Page **1** of **22**

April 1 1 , 2012
EP A

- HSRB

- 12

- 01 Lek Kadeli, Acting Assistant Administrator Of fice of Research and Development U.S. Environmental Protection Agency 1200 Pennsy lvania Av enue, NW Wa shington, DC 20460 Subject: January

26, 2012 EP

A Human Studies Review Board Meeting Report
Dear Mr. Kadeli, The United States Environmental Protection Agency (EP A or Agency) requested that the Human Studies Review Board (HSRB) provide scientific and ethics reviews of one new protocol for a stud y involving intentional exposure o f human subjects to pesticides: a proposed Agricultural Handler Exposure T ask Force, LLC (AHETF) scenario measuring dermal and inhalation exposure of workers who perform mixing, loading and application of pesticides using powered (gasoline or electric) han dgun/hand wand equipment in greenhouses and nurseries (AHE

- 600). The Agency

also requested that the HSRB review a completed stud y of dermal and inhalation exposure of professional janitorial workers who clean indoor surfaces with an antimicrobial pestici de product using hand

- held pressurized aerosol canisters , conducted b y the Antimicrobial Exposure Assessment T ask Force II (AEA

TF II). This study

(AEA

- 04) was conducted after publication of the EP A’ s expanded final rule for protection of subjects in human research. The data will be posted to the Biocide Handlers Exposure Database (BHED ® ), and used generically

to estimate daily

dermal and inhalation exposures of those who wipe indoor surfaces with antimicrobial pesticides. The enclosed report provides the Board’ s response to EP A charge questions presented at the January

26, 2012 meeting. **Assessment of Proposed AHETF Research Study AHE**
**- 600:**  **Mixing, Loading, and Applying Liquid Pesticides in Managed**  **Horticultural Facilities Using Powered Handgun Equipment .**  Science

• The Board concluded that the protocol submitted for review, if modified in accordance with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to generate high quality , reliable and useful data for assessing worker’s pesticide exposures in horticultural settings.

• The Board provided several additional comments or suggestions with respect to the use of personal protective equipment (PPE), the potential effect of unanticipated incidentalPage **2** of **22**

exposures and other variables on proport ionality , and the utility of existing European Crop Protection Association (ECP A) data. Ethics

• The Board concluded that the protocol submitted for review, if modified in accordance with EPA and HSRB recommendations, is likely to meet the applicable requi rements of 40 CFR 26, subparts K and L. **Assessment of Completed AEATF II Research Study AEA**
**- 04:**  **Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide**  **Product Using a Pressurized Aerosol Can for Indo or Surface Disinfecting**  **.** Science

• The Board concurred with the Agency ’s assessment that this study provides scientifically valid results for estimating the dermal and inhalation exposure of those who apply liquid antimicrobial pesticide products for indoo r surface disinfecting using a pressurized aerosol can, but noted several issues, limitations and concerns with the data and proposed anal ys es. Ethics

• The Board concurred with the Agency ’s assessment that the study submitted for review was conducted in s ubstantial compliance with subparts K and L of 40 CFR 26.
Sincerely ,

Sean Philpott, PhD, MSBioethics Chair EP A Human Studies Review BoardPage **3** of **22 NOTICE**  This report has been written as part of the activities of the EP A Human Studies Review Board, a Federal advisory committee providing advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research. This report has not been reviewed for approval by the Agency

and, hence, the contents of this report do no t necessarily

represent the view and policies of the Environmental Protection Agency , nor of other agencies in the Executive Branch of the Federal government, nor does the mention of trade names or commercial products constitute a recommendation for use. Yo u may obtain further information about the EP

A Human Studies Review Board from its website at http://www .epa.gov/osa/hsrb

. Yo u may also contact the HSRB Designated Federal Of ficer, via e

mail at ord

- osa - hsrb@epa.gov In preparing this document, the Board carefull y considered all information provided and presented b y the Agency

presenters, as well as information presented b y public commenters. This document address es the information provided and presented within the structure of the charge b y the Agency

.Page **4** of **22 US ENVIRONMENT** 

**AL PROTECTION**  **AGENCY HUMAN STUDIES REVIEW**  **BOARD** Chair Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union Graduate College and the Mount Sinai School of Medicine, Schenectad y, NY Vi ce Chair Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH), School of Public Health and Human Services, The George W

ashington University

, W ashington, DC Members Janice Chamb ers, PhD, DABT, Fellow AT S, Wi lliam L . Giles Distinguished Professor, Director, Center for Environmental Health Sciences, College of V eterinary Medicine, Mississippi S tate University

, Mississippi S tate, MS George Fernandez, PhD, Professor of Applied Stati stics, Director of the University of Nevada

Reno Center for Research Design and Anal ys is, University of Nevada

- Reno, Reno, NV Vanessa Northington Gamble * , MD, PhD, University Professor of Medical Humanities, Professor of Health Policy

and American Studies , The George W ashington University

, Wa shington, DC Sidney Green, Jr., PhD, Fellow of the AT S, Professor, Department of Pharmacology , Howard University

College of Medicine, W

ashington, DC Jewell H. Halan ych, MD, Assistant Professor, Department of Preventi ve Medicine, Universit y of Alabama at Birmingham, Birmingham, AL Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University , Manhattan, KS Michael D. Lebowitz † , PhD, FCCP , Retired Professor of Public Health & Medicine, Universit y of Arizona, T

ucson, AZ José E. Manautou * , PhD, Associate Professor of T oxicology , Department of Pharmaceutical Science, University

of Connecticut School of Pharmacy , Storrs, CT Jerry A . Menikoff, MD, JD, Director, Of fice for Human Subjects Re search, Of fice of the Secretary , Department of Health and Human Services, Rockville, MD Wi lliam Popendorf, PhD, MPH, Professor Emeritus, Department of Biology , Utah State University

