in a day

This process of identifying cooperating gr owers is basically sound, but represents a changed practice for the AHETF and its research cooperators. The AHETF has promised to document all steps taken a nd assess how well they worked in early field studies, and then to develop an SOP governing this process. EPA has accepted this approach.

From the identified pool of poten tial cooperating growers—correctly characterized as a random sample of grow ers (of the purposively selected crop in the purposively selected st ate and counties)—the Study Director and the Local Site Coordinator will purposively constr uct an “efficient configuration” of potential Monitoring Units (MUs). An efficient configuration will involve a group of growers in the same geographi c area who can provide workers for all five strata of AaiH, who would involve some diversity in spray equipment, and

Page 6 of 51who expect to make applications at approximately the same time. When constructing MUs, three additional restri ctions will be enforced to increase diversity within the cluster:

• No worker may be used more than once

• No airblast sprayer may be utilized more than once

• No more than 2 MUs may be obtained from one grower or grower/commercial applicator pair

The growers and/or commercial applicator s in the chosen co nfiguration provide the pool of workers from which workers wi ll be recruited to f ill each of the five MU slots. If selected growers or work ers drop out as the time of the field study approaches, additional workers appropriat e to fill out the MU design may be recruitable from among those employed by growers already in the working pool of eligible growers. If there are too fe w workers available in the pool to complete a revised efficient configuration, the working pool can be expanded by approaching more growers from the original randomized list. It is not clear what steps would be taken if the original randomized list were exhausted without finding enough cooperating grow ers and interested workers to complete the field study design. The process for selecting workers is defined to include overrecruiting growers, so that there are like ly to be more interested and qualified workers than MU slots, so the workers actually sampled can be selected randomly.

3. Choice of Surrogate Materials: The surrogate chemicals proposed for this scenario are carbaryl and malathion, formulat ed in any of 7 registered products. These pesticides have been successfully used in previous worker/handler exposure monitoring studies and have well established and reliable analytical methods. These are generally approp riate choices for this research.

C. Summary Assessment of the Scientif ic Aspects of the Study Design 3

1. Statistical design: This protocol describes co llecting five Monitoring Units (MUs) reflecting the exposure of subjects ma king airblast applications to trellis crops using closed-cab vehicles. This is one of five clusters in the scenario, each of which will include five MUs. The general rationale for the 5 x 5 cluster configuration is presente d in Appendix C of the revised AHETF Governing Document; details specific to the closed-cab airblast scenario are in the scenario design. No characteristics of this scen ario have been identified which would justify a departure from the 5 x 5 configuration.

3 Supporting details are in Attachment 2.

Page 7 of 512. Proposed pattern of exposure: The proposed exposure duration for each MU will be at least 4 hours, involving applicati on of at least 3 tank-loads. Subjects will only apply the pesticide; mixing and loading of the spray solution will be done by others not participating in the study. Over the course of a day each subject will apply the surrogate active i ngredient in one of the following five

strata of AaiH:

• 5 to 9 pounds

• 10 to 17 pounds

• 18 to 30 pounds

• 31 to 55 pounds

• 56 to 100 pounds

Seven registered products containing one of the two designated surrogate pesticides have been identified, and a cooperating grower may choose to use any of them for a specific MU. Carbaryl formulations include wettable powders enclosed in water-soluble bags and liqui d flowable concentrates. Malathion

formulations include emulsifi able concentrates or liquid flowable concentrates. All of these products will be mixed with water and loaded into the airblast spray tank by workers not participating in the study.

During application subjects may need to leave their enclosed cab to adjust or repair equipment or for other reasons. Whenever they leave the cab applicators will wear all personal protective equipm ent (PPE) required by the label, in

accordance with the Worker Protection St andard (WPS), which requires that in any enclosed cab where reduced PPE is worn handlers must:

• Keep immediately available all PPE lis ted on the labeling for the type of task being performed

• Wear the PPE if it is necessary to leave the cab and contact pesticide treated surfaces in the treated area,

• Take off PPE that was worn in the treatment area before reentering the cab, and

• Store all PPE in a chemical-resistant container, such as a plastic bag, to prevent contamination of the cab.

The exposure pattern of open-cab airblast applicators is generally to the upper body as a result of falling aerosolized sprays or brushing into treated foliage/branches; the enclosed cab is meant to mitigate this exposure potential. However, individual behavior is also expected to affect exposure.

In many of the existing closed-cab studies in PHED, the exposure contact values are based on many measurements that we re below the Limit of Quantification (LOQ). Current analyti cal methods for the surrogate chemicals are more

sensitive than those used in earlier studies populating PH ED, but if the results of this study are measurements below the LOQ, the AHETF is prepared to use half

Page 8 of 51the LOQ or some other statistical method to estimate potential exposures. The investigators also need to record what type of PPE are worn when exiting enclosed cabs so that face/neck wipe samples can be adjusted for the area covered by a respirator or other PPE.

3. Endpoints and Measures: The study will measure dermal and inhalation exposure for each MU. These data will contribute to development of Unit Exposures (exposure per unit of pesticide active ingredient applied) or other exposure metrics, and to estimates of dermal and inhalation exposure to other pesticides applied to orchard or trellis crops with conventional airblast sprayers drawn by vehicles with closed cabs. EP A 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 two pieces representing the upper and lower torso. Residues in socks measured in earlier open-cab airblast studies have been very low (e.g., ≈ 0.1% of dermal exposure). Exposure to the applicator’s feet in a cl osed-cab scenario is expected to be insignificant; socks will not be collected as dosimeters.

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 prior to restroom and lunch breaks, before water breaks if required by the label or reque sted by the subject, and at the end of each exposure period.

Before each subject begins work his/her face and neck will be wiped with a cotton gauze swab to remove any contaminati on not associated with the monitoring event. This face/neck wipe sample w ill be discarded. Subjects will undergo another face/neck wipe sampling prior to the break and again at the end of the exposure period; both samples will be reta ined for analysis. The study team needs to record what type of respirator wa s 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. Th e 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.

Additional measures will record environmental conditions at the time of monitoring. Observers will make field not es of subject activity throughout the

Page 9 of 51monitoring event, and photographs or videos may be taken selectively to illustrate

events.

4. QA/QC Plan: The study will be monitored by three different QAUs: one from the exposure monitoring contractor that conducts the study in the field, one from the analytical laboratory that determines the level of pesticide residues in field samples, and one contracted directly by AHETF.

Analytical and field sampling quality control procedures include complete validation of all analytical methods, field fortification and control samples, laboratory fortification and control 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 closed-cab airblast scenario, and will be posted to the AHED ® database, where they will be available to regulatory agencies for later statistical analysis. The documentation will report a confidenceinterval-based approach to determine the relative accura cy for the arithmetic mean

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

D. Compliance with applicable Scientific standards

The scenario sampling design is generall y sound, but would be strengthened by increasing the numbers of growers and worker s in the working pool, so that individual

workers no fill each MU slot can be selected randomly from among qualified, interested volunteers. In addition, provision is needed for the possibility that the MUs cannot all be filled from among workers employed by growers on the original randomized list.

This protocol itself adequa tely 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

Page 10 of 51• 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).

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 exposure for workers making closed cab airblast applications in California trellis crops. This study will provide a partial answer to the question of what dermal and inhalati on exposures are likely for applicators using conventional airblast equipment and closed-cab tractors. This is a widespread pattern of pesticide applicati on in orchard and trellis crops, for which existing applicator exposure data are inadequate. EPA will use the results of this study, in conjunction with the results fr om one field study conducted in August 2008 and three other field studies planned fo r this scenario, to estimate the dermal and inhalation exposure likely for future applicator-days for a wide range of agricultural pesticides applie d under this exposure scenario.

2. Subject Selection: Subjects will be recrui ted among the employees of commercial growers of trellis crops in Fresno County (and possibly nearby counties) who are identified as commercial growers who “might utilize airblast equipment in their operations” and who m eet AHETF criteria for participation. Eligible growers will be identified from a complete list of growers in the target area, processed in random sequence. Subjects will be recruited who are employees of eligible growers (or of pest icide application service companies used by eligible growers), with recent experience using the closed-cab airblast application equipment to be used in the study, who meet the eligibility requirements of the study. If more empl oyees are available a nd interested than are needed, participants will be selected randomly. Although the design is purposive, and thus participants are not re presentative in a statistical sense, they are expected to be typical of those who us e airblast equipment to treat trellis crops

in California.

