March 28, 2012

1 2 EP A

- HSRB

- 12

- 01 3 4 Lek Kadeli, Acting Assistant Administrator 5 Of fice of Research and Development 6 U.S. Environmental Protection Agency 7 1200 Pennsylvania Av enue, NW 8 Wa shington, DC 20460 9 10 Subject: January

26, 2012 EP

A Human Studies Review Board Meeting Report 11 12 Dear Mr. Kadeli, 13 14 The United States Environmental Protection Agency (EP A or Agency) requested that the 15 Human Studies Review Board (HSRB) provide scientific and ethics reviews of one new protocol 16 for a study involving intentional exposure o f human subjects to pesticides: a proposed 17 Agricultural Handler Exposure T ask Force, LLC (AHETF) scenario measuring dermal and 18 inhalation exposure of workers who perform mixing, loading and application of pesticides using 19 powered (gasoline or electric) han dgun/hand wand equipment in greenhouses and nurseries 20 (AHE

- 600). 21 22 The Agency also requested that the HSRB review a completed study of dermal and 23 inhalation exposure of professional janitorial workers who clean indoor surfaces with an 24 antimicrobial pestici de product using hand

- held pressurized aerosol canisters , conducted b y the 25 Antimicrobial Exposure Assessment T ask Force II (AEA

TF II). This study

(AEA

- 04) was 26 conducted after publication of the EP A’ s expanded final rule for protection of subjects in human 27 research. The data will be posted to the Biocide Handlers Exposure Database (BHED®), and 28 used genericall y to estimate dail y dermal and inhalation exposures of those who wipe indoor 29 surfaces with antimicrobial pesticides. 30 31 The enclosed report provides the Board’ s response to EP A charge questions presented at 32 the January

26, 2012 meeting. 33 34 **Assessment of Proposed AHETF Research Study AHE**

**- 600:**  **Mixing, Loading, and Applying** 35 **Liquid Pesticides in Managed Horticultural Facilities Using Powered Handgun Equipment** 

**.** 36 37 Science 38 39

• The Board concluded that the protocol submitted for review, if modified in accordance 40 with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to 41 generate high quality , reliable and useful data for assessing worker’s pesticide exposures in 42 horticultural settings. 43 44

• The Board provided several additional comments or suggestions with respect to the use of 45 personal protective equipment (PPE), the potential effect of unanticipated incidental 46exposures and other variables on proport ionality , and the utility of existing European Crop 47 Protection Association (ECP A) data. 48 49 Ethics 50 51

• The Board concluded that the protocol submitted for review, if modified in accordance 52 with EPA and HSRB recommendations, is likely to meet the applicable requi rements of 40 53 CFR 26, subparts K and L. 54 55 **Assessment of Completed AEATF II Research Study AEA**

**- 04:**  **Measurement of Potential** 56 **Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide** 57 **Product Using a Pressurized Aerosol Can for Indo or Surface Disinfecting** 

**.** 58 59 Science 60 61

• The Board concurred with the Agency ’s assessment that this study provides scientifically 62 valid results for estimating the dermal and inhalation exposure of those who apply liquid 63 antimicrobial pesticide products for indoo r surface disinfecting using a pressurized aerosol 64 can, but noted several issues, limitations and concerns with the data and proposed anal ys es. 65 66 Ethics 67 68

• The Board concurred with the Agency ’s assessment that the study submitted for review 69 was conducted in s ubstantial compliance with subparts K and L of 40 CFR 26. 70 71 72 Sincerely

, 73 74 75 76 Sean Philpott, PhD, MSBioethics 77 Chair 78 EP A Human Studies Review Board 79**NOTICE** 80 81 This report has been written as part of the activities of the EP A Human Studies Review 82 Board, a Federal a dvisory committee providing advice, information and recommendations on 83 issues related to scientific and ethical aspects of human subjects research. This report has not 84 been reviewed for approval by the Agency

and, hence, the contents of this report do not 85 necessarily

represent the view and policies of the Environmental Protection Agency , nor of other 86 agencies in the Executive Branch of the Federal government, nor does the mention of trade 87 names or commercial products constitute a recommendation for use. Y ou may obtain further 88 information about the EP A Human Studies Review Board from its website at 89 http://www.epa.gov/osa/hsrb

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

90 mail at ord

- osa

- hsrb @epa.gov 91 92 In preparing this document, the Board carefull y considered all information provided and 93 presented b y the Agency presenters, as well as information presented b y public commenters. 94 This document addresse s the information provided and presented within the structure of the 95 charge b y the Agency

. 96**US ENVIRONMENT AL**  **PROTECTION AGENCY**  97 **HUMAN STUDIES REVIEW BOARD**  98 99 Chair 100 101 Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union 102 Graduate College and the Mount Sinai School of Medicine, Schenectady, NY 103 104 Vi ce Chair 105 106 Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH), School of Public Health and Human 107 Services, The George W ashington University

, W ashington, DC 108 109 Members 110 111 Janice Chambe rs, PhD, DABT, Fellow AT S, Wi lliam L . Giles Distinguished Professor, Director
, 112 Center for Environmental Health Sciences, College of V eterinary Medicine, Mississippi S tate 113 University

, Mississippi S tate, MS 114 115 George Fernandez, PhD, Professor of Applied Statis tics, Director of the University of Nevada

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

- Reno, Reno, NV 117 118 Vanessa Northington Gamble * , MD, PhD, University Professor of Medical Humanities, Professor 119 of Health Policy

and American Studies, The George W ashington University

, Wa shington, DC 120 121 Sidney

Green, Jr., PhD, Fellow of the AT S, Professor, Department of Pharmacology , Howard 122 University

College of Medicine, W

ashington, DC 123 124 Jewell H. Halan ych, MD, Assistant Professor, Department of Preventat ive Medicine, Universit y 125 of Alabama at Birmingham, Birmingham, AL 126 127 Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University
, 128 Manhattan, KS 129 130 Michael D. Lebowitz † , PhD, FCCP , Retired Professor of Public Health & Medicine, Universit y 131 of Arizona, T

ucson, AZ 132 133 José E. Manautou * , PhD, Associate Professor of T oxicology , Department of Pharmaceutical 134 Science, University of Connecticut School of Pharmacy , Storrs, CT 135 136 Jerry

A . Menikoff, MD, JD, Director, Of fice for Human Subjects R esearch, Of fice of the 137 Secretary