, Logan, UTPage **5** of **22**

Leonard Ritter * , PhD, Professor Emeritus, School of Environm ental Sciences, Universit y of Guelph, Guelph, ON, Canada Vi rginia Ashb y Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, Ve terans Health Administration, Wa shington, DC Bernard A. Schwetz * , DVM, PhD, Director (Retired), Of fice of Human Research Protections, Department of Health and Human Services, Cadott, WI Linda J. Yo ung, PhD, Professor, Department of Statistics, Institute of Food and Agricultural Sciences, University

of Florida, Gainesville, FL Human Studies Review Board Sta ff Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science Advisor, United States Environmental Protection Agency , W ashington, DC

* Not present on January

26, 2012. † Participated in the January 26, 2012 meeting via tele presence.Page **6** of **22**

**INTRODUCTION** On January

26, 2012, the United States Environmental Protection Agency ’s (EP A or Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues concerning one new protocol for research involving human partic ipants: a study measuring dermal and inhalation exposures associated with the mixing, loading and application of pesticides using powered (gasoline or electric) handgun/hand wand equipment in greenhouses and nurseries. In accordance with 40 CFR 26.1601, EP A sought HSRB review of this proposed study . This study

is discussed more full y below

. In addition, the Agency

has data from one completed study measuring dermal and inhalation exposure of professional janitorial workers who clean indoor surfaces with an antimicrobial pesticide product using hand

- held pressurized aerosol canisters

. Inaccordance with 40 CFR 26.1602, EP

A sought HSRB review of this completed study . This study

is discussed more fully

below

.

**REVIEW**

**PROCESS** On January

26, 2012, the Board co nducted a public face

- to

- face meeting in Arlington, Vi rginia. Advance notice of the meeting was published in the Federal Register as “Human Studies Review Board; Notice of Publi c Meeting” (76 Federal Register 248, 80938). Following welcoming remarks from Agency of ficials, the Board heard presentations from EP A on the following topics: one new stud y protocol to measure dermal and inhalation exposures associated with the mixing, loading and application of pesticides using powered (gasoline or electric) handgun/hand wand equipment in greenhouses and nurseries, and one complete d study measuring dermal and inhalation exposure of professional janitorial workers who clean indoor surfaces with an antimicrobial pesticide product using hand

- held pressurized aerosol c anisters. The Board also asked clarifying questions of several study sponsors and/or research investigators, including: Ms. Megan Boatwright, Analy tical Coordinator, Golden Pacific Laboratories. Dr. V ictor Cañez, Risk Assessment Solutions, Te chnical con sultant to the Agricultural Handler Exposure T

ask Force. Dr. Richard Collier, Administrative Committee Chair, Agricultural Handler Exposure Ta sk Force. Mr. William McCormick III, Clorox, on behalf of the Antimicrobial Exposure Assessment T

ask Force II. Mr

. Robert Testman, V

ice

- President, Golden Pacific Laboratories.Page **7** of **22**

Public oral comments were provided b y: Dr. V ictor Cañez, Risk Assessment Solutions, Te chnical consultant to the Agricultural Handler Exposure T

ask Force Dr. Richard Collier, Administrative C ommittee Chair, Agricultural Handler Exposure Ta sk Force. Mr. Robert Testman, V

ice

- President, Golden Pacific Laboratories. One written public comment from a New Jersey resident was submitted, but the substance of that comment was not directl y related to t he two studies under review by the HSRB at the January 26, 2012 meeting. For their deliberations, the Board considered the materials presented at the meeting, oral comments, and Agency

background documents (e.g., published literature, sponsor and investi gator research reports, study protocols, data evaluation records, and Agency science and ethics reviews of proposed protocols and completed studies). A comprehensive list of background documents is available online at http://www .regulations.gov

.
**CHARGE TO THE BOARD AND BOARD RESPONSE**  **Assessment of Proposed AHETF Research Study AHE**
**- 600:**  **Mixing, Loading, and Applying Liquid Pesticides in Managed**  **Horticultural Facilities Using Powered Handgun Equipment .**  **Overview of the S** **tudy** This proposal presents an agricultural handler exposure scenario involving mixing, loading and application of pesticides using powered (gasoline or electric) handgun/hand wand equipment in greenhouses and nurseries. Pesticides can be formul ated as either liquids or as wettable powders. A total of 30 participants (described in the protocol as “Monitoring Units” [MUs]) will be observed; three volunteers from each of ten geographically distinct growing regions will be enrolled using a purposi ve sampling method (with some elements of random selection). For each monitoring area, volunteers will be randomized to mix and load a defined amount of active ingredient within one of three strata : 0.5 to 1.6 pounds, 1.6 to 4.8 pounds of active ingredient , or 4.8 to 15 pounds of active ingredient. After mixing and loading the pesticide, participants will use powered equipment to treat ornamentals and nonbearing fruit trees in nurseries, or ornamentals and vegetables grown in greenhouses, using spray patter ns that include downward, outward and upward directions. For this protocol, all participants will wear long sleeved shirts, long pants, and shoes plus socks. In addition, all participants will wear chemical resistant gloves. Additional personal protectiv e equipment (PPE) may be required depending on product labeling directions, including the use of chemical

- resistant aprons when mixing and loading the pesticide, and chemical

resistant headgear when making overhead applications.Page **8** of **22**

Dermal exposure will be measured b y a whole body dosimeter worn beneath the subject’ s outer clothing. Hand wash and face/neck wipe samples will also be collected prior to, during, and after completion of pesticide loading and mixing procedures. For study participants wearing chem ical

- resistant headgear, patches placed inside and outside of the headgear will be employ ed to estimate dermal exposure of the protected portions of the body covered by

these garments. Airborne concentrations of the surrogate will be monitored in the participant’ s breathing zone using an OSHA

