Page 1 of 43 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D.C., 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

January 7, 2010

MEMORANDUM

SUBJECT: Ethics Review of Completed AHETF Closed 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: Smith, Larry D. (2010) Determination of Dermal and Inhalation Exposure to Workers During Airblast Applicati ons of Liquid Sprays Using Closed Cab Equipment in Florida Citrus. Study Number AHE55. 377 p. (MRID 48289601) [Volume 1]

Smith, Larry D. (2010) IIRB Corre spondence Report for Cluster Report AHE55. 287 p. (MRID 48303503) [Volume 2]

Smith, Larry D. (2010) Determination of Dermal and Inhalation Exposure to Workers During Airblast Applicati ons of Liquid Sprays Using Closed Cab Equipment in Georgia Pecans. Study Number AHE56. 379 p. (MRID 48289602) [Volume 3]

Smith, Larry D. (2010) IIRB Corre spondence Report for Cluster Report AHE56. 295 p. (MRID 48303504) [Volume 4]

Smith, Larry D. (2010) Determination of Dermal and Inhalation Exposure to Workers During Airblast Applicati ons of Liquid Sprays Using Closed Cab Equipment in Michigan Stone Fruit. Study Number AHE57. 377 p. (MRID 48303501) [Volume 5]Page 2 of 43 Smith, Larry D. (2010) IIRB Corre spondence Report for Cluster Report AHE57. 172 p. (MRID 48289608) [Volume 6]

Bruce, Eric D. (2010) Determinatio n of Dermal and Inhalation Exposure to Workers During Airblast Applicati ons of Liquid Sprays Using Closed Cab Equipment in California Trel lis Crops. Study Number AHE58. 282 p. (MRID 48289604) [Volume 7]

Bruce, Eric D. (2010) IIRB Corre spondence Report for Cluster Report AHE58. 357 p. (MRID 48289609) [Volume 8]

Bruce, Eric D. (2010) Determinatio n of Dermal and Inhalation Exposure to Workers During Airblast Applicati ons of Liquid Sprays Using Closed Cab Equipment in Washington Pome Fruit. Study Number AHE59. 220 p. (MRID 48303502) [Volume 9]

Bruce, Eric D. (2010) IIRB Corre spondence Report for Cluster Report AHE59. 195 p. (MRID 48289610) [Volume 10]

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 five 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 vehicle with an enclosed cab. If these studies are determined to be scientifically acceptable, I find no barrier in regulation to EPA’s
reliance on them in actions under FIFRA or FFDCA.

1.0 Background and Ethics-related Chronology

Five separate field studies were con ducted, each monitoring workers while they sprayed tree or trellis crops in five different states in the U.S where closed cab airblast equipment is commonly used in production ag riculture. The studies are summarized in
Table 1.

Table 1

. Study Summary

Study

ID State Crop Number of
Monitored Workers Gender Ages

AHE55 FL Orange, Tangerine 5 All male 20-70
AHE56 GA Pecan 5 All male 43-68 AHE57 MI Cherry 5 4 males, 1 female 21-58 AHE58 CA Grape 5 All male 27-49 AHE59 WA Apple 4 All male 26-62

The background and ethics-related chronology for each field study is summarized below.Page 3 of 43 1.1 AHE55

The scenario design and protocol fo r AHE55 were approved by the overseeing IRB, the Independent Investigational Review Board, Inc. (IIRB), of Plantation, Florida,
in March 2008 and submitted to EPA for revi ew in April 2008. The protocol and EPA’s review dated May 27, 2008 were discussed by the Human Studies Review Board (HSRB) at its June 2008 meeting. The HSRB revi ew was generally favorable, and the Board’s November 14, 2008 final report of the June 2008 meeting concluded, with respect to ethics, that “with a number of required revisions, [the protocols] appear likely to generate scientifically sound, useful information and to meet the applicable provisions of the EPA regulations in 40 CFR part 26, subparts K and L.”

Following the HSRB review, the protocol, consent form, and recruiting materials
for AHE55 were revised to address EPA and HSRB comments. The re vised protocol was submitted to IIRB on July 18, 2008, and approved on July 21, 2008. There are no other amendments to the protocol documented in the IIRB correspondence volume for AHE55 (Vol 2).

Subject monitoring for AHE55 took place in late October 2008. Five male subjects between the ages of 20 and 70 were monitored for dermal and inhalation exposure while applying pesticid e sprays using closed-cab ai rblast equipment to orange and tangerine crops in Florida. There was one reported deviation during the field phase of the research, and there were no reported deviations during the analytical phase. I noted 4 unreported deviations.

A detailed chronology of the ethics-relat ed study activities for AHE55 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 18.

1.2 AHE56

The scenario design and protocol fo r AHE56 was approved by IIRB in March 2008 and submitted to EPA for review in April 2008. The protocol and EPA’s review dated May 27, 2008 were discussed by the Huma n Studies Review Board (HSRB) at its June 2008 meeting. The HSRB review was generally favorable, and the Board’s November 14, 2008 final report of the June 2008 meeting concluded, with respect to ethics, that “with a number of required revi sions, [this protocol appears] likely to generate scientifically sound, us eful information and to meet the applicable provisions of the EPA regulations in 40 CFR part 26, subparts K and L.”

Following the HSRB review, the protocol, consent form, and recruiting materials
for AHE56 were revised to address EPA and HSRB comments. The re vised protocol was submitted to IIRB on July 18, 2008, and approved on July 21, 2008. There are no other amendments to the protocol documented in the IIRB correspondence volume for AHE56 (Vol 4).
`Page 4 of 43 Subject monitoring for AHE56 took place in August 2008. Five male subjects between the ages of 43 and 68 were monitore d while applying pesticide sprays using closed-cab airblast equipment to pecans in Georgia. There were five reported deviations during the field phase of the research, and th ree reported deviations during the analytical phase. I noted one unreported deviation. EP A presented preliminary recruiting results from AHE56 at the October 2008 HSRB meeting.

A detailed chronology of the ethics-relat ed study activities for AHE56 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 18.

1.3 AHE57

The scenario design and protocol for AHE57 was approved by IIRB 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; the Board’s December 30, 2008 final report of the October 2008 meeting concluded, with respect to ethics, that “if re vised as suggested by the Board, 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, co nsent forms, and recruiting materials
for AHE57 were revised to address EPA a nd HSRB comments. The revised protocols, consent forms, and recruiting materials for AHE57 were submitted to IIRB on January 16, 2009, and approved on January 19, 2009. Th ere are no other amendments to the protocol documented in the IIRB correspondence volume for AHE57 (Vol 6).

Subject monitoring for AHE57 took place in May 2009. Four male subjects and one female subject between the ages of 21 and 58 were monitored while applying pesticide sprays using closed- cab airblast equipment to che rries in Michigan. There was one reported deviation during the field phase of the research and four reported deviations during the analytical phase. I not ed two unreported deviations.

After monitoring, an amendment to the pur ity analysis sectio n of the protocol (Section 7.5.3) was submitted to IIRB. This Amendment was not acknowledged by IIRB until after the study was closed, but II RB concluded that the amendment was “administrative in nature, did not affect s ubject safety, and would not have received a
revision to the consent form.”

A detailed chronology of the ethics-relat ed study activities for AHE57 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 18.Page 5 of 43 1.4 AHE58

The scenario design and protocol for AHE58 was approved by IIRB 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; the Board’s December 30, 2008 final report of the October 2008 meeting concluded, with respect to ethics, that “if re vised as suggested by the Board, 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, co nsent forms, and recruiting materials
for AHE58 were revised to a ddress comments from EPA, HSRB, and the California Department of Pesticide Regulation. The revi sed protocol, consent form, and recruiting materials for AHE58 were submitted to IIRB on March 26, 2009, and approved on April 1 and April 6, 2009. Two subsequent amendm ents were approved by IIRB in June and July 2009.

Subject monitoring for AHE58 took place in June and July 2009. Five male subjects between the ages of 27 and 49 were monitored while applying pesticide sprays using closed-cab airblast equipment to grapes in California. Ther e were four reported deviations in the field phase of the study, a nd one reported deviati on in the analytical phase. I noted three unreported deviations.

A detailed chronology of the ethics-relat ed study activities for AHE58 is provided in Table D in Attachment 1. A summary of amendments and reported and unreported deviations from all studies is pr ovided in Table 2, on page 18.

1.5 AHE59

The scenario design and protocol for AHE59 was approved by IIRB and submitted to EPA for review in August 2008. The protocol and EPA’s review dated September 23, 2008 were reviewed by the HSRB at its October 2008 meeting. The HSRB review was generally favorable; the Board’s December 30, 2008 final report of the October 2008 meeting concluded, with respect to ethics, that “if re vised as suggested by the Board, 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, co nsent forms, and recruiting materials
for AHE59 were revised to address EPA and HS RB. The revised protocol, consent form, and recruiting materials for AHE59 were submitted to IIRB on January 16, 2009, and approved on January 19, 2009. There was one additional amendment in May 2009 to add two additional carbaryl products to the list of approved test substances.

Subject monitoring for AHE59 took place in late April and early May 2009. Four male subjects between the ages of 26 and 62 were monitored while applying pesticidePage 6 of 43 sprays to apple crops in Wash ington using closed-cab airblast equipment. A fifth subject
was not monitored because of a se ries of logistical difficulties. 1

There were two reported fiel d phase deviations, and one reported analytical phase
deviation. I noted thr ee unreported deviations.

A detailed chronology of the ethics-relat ed study activities for AHE59 is provided in Table E in Attachment 1. A summary of amendments and reported and unreported deviations from all studies is pr ovided in Table 2, on page 18.

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 10 study volumes identifi ed on pages 1-2, plus Supplement 1 related
to AHE57.

