UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

May 27, 2008

MEMORANDUM

SUBJECT: Science and Ethics Review of AHET F Scenario Design and Protocol for Exposure Monitoring in Florida Citrus

FROM: John M. Carley

Human Research Ethics Review Officer

Jeff Evans

Health Effects Division

Matthew Crowley

Health Effects Division

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 Florida Citrus. Unpublished protocol dated April 7, 2008, prepared for the Agricultural Handlers Exposure Task Force under Sponsor ID AHE55. 107 p., plus 674 p. supplement containing IRB correspondence.

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 56A. 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 April 7, 2008 (V1:9-52) 1 . The IRB-approved protocol and supporting documents (consent forms, product-sp ecific risk statements, and recruitment flyers in both English and Spanish) app ears in Volume 2 of the AHETF submission.

Documentation of all intera ctions between the investig ators and the Independent Investigational Review Board, Inc., of Plantation FL appear s in Volume 8 of the AHETF submission. Additional supporting materials releva nt to this review also appear in the AHETF Governing Document (V olume 4), in the cited AHETF SOPs (Volume 6), and in

the collection of referenc ed documents (Volume 7).

In addition to the final protocol (V 2:3-46) Volume 2 includes the following supporting documents:

• Study documents in English approved by IIRB:

o Informed Consent Form approved 3/25/08 (pp. 48-56)

o Product-specific risk statemen ts approved 3/25/08 (pp. 69-82)

o Recruiting flyer appr oved 3/4/08 (p. 105)

• Study documents in Spanish approved by IIRB:

o Informed Consent Form approved 3/25/08 (pp. 57-67)

o Product-specific risk statements approved 3/25/08 (pp.83-103)

o Recruiting flyer approved 3/4/08 (pp. 106-107)

Volume 8 of the AHETF submission documents interaction between the investigators and IIRB, Inc.:

• Correspondence between the investig ator and IIRB (pp. 4-10, 230, 274, 372-376, 403, 438-445, 470, 540, 589-590, 652)

• Protocol and supporting documents as in itially submitted to IIRB on 2/28/08 (pp. 11-229)

• Revisions to protocol submitte d to IIRB on 2/29/08 (pp. 231-273)

• SOPs cited in protocol as submitted to IIRB on 2/29/08 (pp. 275-371)

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. “V2” indicates Volume 2 of the AHETF submission, and “V8” refers to Volume 8 of the AHETF submission. Many pages in all volumes bear more than one page number. All page references in this review to Volume 1 are to “page N of 52”, page references to Volume 2 are to “page N of 107”, page references to Volume 4 are to “page N of 153”, page references to Volume 6 are to “pag e N of 154”, page references to Vo lume 7 are to “page N of 54”, and page references to Volume 8 are to “page N of 674.”

Page 2 of 56• IIRB approval letter of March 4, 2008 (pp. 375-376)

• Minutes of 3/4/08 IIRB Meeting (pp. 377-378)

• Track-changes version of English co nsent form and product-specific risk statements showing IIRB changes in 3/4/08 review (pp. 446-468)

• Study documents in English approved by IIRB 3/4/08:

o Informed Consent Form (pp. 379-387)

o Product-specific risk statements (pp. 388-401)

o Recruiting flyer (p. 402; identical to V2:105)

• Spanish translations of study doc uments approved by IIRB on 3/4/08:

o Informed Consent Form (pp. 406-416)

o Product-specific risk statements (pp. 417-437)

o Recruiting flyer (pp. 404-405; identical to V2:106-107)

• Protocol revisions dated 3/21/ 08: Track changes (pp. 471-539)

• Protocol revisions dated 3/24/ 08: Track changes (pp. 541-583)

• Additional SOPs submitted to IIRB on 3/24/08 (pp. 584-587)

• IIRB approval letter of March 25, 2008 (pp. 589-590)

• Minutes of IIRB meeting of March 25, 2008 (pp. 647-650)

• Study documents in English approved by IIRB on 3/25/08:

o Informed Consent Form (pp. 605- 613; identical to V2:48-56)

o Product-specific risk statements (pp. 591-604; identical to V2:69-82)

• Spanish translations of study doc uments approved by IIRB on 3/25/08:

o Informed Consent Form (pp. 614- 624; identical to V2:57-67)

o Product-specific risk statements (pp. 625-647; identical to V2:83-103)

• Additional SOPs transmitted to IIRB on 4/2/08 (pp. 653-674)

The rationale for the proposed sample size a nd cluster configuration is presented in the AHETF Governing Document (V4:49- 52) and its Appendix C (V4:127-153).

The following SOPs are cited in the prot ocol, and can be found in Volume 6:

AHETF-1.B.2 Personnel Responsibilities (V6:8) AHETF-1.F.0 Potential Referable Findings (V6:13) AHETF-2.C.2 Protocol Design and Preparation (V6:18) AHETF-6.B.1 Access to Archived Data (V6:31)

AHETF-6.D.0 Access to Confid ential Worker Info (V6:33) AHETF-8.A.3 Whole Body Sampling – Inner Dosimeters (V6:35) AHETF-8.B.4 Hand Wash Samples (V6:40) AHETF-8.C.4 Dermal Face/Neck Wipe Samples (V6:44)

AHETF-8.D.2 Collection of Air Sa mples Using OVS Tubes (V6:47) AHETF-8.E.4 Fortification of Matrix Samples (V6:51) AHETF-8.F.4 Sample Identification (V6:60) AHETF-8.G.2 Worker Clothing A cceptability Criteria (V6:63) AHETF-8.K.0 Sample Quality (V6:74) AHETF-10.A.0 Rotameter Calibration (V6:100)

AHETF-10.C.3 Worker and St udy Observations (V6:102) AHETF-10.D.0 Application Equipmen t Operation Verification (V6:107)

Page 3 of 56AHETF-10.E.2 Worker Sample Collection Sequence (V6:109) AHETF-10.G.1 Personal Air Sampli ng Pump Calibration (V6:111) AHETF-11.B.1 Recruitment of Study Vo lunteers and Informed Consent (V6:113) AHETF-11.D.0 Pregnancy Testing (V6:130) AHETF-11.F.0 Adverse Events Reporting for IRBs (V6:135)

AHETF-11.G.0 Identification and C ontrol of Heat Stress (V6:137)

Reports of interviews with e xperts knowledgeable about the use of airblast application equipment are provided in Volume 7, pp. 4-31. Reports of interviews directly addressing agronomic and pesticide application practi ces in Florida citrus groves are on pp. 15-18.

