Document ID: EPA-HQ-ORD-2007-0216-0018
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-09T04:00Z

May 7, 2007 

Minutes of the 

United States Environmental Protection Agency (EPA) 

Human Studies Review Board (HSRB) 

April 18-20, 2007 Public Meeting

Docket Number: EPA-HQ-ORD-2007-0216

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

Committee Members:	(See HSRB Members list – Attachment A) 

Dates and Times:  	Wednesday, April 18, 2007, 10:00 AM – 5:30 PM

			Thursday, April 19, 2007, 8:30 AM – 5:30 PM

			Friday, April 20, 2007, 8:30 AM – 5:30 PM 

(See Federal Register Notice – Attachment B) 

Location: 	Environmental Protection Agency, One Potomac Yard (South
Bldg.), 2777 S. Crystal Drive, Arlington, VA  22202

Purpose: 	The EPA Human Studies Review Board (HSRB) provides advice,
information, and recommendations on issues related to the scientific and
ethical aspects of human subjects research. 

Attendees: 	Chair: 			Celia B. Fisher, Ph.D. 

	

	Vice Chair:		William S. Brimijoin, Ph.D.

Board Members: 	Alicia Carriquiry, Ph.D. 

Gary L. Chadwick, PharmD, MPH, CIP 

Janice Chambers, Ph.D., D.A.B.T. 

Richard Fenske, Ph.D., MPH

Susan S. Fish, PharmD, MPH

Suzanne C. Fitzpatrick, Ph.D., D.A.B.T. 

KyungMann Kim, Ph.D., CCRP

Kannan Krishnan, Ph.D. 

Michael D. Lebowitz, Ph.D., FCCP

Lois D. Lehman-Mckeeman, Ph.D. 

Jerry A. Menikoff, M.D.

Sean M. Philpott, Ph.D.

Richard Sharp, Ph.D.

Meeting Summary:	Meeting discussions generally followed the issues and
general timing as presented in the meeting Agenda (Attachment C), unless
noted otherwise in these minutes. 

Introduction and Identification of Board Members

Dr. Celia Fisher (HSRB Chair) welcomed Board members, U.S. Environmental
Protection Agency (EPA or Agency) staff, and members of the public to
the April 2007 HSRB meeting.  She thanked Board members for their
participation and called for introductions.  Dr. Fisher acknowledged the
efforts of Dr. Paul Lewis (Designated Federal Officer [DFO], HSRB,
Office of the Science Advisor [OSA], EPA) and members of EPA’s Office
of Pesticide Programs (OPP) in planning and preparing for this meeting.

Welcoming Remarks 

Dr. Warren Lux (Human Subjects Research Review Official, OSA, EPA)
welcomed and thanked the Board on behalf of Dr. George Gray (Science
Advisor, EPA) and Dr. William H. Benson (Acting Chief Scientist, OSA.
EPA).  He commented that the last HSRB meeting represented the
culmination of a complete review cycle from submission of a protocol to
completion and use of the data in policies established by EPA.

Another Board activity of importance is education.  Regulatory matters
and protocol reviews are necessary to protect human subjects; however,
educational efforts also are needed to ensure appropriate protection. 
Dr. Lux expressed appreciation for the Board’s efforts and requests
for education about matters pertinent to EPA and commended the Board’s
work to ensure its deliberations educate others, including OPP
personnel, third party sponsors, investigators, and interested members
of the public.  He especially wished to highlight the impact of the
Board’s efforts on investigators, because fully educated, informed
investigators will assure appropriate human subject protection.  

Dr. Fisher thanked Dr. Lux for his comments and added that the Board
will continue to learn from Dr. Lux.  The Board expects input from EPA
staff to contribute to the consistency of its review of sponsors and EPA
in-house reviews, and may suggest ways to facilitate this exchange of
information in the future.

Mr. Jim Jones (Principal Deputy Assistant Administrator, Office of
Prevention, Pesticides, and Toxic Substances, EPA) welcomed Board
members to Washington, DC.  He stated that OPP continues to find Board
advice helpful to gain EPA acceptance of study results and improve the
quality of its feedback to investigators.  The Agency implemented new
rules for human subject studies in February 2006.  At that time, there
were controversies and doubts about whether the new rules would still
permit EPA to meet its deadlines and work within the statutory
framework.  The HSRB developed a framework for review, provided EPA with
sound advice, helped to settle controversies, and helped EPA adapt to
these changes.  Stakeholders are adjusting to the new rules and OPP is
meeting critical statutory deadlines.  Together, EPA and the HSRB have
made significant progress in ensuring that human subjects are protected.
 He introduced Dr. Debbie Edwards as the new Director of OPP.

Dr. Edwards described her previous work as Director of the Special
Review and Re-registration Division within OPP.  She commented that the
Board’s high-quality reviews have allowed OPP to be successful.  She
provided a brief overview of the meeting agenda, explaining that the
focus of the first day of the meeting would be devoted to a review of
recently conducted tick and mosquito repellency studies to support
regulatory decisions.  On April 19, 2007, the Board will discuss two
previously performed skin test studies that will raise new scientific
and ethical questions, as well as EPA’s framework for developing best
practices for subject recruitment for occupational exposure research. 
On April 20, 2007, the Board will discuss follow-up on the Agricultural
Handlers Exposure Task Force (AHETF) and Antimicrobial Exposure
Assessment Task Force (AEATF) protocols and will review a summary of the
EPA Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
Scientific Advisory Panel (SAP) January 2007 report “Worker Exposure
Methods.”  OPP also will present a draft framework for recruiting
subjects and ethical considerations for occupational exposure studies.  

Meeting Administrative Procedures

Dr. Lewis welcomed Board members and thanked them for their work.  He
welcomed members of the public and his EPA colleagues.  As DFO, Dr.
Lewis serves as liaison between the HSRB and EPA and ensures that
Federal Advisory Committee Act (FACA) requirements—open meetings,
timely meeting announcements in the Federal Register, and meeting
materials made available at a public docket—are met.  As DFO, he also
works with the appropriate officials to ensure that all applicable
ethics regulations are satisfied.  Each Board member has filed a
standard government financial disclosure form that has been reviewed by
Dr. Lewis and the Office of the Science Advisor Deputy Ethics Officer
in consultation with EPA’s Office of General Counsel (OGC) to ensure
that all ethics disclosure requirements have been met.  Dr. Lewis
reminded participants that meeting times would be approximate and that
public comments would be limited to five minutes. 

Dr. Fisher thanked OPP members for their remarks and commended their
responsiveness to questions and requests from the Board for documents
and information.  She added that she was pleased to see the Board’s
recommendations incorporated into OPP analyses.

Dr. Fisher reviewed the meeting agenda.  For the last few meetings, the
Board has asked OPP to provide critiques of studies rather than
summaries.  Concerning discussion of the FIFRA SAP report, scheduled for
April 20, 2007, the Board requested this discussion because of questions
that arose during review of the handler protocol concerning why these
studies were necessary.  

Meeting Process

Dr. Fisher reviewed the process for meeting operations, HSRB
responsibilities, the HSRB Charter, Board process, and major objectives.
 She stated that the Board seeks to clarify and develop criteria to
evaluate the science and ethics of different types of completed research
and protocols, allowing for fairness and consistency.  A useful set of
criteria for assessing scientific validity has been developed for
sponsors and investigators providing protocols for review.  These
provide guidance for study design and materials needed for Board review
of protocols.  The Board assesses both the scientific and ethical
validity of a protocol, including procedures, dose selection, endpoint
selection, social value of the research, methods including statistical
analyses, selection of target populations, and derivation of sample
sizes.  In its ethics assessments, the Board considers both societal
benefit and participant risks.  It has worked to define prevalent
ethical standards and to develop additional ethics criteria.

EPA Follow-up on HSRB Recommendations 

Mr. William Jordan (OPP, EPA) reviewed EPA follow-up on HSRB
recommendations for the completed IR3535 insect repellent efficacy
studies with lotion and pump spray formulations, EMD-003.1 and 003.2
(laboratory tick repellency) and EMD-004.1 and 004.2 (field mosquito
repellency).  EPA follow-up on the field mosquito repellent efficacy
protocol SCI-001 was also discussed.

Concerning the HSRB’s scientific recommendations for the completed
studies EMD-003.1 and 003.2 and EMD-004.1 and 004.2, the HSRB concluded
that the studies were scientifically sound and suggested alternative
statistical techniques for evaluating duration of efficacy.  The Board
also suggested that EPA consider the most appropriate way to conduct
dosimetry studies to determine typical consumer dose.  Based on these
recommendations, EPA will accept the IR3535 insect repellent efficacy
studies as adequate for the assessment of efficacy and will accept label
claims.

EPA continues to discuss the best statistical approaches for analyzing
data and determining duration of protection.  A challenge to this effort
is the existence of similar products on the consumer market that have
Complete Protection Times (CPTs) that were determined differently in
past studies.  EPA is considering the best ways to implement the
Board’s suggestions and manage the transition to new methods of
determining CPT.  Once EPA has developed an approach to implement new
statistical analysis methods, it will present the plan to the HSRB for
feedback.  EPA also plans to revise its draft repellent efficacy
guidelines to include discussion of methods for establishing doses,
based on typical consumer use.

Concerning ethics recommendations, HSRB concurred with EPA that these
studies met the applicable requirements of 40 Code of Federal Regulation
(CFR) 26, subparts K and L.  The Board noted some ethical deficiencies
and suggested that EPA recommend human research protection training for
investigators.  Based on this review, EPA will accept the IR3535
repellency studies.  Although EPA cannot require investigators to
complete human research protection training, it will informally
encourage such training.

HSRB also reviewed SCI-001 at the January 24, 2007, meeting and found
that the recommendations suggested by EPA and the Board were followed,
and that this protocol was likely to generate scientifically valid data
to assess the efficacy of the test products and to meet applicable
ethics requirements.  EPA agreed with the Board’s assessment, but has
not yet received a revised version of SCI-001 or the results of a
completed study conducted under this protocol.

	

Completed Repellent Efficacy Studies EMD-003.3 and EMD-004.3

Introduction

Mr. John Carley (OPP, EPA) provided background and context for insect
repellent efficacy studies EMD-003.3 and EMD-004.3.  These studies
tested the aerosol formulations of the IR3535 repellents tested as pump
spray and lotion.  Testing on the aerosol formulation was delayed
because of a manufacturing error.  EMD-003.3 tests repellency against
ticks in a laboratory setting.  EMD-004.3 tests repellency against
mosquitoes in two field settings.  Dosimetry testing for these
formulations was performed on October 25-26, 2006, in conjunction with
dosimetry testing for the other formulations.  The report relating the
results of EMD-003.4 and EMD-004.3 was submitted in December 2006, but
was not provided to the HSRB for discussion at the January 2007 meeting.
 These studies, which represent third-party research involving
intentional exposure of human subjects, were initiated after April 7,
2006, and were intended for submission to EPA under the pesticide laws. 
Pre-review of the protocols and supporting materials by EPA and the HSRB
is required, as well as “substantial compliance” with 40 CFR 26
subparts K and L.

The execution and results of these protocols for the lotion and pump
spray formulations were the first completed studies reporting work under
post-rule protocols to be reviewed by the HSRB, and were reviewed
favorably at the January 24, 2007 meeting.  The HSRB review of both
protocols EMD-003.3 and 004.3 took place on October 19, 2006.  Subject
limb measurement and dosimetry testing of all three formulations
occurred between October 23 and November 1, 2006.  Revisions to the
protocols and informed consent forms (ICFs) were submitted to the
Independent Investigational Review Board (IIRB) on October 30, 2006, and
IIRB approval of final changes was granted on November 1, 2006.  Field
testing for protocol EMD-004.3 in Merced County, California,
(marsh/grassland) took place on November 15, 2006, and field testing in
Butte County, California, (forest/flooded marsh) occurred on
November 19, 2006.  Laboratory testing for EMD-003.3 took place on
November 18, 2006.  A final audit by the quality assurance (QA) unit was
performed on November 10, 2006, and final study reports for both
protocols were submitted on February 5, 2007.  The dosimetry phase of
these studies used the ICF changed by Dr. Scott Carroll (Carroll-Loye
Biological Research, Inc.); the efficacy phase used the final November
1, 2006 ICF.

The dosimetry phase involved 12 subjects.  Each subject’s limb surface
areas were calculated, subjects practiced application for “full
coverage,” four gauze “bracelet” dosimeters were placed on the
limbs, and the weight change in dosimeters after application was
measured.  The subject mean of three trials was determined and then the
grand mean of all 12 subject means was calculated.  Based on limb
surface area, the standard dose (gram per square centimeter [g/cm2]) was
converted to a volumetric standard dose (milliliter per square
centimeter [ml/cm2]) and scaled for each subject in the efficacy phase.

EMD-003.3, which tested tick repellency, involved 10 subjects in a
laboratory setting.  After application of a standard volumetric dose by
syringe to the arm, both arms were marked at the edge of the untreated
area and at the 3 centimeter (cm) mark on each side of the area.  New
ticks were placed near the wrist of the untreated arm and observed for
questing behavior.  Questing ticks then were placed at the lowest mark
of the treated arm and ticks crossing 3 cm or more into the treated area
were scored as “crossing.”  A fresh tick was applied every 15
minutes.  Time of efficacy failure was defined as the time of the first
of two crossings occurring within 30 minutes.

EMD-004.3, which tested mosquito repellency, involved 10 treated
subjects at each of two field sites.  Two untreated subjects were
present at each site to confirm mosquito biting pressure at the site.  A
standard volumetric dose scaled to the area of the subjects’ lower
legs was applied by syringe before traveling to the test site.  The
subjects wore Tyvek suits, head nets, and gloves and worked in pairs to
expose treated legs by rolling up their pants for 1 minute every
15 minutes.  The subjects watched for landings with intent to bite
(LIBes), and removed these mosquitoes with aspirators.  Landing
mosquitoes were reported to technicians and recorded.  Treated limbs
were re-covered with the Tyvek suit at the end of each 1-minute exposure
period.  Time of efficacy failure (time to first confirmed LIBe
[FCLIBe]) was defined as time post-treatment of the first of two LIBes
occurring within 30 minutes.

Scientific Considerations

Dr. Clara Fuentes (OPP, EPA) presented the science assessments for
EMD-003.3 and EMD-004.3.  These studies were executed in a manner
consistent with the revised protocols, with minor exceptions.  The study
designs produced scientifically sound data meeting the studies’
objectives to estimate typical consumer doses and quantify the duration
of repellency of the formulations tested against ticks and mosquitoes.  

Deviations from the dosimetry phase of the protocol included a reduction
in the number of pre-test practice applications from three to one; there
were no data to suggest how this might have affected the dosimetry
phase.  Entry errors were not properly handled in all cases, but there
was no obvious ambiguity in the records and the data quality does not
appear to have been compromised.  The dosimetry data capture forms were
modified from those appended to the protocol, but the modification did
not compromise data quality.  The dosimeters were not backed with
impermeable layers but appeared to be sufficiently impermeable to the
test material without backing.  The aerosol spray dosimeter results were
not compared to those for the lotion and pump formulations, but these
comparisons were not required to determine typical consumer dose for
efficacy testing.  

Half the subjects in EMD-003.3 withdrew from the study before a
confirmed crossing into the treated area (i.e., before failure of
efficacy) occurred.  The original analysis of pre-failure withdrawals
underestimated product performance.  Because of this, the data were
re-analyzed using the Kaplan-Meier method as suggested by the Board at
its January 2007 HSRB meeting.

For EMD-004.3, test material was applied 2 to 3 hours before beginning
field testing rather than at the site.  Because the materials were
effective for more than 8 hours, this was unlikely to have affected CPT
results, because CPT was estimated from the time of repellent
application to FCLIBe.  The subjects did not always cover treated limbs
between exposures, but stepped out of the test site or entered a
screened enclosure.  This was unlikely to have affected the results
because the treated limbs were not exposed to mosquitoes between
scheduled exposure periods.

Calculated doses from the dosimetry phase were 0.00134 g/cm2 for arms
and 0.000987 g/cm2 for legs.  For the efficacy phase, the calculated
dose for arms was 0.00143 ml/cm2, and for legs, 0.00105 ml/cm2; these
did not vary significantly from the calculated target doses.

The efficacy phase for EMD-003.3 found a mean CPT of 10.95 hours, +2.8
hours with a 95% confidence interval of 9 to 13 hours.  Range of subject
CPT was 4.25 to 13.5 hours.  After reanalysis using the Kaplan Meier
method, the median CPT was determined to be 13 hours and time to 25
percent failures was 10.75 hours.

The efficacy phase for EMD-004.3 found a CPT of 9.65 hours, ±0.32
hours, with a range of 8.75 to 9.75 hours and 95% confidence interval of
9.45 to 9.88 hours for testing at the forest site.  At the marsh/pasture
site, no confirmed landings occurred and all exposures were ended before
efficacy failure (10.25 hours).

Ethical Considerations

Mr. Carley described EPA’s ethics assessment of EMD-003.3 and
EMD-004.3.  The ethics assessment of these protocols involved review of
the revised submissions of February 5, 2007, (reports MRID 47045901 and
MRID 47045902), the EPA protocol review of September 15, 2006, and the
final report of the October 2006 HSRB meeting (dated
January 21, 2007).  Applicable ethical standards include 40 CFR
§26.1125 (requires prior submission of protocol and supporting
materials), 40 CFR §26.1601 (requires HSRB review of protocol and
supporting materials), 40 CFR §26.1303 (defines standards for
documenting ethical conduct of research), 40 CFR §26.1703 (forbids EPA
reliance on research involving intentional exposure of pregnant or
nursing women or children), and 40 CFR §26.1705 (forbids EPA reliance
on research unless EPA has “adequate information to determine the
research was conducted in substantial compliance with subparts A through
L”).

Deviations from the protocol included commencement of the dosimetry
phase before the IIRB approved final changes to the protocol and ICF;
this is a potentially serious violation of EPA and IIRB rules, but in
this case did not affect the quality of informed consent or subject
safety.  Data collection also preceded QA review; this was a technical
violation without ethical impact.  At its October 2006 meeting, the HSRB
recommended minor changes including designation of a physician on call
and clarification of potential adverse effects in the ICF (for EMD-003.3
only).  These changes were not properly implemented before subject
consent was obtained for the dosimetry phase.  Although the study was
conducted with haste and deviations from the protocol were found, the
research was substantially compliant with ethical standards; all
required documentation is available, and shows no evidence that subjects
were misled or endangered by the initiation of the research before IIRB
approval of changes suggested by the HSRB.  The studies were deemed to
be in compliance with all applicable ethics statutes.

Dr. Michael Lebowitz asked whether requiring ticks to cross at least 3
cm into the treated area and requiring at least 2 crossing within a
30-minute time period was standard for tick repellency studies.  Mr.
Carley answered that this is one of several different ways to test for
tick repellency.  The time to first confirmed crossing is adapted from
time to first bite or FCLIBe, but this concept was not included in the
draft guidelines from June 2006.  These are the first studies to use
this approach in an efficacy test.  EPA believes that this is a
legitimate way to measure failure of efficacy.

Dr. Fisher inquired whether the withdrawal of half of the subjects from
EMD-003.3 before efficacy failure meant only the data from six subjects
was analyzed.  Mr. Carley responded that the data from all 10 subjects
was analyzed.  The repellent was effective for more than 10 hours;
thus, some subjects needed to leave the test before the first confirmed
crossing.  The increased efficacy of insect repellents is leading to a
need for more sophisticated statistical analysis methods that were not
needed when CPTs were in the range of 2 to 3 hours.

Dr. Fisher asked about the rationale for applying the repellent 2 to 3
hours before field testing and whether this was anticipated to mimic
consumer use, given that the original protocol called for application at
the test site.  Dr. Janice Chambers suggested that since the field
testing was conducted in November, when the days are short, the
repellent may have been applied earlier to permit sufficient time to
test efficacy.  Dr. Fisher agreed that this may have been an issue, but
haste is not a reason to deviate from a protocol presumably designed
with scientific rationales.  Mr. Carley explained that if early failure
of efficacy occurred, the circumstances surrounding any difference in
application would be taken into account to determine if deviations from
the protocol had an impact.  Laboratories that perform repellent work do
not have different protocols to use at different times of the year to
accommodate mosquito activity and day length.  A solution to this
problem was to apply the test material immediately before exposure at
times of the year during which appropriate mosquito biting activity is
found, and earlier if the test is performed at times of less activity. 
There is little concern that this deviates significantly from typical
consumer behavior.

Dr. KyungMann Kim commented that according to the summary of data
presented, the statistics calculated were inappropriate; means cannot be
calculated if subjects withdraw.  Additionally, the data was presented
as having no variability; however, variability cannot be estimated if
all subjects do not reach failure of efficacy. Although the mean can not
be calculated (due to missing data), it is possible to state that the
mean is at least 10 hours.  However, no determination of variability can
be made. 

Dr. Fisher asked if the untreated controls also remained in the field
for 10 hours.  Mr. Carley explained that during the field trials,
untreated subjects underwent the same cycles and durations of exposure. 
Addressing Dr. Kim’s comments on the statistical analysis, Mr. Carley
reminded Board members that these studies were conducted before the
Board’s January 2007 discussion on statistical analysis pertaining to
such studies; therefore, the studies cannot be expected to be in
compliance with the Board’s suggestions from the January 2007 meeting.
 Dr. Kim agreed, but added that EPA’s own analysis of the data was
troubling.

Public Comments

Dr. Scott Carroll of Carroll-Loye Biological Research, Inc.

Dr. Carroll thanked the Board for its helpful input and acknowledged the
delay between feedback received and the ability to incorporate it into
scientific protocols.  He explained that the Board would be receiving
information on a protocol that, because of EPA scheduling requirements,
was submitted before the January 2007 HSRB meeting and thus they could
not incorporate Board recommendations.  Dr. Carroll commented that he
would explain how he will incorporate Board recommendations.  For
example, after receiving Dr. Kim’s advice regarding statistical
analysis of the data, Dr. Carroll performed survival analysis on his
data; however, the usefulness of this analysis is questionable because
EPA is currently developing guidelines for statistical analysis.  At
present, the data is reported as censored data, which is not a valid
approach in Dr. Kim’s estimation but does conform to current EPA
requirements.  Dr. Carroll requested feedback for implementing Dr.
Kim’s suggestions regarding statistical analysis, particularly in the
case of the mosquito repellency testing, because subjects were not
bitten.  Dr. Kim stated that because none of the 10 subjects received a
bite, there is no information with which to estimate time to event.  The
minimum CPT is greater than 10 hours, but there is no information for
statistical analysis, contrary to the results presented by EPA.

Dr. Sean Philpott requested the gender distribution for the completed
efficacy studies and whether the control subjects to measure biting
pressure were the same subjects at each site.  Dr. Carroll agreed to
provide this information.  Dr. Philpott broached the subject of
enrolling subjects using an unapproved revised protocol.  The Board
recommended, and what is obligatory by IIRB and regulatory statutes,
that Dr. Carroll report deviations to the IIRB and develop a plan to
correct the deviations.  He asked Dr. Carroll to describe progress on
this matter.  Dr. Carroll explained that he submitted the protocol
deviations to the IIRB and discussed them with the director of the IIRB.
 There is no formal plan to prevent the problem from occurring again,
aside from Dr. Carroll’s assurance that it would not.  He explained
that the problem arose in part based on his inexperience with
interactions with the IIRB and because the IIRB introduced some errors
to the protocol that Dr. Carroll corrected; the IIRB has acknowledged
making these errors.

Dr. Fisher commented that although Dr. Carroll has been very responsive
to the Board, not all registrants will be as responsive and the Board
must be careful not to set precedents regarding its response to
deficiencies in protocols.  She asked Dr. Carroll to clarify whether the
subject pools for the studies overlapped, and if so, whether there is
accommodation for variability among subjects, or any other problem
arising from subject overlap that the Board should be concerned about. 
Dr. Carroll answered that there is some overlap among the studies.  He
stated that there is no reason to believe that there are aberrations
among subjects, and in fact it may be best to use the same 10 subjects
to allow comparison among studies.  He informed the Board that he would
be providing a flow chart to track subjects through studies in the
future.  Dr. Kim commented that for the mosquito repellency test, for
the two sites there is overlap of six subjects.  If data from the two
sites are analyzed separately, this is not a problem, but it could be if
the data from both sites are combined.

Dr. William Brimijoin expressed disappointment that the data do not
encompass the longest possible protection times.  The short days
probably are a problem, but so is the high efficacy of the products.  He
asked whether there was any way to obtain a more accurate CPT.  Dr.
Carroll acknowledged that he did not anticipate the high degree of
efficacy of the products, and that the tests were performed unusually
late in the year (which also was a reason for applying the test
materials before traveling to the sites).  He added that he did not
attempt to influence how long subjects remained in the study because the
renewed emphasis on subject rights and protection required him to
respect the desire of subjects to withdraw.  As part of the recruiting
process, Dr. Carroll will now inform subjects that the studies could
last for more than 12 hours and that the scientific quality of the data
relies on subject participation for extended periods of time.  Dr.
Brimijoin asked whether test material could be applied to subjects 12
hours before traveling to the test site.  Dr. Carroll responded that
this would result in assumptions and label claims based on data he does
not have; however, this approach has been used in the past.

No further public comments were made.

Board Discussion

Scientific Considerations—EMD-003.3

Dr. Chambers opened the science review of EMD-003.3.  This protocol
tested the active ingredient IR3535 in aerosol form.  This protocol was
similar to EMD-003.1 and EMD-003.2, previously reviewed by the Board. 
The product used was produced using Good Manufacturing Practices (GMPs)
and experiments performed using Good Laboratory Practices (GLP). 
Passive dosimetry experiments were recommended and performed; this
allowed a 7 percent lower dose to be tested compared to industry
standards.  Protocol deviations were minor and had no significant
effects on the result.  Four women and six men served as subjects.  Ten
subjects were justified as providing adequate statistical power while
exposing a small number of subjects to risk.  The study found a mean CPT
of 10.95 hours +2.8 hours and mean time to 25 percent failures, adjusted
for censoring, of 10.75 hours.  These are conservative estimates.

With respect to scientific criteria, existing data was not adequate to
test efficacy, thus new studies were required.  The benefits of this
work include identification of an effective tick repellent with better
efficacy and fewer adverse effects.  The risks to subjects included
irritation from tick bites and exposure to vector-borne diseases, but
these risks were minimized because laboratory-reared ticks were used and
were removed before biting occurred.  Regarding study design criteria,
the design was clearly defined and had specific hypotheses.  The study
involved appropriate controls, dosimetry experiments were performed to
quantify dosage, and plans for medical treatment were in place.  The
results are likely to be generalizable.  The subjects were
representative of the population, with respect to applicable ethical
statutes.  The sample did not include vulnerable groups.  Measurements
were accurate, reliable, and appropriate.  Experiments were appropriate
and stopping and safety plans were in place.  In conclusion, the study
is scientifically sound to test the efficacy of IR3535 in an aerosol
formulation for tick repellency.  Dr. Chambers commended Dr. Carroll for
his responsiveness to Board inquiries and the clarity of his data.

Dr. Lebowitz concurred with Dr. Chambers.  He found the dosimetry
testing to be appropriate and useful.  Concerning the efficacy study,
withdrawals would be expected in a study lasting more than 12 hours. 
Comments on conclusions drawn from the data, particularly concerning the
Kaplan-Meier survival analysis, are appreciated.  He agreed with Dr.
Chambers’ conclusions regarding sample size.  Dr. Lebowitz asked about
requiring a second crossing 3 cm or more into the treated area as
failure of efficacy, or whether use of one crossing would give a
reasonable result.  He referred to the table in Figure 19 of the report,
which showed that a number of subjects had only one crossing, which
would change efficacy results if used as evidence of product failure.

Dr. Kim credited Dr. Carroll for trying a different type of analysis. 
He continued Dr. Lebowitz’s line of questioning regarding the
requirement of 2 crossings as product failure.  If a consumer receives
one bite, the consumer would regard this as product failure.  

The definition of CPT in both protocols is unsatisfactory.  He asked
whether the requirement for more than one bite or crossing was an EPA
standard.  Mr. Carley responded that current EPA guidelines and drafts
of new guidelines require a confirmed bite.  The first occurrence of a
bite or crossing is historically considered to be anomalous.  Requiring
a second event to confirm the first has historically been accepted as a
test of efficacy failure.  Dr. Kim remarked that given the raw data, a
different impression of efficacy is gained if the first bite is used as
failure of efficacy.  He recommended sensitivity analysis to determine
which approach was correct.  Dr. Gary Chadwick asked whether both
analyses could be used.  Dr. Chambers remarked that there are existing
products that used the second bite or crossing as efficacy failures, and
consistency with these products must be maintained.  Dr. Fisher
commented that using the second bite or crossing is a conservative
approach for measuring efficacy, but not consumer protection because it
extends the CPT.  To a consumer, one bite is one bite and would indicate
a lack of efficaciousness.  She added that given the apparent lack of
attractiveness to mosquitoes of the 10 test subjects, the question is
whether the judgments should be conservative in favor of protection or
increased efficacy.  The EPA may need to change its determination of
CPT, relative to the efficacy of the products.  Dr. Kim added that the
requirement for ticks to cross 3 cm into the treated area also may
artificially increase CPT.