Inclusion factors listed in th e protocol are appropriate, but the fourth criterion

should be deleted because it is essentiall y a duplicate of the final criterion. The protocol exclusion factors are appropriate, but one of the two duplicate criteria should be deleted. The elig ibility factors listed in the Consent Form (V3:58) differ from those in the protocol (V3: 21-22) in possibly important ways, and

should be harmonized.

4 Supporting details are in Attachment 2.

Page 11 of 51The description of the process for recruiti ng subjects relies heavily on references to AHETF SOP 11.B, which has been ex tensively revised since the June 2008 HSRB meeting and has been appended to th e protocol (V2:269-285). Appropriate steps are proposed to prot ect candidates and subjects from coercion or undue influence to participate. Candidates w ho attend an individual interview will be paid $20 whether or not they agree to pa rticipate; enrolled subjects who once put on the whole-body dosimeter will be paid $80 in addition to their usual pay, whether or not they complete participation.

3. Risks to Subjects: Six kinds of risks to subjects are discussed in the protocol, along with specific steps proposed to minimize them:

• The risk of heat-related illness

• The risk of exposure to surrogate chemicals

• The risk associated with scripting of field activities

• Psychological risk

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

• The background risk of injury a ssociated with ag ricultural work

The surrogate chemical used will be carbaryl, chlorothalonil, or malathion; all three are fully tested and well understood. Individual growers will choose from a list of thirteen registered products contai ning one of these ingredients, for each of which a product-specific supplement to th e consent form describes the specific risks identified on the approved label. Margins of Exposure (MOEs) calculated for the highest levels of exposure proposed in this protocol substantially exceed the target MOE for occupational dermal and inhalation exposure.

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 bene fits to the subjects, but subjects may request their individual resu lts. If they are told only their own results, little benefit would result, but if they are told how their expos ure compared to that of others, it could be of potentia l indirect benefit to them. The principal benefit of this research is likely to be reliable data about the dermal and inhalation exposure of workers applying pesticides to trel lis crops using closed-cab airblast equipment, usable by EPA and other re gulatory agencies to support exposure assessments for a wide variety of pe sticides 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 accurate applicator exposure assessments for a wide range of agricultural pesticides.

Page 12 of 516. 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. S ubjects will sign both the consent form and the product-specific supplement desc ribing the surrogate material chosen by the grower. Oral fluency in English or Spanish is a criterion for inclusion, but literacy is not required. The reading level of the English language consent form is appropriate. Adequate provi sion is made to meet the needs of subjects who do not read either language, but witnesses should not be asked to attest to the subject’s understanding of the material (V2:68). 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.

The following specific deficiencies in the protocol should be addressed before the

research is initiated:

• The Local Site Coordinator, the Principal Field Investigator, th e Field Facility, the Analytical Facility, and the Principal Analy tical Investigator must be identified in the protocol.

• Add to the protocol provision for counti ng and reporting the numb er of potentially eligible workers linked to each grower, and the numbers attending initial group

Page 13 of 51meetings, attending individual consent interviews, signing consent forms, subsequently withdrawing or being wit hdrawn, and completing participation.

• The lists of eligibility factors in the protocol and the consent form must be

harmonized.

• Chlorothalonil was omitted from some porti ons of Section 2.3.2 of the protocol – for example, the last sentence of the first paragraph. This sect ion must be revised to properly reflect that there are three surrogate chemicals.

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.

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 the deficiencies noted above are addressed and the amended protocol is approved by the overseeing IRB, this research should meet the ethical standards of FIFRA §12(a)(2)(P) and 40 CFR 26 subparts K and L.

Attachments:

1. Summary Review of Closed-Cab Airb last Scenario Design dated August 14, 2008 2. Summary Review of Protocol AHE58 dated August 14, 2008 3. §26.1111 Criteria for IRB approval of research 4. §26.1116 General requirements for informed consent 5. §26.1117 Documentation of informed consent 6. §26.1125 Criteria for Completeness of Proposals for Human Research

Page 14 of 51Attachment 1

EPA Scenario Review: AHETF Close-Cab Air Blast Scenario

Title: Closed Cab Airblast Applicator Scenario Sampling Plan: pp. 8-51 in

AHETF Volume I: General Informat ion and Scenario Sampling Plan

Date: 14 August 2008

Sponsor: Agricultural Handlers Exposure Task Force

1. Scope of Scenario Design

“This scenario includes application of liquid sp rays to actively growi ng, foliated crops using conventional airblast equipment a nd closed-cab tractors.” (V1:3)

“The following five crop type/state combinations are proposed for this scenario that will provide the desired diversity in crop and geography:

o Citrus crops in Florida (e.g., oranges)

o Nut crops in Georgia (e.g., pecans)

o Pome fruit in Washington (e.g., apples)

o Stone fruit in Michigan (e.g., cherries)

o Trellis crops in Californi a (e.g., grapes)” (V1:4)

(a) Is the scenario adequately defined?

The scenario is clearly and appropriately defined.

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

“AHETF has identified the closed cab airblast application scenario as being within the scope of the task force goals and one for which data are lacking. A number of AHETF member products are labeled for this use patter n. This application scen ario is applicable to a wide variety of commercially important crops (e.g., fruit trees, nu t trees, and trellis crops). Therefore, it is nece ssary to have data in AHED for the application technique described by this 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 scenar io, the JRC reviewed two closed cab airblast application studies and did not identify any data from existing

studies that were deemed us eful for a generic database.

Page 15 of 51Attachment 1

“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. Data for closed cab airblast application of liquid sprays comprise PHED Scenario 12 –Airblast Application, Closed Cab (APPL). Data within that scenario were graded by EPA as “Low Confidence” for the “No Clothes” and “Single La yer, No Gloves” clothing scenarios. The inhalation exposure data are also graded as “Low Confidence”. The “Single Layer, Gloves” clothing scenario in PHED was gr aded as “High Confidence” but it was noted that there are a large number of non-quantifiable residues for th is clothing scenario. In the

AHETF detailed review of these PHED da ta, one MU from one study was found that possibly met the acceptance cr iteria established by AHETF. However, several issues

associated with this MU make it of dubi ous quality and the logistical problems of obtaining a single MU from a si ngle study provides sufficient rationale for not further pursuing these data (Exponent, 2007). Thus, ther e are no data currently in PHED for this scenario that are useful for a modern generic database.

“Finally, EPA examined data from 13 exis ting airblast exposure studies or exposure assessments (for open and/or closed cabs) that were not available to the AHETF and concluded that none of the exposure data s hould be included in the AHETF database (correspondence from EPA on July 3 as a follow-up to a June 27, 2007 meeting with AHETF). This MU selection plan therefore prop oses to collect a full set of new data for this closed cab airblast application scenario to meet the scientific objectives outlined in the Governing Document.” (V1:7-8)

2. Rationale for Scenario Sampling Design

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

“AHETF experts agree that e xposure potential will be consid erably less for closed cab situations than for open cab situations and be lieve that overhead sp raying, exiting the cab, and contacting surfaces (e.g., while making adju stments or repairs) may be the most important parameters influencing exposure in closed cab situations. . . . AHETF believes the best way to get diversity in these vari ous parameters is to vary the crop type, especially for crop height and foliage dens ity. This will ensure the collection of MUs includes some overhead exposure and a variety of equipment configurations and settings (see Section 6 for more details).

“Crop conditions are therefore considered an important parameter that should be formally diversified. Consequently, any st ratification should distinguish orchard and tr ellis crops, both commonly treated with closed cab airblast sprayers. . . .” (V1:17)

“. . . Five crop categories encompass approxima tely 97% of all the acr eage that might be treated by airblast applicati ons. This suggests the possibili ty of stratifying the crops treated by airblast into these five crop types:

• Nut crops

Page 16 of 51Attachment 1

• Citrus

• Pome fruit

• Stone fruit

• Trellis crops

“The ‘other orchard’ category will be re stricted from the target population because overall acreage is relatively low and agricu ltural experts did not indicate there were fundamental differences in how these crops are treated by airblast. These orchard crops include avocados, dates, figs, guavas, olives, and papayas.