V ersatile Sampler (OVS) tube connected to a personal sampling pump. Additional measures will also record environmental conditions at the time of monitoring, and observers will make field notes, photographs and video s of participant activity throughout the monitoring event. The results of sample analy sis under the powered handgun scenario will be posted to the Agricultural Handlers Exposure Database (AHED ® ), where they will be available to the EP A and other regulatory

agencies for statistical anal ys is. The proposed documentation will report a confidence interval

- based approach to determine the relative accuracy for the geometric mean, arithmetic mean and 95th percentile of unit exposures. The Agency proposes to use these data to estimate daily

dermal and inhalation exposures of agricultural handlers who mix, load and apply pesticides using powered handgun equipment. **Science Charge to the Board**  If the AHETF proposal is revised as suggested in EPA’s review and if the research is performed as described, is the research likel y to generate scientificall y reliable data, useful for assessing the exposure of workers mixing, loading and appl yi ng pesticides in managed horticultural facilities using powered handgun equipment? **Board Response to the Charge** HSRB Recommendation The Board concluded that the protocol submitted for review, if modified in accordance with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to generate high qualit y, reliable and useful data for assessing worker’s pesticide exposures in horticultural settings. Several comments or suggestions were made b y the Board with respect to the use of PPE, the potential effect of unanticipated incidental exposures and other variables on proportionality , and the utility

of existing European Crop Protection Association (ECP A) data.Page **9** of **22**

HSRB Detailed Recommendations and Rationale This protocol, a study

designed to measure dermal and inhalation exposure of agricultural workers who mix, load and apply pesticides in nurseries or greenhouses using a hand

- held spray er or gun, was well thought out and well designed. The stud y sponsors (Collier 201 1) found no suitable existing information that could constitute some of the MUs for this particular scenario; consequently

, the entire scenario has to be conducted. The design requires ten (10) regions with three (3) MUs per region, for a total of 30 MUs. The rationale for this design is that there are relativel y few nurseries and greenhouses that would be suitable for this scenario in most, if not all, regions of the United States. Similarity restrictions will be imposed to assure diversity

. The investigators consulted several information sources to identify locations with suitable nurseries or greenhous es that could be venues for the conduct of this scenario. The areas of the country

selected represent a variet y of climatic and geographic conditions, likely providing the representativeness and diversity sought for the scenario. Given these factors and co nsiderations, the Board determined that the proposed study design is reasonable. The scenario will include several tasks: mixing/loading of the pesticide product, open pouring of the formulated product, application of the product to the plants, and potentially some cleaning. The primary objective is to estimate the geometric mean, arithmetic mean and the 95th percentile of normalized dermal exposure for agricultural workers who mix, load and apply pesticides in nurseries or greenhouses using a hand

- held s pray er or gun. A secondary objective is to demonstrate proportionality between the amount of active ingredient handled (AaiH) and exposure level. One concern that was raised b y the Board was that proportionality may not be observed due to unanticipated ex posures (e.g., accidentally touching a treated plant or contaminated part of spray equipment), and these sources may contribute substantially

to participants’ exposure levels. Because workers may be close to some of the spray ed plants in a setting such as a nursery

, it seems likely

that unintended contact of workers with these plants might easil y occur. I n scenarios where unanticipated exposures like these are likely to occur, it will be important for researchers to observe and document all unintentional co ntacts with treated plants or other events that might contribute to the exposure levels. However, even if proportionality

is not seen

-- particularl y if the results are attributable to observed unanticipated exposures -- this scenario will still provide va lid information about worker exposure when using a powered handgun or hand wand in a horticultural setting. The Board provided additional recommendations and advice to the Agency about personal protective equipment (e.g., chemical

- resistant headgear), res pirators, the many sources of diversity

, and anal ys is of data. For example, the Agency was reminded that, should chemical

resistant headgear be worn, the use of patches inside the headgear should yi eld valid estimates of exposure for those participants wearing such a hat. However, this method may underestimate exposures if attempts were made to extrapolate these data to those not wearing such headgear

. Such extrapolation may

not be an explicit intent, but the Agency states its plans to use the head exposure data to develop mitigation strategies (e.g. Evans, Sarkar and Sherman 201 1, 1 1). The eff ect of the protection afforded b y the brim of the chemical

- resistant headgear would negativel y aff ect that use. Thus, the Board suggested that the sponsors consider : 1) having study participants use chemical

- resistant headgear without a brim (but only if this is allowed by

the W orker Protection Standards); or 2) add a third patch dosimeter against the head below the brim, as thePage **10** of **22**

density of deposition (μg/cm 2 ) onto th is patch could be compared to the deposition onto the rest of the face to estimate the magnitude of protection af forded by such a brim. The Board also discussed the use of respirators and half

- masks in the scenario, and how to handle the impact that use o f such PPE might have on dermal exposure levels. For example, the Board raised concerns about whether the measured skin exposure to the face would be adjusted upward in proportion to the area of the face/neck covered b y a respirator

. Although the Agency responded af

firmatively

, this adjustment was not stated the Agency ’s review of the protocol. After the conclusion of the January 2012 meeting, however, it was pointed out to the Board that the AHETF’ s standard operating procedure (SOP) 9.K.0 provides information about how measured skin exposure to the face will be adjusted upward in proportion to the area of the face/neck covered b y a respirator

. Several Board members noted that there are man y sources of diversity in this scenario. As a result, it may

b e dif ficult for the Agency

to identify

statisticall y significant dif ferences. Variables which may

influence the proposed exposure data include: 1. The predominant direction of spray (downward, outward, or upward); 2. Whether the MU is walking or riding a motor ized vehicle; 3. Whether or not the MU does “minor clean