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 with 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, and

• 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 AHE55 protocol calls for closed-cab airblast application of one of two surrogate insecticides to citrus in Florida. A total of 25 Monitoring Units (MUs) are proposed for the closed-cab airblast s cenario; when the scenario is complete, the five (MUs) to be collected under this protocol will be combined in the AHED database with twenty more to be collect ed under other field study protocols. EPA

intends to use these data to estimate daily dermal and inhalation exposures of pesticide applicators applyi ng liquid pesticides to orch ard and trellis crops using conventional airblast equipment drawn by closed-cab vehicles.

2 Supporting details are in Attachment 1.

Page 4 of 562. 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

The 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 equipment. Of specific relevance to this protocol, Florida grows two-thirds of all citrus in the U.S., and citrus is the only major crop treated by airblast equipment in the “peninsular southeast” growing region.

The specific ‘site’ selected in which to conduct the citrus study is Polk and Hillsborough Counties, adjacent to each ot her in central Florida. The AHETF

choice of these counties was based on Polk County’s high orange production, Hillsborough County’s adjacency to Po lk County and convenience to major transportation routes, and having identifie d a suitable Local Site Coordinator. There are approximately 2500 citrus fa rms in these two counties out of approximately 7000 citrus farms in the state. This is an appropriate choice to efficiently achieve the desired diversity of equipment and scale.

Page 5 of 56In 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

This 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 their 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

Page 6 of 56• 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 could be made stronger by relying less heavily on th e Local Site Coordinator (especially since the LSC’s employees are not excluded as subjects) and if the processes of grower selection and construction of an efficient configur ation of MUs were defined in an appropriate SOP—with pa rticular attention to standards for

documentation and methods for randomization.

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 stat e and county)—the Study Dire ctor and the Local Site Coordinator will purposively construct an “efficient configuration” of potential Monitoring Units (MUs). An efficient configuration will involve a group of growers in the same geographic area, who can provide workers for all five strata of AaiH, who would involve some diversit y in spray equipment, and who expect to make airblast applicati ons at approximately the same time. When constructing MUs, three additional restrict ions 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 growers or workers dr op 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.

The process for selecting workers co uld be strengthened by over-recruiting growers, so that there ar e likely always to be more interested and qualified workers than MU slots, so that the work ers actually sampled could be selected randomly. In addition it would be prefer able if no more than one MU were obtained from a single grower or gr ower/commercial applicator pair.

3. Choice of Surrogate Materials: The surrogate chemicals proposed for this scenario are carbaryl and malathion, formul ated in seven registered products. These pesticides have been successfully used in previous worker/handler exposure monitoring studies and have well established and reliable analytical methods. Between 2005 and 2007, approximately 50,000 to 90,000 acres per year

Page 7 of 56of Florida citrus were treated with these chemicals. These are appropriate choices

for this research

C. Summary Assessment of the Scient ific Aspects of the Study Design 3

1. Statistical design: This protocol de scribes collecting five Monitoring Units (MUs) reflecting the exposure of subjects ma king airblast applic ations to Florida citrus 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.

2. 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 will be done by others not participating in the study. Over the course of a day each subject will apply the surrogate active ingr edient in one if 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 c ontaining one of the two su rrogate pesticides have been identified, and a cooperating grower may choose to use any of them for a specific MU. Carbaryl formulations incl ude wettable powders enclosed in watersoluble bags and liquid flowable concentr ates. Malathion formulations include emulsifiable 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

3 Supporting details are in Attachment 2.

Page 8 of 56• 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 the LOQ or some other statistical me thod to estimate potential exposures.

3. Endpoints and Measures: The AHETF will measure dermal and inhalation exposure for each MU. These data can be used to develop Unit Exposures (exposure per unit of pestic ide active ingredient app lied) or other exposure metrics, and to estimate dermal and inhalation exposure to other pesticides applied to orchard or trellis crops with conventional airblast sprayers drawn by

vehicles with closed cabs. EPA be lieves 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

Page 9 of 56another face/neck wipe sampling prior to the break and again at the end of the exposure period; both samples will be retained for analysis.

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 monitoring event, and photographs or videos may be taken selectively to illustrate

events.

4. QA/QC Plan: The study will be monitored by three different 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 the following changes:

Page 10 of 56• Reducing the role of the Local Site Coordi nator in serving as a consulting expert, influencing the choice of locations in which to conduct the field study, identifying growers, screening growers for eligibility, de veloping an efficient configuration of MUs, and providing his own employees as potential subjects. As a contractor to the AHETF the LSC is a member of the research team, and should not also serve as part of the study population, eith er as an expert or as a cooperating grower or commercial applicator.

• Documenting the processes of diversity se lection of growers and construction of an efficient configuration of MUs in an appropriate SOP.

• Increasing the numbers of growers and workers in the working pool, so that

individual workers to fill each MU sl ot can be selected randomly from among qualified, interested volunteers.

