Page 1 of 26

Wednesday , December 16, 2009 EPA
- HSRB
- 09
- 03 Kevin P. Teichman, PhD Acting Science Advisor Office of the Science Advisor 1200 Pennsylvania Avenue, NW Washington, DC 20460 Subject: October 20

- 21, 2009 EPA Human Studies Review Board Meeting Report Dear D r. Teichman, The United States Environmental Protection Agency (EPA or Agency) requested the Human Studies Review Board (HSRB) to review two completed intentional studies examining the effects of intentional exposure of human subjects to pesticides conta ining p yr ethrins/ py rethroids. The Agency

proposes to rel y on these two studies, conducted prior to publication of the EPA’s expanded final rule for protection of subjects in human research (40 CFR 26) on February 6, 2006 (71 Federal Register 24, 6137), f or regulatory

actions under the pesticide laws. The Agency

asked the HSRB to advise the Agency on a range of scientific and ethics issues regarding how the studies should be assessed against the provisions in 40 CFR sections 26.1701

– 26.1704 of the final human studies rule. The Agency

also requested the HSRB to provide scientific and ethics reviews of two proposed human studies: a proposed Carroll

- Lo ye Biological Research, Inc. (CLBR) insect repellent efficacy

study (LNX

- 003); and a proposed Antimicrobia l Exposure Assessment Task Force II (AEATF II) aerosol spray application protocol (AEA04). The enclosed report provides the Board’s response to EPA charge questions presented at the October 20

- 21, 2009 meeting. Assessment of Completed Research Study: Ne wton, J., Breslin, A. (1983) Asthmatic reactions to a commonly used aerosol insect killer. Medical Journal of Australia 1:378 - 380. Science

• Because of the use of a complex mixture represented by an insecticide product rather than a specific chemical in this study , the Board concluded that the Newton and Breslin study was not relevant when considering the asthmatic or allergic respiratory response for py rethrins/py

rethroids as a class. The Newton and Breslin study was relevant when considering the asthmati c or allergic respiratory response only

for the specific insecticide product that was tested.Page 2 of 26

• Considering the substantial limitations of the study , the Board concluded that the study was of limited utility . The Board recommended that the Agency be cautiou s in its use of these data, limiting it to a qualitative contribution to the overall weight of evidence anal ys is
. Ethics

• Given the limited information available about this study , the Board concluded that there neither was clear and convincing evidence that the study was fundamentally

unethical, nor clear and convincing evidence that the study was significantl y deficient relative to the ethical standards prevailing at the time the research was conducted. Assessment of Completed Research Study: Lisi, P. (1 992) Short Communication: Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26:349 - 350. Science

• The Board concluded that the L isi study was likely scientificall y sound, but the brevity of the report and limited details as to how the study was conducted prevent an accurate assessment of its reliability
.

• If carried out according to accepted guidelines and criteria, the Lisi study likely provides hazard assessment data that are relevant to assessing whether exposures to py rethrins/py

rethr oids may

be associated with allergic contact dermatitis or sensitization responses.

• Unanswered questions about participant history and selection, study

procedures, and outcome definitions should be taken into account when considering these data in the ove rall anal ys is. Ethics

• Given the limited information available about this study , the Board concluded that there neither was clear and convincing evidence that the study was fundamentally

unethical, nor clear and convincing evidence that the study was sign ificantl y deficient relative to the ethical standards prevailing at the time the research was conducted. Assessment of Proposed Carroll - Loye Biological Research Study LNX - 003: Efficacy Test of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellen ts (20% Cream and 20% Spray) with Ticks Under Laboratory Conditions. Science

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

recommendations and conducted accordingl y, will likely yi eld scientifically val id results on the efficacy of these two picaridin

- based insect repellent formulations against ticks.Page 3 of 26

Ethics

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

recommendations and conducted accordingl y, is lik ely to meet the applicable requirements of 40 CFR 26, subparts K and L. Assessment of Proposed AEATF II Scenario and Protocol AEA04: Research on Exposure of Janitorial Works Applying Pesticides Formulated as Aerosol Sprays. Science

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

and HSRB recommendations, will likely generate scientifically

reliable data, useful for assessing the exposure of handlers who apply antimicrobial pesticides formulated as aerosol spray s.

• The Board provided a number of recommendations for how the study could be improved, including: clarifying the criteria for exclusion of subjects who deviate grossly from the protocol; acknowledging that sy stematic differences in the air sampling results are likely to occur between the two methods used; and, considering carefully other variables that may influence exposure measurements.
Ethics
• The Board concluded that the protocol submitted for review, if modified in accordance with Agency

and HSRB recommendations and conducted accordingl y, is likely to meet the applicable requirements of 40 CFR 26, subparts K and L.

• The Board recommended that the protocol be revised to address certain concerns, including: ensuring that documents in Spanish are rev iewed by someone familiar with the dialect written and spoken in the target community ; design and posting of community notification fly ers appropriate for guests staying at the motels where study procedures are likely to take place; and, exclusion of volunteers who may be at greater risk of product

related harm due to immunodeficiency or other underlying conditions.

Sincerel y,
Sean Philpott, PhD, MSBioethics Chair EPA Human Studies Review BoardPage 4 of 26 NOTICE

This report has been written as part of the activities of the EPA Human Studies Review Board, a Federal advisory committee providing advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research. This report has not be en reviewed for approval by the Agency

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

represent the view and policies of the Environmental Protection Agency , nor of other agencies in the Executive Branch of the Federal government, nor does the mention of trade names or commercial products constitute a recommendation for use. You may obtain further information about the EPA Human Studies Review Board from its website at http://www.epa.gov/osa/hsrb
. Y ou may also contact the HSRB Designated Federal Officer, via e - mail at phre@epa.gov In preparing this document, the Board carefull y considered all information provided and presented b y the Agency presenters, as well a s information presented b y public commenters. This document addresses the information provided and presented within the structure of the charge b y the Agency
.Page 5 of 26 US ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD Chair Sean Philpott, PhD, MSBioe thics, Director for Research Ethics, Assistant Professor of Bioethics, The Bioethics Program of Union Graduate College and the Mount Sinai School of Medicine, Schenectad y, NY Vice Chair Janice Chambers, PhD, DABT, William L . Giles Distinguished Professor , Director, Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University , Mississippi State, MS Members Suzanne C. Fitzpatrick, PhD, DABT, Senior Science Policy Anal ys t, Office of the Commissioner, Office of Scie nce and Health Coordination, US Food and Drug Administration, Rockville, MD Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor of Health Policy

and American Studies, The George Washington University , Washington, DC Sidney Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharmacology , Howard University