3.0 Protocol Amendments:

3.1 AHE55

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 July 18, 2008, and approved on July 21, 2008. No further amendments are documented in the IIRB Correspondence Report (Volume 2). The study report (Volume 1) indicates that the protocol was amended three times prior to execution of the field phase, but the re port does not summarize these ch anges. The discrepancy in the reporting of amendments between Volume 1 and Volume 2 is not resolved or explained elsewhere in the AHETF’s submission.

3.2 AHE56

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 July 18, 2008, and approved on July 21, 2008. No further amendments are documented in the IIRB Correspondence Report (Volume 2). The study

1 One subject was enrolled and sign ed the consent form, but he was not ultimately monitored because a research team was not available on the day that he ne eded to make his application. Researchers attempted to enroll and monitor an alternate grower, but that grower’s air conditioned closed cab tractor was not functioning on the day that the appli cation needed to take place, so the gr ower applied the pesticide with an open cab tractor and the research did not take place. The timing of carbaryl appl e-thinning application is dependent on crop growth state and weather, and as a result, the applications could not be pre-scheduled; researchers needed to be available when the grower in tended to make an application. Several attempts were made to find a fifth subject by re-contacting the other Potentially Eligible Growers, but none was
found before the use season ended.Page 7 of 43 report (Volume 1) indicates th at the protocol was amended two times prior to execution of the field phase, but the re port does not summarize these ch anges. The discrepancy in the reporting of amendments between Volume 3 and Volume 4 is not resolved or explained elsewhere in the AHETF’s submission.

3.3 AHE57

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.

In June 2009, the AHETF submitted to IIRB an amendment to the purity analysis section of the protocol (Section 7.5.3). The IIRB Correspondence Report (Volume 6) shows that the amendment was emailed to IIRB on June 7, 2009. In September 2010, after the study was closed, AH ETF realized that it did not have documentation of IIRB’s approval of the amendment, and requested co pies of IIRB’s records on the amendment.
AHETF was informed at that time that IIRB did not have a record of the amendment. On September 14, 2010, IIRB acknowledged receipt of the amendment, and noted that the amendment was “administrative in nature, did not affect subject sa fety, and would not
have received a revision to the consent form .” In EPA’s view, this amendment did not affect subject safety or subj ect autonomy, and therefore the documentation issues are not important in evaluating the ethi cal conduct of this research.

There is agreement between the study report (Volume 5) and IIRB Correspondence Report (Volume 6) that there were two amendments to AHE57 prior to execution of the field phase of the research.

3.4 AHE58

Following EPA’s and HSRB’s reviews, the protocol, consent forms, and recruiting materials were revi sed to address EPA, HSRB, a nd California Department of Pesticide Regulation comments. The revise d protocol, consent form, and recruiting materials for AHE58 were submitted to IIRB on March 26, 2009, and approved on April 1 and April 6, 2009.

In early June 2009, the AHETF consulted EPA about three changes to the AHE58 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 8 of 43 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 incr ease risks of heat-r elated 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 might not be eligible to participate because they normally wear Tyvek coveralls, or because their Pe st Control Advisor, winery, or raisin packer might not approve the use of eith er 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. IIRB approved the amendment on July 22, 2009.

There is agreement between the study report (Volume 7) and IIRB Correspondence Report (Volume 8) for AHE58 th at there were three amendments to
AHE58.

3.5 AHE59

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.

In April 2009, while preparing to co nduct the monitoring for AHE59, the AHETF learned that two eligible growers wanted to us e carbaryl products that were not on the list of approved surrogate products. In order to e xpand the list of surrogates to include these two products, AHETF submitted to IIRB new produc t risk statements (PRSs) for the two carbaryl end-use products on April 24, 2009; IIRB approved the new PRSs on April 29, 2009. On May 11, 2009, the AHETF submitted to IIRB an amendment, which had previously been approved by EPA, to add two carbaryl end-use products to the list of possible products for this study. IIRB approved this amendment on May 19, 2009. This amendment was not timely, however, because tw o subjects were monitored using the two new carbaryl products on May 7 and 9, 2009. This situation was later reported to IIRB as
a deviation. Please refer to the discussi on on page 16 of this review for more
information.Page 9 of 43 There is agreement between the study report (Volume 9) and IIRB Correspondence Report (Volume 10) that ther e was one amendment to AHE59 after the protocol was signed by the study director.

4.0 Protocol Deviations:

4.1 AHE55

4.1.1 Reported Deviations

There was one reported deviation duri ng the field phase of AHE55. On two occasions, a subject was selected for monitori ng from two potential subjects by coin flip rather than by drawing a name as required by the protocol. This deviation occurred on October 28 and October 30, 2008, and was repo rted to IIRB on November 16, 2008. On
November 17 th , IIRB acknowledged the deviation and concluded that it did not place subjects at increased risk. In EPA’s view, this deviation is not significant from an ethics perspective because it did not pl ace subjects at increased risk and was consistent with the general intent of the protocol that subjects be selected randoml y if more than one eligible
individual is available for m onitoring. I defer to the EPA science reviewer about whether this deviation is important from a science perspective.

There were no reported deviations in th e analytical phase of the research.

4.1.2 Unreported Deviations

There were four unreported deviations during the field phase of AHE55.

1) Section 2.4 of the protocol states that growers will be reimbursed for the pesticide used in the study, but fo r AHE55, the Local Site Coordinator purchased the product and delivered it to the application sites. Notwithstanding the study dire ctor’s failure to report this deviation to IIRB, it
raises no ethical issues. I defer to the EPA science reviewer on whether the
deviation raises science issues.

2) One subject was a non-reader who required a witness for the consent process. Section 2.7 of the protocol states that “Witnesses must have no association with AHETF, its member companies, rese archers, growers, or workers.” (Vol 1, p 348). In this study, the non-readi ng worker selected the witness (“The witness was selected by the participan t and monitored the informed consent procedure.” [Vol. 1, p. 10]) This is an unreported protocol deviation because
the witness had an association with the worker. This deviation does not raise concerns about the consent process for this worker, however, because even though the protocol for AHE55 states th at the witness should not have an association with the worker, the protocols for AHE57, AHE58, and AHE59Page 10 of 43 specify that the witness should be se lected by the non-reading prospective subject. Moreover, SOP 11.I.1 states th at subjects may choose a witness, and only specifies that “the witness must be unassociated with the conduct of the research (i.e., not employed by the Spons or or any of its contractors.)”

The HSRB, in its December 18, 2007, re port of the June 2007 HSRB meeting, stated the following on the topic of witnesses:

“The Board expressed support for the Agency's proposal to have impartial third-party witnesses observe the consent process when a research subject is unable to re ad relevant study documents. As specific studies are proposed, however, it will be important for investigators to describe the proce dures to be employed in recruiting these witnesses. It would be inappropriate, for example, to ask
translators to serve as witnesse s (as suggested in the materials reviewed by the Board), because one of the main purposes ofemploying a witness is to ensure that the communication of studyrelated materials is adequate (and the translator would be conflicted with regard to that assessment). If feasible, the Agency may wish to consider using impartial “consent monitors” or “research subject advocates” as witnesses, as is in creasingly done in certain clinical studies.” (p. 64-5 of 67)

Although this protocol deviation should have been reported to IIRB, it raises no ethics issues. It is appropriate, in EPA’s view, for the non-reading subject to select the witness. The important restriction that the witness not be associated with the researchers or study sponsors was not violat ed in this case.

3) One subject touched the cab door while not wearing gloves, and later opened
the cab door with bare hands. There is no record that th e observer reminded the worker to wear his gloves or report ed the behavior to the study director, which violated protocol section 2.3.2 and SOP AHETF-10.C.4. These protocol and SOP violations were not re ported to IIRB. These deviations are discussed in greater detail in se ctions 8.1 and 10.0 of this review.

4) Four of the five subjects in this study did not spray for a minimum of 4 hours, as required in Section 7.8 of the protoc ol (“Each MU shall consist of a period of at least 4 hours of spraying and at leas t 3 tank loads of the spray mixture.”) See Table F in Appendix 2 for indivi dual spray times for each subject. Although this protocol deviation should have been reported to IIRB, it raises
no ethics issues. I defer to the EP A science reviewer on whether this
deviation raises science issues.Page 11 of 43 4.2 AHE56

4.2.1 Reported Deviations

There were five reported deviations during the field phase of AHE56.

1) In the summer of 2008, the AHETF iden tified potential eligible pecan growers in southwest Georgia (located in the five counties adja cent to Tift County), in
accordance with Section 4.0 of the AHE56 protocol (Vol 3, p 347 of 379). By mid-August, the AHETF had identified 22 eligible growers who agreed to participate in the study by providing th e closed-cab equipment and allowing their pecan trees to be sprayed with one of the surrogate products. In the final phase of recruitment, the study director made telephone contact with and/or visited the 22 eligible growers to se lect at least five growers who could participate in a timeframe and schedu le to allow the study to be conducted efficiently. During the course of c onducting the telephone conversations with eligible growers, the study director was informed of two additional pecan growers who might be candidates for part icipation in the study. One of these referrals appeared on the original grower list, but was eliminated because he was no longer growing pecans and was now working as a commercial applicator; the other referral did not app ear on the original grower list because
his farm was not located in one of the fi ve counties adjacent to Tift County.

During the week of August 18, 2008, th e AHETF had six growers ready to participate (five were needed; one was to serve as a back-up). The research team assembled in Tifton, Georgia on August 19, and they planned to begin monitoring on August 21 st . However, a tropical storm struck on August 20 th

, making the field work impossible for se veral days. When the research was ready to proceed during the week of August 25 th , three of the six growers were either no longer willing to participate or unable to be resc heduled within the necessary timeframe to efficiently conduct the research. In order to find the additional two needed growers, the AHETF contacted the two “referrals,” and these two growers eventually agreed to pa rticipate. This was a deviation since the protocol does not provide for recru itment beyond the eligible growers list, and because one of the subjects was not located in a county directly adjacent to Tift County.

