Document ID: EPA-HQ-ORD-2006-0384-0094
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-08-31T04:00Z

Proposed
Final
Draft
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1
Dated
August
28,
2006;
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of
67
EPA­
HSRB­
06­
03
1
2
George
Gray,
Ph.
D.
3
Science
Advisor
4
Office
of
the
Science
Advisor
5
1200
Pennsylvania
Avenue,
NW
6
Washington,
DC
20460
7
8
Subject:
June
27­
30,
2006
EPA
Human
Studies
Review
Board
Meeting
Report
9
10
Dear
Dr.
Gray:
11
12
The
United
States
Environmental
Protection
Agency
(
EPA
or
Agency)
requested
the
13
Human
Studies
Review
Board
(
HSRB)
to
review
scientific
and
ethical
issues
addressing
a
14
human
toxicity
study
involving
one
pesticide
active
ingredient­
chloropicrin;
guidelines
for
15
conducting
insect
repellant
efficacy
testing;
protocols
for
conducting
two
insect
repellent
16
efficacy
studies;
and
protocols
for
conducting
five
occupational
handler
exposure
monitoring
17
studies.
At
the
Chair's
request,
the
Board
developed
scientific
and
ethics
criteria
for
new
18
protocols.
The
enclosed
HSRB
report
addresses
the
Board's
response
to
EPA
charge
questions
19
for
the
Board's
consideration
at
its
June
27­
30,
2006
meeting.
A
summary
of
the
Board's
20
conclusions
is
provided
below.
21
22
Chloropicrin
23
24
Scientific
Consideration
25
26
 
The
chloropicrin
acute
inhalation,
human
toxicity
study,
was
scientifically
sound
27
for
the
purpose
of
estimating
a
safe
level
of
inhalation
exposure
to
chloropicrin.
28
A
LOAEL
of
100
ppb
was
a
scientifically
justified
point
of
departure
(
POD).
29
30
Ethical
Considerations
31
32
 
There
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
33
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
34
participants
or
failed
to
obtain
informed
consent).
35
36
 
There
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
37
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
38
was
conducted.
39
40
Insect
Repellent
Product
Performance
Efficacy
Guidelines
41
42
Actions
to
Minimize
Risks
to
Human
Subjects
43
44
 
The
consensus
of
the
Board
was
that
studies
involving
humans
are
necessary
to
evaluate
45
the
efficacy
of
products
to
repel
insects
and
other
arthropods.
46
Proposed
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2006;
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67
1
 
Risk
identification
and
minimization
is
also
essential.
In
their
protocols,
investigators
2
should
adequately
identify
risk
to
participants
and
describe
adequate
steps
they
will
take
3
to
minimize
these
risks.
4
5
Types
of
Toxicity
Data
That
Should
Be
Generated
6
7
 
The
consensus
of
the
Board
was
that
the
minimum
set
of
toxicity
data
that
should
be
8
routinely
generated
before
an
investigator
conducts
repellent
efficacy
testing
on
human
9
subjects
with
a
new
product
is
that
which
will
assure
that
subjects
would
not
be
at
risk
of
10
permanent
or
irreversible
harm.
11
12
13
Self 
experimentation
14
15
 
It
may
not
be
a
priori
unethical
or
problematic
from
a
scientific
perspective
for
a
16
principal
investigator
to
be
a
subject
in
his/
her
own
study
IF:
17
18
 
The
study
was
approved
by
an
IRB
in
the
same
manner
as
was
required
for
most
19
human
subjects
research;
20
21
 
Scientific
issues:
22
a.
Principal
investigator
met
all
enrollment
criteria;
23
b.
The
study
was
a
well
controlled
trial
with
a
justified
sample
size
adequate
to
24
answer
the
study
question
with
statistical
surety;
25
c.
The
principal
investigator
was
one
of
many
subjects,
accounting
for
normal
26
human
variability,
and
allowing
results
to
be
generalized
to
a
broad
population;
27
and
28
d.
The
outcome
measure
is
objective
and
measured
by
another
(
blinded,
when
29
possible)
investigator;
30
31
 
A
plan
is
in
place
to
assure
integrity
and
safety
of
the
study
while
the
principal
32
investigator
was
a
subject
33
34
 
A
plan
is
in
place
to
ensure
for
study
oversight
if
principal
investigator
becomes
35
incapacitated;
36
37
 
Participation
of
other
research
staff/
employees
should
be
allowed
only
if
the
38
above
criteria
are
satisfied
and
if
issues
of
coercion/
undue
influence
can
be
39
addressed,
which
may
or
may
not
be
possible;
40
41
 
The
investigator
justifies
why
he/
she
should
be
a
research
subject
in
the
study.
42
43
44
45
46
Proposed
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2006;
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3
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67
Negative
Controls
1
2
 
The
Agency
should
modify
the
guideline
to
say
that
negative
controls
"
may
be"
3
needed
(
instead
of
"
are")
and
that
examples
be
given
both
for
when
negative
controls
4
are
needed
and
when
they
are
not.
The
language
on
positive
controls
may
also
5
benefit
from
further
expansion
and
clarification.
6
7
Design
of
Studies
to
Support
Assessment
of
Repellent
Efficacy
8
9
 
The
Board
consensus
was
that
the
time
to
first
confirmed
bite,
or
the
time
to
first
10
confirmed
"
intent
to
bite"
(
if
ascertainable),
has
the
advantage
of
minimizing
risk
of
11
vector­
borne
diseases.
However,
for
some
studies
there
is
a
statistical
advantage
for
12
the
use
of
relative
protection
as
an
appropriate
outcome
measure.
Since
relative
13
protection
procedures
in
field
studies
increases
the
risk
of
vector­
borne
diseases,
14
protocols
must:
(
a)
justify
the
level
of
risk
by
the
probability
and
social
value
of
the
15
benefits;
(
b)
adequately
identify
all
risks;
(
c)
present
a
description
of
adequate
steps
16
to
minimize
the
risks;
and
(
d)
provide
consent
materials
that
include
information
17
about
the
prevalence
and
risks
of
any
vector­
borne
diseases,
consequences
of
18
contracting
disease,
and
alternative
effective
repellents
outside
of
the
research.
19
20
Minimum
number
of
subject
to
evaluate
the
level
of
repellent
efficacy
21
22
 
It
is
critical
that
the
proposed
number
of
subjects
be
justified
on
the
basis
of
good
23
research
design.
Because
experiments
to
test
effectiveness
of
products
to
repel
insect
24
and
tick
bites
are
likely
to
vary
in
terms
of
design,
response
variable,
target
25
population
of
interest,
detectable
effect
size
and
other
important
variables,
requiring
a
26
specific
minimum
sample
size
that
guarantees
sufficient
accuracy
in
all
cases
might
27
be
impractical.
Instead,
the
guideline
might
require
that
registrants
present
their
own
28
sample
size
calculations
and
that
the
methodology
used
in
the
calculations
be
justified
29
relative
to
the
factors
noted
in
the
bullet
list
above.
30
31
Compensating
Research
Subjects
For
Research­
Related
Injuries
32
33
 
It
is
appropriate
that
sponsors
of
repellent
efficacy
research
studies
should
be
required
34
to
assure
that
if
a
subject
is
injured
as
a
result
of
participating
in
a
study,
then
the
35
subject
will
not
have
to
assume
the
costs
of
medical
care
needed
to
treat
such
injuries.
36
37
Special
Considerations
in
Informed
Consent
Materials
38
39
 
To
comply
with
the
human
studies
rule,
consent
information
for
pesticides
studies
40
must
include:
(
a)
detailed
information
on
the
procedure
(
e.
g.,
number
of
insect
bites
41
or
landings
anticipated,
nature
apparatus
or
field
context,
length
of
time
of
exposure);
42
(
b)
a
clear
statement
of
the
risks
involved
(
e.
g.,
discomfort
from
bites,
risk
of
vector­
43
borne
disease,
medical
consequences
of
the
disease,
treatments
available
for
the
44
disease);
(
c)
the
voluntary
nature
of
participation
(
e.
g.,
statements
that
eliminate
the
45
perception
of
coercion
for
students
or
employees;
specific
instructions
on
how
to
46
Proposed
Final
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v.
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August
28,
2006;
Do
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4
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67
signal
desire
to
withdraw
from
the
study);
(
d)
the
fact
that
there
was
no
immediate
1
direct
benefit
to
the
subject
in
participating
as
well
as
a
description
of
alternative
2
available
repellents;
and
(
e)
other
steps
outlined
above.
In
addition,
informed
consent
3
information
should
be
as
detailed
for
experienced
subjects
as
for
naïve
subjects.
4
5
HSRB
Protocol
Criteria
6
7
 
Before
the
Board
reviewed
the
presented
human
studies
proposals,
the
HSRB
developed
8
scientific
and
ethical
criteria
as
a
guide
for
its
evaluation
of
such
studies.
Such
criteria
9
will
be
helpful
for
the
Agency,
study
investigators,
and
other
members
of
the
public
to
10
understand
the
Board's
approach
for
the
review
of
proposed
human
studies.
11
12
Study
EMD­
003
from
Carroll­
Loye
Biological
Research
13
14
Scientific
Considerations
15
16
The
HSRB
recognized
three
major
limitations
to
the
protocol
as
submitted
to
the
HSRB
for
17
review.
These
limitations
included:
(
1)
the
lack
of
a
clear
rationale
underlying
the
conduct
of
the
18
study;
(
2)
the
lack
of
identification
and
characterization
of
the
formulations
to
be
tested
and
(
3)
19
the
scientific
design
of
the
study.
Of
these
issues,
the
design
of
the
study
was
seen
as
the
most
20
significant
shortcoming
of
the
proposed
work.
21
22
Ethical
Considerations
23
24
The
Board
concurred
with
the
initial
assessment
of
the
Agency
that
the
study
submitted
for
25
review
by
the
Board
failed
to
meet
the
ethical
requirements
established
in
the
Agency's
human
26
studies
rule
(
40CFR26).
27
28
The
Board
determined
the
proposed
research
described
in
these
studies
did
not
comport
with
29
the
applicable
requirements
of
40CFR26,
subparts
K
and
L.
The
study
documents
submitted
for
30
review
also
failed
to
comply
with
the
requirements
of
40CFR26,
subpart
M.
However,
the
31
deficiencies
noted,
while
significant,
were
not
irreparable.
32
33
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
34
35
Scientific
Considerations
36
37
 
It
was
not
clear
whether
new
studies
involving
human
subjects
were
necessary;
however,
38
if
the
repellency
had
never
been
tested
with
North
American
mosquitoes,
the
tests
were
39
probably
necessary.
40
41
 
The
potential
benefits
of
the
study
were
clear,
i.
e.,
that
an
effective
repellent
would
be
42
available
that
would
have
either
greater
efficacy
and/
or
fewer
drawbacks
than
what
was
43
currently
approved.
However,
empirical
evidence
or
procedures
to
determine
risks
to
44
subjects
(
e.
g.,
of
vector
borne
disease)
were
not
adequate.
45
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67
 
It
was
not
clear
if
the
stated
numbers
of
subjects
would
be
repeated
in
both
testing
1
locations.
The
basis
for
the
dose
levels
and
formulations
was
not
provided.
There
were
no
2
controls
with
just
the
formulation
matrix
without
the
repellent.
3
 
These
issues
would
need
to
be
addressed
before
the
protocol
could
be
considered
4
acceptable.
5
6
Ethical
Considerations
7
8
 
The
Board
concluded
that
the
proposed
research
did
not
comport
with
the
applicable
9
requirements
of
40
CFR
26,
subpart
K.
10
11
 
The
proposed
research
does
comport
with
40CFR26
subpart
L,
as
pregnant
women
and
12
children
were
excluded.
13
14
 
Although
the
ethical
concerns
identified
by
the
Board
could
be
remedied,
there
were
15
sufficient
questions
raised
about
the
adequacy
of
the
research
design
to
cast
doubt
on
16
whether
the
proposed
research
would
meet
the
criteria
for
IRB
approval
found
under
40
17
CFR
26.1111(
a)
(
1).
In
other
words,
absent
a
sound
research
design,
any
exposure
of
18
human
subjects
to
risk
would
be
unnecessary
and
unjustifiable.
19
20
21
Occupational
Handler
Exposure
Monitoring
Studies
22
23
Scientific
Considerations
24
25
 
The
occupational
handler
exposure
monitoring
studies
were
components
of
a
large­
26
scale
exercise
to
create
a
contemporary
database
on
occupational
exposure
to
27
agricultural
pesticides.
The
undertaking
is
in
itself
likely
to
be
worthwhile
in
28
quantifying
and
improving
our
understanding
of
the
exposures
and
risks
of
pesticide
29
handlers.
30
31
 
The
potential
benefits
are
large
and
the
risks
appear
to
be
relatively
modest.
However,
32
the
materials
supplied
for
HSRB
review
failed
to
deal
adequately
with
risks
and
33
benefits.
None
of
these
protocols
can
be
properly
evaluated
in
regard
to
scientific
34
validity
because
they
lack:
(
1)
a
developed
rationale
documenting
the
need
for
new
35
data;
(
2)
a
clear
and
appropriate
plan
for
the
handling
of
the
data
(
including
its
36
statistical
analysis),
and
(
3)
an
explanation
of
the
uses
to
which
the
data
will
be
put.
37
These
points
need
to
be
addressed
briefly
at
least
in
each
specific
protocol
and,
more
38
fully,
in
a
separate
and
new
"
governing
document"
that
is
not
simply
a
generic
39
description
of
the
planned
activities.
40
41
 
Additional
validation
studies
are
recommended
to
determine
the
extent
to
which
42
dermal
exposure
measurements
may
underestimate
true
exposure.
Laboratory­
based
43
removal
efficiency
studies
or
field­
based
biomonitoring
studies
could
be
conducted
to
44
achieve
this
goal.
Such
studies
should
be
published
in
the
peer­
reviewed
literature.
45
Broader
participation
of
the
scientific
community
and
of
parties
with
a
direct
interest
46
Proposed
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2006;
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67
in
the
database
project,
such
as
the
labor
community,
would
likely
improve
the
1
quality
of
the
database
and
enhance
the
credibility
of
its
use
in
risk
assessments.
2
3
 
The
HSRB
recommended
that
specific
criteria
for
withdrawal
from
study
4
participation
due
to
heat
stress
be
included
in
these
worker
exposure
protocols,
and
5
that
the
protocols
included
a
heat
stress
management
plan.
In
addition,
the
length
of
6
each
study
should
be
truly
representative
of
a
full
workday,
and
each
protocol
should
7
document
the
basis
for
the
proposed
duration
of
the
study.
8
9
 
The
HSRB
was
gratified
to
receive
the
Agency's
response
to
its
query
regarding
the
10
use
of
diazinon
in
the
AHE37.
It
is
the
understanding
of
the
HSRB
that
the
Agency
11
would
inform
the
AHETF
that
it
needs
to
identify
a
pesticide
other
than
diazinon
in
12
this
protocol
to
evaluate
exposures
associated
with
open
pour
activities
and
13
applications
using
open
cabs,
and
that
the
Agency
would
ensure
that
future
protocols
14
comply
with
the
most
current
risk
mitigation
measures
specified
in
IREDs
and
REDs.
15
16
Ethical
Considerations
17
18
 
The
Board
concurred
with
the
initial
assessment
of
the
Agency
that
the
studies
19
submitted
for
review
failed
to
meet
the
ethical
requirements
established
in
the
20
40CFR26.
21
22
 
The
Board
determined
the
proposed
research
does
not
comport
with
the
applicable
23
requirements
of
§
40CFR26,
subparts
K
and
L.
However,
the
deficiencies
noted,
while
24
significant,
were
not
irreparable.
25
26
In
conclusion,
the
EPA
HSRB
appreciated
the
opportunity
to
advise
the
Agency
on
the
27
scientific
and
ethical
aspects
of
human
studies
research
and
looks
forward
to
future
opportunities
28
to
continue
advising
the
Agency
in
this
endeavor.
29
30
31
Sincerely,
32
33
34
35
Celia
Fisher,
Ph.
D.
Chair
36
EPA
Human
Studies
Review
Board
37
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
7
of
67
NOTICE
1
2
This
report
has
been
written
as
part
of
the
activities
of
the
EPA
Human
Studies
Review
3
Board,
a
Federal
advisory
committee
providing
advice,
information
and
recommendations
on
4
issues
related
to
scientific
and
ethical
aspects
of
human
subjects
research.
This
report
has
not
5
been
reviewed
for
approval
by
the
Agency
and,
hence,
the
contents
of
this
report
do
not
6
necessarily
represent
the
view
and
policies
of
the
Environmental
Protection
Agency,
nor
of
other
7
agencies
in
the
Executive
Branch
of
the
Federal
government,
nor
does
mention
of
trade
names
or
8
commercial
product
constitute
a
recommendation
for
use.
Further
information
about
the
EPA
9
Human
Studies
Review
Board
can
be
obtained
from
its
website
at
http://
www.
epa.
gov/
osa/
hsrb/.
10
Interested
persons
are
invited
to
contact
Paul
Lewis,
Designated
Federal
Officer,
via
e­
mail
at
11
lewis.
paul@
epa.
gov.
12
13
In
preparing
this
document,
the
Board
carefully
considered
all
information
provided
and
14
presented
by
the
Agency
presenters,
as
well
as
information
presented
by
public
commenters.
15
This
document
addresses
the
information
provided
and
presented
within
the
structure
of
the
16
charge
by
the
Agency.
17
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
8
of
67
United
States
Environmental
Protection
Agency
Human
Studies
Review
Board
1
2
Chair
3
4
Celia
B.
Fisher,
Ph.
D.,
Marie
Ward
Doty
Professor
of
Psychology,
Director,
Center
for
Ethics
5
Education,
Fordham
University,
Department
of
Psychology,
Bronx,
NY
6
7
Vice
Chair
8
9
William
S.
Brimijoin,
Ph.
D.,
Chair
and
Professor,
Molecular
Pharmacology
and
Experimental
10
Therapeutics,
Mayo
Foundation,
Rochester,
MN
11
12
Members
13
14
David
C.
Bellinger,
Ph.
D.,
Professor
of
Neurology,
Harvard
Medical
School,
Professor
in
the
15
Department
of
Environmental
Health,
Harvard
School
of
Public
Health
16
Children's
Hospital,
Boston,
MA
17
18
Alicia
Carriquiry,
Ph.
D.,
Professor,
Department
of
Statistics,
Iowa
State
University
19
Snedecor
Hall,
Ames,
IA
20
21
Gary
L.
Chadwick,
PharmD,
MPH,
CIP,
Associate
Provost,
Director,
Office
for
Human
Subjects
22
Protection,
University
of
Rochester,
Rochester,
NY
23
24
Janice
Chambers,
Ph.
D.,
D.
A.
B.
T.,
William
L.
Giles
Distinguished
Professor,
Director,
Center
25
for
Environmental
Health
Sciences,
College
of
Veterinary
Medicine,
Mississippi
State
26
University,
Mississippi
State,
MS
27
28
Richard
Fenske,
Ph.
D.,
MPH,
Professor,
Department
of
Environmental
and
Occupational
Health
29
Sciences,
University
of
Washington,
Seattle
WA
30
31
Susan
S.
Fish,
PharmD,
MPH,
Professor,
Biostatistics
&
Epidemiology,
Boston
University
32
School
of
Public
Health,
Co­
Director,
MA
in
Clinical
Investigation,
Boston
University
School
of
33
Medicine,
Boston,
MA
34
35
Suzanne
C.
Fitzpatrick,
Ph.
D.,
DABT,
Senior
Science
Policy
Analyst,
Office
of
the
36
Commissioner,
Office
of
Science
and
Health
Coordination,
U.
S.
Food
and
Drug
Administration,
37
Rockville,
MD
38
39
Kannan
Krishnan,
Ph.
D.,
Professor,
Département
de
santé
environnementale
et
santé
au
travail,
40
Faculté
de
medicine,
Université
de
Montréal,
Montréal,
Canada
*
41
42
KyungMann
Kim,
Ph.
D.,
CCRP,
Professor
&
Associate
Chair,
Department
of
Biostatistics
&
43
Medical
Informatics,
School
of
Medicine
and
Public
Health,
University
of
Wisconsin­
Madison,
44
Madison,
WI
**
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
9
of
67
Michael
D.
Lebowitz,
Ph.
D.,
FCCP,
Professor
Emeritus
of
Medicine.
University
of
Arizona,
1
Tucson,
AZ
2
3
Lois
D.
Lehman­
McKeeman,
Ph.
D.,
Distinguished
Research
Fellow,
Discovery
Toxicology,
4
Bristol­
Myers
Squibb
Company,
Princeton,
NJ
5
6
Jerry
A.
Menikoff,
M.
D.,
Associate
Professor
of
Law,
Ethics
&
Medicine,
Director
of
the
7
Institute
for
Bioethics,
Law
and
Public
Policy,
University
of
Kansas
Medical
Center,
8
Kansas
City,
KS
9
10
Robert
Nelson,
M.
D.,
Ph.
D.,
Associate
Professor
of
Anesthesiology
and
Critical
Care,
11
Department
of
Anesthesiology
and
Critical
Care,
University
of
Pennsylvania
School
of
12
Medicine,
The
Children's
Hospital
of
Philadelphia,
Philadelphia,
PA
19104
13
14
Sean
Philpott,
PhD,
MS,
Bioethics,
Associate
Director,
Alden
March
Bioethics
Institute,
Albany
15
Medical
Center,
Albany,
NY
12208­
3479
16
17
Human
Studies
Review
Board
Staff
18
19
Paul
I.
Lewis,
Ph.
D.,
Designated
Federal
Officer,
United
States
Environmental
Protection
20
Agency,
Washington,
DC
21
22
*
Recused
from
chloropicrin
discussion
and
deliberation
23
**
Not
in
attendance
at
the
June
27­
30,
2006
Public
Meeting
24
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
10
of
67
TABLE
OF
CONTENTS
1
2
INTRODUCTION                              .
11
3
REVIEW
PROCESS                             .
12
4
CHARGE
TO
THE
BOARD
AND
BOARD
RESPONSE              
14
5
1.
Chloropicrin                               ..
14
6
2.
Insect
Repellent
Product
Performance
Testing
Guideline              
21
7
3.
Insect
Repellent
Product
Performance
Efficacy
Studies              ..
43
8
4.
Study
EMD­
003
from
Carroll­
Loye
Biological
Research              
43
9
5.
Study
EMD­
004
from
Carroll­
Loye
Biological
Research              
47
10
6.
Occupational
Handler
Exposure
Monitoring
Studies               
51
11
7.
REFERENCES                              .
67
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
11
of
67
INTRODUCTION
1
2
On
June
27­
30,
2006,
the
United
States
Environmental
Protection
Agency's
(
EPA
or
3
Agency)
Human
Studies
Review
Board
(
HSRB)
met
to
address
scientific
and
ethical
issues
4
surrounding
a
human
toxicity
study
involving
one
pesticide
active
ingredient­
chloropicrin;
5
guidelines
for
conducting
insect
repellant
efficacy
testing;
protocols
for
conducting
two
insect
6
repellent
efficacy
studies;
and
protocols
for
conducting
five
occupational
handler
exposure
7
monitoring
studies.
8
9
The
Pesticide
Registration
Improvement
Act
(
PRIA)
requires
that
EPA
complete
its
10
decision­
making
process
on
certain
types
of
applications
to
register
a
pesticide
product
within
11
specified
amounts
of
time
after
receiving
the
application
for
registration.
In
addition,
PRIA
12
established
deadlines
for
EPA
to
complete
"
reregistration"
of
pesticide
active
ingredients
that
are
13
contained
in
pesticide
products
initially
registered
before
1984.
Reregistration
involves
the
14
systematic
reexamination
of
these
older
pesticides,
applying
contemporary
scientific
and
15
regulatory
standards.
When
a
pesticide
active
ingredient
is
approved
for
use
on
food,
EPA
16
combines
reregistration
with
the
tolerance
reassessment
process
mandated
by
the
Food
Quality
17
Protection
Act
of
1996
(
FQPA).
18
19
Chloropicrin
is
undergoing
reevaluation
in
the
reregistration
process.
As
part
of
the
20
review
of
the
available
toxicity
data
on
chloropicrin,
EPA
had
identified
a
study
involving
21
intentional
exposure
of
human
subjects
which
EPA
intends
to
use
in
its
risk
assessment.
In
22
accordance
with
40
CFR
26.1602,
EPA
sought
HSRB
review
of
this
study.
23
24
EPA
regulates
pesticides
intended
for
use
on
skin
to
repel
arthropod
pests.
As
part
of
the
25
application
for
registration
of
a
new
repellent,
EPA
requires
data
to
demonstrate
that
the
product
26
is
effective.
The
Agency
had
developed
a
guideline
for
the
conduct
of
such
studies,
and
27
presented
it
to
the
Board
for
comment.
The
Agency
had
also
received
protocols
for
two
insect
28
repellent
efficacy
studies,
and
as
required
by
the
recently
promulgated
regulation,
EPA
is
29
required
to
submit
the
protocols
to
the
HSRB
for
its
review
and
comment.
See
40
CFR
26.1601.
30
31
In
addition,
EPA
routinely
considers
the
human
health
risks
of
occupational
handlers
of
32
pesticides
in
both
its
reregistration
program
and
as
part
of
its
review
of
an
application
for
33
registration
pending
under
FIFRA
and
PRIA.
EPA
has
received
five
protocols
for
conducting
34
new
research
involving
human
subjects
to
collect
data
on
the
levels
of
exposure
received
by
35
people
when
mixing,
loading,
and
applying
pesticides
under
various
conditions.
In
accordance
36
with
40
CFR
26.1601,
EPA
sought
HSRB
review
of
these
proposed
protocols.
37
38
For
the
human
studies
or
guidelines
under
consideration,
the
Agency
provided
the
Board
39
with
the
complete
study
report
or
associated
protocols
and
any
supplements
available
to
the
40
Agency.
Similarly,
guideline
documents
were
included
with
appropriate
background
41
information.
Completed
studies
were
assigned
a
unique
identifier
(
e.
g.,
the
Master
Record
42
Identifier­
MRID),
which
the
Agency
uses
to
manage
documents.
When
a
company
submits
43
multiple
documents
pertaining
to
a
single
study,
each
document
is
typically
assigned
a
unique
44
tracking
number.
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
12
of
67
In
addition,
for
each
study,
protocol
or
guideline
to
be
evaluated,
the
Agency
provided
a
1
review
of
the
ethical
conduct.
Each
ethics
review
identified
any
deficiencies
which
were
2
identified
compared
to
appropriate
ethical
standards.
EPA
has
intentionally
deferred
making
a
3
final
determination
of
whether
the
chloropicrin
study
satisfies
the
ethical
standards
for
4
acceptability
in
40
CFR
sections
26.1704
 