College of Medicine, Washington, DC Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University , Manhattan, KS Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, Universit y of Arizona, Tucson, AZ Lois D. Lehman

- Mckeeman, PhD, Distinguished Research Fellow, Discovery Toxicology , Bristol

- My ers Squibb Company , Princeton, NJ Jerry A. Menikoff, M D, JD, Director, Office of Human Subjects Research, Office of the Director, National Institutes of Health, Bethesda, MD Rebecca Parkin, PhD, MPH, Associate Dean for Research and Public Health Practice, School of Public Health and Human Services, The Georg e Washington University , Washington, DC William Popendorf, PhD, MPH, Professor, Department of Biology , Utah State Universit y, Lo gan, UTPage 6 of 26

*Ernest D. Prentice, PhD, Associate Vice Chancellor for Academic Affairs, University of Nebraska Medical Center, Omah a, NE Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural Sciences, University

of Florida, Gainesville, FL Human Studies Review Board Staff
** Paul I . Lewis, PhD, Executive Director, Human Studies Review Board St aff, Office of the Science Advisor, United States Environmental Protection Agency , Washington, DC

* Not in attendance at October 20

- 21, 2009 Public Meeting **Service ending date was November 21, 2009. As of November 22, 2009, the DFO is Jim Downing, Offi ce of the Science Advisor, United States Environmental Protection Agency , Washington, DCPage 7 of 26

INTRODUCTION From October 20

- 21, 2009, the United States Environmental Protection Agency ’s (EPA or Agency) Human Studies Review Board (HSRB) met to address scient ific and ethical issues concerning: two completed human toxicity studies involving one class of pesticide active ingredients

– py

rethrins/py

rethroids

– conducted prior to publication of the EPA’s expanded final rule for protection of subjects in human research. In accordance with 40 CFR 26.1602, EPA sought HSRB review of these completed studies. Each of these completed studies is discussed more fully

below. In addition, the Agency

submitted two protocols for conducting new research involving human subjects : one study measuring the efficacy of two registered insect repellents containing picaridin against ticks under laboratory conditions; and one study measuring levels of exposure received b y janitorial workers when appl yi ng a commercially

- available antimicro bial pesticide formulated as an aerosol spray . In accordance with 40 CFR 26.1601, EPA sought HSRB review of these two proposed protocols. Each of these protocols is discussed more fully below. REVIEW PROCESS On October 20

- 21, 2009, the Board conducted a public face

- to - face meeting in Arlington, Virginia. Advance notice of the meeting was published in the Federal Register as “Human Studies Review Board; Notice of Public Meeting” (74 Federal Register 106, 26861). Following welcoming remarks from Agency off icials, the Board heard presentations from EPA on the following topics: two completed studies involving intentional human exposure to py rethrin/py rethroid pesticides (Newton and Breslin [1983], and L isi [1992]); a proposed Carroll

- Lo ye Biological Research, Inc. (CLBR) insect repellent efficacy study (LNX

- 003); and a proposed Antimicrobial Exposure Assessment Task Force II (AEATF II) aerosol spray application protocol (AEA04). The Board also asked clarifying questions of several study sponsors and/or resear ch investigators, including: Dr. Scott Carroll, Principal, Carroll

- Lo ye Biological Research Dr. Jeffery

Driver, Principal, infoscientific.com, Inc. Mr. Shawn King, Director of Operations, Carroll

- Lo ye Biological Research Dr. Bryce Landenberger, Dow AgroSc iences Dr. Sami Selim, President, Golden Pacific Laboratories Oral comments were provided by : Dr. Scott Carroll, Principal, Carroll

- Lo ye Biological Research Mr. Stephen McFadden, Independent Advocate Dr. Lawrence Plumlee, Independent Advocate No writte n public comments were provided.Page 8 of 26

For their deliberations, the Board considered the materials presented at the meeting, oral comments, and Agency

background documents (e.g., published literature, sponsor and investigator research reports, study protocols, data evaluation records, and Agency science and ethics reviews of proposed protocols and completed studies). A comprehensive list of background documents is available online at http://www.regulations.gov.
CHARGE TO THE BOARD AND BOARD RESPONSE Assessme nt of Completed Research Study: Newton, J., Breslin, A. (1983) Asthmatic reactions to a commonly used aerosol insect killer. Medical Journal of Australia 1:378 - 380. Overview of the Study In the Newton and Breslin (1982) study , seven subjects diagnosed w ith asthma and a history

of chest tightness were evaluated for airway narrowing and chest tightening before and after a controlled exposure to aerosol insecticide spray s. Subjects were exposed to a commercially

- available aerosol insecticide (Mortein Pressure Pak insect killer containing 3.0 g/kg py rethrins, 0.9 g/kg tetramethrin, 15 g/kg piperonyl butoxide, 7.5 g/kg N

- octyl

- bicycloheptene dicarbons, propellants [chlorofluorocarbons and hydrocarbons] and solvents [non

- water based]). The aim of the stud y was three

- fold: to study the response of asthmatic to exposure to insecticides containing py rethrins and tetramethrin; to study

the time

- course of exacerbation of asthma following exposure to the insecticide; and to evaluate bronchial reactivity to histamine after exposure to the insecticide. Data were reported as simple counts or proportions across exposure groups. Science Charge to the Board Is the Newton and Breslin (1983) study scientifically

sound, providing reliable data? Board Response to the Charg e Inlight of the substantial limitations of the study , the Board concluded that the study was of limited utility . The Board recommended that the Agency be cautious in its use of these data, limiting it to a qualitative contribution to the overall weight of evidence. The use of these data should also be limited to assessments of the specific insecticide product tested rather than py rethrins/py

rethroids as a class of pesticides.Page 9 of 26

Charge to the Board Is the Newton and Breslin (1983) study relevant to an assessment of the proposition that exposures to py