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

• Scientific objective

• Experimental design for achieving objectives

• Quantification of the test materials

• Data collection, compilation and summary of test results

• Justification for selection of test substances

• Justification for sample size

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

Additionally, the AHETF has addressed th e 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 Aspects of the Proposed Research 4

1. Societal Value of Proposed Research: The objective of this study is to determine the potential exposure for workers making closed-cab airblast applications in Florida citrus. This study will provide a partial answer to the question of what dermal and inhalation e xposures are likely for applicators using conventional airblast equipment and closed -cab tractors. This is a widespread pattern of pesticide application in orch ard and trellis crops, for which existing applicator exposure data are inadequate. EPA will use the results of this study, in conjunction with the results of four other fi eld studies planned for this scenario, to

4 Supporting details are in Attachment 2.

Page 11 of 56estimate the dermal and inhalation exposure likely for future applicator-days for a wide range of agricultural pesticides applied under this exposure scenario.

2. Subject Selection: Subjects will be recruited among the employees of citrus growers in Polk and Hillsborough Counties in Florida who are identified as “commercial citrus producers [who] might utilize airblast equipment in their operations” and who meet AHETF criteria fo r participation. Eligible growers will be identified from a complete list of citr us growers in the two affected counties, processed in random sequence. Subjects will be recruited wh o are employees of eligible growers (or of pesticide application service companies used by eligible growers), who are experienced in the us e of closed-cab airblast application equipment, and who meet the eligibility requirements of the study; if more employees are available and interested than are needed, participants will be selected randomly. Although the design is purposive, and thus participants are not representative in a statis tical sense, they are expect ed to be typical of those who use airblast equipment to treat Florida citrus.

Inclusion factors are appropriate, requir ing subjects to have recent experience operating the equipment to be used in the study. Exclusion factors are appropriate, with the exception of the une xplained exemption of employees of the

Local Site Coordinator from the exclus ion of all other employees of AHETF contractors. No such exemption is allowed by the AHETF Governing Document (§14.1.4) or by AHETF SOP 11.B .1 (§5.3), and this exemption should be deleted from the protocol.

The description of the process for recruiti ng subjects relies heavily on references to AHETF SOP 11.B. Appropriate steps are proposed to protect candidates and subjects from coercion or undue influence to participate, again with the potential exception of employees of the Local Site Coordinator. Candidates who attend an individual interview will be paid $20 whet her or not they agree to participate; enrolled subjects who once put on the w hole-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 detergents used for hand washing and face wipes

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

The surrogate chemical used will be either carbaryl or malathion; both are fully tested and well understood. Individual gr owers will choose from a list of seven registered products containing one of th ese ingredients, for each of which a

Page 12 of 56product-specific supplement to the consen t form describes the specific risks identified on the approved label. Marg ins 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; no other post-study follow-up is proposed.

4. Benefits: This research offers no direct bene fits to the subjects, but subjects may request their individual results . If they are told only th eir own results little benefit would result, but if they are told how thei r exposure compared to that of others it could be of potential indire ct benefit to them. The principal benefit of this research is likely to be reliable data a bout the dermal and inhalation exposure of workers applying pesticides to citrus orchards 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.

6. Independent Ethics Review: The proposed research has been reviewed and approved by the Independent Investigati onal Review Board, Inc., (IIRB, Inc.) of Plantation FL. The submitted materials include a full record of correspondence between the investigators 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. Appropriate provision is made to meet the needs of subjects who do not read either language . EPA assessments of compliance with the requirements of 40 CFR §26.1116 a nd §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 an arbitrary code. Provision is ma de for discrete handling of pregnancy testing, required of all female subject s on the day of testing. Candidates and subjects will be repeatedly reminded that th ey are free to decline to participate or to withdraw at any time for any reason, without penalty.

Page 13 of 56F. 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 de tailed evaluation of how this proposal addresses applicable standards of et hical conduct is included in

Attachments 2-5 to this review.

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

research is initiated:

• The Local Site Coordinator must be identified in the protocol.

• If employees of the Local Site Coordinato r are to be exempted from the exclusion criterion applying to all other contract ors to AHETF, this exemption must be justified, as should be the departure from the prohibitions of LSC employee participation in the AHETF Governing Do cument and SOP, and special provision must be made to protect such employ ees from any coercion or undue influence that might be brought to bear on th em by the Local Site Coordinator.

• Care must be taken to ensure that a ll materials provided to candidates in the recruiting and interviewing processes, in cluding label and MSDS summaries and other materials described in SOPs, are reviewed and approved by the responsible

IRB before use.

• Clarify whether the questions in Atta chment 11-B-3 to SOP 11.B.1 are intended as examples of the kinds of questions the interviewer might ask to confirm understanding of the consent fo rm, or if they are all to be asked of all candidates.

• The standard of documentation required to support a decision to rely on an interpreter rather than a bilingual investigat or should be defined in the protocol or in an SOP, as should be procedures fo r how interpreters and “impartial bilingual witnesses”, if required, will be recr uited and compensated, and how their competency and impartiality will be assessed.

• 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 meetings, attending individual consent interviews, signing consent forms, subsequently withdrawing or being wit hdrawn, and completing participation.

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

Page 14 of 56Page 15 of 56 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 7 April 08 2. Summary Review of Protocol AHE55 dated 7 April 08 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 ResearchPage 16 of 56 Attachment 1

EPA Scenario Review: AHETF Close-Cab Air Blast Scenario

Title: Closed Cab Airblast Applicator Scenario Sampling Plan: pp. 9-52 in

AHETF Volume 1: General Informat ion and Scenario Sampling Plan

Date: 7 April 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.” (V1:12)

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

• Citrus crops in Fl orida (e.g., oranges) • Nut crops in Georgia (e.g., pecans) • Pome fruit in Washington (e.g., apples) • Stone fruit in Michigan (e.g., cherries) • Trellis crops in California (e.g., grapes)” (V1:13)

(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 scenario, 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 17 of 56 Attachment 1

“AHETF also conducted a detaile d review of the data in PH ED for this scenario to determine if any of the data weresuitable 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.” (V1:16-17)

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 spraying, 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. . . .” (V1:26)

“. . . Five crop categories encompass approxima tely 97% of all the acreage that might be treated by airblast applicati ons. This suggests the possibili ty of stratifying the crops treated by airblast into th ese five crop types:Page 18 of 56 Attachment 1

• Nut crops

• 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 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. 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.” (V1:27-28)

“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.” (V1:28)

“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 pre ssure 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.” (V1:30)

“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-factorPage 19 of 56 Attachment 1

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

“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.” (V1:30-31)

“ 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).Page 20 of 56 Attachment 1

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).