“Trellis crops will be considered as a group with one exception – tall hops. Hops are

treated with conventional airbla st equipment like other trelli s crops, but unlike grapes and caneberries they can grow very tall and i nvolve overhead exposure similar to orchard situations. Since trellis crops are purposivel y included in the sampling plan because they are shorter than orchard crops a nd don’t involve overhead exposu re, this plan will restrict MUs involving trellis crops to si tuations that do not involve overhead exposure (i.e., tall hops will not be included).

“However, exposure potential for workers who us e airblast sprayers in tall hops will still be covered within AHED by data from orchard applications.” (V1:18-19)

“Crop Type Growing Areas: Acreage by state for each of th e five crop types is readily

available from USDA . . . a nd provides a convenient way to identify where important crop types are commonly grown. A ‘predominant growing area’ for each of the five crop types can be defined in terms of states that account for 5% or more of the total crop type acreage.” (V1:19)

“One state will ultimately be se lected from each of these five crop type strata. It should be emphasized, however, that relative crop acreage was used only to delineate states associated with where most of the crops ar e grown. Acreages cannot be used to guide a “representative” sample of airblast applica tion conditions. This is because information on the number of sprays performed per year by airb last with enclosed cabs in particular areas and for particular crops would be needed. This information is not readily available and it varies from year to year based on the amount and type of pest pressure in each crop in each area. Therefore, acreage data are used only as a guide to indentifying locations where enclosed cab airblast applications ar e probably common. Discussions with local agricultural experts are then used to verify that the scenario of interest is common and then specific study sites can be chosen.” (V1:21)

“Geographic Stratification: . . . Closed-cab airblast a pplications are made almost exclusively to orchard and tre llis crops and these crops are grown in many regions of the country. . . . For this reason, geographic di versity between sites is also desired. Geographic diversity between clus ters of monitoring units is . . . viewed as a meta-factor

that is associated with bo th known and unknown effects usua lly classified as simply ‘study effects’. . . .

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“The 13 U.S. Growing Regions established by EPA (Figure 2) provide a convenient basis for geographic stratification. These regions have been used when planning and conducting pesticide residue trials for variou s crop types. The regions were based on natural geography and climatic boundaries (A CPA, 1992) and are therefore useful for indicating when locations selected for exposur e monitoring are geograph ically diverse. . . . The goal in diversity selec tion is to obtain no more than a single state from each EPA growing region.” (V1:21-22)

“ Selecting States from Crop Type and Geographic Strata: . . . The diversity selection goal is to choose one state for each crop type w ith the proviso that no two states are in the same EPA growing region. Guided by this ru le and the information in Table 5, the following five combinations . . . were purposively selected.

1. Citrus / Florida

“This citrus combination was chosen because of the dominant acreage for citrus crops in Florida (66%) and becaus e it is the only combination in Re gion III. Florida was selected over California (the only other combination involving citrus) since California will be chosen for another crop type (see below). Flor ida reflects a hot and humid climate in the peninsular southeastern US (EPA Region III).

2. Trellis Crops / California

“This trellis crop combination was chosen b ecause of the dominant acreage for trellis crops in California (77%). California was selected over Washingt on (the number two acreage state) so that Washingt on could be selected for pome fruits due to its dominance in that crop type (see below). California reflects a hot and dr y climate in the western US (EPA Region X).

3. Nut Crops / Georgia

“This nut crop combination was chosen because California (the highest nut crop acreage) is already selected and because AHETF has a qualified Local Site Coordinator in Georgia that will likely result in a lo calized and efficient study. This state reflects a hot and humid climate in the southeastern US (EPA Region II).

4. Pome Fruit / Washington

“This pome fruit combination was chosen becau se of the dominant acreage available for pome fruits (84%) and because it provides good geographic diversity. This state reflects a

cool climate in the Pacific Northwes tern US (EPA Region XI or XII).

5. Stone Fruit / Michigan

“This stone fruit combination was chosen becau se Michigan has the highest acreage for a stone fruit after California. This combination also provides geographic diversity because it reflects a cool climate in the uppe r Midwestern US (EPA Region V).

Page 18 of 51Attachment 1

“Collectively, these crop type/state combin ations cover five di fferent EPA growing regions including the West, Northwest, South east, and upper Midwest portions of the US. They also cover all five of the crop types th at are desired for diversity. AHETF also has acceptable Local Site Coordinators in each of these states. Finally, local agricultural experts have been contacted from each of these states to confirm airb last applications are common to the crop indicated.” (V1:23-25)

“ Selection of Specific Monitoring Sites for Each Study: The final step for selecting sites is to choose a specific area within each selected state identified above where growers and workers can be recruited to c onduct a study in a reasonable amount of time. This involves staging the study (i.e., site) in a reasonably limited geographic area so that

MU identification and selecti on operations can be conducted e fficiently in one local area

within the state. This is n ecessary primarily to keep the costs of study conduct reasonable so an adequate number MUs can be obtai ned in the AHETF monitoring program.

“Choosing a cost-effective configuration of MUs is necessary since costs escalate rapidly

when a research team makes several visits to a location in order to monitor the desired five MUs. Cost-effectiveness is obviously maximized when all MUs are collected during the same visit so researcher salary, travel , food, lodging, and field fo rtification expenses are minimized.” (V1:26)

“Therefore, for each study (i.e., site), a partic ular area of each state will be selected and identified in the study protocol. This w ill be determined by discussions with local

resources to indicate areas that are most likel y to have sufficient growers, equipment, and workers to allow an efficient study. It may also be restricted based on the availability of

a Local Site Coordinator who is responsible for providing logistical support to the CROs.” (V1:27)

“The primary considerations for site selecti on will be the availability of trellis crops sprayed with airblast equipment, suitable growers that are willi ng to use the AHETF surrogate compounds and are wil ling to participate in the st udy, and the availability of a Local Site Coordinator with experience conducting similar studies and a familiarity with agricultural practices in the area. Full details of the site selection process and

actual sites will be recorded in the study file.” (V3:23)

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

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

“AHETF has determined that a method of randomly choosing a working pool of growers is practical for this scenario. This pool of growers will provide the workers and application conditions needed to construc t MUs for the study. Random selection of growers is preferable, when feasible, to reduce the possibility of sel ection bias that might arise from the Local Site Coordinator (LSC ; i.e., a local agricultural researcher) purposively choosing which growers to contact. Therefore, a procedure for generating a

Page 19 of 51Attachment 1

list of available grower s for each study (i.e., associated w ith each local monitoring site), and randomly selecting a pool of growers from that list, will be established in the protocol for that study. The general procedure to be fo llowed is described in the following steps:

1. Contact local resources from each of the following groups and ask for a list of growers for the crop type of interest at the identified location (generally about one to three counties) . . . .

2. Assemble a list of growers from all of the resources contacted and eliminate any duplicates.

3. Put the list of growers into random order.

4. Contact growers, one at a time, following the random order, and determine whether the grower is ‘eligi ble’ to participate. . . .

5. Each grower identified as eligible (sometimes along with an associated commercial applicator) is placed into a wo rking pool along with information on:

• Crop(s) available, with ac reage that might be treated • Specific location of crop(s ) that might be treated • Description of equipment availa ble (e.g., number, type, and size) • Surrogate chemical(s) th at might be utilized • Approximate timing of surrogate applications

• Number of workers available • AaiH those workers might be able to handle in a day

“Screening of the grower list (in random orde r) continues until a pool of eligible growers (and/or commercial applicators) that is sufficiently large is obtained. . . .