, Department of Health and Human Services, Rockville, MD 138 139 Wi lliam Popendorf, PhD, MPH, Professor Emeritus, Department of Biology , Utah State 140 University

, Logan, UT 141 142Leonard Ritter * , PhD, Professor Emeritus, School of Environmental Sciences, University of 143 Guelph, Guelph, ON, Canada 144 145 Vi rginia Ashb y Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, 146 Ve terans Health Administration, Wa shington, DC 147 148 Bernard A. Schwetz * , DVM, PhD, Director (Retired), Of fice o f Human Research Protections, 149 Department of Health and Human Services, Cadott, WI 150 151 Linda J. Yo ung, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 152 Sciences, University of Florida, Gainesville, FL 153 154 Human Studies Review Board St af f 155 156 Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science 157 Advisor, United States Environmental Protection Agency , W ashington, DC 158 159 160 * Not present on January 26, 2012. 161 † Participated in the January 26, 2012 meeting via tel epresence. 162**INTRODUCTION** 163 164 On January 26, 2012, the United States Environmental Protection Agency ’s (EP A or 165 Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues 166 concerning one new protocol for research involving human parti cipants: a study measuring 167 dermal and inhalation exposures associated with the mixing, loading and application of 168 pesticides using powered (gasoline or electric) handgun/hand wand equipment in greenhouses 169 and nurseries. In accordance with 40 CFR 26.1601, E PA sought HSRB review of this proposed 170 study

. This study

is discussed more full y below

. 171 172 In addition, the Agency has data from one completed study measuring dermal and 173 inhalation exposure of professional janitorial workers who clean indoor surfaces with an 174 antimicrobial pesticide product using hand

- held pressurized aerosol canisters

. Inaccordance with 175 40 CFR 26.1602, EP A sought HSRB review of this completed study . This study

is discussed 176 more fully

below

. 177 178 179 **REVIEW**

**PROCESS** 180 181 On January 26, 2012, the Board c onducted a public face

- to

- face meeting in Arlington, 182 Vi rginia. Advance notice of the meeting was published in the Federal Register as “Human 183 Studies Review Board; Notice of Publi c Meeting” (76 Federal Register 248, 80938). 184 185 Following welcoming remarks from Agency of ficials, the Board heard presentations from 186 EP A on the following topics: one new study protocol to measure dermal and inhalation exposures 187 associated with the mixing, loading and application of pesticides using powered (gasoline or 188 electric) hand gun/hand wand equipment in greenhouses and nurseries, and one complete d study 189 measuring dermal and inhalation exposure of professional janitorial workers who clean indoor 190 surfaces with an antimicrobial pesticide product using hand

- held pressurized aerosol canisters. 191 192 The Board also asked clarifying questions of several study sponsors and/or research 193 investigators, including: 194 195 Ms. Megan Boatwright, Analy tical Coordinator, Golden Pacific Laboratories. 196 Dr. V

ictor Cañez, Te chnical Chair
, Agricultural Handler E xposure Ta sk Force. 197 Dr. Richard Collier
, Administrative Committee Chair
, Agricultural Handler Exposure 198 Ta sk Force. 199 Mr. William McCormick III, Clorox, on behalf of the Antimicrobial Exposure 200 Assessment T ask Force II. 201 Mr. Robert Testman, V ice

- President, Gold en Pacific Laboratories. 202 203 204 Public oral comments were provided b y: 205 206 Dr. V

ictor Cañez, Te chnical Chair
, Agricultural Handler Exposure Ta sk Force 207Dr. Richard Collier
, Administrative Committee Chair
, Agricultural Handler Exposure 208 Ta sk Force. 209 Mr. Robert Testman, V ice

- President, Golden Pacific Laboratories. 210 211 One written public comment from a New Jersey resident was submitted, but the substance 212 of that comment was not directl y related to the two studies under review by the HSRB at the 213 January

26, 2012 meeting. 214 215 For their deliberations, the Board considered the materials presented at the meeting, oral 216 comments, and Agency background documents (e.g., published literature, sponsor and 217 investigator research reports, study protocols, data evaluation records, and Agenc y science and 218 ethics reviews of proposed protocols and completed studies). A comprehensive list of 219 background documents is available online at http://www.regulations.gov

. 220 221 222 **CHARGE TO THE BOARD AND BOARD RESPONSE**  223 224 **Assessment of Proposed AHETF Research Study AHE**

**- 600:**  **Mixing, Loading, and Applying** 225 **Liquid Pesticides in Managed Horticultural Facilities Using Powered Handgun Equipment** 

**.** 226 227 **Overview of the S tudy**  228 229 This proposal presents an agricultural handler exposure sce nario involving mixing, 230 loading and application of pesticides using powered (gasoline or electric) handgun/hand wand 231 equipment in greenhouses and nurseries. Pesticides can be formulated as either liquids or as 232 wettable powders. 233 234 A total of 30 participants (described in the protocol as “Monitoring Units” [MUs]) will be 235 observed; three volunteers from each of ten geographically distinct growing regions will be 236 enrolled using a purposive sampling method (with some elements of random selection). For each 237

scenario, volunteers will be randomized to mix and load a defined amount of active ingredient 238 within one of three strata : 0.5 to 1.6 pounds, 1.6 to 4.8 pounds of active ingredient, or 4.8 to 15 239 pounds of active ingredient. After mixing and loading the pesticide
, participants will use 240 powered equipment to treat ornamentals and nonbearing fruit trees in nurseries, or ornamentals 241 and vegetables grown in greenhouses, using spray patterns that include downward, outward and 242 upward directions. 243 244 For this protocol, all participants will wear long sleeved shirts, long pants, and shoes plus 245 socks. In addition, all participants will wear chemical resistant gloves. Additional personal 246 protective equipment (PPE) may be required depending on product labeling directions, including 247 the use of chemical

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

248 resistant headgear when making overhead applications. 249 250 Dermal exposure will be measured b y a whole body dosimeter worn beneath the subject’ s 251 outer clothing. Hand wash and face/neck wipe samples will also be collected prior to, during, and 252 after completion of pesticide loading and mixing procedures. For study participants wearing 253chemical

