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Minutes of the

United States Environmental Protection Agency (EPA) 

Human Studies Review Board (HSRB)

April 13 – 14, 2011 Public Meeting

Docket Number: EPA-HQ-ORD-2011-0124

HSRB Web Site: http://www.epa.gov/osa/hsrb

Committee Members: (See EPA HSRB Members List—Attachment A) 

Date and Time: Wednesday, April 13, 2011, 9:15 AM – 5:30 PM

Thursday, April 14, 2011, 10:00 AM – 1:10 PM

(See Federal Register Notice—Attachment B) 

Location: Holiday Inn National Airport, 2650 Jefferson Davis Highway,

Arlington, VA 22202

Purpose: The EPA HSRB provides advice, information, and recommendations on issues 

related to the scientific and ethical aspects of human subjects research. 

Attendees: Chair: Sean Philpott, Ph.D., M.S. Bioethics

Vice Chair: Janice Chambers, Ph.D., D.A.B.T.

Board Members: George C.J. Fernandez, Ph.D.

Vanessa Northington Gamble, M.D., Ph.D.

Sidney Green, Jr., Ph.D., Fellow, ATS

Dallas E. Johnson, Ph.D.

Michael D. Lebowitz, Ph.D., FCCP

José E. Manautou, Ph.D.

Jerry A. Menikoff, M.D. 

William J. Popendorf, Ph.D.

Virginia Ashby Sharpe, Ph.D.

Linda J. Young, Ph.D.

Meeting Summary: Meeting discussions generally followed the issues and general timing as 

presented in the meeting Agenda (Attachment C), unless noted otherwise. 

Convene Public Meeting and Review Administrative Procedures

Mr. Jim Downing (Designated Federal Officer [DFO], HSRB [or Board], Office of the 

Science Advisor [OSA], EPA [or Agency]) convened the meeting and welcomed Board 

members, EPA colleagues and members of the public. He thanked the Board members for their 

work in preparing for the meeting deliberations.

Mr. Downing noted that in his role as the DFO under the Federal Advisory Committee 

Act (FACA), he serves as liaison between the Board and EPA and is responsible for ensuring that 

all FACA requirements are met. The DFO must work with appropriate Agency officials to ensure 
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that all appropriate ethics regulations are satisfied regarding conflicts of interest; HSRB members 

have been briefed on federal conflict of interest laws and have completed a standard government 

financial disclosure report. In consultation with the deputy ethics officer for OSA and the Office 

of the General Counsel, Mr. Downing has reviewed the reports to ensure that all ethics 

requirements are met. 

Mr. Downing informed members that there were four challenging topics on the agenda 

for the meeting, and agenda times are approximate. Copies of the meeting materials and public 

comments will be available at http://www.regulations.gov under docket number EPA-HQ-ORD2011-0124. Following the presentations, time has been scheduled for questions of clarification to 

EPA staff and the principal investigator and sponsors of the studies discussed. This time is to be 

used for points of clarification rather than Board discussion. A public comment period will be 

maintained, and remarks must be limited to 5 minutes. During Board discussions, if members 

require clarification from the public, they may request such information through the Chair or 

DFO. All background materials for the meeting will be available in the public docket and most 

also are available on the HSRB Web site. Meeting minutes, including a description of the matters 

discussed and conclusions reached by the Board, will be prepared and must be certified by the 

meeting Chair within 90 days. The HSRB also will prepare a final report as a response to 

questions posed by the Agency that will include the Board’s review and analysis of materials 

presented. EPA will announce the Board review and subsequent approval of the report in the 

Federal Register. Mr. Downing turned the meeting over to the HSRB Chair, Dr. Sean Philpott. 

Introduction and Identification of Board Members

Dr. Philpott thanked the Agency and Board members for all of the planning and 

preparation for the meeting. He asked Board members to introduce themselves, and members 

completed their introductions. Dr. Philpott added that HSRB member Dr. José Manautou would 

be joining the meeting shortly, and invited Dr. Warren Lux (Director of the Program in Human 

Research Ethics, OSA, EPA) to offer welcoming remarks. 

Welcoming Remarks

Dr. Lux welcomed all in attendance on behalf of EPA’s Administrator and Science 

Advisor; they appreciate the Board’s work and thank the members for their service. He thanked 

members for their patience during the previous week’s numerous e-mails while the status of the 

meeting was uncertain due to the potential shutdown of the federal government. 

Opening Remarks

Dr. Steven Bradbury (Director, Office of Pesticide Programs [OPP], EPA) also expressed 

his thanks that members had withstood the confusion during the past week. He noted that the 

Board’s role in the business of the Agency and OPP is instrumental in ensuring that EPA is 

protecting human health and the environment by using the most ethical evaluations possible. He 

thanked the members for all of their hard work before, during and after the meeting. Two agenda 

items are critical: the work of the Agricultural Handler Exposure Task Force (AHETF) and the 

Antimicrobial Exposure Assessment Task Force II (AEATF II). Dr. Bradbury stated that EPA 
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believes that the studies to be reviewed reflect high-quality science and ethics; he expects the 

Board will agree, and having the information from these studies will improve the quality of risk 

assessments. Another agenda item concerns a journal article published in 2010, and this is the 

first time a study published after EPA’s rule will be examined by the Board; EPA looks forward 

to learning from the experience. Ms. Kelly Sherman (OPP, EPA) will be discussing the proposed 

Human Studies Rule, on which the comment period recently closed. A few substantive comments 

were received, and EPA’s goal is to meet its settlement agreement and sign the final rule by 

December 2011. Dr. Bradbury further thanked members for their efforts to examine methods to 

streamline the review and reporting processes so that appropriate studies can be used as promptly 

as possible in the risk assessment process. He thanked Drs. Philpott and Chambers for their role 

as Chair and Vice Chair of the Board. He also thanked Board members, Mr. Downing, and other 

members of OSA who prepared for the meeting. Finally, he thanked the public for their 

participation in the Board’s efforts. He stated that the purpose of the FACA is to ensure that the 

Board’s activities are open and transparent and that all interested parties have an opportunity to 

participate. He wished the Board a successful meeting. 

OPP Follow-up on Previous HSRB Recommendations

Ms. Sherman stated that at the previous HSRB meeting in January 2011 the Board 

examined a completed closed-cab airblast study by AHETF, and EPA has determined that the 

data from the study represent the best available data for this use scenario. Following a review of 

the HSRB report to determine whether any adjustments, corrections or changes are needed on the 

exposure results, it will be used in future risk assessments of workers applying pesticides using 

closed-cab airblast equipment. 

The Board also examined an AHETF protocol for mixing and loading of wettable 

powders. Based on comments from the Board and EPA, the AHETF has implemented 

recommended changes to the consent form, protocol and standard operating procedures (SOPs). 

The revised documents have received approval from Independent Investigational Review Board 

Inc. (IIRB). The AHETF is awaiting California Department of Pesticide Regulation (CDPR) 

approval. Once granted, recruiting will begin, and the AHETF hopes to monitor most of the 

subjects this summer, but monitoring may need to be completed in summer 2012. 

Ms. Sherman informed the Board that the comment period for the proposed revisions to 

EPA’s ―Rule on Protections for Subjects in Human Research Involving Pesticides‖ closed on 

April 4, 2011, with only 10 comments received. This may reflect the fact that the changes being 

made were modest and the result of a settlement agreement with an environmental group. The 

most substantive comments are from some groups asking EPA to reconsider what is deemed an 

intentional exposure study. EPA is carefully reviewing the comments, and the Agency plans to 

have the final rule signed by the Administrator in December 2011. 
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Session 1: Completed AHETF Research on Workers Applying Pesticide Sprays Using Open-Cab 

Airblast Equipment

Background

Ms. Sherman (OPP, EPA) noted that this is a review of a completed study on application 

of pesticide sprays using open-cab airblast equipment. The AHETF is a group of 23 pesticide 

companies working together to develop new handler exposure data on 33 scenarios. The Board 

so far has reviewed protocols from five scenarios, and the reviews have been favorable. The 

completed field studies and monograph on closed-cab airblast received favorable HSRB review 

in January 2011. The open-cab scenario consisted of three field studies with a total of 13 subjects 

monitored. Dermal and inhalation exposure were monitored during pesticide application with 

open-cab airblast equipment to grapes in California (three subjects), grapes in New York (five 

subjects), and pecans in Oklahoma (five subjects). The data from these field studies have been 

combined with existing open-cab airblast applicator data of 15 subjects monitored in Georgia, 

Idaho and Florida. The protocols were reviewed by the HSRB in October 2008, with research 

conducted in July and August 2009, and data submitted to EPA in November 2010. 

Ms. Sherman explained that the Board should consider whether the proposal was 

appropriately amended after review by EPA and the HSRB, executed faithfully, and conducted 

ethically and whether the results achieved the objectives. 

EPA Science Assessment

Mr. Matthew Crowley (OPP, EPA) thanked his colleague Mr. Bayazid Sarkar (OPP, EPA) 

for his statistical analyses of the study data. The research objectives were to provide more robust 

and contemporary data and information for use in regulatory assessments of pesticides applied 

via open-cab airblast equipment by capturing the diversity and range of expected dermal and 

inhalation exposures. The data collected will be posted in a proprietary database. In terms of the 

data analysis, the primary objective is an accuracy objective: for dermal exposure normalized by 

the amount of active ingredient handled (AaiH), key statistics (geometric mean, arithmetic mean, 

95th percentile) should be no more than three-fold lower or higher than their upper and lower 95 

percent confidence limits. This benchmark is useful to guide the sample size. The secondary 

objective is, for dermal exposure and AaiH, to distinguish between a proportional and 

independent relationship with at least 80 percent statistical power. 

The AHETF has shown in its governing document that in general, a 5 x 5 (n = 25) 

sampling configuration could satisfy objectives. In this scenario, there were existing and 

acceptable open-cab airblast applicator data (n = 15). In this case, the goal was 30 monitored 

applicators. Diversity selection was employed, with recruitment randomized to minimize 

selection bias. As a result of this strategy, EPA recognizes that there are limitations in terms of 

statistical inferences that can be made. 

Because this study design was so similar to the closed-cab study, comments were almost 

identical, and EPA believed that the AHETF had addressed the HSRB’s comments. The existing 

study (AHE07) was conducted on five males spraying peaches in Georgia, six males spraying 
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apples and pears in Idaho, and four males spraying oranges in Florida. The new studies consisted 

of three males spraying grapes in California (AHE62), five males spraying grapes in New York 

(AHE63), and five males spraying pecans in Oklahoma (AHE64). In the California grape study, 

five subjects had been planned, but only three could be recruited. To apply the pesticides, 28 

different pieces of equipment were used. Some had shade canopies, as noted in the CDPR’s 

initial review of the protocol. The average number of tank loads was four, the average volume 

sprayed was 1,809 gallons, the average treated area was 16 acres, and the average time was 5.8 

hours. In the existing studies, the subjects handled the high end of the targeted range of AaiH, so 

subjects were placed into specific AaiH strata in the new studies to meet both primary objectives. 

In AHE62, two of the strata were unfilled because there were only three subjects, and in AHE64, 

one stratum was not filled because a subject went outside the predetermined strata. Exposure 

monitoring methods included hand wash, face and neck wipes, inner and outer patches worn 

because a chemical resistant hat also was worn, a whole body dosimeter (WBD), air pump, and 

Occupational Safety and Health Administration Versatile Sampler (OVS) tubes. Socks were used 

in the existing study but not in the new studies. Analytical limits show that measurements below 

the detection limits mainly were avoided. 

Deviations from the protocol included fewer than three tank loads sprayed, spraying time 

of less than 4 hours, unverified field fortification concentrations, failure to meet AaiH strata 

targets, and modifications to analytical methods. In EPA’s opinion, none of these deviations 

undermined or compromised the exposure results. The AHETF’s Quality Assurance Unit ensures 

that studies follow EPA Good Laboratory Practice (GLP) Standards (40 Code of Federal 

Regulations (CFR) part 160), including that the task force personnel are trained, site and 

equipment inspections are conducted, protocols and amendments are reviewed, reports are 

audited, and individual study reports include signed Quality Assurance Statements. Both 

negative controls (blanks) and positive controls (spikes) were included in the study. It was noted 

that some residues were detected in AHE07 blanks in the laboratory, and in the field, the only 

residue greater than the limit of quantitation (LOQ) were in the OVS tube. In the laboratory, all 

spikes were in acceptable range; some unusual results were noted for the field spike samples. 

Some differences also were found between days, and instances of this type occurring in the 

future could perhaps be discussed in the report. Exposure monitoring results represent workers 

wearing long-sleeved shirts, pants, chemical-resistant gloves, shoes/socks, and no respirator, with 

or without chemical-resistant hats. All measurements are adjusted by average recovery of 

corresponding field fortification matrix and level, and a few left-censored measurements were 

noted (mostly OVS back sections). Based on recommendations from previous HSRB meetings, if 

the measured contribution from hands and face/neck represents between 20 and 60 percent of the 

total, measurements are to be adjusted upward by two, or a validation study supporting the 

method’s efficiency must be provided. The HSRB’s greatest concern about combining the data 

would have been if the pre-rule studies were a magnitude higher or lower than the new data set, 

but they fall in the same general range. 

Some of the open-cab vehicles had shade canopies. In the AHE64 study, only one of the 

subjects reported having a canopy, but there were in actuality two additional workers who had 

canopies; still, EPA determined that their presence did not have a significant effect on exposure. 

Estimates of exposures normalized by AaiH (―unit exposures‖) were summarized in task force 

submissions using three methods: empirical estimates; simple random sample (lognormal, 
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independent); and a mixed model (lognormal, nested). Considering data structure, the mixedmodel is most appropriate. Magnitude of exposure was greater for subjects without chemical 

resistant hats. Plots should be examined for the degree to which like symbols are grouped 

together, the intraclass cluster correlation. 

In the inhalation exposure data, one worker (A5) in AHE64, if excluded, decreases the 

arithmetic mean and 95th percentile substantially. In correspondence with the task force and in 

the report, no mismeasure can be attributed to worker A5, so the reasons for the lower inhalation 

exposure in this individual are unclear. A more conservative approach is taken by using the entire 

data set. Data show that the primary objective analytical benchmark was satisfactorily met, with 

no additional monitoring necessary. For the secondary objective examining the relationship of 

the AaiH and exposure, it is noted that for routine EPA handler assessments, exposure is 

predicted from AaiH, which assumes that the two are proportional. The AHETF research design 

is intended to result in 80 percent statistical power to distinguish independence from 

proportionality. Data were found to be consistent with proportional relationship if 95 percent 

confidence intervals (CI) of the regression slope include 1, whereas 80 percent power is achieved 

if the width of the 95 percent CI is 1.4 or less. The secondary benchmark was not met; post-hoc 

analysis shows less-than-expected power. The proportionality with AaiH is consistent with 

dermal exposure data, however, even with less-than-expected power, and proportionality and 

independence with AaiH are consistent with inhalation exposure data. 

In conclusion, the research design is acceptable, despite the lack of random sampling; 

statistical inference requires assumption that the sample is representative of the range of 

exposure for all U.S. open-cab airblast application-days; monitoring methods and results were 

consistent with EPA guidelines and previous studies; acceptable analysis of research objectives 

was conducted, and no additional monitoring is necessary for this scenario; and the data are 

recommended for use in regulatory assessments with AaiH normalization as a default condition, 

but are not applicable for high volatility chemicals. 

Board Questions of Clarification—Science

Dr. William Popendorf inquired whether a test was conducted to determine whether the 

studies and crops were the same in terms of this completed study. Does an intraclass correlation 

of zero mean there are crop differences that affect exposure? Mr. Crowley responded that a test 

was not conducted. Mr. Sarkar added that each cluster had a different crop, but no test had been 

conducted. 

Dr. Dallas Johnson noted that, regarding slide 27 of EPA’s presentation, which deals with 

log normal probability plots, the intraclass correlation might relate if the same amount of active 

ingredient (ai) was applied at each case, but because the AaiH is spread out, no statements can be 

made about what points are clustered together. Dr. Philpott added that this could be an important 

point for discussion. 

Dr. Chambers asked whether analytical methods for the existing study and new studies 

were the same. Mr. Crowley replied that in all cases except for the OVS tubes and WBD there 
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were slight differences in the methods, but remainder were the same. In terms of more specifics, 

he would defer to the AHETF. 