“This process results in a random sample of eligible growers and, by association, a random pool of potential workers associated with eligible growers.” (V1:29-31)

“AHETF researchers will contact local resour ces from each of the following categories in Fresno County and possibly adjacent counties:

• Local Site Coordinator (LCS)

• Commercial Applicator Firms that service vineyard crops

• University Agricultural Resear chers / County Extension Agents

• Crop Consultants (e.g., pest control adviso rs or commercial applicators) that service vineyards

• Chemical Dealers or Sales Representatives

• Grape Grower Associations

Page 20 of 51Attachment 1

“The researchers will brie fly explain the AHETF Exposure Monitoring Program to the

local resources who are then asked for a list of growers in Fresno County who are commercial producers of trellis crops (e.g., gr apes and caneberries) and might utilize airblast equipment in their operations. The lis t of growers from all of the resources will be compiled and duplicate names eliminated. All local resource contacts shall be

documented in a detailed record that shall be maintained in the study file.

“The compiled list of growers from local res ources shall be placed in random order for further consideration. The randomization pro cess will be documented and maintained in the study file.

“The growers shall be contacted, one at a ti me, following the random order, to determine whether the grower is ‘eligible’ to participate in this study.

“Screening of the growers (in the order of the random list) continues until the pool of eligible growers (and/or commercial applicat ors) contains at l east 10 workers who may potentially volunteer for the study, and at le ast 2 workers are available for each of the AaiH strata. This pool will include more gr owers and more worker s than are ultimately needed for the study.” (V3:25)

(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 only 10 workers are in the recruiting pool it is unlikely that the opportuni ty will often arise to select randomly from among interested workers. If the configurati on included a pool of at least 3 or 4 potential workers for each MU, the opportunity to select randomly would arise in nearly all cases.

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

“This is an application scenario defined en tirely by the application equipment, i.e., airblast sprayers with closed cabs. Airblast sprayers ar e used to apply chemicals to orchard trees and trellis crops (e.g., grapes, caneberries, etc.) by delivering pesticides as a liquid carried in a large volume of air. Other crop types, su ch as row and field crops, are not treated by airblast equipment and are theref ore not relevant for th is scenario. The air stream functions to move spray into the tr ees or vines to enhance the uniformity of deposition onto foliage, fruit, and wood. The air stream physically di splaces the air space surrounding the foliage and deposits the chem icals on all surfaces of the leaves and branches.” (V1:6)

“Sprayers are commonly drawn by a tractor or vehicle to move the sprayer through the orchard or vineyard, but can also be mounted on a tractor or other vehicle.” (V1:35)

“AHETF experts ... believe that overhead spraying, exiting the cab, and contacting surfaces (e.g., while making adjustments or repairs) may be the most important parameters influencing exposure in closed cab situations.” (V1:17)

Page 21 of 51Attachment 1

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

scenario definition and do not conflict with EPA’s Worker Protection Standard (WPS) regulations. The duration of the work activity will be partially determined by the amount of AaiH but will involve the application of at least three loads and a minimum duration of

four hours.

“For this particular scenario the applicator will be in a closed cab while the actual spraying takes place. The cab enclosure should reduce dermal and inhalation exposure from airborne spray that would otherwise reach the operator. This protection is due to the physical barrier between the pe sticide spray and the worker . When doors or windows are opened, however, this barrier is no longer effective and the po tential for worker exposure is increased. Opening windows during actual sp raying would be contrary to the WPS and a violation of the label. This will, therefore, not be allowed.

“AHETF suspects that exposure potential, especially dermal exposure, may be impacted by how often the applicator gets out of the closed cab, where that exiting occurs, and

what the worker does while outside the cab. Exiting the cab might occur to make sprayer adjustments, perform repairs, or prepare a new load. Therefore, exiting might occur

within or outside of the treated area. By exiting the cab, the worker might be subjected to lingering airborne sprays and/or surfaces th at may have been sprayed with pesticide including the crop itself, the ground, various parts of the sprayer, and the outside of the cab. Exiting the cab is not, however, somethi ng that can be predicted or controlled in advance since it depends on factors such as worker preference, number of loads performed, and whether repairs or adjustment s are necessary. The agricultural experts consulted by AHETF indicated that exiting the ca b is rare. Number of exits, therefore is not amenable to formal diversification, but will likely vary as a result of purposive diversity in AaiH, and other factors such as crop type, equipment, etc.” (V1:33-34)

“Setup of an airblast sprayer can be very complex involving the following factors and others: nozzle type, nozzle size, nozzle placement, number of nozzles, orientation of air director vanes, liquid pressure setting, spray volume per acre (GPA), engine speed, ground speed, etc... Collectivel y, these factors might also have an impact on exposure potential for airblast applic ators, for example by influenc ing the amount of spray that remains airborne long enough to reach the opera tor or that contaminates surfaces the operator may later contact.” (V1:36)

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

“Airblast applications are sometimes made to dormant cr ops (e.g., to control scale), but agricultural experts for orchard and trellis crops indicate that foliar applications (e.g., to

control diseases and insect s on foliage) are much more common. Overall, dormant applications are estimated to account for 15% or less of all airblast applications (Bruce, 2008). Therefore, because foliar sprays are much more common than dormant sprays, AHETF intends to collect MUs for foliar applic ations only; dormant applications will be excluded from the target population of c onditions for this scenario.” (V1:6-7)

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“Figure 1 summarizes U.S. acr eage statistics for these impor tant groups of orchard and trellis crops. This chart indicates that five crop categories encompass approximately 97% of all the acreage that might be treated by airblast applications.

“The ‘other orchard’ category will be re stricted from the target population because overall acreage is relatively low and agricu ltural experts did not indicate there were fundamental differences in how these crops are treated by airblast. These orchard crops include avocados, dates, figs, guavas, olives, and papayas.

“Trellis crops will be considered as a gr oup with one exception – tall hops. Hops are

treated with conventional airbla st equipment like other trelli s crops, but unlike grapes and caneberries they can grow very tall and i nvolve overhead exposure similar to orchard situations... this plan will re strict MUs involving trellis cr ops to situations that do not involve overhead exposure (i.e., tall hops will not be included)... exposure potential for workers who use airblast sprayers in tall hops will still be covere d within AHED by data from orchard applications.” (V1:18-19)

“Other application equipment types can so metimes be used as an alternative to conventional airblast sprayers. Agricultural e xperts indicated the following are sometimes

alternatives in orchard or tr ellis crops: aerial application, directed-spray rigs, wrap-around sprayers, covered boom sprayers (e.g., tunnel or curtain), electrostatic sprayers, and mist blowers... these alternative sy stems are not nearly as comm on as conventional airblast sprayers for either trellis or orchard crops . AHETF will therefore limit its MU collection to include exposure to workers operating c onventional airblast sprayers.” (V1:36)

3. Are the proposed test materials appropriate surrogates?

“The following active ingredients are approved fo r use on orchards and trellis crops, meet the minimum PPE requirements listed above, and will be considered for use in this closed-cab airblast application scenario. The commercial products of these active ingredients that might be used in particular studies will be listed in study-specific protocols.

• Carbaryl (insecticide; orchards or trellis)

• Malathion (insecticide; orchards or trellis)

“These surrogate active ingredie nts also typically have high us e rates for the potential crops of interest that enables measurements at the high end of AaiH per day. Additionally, cooperating growers who will use th ese products are likely to be available. Finally, these active ingredients have been us ed as surrogates in other studies and are known to have the required stability under field study conditions. Si nce this scenario involves only applications of liquid sprays, any product w ith the proper registration that can be added to water and applied as a liquid spray is su itable. The actual product and p ackaging type has no influence on the potential exposures to these applicators and is, th erefore, not an important consideration for this scenario.” (V1:38)

Page 23 of 51Attachment 1

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 cluster 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 is also a ssumed applicable to the closed cab airblast application scenario. AHETF and the Joint Regulatory Co mmittee agreed there is no evidence to suggest otherwise and no strong opinion to the contrary (meeting with AHETF, June 27, 2007). It is therefore appropriate to use the default relative variation structure consisting of a geometric standard deviation (G SD) of 4.0 and intra-cluster correlation (ICC) of 0.3. Appendix C shows that under these condi tions (and where no suitable MUs exist) a sample of 5 clusters (N C =5) with 5 MUs per cluster (N M =5) is the most cost effective design configuration that meets the 3-fold accuracy requirement. This accuracy is possible with a

variable number of MUs/cluste r as long as the total number of MUs is at least 25 and no

cluster has more than 5 MUs. Each cluste r (i.e. monitoring site) will be addressed by a separate study protocol.