26.1706,
pending
the
advice
of
the
Board.
5
6
For
most
studies
and
protocols,
the
Agency
develops
documents,
called
Data
Evaluation
7
Records
(
DERs),
containing
a
scientific
review.
The
Board
was
provided
with
one
or
more
8
DERs
for
chloropicrin,
the
two
proposed
insect
repellent
efficacy
protocols,
and
each
of
the
five
9
Agricultural
Handlers
Exposure
Taskforce
(
AHETF)
protocols.
DERs
contain
summaries
of
the
10
study
design,
methods
and
results,
describe
potential
deficiencies,
and
provide
conclusions
about
11
the
usefulness
of
the
study
in
risk
assessment.
12
13
In
addition
to
the
DERs,
the
Agency
had
prepared
or
included
several
other
background
14
documents
which
address
various
elements
of
the
issues
to
be
reviewed
by
the
HSRB.
For
15
example,
for
the
AHETF
protocols,
a
number
of
types
of
documents
had
been
provided
including
16
transmittal
documents
and
the
charge
questions,
general
background
information
pertaining
to
17
the
manner
in
which
the
Agency
completes
exposure/
risk
assessments,
the
AHETF
protocols
18
and
various
documents
that
the
AHETF
had
developed
related
to
the
manner
in
which
it
intends
19
to
conduct
studies,
the
background
documents
related
to
the
AHETF
protocol
review
by
the
20
Western
Institutional
Review
Board
of
Olympia,
Washington,
and
the
EPA
science
and
ethics
21
reviews
of
these
protocols.
22
23
The
Agency
asked
the
HSRB
to
advise
the
Agency
on
a
range
of
scientific
and
ethics
24
issues
and
on
how
proposed
and
completed
studies
should
be
assessed
against
the
provisions
in
25
40
CFR
26
of
EPA's
final
human
studies
rule.
This
report
transmits
the
HSRB's
comments
and
26
recommendations
from
its
June
27­
30,
2006
meeting.
27
REVIEW
PROCESS
28
29
On
June
27­
30,
2006
the
Board
had
a
public
face­
to­
face
meeting
in
Arlington,
Virginia.
30
Advance
notice
of
the
meeting
was
published
in
the
Federal
Register
"
Human
Studies
Review
31
Board:
Notice
of
Public
Meeting
(
71
Federal
Register
32536
and
71
Federal
Register
33747).
At
32
the
public
meeting,
following
welcoming
remarks
from
Agency
officials,
Celia
B.
Fisher,
HRSB
33
Chair,
proposed
a
set
of
scientific
and
ethics
criteria
consistent
with
the
language
of
71
Federal
34
Register
6137
to
guide
Board
evaluation
of
completed
studies.
The
Chair's
scientific
criteria
35
asked
the
Board
to
consider
the
following
two
questions:
(
1)
did
the
research
design
and
36
implementation
meet
scientific
standards
and
(
2)
did
the
data
generated
by
the
study
have
37
implications
for
the
Agency's
Weight
of
the
Evidence
(
WOE)
review
and,
when
applicable,
38
aspects
of
the
risk
assessment?
The
Chair
reviewed
the
Chair's
science
criteria
and
the
Board's
39
criteria
for
scientific
standards
for
human
dosing
studies
established
at
the
Board's
May
2006
40
meeting.
The
Chair's
ethics
criteria
asked
the
Board
to
consider
three
questions:
(
1)
did
the
41
study
fail
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
42
conducted;
(
2)
was
the
conduct
of
the
study
fundamentally
unethical
(
i.
e.,
specifically
was
there
43
clear
and
convincing
evidence
that
the
research
was
intended
to
seriously
harm
participants
or
44
failed
to
obtain
informed
consent);
and
(
3)
was
the
conduct
of
the
study
significantly
deficient
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
13
of
67
relative
to
the
ethical
standards
prevailing
at
the
time
(
i.
e.,
was
there
clear
and
convincing
1
evidence
that
identified
deficiencies
that
could
have
resulted
in
serious
harm
based
on
2
knowledge
available
at
the
time
the
study
was
conducted
or
the
information
provided
to
3
participants
could
seriously
impair
informed
consent).
4
5
The
Board
then
heard
presentations
from
the
Agency
on
the
following
topics:
scientific
6
and
ethical
issues
addressing
a
human
toxicity
study
involving
one
pesticide
active
ingredient­
7
chloropicrin;
guidelines
for
conducting
insect
repellant
efficacy
testing;
protocols
for
conducting
8
two
insect
repellent
efficacy
studies;
and
protocols
for
conducting
five
occupational
handler
9
exposure
monitoring
studies.
At
the
Chair's
request
the
Board
developed
scientific
and
ethics
10
criteria
for
new
human
study
protocols.
11
12
The
Board
heard
oral
public
comments
from
the
following
individuals:
13
14
Chloropicrin
15
16
Robert
Sielken,
Ph.
D.,
of
Sielken
and
Associates
and
John
Butala,
Ph.
D.
of
Toxicology
17
Consultants,
Inc.
on
behalf
of
the
Chloropicrin
Task
Force.
18
19
Jennifer
Sass,
Ph.
D.
on
behalf
of
the
Natural
Resources
Defense
Council.
20
21
Guidelines
For
Conducting
Insect
Repellant
Efficacy
Testing
22
23
Scott
Carroll,
Ph.
D.,
on
behalf
of
the
University
California
at
Davis
and
Carroll­
Loye
Biological
24
Research.
25
26
Protocols
For
Conducting
Insect
Repellent
Efficacy
Studies:
Study
EMD­
003
And
Study
EMD­
27
004
28
29
Scott
Carroll,
Ph.
D.,
on
behalf
of
Carroll­
Loye
Biological
Research.
30
31
Mr.
Dan
Giambattisto
on
behalf
of
EMD
Chemicals,
Inc.
32
33
Mr.
Niketas
Spero
on
behalf
of
Insect
Control
and
Research,
Inc.
34
35
Protocols
For
Conducting
Occupational
Handler
Exposure
Monitoring
Studies:
Study
AHE34,
36
Study
AHE36,
Study
AHE37,
Study
AHE38
And
AHE42
37
38
Victor
Canez,
Ph.
D.,
Elliot
Gordon,
Ph.
D.,
Mr.
Curt
Lunchick,
and
Mr.
Larry
Smith
on
behalf
of
39
the
Agricultural
Exposure
Handlers
Task
Force
40
41
Ms.
Shelly
Davis
on
behalf
of
Farmworker
Justice
Fund
42
43
In
addition,
the
Board
received
written
public
comments
from
the
Agricultural
Exposure
44
Handlers
Task
Force,
Carroll­
Loye
Biological
Research,
the
Farmworker
Justice
Fund,
the
FMC
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
14
of
67
Corporation,
Toxicology
Consultants,
Inc.
and
the
Walter
Reed
Army
Institute
of
Research,
1
Vector
Control/
Repellents
Program.
2
3
For
their
deliberations,
the
Board
considered
the
materials
presented
at
the
meeting,
4
written
public
comments
and
Agency
background
documents
(
e.
g.
pesticide
human
study,
5
Agency
data
evaluation
record
(
DER)
of
the
pesticide
human
study,
weight
of
evidence
review,
6
ethics
review,
pesticide
human
study
protocol
and
Agency
evaluation
of
the
protocol).
7
CHARGE
TO
THE
BOARD
AND
BOARD
RESPONSE
8
9
Chloropicrin
10
11
Charge
to
the
Board
12
13
Chloropicrin
is
a
non­
selective
soil
fumigant
whose
primary
toxic
effect
is
sensory
14
irritation
in
which
stimulated
free
nerve
endings
mediate
sensations
and
clinical
signs
in
the
15
nose,
eyes,
throat,
and
upper
respiratory
tract.
Chloropicrin
is
a
unique
soil
fumigant
in
that
it
is
16
also
used
as
an
indicator
chemical
or
warning
agent
(
2%
or
less
by
weight
in
formulations).
The
17
Agency
is
developing
an
assessment
to
estimate
inhalation
risk
to
bystanders
and
workers
from
18
acute
exposures
to
chloropicrin.
19
20
Scientific
considerations
21
22
The
Agency's
"
Weight
of
Evidence"
(
WOE)
document
and
Data
Evaluation
Records
23
(
DER)
for
chloropicrin
described
the
study
design
of
the
acute
inhalation,
human
toxicity
study.
24
The
Agency
had
concluded
that
the
human
toxicity
study
was
appropriate
for
developing
a
point
25
of
departure
for
extrapolation
of
inhalation
risk
to
bystanders
and
workers
exposed
to
26
chloropicrin.
27
28
Please
comment
on
whether
the
study
was
sufficiently
sound,
from
a
scientific
29
perspective,
to
be
used
to
estimate
a
safe
level
of
inhalation
exposure
to
chloropicrin.
30
31
Board
Response
to
the
Charge
32
33
Background
of
Study
34
35
To
determine
a
subject's
sensitivity
for
the
detection
and
characterization
of
feel
to
the
36
human
eye,
nose,
and/
or
throat
produced
by
chloropicrin
vapors,
as
well
as
the
odor
threshold,
37
healthy
volunteers
(
18
to
35
years
of
age,
average
23
years)
were
exposed
to
a
range
of
vapor
38
concentrations
and
exposure
durations
in
a
controlled
laboratory
setting.
The
investigation
39
consisted
of
three
phases,
very
brief
exposures
(
Phase
I)
and
more
extensive
exposures
(
Phases
II
40
and
III).
These
phases
are
described
in
more
detail
below.
41
42
The
study
report
cited
Krieger
(
1996)
as
a
review
of
the
risks
to
workers
from
exposure
43
to
chloropicrin
in
agricultural
applications.
It
appeared
that
this
reference
was
relied
upon
for
44
basing
concentration
and
duration
for
the
human
sensory
study.
From
this
reference,
a
time­
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
15
of
67
weighted
average
of
0.1
ppm
(
100
ppb)
was
indicated
to
evoke
no
response
in
humans.
The
1
report
then
indicated
concentrations
of
0.15
to
0.3
ppm
would
evoke
concentration­
dependent
2
sensory
detection
via
chemesthesis,
as
well
as
reflex
tearing
and
cough.
Concentrations
above
3
0.3
ppm
would
evoke
an
increasing
degree
of
irritation.
Odor
was
noted
as
occurring
at
about
0.9
4
ppm.
The
extended
phases
were
focused
on
concentrations
of
likely
occupational
relevance,
5
both
below
and
just
above
100
ppb,
the
ACGIH
(
American
Conference
of
Governmental
6
Industrial
Hygenists)
threshold
Limit
Value
(
TLV)
and
OSHA
Permissible
Exposure
Limit
7
(
PEL).
8
9
Statistical
analyses
including
all
subjects
for
each
phase
of
the
study
were
provided
in
the
10
study
report.
The
EPA
provided
a
logistical
regression
when
appropriate
as
well
as
an
analysis
11
for
only
those
subjects
positively
detecting
chloropicrin
for
Phases
I
and
II
of
the
study.
12
13
Phases
of
Study
14
15
Phase
I:
The
objective
of
Phase
I
was
the
identification
of
chloropicrin
by
odor
(
both
16
nostrils,
single
sniff),
eye
feel
(
one
eye,
25
seconds),
or
nasal
feel
(
one
nostril,
7
seconds)
at
356
17
ppb,
533
ppb,
800
ppb
and
1200
ppb
generated
from
a
vapor
delivery
device.
Phase
I
consisted
18
of
62
subjects
(
32
male
and
30
female)
for
odor
and
63
subjects
(
32
male
and
31
female)
for
eye
19
feel.
The
same
subjects
participated
for
both
odor
and
eye
feel.
Confidence
of
feel
was
rated
1
to
20
5,
with
1=
very
low,
3=
moderate,
and
5=
very
high
confidence.
Severity
of
feel
was
not
rated
in
21
Phase
I.
For
Phase
I,
approximately
10%
to
13%
of
subjects
failed
to
detect
either
odor
or
eye
22
feel
after
momentary
exposures
to
chloropicrin
over
the
range
evaluated.
Approximately
13%
(
8
23
of
62)
of
subjects
(
5/
30
female
and
3/
32
male)
failed
to
detect
the
odor
of
chloropicrin
over
the
24
range
of
concentrations
evaluated.
Approximately
11%
7/
63
(
11%)
of
subjects
failed
to
detect
25
eye
feel
(
two
male
and
five
female)
at
any
concentration.
The
feel
of
chloropicrin
in
the
nose
was
26
not
a
reliable
endpoint
and
was
therefore
dropped
prematurely
from
the
Phase
I
study
by
the
27
study
director.
The
median
concentration
of
all
subjects
for
detection
of
eye
feel
was
900
ppb,
or
28
790
ppb
for
males
and
1010
ppb
for
females,
although
this
gender
difference
was
not
significant.
29
The
median
for
only
those
subjects
detecting
odor
was
356
ppb
while
eye
feel
was
between
356
30
ppb
and
533
ppb.
31
32
Phase
II:
The
purpose
of
Phase
II
was
the
detection
of
chloropicrin
in
the
eyes,
nose,
33
and/
or
throat
during
exposure
to
50
ppb,
75
ppb,
100
ppb,
or
150
ppb
chloropicrin
vapor
in
a
34
walk­
in
chamber
for
20­
30
minutes.
(
Odor
was
not
studied
in
Phase
II).
A
total
of
62
subjects
35
(
32
male
and
30
female)
participated
in
Phase
II.
12
of
30
female
subjects
and
14
of
32
male
36
subjects
also
participated
in
Phase
I
of
the
study.
Subjects
responded
"
yes"
for
a
positive
feel
or
37
"
no"
for
no
feel.
A
level
of
confidence
to
each
event
(
eye,
nose,
throat)
was
also
recorded
with
38
1=
not
certain,
2=
moderately
certain,
and
3=
very
certain.
The
first
exposure
in
a
day
consisted
39
of
a
known
blank
(
air).
This
exposure
served
to
acclimate
the
subjects
to
the
task
in
the
chamber.
40
The
subjects
were
asked
to
perform
ratings
as
they
would
for
future
blinded
exposures.
One
41
female
subject
left
the
exposure
chamber
after
16
minutes
of
chloropicrin
at
75
ppb.
An
42
explanation
for
this
subject's
premature
exit
from
the
chamber
was
not
provided.
At
150
ppb,
43
this
same
subject
along
with
another
male
in
the
chamber
left
the
chamber
after
15
minutes.
On
44
a
separate
day
of
testing,
one
female
and
one
male
subject
also
left
the
exposure
chamber
after
45
15
minutes
of
exposure
to
150
ppb.
Again,
no
explanation
was
given
for
these
subjects'
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
16
of
67
premature
departure
from
the
chamber.
No
subjects
left
the
chamber
at
50
ppb
or
100
ppb.
The
1
results
of
Phase
II
indicated
that
eye
feel
was
more
sensitive
than
either
nose
or
throat
feel.
2
ANOVA
results
provided
in
the
study
report
indicated
that
concentration
and
duration
were
3
significant
(
p<
0.0001)
for
the
eye
response
only.
As
a
group,
subjects
differentiated
50
ppb
4
chloropicrin
in
the
eyes
from
the
blank
after
20
minutes
of
exposure.
Differentiation
from
blank
5
occurred
after
5
minutes
at
75
ppb,
3
minutes
at
100
ppb,
and
2
minutes
at
150
ppb.
There
were
6
no
significant
statistical
interactions
of
response
with
sex
for
the
eyes,
nose,
or
throat
responses.
7
On
an
individual
basis,
binary
detection
indicators
(
yes/
no)
developed
by
the
Agency
were
8
combined
by
participant
across
dose
levels.
Using
eye
feel
as
a
marker
of
detection
of
the
9
chemical,
20
of
the
62
participants
(
32%)
could
not
detect
chloropicrin
at
any
concentration:
12
10
of
30
(
40%)
females
and
8
of
32
(
25%)
males
failed
to
make
progress
toward
eye
feeling
over
a
11
30
minute
period
of
exposure.
In
addition,
46/
62
(
74%)
and
48/
62
(
77%)
subjects
could
not
12
detect
the
chemical
via
the
nose
or
throat,
respectively
at
any
concentration,
again
indicating
the
13
greater
sensitivity
of
the
eye.
14
15
Phase
III:
The
goal
of
Phase
III
was
the
detection
of
chloropicrin
vapor
as
evidenced
by
16
irritation
to
the
eyes,
nose
and/
or
throat
after
1
hour
(
60
minute)
exposures
repeated
over
4
17
consecutive
days.
Concentrations
tested
included
blank
(
air),
100
ppb,
and
150
ppb.
This
phase
18
included
a
clinical
exam
of
the
eyes,
nose
and
throat,
as
well
as
pulmonary
function
testing
with
19
the
outcome
variable
FEV1
(
Forced
Expiratory
Volume)
and
FVC
(
Forced
Vital
Capacity),
20
rhinomanometry,
and
nasal
cytology.
In
addition,
an
assessment
was
performed
based
on
ocular
21
cytology
from
samples
of
cells
taken
from
the
conjunctival
membrane
inside
the
lower
eyelid
22
and
from
the
concentration
of
exhaled
nitric
oxide
sampled
from
the
lung
(
eNO)
and
nose
23
(
nNO).
Subjects
participated
in
3
cycles
[(
6
days
per
cycle)
of
6
sessions,
each
beginning
on
24
Friday
and
ending
on
the
subsequent
Friday]
(
no
measurements
taken
on
Saturday
or
Sunday).
25
Subjects
remained
in
exposure
chambers
for
1
hour
per
session
on
Monday
through
Thursday
(
4
26
consecutive
days).
The
3
cycles
included
exposure
to
100
ppb,
150
ppb,
and
just
air
(
blank).
The
27
order
in
which
the
subject
was
exposed
to
these
concentrations
was
random
to
prevent
28
confounding.
At
least
one
week
separated
the
end
of
one
cycle
of
exposures
and
the
beginning
29
of
another
for
each
subject.
Subjects
rated
their
symptoms
in
three
setting:
(
1)
severity
of
effect
30
for
eye,
nose,
and
throat
while
in
the
chamber
(
0=
no
symptom
to
3=
severe);
(
2)
before
and
after
31
exposure
in
the
chamber
and
at
the
beginning
and
end
of
each
week
of
exposures;
and
(
3)
at
the
32
beginning
and
end
of
a
cycle
of
exposure.
Symptoms
were
rated
using
the
Rhinconjunctivitis
33
Quality
of
Life
Questionnaire
(
RQLQ),
a
series
of
28
questions
in
seven
domains,
where
the
34
subjects
used
a
seven
point
scale
from
Not
Troubled
to
Very
Troubled.
The
first
two
instruments
35
referred
to
how
the
subject
felt
at
the
time
of
rating,
the
RQLQ
referred
to
how
the
subject
felt
36
over
the
previous
week.
When
in
the
exposure
chamber,
subjects
rated
symptoms
(
0
to
3)
after
37
30
seconds,
at
1
minute,
and
every
minute
until
the
end
of
the
exposure
at
60
minutes.
Every
10
38
minutes,
study
personnel
read
and
recorded
the
subjects'
blood
oxygen
saturation
from
a
pulse
39
oximeter
attached
to
the
finger
(
data
not
included
in
report).
A
total
of
15
males
and
17
females
40
participated
in
Phase
III.
Two
females
in
Phase
III
also
participated
in
Phases
I
and
II.
One
male
41
in
Phase
III
also
participated
in
Phases
I
and
II
and
one
male
in
Phase
III
participated
in
Phase
II
42
only.
43
44
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
17
of
67
Results
of
the
Study
1
2
For
Phase
II,
one
female
subject
left
at
75
ppb
and
again
at
150
ppb
with
another
male.
3
On
a
separate
testing
day,
one
female
and
male
left
the
chamber
prematurely
at
150
ppb.
38%
(
8
4
males
and
8
females)
of
subjects
detected
chloropicrin
initially
at
50
ppb
and
consistently
up
to
5
150
ppb.
Subjects
gave
higher
ratings
to
symptoms
in
the
eye
than
to
those
in
the
nose
and
6
throat.
Subjects
gave
nominally
slightly
higher
ratings
in
the
nose
than
in
the
throat,
but
7
expressed
no
symptoms
of
consequence
at
either
site.
There
was
no
indication
of
intensification
8
of
symptoms
based
on
subject
scoring
for
any
parameter
on
the
consecutive
days
of
exposure.
9
For
the
eye,
the
study
report
ANOVA
indicated
Level
of
Exposure
(
p<
0.001),
and
interaction
of
10
Level
of
Exposure
by
Duration
of
Exposure
was
significant
(
p<
0.001).
An
ANOVA
also
11
revealed
an
effect
of
Level
of
Exposure
by
Day
(
p<
0.02).
As
a
group
with
all
subjects
included
12
(
even
those
not
feeling),
the
analysis
provided
in
the
study
indicated
the
average
rating
of
eye
13
irritation
at
100
ppb
reached
approximately
0.5
(
1=
mild)
with
30
minutes
to
reach
steady
state,
14
which
remained
until
the
final
minutes
and
then
sometimes
regressed.
At
150
ppb,
the
average
15
rating
of
eye
irritation
reached
1
(
mild,
symptom
present,
but
minimal
awareness,
easily
16
tolerated)
with
20
minutes
to
steady
state
until
fading
slightly
in
the
final
minutes.
17
18
On
an
individual
level,
the
severity
of
ocular
irritation
reported
by
subjects
in
Phase
III
19
varied
from
no
symptoms
to
severe
at
both
100
ppb
and
150
ppb.
Five
of
17
females
(
29%)
and
7
20
of
15
males
(
47%)
rated
no
eye
irritation
at
100
ppb
while
3
of
17
females
(
18%)
and
5
of
15
21
males
(
33%)
rated
no
eye
irritation
at
150
ppb.
Nasal
and
throat
irritation
was
never
reported
22
above
a
"
2"
and
mainly
consisted
of
"
0"
or
"
1".
Scores
of
severe
"
3"
ocular
irritation
were
23
sporadic
during
the
first
30
minutes
of
exposure
in
2
females
and
in
4
males
at
100
ppb.
24
25
The
second
half
of
the
exposure
to
100
ppb
(
31­
60
minutes)
revealed
a
more
consistent
26
response
in
ocular
severity
(
in
3
females
and
5
males).
"
Severe"
(
grade
1)
was
defined
as
a
27
symptom
that
was
hard
to
tolerate
and
that
could
interfere
with
activities
of
daily
living
or
28
sleeping.
At
150
ppb,
4
females
and
3
males
reported
consistent
severe
eye
irritation
beginning
29
as
early
as
8
to
9
minutes
of
exposure
until
the
end
of
exposure
at
60
minutes.
Moderate
(
grade
30
2)
eye
irritation
was
also
reported
sporadically
during
the
first
30
minutes
by
the
same
31
individuals
reporting
severe
eye
irritation
but
with
a
more
consistent
response
in
moderate
eye
32
irritation
during
the
second
half
(
31­
60
minutes)
of
exposure.
Two
additional
females
and
two
33
additional
males
reported
moderate
eye
irritation
during
the
second
half
of
exposure
that
did
not
34
report
eye
irritation
during
the
first
half
of
exposure.
Results
for
the
daily
measurements
35
(
Cochran
Q
test)
provided
in
the
study
indicated
the
number
of
times
a
rating
post­
exposure
36
exceeded
a
rating
pre­
exposure
for
nasal
congestion
was
not
significant
(
Q=
0.75)
while
eye
37
irritation
(
redness)
was
significant
(
Q=
28.8,
p<
0.001).
Nasal
congestion
and
ocular
erythema
38
(
redness)
occurred
more
than
the
trivial
frequency.
However,
according
to
the
report,
the
ocular
39
irritation
did
not
translate
into
more
prominent
redness.
No
biologically
significant
changes
40
were
observed
for
the
lower
respiratory
variables.
41
42
For
the
lower
respiratory
variables
(
FVC,
FEV1,
eNO),
ANOVA
analysis
from
the
study
43
report
indicated
a
significant
interaction
of
Level
by
Order
(
p<
0.05)
for
FVC
(
Forced
Vital
44
Capacity),
with
only
3%
variation
in
FVC.
FEV1
(
Forced
Expiratory
Volume),
averaged
93.6%
45
before
exposure
and
93.7%
after
exposure.
The
variation
spanned
3%
with
no
statistical
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
18
of
67
significance
achieved.
Exhaled
nitric
oxide
by
the
lungs
(
eNO)
equaled
37.8
before
exposure
1
and
39.2
after
exposure
with
no
significance
achieved.
Sex
was
not
significant
for
any
of
2
interactions
of
the
three
lower
respiratory
variables.
Two
upper
respiratory
alterations,
nNO
3
(
nasal
nitric
oxide)
and
flow,
were
observed
for
one­
hour
exposures
that
occurred
only
day
by
4
day.
For
the
upper
respiratory
variables
(
nNO,
inspiratory
flow,
expiratory
flow),
nNO
was
5
significant
for
Level
of
Exposure
by
Order
of
Exposure
with
399
ppb
before
exposure
and
425
6
ppb
after
exposure
(
p=
0.012).
Level
of
Exposure
by
Order
of
Exposure
by
Day
was
not
7
significant.
nNO
increased
1%
after
exposure
to
blank,
10%
after
exposure
to
100
ppb,
and
8%
8
after
exposure
to
150
ppb.
The
effect
of
nNO
did
not
continue
from
one
day
to
the
next.
9
Inspiratory
flow
and
expiratory
flow
equaled
450
and
415
mL/
sec,
respectively,
before
exposure
10
and
435
and
406
mL/
sec,
respectively,
after
exposure.
11
12
Chloropicrin
had
a
differential
effect
on
flow.
Level
of
Exposure
by
Order
of
Exposure
13
was
nearly
significant
(
p=
0.087).
However,
Level
of
Exposure
by
Order
of
Exposure
by
Day
14
was
not
significant.
Flow
decreased
2%
after
exposure
to
blank
and
increased
2%
after
exposure
15
to
100
ppb
chloropicrin,
however,
flow
decreased
by
8%
after
exposure
to
150
ppb.
Sex
was
not
16
significant
in
any
of
the
relevant
interactions
for
the
upper
respiratory
variables.
Physiological
17
effects
such
as
changes
in
nNO
and
flow
rate
may
indicate
signs
of
nasal
congestion
and
18
engorgement.
19
20
Cell
types
and
cell
numbers
from
the
Rhinoprobe
samples
were
approximately
the
same
21
at
the
end
of
each
cycle
as
at
the
beginning.
For
the
RQLQ
questionnaire
results,
nasal
22
congestion
was
the
only
parameter
that
reached
a
level
where
more
than
half
of
the
subjects
gave
23
a
response
above
zero.
53%
of
subjects
reported
a
non­
zero
response
to
congestion
after
4
days
24
of
exposure
to
the
blank
vs.
41%
and
34%
after
exposures
to
150
ppb
and
100
ppb,
respectively.
25
The
average
ratings
equaled
0.53,
0.34,
and
0.41
for
the
blank,
100
ppb,
and
150
ppb,
26
respectively,
where
a
rating
of
1
signified
hardly
troubled
at
all.
Watery
eyes,
sore
eyes,
and
27
swollen
eyes
were
scored
higher
by
subjects
after
exposure
to
either
100
or
150
ppb
chloropicrin
28
than
to
the
blank.
The
Q
test
revealed
significance
for
the
sore
eyes
only
(
p<
0.05).
The
highest
29
rating
given
after
exposure
to
swollen
eyes
was
0.47.
30
31
The
LOAEL
was
determined
to
be
100
ppb,
the
lowest
concentration
tested,
based
on
eye
32
irritation,
increased
nasal
nitric
oxide
(
nNO),
and
differential
effect
on
inspiratory
and
expiratory
33
flow.
A
NOAEL
was
not
established
in
Phase
III.
34
35
Critique
of
the
Study
36
37
Strengths:
38
39
This
was
an
excellent
scientific
study
of
eye,
upper
and
lower
respiratory
irritant
effects
40
at
various
concentrations
over
various
short
term
(
i.
e.,
acute
effects)
time
periods.
The
objective
41
and
subjective
measurements
and
the
statistics
were
reasonable.
Most
importantly,
Phase
III
of
42
the
study
provided
evidence
of
upper
airway
(
nasal)
respiratory
effects
and
established
a
43
LOAEL.
44
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
19
of
67
Weaknesses:
1
2
Concentrations
below
100
ppb
were
not
investigated
in
Phase
III
so
as
to
compare
with
3
results
from
Phase
II.
4
5
HSRB
Consensus
and
Rationale
6
7
The
chloropicrin
acute
inhalation,
human
toxicity
study
was
scientifically
sound
for
the
8
purpose
of
estimating
a
safe
level
of
inhalation
exposure
to
chloropicrin.
A
LOAEL
of
100
ppb
9
was
a
scientifically
justified
point
of
departure
(
POD).
10
11
Charge
to
the
Board
12
13
Ethical
considerations
14
15
The
Agency
requests
that
the
Board
provide
comment
on
the
following:
16
17
a.
Was
there
clear
and
convincing
evidence
that
the
conduct
of
the
Cain
study
was
fundamentally
18
unethical?
19
20
b.
Was
there
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
21
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?
22
23
Board
Response
to
the
Charge
24
25
The
Cain
study
was
conducted
from
2002
through
2004.
The
study
was
performed
in
La
26
Jolla,
California
by
researchers
at
the
Chemosensory
Perception
Laboratory
of
the
University
of
27
California,
San
Diego.
The
study
sponsor
was
Chloropicrin
Manufacturers
Task
Force,
whose
28
mailing
address
is
in
care
of
Steptoe
&
Johnson,
LLP,
1330
Connecticut
Avenue,
NW,
29
Washington,
D.
C.
The
documents
provided
by
the
sponsor
specifically
state
that
the
research
30
was
to
be
conducted
with
the
approval
of
an
Institutional
Review
Board
(
IRB)
at
the
University
31
of
California,
San
Diego,
and
in
compliance
with
the
Human
Subject's
Bill
of
Rights
(
a
32
provision
of
California
law).
The
study
was
in
fact
reviewed
and
approved
by
an
IRB
at
that
33
university,
and
the
university
had
provided
documentation
that
it
held
a
Federalwide
Assurance
34
with
the
Department
of
Health
and
Human
Services.
The
documentation
provided
by
the
35
university's
Human
Research
Protections
Program
indicated
that
it
reviewed
this
study
pursuant
36
to
the
standards
of
the
Common
Rule
(
45
CFR
46,
Subpart
A)
and
determined
it
to
be
in
37
compliance
with
that
Rule.
38
39
Critique
of
Study
40
41
The
Board
concurred
with
the
factual
observations
of
the
strengths
and
weaknesses
of
the
42
Cain
study,
as
detailed
by
the
EPA
(
USEPA
2006a).
The
Board
wanted
to
comment
on
several
43
specific
aspects
of
the
study:
44
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
20
of
67
1.
The
consent
forms
stated
that
chloropicrin
"
is
used
commonly
to
fumigate
fields
for
1
planting
and
as
a
warning
agent
in
structural
fumigation."
It
made
no
mention
of
prior
uses
of
2
this
compound
for
the
intentional
purpose
of
harming
and
even
killing
people.
As
noted
in
one
of
3
the
documents
supplied
by
the
EPA
(
Prentiss
1937),
chloropicrin
"
appears
to
have
been
the
most
4
widely
used
combat
gas"
in
World
War
I.
That
reference
further
notes
that
"
as
a
war
gas
[
it]
has
5
a
number
of
desirable
offensive
properties,"
and
like
phosgene
gas,
"
it
is
a
lethal
compound."
6
Some
members
of
the
Board
concluded
that
in
the
context
of
being
asked
to
participate
in
a
study
7
to
determine
more
information
about
the
harmful
effects
of
this
gas
on
human
beings,
the
8
subjects
should
have
been
informed
about
the
historical
use
of
chloropicrin
as
a
war
gas.
Others
9
concluded
that
the
dose
levels
and
other
conditions
were
significantly
distinct
from
the
war
use
10
that
reference
to
those
usages
were
not
necessary
for
an
informed
participation
decision.
11
12
2.
The
consent
forms,
in
describing
the
likely
risks
of
participating
in
the
study,
noted
13
that
"[
e]
xposure
to
chloropicrin
in
amounts
greater
than
anticipated
in
the
studies
have
resulted
14
in
temporary
tearing
and
painful
stinging
eyes
and
nausea
and
vomiting
that
are
completely
15
reversible
after
the
exposure."
Some
members
of
the
Board
believed
that
this
statement
was
16
inaccurate
in
describing
the
possible
risks
of
exposure
to
"
greater"
amounts
of
choloropicrin
17
(
which,
as
noted
in
item
1
above,
if
in
a
sufficiently
high
dose,
is
well
known
to
cause
substantial
18
permanent
effects,
up
to
and
including
death).
Those
members
concluded
that
the
consent
form
19
should
have
been
more
truthful
in
describing
the
possible
consequences
of
exposure
to
high
20
doses
of
chloropicrin
(
though
it
could
also
have
explained
why
it
would
not
be
the
case
that
the
21
subjects
could
ever
end
up
being
exposed
to
such
high
doses
as
a
result
of
participation
in
the
22
study).
23
24
3.
The
consent
form,
in
describing
the
purpose
of
the
study,
stated
that
it
was
"
intended
to
25
provide
information
regarding
safe
levels
of
exposure."
This
language
might
suggest
to
many
26
prospective
subjects
that
the
study
was
being
conducted
to
see
if
it
is
important
to
create
27
increased
restrictions
on
the
use
of
this
compound.
Some
members
of
the
Board
believed
that
28
the
consent
form
should
have
explicitly
stated
that
this
study
was
unlikely
to
lead
to
increased
29
restrictions
and,
in
fact,
its
results,
if
they
led
to
any
regulatory
changes,
would
more
likely
be
30
used
to
allow
greater
exposures
of
people
to
chloropicrin.
31
32
HSRB
Consensus
and
Rationale
33
34
The
Board
concluded
that:
35
36
There
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
37
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
38
to
obtain
informed
consent).
39
40
There
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
41
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
42
43
The
Board
based
these
two
determinations
on
its
conclusion
that
this
study,
based
on
the
44
evidence
presented,
deviated
from,
but
was
not
significantly
deficient
relative
to,
the
ethical
45
standards
prevailing
when
the
study
was
conducted.
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
21
of
67
1
2
3
Insect
Repellent
Product
Performance
Testing
Guideline
4
5
Charge
to
the
Board
6
7
The
U.
S.
EPA
Office
of
Pesticide
Programs
requested
that
the
HSRB
review
and
8
comment
on
the
draft
"
Product
Performance
of
Skin­
Applied
Repellents
of
Insects
and
Other
9
Arthropods"
Testing
Guideline
in
order
to
determine
what
changes,
if
any,
are
necessary
for
the
10
guideline
to
be
made
consistent
with
the
requirements
for
protection
of
human
research
subjects
11
set
forth
in
40
CFR
part
26.
Below
is
a
list
of
questions
that
focus
on
these
topics.
12
13
a.
What
actions
should
an
investigator
routinely
take
to
minimize
the
risks
to
human
subjects
14
exposed
during
laboratory
and
field
research
on
the
efficacy
of
repellents?
15
16
Board
Response
to
the
Charge
17
18
The
Board
began
its
review
by
emphasizing
that
human
studies
are
essential
to
assess
the
19
efficacy
of
repelling
insects
and
other
arthropods.
The
only
way
to
determine
if
these
repellents
20
are
effective
is
to
test
them
on
or
near
humans,
since
animals
would
not
have
the
same
level
of
21
attractiveness
to
the
arthropods
as
humans
will.
22
23
The
following
comprehensive
list
of
conditions
should
be
considered
by
the
investigator
24
in
order
to
minimize
risks
to
human
subjects.
The
Board's
response
to
the
Agency's
charge
25
focused
primarily
on
the
ethical
considerations
and
only
secondarily
on
the
toxicity
data
base
per
26
se.
27
28
(
1)
IRB
approval
is
required
before
initiating
any
human
exposures.
29
30
(
2)
Initial
human
tests
should
be
conducted
in
a
laboratory
setting,
using
insects
and
other
31
arthropods
which
are
known
to
be
disease­
free.
32
33
(
3)
Healthy
volunteers
should
be
selected
who
are
not
sensitive
to
chemical
reactions
or
34
drug/
cosmetic
allergies,
and
not
allergic
or
overly
sensitive
to
arthropod
bites
and
stings.
The
35
subjects
selected
should
not
be
known
to
experience
any
adverse
drug
reactions
or
allergies
to
36
other
substances
or
toxins,
and
the
selected
subjects
should
not
be
taking
any
drugs
which
might
37
elicit
an
adverse
drug
reaction
(
if
the
predictions
from
studies
of
metabolism
of
the
repellent
38
suggest
that
drug­
chemical
interactions
might
occur
at
the
level
of
metabolism).
39
40
(
4)
If
no
known
information
about
exposures
in
humans
is
available,
testing
should
begin
with
41
the
low
dose
levels
and
if
no
adverse
reactions
are
displayed,
rise
gradually
to
the
level
of
42
exposure
anticipated
to
be
used
in
humans.
The
formulations
should
be
the
same
as
that
43
expected
to
be
applied
on
human
skin.
If
another
formulation
is
anticipated,
such
as
a
coil,
then
44
it
should
also
be
tested
in
laboratory
experiments.
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
22
of
67
(
5)
Although
insect
repellents
would
not
be
expected
to
yield
adverse
effects,
test
subjects
should
1
be
under
close
observation
by
an
observer
trained
to
detect,
as
well
as
listen
to
the
subject,
for
2
any
adverse
reactions.
If
such
adverse
reactions
are
observed,
this
would
be
grounds
for
3
terminating
the
exposure
as
soon
and
as
completely
as
possible.
4
5
(
6)
The
laboratory
results
would
need
to
show
a
substantial
likelihood
of
repellency
before
field
6
tests
should
be
initiated
because
of
the
possibility
of
subject
exposure
to
disease­
carrying
7
arthropods.
8
9
(
7)
The
field
region
for
tests
should
have
as
low
as
possible
incidence
of
known
disease­
agent
10
infested
insects
or
arthropods
(
prior
trapping
and
microbial
assays
should
document
this
minimal
11
risk).
12
13
(
8)
The
lowest
possible
number
of
untreated
controls
needed
to
ensure
scientific
validity
should
14
be
used
in
field
tests.
15
16
(
9)
The
overall
toxicity,
in
terms
of
both
the
toxic
effects
and
the
levels
at
which
these
toxic
17
effects
occur,
should
be
determined
from
the
existing
animal
data
base.
The
search
on
existing
18
animal
data
should
include
acute,
chronic,
reproductive,
eye
and
skin
irritation
and
dermal
19
sensitization,
so
that
the
most
reliable
information
on
potential
human
adverse
effects
is
known.
20
21
(
10)
Any
human
data
from
controlled
or
inadvertent
exposures,
or
from
routine
uses
in
the
past
22
or
in
other
countries
should
be
accumulated.
This
information
should
be
analyzed
for
evidence
23
of
direct
toxic
effects
or
any
adverse
side
effects,
including
allergic
or
sensitization
reactions.
24
25
(
11)
The
test
compound
should
be
compared
to
data
bases
on
similar
chemical
classes
of
26
compounds
so
that
educated
predictions
can
be
made
of
types
of
toxicity
that
might
be
elicited
in
27
humans,
the
likelihood
of
allergic
or
sensitization
reactions,
the
likely
disposition
and
28
pharmacokinetics
of
the
compound,
including
absorption,
metabolism
and
clearance.
In
29
addition,
the
metabolism
of
the
compound
should
be
known
from
in
vitro
tests
using
human
liver
30
samples,
in
order
to
predict
the
toxicity
or
lack
thereof
of
probable
metabolites
and
to
predict
the
31
enzymes
involved
in
the
compound's
major
routes
of
metabolism.
This
information
on
32
metabolism
would
be
useful
to
predict
any
likely
interactions
with
drugs
that
an
individual
might
33
be
taking.
34
35
HSRB
Consensus
and
Rationale
36
37
The
consensus
of
the
Board
was
that
studies
involving
humans
are
necessary
to
evaluate
38
the
efficacy
of
products
to
repel
insects
and
other
arthropods.
Risk
identification
and
39
minimization
are
also
essential.
In
their
protocols,
investigators
should
adequately
identify
risk
40
to
participants
and
describe
adequate
steps
they
would
take
to
minimize
these
risks.
41
42
Charge
to
the
Board
43
44
b.
What
types
of
toxicity
data
should
be
routinely
generated
before
an
investigator
conducts
45
repellent
efficacy
testing
on
human
subjects
with
a
new
product?
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
23
of
67
1
Board
Response
to
the
Charge
2
3
In
response
to
the
question,
the
Board
proposed
a
set
of
data
that
would
meet
this
4
requirement
:
5
6
 