Mr. Jordan stated that when EPA discussed the issue of the best way to
evaluate efficacy to the SAP, they agreed that there are problems with
using the first bite as an indicator of failure.  A more reliable basis
for assessing failure would be to determine a reduction in the number of
bites received; however, this requires subjects to be bitten numerous
times and compare the number of bites received by treated versus
untreated subjects.  Because of scientific and ethical concerns, this
approach was not used; instead, efficacy failure was used to determine
CPT.  EPA is mindful of the biological uncertainty of a single bite and
thus requires confirmation of the first bite with a second bite.  EPA
also acknowledges the high degree of variability in the population
regarding attractiveness to mosquitoes and how a repellent works for a
given person.  The CPTs indicated on labels are for informing about the
relative benefits of different products, not to guarantee a specific
CPT.

Dr. Lebowitz commented that, given individual variability, the large
numbers of withdrawals, and the requirement for multiple crossings or
bites, a solution to this problem would be to significantly increase
sample size to have sufficient observations to satisfy crossing
requirements and overcome variability issues.  Dr. Brimijoin reminded
him that the HSRB’s mandate is to ensure protection of research
subjects, not protection of the public.  The Board recognizes the
conflict between assuring good science and minimizing risk to subjects. 
The best science requires many more subjects, and would require more
mosquito bites, but this would significantly increase the risk to
subjects.  Dr. Brimijoin stated that he would prefer a larger sample
size because he believes the risks of these experiments are low, but EPA
standards require minimization of subject exposure.

Dr. Brimijoin also stated that although it is appropriate for the Board
to ask questions outside its realm of expertise and it is legitimate to
question methods that are standard in the field, the Board must
recognize existing standards and why they exist.  For example, use of
the confirmed bite standard might reduce noise in the data.  Dr. Fisher
agreed that although the Board must consider the value of the knowledge
produced for public protection, the Board must focus primarily on
subject risk.  Regarding relative efficacy, Dr. Fisher commented that
consumers may rely on the 10+ hour CPT to know when the product would
need to be re-applied.

Regarding Dr. Carroll’s method as a resolution between other methods,
Mr. Carley stated that using LIBes would have no affect on design, and,
in Dr. Carroll’s view, an actual bite is not needed to confirm
failure; others in the field disagree.

Ethical Considerations—EMD-003.3

Dr. Philpott opened the ethics review by agreeing with the ethical
strengths and weaknesses of EMD-003.3 as detailed by Mr. Carley.  It is
clear that the likely societal benefits of this study justify the
potential risks, which are minimal because IR3535 has been commercially
available for a number of years.  Participants also are unlikely to be
at risk for vector-borne diseases from exposure to the
laboratory-raised, pathogen-free ticks.  Clear stopping rules and
medical management plans are in place.  The protocol has procedures to
minimize coercion during the recruitment process.  Compensation for
participation is reasonable, and children and pregnant women are
excluded from the study.  Because of potential stigmatization for
exclusion, Dr. Carroll has developed a well-designed approach to ensure
confidentiality.  In general, the study comports with the applicable
requirements of 40 CFR 26, subparts K and L.  There is no evidence that
the conduct of this research was unethical.

As noted previously, some serious deviations from accepted practices
occurred, namely using an unapproved ICF containing handwritten changes
during recruitment.  Dr. Philpott commended Dr. Carroll for reporting
this deviation to the IIRB.  Drs. Richard Sharp and Jerry Menikoff
agreed with Dr. Philpott’s assessment and had no further comments.

Dr. Fisher concluded that the Board recommends that the data from this
study can be used by EPA.  She commended Dr. Carroll for his clarity,
GLPs, and performing the dosimetry phase of the study.  The Board
recognized problems with generalizability of the results, but believed
Dr. Carroll has justification for the small sample size.  The reasons
for performing this study are sound (lack of efficacy data on this
formulation, potential societal benefit, and low risk to subjects).  The
deviations from the protocol do not affect the data.

The Board questioned the use of the second crossing to determine loss of
efficacy, but realizes this does not affect this study; however, the
Board recommended that this should be a matter for future consideration
by EPA.  There also were questions concerning comparing the amounts of
IR3535 used in the dosimetry phase to toxic benchmarks.  Regarding
ethics, there is minimal risk to the subjects because of the use of
pathogen-free ticks and removal of ticks before biting occurs.  The
Board reviewed the deviations that occurred and appreciated Dr.
Carroll’s responsiveness to this issue and his willingness to work
with the IIRB.

Scientific Considerations—EMD-004.3

Dr. Chambers opened the science review of EMD-004.3.  This protocol
tested the efficacy of IR3535 in aerosol formulation against mosquitoes
in two field settings (marsh/grassland and forest/flooded marsh).  An
alternate site was used as the second test site because of insufficient
biting pressure at the initial site.  There was no evidence of West Nile
Virus (WNV) or other vector-borne diseases at either site.  Ten subjects
were tested at each site, and untreated controls also were tested to
determine mosquito biting pressure.  The trial terminated after dark and
results allowed only a minimum performance (CPT) to be determined, thus
statistical analysis of variance was not possible.  The scientific
justification for this study was the same as that for EMD-003.3.  In
conclusion, the report on EMD-004.3 contains data that are sufficiently
sound to assess mosquito repellent efficacy of the aerosol formulation
of IR3535.

Dr. Brimijoin agreed with Dr. Chambers’ assessment of EMD-004.3 and
recognized the same issues surrounding statistical analysis of the data.
 Dr. Kim asked if there have been previous efforts to understand the
potency of the different preparations of IR3535.  He commented that the
aerosol formulation appeared to be more potent against mosquito biting
compared to the results for the lotion and pump spray formulations.  Dr.
Fisher agreed that the aerosol formulation appeared to be more potent
and asked whether it was typical that aerosols are more effective.  She
also asked whether perhaps the mosquitoes exhibited different behavior
in this study.  Dr. Chambers said that, in her opinion, questions on
comparison of formulations were beyond the purview of the Board and
added that biting pressure was adequate based on data from the controls.
 Dr. Brimijoin agreed that data from the control subjects showed that
there was substantial biting pressure at the site; therefore, failure to
bite is a treatment effect.  This effect would be more obvious if the
study had enrolled more controls, but this was not possible for ethical
reasons.

Ethical Considerations—EMD-004.3

Dr. Philpott opened the ethics review of EMD-004.3.  The process for
subject enrollment and maintenance of confidentiality was the same as
for EMD-003.3.  EMD-004.3 had a larger number of subjects because
testing was conducted at two field sites, although there was overlap
among some of the subjects at each site.  The two control subjects used
to determine biting pressure were experienced laboratory personnel.  The
study enrolled 26 to 28 volunteers, including alternative subjects to
replace any subjects who withdrew or were unable to participate; this
approach helped protect subject confidentiality.

EMD-004.3 presented some distinct concerns, namely the risk of disease
from infected mosquitoes.  Appropriate efforts were made to minimize
risk.  The studies were intended to be conducted in areas in which
arthropod-borne diseases had not been detected by vector control
agencies for at least one month prior to the study.  This precaution was
violated by the detection of WNV in a sentinel chicken prior to the
study.  The study proceeded because vector control agencies concluded
that there was no further disease activity at the site.

Other ethical issues included the use of an unapproved ICF. 
Additionally, the untreated controls may not have received sufficiently
explicit descriptions of the risk.  Dr. Sharp asked whether, given the
protocol violations described by Dr. Philpott, this protocol could be
deemed to be in substantial compliance with ethics statutes.  Dr.
Menikoff reminded Dr. Sharp that the Board must be consistent with the
meaning of “compliant” as determined during the January 2007 HSRB
meeting.  Dr. Fisher agreed, and noted that further discussion of the
meaning of “compliant” would take place later in the meeting.  She
agreed that the Board should consider whether these protocol violations
were substantial deviations from ethical standards, and asked whether
subjects were informed of the issue with the informed consent documents.
 Mr. Carley responded that subjects participating in the dosimetry
phase signed the September 2006 version of the ICF that Dr. Carroll had
amended in writing to reflect HSRB suggestions.  The final changed
version was approved on November 1, 2006, and was used to consent
subjects for the efficacy phases of both the tick and mosquito studies.

Dr. Fisher inquired whether subjects had been informed about the
detection of WNV in a sentinel chicken.  Dr. Carroll answered that he
noted this information in his report, but the chicken in question was
not part of the flock closest to the site.  Instead this flock was far
enough from the site (approximately 30 miles) that its presence was not
considered a violation of the protocol.  Dr. Philpott expressed concern
that the term “regions,” as used in the ICF, to inform participants
about the possible presence of vector-borne disease is too vague.  If
the flock is in the same county as the test site, it could be considered
to be in the same region, and thus proceeding with the study was a
violation.  Dr. Carroll should remember this when planning similar
protocols that use this approach for minimizing exposure to vector-borne
diseases.  Dr. Carroll also should consider analyzing mosquitoes caught
at the test site.  Dr. Fisher added that at the April meeting approving
the January report the Board recommended that, for future protocols, if
the region tested is not pathogen-free for 30 days, post-study testing
of trapped mosquitoes should be performed. 

Dr. Fisher concluded that the Board comments indicated the EMD-004.3 is
a valid study, regardless of issues with interpretation and analysis of
the data.  CPT could be related as at least 10 hours, rather than 10 or
more hours, in accordance with available data.  There were some issues
concerning the ICFs and the extent to which the study followed some
requirements.  The Board’s consensus was to approve this study.

Carroll-Loye Mosquito Repellent Efficacy Protocol WPC-001

Introduction

Mr. Carley provided background on a proposal for a field test of
mosquito repellency for a conditionally registered formulation
containing Oil of Lemon Eucalyptus (OLE) as its active ingredient. 
Conditional registration means that EPA has the authority to approve
products similar to previously approved products when fewer than all
registration requirements have been satisfied; the unaddressed
requirements are made conditions of registration that must be resolved
within a specific timeframe.  This product was registered with specific
requirements to conduct product-specific studies.  OLE is used in other
similar products at ranges encompassing that used in this product.  The
protocol WPC-001 is adapted from and closely similar to Carroll-Loye
protocols EMD-004 and SCI-001, previously reviewed favorably by the
HSRB.  The few remaining deficiencies in this protocol can be easily
corrected and thus EPA believes this protocol is ready for HSRB review.

Scientific Considerations

Dr. Fuentes presented the scientific considerations for protocol
WPC-001.  The objectives of this study were to test the mosquito
repellent efficacy characteristics of the test material and to satisfy a
condition of registration imposed by EPA.  The test material, Repel 30
LE (EPA Reg. No. 305-62), contains 30 percent OLE in a pump spray
formulation.  The oral Lethal Dose (LD)-50 is less than 5,000 milligrams
per kilogram (mg/kg) and the dermal LD-50 is greater than 2,000 mg/kg.

The study includes a dosimetry phase with 10 subjects, to establish the
typical consumer dose for use in efficacy testing.  Subjects are trained
in the laboratory to aspirate landing mosquitoes before they bite, using
laboratory-reared, pathogen-free mosquitoes.  Because there is only one
treatment, the study is not blinded.  The study involves two field
trials, each enrolling ten treated subjects and two untreated
“experienced” control subjects.  Untreated subjects are included to
monitor biting pressure; each will be attended by two assistants to
aspirate mosquitoes before they can probe or bite.  Both treated and
untreated subjects are exposed to mosquitoes for 1 minute every 15
minutes.  Product efficacy is measured as average time from treatment to
FCLIBe.

The field sites are described in the report as the California Central
Valley or Florida Keys, depending on the season.  Expected wild mosquito
populations include Aedes vexans, Ochlerotatus melanimon, O.
taeniorhynchus, and Culex pipens.  Variables, including biting pressure
(threshold = 1 LIBe/minute), FCLIBe, and time to FCLIBe, will be
measured.  Test results will be analyzed by calculating the mean time to
first confirmed LIBe; untreated controls are not used for comparison of
treatment means.  Means will be reported with 95 percent confidence
interval of the mean and associated standard deviation; other analyses
may be used as appropriate to the results.

The sample size reflects a compromise between financial and ethical
concerns.  Sample size is difficult to predetermine without knowing the
distribution of outcome values.  EPA guidelines recommend six
replicates, which has been widely regarded as sufficient to show
statistical significance at P<0.05; 10 replicates slightly improves
accuracy in estimating the population mean. 

Necessary protocol revisions include deletion of the reference in
§6.2.1 to untreated controls for the dosimetry assay; provision in the
statistical plan for diagnostic statistical tests for normality, and for
analysis of non-normally distributed data; inclusion of roughly equal
proportions of male and female subjects in the sample; and inclusion in
limb surface areas measuring procedures for recording the exact
locations of the four measured circumferences, so that dosimeters can be
placed at the same locations.

If further revised as suggested, this protocol is likely to comply with
scientific standards and yield scientifically reliable information
because it would produce important information that cannot be obtained
except by research with human subjects and it has clear scientific
objectives; the study design should produce adequate data to achieve
those objectives.

Ethical Considerations

Mr. Carley presented ethical considerations for WPC-001.  The proposed
study would field test the mosquito repellent efficacy of a single test
formulation, containing OLE as its active ingredient.  The test
formulation was conditionally registered with claims for “up to 6
hours” of protection; EPA requires product-specific efficacy testing
to maintain the product’s registration.  The proposed study presents
value to society by making available a potentially attractive
alternative to other available repellents, some of which are found
unpleasant by many users.

Subjects will be recruited among “communities of friends, neighbors
and scientists” near the investigator’s laboratory.  Exclusion
factors are students or employees of the investigator; children, or
pregnant or nursing women; those sensitive to repellents or to mosquito
bites; those in poor health or physical condition; and those unable to
speak and understand English.  No subjects come from vulnerable
populations.  More detail is needed about recruitment of the two
“experienced” subjects who will serve as untreated controls.

Risks include irritation of the eyes on contact with the repellent, the
repellent is harmful if swallowed, and possible exposure to biting
arthropods and/or arthropod-borne diseases.  Risk minimization
procedures specific to the repellent include exclusion of sensitive
candidates, closely monitoring use of the repellent during the dosimetry
phase, and having a technician apply the repellent.  Risks from mosquito
bites are minimized by excluding sensitive candidates, training subjects
to aspirate mosquitoes before they have time to bite, and minimizing
exposure of skin.  Risks of disease are minimized by conducting research
where no mosquito-borne viruses have been detected for at least a month,
and by minimizing bites.  The probability of risks is characterized as
“extremely small” because of the low acute and chronic hazard
profile of the product (although the product is a Toxicity Category II
eye irritant), design of the research to minimize exposures, training
subjects to aspirate landing mosquitoes before they have time to probe
or bite, and performing field testing in areas free of WNV.  An
additional way to reduce risk would be to perform post-study serological
testing of mosquitoes caught at the test site.

Regarding benefits, there are no direct benefits to subjects; the
primary direct beneficiary is the sponsor.  If the material is proven
effective, indirect beneficiaries will include repellent users who
prefer this product to other repellents.  No reasonable opportunities
have been overlooked to further reduce risk while maintaining scientific
robustness; the residual risks to subjects are very low and are
reasonable given the expected societal benefits to repellent users,
which are likely to be realized.

The IIRB of Plantation, Florida reviewed and approved the protocol and
informed consent materials on January 23, 2007.  This IIRB is
independent of the sponsors and investigators and is registered with the
Office for Human Research Protections (OHRP).  It is not accredited by
the Association for the Accreditation of Human Research Protection
Programs (AAHRPP) or any other accrediting organization as far as EPA
can determine.  EPA has determined that this IIRB’s procedures meet
regulatory standards.  

Regarding the informed consent process, the description of subject
recruiting and consent processes in California is complete and
satisfactory; however, more detail is needed regarding the recruiting
process in Florida, especially concerning the role of the Mosquito
Control District administration.  The IIRB-approved ICF is appropriate
for both treated and untreated subjects and is included in the protocol,
but misleadingly suggests the test material is not yet registered with
EPA.

The protocol shows adequate respect for subjects through the methods
proposed for managing information about prospective and enrolled
subjects that will generally protect their privacy; however, subject
privacy would be better protected if subject names did not appear on
data collection forms.  Subjects will be free to withdraw at any time,
and will be reminded of this at several points.  Medical care for
research-related injuries will be provided at no cost to the subjects.

This is a proposal for third-party research involving intentional
exposure of human subjects to a pesticide, with the intention of
submitting the resulting data to EPA under the pesticide laws.  The
primary ethical standards applicable to this research are 40 CFR 26,
subparts K and L.  A point-by-point evaluation of how this protocol
addresses the requirements of 40 CFR 26 subparts K and L and the
additional criteria recommended by the HSRB appears as Attachment 1 to
the EPA Review.

Required revisions to this protocol include a description of how
untreated controls will be recruited, and how the process of informing
them will differ from that used for treated subjects.  It will also
include a detailed description of the recruiting process in Florida
equivalent to that used to describe the process used in California, with
particular attention to the role of the Mosquito Control District
administration.

Regarding the status of protocol WPC-001’s compliance with ethical
standards, all requirements of §26.1111, §26.1116, and §26.1117 are
met; with requested revisions, all requirements of §26.1125 are met;
all requirements of §26.1203 are met; all elements of National Academy
of Science (NAS) recommendation 5-1 are satisfied; and all elements of
NAS recommendation 5-2 are satisfied.  If further revised as suggested,
protocol WPC-001 will meet the applicable requirements of 40 CFR 26,
subpart K and L.

Dr. Fisher inquired whether FCLIBe was the same as first confirmed
crossing.  Mr. Carley explained that this was the equivalent of
crossing.  For EMD-004.3, the endpoint for failure of efficacy was the
average time from treatment to the FCLIBe.  Efficacy failure is measured
as the FCLIBe confirmed by another crossing within 30 minutes; CPT is
measured as time to efficacy failure.  Dr. Fisher asked whether data on
“rejected” bites are collected.  Mr. Carley responded that it is
collected as raw data.  An entry is made for every 15 minute time period
to record the numbers of LIBes.  Thus, unconfirmed landings are
recorded, but are not counted if a subsequent landing does not occur
within 30 minutes.  Dr. Fisher asked whether EPA could modify the way it
determines FCLIBe.  Mr. Carley answered that EPA could perform parallel
analyses (using first landing versus first confirmed landing) for this
study, but data from previous studies from which to do this sort of
analysis would not be available.  Dr. Fisher asked whether the Board
should recommend that other investigators record data this way to allow
for other analyses in the future.  Mr. Carley responded that the Board
may want to discuss this issue at the June 2007 meeting after they
review a similar protocol from another investigator.

Dr. Kannan Krishnan asked whether Repel 30 LE is registered.  Mr. Carley
answered that the product is conditionally registered.  Dr. Krishnan
inquired about the concentration of the active ingredient in Repel 30
LE.  Mr. Carley responded that this product has, at 30 percent OLE, a
lower concentration of OLE than in previously registered pump spray
products also containing OLE.  A higher concentration product is
registered with no conditions.  Repel 30 LE is conditionally registered
because data from product-specific test conditions was not available. 
Dr. Krishnan questioned whether there was any concern about changing the
composition or the vehicle of the product.  Mr. Carley replied that the
product is similar enough to other products on the market to be
considered safe.  The product has already met a number of conditions and
the remaining questions strictly concern efficacy.  The results of this
study will be used to modify label claims.  Dr. Krishnan questioned
whether EPA has supporting data on file concerning the toxicity class of
the product.  Mr. Carley explained that EPA has data covering other
product requirements, including chemical and toxicity data.  

Dr. Sharp requested clarification of the recommendation for revision of
the recruitment procedure for untreated controls and whether EPA was
asking for details beyond those provided to the Board.  Mr. Carley
explained that EPA wanted further detail on the process for soliciting
interested subjects, the process by which the investigators will apply
subject criteria, and how subjects will be offered the chance to serve
as untreated controls.

Public Comments

Dr. Scott Carroll of Carroll-Loye Biological Research, Inc.

Dr. Carroll addressed questions concerning the subject recruitment
process, including subject influence on repellent performance, how
subjects may differ with respect to mosquito attractiveness, and how
study developers consider who might participate in the trial.  

Although it is known that gender has a strong influence on mosquito
attractiveness, most studies are inconclusive regarding whether men or
women are more attractive to mosquitoes.  Thus, a gender balance
generally is used for mosquito repellency studies.  Regarding the
sampling frame for this study, comparison of the Carroll-Loye Biological
Research volunteer database to Davis, California, census data shows a
similar ethnic distribution.  Most individuals in the volunteer database
are between 20 and 40 years of age, with a smaller number between
40 and 55 years of age.  The individuals are relatively young,
well-educated, and likely to be life science researchers or students. 
The subjects show substantial interest in participating, but this is not
likely to influence results of the study.  Carroll-Loye Biological
Research investigators do not actively or directly encourage
participation; instead, individuals in the database have requested that
investigators contact them when test subjects are needed.  Persons who
will serve as untreated control subjects are limited to experienced
technical personnel, who are screened with the same exclusion criteria
as are other subjects, and have additional inclusion requirements.

Dr. Carroll requested comments from the Board regarding language on the
ICF for informing untreated controls.  He presented his proposed
language, and added that he would like to use only one ICF for both
treated and untreated subjects.  He also asked whether the Board
recommend that he perform sampling for diseased organisms during
testing.  California has an intensive disease-sampling program and
California vector ecologists suggest a 2-week buffer to ensure the
absence of vector-borne diseases.

Dr. Fisher requested Dr. Carroll explain the size of the “region” as
described in the study protocol.  She said that the testing criteria
would be determined by the extent to which Dr. Carroll can ascertain
that there was no evidence of disease in a region relevant to the test
site for the past 30 days.  Dr. Carroll asked the Board to consider in
its discussion of this protocol how data from mosquito sampling would be
used.

Dr. Philpott inquired whether the recruitment protocol shown to the
Board was similar to the previous one described for testing at the
Florida site.  He expressed concern that flying study subjects from
California to the Florida site would represent undue inducement to
participate.  Dr. Carroll answered that the Florida recruitment process
was still being developed; protocol WPC-001 does not include testing in
Florida.  Dr. Fisher questioned EPA as to why the Board was reviewing a
protocol that appeared to be somewhat undeveloped.  Mr. Carley responded
that his concerns about the inadequate description of the Florida
recruitment procedure could be alleviated by deletion of the reference
to recruiting in Florida; Dr. Carroll informed the Board that this
protocol will be performed only in California.  Dr. Sharp added that, in
his opinion, the protocol is well-developed aside from the gap in the
Florida recruitment process.

Dr. Fisher requested clarification concerning the implications of season
or temperature on the effectiveness of products tested in mosquito
repellency field studies, and whether this would influence the need for
untreated controls.  Dr. Fuentes explained that season and temperature
influence the ability to locate mosquitoes.  The activity of the product
does not change, but the numbers and types of mosquitoes at a given site
do.  The control group provides information on this by providing a
measure of biting pressure.  If biting pressure is adequate, any
difference in the amount of bites received by controls compared to
treated subjects is a treatment effect.  Dr. Fisher asked whether a
control is compared to a treated subject at each of the described
15-minutes intervals.  Mr. Carley responded that data concerning
mosquito landings is collected for controls at the same intervals and
for the same duration as treated subjects.

Board Discussion

Scientific Considerations—WPC-001

Dr. Krishnan questioned why, given that EPA has sufficient data on the
safety of this product, human studies were required and justified.  He
added that although most of the essential elements for the protocol have
been adequately described and are appropriate, he has concerns regarding
sample size and statistical analysis.  The sample size justification is
not convincing.  Dr. Krishnan commented that he had hoped the results of
the completed mosquito repellent efficacy studies could be used to
inform sample size for this study.  Given the concerns of Drs. Alicia
Carriquiry and Kim regarding the confounding of CPT calculations by
subject withdrawal, perhaps guidelines need to be established concerning
how long subjects are required to remain in the study.  Dr. Krishnan
added that once dosimetry studies are complete, the dose should be
compared to a toxic benchmark.   

Dr. Krishnan concluded that based on the available information, this
protocol can provide scientifically reliable data.  The protocol
approval is based only on activities in California, not for the Florida
site.  The investigators also should address issues pertaining to
statistical analysis, which should help obtain more reliable results. 

Dr. Fisher related comments from Dr. Carriquiry regarding protocol
WPC-001.  Dr. Carriquiry noted a great deal of variability in the
dosimetry phase of previous studies, and asked if, given the variability
of consumer use, should more than one dose level be tested to obtain
data that are more meaningful for the consumer.  Mr. Carley responded
that EPA has accepted a single dose for as long as it has required and
reviewed such studies.  For most studies, the dose used is based on a
“rule of thumb” not on actual measurements.  At the last HSRB
meeting, the Board asked EPA to consider best methods for dose studies;
EPA is considering this but has not yet developed a consensus.  Dr.
Lebowitz reminded the Board that it had indicated satisfaction with
single dose protocols reviewed during the morning session of this
meeting.  He expressed dissatisfaction with the use of a single dose
because of inter- and intra-individual variation, but recognized that
adjusting sample size could resolve these issues and permit use of a
single dose.  Dr. Kim questioned whether the dose used was close to that
expected to be used by the consumer.  Mr. Carley explained that labels
for repellents usually informed consumers to “apply for full
coverage.”  Consumers tend to re-apply product if they are bitten. 
Regardless of better ways to cope with the variability inherent in this
work, EPA is not trying to produce an accurate prediction of CPT for
each user.  CPT is used for comparison with products currently on the
market; these are not dose-response studies.

Dr. Brimijoin inquired whether, given the numbers of different
investigators performing these studies, data from different studies are
truly comparable.  Dr. Fisher added that she was surprised these studies
are not more informative concerning the duration of these products’
effectiveness.  Relative efficacy cannot be compared because the studies
are performed under different conditions, with different subjects, and
at different sites.  Dr. Chambers reminded Board members that these are
field studies, which will not be as clean as those performed in a
laboratory setting.  The studies do provide consumers with information
that will help them choose which product to use.  Using multiple doses
in a study would require more subjects and thus increase risk.

Dr. Carriquiry commented that there was no discussion in the protocol of
how CPT is determined if a subject withdraws before FCLIBe.  She asked
whether a power analysis had been performed to determine the number of
subjects needed to show that any effect is not due to chance.  These
calculations typically rely on previous study results.  She asked
whether the Board has given appropriate guidance for justification of
sample size.  Dr. Kim answered that the studies were essentially
descriptive and P-values cannot be appropriately calculated for them. 
Dr. Fisher agreed that the Board had concerns about determining sample
size.  Mr. Carley explained that EPA is considering this issue, but at
present, the sample size of 10 is acceptable.  It is the responsibility
of EPA, not individual investigators, to address general questions
concerning EPA guidelines and standards and how to use results to
determine label language.  Mr. Jordan agreed with Mr. Carley, and added
that Dr. Kim’s comments are helpful for describing the purpose of
including more subjects to give more precision to estimates of CPT. 
Investigators provide data for EPA use; EPA must decide how much
precision is required in this data to make label claims for products. 
These issues are broad and cut across many fields, and will be used by
EPA to consider and perhaps revise its guidelines.  Transitioning from
old to new guidelines also will require planning.  The current rule of
thumb used by EPA, and the onus on investigators, is to determine
whether the current studies are as good as or better than previous
studies.  Dr. Fisher agreed, but added that the Board questions if
changes can be made at the present to achieve standards the Board
believes are necessary.  The Board believed EPA must address these
issues.  Mr. Carley reminded the Board that these protocols represent
regulatory science and regulatory standards.  Guidelines for these
studies must be consistent; a compromise must be reached between
refining the guidelines at every HSRB meeting and accepting protocols
because they follow historical, albeit perhaps less than optimal,
standards.   

Dr. Brimijoin commented that it appeared that similar studies are being
held to progressively more rigorous standards.  This could be unnerving
to proponents, but the Board should continue to push for higher
standards, particularly if a given analysis is inappropriate or there is
an easy way to resolve an issue.  Dr. Kim acknowledged the obvious level
of frustration given that several of the Board’s recommendations have
not been implemented as the Board would like.  EPA does not provide
clear input to registrants (concerning sample size, CPT derivation,
etc.) and thus it may not be realistic to see changes in the protocols
reflecting the Board’s advice.  It is also clear that any change
implemented will have considerable and broad implications, given EPA’s
historical body of data.  Nonetheless, the Board must continue to push
for better science, and especially must address any “fatal flaws” it
discovers.  Mr. Carley clarified that Dr. Kim’s concerns had not been
implemented in the protocol reviewed at this meeting since the protocol
was written before the January 2007 HSRB meeting.  EPA will develop
guidelines based on Board suggestions and disseminate the guidelines to
investigators.  Dr. Chambers suggested that EPA provide the Board with
background about EPA data sets and regulatory constructs to help inform
the Board about insect repellents and regulations.  Mr. Jordan agreed
that this would be helpful and said he would try to provide such
materials for Board review of the occupational handler exposure studies.