“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.” (V1:32-34)

“ 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.” (V1:35)

“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.” (V1:36)

“The primary considerations for site selecti on will be the availability of citrus 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.” (V2:26)

(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.Page 21 of 56 Attachment 1

“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 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 acr eage that might be treated

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

• Description of equipment availabl e (e.g., number, type, and size)

• Surrogate chemical(s) that 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.” (V1:38-40)

“AHETF researchers will contact local resour ces from each of the following categories in Polk and Hillsborough counties in Florida:

• Local Site Coordinator (LCS)

• Commercial Applicator Firms that service citrus grovesPage 22 of 56 Attachment 1

• University Agricultural Resear chers / County Extension Agents

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

• Chemical Dealers or Sales Representatives

• Citrus Grower Associations

“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 Polk and Hillsborough counties who are commercial citrus producers and might utilize airblast equipment in their operations. The list 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.” (V2:26-28)

(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.” (V1:15)Page 23 of 56 Attachment 1

“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.” (V1:44)

“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.” (V1:26)

“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.” (V1:42-43)

“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.” (V1:45)Page 24 of 56 Attachment 1

(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 cond itions for this scenario.” (V1:15-16)

“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.” (V1:27-28)

“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.” (V1:45)

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)Page 25 of 56 Attachment 1

“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.” (V1:46-47)

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.” (V1:22-23)Page 26 of 56 Attachment 2

EPA Protocol Review: AHE55: Closed-Cab Airblast Application to Florida Citrus

Title: Determination of Dermal and Inhalation Exposure to Workers During Airblast Applications of Liquid Sprays Using Clos ed Cab Equipment in Florida Citrus.

Revision Date: 24 March 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: Southeast Ag Research

86 Jim Moore Rd.

Chula GA 31733

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 app lications in Florida citrus.” (V2:7)

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, Analytical Facility, and Prin ciple Analytical Investigator must all be identified.Page 27 of 56 Attachment 2

(b) What research question does it address? Why is this question important? Would the research fill an import ant 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?

In conjunction with the results of four other field studies pl anned for this scenario, EPA will use the results of this study to estimate th e dermal and inhalation exposure likely 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.” (V1:16-17)

(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 28 of 56 Attachment 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.” (V1:12)

“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).” (V1:21)

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.

“If the adequacy analyses... indicate that the target benchmark objectives for a particular scenario are not met, then the AHETF, in c onsultation with the JRC, could decide to

conduct new studies in order to obta in additional clusters.” (V4:73)

2.1 Statistical Design

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

“On balance, a configuration consisting of 5 clusters with 5 MUs/cluster seems to be a reasonable compromise given the existi ng variation seen in the current exposure data. Obviously, fewer resources would be n ecessary when it is felt that the GSD and ICC for normalized exposure can be less than the assumed values of 4 and 0.3, respectively. Smaller sample sizes could also be used when K>3 is considered acceptable. For tighter accuracy requirem ents, additional samples would be needed. The methods described above can be used, as needed, to determine the sample sizes

for other combinations of GSD, ICC, and K.” (V4:144)

“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 strongPage 29 of 56 Attachment 2

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.” (V1:22)

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

No positive or negative controls are propos ed. This is appropriate for the study design and statistical analysis plan.

(c) How is the study blinded?

The study is not blinded, nor could it be.

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

“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.” (V1:40)

“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” (V2:29)Page 30 of 56 Attachment 2

(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.’” (V1:49)

(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).

2. How well the data can be expected to describe a relationship between exposure and AaiH, if one existed.” (V1:49)

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

“To evaluate how well the collected data conform to this benchmark, the 95 percent bound on relative accuracy will be calculated fr om the confidence interval for each of the three parameters given above.” (V1:49-50)

“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.” (V1:50)

(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 believe s the resulting data willPage 31 of 56 Attachment 2

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 reasonable to consider the linear regression of log dermal exposure on log AaiH. Such a regression would use a mixed model formulation in order to incorporate random cluster effects. As described in the Governing Document, in such a model the true slope, β , would be equal to one if dermal exposure were directly proportional to AaiH. If exposure were independent of AaiH, then β =0. This benchmark objective requires that the number of clusters and

the allocation of AaiH levels to MUs should be adequate to ensure that the regression analysis has at least 80% power to reject the hypothesis that β =0 when β is actually equal to one. By symmetry, the mixed m odel 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’.” (V1:50)

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 a pplication of pesticides” to citrus in Florida. (V1:17)

“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.” (V2:31-32)

(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 deve loping a generic databa se 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 scenar io. The commercial products of these activePage 32 of 56 Attachment 2

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.” (V1:46-47)

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

dose administration?

“Since the number of pounds of active ingr edient handled is th e normalizing factor and indirectly influences many other hand ling conditions, efforts will be taken to generate data in as wide a range of AaiH as practical within 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” (V1:36-37)

“A single MU will be conducted in this study from each of the five strata.” (V2:34)Page 33 of 56 Attachment 2

(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.” (V1:43)

2.3 Endpoints and Measures

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

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

described below and in SOP AHETF-10.E.

“Workers will wear one layer of work clot hing over the inner dosimeters. The inner

dosimeter will consist of 100% white cotton long underwear, pre-washed and provided by the AHETF. The inner dosimeter is designed to represent the worker’s

skin and will act as a collecti on medium that will be analyzed.