The
initial
evaluation
of
a
compound
should
include
an
analysis
of
chemical
structure
7
that
emphasizes
the
detection
of
possible
adverse
effects.
The
analysis
can
be
informed
8
by
comparisons
with
repellents
of
similar
chemotypes
for
which
toxicity
data
exist.
A
9
variety
of
computer
applications
and
predictive
models
should
be
used
to
predict
10
potential
alerts
for
metabolic
activation,
target
organ
toxicity
or
mutagenesis.
This
type
11
of
evaluation
can
include
the
comparison
to
similar
chemotypes
of
repellents
for
which
12
toxicity
data
exist.
13
 
Acute
(
single
dose)
toxicity
studies
should
be
conducted,
with
emphasis
on
the
intended
14
route(
s)
of
exposure
to
the
chemical.
15
 
Dermal
and
ocular
irritation
should
be
evaluated.
Characteristics
of
the
potential
for
16
dermal
sensitization
and
nasal­
pharyngeal
sensitization
or
triggering
should
be
17
considered.
18
 
Absorption
of
the
compound
after
administration
by
the
route
of
intended
exposure,
most
19
likely
dermal,
should
be
determined.
This
can
be
done
in
laboratory
animals,
but
may
20
also
be
done
using
in
vitro
assessments
of
percutaneous
absorption
in
human
skin
or
21
human
skin
surrogates.
If
conducted
in
animals,
the
study
should
include
an
assessment
22
of
the
routes
of
elimination
of
the
compound.
23
 
The
mutagenic
and
clastogenic
potential
of
the
compound
should
be
determined.
At
this
24
stage,
this
analysis
could
be
an
abbreviated
battery
of
in
vitro
genetic
toxicology
tests.
25
 
Some
data
on
toxicity
in
a
repeat
dosing
paradigm
should
be
generated.
This
is
26
particularly
important
if
the
compound
is
available
systemically.
27
 
If
the
compound
is
available
systemically,
its
metabolic
fate
should
be
investigated
and
it
28
should
be
determined
whether
humans
are
likely
to
metabolize
the
compound
in
a
29
manner
that
is
qualitatively
or
quantitatively
different
from
laboratory
animals
is
30
recommended.
31
32
It
should
be
noted
that,
although
the
Board
has
made
these
recommendations
for
toxicity
33
data,
it
did
not
specify
the
precise
methods
by
which
the
data
set
listed
above
should
be
34
generated.
The
use
of
animal
models,
validated
in
vitro
methods
or
robust
predictive
tools
could
35
be
used
in
combination
to
generate
the
recommended
data
set.
Furthermore,
if
an
investigator
36
desires
to
carry
out
multiple
exposures
of
a
given
compound
in
human
subjects,
then
additional
37
data,
with
emphasis
on
subacute
and/
or
subchronic
toxicity
and
the
assessment
of
reproductive
38
hazard,
should
be
included
in
the
toxicology
evaluation.
39
40
In
addition
to
the
toxicity
data
summarized
above,
information
on
the
mode
of
action,
41
potency
and
projected
human
dose
is
useful
adjunct
information
for
assessing
any
potential
risk
42
associated
with
human
exposure.
Dose
selection
for
efficacy
studies
in
humans
should
be
43
justified
on
the
basis
of
animal
toxicity
studies
and/
or
other
relevant
data
(
e.
g.,
from
in
44
pharmaco­
kinetic
computer
modeling,
in
vitro
studies,
and
human
case
series).
Present
45
guidelines
specify
that
the
amount
applied
should
be
up
to
the
typical
maximum
dose
applied
by
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
24
of
67
consumers,
with
recognition
that
some
clarification
or
comparison
with
the
toxicology
1
benchmarks
from
animal
studies
will
aid
in
dose
selection
(
e.
g.,
lowest
NOAEL
from
sub­
2
chronic
studies)
and
protect
human
health.
3
4
HSRB
Consensus
and
Rationale
5
6
The
consensus
of
the
Board
was
that
the
minimum
set
of
toxicity
data
(
as
delinieated
above)
7
that
should
be
routinely
generated
before
an
investigator
conducts
repellent
efficacy
testing
on
8
human
subjects
with
a
new
product
is
that
which
will
assure
that
subjects
would
not
be
at
risk
of
9
permanent
or
irreversible
harm.
10
11
Charge
to
the
Board
12
13
c.
In
private
and
university
research
laboratories,
investigators
themselves
have
sometimes
14
served
as
research
subjects
when
assessing
chemicals
for
insect
repellent
activity.
What
scientific
15
and
ethical
issues
would
such
a
practice
raise?
Under
what
conditions,
if
any,
would
such
a
16
practice
be
acceptable?
17
18
Board
Response
to
the
Charge
19
20
The
topic
of
self­
experimentation
has
been
discussed
and
debated
for
many
years,
and
the
21
debate
is
likely
to
continue.
The
scientific
and
ethical
issues
presented
in
the
assessment
of
insect
22
repellents
are
not
different
from
the
issues
of
self­
experimentation
in
clinical
research
in
general.
23
There
is
not
a
clear
overarching
answer;
each
study
may
present
a
different
situation.
24
25
Arguments
in
favor
of
self­
experimentation
26
27
There
is
a
long
and
noble
history
of
investigators
experimenting
on
themselves.
28
Experiments
on
yellow
fever,
pernicious
anemia,
morphine
and
cocaine
as
local
anesthetics,
H.
29
pylori
as
the
causative
agent
for
gastric
ulcers,
and
many
others
have
been
instances
of
30
researchers
using
themselves
as
research
subjects.
31
32
The
Nuremberg
Code,
written
in
1947
as
part
of
the
criminal
trials
of
the
Nazi
doctors,
33
states
"
5.
No
experiment
should
be
conducted
where
there
is
an
a
priori
reason
to
believe
that
34
death
or
disabling
injury
will
occur;
except,
perhaps,
in
those
experiments
where
the
35
experimental
physicians
also
serve
as
subjects"
(
USGPO,
1949).
If
a
researcher
is
not
willing
to
36
assume
the
risk
of
harm
from
research
participation,
how
can
that
same
researcher
ask
anyone
37
else
to
assume
that
same
risk?
38
39
Ethical
research
in
compliance
with
40
CFR
26
requires
voluntary
informed
consent.
40
Who
better
understands
those
risks
than
the
researcher?
Who
best
understands
the
societal
or
41
scientific
benefits
of
the
knowledge
to
be
gained
from
the
experiment?
There
is
no
chance
of
42
misunderstanding
information
in
the
consent
process.
43
44
If
the
ethical
and
scientific
arguments
against
self­
experimentation
can
be
addressed
45
adequately,
then
self­
experimentation
seems
quite
reasonable.
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
25
of
67
1
Arguments
against
self­
experimentation
2
3
Ethical
Considerations
4
5
Many
have
objected
to
self­
experimentation
on
scientific
and
ethical
bases
but
their
6
arguments
can
all
be
addressed
with
proper
planning
and
conduct
of
the
research
protocol.
For
7
this
reason,
self­
experimentation
is
not
per
se
unethical
or
scientifically
flawed
per
se.
8
9
One
argument
against
self­
experimentation
is
that
researchers
may
take
unreasonable
10
risks
with
their
own
health
due
to
a
blinding
belief
in
the
importance
of
the
research
question,
as
11
well
as
and
a
personal
incentives
such
as
of
career
advancement.
Addressing
this
concern
12
properly
requires
independent
review
of
the
study
in
order
to
ensure
that
the
risks
are
reasonable
13
in
relationship
to
the
potential
benefits
of
the
research.
Therefore,
the
study
must
be
IRB
14
approved
prior
to
its
conduct.
As
part
of
its
review,
the
IRB
must
assure
that
"
risks
to
subjects
15
are
reasonable
in
relation
to
anticipated
benefits,
if
any,
to
subjects,
and
the
importance
of
the
16
knowledge
that
may
reasonably
be
expected
to
result"
as
stated
at
40CFR26.1111(
a)(
2).
17
18
Potential
coercion
of
co­
investigators
and
research
staff
by
the
principal
investigator
is
19
another
area
of
concern.
For
this
reason,
self­
experimentation
should
be
limited
to
the
principal
20
investigator
in
most
circumstances.
Co­
investigators
and
research
staff
(
junior
members
of
the
21
research
team)
should
not
be
enrolled
in
a
study
if
the
principal
investigator
has
power
or
22
authority
over
them
in
the
research
setting
or
in
any
other
setting
(
e.
g.,
classroom
or
other
work
23
environment).
Situations
such
as
these
can
lead
to
coercion
or
undue
influence
on
subordinates
24
to
participate
in
the
research,
and
should
be
avoided,
except
when
there
is
an
IRB
approved
25
protocol
that
would
and
allow
for
truly
voluntary
participation.
26
27
Scientific
Considerations
28
29
There
are
many
scientific
issues
that
must
be
addressed
in
order
for
self­
experimentation
30
to
produce
scientifically
sound
data
that
would
be
useful
and
generalizable
at
the
end
of
the
31
experiment.
32
33
One
issue
involves
the
type
of
outcome
measure
used
in
the
research.
If
the
outcome
34
measure
is
a
subjective
one,
then
the
expectation
of
the
self­
experimenter
is
likely
to
influence
35
the
results.
This
bias
may
lead
to
an
incorrect
study
conclusion.
To
address
this
problem,
self­
36
experimentation
should
occur
only
in
research
protocols
with
objective
outcome
measures.
The
37
investigator­
subject
should
not
assess
their
own
outcomes.
The
outcome
assessor
should
be
38
blinded
to
the
subject's
identity,
if
possible.
In
addition,
the
burden
of
proof
is
on
the
principal
39
investigator
to
demonstrate
how
their
participation
does
not
introduce
bias
into
the
study
results.
40
41
Oversight
of
the
study
is
another
issue
of
concern
in
self­
experimentation.
Since
the
42
principal
investigator
is
responsible
for
study
oversight,
this
oversight
can
be
compromised
43
during
the
time
that
the
principal
investigator
is
a
research
subject.
Can
the
experiment
be
safely
44
completed,
for
example,
if
the
investigator
became
incapacitated
while
a
research
subject?
This
45
objection
can
be
addressed
by
identifying
the
person
responsible
for
study
oversight
while
the
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
26
of
67
principal
investigator
is
a
subject
and
if
the
principal
investigator
becomes
unable
to
resume
1
study
responsibilities.
2
3
Many
of
the
stories
of
self­
experimentation
in
the
history
of
medicine
have
used
a
sample
4
of
one;
the
researcher
was
the
only
subject.
These
studies
thus
lacked
proper
controls
and
did
not
5
account
for
inter­
individual
variability.
Such
studies
were
poorly
designed
to
answer
a
research
6
study
question
with
rigorous
methodology.
To
address
this,
a
well­
written
protocol
is
required,
7
which
must
have
a
sample
size
that
is
adequate
to
answer
the
study
question
being
asked.
8
9
Concern
also
has
been
raised
about
whether
investigators
are
thorough
in
their
evaluation
10
of
whether
they
meet
all
of
the
study's
inclusion
and
exclusion
criteria.
If
researchers
are
11
convinced
that
they
should
be
and
really
wants
to
be
subjects,
they
might
not
perform
all
12
screening
tests
that
are
required
by
the
protocol.
This
issue
can
be
easily
addressed
by
having
13
another
investigator
perform
and
assess
the
screening
results.
The
principal
investigator's
14
eligibility
to
participate
in
the
study
should
be
assessed
independently
by
someone
outside
the
15
research
team,
to
avoid
potential
coercive
influence
of
the
principal
investigator
on
the
sub­
16
investigator.
17
18
HSRB
Consensus
and
Rationale
19
20
It
may
not
be
a
priori
unethical
or
scientifically
problematic
for
a
principal
investigator
to
21
be
a
subject
in
his/
her
own
study
IF:
22
23
1.
The
study
was
approved
by
an
by
an
IRB
in
the
same
manner
as
was
required
for
most
human
24
subjects
research;
25
26
2.
The
following
scientific
issues
were
addressed:
27
28
a.
Principal
investigator
met
all
enrollment
criteria;
29
b.
The
study
was
a
well
controlled
trial
with
a
justified
sample
size
adequate
to
answer
30
the
study
question
with
statistical
surety
(
Occasionally
a
study
with
a
small
sample
size
may
be
31
scientifically
and
ethically
appropriate
if
it
is
a
pilot
or
feasibility
study.
However,
justification
32
for
the
sample
size
chosen
is
still
necessary,
although
such
justification
may
not
be
a
statistical
33
one.
In
such
a
situation,
(
c)
does
not
apply);
34
c.
The
principal
investigator
is
one
of
many
subjects,
accounting
for
normal
human
35
variability,
and
allowing
results
to
be
generalized
to
a
broad
population;
and
36
d.
The
outcome
measure
is
objective
and
measured
by
another
(
blinded,
when
possible)
37
investigator;
38
39
3.
A
plan
is
in
place
to
ensure
the
integrity
and
safety
of
the
study
while
the
principal
40
investigator
was
a
subject.
41
42
4.
A
plan
is
in
place
to
ensure
for
study
oversight
if
the
principal
investigator
becomes
43
incapacitated;
44
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
27
of
67
5.
Participation
of
other
research
staff
and
employees
is
prohibited
except
in
those
cases
where
1
issues
of
coercion/
undue
influence
can
be
addressed,
which
may
or
may
not
be
possible;
and
2
3
6.
The
investigator
justifies
why
he/
she
should
be
a
research
subject
in
the
study.
4
5
Charge
to
the
Board
6
7
d.
Please
comment
on
the
scientific
and
ethical
issues
arising
from
the
use
of
(
or
decision
not
to
8
use)
negative
controls
groups
in
repellent
efficacy
studies,
in
both
laboratory
and
field
studies.
9
10
Board
Response
to
the
Charge
11
12
Scientific
Considerations
13
14
Negative
controls
(
i.
e.,
untreated/
unprotected)
are
used
in
repellant
studies
to
show
15
"
biting
pressure".
This
can
be
categorized
as
sufficient,
insufficient,
or
it
can
be
quantitatively
16
measured
(
bites/
minute
over
time).
Negative
controls
are
also
used
in
field
studies
to
confirm
17
effectiveness
that
is
shown
in
laboratory
studies,
18
19
The
use
of
a
control
group
has
been
an
essential
characteristic
of
repellent
efficacy
20
studies
conducted
in
the
laboratory,
because
a
comparison
of
the
data
from
the
treatment
and
21
control
groups
shows
a
measure
of
efficacy.
The
use
of
negative
control
groups
in
laboratory
22
studies
appears
to
be
a
safe
practice,
since
the
insects
involved
are
known
to
be
disease­
free.
In
23
contrast,
the
uncontrolled
nature
of
field
studies
means
that
the
same
assurances
cannot
be
24
provided
to
participants.
Because
negative
controls
are
not
exposed
to
the
pesticidal
active
25
ingredient,
there
is
no
risk
of
toxicity
from
the
chemical.
The
risk
of
harm
and
discomfort
for
26
subjects
is
primarily
of
two
types.
In
laboratory
and
field
studies,
there
is
the
discomfort
of
the
27
bite
itself,
which
might
include
minor
pain,
itching
and
swelling.
The
discomfort
experienced
by
28
humans
is
variable,
some
having
negligible
reaction,
others
having
a
definite
allergic
response.
29
In
addition
to
this
risk,
field
trials
have
the
added
risk
of
subjects
acquiring
a
vector­
borne
30
infection.
Fortunately,
field
procedures,
such
as
capture
of
insects
just
prior
to
biting
can
reduce
31
such
risk
substantially.
In
addition,
because
negative
controls
are
not
exposed
to
the
pesticidal
32
active
ingredient,
there
is
no
risk
of
toxicity
from
the
chemical.
33
34
Nonetheless,
the
Board
failed
to
reach
consensus
regarding
negative
control
groups
in
35
field
studies
of
repellent
effectiveness.
The
basic
scientific
justification
for
such
controls
is
to
36
confirm
that
"
biting
pressure"
exists.
If
that
is
the
only
purpose,
a
single
negative
control
may
37
suffice.
As
some
Board
members
suggested,
biting
pressure
might
even
be
established
through
38
trapping
or
other
methods
that
did
not
involve
an
unprotected
human
subject.
Other
Board
39
members
recognized,
however,
that
it
may
be
important
to
establish
a
particular
level
of
biting
40
pressure
in
order
to
compare
the
extent
and
duration
of
repellency
from
trial
to
trial
and
41
compound
to
compound.
In
fact,
that
condition
appears
to
be
essential
for
accurate
product
42
labeling.
In
any
case,
since
even
one
unprotected
human
subject
could
be
at
risk
of
vector­
borne
43
disease,
the
use
of
negative
control
groups
should
not
be
a
default
component
in
the
design
of
44
repellency
studies.
Instead
it
should
be
justified
in
each
protocol
in
which
it
is
proposed.
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
28
of
67
Ethical
Considerations
1
2
By
minimizing
risk
in
the
laboratory
studies
(
e.
g.
screening
for
past
sensitive
reactions,
3
captive
breeding
of
infection­
free
insects,
and
mechanical
aspiration
at
bite),
the
use
of
negative
4
controls
in
the
laboratory
should
not
be
considered
ethically
problematic
as
long
as
it
is
5
scientifically
justified.
Steps
can,
and
should
be
taken
to
minimize
risk
in
field
studies.
6
However,
the
risk
of
a
significant
life
altering
infection
can
never
be
reduced
to
zero.
Thus,
the
7
potential
benefit
from
such
studies
must
justify
this
risk.
The
science
must
be
sound
and
8
alternative
approaches
­
such
as
live
trapping
or
laboratory
studies
­
must
be
shown
to
be
9
inadequate.
The
consent
process
must
be
truly
informed
and
subjects
must
be
volunteers
with
10
the
full
right
of
withdrawal.
These
issues
must
be
specifically
and
completely
addressed
in
the
11
study
protocol.
12
13
HSRB
Consensus
and
Rationale
14
15
The
HSRB
suggested
that
the
Agency
modify
the
guideline
to
say
that
negative
controls
16
"
may
be"
needed
(
instead
of
"
are")
and
that
examples
be
given
both
for
when
negative
controls
17
are
needed
and
when
they
are
not.
The
language
on
positive
controls
may
also
benefit
from
18
further
expansion
and
clarification.
19
20
Charge
to
the
Board
21
22
e.
Please
comment
on
the
scientific
and
ethical
issues
raised
by
the
design
of
studies
to
collect
23
data
sufficient
to
support
assessment
of
repellent
efficacy
using
the
two
different
efficacy
24
metrics:
time
to
first
confirmed
bite
(
TFCB),
and
time
providing
x%
protection
of
treated
25
subjects
from
bites
relative
to
untreated
controls
(
RP).
26
27
Board
Response
to
the
Charge
28
29
The
distinction
between
efficacy
and
effectiveness
is
useful
in
answering
the
questions
30
about
the
Insect
Repellent
Product
Performance
Testing
Guideline.
Although
the
efficacy
of
a
31
repellent
can
be
established
using
laboratory
techniques,
the
effectiveness
of
a
repellent
can
only
32
be
established
in
the
field
under
actual
use
conditions.
33
34
Scientific
Considerations
35
36
A
particular
study
design
can
either
minimize
risk
to
all
subjects
enrolled
in
a
study
(
for
37
example
by
using
only
laboratory
mosquitoes
or
ticks
to
eliminate
the
possibility
of
vector­
borne
38
diseases,
excluding
those
who
might
adversely
react
to
the
insect
bites),
and/
or
minimize
overall
39
risks
by
reducing
the
number
of
"
at
risk"
subjects
to
the
lowest
number
possible
while
40
maintaining
scientific
integrity,
pretesting
insects
to
confirm
probable
absence
of
vector
borne
41
diseases,
and/
or
utilizing
techniques
to
remove
insects
prior
to
bite
when
feasible.
Risk
42
minimization
strategies
will
depend
upon
knowledge
of
variability
in
subject
attractiveness,
the
43
effectiveness
of
the
repellent,
the
interaction
of
biting
pressure
to
insect
hunger
and
subject
44
attractiveness,
characteristics
of
the
test
environment,
and
the
scientific
reliability
of
generalizing
45
insect
performance
from
the
lab
to
the
field.
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
29
of
67
1
A
question
was
raised
about
the
provision
of
prophylactic
antibiotics
or
use
of
a
2
preventative
vaccine
in
order
to
minimize
risks.
The
difficulty
with
this
approach
is
that
the
3
effectiveness
of
these
interventions
would
need
to
be
established,
and
the
dangers
associated
4
with
such
treatments
would
become
part
of
the
overall
assessment
of
whether
the
risks
of
the
5
research
are
offset
by
the
importance
of
the
knowledge
to
be
achieved.
The
measurement
of
pre­
6
exposure
and
post
exposure
antibodies,
unless
done
in
a
context
to
only
include
subjects
who
are
7
immune
to
the
vector
borne
disease
of
concern,
does
not
minimize
risk
other
than
documenting
8
the
presence
of
the
subject's
immune
response.
Overall,
the
best
approach
is
to
choose
a
study
9
design
that
either
eliminates
or
minimizes
the
risk
of
vector­
borne
diseases.
10
11
Ethical
Considerations
12
13
The
time
to
first
confirmed
bite,
or
the
time
to
first
confirmed
"
intent
to
bite"
(
if
14
ascertainable),
has
the
ethical
advantage
of
minimizing
the
risk
of
exposure
to
vector­
borne
15
diseases.
However,
based
on
the
background
materials
for
the
meeting,
the
use
of
relative
16
protection
can
be
an
appropriate
outcome
measure
based
on
statistical
advantage.
Relative
17
protection
could
thus
would
be
an
appropriate
outcome
measure
for
a
laboratory
based
efficacy
18
study.
As
long
as
there
was
a
sufficient
"
biting
pressure",
one
could
then
do
a
measure
of
the
19
duration
of
relative
protection
for
protected
subjects
in
a
field
study
and
compare
it
to
laboratory
20
based
measurements.
This
could
also
be
done
using
time
to
first
confirmed
bite.
21
22
Participation
in
insect
repellent
research
offers
no
direct
benefit
to
subjects
when
their
23
exposure
to
insects
or
arthropods
is
for
the
purpose
of
the
study
given
the
presence
of
existing
24
insect
repellents
on
the
market.
As
such,
the
sponsors
of
repellent
efficacy
research
are
obligated
25
to
provide
insurance
to
cover
possible
future
medical
costs
that
result
from
injury
or
illness
26
experienced
by
the
subjects
as
a
consequence
of
their
participation
in
the
research.
It
is
less
clear
27
whether
sponsors
would
have
an
obligation
to
provide
for
lost
income
in
such
instances.
As
28
noted
previously
protocols
must
justify
the
level
of
risk
by
the
probability
and
social
value
of
the
29
benefits,
adequately
identify
all
risks,
and
present
a
description
of
adequate
steps
to
minimize
the
30
risks.
31
32
The
informed
consent
materials
also
must
provide
information
about
the
prevalence
and
33
risks
of
any
vector
borne
diseases
(
if
applicable),
the
consequences
of
acquiring
such
a
disease
as
34
a
result
of
the
research,
and
the
availability
of
effective
insect
repellents
outside
of
the
research.
35
36
HSRB
Consensus
and
Rationale
37
38
The
Board
consensus
was
that
the
time
to
first
confirmed
bite,
or
the
time
to
first
39
confirmed
"
intent
to
bite"
(
if
ascertainable),
has
the
advantage
of
minimizing
risk
of
vector­
borne
40
diseases.
However,
for
some
studies
there
is
a
statistical
advantage
for
the
use
of
relative
41
protection
as
an
appropriate
outcome
measure.
Since
relative
protection
procedures
in
field
42
studies
increases
the
risk
of
vector­
borne
diseases,
protocols
must:
(
a)
justify
the
level
of
risk
by
43
the
probability
and
social
value
of
the
benefits;
(
b)
adequately
identify
all
risks;
(
c)
present
a
44
description
of
adequate
steps
to
minimize
the
risks;
and
(
d)
provide
consent
materials
that
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
30
of
67
include
information
about
the
prevalence
and
risks
of
any
vector­
borne
diseases,
consequences
1
of
contracting
disease,
and
alternative
effective
repellents
outside
of
the
research.
2
3
Charge
to
the
Board
4
5
f.
Please
comment
on
appropriate
approaches
for
estimating
the
minimum
number
of
subjects
6
needed
to
evaluate
the
level
of
efficacy
of
a
repellent
in
laboratory
and
field
studies.
7
8
Board
Response
to
the
Charge
9
10
Introduction
11
12
As
written,
the
current
draft
of
the
Guidelines
suggests
that
six
should
be
the
minimum
13
number
of
research
subjects
in
laboratory
or
field
experiments
where
the
efficacy
of
an
insect
14
repellent
is
investigated.
It
is
not
clear
from
the
Guidelines
whether
the
number
refers
to
the
15
entire
experiment
or
to
the
number
of
subjects
allocated
to
each
treatment
under
consideration.
16
The
Board
argues
below
that
establishing
a
single
sample
size
for
all
types
of
experimental
17
designs
and
objectives
is
not
the
most
appropriate
approach.
18
19
Critique
20
21
Correctly
estimating
the
sample
size
that
is
needed
in
an
experiment
(
conducted
either
in
22
a
laboratory
or
in
the
field)
is
important
to
ensure
reliable
inferences
about
the
treatment
under
23
study.
Sample
size
calculations
can
be
carried
out
using
several
approaches,
but
the
two
most
24
common
ones
(
at
least
in
terms
of
usage)
are
based
on:
25
26
 