“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 diversity design for the closed cab airblast scenario should provide adequate power for the minor (i.e., secondary ) objective: the ability to conduct limited examinations of the relationship between AaiH and exposure.” (V1:13-14)

Page 24 of 51Attachment 2

EPA Protocol Review: AHE58: Closed-Cab Ai rblast Application to California Trellis Crops

Title: Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of Liquid Sprays Using Closed Cab Equipment in California Trellis Crops.

Revision Date: July 31, 2008

Study Director and Sub-Investigators: Larry D. Smith, Ph.D.

Brian Lange 5

Tami Belcher 5

Aaron Rotondaro 5

Local Site Coordinator: TBD 6

Field Facility: TBD 6

Analytical Facility: TBD 6

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 closed cab airblast applicatio ns in California trelli s crops (e.g., grapes).” (V3:18)

5 One of these three will be the “Principal Field Investigator” for this study. When the choice is made it will be reflected in the protocol and consent document.

6 The Local Site Coordinator, Field Facility, Analytical Facility, and Principle Analytical Investigator must all be

identified.

Page 25 of 51Attachment 2

(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 applicators using conve ntional airblast equi pment and closed-cab tractors. This is a widespread pattern of pe sticide application in or chard and trellis crops, for which existing data are inadequate.

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

EPA will use the results of this study, in conj unction with the results from one field study conducted in August 2008 and three other field studies planned for this scenario, to estimate the dermal and inhalation exposure like ly for future applicator-days for a wide range of agricultural pesticides.

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

“For this particular scenario, the JRC [Joi nt Regulatory Committee] reviewed two closed cab airblast application studi es and did not identify any da ta from existing studies that were deemed useful for a generic database.

“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 for a modern generic database. . . . In the

AHETF detailed review of these PHED da ta, one MU from one study was found that possibly met the acceptance cr iteria established by AHETF. However, several issues associated with this MU make it of dubious qua lity . . . . Thus there are no data currently

in PHED for this scenario that are useful for a modern generic database.

“Finally, EPA examined data from 13 exis ting airblast exposure studies or exposure assessments (for open and/or closed cabs) that were not available to the AHETF and concluded that none of the exposure data shou ld be included in the AHETF database.” (V1:14-15)

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

There is no alternative to monitoring applicat ors as they apply pest icides for measuring their dermal and inhalation exposure as they apply pesticides.

2. Study Design

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

is it?

Page 26 of 51Attachment 2

The objective of the proposed study is to collect exposure monitoring data “to represent future exposures to an arbitr ary active ingredient under the closed cab airblast application scenario.” (V1:10)

“The primary benchmark objective for this scenario is that a sample from the hypothetical reference sampling distribution a bove be of adequate size to describe selected measures of the (normalized) exposure distribution with a pre-determined level of accuracy.

“The current consensus is that estimates of the geometric mean, the arithmetic mean, and

the 95 th percentile generally need to be accurate to within approximately 3-fold of the actual population value. AHETF and the Joint Regulatory Committee (EPA, California Dept. of Pesticide Registrati on, Pest Management Regulator y Agency [Canada], and the U.S. Department of Agriculture) agreed 3-fo ld accuracy is an appropriate benchmark for this scenario (meeting with AHETF, June 27, 2007).” (V1:19)

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 describes the methodology to calculate sample sizes when the reference model us ed is cluster sampling from a lognormal distribution. For the purposes of determin ing sample sizes, the default variation structure for normalized dermal exposure derived in Appendix C is also assumed applicable to the closed cab airblast a pplication scenario. AHETF and the Joint Regulatory Committee agreed th ere is no evidence to suggest otherwise and no strong opinion to the contrary (meeting with AHETF, June 27, 2007). It is therefore appropriate to use the default relative vari ation structure consisting of a geometric standard deviation (GSD) of 4.0 and intra- cluster correlation (ICC) of 0.3. Appendix C shows that under these conditions (and wher e no suitable MUs exist) a sample of 5 clusters (N C =5) with 5 MUs per cluster (N M =5) is the most cost effective design configuration that meets the 3-fold accur acy requirement. This accuracy is possible

with a variable number of MUs/cluster as l ong as the total number of MUs is at least 25 and no cluster has more than 5 MUs.” (V1:13)

(b) What negative and positive controls are proposed? Are proposed controls appropriate for the study design and statistical analysis plan?

Page 27 of 51Attachment 2

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?

“After the randomly-selected pool of eligible growers is assembled, researchers (e.g., Local Site Coordinator and Study Director) will examine the details of potential MUs and identify a configuration of MUs (i.e., gr owers, chemicals, workers, AaiH, timing) that will result in an efficient study.” (V1:31)

“The Study Director or designated researcher will seek permission from the eligible grower to approach his/her employees to recruit volunteers for the study. . . . The Study Director or researcher shall continue conducting site inspections and potential participant recruitment as de scribed above until an ade quate number of eligible growers and potential participants have been secured for an efficient configuration of all MUs in the study. During this proce ss, the following restrictions will be

maintained:

• At least 10 workers who may potentially volunteer for the study

• At least 2 workers available for each of the AaiH strata

• No more than 2 MUs from any one grower (this effectively requires at least 3 different growers since 5 MUs are desired)

• No workers may be used more than once

• No piece of equipment (tractor plus sp rayer) may be used more than once” (V3:26-27)

(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.’” (V1:40)

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

“As detailed in the Governing Document, the data collected from the studies for this scenario will only be statistically evaluate d with respect to the benchmark measures of adequacy. These two categories of data adequacy are:

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

Page 28 of 51Attachment 2

2. How well the data can be expected to describe a relationship between exposure and AaiH, if one existed.” (V1:40

“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 from the confidence interval for each of the three parameters given above.” (V1:40-41)

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

to the closed cab airblast scenario becaus e the practical range in the amount of active ingredient handled (AaiH) exceeds an orde r of magnitude. 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.” (V1:41)

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

Yes.

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

Since the primary objective of the research is to characterize the distribution of exposure normalized by the amount of active ingredient handled (AaiH), statistical power does not relate to this objective. However, EPA believes the resulting data will reliably characterize the distribution of exposures for the individuals monitored during the closed-cab airblast applications in this study, and that these exposures can inform assessments of the likely exposures for individuals in similar future situations.

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

“This secondary benchmark objective applies to the closed cab airblast scenario because the practical range in the amount of active ingredient handled (AaiH) exceeds an order of magnitude. In this case it is re asonable to consider th e linear regression of log dermal exposure on log AaiH. Such a regression would use a mixed model formulation in order to incorporate random cluster effects. As described in the Governing Document, in such a model the true slope, β , would be equal to one if dermal exposure were directly proportional to AaiH. If exposure were independent of AaiH, then β =0. This benchmark objective requires that the number of clusters and

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

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analysis has at least 80% power to reject the hypothesis that β =0 when β is actually equal to one. By symmetry, the mixed mode l linear regression would also have the same power to reject the hypothesis that β =1 when β =0. This is the precise meaning of being able to ‘discriminate between proportionality and inde pendence’.” (V1:41)

2.2 How and to what will human subjects be exposed?

“The closed cab airblast scenario program will monitor instances of worker exposure resulting from the airblast appl ication of pesticides” to trelli s crops in California. (V1:15)

“The test substances approved for use in this study are list ed in Section 2.3.2 above and Table 1 below. The most appropriate test su bstance, based largely on the preference of the grower, will be used at each of the indi vidual locations. A different test substance may be used at each location and by each wo rker within a locati on if appropriate.” (V3:29)

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

“The AHETF has developed several pesticide active ingredient compounds for use as surrogates . . . . Since the AHETF is developing a generic database that will be applicable to nearly all pesticide products and uses, any of the AHETF surrogates can be used for generating exposure data for this scenario. The choice of surrogate at each location will depend largely upon the preferen ce of the grower and pest pressure on his crop at that time.

“The following active ingredients are approve d for use on orchards and trellis crops, meet the minimum PPE requirements listed ab ove, and will be considered for use in this closed cab airblast application scenario. The commercial products of these active ingredients that might be used in particul ar studies will be listed in study-specific protocols.