Dr. George Fernandez stated he had some difficulty understanding in slide number 9 of 

EPA’s presentation the phrase ―no more than three-fold lower or higher than upper than their 

upper and lower 95 percent confidence limits.‖ Mr. Crowley suggested that members see slide 

31, which provides a better explanation. In each case, 95 percent confidence limits are derived. 

To compare these statistics to the lower confidence limit, the statistic would be the numerator in 

that ratio, and the denominator would be the upper confidence limit. EPA is looking for the larger 

of those to be less than three. Dr. Fernandez noted that in slide number 28, the range is very large 

for the 95th percentile. Mr. Crowley responded that as long as the 16,340 divided by 6,148 is less 

than three, that is acceptable. Dr. Fernandez asked whether there were acceptable biological or 

toxicological limits. Mr. Crowley stated that it was not related to toxicology but rooted in 

uncertainty in the assessments. Dr. Philpott asked, for the products used, whether these numbers 

were within the established range for the handlers. Mr. William Jordan (OPP, EPA) added that, 

from a science policy point of view, the K-factor addresses setting a standard for the degree of 

accuracy in the assessments that are derived from the dataset and various statistical intervals. If 

there were more subjects monitored, the ranges would be smaller. It is a trade-off between the 

cost of generating additional data and the value of having smaller ranges. The ranges of these 

datasets will be large, and there are subsequent science policy questions that EPA addresses in 

risk assessments: What value does the Agency get from the dataset? What values from the 

dataset should be used?

Dr. Sidney Green commented that it was stated that protocol deviations did not 

undermine the study results and asked who makes that determination. Mr. Crowley answered that 

one person is assigned to conduct the review and, in consultation with other experienced 

scientists in this area, makes the determination. Dr. Green asked whether that was EPA’s policy. 

Mr. Jordan stated that Mr. Crowley described the standard review process that EPA uses. A stafflevel reviewer performs the initial examination of the dataset and study report and as part of that 

review, notes any places in the report that a departure from protocol or other irregularity is seen. 

Internally, there is a group of people that has been conducting these sorts of reviews for many 

years, including Mr. Jeffrey Dawson (OPP, EPA) and Mr. Jeff Evans (OPP, EPA). They 

collectively consult on the initial reviews and decide whether they agree with the conclusions of 

the initial review. That is a very standardized process. If an issue does not have consensus, more 

people will be consulted, up to the Scientific Advisory Panel (SAP) if the issue is difficult or 

significant enough. Each reviewer must explain his or her rationale for the positions stated. Mr.

Dawson added that the task force has a quality assurance unit, so there is a process under GLPs 

in which they would make their determinations that would come to EPA in a documentation 

report. 

Dr. Johnson commented that it was important to keep the scale the same when more than 

one graph was presented on the same slide, such as on slide 27 of EPA’s presentation. Dr. 

Michael Lebowitz stated that one method by which to accomplish that is to show the regression. 
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Dr. Linda Young questioned, on slide 34, whether the data that give rise to the slide are in 

table S24 of the members’ handouts, and if not, where they could be found. Mr. Sarkar responded 

that the data for that table are in Appendix G, page 33. 

Dr. Philpott invited representatives of the AHETF to the table to answer questions. Dr. 

Victor Cañez, consultant to the AHETF, and Mr. Richard Collier, chair of the administrative 

committee of the AHETF, joined the members.

Dr. Popendorf noted that the work time varied and asked what the ―gold standard‖ was 

for monitoring time. Dr. Cañez stated that generally the monitoring time is from when the pump 

is turned on to when it is turned off. There may have been some discrepancies in the pump, such 

as a need to change batteries. 

EPA Ethics Assessment

Ms. Sherman noted that in terms of recruiting, the three-phase process outlined in the 

protocols and SOPs generally was followed. The AHETF generated an initial grower list from 

published lists and databases and narrowed the list using qualifying questions. Qualified and 

interested growers were contacted by the study director to identify those who could participate 

within a timeframe and schedule that would allow an efficient study. Several protocol 

amendments were made: the inclusion criteria were amended to allow participation by 

individuals who normally wear two layers of clothing (subjects could wear a coverall over the 

WBD); the recruitment process was modified to allow for use of recruitment letters sent directly 

to growers; and the permissible recruitment area was expanded. 

The consent process outlined in the protocols and SOPs was closely followed in all three 

studies with no reported or unreported deviations. All of the subjects were males. Only three 

subjects were monitored in California, whereas the other two studies each monitored five. All but 

one subject in California, who preferred Spanish, preferred the consent process be conducted in 

English. No subjects made use of a witness. All were farm owners or operators except for one 

farm employee in California. Ages across the studies ranged from 28 to 79, and all requested 

their results. 

Exposure monitoring was conducted without incident, with no adverse events, incidents 

of concern, or withdrawals from the research. The greatest risk in the study was heat-related 

illness. The temperatures did not rise to the heat index cutoffs for the study, and procedures in the 

SOPs were followed in terms of announcing changes in temperature and monitoring the workers. 

The initial protocol was reviewed by IIRB, with seven amendments and seven deviations 

reviewed by IIRB through expedited procedures. Additional amendments included the lowering 

of the heat index stopping rule to 105°, and AHE62 added a new malathion product. Only a few 

minor deviations were noted, and none were of ethical significance. Most involved missing the 

target of three tankloads or 4 hours monitoring time. 

The AHETF successfully responded to both EPA and HSRB comments made during the 

protocol review. Regarding documentation, IIRB correspondence volumes are complete and 
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well-indexed, and requirements of 40 CFR §26.1303 are satisfied. EPA’s substantive acceptance 

standards include 40 CFR §26.1703, which prohibits reliance on data involving intentional 

exposure of pregnant or nursing women or of children; 40 CFR §26.1705, which prohibits 

reliance on data unless EPA has adequate information to determine substantial compliance with 

subparts A through L for 40 CFR part 26; and the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) §12(a)(2)(P), which makes it unlawful to use a pesticide in human tests 

without fully informed, fully voluntary consent. 

Ms. Sherman found that all substantive acceptance standards were met: all subjects were 

at least 18; pregnant or nursing women were excluded; no significant deficiencies were noted in 

the ethical conduct of the research; the protocol was faithfully executed; deviations did not 

compromise the safety or consent of subjects; and subjects were fully informed, and their 

consent was fully voluntary, without coercion or undue influence. 

In conclusion, available information indicates that the AHETF open-cab airblast studies 

(AHE62, 63, 64) were conducted in substantial compliance with subparts K and L of 40 CFR 

part 26.

Board Questions of Clarification—Ethics

Dr. Jerry Menikoff inquired why the amendment to lower the heat index that was made to 

two of the studies was not made to the third study. Ms. Sherman responded that she was unsure 

and had not followed-up with the task force. But, the heat index limit was amended in the SOP 

after this study, which will deal with the issue in the future. 

Dr. Popendorf asked about the list in California being winnowed from 4,000 to four 

potential participants and whether all 4,000 names had been called. Ms. Sherman replied that she 

thought they had called all 4,000. Dr. Cañez confirmed that all were called, and many do not 

answer because of caller identification. Dr. Cañez added that in California only a small 

percentage of the users employed open cabs, and few wore the right type of personal protective 

equipment for the study, so the AHETF was led to a very small number of subjects. Dr. Philpott 

noted that Dr. Manautou had joined the discussion and that Mr. Robert Roogow of IIRB was in 

attendance. 

Dr. Philpott noticed a clarification on the protocol of the AHETF’s raw data retention 

policy. He questioned whether this was a change in the policy or just a modification of the 

protocol to clarify what already was being done. It states, ―In accordance with GLP regulations 

40 CFR part 160.195 and SOP 6.8, raw data will be retained in the archives as long as the task 

force for the other registrar holds a research or a marketing permit to which the study is 

pertinent.‖ Dr. Collier responded that it was a way to document the fact that that is a requirement 

of GLP; the AHETF already was doing this. 

Public Comments

Dr. Philpott offered Drs. Cañez and Collier a chance to make a public comment of up to 5 

minutes, but they declined. Dr. Cañez noted that Dr. Larry Holden, the AHETF’s statistician, was 
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in attendance and available to answer questions. Dr. Philpott then offered Mr. Roogow of IIRB 

an opportunity to give public comment. However, Mr. Roogow did not provide any further 

comments. 

Dr. Philpott invited additional public comment on the AHETF open-cab airblast study; no 

public comments were presented. He noted, however, that one written comment had been 

received in response to the Federal Register notice of the meeting. It is somewhat extensive, so 

he did not read it into the record but noted that it was available in the public docket. It is from 

Ms. Carol Dansereau, Executive Director of the Farm Worker Pesticide Project in Seattle, 

Washington, and Executive Director of the Washington Toxics Coalition. There is some relevant 

information in her statements that is pertinent to the Agency and the Board, particularly with 

respect to questions of engagement of additional stakeholders, whose discussions the Board will 

play closer attention to, and Dr. Philpott will examine whether there is adequate community 

representation and input at future HSRB meetings. He encouraged members to read the comment 

during the break. Dr. Vanessa Northington Gamble mentioned that she had studied the comment 

and noted that it raises questions about public engagement and who is considered an expert. She 

went to the announcement of the meeting, and it says the meeting would be of particular interest 

to people who assess or conduct human studies; people who might be affected or participants of 

studies are not mentioned nor are experts on community engagement. The comment raises 

serious questions about the meeting announcements but also the composition of this Board. 

Charge Questions

Ms. Sherman read into the record the three charge questions: 

1. Was the research reported in the AHETF completed monograph report and 

associated field study reports faithful to the design and objectives of the protocol, 

SOPs and governing documents? 

2. Has the Agency adequately characterized, from a scientific perspective, the 

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

exposure of those who apply conventional pesticides with open-cab airblast 

equipment? 

3. Does available information support a determination that the studies were 

conducted in substantial compliance with subparts K and L of 40 CFR part 26?

Board Science Review

Dr. Philpott requested that the Board members focus their discussion on the two scientific 

charge questions. 

Dr. Popendorf thought that overall, the study addressed many of the concerns expressed 

by the HSRB in its review, and the inclusion of local experts was useful and appropriate. The 

better definition of the recruitment process was useful, as was inclusion of the scripted records. 

Although there was no formal test of the difference between crops, the visual evidence is very 

strong, and he would support grouping the crops and the clusters as proposed by the Agency. It 

also was very useful to have the broader interests examine the differences between open and 
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closed cab. The use of the head patches was innovative. The head accounted for about 18 percent 

of exposure, hands 27 percent, and the rest of body 56 percent. In terms of the hat, good data are 

generated if the hat is used, but if it is always used, it will affect the estimate of ―no hat.‖ The 

brim of the hat always had some effect. Dr. Popendorf is comfortable with an affirmative answer 

on the first charge question.

Dr. Chambers agreed that the study was faithful. She examined the methodology, quality 

assurance and quality control. Recoveries were in a good range, and the AHETF followed the 

protocol with the same sort of sampling as had been conducted in the past, with the same sorts of 

dosimeters. Dr. Young also agreed that that study was satisfactory. Dr. Philpott stated that on the 

teleconference meeting regarding the previous Board report, there was some question about the 

primary objective as described in the study. He asked if Dr. Young and Dr. Johnson wanted to 

speak to that point for this study. 

Dr. Philpott noted that the consensus of the Board is that research reported in the AHETF 

completed monograph report and associated field study reports was faithful to the design and 

objectives of the protocol, SOPs and governing documents. 

On the question of adequate characterization of the limitations of the data that should be 

considered, Dr. Popendorf noted that the brim of the hat probably reduced exposure to the rest of 

the face. A small change would be not including the inner patch when examining the ―no hat‖ 

exposure, because the outer patch on the hat measures what would have been the cause of the 

exposure. At the same time, the face probably was protected by the brim. Because the subjects 

always wore a hat, there is no way to know what that protection was, but the actual face exposure 

without a hat was not measured. On the air samples, the LOQ greater than two was used for the 

backup air sample, which should be zero. Material should not have reached the backup. The 

Kinkelder airblast sprayer should be listed in the limitations, as it is known to be a high drift 

machine. Several comments were made about participant AHE64 A5, but several observations 

were missed. One of the notations was that the nozzle pressure for this monitoring unit (MU) 

was twice the recommended maximum pressure. Additionally, this MU changed from spraying in 

both directions to spraying in only one direction for the last one-third of his application time. 

This is the only MU for whom this notation was made. Information in the record implies that the 

MU made a conscious effort to apply in an upwind direction to minimize wind exposures. 

Dr. Young returned to the measures, particularly the limitations that are present in some 

of the measures. There are ranges of AaiH and therefore exposures over wide space, so what 

does it mean to take the arithmetic mean? The arithmetic mean is taken by exposure divided by 

ai, which makes sense if exposure is proportional to ai. The test of that assumption seems to be 

critical. The geometric mean appears to be based on the assumption that the log of exposure is 

equal to a constant times log ai. If the arithmetic mean makes sense, the geometric mean does not 

and vice versa. In one of the models, the log of exposure divided by ai is equal to some constant;

this would be valid if the ratio of exposure to AaiH is equal to the exponentiation of some 

constant. Three measures are used, each of which makes sense if an assumption is true. Checking 

assumptions is vitally important. Dr. Chambers inquired whether checking the assumptions 

would require experimentation. Dr. Young responded that this goes to analysis of the data and 

must be performed very carefully. 
12

Dr. Philpott summarized that the general consensus is that the Agency has satisfactorily 

characterized limitations, but there are additional limitations that need to be considered with 

respect to using the data and estimating the exposure. These include consideration of whether the 

inner patch is measuring penetrance; it is unclear whether this will affect the results, but it should 

be considered in analysis as well as the protection of the face by the brim. There were concerns 

about the use of LOQ over two for the backup sample; the backup sample should be zero if it 

was a proper sample, and giving it a different value will bias the results. Some consideration 

must be paid to the 28 different types of equipment that were used, particularly the high drift 

machine. With respect to the one participant who had a low exposure, there are some additional 

factors that may explain why, such as the high nozzle pressure he used and change in the 

application approach from two-sided to one-sided. He may have changed application because he 

was on a slope or because of the wind. This should not be taken as a recommendation as to 

whether to exclude that participant from the analysis but may indicate why he has reduced 

exposure. Dr. Young raised some concerns about statistical analyses and that each of the three 

measures all relied on assumptions that must be tested in the analysis of the data. 

Mr. Sarkar noted that to calculate arithmetic mean, geometric mean, and 95th percentile, 

first the log of exposure over AaiH on the intercept is calculated. From there, EPA calculates the 

arithmetic value of intercept, and then the arithmetic mean is calculated. Information on the 

formula is on page 18 and Table 9 of EPA’s report. The geometric mean is calculated exponential 

to the intercept. Dr. Young stated that in performing calculations in this manner, EPA was 

assuming the model was correct. She said that Mr. Sarkar had to address carefully each of the 

assumptions associated with that model. Dr. Philpott noted that the recommendation is that the 

assumptions being used in the fitted model must be checked. 

Dr. Popendorf clarified that the effect of the patch is small, on the order of 1 percent. 

Board Ethics Review

Dr. Menikoff concluded that the available information supports a determination that the 

studies were conducted in substantial compliance with subparts K and L of 40 CFR part 26. This 

is a type of study with which the HSRB is becoming more familiar and gradually has been 

refined based on HSRB recommendations over a period of time. He agrees with Ms. Sherman’s 

determination. Risks generally have been minimized; the studies are well-designed to take 

advantage of activities that would normally be taking place within the subjects’ daily 

employment. There is a positive risk/benefit ratio. Informed consent was obtained appropriately, 

and specifically, noting that 12 of the 13 subjects are owner/operators, there likely is less concern 

about the subjects being vulnerable. Dr. Virginia Ashby Sharpe concurred with Dr. Menikoff’s 

analysis. Dr. Philpott concluded that the general consensus answer to the question is that the 

available information supports a determination that the studies were conducted in substantial 

compliance with subparts K and L of 40 CFR part 26. 
13

Session 2: A Published Report (Gulson et al. 2010) of an Intentional Exposure Human Study 

Measuring Dermal Absorption of Zinc Oxides Contained in Sunscreens

Background

Dr. Jessica Ryman-Rasmussen (OPP, EPA) informed the Board that the Agency has 

pending registrations for articles treated with nanoparticle-based pesticides (e.g., textiles, 

plastics, wood) and is conducting quantitative, screening-level risk assessments for these 

products, including dermal assessments that require quantitative estimates of dermal penetration 

of nanoparticles. Generic Dermal Assessment Questions include: (1) What is the rate and form of 

the compound released (transfer efficiency) from the treated article? (Application Rate × Density 

× Surface Area Exposed × Transfer Efficiency) (2) What is the dose? ([Exposure (milligrams per 

day (mg/day)) × Dermal Absorption Factor]/Body Weight (kilograms (kg)).

