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1 EPA-HSRB-10-02

2

3 Paul Anastas, PhD

4 EPA Science Advisor

5 Office of the Science Advisor

6 1200 Pennsylvania Avenue, NW

7 Washington, DC 20460 

8

9 Subject: October 27-28, 2010 EPA Human Studies Review Board Meeting Report

10

11 Dear Dr. Anastas,

12

13 The United States Environmental Protection Agency (EPA or Agency) requested that the 

14 Human Studies Review Board (HSRB) provide scientific and ethics reviews of two new and one 

15 revised protocols for studies involving intentional exposure of human subjects to pesticides: a 

16 proposed Carroll-Loye Biological Research, Inc. (CLBR) insect repellent efficacy study (No 

17 Mas-003); a proposed Agricultural Handler Exposure Task Force, LLC (AHETF) scenario 

18 measuring dermal and inhalation exposure by pesticide applicators who use backpack sprayers or 

19 hand gun sprayers in utility rights-of-way (AHE-400); and a revised AHETF water-soluble 

20 packaging mixing and loading scenario and protocol (AHE-120) previously reviewed by the 

21 HSRB in June 2009.

22

23 The Agency also requested that the HSRB review a completed study of dermal and 

24 inhalation exposure of professional janitorial workers who clean floors with an antimicrobial 

25 pesticide product using a mop and bucket, conducted by the Antimicrobial Exposure Assessment 

26 Task Force II (AEATF II). This study (AEA-03) was conducted after publication of the EPA’s 

27 expanded final rule for protection of subjects in human research (40 CFR 26) on February 6, 

28 2006 (71 Federal Register 24, 6137). The data will be posted to the Biocide Handlers Exposure 

29 Database (BHED®), and used generically to estimate daily dermal and inhalation exposures of 

30 those who clean floors with antimicrobial pesticides using a mop and pail. 

31

32 The enclosed report provides the Board’s response to EPA charge questions presented at 

33 the October 27-28, 2010 meeting.

34

35 Assessment of Proposed Carroll-Loye Biological Research Study No Mas-003: Field Efficacy

36 Test of 16% Para-menthane-3,8-diol (PMD) and 2% Lemongrass Oil Based Repellent ‘No Mas’

37 Against Mosquitoes.

38

39 Science

40

41 • The Board concluded that the protocol for the proposed field repellency study, if 

42 modified in accordance with Agency and HSRB recommendations and conducted 

43 accordingly, is likely to generate scientifically reliable data, useful for assessing the 

44 efficacy of the tested material in repelling mosquitoes.

45
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46 Ethics

47

48 • The Board concluded that the protocol submitted for review, if modified in accordance 

49 with Agency and HSRB recommendations and conducted accordingly, is likely to meet 

50 the applicable requirements of 40 CFR 26, subparts K and L.

51

52 Assessment of Proposed AHETF Scenario and Protocol AHE-400: Backpack and Handgun Ap53 plication of Liquid Sprays in Utility Rights-of-Way.

54

55 Science

56

57 • The Board concluded the proposed backpack and handgun application scenario, if revised 

58 as suggested and performed as described, is likely to generate scientifically reliable data 

59 that may be useful for assessing the exposure of workers who apply pesticides in utility

60 rights-of-way using backpack or handgun sprayers.

61

62 Ethics

63

64 • The Board concluded that the protocol submitted for review, if modified in accordance 

65 with Agency and HSRB recommendations and conducted accordingly, is likely to meet 

66 the applicable requirements of 40 CFR 26, subparts K and L.

67

68 Assessment of Revised AHETF Scenario and Protocol AHE-120: Water-Soluble Packaging Mix69 ing and Loading.

70

71 Science

72

73 • The Board concluded the submitted protocol, if revised as suggested and performed as 

74 described, is likely to generate scientifically reliable data that may be useful for assessing 

75 the exposure of workers who mix and load pesticides in water-soluble packaging.

76

77 Ethics

78

79 • The Board concluded that the protocol submitted for review, if modified in accordance 

80 with Agency and HSRB recommendations and conducted accordingly, is likely to meet 

81 the applicable requirements of 40 CFR 26, subparts K and L.

82

83 Assessment of Completed AEATF II Research Study AEA-03: A Study for Measurement of Po84 tential Dermal and Inhalation Exposure during Application of a Liquid Antimicrobial Pesticide 

85 Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces (MRID 48210201, 

86 MRID 48231201, MRID 48231901).

87

88 Science

89

90 • The Board concurred with the Agency’s assessment that the research reported in the 

91 completed AEA-03 study report and associated supplemental documents was conducted 
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92 in a manner that was reasonably faithful to the design and objectives of the protocol and 

93 governing documents of AEATF-II. 

94

95 • The Board concluded that the Agency has adequately, if not completely, considered the 

96 limitations on these data that should be considered when using the data in estimating 

97 exposure of those who apply antimicrobial floor-cleaning products with mop and bucket.

98

99 Ethics

100

101 • The Board concurred with the Agency’s assessment that the study submitted for review 

102 was conducted in substantial compliance with subparts K and L of 40 CFR 26.

103

104 • In response to a request from the study sponsor for guidance on how to provide 

105 individual exposure data to participants once the study is complete, the Board elected to 

106 establish a working group that could draft proposed guidance for the Agency and 

107 sponsors, which would be reviewed by the full Board during a future HSRB meeting. 

108

109

110 Sincerely,

111

112

113

114 Sean Philpott, PhD, MSBioethics

115 Chair

116 EPA Human Studies Review Board
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117 NOTICE

118

119 This report has been written as part of the activities of the EPA Human Studies Review 

120 Board, a Federal advisory committee providing advice, information and recommendations on 

121 issues related to scientific and ethical aspects of human subjects research. This report has not 

122 been reviewed for approval by the Agency and, hence, the contents of this report do not 

123 necessarily represent the view and policies of the Environmental Protection Agency, nor of other 

124 agencies in the Executive Branch of the Federal government, nor does the mention of trade 

125 names or commercial products constitute a recommendation for use. You may obtain further 

126 information about the EPA Human Studies Review Board from its website at 

127 http://www.epa.gov/osa/hsrb. You may also contact the HSRB Designated Federal Officer, via e128 mail at ord-osa-hsrb@epa.gov

129

130 In preparing this document, the Board carefully considered all information provided and 

131 presented by the Agency presenters, as well as information presented by public commenters. 

132 This document addresses the information provided and presented within the structure of the 

133 charge by the Agency.
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134 US ENVIRONMENTAL PROTECTION AGENCY

135 HUMAN STUDIES REVIEW BOARD

136

137 Chair

138

139 Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union 

140 Graduate College and the Mount Sinai School of Medicine, Schenectady, NY

141

142 Vice Chair

143

144 Janice Chambers, PhD, DABT, Fellow ATS, William L. Giles Distinguished Professor, Director, 

145 Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State 

146 University, Mississippi State, MS

147

148 Members

149

150 George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada151 Reno Center for Research Design and Analysis, University of Nevada-Reno, Reno, NV

152

153 Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor 

154 of Health Policy and American Studies, The George Washington University, Washington, DC

155

156 Sidney Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharmacology, Howard 

157 University College of Medicine, Washington, DC

158

159 Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University, 

160 Manhattan, KS

161

162 Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of 

163 Arizona, Tucson, AZ 

164

165 Jose E. Manautou, PhD, Associate Professor of Toxicology, Department of Pharmaceutical 

166 Science, University of Connecticut School of Pharmacy, Storrs, CT

167

168 Jerry A. Menikoff, MD, JD, Director, Office for Human Subjects Research, Office of the

169 Secretary, Department of Health and Human Services, Rockville, MD

170

171 Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH) Human Risk Assessment, School of 

172 Public Health and Human Services, The George Washington University, Washington, DC

173

174 William Popendorf, PhD, MPH, Professor Emeritus, Department of Biology, Utah State 

175 University, Logan, UT

176

177 Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, 

178 Veterans Health Administration, Washington, DC

179
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180 Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 

181 Sciences, University of Florida, Gainesville, FL

182

183 Human Studies Review Board Staff

184

185 Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science 

186 Advisor, United States Environmental Protection Agency, Washington, DC
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187 INTRODUCTION 

188

189 On October 27-28, 2010, the United States Environmental Protection Agency’s (EPA or 

190 Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues 

191 concerning two new protocols and one revised protocol for research involving human 

192 participants: one new study measuring the efficacy of an insect repellent containing para193 menthane-3,8-diol (PMD) and lemongrass oil against mosquitoes under field conditions; one 

194 new study measuring levels of exposure received by agricultural handlers when applying 

195 commercially-available pesticides using backpack sprayers or hand gun sprayers in utility rights196 of-way, and a revised study measuring levels of exposure received by agricultural handlers when 

197 mixing and loading pesticides using water-soluble packaging under various conditions. In 

198 accordance with 40 CFR 26.1601, EPA sought HSRB review of these three proposed protocols. 

