Page 1 of 51 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D.C., 20460

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION

March 8, 2011

MEMORANDUM

SUBJECT: Ethics Review of Completed AHETF Op en Cab Airblast Scenario Worker Exposure Monitoring Study

FROM: Kelly Sherman
Human Research Ethics Review Officer Office of Pesticide Programs

TO: Steve Knizner, Associate Director
Health Effects Division

REF: Bruce, Eric D. (2010) Determinatio n of Dermal and Inhalation Exposure to Workers During Airblast Applicat ions of Liquid Sprays Using Open Cab Equipment in California Trel lis Crops. Study Number AHE62. 283 p. (MRID 48289611) [Volume 1]

Bruce, Eric D. (2010) IIRB Corre spondence Report for Cluster Report AHE62. 327 p. (MRID 48289614) [Volume 2]

Bruce, Eric D. (2010) Determinatio n of Dermal and Inhalation Exposure to Workers During Airblast Applicat ions of Liquid Sprays Using Open Cab Equipment in New York Trelli s Crops. Study Number AHE63. 247 p. (MRID 48289612) [Volume 3]

Bruce, Eric D. (2010) IIRB Corre spondence Report for Cluster Report AHE63. 295 p. (MRID 48289615) [Volume 4]

Bruce, Eric D. (2010) Determinatio n of Dermal and Inhalation Exposure to Workers During Airblast Applicat ions of Liquid Sprays Using Open Cab Equipment in Oklahoma Tree Nu ts. Study Number AHE64. 236 p. (MRID 48289613) [Volume 5]Page 2 of 51 Bruce, Eric D. (2010) IIRB Corre spondence Report for Cluster Report AHE64. 172 p. (MRID 48289616) [Volume 6]

I have reviewed the available informa tion concerning the et hical conduct of the research reported in the referenced document s, which describe the execution and results
of a series of three field st udies in which dermal and inha lation exposure of professional pesticide applicators was monitored as they ap plied liquid pesticides to orchard and trellis crops using an airblast sprayer drawn by a trac tor with no cab (known as an “open cab”).
If these studies are determined to be sc ientifically acceptable, I find no barrier in regulation to EPA’s relia nce on them in actions under FIFRA or FFDCA.

1.0 Background and Ethics-related Chronology

Three separate field stud ies were conducted, each monitoring workers while they sprayed trellis or tree crops in three different states in the U.S where open cab airblast equipment is used in producti on agriculture. The studies ar e summarized in Table 1.

Table 1

. Study Summary Study

ID State Crop Number of
Monitored Workers Gender Ages

AHE62 CA Grapes 3 All male 43-79 AHE63 NY Grapes 5 All male 28-66
AHE64 OK Pecans 5 All male 47-74

The background and ethics-related chronology for each field study are summarized
below.

1.1 AHE62

The scenario design and protocol fo r AHE62 were approved by the overseeing IRB, the Independent Investigational Review Board, Inc. (IIRB), of Plantation, Florida, in July 2008 and submitted to EPA for review in August 2008. The protocol and EPA’s review dated September 23, 2008 were discu ssed by the Human Studies Review Board (HSRB) at its October 2008 meeting. The HS RB review was generally favorable, and the Board’s December 30, 2008 final report concl uded, with respect to ethics, that “[i]f revised as suggested by the Board in its revi ew, the research described in these three protocols is likely to meet the applicable requirements of 40 CFR part 26, subparts K and
L.”

Following the HSRB review, the protocol, consent form, California Experimental Research Subject’s Bill of Rights (CaBOR), and recruitment materials for AHE62 were revised to address EPA, California Depart ment of Pesticide Regulation (CDPR), and
HSRB comments. The revised documents were submitted to IIRB in March 2009 and approved in April 2009. Three subsequent am endments were approved by IIRB in June, July, and November 2009.Page 3 of 51 Subject monitoring for AHE62 took place in July 2009. Three male subjects between the ages of 43 and 79 were monitore d for dermal and inhalation exposure while applying pesticide sprays usi ng open-cab airblast equipment to grapes in California. There was one reported deviati on during the field phase of th e research, and one reported deviation during the analytical phase. I noted one unreported deviation.

A detailed chronology of the ethics-relat ed study activities for AHE62 is provided in Table A in Attachment 1. A summary of amendments and reported and unreported deviations from all studies is pr ovided in Table 2, on page 11.

1.2 AHE63

The scenario design and protocol for AHE63 was approved by IIRB in July 2008 and submitted to EPA for review in August 2008. The protocol and EPA’s review dated September 23, 2008 were discussed by the HSRB at its October 2008 meeting. The HSRB review was generally favorable, and the Board’s December 30, 2008 final report concluded, with respect to ethics, that “[i ]f revised as suggested by the Board in its review, the research described in these three protocols is likely to meet the applicable requirements of 40 CFR part 26, subparts K and L.”

Following the HSRB review, the protocol, consent form, and recruiting materials
for AHE63 were revised to address EPA a nd HSRB comments. The revised documents were submitted to IIRB on January 16, 2009, and approved on January 19, 2009. Two subsequent amendments were approved by IIRB in July and August 2009.

Subject monitoring for AHE63 took place in July and August 2009. Five male subjects between the ages of 28 and 66 were monitored for dermal and inhalation exposure while applying pesticide sprays using open-cab airbla st equipment to grapes in New York. There was one reported deviation during the field phase of the research, and two reported deviations during the analytical phase. I noted no unr eported deviations.

A detailed chronology of the ethics-relat ed study activities for AHE63 is provided in Table B in Attachment 1. A summary of amendments and reported and unreported deviations from all studies is pr ovided in Table 2, on page 11.

1.3 AHE64

The scenario design and protocol for AHE64 was approved by IIRB in July 2008 and submitted to EPA for review in August 2008. The protocol and EPA’s review dated September 23, 2008 were discussed by the HSRB at its October 2008 meeting. The HSRB review was generally favorable, and the Board’s December 30, 2008 final report concluded, with respect to ethics, that “[i ]f revised as suggested by the Board in its review, the research described in these three protocols is likely to meet the applicable requirements of 40 CFR part 26, subparts K and L.”Page 4 of 51 Following the HSRB review, the protocol, consent form, and recruiting materials
for AHE64 were revised to address EPA a nd HSRB comments. The revised documents were submitted to IIRB on January 16, 2009, and approved on January 19, 2009. Two subsequent amendments were approv ed by IIRB in June and September 2009.

Subject monitoring for AHE64 took place in August 2009. Five male subjects between the ages of 47 and 74 were monitore d for dermal and inhalation exposure while applying pesticide sprays usi ng open-cab airblast equipment to pecans in Oklahoma. There was one reported deviati on during the field phase of th e research, and one reported deviation during the analytical phase. I noted no unreported deviations.