“Hand exposure will be measured by having the worker wash their hands in a 0.01% Aerosol OT solution according to a standard ized washing procedur e described in the

most recent version of SOP AHETF-8.B. Interim hand wash samples will be

collected whenever a worker would norma lly wash his/her hands (e.g., before using the toilet, etc.)... All hand washes collected during and at the end of the work period will be treated as separate samples.

“Face/neck exposure will be measured by wiping the entire face and neck areas (front and back of neck) with two gauze sponges, sequentially, that have been wetted with

0.01% Aerosol OT as described in the mo st recent version of SOP AHETF-8.C. Interim face/neck wipe samples (consisting of two gauze sponges) will be collected prior to eating... All wipes collected during the study for a worker will be combined in the same container, resulting in a single sample for analysis.Page 34 of 56 Attachment 2

“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. Suitable low-volume personal air-sampling pumps and OVS tubes with a glass fiber filte r and the appropriate sorbent for the test substance being used are required.” (V2:34-36)

(b) What steps are proposed to ensure meas urements 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.

“After fortification, the inner dosimeters a nd OVS tubes will be exposed to ambient conditions (i.e., weathered) for the longest expected exposure m onitoring period in a location away from possible contamina tion (e.g., upwind of mixing/loading and application operations). Inner dosimeter sa mples will be covered with a single layer of shirt material during weathering. Segm ents representing any body area may be used for inner dosimeter fortification samples. An air sampling system will be set up in a manner similar to that of the workers, in which a pump will continuously draw air through the pre-fortified filter and OVS tube for the entire duration of the work period.

“Hand wash and face/neck wipe samples will be fortified and immediately placed in frozen storage without exposure to am bient conditions. In addition, on each fortification day, duplicate samples of the inne r dosimeters fortified in the field at the highest level, and duplicate OVS tubes for tified in the laboratory at the highest fortification level, will be processed for i mmediate frozen storage and used as travel spikes. These travel spikes will be analy zed only if deemed necessary by the Study Director, for example to help determine th e cause of unusually lo w field fortification recovery results.

“Finally, on each fortification day, two untreated control samples of each matrix will be processed similar to the field fortification samples (i.e., some are weathered). Packaging, storage and shipment of the field fortification samples will be the same as for the worker exposure samples.” (V1:37-38)

(c) What QA methods are proposed?

“All aspects of the studies are monitored while they are in progress by appropriate quality assurance units (QAUs) to ensure compliance with GLP regulations and adherence to the protocol and relevant AHETF Standard Operating Procedures. This will typically involve three different QAUs: one from the exposure monitoring

contractor that conducts the st udy in the field, one from the an alytical laboratory thatPage 35 of 56 Attachment 2

determines the level of pesticide residues in field samples, and one contracted directly by the sponsor. For each field study, the follo wing specific activities are conducted by these QAUs:

• Sponsor-contracted QAU inspects all cont ract research organizations and laboratories prior to use in a study to en sure that those researchers operate in compliance with GLPs

• Sponsor-contracted QAU reviews prot ocols prior to finalization

• Sponsor-contracted QAU and/or field contractor QAU observes study conduct

in the field

• Field contractor QAU audits the raw data file from the field and audits the Field Report

• Analytical laboratory QAU audits the ra w analytical data and audits the Analytical Report

• Sponsor-contracted QAU reviews the Fina l Report which includes the Field Report and Analytical Report as appendices

“Each QAU submits an inspection report( s) to the Study Director and AHETF Sponsor Representative and a ny exceptions to full GLP compliance are listed in the Final Report associated with each protocol.

“Chapter 5 of the AHETF SOP Manual provid es details about the responsibilities of and procedures to be followed by the spons or-contracted QAU. Field contractor and laboratory QAU’s follow similar SOPs from their own facility.” (V4:67)

(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.

“Field fortification samples ar e exposure matrix samples that are fortified (or spiked), generally in the field, with known amounts of active ingredient and subsequently analyzed to determine the am ount of active ingredient recovered. Field fortification samples are subjected to the same envi ronmental, handling, shipping and storage conditions as worker samples. Because thes e conditions are similar, and because field fortification samples are analyzed along with worker samples, recovery values calculated from analysis of fo rtification samples are app licable to worker exposure samples. Field fortification recoveries are therefore used to adjust residue levels found in worker samples for residue lo sses that might have occurred during collection, handling, shippi ng and storage.” (V6:51)

“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 exposur e monitoring at each location, or morePage 36 of 56 Attachment 2

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 weat hered). Packaging, storage and shipment of the field fortification samples will be the same as for the worker exposure samples.” (V2:37-38)

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.” (V1:17)

(b) From what populations will subjects be recruited?

Subjects will be recruited among the employees of citrus growers in Polk and Hillsborough Counties in Florida who are identified as “commercial citrus producers [who] might utilize airblast equipment in their operations” (V 2:26) and who meet AHETF criteria for participation.

Implicitly included in this class of comme rcial citrus producers is the unidentified “Local Site Coordinator”, whose employ ees are specifically exempted from the exclusion applying to all other employees of “a pesticide manufacturer or a contractor to AHETF (except employees of the Local Site Coordinator)” (V2:10)Page 37 of 56 Attachment 2

(c) Are expected participants representati ve of the population of concern? If not, why not?

A ‘working pool’ of eligible growers will be identified from a randomized list of citrus growers in the two affected countie s. Based on considerations of equipment type, acreage, anticipate d time of treatment, and geographic location the Study Director and LSC will purposively select from this pool of growers to construct an ‘efficient configuration’ of MU s. All employees of eligible growers included in the efficient configuration (or of pesticide application service companies used by eligible growers included in the efficient configura tion) who are experienced in the use of closed-cab airblast application equipment and who meet the elig ibility requirements of the study will be recruited; if more empl oyees are available and interested than are needed for a specific MU, participants will be selected randomly. Although the design is purposive, and thus participants are not representative in a statistical sense, they are expected to be typical of those who use airblast equipment to treat Florida

citrus.