199 Each of these protocols is discussed more fully below.

200

201 In addition, the Agency has data from one completed study measuring levels of exposure 

202 received by janitorial workers when applying a commercially-available antimicrobial pesticide 

203 using a mop and bucket. In accordance with 40 CFR 26.1602, EPA sought HSRB review of this 

204 completed study. This completed study is discussed more fully below.

205

206 REVIEW PROCESS

207

208 On October 27-28, 2010, the Board conducted a public face-to-face meeting in Arlington, 

209 Virginia. Advance notice of the meeting was published in the Federal Register as “Human 

210 Studies Review Board; Notice of Public Meeting” (75 Federal Register 193, 61748).

211

212 Following welcoming remarks from Agency officials, the Board heard presentations from 

213 EPA on the following topics: one new study protocol to measure the efficacy of an insect 

214 repellent containing PMD and lemongrass oil against mosquitoes under field conditions; one new 

215 study protocol for measuring levels of exposure received by agricultural handlers when applying 

216 commercially available pesticides using backpack sprayers or hand gun sprayers in utility rights217 of-way, and a revised study protocol measuring levels of exposure received by agricultural 

218 handlers when mixing and loading pesticides using water-soluble packaging under various 

219 conditions. In addition, a completed study for the measurement of potential dermal and 

220 inhalation exposure during application of a liquid antimicrobial pesticide product using a bucket 

221 and mop was reviewed.

222

223 The Board also asked clarifying questions of several study sponsors and/or research 

224 investigators, including:

225

226 Dr. Victor Cañez, Technical Chair, Agricultural Handler Exposure Task Force

227 Dr. Scott Carroll, Study Director, Carroll-Loye Biological Research

228 Mr. Shawn King, Director of Operations, Carroll-Loye Biological Research

229 Mr. Robert Roogow, Chief Operations Officer, Independent Institutional Review Board, 

230 Inc. 

231 Dr. Sami Selim, Study Director, Selim & Associates

232
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233 Public oral comments were provided by:

234

235 Dr. Victor Cañez, Technical Chair, Agricultural Handler Exposure Task Force

236 Dr. Scott Carroll, Principal, Carroll-Loye Biological Research

237 Dr. Hasmukh Shah, Manager, AEATF

238

239 No written public comments were submitted.

240

241 For their deliberations, the Board considered the materials presented at the meeting, oral 

242 comments, and Agency background documents (e.g., published literature, sponsor and 

243 investigator research reports, study protocols, data evaluation records, and Agency science and 

244 ethics reviews of proposed protocols and completed studies). A comprehensive list of 

245 background documents is available online at http://www.regulations.gov. 

246

247 CHARGE TO THE BOARD AND BOARD RESPONSE

248

249 Assessment of Proposed Carroll-Loye Biological Research Study No Mas-003: Field 

250 Efficacy Test of 16% Para-menthane-3,8-diol (PMD) and 2% Lemongrass Oil Based 

251 Repellent ‘No Mas’ Against Mosquitoes.

252

253 Overview of the Study

254

255 This protocol describes a study to test the repellent efficacy of a lotion formulation con256 taining 16% PMD and 2% lemongrass oil (‘No Mas’) against three species of mosquitoes in the 

257 field. As submitted to the EPA, the proposed study consists of two interdependent analyses: 1) a 

258 dosimetry study designed to determine the amount of lotion that typical users would typically

259 apply; and 2) an efficacy study designed to measure the effectiveness of the compound as a re260 pellent for those species of mosquitoes likely to be vectors for West Nile Virus (WNV) in the 

261 United States.

262

263 Dosimetry will be determined by direct measurement of compound application. The effi264 cacy of the formulation as a mosquito repellent will be determined by measuring the ability of 

265 the formulations to prevent mosquito landings under field conditions at test sites in California’s 

266 Central Valley. The efficacy study endpoint will be the “Landing with Intent to Bite” (LIBe), and 

267 the criterion for data to calculate complete protection time will be the first confirmed LIBe.

268

269 Science

270

271 Charge to the Board

272

273 If the proposed field repellency study protocol No Mas-003 is revised as suggested in 

274 EPA’s review and if the research is performed as described, is the research likely to generate 

275 scientifically reliable data, useful for assessing the efficacy of the tested material in repelling 

276 mosquitoes?

277
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278 Board Response to the Charge

279

280 HSRB Recommendation

281

282 The Board concurred with the Agency’s assessment that the proposed field repellency

283 study protocol No Mas-003, if revised as suggested in EPA’s review (Fuentes and Sherman 2010) 

284 and performed as described, is likely to generate scientifically reliable data, useful for assessing 

285 the efficacy of the tested material in repelling mosquitoes.

286

287 HSRB Detailed Recommendations and Rationale

288

289 Protocol No Mas-003 from Carroll-Loye Biological Research (Carroll 2010) will be 

290 conducted using methods similar to those presented to and commented on by the Board in the 

291 past. Apart from the new test material, the proposal is generally similar to previous Carroll-Loye 

292 field studies reviewed by the Board.

293

294 The study protocol was relatively clear and addressed adequately a number of key

295 scientific issues, including: scientific justification, objectives, and data collection and 

296 compilation methods. The Board concurred with the Agency’s assessment that the proposed field 

297 repellency study protocol No Mas-003 is likely to generate scientifically reliable data, useful for 

298 assessing the efficacy of the tested material in repelling mosquitoes. In addition, the Board 

299 recommended two minor changes to the protocol and associated study documents. First, the 

300 protocol should be amended to remove erroneous reference to spray repellents (e.g. the first 

301 sentence on page 79, under “Rationale”; Carroll 2010, 79). Second, the Board agreed with the 

302 Agency that reference to sample size standards is now irrelevant in light of recently released 

303 repellency testing guidelines. Rather than refer to a historical standard of 6 study participants, the 

304 proposed sample size should be large enough to be likely to yield a definitive answer to the 

305 research question and its size justified statistically in the protocol. 

306

307 Ethics

308 Charge to the Board

309 If the proposed field repellency study protocol No Mas-003 is revised as suggested in 

310 EPA’s review and if the research is performed as described, is the research likely to meet the ap311 plicable requirements of 40 CFR part 26, subparts K and L?

312

313 Board Response to the Charge

314 HSRB Recommendation

315 The Board concluded that the protocol submitted for review, if modified in accordance 

316 with EPA (Fuentes and Sherman 2010) and HSRB recommendations, is likely to meet the ap317 plicable requirements of 40 CFR 26, subparts K and L.
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318 HSRB Detailed Recommendation and Rationale

319 The submitted documents assert that the study will be conducted in accordance with the 

320 ethical and regulatory standards of 40 CFR 26, Subparts K and L, as well as the requirements the 

321 US EPA’s Good Laboratory Practice ( GLP) Standards described at 40 CFR 160, and the Califor322 nia State EPA Department of Pesticide Regulation study monitoring (California Code of Regula323 tions Title 3, Section 6710) (Carroll 2010). Requirements of FIFRA §12(a)(2)(P) also apply. The 

324 protocol was reviewed and approved by an independent human subjects review committee, 

325 Independent Institutional Review Board (IIRB), Inc. of Plantation, FL prior to submission. IIRB, 

326 Inc. is fully accredited by the Association for the Accreditation of Human Research Protection 

327 Programs (AAHRPP). IIRB is also listed as an active Institutional Review Board (IRB) on the 

328 Office of Human Research Protection ( OHRP) website (Reg. #IORG0002954). Minutes of 

329 IIRB, Inc. meetings (Carroll 2010) and a copy of IIRB, Inc. policies and procedures were pro330 vided to the Agency. These documents indicate that IIRB, Inc. reviewed this protocol pursuant to 

331 the standards of the Common Rule (45 CFR Part 46, Subpart A).

332

333 1. Except as noted below, the Board concurred with the conclusions and factual observations of 

334 the ethical strengths and weaknesses of the study, as detailed in the EPA’s Ethics Review 

335 (Fuentes and Sherman 2010). The proposed study is likely to meet the applicable ethical re336 quirements for research involving human subjects, in accordance with the following criteria: 

337

338 a. Acceptable risk-benefit ratio. The risks as noted in the study protocol are fivefold: 1) al339 lergic reaction to test materials themselves; 2) exposure to biting arthropods; 3) possible 

340 exposure to arthropod-borne diseases; 4) physical stress from the test conditions; and 5) 

341 psychological stress and/or breach of confidentiality for pregnancy test results. These 

342 risks are minimized appropriately and are justified by the potential societal benefits asso343 ciated with data on the efficacy of the active ingredients, PMD and lemongrass oil, as 

344 mosquito repellents.

345

346 • Based on toxicological data currently available for PMD and lemongrass oil, 

347 coupled with appropriate exclusion criteria, study participants are unlikely to be at 

348 risk of adverse side effects with exposure.