- up”; 4. Whether the MU uses a handgun or a hand wand; 5. Whether the MU applies the pesticide indoors or outdoors; 6. The width of the path through which the applicator must pass, as determined by facility t y pe (i.e., ornamental greenhouse, vegetable greenhouse, nursery), which may or may not be a surrogate for the proximity of foliage; 7. The formulation ty

pe mixed (liquid or solid/wettable powder); and 8. The mixing sequence (pre

- mix or tank mix). The Board al so considered issues related to the Agency ’s recommendation to include wettable powder b y at least one partic ipant in each cluster (Evans, S arkar and Sherman 201 1, 4). In particular, concerns were raised about the use of two formulation ty pes (wettable po wder and liquid) in the scenario; this could be seen as akin to conducting two studies. The lack of clarit y as to how many

participants would use the wettable powder in each cluster is problematic for assessing the recommended study design and field conduc t. Not knowing the number of MUs who would handle the powder versus liquid formation, for example, raises statistical and anal yt ical questions that cannot be answered. If both formulations are to be used, the Board recommended that the Agency conduct a se parate anal ys is of each ty pe before combining all of the data for anal ys is. The sponsor could have 15 MUs use the powder formulation and 15 MUs use the liquid formulation. Alternativel y, all MUs could use the wettable powder, as that formulation ty

pe is mo re likely

to generate more conservative exposure data. Finally , the Board cautioned the Agency and the sponsors that the justification for the study may be weak. In particular, the Board raised a question about the utility of ECP A data. The Agency ’s rationale for not using those data was that the proposed AHETF scenario involves individual workers performing both mixing/loading and application activities, whereas the ECP A exposure data was collected from agricultural handlers involved only in the applic ation ofPage **11** of **22**

pesticides. The Board was not convinced, however, that this dif ference precludes the use of existing ECP

A data. While there may be other scenario or data quality issues with the ECP A data, the Board recommended that the Agency consider the viabi lity

of combining the ECP

A application

- only

exposure data with the Ta sk Force’ s mixing/loading

- only exposure data to satisfy the Agency ’s registration needs without further human exposure studies. Despite this, the Board noted that the amount of active ingredient handled might be very different for the proposed scenario and the existing ECP A data set; if true, then the existing data sets might not be useful in assessing worker exposure in this horticultural scenario. **Ethics Charge to the Board**  If the AH ETF proposal is revised as suggested in EPA’s review and if the research is performed as described, is the research likel y to meet the applicable requirements of 40 CFR part 26, subparts K and L ? **Board Response to the Charge** HSRB Recommendation The Bo ard concluded that the protocol submitted for review, if modified in accordance with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to meet the applicable requirements of 40 CFR 26, subparts K and L. HSRB Detailed Recommendations and Rationale The submitted documents assert that the study will be conducted in accordance with the ethical and regulatory

standards of 40 CFR 26, Subparts K and L, as well as the requirements of the US EPA’s Good Laboratory Practice (GLP) Standards des cribed at 40 CFR 160, and, for research conducted in California, the California State EPA Department of Pesticide Regulation study monitoring (California Code of Regulations Title 3, Section 6710) (Collier 2011). Requirements of FIFRA §12(a)(2)(P) also app ly . Researchers who participate in the study and interact with study

participants will be required to undergo ethics training. The training will include the successful completion of the course from the National Institutes of Health (Protecting Human Research Participants) and/or the Basic Collaborative IRB Training Initiative Course. The protocol was reviewed and approved b y an independent human subjects review committee, II RB, Inc. of Plantation, FL , prior to submission. IIRB, Inc. is fully accredited by

the Association for the Accreditation of Human Research Protection Programs (AAHRPP). IIRB, In c. is also listed as an active Institutional Review Board (IRB) on the Office of Human Research Protection (OHRP) website (Reg. #IORG0002954). Copies of all co rrespondence with IIR B, Inc. (Collier 2011) and a cop y of IIR B, Inc. policies and membership roster were provided (IIRB, Inc. 2010; 2011). These documents indicate that IIRB, Inc. reviewed this protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A).Page **12** of **22**

1. The Board concurred with the conclusions and factual observations of the ethical strengths and weaknesses of the study , as detailed in the EPA’s Ethics Review (Evans, Sarkar and Sherman 2011). The proposed study is likely to meet the applicable ethical requirements for research involving human subjects, in accordance with the following criteria:

a. Societal value of the proposed research. The clearly stated purpose of the proposed monitoring study

is to develop data to determine the potential exposure for workers who mix, load, and apply

liquid pesticides using powered handgun equipment in managed horticultural facilities in the United States. This mixing/loading/appl yi ng method is applicable to a large variety of commercially

important crops associated with the nursery and greenhouse industry

across the US and Canada, and the existing exposure data are inadequate. This stud y will provide a partial answer to the question of what dermal and inhalation exposures are likely for worke rs who mix/load and apply pesticide products using handguns and hand wands in nurseries and greenhouses. EPA will use the results of this study to estimate the dermal and inhalation exposure likely for a wide range of agricultural pesticides mixed, loaded, and applied under this exposure scenario. b. Subject selection and informed consent. The inclusion/exclusion criteria are complete and appropriate. Pregnant or nursing women are excluded from participation. Pesticide compan y emplo yees and contractors to the AHETF are also excluded from participation. Protections are adequate even if a subject were from a vulnerable population. Informed consent will be obtained from each prospective subject and appropriatel y documented in the language (Spanish or English) preferred b y the subject. Recruitment materials and interactions with potential subjects will be conducted in English or Spanish, depending on subject preference; the Board agrees with EPA’s suggestion that it is preferable for recruitment discussions to take place away from the work site, to minimize the potential for coercion and that the protocol should describe the ty pes of locations where recruitment discussions between researchers and potential subjects will take place, clarifying whether these discu ssions will take place at the work site or at locations that are away from the work site. The proposed monetary compensation is not so high as to unduly influence participation. Candidates and subjects will be repeatedl y informed that they are free to decl ine to participate or to withdraw at any time for any

reason, without penalty

. Depending on the number of emplo yees and size of the grower’s facility, the Study Director or researcher may contact employ ees using an informational recruitment fly er posted in a common work area. Alternativel y, or subsequent to the use of a flyer, the Study Director or researcher will arrange a meeting with the grower’s employ ees who express interest in participation. Such recruitment meetings will alway s occur without superv isors being present. The Study Director or researcher will describe the AHETF Exposure Monitoring Program, the goals of this specific stud y, the procedures to be used in exposure monitoring, and the risks and benefits to participants. The subject eligibili ty factors listed in the consent form and SOP AHETF