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

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

3.2 Equitable Selection of Subjects

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

“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 practices in accordance with the Worker Protection Standard (WPS), or be exempt from such training

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

• Be at least 18 years old with a government-issued ID to verify age

• Consider themselves to be in good gene ral health with no medical conditions that could impact their ability to participate in the study

• Be willing to follow all label and WPS requirements

“In addition, potential subjects who meet the following exclusion criteria will not be allowed to participate in this study:

• Are pregnant females

• Are nursing mothersPage 38 of 56 Attachment 2

• Normally wear personal pr otective equipment (PPE) that is not required by the label, such as chemical-resistant clothing

• Don’t understand Spanish or English

• Are employed by a pesticide manufacture r or a contractor to AHETF (except employees of the Local Site Coordinator)” (V2:10)

(b) What, if any, is the relationship between the investigators and the subjects?

None, unless a subject is an employee of the Local Site Coordinator.

(d) If any potential subjects are from a vulnerable population, what is the justification for including them?

No justification is provided for exempti ng employees of the Local Site Coordinator from the exclusion applying to all other c ontractors to AHETF. No special provision is made to protect such employees from any coercion or undue influence that might be brought to bear to influence thei r decision whether to participate.

(e) What process is proposed for recruit ing and informing potential subjects?

See sections 2.6 and 2.7 of the protoc ol (V2:20-24) and SOP AHETF 11.B.1 (V6:113-127)

“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 encouraged to contact AHETF if they desire additional information about the study orPage 39 of 56 Attachment 2

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.” (V2:28-29)

(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 indi vidual growers will be asked to sign a non-coercion statement (Employer Cooperation Statement) affirming to their workers and AHETF that they will not coerce or unduly influence th eir 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 participat e or not will have no impact on their employment.” (V2:28)

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?

“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, whet her or not they decide to participate in the study. Workers who decide to participat e in the study will be paid an additional $80 each time they suit up (i.e., put on the l ong underwear) to participate in the study. Usually, workers will participate in the study on only one day unless their participation is terminated due to weat her or other unexpected occurrences. The additional $80 is provided in cash at the e nd of the monitoring period or at the time the volunteer withdraws from the study. All workers who participate will receive the payment, even if they withdraw or their participation is terminated by the study team.” (V2:9-10)Page 40 of 56 Attachment 2

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

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

(d) How and when would subjects be paid?

In cash, immediately afte r their participation.

4. Risks to Subjects

4.1 Risk characterization

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

about the hazards of the test materials?

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

“This study could involve 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 citrus crops. AHETF will only monitor workers making applications in accordance with a ll label and Worker Protection Standard (WPS) requirements. . . . For each of the active ingredients that may be used in this scenario the [Margi ns of Exposure (MOEs) calculated for the highest levels of exposure in this protoc ol] greatly exceeded the required MOE for

both the individual dermal and inhalation ro utes of exposure, as well as for the combined [dermal/inhalation] exposure, and th eir use is acceptable for this scenario.” (V2:14)

(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 orPage 41 of 56 Attachment 2

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, 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.” (V2:11)

Each of the six identified kinds of risk is discussed in V2:11-19

“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 moderate eye i rritation, slight skin irritation, [possible allergic skin reaction,] 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.” (V2:70, 72, 74, 76, 78, 80, 82 product-specific supplements to consent form)

(b) 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

treatmentPage 42 of 56 Attachment 2

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

urgent care

• Observing study participants throughout the monitoring period

• Ensuring that all tank mix products are used according to approved label(s) and do not require any additional PPE.” (V2:19)

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

discussed in V2:11-18

(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 levels of exposure in this protocol] greatly exceeded the required MOE for both the individual dermal and inhalation routes of exposure, as well as for the combined [dermal/inhalation] exposure.” (V2:14)

(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.” (V2:13)

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

“As a precaution, AHETF will have a parame dic, physician’s assistant, nurse or emergency medical technician on site duri ng the study. If neede d, this professional will also observe you for signs of illness a nd will provide medical attention.” (V2:51)

SOP AHETF-11.H (V6:152-154) defines procedures to be followed if a subject in an AHETF study requires emer gency medical attention.Page 43 of 56 Attachment 2

(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 (V6:132-134) calls for researchers to monitor worker compliance with label and Worker Pr otection Standard requirements, and permits the Study Director to remove fr om the study a worker who engages in unsafe work practices.

• SOP AHETF-11.G (V6:137-151) calls fo r the Study Director, the on-site medical professional, and all researcher s and observers to monitor subjects for any indication of heat-related illness.

• SOP AHETF-11.H (V6:152-154) defines procedures to be followed if a subject in an AHETF study requi res emergency medical attention.

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

“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).” (V2:25)

(g) How and by whom will medical care for re search-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 unless you get sick from too much pesticide exposure or from getting too hot, or if we believe you are too sick to make a rational decision about receiving medical treatment. AHETF will cover the cost of reasonable and appropriate medical attention that is not covered by your own insurance or insurance provided through your employer.” (V2:52)

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.” (V2:19)Page 44 of 56 Attachment 2

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.” (V2:19)

(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 fo r 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 will likely realize a benefit by addressing regulatory data requirements generically, at lower cost (and using fe wer human subjects), than if they conducted similar studies for indi vidual pesticide ingredients.” (V2:19)

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

Identified societal benefits are likely to be realized.