rethrins/py

rethroids may

be associated with asthmatic or allergic respiratory responses? Board Response to the Charge The Board concluded that the Newton and Breslin study was relevant only

when consi dering the asthmatic or allergic respiratory response for the specific insecticide product that was tested. It was not relevant when considering the asthmatic or allergic respiratory response for p yrethrins/p yr ethroids as a class because of the use of a co mplex mixture represented by an insecticide product rather than a specific chemical. Charge to the Board What limitations of the Newton and Breslin (1983) study should be taken into account b y EPA in assessing the proposition that exposures to py rethrin s/py

rethroids may

be associated with asthmatic or allergic respiratory responses? Board Response to the Charge The Board cautioned against using the Newton and Breslin study for assessing the proposition that exposures to py rethrins/py

rethroids may

be a ssociated with asthmatic or allergic respiratory

responses. The use of a complex mixture represented by an insecticide product rather than a specific chemical was of considerable concern, as was the more robust response for respiratory

irritation rather th an asthma or allergy reported in the study
. HSRB Detailed Recommendations and Rationale The Newton and Breslin (1982) article provided an incomplete record of the conduct of the study and anal ys is of the data, such that a number of important data gaps were identified. One primary

concern was that the tested material contained a mixture of ingredients, some of those ingredients at higher concentrations than the py rethrins. One such ingredient, piperonyl butoxide, has been identified previously as a po tential respiratory allergen (c.f. FDA warnings on pediculicide products, 21 CFR § 358.601). Accordingl y, the Board concluded that the data obtained b y Newton and Breslin are directly applicable onl y to the product tested, and are not broadly

applicable to py

rethrins/py

rethroids as a pesticide class. Other major issues and limitations noted during the Board’s discussion included: 1. Limited and likely inaccurate exposure data.
a. Exposures to the test material were not directly measured, but were ca lculated based on the assessment of the amount of product delivered per unit time. Study subjects werePage 10 of 26

likely to have been exposed to the experimental product, but the lack of data on the actual exposure rate or concentration precludes an y quantitative eva luation. b. The Newton and Breslin article provides a description that is inadequate to assess whether the facilit y was appropriate for this type of testing. The test chamber was described as a 7

- m 3 room with large windows on one side for observation pur poses and an exhaust fan that “removed fumes between sprays.” There is no indication, however, that there was a standardized protocol that governed spraying procedures or cleaning requirements between exposures. There also was no indication whether the air exchange rate of the room or cleaning procedures between exposures were sufficient to ensure that the exposure levels intended by the investigators were delivered. Thus, there may be a high degree of error in the estimated exposures, as compared to the ac tual exposures.
c. There was no mention of factors that may have affected actual exposures, such as the distance between participant and spray nozzle, spray

droplet size, or any

odorants or deodorants used to “mask” the product spray from the placebo. 2
. Small sample size

. a. Although study

subjects were noted to have a predisposition for asthma, and thus likely to be potentially

susceptible to showing an effect, only seven subjects were evaluated. b. There is insufficient descriptive information for the seven subjects chosen, such as parameters of respiratory function and disease state. It was also noted that the two oldest subjects were both male, but no consideration whether age, gender or other participant characteristics may

have affected the study results. 3. Incomplete results and data analysis.
a. Two subjects did not complete the pretest histamine challenge, and three subjects did not complete the post

- exposure challenge. Maximum mid

- expiratory flow rate (MMEFR) was not measured for one subje ct. More notable is the fact that the onl y subject with a significant decrease in forced expiratory volume in one second (FEV1) did not complete either histamine challenge evaluation. No explanation for subjects ’ failure to complete these study

procedures and tests was provided. b. There are limited details on how FEV1 and MMEFR values were reported. Itwas noted during the Board’s discussion that standard clinical practice is to report the maximum values, but it is unclear if this was done in the Newton and Breslin study
. c. There was no indication that baseline FEV1 or MMEFR values were within the normal ranges for these subjects , nor an y additional detail on participant characteristics that could affect these values, such as age, gender, body size, or underlying disease.Page 11 of 26

d. There was no specific designation of the s ymptoms that each patient experienced. Itis not clear which patient was the person not counted among the “6 of 7” who experienced chest tightness with other sy mptoms.
e. There was no specific indication whether and how the observation of respiratory irritation correlated with changes in FEV or MMEFR values. f. It is unclear which subjects were tested at which levels of exposure (e.g. 10 versus 20 seconds), how man y times each person w as exposed at each exposure duration, or which volunteers received the placebo on day 2. 4. Potential information bias.
a. Subjects were not blinded to treatment, and there was no description of how sy mptoms were self

- diagnosed and reported by voluntee rs. Without the use of standardized definitions as a reference, there is no way to know whether each subject had the same interpretation and reporting practices for self

- diagnosed respiratory

sy mptoms. Ethics Charge to the Board Is there clear and conv incing evidence that the conduct of the Newton and Breslin (1983) study was fundamentall y unethical, or significantly deficient relative to the standards of ethical research prevailing when it was conducted? Board Response to the Charge Given the limited information available about this study , the Board concurred with the Agency ’s assessment (Sherman 2009a) that there was neither clear and convincing evidence that the study was fundamentally

unethical, nor clear and convincing evidence that the study was significantl y deficient relative to the ethical standards prevailing at the time the research was conducted. HSRB Detailed Recommendations and Rationale The Newton and Breslin study was conducted in Australia in 1981 or 1982. The Board concurred with the Agency ’s assessment that most widely recognized ethical standard at that time was the 1975 Declaration of Helsinki, but also noted the importance of placing ethical standards within a specific national context. The Australian National Health and Medical Re search Council (NHMRC)

-- the largest public supporter of research in Australia

-- issued guidelines as earl y as 1966 that required all NHMRC

- funded research to be reviewed b y an independent ethics committee. A 1976 supplementary note to these guidelines, prompted b y and explicitly referencing the Declaration of Helsinki, called upon all Australian research facilities to establish committees to review all research involving human , NHMRC