Ethical Considerations—WPC-001

Dr. Sharp opened discussion on ethical considerations for WPC-001.  He
thanked Mr. Carley for his thorough review of this protocol.  The
social benefits for this study are well articulated.  OLE is an
important alternative repellent, especially for those sensitive to the
smell of other commercially available mosquito repellents.  The limited
risks inherent to this study were minimized appropriately.  Dr. Sharp
commended Dr. Carroll on the improvements Dr. Carroll made to the
protocol.  Recruitment in Florida could be a serious issue because there
was little definition of recruitment procedures to be used in that
state.  However, because the study will be conducted in California,
removal of references to recruitment in Florida could be removed from
the protocol.  In conclusion, this protocol, with minor revisions, meets
the applicable ethical requirements.

Dr. Menikoff agreed with Dr. Sharp’s assessment.  He expressed concern
that there was not a separate ICF for control subjects.  Control
subjects face higher risks than treated subjects and one ICF that does
not indicate whether the risks detailed are for treated subjects or
control subjects may not permit control subjects to recognize that they
are at higher risk.  An addendum should be made that control subjects
signature could be added to the ICF to ensure control subjects are
properly consented.  Dr. Susan Fish agreed with Drs. Menikoff’s and
Sharp’s assessments.  

Concerning the ICF, Dr. Sharp questioned whether the Board wanted to
substantially change an ICF that had been reviewed and approved by an
IIRB, suggesting the Board should defer somewhat to the IIRB’s
assessment.  Dr. Gary Chadwick agreed, but maintained that whether
people have the information necessary to make an informed choice is a
significant ethical issue.  The Board recommended that this issue be
addressed.  Dr. Fisher agreed that it was a significant issue and that
the ICF did not distinguish between control and treated subjects. 
Mr. Carley explained that part of the confusion surrounding this issue
arose from inclusion of the Florida site in the protocol reviewed by EPA
and the Board.  Dr. Carroll currently does not plan to conduct the study
in Florida, so issues surrounding recruitment in Florida may be solved
by reorganizing the protocol.

Dr. Fisher concluded that the Board found the protocol to meet
scientific criteria.  Concerning ethics, she agreed that subjects’
names should not be included on data forms, the ICFs need to be
finalized, and a clearer determination of how control subjects are
recruited and selected was needed.  The protocol also should clarify
that the study will not be performed in Florida.

Research Conducted After April 7, 2006:  Meaning of “Substantial
Compliance” with 40 CFR Part 26

Mr. Jordan presented EPA considerations on the meaning of “Substantial
Compliance” in 40 CFR §26.1705.  EPA has prohibited reliance on
unethical human research with non-pregnant, non-nursing adults conducted
after April 7, 2006, unless EPA has adequate information to determine
the research was conducted in substantial compliance with subparts A
through L of this statute.  Without adequate information, EPA cannot
make a determination of compliance.  An exception to this rule is that
if EPA has data that do not meet ethical standards, the data may be used
to support regulatory action leading to more stringent health protection
or improved public health

This rule was developed from NAS recommendations for “intentional
human dosage studies” (NAS Recommendation 5-6).  The recommendation
was modified slightly to clarify that EPA would consider refusing to
rely on a completed human study only if the study fails to
“substantially” comply with the applicable ethical standard.  This
addition reflects EPA’s judgment that relatively minor administrative
or record-keeping deficiencies in a researcher’s compliance with a
rule as complex as the Common Rule would not in themselves justify
rejecting otherwise scientifically valuable and ethically conducted
research.  

The information contained within the presentation, “Compliance
Oversight in Human Subjects Protection” by Dr. Kristina C. Borror,
Director of Division of Compliance Oversight in Office of Human Research
Protection (OHRP), Department of Health and Human Services (DHHS)
(February 1, 2005) also informed EPA’s decision.  This report
demonstrates that deficiencies often occur in research involving human
subjects, but most are not serious.  The report describes 269
determination letters sent over a period of 4 years to more than
180 institutions.  Most letters were based on review of submitted
documents, although OHRP also conducted site visits at 18 institutions. 
Within the 269 letters were 71,000 citations for non-compliance
(approximately four citations per letter); 142 institutions had at least
one citation; the median was four citations per institution.  During
this time, OHRP suspended or restricted assurances for only 20
institutions, indicating that only 20 institutions had serious or
numerous deficiencies.  This suggests a gradient in terms of the
seriousness of the citations, although the report does not contain
detailed information concerning the kind of violations cited. 
Approximately 51 percent of all institutions cited had deficiencies in
IIRB documentation for informed consent processes, although most of
these deficiencies were not serious.

Public comment was permitted when EPA was in the final phases of
developing this regulation, and most comments indicated a lack of
clarity concerning the definition of key phrases (i.e., “fundamentally
unethical,” “significantly deficient,” or “substantial
compliance”).  Overall, although most investigators wanted EPA to
specifically state the number or types of comments that would lead to a
study being deemed “not in substantial compliance,” EPA believed
this was unnecessary.  EPA agreed with NAS that each study would require
case-by-case evaluation.  EPA also expected the terms to develop greater
clarity over time, through HSRB and public review of EPA decisions
concerning this matter.

The term “substantial compliance” has legal meaning and the phrase
appears in judicial review, often in disputes between two parties when
trying to determine if the complaining party’s requests were met as
detailed in a contract or in support of whether a regulation was met. 
The term involves interpretation of the underlying intent of a
requirement and allows flexibility in judging the acceptability of
behavior.  For example, the way in which the HSRB approached review of
several insect repellent studies in January 2007 reflected good and
thoughtful judgment concerning substantial compliance of the protocols
with ethical standards.

EPA recommended that the Board not attempt to define a priori standards
for “substantial compliance” but instead build a record of specific
decisions taking into account such factors as the nature and number of
deficiencies, the investigator’s intent, any relevant past conduct,
prevailing practices in the field, and the likely significance of the
deficiency for subjects of the research.  The Board is also asked to
explain the reasoning regarding any HSRB conclusions concerning whether
compliance is “substantial.”

Dr. Chadwick discussed the definition of “substantial compliance.” 
He commended EPA’s approach to soliciting HSRB input.  He cautioned
Board members to be sure to understand the difference between ethical
deficiencies and regulatory deficiencies.  Dr. Chadwick added that it
is unrealistic for the Board to determine an investigator’s intent,
and also may be unrealistic for the Board to determine and consider an
investigator’s past conduct.  Dr. Philpott agreed that determining
intent probably is not possible.  Dr. Fisher agreed that the Board
should avoid assessing intent, because intent is not provable.  EPA can
consider intent or relevant past conduct if it chooses, but the Board
determines only if regulations were followed and if not, were these
lapses likely to cause harm or violate subjects’ rights.  The phrase
“substantial compliance” is contradictory because it implies that
following all regulations is not necessary.  Regarding consideration of
relevant past conduct, Dr. Fisher stated that, at some point, sponsors
should be expected to be cognizant of applicable regulations and able to
develop solid ICFs.  The Board must consider precedent; behaviors that
may be acceptable now may not be acceptable in the future.

Dr. Lebowitz stated that the presentation provided legal definitions of
key terms.  The Board assesses whether a protocol is sufficiently
scientifically and ethically sound.  He expressed doubt considering
whether the Board ever used the term “substantial compliance.”  An
education process may be necessary for the Board to be able to define
“substantial compliance.”  Dr. Menikoff stated that he found the
criteria useful.  Intent cannot be directly measured, but assessing the
conduct of an investigator provides reasonable information concerning
what the investigator intended to do.  Problems with ICFs are usually
minor mistakes, such as typographical or version errors; in these cases,
the intent of the investigator was to comply with ICF guidelines.  Past
conduct also can offer clues concerning intent.  Dr. Brimijoin agreed
that EPA has taken a sensible approach to this issue.  It is unlikely
the Board will ever see a perfect protocol; it may have to make
judgments that a protocol is “close enough” to compliant.  EPA
consults the Board on whether it considers a protocol to be in
substantial compliance, but EPA makes the final decision regarding this
issue.

Dr. Richard Fenske requested to see the report discussed in the OHRP
presentation, if such a report exists.  He expressed discomfort with the
legal framework of the guidelines.  For example, identification of a
“complaining party” would be unclear for most scientific protocols. 
A legal context may not be appropriate for a science and ethics advisory
board.  Overall, however, Dr. Fenske found the recommendations helpful
(especially those concerning the nature and number of deficiencies and
the likely significance of the deficiency for research subjects),
although the other suggestions could be amended.  He commented that the
Board acknowledges that errors, such as using the wrong version of an
ICF, may occur in field studies, which speaks to the intent and past
performance of the investigator.  He also recommended that EPA inform
the Board about investigators’ past performance when possible.

Dr. Fisher remarked that there may be differences in “substantial
compliance” when the Board is reviewing a proposed protocol compared
to a completed protocol.  If the HSRB makes recommendations concerning
compliance for a proposed protocol, the investigator should incorporate
the recommended changes.  The HSRB never concludes that it is
permissible for an investigator to disregard its recommendations.  Mr.
Jordan clarified that this rule applies only for EPA use of data from a
completed protocol.  Dr. Fisher agreed that when the Board reviews a
completed protocol, it can determine only the extent to which the
investigators followed the regulations and whether any deficiencies
resulted in harm to the research subjects.  She expressed concern about
using “intent” to decide compliance.  Additionally, past conduct
often is not admissible in legal situations.  The Board can evaluate
only how a protocol was conducted, if it was in compliance with
regulations, and if it violated human subject rights.  Dr. Chadwick
remarked that the Board must understand that no protocol will be 100
percent correct.  There needs to be allowances for accepting data from
studies with minor deficiencies.  Dr. Menikoff agreed that few protocols
would meet all requirements and regulations, and intent should be
considered.  He cited as an example Dr. Carroll’s additional language
to the ICF, which was technically in violation of regulations, but
resulted in a better, more informative ICF.  Dr. Fisher stated that the
Board did not know Dr. Carroll’s intent, but only found that the
changes did not violate subject rights or result in less information for
subjects.  Dr. Chadwick stated that although he agrees with the idea of
flexibility, the HSRB is not in a position to decide or comment
on intent.  

Dr. Sharp also cited Dr. Carroll’s situation, stating that the Board
knew there was a consent violation and proceeded to obtain information
that allowed it to determine this was an honest mistake and not a
protocol violation.  Dr. Fisher responded that if the change to the ICF
had not provided sufficient protection, the HSRB would judge it to be
unethical.  Intent should not be considered in the Board’s assessment.
 Dr. Sharp reminded Dr. Fisher that this rule applied to previously
conducted studies, and the Board would be determining only if the data
was usable by EPA.  Dr. Philpott agreed with Dr. Fisher that determining
intent was not possible.  Mr. Jordan agreed that it could be difficult
to infer intent, but still may be worth pursuing.  Concerning Dr.
Sharp’s point that this consideration applied only to previously
conducted studies, Mr. Jordan explained that EPA’s goal for these
assessments is to try to prevent violations from occurring in the
future.  Having an understanding of an investigator’s motives or
intent that lead to deficiencies is relevant for predicting the type of
response from EPA that will lead to a change in behavior.  He clarified
that EPA operates in a regulatory context, and appreciates the
clarification of deficiencies as regulatory rather than ethical.  The
intent underlying the regulations is to ensure ethical treatment of
human subjects, thus, it is relevant to try to understand the ethical
impact of a regulatory deficiency.  The most powerful response EPA has
to address deficiencies is to inform a sponsor that their data are
unusable and they will have to repeat the study, leading to added
expenses and delays for the sponsor.  EPA also can impose civil or
criminal penalties, report an investigator to OHRP, or disqualify an
investigator from receiving EPA grants.  The choice of which measure to
use depends in part on how effective the measure will be in changing
behavior to avoid repetition of a mistake.

Dr. Brimijoin suggested that the Board not think of EPA’s
recommendations for determining “substantial compliance” as a
checklist, but rather as suggestions.  The first and last
recommendations are the most substantial; the HSRB likely will always
consider the nature and number of deficiencies and the likely
significance of the deficiency for research subjects.  The other
recommendations might have relevance occasionally and might consciously
or unconsciously influence decisions about the seriousness of a
violation.  Overall, the Board should not be rigid on these matters. 
The final conclusion should make no reference to intent, only whether
the protocol achieves substantial compliance or not, the definition of
which likely will evolve over time.  Dr. Fisher agreed in principle with
Dr. Brimijoin, but stated that she would not adopt these recommendations
as HSRB guidelines if “intent” was included.  She agreed that
decisions on compliance would focus mainly on the nature and number of
deficiencies and the likely significance of the deficiency for subjects
of the research.  

Dr. Fisher disagreed that the Board does not judge whether a protocol is
unethical after it has been conducted.  If the HSRB finds evidence of
harm, they must find that the protocol was not in substantial
compliance; the final decision for using the data rests with EPA.  If
the data will offer improved protection for the public, it must be
acknowledged that the study may have been unethical, but the benefits
outweigh this.  Dr. Sharp stated that he was not suggesting that the
HSRB cannot pass judgment if a past study was unethical; however, the
Board cannot protect these subjects from harm but can only perhaps
protect their dignity from harm by recommending against EPA use of the
data.  Dr. Fenske agreed, adding that if the study involves third party
research, such as use of a contractor who may not follow protocols
diligently, the HSRB’s judgment of the study and disapproval may
protect future subjects by bringing scrutiny to the contractor.  Dr.
Fisher agreed, adding that issues of justice apply–recognition of
unethical behavior is justice.  The regulations state that EPA will not
use the data if the data were obtained in an unethical manner.  Dr.
Menikoff suggested that evaluating “intent” may allow the Board to
reject data from a study that did not have egregious violations, but
failure to reject the data could mean that this violation is not taken
seriously by future investigators, which could lead to harm to future
subjects.

Dr. Fisher concluded that EPA recommendations concerning the nature and
number of deficiencies and the likely significance of the deficiency for
research subjects could be formally addressed by the Board.  Other
recommendations may arise during Board deliberations and can be
considered, but will not be formally adopted as guidelines.

Dr. Fisher returned discussion to WPC-001, regarding determination of a
pathogen-free region surrounding the test site.  Dr. Carroll must ensure
that the region is pathogen-free, or must trap mosquitoes during the
study for testing for pathogens.  Mr. Carley stated that the Board must
consider whether using sentinel flocks is the best indicator of a
pathogen-free region or if testing pools of mosquitoes is more
indicative of a pathogen-free region.  It is also critical to determine
the size of the “pathogen-free region.”  Dr. Lebowitz stated that it
is critical to determine that the mosquitoes collected during testing
are pathogen-free.  If this is not the case, a subject may have been
infected, which is a critical ethical issue.  The current standard is to
use pools of trapped mosquitoes.  Entomologists and infectious disease
experts likely have information concerning the region need to consider
an area to be free of potential risk, and also on the behavior of
mosquitoes that informs determination of the risk area.  Sentinel flocks
are a secondary measure of a pathogen-free area, but this information
can be obtained more quickly than mosquito testing.  Dr. Philpott
commented that the best approach may be to rely on experts in this area,
as Dr. Carroll did.  Procedures should be redefined to reflect that if
experts conclude that disease is absent from an area, this is
acceptable.  Dr. Carley asked whether inclusion of a letter from the
local mosquito control agency would suffice.  Dr. Fisher agreed that
this was permissible, or the investigator could include the agency’s
monthly report concerning the presence of pathogens.  She also suggested
that if there was concern because of detection of a pathogen in a
sentinel flock, serological testing of mosquitoes caught during the
study could be performed; a plan for alerting subjects if a pathogen is
found during mosquito testing should be developed.

Follow-up From Previous Day’s Discussion 

Mr. Jordan had no follow-up comments from Wednesday’s discussions. 
Mr. Carley verified that a product containing 40 percent OLE in a pump
spray formulation is registered with EPA.  He also reported that 100
percent of all human studies reviewed by the HSRB to date have been
subject to EPA audit.  All research records have been found to be
complete and there were no GLP issues.

Dr. Fisher introduced two consultants who participated in Board
deliberations at this meeting.  Dr. Yiliang Zhu is a professor and
directs the Biostatistics Ph.D. program and the Center for Collaborative
Research at the Department of Epidemiology and Biostatistics, College of
Public Health, University of South Florida.  He has served on several
advisory committees, including the NAS/National Research Council
committee on EPA’s reassessment of dioxin risks and serves on the
Organ Transplant Advisory Committee at DHHS.  His research focuses on
quantitative methodologies in health risk assessment.  Dr. David Hoel is
Distinguished University Professor in the Department of Biostatistics,
Bioinformatics, and Epidemiology at The Medical University of South
Carolina, Charleston, South Carolina.  Dr. Hoel worked at the National
Institute of Environmental Health Sciences as Director of the Division
of Environmental Risk Assessment.  He has served on a number of advisory
boards and has an interest in the modification of adverse health effects
caused by environmental factors such as chemicals and radiation. 

HSRB Workgroup and EPA Process on Confidential Business Information
(CBI) Redacted Submissions

Mr. Jordan described two skin irritation studies which involved the
first claims of CBI for a study reviewed by the HSRB.  These studies
differ from those quantifying effect levels for hexavalent chromium
because they seek to categorize products within a range of irritators or
sensitizers.  Neither product is expected to cause irritation or
sensitivity; nonetheless, the studies excluded from the study population
those who might be sensitive to the products.  The hexavalent chromium
studies also employed a repeat open application testing procedure,
whereas these studies were conducted by application of the product via
patches placed in direct contact with the skin.

The products involved in these studies also were subject to CBI claims. 
The Board had previously proposed a process for handling CBI issues,
with the goal of providing as much information to the HSRB as possible,
ensuring adequate information for a sound review, and permitting the
review to be conducted during a public meeting.  The Board did not
receive information deemed CBI by the sponsor.  The CBI process also
seeks to encourage sponsors to make CBI claims only when necessary and
to limit their scope, providing for an informal EPA assessment of the
appropriateness of CBI claims.  If EPA finds the claims to be
reasonable, EPA will provide redacted material to the HSRB Chair.  The
Chair will appoint members of the HSRB to a workgroup to review the
redacted material and inform EPA whether the material provided is
adequate for a sound review.  If concerns are raised by work group
members, EPA and the Chair will discuss whether the Board can have
access to additional non-CBI information that addresses the
workgroup’s concerns.

For the protocols discussed at this meeting, initial CBI claims were
broad, but after discussion, the sponsor agreed to limit the CBI claim. 
The Board workgroup reviewed the materials and determined a need for
further information, which OPP has attempted to provide.  The most
important information requested by the work group was toxicity data; a
summary of toxicity information on three major active ingredients in
insect repellents was provided, but the ingredient(s) used in the
studies themselves was not identified.

Dr. Fisher provided further detail on how the process for working with
CBI claims was developed.  An overarching issue was the need for Board
deliberations to remain transparent to the public, and respect both the
CBI claims of the sponsor, and the responsibility of EPA to respect and
protect CBI.  In cases for which EPA believes CBI claims are invalid,
the Board wishes to support EPA.

As part of the process, EPA contacts registrants who may make a CBI
claim to inform them that materials and information not claimed as CBI
will be reviewed by the HSRB in a public session.  EPA encourages the
registrant to provide as much information to the Board as possible, to
facilitate accurate assessment of the scientific validity and value of
the study, the safety risks to subjects, and the human subjects’
protection.  The Board anticipates that toxicity data on an ingredient
whose identity is claimed as CBI and other forms of safety and efficacy
information will frequently be necessary for Board review.  One example
of potential CBI is the name of the sponsor, which could be redacted
from the Investigational Review Board (IRB) report and ICFs. 
Additionally, EPA can provide the Board with a statement that EPA has
identified no unethical conflicts of interest between the sponsor,
investigator, and potential subjects.  The DFO can determine whether
there is a statutory conflict between Board members’ HSRB
responsibilities regarding the protocol and private interests and
activities.  If the active ingredient is claimed as CBI, the registrant
can provide animal or human toxicity data that will assist the Board
with safety and efficacy evaluations.

After completion of the prior tasks and gathering of redacted materials,
EPA holds an planning meeting with the Board Chair and DFO to discuss
the nature of the CBI claim, information the Board will not be able to
view because of the claim, and steps that will be taken to provide the
Board with sufficient information for its review.  After the planning
meeting, the Chair will identify Board science and ethics members who
would be most appropriate to serve as primary reviewers of the protocol.
 These HSRB members will receive the question(s) EPA will ask the Board
to address; a general description of the nature of the CBI and non-CBI
materials; and a description of supporting information regarding the CBI
claims that will be made available to the Board.  Drs. Fisher and Fenske
were chosen to serve as workgroup members for the protocols with CBI
claims discussed at this meeting.

The workgroup analyzes the available information and reports to Dr.
Fisher whether the information would be sufficient to help the Board
answer EPA's questions and if not, what additional non-CBI materials or
statements by EPA regarding the nature of the CBI information would be
required.  The Chair will review the workgroup’s analysis and
communicate to the HSRB DFO the Chair's evaluation of whether additional
information is needed for Board review.  The Chair will request that
EPA, to the extent legally permissible, provide the information to the
Board.

A description of the general nature of CBI and steps taken to provide
background information within legal limits will be included in the
materials submitted to the full Board for review.  A representative of
the registrant may make a presentation and answer questions at the
public meeting to ensure the Board has adequate information to advise
EPA and to ensure that CBI is protected at the open meeting.

The workgroup evaluation of the materials for the patch test studies
discussed during the meeting found an absence of toxicity data; no
rationale for the dose level selected; no information concerning whether
the experimental dose level is the level that consumers would use; an
informed consent document that indicates five insect repellents but
study reports for only two; and a lack of background information to
assess the risks to participants.  During the planning meeting, EPA
stated that this information could be obtained based on publicly
available information.  Dr. Fisher expressed surprise that most of this
information was not initially provided, and that EPA did not know it was
not provided.  A letter from EPA indicating what additional information
they can provide would be useful.

Completed Skin Patch Tests

Background

Mr. Carley presented background information on the completed skin patch
tests conducted with two insect repellent products.  The products tested
in this and the repeat insult patch test (RIPT) study are intended to be
applied repeatedly to large areas of skin and thus should be
non-irritating.  The sponsor has performed these tests to confirm
non-irritation and characterize any irritation or sensitization
potential.

The first submission of documentation occurred in May 2006.  While these
are pre-rule studies, 40 CFR §26.1303 still applies because further
documentation was submitted in November 2006.  The November 2006
submission contained broad claims of confidentiality.  In February 2007,
the sponsor resubmitted the study with narrowed claims of
confidentiality, in both complete and releasable redacted versions. 
Responses to EPA reviewer questions were submitted in March 2007, in
both complete and releasable redacted versions.  These studies involved
third-party research with intentional exposure of human subjects,
intended for submission to EPA under the pesticide laws.  Because the
studies were initiated before April 7, 2007, pre-review of the
protocol was not required and applicable ethical standards are 40 CFR
§26.1703 and §26.1704.

The studies were submitted with supplemental claims of CBI.  FIFRA
§10(d)(1) requires EPA to protect from disclosure the identity or
concentration of pesticide inert ingredients in pesticide products, and
information concerning manufacturing or quality control processes for a
pesticide product.  The scope of supplemental claims can include the
identity of the sponsoring company, product name and form, or the
identity and concentration of the active ingredient.  Claims of
confidentiality must be substantiated.  In this case, the registrant
argued that making public the applicant’s name, trade name of the
proposed product and form, and composition of the new product prior to
registration approval would place the registrant at a competitive
disadvantage.

These studies underwent the pilot process on CBI redacted submissions as
described.  Concerns of the HSRB workgroup included a lack of
information concerning the identity and concentration of active and
inert ingredients in the tested products.  To address this concern, EPA
has received complete information on product composition in the
Confidential Statements of Formula submitted by the registrant and has
informed the HSRB that the active ingredient currently is registered as
a repellent by EPA and occurs in these products at concentration ranges
previously approved for other products containing this ingredient.  The
HSRB workgroup also expressed concern about the lack of toxicity
information provided for the product ingredients.  EPA received other
toxicity information on the formulated products, including toxicity
profiles of the component ingredients, published reports of irritation
and sensitization potential, and provided World Health Organization
(WHO) profiles of registered repellent active ingredients to the HSRB. 
The HSRB workgroup also noted a lack of rationale for dose levels.  EPA
informed the work group that the dose used (0.2 ml of product on a
2 cm-by-2 cm patch) is standard practice in cosmetics and consumer
products patch testing.  Additionally, the patch dose of 0.2 ml/4 cm2 is
equivalent to 30 ml/600 cm2, which is approximately 30 times the typical
user repellent application rate; this elevated dose is appropriate for
these patch tests.  The work group’s final concern focused on the lack
of information reported for other materials included in the studies. 
These studies represent multi-material, multi-sponsor patch studies,
with single-material reports, which is common practice in cosmetics and
consumer products testing.  The patches are separated during testing,
and thus no interference between test materials is expected.

Dr. Fisher questioned why FIFRA considers manufacturing or quality
control processes CBI.  Mr. Carley explained that the purpose behind
this provision was to protect pesticide registrants from being forced to
disclose information that would offer competitors an unfair competitive
advantage.  Dr. Fisher asked whether quality control processes could
impact the safety or quality of the ingredients.  Mr. Carley indicated
that this was not a concern.  He explained that the scope of these
protections actually is narrow.  The U.S. Supreme Court concluded that
the phrase “health and safety data” is broad, but information
concerning manufacturing and quality control processes must be made
public 30 days after registration, and that certain ingredients must be
listed on labels.

Dr. Fenske commented on the lack of rationale for dose.  If the
rationale for a given dose is “standard practice,” documentation
should be included.  For example, if the procedure is Food and Drug
Administration (FDA) approved, some statement to indicate that it is
approved by a government agency for cosmetic and consumer products would
be helpful.  Mr. Carley agreed, adding that EPA does not have
guidelines for accepted protocols for these studies.  Submitters have
attached articles from the Cosmetic, Toiletry and Fragrance Association
describing a range of practices, but the articles do not describe the
best way to perform such testing.  The most accurate way to consider
this is to understand there are different ways to perform these studies
that fall into several general categories; if done often enough by a
given laboratory, the protocols become routine, although they do not
really become standardized.  Dr. Roger Gardner (OPP, EPA) added that for
pesticide tests on animals, there are standard procedures with
recommended doses based on a large database of information.  The goal of
the studies is to determine if irritation can be induced; the criterion
calls for choosing a dose at which irritation is likely to occur.  Dose
also is only qualitatively related to anticipated consumer exposure;
most guidelines call for exceeding this dosage.  Dr. Fenske reiterated
that because there do not appear to be recommendations for human studies
available through EPA, information from other agencies, such as FDA,
would be helpful.  Dr. Gardner explained that late in the review process
for these studies, EPA found that FDA has draft guidelines; however,
insufficient time was available to ascertain the rationale for dosing.

Dr. Fish inquired whether the dose range was consistent with those used
in Dr. Carroll’s studies.  Mr. Carley responded that these are very
limited dose studies and are not appropriate for extrapolating dose to
the very different materials tested in the primary irritation studies. 
For repellent testing, a dose of 1 g/600 or 650 cm2 is used, based on a
survey of DEET users, to approximate consumer dose of a repellent.

Dr. Menikoff noted that five compounds had been applied to subjects, but
the results of only two of these are reported.  He asked if EPA knew the
identity of the other three compounds.  Mr. Carley indicated that EPA
does not know the identity of the compounds; registrants indicated that
these were “developmental compounds.”  Dr. Menikoff remarked that
this had implications for informed consent and asked if it had been
verified that subjects received truthful information about the
compounds.  Mr. Carley explained that these questions would be addressed
during EPA’s review of the studies.  He added that five materials were
used in the 48-hour irritation study, but 16 were used in the RIPT
study; most of these materials were provided by other sponsors and EPA
does not have information on their identities.  Dr. Kim inquired how EPA
could rule out interference among materials if the identity of the other
materials is unknown.  Dr. Gardner responded that dermal effects are
specific and local.  The selection criterion of dosing for sensitization
is different from that of dose selection for irritation.  There also are
dermatologic indicators that differentiate between irritation and immune
responses indicating sensitization.  The effects of irritation studies
are local, similar to the effects of food allergy skin tests.