The decision to use the two referred gr owers in the study was made during the week of August 25 th . The deviation was reported to IIRB on September 5, 2008. On September 15, IIRB acknowledged the deviation and concluded that it did not place subjects at increase d risk. I note that the deviation was reported to have occurred on August 18 th , but the field notes show that the monitoring took place on August 25-28. In EPA’s view, this deviation is not significant from an ethics perspective b ecause after the initial identification of the two referred growers, they were r ecruited using the procedures that arePage 12 of 43 outlined in the protocol and SOP AHETF-11.B.3. I defer to the EPA science
reviewer on whether this devi ation affects the scientific integrity of the data.

2) The second reported deviation involved a departure from Section 2.7 of the protocol, which says that informed cons ent must be obtained before a subject participates in the research. In this in stance, one of the subjects dressed in the dosimeter before he signed the consent form. He is reported to have given oral consent prior to don ning the dosimeter, but he signed the consent form shortly after putting on the dosimeter. Th e reason for the deviation was that the subject (A5) arrived at the field site just before another subject (A1) was expected to return to the staging area to remove his dosimeter and have his samples collected. To avoid the possibil ity of contamination of subject A5’s clean dosimeter while subject A1 was having his samples collected, subject A5 was quickly dressed in his dosimeter before subject A1 entered the staging

area.

Based on the field observation records, the deviation occurred on August 25, 2008, the first day of monitoring. However, the deviation was mistakenly reported to IIRB as having occurred on August 18 th . The deviation was reported to IIRB on September 17, a nd IIRB acknowledged it on September 23rd and concluded subjects were not at increased risk. In EPA’s view, this deviation is not significant from an ethics perspective because the subject gave verbal consent before putting on the dosimeter, and he signed the consent form shortly after putting on the dosimeter. It is questionable whether
this is indeed a deviation since the s ubject gave oral consent prior to putting on the dosimeter, but the AHETF wisely erred on the side of caution by reporting this deviation.

3) The third reported deviation for AHE56 was that travel fortification samples, which should have been prepared on day 1, were not prepared until monitoring day 4. The deviation was reported to IIRB on September 17, and IIRB acknowledged it on September 23rd a nd concluded subjects were not at
increased risk. I note that the deviati on report erroneously indicates that the deviation occurred on August 18-21. Ba sed on the field notes providing the dates that subjects were monitored, th is deviation occurred on August 25-28,
2008. This deviation has no effect on th e ethical conduct of the research. I
defer to the EPA science reviewer on whether this deviation affects the scientific integrity of the study.

4) The fourth reported deviation for AHE56 was that one subject (subject A4)
took a bathroom break without first wa shing his hands and without handwash samples being taken. The subject steppe d away from the tractor to relieve himself behind a tree while his spray ta nk was being refilled. The worker was out of sight of the observer at that time. When the observer realized what had happened, he reminded the worker to fo llow label directions advising that users should wash hands before using th e bathroom. This was a violation ofPage 13 of 43 label directions, and also a deviatio n from SOP AHETF-8.B.4 (section 5.2). From an ethics perspective, the obs erver responded appropriately to the situation by reminding the worker of labe l directions, but he should have also reported the occurrence to the study dire ctor in accordance with SOP AHETF10.C.3. The deviation was reported to IIRB on September 17, and IIRB acknowledged it on September 23rd and conc luded that subjects were not at
increased risk. I note that the deviati on report erroneously indicates that the deviation occurred between August 18-21, 2008. Based on the field notes providing the dates that subjects were monitored, this deviation occurred on August 28, 2008. This deviation raises no ethical issues, but I defer to the EPA science reviewer on whether this deviation affects the scientific integrity
of the data.

5) The fifth reported deviation for AHE56 was that the air pump and sampling train were removed from subjects before the final air flow rate was measured
with a calibrated rotometer. This was a deviation from SOP AHETF-8.D.2 (Section 4.11). The deviation was reported to IIRB on September 17, and IIRB acknowledged it on September 23rd a nd concluded that subjects were
not at increased risk. I note that the deviation report erroneously indicates that the deviation occurred between Augus t 18-21, 2008. Based on the field notes providing the dates that subjects were monitored, this deviation occurred on August 28, 2008. This deviation raises no ethical issues, but I defer to the EPA science reviewer on whether this deviation affects the scientific integrity
of the data.

There were four deviations in the analytical phase of the research that were reported to
IIRB. These deviations raise no ethical issues , but I defer to the EPA science reviewer on whether these deviations affect the scientific integrity of the data.

4.2.2 Unreported Deviations

1) None of the five subjects in this st udy sprayed for a minimum of 4 hours, as required in Section 7.8 of the protocol (“ Each MU shall consist of a period of at least 4 hours of spraying and at leas t 3 tank loads of the spray mixture.”) See Table F in Appendix 2 for indivi dual spray times for each subject. Although this protocol deviation should have been reported to IIRB, it raises
no ethics issues. I defer to the EP A science reviewer on whether this
deviation raises science issues.

4.3 AHE57

4.3.1 Reported Deviations

There was one reported deviation during the field phase of AHE56. Subject A1, who was assigned to the lowest stratum of amount active ingr edient handled (AaiH) –Page 14 of 43 5 to 9 pounds – actually handled 10.68 pounds. In addition, this subject was monitored for only 2 hours and he applied only 2 tank loads, contrary to the prot ocol requirement in Section 7.8 that subjects are monitored for a minimum of 4 hours a nd apply at least 3 tank loads. The reason given for applying an amount outside of the limits of the stratum was that the grower needed the pesticide a pplied at a higher rate to achieve effective control of the target pest. The minimum application time and minimum number of loads specified in the protocol coul d not be achieved because of th e grower’s preference to use his normal tractor speed and spray volu me. The deviation occurred on May 22, 2009, and was reported to IIRB on June 4, 2009. On June 10, 2009, IIRB acknowledged the
deviation and indicated that no additional action is 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 ev aluations of risk. I defer to the EPA
science reviewer on whether this deviation raises science issues.

There were 4 deviations in the analytical phase of the research that were reported
to IIRB. These deviations raise no ethical is sues, but I defer to the EPA science reviewer
on whether these deviations affect th e scientific integrity of the data.

4.3.2 Unreported Deviations

1) None of the five subjects in this study sprayed for a minimum of 4 hours, as required in Section 7.8 of the protocol (“ Each MU shall consist of a period of at least 4 hours of spraying and at leas t 3 tank loads of the spray mixture.”) See Table F in Appendix 2 for indivi dual spray times for each subject. Although this protocol deviation should have been reported to IIRB, it raises
no ethics issues. I defer to the EP A science reviewer on whether this
deviation raises science issues.

4.4 AHE58

4.4.1 Reported Deviations

There were four reported deviations during the field phase of AHE58.

1) The first deviation was that on St udy Day 2, inner whole body dosimeters were inadvertently not folded over afte r field fortifications were conducted and prior to covering with cloth as specified in SOP AHETF-8.E.5. The deviation occurred on July 1, 2009, and wa s reported to IIRB on September 2, 2009. On September 3 rd , IIRB acknowledged the deviation and concluded no further action was required. This deviati on raises no ethical issues. I defer to
the EPA science reviewer on whether it raises science issues.

2) The second deviation was that low level field fortifications for the hand wash and face/neck wipes were conducted in duplicate on day 4 instead of in triplicate. The deviation occurred on August 7, 2009, and was reported to IIRB on September 2, 2009. On September 3 rd , IIRB acknowledged thePage 15 of 43 deviation and concluded no further action was required. This deviation raises
no ethical issues. I defer to the EPA science reviewer on whether it raises
science issues.

3) The third deviation was that subject A5 was monitored for 3 hours 8 minutes, contrary to the requirement in Section 7.8 of the prot ocol that subjects apply
for a minimum of 4 hours. The de viation occurred on August 10, 2009, and was reported to IIRB on September 2, 2009. On September 3 rd , IIRB acknowledged the deviation and concl uded no further action was required.
This deviation raises no ethical issues. I defer to the EPA science reviewer on
whether it raises science issues.

4) The fourth deviation was that the fiel d fortifications were done at levels different than those specified in prot ocol. The deviation was discovered upon inspection of the laboratory records, which showed that the laboratory technician preparing the fortification vials and tubes made several dilution
errors that resulted in the field research ers using incorrect fortification levels.
The deviation occurred on June 10 and 11, 2009, and it was reported to IIRB on December 7, 2009. On December 15t h, IIRB acknowledged the deviation and concluded no further action was require d. This deviation raises no ethical
issues. I defer to the EPA science revi ewer on whether it raises science issues.

There was one deviation in the analytical phase of the research that was reported
to IIRB. This deviation rais es no ethical issues, but I defer to the EPA science reviewer on whether the deviation affects the scientific integrity of the data.

4.4.2 Unreported Deviations

There were four unreported deviations during the field phase of AHE58.

1. One subject touched the equipment while not wearing gloves. There is no
record that the observer reminded the work er to wear his gloves or that the observer reported the behavior to the study director, which violated protocol section 2.3.2, SOP AHETF-10.C.4, and SO P AHETF-11.E.1. These protocol and SOP violations were not reported to IIRB. These deviations are discussed in greater detail in sectio ns 8.1 and 10.0 of this review.

2. Protocol section 7.8 states that “a singl e MU will be conducted in this study from each of the five strata” (Vol 7, p. 253). In the conduct of the study, however, two subjects applied amounts fr om the highest stratum (56-100 lbs) and no worker applied from the second stratum (10-17 lbs) (Vol 7, p 43). This deviation was not reported to IIRB. Notwithstanding th e investigator’s failure to report the deviation to IIRB, I conclude that the deviation does not
raise ethics issues. I defer to th e EPA science reviewer on whether the
deviation raises science issues.Page 16 of 43 3. At least one of the five subjects in th is study failed to spray for a minimum of 4 hours, as required in Section 7.8 of the protocol (“Each MU shall consist of a period of at least 4 hours of spraying and at least 3 tank loads of the spray mixture.”) It is not possible to calc ulate spray times from the observer logs for this study. However, the dermal monitoring time for one of the workers was less than four hours, which means that spray time was indeed below 4 hours for this subject. It is possible that other subjects in AHE58 also sprayed
for less than 4 hours. See Table F in Appendix 2 for individual spray times for each subject. Although this protocol deviation should have been reported to IIRB, it raises no ethics issues. I defer to the EPA science reviewer on
whether this deviation ra ises science issues.