Power
calculations:
sample
size
is
chosen
to
guarantee
that
tests
of
hypotheses
reach
a
pre­
27
determined
power.
Power
is
defined
as
one
minus
the
probability
of
incorrectly
failing
to
28
reject
the
null
hypothesis
of
no
treatment
effect.
In
other
words,
power
is
the
probability
of
29
finding
a
difference
if
such
a
difference
is
"
true".
That
is,
in
under­
powered
experiments,
30
investigators
have
a
high
chance
of
not
detecting
a
"
true"
treatment
effect.
31
32
 
Confidence
interval
calculations:
sample
size
is
chosen
so
that
the
100(
1­
 )%
(
for
 
typically
33
chosen
to
be
0.05)
confidence
interval
around
a
treatment
effect
estimate
is
sufficiently
34
small.
The
narrower
the
confidence
interval,
the
more
reliable
the
point
estimate
of
the
35
treatment
effect
size.
36
37
While
smaller
than
needed
sample
sizes
result
in
under­
powered
studies
and
wide
38
confidence
intervals
for
true
effect
sizes,
excessively
large
samples
are
not
desirable
either.
First,
39
resources
are
wasted
when
samples
are
larger
than
they
need
to
be.
While
it
is
always
possible
40
to
increase
the
power
of
a
study
by
increasing
the
sample
size,
at
some
point
the
cost
of
41
obtaining
an
additional
observation
outweighs
the
potential
gains
in
power.
Second,
very
large
42
sample
sizes
may
result
in
statistically
significant
results
that
have
no
practical
implication.
43
Finally,
including
more
subjects
in
an
experiment
than
is
required
for
statistical
reasons
may
44
unnecessarily
place
subjects
at
risk.
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
31
of
67
Both
the
power
of
a
test
and
the
width
of
the
confidence
interval
around
a
point
estimate
1
depend
on
various
design
and
data
attributes,
including:
2
3
 
Sample
size:
power
increases
as
sample
size
increases;
the
width
of
confidence
intervals
4
decreases
as
sample
size
increases.
5
6
 
Variance
across
experimental
subjects:
the
smaller
the
variability
in
the
response
across
7
experimental
subjects,
the
larger
the
power
and
narrower
the
confidence
interval
for
a
given
8
sample
size.
9
10
 
The
size
of
the
effect
that
needs
to
be
detected:
in
experiments
in
which
detecting
a
very
11
small
difference
between
two
treatments
or
between
a
treatment
and
a
control,
the
minimum
12
required
sample
size
for
achieving
a
certain
power
or
for
keeping
confidence
intervals
to
a
13
desired
width
will
be
larger
than
when
the
difference
to
be
detected
is
larger.
In
other
words,
14
the
smaller
the
difference
sought
between
two
groups,
the
larger
the
required
sample
size,
all
15
other
factors
being
held
constant.
16
17
 
Whether
the
design
calls
for
replicate
measurements
obtained
from
the
same
individuals
in
18
the
study
(
which
induces
correlation
across
measurements)
or
for
"
true"
replication
involving
19
different
individuals
observed
under
the
same
conditions:
correlation
across
measurements
20
(
repeat
measures
in
the
same
individual)
in
general
decreases
the
power
of
an
experiment.
21
22
The
appropriate
approach
for
estimating
the
minimum
required
sample
size
in
insect
23
repellency
studies
in
the
laboratory
or
in
the
field
will
depend
greatly
on
the
design
of
the
study.
24
Factors
to
be
considered
when
estimating
sample
size
include
the
following:
25
26
 
Whether
the
experiment
was
conducted
in
the
laboratory
or
in
the
field:
a
larger
sample
size
27
will
typically
be
required
for
experiments
conducted
in
the
field
because
uncontrollable
28
factors
that
may
affect
the
response
increase
the
variance
across
test
subjects.
29
30
 
The
number
of
treatments
(
e.
g.,
potency
formulations
or
modes
of
application
of
an
insect
31
repellent)
included
in
the
study.
32
33
 
The
presence
of
control
subjects,
and
whether
the
same
volunteers
will
serve
as
both
controls
34
and
experimental
test
subjects
(
as
in
experiments
in
which
one
arm
of
each
subject
is
treated
35
with
a
repellent
while
the
other
one
is
not).
Experiments
in
which
the
same
subjects
act
36
simultaneously
as
controls
and
as
tests
require
smaller
sample
sizes
(
all
other
factors
being
37
equal)
than
those
studies
in
which
different
individuals
act
as
controls
and
tests.
38
39
 
Whether
the
design
calls
for
repeated
measurements
on
experimental
subjects.
40
41
 
The
outcome
variable
of
interest:
this
relates
to
the
between­
subject
variability
mentioned
42
earlier.
The
variance
across
subjects
might
be
larger
for
some
outcome
variables
than
others.
43
For
example,
the
between­
subject
variance
might
be
expected
to
be
larger
when
the
outcome
44
variable
is
repellency
of
a
product
over
a
long
period
than
when
the
product's
repellency
45
over
a
shorter
period
is
of
interest.
Thus,
the
minimum
sample
size
for
adequate
study
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
32
of
67
reliability
(
either
in
the
power
or
the
width
of
confidence
interval
senses)
would
be
larger
in
1
long­
term
studies
than
in
short­
term
ones.
2
3
 
The
presence
and
potential
effect
of
confounders
that
cannot
be
easily
controlled
via
the
4
experimental
design.
For
repellency
studies,
for
example
the
intensity
of
a
person's
odor
5
from
carbon
dioxide
emissions
contribute
to
the
attractiveness
of
the
person
to
blood­
seeking
6
mosquitoes.
The
sample
must
be
large
enough
to
ensure
that
the
variability
in
the
general
7
population
of
consumers
of
the
product
is
represented
in
the
study.
8
9
 
The
heterogeneity
of
the
target
population
from
which
the
sample
is
drawn:
if
the
product
is
10
meant
to
protect
all
individuals
(
e.
g.,
all
ages
and
both
genders)
then
the
minimum
sample
11
size
might
need
to
be
computed
within
population
strata,
to
ensure
that
each
population
sub­
12
group
is
adequately
represented
in
the
sample
and
that
inferences
about
the
effectiveness
of
13
the
product
can
be
reliably
drawn
for
the
entire
population.
14
15
 
The
heterogeneity
of
environments
in
which
the
product
is
expected
to
be
used:
if
the
product
16
is
to
be
used
in
a
variety
of
environments
(
e.
g.,
open
fields,
forests,
marshes,
and
the
typical
17
backyard)
where
a
different
concentration
of
insects
and
ticks
can
be
expected,
the
18
environment
must
be
included
as
a
factor
in
the
experimental
design.
In
laboratory
19
conditions,
field
insect
and
tick
concentrations
can
be
mimicked
by
varying
the
density
of
20
insects
and
ticks
in
experimental
cages.
The
larger
the
number
of
environments
in
the
study
21
design,
the
larger
the
minimum
sample
size
needed
to
achieve
the
desired
level
of
inferential
22
accuracy.
23
24
Actual
calculation
of
minimum
required
sample
size
typically
requires
estimating
the
25
sample
variance
of
the
point
estimate
of
interest.
Point
estimates,
in
turn,
follow
different
26
sampling
distributions
depending
on
the
quantity
that
is
being
estimated.
In
repellency
studies,
27
various
outcomes
are
of
interest
and
these
differ
in
the
distributional
assumptions
that
can
be
28
justified:
29
30
 
When
the
outcome
or
response
variable
is
the
time
to
first
confirmed
bite
(
TFCB),
an
31
appropriate
distribution
for
the
response
might
be
the
exponential
distribution
(
or
the
more
32
general
gamma
family).
A
point
estimate
of
the
mean
response
is
given
by
the
sample
mean
33
of
the
response
variable,
but
construction
of
a
confidence
interval
for
the
true
mean
response
34
must
be
based
on
the
correct
sampling
variance
calculation.
35
36
 