EPA Science Assessment

Few studies in the literature allow a quantitative estimate of dermal absorption from 

nanoparticle exposure, but the Agency recently identified a study by Gulson et al. (2010) that 

quantitatively estimates dermal penetration of zinc (Zn) from zinc oxide (ZnO) nanoparticles in a 

sunscreen formulation in human volunteers. This study was conducted at an aquatic center and a 

Sydney, Australia beach, and its objective is to determine whether Zn from nanoparticles in 

sunscreen can be absorbed through healthy skin under normal conditions of sunscreen use. The 

test substance used was ZnO enriched to 99 percent with 68ZnO (a nonradioactive isotope) in two 

sizes, 110 ± 46 nanometers (nm) (25–284 nm) and 19 ± 8 nm (3–60 nm), in a sunscreen 

formulation containing isopropyl myristate, a penetration enhancer, and 

ethylenediaminetetraacetic acid (EDTA), a Zn chelator. 68Zn can be measured by multicollector 

inductively coupled plasma mass spectrometry (MC-ICP-MS). 

The study applied 68ZnO in sunscreen formulation two times per day for 5 days in the 

amount of 3.7 to 4.6 mg/square centimeter (cm2) to a 500 cm2area of the back in a cut out area 

of an ultraviolet (UV)-protective upper body garment. After the sunscreen was applied to the 

subjects, they were told to lie down in the sun for 30 minutes and allow the sunscreen to absorb 

into the skin. After the 30-minute time period, the subjects were free to participate in beach-like 

activities. A diary of these activities was kept, estimating the amount of UV exposure that 

occurred. The sunscreen was removed at the end of the day with alcohol/lanolin wipes. The 

amount removed was not quantified. Blood and urine samples were taken from all subjects 

before exposure, at Day 5, and after exposure. For some subjects (one per gender for both 110 ± 

46 nm and 19 ± 8 nm), blood also was collected on Days 2–4 of exposure, and for some, 19 ± 8 

nm (three men, one woman) urine samples were taken out to 25 to 40 days post-exposure. For 

urine collection, there is the potential for contamination via hands, particularly in women. 

68Zn levels were measured in the urine and blood by measuring 68Zn/ 64Zn via MC-ICPMS at different times (68Zn% is greater than zero only if 68Zn from sunscreen was absorbed). 

68Zn could be in ionic (68Zn+2) and/or nanoparticle (68ZnO) form. Two methods were used (as a 

result of uncertainties in estimating natural Zn reservoir in individuals). The percentage of 
14

applied 68Zn absorbed into blood was calculated by the change in (Δ) 68Zn% adjusted for fat-free 

body mass (estimated via body mass index) and measured blood Zn and Δ

68Zn% adjusted for 

total blood Zn concentration (based on blood volume). 

Authors stated that 68Zn/64Zn increases in blood for all subjects with and after exposure, 

but no statistical analysis was provided. A Wilcoxan test of Δ

68Zn percentage comparing 

exposure and post-exposure found a highly significant difference (p is less than 0.0001). 

Analyses of variance on Δ

68Zn percentage adjusted for fat-free body mass and/or blood volume 

show the effect of gender and particle size (19 ± 8 nm females is greater than all others) at p = 

0.053 and p = 0.051. These data indicate that blood levels continue to increase after exposure, 

which indicates that there is potential for absorption of skin-bound residues of sunscreen. There 

was a 2-day lag in the ability to detect 68Zn above baseline levels. The researchers also measured 

Δ

68Zn in urine; EPA evaluated these data and considered the results equivocal because there was 

evidence that the samples had been contaminated, but results seemed to support blood results. 

The percentage of the applied dose of 68Zn absorbed from 68ZnO sunscreens was estimated at 

about 0.001 percent.

Study limitations included: the detection method does not discriminate between particles 

and ions; absorption could be underestimated because it is unknown whether 68Zn from 68ZnO is 

partitioned into other organs/tissues (besides blood), it is unknown how much rubbed off, and the 

sunscreen formulation contains Zn chelator EDTA; absorption could be overestimated because 

the sunscreen formulation contains a penetration enhancer, isopropyl myristate; there is 

uncertainty in estimating the magnitude of the natural Zn reservoir in each individual. In 

conclusion, small amounts of Zn in ionic or oxide form (about 0.001 percent) from ZnO 

nanoparticles in sunscreen formulations can penetrate healthy skin in human volunteers. 

Board Questions of Clarification—Science

Dr. Manautou inquired about the length of time between the first and second dose. Dr. 

Ryman-Rasmussen answered that this was not stated in the study. Dr. Manautou asked whether 

the authors provided any justification for the selection of the four individuals from which the 

complete urine samples were analyzed. Dr. Ryman-Rasmussen responded that they did not. Dr. 

Manautou questioned whether there was any indication of how the information on the ai, which 

was 51 percent enriched in the pilot study, was used to influence the final study design that used 

a 99 percent Zn isotope. Dr. Ryman-Rasmussen responded that it was not mentioned in the 

publication, but EPA had some correspondence with the authors, and the pilot studies were 

conducted to determine how much the isotope would need to be enriched to get reliable 

detection. The 51 percent was not efficient. Dr. Manautou asked whether there was justification 

of why frequency and time of garment changes and specific activities were not recorded. Dr. 

Ryman-Rasmussen responded that there was no information about these issues in the published 

study. 

Dr. Popendorf noted that the application site was 500 cm2, and Dr. Ryman-Rasmussen 

confirmed that this was not in the study but information that was received from the authors. 
15

Dr. Chambers asked whether any other insights were received from the authors. Dr. 

Ryman-Rasmussen inquired about the surface area of application and sought further information 

on calculations that was not provided. 

Dr. Green asked whether environmental conditions were monitored. Dr. RymanRasmussen did not ask the authors for this type of information. Dr. Green noted that the 

hydration status of the skin based on temperature and humidity can affect absorption. 

Dr. Fernandez asked whether the Agency analyzed the data, and Dr. Ryman-Rasmussen 

replied that she was told that sample calculations were not available, so EPA did not conduct data 

analysis. Dr. Fernandez asked about female subject 7, who had a high amount of penetration. 

This extreme data point could have contributed to the overall finding affecting the female 

absorption of nanoparticles. Dr. Ryman-Rasmussen noted that the authors addressed this in the 

paper; the female with the adverse skin reaction might have biased that entire treatment group, 

but the data were normalized (log normal), so the authors were confident that the results were not 

biased.

Dr. Northington Gamble noted that skin types from one to four were mentioned in the 

paper, and it is unclear what that means. Dr. Ryman-Rasmussen responded that skin type is a 

standard classification for skin based on pigmentation. Dr. Northington Gamble asked how that 

is determined in terms of gradations. Dr. Ryman-Rasmussen replied that the authors did not say 

how they determined skin type, but skin typing is fairly common in medical and cosmetic

industries. Dr. Johnson asked what would constitute a type 4. Dr. Ryman-Rasmussen noted a data 

table that mentions the countries of origin for the subjects in the study; South American females 

were classified as skin type 4, and German and Australian females were classified as skin type 1. 

Dr. Johnson added that the authors did not address whether the difference in the amount 

of Zn present is significant. Dr. Ryman-Rasmussen stated that there is much debate about 

whether nanoparticles can penetrate intact healthy skin. This is the first study that provided 

evidence that nanoparticles or ions released from nanoparticles penetrate intact skin of human 

volunteers. Although the amounts are small, it still may be important because it is unknown what 

exposure to nanoparticles is hazardous. The method, however, does not discriminate between Zn 

ions or nanoparticles. Dr. Manautou added that the paper does not address whether it is assessing 

Zn ions or Zn nanoparticles in the body. Dr. Ryman-Rasmussen agreed that this could not be 

determined, but if risks are assessed for both particle and ion based on this estimate, then that 

still is helpful to the Agency because it still allows a quantitative estimate of dermal penetration. 

Dr. Manautou noted the difficulty in understanding the utility of the paper because it may have 

nothing to do with nanoparticles. Dr. Ryman-Rasmussen responded that the conservative 

approach is to assess for both nanoparticles and ions using 0.001 percent. 

Dr. Philpott stated that not all skin is the same and asked about vascularization and 

whether it could affect Zn detection. Dr. Ryman-Rasmussen answered that skin is relatively 

avascular compared to other organs. When EPA discusses the dermal absorption, it is assuming 

that the 0.001 percent in the blood is systemically available and is used to calculate an internal 

dose from a topical application. 
16

Dr. Fernandez mentioned that researchers did not conduct comparisons between the skin 

types or address age. Dr. Ryman-Rasmussen agreed that they did not but could not say with any 

certainty whether that would have resulted in different conclusions. The authors have a good 

sampling of age ranges in the study. Skin thickness and hydration status will have the most 

significant influence on absorption. Females tend to have thinner skin than males, and for the 

smaller particles, that may have been a potential explanation for why there was greater 

absorption. 

Dr. Popendorf noted a difference in the natural metabolism of isotopes by their molecular 

weight. Dr. Ryman-Rasmussen commented that she had not conducted any investigations on how 

the particular isotope of Zn may affect the biodistribution. 

EPA Ethics Assessment

Ms. Laura Parsons (OPP, EPA) presented EPA’s ethics assessment. Research was 

conducted in Australia in 2009, so it was subject to the Australian National Statement on Ethical 

Conduct in Human Research, which covers all research with human subjects in Australia and is 

similar to the U.S. Common Rule, with governing principles of respect, research merit and 

integrity, justice and beneficence. This is the first time that EPA has asked the HSRB to review a 

study that EPA located in the public literature that was conducted after the EPA 2006 Human 

Studies Rule. So in this case, 40 CFR §26.1303 and FIFRA §12(a)(2)(P) do not apply. The 

research provides information on dermal absorption of Zn from sunscreen applied to healthy 

human skin under conditions of normal use.

Ten men and 10 women, ages 19 to 66, participated in the study. Recruiting for this study 

was done through personal contacts of the researchers after other recruiting methods failed. Dr. 

Brian Gulson, principal author of the study, noted that researchers attempted to recruit via e-mail 

and a presentation at a local beach club. Several family connections existed among the subjects, 

but it was unclear whether there was connection between the researchers and subjects. The 

Australian National Statement does not preclude this kind of recruiting. Dr. Gulson also stated 

that none of the females in the study were pregnant or nursing; it is unclear if they were tested. 

Researchers identified the main risks as from phlebotomy and adverse reactions to 

sunscreens. A trained professional drew the blood samples, and subjects were questioned 

regarding their sensitivity to personal care products to minimize this risk. One subject had a skin 

reaction, but the nature of the reaction was unclear. The benefits and compensation were not 

discussed in the article. Societal benefits were thought to outweigh the minimal risk. The 

Macquarie University Human Research Ethics Committee oversaw and approved the research. 

Approval was made in May 2008 and covered the period through May 2009; research was 

conducted in March 2009. 

Written consent is not required by the Australian National Statement but was obtained 

before the commencement of this trial. One participant withdrew before the trial began, two 

withdrew during the 5-day application period, and one subject was withdrawn for an adverse 

reaction. Subjects were informed of the risk and were free to withdraw. Dr. Gulson did not 

provide an informed consent form to EPA. 
17

The applicable standards of conduct are the Declaration of Helsinki and the Australian 

National Statement of Ethical Conduct in Human Research. In the publication, the authors 

―certify that the research met with full compliance with all government policies and the Helsinki 

Declaration.‖ The Letter of Final Approval from the Macquarie University Ethics Review 

Committee is the ―usual document that researchers use to show that the research has been 

through the appropriate ethics review process...and meets the requirements of the National 

Statement.‖ Standards of acceptability for EPA’s reliance on these data are 40 CFR §26.1703, 

Prohibition of reliance on research involving intentional exposure of human subjects who are 

pregnant women (and therefore their fetuses), nursing women, or children, and 40 CFR 

§26.1705, Prohibition of reliance on unethical human research with non-pregnant, non-nursing 

adults conducted after April 7, 2006. No pregnant or nursing women were included in the study, 

and the Australian National Statement, complied with by the researchers, is as protective as U.S. 

Common Rule. In conclusion, if the study is deemed scientifically valid and relevant, there are 

no barriers in FIFRA or 40 CFR §26.1703 or §26.1705 to EPA’s reliance on the Gulson et al.

study in actions taken under FIFRA or §408 of the Federal Food, Drug, and Cosmetic Act. 

Board Questions of Clarification—Ethics

Dr. Sharpe remarked that the report stated that blood and urine samples were taken 8 days 

before exposure, and informed consent was received 1 week before exposure. Ms. Parsons 

assumed that the 1 week was prior to the blood and urine samples being taken, but this is not 

stated explicitly in the paper. 

Dr. Northington Gamble noted that in the 2007 National Standards of Australia it is clear, 

in a discussion of power dynamics, that coercion in a relationship between a researcher and the 

participants is prohibited. In one of the letters provided from Dr. Margaret Stuart, Director of 

Research Ethics at Macquarie University, she asked about this issue, because the term ―personal 

contacts‖ is unclear. Ms. Parsons noted that the final letter providing approval did not follow up 

on this point, and she did not specifically ask that question. 

Dr. Sharpe inquired about the rationale for the conclusion that the study is acceptable for 

consideration by EPA. Ms. Parsons responded that she had documentation that the National 

Statement was followed and also considered the parameters of the national statement itself. 

Public Comments

Dr. Philpott called for public comments on the published Gulson et al. study; no public 

comments were presented.

Charge Questions

Ms. Parsons read the charge questions into the record:

1.Is the Gulson et al. study scientifically sound, providing reliable data?
18

2.If so, is the Gulson et al. study relevant to an assessment of the absorption of zinc oxide 

through the skin?

3.Is there adequate information to determine that the Gulson et al. study was conducted in 

substantial compliance with procedures at least as protective as those in subparts A–

L of EPA’s regulation at 40 CFR part 26?

Board Science Review

Dr. Manautou noted that if data reliability is being questioned in terms of skin penetration 

by ionic Zn, the answer to the first charge question is yes. If data on the penetration of 

nanoparticles are being questioned, the answer is no. Regarding the second charge question, if 

dealing with absorption of ZnO or soluble Zn, the answer is yes with some caveats on the 

experimental design. 

Dr. Chambers stated that her interpretation was that only Zn was being addressed, not 

nanoparticles. There was no untreated control, which is a flaw. Additionally, the person who 

applied the Zn was wearing a glove but also had an increase in Zn over time, which leaves the 

data a bit suspect. A controlled study would provide needed answers, but a beach scenario is not 

controlled. The sunscreen contained isopropyl myristate, which would not be used in a controlled 

study. The skin was washed with alcohol and lanolin, which also could affect the absorption of 

the compound. It is unknown whether dissolved Zn or Zn nanoparticles were absorbed. There is 

an overlap in the two size categories, so distinguishing between the two groups will be difficult. 

For what was done, it is scientifically sound, but in terms of how relevant it is to determining 

absorption of ZnO through the skin, many limitations mentioned above must be considered. 

Dr. Fernandez commented that Dr. Ryman-Rasmussen had mentioned controversy about 

whether nanoparticles were absorbed by intact skin and that this study could be considered a 

pilot study because of the small sample size, issues about how the samples were selected, and 

inclusion of an extreme data point. He questioned the reliability of the data and stated that further 

studies are necessary to confirm the data. 

Dr. Manautou stated that although he did see the strengths in the data on dermal 

penetration of soluble Zn, the third bullet on slide 4 of EPA’s presentation mentions penetration 

of nanoparticles. Dr. Ryman-Rasmussen commented that the information needed to perform an 

assessment is a dermal absorption factor; EPA needs to know what percentage of the applied 

dose is absorbed. It is very difficult to detect nanoparticles and measure their absorption even if 

they are injected. These particles are only 20 to 100 nm in size, and an average cell can be 50 

micrometers (μm) in size. Trying to find them in the whole body is almost impossible. 