4.5 AHE59

4.5.1 Reported Deviations

There were two reported deviations during the field phase of AHE59.

1) Two subjects were monitored on May 7 and May 9, 2009 while applying carbaryl products that we re not on the list of appr oved surrogate products in Section 7.5 of the protocol. The reason for the deviation was that two of the growers would agree to participate only if they could use carbaryl products which were not on the list of approved surrogates in the protocol. When the AHETF learned of the two growers’ pr eferences for these two particular carbaryl products, the Task Force co ntacted EPA and provided copies of Product Risk Statements (PRSs) for the two carbaryl products. EPA reviewed the products and approved th eir addition to the list of possible test substances. The AHETF next submitted the new PRSs to IIRB on April 24, 2009, and IIRB approved the new PRSs on April 29, 2009. However, the AHETF erred in not simultaneously submitting an am endment to add the products to the protocol. The AHETF recognized the error, and submitted an amendment to IIRB on May 11, 2009, which was approved on May 19, 2009. But the amendment approval was granted after tw o subjects were monitored using the two new carbaryl products. This situa tion was reported to IIRB as a deviation on June 16, 2009. IIRB acknowledged the deviation on June 24, 2009 and concluded that no further action is requi red. In EPA’s view, this deviation
does not raise ethics concerns. Before the subjects used these two products, EPA reviewed and approved their use in this study. IIRB had also reviewed and approved PRSs for these products, a nd was aware that these two products may be used in the study. The erro r of not submitting a timely amendment was careless, but it is more of an ad ministrative mistake than a substantive one. Both EPA and IIRB had approved the addition of the two carbaryl products to the list of approved surrogat es, and the error of proceeding before a protocol amendment had been approved does not raise serious ethics issues.Page 17 of 43 2) The second deviation was that resear chers neglected to take photographs of the subjects’ clothing after monitoring. This was a deviation from protocol
Section 12 and SOP AHETF-10.C. This deviation occurred twice, on April 30, 2009, and May 7, 2009, and was reported to IIRB on May 12, 2009. On May 20, 2009, IIRB acknowledged the deviatio n and concluded that subjects
were not at increased risk and that no further action was required. This
deviation does not raise et hics issues. I defer to the EPA science reviewer on
whether the deviation affects the scie ntific integrity of the data.

There was one deviation in the analytical phase of the research that was reported
to IIRB. This deviation rais es no ethical issues, but I defer to the EPA science reviewer on whether the deviation affects the scientific integrity of the data.

4.5.2 Unreported Deviations

There were three unreported deviations during the field phase of AHE59.

1) All four subjects had instances of touc hing the cab door, equipment, or other treated surfaces while not wearing gloves. There is no record that the
observer reminded the workers to wear their gloves or that the observer reported the behavior to the study direct or, which violated protocol section 2.3.2, SOP AHETF-10.C.4, and SOP AHETF -11.E.1. These protocol and
SOP violations were not re ported to IIRB. These devi ations are discussed in greater detail in sections 8.1 and 10.0 of this review.

2) Protocol section 7.8 states that “a singl e MU will be conducted in this study from each of the five strata” (Vol 9, p. 201). In the conduct of the study, however, two subjects applied amounts from the second stratum (10-17 lbs) and no worker applied from the third stratum (18-30 lbs) (Vol 9, p 37).

3) Three of four subjects in this study fa iled to spray for a minimum of 4 hours, as required in Section 7.8 of the protoc ol (“Each MU shall consist of a period of at least 4 hours of spraying and at leas t 3 tank loads of the spray mixture.”) See Table F in Appendix 2 for indivi dual spray times for each subject. Although this protocol deviation should have been reported to IIRB, it raises
no ethics issues. I defer to the EP A science reviewer on whether this
deviation raises science issues.Page 18 of 43 Table 2. Summary of Protocol Amendments and Deviations
Deviations Study

ID Amendments Field Phase Analytical Phase

Reported:
1. On two occasions, subjects were selected randomly using a coin flip rather than drawing names as required in protocol. AHE55 1. Amended once to incorporate comments
from EPA and HSRB.

Study report indicates that the protocol was amended 3 times prior to execution of the field phase, however it did not summarize these changes. Unreported:
1. Rather than growers being reimbursed for the pesticide as required by section 2.4 of the protocol, the Local Site Coordinator purchased the product and delivered it to the application sites
2. The witness for the consent process for a non-reader was selected by the prospective subject, contrary to the protocol requirement
that the witness should have no association with the grower or worker.
3. One subject touched th e cab door while not wearing gloves, and later opened the cab door
with bare hands. There is no record that the
observer reminded the worker to wear his gloves or that the observer reported the behavior to the study director, contrary to theprotocol (section 2.3.2) and SOP AHETF10.C.4.
4. Four of five subj ects did not achieve protocol-required 4-hour minimum spray
time. None reported

AHE56
1. Amended once to incorporate comments
from EPA and HSRB.

Study report indicates that the protocol was amended two times prior to execution of the field phase, however it did not summarize these changes. Reported : 1. The original list of eligible growers was exhausted before successfully recruiting enough subjects. Two growers ultimately monitored as subjects were referred to the AHETF by other growers, and did not appear on the eligible grower list. This was a deviation because the protocol did not provide for recruitmen t beyond the eligible growers list.
2. Informed consent form signed by one subject after donning inner dos imeter garment.
3. Travel fortification samples were not prepared until monitoring day 4.
4. One subject took a ba throom break without first washing his hands and having a handwash sample taken.
5. Air flow rotometer measurements taken after removal of sampling gear from workers.

Unreported:1. None of the 5 subjects achieved the protocolrequired 4-hour minimum spray time. 1. OVS sampling tubes
Set 2 was above 15% criteria (reported22.02%) for backcalculation value at 5.0 ng/mL standard.
2. Travel spikes analyzed inadvertently.
3. For Set 2a OVS samples, 3.0 mL aliquot was used
instead of 4.0 mL (deviation reported in IIRB correspondence [Volume 4], but not within Appendix B of AHE56 study report [Volume 3]).Page 19 of 43 Table 2. Summary of Protocol Amendments and Deviations
Deviations Study

ID Amendments Field Phase Analytical Phase

Reported : 1. One subject applied 10.68 lbs (1.68 lbs above stratum 5-9 lbs); was monitored for 2 hours (the protocol prescribes a minimum of 4 hours of application tim e); and applied only 2 tank loads (the protocol prescribes a minimum of 3 tank loads). AHE57 1. Amended once to incorporate comments
from EPA and HSRB.
2. Amended purity analysis section of the protocol (section 7.5.3). Unreported : 1. Protocol section 7.8 st ates that “a single MU will be conducted in this study from each of the five strata” (Vol 5, p. 152). In the conduct of the study, however, two subjects applied amounts from the second stratum (10-17 lbs) and no worker applied from the lowest stratum (5-9 lbs) (Vol 5, p 31).
2. None of the 5 subjects achieved the protocolrequired 4-hour minimum spray time. 1. Inner dosimeter controls and LOQ concurrent recovery samples were diluted
to 5 mL while field samples were diluted
to 10 mL.
2. Protocol lists method
titles not used.
3. Aliquot deviation in
Method ARTF-0001 for 2-piece cotton
inner dosimeters.
4. Back-calculated
calibration standard
values for the 0.001 ug/mL OVS sample and the 0.005 ug/mL face/neck wipe
standard deviated
from the theoretical value by > 20%.

1. Amended once to incorporate comments from EPA, California Department of Pesticide Regulation,
and HSRB.
2. • 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. AHE58

3. Added a new malathion product to possible test products (the active ingredient
malathion was already an approved surrogate) Reported : 1. On study day 2, inner dosimeters were inadvertently not folded over after field
fortifications were c onducted and prior to covering with cloth as specified in SOP
AHETF-8.E.5.
2. Low level field fortifications conducted in duplicate on day 4, instead of triplicate.
3. One subject was monitored for only 3 hours 8 minutes (protocol prescribes a minimum of 4 hours of application time).
4. Field fortifications were done at (known)
levels different than those specified in protocol.