- resistant headgear
, patches placed inside and outside of the headgear will be employed 254
to estimate dermal exposure of the protected portions of the body covered by

these garments. 255 256 Airborne concentrations of the surrogate will be monitored in the participant’ s breathing 257 zone using an OSHA V ersatile Sampler (OVS) tube connected to a personal sampling pump. 258 Additional measures will also record environmental conditions at the time of monitoring, and 259 observers will make field notes, photographs and videos of participant activity throughout the 260 monitoring event. 261 262 The results of samp le analy sis under the powered handgun scenario will be posted to the 263 Agricultural Handlers Exposure Database (AHED®), where they will be available to the EP A 264 and other regulatory agencies for statistical analysis. The proposed documentation will report a 265

c onfidence interval

- based approach to determine the relative accuracy for the arithmetic mean 266 and 95th percentile of unit exposures. The Agency proposes to use these data to estimate daily 267 dermal and inhalation exposures of agricultural handlers who mix, lo ad and apply pesticides 268 using powered handgun equipment. 269 270 **Science** 271 272 **Charge to the Board** 273 274 If the AHETF proposal is revised as suggested in EPA’s review and if the research is 275 performed as described, is the research likel y to generate scientificall y reliable data, useful for 276 assessing the exposure of workers mixing, loading and appl yi ng pesticides in managed 277 horticultural facilities using powered handgun equipment? 278 279 **Board Response to the Charge** 280 281 HSRB Recommendation 282 283 The Board concluded that the protocol sub mitted for review, if modified in accordance 284 with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to generate 285 high qualit y, reliable and useful data for assessing worker’s pesticide exposures in horticultural 286 settings. 287 288 Several comments or suggestions were made by the Board with respect to the use of PPE, 289 the potential effect of unanticipated incidental exposures and other variables on proportionality
, 290 and the utility

of existing European Crop Protection Association (ECP A) data. 291 292 HSRB Detailed Recommendations and Rationale 293 294 This protocol, a study designed to measure dermal and inhalation exposure of agricultural 295 workers who mix, load and apply pesticides in nurseries or greenhouses using a hand

- held 296
sprayer or gun, was well thought out and well designed. The study sponsors (Collier 201 1) 297 found no suitable existing information that could constitute some of the MUs for this particular 298 scenario; consequently , the entire scenario has to be conducted. The design requires ten (10) 299regi ons with three (3) MUs per region, for a total of 30 MUs. The rationale for this design is that 300 there are relativel y few nurseries and greenhouses that would be suitable for this scenario in 301 most, if not all, regions of the United States. Similarity restri ctions will be imposed to assure 302 diversity

. The investigators consulted several information sources to identify locations with 303 suitable nurseries or greenhouses that could be venues for the conduct of this scenario. The areas 304 of the country

selected repres ent a variet y of climatic and geographic conditions, likely providing 305 the representativeness and diversity sought for the scenario. Given these factors and 306 considerations, the Board determined that the proposed study design is reasonable. 307 308 The scenario wi ll include several tasks: mixing/loading of the pesticide product, open 309 pouring of the formulated product, application of the product to the plants, and potentially some 310 cleaning. The objective is to demonstrate proportionality between the amount of active ingredient 311 handled (AaiH) and exposure level. One concern that was raised by the Board was that 312 proportionality

may not be observed due to the high variability of unanticipated incidental 313 exposures (e.g., accidentally touching a treated plant or contamin ated part of spray equipment in 314 some settings but not others), and these sources may contribute substantially

to participants’ 315 exposure levels. Because workers may be close to some of the sprayed plants in a setting such as 316
a nursery

, it seems likel y that unintended contact of workers with these plants might easily occur

. 317 In scenarios where unanticipated incidental exposures are likely to occur, it will be important for 318 researchers to observe and document all unintentional contacts with treated plants or other events 319 that might contribute to the exposure levels. However , even if proportionality

is not seen

-- 320 particularl y if the results are attributable to observed unanticipated exposures

-- this scenario will 321 still provide valid information about worker exp osure when using a powered handgun or hand 322 wand in a horticultural setting. 323 324 The Board provided additional recommendations and advice to the Agency about 325 personal protective equipment (e.g., chemical

- resistant headgear), respirators, the many sources 326 of di versity

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

327 resistant headgear be worn, the use of patches inside the headgear should yi eld valid estimates of 328 exposure for those participants wearing such a hat (an issue previo usl y raised at the April 201 1 329 HSRB meeting [EP A HSRB 201 1]). However, this method may underestimate exposures if 330 attempts were made to extrapolate these data to those not wearing such headgear . Such 331 extrapolation may not be an explicit intent, but the Ag ency states its plans to use the head 332 exposure data to develop mitigation strategies (e.g. Evans, Sarkar and Sherman 201 1, 1 1). The 333 eff

ect of the protection afforded b y the brim of the chemical

- resistant headgear would negativel y 334 aff

ect that use. Thus, th e Board suggested that the sponsors consider: 1) having study participants 335 use chemical

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

the W orker 336 Protection Standards); or 2) add a third patch dosimeter against the head below the brim, a s the 337 density of deposition (μg/cm 2 ) onto this patch could be compared to the deposition onto the rest 338 of the face to estimate the magnitude of protection af forded by such a brim. 339 340 The Board also discussed the use of respirators and half

- masks in the scenario, and how 341 to handle the impact that use of such PPE might have on dermal exposure levels. For example, 342 the Board raised concerns about whether the measured skin exposure to the face would be 343 adjusted upward in proportion to the area of the face/neck co vered b y a respirator

. Although the 344Agency

responded af

firmatively

, this adjustment was not stated in the protocol or the Agency ’s 345 review of the protocol. 346 347 Several Board members noted that there are many sources of diversity in this scenario. 348 As a res ult, it may be dif ficult to test the numerous variables to the degree the Agency intends for 349 identifying statistically significant dif

ferences. V

ariables that may

influence the proposed 350 exposure data include: 351 352 1. The predominant direction of spray (downward, outward, or upward); 353 2. Whether or not the MU does “minor clean

- up”; 354 3. Whether the MU uses a handgun or a hand wand; 355 4. Whether the MU applies the pesticide indoors or outdoors; 356 5. The width of the path through which the applicator must pass, as determined by 357 faci lity t ype (i.e., ornamental greenhouse, vegetable greenhouse, nursery), which may 358
or may not be a surrogate for the proximity of foliage; 359 6. The formulation ty pe mixed (liquid or solid/wettable powder); and 360 7. The mixing sequence (pre