Dr. Lebowitz noted that there may be ionic transformation of the particles. Even the skin 

pH is likely to dissolve the particles. The examination is of risk assessment based on Zn, and it 

does not matter whether it is ionic or nanoparticle. It may be that the blood and urine results are 

underestimates because of the tendency of the organs to store the Zn. In spite of some 

deficiencies in the study design, these data are likely to be useful in EPA’s risk assessments. 
19

Dr. Popendorf commented that he was hearing some opinions about the validity of the 

assumption that the Zn was absorbed through the skin. He expressed concern about the potential 

for hand-to-mouth exposure, which was not addressed. The potential for contamination of the 

hands is strong. There has been inadequate consideration given for the whole result if 

contamination occurred. Dr. Chambers mentioned the lack of a control group. The Zn ratios over 

time were examined in the literature on one person and found an average month-to-month 

variation of 0.6 percent. Lack of a control group or any estimate of the month-to-month 

variability of Zn in the subjects limits the validity of the study. The authors had precise 

laboratory methods, but the field work was rather unsatisfactory. Body weight needs to be taken 

into account. Additionally, there are several studies referenced that discuss isotope fractionation, 

which is the tendency of one isotope to be more or less readily absorbed, and the Gulson data 

included the data of the subjects before exposure, and their ratios were different from the natural 

background. The issues of hand-to-mouth contamination and the lack of a known change over 

time are the most serious weaknesses. 

Dr. Johnson asked how researchers protected other parts of the body. Dr. Philpott 

responded that a non-zinc sunscreen was used. 

Dr. Manautou noticed that after the sunscreen was applied, a tape stripping method was 

used to analyze the shape and integrity of the nanoparticles. Dr. Ryman-Rasmussen responded 

that this was conducted in the pilot group to determine the distribution of the nanoparticles on the 

surface of the skin to ensure a uniform distribution. Dr. Manautou asked whether a similar 

method could have been used after the 30 minutes of exposure to determine how much Zn is 

released after that period. Dr. Ryman-Rasmussen noted that if they had done tape strips on the 

skin after wiping with the alcohol wipes, this is a repeated dose exposure, so they would risk 

compromising the barrier for subsequent parts of the study. The only way they could have 

quantified the amount of sunscreen that was removed from the skin with the alcohol lanolin 

wipes would be to try to extract the sunscreen. Dr. Manautou noted that an alcohol lanolin wipe 

would affect the integrity of the material that remains on the skin after exposure. He asked about 

the EDTA in the sunscreen. Dr. Ryman-Rasmussen noted that it was in the sunscreen as a 

preservative, but it is possible that if there is Zn released from the nanoparticles, the EDTA could 

chelate the Zn ions. This is a common formulation for a nano-oxide based sunscreen. 

Dr. Philpott agreed that this was not a well-controlled study. Therefore, given all of the 

caveats in terms of the lack of controls, the possibility for considerable variations over time, and 

overlap of the particle size, the Agency is asking only about absorption of ZnO. 

Dr. Chambers suggested that if it is viewed as a pilot study, knowing that there are 

tremendous limitations in the design, the data are probably reliable. 

Dr. Sharpe questioned how EPA would use something that is called a pilot study 

differently from a completed study. Dr. Ryman-Rasmussen responded that it would not be relied 

on solely but would be used as part of the weight of evidence with other data. This is the only 

study on ZnO that quantifies it in vivo. Some studies have been published that utilize human skin 

in vitro with ZnO, but the Agency’s opinion for pesticides is that in vitro dermal absorption 

studies have not been sufficiently validated to rely on solely for risk assessment. Dr. Sharpe 
20

asked, in terms of weight of evidence, how would EPA combine information from in vivo and in 

vitro studies. Dr. Ryman-Rasmussen responded that EPA would look for consistencies in the data 

in terms of whether there is any evidence of absorption and relative magnitudes of that 

absorption. If the Gulson at al. study is considered by the HSRB to be a pilot, EPA would likely 

introduce in vitro data to support the findings. 

Dr. Philpott noted that the HSRB was being asked specific questions about the study, and 

the weight of evidence is beyond the scope of the charge questions presented to the Board He 

commented that he was hearing that the Board felt that the answer to the first charge question 

was ―yes, but just barely‖ with a large number of caveats that need to be taken into consideration 

regarding whether the data are scientifically sound and reliable. The Agency has the message 

from the Board that the study cannot be used as a stand-alone study. 

Dr. Popendorf commented that if the Board determined that the data are reliable, it could 

be said that the numbers, not their meaning, are reliable. Dr. Philpott answered that the response 

could be phrased that way, stating that ―these data, given all of the limitations of the study and all 

of the possible factors that may have affected them and how they will be interpreted and used, 

are nevertheless reliable for consideration in the overall weight of evidence analysis.‖ 

Dr. Manautou clarified that the Board must make a statement on the reliability of these 

data from a study that has improper controls. Dr. Philpott responded that this was correct. 

Dr. Lebowitz remarked that the Board was focusing on minutia. Part of the problem is in 

the wording of the charge question. The study can only be called a study of Zn absorption with 

limitations. Dr. Chambers added that if the HSRB deemed the study unreliable, it likely would be 

beyond consideration for EPA, and it might provide some insight to make some decisions along 

with the other available studies. 

Dr. Popendorf mentioned a statement about the sample before exposure, but the number 

used does not apply to a change over any period of time. 

Dr. Philpott stated that the response to both charge questions is ―yes, with many caveats 

and many limitations of the data.‖ EPA should be allowed to use these data as part of the overall 

weight of evidence but not as a stand-alone set of data to assess the absorption of ZnO through 

the skin. Caveats will be listed in detail in the final Board report. 

Board Ethics Review

Dr. Sharpe commented that because this is the first article that has been submitted since 

the Human Studies Rule was published, it might be useful to think about how the Board could 

respond to the charge question relative to this study. Most of the information that the HSRB has 

about the study lacks supporting documentation. The judgments made, then, are largely 

inferential. There is no reason to believe that the reported research is fundamentally unethical, 

but in the absence of an informed consent form and research protocol, there is no documented 

evidence that pregnancy testing was conducted, participant selection was voluntary, and/or 

participants understood the nature of the research or their right to withdraw from the study. It can 
21

only be inferred that those requirements were satisfied because of institutional review board 

(IRB) approval and some other evidence. Does inference meet the ―adequate information‖ 

standard? The Board has information about the risks being low and mitigated by UV-protective 

clothing and a trained phlebotomist who drew participants’ blood. The research was approved by 

an IRB-like process, researchers attested that no women were pregnant, and subjects were 

allowed to cease participation. There is no evidence, however, beyond that attestation of the 

researcher that no women were pregnant. There also is no information about the pilot study, no 

documented evidence that pregnancy testing was conducted, and no knowledge that subject 

selection was voluntary. It is unknown whether subjects were related to the researchers, riskbenefit information was sufficiently communicated, and medical treatment was available and 

provided to subjects. The risk is very low, and if the Board uses a sliding scale, the threshold for 

adequacy should be understood in proportion to the risk. 

Dr. Northington Gamble stated that the answer to the charge question is ―no, there is not 

adequate information‖ for many of the reasons that Dr. Sharpe outlined. She finds it problematic 

to use inference as a conceptual model but agrees completely with Dr. Sharpe’s findings. If the 

Board uses inference without any documentation, that is a ―slippery slope.‖ The HSRB does not 

have documentation of pregnancy tests, although eight out of the 10 women were 

premenopausal. There is no documentation of the consent forms and their contents. There is no 

discussion of coercion in terms of power dynamics. There are too many ―red flags,‖ and without 

additional information, there is not adequate information to support the ethical conduct of this 

research. 

Dr. Manautou asked whether the Agency requested an informed consent form from the 

authors. Ms. Parsons responded that she had asked, and Dr. Gulson believed that she was asking 

for the signed consent forms. The response she received from the ethics secretary stated that the 

documentation for the ethics signoff was adequate. 

Dr. Philpott mentioned that it was important to note that subpart L forbids EPA to use data 

that involve intentional exposure of pregnant and nursing women and children to these 

compounds but does not require demonstration that women are not pregnant or nursing. 

Therefore, the fact that a pregnancy test was not conducted does not mean that regulatory 

obligations were not met. The onus is on EPA to provide the HSRB with enough data for the 

Board to be confident that the study was conducted in compliance with regulations as protective 

as those in the United States. The Board’s consensus seems to be that the answer is the 

―information is not yet adequate.‖ 

Dr. Chambers questioned whether the regulations only applied to pesticides. Dr. Philpott 

responded that it fell under 40 CFR part 26, so it was under the same regulation. Mr. Jordan 

noted that the applicable regulation was 40 CFR §26.1703, which prohibits a study conducted 

with children or pregnant or nursing women. That particular section does not contain an 

evidentiary standard, as Dr. Philpott noted. Subpart L applies to studies that are conducted with 

the intention to submit them to EPA, so it does not apply to this study. The §26.1703 standard 

was satisfied. The second piece of analysis is whether the standard in §26.1705 was satisfied, 

which means that EPA must have evidence that the study was conducted in substantial 

compliance with procedures at least as protective as EPA’s regulations. If it is concluded that 
22

standards in Australia are as least as protective as those in the United States, the next question 

becomes whether this study was conducted in substantial compliance with the Australian 

requirements. Dr. Philpott noted that the Board was in agreement that the Australian standards 

were as protective as those in the United States, but the question is whether adequate information 

to support its compliance with those standards is available. He added that with the pre-rule 

studies, the Board talked in detail about evidentiary standards and what would have to be shown 

to state that the study was not performed in substantial compliance with applicable regulations. 

Dr. Sharpe noted that the Board can provide EPA with a list of the kind of information 

that would be useful. The HSRB is asking whether the study received IRB approval for reasons 

that would allow the Board to assess whether that approval was appropriate. The HSRB does not 

want to set a bad precedent for reviewing post-rule literature. She suggested using the HSRB’s 

recommendations to request the informed consent form and any research proposal that is 

available from the university that approved the study or the researchers. Dr. Philpott added that 

the Board did not believe that its answer to the charge question would always be ―no,‖ but that 

the answer was ―not yet.‖ 

Dr. Johnson asked if the Board would produce a list of items needed to make the 

decision. Dr. Philpott suggested that the HSRB make a list of documents that members would 

like to see. 

Dr. Northington Gamble stated that Dr. Sharpe should be applauded for delineating what 

was and was not adequate in the current information. She agreed that the answer was ―no, not 

yet‖ in terms of having adequate information. 

Dr. Lebowitz inquired whether some questions of clarification on the scientific issues also 

could be asked when the Agency queries Dr. Gulson for information on ethics. Dr. Philpott 

responded that if this was provided, perhaps all of the charge questions could be reconsidered. 

That is a fairly large undertaking but not inappropriate. EPA would be welcome to bring further 

scientific information back to the Board, but ethics information is needed. Dr. Ryman-Rasmussen 

asked what additional information would be needed. Dr. Philpott responded that there was a list 

that could be e-mailed to Dr. Ryman-Rasmussen and Ms. Parsons. 

Dr. Chambers asked whether the science charge questions would be revisited. Dr. Philpott 

answered no, unless the Board was asked to do so. The answers to the first two charge questions 

stand. If EPA receives additional scientific information on which it would like HSRB input, the 

issue can be revisited by the Board. Dr. Chambers noted that the Board’s concerns were with the 

design of the experiment. The Board likely has judged the science as well as it can. 

Dr. Sharpe questioned whether the Board would be identifying what would count as 

adequate information. Dr. Philpott answered that the Board should try to identify some of the 

elements that lack adequate information but not identify particular documents that need to be 

submitted. If members have lists of specific concerns that need to be addressed to have adequate 

information to determine whether the study was conducted in accordance with procedures that 

are as protective as EPA’s regulations, submit them to Dr. Philpott. If the Board could give Ms. 

Parsons some suggested starting points during that day’s meeting, it would be useful. Dr. Sharpe 
23

would like to request the informed consent forms and the study protocol. She also would like to 

see information from the IRB’s deliberations. Dr. Northington Gamble asked for a response to a 

letter sent to Mr. Herbert Wong (Graduate School of the Environment, Macquarie University) in 

January 2006 from the research ethics officer, Kokila De Silva, because in that letter, the 

question was raised about the volunteers. 

Dr. Philpott reiterated that the Board’s consensus as to whether or not there is adequate 

information that the Gulson et al. study was conducted in substantial compliance with procedures 

that are at least as protective as existing EPA human subjects protection regulations is ―not yet,‖ 

and the Board suggested that EPA obtain some additional information such as the informed 

consent document, study protocol, and any IRB recommendations including Dr. Gulson’s and 

Mr. Wong’s response to the question about whether the volunteers were colleagues or students of 

Dr. Gulson. This is the Board’s first review of a post-rule published study, so the fact that the 

HSRB is not finding it in compliance should not be seen as a failure on the part of the Agency or 

the researchers. 

Session 3: Reconsideration of Two Concerns Previously Raised by the HSRB in Its June 2009 

Review of an Intentional Human Dosing Study with Chlorpyrifos (Kisicki et al. 1999); 

Additional Pertinent Information Was Made Available by the Sponsor Related to These Two 

Concerns

Dr. Philpott explained that this reconsidereation of two concerns previously raised by the

Kisicki et al. study was not coming to the Board from the Agency. Rather, the new information 

was raised at a recent FIFRA SAP meeting. This study was discussed at the June 2009 HSRB 

meeting. The Board reviewed three pre-rule studies at the meeting that examined human 

exposure to chlorpyrifos: the Nolan study from 1984 that measured the absorption, distribution 

and excretion of chlorpyrifos; the Honeycutt study from 1992 that examined agricultural worker 

exposure to chlorpyrifos with field re-entry; and the Kisicki study from 1999 that determined the 

no observed effect level as measured using red blood cell (RBC) acetylcholinesterase inhibition 

for chlorpyrifos. 

The Nolan study included six male subjects who received an oral dose of chlorpyrifos as 

0.5 mg/kg in tablet form and a 5.0 mg/kg dermal dose. The endpoints being measured were RBC 

cholinesterase inhibition (ChEI), plasma ChEI, blood 3,5,6-trichloro-2-pyridinol (TCP) levels 

and urine TCP levels. In comparison, the Kisicki study was comprised of 30 male and 30 female 

subjects, with 12 per sex as controls and six per sex per dose group. The doses included 0.0, 0.5, 

1.0 and 2.0 mg/kg in capsules, and the endpoints examined were RBC ChEI, blood TCP levels 

and urine TCP levels. 

The Board was asked whether the blood and urine measurements of chlorpyrifos and/or 

TCP from the Kisicki et al. oral study were reliable, and it had many concerns. The HSRB 

responded that questions about the analytic procedures used, the lack of an appropriate 

gluconamide control, and apparent discrepancies in the absorption data when compared with the 

data from Nolan et al. raised concerns about the reliability and utility of these data for risk 

assessment purposes. The concerns about the reliability and validity of the Kisicki et al. data 

included whether the urine samples were subjected to acid hydrolysis before processing and 
24

quantifying the chlorpyrifos metabolite TCP and why the absorption of chlorpyrifos was so much 

different than in a study of chlorpyrifos by Nolan et al. (35 percent versus 70 percent 

respectively), calling the analytical methods of Kisicki and his colleagues into question. Acid 

hydrolysis is necessary to hydrolyze the gluconamide conjugate of TCP and liberate the 

metabolite for analysis, and whether Kisicki et al. performed this step could not be determined 

from the materials that were presented to the Board at the 2009 HSRB meeting. Because the 

urine TCP data were being used in the analysis and to examine the relative absorption of 

chlorpyrifos, it raised significant concerns. If acid hydrolysis was not used, it could explain the 

difference between Kisicki et al.’s findings and what was seen in the Nolan study. 

The Dow Chemical Company (Dow) provided new information to the Agency at the 

FIFRA SAP meeting that addresses the procedure used for analyzing the urine and explores the 

differences between the tablet and the gelatin capsule formulations that explain the difference in 

absorption. Therefore, the difference in absorption may not bring into question the analytical 

methods used by Kisicki et al. and may be because of the difference in formulation. 

Dr. Manautou inquired whether the analytical method measures free TCP. Dr. Chambers 

responded that the analytical method is for free TCP and would not detect gluconamide 

conjugate of TCP. Dr. Philpott noted that the HSRB had other concerns, such as total mass 

balance and questions about participants in the study, but those are not at issue. The questions to 

reconsider are those about the urine sample being subjected to acid hydrolysis and whether there 

is a better explanation for the difference in the absorption in the Kisicki versus Nolan studies 

other than calling into question the analytical methods used. The Board now has additional 

information provided by Dow to the Agency that raises questions about whether the concerns 

that are written in the June 2009 final report, a publicly available document, now are moot. 