- funded or otherwise.Page 12 of 26

Limited information is available about how the N ewton and Breslin study was conducted. The Agency

attempted to obtain additional information about the conduct of this study , but was unable to do so. The only available information is from the published article, which states that the written informed cons ent of all subjects was obtained. The article also indicates that all subjects were adults, and that none of the female volunteers were pregnant. Although the article does not describe the t ype of ethical oversight of this research that took place, it is a ssumed that independent ethics review occurred in accordance with NHMRC guidelines. Considering the information available, the Board concurred with the conclusions and factual observations of the ethical strengths and weaknesses of the study , as detailed i n the Agency ’s Ethics Review (Sherman 2009a). The Board also concluded that this study met all applicable ethical requirements for such research involving humans, as required by the Agency ’ s expanded human s tudies r ule, according to the following criteria:
a. Not fundamentally unethical . When determining whether or not a study is fundamentally unethical, the Board’s standard approach is to decide if the research was intended to seriously harm human subjects , if it failed to obtain informed consent, or if it was fundamentall y unethical for other reasons. In this case, there was no evidence that the study was intended to seriously harm subjects . The published article also failed to provide evidence supporting a conclusion that the informed consent of subject s was not obtained. Given lack of clear and convincing evidence that for an y other reasons it might have been fundamentall y unethical, the Board concluded that it was not fundamentall y unethical. b. Not significantly deficient . With regard to determining whether a stud y was significantl y deficient relative to the ethical standards prevailing at the time the research was conducted, the Board’s standard is to determine whether or not an y ethical deficiencies identified could have resulted in serious harm to human subjects , based on knowledge available to researchers at the time the study was conducted, or whether the information provided to study subjects could seriously impair informed consent. As noted above, there is limited information available regardin g this study . Only the published article provides an y information, and the information contained therein fails to support a conclusion that the study

was significantly

deficient relative to the standards at the time. Assessment of Completed Research Stud y: Lisi, P. (1992) Short Communication: Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26:349 - 350. Overview of the Study In the Li si (1992) study , 230 volunteers were patch tested with each of seven py rethroids: allethrin, cypermethrin, deltamethrin, fenothrin (assumed phenothrin), fenvalerate, permethrin, resmethrin. The goal was to establish the irritation and sensitization potential of these widel y used p yr ethroids. Of the volunteers who participated, 162 were men and 68 were women
. Subjects ranged from 19 to 78 y ears in age. Approximately

35% of the subjects were agricultural workers, 12% had previouslyPage 13 of 26

worked on a farm, and the remaining 53% were engaged in nonagricultural activities. Fifty

- four subjects had irritant or allergic contact dermatitis of the hands, 18 of which were correlated with agricultural activities. F urther , 176 subjects had non - allergic skin disorders, and 16 subjects were also atopic. Simple counts and proportions were used to compare irritation and sensitizat ion effects across the three occupational groups. Science Charge to the Board Is the Lisi (1992) study

scientificall y sound, providing reliable data? Board Response to the Charge The Board concluded that the L isi study was likely

sound, but the br evity

of the report and limited details as to how the study was conducted prevent an accurate assessment of its reliability
. Charge to the Board Is the Lisi (1992) study

relevant to an assessment of the proposition that exposures to py rethrins/py

rethr oids may

be associated with allergic contact dermatitis or sensitization responses? Board Response to the Charge If the Lisi study

was carried out according to accepted guidelines and criteria, it likely provides hazard assessment data that are relevant to assessing whether exposures to py rethrins/py

rethroids may

be associated with allergic contact dermatitis or sensitization responses. Charge to the Board What limitations of the Lisi (1992) study should be taken into account by EPA in assessing the proposition that exposures to py rethrins/py

rethroids may

be associated with allergic contact dermatitis or sensitization responses? Board Response to the Charge A lack of experimental detail and subject history represent two major limitations of the Lis i study . The Board also noted that the allergic/irritant response rate was extremely low in the study . The low response rate, along with concerns about participant history and selection, study procedures, and outcome definitions, should be taken into accou nt when considering these data in the overall weight of evidence anal ys is.Page 14 of 26

HSRB Detailed Recommendations and Rationale The extremely

brief nature of the report raised a number of questions about how the study was conducted. Because the study was reported ly

performed according to standards and criteria established by

the International Contact Dermatitis Research Group (I CDRG), the Board assumed that standard testing procedures were used. Major issues and limitations noted during the Board’s discussion i ncluded: 1. Poorly defined participant population.
a. It was unclear how the 230 were chosen for study. b. Subjects were identified as “agricultural workers,” “ex

- agricultural workers,” or “other,” but there was no explanation for creating and using these categories.
c. Participant compliance with study procedures was not reported. There was no indication as whether an y withdrew or were otherwise not observed, nor did the report provide an y detail whether all test patches were evaluated for all on d ay s 2 and 3. 2. Lack of protocol detail.
a. ICDRG protocols may have been used, but the report provides few details on how investigators distinguished allergic versus irritant responses or an y information on how they graded response severity
. 3. Low response rate.
a. The low response rate (less than 2% of all study) suggests that the seven compounds tested pose little risk of allergic contact dermatitis or skin sensitization. However, these data could also be indicative of problems in study design and conduct that invalidate the results. Because the appropriate positive and negative controls were not included in the study design, the Board felt that it could not rule out this alternative explanation for the low response rate. Ethics Charge to the Boar d Is there clear and convincing evidence that the conduct of the Lisi (1992) study was fundamentall y unethical, or significantly deficient relative to the standards of ethical research prevailing when it was conducted? Board Response to the Charge Given the extremely

limited information available about this study , the Board concurred with the Agency ’s assessment (Sherman 2009b) that there was neither clear andPage 15 of 26

convincing evidence that the study was fundamentally

unethical, nor clear and convincing evidence that the study

was significantly

deficient relative to the ethical standards prevailing at the time the research was conducted. HSRB Detailed Recommendations and Rationale The L isi study

was conducted in Italy

sometime in 1990 or 1991. The Board concurre d with the Agency ’s assessment that the most widely recognized ethical standard at that time was the 1989 Declaration of Helsinki, but again noted the importance of placing ethical standards within a specific national context. Ital y had established a Natio nal Bioethics Committee in 1990. That Committee may have developed directives applicable to this study . Nevertheless, as explained below, the potential existence of those national standards does not alter the Board’s anal ys is. Extremely