When
the
outcome
variable
is
relative
protection,
the
product
passes
the
efficacy
test
if
37
treated
subjects
receive
95%
fewer
bites
than
control
subjects.
Because
the
number
of
bites
38
can
be
best
modeled
as
a
Poisson
random
variable,
a
point
estimate
of
the
number
of
bites
39
under
different
treatments
and
a
standard
deviation
around
that
point
estimate
must
be
40
estimated
under
that
Poisson
model.
A
normal
approximation
to
the
Poisson
would
be
41
reasonable
only
when
the
number
of
bites
anticipated
for
each
subject
is
large,
a
situation
not
42
likely
to
be
encountered
in
practice.
43
44
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
33
of
67
HSRB
Consensus
and
Rationale
1
2
It
is
critical
that
the
proposed
number
of
subjects
be
justified
on
the
basis
of
good
3
research
design.
Because
experiments
to
test
effectiveness
of
products
to
repel
insect
and
tick
4
bites
are
likely
to
vary
in
terms
of
design,
response
variable,
target
population
of
interest,
5
detectable
effect
size
and
other
important
variables,
requiring
a
specific
minimum
sample
size
6
that
guarantees
sufficient
accuracy
in
all
cases
might
be
impractical.
Instead,
the
guideline
might
7
require
that
registrants
present
their
own
sample
size
calculations
and
that
the
methodology
used
8
in
the
calculations
be
justified
relative
to
the
factors
noted
in
the
bullet
list
above.
9
10
Charge
to
the
Board
11
12
g.
Please
comment
on
whether
or
not
investigators
should
have
an
ethical
obligation
to
provide
13
subjects
of
repellent
efficacy
research
with
insurance
to
cover
possible
future
medical
costs
or
14
other
losses
that
result
from
injury
or
illness
experienced
by
the
subjects
as
a
consequence
of
15
their
participation
in
the
research.
16
17
Board
Response
to
the
Charge
18
19
The
broad
issue
of
compensating
research
subjects
for
research­
related
injuries,
together
20
with
the
somewhat
narrower
one
of
paying
for
the
costs
of
medical
care
for
such
injuries,
has
21
received
substantial
analysis.
The
report
by
the
National
Academy
of
Sciences
on
intentional
22
dosing
studies
(
NAS
2004),
the
principles
of
which
Congress
specifically
required
to
be
reflected
23
in
the
EPA
regulations
on
such
studies,
directly
addressed
this
issue.
24
25
As
the
NAS
Report
notes:
26
27
Debate
continues
in
the
United
States
about
whether
compensation
should
be
provided
28
for
research­
related
injuries.
The
Common
Rule
requires
only
that
when
research
involves
more
29
than
minimal
risk,
information
should
be
disclosed
regarding
whether
medical
treatment
and
30
other
compensation
will
be
provided
for
research­
related
injuries.
Many
critics
of
the
U.
S.
policy
31
believe
there
should
be
more
than
disclosure
of
information
about
compensation
and
call
for
the
32
provision
of
medical
care
for
research­
related
injuries
without
cost
to
the
participants
and,
in
33
addition,
for
compensation
for
lost
wages,
disabilities,
and
death.
These
claims
are
based
on
the
34
belief
that
research
participants,
whatever
their
motivations,
accept
risk
on
behalf
of
society.
35
When
participants
are
injured,
justice,
fairness,
and
gratitude
mandate,
at
a
minimum,
the
36
provision
of
needed
medical
treatment
without
cost
to
the
participant.
Further
study
is
needed
37
regarding
the
provision
of
other
types
of
compensation.
(
NAS
2004.)
38
39
Based
on
this
analysis,
the
NAS
Panel
examined
the
ethical
issues
associated
with
40
intentional
human
exposure
studies,
adopting
the
following
as
one
of
its
Recommendations:
41
42
Recommendation
5­
5:
Compensation
for
Research­
Related
Injuries
43
44
At
a
minimum,
sponsors
of
or
institutions
conducting
intentional
human
dosing
studies
45
should
ensure
that
participants
receive
needed
medical
care
for
injuries
incurred
in
the
study,
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
34
of
67
without
cost
to
the
participants.
In
addition,
EPA
should
study
whether
broader
compensation
1
for
research­
related
injuries
should
be
required.
(
NAS
2004)
2
3
The
Board
agreed
with
the
reasoning
and
recommendations
listed
in
the
NAS
Report
4
with
regard
to
a
research
subject
not
being
required
to
bear
the
costs
of
medical
care
needed
to
5
treat
injuries
incurred
as
a
result
of
participating
in
a
research
study.
6
7
Indeed,
the
conclusions
of
the
NAS
Report
reflect
a
growing
consensus
that
the
provision
8
of
such
free
medical
care
should
be
adopted
as
a
requirement
for
many
categories
of
research
9
studies.
For
example,
in
Volume
1
of
its
1982
Report,
Compensating
for
Research
Injuries,
the
10
President's
Commission
for
the
Study
of
Ethical
Problems
in
Medicine
and
Biomedical
and
11
Behavioral
Research,
concluded
that
"
compensation
of
injured
subjects
is
appropriate
to
the
12
research
enterprise.
A
program
to
assure
compensation
is
thus
a
desirable
policy
goal
for
a
just
13
and
compassionate
government,
both
as
the
sponsor
of
most
biomedical
and
behavioral
research
14
and
as
the
means
through
which
society
acts
on
matters
of
common
interest,
such
as
the
search
15
for
new
biomedical
discoveries"
(
at
page
64).
That
Report
did
not
specifically
call
for
the
16
adoption
for
such
a
program,
since
it
concluded
that
it
did
not
have
enough
information
about
17
whether
subjects
were
indeed
already
receiving
such
compensation,
and
about
the
costs
and
other
18
practicalities
relating
to
adopting
a
program.
19
20
More
recently,
in
its
2001
report
on
Ethical
and
Policy
Issues
in
Research
Involving
21
Human
Participants,
the
National
Bioethics
Advisory
Commission
(
NBAC
2001)
reviewed
the
22
literature
on
this
issue,
concluding
that
a
"
comprehensive
system
of
oversight
of
human
research
23
should
include
a
mechanism
to
compensate
participants
for
medical
and
rehabilitative
costs
24
resulting
from
research­
related
industries.
The
inclusion
of
this
mechanism
has
long
been
25
justified
on
ethical
grounds"
(
at
page
123).
It
echoed
the
President's
Commission's
call
for
a
26
study
of
the
need
for
a
compensation
program.
27
28
Similarly,
in
2003,
the
Institute
of
Medicine,
in
Responsible
Research:
A
Systems
29
Approach
to
Protecting
Research
Participants,
commenting
that
"[
b]
ecause
the
contributions
of
30
science
benefit
society
as
a
whole,
it
seems
indisputable
that
society
is
obligated
to
assure
that
31
the
few
who
are
harmed
in
government­
sponsored
scientific
research
are
appropriately
32
compensated
for
study­
related
injuries.
.
.
.
.
The
same
argument
applies
to
privately
funded
33
research,
perhaps
even
to
a
greater
extent,
as
the
economic
survival
of
a
company
depends
34
largely
on
the
availability
of
participants
to
test
new
therapies,
drugs,
and
other
products.
35
Because
the
participants
are
ultimately
contributing
to
the
profits
of
the
company,
any
costs
that
36
result
from
the
research
should
be
the
responsibility
of
the
sponsor"
(
at
pages
188,
190).
The
37
Institute
of
Medicine
report
also
reviewed
international
standards
relating
to
this
issue,
pointing
38
out
that
Guideline
13
of
the
Council
for
International
Organizations
of
Medical
Sciences
39
(
CIOMS)
requires
that
subjects
be
equitably
compensated
for
"
any
temporary
or
permanent
40
impairment
or
disability."
The
report
concluded
that
although
laws
vary,
"
most
[
nations]
make
41
some
provision
for
compensation"
(
at
page
189).
42
43
These
arguments
have
special
import
in
the
context
of
the
intentional
dosing
studies
that
44
this
Board
will
be
reviewing,
including
repellent
efficacy
research.
These
studies
will
almost
45
never
produce
any
direct
benefits
for
study
participants.
On
the
other
hand,
there
is
frequently
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
35
of
67
the
possibility
that
subjects
will
suffer
significant
injuries
as
a
result
of
their
participation.
In
the
1
repellent
efficacy
studies,
for
example,
subjects
may
be
at
risk
or
contracting
a
serious
vector­
2
born
illness
as
a
result
from
insect
bites
received
during
the
course
of
the
study.
Given
the
lack
3
of
direct
benefits
to
subjects,
and
the
possibilities
of
very
significant
harm,
the
justification
for
4
requiring
sponsors
to
cover
the
costs
of
medical
care
for
research­
related
injuries
is
heightened.
5
6
Three
important
points
also
need
to
be
mentioned
regarding
issues
raised
by
the
wording
7
of
the
charge
to
the
Board.
First,
the
Agency
asked
for
comments
regarding
whether
8
"
investigators"
should
be
required
to
pay
for
the
costs
of
such
medical
care.
In
most
cases,
it
9
would
be
most
appropriate
for
that
obligation
to
be
imposed
upon
the
sponsors
of
research,
who
10
are
usually
the
most
immediate
beneficiaries
of
the
research,
rather
than
the
investigator.
The
11
investigators
should
only
have
this
obligation
when
there
is
no
external
study
sponsor
(
i.
e.,
when
12
they
are
effectively
acting
as
the
sponsor
of
their
own
study).
13
14
Second,
the
Agency's
charge
spoke
of
requiring
that
subjects
be
provided
with
15
"
insurance"
to
cover
the
relevant
medical
costs.
The
Board
believed
that
sponsors
should
be
16
provided
with
some
degree
of
flexibility
in
demonstrating
how
they
will
cover
the
medical
costs
17
of
subjects.
A
sponsor
that
has
sufficient
assets,
for
example,
might
be
able
to
contractually
18
commit
itself
to
pay
for
these
costs.
Given
the
possible
substantial
administrative
costs
of
having
19
a
sponsor
purchase
a
special
type
of
insurance
for
subjects,
it
does
not
appear
appropriate
to
rule
20
out
other
ways
for
assuring
that
a
subject's
medical
costs
are
covered.
21
22
Third,
the
Agency's
charge
raised
the
possibility
of
requiring
payment
for
"
other
losses"
23
beyond
the
costs
of
medical
care.
Payment
for
such
"
other
losses"
(
for
example,
the
cost
of
lost
24
wages
when
a
subject
is
not
able
to
work
for
a
period
of
time)
is
a
more
complicated
and
25
controversial
issue
than
covering
medical
expenses.
With
regard
to
this
issue,
the
Board
agreed
26
with
the
conclusions
of
the
NAS
Report
that
further
study
should
be
required
in
order
to
better
27
evaluate
whether
requirements
to
cover
such
"
other
losses"
should
be
imposed.
28
29
HSRB
Consensus
and
Rationale
30
31
For
the
reasons
discussed
above
(
including
justice,
fairness
and
gratitude),
the
Board
32
concluded
that
it
is
appropriate
that
sponsors
of
repellent
efficacy
research
studies
should
be
33
required
to
ensure
that
if
a
subject
is
injured
as
a
result
of
their
participation,
then
the
subject
will
34
not
have
to
assume
the
costs
of
medical
care
needed
to
treat
such
injuries.
35
36
Charge
to
the
Board
37
38
h.
Please
comment
on
any
special
considerations
that
should
be
addressed
in
the
informed
39
consent
materials
provided
people
who
are
candidates
to
become
subjects
in
insect
repellent
40
efficacy
research.
41
42
Board
Response
to
the
Charge
43
44
The
general
requirements
for
informed
consent
are
outlined
in
40
CFR
26.116
of
the
45
Agency's
final
human
studies
rule.
A
basic
element
in
seeking
informed
consent
is
that
the
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
36
of
67
subject
should
be
told
that
the
study
involved
research
and
given
an
explanation
of
the
purposes
1
of
the
research,
the
expected
duration
of
the
research,
a
description
of
the
procedures
to
be
2
followed,
and
an
identification
of
any
procedures
that
are
experimental.
3
4
The
informed
consent
should
begin
with
a
clear
statement
that
this
study
is
research,
and
5
a
statement
as
to
whether
the
product
being
tested
is
approved
and
marketed
in
the
test
6
formulation
or
still
in
the
experimental
stage.
Information
about
the
potential
efficacy
of
the
7
product
against
the
test
insect
should
also
be
provided.
8
9
For
the
insect
repellent
studies,
it
is
especially
important
to
be
very
clear
about
the
10
experimental
set­
up,
either
the
laboratory
or
the
field,
and
what
the
expectations
are
for
the
11
subject.
Because
there
appears
to
be
a
tendency
in
these
research
studies
to
use
"
seasoned"
12
subjects
(
i.
e.,
those
who
are
in
the
scientific
field
or
have
participated
in
these
studies
before),
a
13
detailed
explanation
of
the
procedures
might
seem
to
be
unnecessary
to
the
investigator.
14
15
Nonetheless,
the
written
details
of
the
experimental
procedure
must
be
sufficient
to
16
inform
a
potential
subject
who
has
never
anticipated
in
this
type
of
study
and
to
remind
one
who
17
has
done
so.
A
video,
PowerPoint
presentation,
or
photographs
might
help
the
subject
to
18
visualize
what
will
occur
to
him/
her
during
the
study.
If
it
is
a
laboratory
study,
it
may
help
to
19
have
the
subject
place
their
arm
into
the
cage.
If
the
subject
is
expected
to
use
an
aspirator,
20
training
on
its
use
should
occur
prior
to
the
beginning
of
the
study.
A
demonstration
of
what
a
21
landing
and
probing
feels
like
might
be
appropriate
because
the
dermal
sensitivity
of
individuals
22
will
vary.
23
24
The
length
of
time
that
the
study
would
take
should
be
clear
in
the
informed
consent
25
document,
including
whether
the
test
would
be
repeated.
The
process
for
randomizing
subjects
26
to
the
test
or
experimental
group
should
be
included.
In
field
studies
that
take
the
entire
day,
it
27
might
be
explained
whether
food
would
be
provided
to
the
subjects.
28
29
A
clear
discussion
of
the
stopping
rules
should
be
included,
especially
for
the
field
30
studies.
For
example,
to
discontinue
participation,
does
the
subject
raise
their
hand,
return
to
the
31
van,
or
find
a
study
monitor
to
express
a
desire
to
stop.
32
33
Another
basic
element
of
informed
consent
is
a
description
of
any
reasonably
foreseeable
34
risks
or
discomforts
to
the
subjects.
Inclusion
of
a
Material
Data
Safety
Sheet
is
not
sufficient
to
35
adequately
inform
the
subject
as
far
as
all
the
inherent
risks
and
benefits
of
study
participation.
36
For
insect
repellent
studies,
three
types
of
risks
are
reasonably
foreseen.
37
38
The
first
is
the
risk
of
being
bitten.
The
informed
consent
document
should
give
an
39
estimate
of
the
potential
number
of
bites
that
a
subject
could
receive
in
the
control
and
40
experimental
groups.
A
statement
that
the
researcher
strives
for
each
subject
to
receive
few
to
no
41
bites
is
not
sufficient.
Additionally,
should
a
subject
have
an
allergic
reaction
to
the
insect
bites,
42
medical
procedures
and
remedies
that
would
be
present
should
be
clearly
described
in
addition
to
43
any
available
follow­
up
treatment
(
e.
g.
will
subjects
be
given
an
antibiotic
or
steroid
cream
for
44
their
bites?
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
37
of
67
The
second
risk
is
that
of
a
sensitivity
or
allergic
reaction
to
the
experimental
product.
A
1
synopsis
of
the
animal
studies
and
any
human
data
should
be
given
to
the
subject
along
with
a
2
discussion
of
the
theoretical
risk
of
a
reaction
occurring.
Emergency
care
procedures
should
be
3
presented
for
a
subject
who
has
a
reaction
to
either
the
bite
itself
or
the
repellent.
4
5
The
third
and
most
serious
risk
is
the
potential
for
acquisition
of
vector­
borne
illness
as
a
6
result
of
insect
bites.
The
severity
of
these
illnesses
should
be
clearly
explained,
even
if
the
7
researcher
believes
the
risk
is
minimal
to
non­
existent
due
to
either
through
the
use
of
disease­
8
free
insects
in
a
laboratory
study
or
the
selection
a
disease­
free
zone
for
the
field
study.
The
risk
9
of
insect­
borne
diseases
might
not
occur
to
a
subject
who
normally
does
not
work
in
the
field.
10
The
investigator
should
make
sure
that
the
subject
clearly
understands
both
the
risks
of
disease
11
transmission
and
what
symptoms
to
look
for
with
any
potential
insect­
borne
diseases.
One
12
suggestion
might
be
to
test
the
subject,
either
verbally
or
in
writing,
about
their
understanding
of
13
the
procedures
and
the
risks.
14
15
Another
basic
element
of
the
informed
consent
process
is
a
clear
and
complete
16
description
of
any
benefits
to
the
subjects
or
others
that
are
reasonably
expected
to
result
from
17
the
research.
It
should
be
very
clear
in
the
informed
consent
document
that
there
are
likely
to
be
18
no
direct
benefits
to
the
subject
as
a
result
of
study
participation.
The
only
potential
benefit
is
to
19
society
at
large
to
have
an
arsenal
of
insect
repellents
available.
Additionally
payment
for
20
participation
in
a
research
study
can
not
be
considered
a
benefit
of
the
study.
21
22
Each
research
participant
should
be
told
the
extent,
if
any,
to
which
confidentiality
of
the
23
records
identifying
the
subject
should
be
maintained.
The
researcher
should
be
careful
to
only
24
include
those
organizations
that
have
jurisdiction
over
the
study
and
might
therefore
have
the
25
right
to
inspect
the
records.
It
is
equally
important
that
access
to
the
records
is
limited
to
as
few
26
individuals
as
possible
and
that
strict
confidentiality
procedures
be
developed
and
are
strictly
27
adhered
to.
28
29
Since
insect
repellent
studies
should
be
classified
as
research
involving
more
than
30
minimal
risk,
the
subject
should
be
clearly
told
if
the
researcher
will
cover
medical
treatment
if
31
an
injury
occurs
(
this
issue
was
reviewed
by
the
Board
in
more
detail
in
response
to
question
g.)
,
32
including
not
only
treatment
during
the
research
study
but
long­
term
care,
if
needed
(
e.
g.
in
those
33
circumstances
in
which
a
study
subject
contracts
an
insect­
borne
disease).
A
phone
number
34
should
be
provided
to
volunteers
so
that
they
can
obtain
additional
information
about
the
risks
35
and
benefits
of
study
participation,
and
their
rights
as
study
subjects.
36
37
The
subject
should
clearly
be
told
that
the
study
is
voluntary
and
refusal
will
not
result
in
38
any
loss
of
benefits
or
privileges.
For
studies
that
use
only
one
control
group,
it
is
especially
39
important
for
a
subject
assigned
to
the
control
group
to
understand
that
they
can
withdraw
even
if
40
this
withdrawal
might
invalidate
the
study.
It
should
also
be
clear
that
the
subject
does
not
need
41
to
give
a
reason
for
withdrawal
from
the
study.
The
consequences
of
a
subject's
decision
to
42
withdraw
from
the
study
should
be
addressed,
including
how
it
will
affect
any
payment
for
43
participation
in
the
study.
44
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
38
of
67
Students
or
employees
used
as
research
subjects
in
this
study
are
considered
"
vulnerable
1
subjects"
because
they
might
feel
coerced
into
participating
either
by
their
supervisor,
thesis
2
advisor,
or
even
fellow
students/
employees.
It
should
be
clear
that
participation
in
these
types
of
3
studies
is
neither
a
condition
of
employment
nor
an
academic
requirement
for
students.
An
4
explanation
of
whom
to
contact
if
the
subject
feels
coerced
should
be
provided.
This
contact
5
should
not
be
associated
with
the
investigator
and
the
subject
should
be
guaranteed
anonymity.
6
Employees
who
report
directly
to
the
investigators
or
study
sponsors,
and
students
of
the
7
investigator
should
be
excluded
from
the
study.
8
9
The
subjects
should
also
be
told
that
they
will
be
informed
if
any
new
information
is
10
found
during
the
course
of
the
study
that
might
affect
the
subject's
willingness
to
participate.
11
Additionally
the
subject
should
be
told
that
they
will
be
informed
if
it
is
found
that
either
a
test
12
site,
or
a
laboratory
strain
of
insects
used
is
discovered
to
have
a
higher
level
of
disease
than
13
previously
thought.
14
15
The
informed
consent
document
should
be
written
in
a
language
understandable
to
the
16
subjects
and
the
subjects
should
be
informed
about
any
potential
conflicts
of
interests
that
the
17
researchers
have.
18
19
HSRB
Consensus
and
Rationale
20
21
The
consensus
of
the
HSRB
was
that
informed
consent
should
comply
with
all
of
the
22
requirements
of
40
CFR
26.1116
of
the
Agency's
final
human
studies
rule.
To
comply
with
the
23
human
studies
rule,
consent
information
for
pesticides
studies
must
include:
(
a)
detailed
24
information
on
the
procedure
(
e.
g.,
number
of
insect
bites
or
landings
anticipated,
nature
25
apparatus
or
field
context,
length
of
time
of
exposure);
(
b)
a
clear
statement
of
the
risks
involved
26
(
e.
g.,
discomfort
from
bites,
risk
of
vector­
borne
disease,
medical
consequences
of
the
disease,
27
treatments
available
for
the
disease);
(
c)
the
voluntary
nature
of
participation
(
e.
g.,
statements
28
that
eliminate
the
perception
of
coercion
for
students
or
employees;
specific
instructions
on
how
29
to
signal
desire
to
withdraw
from
the
study);
(
d)
the
fact
that
there
was
no
immediate
direct
30
benefit
to
the
subject
in
participating
as
well
as
a
description
of
alternative
available
repellents;
31
and
(
e)
other
steps
outlined
above.
In
addition,
informed
consent
information
should
be
as
32
detailed
for
experienced
subjects
as
for
naïve
subjects.
33
34
Charge
to
the
Board
35
36
i.
Does
the
HSRB
recommend
that
the
draft
guideline
be
revised?
If
so,
please
explain
what
37
aspects
or
sections
might
improve
with
revision.
38
39
Board
Response
to
the
Charge
40
41
The
Board
recommended
that
the
Agency
refer
to
Board
responses
to
previous
questions
42
to
address
revisions
to
the
draft
guideline.
43
44
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
39
of
67
Review
of
HSRB
Protocol
Criteria
1
2
Before
the
Board
reviewed
the
presented
proposed
human
studies
research,
the
Board
3
developed
science
and
ethics
criteria
as
a
guide
for
its
evaluation
of
such
studies.
Reference
to
4
such
criteria
would
be
helpful
for
the
Agency,
study
investigators,
and
other
members
of
the
5
public
to
understand
the
Board's
approach
for
the
review
of
proposed
human
studies.
The
6
relative
emphasis
placed
by
the
Board
on
each
criterion
may
be
applied
case­
by­
case
and
may
7
vary
with
the
nature
of
the
chemical
product,
study
design,
and
participants.
Specific
studies
8
may
also
call
for
additional
criteria.
A
list
of
the
science
and
ethics
criteria
identified
by
the
9
Board
are
provided
below:
10
11
Science
Criteria
12
13
The
criteria
for
the
evaluation
of
the
scientific
quality
of
studies
involving
human
14
subjects
was
based
on
a
series
of
questions
which
the
Board
agreed
needed
to
be
addressed
by
15
the
details
provided
in
the
study
protocol.
16
17
1)
Is
a
valid
scientific
question
addressed
by
the
study?
18
2)
Are
existing
data
adequate
to
answer
the
scientific
question?
19
3)
Are
new
studies
involving
human
subjects
necessary
to
answer
the
question?
20
4)
What
are
the
potential
benefits
of
the
study?
21
5)
What
is
the
likelihood
that
the
benefits
would
be
realized?
22
6)
What
are
the
risks?
Are
they
serious
or
irreversible?
23
7)
Is
the
purpose
of
the
study
clearly
defined?
24
8)
Are
there
specific
objectives/
hypotheses?
25
9)
Can
the
study
as
described
achieve
these
objectives
or
test
these
hypotheses?
26
10)
What
is
the
sample
size
and
how
is
it
derived?
27
11)
What
is
the
basis
for
the
proposed
dose
levels
and
formulations
in
the
study?
28
12)
Is
there
a
plan
allocating
individuals
to
treatment?
29
13)
Can
the
findings
from
this
study
be
generalized
beyond
the
study
sample?
30
14)
Is
there
a
justification
for
the
selection
of
the
target
population?
31
15)
Are
participants
representative
of
the
population
of
concern?
If
not,
why
not?
32
16)
Are
the
inclusion/
exclusion
criteria
appropriate?
33
17)
Is
the
sample
a
vulnerable
group?
34
18)
Will
the
measurements
be
accurate
and
reliable?
35
19)
Are
measurements
appropriate
to
the
question
being
asked?
36
20)
Are
adequate
quality
assurance
procedures
described?
37
21)
Can
the
data
be
statistically
analyzed?
38
22)
Is
the
statistical
method
appropriate
to
answer
the
question?
39
23)
Are
point
estimates
accompanied
by
measures
of
uncertainty?
40
24)
Do
laboratory
conditions
simulate
real­
world
conditions?
41
25)
Are
field
conditions
representative
of
intended
use?
42
26)
Does
the
protocol
include
a
stop
rule
plan,
medical
management
plan,
and
a
safety
monitor?
43
44
Ethics
Criteria
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
40
of
67
The
criteria
for
the
ethical
acceptability
of
environmental
research
protocols
involving
1
human
dosing
and
intentional
exposure
proposed
by
the
Board
are
grounded
in
the
general
2
criteria
for
IRB
approval
found
in
Subpart
K
of
the
Agency's
human
studies
rule
(
40
CFR
3
26.1111
and
1116).
This
approach
is
similar
to
that
taken
by
the
National
Academy
of
Sciences
4
(
2004)
in
formulating
the
criteria
for
scientific
and
ethical
acceptability
(
recommendation
5­
1)
5
and
participant
selection
(
recommendation
5­
2).
6
7
Scientific
Validity
and
Social
Value
8
9
One
of
the
most
important
criteria
for
the
ethical
review
of
protocols
in
fact
is
scientific.
10
The
research
design
must
be
sound
(
i.
e.,
scientifically
valid)
and
the
risks
of
the
research
must
be
11
reasonable
(
or
balanced)
in
relation
to
the
importance
of
the
knowledge
that
may
reasonably
be
12
expected
to
result.
Absent
a
sound
research
design,
the
prospect
of
the
research
generating
13
usable
knowledge
is
severely
diminished.
Although
the
risks
to
research
participants
may
be
14
balanced
against
anticipated
benefits
to
these
same
subjects,
much
environmental
research
(
such
15
as
intentional
exposure
studies)
will
not
offer
any
direct
benefit
to
the
research
subjects
16
themselves
(
See
NAS
recommendation
3­
1.).
17
18
The
justifiable
risks
to
which
research
subjects
justifiably
are
exposed
should
be
directly
19
proportional
(
i.
e.
reasonable
or
balanced)
to
the
importance
of
the
knowledge
expected
to
be
20
gained.
In
other
words,
the
information
to
be
gained
from
the
research
study
must
be
"
worth
21
knowing".
The
NAS
took
this
approach
in
recognizing
that
scientific
accuracy
alone
is
22
insufficient
justification
for
exposing
research
subjects
to
anything
more
than
"
no
identifiable
23
risk."
For
example,
there
must
be
a
"
reasonable
certainty
of
no
harm"
to
research
subjects
if
the
24
only
benefit
of
the
research
is
to
improve
the
scientific
accuracy
of
extrapolating
animal
to
25
human
data
(
NAS
recommendation
4­
1).
As
such,
a
research
protocol
needs
to
describe
the
26
benefits
of
the
knowledge
that
may
be
obtained
so
that
the
reasonableness
of
the
risks
can
be
27
judged
against
the
importance
of
that
knowledge.
In
addition
to
improved
scientific
accuracy
of
28
risk
assessment,
such
benefits
may
include
a
more
stringent
regulatory
standard,
new
public
29
health
measures
that
could
be
adopted,
or
new
products
that
may
protect
public
health.
30
31
Federal
regulations
state
that
an
IRB
should
not
consider
the
possible
effects
of
the
32
research
on
public
policy
when
evaluating
those
research
risks
that
fall
within
the
responsibility
33
of
the
IRB
(
40
CFR
26.1111
(
a)
(
2)).
Nevertheless,
the
public
policy
implications
of
the
34
knowledge
that
may
result
from
the
research
does
affect
the
importance
of
that
information.
35
Further,
the
Human
Studies
Review
Board
is
not
limited
by
Subpart
K
in
evaluating
the
ethical
36
acceptability
of
a
proposed
research
study.
As
such,
scientific
accuracy
alone
may
be
an
37
insufficient
justification
for
the
importance
of
a
research
project.
The
protocol
should
address
38
the
potential
benefit
of
improved
scientific
accuracy,
and
to
whom
this
benefit
would
accrue.
As
39
recognized
by
the
NAS
in
recommendation
4­
2,
studies
that
may
have
a
potential
public
health
40
or
environmental
benefit
could
involve
a
somewhat
higher
level
of
risk
while
not
causing
any
41
lasting
harm
to
research
subjects.
42
43
Minimizing
Research
Risk
44
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
41
of
67
The
research
should
not
expose
any
human
subjects
to
unnecessary
risk
(
40
CFR
26.1111
1
(
a)
(
1)).
This
ethical
principle
has
a
number
of
important
corollaries.
First,
the
use
of
human
2
subjects
must
be
absolutely
necessary
in
order
to
answer
an
important
scientific
question
that
3
could
not
otherwise
be
answered
by
using
animal
models.
In
addition,
any
intentional
dosing
4
studies
can
only
be
justified
if
observational
studies
would
neither
answer
the
question
nor
be
5
feasible.
Admittedly,
the
judgment
of
feasibility
may
be
ethically
difficult
especially
if
the
only
6
consideration
is
time
and
expense.
Second,
the
elimination
of
unnecessary
risk
means
that
there
7
is
no
way
to
answer
the
scientific
question
that
involves
less
risk
if
human
subjects
are
to
be
8
used.
Third,
the
scientific
protocol
should
involve
no
additional
exposure
of
study
participants
to
9
risk
unless
absolutely
necessary.
The
ethical
responsibility
for
"
using
procedures
already
being
10
performed
on
the
subjects"
translates,
in
the
environmental
context,
to
studying
those
situations
11
in
which
human
subjects
are
exposed
to
environmental
toxins
as
part
of
their
usual
activities
12
without
increasing
their
exposure
to
those
same
toxins.
In
addition
to
the
ethical
priority
of
13
animal
over
human
studies,
there
is
an
ethical
priority
for
observational
research
over
intentional
14
dosing
research
involving
environmental
toxins
if
scientifically
appropriate.
Whether
a
study
15
meets
the
scientific
and
ethical
criteria
necessary
to
justify
the
exposure
of
human
subjects
to
16
potential
risk
can
only
be
evaluated
in
the
context
of
a
given
research
protocol
if
the
investigator
17
and/
or
sponsor
specifically
addresses
alternative
means
of
obtaining
the
desired
data.
18
19
Equitable
Selection
of
Subjects
20
21
The
selection
of
subjects
should
be
equitable
(
40
CFR
26.1111
(
a)
(
3)).
In
practical
22
terms,
this
means
that
the
selection
of
subjects
should
reflect
the
scientific
purposes
of
the
23
research
and
not
the
availability
of
a
particular
population.
This
ethical
criterion
may
be
24
especially
problematic
in
the
context
of
environmental
hazards
research.
Often
the
exposure
to
25
environmental
hazards
in
the
workplace
or
at
home
is
greater
for
those
who
are
either
26
socioeconomically
or
educationally
disadvantaged.
As
such,
subject
selection
based
purely
on
27
scientific
design
may
be
insufficient
protection
for
the
research
subjects,
with
additional
28
safeguards.
The
need
for
such
safeguards
must
be
assessed
within
the
specific
context
of
a
29
particular
protocols
based
on
an
in­
depth
knowledge
of
the
community
within
which
the
research
30
will
take
place.
The
ability
to
"
minimize
the
possibility
of
coercion
or
undue
influence"
(
40
CFR
31
26.1116)
may
require
the
involvement
of
representatives
from
the
community
from
whom
the
32
research
subjects
will
be
drawn
and
within
which
the
research
will
take
place.
A
research
33
protocol
also
must
include
specific
measures
for
assuring
the
equitable
selection
of
subjects,
34
including
recruitment
practices,
incentives
(
financial
or
otherwise),
impact
on
employment,
and
35
the
possibility
of
retaliation.
In
addition,
any
incentive
for
participation
(
whether
financial
or
36
otherwise,
such
as
time
off
from
work)
should
not
be
included
in
the
analysis
of
risks
and
37
potential
benefits
of
the
research.
38
39
Informed
Consent
40
41
The
information
that
is
included
in
the
informed
consent
process
and
documentation
42
should
include
all
of
the
information
found
under
the
general
requirements
for
informed
consent
43
in
40
CFR
26.1116.
There
are
a
few
specific
features
of
the
informed
consent
information
that
44
are
worth
highlighting
in
the
context
of
environmental
research.
First,
EPA
regulations
do
not
45
allow
for
a
waiver
of
either
informed
consent
or
the
written
documentation
of
informed
consent.
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
42
of
67
Second,
the
informed
consent
information
must
include
the
identity
of
the
pesticide
and
its
mode
1
of
action
if
the
research
involves
intentional
exposure
of
subjects
to
a
pesticide
(
40
CFR
26.1116
2
(
e)).
Given
the
vulnerability
of
the
research
subjects
that
are
likely
to
be
enrolled
in
3
environmental
research
(
as
discussed
above),
the
default
position
for
any
research
on
4
environmental
toxins
(
whether
observational
or
intentional)
should
be
that
the
risks
of
any
5
potential
pesticide
exposure
be
included
in
the
informed
consent
information.
However,
if
the
6
risks
of
the
toxins
are
not
part
of
the
research,
but
instead
are
part
of
daily
work
life,
this
should
7
be
made
clear.
Third,
the
alternatives
to
research
participation
(
40
CFR
26.1116(
a)(
4))
should
8
include
all
steps
that
might
minimize
the
risk
of
exposure
to
environmental
hazards,
up
to
and
9
including
removing
oneself
from
that
environment.
Fourth,
as
noted
previously,
the
HSRB
10
supports
the
view
that
research
subjects
should
receive
needed
medical
care
for
research
related
11
injuries
at
no
cost
to
themselves
(
consistent
with
NAS
recommendation
5­
5).
As
such,
the
oft­
12
used
informed
consent
template
statement
that
"
no
program
of
compensation
is
available"
would
13
be
unacceptable
in
human
dosing
or
pesticide
exposure
research.
The
HSRB
acknowledges
that
14
the
determination
that
any
given
injury
may
be
research­
related
might
be
difficult
when
the
15
protocol
combines
observational
or
interventional
procedures
with
non­
research
related
exposure
16
to
environmental
toxins.
Nevertheless,
the
principle
of
providing
medical
care
for
research
17
related
injuries
at
no
cost
to
research
subjects
must
be
affirmed.
Fifth,
the
voluntary
nature
of
18
participation
must
be
carefully
and
explicitly
described
during
the
consent
process.
Investigators,
19
study
sponsors
and
pesticide
registrants
are
obligated
to
ensure
that
neither
employment
status
20
nor
economic
need
creates
a
coercive
context
for
study
participation.
Finally,
the
process
and
21
documentation
of
informed
consent
needs
take
into
account
special
circumstances
that
may
arise
22
in
the
context
of
any
given
research
setting,
including
language
barriers,
literacy,
comprehension,
23
employment
status,
and
the
confidentiality
of
screening
tests
such
as
for
pregnancy.
24
25
Subject
Safety
26
27
The
research
protocol
must
also
discuss
provisions
for
assuring
the
safety
of
subjects
28
enrolled
in
the
research,
both
during
and
after
the
research
has
been
completed.
This
obligation
29
goes
beyond
simply
"
monitoring
the
data
collected"
to
include
procedures
for
collecting
real­
30
time
exposure
data
to
the
environmental
toxins
during
the
research,
and
procedures
for
31
intervening
should
the
health
of
research
subjects
be
at
risk
from
the
environmental
toxins
32
(
regardless
of
whether
the
exposure
is
intentional
or
not).
The
protocol
should
describe
in
detail
33
any
procedures
for
reversing
experimentally­
induced
harms.
34
35
IRB
Approval
36
37
The
HSRB
believed
that
the
ethical
analysis
of
a
research
protocol
requires
information
38
concerning
the
potential
risks
to
human
subjects,
measures
proposed
to
minimize
risks,
the
39
nature
and
magnitude
of
all
the
expected
benefits,
and
to
whom
they
may
accrue,
alternative
40
means
of
obtaining
information
comparable
to
what
would
be
collected
for
the
proposed
41
research,
and
the
balance
of
risks
and
benefits
of
the
proposed
research
(
40
CFR
26.1125(
a)).
42
Further,
the
HSRB
believes
that
an
IRB
is
unable
to
make
the
determinations
required
under
40
43
CFR
26.1111
absent
this
information.
As
such,
the
HSRB
expects
this
information
to
be
found
44
in
the
protocol
submitted
to
the
responsible
IRB.
Although
an
IRB
may
be
able
to
gather
this
45
information
from
other
sources,
the
lack
of
this
information
in
the
protocol
and
the
lack
of
a
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
43
of
67
substantive
discussion
of
these
issues
in
the
IRB
minutes
would
raise
doubt
about
the
adequacy
1
of
the
IRB
review.
2
3
Insect
Repellent
Product
Performance
Efficacy
Studies
4
5
Study
EMD­
003
from
Carroll­
Loye
Biological
Research
6
7
Charge
to
the
Board
8
9
a.
Does
the
proposed
research
described
in
study
EMD­
003
appear
likely
to
generate
10
scientifically
reliable
data,
useful
for
assessing
the
efficacy
of
the
repellent?
11
12
Board
Response
to
the
Charge
13
14
The
protocol
submitted
for
review
by
the
HSRB
outlined
studies
to
evaluate
the
efficacy
15
of
IR3535
as
a
tick
repellent
in
human
subjects.
The
protocol
described
a
laboratory
study
in
16
which
the
movement
of
the
Western
black­
legged
tick
(
Ixodes
pacificus)
up
the
forearm
was
to
17
be
determined.
Studies
in
humans
are
required
to
assess
the
efficacy
of
such
repellents
because
18
laboratory
animals
differ
in
their
attractiveness
to
the
pest,
and
therefore
do
not
provide
an
19
accurate
assessment
of
efficacy
in
humans.
A
more
general
protocol
(
CL­
001),
which
provided
20
additional
information
relevant
to
study
conduct,
was
also
submitted
for
review
in
combination
21
with
protocol
EMD­
003.
22
23
Overall,
the
protocol
for
EMD­
003
was
poorly
prepared,
with
numerous
errors
in
24
referring
to
the
nature
of
the
material
to
be
applied
(
as
a
lotion,
aerosol
or
spray)
and
the
25
evaluation
of
repellency
against
mosquitoes
was
indicated
in
the
rationale
provided
for
the
study.
26
Furthermore,
the
protocol
indicated
that
the
dose
to
be
applied
was
1
mg
formulation/
600
cm2,
27
when
in
fact,
the
authors
of
the
protocol
intended
the
applied
dose
to
be
1
gram/
600
cm2.
These
28
mistakes
were
not
considered
to
be
fatal
errors
in
the
protocol,
but
suggested
a
lack
of
attention
29
to
the
details
of
protocol
preparation
and
review
by
the
investigators.
Staffers
from
the
USEPA
30
provided
comments
on
the
numerous
shortcomings
of
the
proposed
study,
and
the
HSRB
fully
31
concurred
with
these
weaknesses.
32
33
IR3535
is
commercially
available,
and
there
is
a
large
amount
of
toxicology
data
34
suggesting
that
it
is
a
compound
of
low
toxic
potential.
Therefore,
human
subjects
are
unlikely
35
to
be
at
risk
of
experiencing
adverse
effects
relative
to
exposure
to
the
proposed
formulations.
36
37
The
HSRB
recognized
three
major
limitations
to
the
protocol
as
submitted
to
the
HSRB
38
for
review.
These
limitations
include:
(
1)
the
lack
of
a
clear
rationale
underlying
the
conduct
of
39
the
study;
(
2)
the
lack
of
identification
and
characterization
of
the
formulations
to
be
tested
and
40
(
3)
the
scientific
design
of
the
study.
Of
these
issues,
which
are
discussed
in
more
detail
below,
41
the
design
of
the
study
was
seen
as
the
most
significant
shortcoming
of
the
proposed
work.
42
43
With
respect
to
the
clear
rationale
for
the
conduct
of
the
study,
the
HSRB
understood
that
44
all
new
formulations
must
be
evaluated
for
efficacy,
and
that
such
studies
must
be
conducted
in
45
human
subjects
to
be
valid.
However,
the
investigators
failed
to
identify
what
was
new
about
the
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
44
of
67
formulations
being
studied
and
failed
to
identify
the
potential
benefit
of
the
formulations.
This
1
shortcoming
was
considered
to
be
minor
and
could
readily
be
addressed
by
providing
such
2
additional
information
in
the
study
protocol.
3
4
With
respect
to
the
formulations
to
be
evaluated,
the
investigators
provided
tables
listing
5
the
percent
of
active
ingredient
along
with
incipients
used
to
formulate
the
spray,
aerosol
and
6
lotion
to
be
used
in
the
study.
However,
there
was
no
additional
information
regarding
when
the
7
formulations
would
be
prepared
relative
to
study
execution,
whether
the
formulations
would
be
8
characterized
analytically
to
confirm
active
ingredient
composition,
and
whether
the
stability
of
9
the
formulations
was
to
be
determined.
This
information
is
critical
to
the
overall
valid
execution
10
of
the
study
and
could
be
remedied
by
providing
such
detail
in
the
protocol.
11
12
The
major
limitation
with
the
scientific
conduct
of
the
study
concerned
the
study
design
13
and
data
collection.
In
particular,
the
protocol
outlined
a
study
using
six
test
subjects
for
each
14
product
formulation,
with
two
additional
subjects
serving
as
a
negative
and
a
positive
control.
15
No
information
was
provided
to
justify
the
group
sizes
used
in
the
research.
Given
the
nature
of
16
these
studies
to
evaluate
tick
repellency,
the
HSRB
considered
that
a
test
in
which
each
subject
17
served
as
his
own
control
(
using
one
arm
for
the
untreated,
negative
control
and
one
arm
for
the
18
test)
was
a
more
appropriate
design
that
would
also
be
more
powerful
statistically
and
more
19
likely
to
generate
reliable
results.
20
21
Additional
questions
were
raised
by
the
HSRB
concerning
how
subjects
would
be
trained
22
to
accurately
and
consistently
collect
information
regarding
the
number
of
ticks
crossing
or
23
repelled
from
the
arm
skin.
The
protocol
defined
that
a
crossing
is
scored
by
the
movement
of
a
24
tick
by
at
least
two
centimeters
toward
the
elbow
starting
from
a
line
at
the
wrist,
and
that
25
subjects
select
a
new
tick
from
a
pool
of
unused,
prescreened
ticks
every
15
minutes.
There
was
26
no
information
made
available
to
the
Board
as
to
how
subjects
were
trained
and
qualified
to
27
establish
that
they
could
collect
accurate
data
on
tick
movement.
The
Board
agreed
that
such
28
information
was
important
for
establishing
good
quality
control
of
the
data
collection
concerning
29
repellency.
30
31
HSRB
Consensus
and
Rationale
32
33
Overall,
the
HSRB
concluded
that
there
were
numerous
technical
deficiencies
in
protocol
34
EMD­
003,
and
the
information
provided
in
the
general
protocol
(
CL­
001)
did
not
make
up
for
35
the
deficiencies
in
the
specific
protocol.
Therefore,
the
Board
concluded
that
the
available
36
protocol
did
not
warrant
moving
forward
with
the
study.
37
38
Charge
to
the
Board
39
b.
Does
the
proposed
research
described
in
Study
EMD­
003
from
Carroll­
Loye
Biological
40
Research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
41
L?
42
43
Board
Response
to
the
Charge
44
45
Background
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
45
of
67
1
The
study
proposed
was
to
evaluate
the
efficacy
of
a
compound
known
as
IR3535
as
a
2
tick
repellent
in
human
subjects.
The
study
is
to
be
conducted
by
Carroll­
Loye
Biological
3
Research,
a
private
research
laboratory
in
Davis,
California
by
using
healthy
volunteers
and
a
4
controlled
laboratory
environment.
Two
protocols
were
submitted
for
review,
a
general
protocol
5
(
CL­
001)
that
provided
considerable
background
information
about
tests
of
insect
repellency
in
6
general,
and
the
protocol
for
analysis
of
the
efficacy
of
IR353
as
a
tick
repellent
evaluated
here.
7
8
For
this
protocol,
the
efficacy
of
IR3535
as
a
tick
repellent
would
be
determined
by
9
placing
Western
black­
legged
ticks
(
Ixodes
pacificus)
on
IR3535­
treated
and
 