349

350 • The study is designed to minimize the likelihood of mosquito bites, through the use 

351 of: LIBes rather than actual confirmed bites as a study endpoint; bite removal and 

352 joint observation; clear stopping rules; and limited periods of exposure to mosqui353 toes. Study participants will be trained in proper insect observation and handling 

354 techniques.

355

356 • Mosquito bites, should they occur, are usually mild and easily treated with over-the357 counter steroidal creams. The study will also exclude participants who have a histo358 ry of severe skin reactions to such bites.

359

360 • Possible exposure to vectors of arthropod-borne diseases is minimized through the 

361 use of certified disease-free laboratory-reared insect populations, selection of field 

362 sites in low virus areas, and limited skin exposure.

363
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364 • The potential risks to participants from environmental stress are minimized by the 

365 provision of a climate controlled rest area, food, water and medical supplies, and by 

366 careful monitoring for signs of dehydration, heat stress and hypothermia. Appropri367 ate stopping rules and medical management procedures are in place.

368

369 • Minor and pregnant or lactating women are excluded from participation, with preg370 nancy either confirmed by over-the-counter pregnancy testing on the day of study or 

371 by opt-out. Only volunteers scored as non-pregnant will be allowed to participate. 

372 Information regarding pregnancy test results will be kept confidential.

373

374 b. Voluntary and informed consent of all participants 

375 • There is the possibility that the participants in this study might represent particularly

376 vulnerable populations, susceptible to coercion and undue influence. The study proto377 col, however, includes several mechanisms designed to minimize coercive recruitment 

378 and enrollment.

379

380 • The informed consent materials, if changed as recommended by the HSRB below, will 

381 adequately inform the subjects of the risks, discomforts and benefits from participation, 

382 and of their right to withdraw.

383

384 • Monetary compensation is not so high as to unduly influence participants.

385

386 c. Equitable selection of study participants

387

388 • The majority of research participants will be recruited from the University of California 

389 at Davis student population. Study participants are likely to represent the appropriate 

390 ethnic and racial diversity of individuals in and around the University, but the use of 

391 this convenience sample may limit the broad applicability of the study results to the 

392 general population. The investigators have noted this fact in the protocol (Carroll 2010).

393

394 2. The Board recommended that the study protocol be modified to address the concerns noted in 

395 the EPA’s Ethics Review (Fuentes and Sherman 2010). In addition, the Board also raised the 

396 following concerns:

397

398 • The Board concurred with the Agency’s recommendation that the protocol be revised to ex399 clude as participants employees of the study sponsor. The Board added the recommenda400 tion that this exclusion also be extended to dependents of the study sponsor or sponsor em401 ployees.

402

403 • The consent form and protocol should be modified as follows:

404

405 1) Carroll-Loye should add “child/minor” to the list of exclusion criteria.

406

407 2) The term “treatment” is used ambiguously throughout the protocol and informed 

408 consent form to describe both the application of the test materials and treatment for 
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409 research-related injuries. For example, on page 23 the protocol states that “applica410 tion of a test material is considered a treatment” (Carroll 2010, 23). Elsewhere, 

411 however, the protocol states that “candidates are again encouraged to ask any ques412 tions they have about the study, which may include understanding ... treatment and 

413 compensation for injury more fully” (Carroll 2010, 17, 238). This ambiguity should 

414 be resolved with the use of a different term to describe the application of test mate415 rials.

416

417 3) On page 16, the protocol states that “...dosimetry subjects may be consented before 

418 repellency subjects. Untreated control subjects for the repellency phase (field study) 

419 are consented before the treated subjects for that phase...” (Carroll 2010, 16). The 

420 verb “to consent” is an intransitive verb; from a grammatical point of view, some421 one cannot “be consented.” From an ethical perspective, this infelicitous use of the 

422 verb also employs the passive voice, which is not best practice when the issue is to 

423 affirm that researchers will be accountable for obtaining informed consent. It is 

424 recommended that the protocol be modified to use alternate phrasing such as “Re425 searchers may obtain informed consent from dosimetry subjects before repellency

426 subjects ...”

427

428 4) Carroll-Loye should spell out the acronym “PMD” when it is first used in the proto429 col and consent form.

430

431 5) On page 2 of the consent form, the phrase “You have been offered an opportunity to 

432 participate in this research study because ...” (Carroll 2010, 199, 209, 219) be mod433 ified by Carroll-Loye to minimize the impression that participation in this intention434 al exposure study is somehow a beneficial or favorable occasion. A neutral alterna435 tive might be: “We are asking you to participate in this research study because...”

436

437 6) A description of the symptoms of heat stress and equine encephalitis should also be 

438 included in the consent form. Currently, only the symptoms of West Nile Virus are 

439 listed. 

440

441 Assessment of Proposed AHETF Scenario and Protocol AHE-400: Backpack and Handgun 

442 Application of Liquid Sprays in Utility Rights-of-Way.

443

444 Overview of the Study

445

446 This proposal presents an agricultural handler exposure scenario involving backpack and 

447 handgun application of liquid pesticides along utility rights-of-way. The protocol calls for study 

448 participants to apply (and potentially load) four surrogate pesticides (fosamine, glyphosate, 

449 imazapyr and 2,4-D). A total of 21 participants (described in the protocol as “Monitoring Units” 

450 [MUs]) will be observed for each scenario; three volunteers each from seven geographically

451 distinct growing regions will be enrolled using a purposive sampling method (with some 

452 elements of random selection).

453
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454 Dermal exposure will be measured by a whole body dosimeter (WBD) worn beneath the 

455 subject’s outer clothing. Hand wash and face/neck wipe samples will also be collected prior to, 

456 during, and after completion of pesticide loading and mixing procedures. Airborne concentra457 tions of the surrogate will be monitored in the participant’s breathing zone using an OSHA Ver458 satile Sampler (OVS) tube sample collector connected to a personal sampling pump. Additional 

459 measures will also record environmental conditions at the time of monitoring, and observers will 

460 make field notes, photographs and videos of participant activity throughout the monitoring event.

461

462 The results of sample analysis under the backpack and handgun application scenario will 

463 be posted to the AHED® database, where they will be available to the EPA and other regulatory

464 agencies for statistical analysis. The proposed documentation will report a confidence-intervalbased approach to determine the relative accuracy for the arithmetic mean and 95th 465 percentile of 

466 unit exposures. The Agency proposes to use these data to estimate daily dermal and inhalation 

467 exposures of agricultural handlers who are applying pesticides using backpack and/or handgun 

468 applicators under a variety of scenarios.

469

470 Science

471

472 Charge to the Board

473

474 If the proposed AHETF Right-of-Way application scenario and field study proposal 

475 AHE400 is revised as suggested in EPA’s review and if the research is performed as described, is 

476 the research likely to generate scientifically reliable data, useful for assessing the exposure of 

477 workers who apply pesticides in utility rights-of-way using backpack or handgun sprayers? 

478

479 Board Response to the Charge

480

481 HSRB Recommendation

482

483 The Board concurred with the Agency’s assessment that the proposed AHETF Right-of484 Way application scenario and field study proposal AHE400, if revised as suggested in EPA’s 

485 review (Evans and Sherman 2010a) and performed as described, is likely to generate 

486 scientifically reliable data useful for assessing the exposure of workers who apply pesticides in 

487 utility rights-of-way using backpack or handgun sprayers.

488

489 HSRB Detailed Recommendations and Rationale

490

491 Given the lack of existing reliable and sound data in this area, the Board concurred with 

492 the Agency’s assessment (Evans and Sherman 2010a) that this protocol will likely generate data 

493 that may be useful for assessing the exposure of handlers who apply pesticides using backpack or 

494 handgun sprayers. 

495

496 The study, if conducted as described, will provide newer exposure information on dermal 

497 and inhalation exposures of pesticide handlers using backpack sprayers and handgun sprayers 

498 treating utility rights-of-way in appropriate and distinct geographic locations; some study partic499 ipants will be exposed during loading backpacks or tanks as well. The Board agreed with the 
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500 Agency’s assessment that the protocol adequately addresses a number of scientific questions, in501 cluding having clear scientific objectives, a reasonable experimental design for achieving these 

502 objectives: appropriate quantification of test materials, adequate procedures for collecting, com503 piling and summarizing test results, appropriate justification for selection of test substances, 

504 sample size, and study site selection, and acceptable QA/QC procedures.