A detailed chronology of the ethics-relat ed study activities for AHE64 is provided in Table C in Attachment 1. A summary of amendments and reported and unreported deviations from all studies is pr ovided in Table 2, on page 11.

2.0 Completeness of Submission:

The checklist used by EPA to verify sa tisfaction of the requirements of §26.1303 as they apply to the report of this research appears as Attachment 1 to this review. This review considers the 6 study volumes identi fied on pages 1-2, plus the Heat Index Records from the Raw Data (which were provided separately by the AHETF, upon request from EPA [via an email from V. Can ez to K. Sherman, 3/8/11]). The Heat Index
records are included as Attach ment 4 to this review.

3.0 Protocol Amendments:

3.1 AHE62

Following EPA’s and HSRB’s reviews, the protocol, consent form, and recruiting materials were revised to address EPA, HSRB, and CDPR comments. The revised materials were submitted to IIRB on March 27, 2009, and approved on April 1 and 6,
2008.

In early June 2009, the AHETF consulted EPA about three changes to the AHE62 protocol, and EPA ultimately approved the changes. On June 19, 2009, the AHETF submitted to IIRB an amendment encompassing the three changes, and IIRB approved the amendment on June 23, 2009. Each of the th ree changes is discussed below.

1) The first change was to amend the inclus ion criteria to allow participation by individuals who normally wear two layers of clothing (the inclusion criteria previously stated that only workers who normally wear one layer of clothing would be eligible to participate). Th e change was in response to a discovery by the AHETF that many airblast app licators in Fresno County normally wear two layers of clothing (for example, a typical shirt and pants under a clothPage 5 of 51 coverall). To accommodate these worker s and increase the pool of potentially eligible workers, the AHETF sought to amend the inclusion criteria. EPA approved the change provided that the workers who normally wear two layers agree to substitute their normally-worn i nner layer of clothing for the long underwear dosimeter provided by the AHETF. The change was acceptable to EPA from an ethics perspective becaus e it neither requires participants to wear less clothing than they normally w ould, nor results in subjects wearing a third layer of clothing, which could increas e the risks of heat -related illness.

2) The second change was to expand the pe rmissible recruitment area to any county in California or Washington if th e county previously specified in the protocol (Fresno County, California) doe s not provide a sufficient number of eligible growers. The change appeared to be necessary because many potential subjects in Fresno County might not be eligible to participate because they normally wear Tyvek cove ralls, or because their Pest Control Advisor, winery, or raisin packer might not approve the use of either of the two surrogate compounds.

3) The third change was to remove the effi cient configuration requirement if the recruitment area is expanded.

On July 22, 2009, the AHETF submitted an additional amendment to IIRB to add to the list of approved test substances a malathion end-use product preferred by some growers. EPA approved the addition of this pr oduct to the list of po ssible surrogates, and IIRB approved the amendment on July 22, 2009.

In November 2009, the AHETF submitted an amendment to specify the analytical methods to be used for head patches; IIRB approved the amendment on November 24,
2009.

In EPA’s view, the amendments to AHE62 are not problematic from an ethics perspective because they do not increase risks to subjects or jeopardize informed consent.
I defer to the EPA science reviewer about wh ether these amendments are important from a science perspective.

3.2 AHE63

Following EPA’s and HSRB’s reviews, the protocol, consent form, and recruiting
materials were revised to address EPA and HS RB comments. The revised materials were submitted to IIRB on January 16, 2009, and approved on January 19, 2009.

On June 26, 2009, the AHETF submitted to IIRB two proposed recruitment letters that would be sent to grape growers in Ne w York State before the initial recruiting telephone calls. The letters were approved by IIRB on the same day that they were
submitted.Page 6 of 51 On July 17, 2009, the AHETF submitted to IIRB an amendment encompassing the changes listed below. IIRB approved the amendment on July 21, 2009.

1) The first change was a modification to the recruitment process to allow for use
of the two recruitment letters that were approved by IIRB on June 26, 2009. In EPA’s view, adding this new step to the recruitment process does not raise ethics concerns because (a) researchers intend to send one of the two letters to all of the grape growers whose names a ppear on the master list of New York grape growers; (b) the lette rs have been IRB-approved; and (c) the letters may help to increase the number of grower s who are willing to take part in an
initial recruitment te lephone conversation.

2) The second change was to reduce the heat index threshold for stopping the
research from 120° F to 105° F. The change was made, in part, to address concerns from the HSRB that the previ ous heat index threshold of 120° F was too high. EPA supports this change because it increases protection for subjects.

3) The third change was to revise the dermal exposure sampling procedure to specify that the inner dosimeters would be cut into 6 secti ons after collection rather than 2 sections. Analyzing the dosimeters in more sections allows the AHETF to determine body-specific resi dues for more body parts, which may be important because this exposure scenar io is expected to result in relatively high dermal exposure potential. It may be useful have to ability to more precisely pinpoint the areas of highest e xposure. This change does not impact any ethics considerations.

4) The fourth change was to revise the an alytical methods to make them more appropriate for whole-body dosimeters sec tioned into 6 pieces. This change does not impact any ethics considerations.

5) The fifth change was to clarify in the protocol the AHETF’s raw data retention policy. The following se ntence was added to the protocol:

“In accordance with GLP regulations (40 CFR 160.195) and SOP AHETF-6.A, raw data will be retained in archives as long as the AHETF or other registrant holds a research or marketing permit to which the study is pertinent.”

This change does not impact any ethics considerations.

In EPA’s view, the five changes enco mpassed in this amendment are not problematic from an ethics perspective because they do not increase risks to subjects or jeopardize informed consent, and they were approved by IIRB before implementation. I
defer to the EPA science reviewer about wh ether these changes are important from a science perspective.Page 7 of 51 The AHETF submitted an additional prot ocol amendment to IIRB on August 13, 2009, changing the procedures for chemical an alysis of the head patches. This amendment does not affect any ethics consid erations, but I defer to the EPA science
reviewer about whether this amendment is important from a science perspective.

3.3 AHE64

Following EPA’s and HSRB’s reviews, the protocol, consent form, and recruiting
materials were revised to address EPA and HS RB comments. The revised materials were submitted to IIRB on January 16, 2009, and approved on January 19, 2009.

On June 15, 2009, the AHETF submitted to IIRB two proposed recruitment letters that would be sent to Oklahoma pecan grow ers before the initial recruiting telephone calls, plus an amendment encompassing the changes discussed below. IIRB approved the letters and the amendment on June 19, 2009.

1) The first change was a modification to the recruitment process to allow for use of the two recruitment letters which were submitted in conjunction with the amendment. In EPA’s view, adding this new step to the recruitment process
does not raise ethics con cerns because (a) research ers intend to send one of
the two letters to all of the pecan growers whose names appear on the master list of Oklahoma pecan growers; (b) th e letters have been IRB-approved; and (c) the letters may help to increase th e number of growers who are willing to take part in an initial recr uitment telephone conversation.