untreated
forearms
10
and
measuring
the
speed
and
distance
that
moving
insects
would
penetrate
into
the
treated
area.
11
12
Strengths
and
Limitations
13
14
The
Board
concurred
with
the
factual
observations
of
the
strengths
and
weaknesses
of
the
15
study,
as
detailed
in
the
EPA's
Initial
Ethics
Review
(
USEPA
2006b).
This
study,
it
was
argued,
16
would
provide
critical
data
on
the
efficacy
of
IR3535
as
a
tick
repellent.
IR3535
is
commercially
17
available
and
has
been
used
as
a
repellent
in
Europe
for
years
with
no
evidence
of
toxicity,
so
the
18
subjects
enrolled
in
this
study
were
unlikely
to
be
at
increased
risk
of
experiencing
adverse
side
19
effects
upon
exposure.
The
ticks
used
for
the
study
also
were
bred
and
raised
in
a
laboratory
20
environment
and
are
considered
to
be
pathogen­
free,
minimizing
the
risk
of
vector­
borne
21
diseases.
22
23
The
Board
concluded,
however,
that
given
the
deficiencies
noted
by
the
Agency,
the
24
proposed
research
described
in
Protocol
EMD­
003
did
not
comport
with
the
applicable
25
requirements
of
§
40CFR26,
particularly
subpart
K.
Carroll­
Loye
Biological
Research
and
the
26
IRB
of
record
also
failed
to
obtain
or
to
provide
all
of
the
documents
necessary
to
be
in
27
compliance
with
the
requirements
of
§
40CFR26,
subpart
M.
The
IRB,
for
example,
refused
to
28
release
copies
of
the
minutes
documenting
the
discussion
of
EMD­
003
protocol,
preventing
the
29
Board
from
evaluating
whether
or
not
they
considered
fully
the
issues
listed
under
the
EPA's
30
Final
Human
Studies
Rule
as
part
of
their
review.
Furthermore,
the
protocol
and
supplementary
31
documents
submitted
to
the
Board
were
poorly
written
which,
while
not
a
fatal
flaw
in
and
of
32
itself,
should
have
precluded
IRB
and
HSRB
review
and
approval.
33
34
The
HSRB
recognized
several
significant
limitations
to
the
protocol,
as
submitted
to
the
35
Board
for
review.
There
was,
for
example,
lack
of
a
clear
rationale
justifying
the
conduct
of
the
36
study
as
designed.
The
Board's
concerns
about
this
are
discussed
in
detail
with
respect
to
the
37
companion
protocol
submitted
by
Carroll­
Loye,
EMD­
004,
but
it
was
felt
that
absent
any
clear
38
scientific
rationale
for
conducting
such
a
study,
exposure
of
human
subjects
to
the
risks
inherent
39
in
this
protocol
would
be
unnecessary
and
unjustifiable.
40
41
Additional
limitations
of
the
study
protocol
provided
to
the
Board
can
be
grouped
into
42
two
broad
categories:
(
1)
concerns
about
equitable
study
subject
selection
and
recruitment;
and
43
(
2)
questions
about
whether
or
not
the
documentation
and
process
of
study
subject
enrollment
44
was
sufficient
to
meet
prevailing
standards
of
voluntary
informed
consent.
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
46
of
67
Subject
Recruitment
1
2
The
Board
expressed
concern
about
the
potentially
coercive
nature
of
study
subject
3
recruitment.
Although
the
study
is
to
be
conducted
by
Carroll­
Loye
Biological
Research,
a
4
private
research
laboratory
in
Davis,
California,
the
Principal
Investigator
of
the
study
and
Co­
5
Owner
of
the
research
laboratory,
Dr.
Scott
P.
Carroll,
also
is
an
adjunct
faculty
member
of
the
6
Department
of
Entomology
at
the
University
of
California,
Davis.
As
the
majority
of
research
7
participants
will
be
recruited
from
the
University's
student
population,
including
from
Dr.
8
Carroll's
own
department,
the
protocol
and
consent
documents
need
to
be
altered
to
define
9
clearly
the
mechanisms
in
place
to
prevent
any
coercive
enrollment,
as
well
as
the
additional
10
concerns
listed
below.
11
12
Voluntary
Informed
Consent
13
14
The
Board
believed
that
the
protocol
and
consent
documents,
as
provided,
lacked
15
sufficient
information
to
ensure
that
all
study
participants
were
adequately
informed
about
the
16
risks,
benefits
and
alternatives
to
participation
in
the
study.
It
was
unclear,
for
instance,
that
17
participation
in
the
study
would
have
no
direct
benefit
for
volunteers
or
that
the
study
was
being
18
conducted
solely
for
marketing
research.
The
major
risks
of
participation
in
the
study
also
19
needed
to
be
more
clearly
identified
in
the
informed
consent
form
and
in
supplementary
20
documents
provided
to
study
subjects.
For
example,
one
additional
risk
that
the
study
21
investigators
may
have
failed
to
consider
arises
from
the
plan
to
pre­
screen
female
volunteers
in
22
order
to
exclude
any
subjects
who
may
be
pregnant.
In
accordance
with
the
newly
promulgated
23
provisions
in
the
EPA's
final
human
studies
rule
(
§
40CFR26.1701
­
26.1704),
minors
and
24
pregnant
women
are
explicitly
excluded
from
participation,
the
latter
being
confirmed
by
25
requiring
all
female
volunteers
to
undergo
a
self­
administered
over­
the­
counter
pregnancy
test
on
26
the
day
of
the
study.
Because
many
of
the
volunteers
are
undergraduate
or
graduate
students
at
a
27
nearby
college,
the
unexpected
revelation
that
a
subject
may
be
pregnant
could
have
a
profound
28
psychological
or
social
impact;
Dr.
Carroll
also
may
have
a
professional
relationship
with
these
29
students
through
his
affiliation
with
the
University.
These
risks
should
be
specifically
addressed,
30
and
the
Board
recommended
that
a
separate
consent
document
for
female
volunteers
be
prepared
31
that
addresses
these
risks
as
well
as
the
safeguards
established
by
study
investigators
to
ensure
32
that
the
results
of
over­
the­
counter
pregnancy
tests
would
be
kept
private.
33
34
Study
investigators
also
may
wish
to
provide
either
a
more
detailed
explanation
of
the
35
study
protocol
 
including
a
detailed
method
for
manipulating
the
ticks
used
in
the
experiment
36
and
a
clear
description
of
the
study's
duration.
37
38
Finally,
it
was
felt
that
the
informed
consent
documents
should
be
re­
written
to:
(
a)
39
comport
with
the
reading
and
comprehension
level
of
the
likely
subject
population;
and
(
b)
40
clarify
the
section
on
compensation
for
research
related
injury.
41
42
HSRB
Consensus
and
Rationale
43
44
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
47
of
67
The
Board
concurred
with
the
initial
assessment
of
the
Agency
that
the
study
submitted
1
for
review
by
the
Board
failed
to
meet
the
ethical
requirements
established
in
the
Agency's
final
2
human
studies
rule
(
§
40CFR26).
3
4
The
Board
determined
the
proposed
research
described
in
this
study
did
not
comport
with
5
the
applicable
requirements
of
§
40CFR26,
subparts
K
and
L.
The
study
documents
submitted
for
6
review
also
failed
to
comply
with
the
requirements
of
§
40CFR26,
subpart
M.
However,
the
7
deficiencies
noted,
while
significant,
were
not
irreparable.
8
9
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
10
11
Charge
to
the
Board
12
13
a.
Did
the
proposed
research
described
in
Study
EMD­
004
from
Carroll­
Loye
Biological
14
Research
appear
likely
to
generate
scientifically
reliable
data,
useful
for
assessing
the
efficacy
of
15
a
test
substance
for
repellent
ticks?
16
17
Board
Response
to
the
Charge
18
19
Introduction
20
21
The
Board
began
its
review
noting
that
this
protocol
addresses
repelling
insects,
not
ticks.
22
The
Board
concluded
that
the
proposed
research
should
generate
scientifically
useful
data
for
23
assessing
efficacy.
Protocol
EMD­
004
describes
a
test
of
the
efficacy
of
3­[
N­
butyl­
N­
acetyl]­
24
aminopropionic
acid,
ethyl
ester
(
IR3535)
to
repel
mosquitoes
in
field
experiments.
It
describes
25
the
formulation
and
dose
of
the
repellent
and
the
number
of
replications
(
6­
10
for
each
26
formulation).
The
components
of
the
three
formulations
were
provided
by
the
Agency.
There
27
would
be
one
to
two
untreated
controls
and
one
to
two
positive
(
DEET­
treated)
controls.
Two
28
locations
would
be
used,
in
or
adjacent
to
the
Central
Valley
in
California
and
the
Florida
Keys.
29
The
experiment
would
be
double­
blinded.
The
compound
has
a
very
low
toxicity
profile
in
30
animal
tests
and
has
been
used
in
Europe
for
over
20
years
as
a
repellent
for
many
years
without
31
reports
of
adverse
effects
in
humans.
32
33
General
Scientific
Criteria
34
35
 
The
scientific
question
was
stated
(
i.
e.,
to
test
the
efficacy
of
IR3535
in
repelling
36
mosquitoes).
37
 
It
was
not
clear
whether
existing
data
were
adequate
to
answer
the
question.
38
 
It
was
not
clear
whether
new
studies
involving
human
subjects
were
necessary;
however,
39
if
the
repellency
had
never
been
tested
with
North
American
mosquitoes,
the
tests
may
be
40
necessary.
41
 
The
potential
benefits
of
the
study
were
clear,
i.
e.,
that
an
effective
repellent
would
be
42
available
that
would
have
either
greater
efficacy
and/
or
fewer
drawbacks
than
what
was
43
currently
approved.
44
 
It
was
likely
that
the
benefits
would
be
realized
(
i.
e.,
efficacy
as
a
repellent)
because
there
45
was
a
long
positive
history
on
this
compound
from
its
European
use.
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
48
of
67
 
The
risks
were
not
specifically
noted.
1
 
The
most
likely
relevant
risk
would
be
disease
transmitted
by
the
mosquitoes,
if
the
2
mosquitoes
carried
pathogens,
and
some
mosquito­
borne
diseases
(
e.
g.,
West
Nile
virus­
3
mediated
disease)
were
serious.
The
protocol
did
not
indicate
the
likelihood
of
the
4
mosquitoes
in
the
two
test
areas
to
be
carriers
of
disease
organisms
that
could
be
5
transmitted
to
humans.
However,
using
the
fewest
number
of
untreated
controls
would
6
provide
the
least
risk
of
disease
to
the
participants.
The
protocol
did
not
indicate
whether
7
all
the
inert
ingredients
in
the
formulations
are
GRAS
compounds
or
have
documented
8
lack
of
toxicity
at
the
exposure
levels
anticipated.
9
10
Study
Design
Criteria
11
 
The
purpose
of
the
study
was
clearly
defined
(
i.
e.,
efficacy
testing).
12
 
There
were
specific
objectives/
hypotheses
(
i.
e.,
that
IR3535
is
an
effective
repellent).
13
 
The
study
as
described
can
test
this
hypothesis.
14
 
The
sample
size
and
how
it
was
derived
was
not
clear,
but
seems
to
have
been
taken
from
15
the
guidelines.
The
number
of
subjects
listed
in
section
9.1.3
of
the
protocol
listed
16
potentially
more
subjects
than
in
the
table
in
section
8.3.2.
It
was
not
clear
if
the
stated
17
number
of
subjects
would
be
repeated
in
both
locations.
The
basis
for
the
dose
levels
and
18
formulations
were
not
provided.
There
were
no
controls
with
just
the
formulation
matrix
19
without
the
repellent.
20
 
There
was
a
plan
allocating
individuals
to
treatments.
21
 
The
findings
from
this
study
can
probably
be
generalized
beyond
the
study
sample.
22
23
Participation
Criteria
24
 
There
was
partial
justification
for
the
selection
of
the
target
population.
25
 
The
participants
were
representative
of
the
population
of
concern.
26
 
The
inclusion/
exclusion
criteria
were
appropriate.
27
 
The
sample
was
not
a
vulnerable
group.
28
29
Measurement
Criteria
30
 
The
measurements
were
expected
to
be
accurate
and
reliable.
31
 
The
measurements
were
appropriate
to
the
question
being
asked.
32
 
Quality
assurances
issues
did
not
appear
to
be
addressed.
33
34
Statistical
Analysis
Criteria
35
 
The
data
should
be
able
to
be
analyzed
statistically
if
the
efficacy
with
time
was
the
36
subject
of
the
analysis
and
the
comparisons
are
made
across
time.
However,
if
there
is
37
only
one
untreated
control
(
which
would
be
more
protective
against
possible
disease
38
transmission),
then
there
would
be
difficulties
with
statistical
analysis
with
comparisons
39
to
the
untreated
control.
40
 
The
statistical
method
seems
to
be
appropriate.
41
 
Measures
of
uncertainty
were
not
addressed.
42
43
Laboratory
and
Field
Conditions
44
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
49
of
67
 
No
laboratory
experiments
were
proposed
in
this
protocol,
probably
because
of
the
data
1
already
available
due
to
the
compound's
long
previous
use.
2
 
