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 Dr. 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 containing pyrethrins/ 

pyrethroids. The Agency proposes to rely 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), for 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-Loye 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 enclosed report provides the Board’s response to EPA charge questions presented at 

the October 20-21, 2009 meeting. 

Assessment 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. 

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 

pyrethrins/pyrethroids as a class. The Newton and Breslin study was relevant when 

considering the asthmatic or allergic respiratory response only for the specific insecticide 

product that was tested. 

Page 1 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 cautious in its use of these 

data, limiting it to a qualitative contribution to the overall weight of evidence analysis. 

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 significantly deficient relative to the 

ethical standards prevailing at the time the research was conducted. 

Assessment of Completed Research Study: Lisi, P. (1992) Short Communication: 

Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26:349-350. 

Science 

• The Board concluded that the Lisi study was likely scientifically 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 

pyrethrins/pyrethroids 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 overall 

analysis. 

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 significantly 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 Repellents (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 accordingly, will likely yield scientifically 

valid results on the efficacy of these two picaridin-based insect repellent formulations 

against ticks. 

Page 2 of 26 
Ethics 

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

with Agency recommendations and conducted accordingly, is likely 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 sprays. 

• 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 systematic 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 accordingly, 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 reviewed by someone familiar with the 

dialect written and spoken in the target community; design and posting of community 

notification flyers 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 productrelated harm due to immunodeficiency or other underlying conditions. 

Sincerely, 

Sean Philpott, PhD, MSBioethics 

Chair 

EPA Human Studies Review Board 

Page 3 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 

been 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. You may also contact the HSRB Designated Federal Officer, via 

e-mail at phre@epa.gov 

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

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

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

charge by the Agency. 

Page 4 of 26 
US ENVIRONMENTAL PROTECTION AGENCY 

HUMAN STUDIES REVIEW BOARD 

Chair 

Sean Philpott, PhD, MSBioethics, Director for Research Ethics, Assistant Professor of Bioethics, 

The Bioethics Program of Union Graduate College and the Mount Sinai School of Medicine, 

Schenectady, 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 Analyst, Office of the 

Commissioner, Office of Science 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, University of 

Arizona, Tucson, AZ 

Lois D. Lehman-Mckeeman, PhD, Distinguished Research Fellow, Discovery Toxicology, 

Bristol-Myers Squibb Company, Princeton, NJ 

Jerry A. Menikoff, MD, 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 George Washington University, Washington, DC 

William Popendorf, PhD, MPH, Professor, Department of Biology, Utah State University, 

Logan, UT 

Page 5 of 26 
*Ernest D. Prentice, PhD, Associate Vice Chancellor for Academic Affairs, University of 

Nebraska Medical Center, Omaha, 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 Staff, 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, Office of the Science Advisor, United States Environmental Protection Agency, 

Washington, DC 

Page 6 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 scientific and ethical issues 

concerning: two completed human toxicity studies involving one class of pesticide active 

ingredients – pyrethrins/pyrethroids– 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 by janitorial workers when applying a commercially-available antimicrobial 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 officials, the Board heard presentations from 

EPA on the following topics: two completed studies involving intentional human exposure to 

pyrethrin/pyrethroid pesticides (Newton and Breslin [1983], and Lisi [1992]); a proposed 

Carroll-Loye 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 research 

investigators, including: 

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

Dr. Jeffery Driver, Principal, infoscientific.com, Inc. 

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

Dr. Bryce Landenberger, Dow AgroSciences 

Dr. Sami Selim, President, Golden Pacific Laboratories 

Oral comments were provided by: 

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

Mr. Stephen McFadden, Independent Advocate 

Dr. Lawrence Plumlee, Independent Advocate 

No written public comments were provided. 

Page 7 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 

Assessment 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 with asthma 

and a history of chest tightness were evaluated for airway narrowing and chest tightening 

before and after a controlled exposure to aerosol insecticide sprays. Subjects were 

exposed to a commercially-available aerosol insecticide (Mortein Pressure Pak insect 

killer containing 3.0 g/kg pyrethrins, 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 study was three-fold: to 

study the response of asthmatic to exposure to insecticides containing pyrethrins 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 Charge

 In light 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 

pyrethrins/pyrethroids as a class of pesticides. 