2) The second change was to expand the perm issible recruitment area from Tulsa County, Oklahoma, to also include the adjacent Oklahoma counties of Creek, Okmulgee, Wagoner, Rogers, Washingt on, and Osage. The reason for the change was that obtaining a list of nut growers in Oklahoma was proving difficult, and indications were that op en cabs are less prevalent than closed cabs in Oklahoma. Only pecan grower names could be obtained, but this represents the majority of nut crops in Oklahoma. The U.S. Census of Agriculture indicates there are 95 grow ers of pecans in Tulsa County that grow the minimum necessary acreage (a t least 5 acres). Based on response rates from other studies, the AHETF obs erved that a list of 95 growers was likely too small to yield 5 potentially eligible growers. Expanding the
recruitment area to include the surro unding counties results in a list of 279 growers which should provide a suffici ent number of poten tially eligible growers. In EPA’s view, this change is not problematic from an ethics perspective because it does not increa se risks to subjects or jeopardize
informed consent. I defer to the EP A science reviewer about whether this change is important from a science perspective.

3) The third change was to remove the effi cient configuration requirement if the recruitment area is expanded.Page 8 of 51 4) The fourth change was to revise the dermal exposure sampling procedure to specify that the inner dosimeters would be cut into 6 secti ons after collection rather than 2 sections. Analyzing the dosimeters in more sections allows the AHETF to determine body-specific resi dues for more body parts, which may be important because this exposure scenar io is expected to result in relatively high dermal exposure potential. It may be useful have to ability to more precisely pinpoint the areas of highest e xposure. This change does not impact any ethics considerations.

5) The fifth change was to revise the an alytical methods to make them more appropriate for whole-body dosimeters sec tioned into 6 pieces. This change does not impact any ethics considerations.

On September 14, 2009, the AHETF submitted to IIRB a second protocol amendment, changing the study director from Eric D. Bruce to Larry D. Smith. The effective date for the change in study dire ctor was September 14, 2009, after the close of the study. This amendment does not affect any ethics considerations. IIRB approved the amendment on September 16, 2009.

4.0 Protocol Deviations:

4.1 AHE62

4.1.1 Reported Deviations

There was one reported deviation during the field phase of AHE62. Inner and outer head patch field fortifica tions were performed in duplicate rather than in triplicate. In addition, no samples were taken for the highe r fortification level (100 ug) for the inner head patches. The deviation occurred because a researcher initially fortified head patch matrices in a way that was not in accord ance with the relevant SOP (AHE-8.E.5). The error was discovered while still in the field, so correct matrices were fortified. However, there were only enough extra fortification vi als remaining for duplicate samples and there were no vials available for the 100 ug high fortif ication rate for inner head patches. This deviation occurred on July 2, 2009, and was re ported to IIRB on September 2, 2009. On September 3rd, IIRB acknowledged the deviatio n and concluded that it did not place subjects at increased risk. In EPA’s view, this deviation is not significant from an ethics perspective. I defer to the EPA science reviewer about whethe r this deviation is important from a science perspective.

There was one reported deviation in the an alytical phase of th e research. Field
fortification solutions for some lots were not verified to establish concentration. This
deviation raises no ethical issu es, but I defer to the EPA sc ience reviewer on whether it affects the scientific integrity of the data.Page 9 of 51 4.1.2 Unreported Deviations

I noted one unreported deviation during th e field phase of AHE62. Subject A2 was monitored for only 174 minutes, although the protocol requires a minimum 4-hour monitoring period. This deviation raises no et hical issues, but I defer to the EPA science reviewer on whether it affects the scientific integrity of the data.

4.2 AHE63

4.2.1 Reported Deviations

There were two reported deviations during the field phase of AHE63. One subject (A5) applied only 2 tank loads of spray mixture and sprayed for only 2 hours, although the protocol specifies “Each MU shall consist of a period of at least 4 hours of spraying and at least 3 tank loads of the spra y mixture.” The deviation occurred because the pesticide needed to be applied at a specifi c concentration in orde r to achieve efficacy. It was not possible to increas e the spray volume or reduce the tractor ground speed to reach the protocol-required targets without sacrificing efficacy.

The second deviation was that the hi ghest stratum (56 to 100 lbs active ingredient) was not filled; the highest amount of active ingredient sprayed by a subject in this study was 48 lbs. This deviation occu rred because New York grape applicators typically apply at a rate of 32 lbs active ingredient per day, and thus could not achieve the amount in stratum 5 without working an abnor mally long day. Both of the deviations occurred between July 28 and August 6, 2009, and were reported to IIRB on September 11, 2009. On September 15th, IIRB acknowledged the deviation and concluded that it did not place subjects at increased risk. The deviation does not raise ethical issues because the expected exposure as a result of this deviation is not out of the range of safe exposures based on pre-study evaluations of ri sk. I defer to the EPA science reviewer about whether this deviation is impor tant from a science perspective.

There also were two method deviations re lated to analysis of carbaryl in inner dosimeters and face/neck wipe samples that were reported to IIRB. These analytical deviations raise no ethical issues, but I defer to the EPA science reviewer on whether they affects the scientific integrity of the data.

4.2.2 Unreported Deviations

I noted no unreported deviations dur ing the field phase of AHE63.Page 10 of 51 4.3 AHE64

4.3.1 Reported Deviations

There was one reported deviation during the field phase of AHE64 that involved departures from the protocol-r equired minimum application ti me, number of spray loads, and active ingredient strata. Four of the fi ve subjects (A2, A3, A4, and A5) each sprayed only 2 tank loads of spray mixture for less th an 4 hours each, contrary to the protocol requirement that subjects should be monito red for a minimum of 4 hours and apply at
least 3 tank loads. In additi on, the lowest stratum (5 to 9 lbs active ingredient) was not achieved by any of the subjects. The reason gi ven for the deviation was that highest label rate was required for controlling the target pe st. It was not possibl e to increase the spray volume or reduce the tractor ground speed and still achieve efficacy. Application times were dictated by the grower spray patterns and orchard configurat ions. The deviation occurred between August 22-29, 2009, and wa s reported to IIRB on September 18, 2009. On September 23, 2009, IIRB acknowledged th e deviation and indicated that no additional action was required. The deviation does not raise ethical issues because the expected exposure as a result of this deviation is not out of the range of safe exposures based on pre-study evaluations of risk. I de fer to the EPA science reviewer on whether
this deviation raises science issues.

There also was one method deviation in the analytical phase, related to analysis of carbaryl in inner dosimeters, re ported to IIRB. This deviati on raises no ethical issues, but
I defer to the EPA science reviewer on whether it affects the scientific integrity of the
data.