Unreported : 1. One subject touched contaminated equipment while not wearing gloves. There is no record
that the observer reminded the worker to wear his gloves or that the observer reported the behavior to the study director, contrary tothe protocol (section 2.3.2) and SOP AHETF10.C.4.
2. Protocol section 7.8 states that “a single MU will be conducted in this study from each of the five strata” (Vol 7, p. 253). In the conduct of the study, however, two subjects applied amounts from th e highest stratum (56-100 lbs) and no worker applied from the second stratum (10-17 lbs) (Vol 7, p 43).
3. At least 1 of the 5 subjects did not achieve the protocol-required 4-hour minimum spray
time. 1. Concentrations of
some field
fortification
solutions corrected
for volume based on density, not gravimetrically, resulting in incorrect
field fortification
concentrations.Page 20 of 43 Table 2. Summary of Protocol Amendments and Deviations
Deviations Study

ID Amendments Field Phase Analytical Phase Reported : 1. Two subjects were m onitored using carbaryl products before those products were formally approved by IIRB for use in the research.
2. Post-monitoring photographs of worker clothing were inadve rtently not taken. AHE59 1. Amended once to incorporate comments
from EPA and HSRB.
2. Two carbaryl products were added to possible
test substances Unreported : 1. Each of the four subjects contacted a
contaminated surface at least one time while not wearing gloves. There is no record that
the observer reminded the worker to wear his gloves or that the observer reported the behavior to the study director, which violatedthe protocol (section 2.3.2) and SOP AHETF10.C.4.
2. Protocol section 7.8 states that “a single MU will be conducted in this study from each of the five strata” (Vol 9, p. 201). In the conduct of the study, however, two subjects applied amounts from the second stratum (10-17 lbs) and no worker applied from the third stratum (18-30 lbs) (Vol 9, p 37). 3. Only 1 out of 4 subjects achieved the protocol-required 4-hour minimum spray
time. 1. Curve standard off by 25.89% more
than 15% criteria – (deviation reported in IIRB Corresp. Report (Vol 10) but
not detailed in Appendix B of study report (Vol 9)

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 generally followed in all five studies. In all studies, an initial grower universe list was generated from published lists or databases. Duplicate entries were suppr essed and, for AHE55 and AHE56, growers not having sufficient acreage were removed, to pr oduce the master grower list. For AHE55,
the initial list was so large (1,381 names), even afte r suppression of duplicates and growers with less than 10 acres, that the ma ster grower list was a randomly generated subsample of 425 contacts. After protoc ols were finalized and signed by the study director, qualifying calls were pl aced to the names on the master grower list, and the lists were narrowed by eliminating names based on responses to qualifying questions, being unreachable, or lack of interest in particip ating in the research. The resulting lists contained names of growers who were qualifie d and interested in participating in the research. For the final stage of recruiting, th e study director contac ted and/or visited all qualified growers, to identify growers who could participate in a timeframe and schedule to allow the study to be conducted efficiently. Table 2 in each of the Study Reports (Vol 1, p. 31; Vol 3, p. 31; Vol 5, p. 28; Vol 7, p. 39; Vol 9, p. 33) details the number of growers/workers in each stage of the recruitment process.

There was a reported deviation in recru iting for AHE56, when a tropical storm struck the day before monitoring was schedul ed to begin. The storm necessitated the cancellation of the field work for several days . When the research was ready to proceedPage 21 of 43 the following week, three of the six growers were either no longer wi lling to participate
or unable to be rescheduled within the n ecessary timeframe to efficiently conduct the
research. In order to find the additional two needed growers, th e AHETF contacted two growers who had been referred to them by ot her growers on the master grower list, and those two growers ultimately participated in th e research. This devi ation is discussed in more detail on page 11 of this review.

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/applicators 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 regi on. For AHE55, AHE56, and AHE57, all of the area experts that responded to the surv ey (4/4 for AHE55; 4/4 for AHE56, 5/5 for AHE57) agreed that study participants were typical of growers/applicators in the areas where the study was performed. For AHE58, fo ur of five area experts agreed the growers/applicators were typical, and one stated that she was not familiar enough to provide an opinion. In AHE59, three of four area experts that responded to the survey opined that the growers/applicators were typical, whereas one responded that the monitored growers were not representative because their average farm size was below average and they did not use newer spray te chnologies that apply at lower gallons per

acre.

6.0 Consent Process

The consent process outlined in the prot ocols and SOPs was closely followed in all studies. The only deviations related to the consent were in AHE55, where the witness for a non-reading subject was selected by the subject, contrary to the protocol requirement that the subject be unknown to the subject, and in AHE56, where one subject donned the inner dosimeter after giving verbal consent but before signing the consent form, although he signed the form shortly thereaf ter. The two deviations are discussed in
detail in Sections 4.1.2 and 4.2.1 of this review.

7.0 Subject Demographics

Demographic information on the monitored subjects is summarized in Table 3
below.

7.1 Years of Experience

In AHE55, one worker listed his age as 20 years old, but self-re ported that he had 10 years of experience (Vol 1, p. 32). Likewi se, in AHE57, one subject listed her age as 21 years old, but self-reported that she had 6 years of experi ence. The unexpectedly largePage 22 of 43 number of years of experience compared w ith the reported ages of these two subjects raises questions about the accuracy of these subjects’ reporting of their age and/or years of experience.

7.2 Health Status

Prospective subjects were asked about their health status during the consent process, based on the procedures de scribed in SOP AHETF 11.C.0/11.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 health with no medication conditions that could impact thei r ability to participat e in the study” in order to be eligible to participate (protocol section 2.1).

7.3 Pregnancy Testing

There was one female subject in AHE57; there were no female subjects in the other studies. Supplement 1 (email from D. Johnson to J. Evans and K. Sherman) confirms that the female subject took a pregna ncy test, the test show ed that she was not pregnant, and she stated that she was not nursing.

Table 3: Subject Characteristics Number of Subjects
AHE55 AHE56 AHE57 AHE58 AHE59
Males 5 5 4 5 4
Females 0 0 1 0 0 Preferred consent process in English 4 Not reported 5 3 4

Preferred consent process in Spanish 1 Not reported 0 2 0

Self-identified as non-reader
and used witness 1 (in English) 0 0 0 0

Employment Farm Employee 5 0 2 3 3

Farm Owner 0 4 3 0 1 Commercial Applicator 0 1 0 2 0 Years of Experience 3-48 7-44 6-50 7-28 5-40 Age Range 20-70 43-68 21-58 27-49 26-62 Requested Results 5 5 5 4 4
Withdrew 0 0 0 0 0 Removed from participation by AHETF 0 0 0 0 0Page 23 of 43 8.0 Monitoring

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

8.1 Instances of Failure to Wear Gloves

In AHE55, AHE58, and AHE59, the field not es report instances in which a subject, who was outside of his enclosed cab, contacted surfaces contaminated with pesticide residues while not wear ing chemical-resistant gloves.

Below in Table 4 are the log entries, pr epared by the study observers in each of the studies, documenting the observations of instances in which a subject contacted a contaminated surface while not wearing gloves.

Table 4. Observations Noting In stances of Failure to Wear Gloves

Study ID MU
ID Log
Time Observation

11:44 “...exits cab without gloves...shuts the door...contacting the side edge.” AHE55 A3 12:14 “...opens doo r with bare hands...”
AHE58 A5 08:14 “Turned off water near tank with bare hand...” A1 08:58 “Climbed back into cab, opened door with bare hands.”

A2 Gen.
obs. “Door opened with bare hand.”

A3 09:56 “Opened truck door with bare hands...” 11:02 “...exited cab and with bare hands picked up a marker from ground...” 13:20 “Exited cab, walked back to sprayer and with bare hands, turned lever...” 14:32 “Walked to front of spray tank and with bare hand turned lever...” AHE59

A4 15:49 “...walked back to sp r ayer and with bare hands, turned off a couple

n ozzles...”

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. . . .Page 24 of 43 In addition, §12(a)(2)(P) of the Federal In secticide, Fungicide and Rodenticide Act (FIFRA) applies. This 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 4 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. There was one female subject; she tested negative for pregnancy and c onfirmed that she was not nursing. The prohibition in 40 CFR §26.1703 of research involv ing 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. This research would not comply with Subpart L if any of the subjects was a child, or a pregnant or nursing woman. The study reports document compliance with subpart L.

10.3.1 Subjects not wearing gloves when contacting treated
surfaces

Based on the study report, I find that th e AHETF violated th e protocol by not ensuring that all study participants wore label-specified PPE when they contacted surfaces contaminated with pe sticide residues. As summarized in Table 4, the log for AHE55 reports that there was one subject (A3), who exited and contacted contaminated surfaces twice. The log for AHE58 reports that there was one subject who exited and
contacted a contaminated surface one time. The log for AHE59 reports that there were three subjects, each of whom exited and cont acted a contaminated surface one time, asPage 25 of 43 well as one subject (A4), who exited and contac ted contaminated surfaces at least four
times. 2

In addition to the failure to enforce the use of PPE, as required by section 2.3.2 of the protocol, there is no docum entation indicating that the ob server(s) notified the study director, principal field inves tigator, or quality assurance un it of any of these occurrences as required by section 6.12 of SOP AHETF-10.C.4. Fina lly, the study reports do not indicate that any of these subjects we re reminded by the observer of the gloves requirement. The failure to warn the subj ects would also violate SOP AHETF-11.E.1 if deemed a “safety issue.”

As noted above, section 2.3.2 of the study protocols provides that the AHETF will “enforc[e] the use of label-specified PPE (esp ecially the use of glove s outside the cab if contacting contaminated surfaces) during partic ipation.” Two of the SOPs also contain language relevant to this situ ation. SOP AHETF-10.C.4 states:

Section 6.12: “Observers shoul d contact the Study Direct or, PFI or QAU if they observe any activity contrary to th e study design, label requirements, or dangerous activities undertaken by the work er. Based on the event, the SD has the
discretion to terminate the MU.”

AHETF-11.E.1 states:

Section 3.3: “During the study conduct, re searchers will ensure compliance with safety requirements on the product label a nd with the Worker Protection Standard (WPS). For example, workers will be remi nded to use the label specified PPE and
to follow use directions on the label

“a. Each worker will be observed by a researcher during the entire monitoring period unless the work er travels out of sight of the observer ( e.g. , aerial application, driving beyond view in a field).

2 In examining the records, EPA has determined that none of the subjects violated either the labeling of the pesticides or EPA’s Worker Protection Standard (WPS). The WPS states at 40 CFR 170.240(d)(5)(iv):

“persons occupying an enclosed cab shall have all labeling-specified personal protective equipment immediately available and stored in a ch emical-resistant container, such as a plastic bag. They shall wear such personal protective equipment if it is necessary to exit the cab and contact pesticide-treated surfaces in the treated area. Once personal protective equipment is worn in the treated area, it must be removed before reentering the cab.”