Questions for discussion include: 

• Do the recommendations provided by the HSRB at its June 2009 meeting and in its 

subsequent report regarding the reliability of data on the urinary metabolite 

trichloropyridinol in the Kisicki et al. (1999) study change in light of the new 

information provided?

• Do the recommendations provided by the HSRB at its June 2009 meeting and in its 

subsequent report regarding the level of absorption of chlorpyrifos in the Kisicki et al. 

(1999) study change in light of the new information provided?

Dr. Chambers stated that Dow was asked specific questions later in 2009 and provided 

some information to EPA, but that information was not shared with the HSRB. At the February 

2011 FIFRA SAP meeting on chlorpyrifos, the HSRB report from the June 2009 meeting was 

part of the documentation. Dow scientists pointed out that they had answered those questions and 

produced a document that was delivered to the SAP. If the HSRB had received this information 

prior to finalizing its report, the recommendations might have been different. The Nolan and 

Kisicki studies are linked because the HSRB was concerned that the methods description in the 

Kisicki study indicated that the blood was acid hydrolyzed to free the TCP, but the description of 

the urine methodology did not describe acid hydrolysis. If it was not conducted, that could have 

been part of the difference between the absorption in the two studies at the same dose. The 
25

explanation at the time that the gelatin capsule took longer to dissolve and absorption was 

therefore lower did not seem adequate to the Board. Dow’s document states that the acid 

hydrolysis method used in the study was the same as in the Nolan 1987 rat metabolism study. 

With respect to the absorption, the Board did not have sufficient information at that time to 

indicate the form of the chlorpyrifos that was administered to those in the Nolan and Kisicki 

studies. In the Nolan study, in which there was 70 percent absorption at the 0.5 mg/kg dose, the 

chlorpyrifos material was dissolved in methylene chloride, and the resulting solution was applied 

to a lactose tablet. In contrast, in the Kisicki study, the chlorpyrifos material was formulated by 

weighing a crystalline test material into a gelatin capsule and filling the remainder of the capsule 

with lactose powder. These were much larger particles of chlorpyrifos than in the Nolan study. 

The difference in formulation is sufficient to say that a difference in the absorption would be 

expected between the two studies. 

Dr. Philpott noted that the Board now could have a discussion about whether to amend 

the June 2009 recommendations. Dr. Chambers stated that Dr. Michael Bartels from Dow was 

present and could answer any questions of clarification. 

Dr. Manautou asked whether the different formulations would bring sufficient difference 

in dissolution rates to explain the magnitude of differences in absorption between the two 

studies. Dr. Chambers responded that she did not know if that was the case, but it is more logical 

knowing that the formulation is that different. 

Dr. Lebowitz commented that the evidence presented could indicate that smaller particle 

sizes could be absorbed better, but the sizes of the particles are not known. Dr. Philpott explained 

that at the June 2009 HSRB meeting, the Board stated that it did not believe that the differences 

between the formulations could explain the differences in absorption and raised concerns about 

the analytical methods used. The additional information suggests that it might explain the 

differences in absorption. 

Dr. Chambers read the statement that the Board had made at the June 2009 meeting: 

―Kisicki et al. suggested that the oral absorption is slowed by the dissolution of the gelatin 

capsule with the concurrent reduction in the total amount absorbed.‖ Although the Board agreed 

that absorption of chlorpyrifos from the gelatin capsule might be slower than that from the 

lactose tablet, there was some skepticism that the difference in dosage form would yield this 

large discrepancy in total percent absorbed in the two studies. She noted that the Board now had 

other information about what might have contributed to the difference in that same dose level in 

the two studies. 

Dr. Green asked about the lactose in the capsules. Dr. Chambers replied that it was not 

bound to the crystalline chlorpyrifos. 

Dr. Popendorf noted that it was the crystals within the capsule, not the capsule itself, 

making the difference in absorption. Dr. Chambers stated that this was correct, but the report 

indicated skepticism that the gelatin capsule would have taken long enough to dissolve to 

account for the difference. She added that the difference seems to be real with the new 

information taken into account. Dr. Popendorf commented that the Board wanted to say 
26

something new, not change what had been said in 2009. Dr. Philpott answered that any change 

would amend the 2009 report to say, ―in light of information that the Board did not have at the 

time, some of these concerns no longer are valid.‖ 

Dr. Manautou questioned whether the differences in absorption defined by blood levels at 

a given time were indicated in the two studies. Dr. Chambers answered that the Board’s concern 

had been with the urine levels. Dr. Manautou asked whether chlorpyrifos undergoes antihepatic 

circulation, and the lactose could be converted in the intestine to lactic acid. Dr. Chambers 

replied that there is lactose in both formulations. Dr. Philpott added that there was a real 

discrepancy because both the Nolan and Kisicki studies had a 0.5 mg/kg oral dose, and the urine 

TCP data was very different in each. This led the Board to determine that there were some 

methodological problems with the Kisicki study. Some of those concerns appear to have been 

addressed with the information that Dow provided to the Agency. 

Dr. Chambers asked Mr. Bartels if she had misrepresented anything in the study. Mr. 

Bartels stated that Dr. Chambers had described the supplementary information appropriately. The 

methods used in the Kisicki study are well described in another report that was submitted to the 

Agency, and he has the master record identification number if that is needed. In the Kisicki study 

the methods used, as Dr. Chambers described, were identical to those used in many prior studies. 

The TCP can be measured directly once the conjugate is treated with acid. In this study, the 

laboratory conducted repeat analysis of selected samples and extended the hydrolysis time for 

another 2 hours. The bioavailability of the absorption is most easily analyzed by examining the 

urine levels. In the document provided to the Agency, Dow listed several examples of moderate 

changes in particle size giving a two- to four-fold increase in absorption. 

Dr. Lebowitz inquired about the particle size used by Nolan and by Kisicki. Mr. Bartels 

responded that those measurements were not taken, but the material in the Nolan study was 

dissolved in a small volume of methylene chloride and applied as a solution to a tablet. That 

would be a very small particle size with very large surface area to mg of test material. In the 

Kisicki report, there is documentation that the material used was a crystalline solid; there was no 

further milling of the material beyond what was generally done to prepare this kind of product. 

When animal toxicology studies are performed, Dow routinely takes white crystalline solids and 

further reduces the particle size to obtain homogeneous preparations. 

Dr. Popendorf asked, if the Board accepts the fact that the data from Kisicki show onehalf of the absorption of the Nolan data, then the dose in the Kisicki study is one-half of what 

was absorbed in the Nolan study. Mr. Bartels responded that this was correct, and that conclusion 

was put forward in a publication in 2002 using the Nolan and the Kisicki data. 

Dr. Chambers noted that reevaluating and interpreting the data were not the point of the 

discussion. If the Board’s recommendations would have been different in light of this new 

material when the report was written, should the Board amend the report so that the record is 

corrected? Dr. Philpott added that the Board is not correcting anything nor reevaluating the 

Kisicki study. The question is whether the Board should amend its recommendations to be less 

skeptical in terms of the acid hydrolysis and the explanation of the difference in absorption. The 

analytical methodology probably was appropriate. The difference in formulation does not 
27

necessarily explain the entire difference in absorption between Kisicki and Nolan, and the Board 

can consider whether it wants to say it may have had an effect. 

Dr. Young clarified that the Board just was discussing the two affected recommendations. 

Dr. Philpott confirmed that the other two concerns and recommendations will remain. 

Dr. Johnson suggested that the Board should amend the record and asked whether the 

Board would include a paragraph on this matter in the current report. Dr. Philpott answered that 

this had not been done before. The proposal is that the Board write something brief about this, 

and this report will cross-reference the June 2009 report; the June 2009 report on the Web site 

will link to this report. 

Dr. Lebowitz recommended that the Board amend the 2009 report to reflect the new 

knowledge. It should amend statement number one to say that the difference in formulation of 

the chlorpyrifos in the two studies may explain the difference in urinary results, and statement 

two should say that the analytical method was correct. Dr. Chambers suggested that she draft the 

amended recommendations and present it to the Board the following morning. 

Dr. Philpott asked whether any Board member had serious concerns about whether or not 

the HSRB should amend the June 2009 report. He noted that the consensus agreement was that 

Dr. Chambers would write brief statements answering these two questions, and the Board would 

discuss them briefly at the beginning of the meeting the following day. Mr. Downing added that 

there would be an opportunity at the next teleconference meeting to review the statement. Dr.

Philpott stated that he would prefer to get a consensus statement during the current meeting. 

Mr. Downing concluded the meeting for the day at 4:35 p.m. He announced that the next 

day’s public meeting would begin at 10:00 a.m., but Board members have an administrative 

meeting at 8:30 a.m. at which the Board’s bylaws would be discussed. 

Thursday, April 14, 2011 Introduction and Identification of Members

Mr. Downing welcomed attendees and members to the second day of the HSRB meeting 

and turned the meeting over to the Chair, Dr. Philpott.

Dr. Philpott thanked the Agency and the Board members for their diligent work in 

preparation for this meeting and asked members to identify themselves and their affiliation. 

Follow-up from Previous Day

Ms. Sherman stated that the regulatory framework discussed the previous day may not 

reoccur based on the fact that proposed changes to the rule would change the standard applicable 

to studies such as Gulson that were not conducted by people intending to submit them to the 

Agency or not conducted under EPA’s rules. The current standard is 40 CFR §26.1703, which 

prohibits reliance on studies involving pregnant or nursing women or children, and 40 CFR 

§26.1705, which states that EPA needs to have adequate information to determine whether the 

research was conducted in substantial compliance with standards as stringent as EPA’s. The new 
28

standards proposed for these types of research would be §26.1703 and §26.1705, which state that 

EPA must not rely on data from research subjects if there is clear and convincing evidence that 

the research was fundamentally unethical or the research failed to obtain informed consent or if 

the research was deficient relative to the ethical standards prevailing at the time. The thinking 

was that in holding research to the standard that researchers would not know that they were 

subject to at the time of the study, good research found in the literature could potentially be 

eliminated. 

Dr. Philpott clarified that the framework under which both the pre- and post-rule studies 

and peer-reviewed studies would be standardized. Ms. Sherman responded that EPA was 

adjusting the standard for research not otherwise subject to this rule. 

Dr. Northington Gamble asked about the status of the proposal. Ms. Sherman replied that 

the Agency completed a rulemaking process, and most of the other changes to the rule were a 

result of a settlement agreement with the Natural Resources Defense Council. The comments 

received on the proposed rule will be evaluated, and a determination will be made whether 

adjustments are needed. EPA plans to issue the final rule in December 2011. 

Follow-Up to Kisicki et al. Study Discussion 

Dr. Philpott noted that the Board had proposed that Dr. Chambers craft some draft 

language for the Board members to examine, which would be incorporated into a supplement to 

the June 2009 and the April 2011 final meeting reports and discussed on the next public 

teleconference meeting. 

Dr. Chambers explained that the text she supplied to the HSRB includes paragraphs to 

inform the reader why the recommendations were reconsidered, but the important part is the final 

paragraph. The language will be edited before appearing in the final report, but the two critical 

points decided the previous day were addressed: (1) the differences in absorption between the 

Nolan and Kisicki studies and (2) the concern about the urinary metabolite extraction.

―The Board considered this additional information and indicated that its 

original recommendations on these two points only about the Kisicki study 

should be amended as follows: (1) it is logical that larger particles of 

materials such as chlorpyrifos would be absorbed more slowly than smaller 

particles. The differences in absorption between the Nolan and Kisicki studies 

may have resulted, at least in part, from the different sizes of chlorpyrifos 

particles in the two formulations; and (2) the quantitation of urinary TCP was 

accurate because the urine was subjected to acid hydrolysis and heat to 

liberate conjugated TCP.‖ 

Dr. Chambers added that if there are no major substantive changes to the content, it can 

be edited before the meeting report is finalized. 

Dr. Manautou suggested that the second sentence of the first statement read, ―The 

different sizes of chlorpyrifos particles in the two formulations may have contributed to the 
29

differences in absorption between the Nolan and Kisicki study.‖ Dr. Chambers responded that 

―may‖ was included as a caution, as was ―at least in part.‖ 

Dr. Philpott asked whether the general consensus of the Board was that the difference in 

particles between the two formulations in the Nolan and Kisicki studies may explain, at least 

partially, the difference in the absorption. Dr. Popendorf added that the statement made 

previously that the difference in handling may have contributed to the difference in absorption 

should be rescinded, and this could be added to the second recommendation. Dr. Philpott 

suggested addressing within the original recommendation the fact that because the urine was 

subjected to acid hydrolysis to free the conjugated TCP, the Board no longer believes that 

differences in handling likely explain the differences in absorption. Dr. Chambers and Dr. 

Philpott will edit the language and incorporate the text into a draft document that will be sent to 

the Board members for comment, and it will be discussed during the public teleconference 

meeting to finalize the April 2011 HSRB meeting report. Dr. Philpott commented that these 

amendments address only two of four major concerns that the Board has with the Kisicki study. 

Session 1: Completed AEATF II Research on Exposure of Professional Janitorial Workers When 

Wiping an Indoor Surface with an Antimicrobial Pesticide

Mr. Timothy Leighton (OPP, EPA) explained that EPA had reviewed AEATF II research 

on exposure of workers to an antimicrobial pesticide while wiping indoor surfaces. He noted that 

EPA’s contractor, statistician Dr. Jonathan Cohen of ICF International, was available by 

telephone to answer any questions. Mr. Leighton explained that the study involved two exposure 

scenarios: the ready-to-use (RTU) wipe and the trigger spray and wipe. 

EPA Science Assessment

Mr. Leighton noted that the Board had reviewed the scenario for this study in April 2008. 

The wipe studies were conducted at the same time as the AEATF II mop study that was reviewed 

in October 2010. Therefore, the lessons learned from the mop study are not incorporated. 

Individuals wiping indoor surfaces are being monitored, and pouring the concentrate into the 

trigger spray bottle was excluded because this can be conducted in a variety of ways and will be 

examined as a separate scenario. 

The RTU wipes come in an 8.5‖ x 5‖ cylindrical container that contains 75 wipes. There 

is roughly one-half a liter of diluted production (0.04 percent ai) in the wipes, or approximately 

2.5 mg of didecyl dimethyl ammonium chloride (DDAC) per 8‖ x 7‖ wipe. Subjects used up to 

250 wipes in a monitoring event (ME). The trigger spray is a 32-ounce container with a trigger 

and rag used for wiping. 

The locations of the study were three randomly selected vacant buildings in Fresno, 

California, the same sites as the previously conducted mop study, with each subject only 

monitored once. To ensure the diversity of individual exposures, at each site one enrolled subject 

was assigned to each of six MEs, defined by the planned duration of wiping. The maximum 

duration was 120 minutes; the Board had suggested that this was too short of a time period, and 

it was increased to 210 minutes. All but one study participant was within 1–2 minutes of the 
30

timeframes. One at the higher timeframe was only 165 minutes instead of 180 to 210. There were 

six subjects at each of three sites (n = 18) exposed to DDAC. Subjects wore WBDs and breathing 

zone OVS air samplers and wiped as they normally would with the RTU wipes in one scenario 

and a trigger spray and wipe in the second scenario. 

The wipe protocol’s stated objective was to ―...sample estimates of the arithmetic mean 

and 95th percentile of normalized exposure are accurate to within three-fold 95 percent of the 

time.‖ Both EPA and AEATF II II recognize that drawing statistical inference from the results of 

the purposive sampling design to the universe of people wiping is not statistically justifiable. 

EPA asked the AEATF II to specify the type of wipe/rag in the trigger spray and wipe scenario 

(cotton rags from Bag-o-Rags) and provide data on recovery efficiency of hand-wash/face-wipe 

methods for DDAC (provided existing study on efficiency of DDAC residue removal from 

hands). The HSRB asked the AEATF II to consider repeat measurements, but there is a tradeoff 

of knowledge about within-worker variability for more samples of between-worker variability.

The HSRB suggested longer monitoring duration, and based on industry information, maximum 

monitoring time was increased. The HSRB recommended that the AEATF II consider defining 

ME by AaiH rather than duration, but the best information on wiping was by duration. Finally, 

the HSRB suggested a review of proportionality between exposure and AaiH, which EPA itself 

conducted. 

Protocol deviations were similar to the mop study. There were 23 deviations reported, 

none of which negate the use of the exposure results. The same hand residue removal efficiency 

study used in the mop study was employed, but the wipe study hand wash and face/neck wipe 

procedures are similar. The WBD was used inside and outside, and each body part was analyzed. 