505

506 However, the Board noted a few weaknesses in the proposed study design. In particular, 

507 the variability in individual dermal and inhalation exposure levels may be extremely high be508 cause of the diversity of terrains and locations selected for the study and the opportunity for large 

509 (but potentially categorical) personal differences in application practices. The proposal to impose 

510 a minimum exposure duration of at least 4 hours will also create opportunities for the applica511 tor’s exposures to be influenced by variables that by their nature are likely to be unrelated to the 

512 amount of active ingredient handled (AaiH). Should this diversity yield high variability in the 

513 data sets, then the proportionality of exposure with AaiH may not be apparent. If the 4-hour min514 imum is not removed, the Task Force may want to ensure that field notes are adequate to report 

515 time-on-task as a fraction of the total monitored time for use in later data analysis and usage 

516 within AHED. he rationale for having and using this “fraction” is discussed more fully in the 

517 Board’s discussion of protocol AHE120 below. Even if the proportionality hypothesis is not sup518 ported by the resultant data sets, these data are likely to still be useful and relevant to assessing 

519 the levels of exposure to workers applying pesticides to utility rights-of-way. 

520

521 Ethics

522 Charge to the Board

523 If the proposed AHETF Right-of-Way application scenario and field study proposal 

524 AHE400 is revised as suggested in EPA’s review and if the research is performed as described, is 

525 the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L? 

526

527 Board Response to the Charge

528 HSRB Recommendation

529 The Board concluded that the protocol submitted for review, if modified in accordance 

530 with EPA (Evans and Sherman 2010a) and HSRB recommendations, is likely to meet the ap531 plicable requirements of 40 CFR 26, subparts K and L.

532 HSRB Detailed Recommendation and Rationale

533 The submitted documents assert that the revised study will be conducted in accordance 

534 with the ethical and regulatory standards of 40 CFR 26, Subparts K and L, as well as the re535 quirements the US EPA’s GLP Standards described at 40 CFR 160 (AHETF 2010a; Collier 

536 2010a). FIFRA §12(a)(2)(P) also applys. The protocol was reviewed and approved by an inde537 pendent human subjects review committee, IIRB, Inc. of Plantation, FL prior to submission. Mi538 nutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures were provided. 

539 This IRB is fully accredited by AAHRPP and listed by OHRP (see details above).

540
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541 1. Except as noted below, the Board concurred with the conclusions and factual observations of 

542 the ethical strengths and weaknesses of the study, as detailed in the EPA’s Ethics Review 

543 (Evans and Sherman 2010a). The proposed study is likely to meet the applicable ethical re544 quirements for research involving human subjects, in accordance with the following criteria: 

545

546 a. Acceptable risk-benefit ratio. Risks as noted in the study protocol are four-fold: 1) heat547 related illness; 2) injury associated with scripted field activities; 3) allergic reaction to 

548 surfactants using for hand washing; and 4) psychological stress and/or breach of confi549 dentiality for pregnancy test results. These risks are minimized appropriately and are jus550 tified by the potential societal benefits, particularly data for new exposure assessments 

551 for occupational risks associated with spraying pesticides to rights-of-way using back552 pack and handgun sprayers.

553

554 • Only experienced pesticide handlers, with specific experience with the type of ap555 plication equipment to be used, and who consider themselves to be in good health, 

556 will be enrolled. 

557

558 • Risk of heat-related illness is minimized appropriately. Heat index will be moni559 tored with an associated stopping rule. A medical professional will be on site to ob560 serve the workers and provide urgent care. Nearby medical facilities have been 

561 identified in case of emergency, and transportation to medical treatment will be 

562 provided, if needed. 

563

564 • Subjects will be reminded about safe chemical handling practices and procedures, 

565 wearing appropriate personal protective equipment (PPE), and will be monitored for 

566 any accidental or unintended product exposure. 

567

568 • Minors and pregnant or lactating women are excluded from participation, with 

569 pregnancy either confirmed by over-the-counter pregnancy testing on the day of 

570 study or by opt-out. The potential stigma resulting from study exclusion due to 

571 pregnancy is appropriately minimized. 

572

573 The Board disagreed with the AHETF conclusion, however, that “the risk of toxicity from 

574 pesticide handling [is not] strictly due to study participation [and therefore], the risk of 

575 surrogate toxicity will not be listed in consent forms or this protocol” (Collier 2010a, 

576 309). This study is subject to 40 CFR 26 subparts K and L precisely because it is consi577 dered to be a study in which the subjects are “intentionally exposed,” for research pur578 poses, to pesticides. Given its scripted nature, the AHETF protocol influences the beha579 vior of workers and their employers in a number of ways. That a particular agricultural 

580 worker will be applying a particular pesticide on a particular day is due, to a large extent, 

581 to the fact that the study is being conducted. Accordingly, the risk from exposure to the 

582 pesticides being applied should clearly be categorized as a risk of study participation.

583

584 The Board does agree, however, that the risk from exposure to those pesticides is a rea585 sonable one, and that it has been appropriately minimized. The products being used in 
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586 this study are ones already registered by EPA for vegetation control in rights-of-way, and 

587 will be applied in accordance with label requirements. 

588

589 b. Voluntary and informed consent of all participants 

590 • There is the possibility that the participants in this study might represent particularly

591 vulnerable populations, susceptible to coercion and undue influence. The study proto592 col, however, includes several mechanisms designed to minimize coercive recruitment 

593 and enrollment.

594

595 • The informed consent materials, if changed as recommended by the HSRB below, will 

596 adequately inform the subjects of the risks, discomforts and benefits from participation, 

597 and of their right to withdraw.

598

599 • Monetary compensation is not so high as to unduly influence participants.

600

601 • Spanish translations of the informed consent documents, informational packets, and re602 cruitment flyers were provided. Researchers will be working with local Spanish603 speaking community members to ensure that the appropriate regional dialect of Spanish 

604 is used (AHETF 2010b).

605

606 c. Equitable selection of study participants

607

608 • The study is designed to recruit an appropriately diverse population of participants who 

609 represent skilled workers in the study locations.

610

611 • The study will first involve identifying and contacting the employers involved in right612 of-way application of pesticides. Only employees of these employers are eligible to be 

613 recruited. The recruitment process has been carefully designed to assure that employees 

614 will not be coerced into participating: recruitment will take place using brochures and 

615 meetings with employees at which the employer and supervisors will not be present.

616

617 2. The Board recommended that the study protocol be modified to address the concerns noted in 

618 the EPA’s Ethics Review (Evans and Sherman 2010a). In addition, the Board also raised the 

619 following concerns:

620

621 • As noted above, the Board concluded that the risk of toxicity from pesticide handling is in622 deed a risk of participating in the study, and accordingly it should be described as such, and 

623 discussed appropriately, in the consent form.

624

625 • The consent form should explain that the pregnancy test will be provided by the research626 ers, and explain when it will take place.

627

628 • There appears to be a discrepancy between the exclusion criteria stated in the EPA review 

629 (Evans and Sherman 2010a, 36), which refer to training in handling pesticides, and the 

630 AHETF-provided consent form (AHETF 2010a, 267), which notes that the subject might 
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631 need only to confirm that “you are not required to take this training.” This discrepancy 

632 should be clarified.

633

634 • Study participants will undergo hand washes prior to eating anything, which will reduce 

635 their risk of accidental ingestion of the surrogate compounds. As many of the adults in the 

636 US still smoke, however, hand washes should also occur before any smoking break to fur637 ther reduce participant’s risk of accidental pesticide ingestion.

638

639 Assessment of Completed AEATF II Research Study AEA-03: A Study for Measurement of 

640 Potential Dermal and Inhalation Exposure during Application of a Liquid Antimicrobial 

641 Pesticide Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces (MRID 

642 48210201, MRID 48231201, MRID 48231901).

643

644 Overview of the Study

645

646 The objective of this study was to measure individual exposures to a surrogate antimicro647 bicidal pesticide (didecyl dimethyl ammonium chloride; DDAC) while mopping floors and emp648 tying mop buckets. Eighteen volunteers participated in the study, mopping floors in one of three 

649 building types (an office building, a Rite Aid pharmacy building, or a retired teacher’s memorial 

650 building in Fresno, CA) for one of six pre-determined mopping times (30-40, 40-50, 50-60, 60-

651 70, 70-80 and 80-90 minutes total mopping time, respectively).

652

653 Dermal and inhalation exposure monitoring was conducted while study participants 

654 mopped floors and emptied the mop buckets; all participants wore long-sleeved shirts, long 

655 pants, shoes, socks, and no gloves. Dermal exposure was measured by inner and outer body do656 simeters. Airborne concentrations of the surrogate compound were monitored in the participant’s 

657 breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector connected to a 

658 personal sampling pump. Environmental conditions were also recorded at the time of monitoring, 

659 and observers made notes, photographs and videos of participant activity throughout the mop660 ping period.

661

662 These exposure data will be used to populate a database representing inhalation and der663 mal exposure during a number of antimicrobial handler scenarios. A scenario is defined as a pes664 ticide handling task based on activity (e.g., application) and equipment type (e.g., mop & bucket, 

665 ready-to-use wipes, pressure treatment of wood facilities, painting). These data will be used by

666 the Agency to estimate dermal and inhalation exposures of antimicrobial handlers who are apply667 ing pesticides using a mop and bucket under a variety of scenarios. 