The WPS requires gloves when contacting “pesticide-tr eated surfaces,” whereas the protocol refers to “enforcing the use of label-specified PPE (especially the use of gloves outside the cab if contacting contaminated surfaces) during particip ation.” In EPA’s view, all of th e surfaces contacted by subjects not wearing gloves (summarized in Table 4) were “cont aminated” with pesticide residues, but, for WPS compliance purposes, were no t “pesticide-treated surfaces.”Page 26 of 43 “b. Worker observers will not advise workers on how to perform their work unless a safety issue is involv ed. If the observer advises a worker about a safety issue and the worker does not comply, the observer will then immediately notify the Study Di rector and ask the worker to cease any activity.”

In sum, the behavior of the research team related to the instances of subjects not wearing gloves violates section 2.3.2 ofthe protocol, section 6.12 of SOP AHETF10.C.4, and possibly section 3.3 of SOP AHETF-11.E.1. Specifically:

1) The use of “label-specified PPE (especi ally the use of gloves outside the cab if contacting contaminated surfaces)” was not enforced, as required in section 2.3.2 of the protocols.

2) There is no documentation indicating that the observer(s) notified the study director, principal field i nvestigator, or quality assu rance officer of the label violations, as required by s ection 6.12 of SOP AHETF-10.C.4.

3) There is no documentation indicating how observers determined whether they needed to advise the non-glove-wearing wo rkers to wear their gloves, as required by section 3.3 of SOP AHETF-11.E.1.

These protocol and SOP violations are devi ations that should have been immediately reported to IIRB. The AHETF di d not report these deviations.

10.3.2 Considerations regarding the compliance of AHE55, AHE58, and AHE59 with Subparts A through L

This section addresses additional considerations that I regard as relevant to making a decision about whether, in light of the deviati ons discussed in Section 8.1 related to glove usage, the reported resear ch was “conducted in substantial compliance with subparts A through L” of 40 CFR part 26. See 40 CFR 26.1705.

The ethical duty to warn arising from the principle of beneficence . There is a recognized ethical obligation on researchers to intervene when they become aware of behavior of a participant in human research that endangers the safety of the subject. Under the prevailing understanding of the et hical principles gove rning the conduct of human research, a researcher has a duty to warn subjects and/or intervene when the subjects engage in behavior potentially dangero us to themselves. This duty arises from the principle of beneficence from the Belmont Report, which obligates the researcher to secure the well-being of all rese arch participants and protect participants from harm while the research is being conducted. The safety of the subjects must be prioritized above the desire to gather data. In making my determ ination about the ethica l acceptability of the reported research, I consider ed the following factors.Page 27 of 43 Intent of the investigators. There is no evidence to indicate that the investigators intended to place the participants at risk. In fact, all of the available information indicates the opposite, that the investigators were conc erned about and took step s to reduce risks to the participants. These incl ude their overall responsiven ess to EPA’s and the HSRB’s comments and the concrete steps they took to minimize risks to subjects including:

• Selecting only experienced pesticide handlers

• Requiring experience operating the equipment to be used

• Reminding workers of safe chemical handling practices

• Identifying nearby hospitalization fa cilities in case of emergency

• Monitoring the heat index and stopping the study if conditions warrant

• Providing transportation to medical tr eatment and covering the costs of

• Treatment, if needed

• Having a medical professional on site to observe the workers and, if needed, to provide urgent care

• Observing study participants th roughout the monitoring period

• Ensuring that all tank mix products were us ed according to approved label (s) and did not require any additional PPE.

The extent to which the ethical deficien cy jeopardized (or could have jeopardized) the subjects’ safety. By not intervening during th e study, the inves tigators allowed certain subjects to continue to engage in be haviors that increased their exposure and thus their risk. There was some variety in both the kind of conduct and the frequency of the conduct that observers reporte d. For four of the workers (one in AHE55; three in AHE58), the behavior involved only a very br ief contact with a contaminated surface (e.g. removing gloves before rather than afte r entering the closed-cab, or touching the door handle while not wearing gl oves) and likely did not meas urably increase exposure. In other instances, the behavior was of a na ture that the subject was likely getting a measurable increased increment of exposure to his hands (i.e., subject A4 in AHE59 who was not wearing gloves while contacting it ems on the ground [milk carton, rock]) that were likely contaminated with freshly app lied residues). Four workers only had one instance each where they were observed cont acting a treated surface without gloves, one worker had two instances, and one worker had at four. None of the subjects’ actions were atypical of the behavior that EPA would expe ct pesticide applicators to exhibit. The gradations of vi olations and the likely impact of the violations on the levels of exposure make it difficult for an observer to determine which, if any, of the behaviors would have risen to a point triggering the duty to intervene. It is worth noting that none of the subjects reported any discomfort or symptoms of illness. Further, although it could not have been known at the time, EPA analysis of the levels of exposure received by the individual subjects showed th at all of them had acceptably safe levels of exposure.

The extent to which the investigators kn ew or should have known how they should have responded. As discussed above, observers not ed a variety of actions that ranged from very brief contacts with contaminated surfaces to more serious and repeated
instances of contact with contaminated surf aces. While the applicable sections of the SOPs describe a general oblig ation to ensure study subjec ts follow applicable safety requirements and otherwise ensure they avoi d dangerous practices, the directions lackPage 28 of 43 specificity with respect to wh at kinds of behavior raises a “safety issue” triggering the requirement to provide a warning and/or halt the research. The researchers could quite reasonably have thought that th ey had and should exercise judgment about whether and how to address instances of subject noncomp liance. Certainly, until now, neither EPA nor the HSRB has focused on the application of the protocol and SOPs to the kinds of
situations described in this report.

10.3.3 Conclusion regarding the compliance of AHE55, AHE58, and AHE59 with Subpart K

I have determined that the researchers fa iled to follow the protocol and the SOPs in several different ways and on multiple inst ances, as discussed above. I identified a number of unreported deviations which were of a minor or technical nature. This reflects a lack of thoroughness on the part of the AH ETF in comparing the actual conduct of the research with the requirements of the protocol. In the future, EPA will expect the AHETF to examine field reports for possible de viations and to report them promptly to the supervising IRB. Apart from the glove s deviations discussed in Section 10.3.1 above, I identified no other noteworthy de ficiencies in the ethical conduc t of these five studies. The protocols were faithfully executed, pr operly amended when necessary, and only one amendment was not approved by the overseeing IRB before it was implemented. The reported and unreported deviations are of the nature to be expected in complicated field research of this kind, and did not affect th e welfare or safety of the subjects, or compromise their informed and voluntary consent.

Of the unreported deviations, I am most concerned that the observer(s) did not ensure that the subjects wo re their gloves as required by the protocol, and that the
observers did not alert the st udy director about these incidents and appear not to have advised the subjects to wear gloves. These violations resu lted in some, generally minor increased exposure and increased risk for the subjects. In addition, the protocol and SOP deviations should have been promptly reporte d to IIRB. Failure to report deviations prevents the IRB from exercising oversight and making recommendations for corrective action. It is my view, however , that despite these violations , the research substantially complied with the applicable regulations.

With respect to evaluating the failure to ensure that subjects wore gloves against the requirements of subpart K, I find that the researchers’ violation consisted of a failure to report the deviations from the protocol pursu ant to the rules of IIRB. While this failure to report is not strictly a violation of the regulations, it is inconsistent with the intended protections of the rule (See 40 CFR 26.1108). As discussed above, I do not think the failure to report the deviations placed the subjects at significan t risk. Further, there is no evidence of any attempt by the researchers to evade IRB review and oversight, and the researchers have a long and cons istent history of instituti ng corrective actions when EPA
and the HSRB identifies ethical deficiencies . Consequently, I think that there is
sufficient information to conc lude the researchers’ conduct with respect to subjects’ failure to wear gloves substant ially complied with subpart K.Page 29 of 43 With respect to whether the research wa s deficient under the more general ethical duty to warn or otherwise interv ene to protect the safety of study participants, I note that neither EPA nor the HSRB has provided th e researchers with guidance on their responsibilities under this ethical principle. Fu rther, in assessing thei r actions, I note that the subjects’ behavior was not plainly dangerous . In most cases, a subject failed to wear gloves only on a single occasion. While a warn ing might have helped to protect these subjects from additional higher exposure, the degree of increased exposure actually experienced by these subjects was quite minor . As for subject A4 in study AHE59, the subject who repeatedly failed to wear his gl oves, I think it would have been reasonable
for the research team also to conclude the subject’s actions, although concerning, were not so dangerous that they required special wa rnings or intervention, such as termination of his participation in the study. This a pplicator’s actions di d not involve prolonged contact with pesticide treated surfaces and ar e not atypical of the be havior of at least some pesticide applicators. Certainly, there was no indication that a ny of the participants experienced any physical distress during the research. Finally, EPA’s post hoc risk assessment, finding an acceptable level of exposure for all study subjects, supports the reasonableness of a judgment that the behavi or of subjects, incl uding A4, was not overly risky. In sum, in view of the researchers’ likely understanding of their ethical duties and
a reasonable view of the da ngers posed by the subjects’ be havior, I cannot find that the researchers violated the principle of beneficence in this study.

Taking into account the overall care with which the research was defined and conducted, these deficiencies noted in the c onduct and documentation of the research fall
far below the level of substa ntial non-compliance with s ubparts A through L of 40 CFR part 26. I conclude that 40 CFR §26.1705 does not prohibit EPA reliance on this study.