The same three clothing configurations presented in the mop study were used. For the scenarios, 

people worked as they normally did; people using the RTU wipe wiped up to 5,030 square feet 

and used from 27 to 250 wipes in an ME, with an average use of 127 wipes. The trigger spray 

use averaged just less than 0.5 gallons. The area wiped was slightly less than with the RTU 

wipes, and the maximum area wiped was 3,629 square feet. The concentration of spray used was 

roughly the same as the amount in the RTU wipes. DDAC was used because it has a sensitive 

method, and the LOQs are very low. The controls showed that everything was less than the LOQ, 

and there were no contamination issues. The laboratory and field recoveries were good, and the 

field recoveries were used to correct the field samples. 

In terms of statistical analysis, three methods were used to estimate unit exposures: 

empirical estimates, a simple random sample and a mixed model. The mixed model was selected 

to best represent the unit exposure results. In the mop study, one of the Board members 

suggested examining the quadratic model, degrees of freedom and the nonparametric bootstrap, 

so Dr. Cohen conducted those three analyses. He conducted the same procedures with the wipe 

study results. 

The fitted mixed model results were used to examine inhalation, with the results provided 

as mg and mass per ai. Comparing the two scenarios, dermal exposures are higher with the RTU 

wipes. The inhalation with RTU wipes, conversely, is much lower than the trigger spray. All of 

the RTU hand exposures were greater than the LOQ, and 12 of the 18 air samples were 

detectable. Most of the inner dosimeters were non-detects, and the outer dosimeters were 
31

detectable. For the trigger spray, all of the hands and face levels were greater than the limit of 

detection. Most of the inner dosimeters were less than LOQ, and of the outer, only two were less 

than LOQ. 

The benchmark objective of three-fold relative accuracy was met for the mixed-model 

results using the ―3 cluster x 6 ME‖ study design, so no additional MEs are needed; the sample 

was large enough to satisfy EPA’s needs. Proportionality between exposure and AaiH is an 

assumption EPA uses in handler exposure assessments, and the results of most scenarios are 

expected to show an increase in exposure with an increase in AaiH. The wipe data are consistent 

with the assumption of increasing exposure with increasing AaiH, except inhalation exposure for 

the RTU wipes, which showed no evidence of a positive relationship between RTU inhalation 

exposure and AaiH. The unit exposure for RTU wipes, using the slope of the regression of the 

log exposure against the log ai, was 2,400 mg per pound (mg/lb) ai, which is the RTU threshold. 

In terms of limitations on the data generalization: the wipe study population is not a true 

random sample; statistical inference from these results to the universe of people wiping is not 

justifiable; and surrogate assessments applying less than the threshold of AaiH will 

underestimate exposure, whereas AaiH greater than the threshold will overestimate exposure. 

EPA’s plan for the data is to use unit exposure data generically to estimate potential exposure to 

low- or moderate-volatility pesticides used in wiping scenarios and to use chemical-specific 

hazard and dermal absorption data to estimate internal dose and risk. 

In conclusion, study results are sufficiently sound to support estimates of dermal and 

inhalation unit exposures in the two wiping scenarios, an adequate number of samples were 

collected, and data limitations must be acknowledged in the risk assessments. 

Board Questions of Clarification—Science

Dr. Young asked whether slide 26 of EPA’s presentation showed log exposure and log ai, 

because it is labeled exposure and ai. Dr. Cohen answered that the purple line was calculated 

using the unit exposure or exposure lbs AaiH. Dr. Johnson remarked that he thought the model 

was fit on the log scale but demonstrated on the non-log scale. Dr. Cohen responded that this was 

correct. 

Dr. Lebowitz examined the report and slides, and per unit exposure does not appear to 

correspond with Tables 2 and 7, but there may be an explanation for this. The numbers do not 

correspond. Mr. Leighton replied that Table 1 is a summary of the mixed model results, and 

Tables 2 through 7 report the empirical results. Results of this study are similar to the previous 

wipe studies. Dr. Lebowitz asked, with all of the non-detects in the new study and the LOQs, if 

EPA is saying there is no effect. Mr. Leighton responded that in the mop study, the same 

conversation was held, and EPA re-examined whether it should be using something other than 

one-half of LOQ for non-detects. Based on the percentage change in the results, it was decided 

not to do anything different. Dr. Lebowitz inquired whether the non-detects were included as 

zero or one-half of the LOQ in the different regressions. Dr. Cohen responded that one-half of 

the LOQ was used for the non-detects. Dr. Lebowitz noted that all of the dermal exposures were 

combined, and because there were so many non-detects, the hand became the most important 
32

because there were no non-detects in this measurement. Therefore, what is shown in the 

regression is almost entirely from the hand. Dr. Lebowitz noted that this needed to be stated more 

clearly in the results. He stated that he had found a fair number of non-detects and deviations in 

the fortified samples. He asked whether in the analysis of quality assurance/quality control, the 

large number of exceedances of the fortified samples and deviations would affect the results of 

the study. Dr. Lebowitz questioned whether EPA thinks that by correcting the samples for the 

actual results of the fortified samples that this problem has been addressed so that there is no 

bias. Mr. Leighton stated that was correct.

Dr. Lebowitz asked why EPA thinks a regression slope of 0.5 is important. Mr. Leighton 

responded that the lower the slope when EPA’s equation is used, the higher the overestimate of 

exposure. Dr. Lebowitz asked if the regression is 0.25, whether EPA still would use that as 

extrapolating from unit to the lbs ai. Mr. Leighton replied that there was additional uncertainty, 

but it still would be used. 

Dr. Lebowitz questioned why the nonparametric bootstrap would be excluded when the 

CI was even narrower than with the parametric. Dr. Cohen stated that both had been presented. 

Dr. Lebowitz commented that EPA had decided to ignore the nonparametric results or revert to 

using the parametric. Mr. Leighton commented that perhaps this could be added to the discussion 

within the review. Dr. Lebowitz noted that in Table 7, a great amount of variability is shown 

among the cluster results. How did EPA determine to combine results from different clusters 

when one cluster might have results that are twice or one-half as great as the others? Mr. 

Leighton answered that variation between the clusters could have to do with the amount of 

wipes, or ai, used. This could be examined among the clusters. 

Dr. Fernandez noted, on slide number 10 of EPA’s presentation, that under the study 

objective it only states the estimates of arithmetic mean and the 95th percentile of normalized 

exposure. He assumed that these analyses had been conducted based on log-transformed data. 

Mr. Leighton said that geometric mean also had been calculated. Dr. Fernandez stated that it 

looked as though the data had not been transformed based on normal distribution. Is the data 

coming from log-transformed data and then adjusted for the arithmetic mean? Dr. Cohen 

answered that this was correct. Dr. Fernandez noted that the main concern is the upper limit, so 

why should EPA be concerned about including the lower limit? Mr. Leighton stated that he was 

correct, and the process could be streamlined by only examining the upper 95th percentile. 

Dr. Popendorf asked about chronic versus acute exposure. Mr. Leighton responded that in 

EPA’s assessments, if examining a chronic exposure, the Agency would not be using the 95th 

percentile. The 95th percentile is to examine a 1-day, short-term effect. The Joint Regulatory 

Committee wanted to examine all of the statistics within the study, so even if the arithmetic mean 

is used, EPA still wants to be able to report the 95th percent confidence limits. 

Dr. Fernandez asked, regarding slide number 19, if the recovery percent was for the three 

clusters, and why there was more than 100 percent recovery. Mr. Leighton responded that the 

percent was for the three clusters, and the figure was greater than 100 because sometimes x 

amount is fortified on a patch, and if it comes back as 109 percent, that is the range of the 
33

analytical technique. EPA does not correct anything that is above 1,000 percent. Corrections are 

made upwards but not downwards. 

Dr. Popendorf asked how long the material was on the skin in the hand removal 

efficiency study referenced in the report. Two levels of exposure were tested, but the time on the 

skin was not reported. Mr. Leighton replied that after it was fortified on the hand in the removal 

efficiency study, it was allowed to dry for 30 minutes. 

Dr. Philpott invited Dr. Has Shah (AEATF II), Dr. Robert Testman (Golden Pacific 

Laboratory) and Ms. Megan Boatwright (Golden Pacific Laboratory) to answer Board questions. 

Dr. Popendorf noted that the instructions to subjects stated that subjects were advised not 

to re-wipe any surface during the given ME and wondered what was intended and how this 

instruction was interpreted. He asked how the applicators figured out how much wiping they 

were supposed to do and how much ai they should use. Dr. Testman answered that the subjects 

were asked to do their job as they normally would, but they were to wipe new surfaces 

continually rather than going back over surfaces. Mr. Leighton added that the Joint Regulatory 

Committee (EPA, Health Canada, and California) asked for the same method. Originally, this 

study was going to be performed in the laboratory, but it was decided that there would not be 

enough surface area. 

Dr. Popendorf added that the study described the subjects as having both training and 

experience, and he asked what sort of training the subjects have. Dr. Testman answered that it 

would be considered on-the-job training. Researchers did not provide any training but did screen 

subjects to ensure that they had janitorial experience and had wiped surfaces professionally. 

Dr. Popendorf asked how the workers knew when they had cleaned enough. Dr. Testman 

responded that it was largely left to their discretion to clean as they would in their day-to-day 

job. Dr. Popendorf questioned if there were similar levels of wetness that resulted from the 

cleaning or distinct differences among the subjects. Ms. Boatwright replied that variability could 

be seen from person to person, but within-person results were fairly consistent. Mr. Leighton 

added that square foot wiped per minute could be examined in the review. When this information 

is used to label a product, the label will state only ―wipe surfaces,‖ not how to wipe. 

Dr. Philpott thanked the sponsors and noted that they would be given a chance to make a 

public comment later in the meeting. Dr. Shah stated that Dr. Sami Selim had resigned from 

Golden Pacific Laboratory and Dr. Testman has taken over. 

EPA Ethics Assessment

Ms. Sherman noted that the protocol was reviewed in April 2008, the recruiting and 

subject enrollment occurred in April to July 2009, and the field monitoring took place in 2009. 

The comments and input on the mop study were reviewed in October 2010 and, therefore, have 

not been applied to this research. The report was submitted to EPA in January 2011.

Recruiting initially followed procedures in the protocol, but this proved unproductive. 

The protocol was amended to allow subjects to be recruited and enrolled as they came forward 
34

and further amended to allow recruiting through newspaper advertisements. An advertisement 

was approved by IIRB and appeared in three newspapers in the Fresno, California area. Ms. 

Sherman found that the recruiting process was equitable and free of coercion or undue influence.

In one unreported deviation, three subjects reported that they were in ―fair health.‖ This 

was contrary to the protocol, which stated that subjects should be in ―good health‖ to participate. 

This issue was discussed at the October 2010 HSRB meeting, and the conclusion was that this 

deviation did not render the results unacceptable, but the HSRB and EPA recommended that the 

AEATF II in the future clarify the criteria used to establish health status. Only one of these 

subjects was monitored; the others were alternates. 

Thirty-six subjects were monitored, of which 20 were male and 16 female; 33 were 

English-speaking, whereas three were Spanish-speaking. The mean age was 42.8 years, with 13.5 

mean years of experience; 72 percent requested to receive their exposure results. 

Four instances of a subject speaking to the medical professional or reporting feeling ill 

occurred, possibly as a result of inhaling fumes. In all of these cases, the subjects continued 

working, and none of these situations resulted in an adverse event. One subject left early because 

he was feeling ill, but it was not reported whether his illness was related or unrelated to his 

participation in the study. The subject that reported fair health was not one of these five subjects. 

Ms. Sherman believed that the AEATF II was successful in responding to EPA and HSRB 

comments in the protocol review process. 

The initial protocol was reviewed by the IIRB in January 2008, with a revised protocol 

incorporating comments from the HSRB and EPA approved by IIRB in February 2009. Eight 

amendments were approved during the course of the study, and two deviation reports included 23 

deviations from the protocol. 

The deviations that were important from an ethics standpoint included two reported 

deviations: some subjects omitted or shortened rest breaks, and there were photographs showing 

subjects’ faces taken at one monitoring site, but none of these images were included in the report. 

The unreported deviation was the aforementioned enrollment of subjects with self-described fair 

health. 

The documentation that EPA received from the AEATF II was complete and well 

indexed, and the ethics portion was thorough; requirements of 40 CFR §26.1303 are satisfied. 

Substantive acceptance standards include 40 CFR §26.1703, which prohibits reliance on 

data involving intentional exposure of pregnant or nursing women or of children; 40 CFR 

§26.1705, which prohibits reliance on data unless EPA has adequate information to determine 

substantial compliance with subparts A through L for 40 part CFR 26; and FIFRA §12(a)(2)(P), 

which makes it unlawful to use a pesticide in human tests without fully informed, fully voluntary 

consent. EPA found that all subjects were at least 18 years of age; pregnant or nursing women 

were excluded; all females were tested for pregnancy; there were no noteworthy deficiencies in 

the ethical conduct of the research; the protocol was faithfully executed and amended when 
35

needed; minor deviations did not compromise safety or consent of subjects; and subjects were 

fully informed and their consent was fully voluntary, without coercion or undue influence. 

In conclusion, available information indicates that the AEATF II II Wipe Study was 

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

Board Questions of Clarification—Ethics

Dr. Northington Gamble stated that regarding responsiveness to HSRB comments, 

Ms. Sherman noted two instances in which they were not addressed. One related to the purpose 

of the study that would be to collect information to be provided to EPA, and the second related to 

the flyer’s notation that it would measure inhalation as well as dermal exposure. Dr. Northington 

Gamble questioned why these issues were not addressed. Ms. Sherman responded that she did 

not have additional information. 

Drs. Shah and Testman and Ms. Boatwright responded to questions from the Board. 

Dr. Northington Gamble asked about follow-up on the subject who left early because he was not 

feeling well, and it was unclear whether that was because of the research. Ms. Boatwright 

answered that the subject had reported to the study stating that he was not feeling well, but that 

he wanted to participate in the study. Dr. Northington Gamble stated that she was referring to the 

subject who left early, RTU wipe cluster 3, W39. Dr. Philpott stated that the change in participant 

numbers was difficult to follow, so perhaps in the future, participants can receive one number for 

the entire study. Dr. Testman responded that he would have to look at the study notes and would 

follow up through EPA. 

Dr. Northington Gamble noted that the HSRB had recommended that the recruitment 

flyer note that inhalation as well as dermal exposure would be measured, but there was no 

change in the flyer. Dr. Testman responded that he would have to follow up on that subject as 

well. Dr. Northington Gamble stated that the matter of stating what EPA would use the data for 

on the consent form also was not addressed and asked for information on this as well. 

Dr. Popendorf commented that the field notes contained notations such as ―+1‖ and ―+6‖ 

and asked what this referenced. Ms Boatwright answered that one of the observers used the 

notation to note how many times a subject performed an action. 

Dr. Philpott stated that in Ms. Sherman’s review, it is noted that an IRB-unapproved form 

was used to collect information about volunteers and also that volunteers signed a worker health 

statement that was not approved by the IRB. The report states that these forms have been stored 

separately from the field phase data. He asked for an explanation as to the purpose of the 

documents and why they had not been approved by the IRB. Dr. Testman responded that the 

initial cluster 1 was performed by an investigator who had developed his own forms and was

using those for the subjects without IRB approval. This was discovered by Dr. Selim, addressed 

with EPA, and that investigator was removed from the study. So the forms would not be 

intermingled with the main study data, they were added to a confidential safe file stored 

separately from other study data. Dr. Philpott asked if this was reported as a deviation to the IRB. 

Mr. Roogow (IIRB) answered that it had been reported. 
36

Dr. Philpott noted that a 46-year-old man reported he possessed 37 years of experience. 

Dr. Testman responded that there were these types of cases in the mop study as well. They are 

self-reported, and in one case, a subject volunteered that he had started working as a child for his 

parents’ business. 

Dr. Philpott invited Drs. Shah and Testman and Ms. Boatwright to make comments if 

they chose. Dr. Shaw emphasized to the HSRB that many lessons were learned from the mop 

study, but they could not be incorporated in the wipe study because these two studies were 

performed simultaneously. Many of these lessons, however, are now incorporated in the ongoing 

aerosol study, and lessons learned today will be incorporated into future studies, such as the 

upcoming study on pouring liquid. 