- mix or tank mix). 361 362 The B oard also considered issues related to the Agency ’s recommendation to include 363 wettable powder b y at least one partic ipant in each cluster (Evans, S arkar and Sherman 201 1, 4). 364 In particular, concerns were raised about the use of two formulation ty pes (wett able powder and 365 liquid) in the scenario; this could be seen as akin to conducting two studies. The lack of clarity as 366 to how many

participants would use the wettable powder in each cluster is problematic for 367 assessing the recommended study design and field conduct. The number of MUs who would 368 handle the powder versus liquid formation is critical for statistical and analytical questions to be 369 fully

answered. If both formulations are to be used, the Board recommended that the Agency 370 conduct a separate anal ys i s of each t ype before combining all of the data for anal ys is. If the 371 intent is to maximize the power of detecting a difference attributable to this variable, then the 372 sponsor could have 15 MUs use the powder formulation and 15 MUs use the liquid formulatio n. 373 Alternatively

, all MUs could use the wettable powder, as that formulation ty pe is more likely

to 374 generate more conservative exposure data. 375 376 Finally

, the Board cautioned the Agency and the sponsors that the justification for the 377 study

may be weak. In p articular, the Board raised a question about the utility of ECP A data. 378 The Agency ’s rationale for not using those data was that the proposed AHETF scenario involves 379 individual workers performing both mixing/loading and application activities, whereas the ECP A 380 exposure data was collected from agricultural handlers involved only in the application of 381 pesticides. The Board was not convinced, however, that this dif ference precludes the use of 382 existing ECP

A data. While there may be other scenario or data qual ity issues with the ECP

A 383 data, the Board recommended that the Agency consider the viability

of combining the ECP

A 384 application

- only

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

- only exposure data to 385 satisfy

the Agency ’s registration needs without further human exposure studies. Despite this, the 386 Board noted that the amount of active ingredient handled might be very different for the 387 proposed scenario and the existing ECP A data set; if true, then the existing data sets might not be 388 useful in assessing w orker exposure in this horticultural scenario. 389 390**Ethics** 391 392 **Charge to the Board** 393 394 If the AHETF proposal is revised as suggested in EPA’s review and if the research is 395 performed as described, is the research likel y to meet the applicable requirements of 40 CFR part 396 26, subparts K and L ? 397 398 **Board Response to the Charge** 399 400 HSRB Recommendation 401 402 The Board concluded that the protocol submitted for review, if modified in accordance 403 with EPA (Evans, Sarkar and Sherman 2011) and HSRB recommendations, is likely to meet the 404 applicable requirements of 40 CFR 26, subparts K and L. 405 406 HSRB Detailed Recommendations and Rationale 407 408 The submitted documents assert that the study will be conducted in accordance with the 409 ethical and regulatory standards of 40 CFR 26, Subparts K and L, a s well as the requirements of 410 the US EPA’s Good Laboratory Practice (GLP) Standards described at 40 CFR 160, and, for 411 research conducted in California, the California State EPA Department of Pesticide Regulation 412 study

monitoring (California Code of Regulat ions Title 3, Section 6710) (Collier 2011). 413 Requirements of FIFRA §12(a)(2)(P) also appl y. Researchers who participate in the study and 414 interact with study participants will be required to undergo ethics training. The training will 415 include the successful completion of the course from the National Institutes of Health (Protecting 416 Human Research Participants) and/or the Basic Collaborative IRB Training Initiative Course. 417 418 The protocol was reviewed and approved b y an independent human subjects review 419 committee, IIRB, Inc. of Plantation, FL , prior to submission. IIRB, Inc. is fully accredited b y the 420 Association for the Accreditation of Human Research Protection Programs (AAHRPP). IIRB, 421 In c. is also listed as an active Institutional Review Board (IRB) on the O ffice of Human 422 Research Protection (OHRP) website (Reg. #IORG0002954). Copies of all correspondence with 423 IIRB, Inc. (Collier 2011) and a cop y of IIRB, Inc. policies and membership roster were provided 424 (IIRB, Inc. 2010; 2011). These documents indicate that IIRB, Inc. reviewed this protocol 425 pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A). 426 427 1. The Board concurred with the conclusions and factual observations of the ethical strengths 428 and weaknesses of the study , as detailed in the EPA’ s Ethics Review (Evans, Sarkar and 429 Sherman 2011). The proposed study is likely to meet the applicable ethical requirements for 430 research involving human subjects, in accordance with the following criteria: 431 432

a. Societal value of the proposed research. The clearly stated purpose of the proposed 433 monitoring study is to develop data to determine the potential exposure for workers who 434 mix, load, and apply liquid pesticides using powered handgun equipment in managed 435 horticultural facilities in the United States. This mixing/loading/appl yi ng method is 436applicable to a large variety of commercially

important crops associated with the nursery 437 and greenhouse industry across the US and Canada, and the existing exposure data are 438 likely

inadequate. This study

will provide a partial answer to the question of what dermal 439 and inhalation exposures are likel y for workers who mix/load and apply pesticide 440 products using handguns and hand wands in nurseries and greenhouses. EPA will use the 441 results of this study to estimate the de rmal and inhalation exposure likely for a wide 442 range of agricultural pesticides mixed, loaded, and applied under this exposure scenario. 443 444 b. Subject selection and informed consent. The inclusion/exclusion criteria are complete 445 and appropriate. Pregnant or nursing women are excluded from participation. Pesticide 446
compan y emplo yees and contractors to the AHETF are also excluded from participation. 447 Protections are adequate even if a subject were from a vulnerable population. Informed 448 consent will be obtained f rom each prospective subject and appropriatel y documented in 449 the language (Spanish or English) preferred b y the subject. Recruitment materials and 450 interactions with potential subjects will be conducted in English or Spanish, depending 451 on subject preference . The Board agrees with EPA’s suggestion that it is preferable for 452 recruitment discussions to take place away from the work site, to minimize the potential 453 for coercion and that the protocol should describe the ty pes of locations where 454 recruitment discussi ons between researchers and potential subjects will take place, 455 clarifying whether these discussions will take place at the work site or at locations that 456
are away

from the work site. The proposed monetary compensation is not so high as to 457 unduly

influence participation. Candidates and subjects will be repeatedl y informed that 458 they

are free to decline to participate or to withdraw at any time for any

reason, without 459 penalty

. 460 461 Depending on the number of emplo yees and size of the grower’s facility, the Study 462 Director or researcher may contact employees using an informational recruitment flyer 463 posted in a common work area. Alternativel y, or subsequent to the use of a flyer, the 464 Study