- 11.B.6 are appropriate. Candidates who attend an individual interview will be paid $20 whether or not they agree to participate; enrolled subjects who put on the whole

- body dosimeter will be paid $80 in a ddition to their usual pay , whether or not they complete participation.Page **13** of **22**

c. Risks to subjects. The proposed test materials are EPA

- registered products registered for nursery and/or greenhouse use and the specific application planned by the grower, and will be used in full compliance with the approved labels. All identified risks are characterized as of low probability , and risks are further minimized by exclusion of candidates who self

- report that they

are in less than “good” health; alerting subjects to si gns and s ymptoms of heat stress; monitoring heat index with associated stopping rules; close observation of subjects; training of experienced technicians to minimize embarrassment; incorporation of procedures to keep results of pregnancy testing private an d to permit discrete withdrawal; provision of appropriate work clothing and PPE. Provision is made for discrete handling of the pregnancy testing that is required of female subjects on the day

of testing. Five kinds of risks to subjects are discussed in the protocol, along with specific steps proposed to minimize them: the risk of heat

- related illness; the risk associated with scripting of field activities; psy chological risk; the risk of exposure to surfactants, and; the risk of exposure to surrogate che micals. In this study , risks to subjects are classified as ‘greater than minimal’ since the likelihood of harm or discomfort is greater than what is encountered in ordinary dail y life. In particular, the risk of heat

- related illness (resulting from wearin g an extra lay er of clothing to trap chemical) will be increased due to study participation. AHETF has adopted an extensive program to minimize these risks. Appropriate provision is made for safet y and medical monitoring. The protocol also incorporates pro cedures to keep results of pregnancy testing private and to permit discrete withdrawal of a study

subject. Finall y, the protocol incorporates procedures to ensure that no photographs or videos will be taken in which a worker can be readily identified. d

. Benefits to participants . This research offers no direct benefits to the subjects. The principal benefit of this research is likely to be reliable data about the dermal and inhalation exposure of people mixing, loading and application of pesticides usin g powered handgun equipment. These data are intended to be used b y EPA and other regulatory

agencies to support exposure assessments for a wide variet y of pesticide products and their uses.

e. Risk/benefit balance. Risks to subjects have been thoughtfull y and thoroughly minimized in the design of the research. The low residual risk is reasonable, in light of the likely benefits to societ y from new data supporting more accurate exposure assessments for pesticide products. 2. In addition to this analy sis, the Board recommended a few edits to improve the clarit y of the In formed Consent Form. These are listed below, organized according to the section within the Informed Consent Form in which they appear. In particular, in the past the Agency and the Board have suggested that protocols and consent forms clarify the steps that participants should take if participants have an adverse reaction within 24 hours. This was not included in the materials provided b y the AHETF, and the Board recommends that such information be included on the consent form.Page **14** of **22**

• Introduction and Purpose :

“ If you do **In order to** take part in this study , y ou must read and sign this consent form” (L ine 4).

• Procedures Before the Start of the Study : Modify the language per the protocol (p. 248/ SOP II.D.2) to clarify that the pregnancy

test will be taken prior to the start of the study : 8. If you are female, within 24 hours of **prior to** starting the study y ou will perform an over - the

- counter pregnancy test. If there is a delay in the start of the study of more than 24 hours, another pregnancy test may be needed. The negative results of y our pregnancy test will be verified by a female member of the study

.

• Injury to Participants: Add a line indicating the name and contact information of the Study Director or other individual to be contacted if the participant experiences an adverse event within 24 hours. 3. The Board agreed with the Agency that information about potential psy chological and social harms related to unwanted disclosure of test result s and breach of confidentiality associated with photographs or video may be included in the protocol (Evans, Sarkar and Sherman 2011). However, the Board recommended that this information not be included in the informed consent form as it might give parti cipants the erroneous impression that these risks are particularl y significant or that appropriate steps have not been taken to mitigate them.

**Assessment of Completed AEATF II Research Study AEA**
**- 04:**  **Measurement of Potential Dermal and Inhalation Exposu**  **re During Application of a Liquid Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting**  **. Overview of the S** **tudy** AEATF II aerosol spraying scenario was designed to measure a t ypical occupational handler’s dail y ex posure to an antimicrobial spray (containing C14 alkyl dimethyl benz yl ammonium chloride [ADBAC]) packaged in a commercially

- available pressurized aerosol spray can. Eighteen (18) professional janitors were enrolled in the study , and applied (but did no t wipe) the product on surfaces at one of three motels in the Fresno, CA area. Study participants were randomized to apply different amounts of product, from one (1) to four (4) cans of product in 1/2

- can increments (i.e., 1 to 1.5 cans, 1.5 to 2 cans, and so on up to 3.5 to 4 cans). These are described in the completed study and associated documents as “Monitoring Events” (MEs).Page **15** of **22**

Participants all wore long pants and long sleeved shirts with shoes plus socks. The clothing was anal yz ed in pieces to allow e stimation of the expected exposure of people wearing other clothing combinations, such as shorts or short