Dr. Lebowitz questioned if EPA asks toxicologists to verify information
from registrants concerning the toxicity of ingredients found in the
products.  Mr. Carley confirmed that this was the case.  Dr. Lebowitz
also asked whether animal toxicity skin testing literature was used to
determine if products had potential sensitization capabilities before
testing the products in humans.  Dr. Gardner explained that animal test
results (using guinea pigs) are available for sensitization potential of
active ingredients in pesticide products.  This information is required.
 EPA relies on background data as well as toxicity tables to assess
sensitization potential.  Dr. Fisher noted that these tests use the
assumption that each patch has independent effects.  She cautioned that
there are practices over which EPA has no control, such as the
participation of multiple sponsors and use of multiple materials in a
single study.  The Board must be alert to potential problems arising
from this situation.

48-hour Primary Dermal Irritation Study

Background

Mr. Carley presented background information on the 48-hour Primary
Dermal Irritation Study.  Documents were submitted covering product A
(MRID 47077101, Code 1000718-008) and product B (MRID 47093901, Code
1004006-005).  Supplements, both identical in content, were also
submitted for each product (MRIDs 47077201, 47077601 for products A and
B, respectively).  Products A and B are both repellents containing the
same EPA-registered active ingredient at concentrations within a
previously accepted range, and contain similar pesticide inert
ingredients.

Each of the two study reports describes results for one of five
substances tested in a single execution of the protocol with a single
subject panel; results have been submitted for two of the five
substances tested.  All subjects were non-pregnant, non-nursing
consenting adults, free of skin disease, not sensitive to similar
products, and not using medications.  The study enrolled 54 subjects; 53
completed the study.

The study schedule called for application of 0.2 ml of five test
materials to 2 cm-by-2 cm Webril patches (five patches per subject),
followed by air-drying for 30 minutes before application of the patches
to each subject’s back.  Forty-eight hours after application, the
patches are removed and sites evaluated.  If the first evaluation is
positive, a second reader re-evaluates the site.  Seventy-two hours
after application, the sites are evaluated again.

The dermal LD50 limit dose is greater than 2,000 mg/kg for the active
ingredient.  The margin of exposure (MOE) for an applied dose of 0.2 ml
to a 70 kg adult is greater than 350.  Skin loading of 0.2 ml/4 cm2 is
approximately 30 times loading at the “typical consumer dose” of a
repellent (1 g/600 cm2).

Science Assessment

Dr. Gardner presented EPA’s science assessment of the 48-hour Primary
Dermal Irritation Study.  EPA requires primary dermal irritation data
under 40 CFR Part 158 for registration of all products.  Guidance for
conducting animal tests of irritation is published under EPA’s Office
of Prevention, Pesticides and Toxic Substances Test Guideline 870.2500
and corresponds to Organisation for Economic Cooperation and Development
Test Guideline 404.  The results from such studies are used to identify
possible effects from exposure of the skin to the test substance and are
used to support precautionary labeling.

EPA classifies irritants according to toxicity category.  Category I
substances are corrosive and/or scarring; Category II substances can
cause severe irritation at 72 hours (severe erythema or edema); Category
III substances can cause moderate irritation at 72 hours (moderate
erythema); and Category IV substances cause only mild or slight
irritation (no irritation or slight erythema).  Standard precautionary
statements are based on the toxicity category.  For example, the label
for a Toxicity Category III substance might include language cautioning
consumers to avoid contact with skin or clothing and to wash thoroughly
with soap and water after handling.  Toxicity Category IV substances do
not require precautionary statements, but registrants may choose to use
Category III labeling standards.

EPA encourages minimization of unnecessary animal testing.  EPA does not
encourage human irritancy testing, but has accepted it in place of
animal testing in some cases.  The submitter of this study requested a
waiver of the usual requirements for animal testing of dermal
irritation, because each component in the products tested is discussed
in published literature, has a history of use as an intentional food
additive or in cosmetics products directly applied to human skin, and is
well-known to EPA.  The waiver request also argues that there is
published literature on product components that indicates most are mild
to slight irritants that would be classified as Toxicity Category IV.  A
few of the substances are moderate irritants that would be classified in
Toxicity Category III, with labeling to “avoid contact with skin.”

Subject inclusion criteria called for males or females who were at least
18 years old and in general good health; were free of any systemic or
dermatologic disorder which would interfere with the results of the
study or increase the risk of adverse events; were of any skin type or
race, given that the skin pigmentation allowed discernment of erythema;
had completed a medical screening procedure; and had signed an ICF. 
Exclusion criteria excluded subjects who had any visible skin disease
which would interfere with the evaluation; were receiving systemic or
topical medication which would interfere with the study results; had
psoriasis or active atopic dermatitis or eczema; were pregnant, planned
to become pregnant during the study, or were breast-feeding; and/or had
a known sensitivity to cosmetics, skin care products, insect repellents,
or to topical drugs related to the material being evaluated.

The study enrolled 54 participants; one participant withdrew.  The
participants included 48 females and six males, ranging in age from 19
to 71 years (average age was 51 years).  Subjects were primarily
Caucasian.

The study protocol involved application of 0.2 ml of five test materials
to 2-by-2 cm Webril patches (five patches per subject), followed by
air-drying for 30 minutes before application of the patches to each
subject’s back.  Forty-eight hours after application, the patches are
removed and sites evaluated.  If the first evaluation is positive, a
second reader re-evaluates the site.  Seventy-two hours after
application, the sites are evaluated again.

Reactions were graded using a +/- system.  The reaction categories were
no reaction (-); minimal or doubtful response, slightly different from
surrounding skin (?); definite erythema, no edema (+); definite
erythema, definite edema (++); and definite erythema, definite edema,
vesiculation (+++).  The Primary Irritation Index (PII), used for
classification, was calculated as the higher mean score at either the
48-hour or 72-hour observation, calculated by dividing the sum of
reaction scores for all subjects at each observation time by the number
of subjects in the group.  A PII of 0.50 or less indicates that the
product is essentially non-irritating; these products are the equivalent
of Toxicity Category IV.

Results and Discussion

Most of the responses in this study were in the marginal category.  A
“?” was used when response effects were reversible, and thus
indicate irritation, not sensitization.  A high proportion of subjects
had marginal responses, which could be a result of having an occlusive
patch on the skin.  Two areas of concern include a lack of untreated
patches as negative controls, rendering questionable the association of
observed responses with the test substance.  Additionally, the patches
were dried before application, which resulted in a markedly different
pattern of exposure from typical use of a topically applied repellent. 
The rationale for this approach was to ensure that the liquid product
remained at the test site so that a dose exceeding the typical consumer
dose was achieved.  Dr. Gardner expressed concern that this approach
resulted in a lack of skin contact by volatile components of the
products, which would evaporate before patch application.  Changes in
the products’ physical characteristics as they dry could affect the
irritation potential of the products.

The lack of negative controls and different pattern of exposure
represent significant scientific limitations; however, the data are
considered sufficiently reliable to be used in conjunction with other
information on the irritancy potential of product ingredients to support
the conclusion that these formulations do not cause more than mild skin
irritation.

Ethics Assessment

Mr. Carley presented EPA’s ethics review of the 48-hour Primary Dermal
Irritation Study.  He noted that the Board had expressed concern that if
the identity of the sponsor was subject to CBI, conflict of interest
issues could arise; he informed the Board that EPA had not identified
any conflicts of interest.

Applicable ethical standards include 40 CFR §26.1303 (defines standard
for documenting ethical conduct of research), 40 CFR §26.1703 (forbids
EPA reliance on research involving intentional exposure of pregnant or
nursing women or children), and 40 CFR §26.1704 (forbids EPA reliance
on research if there is “clear and convincing evidence” that its
conduct was fundamentally unethical or significantly deficient relative
to standards prevailing when it was conducted).  The initial submissions
did not address the requirement of 40 CFR §26.1303 to document ethical
conduct.  Resubmissions are adequate to support review; however,
discussions of risk, risk minimization, benefits, and risk/benefit are
weak, but acceptable for pre-rule studies.

The purpose of this study was to determine the ability of two
experimental repellent products (and three other unidentified materials)
to cause immediate irritation by application to human skin under
controlled patch conditions.  The sponsor’s policy is to avoid
“unnecessary use of animals in testing;” thus, this study was
submitted to support a request for waiving EPA’s normal requirement
for animal testing of irritancy.

The 54 subjects enrolled in the study (53 completed it) were selected
from among subjects who previously participated in research at this
laboratory; they were recruited as they completed a previous study.  The
subjects received $30 compensation for three visits, which was
considered likely to attract primarily economically disadvantaged
subjects.  There were no other indications that subjects were from
vulnerable groups.  The risks associated with participation were
described to subjects in generic terms; both the irritation and RIPT
studies were described identically.  Although identifying weak irritants
before marketing and use has potential societal benefit, this assay is
unable to identify weak irritants.  EPA concluded that, if
scientifically acceptable, the benefit of this study probably justifies
the low incremental risks to subjects.

The study was reviewed by the Allendale IRB (AIRB) of Allendale,
Pennsylvania, which is registered with OHRP but not known to be
accredited.  The submitted documentation of IRB composition, procedures,
and review meets regulatory requirements.  General compliance with FDA
rules was asserted by TKL Research, which performed the study.

Written consent was obtained from all subjects, using an ICF approved by
the AIRB.  This document was highly generic and sometimes unclear, and
the consent process emphasized reliance on frequent test subjects, and
on establishing their eligibility rather than their fully informed
understanding.  Review of applicable documentation found that subject
privacy was not compromised in the reports.  The subjects were paid only
upon completion of the study, which may have unduly influenced subjects
not to withdraw.  Subjects also were offered a “finder’s fee” for
referring others, but were paid only if the referral completed testing,
which also may have unduly influenced referral subjects not to withdraw.

Ethical concerns include recruitment of subjects from a population of
frequent test subjects, without explicit consideration of
representativeness.  The compensation was low and may have
disproportionately attracted economically disadvantaged subjects. 
Compensation was tied to completion of the study, which may have
compromised freedom to withdraw.  Additionally, although possible
lasting effects (change in skin pigmentation, generation of allergies)
were acknowledged, treatment promised only “to relieve the immediate
problem,” and only for undefined “significant reactions.”  A
troubling qualified promise was made to identify the agent that induced
an allergic reaction.  There was unnecessary identification of subjects
by Social Security Number.  Because the assay may be inadequate for
identifying weak irritants, this study may be inappropriate for
determining irritation category.

There were some gaps in documentation of ethical conduct, but
documentation was relatively complete for pre-rule research.  There was
no clear and convincing evidence that the research was fundamentally
unethical and no intentional exposure of children or pregnant or nursing
women occurred.  EPA had many ethical concerns about this study, but
concluded that the research was consistent with common practice in
testing cosmetics and other consumer products not regulated as
pesticides.  There was no clear and convincing evidence that the
research was significantly deficient relative to prevailing standards.

The charge to the HSRB was to determine whether these studies are
sufficiently sound, from a scientific perspective, to be used as part of
a weight-of-evidence assessment to evaluate the potential of the
formulations tested to irritate human skin and to determine if there is
clear and convincing evidence that the conduct of these studies was
fundamentally unethical, or significantly deficient relative to the
ethical standards prevailing at the time the research was performed.

Mr. Jordan corrected the MOE for subjects in this trial as being greater
than 60,000 to 70,000, not 350 as previously reported.

Dr. Fisher inquired if the data, if used, would increase consumer
protection.  Mr. Carley explained that the basic requirement for
consumer protection is an animal study.  This protocol was submitted to
request EPA waive animal tests.  Thus, EPA cannot determine if testing
in humans would provide information significantly different from that
derived from animal testing.

Dr. Fish inquired whether readers of the dermal reaction were blinded. 
Dr. Gardner responded that no information was provided on blinding. 
Because control patches were not used, blinding would only mask the
identity of the different products.

Dr. Menikoff asked about the relationship between human and animal
testing, particularly whether a company could seek EPA approval for a
product based only on animal testing.  Mr. Carley explained that the
standard data requirement for these products is a standard animal test
of dermal irritation.  Dr. Gardner added that in the waiver rationale,
the registrant argues that because the products would be applied
directly to the skin, the results would confirm a body of evidence on
separate components that suggest no irritation.  With potentially
dangerous products, EPA labels reflect the most dangerous component,
regardless of product composition.  For these products, a person who
experiences irritation likely will discontinue use; further
consideration of consumer behaviors falls under risk management.

Dr. Brimijoin asked Mr. Carley to expand on concerns that the assay is
of dubious value because it does not identify minor irritants.  Mr.
Carley explained that the study report indicates the evaluation method
used will screen out strong irritants, but not weaker irritants that
require multiple exposures.  Dr. Brimijoin inquired if this affected the
Board’s response to the first charge question, concerning whether the
studies were sufficiently sound to evaluate the potential of the
products to irritate human skin.  He asked whether knowledge that the
registrants have excluded the possibility of major irritation could be
considered a major part of a weight-of-evidence assessment.  Dr. Fisher
questioned whether the purpose of the study was to identify all levels
of irritation or only severe levels; the registrants admit they cannot
evaluate low levels of irritation.  She requested clarification on the
value of the study claimed by registrants and the value of the study to
EPA.  Mr. Jordan explained that EPA has a large amount of information
about this formulation and its ingredient.  EPA requested the Board’s
opinion concerning the scientific soundness of the study, and to
describe its strengths and limitations.  EPA seeks to assign this
formulation to one of four irritant categories.  The product is likely
to fall into Category IV (non-irritant) or Category III (slightly or
mildly irritating).  EPA will make labeling decisions based on the
assigned category.

Dr. Philpott raised the issue of the registrant’s request for a waiver
for animal testing, and whether EPA believes there is sufficient
evidence from animal and in vitro testing to support this request.  Dr.
Gardner explained that data were provided as published literature.  EPA
has significant experience with these types of pesticide studies, and it
is not difficult to make extrapolations based on data from individual
components.  EPA takes a conservative approach to identifying risk;
labeling is based on the highest toxicity category of an ingredient in a
product.

Dr. Lois Lehman-McKeeman asked Dr. Gardner if EPA had confirmation of
product composition and whether, under standard clinical practices,
analytical verification of composition is required.  Dr. Gardner
responded that analytical verification was not required because the
products in the study are of known composition; product composition
information was supplied and certified by the registrants.  They
provided a confidential statement of the formula that reports a range of
ingredients and product chemistry characteristics, such as stability.

Dr. Krishnan inquired whether, given that five products were tested
simultaneously, there was concern that the actual MOE is lower than that
calculated.  Dr. Gardner stated that this was not a concern because the
products are already known to be of low toxicity.  If there is a direct,
acute effect; this effect will not extend to the other products unless
the other products are sensitizers, which this assay cannot determine. 
The MOE for all the products likely is low, and aggregation of MOEs
would result in a low MOE.

Public Comments

Dr. James Milbauer and Ms. Milena Reckseit of TKL Research

Dr. James Milbauer (TKL Research consultant) explained that TKL Research
performed the patch testing for a corporate sponsor seeking
weight-of-evidence to address the issue of a waiver for animal testing. 
The patch test protocol used is based on a long record of literature
published since the 1950s by academic dermatologists and others. 
Despite this record, specific protocols for performing patch testing are
not available, although most investigators perform the testing
similarly.  The patch test commonly is used for diagnosis of contact
dermatitis.

The manufacturer performed preclinical testing before beginning human
testing to determine the safety of the product.  The sponsor believes
that, because different species react differently to substances, human
patch testing, although not required by EPA, would further ensure the
safety of those using the products.

Dr. Milbauer addressed the inability of this test to measure weak
irritants.  He commented that most irritants are distributed along a
gradient of irritation potential, and pre-clinical testing screens out
the greatest risk associated with the product.  This test widens the
sponsor’s “comfort level” concerning this product.  The sponsor
realizes that the weakest irritants that require repeat exposure to
induce irritation will not be identified in this test.  Additionally, no
test can ensure that no one in a population will react to a product, but
testing can determine that the product will be safe for most users.

Ms. Milena Reckseit (TKL Research) addressed the Board’s questions
concerning the attractiveness of the low amount of compensation ($30) to
primarily financially disadvantaged people.  She explained that most
subjects lived in New Jersey or in one of four New York metropolitan
areas and hale from a range of socioeconomic and demographic
populations.  The majority of the subjects (71.5 percent) are from towns
with average household incomes greater than $66,000, in contrast to the
average American household income of approximately $42,000.  On average,
60 percent of inhabitants of the areas from which subjects came are in
the labor force, and slightly more than 60 percent own their own home;
approximately 4.3 percent of the population live below the poverty
level.  Approximately 93 percent of study participants were white, were
largely female, and most ranged in age from 35 to 64 years.  Roughly 71
percent of study participants live in towns approximately 3 miles from
the site; the subject fee of $30 ($10 per visit) was considered
reasonable in part because participation required little travel.

Dr. Fisher asked Dr. Milbauer and Ms. Reckseit to clarify the AIRB’s
response to the lack of information on three of the five materials
tested in the 48-hour Primary Dermal Irritation Study.  Dr. Milbauer
explained that the AIRB received verbal communication from the sponsors
that the other three products are approved and marketed repellents.  The
sponsor wanted to ensure that the new products were no more or less
irritating than the other three products.  Dr. Fisher inquired whether
the AIRB received a risk-benefit analysis for all five products and how
the AIRB could determine the ICFs are appropriate across all five
products.  Dr. Milbauer responded that he was not involved in the
informed consent process, but believed that the AIRB received
information for all five products.

Dr. Fish asked Dr. Milbauer to explain the practice of using a second
reader to assess irritation and why the study was not blinded.  Dr.
Milbauer explained that it is not standard to use blinding in these
types of studies.  An objective reaction—is the skin red or not, or is
the reaction questionable—was being assessed.  A second reading was
performed after 15 minutes; the report indicated that if a reading was
positive, a second reading was performed by a different reader.  Dr.
Milbauer could not confirm whether the same person had performed all
readings.

Dr. Chadwick asked whether the sponsor or TKL Research, or another body,
developed the protocols.  Dr. Milbauer answered that a Board-certified
dermatologist (Dr. Jonathan Dosik) was listed as the investigator on the
protocol.  TKL Research does write protocols for clients, but
Dr. Milbauer could not confirm whether this was the case for this
study.

Dr. Philpott inquired whether the AIRB read and approved the telephone
script for recruitment.  Ms. Reckseit explained that no advertising or
telephone screening was performed for the Primary Dermal Irritation
Study.  The subjects participating in this study had participated in a
previous TKL Research dermal safety study.  TKL Research has processes
in place to determine that subjects were eligible to participate in the
Primary Dermal Irritation Study.  TKL Research maintains a large
database of subjects who participate in dermal safety studies.  The
processes are routine, because TKL Research has data indicating that
these subjects are “patch qualified.”  At the recruitment level, the
subjects are considered “prospective subjects” during the in-person
interview and undergo onsite medical screening and a formal consent
process before enrollment in the study.  Dr. Philpott noted that because
a telephone interview would collect personal health information, verbal
informed consent should have been obtained from participants, despite
their being considered “prospective subjects.”  Ms. Reckseit
explained that for the Primary Dermal Irritation Study, experienced
recruiters privately interviewed each subject and informed them about
this new study.  The subjects were already known to be “patch
qualified.”  TKL Research has the subject information, and upon
enrollment in the new study, their information was re-entered into the
database and labeled with a start date of April 26.  Based on this date,
eligibility reports were issued indicating the subject’s correct age,
patch-qualification, current residence, and any dermatologic conditions
indicated in their medical history.  The reports are issued to clinic
staff; the informed consent process begins at the in-person medical
screen.  The ICF is signed after completion of the medical screen.

Dr. Fenske questioned whether allowing the test materials to evaporate
on the patch for 30 minutes would affect the irritation potential of
the materials.  Dr. Milbauer explained that this is standard procedure
in clinical and industry practice.  Volatile compounds evaporate rapidly
during use of a product and thus will not be persistent against the
skin.  Trapping these compounds against the skin with an occlusive patch
creates an artificial, potentially irritating situation that could
obscure the irritation potential of the product itself.  Dr. Fenske
requested clarification of the fifth exclusion criterion that excludes
anyone with known sensitivity to products related to the material being
evaluated and how many people this was expected to encompass.  Dr.
Milbauer stated that he would expect a small number of people to be
affected by this; subjects are asked if they are allergic to repellents
or cosmetics and are excluded if they are.  The rationale for this
exclusion criterion is to avoid testing people with a history of
allergies.  Allergies probably are irrelevant to the testing of these
products, but the sponsor believed it was safer to exclude people with
known allergies.  Dr. Fenske inquired whether Dr. Milbauer would expect
the product to be labeled in such a way that would caution this
population against using it.  Dr. Milbauer responded that they try not
to provoke allergic reactions when testing irritation.  Allergies do
not, however, predispose people to irritation.

Dr. Fish asked whether Social Security Numbers were collected for
payment purposes and if they were kept separate from research data.  Ms.
Reckseit explained that both these conditions were true.  Dr. Fish noted
that the study documentation includes Health Insurance Portability and
Accountability Act (HIPAA) language, but most contract laboratories are
not covered by HIPAA.  Ms. Reckseit added that TKL Research wants to be
conservative and assure subjects their health information will not be
used beyond the scope of the study, and therefore works to be
HIPAA-compliant.

Dr. Suzanne Fitzpatrick inquired if investigators ensured that test
patches were not applied to the same spot on the back as patches tested
by repeat subjects in previous studies.  Ms. Reckseit explained that
the test area is delineated by a line on the subject’s back, and that
area is not used in a subsequent study.  As part of enrolling in a
second study, clinical staff determine that subjects have no residual
irritation or other problems on the skin on their backs.

Mr. William McCormick of The Clorox Company

Mr. William McCormick identified himself as a Board-certified
toxicologist working for The Clorox Company.  He performs toxicity
testing related to EPA registration of products.  He clarified the
endpoint—primary skin irritation—addressed in the study under
discussion.  The primary irritation index in humans measures acute
irritation, thus, non-identification of weak irritants is accurate.  A
second study of irritation in humans is the cumulative irritancy study,
which involves 21 days of application to identify weak irritants.  The
Primary Dermal Irritation Study tests for the primary irritation
endpoint and thus is a grosser estimate of irritation.  He added in
response to Dr. Fisher that companies often tend to prefer using humans
for these studies, rather than animals, such as rabbits.  Dr. Fenske
asked whether the primary skin irritation test would be sufficient to
determine if the products are Category III or Category IV irritants. 
Mr. McCormick answered that this test would permit such categorization. 

Board Discussion

Dr. Hoel expressed surprise that EPA and HSRB are discussing what
appears to him to be more suitable for FDA consideration, considering
the human health effects associated with the products.  Because FDA
regulates cosmetics, the approaches used in this regulation could be
applied to these studies.  He commented on the lack of eye test data for
these products, which is a primary concern, particularly if a product is
applied using a sprayed-on formulation.  Possible inhalation also could
be a concern.  He questioned why, if the active ingredients and vehicle
used in the products are approved, the products themselves were not,
unless there was concern over interaction of the ingredients.  Dr. Hoel
also questioned why, given that three animals are usually considered
sufficient for an animal test, a company would decide to test its
products on 50 humans.

Dr. Hoel commented that the $30 compensation payment to research
subjects could be considered almost a volunteer-level of compensation. 
He added that the subject population selected did not appear to be
representative of the population as a whole.

Concerning analysis of outcomes, Dr. Hoel noted that three of the 50
subjects had adverse events, the rest had minor or no outcomes, but the
average score was the same.  Ordering could be used to strengthen the
statistical analysis; however, problems include determining who a group
would be compared to, how power is determined, and lack of negative
controls.  

Scientific Considerations—48-hour Primary Dermal Irritation Study

Dr. Fenske opened the HSRB scientific review of the study.  He stated
that EPA’s decision to label the product as Category III prompted the
sponsor to perform the study.  EPA raised concerns related to applying
the product to a patch and allowing it to dry before application.  Dr.
Milbauer explained the rationale for this approach.  In Dr. Fenske’s
opinion, the application procedure is valid because use of an occlusive
patch could permit moisture to develop and allow product and/or solvents
to penetrate into the skin and cause irritation.  The occlusive nature
of the patch itself would be a confounder for irritation.

Of those cases marked as positive for irritation (7), the irritation had
resolved to questionable status by 72 hours after application of the
patch, indicating reversal of irritation.  Testing for 72 hours is
considered acceptable.  Negative controls are not routinely used for
testing of this sort, which is a difference between academic and
third-party research.  Dr. Fenske speculated that an unfavorable finding
could be a serious consequence for third-party researchers; although
well-trained and scrupulous, there is the potential for bias if
third-party researchers seek subsequent contracts from a sponsor.  A
negative control and blinding would have strengthened the study, but
this is not a fatal flaw.  Inclusion of these conditions would help
determine whether the questionable findings were caused by the product
or the patch itself.

In its data evaluation, EPA states that the studies were incomplete and
could not be used for regulatory purposes, but in its presentation EPA
stated that the studies could be used for determining the irritancy
potential of the ingredients.  Dr. Fenske agreed with Dr. Hoel that it
would be important to determine the number of people in each of the
reaction categories; however, the study identifies the numbers. 
Additionally, no subjects had high irritancy scores by 72 hours after
patch application.  Dr. Fenske concluded that irritation noted at 48
hours had reversed at 72 hours, which suggests that application of the
products resulted in minimal response in the test population.

Dr. Lehman-McKeeman concurred with Dr. Fenske’s assessment.  Her
overall sense of the data was that the study was designed to assess
dermal hazard and there was no indication of this in any of the
subjects.  There are some limitations to the study, but no flaws that
preclude use of the data.  She stated that she was personally
scientifically unconvinced that performing this study in humans was
necessary, because rabbit studies would have adequately addressed the
issue of dermal irritation.  Dr. Fisher reminded Board members that the
HSRB also was asked to consider if the study provided useful information
for categorization of the products as Category III or IV irritation
hazards.  Dr. Lehman-McKeeman responded that tests using rabbits would
yield more compelling results, because this study identified only
products that cause significant irritation.  At this point, she believed
the study data were insufficient to distinguish between Category III and
IV.  Dr. Fenske reminded Board members that they did not have
information concerning how EPA distinguishes between Category III and IV
substances.  Although he agreed with Dr. Fisher’s point that the study
does not identify mild reactions, Dr. Fenske argued that the data do
distinguish between moderate and mild irritation and the decision for
how to use this information lies with EPA.

Dr. Fitzpatrick commented that the redacted information did not
significantly interfere with the HSRB’s review, with the exception of
determining risk to subjects during the ethics review.  She concurred
with Drs. Fenske and Lehman-McKeeman, but argued that some questions
were not answered, such as the relationship between dose and actual
amount used, specifics concerning the formulation of the products,
subject recruitment procedures, grading of reactions, and identification
of the reaction graders.  Therefore, she concluded that this report
could not be considered a good example of such a study report because of
the many unanswered questions.  She also commented on the lack of
rationale for the need for human studies and that AIRB procedures may be
less than optimal.

Dr. Kim stated that although grading the reactions of exposure using a +
or – designation is acceptable at the individual level; however,
problems arise when an average of multiple subjects’ reactions is used
to classify the products.  Given the proportion of subjects with
definite erythema and a one-sided 95 percent confidence interval (CI), a
reaction rate of up to 14 percent for one product and 16 percent for the
other cannot be ruled out.  He suggested that EPA may wish to consider
different ways of categorizing such materials.

Dr. Fisher summarized that the absence of negative controls was not a
significant problem, the data from the study were usable, and air-drying
of the patches before application was not a fatal flaw.  Considering the
reversal of reactions, another way to analyze the data could be
considered, but this also was not a significant flaw.  The study cannot
detect weaker reactions.  A lack of blinding also may be an issue.  Dr.
Chadwick responded that blinding in this study design probably would not
significantly strengthen the data because the incentive was to not find
a reaction.  

Dr. Chadwick requested clarification of the 30-minute drying procedure,
asking whether the properties of the product change when the product is
dried and whether the product was water soluble.  Dr. Gardner replied
that these matters were part of the sponsor’s CBI claims.  In his
opinion, the characteristics of the product are not likely to change
significantly when the product was dried.  Dr. Lebowitz commented that
he had concerns that volatile compounds could make the skin more
susceptible to irritation; these compounds do not contact the skin in
the study.  He added that a negative control to determine that
irritation was not caused by the patch would have been useful.  Dr.
Krishnan expressed concern about the approval of multiple products.  He
considered the issue of volatile compounds to be of less concern because
such compounds volatilize quickly with normal use and are thus less
likely to contribute to irritation.

Dr. Fisher summarized the discussion.  She stated that negative controls
would be desirable, but the data remain useful.  There was no consensus
among Board members concerning whether air drying would impact
irritation.  Dr. Fenske commented that this study resulted in 48 hours
of skin contact with the test materials, which is significantly more
contact than the average user would experience.  Unless the volatile
compounds in the product dramatically change the properties of the
active ingredients, 48 hours of occlusion offsets concerns about these
compounds.  Dr. Chadwick argued that in the absence of other
information, he remained unconvinced that the volatile compounds were
not a concern.  In response to a question from Dr. Fisher, Dr. Gardner
speculated that any additional information he could provide might not
suffice to conclusively resolve this issue.