• Carbaryl (insecticide; orchards or trellis)

• Malathion (insecticide; orchards or trellis)

“These surrogate active ingred ients also typically have hi gh use rates for the potential crops of interest that enables measurem ents at the high end of AaiH per day. Additionally, cooperating growers who will use these products are likely to be available. Finally, these active ingredients have been used as surrogates in other studies and are known to have the require d stability under field study conditions.” (V1:45-46)

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

dose administration?

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“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 ea ch cluster of MUs. AaiH is selected since EPA currently nor malizes closed cab airblast exposure by AaiH during pesticide product exposure asse ssments and there is no other factor identified as being more appropriate.

“In addition to its potentia l direct relationship to e xposure, the amount of active ingredient handled is also vi ewed as a meta-factor affecting parameters such as tank size, number of loads applied, etc. T hus, diversification of AaiH induces

diversification of such associated factors as well.

“The MUs for this scenario will span the practical AaiH range of 5 to 100 pounds, just over 1 order-of-magnitude. As noted in Section 4.5 above, it is also important

that the AaiH levels be well-diversified with in each cluster. This allows the data for

this scenario to be used to discriminate a completely proportional relationship from a completely independent relationship between exposure and AaiH (if one of those two relationships were true). Within-cluster diversification of AaiH will be accomplished by following the standard approach of partit ioning the practical AaiH range into five

strata. These strata are:

• 5 to 9 pounds ai handled

• 10 to 17 pounds ai handled

• 18 to 30 pounds ai handled

• 31 to 55 pounds ai handled

• 56 to 100 pounds ai handled” (V1:27-28)

“A single MU will be conducted in this st udy from each of the five strata.” (V3:33)

(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. Airblast applicators often spend several hours making applicati ons, so all MUs for

this scenario must meet th e general rule of being at least 4 hours long. This is designed to overcome the criticism of early exposure studies where many of the sampling regimes monitored workers for onl y a few minutes. Avoiding very short monitoring intervals will ensure that daily exposure estimates are not biased by unusual conditions during that short interval . If necessary, some minor scripting of

worker activities will be done to ensure the lowest levels of AaiH are handled and/or a minimum of four hours are monitored. For example, a worker might be asked to use a smaller tank, make smaller loads, or in crease the spray volume slightly in order to apply 3 loads in four hours for the lowest AaiH.” (V1:34)

2.3 Endpoints and Measures

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

asked?

“At the completion of the monitoring period, exposure samples will be taken in the following order to minimize cross contaminatio n: inhalation samples (discussed in the next section), then hand washes, then face/n eck wipes, and finally inner dosimeters as

described in SOP AHETF-10.E.

For this study, inner dosimeters will be cut into two sections.

“Full details of the personal air-sampli ng method, attachment of pumps, monitoring of workers, and pump calibration are give n in the most recent versions of SOP AHETF-8.D and 10.G. (V3:33-34)

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

“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 conditions.

“All field fortification and untreated control samples will be identified as described in SOP AHETF 11F.” (V3:34-35)

(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 si 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)). The final report will be audited by the QAU specified in Section

1.15 to ensure that the cont ents of the report accuratel y describe the conduct and findings of the study.

The final report will contain a Quality Assurance Statement from the QAU of each contributing laboratory conducting QA audits , and from the QAU specified in section 1.15. (V3:42)

(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.

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“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 conditions. . . . On each fortification day, 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.” (V3:34-35)

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?

“The closed cab airblast scenario progra m will monitor instances of worker exposure resulting from the airblast application of pesticides. Each instance is termed a monitoring unit (MU). Each MU consists of a set of airblast application conditions (including the particular worke r) that are intended to represent the scenario activities for a single workday. In many cases monitoring units will be selected from ‘naturally occurring’ airblast applicator-days. Howeve r, the selected application conditions are sometimes modified or scripted slightly to ensure that the sample of MUs reflects the expected diversity in the entire population of future airblast application-days. Thus, MUs are technically not ‘sampled’ from a population. More correctly, they should be viewed as synthetic closed cab airblast application-days derived from both selected and constructed conditions.” (V1:15)

(b) From what populations will subjects be recruited?

Subjects will be recruited among the employ ees of commercial growers of trellis crops (e.g., grapes or caneberries) in Fresno County and possibly adjacent counties who might utilize airblast equipment in their operations and who meet AHETF criteria for participation. (V3:36)

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

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A ‘working pool’ of eligible growers will be identified from a randomized list of growers in the target area. Based on c onsiderations of equipment type, acreage, anticipated time of treatment, and geogr aphic location the Study Director and LSC will purposively select growers from this pool to construct an ‘efficient configuration’ of MUs. All employees of eligible growers included in the efficient configuration (or of pesticide application service companies us ed by eligible growers included in the efficient configuration) who are experien ced in the use of closed-cab airblast application equipment and who meet the elig ibility requirements of the study will be recruited; if more employees are availabl e and interested than are needed for a specific MU, participants will be sel ected randomly. Although the design is purposive, and thus participants are not repr esentative in a statistical sense, they are expected to be typical of those who use ai rblast equipment to treat California trellis

crops.

(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:

• Be freely willing to participate and to understand and sign the consent form

• Handle pesticides as part of their job

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

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

• Be at least 18 years old with a gove rnment-issued ID to verify age.

• Consider themselves to be in good gene ral health with no medical conditions that could impact their ability to pa rticipate in the study. See SOP AHETF11.C for health status determination.

• Be willing to follow all label and WPS requirements

• Understand English or Spanish

• Understand and sign the consent form a nd the Product Risk Statement for the pesticide they will handle

• Have experience within the past year with making airblast applications to vines using open cab tractors and airbla st sprayers (including the particular equipment to be used).

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“Exclusion criteria:

• Are pregnant females

• Are nursing mothers

• Normally wear personal pr otective equipment (PPE) that is not required by the label and might adversely impact the objectives of the study, such as chemical-resistant clothing

• Are employed by a pesticide manufacture r or a contractor to AHETF” (V3:21- 22)

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

None.

(c) If any potential subjects are from a vulnerable population, 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 growers and by requiring growers to promise in wr iting not to influence their employee’s

decisions.

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

“AHETF will follow standard procedures (see SOP AHETF-11.B) to recruit potential participants for this closed cab airblast application study. Individual workers will be recruited during an initial site inspection or subsequent visit(s) to an eligible grower facility.

“The Study Director or designated researcher will seek permission from the eligible grower to approach his/her employees to recruit volunteers for the study. Depending on the number of employees and size of the grower facility the Study Director or researcher may contact employees through th e use of an informational recruitment flyer posted in a common work area. Such a flyer will briefly describe the research study and provide contact information for employees who may have an interest in participation in the study. The flyer sh all have been previously reviewed and approved by an IRB.

“Alternatively, or subsequent to the use of a flyer, the Study Director or researcher will arrange a meeting with the grower’s employees who express an interest in participation. Such meeti ngs will always occur without the grower or supervisors being present (SOP AHETF-11.B). The Study Director or researcher shall make a presentation describing the AHETF Exposur e Monitoring Program, the goals of the research study, the procedures used in e xposure monitoring, and the risks and benefits to participants. Contact information will be provided, and individuals will be

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encouraged to contact AHETF if they desi re additional information about the study or are interested in participa ting 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.” (V3:39)

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

“In accordance with SOP AHETF-11.B, the individual growers will be asked to sign a non-coercion statement (Employer Coopera tion 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. Growers must also certify that alternate work will be provided on study days for workers who choose not to volunteer; and that the employee’s decision to participate or not will have no impact on their employment.” (V3:38-39)

If both of the candidate workers identified for a specific MU decline to participate, the investigators would have to repeat seve ral preliminary steps to identify potentially appropriate workers employed by growers in the working pool already identified, or to screen additional growers for inclusi on in the working pool. The cost and time associated with repeating these steps c ould result in some pressure on the second candidate originally identified. This problem could be largely eliminated by identifying a larger pool of candidate work ers—at least 3 or 4 for each defined MU—

in the first iteration.

3.3 Remuneration of Subjects

(a) What remuneration, if any, is proposed for the subjects?