The
field
conditions
were
representative
of
the
intended
use.
3
 
The
protocol
did
not
include
a
stop
rule
plan,
medical
management
plan,
and
a
safety
4
monitor.
5
6
HSRB
Consensus
and
Rationale
7
8
It
was
not
clear
whether
new
studies
involving
human
subjects
were
necessary.
If
the
9
repellency
had
never
been
tested
with
North
American
mosquitoes,
however,
the
tests
were
10
probably
necessary.
The
potential
benefits
of
the
study
were
clear,
i.
e.,
that
an
effective
repellent
11
would
be
available
that
would
have
either
greater
efficacy
and/
or
fewer
drawbacks
than
what
12
was
currently
approved.
However,
empirical
evidence
or
procedures
to
determine
risks
to
13
subjects
(
e.
g.,
risks
of
contracting
a
vector­
borne
disease)
were
not
adequate.
It
was
not
clear
if
14
the
stated
number
of
subjects
would
be
repeated
in
both
testing
locations.
The
basis
for
the
dose
15
levels
and
formulations
were
not
provided.
There
were
no
controls
with
just
the
formulation
16
matrix
without
the
repellent.
Therefore,
the
Board
concluded
that
some
of
the
more
critical
17
deficiencies
in
information
identified
above
would
have
to
be
adequately
addressed
before
this
18
protocol
could
receive
a
positive
recommendation.
19
20
Charge
to
the
Board
21
22
b.
Did
the
proposed
research
described
in
Study
EMD­
004
from
Carroll­
Loye
Biological
23
Research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
24
L?
25
26
Brief
Overview
of
the
Study
27
28
The
proposed
study
would
evaluate
the
efficacy
of
three
different
skin
applied
29
formulations
of
an
already
registered
and
marketed
(
in
Europe)
insect
repellent
IR3535.
There
30
would
be
two
study
sites,
one
located
in
central
California
and
the
other
located
in
the
Florida
31
Keys.
The
test
compounds
would
be
administered
to
a
standardized
skin
surface
area,
with
a
32
comparison
to
one
positive
control
and
one
negative
control.
The
subjects
allocated
to
the
33
intervention
groups
would
be
blinded
to
the
treatment.
The
chosen
outcome
measures
are
34
"
percent
reduction
in
the
rate
of
alightments"
and
"
complete
protection
time."
The
protocol
35
stated
that
there
would
be
6
to
10
subjects
per
treatment
group,
with
one
subject
per
control
36
group.
However
there
was
no
discussion
of
sample
size
justification.
As
discussed
below,
the
37
protocol
lacked
any
discussion
of
risks.
38
39
Ethics
and
Regulatory
Compliance
40
41
Subpart
K
of
the
Agency's
final
human
studies
rule
requires
that
the
investigator
submit
42
to
the
EPA
all
information
that
pertains
to
the
IRB
review
of
proposed
research
(
40
CFR
43
26.1115a)
as
well
as
additional
information
specified
in
40
CFR
26.1125,
if
not
already
included
44
in
the
IRB
documentation.
The
information
requested
under
40
CFR
26.1125
includes
a
45
discussion
of
the
potential
risks
to
human
subjects,
the
measures
proposed
to
minimize
these
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
50
of
67
risks,
expected
benefits
if
any
and
to
whom,
alternative
means
to
obtain
comparable
information,
1
and
the
balance
of
risk
and
benefits
of
the
research.
In
addition,
subject
information
sheets
and
2
approved
written
informed
consent
agreements
should
be
provided,
along
with
any
information
3
about
recruitment
and
the
presentation
of
this
subject
information.
Finally,
the
investigator
4
should
provide
copies
of
all
correspondence
with
the
IRB,
including
official
notification
of
IRB
5
review
and
approval.
6
7
In
the
case
of
this
protocol,
the
principal
investigator
made
a
request
to
the
reviewing
8
IRB
(
Independent
Investigational
Review
Board
Inc.
located
in
Plantation,
Florida)
for
the
9
documents
required
under
40
CFR
26.1125.
The
response
from
the
IRB,
dated
May
12,
2006,
10
did
not
include
the
minutes
of
IRB
meetings
at
which
the
protocol
was
discussed.
As
a
result,
11
the
Board
was
unable
to
assess
whether
the
IRB
discussed
or
was
even
aware
of
the
controversial
12
issues
raised
by
this
protocol.
The
IRB
did
provide
templates
of
two
different
forms,
the
EPA
13
Protocol
Checklist
and
Research
Evaluation
Form.
Although
these
forms
were
fairly
14
comprehensive,
the
Board
was
not
provided
with
copies
of
the
forms
used
for
the
specific
15
protocol
review
and
thus
cannot
assess
whether
or
not
the
forms
were
used
or
the
content
of
the
16
IRB
analysis
and
discussion.
The
membership
roster
of
the
IRB
was
included.
Although
the
17
membership
was
diverse
and
meets
the
regulatory
requirements,
there
was
no
scientific
member
18
that
appears
to
have
sufficient
expertise
in
the
scientific
issues
involved
in
field
testing
of
insect
19
repellents
to
assure
that
the
IRB
was
qualified
to
make
an
adequate
assessment
of
this
protocol.
20
The
scientific
and
ethical
assessment
may
have
been
adequate,
but
the
lack
of
IRB
minutes
made
21
this
determination
impossible.
In
effect,
the
IRB
response
was
to
provide
procedural
22
documentation
of
the
IRB's
compliance
with
40
CFR
26.1115
but
to
withhold
any
substantive
23
documentation
that
this
procedural
compliance
resulted
in
an
adequate
ethical
and
scientific
24
review
of
the
submitted
protocol.
As
such,
the
proposed
research
failed
to
meet
the
requirements
25
of
40
CFR
part
26,
subpart
K.
26
27
The
investigator,
to
his
credit,
remedied
some
of
these
deficiencies
in
a
supplementary
28
document
submitted
to
the
EPA
as
part
of
the
Board's
review.
This
undated
document
was
29
presumably
written
after
the
IRB
review.
In
this
document,
the
investigator
addressed
the
30
potential
risks
to
human
subjects,
the
measures
proposed
to
minimize
these
risks,
the
nature
and
31
magnitude
of
all
expected
benefits
of
the
proposed
research
and
to
whom
they
would
accrue,
the
32
balance
of
risks
and
benefits
of
the
proposed
research,
and
alternative
means
of
obtaining
33
information
comparable
to
what
would
be
collected
through
the
proposed
research.
34
35
Several
observations
are
in
order.
First,
none
of
this
material,
including
the
discussion
of
36
risks
and
benefits
can
be
found
in
the
protocol
submitted
to
the
IRB.
The
absence
of
this
37
information
in
the
protocol
further
compounds
the
uncertainty
created
by
the
absence
of
minutes
38
showing
how
the
IRB
made
the
determinations
required
under
40
CFR
26.1111.
The
39
information
about
the
potential
risks
to
human
subjects,
the
measures
proposed
to
minimize
these
40
risks,
the
nature
and
magnitude
of
all
expected
benefits
of
the
proposed
research
and
to
whom
41
they
would
accrue,
and
the
balance
of
risks
and
benefits
of
the
proposed
research
should
be
part
42
of
the
research
protocol
submitted
for
initial
IRB
review.
Otherwise,
the
IRB
lacked
sufficient
43
information
to
make
an
appropriate
assessment
of
the
proposed
research.
This
was
not
to
say
44
that
the
protocol
would
fail
to
meet
the
criteria
for
IRB
approval,
only
that
there
was
no
evidence
45
that
the
IRB
had
sufficient
information
or
expertise
to
make
these
determinations.
Second,
the
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
51
of
67
protocol
did
minimize
the
risk
of
vector­
borne
diseases
by
limiting
the
untreated
control
group
to
1
a
single
subject
who
was
experienced
in
field
biology
or
entomology.
The
risk
was
minimized
2
further
by
using
an
outcome
measure
that
does
not
require
biting,
but
rather
preparatory
activities
3
on
the
part
of
the
mosquito
after
lighting
on
the
subject
followed
by
aspiration
and
removal
of
4
the
mosquito.
However,
this
approach
raised
concerns
about
the
scientific
adequacy
of
the
5
protocol
design.
Third,
the
investigator
addressed
the
question
of
alternative
means
of
obtaining
6
information
by
arguing
that
the
protocol
was
designed
in
compliance
with
previous
EPA
7
guidelines
for
registration
of
these
products.
The
Board
did
not
take
a
position
on
whether
the
8
protocol
was
indeed
in
compliance
with
these
previous
guidelines.
However,
there
was
9
sufficient
discussion
by
the
Board
of
the
new
draft
EPA
guidance
on
"
Insect
Repellent
Product
10
Performance
Testing"
to
cast
doubt
on
the
scientific
adequacy
and
necessity
of
the
approach
11
taken
in
this
protocol.
12
13
Finally,
the
Board
agreed
with
the
ethical
deficiencies
noted
by
the
EPA
(
USEPA
2006c)
14
With
the
exception
of
amending
the
protocol
to
include
the
applicability
of
additional
standards
15
of
ethical
conduct
and
the
process
of
informing
appropriate
regulatory
authorities
of
any
16
amendments
or
deviations
from
the
approved
protocol,
all
of
these
deficiencies
related
to
the
17
informed
consent
discussion
and
document.
These
included
a
more
accurate
discussion
of
18
subject
assignment,
a
more
extensive
discussion
of
the
risks
(
with
specific
information
about
the
19
risk
of
vector
borne
diseases),
the
correction
of
an
important
typographical
error
in
the
20
pregnancy
section,
a
clarification
of
the
section
on
compensation
for
research
related
injury,
a
21
clarification
of
the
lack
of
direct
benefit
to
research
subjects
and
additional
information
under
the
22
heading
of
confidentiality.
The
Board
also
discussed
the
topic
of
pregnancy
testing
and
whether
23
there
should
be
a
separate
consent
for
such
testing.
As
many
of
the
research
subjects
may
be
in
a
24
professional
relationship
to
the
principal
investigator
(
such
as
graduate
students
or
colleagues),
a
25
protocol
and
consent
document
needs
to
discuss
how
the
confidentiality
of
such
pregnancy
26
testing
would
be
protected.
27
28
HSRB
Consensus
and
Rationale
29
30
The
Board
thus
concluded
that
the
proposed
research
described
in
Study
EMD­
004
from
31
Carroll­
Loye
Biological
Research
did
not
comport
with
the
applicable
requirements
of
40
CFR
32
part
26,
subpart
K.
The
proposed
research
does
comport
with
subpart
L,
as
pregnant
women
and
33
children
were
excluded.
Although
the
ethical
concerns
identified
by
the
Board
could
be
34
remedied,
there
were
sufficient
questions
raised
about
the
adequacy
of
the
research
design
to
cast
35
doubt
on
whether
the
proposed
research
would
meet
the
criteria
for
IRB
approval
found
under
40
36
CFR
26.1111(
a)
(
1).
In
other
words,
absent
a
sound
research
design,
any
exposure
of
human
37
subjects
to
risk
would
be
unnecessary
and
unjustifiable.
38
39
Board
Response
to
the
Charge
40
41
Occupational
Handler
Exposure
Monitoring
Studies
42
43
Charge
to
the
Board
44
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
52
of
67
The
Agricultural
Handlers
Exposure
Task
Force
(
AHETF)
had
submitted
protocols
for
1
five
pesticide
exposure
studies
that
are
part
of
a
larger
research
program
the
AHETF
is
2
conducting.
The
premise
of
the
AHETF
research
program
is
that
data
can
be
used
generically
by
3
various
stakeholders
(
e.
g.,
applicants,
registrants,
EPA,
and
others)
for
calculating
exposures
for
4
the
occupational
handlers
of
pesticides.
The
scope
of
the
AHETF
research
program
was
very
5
broad
in
that
it
intends
to
address
exposures
related
to
many
job
functions
in
agriculture
and
also
6
to
assess
generally
the
impacts
of
various
parameters
on
exposure
(
e.
g.,
How
do
changes
in
the
7
pounds
of
pesticide
handled
or
acres
treated
affect
exposure
levels?).
The
protocols
submitted
8
for
HSRB
review
described
studies
to
measure
exposures
for
five
specific
scenarios.
9
10
The
Agency
believed
these
studies
had
the
potential
to
improve
EPA's
ability
to
assess
11
the
risks
of
using
pesticides
because
the
data
would
reflect
current
agricultural
practices,
12
equipment
and
techniques
and
would
allow
for
more
refined
exposure
estimates.
Further,
the
13
monitoring
techniques
to
be
used
for
these
studies
have
been
standardized
for
use
across
the
14
AHETF
research
program.
These
more
refined
and
reliable
data
would
allow
the
Agency
to
15
estimate
better
how
worker
exposure
levels
are
affected
by
changes
in
various
factors
such
as
the
16
amount
of
active
ingredient
handled,
type
of
application
equipment
used,
application
rate
used,
17
volumes
handled,
and
personal
protective
equipment
used.
18
19
It
should
be
noted,
however,
that
the
use
of
the
data
generated
in
this
study
by
the
EPA
20
and
other
stakeholders
would
depend
upon
the
nature
of
the
results.
For
example,
the
adequacy
21
of
the
field
or
laboratory
quality
control
data
may
dictate
that
correction
factors
are
applied
to
22
adjust
monitored
exposure
levels
to
account
for
losses
from
field
samplers
or
low
performing
23
analytical
methods.
24
25
1.
AHETF
Closed
System
Mixing/
Loading
of
Liquids
Protocol
(
AHE34)
26
27
a.
Does
the
proposed
research
described
in
Study
No.
AHE34
from
the
Agricultural
Handlers
28
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
would
be
29
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
30
by
people
when
mixing,
loading
or
applying
a
liquid
pesticide
with
closed
systems?
[
Note:
In
a
31
few
cases,
corresponding
application
events
are
also
to
be
monitored;
the
same
question
applies
32
to
those
elements
of
the
study.]
33
34
b.
Does
the
proposed
research
described
in
Study
No.
AHE34
from
the
Agricultural
Handlers
35
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
36
subparts
K
and
L?
37
38
2.
AHETF
Airblast
Application
to
Trellis
Crops
in
the
West
Protocol
(
AHE36)
39
40
a.
Does
the
proposed
research
described
in
Study
No.
AHE36
from
the
Agricultural
Handlers
41
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
would
be
42
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
43
by
people
when
making
an
airblast
application
of
a
pesticide
to
a
trellis
crop
under
conditions
44
found
in
the
western
United
States?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
45
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
53
of
67
1
b.
Does
the
proposed
research
described
in
Study
No.
AHE36
from
the
Agricultural
Handlers
2
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
3
subparts
K
and
L?
4
5
3.
AHETF
Airblast
Application
to
Trellis
Crops
in
the
East
Protocol
(
AHE37)
6
7
a.
Does
the
proposed
research
described
in
Study
No.
AHE37
from
the
Agricultural
Handlers
8
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
would
be
9
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
10
by
people
when
making
an
airblast
application
of
a
pesticide
to
a
trellis
crop
under
conditions
11
found
in
the
eastern
United
States?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
12
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]
13
14
b.
Does
the
proposed
research
described
in
Study
No.
AHE37
from
the
Agricultural
Handlers
15
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
16
subparts
K
and
L?
17
18
4.
AHETF
Closed
Cab
Airblast
Application
to
Orchards
Protocol
(
AHE38)
19
20
a.
Does
the
proposed
research
described
in
Study
No.
AHE38
from
the
Agricultural
Handlers
21
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
would
be
22
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
23
by
people
when
making
an
airblast
application
of
a
pesticide
to
orchard
crops?
[
Note:
In
a
few
24
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
25
to
those
elements
of
the
study.]
26
27
b.
Does
the
proposed
research
described
in
Study
No.
AHE38
from
the
Agricultural
Handlers
28
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
29
subparts
K
and
L?
30
31
5.
AHETF
Fixed­
Wing
Aerial
Application
Protocol
(
AHE42)
32
33
a.
Does
the
proposed
research
described
in
Study
No.
AHE42
from
the
Agricultural
Handlers
34
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
would
be
35
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
36
by
people
making
an
aerial
application
of
a
pesticide
from
fixed­
wing
aircraft?
[
Note:
In
a
few
37
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
38
to
those
elements
of
the
study.]
39
40
b.
Does
the
proposed
research
described
in
Study
No.
AHE42
from
the
Agricultural
Handlers
41
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
42
subparts
K
and
L?
43
44
Board
Response
to
the
Charge
45
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
54
of
67
For
the
Board's
review
of
the
agricultural
handler
protocols,
the
Board
decided
to
focus
1
its
analysis
addressing
the
common
strengths,
limitations
and
overall
conclusion
of
the
five
2
protocols.
3
4
5
Scientific
Considerations
6
7
Study
Overview
8
9
The
pesticide
handler
exposure
study
protocols
submitted
to
the
HSRB
were
part
of
a
10
larger
project
that
was
initiated
in
December
2001
by
the
Agricultural
Handler
Exposure
Task
11
Force
(
AHETF).
The
project
will
produce
a
generic
agricultural
handler
exposure
database
12
(
AHED
 
)
.
EPA
and
other
regulatory
agencies
would
use
this
database
to
calculate
pesticide
13
handler
exposures
across
a
wide
range
of
work
conditions.
All
of
the
protocols
follow
a
similar
14
pattern.
They
involve
personal
measurements
of
inhalation
and
dermal
exposure
among
a
group
15
of
workers
who
conduct
what
is
referred
to
as
a
"
scenario";
that
is,
the
study
participant
would
16
conduct
a
specified
job
task
with
specified
equipment,
handling
a
particular
product
formulation
17
that
contains
one
of
six
pesticides.
18
19
These
studies
can
be
referred
to
as
scripted,
so
as
to
distinguish
them
from
purely
20
observational
studies.
Workers
are
asked
to
conduct
their
work
activities
under
a
set
of
scripted
21
conditions
similar,
but
maybe
not
identical,
to
those
they
experience
in
their
normal
work
22
activities.
The
overall
plan
for
the
exposure
database
had
been
discussed
with
regulators
from
23
EPA,
California
EPA,
and
Health
Canada
on
a
regular
basis.
The
presentation
of
these
protocols
24
to
the
HSRB
is
the
first
independent
scientific
review
of
the
task
force
project.
25
26
The
task
force
had
proposed
33
handler
exposure
scenarios,
distinguished
by
equipment
27
type,
work
task,
and
pesticide
formulation.
The
task
force
has
already
conducted
or
initiated
14
28
exposure
studies,
and
has
sponsored
four
studies.
In
addition
to
the
five
protocols
presented
to
29
the
HSRB,
the
task
force
planned
to
conduct
approximately
40
additional
studies
over
the
next
30
several
years.
31
32
Each
of
the
protocols
focuses
on
one
primary
exposure
scenario,
but
all
of
the
protocols
33
include
more
than
one
scenario.
The
five
protocols
reviewed
by
the
HSRB
are
summarized
in
34
Table
1.
35
36
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
55
of
67
Table
1.
Exposure
Scenarios
Included
In
The
Five
AHETF
Protocols
(
N
=
anticipated
number
of
1
independent
observations
for
a
particular
scenario)
2
3
AHE34
AHE
36
AHE37
AHE38
AHE42
Scenario
1
Closed
system
mixload
of
a
liquid
Open
cab
trellis
crop
airblast
application
Open
cab
trellis
crop
airblast
application
Closed
cab
orchard
crop
airblast
application
Closed
cockpit
fixed­
wing
aircraft
application
N
10
5
5
8
7
Scenario
2
Open
or
closed
cab
airblast
application
Closed
cab
trellis
crop
airblast
application
Closed
cab
trellis
crop
airblast
application
Open
pour
mix­
load
of
a
liquid
Open
pour
mix­
load
of
a
liquid
N
0­
3
4
4
not
specified
0­
3
Scenario
3
Closed
cockpit
fixed­
wing
aircraft
application
Open
pour
mix­
load
of
a
liquid
Open
pour
mix­
load
of
a
wettable
powder
Closed
system
mix­
load
of
a
liquid
N
0­
3
0­
4
4
0­
3
Scenario
4
Closed
cockpit
rotary­
wing
aircraft
application
Closed
system
mixload
of
a
liquid
N
0­
3
0­
4
Total
N
13
13
13
not
specified
10
Chemical
Malathion
8
(
80%
a.
i.)
Malathion
8
(
80%
a.
i.)
Diazinon
50%
WP
Carbaryl
4lb
a.
i./
gal
Chlorothalonil
6lb
a.
i./
gal
Location
CA
West
(
CA)
East
(
NY)
FL
and
GA
Pacific
NW
4
The
task
force
studies
are
using
six
different
pesticides:
three
organophosphorus
5
insecticides
(
acephate,
diazinon,
malathion),
one
carbamate
insecticide
(
carbaryl),
one
6
organochlorine
fungicide
(
chlorothalonil),
and
one
triazine
herbicide
(
simazine).
A
description
of
7
the
selection
criteria
for
these
compounds
was
provided
as
a
part
of
the
task
force
documentation
8
package.
These
selection
criteria
did
not
include
the
toxicity
of
the
compounds,
and
toxicity
was
9
not
discussed
in
the
Agency
reviews
of
the
protocols.
However,
oral
comments
from
task
force
10
representatives
at
the
June
HSRB
meeting
indicated
that
the
formulations
of
these
pesticides
11
have
been
selected
such
that
all
fall
into
EPA
toxicity
categories
III
or
IV;
i.
e.,
relatively
low
12
toxicity
formulations.
It
was
also
stated
that
all
workers
in
these
studies
wear
long­
sleeve
shirts,
13
long­
legged
pants,
as
well
as
socks
and
shoes.
Protective
equipment,
such
as
chemical­
resistant
14
gloves
and
eye
protection,
are
provided
to
the
workers
if
required
by
the
pesticide
label.
15
16
The
database
to
be
developed
from
the
task
force
studies
is
intended
to
supersede
an
17
existing
database
 
the
Pesticide
Handler
Exposure
Database
(
PHED).
This
database
was
18
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
56
of
67
developed
in
the
late
1980'
s
and
early
1990'
s
through
the
compilation
of
existing
data.
These
1
data
were
drawn
from
both
registrant­
sponsored
studies
and
studies
published
in
the
scientific
2
literature.
The
studies
included
in
PHED
used
a
different
method
for
measuring
dermal
exposure.
3
This
method,
known
as
the
"
patch
technique"
(
deposition
coupons
distributed
over
body
regions
4
attached
to
the
outer
layer
of
clothing),
has
served
as
the
standard
method
for
such
studies
since
5
the
1960'
s.
When
coupled
with
a
hand
rinse
technique,
it
provides
an
estimate
of
exposure
to
all
6
body
surfaces.
7
8
The
documents
submitted
by
the
AHETF
in
support
of
the
proposed
exposure
studies
9
consisted
of
the
following:
10
11
 
Cover
letter
dated
May
24,
2006
12
 
Analytical
method
validation
reports
for
5
of
the
6
pesticides
(
missing
simazine)
13
 
List
of
33
exposure
scenarios
14
 
Description
of
selection
requirements
for
surrogate
compounds
15
 
32
standard
operating
procedure
(
SOP)
documents
16
 
A
generic
field
exposure
monitoring
protocol
17
 
5
exposure
study
protocols:
AHE34,
36,
37,
38,
and
42
18
 
IRB
documents
related
to
each
protocol
19
20
In
addition,
the
HSRB
received
an
EPA
review
for
each
protocol,
EPA,
Office
of
Pesticide
21
Program
guideline
documents,
and
several
general
documents
on
pesticide
handler
exposure.
22
Finally,
the
AHETF
provided
public
comments
(
AHETF
2006)
containing
comments
on
the
23
EPA
review
of
the
five
protocols.
24
25
Critique
of
Study
26
General
Scientific
Criteria
27
28
The
primary
aim
of
these
studies
is
to
generate
personal
measurement
data
on
pesticide
29
handlers
suitable
for
use
in
an
agricultural
handler
exposure
database.
The
notion
that
such
a
30
generic
database
for
pesticide
handlers
can
be
developed
is
supported
by
substantial
scientific
31
evidence.
This
evidence
indicated
that
occupational
pesticide
exposure
in
agriculture
is
largely
32
process
rather
than
chemical­
dependent
(
excluding
chemicals
with
high
volatility).
Thus,
if
33
sufficient
data
can
be
collected
on
the
key
variables
that
influence
exposure,
then
a
database
can
34
be
developed
to
estimate
exposure
for
a
wide
range
of
exposure
scenarios.
A
major
concern
of
35
the
HSRB
was
that
these
protocols
included
too
many
variables,
and
that,
even
when
combined
36
with
the
full
complement
of
studies
proposed,
the
database
would
be
inadequate
for
meaningful
37
exposure
estimates.
38
39
The
process
that
has
guided
the
exposure
database
project
had
some
significant
40
limitations.
The
database
project
has
been
developed
over
the
past
5
years
by
a
pesticide
industry
41
task
force
with
the
input
of
regulatory
staff
from
EPA,
California,
and
Canada.
Such
an
42
ambitious
undertaking
would
have
benefited
from
an
initial
independent
scientific
peer
review,
43
particularly
of
the
study
design
and
statistical
plan,
as
the
HSRB
finds
itself
raising
some
44
fundamental
questions
mid­
stream
in
the
project.
Input
from
the
labor
community
would
also
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
57
of
67
have
enhanced
the
project
regarding
procedures
such
as
subject
recruitment,
selection
of
1
pesticides
to
be
used
in
individual
studies,
and
informed
consent.
The
purpose
of
the
project,
2
after
all,
is
to
develop
data
to
estimate
worker
risks.
It
seems
reasonable
to
give
those
who
would
3
be
taking
the
risks
an
opportunity
to
contribute
to
the
design
of
the
project.
4
5
In
regard
to
justification
for
new
human
studies,
the
Agency
currently
uses
an
existing
6
generic
pesticide
handler
exposure
database,
known
as
PHED.
It
is
recognized
that
new
data
7
have
not
been
added
to
PHED
in
a
number
of
years,
and
that
the
existing
data
have
a
number
of
8
scientific
limitations.
However,
the
inadequacy
of
PHED
was
not
documented
in
the
protocols.
9
The
Agency
had
not
provided
a
compelling
justification
for
these
new
human
studies
in
the
10
materials
provided.
11
12
Benefits
of
the
study
were
not
described
in
the
protocols.
However,
the
AHETF
13
comments
(
AHETF
2006)
and
the
EPA
review
documents
provided
some
general
information
14
regarding
the
role
of
a
handler
exposure
database
in
EPA's
regulatory
process.
It
was
not
15
possible
to
determine
the
likelihood
that
the
benefits
would
be
realized,
since
the
protocols
did
16
not
include
a
description
of
the
full
database
and
how
it
would
be
used.
17
Study
Design
Criteria
18
The
purpose
of
these
studies
was
clearly
defined.
The
objective
was
to
collect
high
19
quality
personal
measurement
data
for
use
in
a
generic
exposure
database.
The
protocols
20
reviewed
by
the
Board
should
be
able
to
produce
such
data.
21
22
Approximate
sample
sizes
were
presented
in
the
protocols
and
discussed
in
more
detail
in
23
the
Agency
reviews
of
the
protocols.
Within
each
protocol,
the
sample
sizes
for
particular
24
scenarios
were
quite
small.
All
of
the
protocols
contained
multiple
scenarios,
with
sample
size
25
per
scenario
ranging
from
1­
10
(
see
Table
1).
The
inability
to
define
exactly
how
many
samples
26
would
be
collected
in
each
proposed
study
was
understandable,
since
the
task
force
was
27
attempting
to
take
advantage
of
`
real­
world'
conditions.
Weather,
logistical
challenges,
and
28
grower
decisions
regarding
pest
management
can
all
affect
the
number
of
workers
available
for
a
29
given
study.
The
effort
to
study
exposures
under
realistic
conditions
required
expenditure
of
30
significant
resources,
and
was
viewed
by
the
HSRB
as
highly
commendable.
The
HSRB
31
understood
that
these
protocols
should
not
be
viewed
as
"
stand­
alone"
studies,
since
data
from
32
these
studies
would
be
combined
with
other
similar
studies.
Presumably
all
of
the
data
collected
33
in
these
five
studies
would
be
allocated
to
one
of
the
33
exposure
scenarios
outlined
by
the
task
34
force.
Under
these
circumstances,
there
was
insufficient
information
for
the
HSRB
to
evaluate
35
the
adequacy
of
the
sample
size.
36
37
In
regard
to
dose
levels,
participants
would
be
handling
varying
amounts
of
pesticides
38
under
variable
exposure
conditions.
The
HSRB
presumed
that
the
conditions
outlined
in
the
39
protocols
and
reviewed
by
the
Agency
all
fall
within
parameters
on
the
label.
Actual
dose
during
40
these
studies
would
likely
be
lower
than
normal,
due
to
the
wearing
of
a
whole­
body
cotton
41
garment,
and
strict
observance
of
label
instructions.
42
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
58
of
67
Participation
Criteria
1
2
Participants
are
referred
to
as
`
replicates'
both
in
the
AHETF
protocols
and
in
the
Agency
3
reviews.
This
term
is
problematic
from
a
scientific
perspective,
since
it
is
used
to
refer
to
both
a
4
series
of
independent
observations
(
e.
g.,
three
persons
doing
the
same
thing
one
time)
and
a
5
series
of
repeated
measures
(
e.
g.,
one
person
doing
the
same
thing
three
times).
This
language
6
needs
to
be
altered
such
that
different
terms
are
used
for
repeated
measures
on
one
person
as
7
compared
to
observations
on
unique
individuals.
The
AHE34
protocol,
for
example,
indicated
8
that
"
ten
different
mixer/
loader
workers
(
or
replicates)
will
be
monitored
.
.
.
each
mixer/
loader
9
replicate
should
be
performed
by
a
separate
worker."
This
type
of
awkward
description
could
be
10
eliminated
through
use
of
unambiguous
terminology.
11
12
The
protocols
indicated
that
the
participants
would
be
"
experienced
workers"
recruited
13
through
their
employers,
but
there
was
no
detailed
description
of
the
recruitment
procedures,
nor
14
were
there
clear
inclusion/
exclusion
criteria
other
than
age
and
pregnancy
status.
It
was
hard
to
15
tell
whether
the
workers
who
volunteer
for
a
protocol
exposure
study
would
be
representative
of
16
the
typical
worker.
Random
sampling
from
a
group
of
eligible
workers
would
improve
this
17
aspect
of
the
protocols.
18
Measurement
Criteria
19
AHETF
investigators
are
using
three
different
methods
to
measure
skin
exposure:
cotton
20
garments
(
whole
body
dosimeters),
hand
rinse,
and
face/
neck
wipes.
The
cotton
garments
should
21
be
able
to
capture
pesticide
that
would
normally
be
deposited
on
skin.
However,
no
method
for
22
preventing
or
monitoring
garment
breakthrough
was
presented.
If
breakthrough
occurs,
the
23
dermal
exposure
measurements
would
underestimate
true
exposure.
The
hand
rinse
method
and
24
face/
neck
wipe
both
measure
the
amount
of
material
that
can
be
removed
from
the
skin
at
the
25
particular
time
of
the
sampling.
This
amount
is
some
fraction
of
the
total
material
deposited
on
26
the
skin,
since
some
of
the
material
would
have
been
absorbed
into
the
skin.
This
method
is
27
likely
to
underestimate
the
true
exposure.
Published
laboratory
and
field
studies
have
indicated
28
that
the
fraction
of
the
amount
deposited
on
skin
that
can
be
removed
by
rinsing
or
wiping
can
be
29
quite
variable,
depending
on
the
nature
of
the
chemical,
its
formulation,
skin
characteristics,
and
30
the
length
of
time
the
chemical
has
been
in
contact
with
the
skin.
In
particular,
the
face/
neck
31
wipe
method
may
seriously
underestimate
exposure
to
these
surfaces.
This
method
was
not
32
among
the
methods
presented
by
the
Agency
in
its
875
guidelines
(
Occupational
and
Residential
33
Exposure
Test
Guidelines:
OPPTS
875.1100
Dermal
Exposure
 