limited informatio n is available about how the L isi study was conducted. The EPA attempted to obtain additional information about the design and conduct of the study , but was unable to do so. The only available information is from the published article, which does not state whether written informed consent of the subjects was obtained. The published article also does not address what ty pe of ethical oversight took place (e.g. review by an independent ethics committee). Study subjects were reported to be adults, and there is no indication that any of the subjects were pregnant or nursing. Although the EPA ethics review states that “there is no evidence suggesting that an y subjects came from an especiall y vulnerable group,” several of were current and former agricultural worker s. Such may be socioeconomically or educationall y disadvantaged, and thus may be vulnerable. The Board recommended that the Agency more clearl y articulate or standardize its definition of vulnerability. Considering the information available, the Board conc urred with the conclusions and factual observations of the ethical strengths and weaknesses of the study , as detailed in the Agency ’s Ethics Review (Sherman 2009b). The Board also concluded that this study met all applicable ethical requirements for such r esearch involving human, as required by the Agency ’s expanded human s tudies r ule, according to the following criteria:
a. Not fundamentally unethical . When determining whether or not a study is fundamentally unethical, the Board’s standard approach is to decide if the research was intended to seriously harm , if it failed to obtain informed consent, or if it was fundamentally unethical for other reasons. In this case, there was no evidence that the study was intended to seriously

harm . The published artic le also failed to provide evidence supporting a conclusion that the informed consent of was not obtained. Given the lack of clear and convincing evidence that for an y other reasons it might have been fundamentall y unethical, the Board concluded that it was not fundamentall y unethical. b. Not significantly deficient . With regard to determining whether a stud y was significantl y deficient relative to the ethical standards prevailing at the time the research was conducted, the Board’s standard is to determine whether or not an y ethical deficiencies identified could have resulted in serious harm to subjects , based on knowledge available to researchers at the time the study was conducted, or whether the information providedPage 16 of 26

to study subjects could seriously impa ir informed consent. Onl y the published article provides an y information, and the information contained therein fails to support a conclusion that the study

was significantly

deficient relative to the standards at the time. Assessment of Proposed Carroll - Loye Biological Research Study LNX - 003: Efficacy Test of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and 20% Spray) with Ticks Under Laboratory Conditions. Overview of the Study The protocol describes a study to measure the effectiveness of picaridin as a tick repellent when used in one of two compound formulations (20% picardin KBR 3032 All

- Family Insect Repellent Cream and 20% picaridin KBR 3023 All

- Family Insect Repellent Spray). Dosimetry data accumulated in previous Carroll

- Lo ye studies (LNX

- 001 and LNX

- 002) would be used for dose selection. The efficacy of picaridin as a tick repellent will be determined in a controlled laboratory

setting by

placing both Western black

- legged ticks ( Ixodes pacificus) and American dog ticks (

Dermacentor variabilis) on picaridin

- treated and untreated forearms and measuring the speed and distance that moving ticks would penetrate into the treated area at 15

- minute intervals. A total of 20 subjects will be enrolled. Science Charge to the Board If the proposed laboratory tick repellency study protocol L

NX
- 003 is revised as suggested in EPA’s review and if the research is performed as described, is the research likel y to generate scientifically

reliable data, useful for assessing the effi cacy of the tested materials in repelling ticks? Board Response to the Charge The Board concluded that the protocol submitted for review, if modified in accordance with Agency

recommendations and conducted accordingl y, will likely yi eld scientifically valid results on the efficacy

of these two picaridin

- based insect repellent formulations against ticks. HSRB Detailed Recommendations and Rationale Protocol L

NX
- 003 from Carroll

- Lo ye Biological Research (Carroll 2009a, 2009b) will be conducted using methods similar to those presented to and commented on by the Board in the past. Although the stud y protocol was overly long and includes redundant or unnecessary text, it was relativel y clear and addressed adequatel y a number of key scientific issues, inc luding: scientific justification, objectives, and data collection and compilation methods. The proposed methods largely follow EPA’s guidelines, with the one notable exception being the use of ten volunteers per stud y aim, rather than the Agency ’s existi ng recommendationPage 17 of 26

of six volunteers per study aim. The greater number of study subjects should yield more useful information than might otherwise be obtained. The protocol also incorporated the use of dosimetry

- generated data, which will likely generate data representative of real

- world use by consumers. As has been pointed out previously in Board reviews of other repellency protocols, the proposed statistical approach fails to account for censoring of data and the calculation of complete protection time is not the best end

- use of the study data. Calculating the proportion of individuals protected for a given time may be a better way

to report this ty

pe of data and should be considered b y the Agency. Ethics Charge to the Board If the proposed laborato ry tick repellency

study protocol L

NX
- 003 is revised as suggested in EPA’s review and if the research is performed as described, is the research likel y to meet the applicable requirements of 40 CFR part 26, subparts K and L ? Board Response to the Charge The Board concluded that the proposed laboratory tick repellency study protocol L

NX
003, if modified in accordance with EPA (Sherman and Sweeney 2009) recommendations, and performed as described, will likely meet the applicable requirements of 40 CFR 26, subparts K and L
. HSRB Detailed Recommendations and Rationale The submitted documents assert that the study will be conducted in accordance with the ethical and regulatory

standards of 40 CFR 26, Subparts K and L, as well as the requirements of US EP A’s GLP Standards described at 40 CFR 160, and the California Department of Pesticide Regulation stud y monitoring (California Code of Regulations Title 3, Section 6710) (Carroll 2009a, 2009b). Requirements of FIFRA §12(a)(2)(P) also apply . The protocol was reviewed and approved b y an independent human subjects review committee, Independent Investigational Review Board, Inc. (IIRB, Inc.), of Plantation, FL, prior to submission. Minutes of IIRB, Inc. meetings and a cop y of IIRB, Inc. policies and procedures w ere provided to the EPA as a separate document (IIRB, Inc. 2009). These documents indicate that IIRB, Inc. reviewed this protocol pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A). 1. The Board concurred with the conclusions and fa ctual observations of the ethical strengths and weaknesses of the study , as detailed in the EPA’s Ethics Review (Sherman and Sweeney 2009). The proposed study is likely to meet the applicable ethical requirements for research involving human subjects , in a ccordance with the following criteria:
a. Acceptable risk

- benefit ratio . The risks as noted in the study protocol are fivefold: 1) allergic reaction to test materials themselves; 2) exposure to biting arthropods; 3) possiblePage 18 of 26

exposure to arthropod

- borne di seases; 4) phy sical stress from the test conditions; and 5) psychological stress and/or breach of confidentiality for pregnancy

test results. These risks are minimized appropriately and are justified by

the potential societal benefits, particularl y data on the efficacy of these new formulations as personal tick repellents.