Concerning the ability of the study to detect weaker reactions, Dr.
Fisher stated that the results were inconclusive.  If a positive
reaction is not observed after 72 hours, and if the test was not
designed to detect weak reactions, the Board cannot conclude that the
study tested the full range of possible reactions.  EPA will discuss
this issue when deciding labeling language.

Ethical Considerations—48-hour Primary Dermal Irritation Study

Dr. Fish discussed the HSRB’s ethics assessment of the study.  She
agreed with Mr. Carley’s assessment and re-emphasized that this study
would not meet current requirements.  Concerning general ethical issues,
the study used a convenient sample, which was appropriate.  Board
concerns regarding unfair inducement to the economically disadvantaged
to participate were well addressed by TKL Research staff.  The issues of
confidentiality and use of Social Security Numbers also were adequately
addressed. 

Remaining concerns include enrollment of 54 subjects although the
protocol called for 50; this would be unacceptable in academic research.
 Concerning payment, a lack of prorating payment for those who did not
finish the study is a concern.  In this regard, TKL Research did not
follow EPA guidelines for payment of research subjects.  Other concerns
include the non-payment to subjects for failing to follow protocol
instructions, and the issue of “finder’s fees” may have resulted
in undue coercion to remain in the study.

The quality of the review by the AIRB also is questionable.  The Board
must assume that the AIRB had sufficient information to identify and
weigh the risks of all substances used in the study.  Another troubling
issue is the language regarding treatment for research related injury
only if it is “significant” and an “immediate” result of the
study.  The study met 40 CFR §26.1703 and did not enroll children or
pregnant or nursing women.  Dr. Fish agreed, with some misgivings, that
there was no clear and convincing evidence of fundamental ethical flaws.

Dr. Philpott agreed with Dr. Fish.  He emphasized his concerns about the
AIRB review, including the independence of each member’s activity,
whether there was sufficient information about justification of a human
study, and the lack of information regarding subject recruitment.  Dr.
Philpott stated that there were problems with the informed consent
process, including use of verbal consenting, medical screening occurring
before subjects signed the ICF, and the associated HIPAA waiver.  He
noted that these are matters that the AIRB should have questioned.  Dr.
Philpott noted that although a subject may have withdrawn from the
study, the ICF indicated that their information may still be used.  To
preserve scientific integrity, the study design should compensate for
possible subject withdrawal from a study.  Dr. Fisher informed
Dr. Philpott that under HIPAA regulations, researchers are permitted to
use collected information even in the event of subject withdrawal.  Dr.
Philpott argued that the language on this ICF, which indicated that
“all” information could be used, was too broad.

Dr. Menikoff agreed with the comments made by Drs. Fish and Philpott. 
He stated that the Board did not have resolution concerning the
information the AIRB had on the other three products.  The study was
performed prior to establishment of the current rule and is not
fundamentally unethical but is deficient.  The failure to test the
products on animals also could be considered a deficiency, because it is
beneficial to initially test products on animals to detect serious
adverse reactions, despite the possibility of obtaining better data from
human studies.  Dr. Brimijoin noted that although the Board does not
know the identities of the tested products, they do know that the active
ingredient is one of three that are currently registered and have been
previously subjected to extensive animal testing.  This particular
formulation is new and did not undergo animal testing, but the active
ingredient was tested.  Dr. Menikoff countered that EPA requires new
combinations of ingredients to be tested; therefore, animal testing
should have occurred before human tests.

Dr. Fisher asked whether the language of the ICF adequately described
worst-case scenarios.  Irritation is listed as a worst-case event and
described side effects included redness, swelling, peeling, and small
blisters or sores—these effects are worse than those caused by a
typical Category III product.  Dr. Menikoff agreed that EPA regulations
require minimization of risk to humans; therefore, the sponsors should
have ensured no strong reactions in humans would occur.  Dr. Brimijoin
stated that WHO lists compounds that produce significant irritation in
animals, but did not produce irritation in humans.  Failure to test
these products in humans could result in the product being labeled with
a more severe toxicity category.  The intention of the sponsor was to
confirm that the products did not cause irritation in humans.

Dr. Fisher summarized that the study was deficient relative to some
accepted standards.  The Board had concerns about the lack of
willingness to prorate payment, the quality of the AIRB review, the
language for treatment of research-related injuries, medical screening
of participants before official entry into the study, and about
inclusion of HIPAA information on the ICF.  There were potential
coercive elements to the study.  The HSRB also found the justification
for human versus animal studies lacking.  Although these deficiencies
are noted, the Board considers them unlikely to have resulted in serious
harm.  Subjects were adequately informed of risks during the informed
consent process and the lack of prorating for participation likely does
not reach the level of serious harm.

Dr. Menikoff added that the AIRB approval of subject exposure to the
five compounds could have led to serious harm if the AIRB was not fully
informed about the identities and/or risks of the compounds; this issue
needs to be resolved.  Dr. Fisher added that EPA staff had indicated
that the AIRB was fully informed about all compounds tested.

Dr. Sharp requested clarification concerning whether the data were
useful to EPA versus whether the study was necessary (or could animal
studies generate equivalently useful data).  Dr. Fisher answered that
although this study may not be useful for identifying minor irritants,
the Board cannot comment on whether the data are useful to EPA for
determining its toxicity category.  Dr. Chambers stated that human
studies can be deemed necessary because many people believe animals
should not be used to test products intended for use in humans.  She
asked whether it is possible for a registrant to receive a waiver from
EPA to test products directly on humans.  Mr. Jordan stated that the
Board’s deliberations have been useful for EPA understanding of the
relative value of animal versus human testing for evaluation of
irritation potential.  At present, EPA does not have a policy on waiving
animal studies; however, in the future, if a company wishes to test on
humans a new formulation not tested in animals, but information is
available on components and possible interactions, a waiver might be
considered.

Repeated Insult Patch Test (RIPT) for Sensitization

Background

Mr. Jordan and Mr. Carley presented background information on EPA’s
review of the RIPT for Sensitization.  This study tested the same
products (products A and B) as those described for the 48-hour Primary
Dermal Irritation Study.  Sodium lauryl sulfate was included as a
positive control.  Products A and B are both repellents and contain the
same EPA-registered active ingredient(s) and similar pesticidally inert
ingredients.  The two submitted study reports describe results for one
of 15 or 16 substances tested in two parallel executions of the protocol
using two sub-panels of subjects.  The sponsor’s three patches are
reported to have remained in place for 48 to 72 hours; all others were
removed by subjects after 24 hours.  Both protocols used a single patch
containing sodium lauryl sulfate as a “compliance check;” this
reflects use of a known concentration of a weak irritant to ensure that
patches were not removed early.  All subjects were non-pregnant,
non-nursing consenting adults, free of skin disease, not sensitive to
similar products, and not using medications.

Of 246 enrolled subjects, 210 completed the entire 6 weeks of the study.
 Target enrollment was 200 to complete the study.  The test encompassed
three phases.  The induction phase involved nine consecutive
applications of patches and readings of patch sites, occurring on
Monday, Wednesday, and Friday over the course of 3 weeks.  This was
followed by a rest period of 10 to 15 days, and then by a challenge
phase, in which identical patches were applied to naïve sites and read
after 48 and 72 hours.  During weeks 4 through 6 of the protocol, the
subjects could miss application of one patch and receive a “make-up”
patch.

Science Assessment

Dr. Gardner provided EPA’s science assessment of the RIPT study.  The
goal of this study was to determine if the products in question cause
skin sensitization.  Skin sensitization data are required under 40 CFR
Part 158 for registration of all pesticide products.  Results of such
studies indicated possible induction of allergic contact dermatitis from
exposure of the skin to the test substance, and support precautionary
labeling.  Labeling is based on the sensitization potential of a
product; a standard precautionary statement for a skin sensitizer is
“Prolonged or frequently repeated skin contact may cause allergic
reactions in some individuals.”

EPA encourages minimization of animal testing.  Although EPA does not
encourage human sensitization testing, the Agency has sometimes accepted
it in place of animal testing.  The submitter is seeking a waiver of
animal testing because the components of the tested products are
discussed in published literature; have histories of use as intentional
food additives or in cosmetic products directly applied to human skin;
and are well-known to EPA.  Skin sensitization tests with animals were
reported in the literature for eight of the 12 ingredients in the two
products (evaluated by the Buehler Test and Guinea Pig Maximization
Test).  The physical characteristics of two ingredients prevent direct
sensitization testing.  No published information was found by the
sponsor concerning the remaining two ingredients; both occur in the
products at low concentrations.

Skin sensitization (allergic contact dermatitis) is a delayed
cell-mediated immune response, which begins with dermal exposure to a
chemical.  After absorption into the skin, a reaction with proteins in
the skin must occur to induce the cellular processes of the immune
response.  Skin sensitization test methods include an induction phase
when the capacity to respond to a challenge may develop.  The standard
test methods also include a challenge phase to determine if a test
substance has sensitized the test animal.

Eligible individuals for this study included males or females who were
at least 18 years old; in general good health; free of any systemic or
dermatologic disorder which would interfere with the results of the
study or increase the risk of adverse events; of any skin type or race,
given that the skin pigmentation allowed discernment of erythema; had
completed a medical screening procedure; and had signed an informed
consent document.  Excluded candidates included those who had any
visible skin disease which would interfere with the evaluation; were
receiving systemic or topical medication which would interfere with the
study results; had psoriasis or active atopic dermatitis or eczema; were
pregnant, planned to become pregnant during the study, or were
breast-feeding; and/or had a known sensitivity to cosmetics, skin care
products, insect repellents, or to topical drugs related to the material
being evaluated.  The subjects were largely female and Caucasian.

The dosing method was similar to that used in the 48 h Primary Dermal
Irritation Study.  For the RIPT, 0.2 ml of each test material was
applied to a 2 cm-by-2 cm Webril pad attached to a non-porous plastic
film adhesive bandage.  The patches were then air-dried for 30 minutes
before application and secured with hypoallergenic tape.  Patches were
applied to the skin of the infrascapular area of the back, to the right
or left of the midline, or to the upper arm.

The duration of the dosing is reported inconsistently.  The protocol
stated that all patches were removed by the subjects after 24 hours, but
the ICF states that patches remain in place for 24 or 48 hours.  There
was no documentation of instructions to subjects informing them which
patches to leave in place until their next visit.  A letter to the AIRB
explains that this is a “multi-sponsor” study with patches applied
for differing durations.  Upon request from EPA, the sponsor provided a
supplement statement that the sponsor’s patches remained in place for
48 to 72 hours, until the subject’s next visit, and were removed by
staff.  

The system used for grading irritation response was the same as that
used in the 48-hour Primary Dermal Irritation Study.  The irritation
responses noted in the RIPT are inconsistent with those observed in the
48-hour Primary Dermal Irritation Study.  In the Primary Dermal
Irritation Study, more than 50 percent of the subjects had a positive
response 48 hours after application.  In the RIPT study, less than 2
percent of subjects had a positive irritation response at any interval
after patch application.

Irritation responses differ from sensitization in that they are
localized and do not extend beyond the patch site.  Irritation reactions
also are usually reversible and are similar in the challenge and
induction phases.

Results and Discussion

Mr. Carley presented the results of the RIPT.  The data are presented in
tables, and each square in the table represents one of nine induction
phases.  The numbers reported are the numbers of readings of each
product at that point in time for the indicated level of irritation. 
Each page reports data for only one product.  The data indicate that a
subject reacted to both products in the induction phase as (++), and as
(?) to both products in the challenge.  In addition, two subjects
reacted to both products in the induction phase as (?) and two subjects
reacted to one product each in the induction phase as (?). 

Mr. Carley described several sources of uncertainty.  The patches were
dried before application to the skin, which represents a different
pattern of exposure from typical use of a topically applied repellent. 
The duration of exposure to the product is inconsistently reported.  The
results of this study are inconsistent with those from the 48-hour
Primary Dermal Irritation Study.  The study did not include control data
adequate to ensure appropriate differentiation between irritation and
sensitization responses.  All the subjects who responded were in Panel
1, which could indicate that readings may have been inconsistent between
the two panels.

Based on this information, EPA concludes that the RIPT by itself cannot
replace the required animal test of sensitization potential. 
Additionally, human experience with the components in cosmetics and
foods, and the absence of skin sensitization in animal studies with most
product components provide stronger evidence than this RIPT study to
support the conclusion that the two products are not likely to be
sensitizers.

Ethics Assessment

Mr. Carley presented EPA’s ethics review of the RIPT.  Applicable
ethical standards include 40 CFR §26.1303 (defines standard for
documenting ethical conduct of research), 40 CFR §26.1703 (forbids EPA
reliance on research involving intentional exposure of pregnant or
nursing women or children), and 40 CFR §26.1704 (forbids EPA reliance
on research if there is “clear and convincing evidence” that its
conduct was fundamentally unethical or significantly deficient relative
to standards prevailing when it was conducted).  The initial submissions
did not address the requirement of 40 CFR §26.1303 to document ethical
conduct.  Resubmissions were adequate to support review; however,
discussions of risk, risk minimization, benefits, and risk/benefit are
weak, but acceptable for pre-rule studies.

The purpose of this study was to determine the ability of two
experimental repellent products to cause allergic sensitization by
application to human skin under controlled patch conditions.  The
sponsor’s policy is to avoid “unnecessary use of animals in
testing;” thus, these studies were submitted to support a request for
a waiver of EPA’s normally required animal testing for sensitization
potential.

The study enrolled 246 subjects in two parallel panels; 52 subjects were
male, 194 were female.  The gender distribution was the same at both the
beginning and the end of the study.  The subjects ranged in age from 18
to 70 years, with an average age of 45 years.  The subjects were largely
Caucasian (178), and also Hispanic (54), Black (10), and “Other”
(4).  Of those enrolled, 210 subjects completed the study.  The subjects
were selected from people who had previously participated in research at
this laboratory.  The subjects received $110 in compensation for 13
visits, which EPA considers likely to attract primarily economically
disadvantaged subjects.  There was no other indication subjects were
from vulnerable groups.

The risks for participation were described to subjects in generic terms
(identically for both the primary irritation and RIPT studies). 
Identification of sensitizers before marketing and use has potential
societal benefit, but the ability of this assay to identify weak
sensitizers is unclear.  If the results of this study are scientifically
acceptable, the benefit probably justifies the incremental risks to
subjects.  The study was overseen by the AIRB, as described for the 48
hour Primary Dermal Irritation Study.  The sponsors have submitted
documents indicating that AIRB composition, procedures, and review meet
regulatory requirements.  A general compliance with FDA rules was
asserted by TKL Research.

Written consent was obtained from all subjects, using a form approved by
the AIRB.  The ICFs were generic and sometimes unclear, especially in
characterizing test materials and explaining 24-hour versus 48-hour
patches.  The consent process described emphasizes reliance on frequent
test subjects, and on establishing their eligibility rather than their
fully informed understanding.  Regarding respect for subjects, subject
privacy was not compromised in study reports.  Subjects were paid only
upon completion or if they withdrew for “personal reasons beyond their
control,” which may have unduly influenced subjects not to withdraw.

Ethical concerns for this study include recruitment of subjects from a
population of frequent test subjects, without explicit consideration of
representativeness; low compensation that might attract only
economically disadvantaged subjects; and a compensation scheme tied to
completion or withdrawal for an approved reason, which may have unduly
influenced subjects not to withdraw.  The ICF acknowledges possible
lasting effects, but treatment is promised only to “relieve the
immediate problem,” and only for undefined “significant
reactions.”  There was a troubling qualified promise to identify the
agent inducing an allergic reaction.  Subjects were also unnecessarily
identified by Social Security Number.

EPA found some gaps in documentation of ethical conduct, but the study
was relatively complete by pre-rule research standards.  EPA found no
clear and convincing evidence the research was fundamentally unethical
and no intentional exposure of children or pregnant or nursing women. 
EPA has many ethical concerns regarding this work, but the research was
consistent with common practice in testing of cosmetics and other
consumer products not regulated as pesticides.  There was no clear and
convincing evidence the research was significantly deficient relative to
prevailing standards.

The charge to the HSRB was to determine whether these studies were
sufficiently sound, from a scientific perspective, to be used as part of
a weight-of-evidence assessment to evaluate the potential of the
formulations tested to irritate human skin and to determine if there is
clear and convincing evidence that the conduct of these studies was
fundamentally unethical, or significantly deficient relative to the
ethical standards prevailing at the time the research was conducted.

Dr. Fisher requested clarification of the risks involved in a
sensitization study compared to an irritation study.  Mr. Carley
explained that this study excluded individuals known to be sensitive;
therefore, if a subject responds positively during the challenge phase,
the subject has been made allergic to a component of the product.  The
chances of inducing an allergic reaction are much lower in a single dose
study; the RIPT involves nine instances of exposure to the test
products.  Dr. Fenske questioned whether EPA seeks assistance from a
dermatologist for evaluation of these types of studies.  Mr. Carley
responded that EPA did not seek such assistance.

Dr. Menikoff stated that these types of studies have been performed for
many years, are regarded as valuable by industry, and are performed for
regulatory purposes.  Many perform this testing in addition to animal
tests to confirm that their products are safe for humans.  He disagreed
that sensitizing people is a significant side effect of the RIPT.  In
this case, no subjects were sensitized during the study.

Public Comments

Dr. James Milbauer and Ms. Milena Reckseit of TKL Research

In response to a question from the Board, Ms. Reckseit explained that
one screener was used to assess reactions in the RIPT study.  The
demographics and socioeconomic characteristics of the participants in
this study are similar to those described for the 48-hour Primary Dermal
Irritation Study.  Concerning compensation, the ICF clearly stated that
subjects would be paid $110 only upon completion of the study; however,
if a clinician indicated that a subject must withdraw from the study,
the subject was paid.  Subjects who had a sound personal reason for
withdrawing (i.e., car accident, death in the family) also were paid on
a prorated basis.  This practice also was followed for the 48-hour
Primary Dermal Irritation Study, but was inadvertently not described in
the ICF.  Ms. Reckseit continued that the scientific integrity of the
study would have been compromised if a large number of subjects
withdrew.  This prompted the clear statement that subjects would only be
paid if they met the previously described conditions.

Dr. Menikoff requested clarification concerning the potential 48-hour
patch application indicated in the ICF.  Mr. Carley clarified that the
sponsor’s supplemental response to EPA questions indicated that this
was a mixed sponsor study; some sponsors requested a 24-hour
application, while others asked for 48 hours, despite indications on the
protocol and study report that all applications took place for 24 hours.

Dr. Milbauer explained that the lower erythema ratings during induction
were based on the 24-hour application, which could account for the
inconsistencies between the RIPT and the 48-hour Primary Dermal
Irritation Study.  He added that two different graders were used for
each test, although both were trained by the same dermatologist.

Dr. Philpott commented that subject #55 had evidence of a reaction
during the induction phase.  This subject’s patches were exchanged for
semi-occlusive patches and the subject proceeded to participate in the
challenge phase.  He asked whether this subject was considered to have
been sensitized to the product.  Dr. Milbauer answered that because the
subject did not react after the challenge, the subject is not considered
to have been sensitized.

Dr. Philpott expressed concerns with the conditions for payment, stating
that these conditions were coercive.  He also questioned whether the
AIRB had reviewed the telephone script.  Ms. Reckseit explained that
because the study is an IRB study, she assumed that the AIRB had
reviewed the script, but was not certain.

Dr. Fenske returned to the issue of sensitization.  Products A and B
have similar active and other ingredients.  He questioned whether
challenge on another part of the skin with a given product leading to a
reaction is the effect of product A induction or the effect of the
multiple patches tested.  Dr. Milbauer answered that sensitization is a
specific reaction and occurs in isolation.  It is possible that a person
could develop sensitivity to one ingredient, and, upon challenge, would
develop sensitization at both sites.  If this occurs, separate
ingredient testing could be performed.  Dr. Fenske asked if a positive
rating upon challenge would be considered positive for sensitization. 
Dr. Milbauer confirmed this.

Dr. Carriquiry inquired how the criterion of 200 subjects had been
determined and who had determined it.  Ms. Reckseit responded that she
did not know who made this determination or how it had been made.  TKL
Research’s role in this study was to recruit subjects.  Dr. Fenske
clarified that TKL Research recruits, consents, screens, and performs
the test, and asked who performed the power calculations to determine
sample size.  Dr. Milbauer explained that this protocol was written by
TKL Research and power calculations were determined by a staff
statistician.  A sample size of 200 subjects is considered typical for
studies of this type.  Dr. Carriquiry countered that the term
“typical” was imprecise.  In a study review, she expects to see the
calculations used to determine a need for 200 subjects.  Without this
information, the Board has no way of assessing whether this sample size
is excessive or does not have adequate power.  Dr. Fisher questioned
whether any data were available concerning the demographics of those who
withdrew from the study.  Ms. Reckseit indicated that she did not have
this information.

Dr. Chadwick asked for further clarification of the authorship of both
protocols.  Dr. Milbauer answered that one primary investigator for the
protocol is a dermatologist; the other is a dermatologic safety person.
 A medical writer and statistician also contributed to the protocol.

Dr. Lebowitz asked whether the compounds used in this study were tested
prior to the study to determine that they were not adjuvant to
sensitization.  Dr. Milbauer responded that this information was
determined in preclinical reviews by the sponsor and provided to EPA.

Dr. Fisher questioned whether the AIRB had reviewed information for all
patches used in the study, given that there were multiple sponsors for
the different patches.  Dr. Milbauer answered that the other patches
contained cosmetics and IRB approval is not required for cosmetics. 
Dr. Fisher requested clarification that the ICF for testing products A
and B also indicated that participants were obligated to have the other
substances applied to their skin, but the AIRB did not have information
on these materials.  Dr. Milbauer clarified that the AIRB had been
informed that the other substances were cosmetics.  Dr. Fisher commented
that this protocol likely would not have been approved if submitted
under the new rules.

Dr. Philpott questioned the use of sodium lauryl sulfate as a control to
assess compliance and asked how this was done and if sensitization was
observed.  Dr. Milbauer explained that this substance causes irritation,
not sensitization.

Board Discussion

Scientific Considerations—RIPT Study 

Dr. Fisher commented that an issue for the scientific review is to
determine whether the study produces useful data.  The answer to this
question will impact the ethics review.

Dr. Zhu began the science review.  Concerning demographics, the gender
composition was uneven and the sampling scheme was likely to have led to
a non-representative sample.  The study protocol called for switching
subjects from an occlusive to semi-occlusive patch (or to switch the
patch to a new site) if the subject showed irritation of more than (++).
 The results of the study indicate no positive reaction to the products.
 Dr. Zhu cautioned that if subjects withdrew from the study for reasons
associated with their reaction to the patches, ignoring the data from
these subjects would lead to bias.  If attrition is due to random
reasons (i.e., the subject found participation to be inconvenient), this
will reduce the statistical power, but not bias the results of the
study.  The data for this study indicated that there were no positive
reactions among those who withdrew.

Dr. Zhu considered the results concerning subject #55 to have been
downplayed.  These results were not reported in the summary statistics;
therefore, the number of positive reactions was under reported.  This
subject appears to be allergic or sensitive to the patch.  Information
on subsequent reactions was missing from the report for product B, but
Dr. Zhu speculated that subject #55 was sensitive to both products.  Dr.
Fisher questioned why, given the exclusion criteria, a subject was not
excluded if found to be sensitive during the indication phase. 
Mr. Carley clarified that the criteria are applied before the study
begins.  Dr. Zhu added that the study protocol specifies termination
only if the subject experiences a serious adverse event.  Dr. Lebowitz
cautioned Board members against confusing multiple times of irritation
with sensitization.  Irritation does not necessarily imply that a
humoral response through hypersensitivity occurred.  Dr. Philpott
commented that his assessment of this data indicated that the irritation
was residual at the original induction site after removal of the
original occlusive patch.  Dr. Zhu disagreed and noted a footnote
indicating that data for this subject, after switching the patch to a
different site and changing patches, were reported in a different table.

Limitations to this study included use of a single rater for
observations, which could lead to variation or error in readings.  No
information was available on dose or mixture; decisions regarding this
issue need to be made by EPA.  The study population also may not be
generalizable.  If subjects have participated in multiple studies with
TKL Research, they may be more likely to develop resistance (or
sensitivity) to chemicals with similar structures.  The study
participants were mostly female, and males and females may have
different sensitivities to the products.  Concerning data analysis, the
conclusion of “no evidence of sensitization” ignores the response of
subject #55.

Dr. Zhu recommended considering multiple raters to independently
evaluate each subject; statistically quantifying the chance of
meaningful (timed) patterns of positive reactions of the same subject;
developing standards for data reporting and analysis in accordance to
repeated outcome data (i.e., do not ignore attrition and consider the
subject as a unit of analysis, as well as the data point); and requiring
analysis that differentiates outcome of a susceptible sub-population
(incidence of severe reaction) from the average.

Dr. Fenske commented that EPA indicated in its review that there were
concerns with this study, given that the components of the products have
already been marketed and people already have been exposed to them. 
This may have led to more subjects showing signs of sensitization, but
this was not the case.  Concerning the evaporation of solvents, Dr.
Fenske indicated that he was comfortable with the rationale for allowing
the materials to dry on the patch before application and did not believe
this approach negatively impacted the study results.  Regarding the
scoring system used, the European Commission has clear guidance for
48-hour primary irritation tests, but Dr. Fenske was unsure if such
guidance existed for the RIPT for sensitization.  The report does not
provide sufficient information to determine if this is a standard method
for scoring.  Given the substantial amount of data from animal testing
of these products, it was predictable that any sensitization reaction
would be weak.  EPA believes that this study is less able to identify
weak reactions than are animal studies.  This implies that EPA found the
animal data to be adequate and this study did not contribute
significantly to the knowledge base.  The duration of exposure was
inconsistently reported.  The protocol and study report indicate removal
of patches after 24 hours and examination after 48 hours, but there is
ambiguity in the supplemental materials concerning this issue.  The
duration of exposure should be clarified.  Dr. Fenske addressed
concerns about inconsistencies with the 48-hour primary irritation
study.  Less irritation would be expected for this study, because
patches were applied for only 24 hours.  There was no control data to
differentiate between irritation and sensitization; the sodium lauryl
sulfate control patch was used to assess compliance.  There was
insufficient justification for the sample size.  

The reports lack a startling amount of detail concerning the results of
the study, which are limited to two sentences within the report (further
information is reported in the Appendices).  In general, studies of this
sort are not required; rather, their purpose is to add a level of
confidence in the safety of a product that many consumers will use. 
Manufacturers wish to avoid product recalls, which are deleterious both
for them and for the public.  The Board’s critique implies there was
no good reason to perform this study; however, additional confidence in
product safety may be a good reason.  Dr. Fenske stated that he was not
averse to human studies, if they are carefully designed.  This study
included appropriate protocols to detect irritation during induction and
procedures to limit such irritation (use of semi-occlusive patches,
applying patches to new locations).

Dr. Fitzpatrick stated that the study report required more detail
concerning why the study was performed on humans, justification of dose
and sample size, how subjects were chosen, and discussion of the
representativeness of the sample.  The results and analysis are lacking,
as is information concerning who performed irritation/sensitivity rating
and their qualifications.

Dr. Carriquiry stated that she disagreed with Dr. Fenske and believed
that this study was not carefully designed or implemented.  The Board
cannot determine whether the sample size was adequate, but the sample
itself was not representative.  Confounding of cohort location and
raters occurred and thus the cohorts cannot be compared.  This is an
artifact of having only one person score the first reaction and a
different person score the second.  EPA should find no use for these
results.  There was no information concerning the demographics of those
who withdrew from the study, although it is likely that they did not
withdraw because of reaction issues.  The study included no statistical
analysis whatsoever.  This data cannot conclude that the products do not
cause sensitization.

Dr. Brimijoin requested clarification of “sensitive” versus being
“sensitized” and added that the criteria presented to indicate
“sensitized” were not satisfactory.  When a challenge is
administered after the rest period to a naïve site, a reaction must be
seen to conclude that sensitization occurred.  By these standards,
subject #55 was not sensitized.  Dr. Lebowitz explained that
sensitization, encompassing delayed-type hypersensitivity reactions are
obvious; he was certain that no subjects were actually sensitized to
product A or B.  Dr. Fish questioned whether the obviousness of a
sensitization reaction means that the issue of inter-rater reliability
is less serious.  Dr. Lebowitz said that this was a true statement.  A
dermatologically trained observer can easily distinguish a sensitization
reaction from irritation.

Dr. Carriquiry inquired, given the sample size, how often sensitization
might expect to be seen.  This information should drive the
determination of sample size in such studies.  Dr. Zhu commented that
although he understands the clinical definition of sensitization, he
believes immunological testing would be needed to determine
sensitization because observation was not sufficient due to the
different exposure conditions.  Dr. Lebowitz explained that a person who
has been sensitized exhibits a characteristic delayed-type
hypersensitivity reaction to a lower dose upon challenge.  He added that
historically, the U.S. government could not decide whether formaldehyde
was a sensitizer, given that approximately 1 to 5 percent of those
exposed to it develop sensitization.  There is disagreement among the
United States and other countries concerning whether a 1 to 5 percent
rate of sensitization is sufficient to deem a substance a sensitizer.