4.3.2 Unreported Deviations

I noted no unreported deviations dur ing the field phase of AHE64.Page 11 of 51 Table 2. Summary of Protocol Amendments and Deviations Study

ID Amendments Deviations
Field Phase Analytical Phase

AHE62 1. Amended to incorpor ate comments from EPA, California Department of Pesticide Regulation,
and HSRB. Reported : 1. On study day 1, inner and outer head patch field
fortifications were conducted in duplicate instead of triplicate, and on study day 1, no samples were taken for the higher fortification level (100 ug) for the inner head patches.

Unreported : 1. Subject A2 was monitored for 174 minutes, although the protocol requires a minimum 4-hour period. 1. Field
fortification
solutions for
some lots

were not verified to
establish
concentration 2. Protocol Amendment 1

• Inclusion criteria amended to allow participation of workers who normally wear two layers of clothing.

• Recruitment area expanded to allow any county in CA or WA.

• Removed efficient configuration requirement if recruitment area is expanded.
3. Protocol Amendment 2

• Added a new malathion product to possible test products (the active ingredient malathion was already an approved surrogate)

4. Protocol Amendment 3

• Specified the analytical methods to be used for head patches

AHE63 1. Amended to incorporate comments from EPA
and HSRB. Reported : 1. Subject A5 applied only 2 tank loads and sprayed for only 2 hours, although the protocol specifies that each subject should apply a
minimum of 3 tank loads
over a minimum time of 4 hours; also, the highest stratum (56 to 100 lbs a.i.) was not achieved; the highest amount sprayed was
48 lbs a.i.

Unreported : 1. None 1. The analytical laboratory
deviated from methodologies
related to analysis of carbaryl in
inner
dosimeters
2. The analytical
lab deviated
from methodologies
related to analysis of carbaryl in
face/neck wipe samples 2. Protocol Amendment 1

• Recruitment process modified to permit
use of recruitment letters

• Reduce heat index stopping rule from 120°
F to 105° F

• Amend dermal exposure sampling procedure to specify that the inner
dosimeters would be cut into 6 sections
rather than 2 sections

• Revise analytical methods to make them appropriate for dosimeters cut into 6 pieces

• Amend protocol to clarify the AHETF’s raw data retention policy

3. Protocol Amendment 2

• Amended analytical method for head patches

AHE64 • Amended to incorporate comments from EPA
and HSRB. Reported : 1. Subjects A2, A3, A4, A5 each applied only 2 tank loads and sprayed for less than 4 hours, although the protocol specifies that each subject should apply a
minimum of 3 tank loads
over a minimum time of 4 hours. Also, the lowest stratum (5 to 9 lbs a.i.) was not achieved; the lowest amount sprayed was 10 lbs
a.i. Unreported : 1. None 1. The analytical laboratory
deviated from analytical methodologies
related to analysis of carbaryl in
inner
dosimeters • Protocol Amendment 1

• Recruitment process modified to permit
use of recruitment letters

• Recruitment area expanded to allow counties adjacent to Tulsa County, OK.

• Removed efficient configuration requirement if recru itment area expanded.

• Amended dermal exposure sampling procedure to specify that the inner
dosimeters would be cut into 6 sections

• Revise analytical methods to make appropriate for dosimeters cut in 6 sections

3. Protocol Amendment 2

• The study director was changed from Eric D. Bruce to Larry D. Smith, effective September 14, 2009 (after study closure)Page 12 of 51 5.0 Recruiting

The three-phase recruiting process outlined in the protocol and SOPs AHETF11.K.O, 11.L.0, and 11.M.0 appears to have been followed in all three studies. An initial grower universe list was generated from publishe d lists or databases. Duplicate entries and growers with missing phone numbers were suppressed, to produce the master grower lists (which ranged in size from 330 names to 4,064 names in the three studies). After protocols were finalized and si gned by the study director, qua lifying calls were placed to the names on the master grower list, and th e lists were narrowed by eliminating names based on responses to qualifying questions, be ing unreachable, or lack of interest in participating in the research. The resulting lists contained names of growers who were qualified and interested in par ticipating in the research. Fo r the final stag e of recruiting, the study director contacted and/ or visited all qualified grow ers, to identify growers who could participate in a timeframe and sche dule to allow the study to be conducted efficiently. Table 2 in each of the St udy Reports (Volume 1, p. 38; Volume 3, p. 32; Volume 5, p. 33) details the number of growers/ workers in each stage of the recruitment

process.

The AHETF encountered difficulties recr uiting growers for AHE62. This study required open cab airblast equipment and bush trellis crops in commercial production. In the initial phase of recruiti ng, lists of growers of grap es, blackberries, blueberries, boysenberries, loganberries, and raspberries we re generated. Because less than 0.3% of the growers grew a trellis cr op other than grapes, and none of the “other bush crop” growers qualified for inclusion in the study, the remainder of the recruitment efforts were directed toward grape growers. Recruitmen t initially focused on Fresno, California, but the many of the qualified handlers in Fr esno wore additional personal protective equipment (PPE) (for example, coveralls or rain suits) or did not want to use the surrogate chemicals listed in th e protocol, and therefore coul d not be recruited. Due to these difficulties, the protocol was amended to allow recruitment from all counties in California and Washington (see discussion of the protocol amendment in section 3.1of this review). The early-pha se recruitment efforts result ed in a master grower list containing 4,064 names. The relatively large master grower list yielded a small qualified grower list (259 names), however, because a great majority of the growers who were contacted were not qualified because they wo re chemical-resistant PPE, grew less than 10 acres, did not use open cab equipment, refused the interview, or were not able to be contacted. Ultimately, the 259 names on the quali fied grower list only yielded 4 growers on the eligible grower list because many of the growers were either unwilling to participate or unable to use either of the pl anned surrogates. Three of the 4 eligible growers were ultimately monitored in AHE62. The fourth grower did not participate because his Pest Control Advisor did not appr ove use of either of the AHETF surrogates, and instead recommended a different pesticide.

5.1 Subject Representativeness

At the conclusion of the field phase of each of the studies, the AHETF conducted a survey of area experts to evaluate the re presentativeness of the growers/applicatorsPage 13 of 51 participating in the study. These surveys we re responsive to the HSRB’s request that the AHETF attempt to characterize whether the mon itored workers were typical of that type of worker/grower in the particular region.

For AHE62, four out of five area experts that responded to the survey opined that the growers/applicators were typical. The fifth local farm expert, who was from San Joaquin County, commented that the study acreage seemed to be smaller than would be typical for San Joaquin County. He also sp eculated that the study acreage seemed to be larger than would be typical for Fresno County, although he said that he said that he is not very familiar with Fresno. He said that he thought the acreage was typical for El Dorado County.