Outdoor),
and
has
not
been
34
validated.
The
accuracy
of
these
measurements
could
be
improved
through
the
conduct
of
35
laboratory
removal
efficiency
studies.
The
875
guidelines
do
not
require
removal
efficiency
36
studies,
but
they
do
indicate
that
investigators
should
address
this
concern.
If
such
method
37
validation
studies
are
contemplated,
the
HSRB
recommended
that
they
be
conducted
as
38
independent
scientific
studies
published
in
the
peer­
reviewed
literature.
39
40
In
summary,
all
of
the
methods
for
dermal
exposure
measurements
have
the
potential
to
41
underestimate
exposure.
The
study
investigators
should
acknowledge
this
problem
in
the
42
protocols,
and
explain
what
steps,
if
any,
they
have
taken
to
improve
or
verify
the
accuracy
of
43
the
measurements.
44
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
59
of
67
1
The
protocols
stated
that
hand
rinse
and
wipe
samples
may
be
collected
multiple
times
2
during
the
work
period
(
e.
g.,
prior
to
eating,
whenever
a
worker
would
normally
wash
hands),
3
and
that
this
would
vary
from
worker
to
worker.
The
protocols
did
not
explain
how
multiple
4
measurements
from
a
single
worker
would
be
combined.
They
also
did
not
discuss
whether
or
5
not
samples
across
workers
with
different
rinse/
wipe
regimens
can
be
considered
comparable.
6
For
example,
can
the
amount
of
pesticide
recovered
in
a
single
hand
rinse
from
a
worker
at
the
7
end
of
the
study
period
be
put
in
the
same
database
as
that
from
a
worker
who
had
four
hand
8
rinses
across
the
study
period?
The
answer
would
seem
to
be
"
no"
from
a
sampling
perspective,
9
given
the
nature
of
dermal
absorption
processes.
10
11
The
quality
assurance
components
of
the
protocols
are
of
high
quality.
There
was
12
substantial
documentation
regarding
the
reliability
of
analytical
methods
available
for
each
of
the
13
sampling
media
to
be
used.
There
were
detailed
standard
operating
procedure
documents
for
14
field
and
laboratory
quality
assurance
activities.
15
Statistical
Analysis
Critera
16
An
inadequate
statistical
analysis
plan
was
provided
in
the
protocols.
The
HSRB
17
identified
this
deficiency
as
the
most
critical
scientific
limitation
for
these
protocols.
There
was
18
a
need
for
a
more
professional
and
comprehensive
treatment
of
statistical
issues
in
the
analysis
of
19
data,
and
in
the
design
of
individual
protocols.
Chief
among
these
issues
was
the
question
of
20
statistical
power.
It
is
critical
to
address
the
HSRB's
concern
that
the
present
design
calls
in
most
21
cases
for
a
single
observation
per
experimental
condition.
In
other
words,
it
appears
that
the
22
present
studies
are
intended
to
be
parsed
in
terms
of
formulation,
container
size,
frequency
of
23
worker
activity,
equipment,
air
temperature,
wind
speed,
relative
humidity,
amount
of
cloud
24
cover,
rainfall,
crop,
amount
of
material
handled,
rate
of
application,
acreage
treated,
and
25
geographic
location
(
along
with
other
possible
qualifiers).
As
a
result,
the
number
of
variables
to
26
be
evaluated
appears
to
approach
or
even
exceed
the
total
number
of
subjects
for
a
given
27
scenario.
One
may
hope
that
some
useful
information
might
yet
emerge
from
a
properly
28
performed
analysis
of
the
full
data
set
coming
from
studies
involving
different
chemicals,
sites,
29
and
conditions.
What
is
needed
now,
however,
is
a
cogent
and
thoughtful
discussion,
in
the
30
protocol,
of
just
what
can
be
accomplished
along
these
lines,
and
an
explanation
of
how
it
can
be
31
accomplished.
Further
thought
may
lead
to
the
conclusion
that
the
current
data­
gathering
plan
is
32
in
fact
overly
optimistic
in
regard
to
the
issue
of
statistical
power.
It
would
then
be
essential
to
33
restructure
the
plan
and
change
the
study
design
to
ensure
that
the
enormous
effort
in
this
large
34
and
important
project
would
not
be
wasted.
35
36
If
the
goal
of
these
studies
was
to
estimate
the
distribution
of
exposures
across
a
variety
37
of
application
scenarios,
it
would
be
important
to
include
true
repeated
measures
for
at
least
38
some
of
these
scenarios
to
assess
the
extent
of
within­
worker
variability.
39
Laboratory
and
Field
Conditions
40
41
The
protocol
states
that
the
field
conditions
were
selected
to
be
representative
of
real­
42
world
use
of
pesticides.
In
this
regard,
participants
are
experienced
workers,
are
allowed
to
wear
43
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
60
of
67
their
own
clothing,
and
conduct
normal
work
activities
in
an
actual
agricultural
setting.
Studies
1
are
distributed
across
the
U.
S.
and
across
the
year
in
an
attempt
to
develop
a
range
of
exposure
2
conditions.
While
laudable
in
scope,
it
is
important
to
restate
the
concern
that
the
large
number
3
of
variables
included
in
these
studies
may
prove
extremely
problematic
for
analysis.
4
5
The
issue
of
potential
heat
stress
was
discussed
at
length
at
the
HSRB
public
meeting.
6
The
HSRB
concluded
that
the
protocols
should
include
explicit
criteria
for
halting
a
study
due
to
7
heat
stress
risk.
8
The
protocols
stated
that
workers
would
be
monitored
"
during
a
period
of
time
9
representative
of
a
full
day's
work".
The
protocols
also
indicated
that
monitoring
times
would
10
conform
to
a
"
typical"
workday.
However,
none
of
the
protocols
defined
the
typical
work
period
11
for
the
specific
tasks
to
be
studied.
Instead,
the
protocols
stated
that
monitoring
time
"
will
12
involve
work
periods
with
a
target
of
4
hours."
This
language
suggested
that
even
four
hours
of
13
monitoring
might
not
be
achieved
in
some
cases,
and
there
was
no
indication
that
workdays
as
14
long
as
8
or
9
hours
would
ever
be
monitored.
It
was
not
clear
to
the
HSRB
that
these
studies
15
would
necessarily
reflect
a
full
workshift
or
a
"
typical"
workday.
Many
factors
can
influence
the
16
length
of
the
workday,
including
weather
conditions,
and
the
need
to
"
get
the
job
done"
due
to
17
pest
pressures
or
the
stage
of
crop
development.
Fatigue
is
an
important
factor
that
can
affect
18
exposure,
and
usually
inattention
occurs
at
the
end
of
the
day.
The
HSRB
recommended
that
the
19
protocols
document
the
time
of
a
typical
workday
(
or
the
range
of
these
times)
for
each
scenario,
20
and
that
the
monitoring
time
be
based
on
this
information.
21
22
Special
Concerns
Regarding
Use
of
Diazinon
in
Protocol
AHE37
23
24
Protocol
AHE37
involves
handling
a
wettable
powder
(
50WP)
formulation
of
diazinon.
25
Workers
would
be
monitored
during
open
cab
trellis
crop
airblast
applications
and
open
pour
26
mixing­
loading
operations.
The
HSRB
was
concerned
that
these
practices
are
not
consistent
with
27
current
Agency
policy.
The
Agency's
May
2004
interim
registration
eligibility
document
28
(
IRED)
for
diazinon
stated
that
engineering
controls
are
required
during
handling.
The
"
IRED
29
Facts
for
Diazinon"
states,
"
All
application
equipment
must
use
lock
and
load
engineering
30
controls.
All
wettable
powder
formulations
must
be
packaged
in
water­
soluble
bags.
Closed
cabs
31
are
required
for
all
ground
equipment,
except
for
applications
to
apples."
The
IRED
Executive
32
Summary
further
stated,
"
Occupational
exposure
to
diazinon
is
of
concern
to
the
Agency.
For
33
agricultural
uses
of
diazinon,
most
mixer/
loader/
applicator
risk
scenarios
currently
exceed
the
34
Agency's
level
of
concern
(
i.
e.,
MOEs
are
less
than
100
for
dermal
exposure
and
MOEs
are
less
35
than
300
for
inhalation
exposure).
Taking
into
consideration
both
the
risks
and
benefits
of
these
36
uses,
EPA
has
determined
that
most
agricultural
uses
may
continue
with
the
adoption
of
the
37
following
mitigation
measures:
.
.
.
engineering
controls
for
mixers
and
loaders
and
closed
cabs
38
for
applicators
for
all
application
scenarios
.
.
."
The
above
statements
indicate
that
open
pouring
39
of
diazinon
is
not
permitted,
and
that
open
cab
airblast
applications
are
not
permitted
in
trellis
40
crops.
41
42
43
44
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
61
of
67
HSRB
Consensus
and
Rationale
1
2
The
five
studies
presented
for
HSRB
review
were
components
of
a
large­
scale
exercise
to
3
create
a
contemporary
database
on
occupational
exposure
to
agricultural
pesticides.
The
4
undertaking
is
in
itself
likely
to
be
worthwhile
in
quantifying
and
improving
our
understanding
5
of
the
exposures
of
and
risks
to
pesticide
handlers.
The
potential
benefits
are
large
and
the
risks
6
appear
to
be
relatively
modest.
However,
the
materials
supplied
for
HSRB
review
failed
to
deal
7
adequately
with
risks
and
benefits.
None
of
these
protocols
can
be
properly
evaluated
in
regard
8
to
scientific
validity
because
they
lacked:
(
1)
a
developed
rationale
documenting
the
need
for
9
new
data;
(
2)
a
clear
and
appropriate
plan
for
the
handling
of
the
data
(
including
its
statistical
10
analysis),
and
(
3)
an
explanation
of
the
uses
to
which
the
data
would
be
put
and
adequate
sample
11
sizes
and
protocols
for
repeated
measures
to
appropriately
estimate
exposures
within
individuals
12
and
between
scenarios.
These
points
need
to
be
addressed,
at
least
briefly,
in
each
specific
13
protocol
and,
more
fully,
in
a
separate
and
new
"
governing
document"
that
is
not
simply
a
14
generic
description
of
the
planned
activities.
15
16
Additional
validation
studies
are
recommended
to
determine
the
extent
to
which
dermal
17
exposure
measurements
may
underestimate
true
exposure.
Laboratory­
based
removal
efficiency
18
studies
or
field­
based
biomonitoring
studies
could
be
conducted
to
achieve
this
goal.
Such
19
studies
should
be
published
in
the
peer­
reviewed
literature.
Broader
participation
of
the
scientific
20
community
and
of
parties
with
a
direct
interest
in
the
database
project,
such
as
the
labor
21
community,
would
likely
improve
the
quality
of
the
database
and
enhance
the
credibility
of
its
22
use
in
risk
assessments.
23
24
The
HSRB
recommended
that
specific
criteria
for
cessation
due
to
heat
stress
be
included
25
in
these
worker
exposure
protocols,
and
that
the
protocols
included
a
heat
stress
management
26
plan.
In
addition,
the
HSRB
recommended
that
the
length
of
each
study
should
be
truly
27
representative
of
a
full
workday,
and
that
each
protocol
should
document
the
basis
for
the
28
proposed
duration
of
the
study.
29
30
The
HSRB
was
gratified
to
receive
the
Agency's
response
to
its
query
regarding
the
use
31
of
diazinon
in
the
AHE37.
It
is
the
understanding
of
the
HSRB
that
the
Agency
would
inform
the
32
AHETF
that
it
needs
to
identify
a
pesticide
other
than
diazinon
in
this
protocol
to
evaluate
33
exposures
associated
with
open
pour
activities
and
applications
using
open
cabs,
and
that
the
34
Agency
would
ensure
that
future
protocols
comply
with
the
most
current
risk
mitigation
35
measures
specified
in
IREDs
and
REDs.
36
37
Board
Response
to
the
Charge
38
39
Ethical
Considerations
40
41
Background
42
43
These
five
studies
are
part
of
a
series
of
studies
that
are
to
be
conducted
by
the
AHETF,
a
44
coalition
of
19
pesticide
registrants
that
was
formed
in
December
2001
to
share
resources
in
the
45
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
62
of
67
design,
evaluation,
and
development
of
a
proprietary
agricultural
mixer/
loader
and
applicator
1
exposure
database
for
use
in
regulatory
risk
assessments.
2
3
The
study
protocols
were
designed
by
AHETF
investigators
after
joint
discussions
with
4
the
US
EPA,
Health
Canada,
and
the
California
Department
of
Pesticide
Regulation,
in
5
accordance
with
the
recommendations
of
such
guidance
documents
as:
1)
US
EPA,
Occupational
6
and
Residential
Exposure
Test
Guidelines,
Series
875.1000
through
875.1600
(
1996);
and
2)
US
7
EPA,
Working
Draft
­
Occupational
and
Residential
Exposure
Test
Guidelines,
Series
875
8
Group­
B,
Postapplication
Exposure
Monitoring
Test
Guidelines
Version
5.4
(
1998).
The
9
supporting
and
supplementary
study
documents
also
assert
compliance
with
the
Good
10
Laboratory
Practice
(
GLP)
Standards
established
by
the
1972
amendment
to
the
Federal
11
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
(
§
40CFR160).
Finally,
these
protocols
12
were
reviewed
and
approved
by
the
Western
Institutional
Review
Board
(
WIRB)
of
Olympia,
13
Washington,
prior
to
submission
to
the
Agency.
14
15
The
aims
of
these
studies
are
to
provide
critical
exposure
information
for
individuals
who
16
mix,
load,
and
apply
agricultural
pesticides.
Agricultural
producers
("
growers")
would
be
17
recruited
by
the
study
coordinators
several
months
prior
to
initiation
of
the
study;
in
exchange
18
for
their
participation
in
the
study,
each
grower
would
receive,
free
of
charge,
an
amount
of
19
liquid
pesticide
equivalent
to
the
normal
quantity
mixed
and
loaded
into
closed­
mixing
systems
20
and
spray
rigs
for
the
duration
of
the
study
(
expected
to
be
a
single
day).
Participating
growers
21
also
may
be
asked
to
recruit
other
growers
and
pesticide
applicators
into
the
research
study.
22
23
Study
investigators
would
recruit
agricultural
handlers
on­
site;
volunteers
would
receive
24
$
100/
day
for
their
participation
in
addition
to
their
regular
pay.
Voluntary
informed
consent
25
would
be
solicited
by
study
investigators,
and
will
be
documented
using
a
standardized
informed
26
consent
form.
Because
the
study
participants
would
be
recruited
from
a
pool
of
experienced
27
agricultural
workers
who
routinely
mix
and
load
liquid
pesticides
as
part
of
their
normal
duties,
28
the
AHETF
had
argued
that
participation
in
this
study
presents
a
negligible
increase
in
pesticide
29
exposure
risk
to
volunteers.
In
accordance
with
the
newly
promulgated
provisions
in
the
EPA's
30
Final
Human
Studies
Rule
(
§
40CFR26.1701
­
26.1704),
minors
and
pregnant
women
are
31
explicitly
excluded
from
participation,
the
latter
being
confirmed
by
requiring
all
female
32
volunteers
to
undergo
a
self­
administered
over­
the­
counter
pregnancy
test
on
the
day
of
the
33
study.
34
35
Dermal
exposure
to
pesticides
would
be
ascertained
through
hand
rinses
and
face/
neck
36
wipes,
as
well
as
the
use
of
long
cotton
underwear
 
as
a
surrogate
for
skin
 
to
be
worn
under
37
the
study
participant's
clothing.
In
addition
to
the
long
underwear,
all
participants
would
be
38
required
to
wear
long
sleeved
shirts
and
long
pants,
shoes
plus
socks,
in
accordance
with
39
accepted
worker
protection
standards.
Volunteers
may
wear
their
own
clothing
provided
they
are
40
freshly
laundered;
alternatively,
the
AHETF
would
provide
freshly
laundered
clothing.
Any
41
personal
protective
equipment
(
PPE)
that
may
also
be
required,
such
as
chemical
resistant
gloves
42
and
protective
eyewear,
will
be
provided.
At
the
conclusion
of
the
four­
hour
study
observation,
43
the
long
underwear
would
be
removed
and
subjected
to
laboratory
analyses
to
estimate
whole­
44
body
dermal
pesticide
exposure.
Study
participants
would
also
be
asked
to
wear
OSHA
Versatile
45
Samplers
(
OVS)
outfitted
with
glass
filters,
XAD­
2
sorbent,
and
tygon
tubes
to
measure
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
63
of
67
inhalation
exposure.
The
tubes
would
be
attached
to
the
volunteer's
collars
with
the
openings
1
positioned
in
their
breathing
zones.
By
using
such
state­
of­
the­
art
monitoring
techniques,
the
2
AHETF
argues,
this
study
would
provide
critical
exposure
information
for
individuals
who
3
mix/
load
liquid
agricultural
pesticides.
4
5
Strengths
and
Limitations
6
7
These
studies
would
provide
critical
exposure
information
for
individuals
who
mix/
load
8
and
apply
agricultural
pesticides.
It
is
also
believed
that
the
monitoring
techniques
proposed
for
9
these
studies
represent
the
current
state­
of­
the­
art.
However,
the
Agency
also
recognized
that
use
10
of
the
data
resulting
from
this
studies
would
take
careful
scrutiny
and
may
require
a
number
of
11
adjustments
depending
upon
the
results.
Finally,
the
overall
design
of
these
studies
should
be
12
considered
in
the
context
of
the
goals
of
the
AHETF
which
are
to
develop
a
broad­
based
13
database
that
can
be
generically
used
as
a
predictive
tool
for
estimating
exposures
to
pesticide
14
handlers
and
that
the
interpretation
of
the
results
of
these
studies
may
or
may
not
necessitate
the
15
need
for
additional
monitoring
data.
16
17
The
Board
concurred
with
the
factual
observations
of
the
strengths
and
weaknesses
of
the
18
studies,
as
detailed
in
the
EPA's
Initial
Ethics
Review
of
the
AHETF
Template
Protocol
and
19
each
individual
study
protocol.
The
Board
concluded
that,
given
the
deficiencies
noted
by
the
20
EPA,
the
proposed
research
described
in
the
AHETF
Template
Protocol
and
each
individual
21
study
protocol
do
not
comport
with
the
applicable
requirements
of
§
40CFR26,
subparts
K
and
L.
22
Furthermore,
the
AHETF
and
WIRB
failed
to
provide
all
of
the
documents
necessary
to
be
in
23
compliance
with
the
requirements
of
§
40CFR26,
subpart
M.
24
25
Although
public
comments
from
several
members
of
the
AHETF
helped
assuage
some
of
26
the
Board's
concerns,
the
members
of
the
HSRB
believed
that
further
comments
about
this
27
protocol
were
warranted.
The
comments
below
are
grouped
into
four
broad
categories:
(
1)
28
whether
the
study
was
designed
to
adequately
minimize
risk
to
study
participants;
(
2)
whether
29
the
documentation
and
process
of
study
subject
enrollment
was
sufficient
to
meet
prevailing
30
standards
of
voluntary
informed
consent;
(
3)
whether
study
participants
would
be
adequately
31
compensated
in
the
event
of
a
study­
related
injury;
and
(
4)
whether
appropriate
alternatives
to
32
participation
are
provided.
33
34
Minimization
of
Risks
to
Study
Participants
35
36
This
study
proposes
to
measure
dermal
and
inhalation
exposure
to
liquid
pesticides
by
37
agricultural
handlers
who
usually
perform
pesticide
mixing,
loading,
and
application
as
part
of
38
their
daily
routine.
However,
it
was
unclear
to
Board
members,
given
the
semi­
scripted
nature
of
39
the
protocol
provided,
as
to
whether
or
not
study
participants
would
be
exposed
to
greater
40
quantities
of
these
compounds
than
would
normally
occur.
Are
the
studies
proposed
purely
41
observational
in
nature,
or
are
study
investigators
intervening
by
requesting
that
study
42
participants
use
different
types
and
quantities
of
pesticide,
or
different
mixing,
loading,
and
43
application
methods,
than
they
normally
would?
If
the
latter
is
true,
the
assumption
that
this
44
study
represents
a
negligible
increase
in
pesticide
exposure
risk
to
volunteers
may
be
unfounded.
45
Several
Board
members
also
expressed
concern
that
the
additional
requirements
for
donning
and
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
64
of
67
removing
the
equipment
used
to
measure
pesticide
exposure
may
inadvertently
lengthen
the
1
participant's
normal
work
day.
If
so,
this
should
be
clearly
described
during
the
consent
process,
2
as
should
the
question
of
whether
the
$
100
paid
for
study
participation
is
expected,
in
whole
or
3
in
part,
to
compensate
for
the
extension
of
the
work
day.
4
5
The
protocol
failed
to
detail
the
approach
taken
to
ensure
that
agricultural
handlers
are
6
adequately
trained
in
the
proper
mixing,
loading,
and
application
of
these
compounds.
Although
7
pesticide
mixing
instructions
and
Material
Safety
Data
Sheets
are
made
available
to
study
8
participants,
given
that
many
agricultural
workers
may
not
be
fluent
in
English
(
or
may
even
be
9
illiterate),
a
clear
plan
for
ensuring
that
volunteers
are
properly
educated
in
minimizing
their
10
exposure
to
these
compounds
should
be
included.
Furthermore,
study
investigators
may
want
to
11
make
arrangements
to
provide
volunteers
with
the
results
of
the
study
following
completion.
12
13
One
of
the
greatest
risks
to
study
participants
is
heat­
related
illness,
given
that
dermal
14
exposure
to
pesticides
will
be
determined
by
asking
volunteers
to
wear
long
underwear
in
15
addition
to
their
normal
protective
equipment
(
e.
g.,
long
sleeved
shirts
and
long
pants,
and
other
16
applicable
protective
gear).
Although
study
coordinators
are
expected
to
be
vigilant
for
signs
of
17
heat­
related
illness
among
volunteers,
in
order
to
minimize
the
risks
posed
to
the
study
18
participants
the
protocol
also
should
include:
a)
explicit
starting
and
stopping
criteria
based
on
a
19
quantifiable
measure
like
ambient
temperature
or
heat
index;
and
b)
a
clear
description
of
the
20
symptoms
of
heat­
related
illness
in
the
informed
consent
documents.
There
should
also
be
a
clear
21
plan
for
reporting
any
heat­
related
illness
(
or,
for
that
matter,
any
other
adverse
event)
to
the
22
study
investigators,
Western
IRB,
and
the
EPA.
23
24
Because
some
of
the
study
participants
may
be
undocumented
immigrants,
measures
to
25
ensure
strict
confidentiality
should
be
developed.
Many
undocumented
workers,
for
example,
26
may
be
loathe
to
report
any
adverse
study­
related
event
requiring
medical
attention
or
27
hospitalization
if
they
believe
that
their
illegal
status
will
be
reported
to
immigration
authorities.
28
Alternatively,
study
investigators
may
wish
to
require
documentation
of
citizenship
or
29
immigration
status
as
part
of
the
inclusion
criteria
for
recruiting
study
participants.
In
addition,
30
because
many
pregnant
day­
laborers
may
fear
job
loss
in
the
event
that
their
employer
learns
of
31
their
condition,
extra
care
should
be
taken
to
keep
the
results
of
over­
the­
counter
pregnancy
tests
32
private.
33
34
Voluntary
Informed
Consent
35
36
Several
Board
members
felt
that
the
AHETF
protocol,
as
provided,
lacked
sufficient
37
safeguards
to
ensure
that
all
study
participants
were
adequately
informed
about
the
risks,
benefits
38
and
alternatives
to
participation
in
the
study.
For
example,
it
was
felt
that
the
informed
consent
39
documents
provided
were
written
at
too
high
of
a
reading
and
comprehension
level.
Given
the
40
sociodemographic
characteristics
of
the
farm
worker
population,
many
of
the
study
participants
41
may
have
limited
education,
may
speak
English
as
a
second
or
even
a
third
language,
or
may
42
even
be
illiterate.
Study
investigators
should
develop
a
clear
consent
document
which
 
in
43
addition
to
including
a
more
detailed
description
of
risks
(
including
the
risks
of
the
pesticides
44
being
handled)
as
described
previously,
as
well
as
a
clear
distinction
between
what
comprises
45
research
versus
normal
activities
 
is
written
at
a
lower
grade­
level
and
translated
into
the
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
65
of
67
various
languages
likely
to
be
spoken
by
study
participants.
A
brief
oral
test
of
comprehension
1
should
also
be
developed,
with
volunteers
required
to
demonstrate
a
clear
understanding
of
the
2
purposes
and
the
risks
of
the
study
prior
to
enrollment.
3
4
The
Board
also
expressed
concern
about
the
potentially
coercive
nature
of
the
study,
5
given
the
potential
for
study
participants
to
believe
that
there
is
a
direct
relationship
between
6
study
investigators
and
growers.
Absent
additional
safeguards,
the
"
gift"
of
study
pesticide
to
the
7
growers
may
contribute
to
undue
influence
on
employees
to
participate
in
the
research.
Western
8
IRB,
in
its
initial
review
of
several
of
the
AHETF
protocols,
recommended
that
"
extra
care"
be
9
taken
during
the
recruitment
and
consent
process
to
minimize
coercion
or
undue
influence
on
10
study
participants.
However,
no
documentation
was
provided
to
the
HSRB
as
to
how
the
AHETF
11
addressed
WIRB's
concern.
For
example,
there
was
no
evidence
to
suggest
that
AHETF
12
researchers
solicited
the
help
of
the
farm­
workers
themselves
or
other
community
leaders
to
13
ensure
that
study
participants
would
not
be
covertly
or
overtly
coerced
into
participating
in
the
14
study.
The
rights
of
participants
to
withdraw
from
the
study
at
any
time
also
should
be
15
emphasized.
It
is
unclear
from
the
informed
consent
or
other
study
documents,
for
instance,
as
to
16
whether
volunteers
are
entitled
to
receive
monetary
payment
even
if
they
chose
to
withdraw
17
during
the
course
of
the
study.
Although
the
Board
was
reassured
during
the
discussion
that
18
sufficient
alternate
work
was
available,
the
protocol
also
failed
to
specify
that
workers
would
19
still
be
paid
for
a
day's
labor
even
if
they
refused
to
participate
in
the
research.
20
21
Compensation
for
Injury
to
Study
Participants
22
23
The
study
protocol
and
informed
consent
documents
state
that:
"
If
[
a
study
participant
is]
24
injured
as
a
result
of
being
in
this
study,
treatment
will
be
available
from
a
health
professional
at
25
a
nearby
medical
facility.
The
costs
of
such
treatment
will
be
covered
by
the
AHETF.
This
does
26
not
cover
any
injuries
resulting
from
[
the
volunteer's]
normal
activities."
Given
the
nature
of
the
27
study
design,
however,
it
is
unclear
whether
a
distinction
between
injuries
resulting
from
normal
28
work
activities
versus
participation
in
this
study
can
be
made.
Two
of
the
symptoms
of
heat
29
exhaustion,
for
example,
are
dizziness
and
loss
of
coordination
 
will
study
coordinators
be
able
30
to
distinguish
between
an
accidental
injury
caused
by
clumsiness
versus
an
injury
resulting
from
31
potentially­
unrecognized
symptoms
of
heat­
related
illness?
In
light
of
these
concerns,
the
Board
32
recommends
that
the
AEHTF
cover
medical
treatment
for
all
participant
illness
and
injury
33
occurring
during
the
study
period
(
i.
e.,
the
day
of
the
test).
34
35
Alternatives
to
Participation
36
37
As
noted
above,
the
design
of
this
study
involves
collaboration
between
the
researchers
38
and
growers
in
which
the
growers
receive,
free
of
charge,
a
particular
pesticide
that
they
are
39
required
to
apply
to
their
fields
on
the
day
of
the
study.
That
arrangement
will
lead
in
many
40
circumstances
(
except
of
the
few
coincidental
instances
when
the
grower
had
already
planned
to
41
use
that
chemical
on
that
day)
to
a
change
in
the
pesticide
being
applied
by
the
grower.
42
43
The
following
question
thus
arises:
What
alternatives
are
offered
to
agricultural
handlers
44
working
for
that
grower
who
choose
not
to
participate
in
the
study?
One
option
is
that
they
could
45
be
offered
the
choice
of
applying
that
pesticide
that
day,
but
not
needing
to
participate
in
any
46
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
66
of
67
other
study
procedures
(
such
as
wearing
the
long
underwear).
Some
members
of
the
Board
1
believed
that
if
that
is
the
only
alternative
to
participation,
then
this
aspect
of
the
study
would
not
2
comply
with
40
C.
F.
R.
Part
26,
Subpart
K.
A
primary
purpose
of
the
EPA
rule
is
to
prevent
a
3
person
from
being
intentionally
exposed
to
a
pesticide
without
their
voluntary
informed
consent.
4
The
EPA
emphasized
this
point
when
it
promulgated
the
final
version
of
its
rule,
commenting
5
that
the
term
"
research
involving
intentional
exposure"
covers
"
any
research
on
a
substance,
6
unless
the
subjects
of
the
research
retain
complete
control
over
whether,
when,
and
how
they
are
7
exposed
to
the
substance."
71
Fed.
Reg.
6138,
6146
(
2006).
8
9
Some
members
of
the
Board
accordingly
concluded
that
for
agricultural
workers
who
had
10
pre­
existing
expectations
of
earning
money
working
for
the
grower
on
the
day
of
the
study
11
(
either
as
employees
or
as
independent
contractors
with
contractual
expectations
of
working
that
12
day),
the
protocol
must
provide
them
alternatives
for
earning
that
same
amount
of
money
that
do
13
not
require
them
to
apply
the
pesticide
used
in
the
study.
Acceptable
alternatives
could
include
14
applying
some
other
pesticide
they
have
in
the
past
applied,
performing
some
other
task
they
15
regularly
perform,
or
being
paid
their
expected
earnings
without
needing
to
work.
Absent
such
16
alternatives,
the
protocol
would
appear
to
be
inappropriately
coercing
such
persons
into
applying
17
the
study
compound
or
else
losing
the
money
they
expected
to
earn
that
day.
18
19
20
HSRB
Consensus
and
Rationale
21
22
The
Board
concurred
with
the
initial
assessment
of
the
Agency
that
the
studies
submitted
for
23
review
failed
to
meet
the
ethical
requirements
established
in
the
40CFR26.
24
25
The
Board
determined
the
proposed
occupational
handlers
exposure
studies
do
not
comport
26
with
the
applicable
requirements
of
40CFR26,
subparts
K
and
L.
However,
the
deficiencies
27
noted,
while
significant,
were
not
irreparable.
28
29
Proposed
Final
Draft
v.
1
Dated
August
28,
2006;
Do
Not
Cite
or
Quote
67
of
67
REFERENCES
1
2
AHETF
2006.
Comments
to
the
Human
Studies
Review
Board
(
HSRB)
Regarding
Five
3
Protocols
Submitted
for
Review.
June
20,
2006.
4
5
NAS
2004.
Intentional
Dosing
Studies
for
EPA
Regulatory
Purposes:
Scientific
and
Ethical
6
Issues.
National
Academy
Press.
7
8
NBAC
2001.
Ethical
and
Policy
Issues
in
Research
Involving
Human
Participants.
National
9
Bioethics
Advisory
Commission.
www.
bioethics.
gov
10
11
Prentiss
AM.
1937.
Chemical
in
War:
A
Treatise
on
Chemical
Warfare.
McGraw­
Hill
Book
12
Company,
Inc.
New
York.
13
14
USEPA
2006a.
Human
Studies
Review
Board.
Weight
of
Evidence
Determination
for
15
Chloropicrin.
June
7,
2006
16
17
USEPA
2006b.
Ethics
Review
of
Protocol
for
Human
Study
of
Tick
Repellent
Performance.
18
June
9,
2006.
19
20
USEPA
2006c.
Ethics
Review
of
Protocol
for
Human
Study
of
Mosquito
Repellent
Performance
21
June
9,
2006.
22
23
USGPO.
1949.
Trials
of
War
Criminals
before
the
Nuremberg
Military
Tribunals
under
Control
24
Council
Law
No.
10,
Vol.
2,
pp.
181­
182.
Washington,
D.
C.
25
26
27