Dr. Fisher summarized that the Board concluded that this report was of
poor quality, and the use of single raters was not optimal.  There was
no rationale for the number of subjects included in the study, which is
a weakness for interpreting the results and their meaningfulness. 
Confounding among cohorts and raters occurred.  There is no evidence
concerning whether the study was well-implemented or not, but it was
carelessly reported.  Dr. Fenske countered that the report provided a
great deal of information, but not in a user-friendly format.  He
considered the protocol to have been generally well planned and
executed, and employed appropriate safety measures.

Dr. Fisher inquired if EPA had received resolution to its questions
concerning dosing, which was reported inconsistently.  Mr. Carley agreed
that duration of patching was reported inconsistently.  If patching did
take place for only 24 hours, this might explain the inconsistencies
between the results of the primary irritation study and the RIPT.  Dr.
Fisher commented on the lack of differentiation between irritation and
sensitization.  Dr. Lebowitz agreed that there was no control for this,
but this is not relevant for distinguishing sensitization.  Dr. Fisher
commented that the readings appeared inconsistent and that this could be
related to the issue of using only a single rater and lack of a negative
control.  The sample was not representative, but it is unknown whether
this would have affected sensitization rates.  Dr. Fisher stated that
there appeared to be no evidence of sensitization.  The study design is
sufficient to assess sensitization, but whether the population is
representative and the sample size adequate is questionable.  

Dr. Fisher commented that confirming in humans what is known in animals
is admirable, but the Board is unsure whether this study contributes to
EPA’s knowledge base.  Dr. Lebowitz stated that given his experience
with sensitization reactions, he would want to know that sensitization
was not observed in animal models before testing for sensitization in
humans.  Dr. Fenske reminded Dr. Lebowitz that animal studies of
individual ingredients had been performed.  Dr. Lebowitz countered that
it was unclear if animal studies had been performed using these
particular combinations of ingredients.  If such studies have not been
performed, the investigators could not conclude that the ingredients
would not synergize to create sensitization in humans.  

Dr. Fisher concluded that sensitization was not observed in this study,
but there was a rationale for testing in humans.  The sample size and
the representativeness of the sample were questionable; the report was
poorly written.  At this point, the Board cannot conclude whether the
study will contribute to EPA’s knowledge base concerning products of
this type.

Mr. Carley clarified that he had received indication from the sponsor
indicating that the patches remained in place for 48 hours, in contrast
to what was reported in supplemental materials.  The ICF permits patches
to remain in place for 24 to 48 hours, and in some cases 72 hours, if
the patch is applied on a Friday.  The IRB questioned this, and the
response from TKL Research was that the study was a multi-sponsor,
multi-substance test, necessitating different durations of exposure.

Dr. Brimijoin commented that although there was no rationale for the
study population composition, the characteristics of this population
appear reasonable.  Women and children are most likely to use insect
repellents.

Ethical Considerations—RIPT Study 

Dr. Fish opened discussion of the ethics of the RIPT study.  She stated
that the Board cannot judge whether there was sufficient animal data on
sensitization provoked by these products to support human studies.  The
issues of subject compensation and prorating of payment are similar to
those from the primary dermal irritation study, ameliorated somewhat by
clarification by Ms. Reckseit that the explanation of prorating payments
had been inadvertently omitted from the ICF.  Dr. Fish expressed concern
that subjects who chose to withdraw would not be paid, which could be
construed as coercion to remain in the study.

Dr. Fish also expressed concern about the AIRB.  The ICF presented to
the AIRB was generic and nonspecific.  The section describing risk is
the same as that on the ICF for the Primary Dermal Irritation Study, but
risks associated with sensitization would seem to be higher than risks
associated with primary irritation.  The statement concerning treatment
for injuries is vague, as was the case for the Primary Dermal Irritation
Study.  Dr. Fish expressed concern that the AIRB only had information
for products A and B, and not for the other products that would be
applied to the subjects.  The telephone script for recruitment refers to
“testing fragrances,” which seems deceptive.  Mr. Carley clarified
that there were two telephone scripts, one of which included mention of
repellents.

Dr. Sharp commented that all human studies could trouble ethicists,
because humans are being placed at risk to further corporate interests. 
The idea of human testing as an alternative to animal testing is
troubling.  Researchers should never expose humans to risk when
alternative testing methods are available, unless there is a significant
benefit to human testing.  The moral consensus is that all risk should
be minimized, which implies that animal testing should always occur
first; it would be fundamentally unethical not to do so.  The 246
volunteers in this study may have needlessly been placed at risk.  Dr.
Fisher clarified that to declare a study “fundamentally unethical”
there must be evidence of intent to cause serious harm or failure to
obtain informed consent.  Other Board members disagreed, considering
“fundamentally unethical” to include, but not be limited to, these
acts. Dr. Fisher thanked these Board members for the clarification.

Dr. Chadwick commented that for corporate sponsors who have a reputation
of not testing on animals, asking them to do animal testing is akin to
asking a vegetarian to eat meat; it conflicts with their own moral
standards.  In some cases, it might be reasonable to ask humans to
participate in testing.  In this case, the quality of the protocol and
specificity of risk raise questions about the underlying science.  Dr.
Chadwick described his concerns, including the 30-minute drying period
before application, the apparent lack of consent for medical screening,
and the lack of detail in the protocol about the risk of sensitization. 
He stated that the procedures followed by the AIRB give the impression
that this IRB is not compliant with EPA, FDA, or DHHS practices.  When
an IRB reviews a study that will be used by EPA for regulatory purposes,
the IRB should follow EPA regulations for these studies.  Mr. Carley
reminded Dr. Chadwick that at the time this protocol was developed and
implemented, EPA rules concerning human subject protection did not apply
to third-party data.

Dr. Chadwick continued his analysis, asking whether the consent obtained
using the ICFs described for this protocol were valid.  It is
questionable whether participants understood the procedures, risk,
purpose of the study, and possible benefits.  The ICF did not describe
research procedures.  Dr. Chadwick added that he also was troubled by
the phrase “sodium lauryl sulfate was used for control comparison.” 
Sodium lauryl sulfate routinely is used as a skin irritant, and it
appears that subjects were not adequately informed of this.  Concerning
payment, there are ways to use payments, prorating, or bonuses to ensure
compliance that are not coercive.  The procedures used in this protocol
indicate a lack of understanding of this issue on the parts of the AIRB
and TKL Research.  The lack of a plan for informing subjects about
potential sensitization reactions also is a flaw.  The use of HIPAA
language is a confounder in this study.  Dr. Chadwick concluded that
the AIRB and perhaps TKL Research are content to use a generic ICF
instead of individual ICFs for each protocol.  This practice violated
ethical and regulatory standards and raises concerns about the quality
of consent.

Dr. Fisher definitively stated that the consent was either significantly
deficient or fundamentally unethical because the AIRB had no information
about materials used in the study, other than products A and B;
therefore, subjects were not informed about the study’s risk. 
Therefore, there is no informed consent if the AIRB cannot determine the
nature of the risk.  Dr. Fenske countered that the other materials used
were cosmetics that were registered and did not require IRB review
because they are considered safe for human use.  Dr. Fisher remarked
that the TKL Research representative stated that the AIRB did not
consider any information concerning the other products, considering them
to be outside their purview because cosmetics are not subject to IRB
review.  Dr. Fenske commented that the Board cannot conclude that the
products were hazardous and the subjects were deliberately misled.  Dr.
Fisher agreed, but repeated her opinion that the subjects were not
informed because the AIRB did not have all the necessary information. 
Dr. Fenske stated that TKL Research knew the identity of the other
products and may have told the AIRB that these products were cosmetics
that did not require IRB review.  Dr. Philpott requested clarification
concerning the information submitted to the AIRB.  It appears that the
AIRB was informed only about the repellents, but approved the ICF
without information on the other materials used.  Dr. Fisher reiterated
that if an IRB does not have all necessary information, it cannot do its
job.  From an ethics perspective, there is no informed consent because
the IRB could not complete its review.  Dr. Krishnan asked whether EPA
had information on the other products.  Mr. Carley responded that EPA
does not have this information, and it is not clear from the ICF whether
subjects were told the exact number of patches they would receive or
what the patches would contain.  The duration of exposure also was not
clear on the ICF.

Dr. Fisher concluded that the failure of the AIRB to review all
materials fits the idea of lack of informed consent.  The Board’s
consensus was that there was clear and convincing evidence that the
study was significantly deficient regarding ethics.  She added that this
was the first protocol with supplemental CBI claims that the Board
reviewed, and commented that the flaws in the protocol were not related
to the CBI claims.  Overall, the process for review of protocols with
CBI claims proceeded smoothly.  Mr. Carley agreed that the process
worked well in this case, because of the scope of the claims.  Reviews
of other protocols may be more problematic.

Dr. Chambers commented that it would be unethical to force companies
with philosophical objections to animal research to perform animal
testing.  Additionally, there is merit to exposing a small group of
people to risk before exposing large populations to risk when the
product is marketed.

Draft Framework for Developing Best Practices for Recruiting, Screening,
Informing, and Obtaining Consent from Human Subjects of Occupational
Exposure Studies with Pesticides

Mr. Carley presented EPA’s draft framework for best practices for
occupational pesticide exposure studies.  The goal of this exercise is
to develop a process to interpret the provisions of the rule requiring
documentation of informed consent and application of the rule to the
specific circumstances of occupational pesticide exposure studies.  The
framework will help define a structure for compilation of best practices
for occupational exposure studies such as agricultural handlers’
exposure, non-agricultural handlers’ exposure, and re-entrant worker
exposure (re-entrant workers enter areas that have been treated with
pesticides).  Major concerns for these studies include ensuring
equitable subject selection, fully informed choice to participate, fully
voluntary choice to participate, and respect for prospective and
enrolled subjects.

IRB approval of research requires equitable selection of subjects, which
considers the purposes of the research and the setting in which the
research will be conducted.  The investigators should be particularly
cognizant of special problems when research involves vulnerable
populations.  Equitable subject selection requires fair distribution of
research risks, assessment of which should consider the
representativeness of the sample, appropriate use of inclusion/exclusion
factors, special considerations for vulnerable populations, and
appropriate recruiting strategies.  To meet the requirement of
representativeness, an ideal sample would be derived from random
selection of subjects from the target population of concern; this will
help ensure broad applicability of research results and greater
potential societal benefit.  Representativeness of the sample thus is a
crucial element for justification of the research.  Representativeness
can be maximized by identifying and characterizing the appropriate
target population, defining the sampling frame relative to the target
population, selecting a sample from the frame that preserves
representativeness of the target population, and ensuring that the
sample serves the scientific purposes of the research and has not been
chosen for convenience. 

Appropriate exclusion factors for these studies protect potentially
vulnerable populations, including children, pregnant or nursing women,
and prisoners.  Inclusion factors to preserve representativeness include
speakers of English and other languages, and both men and women. 
Special concerns for occupationally exposed populations include limited
English skills, subordinate relationships to decision makers, and being
an employee of the entities cooperating with the research or of the
investigators or sponsors.

Recruiting strategies should be tailored to the purpose and design of
the research to ensure equity and representativeness, offer candidates
the opportunity to express interest in participating, and provide
appropriate recruiting material for IRB review.  Fully informed consent,
i.e., knowing consent was obtained without undue inducement, force, or
coercion and using a process in which the subject has sufficient
information to make decisions about participation, is required.  All
ICFs must be signed by both subjects and project representatives to
ensure that the consent process is complete and appropriate, subject
participation is entirely voluntary; it also ensures that the subject
has read the information provided, has had a chance to discuss the
information and ask questions, and has been notified of the freedom to
withdraw.

Next steps in developing the framework include refinement of the draft
framework based on the HSRB discussions, solicitation of comments from
stakeholders, populating the framework with best practices, establishing
a process for ongoing maintenance of the framework, and making the best
practices guidance widely and easily available.

The HSRB is asked to consider and identify any additional elements that
need to be addressed concerning recruiting and enrolling subjects in
handler exposure research, and, for each element of the framework,
identify additional sources of guidance that could be useful for an
investigator who is designing a process for recruiting and enrolling
subjects in handler exposure research.

Dr. Fitzpatrick inquired if the short form for consent could be used. 
Mr. Carley responded that this form could not be used because of
concerns about obtaining fully informed consent from people with low
English skills.  Dr. Menikoff commended Mr. Carley and EPA on the
quality of the draft framework.  He agreed that more specifics
concerning some issues are needed.  The subjects likely to enroll in
these studies are likely to be considered “vulnerable” in a number
of ways—socioeconomic status, immigration status, and English skills. 
Questions must be developed to ensure that participation is entirely
voluntary.  Mr. Carley agreed, and added that EPA expects that answers
to questions will differ given the contexts (i.e., agricultural handlers
versus non-agricultural handlers) because of different complication
factors.  

Dr. Menikoff raised the issue of ensuring workers are not penalized for
not participating in the research.  Much of this research will take
place at employment sites and the research will be tied to work
situations.  The workers face the risk that they will be vulnerable to
losing money or suffering other consequences in the workplace for
failure to participate.  There need to be clear rules to forbid this and
procedures in place to ensure that it does not happen.  Dr. Menikoff
described an example of this situation.  A farmer could agree to allow
one of his fields to be used in research involving sprayed pesticides. 
This could result in the pilot who applies the pesticide being forced to
work with a different substance than the pesticide normally used.  The
choice of the pilot to participate may not be entirely voluntary; if the
pilot declines to participate, he could face a significant financial
penalty by not performing his usual job.  The Board discussed whether
they would try to develop specific answers for specific situations such
as this one, or develop general principals.  Dr. Fisher asked the Board
to consider a situation such as this in an ethical framework, for
example, is the pilot being forced into a coercive situation.  Dr.
Menikoff stated that the general question for this situation was whether
people do not receive their usual pay if they choose not to participate,
and if this is acceptable.  Dr. Fisher agreed that the guidelines should
ensure that no one should be deprived of expected pay because of refusal
to participate in research.  She continued that specific issues to be
addressed for this situation include whether the pilot would apply the
usual pesticide with no measure of exposure, or whether additional risk
could be incurred by applying a different pesticide.  Dr. Menikoff
stated that the general principle should be that no one should be worse
off as the result of a study.  Workers should receive their usual pay
and not be forced to expose themselves to risk.  Dr. Fisher agreed that
the general principles should be that people 1) should not be worse off
and 2) should not feel coerced to be exposed to something to which they
normally would not be exposed.

Dr. Lebowitz commented that although this document must focus on EPA
needs, it may be helpful to consider rules or regulations from other
agencies, such as OHRP and FDA.  Certain areas were emphasized by Mr.
Carley in his presentation of the framework.  Minimization of risk is
paramount and there should be discussions to develop approaches to risk
minimization applicable to subject recruitment and retention. 
Concerning avoidance of members of vulnerable populations, Dr. Lebowitz
explained that in biomedical research, it is essential to include
members of these groups, when not excluded by statute, to ensure
representativeness.  In the case of the occupational exposure studies,
stratified random samples may be needed to allow appropriate conclusions
to be drawn.  Any lack of representativeness should be treated in
analysis to determine any bias affects on the research conclusions.  In
his opinion, investigators must make an effort to ethically include
members of vulnerable groups, perhaps by employing translators or
writing ICFs in languages other than English.  Dr. Lebowitz remarked
that this research may have a potential future benefit to individual
workers by improving assessment of exposure risk.  Best practices must
include assessment of study design, exposure, statistical analyses,
measures of biological response, and other scientific issues.

Dr. Kim addressed scientific issues.  Exposure studies will involve
sampling that differs from other studies and there will be problems with
calculating sample size.  Community-based participatory studies in
clinical settings may provide suggestions for addressing this.  Dr.
Sharp agreed that the idea of community consultation should be developed
for the exposure studies.  Dr. Sharp continued that exclusion of
children and the decisionally impaired from the exposure studies may
impede progress to improve public health.  Dr. Fisher noted that it is
illegal to enroll children in non-observational pesticide studies.  Mr.
Carley agreed that because these studies involve intentional exposure,
children cannot participate.  Drs. Fisher and Sharp discussed the
definition of “intentional exposure” versus “observational” and
agreed that this would be discussed further at the June 2007 HSRB
meeting, with input from EPA.

Dr. Sharp continued that he would like to further discuss the risk
created by observation of pesticide application—what is the role of
the investigator if he observes improper or illegal application
procedures.  Concerning the language and tone of the document, it is
likely that many potential subjects will be Spanish speakers.  He
suggested that both English and Spanish speakers work in the consent
process to help ensure fully informed consent of Spanish-speaking
subjects.

Dr. Fisher commented that the Board should discuss risk-benefit balance.
 To be ethical, a study must have social or scientific values.  The
definition of “benefit” should be established, and could include
social value.  Dr. Lux reminded the Board that the draft framework
focuses on recruitment, not study design.  Mr. Carley explained that at
the January 2007 SAP meeting, study design and methodology were
discussed, but were treated as scientific issues for protocol design. 
These discussions revealed the need to discuss the best ways to recruit
and obtain informed consent for the occupational exposure studies.  Dr.
Fisher indicated her understanding of the limitations of this document,
but stated that benefit is nonetheless an important issue.  Mr. Carley
remarked that EPA does inform sponsors of the scope of EPA concerns. 
Dr. Philpott agreed that lack of recognition of the importance of the
study design could hinder equitable subject selection; subject selection
is difficult if questions and applicable populations have not been
defined beforehand.  Dr. Menikoff suggested that, at the outset of the
document, the Board could comment that this document specifically
addressed recruitment, but information on design also is needed to
ensure recruitment is ethical.  

Dr. Philpott addressed the issue of enrollment of the decisionally
impaired.  He recognized that even if a study is ethical and answers
important questions, there may be state level issues that supersede the
protection guidelines of the study.  For example, there may be
situations for occupational exposure studies that permit inclusion of
people who can only consent by proxy; this would not be allowed in New
York State, which has no proxy law for non-therapeutic research.  Dr.
Fisher noted that investigators are alerted to state and local laws that
may be more stringent than EPA requirements.  Dr. Menikoff commented
that it is unlikely that decisionally impaired people will participate
in exposure studies, but this issue does give guidance for considering
the representativeness of the study.

Dr. Fisher addressed the complexity of consent materials.  ICFs can
easily overwhelm potential subjects, thus, to be ethical, ICF materials
should be well written and undergo careful editing to eliminate
ambiguity.  Mr. Carley noted that sponsors must send EPA their protocols
before implementing the study.

Dr. Hoel’s comments related to both exposure and effect studies.  He
noted that there is increasing scientific interest in deoxyribonucleic
acid (DNA)-environment interactions, which gives rise to questions
concerning the ethics of collecting genetic materials.  He agreed with
Dr. Lebowitz that stratification of sampling may be needed to ensure
representativeness.  He expressed curiosity about the exclusion of
children from exposure studies, given that in the past he has performed
motor and neurodevelopmental testing on children whose mothers may have
been occupationally exposed to pesticides—this could not be done under
strict rules excluding children. 

Dr. Hoel addressed the lack of discussion of inclusion of labor unions. 
Unions serve as advocates for workers, and may help represent and
explain the research and improve participation by the workers. 
Regarding expression of interest in the research, he cautioned that bias
may occur because of self-selection by workers for participation.  He
added that exposure studies may also include work in developing
countries and EPA must be aware of potentially less protective research
regulations in those countries.  Mr. Carley explained that if EPA uses
the data, the Agency must review the protocol, regardless of where the
research is performed.  Dr. Fisher added that OHRP states that U.S.
standards must apply internationally, unless the host country has higher
standards; at a minimum, equivalent protection must be achieved.

Dr. Chambers stated that although science should not compromise ethics,
there must be an acknowledgement that in some cases ethics may
compromise science.  For example, subjects withdrawing from the protocol
before completion will result in censored data.  If the EPA seeks true
representativeness of studies, only large farms with many workers will
be able to participate.  It may be challenging to ensure scientific
parameters, such as complete data sets and representativeness, and
maintain ethical requirements.  Dr. Fisher responded that this balance
has always been an issue.  There are ways to balance science and ethics
to ensure that studies are both scientifically valid and protect
subjects’ rights.

Dr. Fenske noted that the framework document was well designed.  The
scope of the document was adequate when considering the recruitment,
screening, and informed consent processes, but he expressed concern that
the workers did not appear to be involved in the process.  The process
is driven largely by registrants and employers, but members of the
workers’ communities will be best able to communicate with other
workers and assist researchers.  A community-based participatory
research model should be considered, because engagement of the community
is important for exposure studies.  Concerning exclusion of children,
the National Institutes of Health requires that children under 21 years
of age must be included in human research unless there are scientific
and ethical reasons not to do so.  A substantial portion of the
agricultural worker population is under 21 years of age.  They are the
most at-risk members of the population because of a lack of education
and a propensity for risky behavior.  It is legal to handle pesticides
at 16 years of age.  Dr. Fisher asked Mr. Jordan if EPA had exceptions
for inclusion of emancipated and mature minors.  Mr. Jordan responded
that EPA defines “child” as younger than 18 years of age.  He
clarified that EPA does not allow participation of people younger than
18 years of age in research involving intentional exposure.  People of
all ages can participate in observational research.

Dr. Fisher asked Board members to review Dr. Chadwick’s draft of Board
recommendations for the Best Practices Framework.

Day 3 Introduction

Dr. Fisher introduced the day’s topics, including clarification of
issues concerning the AHETF and AEATF protocols, EPA’s need for new
research on occupational handler exposure, and a review of the EPA FIFRA
SAP January 2007 report, “Worker Exposure Methods.”  

Dr. Fenske recommended a modified agenda that would maximize Board
discussion of the AHETF and AEATF protocols and the FIFRA SAP report. 
He noted that the EPA written materials documenting the need for new
research on occupational handler exposure had made a convincing case and
that less discussion might be required for that topic, with more time
devoted to the SAP recommendations and Board discussion. Board members
agreed with Dr. Fenske’s suggestions.

Dr. Fisher suggested that it might be helpful at this juncture in the
meeting to remember the points that the Board had raised regarding the
AHETF studies in its June 2006 report. Dr. Fisher provided a summary of
the major recommendations from that meeting. She noted that in that
report the Board considered the occupational handler exposure monitoring
studies, which were described as components of a large-scale exercise to
create a database on occupational exposure to agricultural pesticides,
to be largely worthwhile for quantifying and improving understanding of
the exposures and risks to pesticide handlers.  Although the potential
benefits of this exercise were deemed to be significant, and the risks
relatively modest, the Board found that the materials supplied for HSRB
review did not adequately address risks and benefits.  The protocols
reviewed could not be properly evaluated for scientific validity for a
number of reasons.  The HSRB found the protocols to be lacking in sound
rationales for how data generated by a given protocol would address the
EPA’s need for new data.  The protocols lacked clear and appropriate
plans for handling data, including statistical analyses.  For example, a
meta-analysis was proposed that would include studies with one subject
to represent a particular pesticide and use context.  A meta-analysis
seemed inappropriate, and neither the sponsors nor EPA could provide an
appropriate alternative statistical design for data analysis.  Also
lacking were clear explanations of how the data would be used.  The HSRB
understands that the data will be used to create reference points, which
underscores the need for well-planned studies and good quality data.

At its June 2006 meeting, the Board recommended additional validation
studies such as laboratory-based removal efficiency studies or
field-based biomonitoring studies to determine the extent to which
dermal exposure measurements may underestimate true exposure.  The Board
also recommended publishing the results of such studies in peer-reviewed
journals and to inform and encourage participation of both the
scientific and labor communities.  Greater participation likely would
improve the quality of the database and enhance its credibility. 

The Board also recommended that a heat stress management plan be
designed to include specific criteria for withdrawal from the study
because of heat stress.  The protocols should represent, as closely as
possible, the conditions of a true work day and should document the
reasons for and proposed duration of the study.  The protocols also
should include plans for the proposed number of subjects and plans to
manage subject withdrawal—power analyses and statistics will be
needed.

The Board commended EPA’s response to its questions regarding use of
diazinon in the AHE37 protocol.  The Board understands that the Agency
will require AHETF to identify a pesticide other than diazinon to use in
this protocol to assess exposures associated with open pour activities,
and that EPA will ensure that future protocols comply with the most
current risk mitigation measures.

Public comments from several members of the AHETF at a previous meeting
addressed some of the Board’s concerns, namely the documentation and
process of subject enrollment, appropriate alternatives to
participation, and adequate compensation of participants for
study-related injury; however, the Board did not consider that questions
concerning adequate minimization of risk to study participants were
adequately addressed.  Participants in these studies may be exposed to
higher levels of pesticides than they are during their usual work
duties; this should be mentioned in the protocols. The protocols also
failed to detail proper subject use of the pesticides and failed to
address educational issues arising when subjects do not speak English. 
Study investigators also should consider providing subjects with the
results of the study.

The HSRB considers the likelihood of heat-related illness to be a
significant matter for the protocols.  Many of the studies will require
participants to wear what is essentially long underwear while working in
high temperature environments.  The protocol needs clear stop criteria,
clear descriptions of the symptoms of heat stroke in the ICF, and a
clear plan for reporting any heat-related illnesses.

Because some agricultural workers may be undocumented immigrants,
maintenance of strict confidentiality is paramount.  Additionally,
investigators should be aware that undocumented workers may be reluctant
to report adverse events, such as heat-related illness.  The Data and
Safety Monitoring (DSM) plan must be sensitive to this issue. 
Development of recruitment and ICF documents also must consider
potential problems related to worker immigration status.

Board Discussion

Dr. Menikoff commented that the key goal of this research, in terms of
how the studies are designed, is risk minimization.  He added that it
can be difficult to distinguish between “intentional exposure” and
“observational” research.  Subpart B clarifies the extent to which
investigators cannot change what a person experiences—this leads to
questions concerning whether these studies can be performed using
workers who are already using the compounds as part of their work
activities.  He stated that the protocol should provide more information
on ways to perform the study that do not alter the identities of the
pesticides that are applied or the ways they are applied.  Dr. Fisher
responded that if handlers will be asked to use pesticides or wear
clothing that increases risk beyond their usual risk, a risk management
plan is crucial.  This also relates to the issue of whether recruitment
is truly voluntary.  Risk minimization related to changes in use or
exposure must be assessed.  Dr. Lebowitz commented that the Board was at
a disadvantage, having not yet seen the revised AHETF protocol referred
to in the FIFRA SAP minutes.  He also recommended that staff from
EPA’s Office of Research and Development  should be invited to the
June 2007 HSRB meeting to provide further input on the distinction
between observational and intentional exposure research and other issues
concerning exposure.

Dr. Fish stated that although scientific considerations are of
importance for these protocols, a significant amount of risk relates to
confidentiality protection (i.e. of undocumented or pregnant workers). 
Consultation from a person knowledgeable about worker issues could help
provide perspective from the worker’s perspective.  Dr. Fisher noted
that in the report and SAP discussions, it was recommended that people
representing the handlers were included as part of the risk-benefit
discussion.

Dr. Lehman-McKeeman commented on issues related to development of a
large database with scientific validity and rigor.  She acknowledged
that the Board did not have access to many of the protocols, but did
have documentation on how the database will be useful to EPA.  She
questioned whether (and which) procedures would be employed to determine
whether a protocol was performed in a way to give consistent and
reliable data.  Investigators developing these protocols will need a
method for assessing that the work was executed in such a way as to
yield sound data.

Dr. Fenske reviewed the Board’s response to the HSRB charge questions
regarding EPA’s need for new research on occupational handler
exposure.  The Board agreed that new data would be useful for EPA’s
pesticide risk assessments for agricultural workers, and commended the
FIFRA SAP for clearly defining the rationale for the collection of new
data.  The idea of a database is robust and a sound way to develop a
scientific approach to exposure assessment.  Regarding additional
information needed by the HSRB to assess handler research in general or
individual protocols, Dr. Fenske commented that the draft framework on
recruitment could be used to broaden discussion to include all
occupational exposure to pesticides.  This would include existing
research on agricultural exposure to pesticides.  For example, the
completed Agricultural Reentry Task Force (ARTF) study could be used to
inform the HSRB discussion concerning the agricultural handlers exposure
database.

Concerning the distinction between intentional versus observational
exposure, Dr. Fenske suggested that the HSRB consider occupational
pesticide exposure studies to be intentional exposure studies, unless
shown otherwise.  These studies call for enough interaction with
subjects and changes in their activities to be considered intentional
exposures in most cases.  The Board also should discuss issues related
to employer-employee relationships, rather than ceding this manner to
individual IRBs.  Incentives to participate are provided to employers
(such as free pesticides), which could impact the employer-employee
relationship concerning employee participation.  More clarity also is
needed on the consequences to a worker who opts not to participate; such
a worker may not be able to participate in his normal work activities. 
The complexities of recruitment of agricultural workers (i.e., language
barriers, comprehension of risk, and true informed consent) also must be
considered.  Comprehending risk will involve not only surmounting
language barriers but also addressing cultural differences in
comprehending risk and ideas of health.  A program in “cultural
competencies” could help ensure that an investigator understands and
is understood by the subject population.