For AHE63, three of the four local farm experts who responded to the survey agreed that the study participants were typical of local grape grower s/applicators in the county where the study cluster was performed. Th e fourth expert said that the types of airblast sprayers used in th e study were not entirely repr esentative since the Kinkelder airblast sprayer, an older model sprayer that is more prone to pr oducing drift, was not included in the study.

For AHE64, four out of the seven local fa rm experts who responded to the survey agreed that the study participan ts were typical of local pecan growers/applicators in the counties where the study cluste r was performed. Of the thr ee experts who did not agree that the study participants we re typical, one indicated that a typical grower would have larger acreage than the pecan groves encounter ed in this study. The other two experts opined that the pecan growers in the study we re not typical because most pecan growers in the area use closed cabs, not open cabs.

6.0 Consent Process

The consent process outlined in the prot ocols and SOPs was closely followed in all studies. There were no repor ted deviations related to th e consent process, and I did not note any unreported deviat ions related to consent during my review of the study reports. Twelve of the 13 subjects complete d the consent process in English, and none of the subjects used a witness.

7.0 Subject Demographics

Demographic information on the monitored subjects is summarized in Table 3
below.Page 14 of 51 Table 3: Subject Characteristics Number of Subjects
AHE62 AHE63 AHE64
Males 3 5 5
Females 0 0 0 Completed consent process in English 2 5 5 Completed consent process in Spanish 1 0 0
Self-identified as non-reader and used witness 0 0 0 Employment Farm Owner or Operator 2 5 5 Farm Employee 1 0 0 Commercial Applicator 0 0 0 Years of Experience 8-30 4-39 3-40 Age Range 43-79 28-66 47-74 Requested Results 3 5 5
Withdrew 0 0 0 Removed from participation by AHETF 0 0 0

7.1 Health Status

Prospective subjects were asked about their health status during the consent process, using the procedures described in SOPs AHETF-11.B.4 and AHETF-11.C.1. No prospective subjects were eliminated due repor ted health status. Th e inclusion criteria in the protocol state that subjects must re port “good general heal th with no medical conditions that could impact thei r ability to participat e in the study” in order to be eligible to participate (protocol section 2.1).

8.0 Monitoring

Exposure monitoring was conducted without incident. No subjects withdrew
from the research. No adverse events or other incidents of c oncern were reported.

8.1 Heat Index

The greatest risk to subjects in this research is that of heat-related illness. The
SOP titled “Identification and Control of Heat Stress” (AHETF-11.G.1) provides information about recognition of conditions that contribute to heat-related illness,
measures to minimize the risk of heat-related i llness, measures to be taken if a worker is affected by heat-related illness, proce dures for AHETF researchers to monitor environmental conditions, and stopping rules rela ted to heat-related illness. The version of the SOP that was in place at the time th at these three field studies were conducted (AHETF-11.G.1) provided that the research sh ould not begin, or should be halted, if the ambient heat index (temperature adjusted fo r humidity and direct sunlight) was greater than or equal to 120° F. In November 2009 (a fter this research was completed), the SOP
was revised to lower the heat index threshol d from 120° F to 105° F (revised version is AHETF-11.G.2).Page 15 of 51 Although the SOP in effect at the time of the resear ch specified a heat index threshold of 120° F, the protocols for AHE62 and 63 were amended to lower the heat index threshold to 105° F. The protocol for AHE64 was not revised in the same manner
– the heat index threshold for AHE64 remained at 120° F.

Table 4, below, provides the maximum heat index measurements in AHE62, 63,
and 64. None of the measured heat index valu es exceeded the cut-off values of 105° F or
120° F.

Table 4. Heat Index Values (°F)

Study

ID A1 A2 A3

Time Heat
Index Time Heat
Index Time Heat
Index

AHE62 0723 <80 0622 <80 0742 <80
0816 <80 0651 <80 0814 <80
0901 <80 0720 <80 0910 91
1001 <80 0810 <80 0958 93

1112 83 0835 <80 1038 93
1126 95

AHE63 A1* A2 A3 A4 A5
0820 <80 1000 <80 1000 <80

Ambient temperature did
not reach 70 °F Ambient temperature did
not reach 70 °F 0920 <80 1100 <80 1100 <80
1020 <80 1200 <80 1200 <80
1120 <80 1300 <80 1300 <80
1220 95
1320 98
1420 85
1520 98
1620 88
1720 94
1820 95

AHE64 A1* A2 A3 A4 A5
1003 <80 0930 <80 1100 88 0850 <80 0834 <80
1102 92 1026 81 1200 91 0950 <80 0930 <80
1201 82 1300 94 1052 <80 1030 <80
1301 82
1401 83 * The heat index values for fluctuated due to passing periods of cloudiness.
“Caution” = heat index between 80-89°F
“Extreme caution” = heat index between 90-104°F

8.1.1 AHE62

When subject A1 was monitored, the heat index rose into the “caution” range (heat index between 80-89° F; see SOP AH ETF-11.G.1). As documented in Supplement 1 and reported in the worker observation log for subject A1 (p. 45, Volume 2), the study
director announced the “caution” heat i ndex at 11:12 am, in compliance with SOP AHETF-11.G.1. Eight minutes later (11:20 am), the log states that the subject “confirmed he still felt fine.” The sprayi ng was complete at th at point, and the logPage 16 of 51 reports that at 11:21 am, the subject rode to the staging area in the Study Director’s
vehicle.

When subject A3 was monitored, the heat index rose into the “Extreme Caution” category. According to the raw data report (s ee Supplement 1), the observer was also the weather monitor, so separate notification of the observer was not nece ssary. It does not appear that the worker was in danger of su ffering heat illness at any point during the study. The log shows that the worker talked to the nurse and drank Gatorade at 8:02 am, resumed spraying at 8:18 am, and “checked w ith nurse” at 11:10 am, saying that he “feels ok” (p. 47-49, Volume 2).

8.1.2 AHE63

When subject A1 was monitored, the h eat index rose into the “Caution” and “Extreme Caution” categories. According to the raw data report (see Supplement 1), the person responsible for monitoring the weather notified the observer of the heat index category changes, in compliance with SOP AHETF-11.G.1. It does not appear that the worker was in danger of suffering heat illnes s at any point during th e study. The worker observation log shows that the worker got a dr ink and “stated he was fine” at 10:11; took a break and had lunch between 11:10 and 12:11; drank water and “sta ted he was feeling fine” at 13:35; had more to drink and “stated he is feeling fine” at 15:09; “stated he was feeling fine” at 16:15; and had a drink at 17:37 (p. 40-41, Volume 4).

8.1.3 AHE64

When subject A1 was monitored, the h eat index rose into the “Caution” and “Extreme Caution” categories. According to the raw data report (see Supplement 1), the person responsible for monitoring the weather notified the observer of the heat index category changes, in compliance with SOP AHETF-11.G.1. It does not appear that the worker was in danger of suffering heat illnes s at any point during th e study. The worker observation log shows that the worker had a dr ink at 07:43; “stated he was feeling fine” at 09:27; took a break for lunch betw een 12:11 and 13:11. (p. 39-40, Vol. 6).