· Based on toxicological data currentl y available for picaridin, coupled with appropriate exclusion criteria, stud y subjects are unlikely to be at risk of adverse side effects with exposur e.

· The risk of bites is negligible and minimized by the study design; tick questing and biting behavior is slow, and study subjects are trained to remove ticks from their forearms prior to biting. Study subjects will be trained in proper tick observation and handling techniques.

· The ticks used for the study are bred and raised in a laboratory environment and are considered to be pathogen

- free, minimizing the risk of vector

- borne disease. Tick colonies and their rabbit hosts are also screened regularl y for known tick

- borne diseases, including the rickettsial illness Rocky Mountain Spotted Fever that has been observed in the past to be transmitted within laboratory tick colonies through a trans

ovarian mechanism.

· The potential risks to subjects from ph ys ica l stress are minimized. Although the 12

- hour duration of the study protocol raises some concerns about phy sical stress and exhaustion, the study

investigators attest that similar protocols of equivalent length have never been seen as unduly stressful b y study subjects . Appropriate stopping rules and medical management procedures are in place. Subjects are also given frequent breaks and can withdraw from the stud y at an y time should the investigational procedures prove too strenuous.

· Minors and pregnant or lactating women are excluded from participation, with pregnancy

either confirmed by

over - the

- counter pregnancy testing on the day

of study or by opt - out. The potential stigma resulting from study exclusion due to pregnancy is also appropriatel y minimized. b. Voluntary and informed consent of all

· The study

protocol includes several mechanisms designed to minimize coercive recruitment and enrollment. For example, although many of the research subjects will be recruited from the University of California at Davis student population, where Dr. Carroll holds an adjunct appointment, student and employ ees of the Study Director are excluded from participation. Additional mechanisms designed to minimize coercive recruitment, developed in response to earlier HSRB c oncerns and recommendations (c.f. EPA HSRB 2006a; 2006b) are also in place.

· Monetary

compensation is not so high as to unduly influence study subjects
.Page 19 of 26

c. Equitable selection of study

· The majority

of research subjects will be recruited from the Univers ity of California at Davis student population. Study subjects are likely to reflect the ethnic and racial diversity of individuals in the City of Davis, but the use of this convenience sample may limit the broad applicability of the stud y results to the ge neral population. The investigators have noted this fact in the protocol. Assessment of Proposed AEATF II Scenario and Protocol AEA04: Research on Exposure of Janitorial Workers Applying Pesticides Formulated as Aerosol Sprays. Overview of the Study A EATF II aerosol spraying scenario is designed to measure a typical occupational handler’s dail y exposure to an antimicrobial spray packaged in a pressurized aerosol spray can. These data will be used generically to estimate dermal and inhalation exposures and risks for other antimicrobial ingredients where the product is packaged in a pressurized aerosol spray can. The Task Force expects these data to be useful for estimating exposures for various types of aerosol spray

products, different t ypes of surfaces , different room configurations, different t ypes of buildings, different handlers, and various antimicrobial active ingredients. Eighteen professional janitors will be enrolled in the study, and asked to appl y (spray , but not wipe) the product at one of three motels in the Fresno, CA area. Study subjects will be randomized to apply different amounts of product, from 1 to 4 cans of product in 1/2

- can increments (i.e., 1 to 1.5 cans, 1.5 to 2 cans, up to 3.5 to 4 cans). Dermal and inhalation exposure will be measured using whole

- body

dosimeters (inner and outer), hand and face washes, and personal air monitors. Science Charge to the Board If the proposed AEATF II aerosol application scenario and field study protocol AEA04 is revised as suggested in EPA’s r eview and if the research is performed as described, is the research likel y to generate scientificall y reliable data, useful for assessing the exposure of handlers who appl y antimicrobial pesticides formulated as aerosol spray s? Board Response to the Cha rge The Board concluded that this protocol, if modified in accordance with EPA (Leighton, Walls and Sherman 2009) and HSRB recommendations will likely generate scientificall y reliable data, useful for assessing the exposure of handlers who apply antimic robial pesticides formulated as aerosol spray s. The Board also recommended a number of protocol modifications, as listed below. Additional Board review of the protocol is not required prior to study implementation.Page 20 of 26

HSRB Detailed Recommendations and Ratio nale The Board concluded that the protocol (AEATF II 2009a, 2009b) and supplemental SOPs (AEATF II 2009b) address adequatel y a number of key scientific issues, including: scientific objective, quantification of the test materials, data collection and comp ilation methods and summary of test results, justification for selection of the test substances, and QA/QC requirements. The process used to select the product to be tested seems rational. The AEATF II has described in detail their sampling design for the aerosol scenario, and has incorporated random elements where feasible. The aerosol scenario is well defined, and the diversity of dail y exposures under the aerosol scenario as defined in this proposal is likely to describe adequately

a ty pical occupational handler’s dail y exposure to this antimicrobial application. The environmental monitoring, exposure monitoring and anal yt ic techniques appear to be adequate. The variation in exposure should be sufficient to determine a distribution of exposures. The B oard did raise a number of concerns about perceived inadequacies in the study design, as summarized below: 1. Use of the results : EPA plans to use the data generated from the proposed aerosol study generically

to estimate dermal and inhalation exposures and risks for other antimicrobial ingredients where the product is packaged in a pressurized aerosol spray can. However, other variables can affect rates of exposure, including different nozzle sizes, spray and ejection rates, the size of the particles generat ed, and the generation of nonvolatile active ingredients. Inhalation versus dermal exposure may also vary with these variables. It is also unclear if occupational handler exposure can be used to estimate exposures of nonprofessionals using similar consume r products. However, for risk assessment purposes it was felt that exposure among occupational users is likely to exceed that of consumers; the higher frequency

of exposures among occupational users is likely to exceed a plausibly higher individual but les s frequent exposure among nonprofessional users. 2. Sample Size & Analysis : Raw and descriptive data will be provided, but no statistical anal ys es have been planned. Sample size adequacy cannot be judged without a statistical anal ys is plan. Placing 18 s ubjects into three clusters of six each requires consideration of cluster effects, and may

complicate anal ys is of the results. Assumed constants related to exposure to the active ingredient may also prove to be incorrect, and additional subjects may need t o be enrolled. 3. Application of spray : The target number of cans spray ed in each location by each worker on each day could be specified better within the protocol. For example, does a worker need to continue spraying a room if the target application is m et before completion of that room? Additional protocol clarifications needed include: addressing the issue of the interval between sampling at different sites (currentl y, it appears that no two monitoring events can occur within the same building within on e week); clarifying the issue of using empt y apartments rather than motel rooms; and clarifying the effect of exhaust vent effects on exposure, which could be different than indicated in the protocol.Page 21 of 26