10.4 Compliance with 40 CFR §26 subpart M

As is documented in Attachment 3 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 isPage 30 of 43 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-E) Attachment 2: Time Spent Spraying (Table F) Attachment 3: §26.1303 completeness checks Attachment 4: Responsiveness to EPA and HSRB Comments on protocols (Tables G, H)Attachment 1 Ethics-Related Study Chronologies

Page 31 of 43 Table A: AHE55
Date 06/24-25/08 HSRB reviewed protocol and approved with recommendations 07/11/08 Phase 1 recruiting (creation of grower list). 7/11/08 to 9/2/08 07/18/08 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following June 2008 HSRB meeting) 07/21/08 IIRB approves revised documents 07/28/08 Protocol finalized and signed by Study Director 09/03/08 Phase 2 recruiting (calls to grower list). 9/3/08 to 10/7/08 10/08/08 Phase 3 recruiting (site visits and participant selection) - 10/8/08 to
10/26/08
10/27/08-
10/31/08 Five subjects monitored 10/27/08 – 10/31/08

11/16/08 Protocol Deviation 1 reported to IIRB [see Volume 2, pp. 21-220]

• Deviation occurred 10/28/08, 10/30/08

• On two occasions, subjects were selected by flipping a co in to select a worker to participate from among two possible workers, rather than by drawing names from a container as described in the protocol
11/17/08 IIRB concludes Protocol De viation 1 did not place subjects at increased risk; no further action required 03/02/09 Annual progress report submitted to IIRB 03/03/09 IIRB approves ongoing research; extends approval of research from 3/3/09 to 3/2/10 02/04/10 Close out report submitted to IIRB 02/04/10 IIRB accepts Study Completion Report; study considered closedAttachment 1 Ethics-Related Study Chronologies

Page 32 of 43 Table B: AHE56
Date 06/24-25/08 HSRB reviewed protocol and approved with recommendations 07/11/08 Phase 1 recruiting (creation of grower list). 7/11/08 to 7/24/08 07/18/08 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following June 2008 HSRB meeting) 07/21/08 IIRB approves revised documents 07/24/08 Protocol finalized and signed by Study Director 07/24/08 Phase 2 recruiting (calls to grower list). 7/24/08 to 9/04/08 08/08/08 Phase 3 recruiting (site visits and participant selection) - 8/8/08 to
8/23/08 8/25/08 Five subjects monitored 08/25/08 – 08/28/08 09/05/08 Protocol Deviation 1 reported to IIRB [see Volume 4, pp. 227-231]

• Two growers whose names did not appear on the list of eligible growers were referred to investigators. The two referred subj ects volunteered, were selected, and were monitored as subjects.
09/15/08 IIRB concludes Protocol De viation 1 did not place subjects at increased risk; no further action required 09/17/08 Protocol Deviations 2, 3 reported to IIRB [see Volume 4, pp. 232-238]

• Deviation 2 occurred on 8/18/10

- One subject was dressed in his inner do simeter before signing his informed
consent form

• Deviation 3 (three different deviations) occurred between 8/18/10 and 8/21/10

- Deviation : Travel fortification samples were not prepared until monitoring day 4.

- Deviation : During monitoring, a subject stepped away from the tractor to relieve himself behind a tree while the spray tank wa s being re-filled. He was out of sight
of the observer at the time. After th e deviation was recognized, the observer reminded the worker that he should follow label user safety recommendations, “users should was hands before...using the toilet.” This was also a deviation from AHETF SOP 8.B.4, section 5.2, which requires hand samples to be collected prior to workers using the restroom.

- Deviation : Air flow rotometer measurements were taken after removal of sampling gear from workers; this is a deviation from AHETF SOP 8.D.2, section 4.11.
09/23/08 IIRB concludes Protocol Devi ations 2, 3 did not place subjects at increased risk; no further action required 01/02/09 Analytical phase deviations reported (dated 12/16/10) reported to IIRB [see Volume 4, pp. 239-244]

• Deviation : The back-calculation value for the second lowest standard at 5.0 ng/mL was +22.02%, which does not meet the ±15% acceptance criteria in Protocol AHE56,
Section 15.3.

• Deviation : The two travel spikes were analyzed along with the other field spikes. This deviates from Protocol AHE56, Section 11.1 where it states the travel spikes are only analyzed if deemed necessa ry by the Study Director.

• Deviation : For analysis of carbaryl in OVS air sampling tubes, Set 2a, a 3.0 mL aliquot was process through the method rather than a 4.0 mL aliquot, which then required a 0.6 mL (instead of 0.8 mL) final volume for HPLC analysis. This was a deviation from AHETF Analytical Method ARTF-AM-013, Revision #1. 01/07/09 IIRB concludes no further action required on protocol and method deviations dated 12/16/08 and reported on 1/02/09 03/03/09 Annual progress report submitted to IIRB 03/10/09 IIRB approval of ongoing research 02/15/10 Close out report submitted to IIRB 02/19/10 IIRB accepts Study Completion Report; study considered closedAttachment 1 Ethics-Related Study Chronologies

Page 33 of 43 Table C: AHE57
Date 10/21-22/08 HSRB reviewed protocol and approved with recommendations 01/16/09 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following June 2008 HSRB meeting) 01/19/09 IIRB approves revised documents 1/23/09 Protocol finalized and signed by Study Director 01/26/09 Phase 1 recruiting (creation of Master Grower List and Qualified Grower List). 1/26/09 to
3/5/09 02/17/09 Phase 2 recruiting (calls to grower list). 2/17/09 to 4/2/09 4/02/09 Phase 3 recruiting (site visits and participant selection) – 4/2/09 to
5/22/09 5/15/09 Subjects monitored 5/15/09 to 5/22/09 6/4/09 Protocol Deviation 1 reported to IIRB [see Volume 6, pp. 105, 106, 110, 111]

• Deviation occurred 5/22/09

• The subject assigned to Stratum 1 (5.0 lbs a.i. to 9.0 lbs a.i.) sprayed 10.68 lbs a.i.,
which exceeded the stratum limit of 9.0 lbs a.i. In addition, this subject applied only 2 tank loads for a period of 2 hours, whereas section 7.8 of the protocol states that each subject shall spray at least 3 tank loads of spray mixture over a period of at least
4 hours. 6/7/09 AHETF submits to IIRB an Amendment to the purity analysis section of the protocol (Section 7.5.3) [see Volume 6, pp. 107-109, 170-172]

• This Amendment was emailed to IIRB on 6/7/09, but it was not immediately acknowledged by IIRB

• In September 2010, after the study was cl osed, AHETF requested copies of IIRB’s records on the Amendment, an d was informed at that time that IIRB did not have a
record of the Amendment.

• On 9/14/10, IIRB acknowledged receipt of the Amendment after study closure, and noted that the change was “administrative in nature, did not affect subject safety, and
would not have received a revision to the consent form.” 6/10/09 IIRB concludes no further action required on Protocol Deviation 1 7/15/09 IIRB provides notification of risk of study closure 7/16/09 Progress report submitted to IIRB 8/04/09 IIRB approves ongoing research; extends approval of research from 8/04/09 to 8/03/10 7/07/10 Problems in Research Report submitted to IIRB for review [see Volume 6, pp. 134-141, 144-145]

• Reports four deviations from analytic procedures methodologies that occurred on 2/25/10, 3/1/10, 3/4/10, and 4/9/10. 7/08/10 IIRB notifies AHETF of risk of study closure 7/13/09 IIRB concludes no further action required on the four analytical protocol deviations reported on 7/7/09 07/21/10 Close out report submitted to IIRB 07/23/10 IIRB accepts Study Completion Report; study considered closedAttachment 1 Ethics-Related Study Chronologies

Page 34 of 43 Table D: AHE58
Date 10/21-22/08 HSRB reviewed protocol and approved with recommendations 03/26/09 Submitted changes to protocol, consent form, California Bill of Rights , recruitment flyer, and product risk statements (following June 2008 HSRB meeting) 04/01/09 IIRB approves revised recruitment flyer 4/06/09 IIRB approves revised informed consent document, California Bill of Rights, and product
risk statements 4/20/09 Protocol finalized and signed by Study Director 04/21/09 Phase 1 recruiting (creation of Master Grower List and Qualified Grower List). 4/21/09-
7/27/09 05/12/09 Phase 2 recruiting (calls to qualified growers). 5/12/09 to 8/14/09 6/01/09 Phase 3 recruiting (site visits and participant selection). 6/01/09 to
8/09/09
6/19/09 Amendment 1 submitted to IIRB

• Amend inclusion criteria to allow particip ation of workers who normally wear two layers of clothing

• Amend protocol to allow recruitment in any county in California or Washington

• Remove the efficient configuration require ment if recruitment area is expanded 6/23/09 Amendment 1 approved by IIRB 6/26/09 Two subjects monitored, 6/26/09 and 7/01/09 7/14/09 IIRB provides notification of risk of study closure 7/16/09 Progress report submitted to IIRB 7/22/09 Amendment 2 (adding one malathion product) submitted to IIRB 7/22/09 Amendment 2 approved by IIRB 07/25/09 Supplemental information for progress report submitted to IIRB 07/28/09 Subject monitored 07/29/10 IIRB approves ongoing research; extends approval of research from 7/28/09 to 7/27/10 08/07/09 Two subjects monitored, 08/07/09 and 08/10/09 9/02/09 Protocol Deviations 1, 2, 3 reported to IIRB (deviations occurred 7/6/2009, 8/11/09, and 8/11/09) [see Volume 8, pp. 307-314]

• Deviation 1: Whole body dosimeter fortification samples not folded before covering

• Deviation 2: Some low level fortifications done in duplicate instead of triplicate on one day

• Deviation 3: Monitoring time for subject A5 was less than 4 hours 9/03/09 IIRB acknowledges Deviations 1, 2, and 3; no further action required 12/7/09 AHETF submits to IIRB Deviation 4 (deviations occurred 6/10/09 and 6/11/09) [see Volume 8, pp. 315-318]

• Some field fortification samples were incorre ctly prepared in the laboratory, so the
fortification levels were not correct. Ho wever, the researchers know the actual amounts fortified, so no field fortification samples are missing. 12/15/09 IIRB acknowledges Deviation 4; concludes no further action required 2/24/10 IIRB provides notification of risk of study closure 02/21/10 Close out report submitted to IIRB 02/25/10 IIRB accepts Study Completion Report; study considered closed 4/19/10 Two deviations reported to IIRB [see Volume 8, pp. 354-357]

• Field phase : Calculations were performed incorrectly in preparation of field fortification samples. The solution was pr epared using volume corrected for density instead of gravimetrically.