(b) “During recruitment, workers will be offe red an opportunity to take part in a group meeting with the Study Director or other designated member of the study team (but without the workers’ supervis ors) to learn about particip ating in this study (Section 6.2). No remuneration is offered for this introductory meeting. Wo rkers who are still interested will attend a private meeting with a researcher who will obtain the informed consent of the worker (Section 2.7). Workers will be paid $20 for their attendance right after the consent meeting, whether or not they decide to participate in the study. Workers who decide to participate in the study will be paid an additional $80 each time they suit up (i.e., put on the long underw ear) to participate in the study. Usually, workers will participate in the study on onl y one day unless thei r participation is terminated due to weather or other unexpected occurrences. The additional $80 is provided in cash at the end of the monito ring period or at the time the volunteer withdraws from the study. All workers who pa rticipate will receive the payment, even if they withdraw or their participation is terminated by the study team.” (V3:22)

(c) Is proposed remuneration so high as to be an undue inducement? No.

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(d) Is proposed remuneration so low that it will only be attractive to economically disadvantaged subjects? No.

(e) How and when would subjects be paid?

In cash, immediately afte r their participation.

4. Risks to Subjects

4.1 Risk characterization

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

about the hazards of the test materials?

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

This study could involve either of two active ingredients: carbaryl or malathion. “The pesticide products containing these active i ngredients and potentia lly used in this study are currently registered for airblast applications to grapes and caneberries. AHETF will only monitor workers making appl ications in accordance with all label and Worker Protection Standard (WPS) requi rements. Margins of Exposure (MOEs) are presented below for the highest amount of active ingredient that will be handled in this scenario (100 lb a i/day). For each of the active ingr edients (a.i.) th at may be used in this scenario the calculated MOEs exceed the required MOE for both the individual dermal and inhalation routes of exposure, as well as for the combined exposure, and their use is acceptable for th is scenario.” (V3:24-25)

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

“Six kinds of risks are associated with the conduct of the current exposure monitoring study. These are:

• The risk of heat-related illness

• The risk of exposure to surrogate chemicals

• The risk associated with scripting of field activities

• Psychological risks

• The risk of exposure to detergents

• The background risk of injury a ssociated with ag ricultural work

“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 encounter ed in ordinary daily life. In particular, this study involves the operation of tractors and airblast sprayers which present risks of accidents and physical injury, as well as the use of chemicals (pesticides,

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fertilizers, additives, etc.) which presents a ri sk of adverse health effects. In addition,

AHETF believes the risk of h eat-related illness (resulting from wearing an extra layer of clothing to trap chemical) will be incr eased due to study part icipation.” (V3:22-23)

Each of these six kinds of risk is discussed in V3:23-31.

“The following signs and symptoms of t oxicity from short-term exposure might occur. These effects are not anticipated with normal use, but might occur following a spill or other accidental exposure.

“This [carbaryl/malathion] product is clas sified as [low/moderate] toxicity for exposure by mouth, by skin, a nd by breathing. Signs and symptoms of too much short-term exposure include [slight/moderate] eye irritation, [slight skin irritation,] and inhibition of cholinesterase (cholinesterase is a chemical in our nervous system that allows the nerves to work correctly ; when chemicals prevent it from working correctly, there is a stimulation of the nervous system.)

“Inhibition of cholinesterase may result in headache, dizziness, nausea, vomiting, cramps, diarrhea, blurred vision, pinpoint pupils, tightness in the chest, difficulty breathing, nervousness, sweati ng, watering of the eyes, drooling, muscle spasms, and coma.” (V3:69, 71, 73, 75, 79, 81 Product Risk Statements supplemental to consent form)

(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:

• Selecting only experienced pesticide handlers

• Requiring experience operating the equipment to be used

• Reminding workers of safe chemical handling practices

• Identifying nearby hospitalization fa cilities 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

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

urgent care

• Observing study participants th roughout the monitoring period

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• Ensuring that all tank mix products are used according to approved label(s) and do not require any additional PPE.” (V3:30-31)

Risk reduction actions specific to each of the six identified kinds of risk are

discussed in V3:23-31.

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

for the test materials?

“For each of the active ingredients that may be used in this scenario the [Margins of Exposure (MOEs) calculated for the highest le vel of exposure in th is protocol] greatly exceeded the required MOE for both the indi vidual dermal and inhalation routes of exposure, as well as for the combined [dermal/inhalation] exposure.” (V3:25)

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

“Since workers may exit the cab, AHETF w ill monitor ambient conditions outside the

cab to determine the heat index and base monitoring decisions on the external heat

index. A heat index of 120 o F is the cutoff, as measured outside the cab. When the

worker is inside an air conditioned closed cab the external heat index will not be applicable to that subject and exposure monito ring will not necessarily stop if the heat

index cutoff is reached or exceeded. A worker will be allowed to exit the cab for short periods of time even if the heat index cutoff is exceeded; however, if the duration of exiting becomes prolonged (more th an 30 minutes), the Study Director or other researcher shall stop the monitoring and/or move the worker to a cooler environment until monitoring can be resumed.” (V3:24)

(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 obs erve you for signs of illness. They will provide medical attentio n as needed.” (V3:61)

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

(e) How does the protocol provi de for safety monitoring?

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

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

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

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

indication of heat-related illness.

• SOP AHETF-11.H defines procedures to be followed if a subject in an AHETF study requires 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 the various body areas measured so the

worker can be aware of where most dermal exposure occurs and a comparison to the results for other workers performing the same task. Results are typically available six to nine months after monitoring occurs. The personal information related to this follow-up will be retained as described in SOP AHETF-6.D.

“Just prior to the completion of the 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.B).” (V3:35)

(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 during or af ter the day of the st udy, medical treatment will be available at your workplace and at a nearby health care f acility. If necessary, AHETF will arrange transportation for you to receive medical attention. You may

refuse medical treatment. You cannot refu se medical treatment if you get sick from too much exposure to pesticides or from ge tting 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 insurance provided through your employer. The medical treatment records will not become part of the research records. AHETF will make note of the event. The event will be reported in the study report. For further information about th is you may call to AHETF Manager (David Johnson) toll free at (8 66) 925-1421.” (V3:61-62)

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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.” (V3:31)

Although there are no direct benefits to study participants, a potent ial indirect benefit is knowledge about how their exposure compares to that of others doing similar work; this is not addressed in the protocol.

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

“Since there are no existing data suitable fo r use in a generic database describing the exposure of closed cab airblast application wo rkers, society will likely benefit from data generated by this study through the impr oved risk assessments by EPA and other regulatory agencies.

“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 using airblast equipment and closed-cab tractors. The knowledge likely to be obtained from this st udy is generalizable and will contribute to

assessments of the risks of both ne w and existing pesticides.” (V3:31)

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

research?

“Growers who allow the study to be conducted using their equipment, crops and facilities will be reimbursed for the pesticides used for the study. While this is beneficial to the grower, it is considered a minor benefit when compared to the costs of running their businesses. The AHETF member companies wi ll likely realize a benefit by addressing regulatory data requirements ge nerically, at lower cost (and using fewer human subjects), than if they conducted similar studies for individual pesticide ingredients.” (V3:31)

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

Identified societal benefits are likely to be realized.

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

“This study presents a greater than minimal risk to participants. The primary risk comes from their employment as an agricultural worker where accidents and chemicals contribute to injury and illness. In particular, this scenario involves the use of mechanical equipment that could cause physical injury and handling chemical s that could cause adverse health effects.

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However, workers will be experienced with the equipment they will be using and will follow their usual practices while handling pest icides approved for this use pattern.

“Participating in this study increases the risk of heat-related illness, but this risk is mitigated by a medical management program which empha sizes prevention measures and guidelines for stopping participation when warranted based on environmental conditions.