When subject A2 was monitored, the heat index rose into the “Caution” range. According to the raw data report (see Supplement 1), the person responsible for monitoring the weather notified the observer and researchers of the heat index category changes, in compliance with SOP AHETF-11.G.1. It does not appear that the worker was in danger of suffering heat illness at any point during the study.

When subject A3 was monitored, the heat index rose into the “Caution” and “Extreme Caution” categories. According to the raw data report (see Supplement 1), the person responsible for monitoring the weather no tified the observer and researchers of the heat index category changes, in compliance with SOP AHETF-11.G.1. It does not appear that the worker was in danger of suffering he at illness at any point during the study. The worker observation log shows that the worker had a drink at 10:11 am. (p. 42, Volume 6).Page 17 of 51 9.0 Applicable Ethical Standards

The following provisions of 40 CFR 26 Subpa rt Q, as amended effective August 22, 2006, define the applicable ethical standa rds, which read in pertinent part:

§26.1703: Except as provided in §26.1706, . . . EPA shall not rely on data from any research involving intentio nal exposure of any human subject who is a pregnant woman (and theref ore her fetus), a nursing woman, or a
child.

§26.1705: Except as provided in §26.1706, . . . EPA shall not rely on data from any research initiated after April 7, 2006, unless EPA has adequate
information to determine that the re search was conducte d in substantial compliance with subparts A through L of this part. . . .

In addition, §12(a)(2)(P) of the Federal In secticide, Fungicide and Rodenticide Act (FIFRA) applies. Th is passage reads:

In general, [i]t shall be unlawful for any person . . . to use any pesticide in tests on human beings unless such human beings (i) are fully informed of the nature and purposes of the test a nd of any physical and mental health consequences which are reasonably fore seeable therefrom, and (ii) freely volunteer to participate in the test.

10.0 Findings

10.1 Responsiveness to EPA and HSRB reviews

EPA’s and HSRB’s comments on these prot ocols were satisfactorily addressed
before the research was conducted. Pleas e see Attachment 3 for details.

10.2 Prohibition of research involving in tentional exposure of pregnant or nursing women or of children

All enrolled subjects were at least 18 years old and there were no female subjects. The prohibition in 40 CFR §26.1703 of research involving intentional exposure of pregnant or nursing women or of children under 18 was satisfied.

10.3 Substantial compliance with 40 CFR 26 subparts A through L

40 CFR §26.1705 requires that EPA have “adeq uate information to determine that
the research was conducted in substantial co mpliance with subparts A through L of this part.” Within this range, only subparts K and L are directly applicab le to the conduct of third-party research such as this. The study reports for AHE62, AHE63, and AHE64 document compliance with subparts K and L.Page 18 of 51 10.4 Compliance with 40 CFR §26 subpart M

As is documented in Attachment 2 to this review, the central requirements of 40 CFR §26 subpart M, §26.1303 to document the et hical conduct of th e research were satisfactorily addressed.

10.5 Compliance with FIFRA §12(a)(2)(P)

The requirement of FIFRA §12( a)(2)(P) that human subjects of research be “fully informed of the nature and pur poses of the test and of a ny physical and mental health consequences reasonably foreseeable therefro m,” and “freely voluntee r to participate in the test,” was met for this study.

11.0 Conclusion

This study reports research conducted in substantial compliance with the requirements of 40 CFR 26 subparts A through L. In its conduct it met all applicable ethical standards for the prot ection of human subjects of re search, and all requirements
for documentation of ethical c onduct of the research were sa tisfied. If this study is determined to be scientifically valid and re levant, there is no regul atory barrier to EPA’s
reliance on it in actions unde r FIFRA or §408 of FFDCA.

Attachment 1: Ethics-related study chronologies (Tables A-C) Attachment 2: §26.1303 completeness checks Attachment 3: Responsiveness to EPA a nd HSRB Comments on protocols (Table D)
Attachment 4: Heat Index Records from Raw Data for AHE62, AHE63, AHE64Attachment 1

Ethics-Related Study Chronologies

Page 19 of 51 Table A: AHE62

Date 10/21-22/08 HSRB reviewed protocol and approved with recommendations
3/27/09 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following October 2008 HSRB meeting)
4/1/09 & 4/6/09 IIRB approves revised documents 4/20/09 Protocol finalized and signed by Study Director 4/21/09 Phase 1 recruiting (creation of grower list). 4/21/09 to 7/27/09 5/12/09 Phase 2 recruiting (calls to grower list). 5/12/09 to 8/14/09 6/01/09 Phase 3 recruiting (site visits and participant selection) - 6/01/09 to 8/14/09
6/19/09 Submission to IIRB of Protocol Amendment 1 to include workers normally wearing 2 cloth layers and expand recruitment area
6/23/09 Approval of Protocol Amendment 1 by IIRB 7/02/09, 7/20/09 Two subjects monitored (MUs A1, A2) 7/16/09 Submission of annual progress report to IIRB
7/22/09 Submission to IIRB of Protocol Amendment 2 adding an additional malathion product
7/22/09 Approval of Protocol Amendment 2 by IIRB
7/24/09 Third subject monitored (MU A3) 7/25/09 Submission of supplemental information for Progress Report to IIRB 7/29/09 Approval by IIRB of ongoing research (i.e., extension granted)
9/02/09 Protocol Deviation 1 reported to IIRB

• Deviation occurred 7/02/09

• Inner and outer head patch fortification deficiencies
9/03/09 IIRB acknowledges Protocol Deviation 1 ; no further action required
11/21/09 Submission to IIRB of Protocol Amendment 3 specifying the analytical method and LOQ for head patches
11/24/09 Approval of Protocol Amendment 3 by IIRB 02/23/10 Close out report submitted to IIRB 02/25/10 IIRB accepts Study Completion Report; study considered closed
4/19/10 Laboratory Deviation reported to IIRB

• Deviation occurred 6/05/09

• Field fortification solution concentration not verified
4/20/10 IIRB acknowledges Laboratory Deviation ; no further action requiredAttachment 1