668

669 Science

670

671 Charges to the Board

672

673 1) Was the research reported in the Antimicrobial Exposure Assessment Task Force II (AEATF–

674 II) completed study report AEA-03 and associated supplemental reports faithful to the design 

675 and objectives of the protocol and governing documents of AEATF-II?

676
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677 2) Has the Agency adequately characterized, from a scientific perspective, the limitations on 

678 these data that should be considered when using the data in estimating exposure of those who 

679 apply antimicrobial floor-cleaning products with mop and bucket? 

680

681 Board Response to the Charge

682

683 HSRB Recommendation

684

685 The Board concurred with the Agency’s assessment (Leighton 2010) that the research 

686 reported in the completed AEA-03 study report and associated supplemental documents (Selim 

687 and Taylor 2010a, 2010b, 2010c) was conducted in a manner that was reasonably faithful to the 

688 design and objectives of the protocol and governing documents of AEATF-II. The Board also 

689 concluded that the Agency has adequately, if not completely, considered the limitations on these 

690 data that should be considered when using the data in estimating exposure of those who apply 

691 antimicrobial floor-cleaning products with mop and bucket.

692

693 HSRB Detailed Recommendations and Rationale

694

695 The study was conducted in a manner that was reasonably faithful to the design of the 

696 protocol and governing documents. The study report (Selim and Taylor 2010a) contains sections 

697 that adequately describe the test substance, recruitment procedures, field procedures, sample 

698 collection and handling, sample analysis, and data analysis. Previous Board recommendations 

699 (EPA HSRB 2008) for the use of a double layer of socks and provision of more detail about staff 

700 activities during the observation period were adopted. Appropriate rationale for changes in key

701 elements of the study design, including justification for the purposive sampling of monitoring 

702 events (MEs) and the sample size of 18, was also provided. Finally, assuming that only one 

703 participant was present in the cluster when an ME was conducted, it also appears that no 

704 participant observed another participant’s activities during the study, as previously

705 recommended. However, some of the issues raised by the Board in its initial review of the mop 

706 and bucket scenario (EPA HSRB 2008) were not addressed, including: the bases for the 90-

707 minute maximum mopping period choice, the possibility (or not) of “carry-over effects” between 

708 MEs, and the interaction between aerosolized particles, heating, ventilation and air conditioning 

709 (HVAC) systems, and inhalation exposure estimates. Although the importance of measuring the 

710 impact of HVAC systems on inhalation exposures was mentioned in the protocol (Selim and 

711 Taylor 2010a, 28), it was not given appropriate attention nor were HVAC operations consistently

712 documented during the conduct of the study. While this lack of information places potentially 

713 important limitations on how the inhalation data should be interpreted, in the professional 

714 opinion of at least one Board member the impact of differences among the test sites are likely to 

715 be within a factor of about two and thus not substantively change the overall mean exposure 

716 levels. The study was also conducted in a manner that was reasonably faithful to the objectives 

717 of the protocol and governing documents. As stated in the final report, the study was conducted 

718 primarily to “determine potential dermal and inhalation exposures to professional janitorial 

719 workers when mopping indoor surfaces with a liquid antimicrobial pesticide product containing 

720 didecyl dimethyl ammonium chloride (DDAC)” (Selim and Taylor 2010a, 28). Dermal exposures 

721 were reported, with estimates based on total collected residue from all matrices (face and hand 

722 wipes, socks, and all parts of the inner dosimeter). Dermal exposures were expressed as 
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723 micrograms of active ingredient (AI) handled per subject and as milligrams of AI per 

724 subject/pound of AI applied. Inhalation exposure was also presented as units of concentration. 

725 However, sufficient data is available (i.e., the duration of each exposure) to express those results 

726 in the same units as dermal exposures if an average respiratory minute volume for the appicators 

727 is also applied to the calculation.

728

729 The overall study objective was listed differently in the Agency’s scientific review than in 

730 the protocol, stating it as: “the study objective is to monitor inhalation and dermal exposures to 

731 be used as inputs in exposure algorithms to predict future exposures to persons mopping floors.” 

732 (Leighton 2010, 5). The Agency added two sub-objectives not found in the protocol: “to be 95% 

733 confident that key statistics of normalized dermal exposure are accurate within 3-fold” and “to 

734 evaluate the presumption of proportionality between exposure and amount of active ingredient 

735 handled,” respectively. The Agency provided a thorough assessment of their first sub-objective 

736 supporting the sample size and analyses used to achieve the 3-fold accuracy goal. However, 

737 although the presumption of proportionality was demonstrated for dermal exposure and the 

738 amount of AI handled, the rationale supporting the presumption of proportionality for inhalation 

739 exposure needs to be recalculated but based on current data may not be as clear and consistent as 

740 for the dermal exposure. 

741

742 The Agency’s scientific review (Leighton 2010) discussed the limitations of the dermal 

743 and inhalation exposure data. The Agency also presented alternative models for estimating 

744 dermal and inhalation exposures, evaluated the impacts of non-detects and of assigning low 

745 limits of quantification (LOQs) at 3 different values (0, 1⁄2 and full LOQ). The Agency concluded 

746 that dermal exposures and pounds of active ingredient are related in a proportional manner, while 

747 accounting for sampling efficiency and normalizing the data in terms of milligrams/pounds of 

748 active ingredient applied. The Agency also discussed the dermal exposure estimates in 

749 relationship to its sub-objectives of the study (accuracy within 3-fold and proportionality). Their 

750 assessment acknowledged that some estimates included a high level of uncertainty and some 

751 bias. The Board concluded that the Agency adequately, if not completely, considered limitations 

752 in its interpretation and subsequent estimates of dermal exposure data. One Board member 

753 observed, however, that the Agency’s reliance on hand wash data may have over-corrected face 

754 and neck residue estimates. Another Board member questioned whether the model actually 

755 supports the conclusion of proportionality for some of the dermal configurations.

756

757 With respect to limitations of the inhalation exposure data due to study deviations, some 

758 (but not all) of the limitations that need to be considered when estimating inhalation exposure 

759 were discussed. In its initial 2008 review (EPA HSRB 2008), the Board noted several factors that 

760 could influence these estimates, including: ventilation, room temperature, total area mopped, 

761 duration of mopping, and volume of the enclosed space and respiration rate of the study

762 participants. Although the final study report provides some of these data for the facilities in 

763 which mopping activities were conducted (Selim and Taylor 2010a, 105-7), neither ventilation 

764 data nor a discussion of these factors were provided, thus limiting the Board’s and Agency’s

765 ability to interpret fully the reported environmental data. Furthermore, the rationale for the 

766 Agency’s conclusion that air changes per hour was not a significant factor influencing inhalation 

767 exposure estimates, based on the low vapor pressure of DDAC and the LOQs observed, does not 

768 recognize fully how HVAC parameters could have affected reported air concentrations from 
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769 mopping activities. The Agency also failed to consider whether the limited areas available for 

770 mopping in Clusters 1 and 3 could have compromised the study design or affected inhalation 

771 exposure estimates. Similarly, although surface areas of the floors mopped were noted, the 

772 ceiling heights were not reported. The Agency’s review also fails to consider the impact that 

773 ceiling height and room volume may have had on the reported air concentration data. The 

774 respiration rates of study participants were not discussed by the Task Force researchers or the 

775 Agency; ignoring this factor could introduce important uncertainties into exposure estimates. 

776 Finally, the Board’s previous recommendation to consider particle size (e.g., whether DDAC is 

777 aerosolized) and its potential impact on inhalation exposures were not addressed by the Agency. 

778 Although not discussed in detail by the Board at the October 2010 meeting, several of these 

779 factors are discussed in Appendix 1 below (written as a separate report by HSRB member Dr. 

780 William Popendorf).

781

782 Ethics

783 Charge to the Board

784 Does available information support a determination that the study was conducted in sub785 stantial compliance with subparts K and L of 40 CFR Part 26? 

786

787 Board Response to the Charge

788 HSRB Recommendation

789

790 The Board concurred with the Agency’s assessment (Carley 2010) that the study was 

791 conducted in substantial compliance with subparts K and L 40 CFR 26. 

792

793 HSRB Detailed Recommendation and Rationale

794

795 The documents provided by Golden Pacific Laboratories, LLC, under Project No. AEA796 03, state that the study was conducted in compliance with the requirements of 40 CFR 26 

797 subparts K, L and M; FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3, 

798 Section 6710 (Selim and Taylor, 2010a, 2010b, 2010c). The protocol was reviewed and approved 

799 by an independent human subjects review committee, IIRB, Inc. of Plantation, FL prior to 

800 submission. Minutes of IIRB, Inc. meetings and a copy of IIRB, Inc. policies and procedures 

801 were provided. This IRB is fully accredited by AAHRPP and listed by OHRP (see details above).