4. Quality assurance and control (QA/QC): QA/QC can be improved b y:
a. Determining likel y differences in the air sampling results depending on the method used (e.g. depending on the air sampling equipment used, differences in the orifice diameters and air flow sampling rates could affect aerosol collection efficiencies and effects). b. Setting the minimal spike to two to four times that of the limit of quantitation (LOQ; cf. AEATF II 2009b: 42, 46).
c. Considering other variables that may influence the measurement of exposure, including whether the surfa ce being treated is dry or wet at the time of the next spray application, and whether the applicant accidentall y wiped the surface after spraying. Data a ccumulated during gross deviations from the protocol should also be excluded. Finall y, the protocol sho uld indicate that there will be a maximum of two workers on any given day in the same location. Ethics Charge to the Board If the proposed AEATF II aerosol application scenario and field study protocol AEA04 is revised as suggested in EPA’s review and if the research is performed as described: Is the research likel y to meet the applicable requirements of 40 CFR part 26, subparts K and L ? Board R esponse to the Charge The Board concluded that the protocol submitted for review, if modified in accordanc e with EPA (Leighton, Walls and Sherman 2009) and HSRB recommendations, is likely to meet the applicable requirements of 40 CFR 26, subparts K and L
. HSRB Detailed Recommendations and Rationale This is a protocol for third

- part y research involving intentional exposure of human subjects to a pesticide, with the intention of submitting the resulting data to EPA under the pesticide laws (AEATF II 2009a, 2009b, 2009d). Thus, it is subject to the ethical and regulatory standards of 40 CFR 26, Subparts K and L. The requirements of FIFRA §12(a)(2)(P) relating to informed, voluntary

consent and those of the California Department of Pesticide Regulation study monitoring (California Code of Regulations Title 3, Section 6710) also apply . The protocol was reviewed and approved by an independent human subjects review committee, Independent Investigational Review Board, Inc. of Plantation, Florida, prior to submission (AEATF 2009b, 2009c). 1. Except as noted below, the Board concurred with the conclusions and factual observations of the ethical strengths and weaknesses of the stud y, as detailed in the EPA’s Ethics Review (Leighton, Walls and Sherman 2009). The proposed study is likely to meet the applicable ethical requirements for research involving human subjects , i n accordance with the following criteria:Page 22 of 26

a. Acceptable risk

- benefit ratio . The risks from participation in the study include: 1) discomfort and heat

- related illness from wearing two lay ers of clothing; 2) discomfort from wearing an air sampling device; 3 ) reactions from exposure to the test material (including accidental exposure) or to solvents used to obtain residues from hands, face and neck; 4) embarrassment from disrobing in the presence of a research technician; and 5) psychological stress and/or br each of confidentiality for pregnancy

test results. These risks are minimized appropriately and are justified by

the potential societal benefits, particularl y data for new exposure assessments for antimicrobial products applied with pressurized aerosol can s.

· The surrogate materials consist of a commonly used commercial antimicrobial product , which is known to have low risks. The subjects will only be exposed to concentrations of the surrogate compound at accepted exposure thresholds. Candidates who are kno wn to be sensitive to that compound, or who are in poor health, or who have broken skin on their hands, face, or neck will be excluded.

· Risk of heat

- related illness is minimized appropriately . Testing will take place in a temperature - controlled environment, and the heat index will be monitored with associated stopping rule. There will be a limited time of exposure with rest periods at 30
- minute intervals, or more frequentl y if requested. There also will be close observation of subjects , with subjects alert ed to the signs and s ymptoms of heat stress.

· Subjects will be reminded about safe handling practices and procedures, wear appropriate personal protective equipment (PPE), and will be monitored for any accidental or unintended product exposure.

· Minors an d pregnant or lactating women are excluded from participation, with pregnancy

either confirmed by

over - the

- counter pregnancy testing on the day

of study or by opt - out. The potential stigma resulting from study exclusion due to pregnancy is appropriatel y mi nimized.

· The purpose of the study is to develop more accurate information on worker exposures to liquid antimicrobial products applied using pressured aerosol cans for indoor surface disinfecting. Although there is no clear benefit to study participation, Subjects may

benefit by

requesting their results and using these results to change their working practices. Benefits and risks of participation are clearl y articulated in the protocol and informed consent documents.

· Possible subjects for this study may b e undocumented immigrants. Recruitment materials should state that government

- issued identification is necessary for enrollment in this study
.

· A valid government

- issued form of identification is necessary for enrollment. Volunteers who lack proper identif ication are excluded from study participation butPage 23 of 26 no other action is taken, minimizing an y social risks to undocumented workers from disclosure of their status to law

- enforcement or immigration authorities. b. Voluntary and informed consent of all

· The i nformed consent documents clearly state that study subject can withdraw at any time without penalty
.