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

“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. 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.Page 45 of 56 Attachment 2

“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. Airbla st applications are common in both orchard and trellis crops across the country, and a wide va riety of experts 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 indi cate that subjects ar e very unlikely to experience acute toxic effects, and because extensive procedures will be in place to minimize these and other risks to participants, the likelihood of serious adverse effects is very small. In sum, AHETF believes the risks to study partic ipants from participating in th is study are reasonable in light of the likely benefit to society of the knowledge to be gained.” (V2:20)

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 investigators 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 Federa l-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 consen t form, and other required documentation for this study will be approved by an institutional review board (IRB) and submitted to the EPA as required by 40 CFR 26.1125. The report of the completed research is subject to 40 CFR 26.1303 requirements to document its ethical conduct.Page 46 of 56 Attachment 2

“The proposed research described by this pr otocol, the informed consent form, and all recruitment materials, such as handouts or vi sual aids, shall be reviewed and approved by Independent Investigational Re view Board Inc. (IIRB) of Plantation, Florida. Complete records of the IRB review as required by 40 CFR 26.1125 will be submitted to EPA for review along with this pr otocol 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 (NIH; Human Participant Protections Education for Research Teams) and/or the Basic Collaborative IRB Training Initiative Course (CITI; Th e Protection of Human Research Subjects). Copies of the certificates of completion for the ethics course s will be submitted to the IRB and stored in the respective personnel files (maintained by the AHETF an d all contract facilities.)” (V2:9-10)

8. Informed Consent

(a) Will informed consent be obtain ed from each prospective subject? Yes

(b) Will informed consent be appropriately documented, consistent with the requirements of 40 CFR §26.1117? Yes. See also Attachment 5.

(c) Do the informed consent material s 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. See also Attachment 4.

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

Not addressed in protocol. Appropriate provi sion is made for informing candidates who

cannot read the consent form in English or Spanish.

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

“Study participation will be limited to English or Spanish speakers. When Spanish speakers are involved, a bilingual researcher will conduct the interview. Potential participants that have limited reading ab ility will have the consent form verbally explained in their preferred language (Englis h or Spanish) with an impartial witness (bilingual as appropriate) pres ent. Witnesses must have no association with AHETF, its member companies, researchers, growers, or workers. Witnesses must have some familiarity with farming and will be recruite d from any appropriate source such as a university, grower association, or other orga nization. The witness ca nnot serve as thePage 47 of 56 Attachment 2

interpreter or an advisor to the volunteer. The witness will sign the consent form to acknowledge that the study participant appare ntly understood the information presented to him/her.” (V2:22)

“However, if all reasonable efforts to obtain a bilingual researcher have been exhausted, it is acceptable to instead use an interpreter.” (V6:117)

(f) What measures are proposed to en sure subject comprehension of risks and

discomforts?

“During the discussions with potential par ticipants, ample time will be provided for questions and any additional information or clarification that is requested will be provided. When the Study Director or designa ted member of the study team is satisfied that the volunteer understands the requiremen ts and risks of the study, and if the worker still wants to participate, he/she will be aske d to sign and date the informed consent form and the Product Risk Statement.” (V2:23)

“If the AHETF interviewer is not comforta ble that the worker fully understands the

discussions and the contents of the consen t form, the worker will be excluded from consideration to partic ipate in the study. This will be ascertained by providing repeated opportunities to ask questions and by asking que stions of the potenti al volunteers that would require a response that indicates understa nding of key issues for all sections of the consent form. These responses will be documented and if necessary the person conducting the consent meeting will re-explain topics until the volunteer demonstrates an appropriate understanding.” (V2:23-24)

Attachment 11-B-3 to SOP 11.B.1 (V6:124-126) lis ts questions which might be asked to confirm understanding of the consent form.

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

and obtain their consent?

“The Study Director or designated member of the study team will obtain informed consent from all study volunteers prior to thei r participation in th e study. The consenting process is conducted in a private meeting be tween the researcher and the volunteer (and possibly other individuals as described below). Depending on the circumstances, consenting may occur several days prior to the study up to the day of the study. The volunteer will be given a copy of the consent fo rm to review at least one day before the consent meeting, and advised of study provisions to accommodate their language preference, the need for readers, witnesses, and their desire to have a confidant or counselor present during an informed cons ent meeting. For example, the volunteer may

feel more comfortable with a confidant or c ounselor in the consent meeting with him/her.

“During the private consent meeting the work er will be provided with a full explanation of the study, its requirements, a ny potential risks, and its likel y benefits. Workers will bePage 48 of 56 Attachment 2

informed that the grower or their employer wi ll be reimbursed for the product used in the conduct of the study on their farms. Workers will be advised of thei r right to withdraw from the study at any time and for any reas on without jeopardizing their normal position with their employers. Each volunteer will be provided a copy of the supervisor’s signed Employer’s Cooperation Statement (in the worker ’s preferred language) that states they will not suffer any consequence if they decide to participate or not and they will receive their usual pay for the day when the study is conducted.

“The volunteer will be informed that he/s he will receive the $20 remuneration payment even if he/she decides not to participate.

“The volunteer will be provide d information about the risk of the particular product he/she will handle, including signs and sy mptoms of acute overexposure. The product

and its risks will be identified in a Product Ri sk Statement that is an attachment to the consent form. Appropriate sections of the pr oduct label and Material Safety Data Sheet will be discussed by the person conducting th e consent meeting and made available for review by the volunteer. WPS requirements, especially proper use of clothing, personal protection equipment, and cleani ng facilities will be discussed.

“The Study Director or desi gnated member of the study te am will discuss the germane aspects of the AHETF medica l management plan with the prospective participants. Information will be provided about the risk of heat stress, including signs and symptoms, and ways to prevent it.

“The IRB-approved consent form will be pres ented in the preferred language (English or Spanish) of the volunteer. All sections of the consent form including the test substance

Product Risk Statement will be discussed in detail.