802

803 1. The Board concurred with the conclusions and factual observations relating to the study, as 

804 detailed in the EPA’s Ethics Review (Carley 2010) and summarized briefly below. 

805

806 a. Prior HSRB and Agency Review. Because this study was initiated after 7 April 2006, 

807 prior submission of the protocol and supporting materials to EPA was required by 40 

808 CFR §26.1125. The requirements of 40 CFR §26.1125 for prior submission of the 

809 protocol to EPA and of §26.1601 for HSRB review of the protocol were satisfied. The 

810 scenario design and study were approved by IIRB, Inc. and submitted to the EPA in 

811 February 2008. The HSRB discussed the protocol at its April 2008 meeting, concurring 

812 with the Agency’s assessment that the proposed mop and wipe scenario, if revised as 
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813 suggested by the Agency and the HSRB, would meet the applicable requirements of 40 

814 CFR part 26, subparts K and L.

815

816 b. Responsiveness to HSRB and Agency Recommendations.

817

818 The Agency’s initial ethics review noted two deficiencies to be corrected before the study

819 was initiated. The first focused on measures to improve the informed consent process for 

820 Spanish-speaking candidates. The Agency called for the candidate interviews for Spanish 

821 speakers to be conducted by a member of the research team fluent in Spanish, rather than 

822 an independent translator. The second deficiency focused on references in the informed 

823 consent forms to “normal business hours”. The Agency asked that the researchers revise 

824 the consent form to show hours for calling in local (Pacific) time. 

825

826 In the revisions submitted to IIRB, Inc. in February 2009, the researchers addressed these 

827 ethical concerns. Because the study was conducted in California, the approval of the 

828 California Department of Pesticide Regulation (CDPR) was also required. CDPR granted 

829 final approval of the amended protocol and supporting documents in April 2009.

830

831 b. Responsiveness to HSRB and Agency Reviews. The Agency’s and HSRB’s comments 

832 were satisfactorily addressed in the revisions approved by the IIRB in March 2009 (Selim 

833 and Taylor 2010a). 

834

835 At its April 2008 meeting, the HSRB made several specific recommendations for 

836 refinements of the study. As noted in Amendment 4 of the Agency’s ethics review 

837 (Carley 2010), the investigators addressed fully most of these recommendations, 

838 addressed partially some of these recommendations, and did not address two of these 

839 recommendations. The Board agreed with the Agency conclusion, however, that the 

840 investigators’ failure to address all of the recommendations did not violate applicable 

841 ethical standards for the protection of human participants of research.

842

843 c. Substantial Compliance with Reporting Requirements (40 CFR §26 subpart M). 

844

845 The study sponsor initially did not provide adequate documentation to demonstrate that 

846 they had satisfied the requirements of §26.1303. The initial report (Selim and Taylor, 

847 2010a) contained several reporting deficiencies, including: inadequate documentation of 

848 interaction between the investigators and the overseeing IRB, incomplete study

849 chronology, and a lack of tracked consent forms showing how they were revised to 

850 address Agency and HSRB concerns. These deficiencies were corrected by the 

851 submission of supplemental documents (Selim and Taylor, 2010b, 2010c). 

852

853 IRB minutes documenting discussion and review of these revised documents were not 

854 provided for review. All IIRB, Inc. reviews subsequent to the HSRB’s April 2008 

855 meeting were conducted using an expedited procedure and did not require a full meeting 

856 of the IRB. Neither the IRB roster nor the operational procedures were submitted as part 

857 of the study documents. 

858
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859 The HSRB agreed with the Agency that these deficiencies in the conduct and the 

860 documentation of the research did not compromise the ethical conduct of the study, and 

861 concluded that the requirements of 40 CFR §26.1303 were satisfactorily addressed. The 

862 HSRB did recommend, however, that the Agency require the submission of reports for all 

863 research that undergoes expedited IRB review in the future. 

864

865 2. The Board concluded that this study, as conducted, met all applicable ethical requirements for 

866 research involving human participants, in accordance with the following criteria that had 

867 been stated in the Board’s prior review of this protocol (EPA HSRB 2008).

868

869 a. Acceptable risk-benefit ratio. The risks to study participants were minimized 

870 appropriately and were justified by the potential societal benefits, particularly data on the 

871 dermal and inhalation exposure of professional janitorial workers to antimicrobial 

872 pesticides as they mopped indoor floors and disposed of spent mop water. These data 

873 could be used to develop mechanisms to protect future users of these antimicrobial

874 pesticides.

875

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

877 pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by 

878 opt-out. The potential of stigma resulting from study exclusion was also appropriately 

879 minimized. 

880

881 • Clear stopping rules and medical management procedures were in place, and no adverse 

882 events or other incidents of concern related to product exposure were reported.

883

884 • The study was designed to minimize the risks of exposure to the test compounds.

885

886 b. Voluntary and informed consent of all participants

887

888 • The study protocol included several mechanisms designed to minimize coercive 

889 recruitment and enrollment. 

890

891 • Monetary compensation was not so high as to unduly influence participation.

892

893 3. Three minor protocol deviations were reported. These included: 1) most study participants 

894 declining to take rest breaks or taking less than the 10 minutes provided for in the protocol; 

895 2) full facial photographs taken of participants at one monitoring site; and 3) enrollment of 

896 participants who self-reported that their health was only “fair,” despite the requirement that 

897 all participants be in “good health” (Selim and Taylor, 2010b, 31). The Board concluded, 

898 however, that these minor deviations did not affect the integrity of the research or the safety 

899 of participants. The Board did recommend, however, that sponsors clarify the criteria used to 

900 establish participants’ health status prior to study enrollment.

901
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902 Assessment of Revised AHETF Scenario and Protocol AHE-120: Water-Soluble Packaging 

903 Mixing and Loading.

904

905 Overview of the Study

906

907 This revised proposal presents an agricultural handler exposure scenario involving 

908 mixing/loading of pesticides enclosed in water-soluble packets (WSP). The original protocol, 

909 which was favorably reviewed by the Board at its June 2009 meeting (EPA HSRB 2009), called 

910 for study participants to mix and load one of two WSP-enclosed surrogate pesticides (acephate 

911 and carbaryl) into a variety of tanks containing water in a variety of agricultural spraying 

912 operations. Carbaryl in water-soluble packaging is no longer being produced by pesticide 

913 manufacturers; however, the AHETF proposed substituting three additional surrogate compounds 

914 for carbaryl: dithiopyr, imidacloprid, and thiophanate-methyl. Because of use patterns of these 

915 surrogate compounds, the AHETF also identified additional study sites. The previously reviewed 

916 study was to be conducted at three cool dry sites in Michigan, New York, and Washington State, 

917 one hot humid site in Louisiana, and one hot dry site in California. The revised protocol will also 

918 be conducted at five sites, including two cool dry sites in New York and North Dakota, two hot 

919 humid sites in Florida and Louisiana, and one hot dry site in California.

920

921 A total of 25 participants (described in the protocol as “Monitoring Units” [MUs]) will be 

922 observed; five volunteers each from five different growing regions will be enrolled using a 

923 purposive sampling method. Dermal exposure will be measured by a whole body dosimeter 

924 (WBD) worn beneath the subject’s outer clothing. Hand wash and face/neck wipe samples will 

925 also be collected prior to, during, and after completion of pesticide loading and mixing 

926 procedures. Airborne concentrations of the surrogate will be monitored in the participant’s 

927 breathing zone using an OSHA Versatile Sampler (OVS) tube sample collector connected to a 

928 personal sampling pump. Additional measures will also record environmental conditions at the 

929 time of monitoring, and observers will make field notes, photographs and videos of participant 

930 activity throughout the monitoring event.

931

932 The results of sample analysis under the mixing/loading of water-soluble packets 

933 scenario, and will be posted to the AHED® database, where they will be available to the EPA

934 and other regulatory agencies for statistical analysis. The Agency proposes to use these data to 

935 estimate daily dermal and inhalation exposures of agricultural handlers who are mixing/loading 

936 pesticides in water-soluble packets under a variety of mixing and loading scenarios.

937

938 Science

939

940 Charge to the Board

941

942 If the revised AHETF scenario and field study proposal AHE120 is revised as suggested 

943 in EPA’s review and if the research is performed as described, is the research likely to generate 

944 scientifically reliable data, useful for assessing the exposure of handlers who mix and load pesti945 cides in water-soluble packaging? 

946
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947 Board Response to the Charge

948

949 HSRB Recommendation

950

951 The Board concurred with the Agency’s assessment (Evans and Sherman 2010b) that this 

952 protocol will generate data that are scientifically valid and that may be useful for assessing the 

953 exposure of handlers who mix and load soluble or wettable powder pesticides in water-soluble 

954 packaging. The Board cautioned, however, that these data might not be useful for creating 

955 distributions of worker exposure that are scientifically accurate or that are precise.