Page 8 of 26 
 

Charge to the Board 

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

exposures to pyrethrins/pyrethroids 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 

considering 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 pyrethrins/pyrethroids as a class because of the use of a complex 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 by 

EPA in assessing the proposition that exposures to pyrethrins/pyrethroids 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 pyrethrins/pyrethroids may be associated 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 than 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 analysis 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 pyrethrins. One such ingredient, 

piperonyl butoxide, has been identified previously as a potential respiratory allergen (c.f. FDA 

warnings on pediculicide products, 21 CFR § 358.601). Accordingly, the Board concluded that 

the data obtained by Newton and Breslin are directly applicable only to the product tested, and 

are not broadly applicable to pyrethrins/pyrethroids 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 calculated based on 

the assessment of the amount of product delivered per unit time. Study subjects were 

Page 9 of 26 
 

likely to have been exposed to the experimental product, but the lack of data on the actual 

exposure rate or concentration precludes any quantitative evaluation. 

b. The Newton and Breslin article provides a description that is inadequate to assess 

whether the facility was appropriate for this type of testing. The test chamber was 

described as a 7-m3 room with large windows on one side for observation purposes 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 actual 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 subject. More notable is the fact that the only 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. It was 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 any additional detail on participant characteristics that 

could affect these values, such as age, gender, body size, or underlying disease. 

Page 10 of 26 
 

d. There was no specific designation of the symptoms that each patient experienced. It is 

not clear which patient was the person not counted among the “6 of 7” who experienced 

chest tightness with other symptoms. 

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 many times each person was 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 symptoms 

were self-diagnosed and reported by volunteers. 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 symptoms. 

Ethics 

Charge to the Board 

Is there clear and convincing evidence that the conduct of the Newton and Breslin (1983) 

study was fundamentally 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 

significantly 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 

Research Council (NHMRC) -- the largest public supporter of research in Australia -- issued 

guidelines as early as 1966 that required all NHMRC-funded research to be reviewed by an 

independent ethics committee. A 1976 supplementary note to these guidelines, prompted by 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 11 of 26 
Limited information is available about how the Newton 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 consent 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 type of ethical oversight of this research that took 

place, it is assumed 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 in 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 studies rule, 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 

fundamentally 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 subjects was not obtained. 

Given lack of clear and convincing evidence that for any other reasons it might have been 

fundamentally unethical, the Board concluded that it was not fundamentally unethical. 

b. Not significantly deficient. With regard to determining whether a study was significantly 

deficient relative to the ethical standards prevailing at the time the research was 

conducted, the Board’s standard is to determine whether or not any 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 regarding this study. Only the published article 

provides any 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 Study: Lisi, P. (1992) Short Communication: 

Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26:349-350. 

Overview of the Study 

In the Lisi (1992) study, 230 volunteers were patch tested with each of seven 

pyrethroids: allethrin, cypermethrin, deltamethrin, fenothrin (assumed phenothrin), 

fenvalerate, permethrin, resmethrin. The goal was to establish the irritation and 

sensitization potential of these widely used pyrethroids. Of the volunteers who 

participated, 162 were men and 68 were women. Subjects ranged from 19 to 78 years in 

age. Approximately 35% of the subjects were agricultural workers, 12% had previously 

Page 12 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. Further, 176 subjects had non-allergic skin 

disorders, and 16 subjects were also atopic. Simple counts and proportions were used to 

compare irritation and sensitization effects across the three occupational groups. 

Science 

Charge to the Board 

Is the Lisi (1992) study scientifically sound, providing reliable data? 

Board Response to the Charge 

The Board concluded that the Lisi study was likely sound, but the brevity 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 

pyrethrins/pyrethroids 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 

pyrethrins/pyrethroids 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 pyrethrins/pyrethroids 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 

Lisi 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 account when considering these data 

in the overall weight of evidence analysis. 

Page 13 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 reportedly performed according to standards and criteria 

established by the International Contact Dermatitis Research Group (ICDRG), the Board 

assumed that standard testing procedures were used. 

Major issues and limitations noted during the Board’s discussion included: 

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 any withdrew or were otherwise not observed, nor did the report provide any 

detail whether all test patches were evaluated for all on days 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 any 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 Board 

Is there clear and convincing evidence that the conduct of the Lisi (1992) study was 

fundamentally 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 and 

Page 14 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 Lisi study was conducted in Italy sometime in 1990 or 1991. The Board concurred 

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. Italy had established a National 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 

analysis. 