Director or researcher will arrange a meeting with the grower’s employees who 465 express interest in participation. Such recruitment meetings will alway s occur without 466 supervisors being present. The Study Director or researcher will describe the AHETF 467 Exposure Monitoring Program, the goals of this specific study, the procedures to be used 468 in exposure monitoring, and the risks and benefits to participants. The subject eligibility 469 factors listed in the consent form and SOP AHETF

- 11.B.6 are appropriate. Candidates 470 who attend an individual interview will be paid $20 whether or not they agr ee to 471 participate; enrolled subjects who put on the whole

- body dosimeter will be paid $80 in 472 addition to their usual pay, whether or not they complete participation. 473 474

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

- registered products registered for 475
nursery

and/or greenhouse use and the specific application planned by the grower, and 476 will be used in full compliance with the approved labels. All identified risks are 477 characterized as of low probability , and risks are further minimized by exclusion o f 478 candidates who self

- report that they

are in less than “good” health; alerting subjects to 479 signs and s ymptoms of heat stress; monitoring heat index with associated stopping rules; 480 close observation of subjects; training of experienced technicians to minim ize 481 embarrassment; incorporation of procedures to keep results of pregnancy testing private 482and to permit discrete withdrawal; provision of appropriate work clothing and PPE. 483 Provision is made for discrete handling of the pregnancy testing that is required of female 484 subjects on the day of testing. 485 486 Five kinds of risks to subjects are discussed in the protocol, along with specific steps 487 proposed to minimize them: the risk of heat

- related illness; the risk associated with 488 scripting of field activities; psych ological risk; the risk of exposure to surfactants, and; 489 the risk of exposure to surrogate chemicals. In this study , risks to subjects are classified 490 as ‘greater than minimal’ since the likelihood of harm or discomfort is greater than what 491 is encountered in ordinary dail y life. In particular, the risk of heat

- related illness 492 (resulting from wearing an extra layer of clothing to trap the chemical) will be increased 493 due to study participation. AHETF has adopted an extensive program to minimize these 494 risks. Appropriate provision is made for safety and medical monitoring. The protocol also 495 incorporates procedures to keep results of pregnancy testing private and to permit discrete 496 withdrawal of a study subject. Finall y, the protocol incorporates procedures to e nsure 497 that no photographs or videos will be taken in which a worker can be readily identified. 498 499 d. Benefits to participants . This research offers no direct benefits to the subjects. The 500 principal benefit of this research is likely to be reliable data abo ut the dermal and 501 inhalation exposure of people mixing, loading and application of pesticides using 502 powered handgun equipment. These data are intended to be used b y EPA and other 503 regulatory agencies to support exposure assessments for a wide variet y of ant imicrobial 504 products and their uses. 505 506

e. Risk/benefit balance. Risks to subjects have been thoughtfull y and thoroughly minimized 507 in the design of the research. The low residual risk is reasonable, in light of the likely 508 benefits to societ y from new data su pporting more accurate exposure assessments for 509 antimicrobial products. 510 511 2. In addition to this analy sis, the Board recommended a few edits to improve the clarit y of the 512 In formed Consent Form. These are listed below, organized according to the section within 513 the Informed Consent Form in which they appear. In particular, in the past the Agency and 514 the Board have suggested that protocols and consent forms clarify the steps that participants 515 should take if participants have an adverse reaction within 24 hours . This was not included in 516 the materials provided b y the AHETF, and the Board recommends that such information be 517 included on the consent form. 518 519

• Introduction and Purpose : 520 521

“ If you do **In order to** take part in this study , you must read and sign this consent form” 522 (L ine 4). 523 524

• Procedures Before the Start of the Study : 525 526 Modify

the language per the protocol (p. 248/SOP II.D.2) to clarify that the pregnancy

test 527 will be taken prior to the start of the study : 528529 8. If you are female, within 24 hours of **prior to** start ing the study you will perform an 530

over

- the

- counter pregnancy test. If there is a delay in the start of the study of more than 24 531 hours, another pregnancy test may be needed. The negative results of your pregnancy test 532 will be verified b y a female member of the study

. 533 534

• Injury

to Participants: 535 536 Add a line indicating the name and contact information of the Study Director or other 537 individual to be contacted if the participant experiences an adverse event within 24 hours. 538 539 3. The Board agreed with the Agency that information about potential psychological and social 540 harms related to unwanted disclosure of test results and breach of confidentiality associated 541 with photographs or video may be included in the protocol (Evans, Sarkar and Sherman 542 2011). However, the B oard recommended that this information not be included in the 543 informed consent form as it might give participants the erroneous impression that these risks 544 are particularl y significant or that appropriate steps have not been taken to mitigate them. 545 546 547 **Asse ssment of Completed AEATF II Research Study AEA** 

**- 04:**  **Measurement of Potential** 548 **Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide** 549 **Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting**

**.** 550 551 **Overview of the S tu**  **dy** 552 553 AEATF II aerosol spraying scenario was designed to measure a typical occupational 554 handler’s dail y exposure to an antimicrobial spray ( containing C14 alkyl dimethyl benz yl 555 ammonium chloride [ADBAC ]) packaged in a commercially

- available pressurized aero sol spray 556

can. 557 558 Eighteen (18) professional janitors were enrolled in the study , and applied (but did not 559 wipe) the product on surfaces at one of three motels in the Fresno, CA area. Study participants 560 were randomized to apply different amounts of product , from one (1) to four (4) cans of product 561 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). 562 563 Participants wore a variety of clothing combinations, ranging from short pants and short 564 sleeved shirts with shoes plus socks, to long pants and long sleeved shirts with shoes plus socks. 565 No participant wore gloves, but participants were given the option of wearing a respirator during 566 product application; all 18 subjects elected to wear respirators during monitoring. All 567
participants wore inner and outer sets of whole

- body dosimeters that were sectioned and 568 anal yz ed separatel y. 569 570 Dermal exposures were measured using whole