- sleeved shirts. No participant wore gloves, but participants were given the option of wearing a respirator during product application; all 18 subjects elected to wear respirators during monitoring. Dermal exposures were measured using whole

- body dosimeters (inner and outer), and hand and face washes. Dermal unit exposures (reported in mg/lb AaiH) were calculated b y dividing the summed total exposure by AaiH. The study

sponsor report normalized the dermal exposures by

milligrams (mg) of active ingredient applied, but these exposure data were recalculated b y the Agency and expressed as mg/lb of active ingredient applied. Inhalation exposures were meas ured using a personal air sampling pump and OVS tubes plus a separ ate pump used to run a RespiCon Particle Sampler. This allows for collection and anal ys is of inhalation exposure monitoring results as total particles, as inhalable particles (<100 μm), as thoracic particles (<10 μm), and as respirable particles (<2.5 μm). Inhalation unit exposures (reported in mg/m 3 /lb AaiH) were calculated by dividing the air concentrations by AaiH. The data will be posted to the Biocide Handlers Exposure Database (BHED ® )

. The Agency plans to use these data generically to estimate dermal and inhalation exposures and risks for other antimicrobial ingredients where the applied product is packaged in a pressurized aerosol spray

can. Although the scenario as performed did not include the subsequent wiping of the aerosol spray

solution, the Agency

believes that dermal and inhalation exposure that results from the subsequent wiping of spray ed antimicrobial solutions can be determined by combining the results of this study

with th e results of the previously AEATF II conducted ready

- to

- use (RTU) wipe stud y (favorably reviewed at the April 2011 HSRB meeting; EPA HSRB 2011). **Science Charges to the Board**  Was the research reported in the AEATF II completed aerosol study report faith ful to the design and objectives of the protocol and governing documents of the AEATF? Has EPA adequately

characterized, from a scientific perspective, the limitations on these data that should be considered when using the data in estimating the exposure of professional janitorial workers who apply liquid antimicrobial pesticide products to indoor surfaces using pressurized aerosol cans? **Board Response to the Charge** HSRB Recommendation The Board concluded that the research reported in the complete d monograph, associated field study

reports, and associated supplemental documents was conducted in a manner that wasPage **16** of **22**

reasonabl y faithful to the design and objectives of the protocol and governing documents of the AEATF. The Board also concluded that th e Agency has adequatel y, but not completely, considered the limitations in this study when using the data in estimating the dermal and inhalation exposure of those who appl y liquid antimicrobial pesticide products for indoor surface disinfecting using a pr essurized aerosol can. In particular, the Board noted several issues, limitations and concerns with the data and anal ys es. These are described in greater detail below. HSRB Detailed Recommendations and Rationale The Board concluded that the study (Testm an and Boatwright 2011) was done thoroughl y, yi elding detailed and helpful data which appear to be reliable. Some data trends were not explained in the accompan yi ng Agency analy sis, but overall the diversity of subjects and settings were strengths of the study

. The Board agreed with the Agency that the number of participants was adequate to achieve the primary

benchmark accuracy

goal. The Board also agreed that the modest diversity of application settings was a reasonable attempt to offset the practica l limitation of recruiting and assessing all exposures within one geographic area. The documented diversity in application behaviors indicates the robust nature of the resulting exposure data. The Agency's anal ys es of protocol deviations and of the blank, fortified field, and lab samples were acceptable. In addition to the deviations noted in the final report (Testman and Boatwright 2011, 1033

- 104) or by the Agency

(Leighton 2012, 9), however, the Board identified a few more. For example, subject AE4 wa s apparently observed to be appl ying the product to surfaces at much heavier rates than usual. About 20% of the way into the sampling time, the study director instructed this subject to “lighten up” in their application (Testman and Boatwright 2011, 488). This intervention comprises an unknown limitation that may have had a large effect on reducing a potentiall y high exposure. Alternatively , it may have had no significant effect and was unjustified in terms of protecting the subject. No specific prohibiti on against such interventions was found in the protocol, such instructions regarding applicator behavior were counter to the intent of the protocol (i.e., that the study participants “spray

surfaces as they would normally do” [T estman and Boatwright 201 1, 18]). Thus, it is unclear whether this event actually qualifies as a protocol deviation. However, the lack of an explicit prohibition of study director intervention raised issues in this study ’s anal ys is and interpretation. Guidance about how to handle int erventions should be incorporated into future protocols and SOPs. Subject AE18 (in cluster #1) was a borderline outlier without any indication in the note of intervention by

the researchers. The Board did not disagree completel y with the Agency’s concl usion that AE18’s data was not an outlier (Leighton 2012, 15), but believed that one particular combination of these data

-- application rate

-- reflects the characteristics of an outlier. However, the Board did not advocate excluding this data point from subsequent anal ys es. Rather, these sometimes statistically significant differences provide additional support for the diverse and therefore broadl y representative nature of the subjects and the qualitatively robust nature of the study results.Page **17** of **22**

The Board also discussed outliers in laboratory recovery data. These data were not used by the Agency

to correct field samples; the Board agreed with the EPA’s approach. However, the lack of explicit procedures for handling outliers raised questions among Board m embers. Explicit discussions about when data should or should not be excluded should be incorporated into future protocols and SOPs. The Board raised concerns that the 20% higher flow rates (or discharge rates) from the batch of aerosol cans used in the f irst four MEs, as compared with the flow rates from those cans used in the last 14 MEs, could cause an appreciable difference in exposure (Leighton 2012, 9). Ty pically , a faster discharge rate through a given nebulizer produces smaller droplets. An anal y sis of variance for data in this study found a statistically

significant difference between the average fraction of the a.i. <10 μm in the first four RespiCon samples and the last 14 samples (44% versus 55%, respectively ; p < 0.00001). This difference is consistent with the expectation that the first batch of canisters may have produced particles with a mass median aerody namic diameter just over 10 μm and the last batch particles with a mass median aerodynamic diameter just under 10 μm. The difference in p article size is more likely to have been due to the reported difference between flow rates than the difference in ADBAC concentration in the product. Notably , the impact of this probable shift to slightly smaller droplets is small in comparison to the muc h wider variation in flow rates and particle sizes among the many other products these studies are intended to represent. The Board also raised concerns that the ventilation data presented were unclear, inadequatel y recorded, and inadequatel y interpreted (Testman and Boatwright 2011, 119