956

957 HSRB Detailed Recommendations and Rationale

958

959 The protocol is largely the same as when it was first reviewed by the HSRB in June 2009 

960 (EPA HSRB 2009). The major changes are that one of the surrogate active ingredients (carbaryl) 

961 was deleted and three other active ingredients (dithiopyr, imidacloprid, and thiophanate-methyl) 

962 were added. This change necessitated revising the geographical regions in which the study could 

963 be conducted and a slight lowering of each of the five strata in the amounts of active ingredient 

964 handled. 

965

966 Each of these changes seems justified. Assuming that the AHETF can provide adequate 

967 evidence of the validity of the analytical methods for each of the new compounds, the revised 

968 study protocol still allows a good probability of the study successfully obtaining its primary and 

969 secondary objectives (i.e., “that selected lognormal-based estimates of normalized dermal expo970 sure distribution be accurate to within 3-fold, at least 95% of the time,” and the ability to distin971 guish “a proportional from an independent relationship between exposure and AaiH,” respective972 ly (Evans and Sherman 2010b, 28-9).

973

974 However, the Board pointed out that many of the same concerns it raised in June 2009 

975 remain for the revised protocol. Of particular note is the conflict between the non-random, pur976 posive study design and the statistical methods proposed to analyze the exposure data. Moreover, 

977 the protocol does not control for ecological, engineering, and statistical factors that may obscure

978 a linear relationship between AaiH and worker exposure. Previously the Board said that “there is 

979 no statistical theory that can be applied to non-random samples of this type. Thus, the statistical 

980 analyses proposed, including mixed model approaches, are not valid” (EPA HSRB 2009, 34). In 

981 contrast to the prior version, this protocol indicates that AHETF will not statistically analyze the 

982 monitoring data; that begs the question as to what statistical methods are appropriate to use on 

983 these data. 

984

985 The Board also raised one new concern regarding the potentially adverse impact of the 

986 protocol’s call for an exposure duration of at least 4 hours for all of the MUs. This constraint 

987 seems unnecessary and may introduce unintended and undesired variability into the results. The 

988 Board noted that scripting activities to include more time than would otherwise be required to 

989 apply the amount of active ingredient in the designated stratum is likely to change the applica990 tor’s exposures by introducing variables that by their nature are unrelated to the AaiH. In partic991 ular, other tasks within those hours are likely to result in the transfer of active ingredient either to 

992 or from other surfaces from or onto the subject. For this study, the fraction of the total monitored 
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993 time that is time on-task is likely to be highly variable, probably among strata (particularly if the 

994 artificial constraint on the minimum time monitored affects the low AaiH preferentially) and po995 tentially even within strata. While omitting this time constraint would avoid these random va996 riables, the Board recommended that all field notes for this study report the time on-task as a 

997 fraction of the total monitored time, and that the total monitored time and the fraction of the total 

998 time on-task be tabulated for this study. This fraction can be used later by the Agency, sponsors 

999 and AHED users to reliably extrapolate from the time-weighted average concentrations or rates 

1000 of exposure measured by the existing protocols to task-specific concentrations or rates of dermal 

1001 and inhalation exposure per AaiH.

1002

1003 Ethics

1004 Charge to the Board

1005 If the revised AHETF scenario and field study proposal AHE120 is revised as suggested 

1006 in EPA’s review and if the research is performed as described, is the research likely to meet the 

1007 applicable requirements of 40 CFR part 26, subparts K and L? 

1008

1009 Board Response to the Charge

1010 HSRB Recommendation

1011 The Board concluded that the protocol submitted for review, if modified in accordance 

1012 with EPA (Evans and Sherman 2010b) and HSRB recommendations, is likely to meet the appli1013 cable requirements of 40 CFR 26, subparts K and L.

1014

1015 HSRB Detailed Recommendation and Rationale

1016 The submitted documents assert that the revised study will be conducted in accordance 

1017 with the ethical and regulatory standards of 40 CFR 26, Subparts K and L, as well as the re1018 quirements the US EPA’s GLP Standards described at 40 CFR 160 (AHETF 2010c; Collier 

1019 2010b). FIFRA §12(a)(2)(P) and the California State EPA Department of Pesticide Regulation’s 

1020 study monitoring requirements (California Code of Regulations Title 3, Section 6710) also apply. 

1021 The protocol was reviewed and approved by an independent human subjects review committee, 

1022 IIRB, Inc. of Plantation, FL prior to submission. Minutes of IIRB, Inc. meetings and a copy of 

1023 IIRB, Inc. policies and procedures were provided. This IRB is fully accredited by AAHRPP and 

1024 listed by OHRP (see details above).

1025

1026 1. Except as noted below, the Board concurred with the conclusions and factual observations of 

1027 the ethical strengths and weaknesses of the revised study, as detailed in the EPA’s Ethics Re1028 view (Evans and Sherman 2010b). The proposed study is likely to meet the applicable ethical 

1029 requirements for research involving human participants, in accordance with the following cri1030 teria:

1031

1032 a. Acceptable risk-benefit ratio. Risks as noted in the study protocol are four-fold: 1) heat1033 related illness; 2) injury associated with scripted field activities; 3) allergic reaction to 

1034 surfactants used for hand washing; and 4) psychological stress and/or breach of confiden1035 tiality for pregnancy test results. These risks are minimized appropriately and are justified 
Final Draft Document Dated December 8, 2010

Page 26 of 31

1036 by the potential societal benefits, particularly data on occupational exposure of agricul1037 tural workers to pesticides during mixing and loading activities.

1038

1039 • The greatest risk to participants is that of heat-related illness, given that the partici1040 pants will be required to wear two layers of clothing during the scenario activities. 

1041 This risk is lessened but not eliminated by the application of appropriate stopping 

1042 rules (including cessation of all monitoring activities when the ambient heat-index 

1043 exceeds 105°F) and frequent monitoring of participants. Participants will be given 

1044 frequent breaks, access to ample amounts of water or sports drinks, and educated 

1045 about the dangers and symptoms of heat-related illness. Appropriate medical man1046 agement procedures are also in place.

1047

1048 • The surrogate materials consist of four common pesticides: acephate, dithiopyr, im1049 idacloprid, and thiophanate-methyl. The participants will only be exposed to con1050 centrations of the surrogate compound at accepted exposure thresholds. 

1051

1052 • Participants will be selected from volunteers with experience handling these or sim1053 ilar compounds in WSP mixing and loading scenarios. Thus, all of the participants 

1054 will have extensive experience in using these or similar products, and thus will be 

1055 unlikely to misuse them in a way that might increase their likelihood of being acci1056 dentally exposed.

1057

1058 • Participants will be reminded about safe handling practices and procedures, about 

1059 wearing appropriate PPE, and will be monitored for any accidental or unintended 

1060 product exposure.

1061

1062 • Allergic reactions to the surfactants used in hand washing are usually mild and easi1063 ly treated with over-the-counter steroidal creams. The study will exclude partici1064 pants who have a history of severe skin reactions to such detergents.

1065

1066 • Minors and pregnant or lactating women are excluded from participation, with 

1067 pregnancy either confirmed by over-the-counter pregnancy testing on the day of 

1068 study or by opt-out. The potential stigma resulting from study exclusion due to 

1069 pregnancy is also appropriately minimized.

1070

1071 Several members noted, however, that exposure to the surrogate chemicals is no longer 

1072 listed as a potential risk to study participants in either the protocol or in the informed con1073 sent documents. Study volunteers, it was argued, are likely to handle these chemicals as 

1074 part of their daily activities and the possibility of exposure is thus a risk of employment 

1075 and not a risk of study participation. However, because of the nature of the study (includ1076 ing scripted handling of specific amounts of chemical), the Board felt that exposure to the 

1077 surrogate chemicals was a potential risk of study participation and recommended that the 

1078 sponsor explicitly list this risk in the protocol and informed consent documents. 

1079
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1080 b. Voluntary and informed consent of all participants

1081

1082 • There is the possibility that the participants in this study might represent particularly

1083 vulnerable populations, susceptible to coercion and undue influence. The study proto1084 col, however, includes several mechanisms designed to minimize coercive recruitment 

1085 and enrollment.

1086

1087 • Monetary compensation is not so high as to unduly influence participants.

1088

1089 • Spanish translations of the informed consent documents, informational packets, and re1090 cruitment flyers were provided. Researchers will be working with local Spanish1091 speaking community members to ensure that the appropriate regional dialect of Spanish 

1092 is used (AHETF 2010d).

1093

1094 c. Equitable selection of study participants

1095

1096 • The study is designed to recruit an appropriately diverse population of participants who 

1097 represent skilled agricultural workers in the five study locations.

1098

1099 • Community representatives and advocates are appropriately involved in the recruitment 

1100 and enrollment of study participants.