Ethics-Related Study Chronologies

Page 20 of 51 Table B: AHE63

Date 10/21-22/08 HSRB reviewed protocol and approved with recommendations
1/16/09 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following October 2008 HSRB meeting)
1/19/09 IIRB approves revised documents 1/23/09 Protocol finalized and signed by Study Director 6/09/09 Phase 1 recruiting (creation of Master Grower List and Qualified Grower List). 6/9/09
to 7/17/09 6/26/09 Grower letters submitted to and approved by IIRB 7/10/09 Phase 2 recruiting (calls to Qualified Grower List). 7/10/09 to 7/27/09 7/15/09 Phase 3 recruiting (site visits and participant selection) - 7/15/09 to 8/5/09 7/16/09 Annual progress report submitted to IIRB
7/18/09 Submission to IIRB of Protocol Amendment 1 to allow use of recruitment letters, lower the heat index threshold from 120° F to 105° F, change dermal sampling procedure (dosimeter cut into 6 sections, no t 2), and clarify raw data retention policy
7/21/09 Approval of Protocol Amendment 1 by IIRB
7/28/09 - 8/06/09 Five subjects monitored (MUs A1, A2, A4, A4, A5) 7/29/09 IIRB approves ongoing research and annual progress report (submitted on 7/16/09)
8/13/09 Submission to IIRB of Protocol Amendment 2 providing changes in analytical procedures
8/13/09 Approval of Protocol Amendment 2 by IIRB
9/11/09 Protocol Deviation 1 reported to IIRB

• Deviations occurred 7/28/09-8/06/09

• Involved departures from minimum spray time and spray load requirements; highest stratum not achieved
9/15/09 IIRB acknowledges Protocol Deviation 1 ; no further action required
7/06/10 2 analytical deviations reported to IIRB

• Deviations occurred 8/19/09, 4/20/10

• Deviations from analytical methodologies re lated to analysis of carbaryl in inner dosimeters and face/neck wipe samples
7/09/10 IIRB acknowledges 2 analytical deviations ; no further action required 07/15/10 Close out report submitted to IIRB 07/20/10 IIRB accepts Study Completion Report; study considered closedAttachment 1

Ethics-Related Study Chronologies

Page 21 of 51 Table C: AHE64

Date 10/21-22/08 HSRB reviewed protocol and approved with recommendations
1/16/09 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following October 2008 HSRB meeting)
1/19/09 IIRB approves revised documents 1/23/09 Protocol finalized and signed by Study Director 3/02/09 Phase 1 recruiting (creation of Master Grower List and Qualified Grower List). 3/2/09
to 7/29/09
6/15/09 Submission to IIRB of Protocol Amendment 1 to allow use of recruitment letters, expand grower search area, and change derm al sampling procedure (dosimeter cut into 6 sections, not 2)
6/19/09 Approval of Protocol Amendment 1 by IIRB 7/07/09 Calls to growers on Master Grower List. 7/07/09 to 7/28/09 7/16/09 Phase 2 recruiting (calls to Qualified Grower List). 7/16/09 to 8/16/09 7/16/09 Annual progress report submitted to IIRB 8/04/09 IIRB approves ongoing research and annual progress report (submitted on 7/16/09) 8/10/09 Phase 3 recruiting (site visits and participant selection) - 8/10/09 to 8/24/09
8/22/09 - 8/29/09 Five subjects monitored (MUs A1, A2, A4, A4, A5)
9/14/09 Submission to IIRB of Protocol Amendment 2 changing study director and Change in Principal Investigator Form
9/16/09 Approval of Protocol Amendment 2 by IIRB
9/18/09 Protocol Deviation 1 reported to IIRB

• Deviations occurred 8/22/09 - 8/29/09

• Involved departures from minimum spray time and spray load requirements;
lowest stratum not achieved
9/23/09 IIRB acknowledges Protocol Deviation 1 ; no further action required
7/10/10 Analytical deviation reported to IIRB

• Deviation occurred 5/4/10

• Deviation from analy tical methodologies related to analysis of carbaryl in inner
dosimeters
7/13/10 IIRB acknowledges analytical deviation ; no further action required 07/22/10 Close out report submitted to IIRB 07/23/10 IIRB accepts Study Completion Report; study considered closedAttachment 2

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE62 (MRID 48289614)

Page 22 of 51 Any person who submits to EPA data derived from human research covered by this su bpart shall provide at the time of submission information concerning the ethical conduct of such research. To t he extent available to the submitter and not previously provid ed to EPA, such information should include:

Requirement Y/N Comments/Page References(a) Copies of all of the records relevant to the research specified by§26.1115(a) to be prepared and maintained by an IRB §1115(a)(1): Copies of

• all research proposals reviewed,

• scientific evaluations, if any, that accompany the proposals,

• approved sample consent documents,

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

Progress Rpt 244 Close Out Report 318 §1115(a)(2): Minutes of IRB meetings whic h shall be in sufficient detail to show

• attendance at the meetings;

• actions taken by the IRB;

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

• the basis for requiring changes in or disapproving research;

• a written summary of the discussion of controverted issues and their
resolution. Y p. 303 [Approval of Ongoing Research for AHE62]

All other post-protocol approval
reviews were done under expedited procedures and minutes
were not created.

§1115(a)(3): Records of continuing review activities. Y 301
§1115(a)(4): Copies of all correspondence betw een the IRB and the investigators. Y 17-327 §1115(a)(5):

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

• any employment or other relationship between each member and the
institution N Already available to EPA

§1115(a)(6): Written procedures for the IR B in the same detail as described in § 26.1108(a) and § 26.1108(b). N Already available to EPA

§1115(a)(7): Statements of significant new findings provided to subjects, as required by § 26.1116(b)(5). n/a(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)§1125(a)A discussion of: (1) The potential risks to human subj ects; Y Addressed in protocol
(2) The measures proposed to minimize risks to the human subjects; Y Addressed in protocol (3): The nature and magnitude of all ex pected benefits of such research, and to whom they would accrue; Y Addressed in protocol

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

(5) The balance of risks and benefits of the pr oposed research. Y Addressed in protocol §1125(b): All information for subjects and written informed consent agreements as originally provided to the IRB, and as approved by the IRB. Y Orig. submitted 73-105,148-151 Approved 154-213, 220-241 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Addressed in protocol Flyers (Spanish&English) 149-150 §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 Addressed in protocol

§1125(e): All correspondence between the IRB and the investigators or sponsors. Y 17-327 §1125(f): Official notification to the sponsor or investi gator, in accordance with the requirements of this subpart, that res earch involving human subjects has been reviewed and approved by an IRB. Y Original approval provided in protocol submission; approved amendments 148, 152-3, 279 (c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y 220 English 230 Spanish (d) If any of the information lis ted in paragraphs (a) through (c) of this section is not provided, the person shall describe the e fforts made to obtain the information. n/aAttachment 2

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE63 (MRID 48289615)

Page 23 of 51 Any person who submits to EPA data derived from human research covered by this su bpart shall provide at the time of submission information concerning the ethical conduct of such research. To t he extent available to the submitter and not previously provid ed to EPA, such information should include:

Requirement Y/N Comments/Page References(a) Copies of all of the records relevant to the research specified by§26.1115(a) to be prepared and maintained by an IRB §1115(a)(1): Copies of

• all research proposals reviewed,

• scientific evaluations, if any, that accompany the proposals,

• approved sample consent documents,

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

Progress Rpt 105 Close Out Report 198 §1115(a)(2): Minutes of IRB meetings whic h shall be in sufficient detail to show

• attendance at the meetings;

• actions taken by the IRB;

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

• the basis for requiring changes in or disapproving research;

• a written summary of the discussion of controverted issues and their
resolution. Y p. 163 [Approval of Ongoing Research for AHE63]

All other post-protocol approval
reviews were done under expedited procedures and minutes
were not created.