- body dosimeters (inner and outer), and 571 hand and face washes. Dermal unit exposures (reported in mg/lb A aiH) were calculated b y 572 dividing the summed total exposure by AaiH. The study

sponsor report normalized the dermal 573exposures by milligrams (mg) of active ingredient applied, but these exposure data were 574 recalculated b y the Agency and expressed as mg/lb of active ingredient applied. 575 576 Inhalation exposures were measured using a personal air sampling pump and OVS tubes 577 plus a separate pump used to run a RespiConTM Particle Sampler. This allows for collection and 578 anal ys is of inhalation exposure monitoring result s as total particles, as inhalable particles (<100 579 μm), as thoracic particles (<10 μm), and as respirable particles (<2.5 μm). Inhalation unit 580 exposures (reported in mg/m 3 /lb AaiH) were calculated by dividing the air concentrations by 581 AaiH. 582 583 The data will be posted to the Biocide Handlers Exposure Database (BHED ® ). The 584 Agency

plans to use these data generically to estimate dermal and inhalation exposures and risks 585 for other antimicrobial ingredients where the applied product is packaged in a pressurized 586

ae rosol spray

can. Although the scenario as performed did not include the subsequent wiping of 587 the aerosol spray

solution, the Agency

believes that dermal and inhalation exposure that results 588 from the subsequent wiping of spray ed antimicrobial solutions can be determined by combining 589 the results of this study with the results of the previously AEATF II conducted ready

- to

- use 590 (RTU) wipe study (favorably reviewed at the April 2011 HSRB meeting; EPA HSRB 2011). 591 592 **Science** 593 594 **Charges to the Board** 595 596 Was the research reported in the AEATF II completed aerosol study report faithful to the 597 design and objectives of the protocol and governing documents of the AEATF? 598 599 Has EPA adequately characterized, from a scientific perspective, the limitations on these 600 data that should be considered when using the data in estimating the exposure of professional 601 janitorial workers who apply liquid antimicrobial pesticide products to indoor surfaces using 602 pressurized aerosol cans? 603 604 **Board Response to the Charge** 605 606 HSRB Recommendation 607 608 Th e Board concluded that the research reported in the completed monograph, associated 609 field study

reports, and associated supplemental documents was conducted in a manner that was 610 reasonabl y faithful to the design and objectives of the protocol and governing documents of the 611 AEATF. 612 613 The Board also concluded that the Agency has adequatel y, but not completely, 614 considered the limitations in this study when using the data in estimating the dermal and 615 inhalation exposure of those who appl y liquid antimicrobial p esticide products for indoor surface 616 disinfecting using a pressurized aerosol can. In particular, the Board noted several issues, 617 limitations and concerns with the data and anal ys es. These are described in greater detail below. 618 619HSRB Detailed Recommendati ons and Rationale 620 621 The Board concluded that the study (Testman and Boatwright 2011) was done 622 thoroughl y, yi elding detailed and helpful data that appear to be reliable. Some data trends were 623 not explained in the accompanying Agency anal ys is, but overall th e diversity of subjects and 624 settings were strengths of the study

. 625 626 The Board agreed with the Agency that the number of participants was adequate to 627 achieve the primary benchmark accuracy

goal. The Board also agreed that the modest diversity 628 of applicati on settings was a reasonable attempt to offset the practical limitation of recruiting and 629 assessing all exposures within one geographic area. The documented diversity in application 630 behaviors indicates the robust nature of the resulting exposure data. 631 632 T he Agency's anal ys es of protocol deviations and of the blank, fortified field, and lab 633 samples were acceptable. In addition to the deviations noted in the final report (Testman and 634 Boatwright 2011, 1033

- 104) or by the Agency

(Leighton 2012, 9), however, the Board identified 635 a few more. For example, subject AE4 was apparently observed to be appl ying the product to 636 surfaces at much heavier rates than usual. About 20% of the way into the sampling time, the 637 study

director instructed this subject to “lighten up ” in their application (Testman and Boatwright 638 2011, 488). This intervention comprises an unknown limitation that may have had a large effect 639 on reducing a potentiall y high exposure. Alternatively , it may have had no significant effect and 640 was unjustified in terms of protecting the subject. Although no specific prohibition against such 641 interventions was found in the protocol, such instructions regarding applicator behavior were 642 counter to the intent of the protocol (i.e., that the study participants “spra y surfaces as they would 643 normally

do” [T estman and Boatwright 201 1, 18]). Thus, it is unclear whether this event actually 644 qualifies as a protocol deviation. However, the lack of an explicit prohibition of study director 645 intervention raised issues in this s tudy ’s anal ys is and interpretation. Guidance about how to 646 handle interventions should be incorporated into future protocols and standard operating 647 procedures (SOPs). 648 649 Subject AE18 (in cluster #1) was a borderline outlier without any indication in the fie ld 650 notes of intervention b y the researchers. The Board did not disagree completely with the 651 Agency ’s conclusion that AE18’s data was not an outlier (Leighton 2012, 15), but believed that 652 one particular combination of these data

-- application rate

-- refl ects the characteristics of an 653 outlier. However, the Board did not advocate excluding this data point from subsequent 654 anal ys es. Rather, these sometimes substantial differences provide additional support for the 655 diverse and therefore broadly representative nature of the subjects and the qualitatively robust 656 nature of the study results. 657 658 The Board also discussed outliers in laboratory recovery data. These data were not used 659 by the Agency

to correct field samples; the Board agreed with the EPA’s approach. However, 660 the lack of explicit procedures for handling outliers raised questions among Board members. 661 Explicit discussions about when data should or should not be excluded should be incorporated 662 into future protocols and SOPs. 663 664The Board raised concerns that the 20% higher flow rates (or discharge rates) from the 665 batch of aerosol cans used in the first four MEs, as compared with the flow rates from those cans 666 used in the last 14 MEs, could cause an appreciable difference in exposure (Leighton 2012, 9). 667 Ty

pi cally , a faster discharge rate through a given nebulizer produces smaller droplets. An 668 anal ys is of variance for data in this study found a statistically

significant difference between the 669 average fraction of the a.i. <10 μm in the first four RespiConTM samples and the last 14 samples 670 (44% versus 55%, respectively ; p < 0.00001). This difference is consistent with the expectation 671 that the first batch of canisters may have produced particles with a mass median aerody namic 672 diameter just over 10 μm and the last batch particles with a mass median aerody namic diameter 673 just under 10 μm. The difference in particle size is more likely to have been due to the reported 674 difference between flow rates than the difference in ADBAC concentration in the product. 675 Notably , th e impact of this probable shift to slightly smaller droplets is small in comparison to 676 the much wider variation in flow rates and particle sizes among the many other products these 677 studies are intended to represent. 678 679 The Board also raised concerns that the ventilation data presented were unclear, 680 inadequatel y recorded, and inadequatel y interpreted (Testman and Boatwright 2011, 119