1101

1102 2. The Board recommended that the study protocol be modified to address the concerns noted in 

1103 the EPA’s Ethics Review (Evans and Sherman 2010b). In addition, the Board also raised the 

1104 following concerns:

1105

1106 • The Board raised concerns that the revised water-soluble packaging protocol was reviewed 

1107 by IIRB, Inc. using an expedited procedure. Future protocol revisions that involve major 

1108 changes like substitution of surrogate compounds and/or change in study site should be re1109 viewed under full-board procedures and reflected properly in the IRB minutes.

1110

1111 • As noted above, the Board recommended that accidental exposure to the surrogate chemi1112 cals be listed in the protocol and that the informed consent form also list surrogate exposure 

1113 as a potential risk of study participation.

1114

1115 • The protocol excludes participants who normally wear additional personal protective 

1116 equipment (such as chemical-resistant clothing) that is not required by the chemical label 

1117 and that might impact the objectives of the study. The Board recommended that this as1118 sessment be done in a non-directive way, so as not to encourage participants to wear less 

1119 PPE than they would normally in order to participate in the study.

1120

1121 • Study participants will undergo hand washes prior to eating anything, which will reduce 

1122 their risk of accidental ingestion of the surrogate compounds. As many of the adults in the 

1123 U.S. still smoke, however, the Board recommended that hand washes also occur before any 

1124 smoking break to further reduce their risk of accidental pesticide ingestion.

1125
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1126 • The informed consent document states that “you may refuse medical treatment unless you 

1127 get sick from too much exposure to pesticides or from getting too hot, or if we believe you 

1128 are too sick to make a rational decision about getting medical treatment” (Collier 2010b, 

1129 emphasis added). It was unclear how this determination of rationality will be made, howev1130 er. The protocol and informed consent document should be more explicit as to who will 

1131 make this determination, and what criteria would be used.

1132

1133 • The Board raised some concerns about how the Task Force plans to release individual ex1134 posure data to individual study participants who request this information. For example, the 

1135 Board encouraged the sponsor to consider how this information might be provided to par1136 ticipants who do not speak English and/or are illiterate. The Board also recommended that 

1137 the request for individual study results be included as a check box on the informed consent 

1138 document. The HSRB will be establishing a small working group to develop some guid1139 ance for the Agency and sponsors regarding the release of individual exposure data to study 

1140 participants.

1141
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1142 REFERENCES

1143

1144 Agricultural Handler Exposure Task Force (AHETF). 2010a. Supplemental 1 to the Backpack 

1145 and Handgun Application of Liquid Sprays in Utilities Rights-of-Way Scenario Submission 

1146 (AHE-400): SOPs Cited in AHE-400 ROW Submission. Undated and unpublished document 

1147 prepared by the AHETF.

1148

1149 AHETF. 2010b. Supplemental 2 to the Backpack and Handgun Application of Liquid Sprays in 

1150 Utilities Rights-of-Way Scenario Submission (AHE-400): Providing Individual Exposure 

1151 Information to Subjects. Undated and unpublished document prepared by the AHETF.

1152

1153 AHETF. 2010c. Supplemental 1 to the Revised Water Soluble Packet Mixer/Loader Scenario 

1154 Submission (AHE-120): SOPs Cited in AHE-120 ROW Submission. Undated and unpublished 

1155 document prepared by the AHETF.

1156

1157 AHETF. 2010d. Supplemental 2 to the Revised Water Soluble Packet Mixer/Loader Scenario 

1158 Submission (AHE-120): Providing Individual Exposure Information to Subjects. Undated and 

1159 unpublished document prepared by the AHETF.

1160

1161 Carley, J.M. 2010. Ethics Review of Completed AEATF II Mop Scenario Worker Exposure 

1162 Monitoring Study AEA-03. Dated October 4, 2010. Unpublished document prepared by the 

1163 Office of Chemical Safety and Pollution Prevention, United States Environmental Protection 

1164 Agency. 

1165

1166 Carroll, S. 2010. Efficacy Test Protocol: Field Efficacy Test of PMD and Lemongrass Oil Based 

1167 Repellent ‘No Mas’ Against Mosquitoes. Dated July 15, 2010. Unpublished document prepared 

1168 by Carroll-Loye Biological Research.

1169

1170 Collier, C.H., for the Agricultural Handler Exposure Task Force (AHETF). 2010a. Backpack and 

1171 Handgun Application of Liquid Sprays in Utilities Rights-of-Way Scenario Submission (AHE1172 400). Dated June 18, 2010. Unpublished document prepared by the AHETF.

1173

1174 Collier, C.H., for the Agricultural Handler Exposure Task Force (AHETF). 2010b. Revised Water 

1175 Soluble Packet Mixer/Loader Scenario Submission (AHE-120). Dated August 19, 2010. 

1176 Unpublished document prepared by the AHETF.

1177

1178 EPA Human Studies Review Board. 2008. April 9-10, 2008 Human Studies Review Board Meet1179 ing Report.

1180

1181 EPA Human Studies Review Board. 2009. June 24-25, 2009 Human Studies Review Board 

1182 Meeting Report.

1183

1184 Evans, J., and K. Sherman. 2010a. Science and Ethics Review of AHE400: A New Scenario 

1185 Design and Associated Protocol from the Agricultural Handler Exposure Task Force (AHETF) 

1186 Describing Proposed Research to Measure Dermal and Inhalation Exposure to Applicators Who 

1187 Use Backpack or Hand Gun Sprayers to Apply Pesticides in Utility Rights-of-Way. Dated 
Final Draft Document Dated December 8, 2010

Page 30 of 31

1188 September 30, 2010. Unpublished document prepared by the Office of Chemical Safety and 

1189 Pollution Prevention, United States Environmental Protection Agency.

1190

1191 Evans, J., and K. Sherman. 2010b. Science and Ethics Review of Revised AHETF Scenario De1192 sign and Protocol AHE120 for Exposure Monitoring of Workers during Mixing and Loading of 

1193 Pesticide Products in Water Soluble Packets in Five Regions of the United States (August 2010). 

1194 Dated October 1, 2010. Unpublished document prepared by the Office of Chemical Safety and 

1195 Pollution Prevention, United States Environmental Protection Agency.

1196

1197 Fuentes, C., and K. Sherman. 2010. Science and Ethics Review of Protocol for Human Study of 

1198 Mosquito Repellent Performance: Proposed Carroll-Loye Field Efficacy Test of PMD and 

1199 Lemongrass Oil-Based Repellent ‘No Mas’ Against Mosquitoes. Dated October 1, 2010. 

1200 Unpublished document prepared by the Office of Chemical Safety and Pollution Prevention, 

1201 United States Environmental Protection Agency. 

1202

1203 Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Roster and Procedures. 

1204 Unpublished materials prepared by IIRB.

1205

1206 Johnson, D., for the Agricultural Handler Exposure Task Force (AHETF). 2010a. Supplemental 3 

1207 to the Backpack and Handgun Application of Liquid Sprays in Utilities Rights-of-Way Scenario 

1208 Submission (AHE-400): Explanation of AHETF Spanish Translation Project. Dated September 

1209 30, 2010. Unpublished document prepared by the AHETF.

1210

1211 Johnson, D., for the Agricultural Handler Exposure Task Force (AHETF). 2010a. Supplemental 3 

1212 to the Revised Water Soluble Packet Mixer/Loader Scenario Submission (AHE-120): 

1213 Explanation of AHETF Spanish Translation Project. Dated September 30, 2010. Unpublished 

1214 document prepared by the AHETF.

1215

1216 Leighton, T. 2010. Science Review of the AEATF II Mop Human Exposure Monitoring Study 

1217 (AEA-03). MRID Numbers 48210201, 48231201, and 48231901 . Dated October 4, 2010. 

1218 Unpublished document prepared by the Office of Chemical Safety and Pollution Prevention, 

1219 United States Environmental Protection Agency.

1220

1221 Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment Task Force II (AEATF 

1222 II). 2010a. A Study for Measurement of Potential Dermal and Inhalation Exposure during 

1223 Application of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop Equipment for 

1224 Cleaning Indoor Surfaces. Dated August 2, 2010. Unpublished document prepared by the 

1225 AEATF II. MRID 48210201.

1226

1227 Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment Task Force II (AEATF 

1228 II). 2010b. Supplement 1 to A Study for Measurement of Potential Dermal and Inhalation 

1229 Exposure during Application of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop 

1230 Equipment for Cleaning Indoor Surfaces. Dated September 15, 2010. Unpublished document 

1231 prepared by the AEATF II. MRID 48231201.

1232

1233 Selim, S., and M.N. Taylor for the Antimicrobial Exposure Assessment Task Force II (AEATF 
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1234 II). 2010c. Supplement 2 to A Study for Measurement of Potential Dermal and Inhalation 

1235 Exposure during Application of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop 

1236 Equipment for Cleaning Indoor Surfaces. Dated September 21, 2010. Unpublished document 

1237 prepared by the AEATF II. MRID 48231901.

1238

1239 Appendix 1

1240

1241 [to be added at a later date]