Extremely limited information is available about how the Lisi 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 type 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 any subjects came from an especially vulnerable group,” several of 

were current and former agricultural workers. Such may be socioeconomically or educationally 

disadvantaged, and thus may be vulnerable. The Board recommended that the Agency more 

clearly articulate or standardize its definition of vulnerability. 

Considering the information available, the Board concurred 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 research involving human, as required by the Agency’s 

expanded human studies rule, 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 article 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 any other reasons it might have been 

fundamentally unethical, the Board concluded that it was not fundamentally unethical. 

b. Not significantly deficient. With regard to determining whether a study was significantly 

deficient relative to the ethical standards prevailing at the time the research was 

conducted, the Board’s standard is to determine whether or not any 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 provided 

Page 15 of 26 
 

 

 

to study subjects could seriously impair informed consent. Only the published article 

provides any 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-Loye 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 LNX-003 is revised as 

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

generate scientifically reliable data, useful for assessing the efficacy 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 accordingly, will likely yield scientifically valid 

results on the efficacy of these two picaridin-based insect repellent formulations against ticks. 

HSRB Detailed Recommendations and Rationale 

Protocol LNX-003 from Carroll-Loye 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 study protocol was overly long and includes redundant or unnecessary text, it 

was relatively clear and addressed adequately a number of key scientific issues, including: 

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 study aim, rather than the Agency’s existing recommendation 

Page 16 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 type of data and should 

be considered by the Agency. 

Ethics 

Charge to the Board 

If the proposed laboratory tick repellency study protocol LNX-003 is revised as 

suggested in EPA’s review and if the research is performed as described, is the research likely 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 LNX003, 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 EPA’s GLP Standards described at 40 CFR 160, and the California Department of Pesticide 

Regulation study 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 by 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 copy of IIRB, Inc. policies and procedures were 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 factual 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 accordance 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) possible 

Page 17 of 26 
exposure to arthropod-borne diseases; 4) physical 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, 

particularly data on the efficacy of these new formulations as personal tick repellents. 

·	 Based on toxicological data currently available for picaridin, coupled with 

appropriate exclusion criteria, study subjects are unlikely to be at risk of adverse side 

effects with exposure. 

·	 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 regularly 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 transovarian mechanism. 

·	 The potential risks to subjects from physical stress are minimized. Although the 12­

hour duration of the study protocol raises some concerns about physical stress and 

exhaustion, the study investigators attest that similar protocols of equivalent length 

have never been seen as unduly stressful by study subjects. Appropriate stopping 

rules and medical management procedures are in place. Subjects are also given 

frequent breaks and can withdraw from the study at any 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 appropriately 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 employees of the Study Director 

are excluded from participation. Additional mechanisms designed to minimize 

coercive recruitment, developed in response to earlier HSRB concerns 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 18 of 26 
c. Equitable selection of study 

·	 The majority of research subjects will be recruited from the University 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 study results to the general 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 

AEATF II aerosol spraying scenario is designed to measure a typical occupational 

handler’s daily 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 types of surfaces, different room configurations, different types 

of buildings, different handlers, and various antimicrobial active ingredients. Eighteen 

professional janitors will be enrolled in the study, and asked to apply (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 review and if the research is performed as described, is the 

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

handlers who apply antimicrobial pesticides formulated as aerosol sprays? 

Board Response to the Charge 

The Board concluded that this protocol, if modified in accordance with EPA (Leighton, 

Walls and Sherman 2009) and HSRB recommendations will likely generate scientifically reliable 

data, useful for assessing the exposure of handlers who apply antimicrobial pesticides formulated 

as aerosol sprays. 

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 19 of 26 
HSRB Detailed Recommendations and Rationale 

The Board concluded that the protocol (AEATF II 2009a, 2009b) and supplemental SOPs 

(AEATF II 2009b) address adequately a number of key scientific issues, including: scientific 

objective, quantification of the test materials, data collection and compilation 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 daily 

exposures under the aerosol scenario as defined in this proposal is likely to describe adequately a 

typical occupational handler’s daily exposure to this antimicrobial application. The 

environmental monitoring, exposure monitoring and analytic techniques appear to be adequate. 

The variation in exposure should be sufficient to determine a distribution of exposures. 

The Board 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 generated, 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 consumer 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 less frequent exposure among nonprofessional users. 