Dr. Fenske recommended that the Board have the opportunity to review
material related to the ARTF, which was developed in response to EPA
requests for exposure data on workers who entered fields after pesticide
treatments.  Data were needed for a number of different “scenarios”
involving multiple combinations of pesticide type, crop type, and worker
activities.  Data collection was funded in part by registrants and EPA
has used this database for risk assessment activities since
approximately 1999.  The studies providing data to this database are
similar to those expected to provide data for the occupational handlers
exposure database.

Dr. Fenske concluded that the HSRB accepted EPA’s rationale for its
need for new data.  Additional materials needed include a separate and
new “governing document” that is not a generic description of the
planned activities; a clear and appropriate plan for handling data,
including its statistical analysis; and an explanation of the uses to
which the data will be applied.  Dr. Fenske also requested that the
HSRB receive any plans for additional validation studies to determine
the extent to which dermal exposure measurements may underestimate true
exposure; any plans to broaden participation of the scientific community
and parties with a direct interest in the database, such as the labor
community; and any plans to meet the requirements of 40 CFR Part 26,
as recommended by the HSRB.

Drs. Brimijoin, Lebowitz, and Krishnan commended Dr. Fenske on his
analysis.  Dr. Krishnan took exception to the language regarding the
Board’s policy on the definition of intentional exposure, commenting
that the statement over-reached suitable boundaries.  Dr. Fisher
replied that the Board should discuss this matter further at the June
2007 HSRB meeting.  Dr. Krishnan continued that EPA’s need for new
data was made very clear.  He added that EPA and others should provide
responses to the Board’s suggestions of strategies to address
scientific concerns.  Dr. Carriquiry noted that, concerning what to
expect from an appropriate, well-executed exposure study, WHO recently
published a report on studies to establish exposure to pesticide in
food, which could guide these discussions.

Dr. Lebowitz described a workshop held by EPA’s ORD National Health
and Environmental Effects Research Laboratory (NHEERL) to assess a
variety of exposure types.  At this workshop, discussion concerning
development of a distinction between intentional exposure versus
observational versus intervention studies was held.  WHO regional
offices published materials on various types of exposure pertinent to
this issue.  Dr. Fish agreed that the Board should attempt to educate
themselves on these various matters before the June 2007 HSRB meeting.

Dr. Fisher summarized information to consider at the June 2007 HSRB
meeting as including strategies for addressing scientific and ethics
concerns indicated in the June 2006 HSRB meeting report; discussion of
helpful analytic plans or models from other agencies (such as WHO),
particularly statistical analysis plans to ensure scientific validity;
and addition of statisticians to planning procedures.  She stated that
the Board would like to be presented with an overall plan for research,
but noted that despite the existence of such a plan, each site protocol
will need to be evaluated for human subject protections.  She commented
that there appear to be two tiers to this issue, namely whether the
model and general plan are scientifically and ethically valid and how
the protocol will be implemented at each site, i.e., how issues such as
compliance with data collection and entry will be managed, subject
safety, and monitoring of recruitment.  She also recommended reviewing
the information from EPA’s ORD NHEERL as suggested by Dr. Lebowitz,
and discussing potential plans for community representation.

EPA’s Need for New Research on Occupational Handler Exposure

Dr. Fisher presented the charge questions addressing EPA’s need for
new research on occupational handler exposure.  She noted the Board’s
consensus that EPA’s case for the need for new research was well made,
based in part on the written material provided at this week's meeting.

Background

Mr. Jordan provided an overview of presentations related to EPA’s
pesticide handler exposure research programs.  He described how EPA
would use the data generated by the occupational exposure protocols.

EPA evaluates pesticides under the authority of FIFRA.  For a pesticide
to be registered, which is required before sale, EPA must determine that
its use will not cause “unreasonable adverse effects” when used as
directed.  EPA must balance risks and benefits as part of the
registration process.  A wide range of potential risks are considered,
including those to people who mix, load, or apply pesticides, i.e.,
handlers.  To evaluate handler risks, EPA compares toxicity information
with exposure information to determine the MOE, which is calculated by
dividing the toxicity endpoint by exposure.  Thus, a smaller MOE
indicates increased risk.  If the MOE does not meet EPA standards for
registration, the sponsor could be asked to change the formulation of
the pesticide or how it is handled, or to require the use of protective
equipment.  If these conditions fail to reduce risks associated with use
of the pesticide, EPA can prohibit its use.  

Data gathered as part of the Pesticide Handler Exposure Research
Programs will be used to refine and improve EPA’s ability to assess
exposure.  The research conducted under these programs will measure
handler exposures for different use scenarios; assess the extent to
which handler exposure is proportional to the amount of pesticide active
ingredient handled; and characterize the distribution of unit exposures
across handlers.

At present, EPA assumes a linear relationship between exposure and risk.
 Data gathered through handler exposure research will help to confirm
this, or will provide evidence that the assumption is faulty.  EPA has
attempted to address this issue in the past.  At the January 2007 SAP
meeting, EPA requested advice on scientific issues affecting this and
has been working to translate SAP advice into concrete decisions
affecting how the advice can be effectively implemented in the design of
research protocols.  EPA also is cognizant of WHO protocols for
assessing exposure.  Mr. Jordan suggested that at the June 2007 HSRB
meeting, it may be useful for the Board to delve more deeply into
aspects of protocol design before addressing specific protocols.  This
depends on the ability of members of the AHTF and AEATF, along with
other regulatory agencies, to use the general guidelines from the SAP
report to generate concrete protocols.

Mr. Jordan clarified the distinction between observational research and
intentional exposure research, as discussed previously by the HSRB.  The
draft language in regulations for research involving exposure of human
subjects states that intentional exposure research encompasses the study
of a substance in which exposure experienced by a human would not have
occurred except by participation in the study.  EPA decides which
studies fall under these regulations and which do not.  For example,
worker re-entry studies would be considered intentional exposure
research.  The Board has not reviewed many such studies because most of
the intentional exposure studies in the EPA database do not involve
intentional exposure to toxicity and occurred before the new regulation
regarding human subject protection went into effect.  EPA is only
required to bring older studies to the HSRB for review if the studies
were conducted to identify or quantifying a toxic effect.  The re-entry
studies were not performed for this purpose, and thus were reviewed for
ethics only within EPA.

Mr. Jordan concluded by offering to answer any Board questions about
EPA’s need for new data.  If the HSRB approves, EPA will work with the
task forces and other regulatory partners to design the best possible
studies to evaluate pesticide handler exposure.

Board Discussion

Dr. Fisher asked whether the data from the ARTF studies had any
relationship to the agricultural handler exposure data that will be
collected.  Mr. Jordan answered that both concern risks that may arise
from pesticide use.  He explained that EPA recognized two categories of
occupational exposure.  The first applies to handlers who mix, load, and
apply pesticides.  The second applies to those who are exposed to
pesticides when they engage in work activities that bring them into
contact with the pesticides.  There are similarities in the methods used
to assess worker exposure after re-entry and handler exposure, but the
two assessments are not equivalent.  Mr. Carley described examples of
these similarities.  Both studies use whole-body dosimetry rather than
biomonitoring; ethics concerns about heat-related illnesses apply to
both studies.  Differences between the studies include the likelihood
that language issues will be a larger concern for the re-entry studies
than the handler studies.  Third-party involvement in recruitment also
is likely to be different, because re-entry workers are more likely to
be hired as a crew, whereas handlers are more likely to be considered
independent employees (such as members of an agricultural flying
service).  Different sets of best practices regarding recruitment will
be needed for the two groups.

Dr. Fisher inquired if the HSRB would have the opportunity to discuss a
statistical analysis plan, and whether the Board would receive
background information on alternatives to such plans to prepare for
review of specific protocols.  Mr. Jordan responded that EPA would
attempt to provide this information.  Dr. Fisher noted that, for agenda
planning, the Board would like to have an opportunity in June to 
discuss analytic approaches before reviewing protocols in October.  Dr.
Fenske commented that the ARTF studies address similar issues.  He
expressed concern that because the measurement methods are similar for
the re-entry and handler exposure studies, the lessons learned are of
interest more to EPA than the HSRB.  EPA has a large database consisting
of individual worker monitoring units and multiple scenarios (i.e., crop
type, pesticide activity, etc.).  There are a finite number of
monitoring units and statistical analysis is being performed for this
research because EPA is using the data to assess exposure.  Given that
this database was complete in 2001 and given the demonstrated utility of
the database, Dr. Fenske suggested that it may be instructive for the
HSRB to hear from a member of the task force or EPA how the worker
re-entry data are used.  Mr. Jordan responded that EPA needs a better
understanding of the relevance of the re-entry questions for preparation
for review of the agricultural handler exposure protocols.  With respect
to Dr. Fenske’s interest in the re-entry database, because it is a
large database, EPA has not reviewed all the data or determined the
statistical treatment of it.  EPA has decided to discuss with the SAP
issues for database use and incorporation of the data into a risk
assessment database.  This will take place during 2008.  Depending on
the HSRB agenda, coordination of this discussion with HSRB activity
could be an option.

Dr. Carriquiry requested clarification of the relevance of the ARTF
studies to the agricultural handler exposure studies and how review of
the re-entry studies would help the HSRB assess the handler studies. 
Dr. Menikoff inquired whether there was a standard in the re-entry
studies regarding how these new protocols handled subject protection if
the studies required a change in pesticide use, or if these studies were
more observational in nature.  Mr. Carley explained that he and members
of his team have reviewed all the studies in the re-entry and other
databases, or sets of exposure studies, involving human subjects between
February 2006 and six months later.  These were all pre-rule studies,
thus the distinction between intentional exposure and observational is
less important.  He considered his experience working with the ARTF and
other task forces to be similar to that of his work with the AHETF. 
Both task forces encompass research to meet the needs of EPA and require
sound, well-executed protocols.  Similar to other pre-rule studies,
these vary widely in the completeness of ethics reporting.  The standard
used for ethics review was to require clear and convincing evidence that
the study was intentionally or seriously deficient and ensure that
neither children nor pregnant or nursing women were involved as
subjects.  Based on information available in the archive, these studies
were not reviewed as intensely as current studies.

Dr. Menikoff questioned whether information from the ARTF studies could
inform review or development of the AHETF studies.  Mr. Carley explained
that the activities of re-entrant workers and handlers are different. 
In addition, the change in the rule regarding human subject protection
will have a significant impact.  Dr. Fenske clarified that he was not
asking the HSRB to review the ARTF studies.  His intention was to
determine if information useful for review of the AHETF studies could be
garnered from the existing ARTF database.  His major concern is that a
statistical plan is not in place for the AHETF study, despite the fact
that this study is already underway.  If a statistical plan for ARTF
exists, it could be shared with the HSRB because these studies also
involve monitoring activities similar to those in the professional
handler scenarios.  Dr. Fisher noted that because the ARTF work was
performed pre-rule, issues concerning human subject protection will not
be relevant.  A statistical plan would be relevant to the HSRB only if
it is equivalent to what will be used for AHETF protocols.  She stated
that it is EPA’s role to determine the relevance of ARTF to AHETF.

Dr. Carriquiry questioned whether the Board will receive background
material when they review the handler exposure protocols.  She noted
that the AHETF proposed a set of guidelines that the SAP reviewed and
critiqued, but was uncertain if an agreement was reached on some
important study aspects, such as collecting repeated observations on the
same person, random versus systematic sampling of scenarios (termed
factor sets for AHETF), and the appropriate number and levels of factor
sets.  She inquired if any consensus had been achieved on these items. 
Dr. Carriquiry also asked under which guidelines the protocols had been
written.  Mr. Jordan said that the SAP has offered advice that could be
characterized as asking EPA to consider these issues, but did not
provide definitive answers.  He added that he had only recently received
the SAP report.  EPA has been considering these issues and making
progress internally, but does not currently have answers to these
questions.  Conversations among EPA and AHETF personnel will lead to
development of a statistical design for the study that will address
these issues.  There must be consideration of matters, such as the
quality of the scientific information and its applicability, cost, level
of understanding, how to choose the most important factors, and EPA’s
intended use of the information that must be balanced in the development
of specific protocols.

Drs. Brimijoin, Carriquiry, and Chambers reviewed the HSRB’s response
to whether EPA had justified that additional data were needed.  Dr.
Chambers agreed with EPA’s need for additional data.  Dr. Brimijoin
also agreed, and commented that in June 2006 HSRB meeting he heard
EPA’s elaborate plans for collecting large amounts of data, but a
sense of how that data would be analyzed was lacking; EPA should have a
plan in place for analyzing the data before data collection begins.  Dr.
Carriquiry added that EPA should be aware of the expertise of the HSRB
members who could help review such a plan.

Dr. Fisher asked Drs. Hoel and Zhu for comments on EPA’s justification
for its need for additional handler exposure data.  Dr. Hoel opened by
asking whether the data would have a significant impact on setting
standard.  He stated that he was unconvinced that, given the human
exposure involved in these studies, the data could not be obtained
through observational studies.  He commented that for toxic substances,
information on pharmacokinetics and genetic variability of the exposed
population is needed.  He found the idea of intentional exposure of
human subjects to toxic substances troubling.  Dr. Fisher explained that
the products used in these studies are already in use.  The goal of the
handler exposure research is to determine handlers’ exposure levels
that occur during the course of their normal work activities.  In this
case, “intentional” refers to the nature of the control.  The
pesticides are the same as or similar to those the workers ordinarily
use.  The workers will not be exposed to any level or quality of
pesticide to which they would not ordinarily be exposed.  Dr. Zhu noted
that a controlled exposure study would be more definitive than an
occupational exposure study.  

EPA FIFRA SAP January 2007 Review and Report:  Worker Exposure Methods

Background

Dr. Steven Heeringa introduced himself as the FIFRA SAP Chair.  Dr.
Heeringa, a statistician at the University of Michigan, is an expert in
statistical design and analysis for population-based research.  He
acknowledged Dr. William Popendorf of Utah State University, who also
serves on the FIFRA SAP.  Dr. Popendorf introduced himself as a
professor of industrial hygiene at Utah State University who has
conducted exposure studies for approximately 30 years.  Dr. Heeringa
stated that he would outline the FIFRA SAP report and describe the main
topics.  The SAP operates as an advisory panel under FACA.  SAP
deliberative sessions involve review of advance material by a permanent
panel of seven members and an ad hoc set of 10 to 12 other specialists. 
The deliberations of the SAP are public and information included in the
SAP report must have been discussed openly at the public meeting.

Dr. Heeringa began review of the FIFRA SAP report by stating that the
SAP supported EPA’s assessment of the limitations of existing
pesticide handler exposure data.  The panel identified eight
limitations:  1) inadequate QA/quality control documentation; 2) high
levels of measurement uncertainty due to the methodology used; 3) large
amounts of censored (undetectable) data; 4) incomplete dermal sampling
data; 5) high levels of observation clustering with unknown intra-class
correlation; 6) data based on short sampling periods, creating
difficulties with extrapolating to full day exposures; 7) many scenarios
with too little data; and 8) scenarios that do not reflect modern work
practices and technologies.

The SAP judged the AHETF plan to be reasonable, with some critiques. 
The monitoring duration criteria were considered too stringent to
capture real-world, short-term use scenarios.  The biomonitoring data
criteria were deemed too restrictive because they did not allow for
extrapolation to humans from rat or pig.  The air sampling criteria
needed to be refined and dermal sampling criteria improved. 

Dr. Heeringa explained that the SAP recommended whole body passive
dosimetry because it would provide minimum uncertainty and maximum
protections (by minimizing skin exposure).  Patch dosimeters are subject
to uncertainty because of the need to extrapolate to the whole body
surface.  Biomonitoring was permitted, but not required in the
protocols.  The primary use of biomonitoring was considered to be as an
indication of whole body dosimeter breakthrough, but occurrence of a
small breakthrough would not require data to be discarded and was not
required for acceptance of dosimeter results.  Hand rinsing was
considered as a way to evaluate hand exposure.  Hand rinsing methods
were recommended over wiping (which may underestimate exposure), but
this method carries uncertainty because of the effect of rate of
adsorption on recovery efficiency.  Field conditions also may confound
these measurements, because participants might rinse their hands more or
less frequently than anticipated.  The SAP agreed that a passive
dosimetry approach was sufficient to support EPA’s data needs and can
generate data that can be used to develop acceptably predictive
estimates of worker exposure for a wide variety of scenarios and worker
activities.

Dr. Heeringa explained that the SAP considered the issues surrounding
the assumption of linearity of exposure to be a statistical issue. 
Model assumptions were built into the AHETF proposal, including that of
a linear relationship between exposure and active ingredient handled. 
Sample design decisions will depend on this linear assumption.  If the
assumption holds, statistical plans can be streamlined.  If this
relationship is found not to be linear, it will be more difficult to
develop these plans.  AHETF plans to measure covariates that are not
currently included in the pesticide handler exposure database, such as
temperature, humidity, and certain behaviors, that might be used to
better model the relationship between exposure and active ingredient
handling.  The SAP recommended additional research concerning the
potential role of these other covariates in modeling exposure.

The SAP also considered the issue of repeated measurements.  A majority
of the SAP members recommended de-emphasizing within-worker variability
(repeated measures) and using resources to add clusters (i.e., sites,
days, or locations) and increase sample size to improve precision.  A
minority of members recommended repeated measures to capture measures of
intra-class correlation.  This approach would provide better information
concerning the relationship between repeated measures and biomonitoring
to help understand the results of biomonitoring relative to exposure. 
For the database itself, the SAP recommended spending funds on
individual worker observations over repeat observations of an individual
worker.

The SAP also responded to statistical questions concerning sample size
and allocation.  In general, the SAP accepted AHETF recommendations
concerning the cost of the studies.  Most studies would cost in the
range of hundreds of thousands of dollars.  The applicability of the
linear model is a critical assumption, because sample size and
allocation recommendations in the AHETF report were based on this model.
 AHETF and EPA will need to discuss precision requirements, because EPA
ultimately must judge whether the data meet fundamental precision
requirements for their use in regulatory activities.  A range of a
factor of three was placed on the geometric mean for the 95 percent CI;
EPA would tolerate an estimate that was acceptable within a threefold
increase over the geometric mean or a one-third decrease under the
geometric mean, essentially a nine-fold range in the predicted unit
exposure.

EPA originally recommended minimum studies consisting of approximately
1,500 workers each to populate the initial database.  The SAP
encouraged EPA to use larger numbers of clusters.  Dr. Heeringa
commented that in his research, 500 clusters is typical, but
five clusters, as determined by EPA, may be sufficient given the model
assuming linearity between exposure and active ingredient and the level
of precision that can be tolerated for risk assessment activities; small
studies of five clusters and five workers may be an adequate starting
point.  The SAP noted, however, that the acceptance of small sample
sizes depends heavily on the assumptions made in the statistical design.
 The SAP also was concerned with the proposed purpose of the nature of
sample selection and the dependency on the linear model.  The SAP
discussed the potential for bias and offered an alternative stratified
approach, but understood that the high costs of worker exposure
measurements constrain sample design options.

Dr. Heeringa summarized SAP’s findings by stating that the Panel
supported EPA’s position on the need for updated standardized exposure
data to replace or supplement existing data, supported passive dosimetry
with a preference for whole body dosimeters, recognized the large
uncertainties inherent in measuring worker exposures, and had concerns
about the exposure model and sample selection.

Dr. Carriquiry opened discussion by stating that she believed the SAP
report was incorrect regarding the issue of repeated measurements.  If
the objective of the data is to determine an estimate of the range of
typical exposures, failing to collect replicate data on a subject of
workers would result in a biased estimate.  The mean and median would be
correct, but the range would be too large.  Some replicate observations
are needed to remove within-worker variability.  For EPA, the estimates
at either end of the range of exposures may be significantly
over-estimated if this step is not performed.  Dr. Heeringa explained
that the SAP recommended 15 to 20 observations, but repeat measures did
not need to be a part of each study.  The report does note the need to
capture repeat observations in some studies.  Dr. Carriquiry added that
although within-worker variance would not always be the same, an
estimate from one study could be used to adjust the data from other
studies that may have only one observation per worker.  Dr. Heeringa
remarked that the SAP believed that repeat observations should be
relevant to actual practices.  For example, if a pesticide is applied
every 2 weeks, repeat measurements should be performed every 2 weeks. 
Dr. Popendorf added that this also is relevant to sample and pesticide
selection, because workers should not be forced to use the same
pesticide twice (or only twice). 

Dr. Lebowitz expressed his appreciation for the review of the SAP
report, particularly the review of different methods and comparison of
passive dosimetry to biomonitoring, and commented on the report’s
discussion of issues of biomonitoring exposure related to the
possibility of other substances giving rise to the same metabolites as
the monitored pesticides.  He agreed with the discussion of the
importance of measuring within-worker variability, particularly the
recognition that in certain settings this activity is more important
than in others.  Dr. Lebowitz addressed the issue of costs by suggesting
that extending the time over which observations occur could address the
need to satisfy both sample size and measurement replicates.  He
considered that exposure dose calculations needed to be assessed,
particularly in terms of how the data will be used in risk assessment,
and the issue of aggregate and cumulative exposure.  He commended the
SAP on its discussion of covariates, effect modifiers, and confounders. 

Dr. Lebowitz asked Drs. Heeringa and Popendorf to comment further on the
importance of biomonitoring.  Dr. Popendorf responded that the SAP
considered the tradeoffs between biomonitoring and dosimetry.  Using
passive dosimetry meant that the back calculations performed by using
exposure data to drive recommendations results in the least amount of
uncertainty for EPA.  Dr. Heeringa added that during the meeting, the
issue of biomonitoring was discussed in the context as a necessary step
to measure exposure, not necessarily dose.  The SAP understood the next
steps beyond determining dose would include determining dose at target
organs and subsequent biological processes.  For certain well-understood
compounds with established clearance rates, biomonitoring can be useful,
but to assess the distribution of exposures in the population by
back-calculating from the presence of a pesticide metabolite in urine
back to skin exposures was considered less optimal.  Dr. Chambers
agreed, adding that there was insufficient pharmacokinetic information
on most pesticides to perform back-calculations from presence in urine
to skin exposures.  Dr. Heeringa continued that passive dosimetry data
could be compared to biomonitoring results for some well-characterized
substances, but the panel believed that the data would be similar enough
to warrant passive dosimetry.

Dr. Krishnan commented that reverse calculations can be performed if
physiology-based kinetic models are available.  He also noted that he
believed the inability to extrapolate from rat data to interpret
biomonitoring data may be too restrictive.  If the permeability constant
or coefficient from rat studies is used, exposure concentrations could
be underestimated by a factor of approximately 10.  Unless there is
evidence that the permeability for a particular pesticide is similar in
rats and humans, reconstructing based on biomonitoring data using rat
pharmacokinetics is acceptable; if not, this would introduce greater
uncertainty.  In these cases, equating the metabolite or pesticide
present in urine to the absorbed dose is acceptable.  

Dr. Krishnan continued by asking if collection of biomonitoring data
would help address the effectiveness of the dosimetry monitoring.  Dr.
Heeringa replied that the SAP recommended that some biomonitoring data
be collected to detect breakthrough on the whole body dosimetry.  The
SAP did not, however, recommend that all observations include
biomonitoring as a method for quality control.  Biomonitoring data could
be used to develop qualitative and quantitative parameters, or in
calibration studies.  Dr. Chambers added that the SAP was not
enthusiastic about biomonitoring because many of the metabolites of the
pesticides are scarce or have long half-lives.  Dr. Heeringa agreed,
adding that the SAP did not want to require that observations be
excluded from the database because biomonitoring indicated breakthrough
occurred; also, the SAP did not want workers to be excluded if they
declined to participate in urine testing.  Dr. Fisher summarized that
the SAP was not highly enthusiastic about including biomonitoring
because the major metabolites for many pesticides were only a small
portion of metabolites, and long half-lives would require extensive
urine collections with likely poorer compliance of participants.

Dr. Fisher asked Dr. Heeringa to comment on the lack of information on
the workers themselves or their work activities, and what sort of data
would be needed to develop a design that accounts for the expected
variability.  Dr. Heeringa explained that there were two dimensions to
this question.  First, EPA and the registrant’s agriculture experts
understand many of the practices workers use for applying pesticides. 
This is important for understanding factors critical to exposure, and
understanding these factors will help design the study.  However,
although the practices are known, their frequency and distribution,
across individuals in space and time, is not well known.  Exposure can
be different depending on variables such as site and crops grown.  This
information would be used in the design to determine sample allocation. 
The goal of the protocols is to maximize procedures or measures that
have high variability of exposure, but it is unknown how many workers
these practices affect.  Dr. Fisher questioned if much of the
information gathered would be product- or context-specific.  She
inquired about the nature of the data in terms of specificity versus
breadth, what elements would be most useful, and the dangers of
over-generalization of data to specific product context.  Dr. Popendorf
explained that the database will be generic, not product-specific.  Data
would be categorized by use scenarios, which currently are being
defined.  The chemicals used were selected on the basis of available
methods to detect these chemicals at low levels.  Exposure information
should be broadly applicable to the products used in that setting and
for that formulation.  Dr. Popendorf continued that in terms of sample
allocation, a stratified approach in terms of a given exposure or
handling amount could be used to predict exposures to the population. 
Dr. Heeringa commented that the AHETF plan defined a restricted set of
scenarios, formulations, and activity types.  These were considered to
be realistic starting points, and eventually subactivities could be
determined and differentiated. 

Dr. Fenske commented that the Board had concerns when it reviewed some
of the AHETF protocols in June 2006.  For example, a protocol was
designed to have 10 people in one scenario involving open loading of
liquid in an air-blast application.  Within that scenario, one person
may have used five containers containing 5 gallons each, while another
person may have used one 25-gallon container.  Other conditions, such as
wind speed, also could affect exposure.  The HSRB had the sense that
there was a high degree of variability within a scenario, and it was not
clear if within-scenario variations in the size of the containers used,
frequency of opening the containers, and so forth, were included to
create a range of values or to use as a variable in statistical
analysis.  Dr. Fenske questioned whether the study had sufficient power
to use these variables in an analysis.  Dr. Heeringa responded that
study design is under the purview of EPA, but the SAP considered this. 
The SAP considered whether the experiments should be structured with
control variables, but given the many behavioral and other variables
involved, it is not possible to control for all sources of variability. 
The goal is to capture data on the covariates, although it will not be
possible to statistically control for their presence.  It was deemed
important to capture this data so database users could have an idea of
the variability involved and know how the data were captured.

Dr. Lebowitz questioned if there was sufficient discussion at the SAP
meeting about the quality and acceptability of existing data in the
pesticide handler exposure database for certain factor sets that would
allow dose data to be used.  He added that air monitoring might be
important in certain settings and contribute to total dose.  He asked
whether the SAP had discussed measuring ingestion through food or water
contamination and how these exposure pathways might contribute to
estimates of exposure.  Dr. Popendorf explained that there was little
discussion of secondary exposures.  These measurements could be more
applicable to biomonitoring experiments.  Most existing data demonstrate
that excretion and dermal monitoring appear to correlate well
numerically; in general, oral ingestion is not considered an important
component of exposure.  Dr. Chambers agreed, and noted that ingestion
data could confound biomonitoring results.  Dr. Heeringa added that the
SAP did not discuss incidental contamination at length, which was judged
to be small.  Including hand rinsing as part of some protocols may help
assess this.

Dr. Heeringa continued that the SAP did not consider the data in the
existing pesticide handler exposure database to be obsolete for risk
assessment.  If qualified studies exist in the database (i.e.,
observations on techniques and scenarios currently in use by pesticide
handlers), this data could be used for current risk assessment
activities.  However, the SAP made no recommendations concerning the
incorporation of this data into the new database.

Dr. Sharp commented on medical monitoring issues, including the absence
of the involvement of occupational health physicians in these protocols.
 He questioned if the SAP had considered recommending inclusion of such
professionals to help determine actions to take if a level of exposure
is identified that should trigger medical assessment.  Dr. Heeringa
stated that the SAP discussed health concerns, such as heat and duration
of exposure to heat.  Dr. Chambers added that the SAP is asked to review
scientific issues, not health issues.  Dr. Fisher asked whether SAP
thought data that already has been collected, could be used,
implications for models and procedures, and whether it could provide
pilot information for the design of this study.  Dr. Chambers added that
the quality of the existing data has been graded, and she believed that
high quality data would be used.