“During the discussions with potential par ticipants, ample time will be provided for questions and any additional information or clarification that is requested will be provided. When the Study Director or designa ted member of the study team is satisfied that the volunteer understands the requiremen ts and risks of the study, and if the worker still wants to participate, he/she will be aske d to sign and date the informed consent form

and the Product Risk Statement. The member of the study team c onducting the interviews (and witness, if applicable) will also sign the consent form and provide a copy of the signed form (and signed attachment s) to the worker.” (V2:22-23)

(h) What measures are proposed to ensu re 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 al so certify that alternate work will bePage 49 of 56 Attachment 2

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.” (V2:28)

“Workers will be informed that the grower or their employer will be reimbursed for the product used in the conduct of the study on thei r farms. Workers will be advised of their right to withdraw from the study at any time and for any reason without jeopardizing their normal position with their employers. E ach volunteer will be provided a copy of the supervisor’s signed Employer’s Cooperation Statement (in the worker’s preferred language) that states they will not suffer any c onsequence if they decide to participate or not and they will receive their usual pay for the day when the study is conducted.” (V2:22)

9. Respect for Subjects

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

“Initial contact with workers during recruitment will be ma de without the presence of their employer as described in detail in Secti ons 2.7 and 6.2 of this protocol. If workers are interested in participa ting, a private meeting with th e Study Director or his/her designee will be used to e xplain the study further, addre ss any questions, and seek the candidate’s consent to participate.

“Pregnancy tests, required for female partic ipants, must be conduc ted within 24 hours of the start of the monitoring period. These will be self-administered in a private restroom, but under the supervision of a female resear cher. Positive results from pregnancy tests will not be documented or given to a woma n’s employers or co-workers. If a female volunteer has a positive pregnanc y test result, she must wit hdraw from participation but can do so without stating a reason. Consent fo rms and all other records associated with the worker will be promptly shredded (SOP AHETF-11.D). Negative results must be confirmed by a female researcher and recorded in the study files.

“Certain worker information will be collected during the course of this worker exposure monitoring study. The information collected, su ch as notes taken by study observers, will not be available to a participant’s employer. Most information identifies subjects only by a unique worker identifier. Forms and pape rwork that contain personal information (including a worker’s name or address) will be kept confid ential in a sealed envelope

while in the field. After the st udy is completed, this confidentia l envelope will be sent to

AHETF archives with the other raw data. Unrestricted access to this confidential information is allowed only to the AHETF Administrative Chair (SOP AHETF-6.B).

“The information collected inthis study may, under certain regulatory circumstances, be given to the U.S. Environmental Protection Agency (EPA) or to state governmental agencies and other countries. Participants in the study will be informed that their namesPage 50 of 56 Attachment 2

will not be disclosed, but that absolute conf identiality cannot be guaranteed because of the need to give informa tion to these parties.

“The results of this research may be presen ted at meetings or in publications; however, only a unique worker identification number will identify each worker in reports or presentations.” (V2:20-21)

“Your name will appear on the consent form, the Product Risk Statement, and an optional form for you to request your personal study results. All other study information will identify you only by a unique code. Records with your name will be stored in a secure,

limited access archive.

“Information about your participation 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 included in any study report.

“We cannot promise you absolute confidentiality because of the need to give information to some organizations or to parties in le gal actions, as requir ed by law. All study information, including records which identi fy you, may be looked at or copied by the sponsor and any consultants working with the sponsor, by EPA or other government agencies, and by the Independent Investigational Review Bo ard, Inc., (IIRB). IIRB is a group of people who review and monitor re search to make su re the people who participate in it 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.” (V2:52)

(b) How will subjects be informed of their fr eedom to withdraw from the research at any time without penalty?

“The absolute right for subjects to withdraw from the research is the cornerstone of protection of human subjects. Pr ospective and enrolled subjects will be informed of their right to withdraw w ithout consequence prior to and during the conduct of the research. Any volunteer expressing a need or desire to withdraw from the research after exposure monitoring begins will be paid $80 and allowed to return to their normal work duties for their employer. If a 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).” (V2:21-22)

“Your employer has agreed to let us do this re search and has confirmed that he/she does not care whether you participate in this study. Your decision to be in this study isPage 51 of 56 Attachment 2

voluntary and entirely up to you. If you deci de to participate, you may change your mind later and drop out of the study at any tim e and for any reason. A decision not to participate, or to withdraw from the study af ter it begins, will have no effect on your job or pay or [involve] any penalty or loss of be nefits to which you ma y be entitled.” (V2:53)

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

dealt with?

“No one can require you to partic ipate in this study. Particip ation is entirely voluntary. If you choose not to participate in this study, then on the day of the study you will perform your ordinary activi ties. Your alternative is to not participate.

“If you withdraw or are removed from the study, or if the study does not last an entire workday, you will be released to re sume your usual activities.” (V2:54)Page 52 of 56 Attachment 3

§ 26.1111 Criteria for IRB approval of research AHETF Protocol AHE55: Florida Citrus: April 7, 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. YPage 53 of 56 Attachment 4

§26.1116 General requirements for informed consent AHETF Protocol AHE55: Florida Citrus: April 7, 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. OKPage 54 of 56 Attachment 5

§26.1117 Documentation of informed consent AHETF Protocol AHE55: Florida Citrus: April 7, 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/aPage 55 of 56 Attachment 6 40 CFR 26.1125 Prior submission of proposed human research for EPA review AHETF Protocol AHE55: Florida Citrus: April 7, 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 V8:11-229; 231-273; 471-587

V2:48-67

(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 V8:377-378; 647-650

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 V8:4-10, 230, 274, 372-376, 403, 438-445, 540, 589-90,

652 (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. N No list of IRB members was provided

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). N Previously submitted to EPA under claim of confidentialityAll 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 V2:11-19; (2) The measures proposed to minimize risks to the human subjects; Y V2:12-19

(3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y V2:19

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y Addressed in Governing

Document V4§1125(a)a discussion of:

(5) The balance of risks and benefits of the proposed research. Y V2:20 §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 V8:18-25, 379-437

V2:48-103 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y V1:40-41; V2:20-24, 28-30,

105-107 §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 V2:22-24

§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 V8:375-376; 589-590Page 56 of 56