Public Comments

Dr. Philpott invited additional public comments on the AEATF II wipe study; none were 

received. 

Charge Questions

Ms. Sherman read the charge questions into the record:

1. Was the research reported in the AEATF II completed wipe study report faithful to the 

design and objectives of the protocol and governing documents of the AEATF II? 

2. Has EPA adequately characterized, from a scientific perspective, the limitations on 

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

those who clean indoor surfaces with antimicrobial pesticides using a trigger-spray 

bottle and wipes or ready-to-use wipes? 

3. Does available information support a determination that the study was conducted in 

substantial compliance with subparts K and L of 40 CFR part 26?

Board Science Review

Dr. Green noted that this was a somewhat complicated study to review. The Agency 

should be commended for an extensive job in responding to the comments of the HSRB and 

amending their results accordingly. He also believed the Agency responded well to the 

limitations of the study. He answered both of the science charge questions in the affirmative. 

Dr. Lebowitz complimented the Agency because he believed that the study benefited 

from the statistical analyses performed. Other statistical issues, such as not using the results on 

nonparametric bootstrapping examination, lack of sensitivity analysis to a large number of nondetects, and the differences in results between clusters, are questionable. The interpretation of the 

statistical results, especially the importance of slopes that were small and when the K-factor was 

greater than three also are questionable. He believed that inhalation is not related to AaiH, even 

though the Agency probably still will use the data. Further conclusions that results of the high 

AaiH are overestimates appear to be incorrect. High exposure results in the middle of the AaiH 
37

range have affected the slopes too much, and it could be concluded that the response is 

underestimated at the high end of the AaiH. His responses to the charge questions were yes to the 

first charge question and no to the second charge question. 

Dr. Johnson stated that he appreciated the fact that the Agency referred to geometric 

standard deviations and geometric means as characteristics of the data generated. He believed 

that the answer to both of the charge questions was yes. 

Dr. Philpott commented that the discussants thought that the answer to the first charge 

question is ―yes, the study is faithful to the design and objectives of the protocol and governing 

documents,‖ but there is still some question as to whether the limitations have been characterized 

adequately.

Dr. Young mentioned page 35, Figure 21 in the ICF International document. This appears 

to have a cluster of points in the left corner and another cluster in the upper right corner. The 

cluster in the left corner could be an artifact of the non-detects, which are probably driving the 

whole regression. If this cluster is covered, the figure looks like a scatter plot. She is not sure that 

there is evidence of a relationship. It may be that officials examine the hands-only analysis 

because there are no non-detects, so that it can be discovered how much the non-detects are 

influencing the analysis. Mr. Leighton clarified that her recommendation would be to return to 

those analyses and examine the non-detects. Dr. Young stated that the hand data should be 

examined because there are no non-detects and then non-detects could be marked to see how 

much they are driving the analysis. Additionally, what is referred to as an arithmetic mean is a 

model-based estimate of the mean. 

Dr. Popendorf stated that the target application rate was 7 mg per square meter (mg/m2) 

of treated surface as noted in the protocol. The data show that few people reached that target. 

Subjects worked as they normally did, which is another goal; perhaps the two goals are 

conflicting. He did not know how that affected achieving the first charge question. Dr. Philpott 

commented that the way the first charge question had been interpreted by the HSRB was by 

asking whether there were any gross deviations from the protocol that called into question the 

validity of the results. Dr. Popendorf stated that in light of this interpretation, his comment did 

not indicate a fatal flaw. He commented that the RTU and trigger spray data are internally 

consistent, but he is not sure that they are applicable to the per unit AaiH concept. He further 

observed that the combination of predominance of the hand exposure and the design of the wash 

recovery study might help explain why there is less than a linear correlation between AaiH and 

exposure. The areas treated and the doses in the two studies were similar; the only difference is 

in the amount used. That difference is an artifact of the study design, and it may not be 

significant in and of itself but will have an impact in the way the data are used. The amount of 

liquid in the trigger bottles was measured, and one would assume that the amount used was 

applied to the surfaces, was deposited on the worker, or stayed on the rag. In the RTU case, the 

number of wipes used was counted. The biggest contributor to the difference was the amount of 

ai that stayed on the rag or wipe. The amount used is not equal between the two. With the way 

the amount used is calculated, the resulting unit exposures may not be very useful. Mr. Leighton 

noted that if a wipe with 0.04 percent ai was used, x amount of hand exposure would occur, and 

if a product that was 10 times more concentrated was used, it would be assumed that more ai 
38

would be deposited on the hands. Dr. Popendorf noted that because the 7 mg/m2 was not 

achieved, there might be some extrapolation. 

Dr. Popendorf observed that data indicate that the trigger spray bottle users had an 

average of 92 percent of the total dose on their hands, and the RTU users had 98 percent. In this 

study, the lowest exposure time was 37 minutes, and the highest was 201 minutes. There is no 

information to indicate the effect of residence time. The fact that a fixed recovery factor is used 

for task durations that span a great deal of time means more exposure is being added to the long 

task performers. The dermal dose versus the duration of task is fairly linear. If dose 

measurements are examined as a function of task duration, they are spread out. If the rate of dose 

is examined, measurements show that a higher dose is seen at short duration, which would be 

exactly compatible with the pesticide recovery. A linear factor would predict a nonlinear 

correlation with Aai handling. The results are compatible with the limitation of how wash 

recovery is corrected for. Mr. Leighton noted that for DDAC, the dermal absorption is very low, 

less than 1 percent. Dr. Popendorf commented that the recovery study was not a problem, just a 

limitation. The implication is that there would be an exponential recovery, and the data show an 

exponential measure of deposition, so they are compatible. 

Dr. Fernandez recommended that the raw data used in the analyses be included in the 

report so that the statisticians can use the data and run the analyses themselves. 

Dr. Philpott stated that the consensus statement for the first charge question would be yes 

with the caveat that the target application rate of 7 mg/m2 was not achieved, and although this 

was not a fatal flaw, it does mean that perhaps one of the objectives was not met. Dr. Shah 

commented that even though 7 mg/m2 was the target, the maximum duration a subject can work 

was examined, and 210 minutes was the answer determined. Dr. Philpott stated that the target 

was something to be considered, and perhaps also in future study designs. The stated objective of 

amount of surface area to be covered was not achieved. Dr. Popendorf added that it could be 

mentioned that there was an unrecognized conflict with the other objective of letting subjects 

work as they normally would. 

Dr. Philpott noted, with respect to the second charge question, that although there was 

general consensus that the Agency has characterized the limitations on the data well, the Board 

noted a few additional limitations to consider, mainly: the fact that the large number of nondetects seem to be causing an anchoring effect in the analysis, and it might be beneficial to 

examine how these non-detects are driving the statistical analysis by examining the hand 

exposure; the observation to be careful in the comparison between the spray and the RTU wipes 

because although there is confidence that the AaiH in the spray was the AaiH on the surface, for 

the RTU wipes, some residue would remain on the wipe, and this was not quantified; and there 

was concern about the recovery factor as applied to the hand-wash studies, particularly because 

the effect of residence time in terms of recovery was not really addressed. 

Dr. Lebowitz will add in his report that the main concern about the interpretation of 

statistical results, and the over-reliance on small slopes raises real questions about the true 

relationship with the AaiH. 
39

Dr. Green raised the point that the term ―wipe study‖ was used for both trigger spray and 

wipe scenarios, which was unclear. Dr. Philpott noted that the HSRB and EPA will work to 

ensure that the charge questions are clearer next time. 

Board Ethics Review

Dr. Northington Gamble thanked Ms. Sherman for a very comprehensive report. She 

commented that on page 5, in discussion of demographics, the terms English and Spanish are 

used, and English-speaking and Spanish-speaking should be used instead. Additionally, it is 

mentioned in the report that this study was discussed at the October 2010 HSRB meeting. The 

use of subjects who were in fair health was discussed, and in the report, it was mentioned that in 

the future better specificity on health status should be used. Not mentioned in this report was 

another issue raised at the October 2010 meeting: the fact that reports of all research that undergo 

expedited IRB review should be submitted to the Agency. Dr. Northington Gamble noted that 

earlier in the meeting she had raised the issue of lack of response to HSRB comments about the 

consent form and the flyer, but this did not compromise the ethical content of the research; 

however, a follow-up with the sponsor is highly recommended. Ms. Sherman responded that EPA 

provides its review to the sponsor before the Board meeting, and the documents are not seen 

again. She assumed it was an oversight that inhalation monitoring was not included on the flyer. 

Dr. Northington Gamble noted that the subject who left early because he was not feeling well 

was a problem. If she knew more about what happened, she would feel more comfortable stating 

that this study met all of the ethical standards. 

Dr. Menikoff stated that he would be comfortable saying that the study was in substantial 

compliance with the standards. The study does not deal with experimental compounds, but one 

that is used by thousands every day. Appropriate medical personnel were on site, and at the 

worst, regarding the individual who left early, the nurse made an error in medical judgment. 

Information is missing on why this subject left, but that does not need to be answered to make 

the determination that ethical standards were met. Ms. Sherman commented that if the subject 

thought that he was ill as a result of participation in the study, she would hope that he would have 

gotten back in contact. Dr. Northington Gamble noted that it was unclear in the information logs. 

Dr. Philpott added that if a person came to the study and self-reported feeling ill, they should not 

be part of the study. 

Dr. Sharpe stated that substantial compliance probably has been met, but there is no harm 

in seeking additional information to obtain an answer to the question or to learn that the answer 

cannot be determined. Dr. Philpott noted that policies and procedures were in place for medical 

care, and the follow-up requirement is only for those who require emergency medical care. 

Perhaps the sponsors should adjust the SOP slightly to follow up on anyone who feels ill.

Dr. Philpott stated that the general consensus is that overall, there was substantial 

compliance with subparts K and L of 40 CFR part 26, but the sponsor is encouraged to determine 

what happened to the individual who left early and let the Agency and the IRB know. Dr. 

Northington Gamble added, independent of the charge question, that there should be policies in 

place to address a situation in which someone comes to the study and self-reports as ill. Ms. 

Sherman commented that the AEATF II had good procedures in place, and it generally followed 
40

the procedures. She agrees that there is not enough information in the log regarding the subject 

who left early, but she believed that the study was in substantial compliance. Dr. Philpott agreed 

that the Board’s consensus was that the study was conducted in substantial compliance with 

applicable standards. 

Preview of Upcoming Meetings

Ms. Sherman noted that there would be no June meeting of the HSRB. For the meeting in 

October, EPA expects to receive two new protocols from the AHETF and a protocol from the 

AEATF II on pouring liquids. A completed mosquito repellant study on No Mas repellant also 

may be ready for Board review because the research may be conducted this summer. 

Dr. Philpott thanked the Board for their hard work and participation and turned the 

meeting over to Mr. Downing. 

Adjournment 

Mr. Downing thanked the Board for a productive meeting and noted that the next meeting 

would be 2 or 3 days in length and held between October 18 and 22, 2011. He adjourned the 

meeting at 12:45 p.m.

Respectfully submitted:

Jim Downing

Designated Federal Officer

Human Studies Review Board

United States Environmental Protection Agency

Certified to be true by:

Sean Philpott, Ph.D., M.S. Bioethics 

Chair

Human Studies Review Board

United States Environmental Protection Agency
41

NOTE AND DISCLAIMER: The minutes of this public meeting reflect diverse ideas and 

suggestions offered by Board members during the course of deliberations within the meeting. 

Such ideas, suggestions and deliberations do not necessarily reflect definitive consensus advice 

from the Board members. The reader is cautioned to not rely on the minutes to represent final, 

approved, consensus advice and recommendations offered to the Agency. Such advice and 

recommendations may be found in the final report prepared and transmitted to the EPA Science 

Advisor following the public meeting.
42

Attachments 

Attachment A HSRB Members

Attachment B Federal Register Notice Announcing Meeting 

Attachment C Meeting Agenda 
43

Attachment A

EPA HUMAN STUDIES REVIEW BOARD MEMBERS

Chair

*Sean Philpott, Ph.D., M.S. Bioethics Term: 3/27/2006–10/31/2011

Director, Research Ethics

The Bioethics Program

Union Graduate College–Mt. Sinai School of Medicine

Schenectady, NY

Vice Chair

*Janice Chambers, Ph.D., D.A.B.T. Term: 3/27/2006–10/31/2011

William L. Giles Distinguished Professor

Director, Center for Environmental Health Sciences

College of Veterinary Medicine 

Mississippi State University 

Mississippi State, MS 

Members

*George C.J. Fernandez, Ph.D. Term: 5/1/2010–8/31/2013

Director, Center for Research Design and Analysis 

University of Nevada–Reno

Reno, NV

*Vanessa Northington Gamble, M.D., Ph.D. Term: 10/19/2009–10/31/2012

University Professor of Medical Humanities and

Professor of History

Gelman Library

The George Washington University

Washington, DC

*Sidney Green, Jr., Ph.D., Fellow ATS Term: 10/19/2009–10/31/2012

Department of Pharmacology

Howard University College of Medicine

Howard University

Washington, DC

*Dallas E. Johnson, Ph.D. Term: 8/31/2007–8/31/2013

Professor Emeritus

Department of Statistics

Kansas State University

Manhattan, KS
44

*Michael D. Lebowitz, Ph.D., FCCP Term: 3/27/2006–8/31/2012

Retired Professor of Public Health

(Epidemiology) & Medicine & Research Professor of Medicine

University of Arizona

Tucson, AZ

*José E. Manautou, Ph.D. Term: 5/1/2010–8/31/2013

Associate Professor of Toxicology 

Department of Pharmaceutical Sciences

School of Pharmacy

University of Connecticut

Storrs, CT

Jerry A. Menikoff, M.D. Term: 3/27/2006–8/31/2012

Director, Office for Human Research Protections

Department of Health and Human Services 

Rockville, MD 

*^Rebecca T. Parkin, Ph.D., M.P.H. Term: 10/1/2007–8/31/2013

Associate Dean for Research and Public Health Practice

School of Public Health and Health Services

The George Washington University

Washington, DC

*William J. Popendorf, Ph.D. Term: 10/19/2009–10/31/2012

Professor

Department of Biology

Utah State University

Logan, UT

Virginia Ashby Sharpe, Ph.D. Term: 5/1/2010–8/31/2013

National Center for Ethics in Health Care

Veterans Health Administration

Department of Veterans Affairs 

Washington, DC

*Linda J. Young, Ph.D. Term: 3/28/2008–8/31/2012

Department of Statistics

Institute of Food and Agricultural Sciences

University of Florida

Gainesville, FL 

*Special Government Employee (SGE)

^Not in attendance on April 13-14, 2011
45

Attachment B

Federal Register Notice Announcing Meeting

[Federal Register Volume 76, Number 59 (Monday, March 28, 2011)]

[Notices]

[Pages 17121-17123]

From the Federal Register Online via the Government Printing Office [www.gpo.gov]

[FR Doc No: 2011-7198]

---------------------------------------------------------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-ORD-2011-0124; FRL-9287-1]

Human Studies Review Board (HSRB); Notification of a Public Meeting

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

---------------------------------------------------------------------------------------------------------------------

SUMMARY: The U.S. Environmental Protection Agency (EPA) Office of the Science Advisor 

(OSA) announces a public meeting of the HSRB to advise the Agency on EPA’s scientific and 

ethical reviews of research with human subjects.

DATES: This public meeting will be held on April 13-14, 2011, from approximately 8:30 a.m. to 

approximately 5 p.m. Eastern Time.

ADDRESSES: Submit your written comments, identified by Docket ID No. EPA-HQ-ORD2011-0124, by one of the following methods:

 Internet: http://www.regulations.gov: Follow the on-line instructions for submitting comments.

 E-mail: ORD.Docket@epa.gov.

 Mail: Environmental Protection Agency, EPA Docket Center (EPA/DC), ORD Docket, 

Mailcode: 28221T, 1200 Pennsylvania Avenue NW., Washington, DC 20460.

 Hand Delivery: The EPA/DC Public Reading Room is located in the EPA Headquarters 

Library, Room Number 3334 in the EPA West Building, located at 1301 Constitution Avenue 

NW., Washington, DC 20460. The hours of operation are 8:30 a.m. to 4:30 p.m. Eastern Time, 

Monday through Friday, excluding Federal holidays. Please call (202) 566-1744 or e-mail the 

ORD Docket at ord.docket@epa.gov for instructions. Updates to Public Reading Room access 

are available on the Web site (http://www.epa.gov/epahome/dockets.htm).