• Analytical Phase : Concentrations of some field fortification solutions corrected for volume based on density, not gravimetrically, resulting in incorrect field fortification
concentrations. 4/20/10 IIRB acknowledges two deviations that were reported after study closureAttachment 1 Ethics-Related Study Chronologies

Page 35 of 43 Table E: AHE59
Date 10/21-22/08 HSRB reviewed protocol and approved with recommendations 01/16/09 Submitted documents to IIRB to amend protocol, consent form, and product risk statements (following June 2008 HSRB meeting) 01/19/09 IIRB approves revised documents 1/23/09 Protocol finalized and signed by Study Director 01/26/09 Phase 1 recruiting (creation of Master Grower List and Qualified Grower List). 1/26/09 to
3/5/09 02/06/09 Phase 2 recruiting (calls to grower list). 2/06/09 to 3/28/09 3/30/09 Phase 3 recruiting (site visits and participant selection) – 3/30/09 to
5/30/09
4/30/09-
5/09/09 4 Subjects monitored on 4/30/09, 5/07/09, 5/08/09, 5/09/09

5/11/09 Protocol Amendment 1 and Deviation 1 submitted to IIRB [see Volume 10, pp. 140-152]

• Amendment 1: Adding 2 carbaryl products were added to the protocol

• Deviation 1: No photographs were taken of the subjects after monitoring, in violation
of SOP AHETF-10.C.4 5/19/09 IIRB approves Amendment 1 5/20/09 IIRB acknowledges Deviation 1; concludes no further action necessary
6/16/09 Protocol Deviation 2 submitted to IIRB [see Volume 10, pp. 153-156]

• Deviation was the use by two monitored subjects of carbaryl products not previously approved by IIRB (deviation occurred on 5/07/09 and 5/09/09) 6/24/09 IIRB concludes no further action required on Protocol Deviation 2 7/14/09 IIRB provides notification of risk of study closure 7/16/09 Progress report submitted to IIRB 7/29/09 IIRB approves ongoing research; extends approval of research from 7/28/09 to 7/27/10 02/22/10 Close out report submitted to IIRB 02/25/10 IIRB accepts Study Completion Report; study considered closedAttachment 2

Time Spent Spraying

Page 36 of 43 Table F. Amount of Time Re ported Spraying (in Minutes)

MU ID AHE55 AHE56 AHE57 AHE58* AHE59

A1 192 107 68 [345] 195
A2 78 179 117 [299] 77
A3 208 159 142 [255] 156
A4 178 151 201 [360] 384
A5 331 166 218 [188] --- *AHE58 spray times could not be determined from observati on log. Dermal monitoring times are provided in the column for AHE58, as a substitute for spray time. Spray ti me is shorter than monitoring tim e, so AHE58/A5 clearly did not spray for 4 hours. It is unclear if the othe r MUs in AHE58 sprayed for at least four hours.

Section 7.8 of the protocol stat es that: “Each MU shall consis t of a period of at least 4 hours of spraying and at least 3 tank loads of the spray mixture.”

Table F shows the number of minutes for whic h the subjects operated their sprayers. This time included moving from one application site to another with a tank of spray, but did not include break time or time spent mixing and loading and driving between the application site and the mixi ng/loading station.

Gray shading highlights the subjects who did not operate their sprayers for at least 4 hours, as required in Section 7.8 of the protoc ol. Only two of the 19 subjects for which spray time could be determined had thei r spray equipment on for “at least 4 hours.”Attachment 3

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE55 (MRID 48303503 )

Page 37 of 43 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 informati on should include:

Requirement Y/N Comments/Page References

§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; Approved English CFs: p 259 Approved Spanish CFs:
272 Progress Rpt 223 Close Out Report 287 §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. N All post-HSRB IIRB reviews were under expedited procedures; no minutes were made.

§1115(a)(3): Records of continuing review activities. Y 220, 223, 287
§1115(a)(4): Copies of all correspondence betw een the IRB and the investigators. Y 13-287 §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(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)(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 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§1125(a)A discussion of:

(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 61-214

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Flyers & Ads in English & Span

§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 13-287(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)

§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 163

(c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y 259-268 English 272-281 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 3

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE56 (MRID 48303504)

Page 38 of 43 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 informati on should include:

Requirement Y/N Comments/Page References

§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; Approved English CF:167 Approved Spanish CF: 188 Progress report 246 Close-out report 294

§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. N All post-HSRB IIRB reviews were under expedited procedures; no minutes were made.

§1115(a)(3): Records of continuing review activities. Y Progress report 246
§1115(a)(4): Copies of all correspondence be tween the IRB and the investigators. Y 16-295 §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(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)(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 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§1125(a)A discussion of:

(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 English versions 140 Spanish versions 188 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Approval of Flyers & Ads in English & Spanish 218 §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 16-295(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)

§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 224-225

(c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y 251-259 English No Spanish speakers enrolled (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

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE57 (MRID 48289608)

Page 39 of 43 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 informati on should include:

Requirement Y/N Comments/Page References

§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; English 80, Spanish 90 Progress report 115 Close-out report 147

§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. N 155-164

§1115(a)(3): Records of continuing review activities. Y 105-145
§1115(a)(4): Copies of all correspondence be tween the IRB and the investigators. Y 13-172 §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 157

§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(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)(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 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§1125(a)A discussion of:

(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 Addressed in protocol

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Addressed in protocol

§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 13-172(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)

§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 Approval of all submitted documents 79

(c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y English 120 No Spanish speakers enrolled (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

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE58 (MRID 48289609)

Page 40 of 43 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 informati on should include:

Requirement Y/N Comments/Page References

§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; English 151, Spanish 176 Progress report 242 Close-out report 320

§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. N Some approvals under expedited review, minutes on progress report 300

§1115(a)(3): Records of continuing review activities. Y 301-318
§1115(a)(4): Copies of all correspondence be tween the IRB and the investigators. Y 17-357 §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 302

§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(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)(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 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§1125(a)A discussion of:

(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 Addressed in protocol

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Addressed in protocol

§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 17-357(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)

§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 Approval of all submitted documents 149

(c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y English 257 Spanish 286

(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

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review AHE59 (MRID 48289610)

Page 41 of 43 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 informati on should include:

Requirement Y/N Comments/Page References

§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; English 90, Spanish 77 Progress report 159 Close-out report 193

§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. N 184-188

§1115(a)(3): Records of continuing review activities. Y 140-182
§1115(a)(4): Copies of all correspondence be tween the IRB and the investigators. Y 14-195 §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 189

§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(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)(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 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§1125(a)A discussion of:

(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 Addressed in protocol

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y Addressed in protocol

§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 14-195(b) Copies of all of the records relevant to theinformation identified in §26.1125(a)-(f)

§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 Approval of all submitted documents 74

(c) Copies of sample records used to document informed consent as specified by §26.1117, but not identifying any subjects of the research Y English 164 No Spanish speakers enrolled (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 4 Responsiveness to Major EPA and HSRB Comments

Page 42 of 43 Table G. Responsiveness to Major EPA and HS RB Comments on Protocols for AHE55, AHE56 (reviewed at the June 2008 HSRB Meeting)

EPA or HSRB Comment Addressed before executing AHE55, AHE56? Addressed before executing AHE57, AHE58, AHE59?
1. Characterize subject repr esentativeness Yes, information gathered for
AHE55 and AHE56 Yes, information gathered for AHE57, AHE58, and AHE59
2. Disallow participation by employees of
Local Site Coordinator Yes Yes

3. Use bilingual researchers rather than interpreters Yes Yes

4. Explain how Study Director will determine understanding of subjects in consent interviews conducted in Spanish Yes Yes

5. Provide toll-free English and Spanish
information numbers Yes Yes

6. Capture ethnicity and sex of participating
workers Yes Yes

7. Clarify intended purpose of photos/videos Yes Yes
8. Minimize identifiable photos/videos Yes Yes
9. Refer to “AHETF ” consistently vice “AHETF” and “Sponsor” Yes Yes

10. Drop reference to “cognitively impaired” from recruitment flyer Yes Yes

11. Change “liquid pesticides” to “airblast application of liquid sprays” Yes Yes

12. Minimize paraphrasing of SOPs in protocols No Yes

13. Simplify submissions No Yes
14. Explain voluntary nature of participation at the beginning of consent forms No No, but has been addressed in subsequent protocols
15. Ensure accurate Spanish translations No No, but has been addressed in subsequent protocols
16. Update SOPs to:

• Insure all materials provided to candidates are approved by IRB

• Insure label and MSDS summaries are approved by IRB

• Clarify role of impartial witness to
consent interviews with non-readers

• Replace references to WIRB with generic references

• Account for number of workers
associated with each grower

• Define processes of diversity selection of growers and construction of an efficient configuration of MUs in a
new SOP No Yes

17. Better justify judgments of infeasibility of incorporating additional elements of
random selection No No, but has been addressed in subsequent protocols

18. Considering restriction to monitoring no more than one worker per employer Only 1 worker monitored per employer. Restriction added in subsequent protocols. Only 1 worker monitored per employer. Restriction added in subsequent protocols.Attachment 4 Responsiveness to Major EPA and HSRB Comments

Page 43 of 43 Table H. Responsiveness to Major EPA and HSRB Comments on Protocols for AHE57, AHE58, AHE59 (reviewed at the October 2008 HSRB Meeting)

EPA or HSRB Comment Addressed before executing AHE57, AHE58, AHE59? Addressed in subsequent AHETF protocols?
1. Characterize representativeness of subjects Yes 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. Yes

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 Yes

3. The Local Site Coordinator, the 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 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. Yes.

5. Revise subject recruitment plan to specifically address the probability that subjects may also be growers. No Yes; relevant SOP revised

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

7. Identify risks of pesticide products that are due to scripting. Yes Yes