Dr. Fisher asked if drop-outs or partial data were anticipated and
whether there was advice for using (or eliminating) such data.  She
questioned if these issues were considered in discussion of study design
and sample size and selection.  Dr. Heeringa explained that the SAP did
not discuss drop-out issues at length, but did discuss length of
observation.  The protocols in question cannot strictly control the
length of time taken to apply materials, thus, the task force developed
targets for exposure periods to reflect normal work activities.  These
values would be normalized.  The SAP did not discuss individual
drop-outs, but concluded that the protocols should reflect typical work
day activities.

Dr. Zhu commented that he felt strongly that
pharmacokinetic-pharmacodynamic data should be used to reduce
uncertainty.  Occupational exposures should be high enough for
biomonitoring.  He did not believe there was good evidence that
biomonitoring would be unsuccessful in this setting, and that, in the
future, investigators would regret that such data were not collected. 
Biomonitoring data are useful because it can provide the physiological
link to the next processes occurring after exposure and will help
estimate total and cumulative exposures.  If a physiologically based
modeling approach is desired, repeat measurements are needed to provide
reliable physiology data, and will help ensure the data are useful in
the future.  Dr. Zhu stated that he was troubled by the sample sizes
described for this research.  Exposure is likely to be linear, but
sample size determination is based solely on this assumption of
linearity, and perhaps does not provide the best basis for sample or
cluster size estimation.  He added that collecting covariates (such as
use and application methods) is useful, but standards are required for
collection of those data.

Dr. Heeringa explained that these data will be used for evaluation in
the context of a general database that has information on a distribution
of exposures.  The arguments for biomonitoring and repeated measurements
are valid; however, most biomonitoring and physiological models are not
appropriate for these settings.  These are tier 1 or 2 screening studies
to determine if a significant risk exists.  Dr. Heeringa agreed that if
the interest was in developing physiological models, repeated
measurements were needed; however, measurements for such modeling
activities are more properly made under controlled laboratory
conditions, rather than in the field.  Dr. Chambers added that
pharmacokinetic-pharmacodynamic models are available only for a small
number of compounds and may not apply to all the compounds being
measured.  Dose applies to all compounds.  Dr. Brimijoin noted that if
passive dosimetry is performed in a reliable manner to monitor exposure,
biomonitoring can only be considered a supplemental tool that will
provide little information on absorption; if the dosimetry garments
function properly, most pesticide absorption/uptake will be blocked. 
Dr. Brimijoin agreed with Dr. Heeringa concerning the issue of
developing pharmacokinetic-pharmacodynamic models; collecting
biomonitoring data for this is a sound idea, but should be performed in
a different setting.  Dr. Fenske stated that biomonitoring is important,
but the protocols reviewed in June 2006 called only for passive
dosimetry.  The task force chose specific compounds based on their low
toxicity, and good pharmacokinetic-pharmacodynamic models may not be
available for many of these.  The goal of this work is to collect good
quality exposure data across a number of scenarios for risk assessment
activities.  Validation of hand washing, face washing, biomonitoring, or
other exposure assessment techniques should be considered side studies.

Dr. Popendorf clarified questions concerning sample size.  He stated
that the design the SAP was shown estimated that five people in five
clusters for a given scenario was reasonable to achieve a precision
factor of 3.  A secondary goal of these analyses was to detect
linearity.  If linearity is not shown, it is true that data collected on
potential covariates likely will not help determine which covariates
correlate with variability.  The SAP suggested, that, as a backup to the
linearity assumption, some other hypotheses be developed in terms of the
major potential drivers for exposure in a given scenario and use the
covariate as a potential way to validate and use data in a regulatory
process.  He summarized that precision and linearity were the major
drivers for sample size determination.  Dr. Heeringa added that the SAP
understood that, if the linearity assumption does not hold, increased
sample size will be needed to retain the same level of precision.  The
SAP’s recommendation for this is to increase the number of clusters. 
The Panel also recommended that assumptions be revisited as data are
gathered.

Dr. Brimijoin commented that in the statistical treatment of data, the
focus would be on multiple clusters with multiple individuals involving
a particular mode of application, regardless of the type of compound, or
also stratified by compound.  He stated that when he first saw the AHETF
protocols, he did not think the protocols included sufficient replicates
to be of use.  He asked whether data would be consolidated by putting
together information from different compounds, but that had the same
amount (milligrams) of active ingredient.  Dr. Fisher summarized that a
difficulty in review of this work seemed to be how to understand that
there is a great deal of information that cannot be specific.  The data
are needed, and there is no way to have a sample size large enough to
answer exposure questions for every ingredient, timeframe of exposure,
or application method.  A rationale is needed to determine which
covariates are most important.  Other questions concern the validity of
the assumption of a linear model and how the data can be used, given
this lack of specificity, the variability of ingredients, etc., to
support risk assessment activities.  Dr. Chambers stated that the
assumption is that the handling activity and formulation will determine
exposure.  The identity of the pesticide measured is less important; if
two pesticides have the same formulation and are handled in the same
amounts and in relatively the same manner, exposure will be similar. 
These protocols are intended only to measure dose, not toxicity
equivalents.  Dr. Popendorf agreed, noting that the data would be used
only to assess exposure; absorption and toxic effect would be
chemical-specific.  Different formulations, i.e., liquid or powder,
will be measured separately.

Public Comments

Dr. Fisher invited oral public comment on the EPA FIFRA SAP January 2007
Report on Worker Exposure Methods.  No oral public comments were
received.

Board Discussion

Dr. Fisher asked Board members to respond to the question concerning
additional information needed for review of handler research in general
or individual protocols.  Dr. Fenske began, stating that the Board needs
information from EPA concerning the use of information in the re-entry
workers database, which has parallels to AHETF, for risk assessment
activities.  He also requested clarification of the definition of
“intentional exposure” versus “observational” research.  He
recommended consideration of the term “scripted” instead of
“intentional exposure,” because the exposure is not
“intentional” but is staged or modified to meet the practical
considerations of obtaining useful data.  The HSRB should discuss this
with EPA.  Dr. Fenske added that Mr. Jordan had indicated that
discussions on these terms were in progress at EPA, and perhaps could
share any relevant information concerning these matters.  Dr. Fenske
related other information requests, including a governing document, such
as that submitted to the SAP, or the joint document from EPA, California
EPA, and Health Canada, which aptly justified and explained data needs. 
He also requested feedback on stated EPA plans for additional validation
studies to determine whether dermal exposure measurements underestimate
true exposure; broaden participation of the scientific community and
parties with direct interest, such as the labor community; and plans for
meeting the requirements of 40 CFR Part 26.

Dr. Lebowitz observed that his points had been expressed in the SAP
discussion, which also clarified many of his questions.  Concerning
additional information, Dr. Lebowitz stated that the Board did not yet
have a clear understanding of the study designs that would be employed
and final decisions regarding sample size, analyses, and handling
biases.  As a general recommendation, he suggested that the AHETF
attempt to save time and money by including appropriate studies in the
existing pesticide handlers exposure database in its own database.  He
added that he will be interested in seeing how the revised protocols
address issues, such as standardization of exposure monitoring, and
other subjects raised by the SAP.

Dr. Lehman-McKeeman stated that additional information was needed to
clarify how recognized covariates would be handled and integrated into
data analyses and how this would affect study design.  She also asked
for identification of the study director regarding who would approve a
study or oversee the execution of the studies.

Dr. Menikoff requested more discussion of how pesticides are chosen for
studies and how that changes conditions for workers.  He stated that
“intentional” exposure means exposure to a substance that would not
otherwise occur.  He inquired whether ethical justification was needed
to alter the pesticide used, and whether investigators could instead
locate a setting in which the desired pesticide already was in use; this
would help eliminate some ethical issues.  

Dr. Chambers disagreed with comments on the definition of intentional
exposure.  In her opinion, EPA’s analysis of this issue should be
heard before the Board develops its own definition.  Dr. Fenske agreed,
adding that it is not the HSRB’s role to develop the definition, but
to provide advice.  He commented to Dr. Menikoff that, in his
understanding, the AHETF always attempts to find conditions that do not
have to be altered for research purposes, but this is limited by the
availability of analytical capabilities for a given compound. 
Appropriate substitutes must sometimes be suggested.  Dr. Fenske also
addressed the issue of heat related illnesses.  The procedure for
collecting data places workers at risk for heat stress; Dr. Fenske asked
Dr. Menikoff if this was related to the idea of changing working
conditions.  Use of the dosimeter garments may decrease pesticide
exposure, but increase another type of hazard.  Dr. Menikoff responded
that this did meet his idea of changing conditions.  He added that he
was not debating whether the research fit within the applicable
statutes.  His recollection was that in many cases, the investigators
supplied the pesticide.  If this is the case, the investigators must
justify why they cannot find a location at which that pesticide already
is in use.  Dr. Fisher cautioned against assuming that use of a
different pesticide increases risk.

Dr. Fisher summarized the HSRB informational needs.  A plan similar to
that provided to the SAP is needed, not for critique, but to further
understanding of the AHETF.  Information also is needed concerning how
EPA will evaluate its linear model assumption, given the SAP’s
recommendations about evaluating this model during the data collection
process and identifying an alternate approach, if necessary.  The HSRB
members also asked for information concerning how sample size would be
determined; strategies for replacement of missing or partial data; a
statistical analysis plan; identification of covariates to be collected
and a rationale for emphasis on some covariates versus others;
assessment of the need for a subset of repeated measurements to control
for some variability; identification of the type of biomonitoring data
that would be collected as a check for passive dosimetry; information
concerning validation of data collection, entry, training at the site,
and identification of relevant IRBs; information on whether passive
dosimetry over- or under-estimates dosage and whether statistical
analyses or biomonitoring data will help determine if a bias exists;
information on sampling frame and where to focus data collection, based
on usage patterns for products; and a rationale for the use of
pesticides at each site if they differ from those normally used, to
inform ethics discussions on toxicity and side effects.

Dr. Lewis thanked the Board members for their work and EPA for preparing
the meeting.  He stated that the next HSRB meeting is tentatively
scheduled for June 27-29, 2007.

Dr. Fisher adjourned the meeting.

Respectfully submitted:

Paul I. Lewis, Ph.D.

Designated Federal Officer

Human Studies Review Board

United States Environmental Protection Agency

Certified to be true by:

Celia B. Fisher, Ph.D.

Chair

Human Studies Review Board

United States Environmental Protection Agency

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 for
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.

Attachments 

Attachment A 		List of HSRB Members 

Attachment B 		Federal Register Notice Announcing Meeting 

Attachment C 		Meeting Agenda 

 

Attachment A

EPA HUMAN STUDIES REVIEW BOARD MEMBERS 

Chair

Celia B. Fisher, Ph.D.

Marie Ward Doty Professor of Psychology

Director, Center for Ethics Education

Fordham University

Bronx, NY 

Vice Chair

William S. Brimijoin, Ph.D.

Chair and Professor 

Molecular Pharmacology and Experimental Therapeutics

Mayo Foundation

Rochester, MN 

Members

David C. Bellinger, Ph.D. *

Professor of Neurology

Harvard Medical School

Professor in the Department of Environmental Health

Harvard School of Public Health

Children's Hospital

Boston, MA  

Alicia Carriquiry, Ph.D.

Professor 

Department of Statistics

Iowa State University

Ames, IA 

Gary L. Chadwick, PharmD, MPH, CIP

Associate Provost

Director, Office for Human Subjects Protection

University of Rochester

Rochester, NY 

Janice Chambers, Ph.D., D.A.B.T.

William L. Giles Distinguished Professor

Director, Center for Environmental Health Sciences

College of Veterinary Medicine

Mississippi State University

Mississippi State, MS 

Richard Fenske, Ph.D., MPH 

Professor

Department of Environmental and Occupational Health Sciences

University of Washington

Seattle, WA 

Susan S. Fish, PharmD, MPH

Associate Professor, Biostatistics & Epidemiology

Boston University School of Public Health

Co-Director, MA in Clinical Investigation

Boston University School of Medicine

Boston, MA 

Suzanne C. Fitzpatrick, Ph.D., DABT

Senior Science Policy Analyst

Office of the Commissioner

Office of Science and Health Coordination

U.S. Food and Drug Administration

Rockville, MD 

KyungMann Kim, Ph.D., CCRP

Professor and Associate Chair

Department of Biostatistics & Medical Informatics

School of Medicine and Public Health

University of Wisconsin-Madison

Madison, WI 

Kannan Krishnan, Ph.D. 

Professor

Département de santé environnementale et santé au travail

Faculté de médicine 

Université de Montréal

Montréal, QC  Canada

Michael D. Lebowitz, Ph.D., FCCP

Professor of Public Health & Medicine

University of Arizona

Tucson, AZ 

Lois D. Lehman-Mckeeman, Ph.D. 

Distinguished Research Fellow, Discovery Toxicology

Bristol-Myers Squibb Company

Princeton, NJ 

Jerry A. Menikoff, M.D.  

Associate Professor of Law, Ethics & Medicine 

Director of the Institute for Bioethics, Law and Public Policy

University of Kansas Medical Center

Kansas City, KS 

Sean M. Philpott, Ph.D.

Policy and Ethics Director

Global Campaign for Microbicides

Program for Appropriate Technology in Health

Washington, DC  

Richard Sharp, Ph.D. 

Assistant Professor of Medicine

Center for Medical Ethics and Health Policy 

Baylor College of Medicine 

Houston, TX 

* Not in attendance

Attachment B

Federal Register Notice Announcing Meeting

Human Studies Review Board; Notice of Public Meeting   

[Federal Register: March 26, 2007 (Volume 72, Number 57)]

[Notices]

[Page 14101-14103]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:E7-5492]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-ORD-2007-0216; FRL-8291-4]

Human Studies Review Board; Notice of Public Meeting

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The U.S. Environmental Protection Agency's (EPA or Agency)
Office of the Science Advisor (OSA) announces a public meeting of the
Human Studies Review Board (HSRB) to advise the Agency on EPA's
scientific and ethical reviews of human subjects' research.

DATES: The public meeting will be held on April 18, 2007 from 10 a.m. to
approximately 5:30 p.m., Eastern Time and April 19-20, 2007 from 8:30
a.m. to approximately 5:30 p.m., Eastern Time.

LOCATION: Environmental Protection Agency, Conference Center—Lobby
Level, One Potomac Yard (South Bldg.), 2777 S. Crystal Drive, 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 person listed
under FOR FURTHER INFORMATION CONTACT at least 10 business days prior to
the meeting, to allow EPA as much time as possible to process your
request.

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 Unit I.D.
of this notice.

FOR FURTHER INFORMATION CONTACT: Any member of the public who wishes
further information should contact Paul Lewis, EPA, Office of the
Science Advisor, (8105R), Environmental Protection Agency, 1200
Pennsylvania Ave., NW, Washington, DC 20460; telephone number: (202)
564-8381; fax: (202) 564 2070; e-mail address:   HYPERLINK
"mailto:lewis.paul@epa.gov"  lewis.paul@epa.gov . General information
concerning the EPA HSRB can be found on the EPA Web site at   HYPERLINK
"http://www.epa.gov/osa/hsrb/"  http://www.epa.gov/osa/hsrb/ .

ADDRESSES: Submit your written comments, identified by Docket ID No. 

EPA-HQ-ORD-2007-0216, by one of the following methods:

    Internet:   HYPERLINK "http://www.regulations.gov" 
http://www.regulations.gov : Follow the on-line instructions for 

	submitting comments.

    E-mail:   HYPERLINK "mailto:ORD.Docket@epa.gov"  ORD.Docket@epa.gov
.

    Mail: Environmental Protection Agency, EPA Docket Center (EPA/DC),

[[Page 14102]]

ORD Docket, Mailcode: 28221T, 1200 Pennsylvania Ave., 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 Ave., NW, Washington DC. The hours of

	operation are 8:30 AM to 4:30 PM Eastern Standard Time (EST), Monday

	through Friday, excluding Federal holidays. Please call (202) 566-1744

or email the ORD Docket at   HYPERLINK "mailto:ord.docket@epa.gov" 
ord.docket@epa.gov  for instructions. Updates to Public Reading Room
access are available on the Web site 

	(  HYPERLINK "http://www.epa.gov/epahome/dockets.htm" 
http://www.epa.gov/epahome/dockets.htm ).

    Instructions: Direct your comments to Docket ID No.
EPA-HQ-ORD-2007-0216. EPA's policy is that all comments received will be
included in the public docket without change and may be made available
online at   HYPERLINK "http://www.regulations.gov" 
http://www.regulations.gov , including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  or e-mail. The
  HYPERLINK "http://www.regulations.gov"  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   HYPERLINK "http://www.regulations.gov" 
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 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.

SUPPLEMENTARY INFORMATION:

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 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 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 the person 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   HYPERLINK
"http://www.epa.gov/fedrgstr/"  http://www.epa.gov/fedrgstr/ .    

Docket: All documents in the docket are listed in the

  HYPERLINK "http://www.regulations.gov"  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   HYPERLINK
"http://www.regulations.gov"  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 Ave., NW,
Washington DC. The hours of operation are 8:30 a.m. to 4:30 p.m. Eastern
Standard Time, Monday through Friday, excluding Federal holidays. Please
call (202) 566-1744 or e-mail the ORD Docket at   HYPERLINK
"mailto:ord.docket@epa.gov"  ord.docket@epa.gov  for instructions.
Updates to Public Reading Room access are available on the Web site ( 
HYPERLINK "http://www.epa.gov/epahome/dockets.htm" 
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 late March 2007. 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 HSRB Internet
Home Page at   HYPERLINK "http://www.epa.gov/osa/hsrb/" 
http://www.epa.gov/osa/hsrb/ . For questions on document availability or
if you do not have access to the Internet, consult the person 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:

    a. Explain your views as clearly as possible.

    b. Describe any assumptions that you used.

    c. Provide copies of any technical information and/or data you used
that support your views.

    d. Provide specific examples to illustrate your concerns and suggest
alternatives.

    e. 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-2007-0216 in the subject line on
the first page of your request.

    a. Oral comments. Requests to present oral comments will be accepted
up to April 11, 2007. 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 the person listed under
FOR FURTHER INFORMATION CONTACT no later than noon, Eastern Standard
Time, April 11, 2007 in order to be included on the meeting agenda and
to provide sufficient time for the HSRB Chair and HSRB Designated
Federal Officer (DFO) to review the agenda to provide an appropriate
public comment period. The request should identify the name of the
individual making the presentation, the organization (if any) the
individual will represent, and any requirements for audiovisual
equipment (e.g., overhead projector, LCD projector, chalkboard). Oral
comments before the HSRB are limited to five minutes per individual or
organization. Please note that this limit applies to the cumulative time
used by all individuals appearing either as part of, or on behalf of an
organization. While it is 

[[Page 14103]]

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 these time limitations by having numerous
individuals sign up separately to speak on their behalf. If additional
time is available, there may be flexibility in time for public comments.
Each speaker should bring 25 copies of his or her comments and
presentation slides for distribution to the HSRB at the meeting. 

    b. Written comments. Although you may submit written comments at any
time, 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 the
meeting. If you submit 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 Standard Time, April 11, 2007. You should submit your
comments using the instructions in Unit I.C. of this notice. In
addition, the Agency also requests that person(s) submitting comments
directly to the docket also provide a copy of their comments to the
person listed under FOR FURTHER INFORMATION CONTACT. There is no limit
on the length of written comments for consideration by the HSRB.

E. Background

A. Topics for Discussion

    The HSRB is a Federal advisory committee operating in accordance
with the Federal Advisory Committee Act (FACA) 5 U.S.C. app.2 section 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: (a) Research proposals and protocols; (b) reports of
completed research with human subjects; and (c) 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. 

    At the April 2007 meeting of the HSRB, EPA will present for HSRB
review: 

    • The results of two completed insect repellent efficacy studies
on an aerosol formulation of the active ingredient IR3535, studies which
the Agency intends to rely in making registration decisions. Protocols
for this research were reviewed by the Board at its June and October
2006 meetings. 

A proposal for a new field study of the effectiveness of products
containing oil of lemon eucalyptus in repelling mosquitoes. 

    • Completed studies of human skin irritation and skin
sensitization on two pending pesticide products whose use would involve
extensive dermal exposure. These studies were conducted before the
effective date of EPA’s human studies rules (April 7, 2006). 

    • EPA’s assessment of the need for new research on the exposure
received by occupational handlers who mix, load, or apply agricultural
or antimicrobial pesticides. 

    • An EPA “draft framework” concerning best practices for
recruiting and enrolling subjects in studies of occupational exposure. 

    In addition, at the Board’s request, EPA will present its
interpretation and application of the standard in 40 CFR 26.1705: “EPA
shall not rely on data from any research initiated after April 7, 2006,
unless EPA has adequate information to determine that the research was
conducted in substantial compliance with [EPA’s human studies
rules].” Finally, the Board may also discuss planning for future HSRB
meetings. 

B. 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   HYPERLINK "http://www.epa.gov/osa/hsrb/" 
http://www.epa.gov/osa/hsrb/  and   HYPERLINK "

http://www.regulations.gov"  

http://www.regulations.gov .  In addition, information concerning a
Board meeting report, if applicable, can be found at   HYPERLINK
"http://www.epa.gov/osa/hsrb/"  http://www.epa.gov/osa/hsrb/  or from
the person listed under FOR FURTHER INFORMATION CONTACT.

Dated: March 19, 2007.

George M. Gray,

Science Advisor

[FR Doc. E7-5492 Filed 3-23-07; 8:45 am]

BILLING CODE 6560-50-P

Attachment C

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD (HSRB)

PUBLIC MEETING

APRIL 18-20, 2007*

ONE POTOMAC YARD

ARLINGTON, VA

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

Docket Telephone: (202) 566-1752

Docket Number: EPA-HQ-ORD-2007-0216

Wednesday, April 18, 2007

10:00 a.m.	Convene Meeting and Identification of Board Members

		Celia Fisher, Ph.D. (HSRB Chair)

10:15 a.m.	Welcome

	Warren Lux, MD (Human Subjects Research Review Official, Office of the
Science Advisor, EPA) 

10:25 a.m.	Opening Remarks

			Mr. Jim Jones (Principal Deputy Assistant Administrator, Office of 

			Prevention, Pesticides, and Toxic Substances, EPA) and 

			Debbie Edwards, Ph.D. (Director, Office of Pesticide Programs)

10:40 a.m.	Meeting Administrative Procedures

		Paul Lewis, Ph.D. (Designated Federal Officer [DFO], HSRB, OSA, EPA) 

10:45 a.m.	Meeting Process

		Celia Fisher, Ph.D. (HSRB Chair) 

10:55 a.m.	EPA Follow-up on HSRB Recommendations

		Mr. William Jordan (EPA, OPP)   

Completed Repellent Efficacy Studies: IR3535 Aerosol (EMD-003.3 and
EMD-004.3)

11:10 a.m.	Science and Ethics of Repellent Efficacy Studies

		Clara Fuentes, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA) 

11:50 a.m.	Public Comments 

12:15 p.m.	Lunch

1:15 p.m.	Board Discussion 

EMD-003.3: Tick Repellency with Aerosol Spray Formulations

a.	Is this study sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy of the formulation tested
against ticks?  

b.	Does available information support a determination that this study
was conducted in substantial compliance with subparts K and L of EPA
regulations at 40 CFR part 26?

EMD-004.3: Mosquito Repellency with Aerosol Spray Formulations

a.	Is this study sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy of the formulation tested
against mosquitoes?  

b.	Does available information support a determination that this study
was conducted in substantial compliance with subparts K and L of EPA
regulations at 40 CFR part 26?

Carroll-Loye Mosquito Repellent Efficacy Protocol WPC-001

2:15 p.m.	Science and Ethics of Protocol WPC-001

		Clara Fuentes, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA) 

3:00 p.m.	Break

3:15 p.m.	Public Comments 

3:40 p.m.	Board Discussion   

a.	If the proposed research described in Protocol WPC-001 from
Carroll-Loye Biological Research is revised as suggested in EPA’s
review, does the research appear likely to generate scientifically
reliable data, useful for assessing the efficacy of the test substances
for repelling mosquitoes? 

 

If the proposed research described in Protocol WPC-001 from Carroll-Loye
Biological 

Research is revised as suggested in EPA’s review, does the research
appear to meet the applicable requirements of 40 CFR part 26, subparts K
and L?

Research Conducted After April 7, 2006: Meaning of “Substantial
Compliance” with 40 

CFR Part 26 

4:40 p.m.	Meaning of “Substantial Compliance”

		Mr. William Jordan (OPP, EPA) and Mr. Keith Matthews (OGC, EPA)

5:00 p.m.	Public Comment

5:20 p.m.	Board Discussion 

6:00 p.m.	Adjournment  

Thursday, April 19, 2007

8:30 a.m.	Convene Meeting

		Celia Fisher, Ph.D. (HSRB Chair)

8:40 a.m.	Follow-up From Previous Day’s Discussion

		Mr. William Jordan (OPP, EPA)  

Completed Patch Test Studies

8:50 a.m.	HSRB Workgroup and EPA Process on CBI Redacted Submissions

		Celia Fisher, Ph.D. (HSRB Chair) and Mr. William Jordan (OPP, EPA) 

Part I. 48-Hour Dermal Irritation Patch Test 

9:00 a.m.	Science and Ethics of 48 Hour Dermal Irritation Patch Test

		Roger Gardner, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA) 

10:00 a.m.	Public Comments 

10:30 a.m.	Break

10:45 a.m.	Board Discussion 

a.   Is this study sufficiently sound, from a scientific perspective, to
be used as part of a 

weight-of-evidence assessment to evaluate the potential of the
formulations tested to irritate human skin?  

b.   Is there clear and convincing evidence that the conduct of this
study was fundamentally 

unethical or significantly deficient relative to the ethical standards
prevailing at the time the research was conducted?

12:15 p.m.	Lunch 

Part II. Repeated Insult Patch Test 

1:30 p.m.	Science and Ethics of Repeated Insult Patch Test

		Roger Gardner, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA) 

2:15 p.m.	Public Comments 

2:45 p.m.	Board Discussion  

Is this study sufficiently sound, from a scientific perspective, to be
used as part of a 

weight-of-evidence assessment to evaluate the potential of the
formulations tested to cause sensitization of human skin?  

Is there clear and convincing evidence that the conduct of this study
was fundamentally 

unethical or significantly deficient relative to the ethical standards
prevailing at the time the research was conducted?

3:45 p.m.	Break

Framework for Developing Best Practices for Subject Recruitment for
Handler Exposure 

Research

4:00 p.m.	Framework for Developing Best Practices for Subject
Recruitment for Handler Exposure Research

		Mr. John Carley (OPP, EPA)  

4:30 p.m.	Public Comments

4:45 p.m.	Board Discussion 

a.	What additional elements of the process of recruiting and enrolling
subjects in handler 

exposure research should be addressed in a “Best Practices
Framework”?

For each of the elements in the “Best Practices Framework,” please
identify any 

additional sources of guidance that could be useful for an investigator
who is designing a process for recruiting and enrolling subjects in
handler exposure research.  

5:45 p.m.	Adjournment  

Friday, April 20, 2007

8:30 a.m.	Convene Meeting

			Celia Fisher, Ph.D. (HSRB Chair)

8:40 a.m.	Follow-up From Previous Day’s Discussion

			Mr. William Jordan (OPP, EPA)  

Follow-up on AHETF and AEATF Protocols 

8:50 a.m.	EPA’s Need for New Research on Occupational Handler Exposure

	Mr. William Jordan (OPP, EPA), Mr. Jeff Evans (OPP, EPA), Mr. Jeff
Dawson (OPP, EPA), and Mr. Matthew Crowley (OPP, EPA)  

10:00 a.m.	Break

10:15 a.m.	EPA’s Need for New Research on Occupational Handler
Exposure 

	(continued)

		Mr. William Jordan (OPP, EPA), Mr. Jeff Evans (OPP, EPA), Mr. Jeff 

		Dawson (OPP, EPA), and Mr. Matthew Crowley (OPP, EPA)  

11:15 a.m.	Summary of EPA FIFRA SAP January 2007 Report “Worker
Exposure Methods”

		FIFRA SAP Chair and/or Designee 

11:45 a.m.	Public Comments

12:15 p.m.	Lunch 

1:15 p.m.	Board Discussion 

Recognizing that protocol-specific science and ethics issues will be
addressed in later HSRB meetings, EPA has attempted to explain the basis
for its conclusion that additional information on exposure for people
who mix, load, and apply pesticides (handlers) would be useful in EPA's
regulatory decision-making and therefore new research would be valuable.
 Do the materials provided by EPA regarding the quality of the
scientific data currently available for assessing exposures for handlers
contain useful information to establish the societal value of proposed
new handler exposure research, assuming individual protocols would
generate scientifically valid information?  

What additional information, if any, would the Board want with respect
either to handler research in general or to individual protocols?

2:15 p.m.	Adjournment  

Please be advised that agenda times are approximate and subject to
change. For further information, please contact the Designated Federal
Officer for this meeting, Paul Lewis via telephone: (202) 564-8381 or
email:   HYPERLINK "mailto:lewis.paul@epa.gov"  lewis.paul@epa.gov . 

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