- 20). For example, “fresh air” was presented using different metrics (e.g., %, total fan cubic feet per minute [CFM], and CFM fresh air). Furthermore, the reported air changes per hour seem to differ from separatel y calcu lated values b y factors of 1.5

- to 3

- fold. Although the deficiencies noted could have seriously affected the sampling results, analy ses by one Board member suggest that the overall effect may have been small; the amount of time that participants spent in e ach room was so short that airborne ABDAC was just beginning to accumulate by the time the subjects left the space, limiting the effect of ventilation on overall rates of exposure. However, the Board recommended that the Agency consider the potential limi tations associated with the heating, ventilation and air conditioning s ys tems in the test facilities. The Agency

requested the Board's advice on the use of RespiCon versus OVS results. The major advantage of the RespiCon air samples is the ability to look at the data by

size ranges. A disadvantage of collecting RespiCon samples is the challenge of confronting the difference inherent in the entrance losses of an y two air samplers. Such losses are a characteristic primaril y of entrance diameters and flow rates, but also of the shape of those entrances and their orientation, and the air velocity and particle diameters in an y given setting. These characteristics aff ect both the RespiCon and OVS samples. There is no reliable basis available for comparing the two ty pes of samplers (see, e.g., the articles cited b y Leighton 2012, 35

- 7). For the purposes of calculating dose via inhalation, the Board thus recommended that the <10 micron

- size results from RespiCon monitors be used because this size range represents the fraction that enters the lower respiratory tract and thus wasPage **18** of **22**

believed to provide a more accurate estimate of respiratory exposure. The Agency ’s Office of Pesticide Programs has recommended OVS sampling results of <100 microns be used in estimation of risk because most of the information they have collected has been with OVS monitors and there is some benefit to having continuity in their estimation of risk. This would provide a more conservative estimate of particles. The Board suggested that the dermal and inhalation exposure data be combined to obtain total exposure results. The Board also questioned whether a slope of 1.5, with a confidence interval (CI) including one (1), should be considered as evidence of 1:1 proportionality . The Board thus recommended that the Agency alway s address how estimates of coefficients will be used. Finall y, the Board recommended that the Agency and the Task Force refrain from using the word ‘proportional’ without preceding it b y an adjective such as 1:1 proportiona l or 1:2 proportional. **Ethics Charge to the Board**  Does available information support a determination that the study was conducted in substantial compliance with subparts K and L of 40 CFR Part 26? **Board Response to the Charge** HSRB Recommendation
T he Board concurred with the Agency ’s assessment (Sherman 2012) that the study submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR Part 26. HSRB Detailed Recommendation and Rationale The documents prepared by Gold en Pacific Laboratories, LL C, and submitted by American Chemistry

Council Antimicrobial Exposure Assessment Ta sk Force II under Project No. AEA

- 04, state that the study was conducted in compliance with the requirements of the EP A’ s Good Laboratory

Practice (GL P) Standards; FIFRA §12(a)(2)(P); and the applicable subparts of 40 CFR 26 (T estman and Boatwright 201 1). The protocol was reviewed and approved b y an independent human subjects review committee, II RB, Inc. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and a cop y of IIRB, Inc. policies and procedures were provided. This IRB is fully accredited b y AAHRPPand registered with OHRP (see details above). Documentation provided to the EPA indicated that IIRB, Inc. reviewed this stud y pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A) and found it in compliance (IIRB, Inc. 2010; 2011). 1. The Board concurred with the conclusions and factual observations relating to the study , as detailed in the EPA’s Ethics Revie w (Sherman 2012). Specificall y:Page **19** of **22**

a. Prior HSRB and Agency Review. The requirements of 40 CFR §26.1125 for prior submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol were satisfied. The stud y ( Te stman and Boatwright 2011) was c onducted in accordance with the protocol previously reviewed b y the Agency (Leighton, Walls and Sherman 2009) and b y the HSRB (EPA HSRB 2009). Neither the Agency’s nor the HSRB’s ethics reviews identified an y significant deficiencies requiring correction r elative to 40 CFR 26, subparts K and L, or to FIFRA § 12(a)(2)(P) (Leighton, Walls and Sherman 2009). Because the stud y was conducted in California, the approval of the California Department of Pesticide Regulation (CDPR) was also required before the study could be initiated. CDPR granted final approval of the amended protocol and supporting documents on April 19, 2010. b. Responsiveness to HSRB and Agency Reviews. Following HSRB review, the protocol and consent form were modified to incorporate changes re sponsive to the all of the comments of EPA (Leighton, Walls and Sherman 2009) and the HSRB (EPA HSRB 2009). Additional corrections and amendments were also requested b y CDPR. IIRB, Inc. granted approval to the amended protocol and supporting documents on April 6 and April 7

- 9, 2010, respectivel y ( Te stman and Boatwright 2011; Sherman 2012).

c. Substantial Compliance with Reporting Requirements (40 CFR Part 26 subpart M). The AEATF II’s submission ( Te stman and Boatwright 2011), along with the separatel y sub mitted documents describing the procedures and roster of the IR B ( IIRB, Inc. 2010; 2011), fully

meet the requirements of 40 CFR §26.1303 to document the ethical conduct of the research. 2. The Board concluded that this study , as conducted, met all applica ble ethical requirements for research involving human participants, in accordance with the following criteria that had been stated in the Board’s prior review of this study protocol (EPA HSRB 2009):

a. Acceptable risk

- benefit ratio. The risks to study participants were minimized appropriatel y and were justified by the potential societal benefits, particularly data on the dermal and inhalation exposure of professional janitorial workers to antimicrobial compounds as they

sprayed indoor surfaces with aerosol ized pesticides. These data could be used to develop mechanisms to protect future users of these antimicrobial pesticides.