- 20). 681 For example, “fresh air” was presented using different metrics (e.g., %, total fan cubic feet per 682 minute [CFM], and CFM fr esh air). Furthermore, the reported air changes per hour seem to 683 differ from separatel y calculated values b y factors of 1.5

- to 3

- fold. Anal ys es by one Board 684 member suggest that the overall effect of the deficiencies may have been small; the amount of 685 tim e that participants spent in each room was so short that airborne ABDAC was just beginning 686 to accumulate b y the time the subjects left the space, limiting the effect of ventilation on overall 687 rates of exposure. However, the Board recommended that the Agen cy consider the potential 688 limitations associated with the heating, ventilation and air conditioning s ys tems in the test 689 facilities. 690 691 The Agency requested the Board’s advice on the use of RespiConTM versus OVS results. 692 The major advantage of the RespiConTM ai r samples is their ability to look at the data b y size 693 ranges. A disadvantage of collecting RespiConTM samples is the challenge of confronting the 694 difference inherent in the entrance losses of an y two air samplers. Such losses are a 695 characteristic primaril y of entrance diameters and flow rates, but also of the shape of those 696 entrances and their orientation, and the air velocity and particle diameters in any given setting. 697 These characteristics affect both the RespiConTM and OVS samples. Unfortunately , it a ppears 698 that no tests could be found in the literature comparing the OVS with the RespiConTM sampler 699 (e.g., Leighton 2012, 35

- 7). Thus, there is no reliable basis upon which to correct the 700 RespiConTM to the OVS data. For the purposes of calculating dose via inhalation, however, the 701 Board recommends that the <10 micron

- size results from RespiConTM monitors be used because 702 this size range represents the fraction that enters the respiratory tract and thus provides a more 703 conservative estimate of inhalation exposure. 704 705 The Board suggested that the dermal and inhalation exposure data be combined to obtain 706 total exposure results. The Board also questioned whether a slope of 1.5, with a confidence 707 interval (CI) including one (1), should be considered as evidence of proportionality

. 708 Furthermore, a CI that does not include one may not provide adequate protection. The Board 709 thus recommended that the Agency alway s clarify coefficients over one. Finally , the Board 710recommended that the Agency and the Task Force refrain from using the word ‘proportional’ 711 without preceding it by an adjective such as 1:1 proportional or 1:2 proportional. 712 713 **Ethics** 714 715 **Charge to the Board** 716 717 Does available information support a determination that the study was conducted in 718 substantial compliance with subparts K and L of 40 CFR Part 26? 719 720 **Board Response to the Charge** 721 722 HSRB Recommendation 723 724 The Board concurred with the Agency ’s assessment (Sherman 2012) that the study 725 submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 726 Part 26. 727 728 HSRB Detailed Recommendation and Rationale 729 730 The documents prepared by Golden Pacific Laboratories, LL C, and submitted by 731 American Chemi stry Council Antimicrobial Exposure Assessment Ta sk Force II under Project 732 No. AEA

- 04, state that the stu dy was conducted in compliance with the requirements of the 733 EP

A’ s Good Laboratory

Practice (GLP) Standards; FIFRA §12(a)(2)(P); and the applicable 734 subparts of 40 CFR 26 (T estman and Boatwright 201 1). 735 736 The protocol was reviewed and approved b y an independ ent human subjects review 737 committee, IIRB, Inc. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and 738
a cop y of IIRB, Inc. policies and procedures were provided. This IRB is fully accredited b y 739 AAHRPPand registered with OHRP (see detai ls above). Documentation provided to the EPA 740 indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule (45 741 CFR Part 46, Subpart A) and found it in compliance (IIRB, Inc. 2010; 2011). 742 743 1. The Board concurred with the conclus ions and factual observations relating to the study , as 744 detailed in the EPA’s Ethics Review (Sherman 2012). Specificall y: 745 746

a. Prior HSRB and Agency Review. The requirements of 40 CFR §26.1125 for prior 747 submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol 748 were satisfied. The study ( Te stman and Boatwright 2011) was conducted in accordance 749 with the protocol previously reviewed b y the Agency (Leighton, Walls and Sherman 750 2009) and b y the HSRB (EPA HSRB 2009). Neither the Agency’s no r the HSRB’s ethics 751 reviews identified an y significant deficiencies requiring correction relative to 40 CFR 26, 752 subparts K and L, or to FIFRA § 12(a)(2)(P) (Leighton, Walls and Sherman 2009). 753 Because the study was conducted in California, the approval of the California 754 Department of Pesticide Regulation (CDPR) was also required before the study could be 755initiated. CDPR granted final approval of the amended protocol and supporting 756 documents on April 19, 2010. 757 758 b. Responsiveness to HSRB and Agency Reviews. Fo llowing HSRB review, the protocol and 759 consent form were modified to incorporate changes responsive to the all of the comments 760 of EPA (Leighton, Walls and Sherman 2009) and the HSRB (EPA HSRB 2009). 761 Additional corrections and amendments were also requested by CDPR. IIRB, Inc. granted 762 approval to the amended protocol and supporting documents on April 6 and April 7

- 9, 763 2010, respectivel y ( Te stman and Boatwright 2011; Sherman 2012). 764 765

c. Substantial Compliance with Reporting Requirements (40 CFR Part 26 subpart M). The 766 AEATF II’s submission ( Te stman and Boatwright 2011), along with the separatel y 767 submitted documents describing the procedures and roster of the IRB ( IIRB, Inc. 2010; 768 2011), fully meet the requirements of 40 CFR §26.1303 to document the ethical condu ct 769 of the research. 770 771 2. The Board concluded that this study , as conducted, met all applicable ethical requirements 772 for research involving human participants, in accordance with the following criteria that had 773 been stated in the Board’s prior review of this study protocol (EPA HSRB 2009): 774 775

a. Acceptable risk

- benefit ratio. The risks to study participants were minimized 776 appropriatel y and were justified by the potential societal benefits, particularly data on the 777 dermal and inhalation exposure of professional janitorial workers to antimicrobial 778 compounds as they sprayed indoor surfaces with aerosolized pesticides. These data could 779 be used to develop mechanisms to protect future users of these antimicrobial pesticides. 780 781