 Instructions: Direct your comments to Docket ID No. EPA-HQ-ORD-2011-0124. EPA's policy 

is that all comments received will be included in the public docket without change and may be 
46

made available online at http://www.regulations.gov, including any personal information 

provided, unless the comment includes information claimed to be Confidential Business 

Information (CBI) or other information the disclosure of which is restricted by statute. Do not 

submit information that you consider to be CBI or otherwise protected through 

http://www.regulations.gov or e-mail. The http://www.regulations.gov Web site is an 

―anonymous access‖ system, which means EPA will not know your identity or contact 

information unless you provide it in the body of your comment. If you send an e-mail comment 

directly to EPA without going through http://www.regulations.gov, your e-mail address will be 

automatically captured and included as part of the comment that is placed in the public docket 

and made available on the Internet. If you submit an electronic comment, EPA recommends that 

you include your name and other contact information in the body of your comment and with any 

disk or CD-ROM you submit. If EPA cannot read your comment due to

[[Page 17122]]

technical difficulties and cannot contact you for clarification, EPA may not be able to consider 

your comment. Electronic files should avoid the use of special characters, any form of 

encryption, and be free of any defects or viruses.

FOR FURTHER INFORMATION CONTACT: Any member of the public who wishes to 

receive further information should contact Jim Downing at telephone number: (202) 564-2468; 

fax: (202) 564-2070; e-mail address: downing.jim@epa.gov, or Lu-Ann Kleibacker at telephone 

number: (202) 564-7189; fax: 202-564-2070; e-mail address: kleibacker.lu-ann@epa.gov; 

mailing address: Environmental Protection Agency, Office of the Science Advisor (8105R), 1200 

Pennsylvania Avenue NW., Washington, DC 20460. General information concerning the EPA 

HSRB can be found on the EPA Web site at http://www.epa.gov/osa/hsrb/.

SUPPLEMENTARY INFORMATION:

 Location: Holiday Inn National Airport, 2650 Jefferson Davis Highway, Arlington, VA 22202.

 Meeting access: Seating at the meeting will be on a first-come basis. To request 

accommodation of a disability, please contact the persons listed under FOR FURTHER 

INFORMATION CONTACT at least ten business days prior to the meeting using the 

information under FOR FURTHER INFORMATION CONTACT, so that appropriate 

arrangements can be made.

 Procedures for providing public input: Interested members of the public may submit relevant 

written or oral comments for the HSRB to consider during the advisory process. Additional 

information concerning submission of relevant written or oral comments is provided in section I. 

―Public Meeting,‖ under subsection D. ―How May I Participate in this Meeting?‖ of this notice.

I. Public Meeting

A. Does this action apply to me?

 This action is directed to the public in general. This action may, however, be of particular 

interest to persons who conduct or assess human studies, especially studies on substances 

regulated by EPA, or to persons who are, or may be required to conduct testing of chemical 
47

substances under the Federal Food, Drug, and Cosmetic Act (FFDCA) or the Federal Insecticide, 

Fungicide, and Rodenticide Act (FIFRA). Since other entities may also be interested, the Agency 

has not attempted to describe all the specific entities that may be affected by this action. If you 

have any questions regarding the applicability of this action to a particular entity, consult Jim 

Downing or Lu-Ann Kleibacker listed under FOR FURTHER INFORMATION CONTACT.

B. How can I access electronic copies of this document and other related information?

 In addition to using regulations.gov, you may access this Federal Register document 

electronically through the EPA Internet under the Federal Register listings at 

http://www.epa.gov/fedrgstr/.

 Docket: All documents in the docket are listed in the http://www.regulations.gov index. 

Although listed in the index, some information is not publicly available, e.g., CBI or other 

information whose disclosure is restricted by statute. Certain other material, such as copyrighted 

material, will be publicly available only in hard copy. Publicly available docket materials are 

available either electronically in http://www.regulations.gov or in hard copy at the ORD Docket, 

EPA/DC, Public Reading Room. The EPA/DC Public Reading Room is located in the EPA 

Headquarters Library, Room Number 3334 in the EPA West Building, located at 1301 

Constitution Avenue NW., Washington, DC 20460. The hours of operation are 8:30 a.m. to 4:30 

p.m. Eastern Time, Monday through Friday, excluding Federal holidays. Please call (202) 566-

1744 or e-mail the ORD Docket at ord.docket@epa.gov for instructions. Updates to Public 

Reading Room access are available on the Web site (http://www.epa.gov/epahome/dockets.htm). 

EPA's position paper(s), charge/questions to the HSRB, and the meeting agenda will be available 

by the end of March 2011. In addition, the Agency may provide additional background 

documents as the materials become available. You may obtain electronic copies of these 

documents, and certain other related documents that might be available electronically, from the 

Building, located at 1301 Constitution Avenue NW., Washington, DC 20460. The hours of 

operation are 8:30 a.m. to 4:30 p.m. Eastern Time, Monday through Friday, excluding Federal 

holidays. Please call (202) 566-1744 or e-mail the ORD Docket at ord.docket@epa.gov for 

instructions. Updates to Public Reading Room access are available on the Web site 

(http://www.epa.gov/epahome/dockets.htm). EPA's position paper(s), charge/questions to the 

HSRB, and the meeting agenda will be available by the end of March 2011. In addition, the 

Agency may provide additional background documents as the materials become available. You 

may obtain electronic copies of these documents, and certain other related documents that might 

be available electronically, from the regulations.gov Web site and the EPA HSRB Web site at 

http://www.epa.gov/osa/hsrb/. For questions on document availability, or if you do not have 

access to the Internet, consult either Jim Downing or Lu-Ann Kleibacker listed under FOR 

FURTHER INFORMATION CONTACT.

C. What should I consider as I prepare my comments for EPA?

 You may find the following suggestions helpful for preparing your comments:

 1. Explain your views as clearly as possible.

 2. Describe any assumptions that you used.

 3. Provide copies of any technical information and/or data that you used to support your 

views.
48

 4. Provide specific examples to illustrate your concerns and suggest alternatives.

 5. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this 

action in the subject line on the first page of your response. You may also provide the name, date, 

and Federal Register citation.

D. How may I participate in this meeting?

 You may participate in this meeting by following the instructions in this section. To ensure 

proper receipt by EPA, it is imperative that you identify docket ID number EPA-HQ-ORD-2011-

0124 in the subject line on the first page of your request.

 1. Oral comments. Requests to present oral comments will be accepted up to Wednesday, April 

6, 2011. To the extent that time permits, interested persons who have not pre-registered may be 

permitted by the Chair of the HSRB to present oral comments at the meeting. Each individual or 

group wishing to make brief oral comments to the HSRB is strongly advised to submit their 

request (preferably via email) to Jim Downing or Lu-Ann Kleibacker, under FOR FURTHER 

INFORMATION CONTACT, no later than noon, Eastern Time, Wednesday, April 6, 2011, in 

order to be included on the meeting agenda and to provide sufficient time for the HSRB Chair 

and HSRB Designated Federal Official (DFO) to review the meeting agenda to provide an 

appropriate public comment period. The request should identify the name of the individual 

making the presentation and the organization (if any) the individual will represent. Oral 

comments before the HSRB are generally limited to five minutes per individual or organization. 

Please note that this includes all individuals appearing either as part of, or on behalf of, an 

organization. While it is our intent to hear a full range of oral comments on the science and ethics 

issues under discussion, it is not our intent to permit organizations to expand the time limitations 

by having numerous individuals sign up separately to speak on their behalf. If additional time is 

available, further public comments may be possible.

 2. Written comments. Submit your written comments prior to the meeting. For the HSRB to 

have the best opportunity to review and consider your comments as it deliberates on its report, 

you should submit your comments at least five business days prior to the beginning of this 

meeting. If you submit

[[Page 17123]]

comments after this date, those comments will be provided to the Board members, but you 

should recognize that the Board members may not have adequate time to consider those 

comments prior to making a decision. Thus, if you plan to submit written comments, the Agency 

strongly encourages you to submit such comments no later than noon, Eastern Time, Wednesday, 

April 6, 2011. You should submit your comments using the instructions in section I., under 

subsection C., ―What Should I Consider as I Prepare My Comments for EPA?‖ In addition, the 

Agency also requests that persons submitting comments directly to the docket also provide a 

copy of their comments to Jim Downing or Lu-Ann Kleibacker listed under FOR FURTHER 

INFORMATION CONTACT. There is no limit on the length of written comments for 

consideration by the HSRB.
49

E. Background

 The HSRB is a Federal advisory committee operating in accordance with the Federal Advisory 

Committee Act (FACA) 5 U.S.C. App.2 Sec. 9. The HSRB provides advice, information, and 

recommendations to EPA on issues related to scientific and ethical aspects of human subjects 

research. The major objectives of the HSRB are to provide advice and recommendations on: (1) 

Research proposals and protocols; (2) reports of completed research with human subjects; and 

(3) how to strengthen EPA's programs for protection of human subjects of research. The HSRB 

reports to the EPA Administrator through EPA's Science Advisor.

 1. Topics for discussion. At its meeting on April 13 and 14, 2011, EPA's Human Studies 

Review Board will consider scientific and ethical issues surrounding these topics:

 a. The report of a completed scenario monograph and study reports from the Agricultural 

Handler Exposure Task Force (AHETF) measuring the dermal and inhalation exposure of 

professional agricultural workers applying liquid spray pesticides to tree or trellis crops using 

open cab airblast equipment.

 b. The report of a completed scenario monograph and study report from the Antimicrobial 

Exposure Assessment Task Force II (AEATF II) in which the dermal and inhalation exposure of 

professional janitorial workers was monitored as they applied a liquid antimicrobial product to 

indoor surfaces using a trigger spray bottle and wipes or ready-to-use wipes.

 c. A published report by Gulson et al (2010) of an intentional exposure human study 

measuring dermal absorption of zinc oxides contained in sunscreen.

 d. A reevaluation of an intentional human dosing study with chlorpyrifos (Kisicki) previously 

reviewed by the HSRB; pertinent new information from the sponsor has been made available.

 2. Meeting minutes and reports. Minutes of the meeting, summarizing the matters discussed 

and recommendations, if any, made by the advisory committee regarding such matters, will be 

released within 90 calendar days of the meeting. Such minutes will be available at 

http://www.epa.gov/osa/hsrb/ and http://www.regulations.gov. In addition, information 

concerning a Board meeting report, if applicable, can be found at http://www.epa.gov/osa/hsrb/

or from the person listed under FOR FURTHER INFORMATION CONTACT.

 Dated: March 23, 2011.

Paul T. Anastas,

EPA Science Advisor.

[FR Doc. 2011-7198 Filed 3-25-11; 8:45 am]

BILLING CODE 6560-50-P
50

Attachment C

U.S. ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD

APRIL 2011 PUBLIC MEETING AGENDA

Holiday Inn National Airport

2650 Jefferson Davis Highway

Arlington, VA 22202 

HSRB WEB SITE: http://www.epa.gov/osa/hsrb/

Docket Telephone: (202) 566-1752

Docket Number: EPA-HQ-ORD-2011-0124

Wednesday, April 13, 2011

9:00 AM* Convene Public Meeting and Review Administrative Procedures – Mr. Jim 

Downing (Designated Federal Officer [DFO], Human Studies Review Board 

[HSRB], Office of the Science Advisor [OSA], EPA)

Introduction and Identification of Board Members – Sean Philpott, Ph.D. (HSRB 

Chair)

Welcome – Warren Lux, M.D. (Director of the Program in Human Research 

Ethics, OSA, EPA)

Opening Remarks – Steven Bradbury, Ph.D. (Director, Office of Pesticide Programs 

(OPP), Office of Chemical Safety and Pollution Prevention, EPA) 

Office of Pesticide Programs Follow-up on Previous HSRB Recommendations – Ms. 

Kelly Sherman (OPP, EPA)

Session 1: Completed AHETF research on exposure of workers applying pesticide sprays 

using open-cab airblast equipment

9:30 AM EPA Science and Ethics Reviews – Mr. Matthew Crowley (OPP, EPA) and 

Ms. Kelly Sherman (OPP, EPA) 

10:30 AM Board Questions of Clarification – Sean Philpott, Ph.D. (HSRB Chair)

11:00 AM Public Comments 

11:15 AM Break

11:30 AM Board Discussion – Science

Charge to the Board:

Was the research reported in the Agricultural Handler Exposure Task Force (AHETF) 

completed monograph report and associated field study reports faithful to the design and 

objectives of the protocol, SOPs, and governing documents?

Has EPA adequately characterized, from a scientific perspective, the limitations on these 

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

apply pesticides with open cab airblast equipment?
51

12:15 PM Board Discussion – Ethics

Charge to the Board:

Does available information support a determination that the studies were conducted in 

substantial compliance with subparts K and L of 40 CFR part 26?

12:45 PM Lunch

Session 2: A published report (Gulson et al. 2010) of an intentional exposure human study 

measuring dermal absorption of zinc oxides contained in sunscreens

1:30 PM EPA Science and Ethics Reviews – Jessica Ryman, Ph.D. (OPP, EPA) and 

Ms. Laura Parsons (OPP, EPA) 

2:15 PM Board Questions of Clarification – Sean Philpott, Ph.D. (HSRB Chair)

2:45 PM Public Comments

3:00 PM Board Discussion – Science

Charge to the Board:

Is the Gulson et al. (2010) study scientifically sound, providing reliable data? 

If so, is the Gulson et al. (2010) study relevant for qualitative use in support of an 

assessment of the absorption of zinc oxide through the skin?

3:45 PM Break

4:00 PM Board Discussion – Ethics

Charge to the Board:

Is there adequate information to determine that the Gulson et al. (2010) study was 

conducted in substantial compliance with procedures at least as protective as those in 

subparts A - L of EPA’s regulation at 40 CFR part 26?

Session 3: Reconsideration of two concerns previously raised by the HSRB in its June 2009 

review of an intentional human dosing study with chlorpyrifos (Kisicki et al., 

1999); additional pertinent information was made available by the sponsor related 

to these two concerns

4:30 PM Introduction of Topic – Sean Philpott, Ph.D. (HSRB Chair)

4:45 PM Board Discussion – Science

Issues for Discussion:

Do the recommendations provided by the HSRB at its June 2009 meeting and in its 

subsequent report regarding the reliability of data on the urinary metabolite 

trichloropyridinol in the Kisicki et al. (1999) study change in light of the new information

provided?
52

Do the recommendations provided by the HSRB at its June 2009 meeting and in its 

subsequent report regarding the level of absorption of chlorpyrifos in the Kisicki et al. 

(1999) study change in light of the new information provided?

5:30 PM Adjournment
53

U.S. ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD

APRIL 2011 PUBLIC MEETING AGENDA

Holiday Inn National Airport

2650 Jefferson Davis Highway

Arlington, VA 22202 

HSRB WEB SITE: http://www.epa.gov/osa/hsrb/

Docket Telephone: (202) 566-1752

Docket Number: EPA-HQ-ORD-2011-0124

Thursday, April 14, 2011

10:00 AM* Convene Public Meeting – Mr. Jim Downing (DFO, HSRB, OSA, EPA) 

Introduction and Identification of Members – Sean Philpott, Ph.D. (HSRB Chair)

Follow-up from Previous Day – Ms. Kelly Sherman (OPP, EPA)

Session 1: Completed AEATF II research on exposure of professional janitorial workers when 

wiping indoor surfaces with an antimicrobial pesticide

10:15 AM EPA Science and Ethics Reviews – Mr. Timothy Leighton (OPP, EPA) and 

Ms. Kelly Sherman (OPP, EPA) 

11:00 AM Board Questions of Clarification – Sean Philpott, Ph.D. (HSRB Chair), EPA, 

Principal Investigator/Sponsor

11:30 AM Public Comments

11:45 AM Board Discussion – Science

Charge to the Board:

Was the research reported in the Antimicrobial Exposure Assessment Task Force II 

(AEATF II) completed wipe study report faithful to the design and objectives of the 

protocol and governing documents of AEATF II?

Has EPA adequately characterized, from a scientific perspective, the limitations on these 

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

clean indoor surfaces with antimicrobial pesticides using a trigger-bottle and wipes or 

ready-wipes?

12:30 PM Board Discussion – Ethics

Charge to the Board:

Is the research likely to meet the applicable requirements of 40 CFR part 26, subparts K 

and L?

1:00 PM Preview of Upcoming Meetings – Ms. Kelly Sherman (OPP, EPA)

1:10 PM Adjournment