• Minors and pregnant or lactating women were excluded from participation, with pregnancy

confirmed by

over- the

- counter pregnancy test ing on the day

of study or b y opt

- out. The potential of stigma resulting from study exclusion was also appropriatel y minimized.

• Clear stopping rules and medical management procedures were in place, and no adverse events or other incidents of concern related to product exposure were reported.

• The study

was designed to minimize the risks of exposure to the test compounds.Page **20** of **22**

b. Vo luntary and informed consent of all participants.

• The study

protocol included several mechanisms designed to minimize coercive re cruitment and enrollment.

• Monetary

compensation was not so high as to unduly influence participation. Minors and pregnant or lactating women were excluded from participation, with pregnancy confirmed b y over - the

- counter pregnancy testing on the day

of study or b y opt

- out. The potential of stigma resulting from stud y exclusion was also appropriatel y m inimized. 3. Although the first stud y participants were enrolled in April 2010 and monitoring began in June 2010, shortly

thereafter the study

was placed on ‘h old’ as the result of an issue raised by CDPR. In response to a request from some participants to wear a respirator while engaged in stud y related tasks, the AEA TF II decided to of

fer all study

subjects the option of wearing a half

- mask respirator fitted w ith organic vapor cartridges. This decision was made after consulting with the Agency and with the I RB, and the amended protocol and informed consent forms were reviewed and approved by the IRB. Upon receipt of the approved protocol amendment, CDPR request ed that the study be halted temporarily

until Golden Pacific Laboratories could conduct an additional review of its procedures for respirator use. CDPR granted approval for the amended protocol on May 1 1, 201 1. This hold is unlikely

to have affected the i ntegrit y of the research or the safety of participants. In fact, b y al lowing subjects to wear a respirator, the researchers further minimized potential risks to study participants. All 18 monitored subjects used a respirator, which was fitted b y a trained study investigator and worn under the supervision of a registered stud y nurse. 4. There were s everal minor deviations from GLP were reported b y the stud y sponsors (T estman and Boatwright 201 1, 3) but these were unlikely to have affected the integrit y of the research or the safet y of participants. Onl y one of these deviations bears further discussion, namely

the enrollment of a participant who self

- reported that his health was only “fair,” despite the requirement that all participants be in “good health” (T estman and Boatwright 201 1, 227). This same issue was discussed by the HSRB during its October 2010 and April 201 1 meetings (EP A HSRB 2010; 201 1), at which time the Board recommended that the study sponsors clarify

the criteria used to establish participants’ health status prior to enrollment. Enrollment of this particular participant, however , happened prior to those two Board meetings. Furthermore, although formally enrolled in the study , this participant was not one of the 18 subjects monitored. Thus, the B oard concluded that this deviation did not put the participant at increased risk.Page **21** of **22**

**REFERENCES** Collier, R. for the Agricultural Handler Exposure T ask Force (AHETF). 2011. Mixing, L oading and Application of Pesticides in Managed Horticultural Facilities usin g Powered Handgun Equipment (AHETF Study No. AHE600). Dated October 24, 2011. Unpublished document prepared for the AHETF, 474 p.
EP A Human Studies Review Board. 2009. October 21

- 22, 2009 Human Studies Review Board Meeting Report. 26p.
EP A Human Studies Review Board. 2010. October 27

- 28, 2010 Human Studies Review Board Meeting Report. 31p.
EP A Human Studies Review Board. 201 1. April 13

- 14, 201 1 Human Studies Review Board Meeting Report. 31p. Evans, J., B. Sarkar, and K. Sherman. 201 1. Science and Ethics Review of AHETF Scenario Design and Protocol AHE600 for Exposure Monitoring of W orkers during Mixing, Loading and Application of Pesticides in Managed Horticultural Facilities using Powered Handgun Equipment. Dated December 30, 201 1. Unpublished document prepared by the Of fice of Pesticide Programs, United States Environmental Protection Agency . 57p. Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Human Research Protection Program Plan (HRPP

Plan). Dated November 3, 2010. Unpublished doc ument prepared b y IIR B, In c. 131p.
IIR B, Inc., 201 1. IRB Membership Roster. Dated September 12, 201 1. Unpublished document prepared b y IIR B, Inc. 1p. Leighton, T., C. Walls and K. Sherman. 2009. Science and Ethics Review of AEATF II Aerosol Scenario Desi gn and Protocol for Exposure Monitoring. Dated September 21, 2009. Unpublished document prepared b y Office of Pesticide Programs, United States Environmental Protection Agency . 52p. Leighton, T. 2012. Science Review of the AEATF II Aerosol Human Exposure Monitoring Study . Dated January

3, 2012. Unpublished document prepared by Office of Pesticide Programs, United States Environmental Protection Agency . 38p. Sherman, K. 2012. Ethics Review of Completed AEATF II Aerosol Scen ario Worker Exposure Monitoring Study

. Dated January 4, 2012. Unpublished document prepared by the Of fice of the Director, Of

fice of Pesticide Programs, United States Environmental Protection Agency . 20p. Te stman, R.J. and M.T . Boatwright, for the AEA TF I I. 201 1. A Study for Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting. DatedPage **22** of **22**

November 14, 201 1. Unpublished document prepared b y the Golden Pacific L aboratories, LLC, for the AEA

TF II. 1851p. MRI D 48659001.