§1115(a)(3): Records of continuing review activities. Y 100
§1115(a)(4): Copies of all correspondence betw een the IRB and the investigators. Y 13-219 §1115(a)(5):

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

• any employment or other relationship between each member and the
institution N Already available to EPA

§1115(a)(6): Written procedures for the IR B in the same detail as described in § 26.1108(a) and § 26.1108(b). N Already available to EPA

§1115(a)(7): Statements of significant new findings provided to subjects, as required by § 26.1116(b)(5). n/a(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)§1125(a)A discussion of: (1) The potential risks to human subj ects; Y Addressed in protocol
(2) The measures proposed to minimize risks to the human subjects; Y Addressed in protocol (3): The nature and magnitude of all ex pected benefits of such research, and to whom they would accrue; Y Addressed in protocol

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

(5) The balance of risks and benefits of the pr oposed research. Y Addressed in protocol

§1125(b): All information for subjects and written informed consent agreements as originally provided to the IRB, and as approved by the IRB. Y Orig. submitted – In protocol submission; also 54-64 Approved 67-97 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Addressed in protocol; 96-97 Flyers (Spanish&English) 67, 81 §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 Addressed in protocol

§1125(e): All correspondence between the IRB and the investigators or sponsors. Y 13-219 §1125(f): Official notification to the sponsor or investi gator, in accordance with the requirements of this subpart, that res earch involving human subjects has been reviewed and approved by an IRB. Y Original approval provided in protocol submission; approved amendments 66, 95, 159,174,194 (c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y 202 (English); None of the subjects in this study chose to use the Spanish version of the forms (d) If any of the information lis ted in paragraphs (a) through (c) of this section is not provided, the person shall describe the e fforts made to obtain the information. n/aAttachment 2

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE64 (MRID 48289616)

Page 24 of 51 Any person who submits to EPA data derived from human research covered by this su bpart shall provide at the time of submission information concerning the ethical conduct of such research. To t he extent available to the submitter and not previously provid ed to EPA, such information should include:

Requirement Y/N Comments/Page References(a) Copies of all of the records relevant to the research specified by§26.1115(a) to be prepared and maintained by an IRB §1115(a)(1): Copies of

• all research proposals reviewed,

• scientific evaluations, if any, that accompany the proposals,

• approved sample consent documents,

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

Progress Rpt 156 Close Out Report 200 §1115(a)(2): Minutes of IRB meetings whic h shall be in sufficient detail to show

• attendance at the meetings;

• actions taken by the IRB;

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

• the basis for requiring changes in or disapproving research;

• a written summary of the discussion of controverted issues and their
resolution. Y p. 182 [Protocol Amendment 2] p. 195 [Approval of Ongoing Research for AHE64]

All other post-protocol approval
reviews were done under expedited procedures and minutes
were not created.

§1115(a)(3): Records of continuing review activities. Y 156
§1115(a)(4): Copies of all correspondence be tween the IRB and the investigators. Y 14-217 §1115(a)(5):

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

• any employment or other relationship between each member and the
institution N Already available to EPA

§1115(a)(6): Written procedures for the IR B in the same detail as described in § 26.1108(a) and § 26.1108(b). N Already available to EPA

§1115(a)(7): Statements of significant new findings provided to subjects, as required by § 26.1116(b)(5). n/a(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)§1125(a)A discussion of: (1) The potential risks to human subj ects; Y Addressed in protocol
(2) The measures proposed to minimize risks to the human subjects; Y Addressed in protocol (3): The nature and magnitude of all ex pected benefits of such research, and to whom they would accrue; Y Addressed in protocol

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

(5) The balance of risks and benefits of the pr oposed research. Y Addressed in protocol

§1125(b): All information for subjects and written informed consent agreements as originally provided to the IRB, and as approved by the IRB. Y Orig. submitted – In protocol submission; also 54-64 Approved 66-86 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Addressed in protocol; 153-4 Flyers (Spanish&English) 88, 89 §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 Addressed in protocol

§1125(e): All correspondence between the IRB and the investigators or sponsors. Y 14-217 §1125(f): Official notification to the sponsor or investi gator, in accordance with the requirements of this subpart, that res earch involving human subjects has been reviewed and approved by an IRB. Y Original approval provided in protocol submission; approved amendments 152, 182 (c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y 203 (English); None of the subjects in this study chose to use the Spanish version of the forms (d) If any of the information lis ted in paragraphs (a) through (c) of this section is not provided, the person shall describe the e fforts made to obtain the information. n/aAttachment 3 Responsiveness to Major EPA and HSRB Comments

Page 25 of 51 Table D. Responsiveness to Major EPA and HSRB Comments on Protocols for AHE62, AHE63, AHE64 (reviewed at the October 2008 HSRB Meeting)

EPA or HSRB Comment Addressed before executing AHE62, AHE63, AHE64?
1. Characterize representativeness of subjects Yes

1. 5 monitoring units in each cluster, each from a different farm, is needed to ensure that the design and analyses are scientifically sound. Only 1 worker monitored per employer

2. Select of Local Site Coordinators with demonstrable training and expertise in survey implementation to ensure optimal recruiting and thereby enhance the usefulness of the
data Yes

3. The Local Site Coordinator, th e Principal Field Investigator, the Field Facility, the Analytical Facility, and the Principal Analytical Investigator must be identified in the protocol Yes, addressed prior to study initiation

4. Any key members of the research team who will have contact with the research subjects or their identifiable data
must receive and document their recent (not expired) training in human subjects’ protection Yes, and relevant SOP subsequently revised (SOP AHETF-10.C.4)

5. Revise subject recruitment plan to specifically address the probability that subjects may also be growers. Yes (SOP AHETF-11.B.4)

6. Remove risks of agricultural work from the listing of risks
related to the research. Yes

7. Identify risks of pesticide products that are due to scripting. Yes
8. Harmonize the lists of eligibility factors in the protocol and
the consent form Yes

9. The number of potentially el igible workers linked to each grower, the numbers attending initial group meetings, attending individual consent interviews, signing consent forms, subsequently withdraw ing or being withdrawn, and completing participation should all be recorded and reported Yes

### ATTACHMENT 4:

Heat Index Records from Raw Data for

AHE62, AHE63, AHE64