2. Sample Size & Analysis: Raw and descriptive data will be provided, but no statistical 

analyses have been planned. Sample size adequacy cannot be judged without a statistical 

analysis plan. Placing 18 subjects into three clusters of six each requires consideration of 

cluster effects, and may complicate analysis of the results. Assumed constants related to 

exposure to the active ingredient may also prove to be incorrect, and additional subjects may 

need to be enrolled. 

3. Application of spray: The target number of cans sprayed 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 met before completion of that room? 

Additional protocol clarifications needed include: addressing the issue of the interval 

between sampling at different sites (currently, it appears that no two monitoring events can 

occur within the same building within one week); clarifying the issue of using empty 

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 20 of 26 
4. Quality assurance and control (QA/QC): QA/QC can be improved by: 

a. Determining likely 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 surface being treated is dry or wet at the time of the next spray application, 

and whether the applicant accidentally wiped the surface after spraying. Data 

accumulated during gross deviations from the protocol should also be excluded. Finally, 

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

Board Response to the Charge 

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

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-party 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 study, 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, in accordance with the following 

criteria: 

Page 21 of 26 
a. Acceptable risk-benefit ratio. The risks from participation in the study include: 1) 

discomfort and heat-related illness from wearing two layers 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 breach of confidentiality for pregnancy test results. These 

risks are minimized appropriately and are justified by the potential societal benefits, 

particularly data for new exposure assessments for antimicrobial products applied with 

pressurized aerosol cans. 

·	 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 known 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 frequently if requested. There also will be close 

observation of subjects, with subjects alerted to the signs and symptoms 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 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 

appropriately minimized. 

·	 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 clearly articulated in the 

protocol and informed consent documents. 

·	 Possible subjects for this study may be 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 identification are excluded from study participation but 

Page 22 of 26 
no other action is taken, minimizing any social risks to undocumented workers from 

disclosure of their status to law-enforcement or immigration authorities. 

b. Voluntary and informed consent of all 

·	 The informed 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 particularly vulnerable populations and thus might be 

susceptible to coercion or undue influence. Some subjects may be educationally or 

economically 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 roughly 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	 Spanish translations of all informed consent documents, informational 

packets, and recruitment flyers 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 directly with the researchers about their interest in 

enrolling in the study. Recruitment is not conducted through employers. 

c. Equitable selection of study 

·	 The study is designed to recruit an appropriately diverse population of subjects who 

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 recommended 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 reviewed 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” instead of “spray can”, and 

assuming that the volunteer knows what a Material Safety Data Sheet is). 

Page 23 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 own 

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 by someone familiar with the dialects written and spoken in the target 

community. The National Standards for Culturally and Linguistically 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 

“culturally and linguistically appropriate manner” (Office of Minority Health 2001, 

3). The same practice should be extended to subjects in EPA- or third partyconducted research, with materials such as informed consent forms and recruitment 

flyers written in ways that reflect “the dialectic and cultural nuances as well as the 

acculturation, educational, and literacy levels of the local target population” (Office 

of Minority Health 2001, 80). 

·	 The protocol provides for use of a community notification flyer. However, one 

neglected community includes persons who might be staying in the hotels where the 

study is conducted. The flyer should be revised so that it communicates the goals of 

the study and risks to that group. These flyers, 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 physical harm but are not presently excluded. This might include 

subjects who might be immunosuppressed for a variety of reasons, those with severe 

diabetes, and those with other conditions that pose a health risk. 

Page 24 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 by 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 by the AEATF II. 

Antimicrobial Exposure Assessment Task Force II (AEATF II). 2009c. AEATF II 

Aerosol Study Vol. 3 Primary 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; Icaridin)-Based Personal 

Insect Repellents (20% Cream and 20% Spray) with Ticks under Laboratory Conditions. Dated 

July 30, 2009. Unpublished protocol prepared by Carroll-Loye Biological Research. MRID 

47836801. 

Carroll, S. 2009b. Carroll-Loye Study LNX-003 Proposed Amended Language. Dated 

September 18, 2009. Unpublished protocol amendment prepared by Carroll-Loye 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. 

Independent 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 by Office of Pesticide Programs, United States Environmental 

Protection Agency. 

Lisi, P. 1992. Sensitization Risk of Pyrethroid Insecticides. Contact Dermatitis 26:349-350. 

MRID 47852801. 

Page 25 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. 2001. National Standards 

for Culturally and Linguistically 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 

(Lisi 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. 

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