“The likely benefit to agricultural workers as a w hole and to society in general, in the form of more accurate measurements of potential exposure to pesticides, must be weighed against the risks to participants. Airblast applications are common in both orchard and trellis crops across the country and a wide variety of expert s consulted by AHETF reported that closed cabs are most common now, and are becoming ev en more common. Exposure data for this scenario meeting contemporary standards of re liability and quality will likely provide a significant benefit to society. Because the margins of exposure (MOEs) calculated for the exposures in this research st udy indicate that subjects are very unlikely to experience acute toxic effects, and because extensive procedures will be in place to minimize these and other risks to participants, the like lihood of serious adverse effects is very small. In summary, AHETF believes the risks to study participants from participati ng in this study are reasonable in light of the likely benefit to society of the knowledge to be gained.” (V3:31-32)

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 w ith EPA’s final regulation published at 40 CFR Part 26 that establishes requirements for the protection of subjects in human research. The protocol, informed consent fo rm and other required documentation for this study will be approved by an institutional re view board (IRB), and submitted to the EPA

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as required by 40 CFR 26.1125. The report of the completed research is subject to 40 CFR 26.1303 requirements to docum ent 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 National 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 AHETF and all contra ct facilities.)” (V2:21-22)

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 §6 of SOP AHETF-11.B.2 (V3:233-236)

(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

Page 43 of 51Attachment 2

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-B-3 will be used to ascertain general understanding.” (SOP AHETF-11.B.2 §7.10.a; V3:237-238. The form is at V3:241-243)

(g) What specific procedure will be followed to inform prospective subjects and to seek

and obtain their consent?

“The SD (or a researcher designated by th e SD) will be responsible for obtaining informed consent from all study workers prior to their partic ipation in the study. Generally, a PowerPoint presentation will be made that covers all aspects of the study that should be covered during this consent meeting Any mate rials used during the consent meeting will be approved by the IRB before use.

“Informed consent discussions will be conducte d by the SD (or designee) in private with each worker and others that the worker may want to have present. Witnesses may also be present as described above in Section 6.0. When a bilingual res earcher is obtaining consent from a Spanish-speaking worker, the Study Director may also be present during the private meeting to answer study-specific questions.

“The SD (or designee) will inform the worker that he/she will receive $20, or the amount specified in the protocol, ev en if he/she decides not to participate in the study.

“During the private meeting the SD (or desi gnee) will provide each worker with a full explanation of the study, its requi rements, any potential risks, its benefits, alternatives to participation, etc . Workers will be advised of their right to withdraw from the study at any time and for any reason without jeopard izing their normal position with their employers or their daily wages. Workers will be told they will re ceive an additional $80, or the amount specified in the protocol, if they decide to participate (don the dosimeters), even if they withdraw before th e end of the monitoring period.

“The SD (or designee) will provide informati on about the risk of the surrogate chemical in the study, including signs and symptoms of acute overexposure. This information will be presented as an attachment to the Cons ent Form (called a Product Risk Statement or PRS) and shall be signed by the worker. WP S requirements, especially proper use of clothing, personal protective equipment, etc ., will be discussed. Refer to SOP AHETF11.E for details.

“The SD (or designee) will discuss the medi cal management plan with the prospective participants. Information will be provided a bout the risk of heat stress, including signs and symptoms, and ways to prevent it. Deta ils on heat stress are outlined in SOP AHETF-11.G, while details on emergency me dical procedures are outlined in SOP

AHETF-11.H.

Page 44 of 51Attachment 2

“During the discussions between potential part icipants and the SD (or designee), ample time will be provided for questions and the SD will provide any additional information or clarification that is requested.

“The IRB-approved Consent Form (and all s upporting documents) will be presented in the preferred language (English or Spanish) of the worker. All sec tions of the Consent Form will be explained in detail. When the SD (or designee) is satisfied that the worker understands the requirements a nd 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 SD (or designee) will provide a copy of the signed form to the worker.

“An additional IRB-approved document, ‘Product Risk Statements,’ will be attached to the Consent Form. If the study is conduc ted in California, the IRB-approved ‘Experimental Subject’s Bill of Rights’ will also be attached. These documents (in the appropriate language) will be reviewed, signe d and dated by the worker, and copies will be provided.”

“The SD (or designee) will not sign the Cons ent Form unless he/she believes that the process has been free of any element of coercion or undue influence and the witness (when required) has signed the consent form.” (SOP AHETF-11.B.2 §7.2-7.11; V3:236- 238)

(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 indi vidual growers 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. Growers must also certify that alternate work will be provided on study days for workers who choose not to volunteer; and that the employee’s decision to participate or not will have no impact on their employment.” (V3:38)

9. Respect for Subjects

(a) How will information about prospective and enrolled subjects be managed to ensure their privacy?

“The AHETF employs many procedures to prot ect subject privacy during recruitment, consent, study conduct, and maintenance of study records. The consent form also summarizes important confidentiality issues for subjects. These procedures are described in SOPs AHETF- 6.B, 6.D, 11.B, and 11.D.” (V3:32)

“Your name will only appear on the consent form, the Product Risk Statement, and an optional form for you to request your personal study results. In al l other parts of the

Page 45 of 51Attachment 2

study you will be identified by a code. Records w ith your name will be stored in a secure place with limited access.

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

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

It will be sent to the US 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 a nd a mail or e-mail address.” (V3:62)

(b) How will subjects be informed of their freed om 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 during 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 and air sampling pump will be removed, and the hand and face/neck samples will be collected with the worker’s consent. The Study Director will decide whether these samples will be analyzed (SOP AHETF-8.K).” (V3:32)

“Your employer has agreed to let us do the re search and has confirmed that he/she does not care whether you take part in this study or not. Your deci sion 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.” (V3:63)

(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

Page 46 of 51Attachment 2

Page 47 of 51 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 and ai r sampling pump will be removed. The hand and face/neck samples may be collected if you agree.

“Your part in this study may be stopped at any time by the resear chers or the AHETF. The long underwear and air sampling pump will be removed. The hand and face/neck samples may be collected if you agree. If you withdraw or are removed from the study, you can go back to your usual work activities. If the study does not last an entire workday, you can go back to your usual work activities.

“No one can force you to take 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 a lternative is to not take part.” (V3:63)Attachment 3

Page 48 of 51 § 26.1111 Criteria for IRB approval of research AHETF Protocol AHE58: California Trellis Crops: August 14, 2008

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 reasonable 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 research (as distinguished from risks and benefits subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of 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 49 of 51 §26.1116 General requirements for informed consent AHETF Protocol AHE58: California Trellis Crops: August 14, 2008

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 Ensure bilingual competence among investigators who conduct

recruitment and consent interviews 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 procedures 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 Although research doesn’t involvemore than minimal risk, compensation and treatment of injuries are provided for (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 Ensure Spanish capability at all listed phone numbers(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 the 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 50 of 51 §26.1117 Documentation of informed consent AHETF Protocol AHE58: California Trellis Crops: August 14, 2008

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 copy 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 51 of 51 40 CFR 26.1125 Prior submission of proposed human research for EPA review AHETF Protocol AHE58: California Trellis Crops: August 14, 2008

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 investigators, and reports of injuries to subjects. Y

n/a

Y
n/a V2:16-57; 169-210; 293-335

V2:58-150

(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 discus sion of controverted issues and

their resolution. Y

Y

Y

N

n/a V2:350-356

Basis for changes not shown

No controverted issues

(3) Records of continuing review activities. n/a (4) Copies of all correspondence between the IRB an d the investigators. Y V2:11-14,156-167, 288, 291- 292, 345-349 (5) ● A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member’s chief anticipated contributions to IRB deliberations;

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

file with EPA.

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). Y Separately submitted to EPA under confidentiality 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 V2:23-32 (2) The measures proposed to minimize risks to the human subjects; Y V2:23-32

(3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y V2:32-33

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y V1:14§1125(a)a discussion of:

(5) The balance of risks and benefits of the proposed research. Y V2:33-34 §1125(b): All information for subjects and written informed consent agreements as originally provided to t he IRB, and as approved by the IRB. Y Original V2:211-248 Approved V2:58-150

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y V1:39-40; V2:23; 34; 39-41; 96-97; 151-153; 269-285; 336-

342 §1125(d): A description of the circumstances and methods proposed for presenting information to potential human subjects for the purpose of obtaining their informed consent. Y V2: 40-41; 269-285

§1125(e): All correspondence between the IRB and the investigators or

sponsors. Y See page references aboveThe following Information, to theextent not already included:

§1125(f): Official notification to the sponsor or investigator . . . that research involving human subjects has been reviewed and approved by

an IRB. Y V2:11-14