· The Board disagrees with the EPA comment that “no potential subjects are from a vulnerable population” (Leighton, Walls and Sherman 2009: 11). In fact, subjects in this study might represent particularl y vulnerable populations and thus might be susceptible to coercion or undue influence. Some subjects may be educationally

or economicall y disadvantaged, or may not be native speakers of English. However, the risk of coercion or undue influence is appropriately minimized as follows:
o Monetary

compensation is roughl y equivalent to the average daily wage of janitorial workers in Fresno, California, and so is not so high as to unduly influence the subjects
. o Spani sh translations of all informed consent documents, informational packets, and recruitment fly ers are available. If necessary , the informed consent process will be conducted in Spanish by a member of the research team fluent in that language.
o The subjects communicate directl y with the researchers about their interest in enrolling in the stud y. Recruitment is not conducted through employ ers.
c. Equitable selection of study

· The study

is designed to recruit an appropriatel y diverse population of subjects wh o represent professional janitorial workers in the Fresno County area. The researchers plan to place recruitment notices in three newspapers that cater to the general population, the African

- American population, and the Latino population. 2. The Board rec ommended that the study protocol be modified to address the few concerns noted in the EPA’s Ethics Review (Leighton, Walls and Sherman 2009). The Board also made the following additional recommendations:

· The Board recommended that the consent form be revi ewed to make sure that it is at an appropriate reading level for the proposed participant population. In some instances, there appear to be word choices that could be simplified (e.g., wording such as “non

- porous surfaces”, “pressurized aerosol can” instea d of “spray can”, and assuming that the volunteer knows what a Material Safet y Data Sheet is).Page 24 of 26

· The Board agrees with the EPA ethics review that the informed consent form should read, “We will pay

for needed medical treatment that is not paid for by your o wn insurance or the insurance of a third party under which you are covered.”

· As some possible subjects for this study may be undocumented immigrants, recruitment materials should more explicitly state that a valid government

- issued form of identification is necessary for enrollment.

· The Board recommended that the Task Force ensure that documents in Spanish are reviewed b y someone familiar with the dialects written and spoken in the target community . The National Standards for Culturally and L inguisticall y Appropriate Services in Health developed by the Department of Health and Human Services, the Office of Minority

Health has stressed the importance of treating medical patients in a “culturall y and linguistically appropriate manner” (Office of Minority He alth 2001, 3). The same practice should be extended to subjects in EPA

- or third part y conducted research, with materials such as informed consent forms and recruitment fly ers written in way s that reflect “the dialectic and cultural nuances as well as the acculturation, educational, and liter acy levels of the local target population” (Office of Minority

Health 2001, 80).

· The protocol provides for use of a community notification fly er. However, one neglected community

includes persons who might be staying i n the hotels where the study is conducted. The fly er should be revised so that it communicates the goals of the study and risks to that group. These fl ye rs, in both English and Spanish, should also be posted in locations so that hotel guests are likely to see it. Alternatively , the researchers should consider conducting the research in areas away from hotel guests.

· The exclusion criteria should be revised to eliminate some groups that might be at higher risk of ph ys ical harm but are not presently excluded. This might include subjects who might be immunosuppressed for a variet y of reasons, those with severe diabetes, and those with other conditions that pose a health risk.Page 25 of 26

REFERENCES Antimicrobial Exposure Assessment Task Force II (AEATF II). 2009a. AEATF II Aerosol Study

Vol. 1 Primary

Documentation: Aerosol Application Scenario Design. Dated August 4, 2009. Unpublished protocol prepared b y the AEATF II. Antimicrobial Exposure Assessment Task Force II (AEATF II). 2009b. AEATF II Aerosol Study

Vol. 2 Primary

Documentation: Study

Protocol and IIRB Approval and Documentation. Dated August 4, 2009. Unpublished protocol and documentation prepared b y the AEATF II. Antimicrobial Exposure Assessment Task Force II (AEATF II). 2009c. AEATF II Aerosol Study

Vol. 3 P rimary

Documentation: IIRB Communications. Dated August 4, 2009. Unpublished documentation prepared by the AEATF II. Antimicrobial Exposure Assessment Task Force II (AEATF II). 2009d. AEATF II Aerosol Study

Vol. 4 Standard Operating Procedures for a Multi

- Year Antimicrobial Chemical Exposure Monitoring Program. Dated August 4, 2009. Unpublished documentation prepared by the AEATF II. Carroll, S. 2009a. Efficacy Test of KBR3023 (Picaridin; I caridin)

- Based Personal Insect Repellents (20% Cream and 20% Spray) with Ticks under Laboratory Conditions. Dated July 30, 2009. Unpublished protocol prepared b y Carroll

- Lo ye Biological Research. MRID 47836801. Carroll, S. 2009b. Carroll

- Lo ye Study L NX
- 003 Proposed Amended Language. Dated September 18, 2009. Unpublished protocol amendment prepared b y Carroll

- Lo ye Biological Research. EPA HSRB. 2006a. June 27
- 30, 2006 EPA Human Studies Review Board Meeting Report. EPA Human Studies Review Board. 2006b. October 18

- 19, 2006 Human Studies Review Board Meeting Report. Ind ependent Institutional Review Board, Inc. (IIRB, Inc.). 2009. Supplemental IIRB, Inc., Documentation Package. Unpublished materials prepared by IIRB. Leighton, T., C. Walls and K. Sherman. 2009. Science and Ethics Review of AEATF II Aerosol Scenario Design and Protocol for Exposure Monitoring. Dated September 21, 2009. Unpublished document prepared b y Office of Pesticide Programs, United States Environmental Protection Agency
. Lisi, P. 1992. Sensitization Risk of Py rethroid Insecticides. Contact Dermatit is 26:349
- 350. MRID 47852801.Page 26 of 26

Newton, J.G. and A.B. Breslin. 1983. Asthmatic Reactions to a Commonly Used Aerosol Insect Killer. Medical Journal of Australia 1:378
- 380. MRID 47686201. Office of Minority

Health, Department of Health and Human Services. 20 01. National Standards for Culturally

and L inguistically

Appropriate Services in Health Care: Final Report. Washington, DC: U.S. Department of Health and Human Services. Sherman, K. 2009a. Ethics Review of Pre

- Rule Intentional Exposure Human Toxicity Study (Newton and Breslin 1983). Dated September 16, 2009. Unpublished document prepared by Office of Pesticide Programs, United States Environmental Protection Agency
. Sherman, K. 2009b. Ethics Review of Pre

- Rule Intentional Exposure Human Toxicity Study (L isi 1992). Dated September 16, 2009. Unpublished document prepared by Office of Pesticide Programs, United States Environmental Protection Agency
. Sherman, K., and K. Sweeney . 2009. Science and Ethics Review of Protocol for Human Study of Tick Repellent Performance. Dated September 21, 2009. Unpublished document prepared by Office of Pesticide Programs, United States Environmental Protection Agency
.