• Minors and pregnant or lactating women wer e excluded from participation, with 782
pregnancy confirmed by

over

- the

- counter pregnancy testing on the day

of study or b y 783 opt

- out. The potential of stigma resulting from study exclusion was also appropriatel y 784 minimized. 785 786

• Clear stopping rules and medical man agement procedures were in place, and no adverse 787 events or other incidents of concern related to product exposure were reported. 788 789

• The study was designed to minimize the risks of exposure to the test compounds. 790 791 b. Vo luntary and informed consent of all part icipants. 792 793

• The study protocol included several mechanisms designed to minimize coercive 794 recruitment and enrollment. 795 796

• Monetary compensation was not so high as to unduly influence participation. Minors 797 and pregnant or lactating women were excluded from part icipation, with pregnancy 798 confirmed b y over

- the

- counter pregnancy testing on the day

of study or b y opt

- out. The 799 potential of stigma resulting from study exclusion was also appropriatel y m inimized. 800 8013. Although the first study participants were enrolled in April 2010 and monitoring began in 802 June 2010, shortly thereafter the study

was placed on ‘hold’as the result of an issue raised 803 by

CDPR. In response to a request from some participants to wear a respirator while 804 engaged in study related tasks, the AEA TF II decided to of

fer all study

subjects the option 805 of wearing a half

- mask respirator fitted with organic vapor cartridges. This decision was 806 made after consulting with the Agency and with the IRB, and the amended protocol and 807 informed consent forms were revie wed and approved by the IRB. Upon receipt of the 808 approved protocol amendment, CDPR requested that the study be halted temporarily

until 809 Golden Pacific Laboratories could conduct an additional review of its procedures for 810 respirator use. CDPR granted approv al for the amended protocol on May 1 1, 201 1. 811 812 This hold is unlikely to have affected the integrity of the research or the safety of 813 participants. In fact, b y al lowing subjects to wear a respirator, the researchers further 814 minimized potential risks to study participants. All 18 monitored subjects used a respirator, 815 which was fitted b y a trained study investigator and worn under the supervision of a 816 registered study nurse. 817 818 4. S everal minor deviations from GLP were reported by

the study sponsors (Testman and 819 Boatwright 201 1, 3), but these were unlikel y to have affected the integrity of the research 820 or the safet y of participants. Only one of these deviations bears further discussion, namely 821 the enrollment of a participant who self

- reported that his health was onl y “fair,” despite the 822 requirement that all participants be in “good health” (T estman and Boatwright 201 1, 227). 823 This same issue was discussed by the HSRB during its October 2010 and April 201 1 824 meetings (EP A HSRB 2010; 201 1), at which time the Board recommen ded that the study 825 sponsors clarify the criteria used to establish participants’health status prior to enrollment. 826 Enrollment of this particular participant, however, happened prior to those two Board 827 meetings. Furthermore, although formall y enrolled in the study , this participant was not 828 one of the 18 subjects monitored. Thus, the Board concluded that this deviation did not put 829 the participant at increased risk. 830**REFERENCES** 831 832 Collier, R. for the Agricultural Handler Exposure T ask Force (AHETF). 2011. Mixing , L oading 833 and Application of Pesticides in Managed Horticultural Facilities using Powered Handgun 834 Equipment (AHETF Study No. AHE600). Dated October 24, 2011. Unpublished document 835 prepared for the AHETF, 474 p. 836 837 EP

A Human Studies Review Board. 2009. October 21

- 22, 2009 Human Studies Review Board 838 Meeting Report. 26p. 839 840 EP

A Human Studies Review Board. 2010. October 27

- 28, 2010 Human Studies Review Board 841 Meeting Report. 31p. 842 843 EP

A Human Studies Review Board. 201 1. Apri l 13

- 14, 201 1 Human Studies Review Board 844 Meeting Report. 31p. 845 846 Evans, J., B. Sarkar, and K. Sherman. 201 1. Science and Ethics Review of AHETF Scenario 847 Design and Protocol AHE600 for Exposure Monitoring of W orkers during Mixing, Loading and 848 Application of P esticides in Managed Horticultural Facilities using Powered Handgun 849 Equipment. Dated December 30, 201 1. Unpublished document prepared by the Of fice of 850 Pesticide Programs, United States Environmental Protection Agency . 57p. 851 852 Independent Institutional Revie w Board, Inc. (IIRB, Inc.). 2010. Human Research Protection 853 Program Plan (HRPP Plan). Dated November 3, 2010. Unpublished document prepared b y IIRB, 854 In c. 131p. 855 856 IIRB, Inc., 201 1. IRB Membership Roster. Dated September 12, 201 1. Unpublished document 857
prepare d by

IIRB, Inc. 1p. 858 859 Leighton, T., C. Walls and K. Sherman. 2009. Science and Ethics Review of AEATF II Aerosol 860 Scenario Design and Protocol for Exposure Monitoring. Dated September 21, 2009. 861 Unpublished document prepared b y Office of Pesticide Programs, United States Environmental 862 Protection Agency . 52p. 863 864 Leighton, T. 2012. Science Review of the AEATF II Aerosol Human Exposure Monitoring 865 Study . Dated January 3, 2012. Unpublished document prepared by Office of Pesticide Programs, 866 United States Environment al Protection Agency . 38p. 867 868 Sherman, K. 2012. Ethics Review of Completed AEATF II Aerosol Scenario Worker Exposure 869 Monitoring Study

. Dated January 4, 2012. Unpublished document prepared by the Of fice of the 870 Director, Of

fice of Pesticide Programs, United St ates Environmental Protection Agency . 20p. 871 872 Te stman, R.J. and M.T . Boatwright, for the AEA TF II. 201 1. A Study for Measurement of 873 Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial 874 Pesticide Product Using a Pressurized Ae rosol Can for Indoor Surface Disinfecting. Dated 875November 14, 201 1. Unpublished document prepared by the Golden Pacific L aboratories, LLC, 876 for the AEA

TF II. 1851p. MRID 48659001. 877