Document ID: EPA-HQ-ORD-2006-0384-0057
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-28T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
JUNE
27­
30,
2006
*
PUBLIC
MEETING
Wednesday,
June
28,
2006
Arlington,
VA
22202
Insect
Repellent
Product
Performance
Testing
Guidelines
Written
Comments
The
U.
S.
EPA
Office
of
Pesticide
Programs
requests
that
the
HSRB
review
and
comment
on
the
draft
"
Product
Performance
of
Skin­
Applied
Repellents
of
Insects
and
Other
Arthropods"
Testing
Guideline
in
order
to
determine
what
changes,
if
any,
are
necessary
for
the
guideline
to
be
made
consistent
with
the
requirements
for
protection
of
human
research
subjects
set
forth
in
40
CFR
part
26.
Below
is
a
list
of
questions
that
focus
on
these
topics.

a.
What
actions
should
an
investigator
routinely
take
to
minimize
the
risks
to
human
subjects
exposed
during
laboratory
and
field
research
on
the
efficacy
of
repellents?

Two
risks
are:
(
1)
toxicity
of
repellent;
and
(
2)
bites
from
infected
vectors
(
usually
only
field
studies).

1.
Toxicity
of
the
repellent
chemical.
The
repellent
chemical
may
pose
limited
toxicity
to
the
research
subject
(
depending
on
chemical,
dose,
and
formulation).
To
minimize
the
toxicity
of
the
repellent
chemical
to
the
research
subject,
investigators
should
wash
exposed
skin
that
has
been
treated
with
repellent
(
or
a
positive/
negative
control)
with
a
fragrance
free
soap
and
rinse
with
water/
isopropanol
(
35%)
solution
before
and
after
treatment.

2.
Bites
from
infected
vectors.
Bites
from
infected
vectors
are
a
concern
in
field
locations
where
a
repellent
compound
is
being
evaluated
against
vector
flies
and
other
arthropods.
For
studies
that
use
landing/
biting
counts,
it
may
be
feasible
to
recruit
local
subjects
who
are
naturally
exposed
to
such
vectors
on
a
daily
basis
anyway.
It
is
prudent
to
have
a
helper
collect
flies
landing
on
the
test
subject
before
vectors
have
an
opportunity
to
bite.
Depending
on
the
nature
of
the
study,
subjects
may
require
follow­
up
monitoring
for
disease
afterwards.

b.
What
types
of
toxicity
data
should
be
routinely
generated
before
an
investigator
conducts
repellent
efficacy
testing
on
human
subjects
with
a
new
product?

Standard
6­
pack
toxicology.
c.
In
private
and
university
research
laboratories,
investigators
themselves
have
sometimes
served
as
research
subjects
when
assessing
chemicals
for
insect
repellent
activity.
What
scientific
and
ethical
issues
would
such
a
practice
raise?
Under
what
conditions,
if
any,
would
such
a
practice
be
acceptable?

The
investigator
serving
as
the
only
research
subject
raises
both
ethical
and
scientific
red
flags.
It
would
be
difficult
to
monitor
a
study
where
s/
he
is
the
research
subject.
Even
the
best
researcher
may
unintentional
introduce
bias
while
serving
as
his/
her
only
research
subject.
With
the
understanding
that
there
may
be
circumstances
where
this
is
warranted
and
acceptable,
it
should
be
a
method
of
last
resort.
For
instance,
such
a
practice
may
be
the
only
way
that
a
chemical
can
be
assessed
to
obtain
preliminary
data
to
support
a
research
proposal
for
future
studies.

d.
Please
comment
on
the
scientific
and
ethical
issues
arising
from
the
use
of
(
or
decision
not
to
use)
negative
controls
groups
in
repellent
efficacy
studies,
in
both
laboratory
and
field
studies.

Negative
controls
groups
are
necessary,
because
they
indicate
whether
biting
insects
and
other
arthropods
are
exhibiting
"
normal"
host­
seeking/
landing/
feeding
behavior.
I.
e.,
as
negative
controls,
human
subjects
must
be
naturally
attractant
to
biting
insects
in
order
to
show
that
a
repellent
is
effective.
However,
the
use
of
negative
controls
poses
a
serious
issue
when
field
evaluations
of
repellent
efficacy
are
conducted
in
areas
where
vectorborne
diseases
are
present.
Two
options
are
to
(
1)
recruit
indigenous
subjects
from
the
local
population
who
would
naturally
be
exposed
to
the
same
number/
rate
of
bites
from
insect
vectors
that
are
potentially
infectious;
and
(
2)
perform
landing
catches
instead
of
biting
catches,
thereby
precluding
the
possibility
that
disease
transmission
might
occur
(
e.
g.
volunteers
can
wear
Tyvek
coveralls
that
consist
of
a
breathable
material
but
prevent
insects
from
biting
through
the
material).
Recording
landing
catches
is
acceptable
practice
and
may
indeed
be
the
better
course
of
action
in
some
studies,
however
one
must
be
careful
interpreting
such
data
as
it
is
not
a
direct
measure
of
efficacy
as
described
below
in
Section
`
e'.

e.
Please
comment
on
the
scientific
and
ethical
issues
raised
by
the
design
of
studies
to
collect
data
sufficient
to
support
assessment
of
repellent
efficacy
using
the
two
different
efficacy
metrics:
time
to
first
confirmed
bite
(
TFCB),
and
time
providing
x%
protection
of
treated
subjects
from
bites
relative
to
untreated
controls
(
RP).

The
ethical
concerns
over
comfort
level
of
human
subjects
when
using
RP
can
be
addressed
by
ensuring
that
informed
consent
includes
this
particular
issue.
RP
is
a
more
realistic
assessment
of
insect
repellent
efficacy
and
should
be
used
as
the
benchmark.
If
TFCB
is
a
less
realistic
assessment
of
efficacy
and
is
used
to
test
and
subsequently
approve
a
repellent
for
widespread
usage,
this
could
present
its
own
ethical
problems
if
this
isn't
the
most
rigorous
test
of
the
product.

f.
Please
comment
on
appropriate
approaches
for
estimating
the
minimum
number
of
subjects
needed
to
evaluate
the
level
of
efficacy
of
a
repellent
in
laboratory
and
field
studies.
Repellent
efficacy
is
assessed
relative
to
an
individual
subject's
relative
attractiveness
to
an
insect;
therefore,
the
larger
the
number
of
subjects
participating,
the
greater
the
reduction
in
the
variation
of
the
attractiveness
between
individual
subjects.
Efforts
should
be
made
to
maximize
the
number
of
subjects
who
participate
while
adhering
to
a
solid
experimental
design
that
produces
statistically
robust
data.
Bearing
in
mind
that
usually
more
than
one
formulation
is
tested
(
and
perhaps
evaluated
in
comparison
with
the
DEET
"
gold
standard"),
it
is
best
to
conduct
a
greater
number
of
replicates
using
the
same
subject
(
i.
e.,
randomly
assign
each
treatment
to
a
subject
over
several
trials)
than
increase
the
number
of
subjects
(
i.
e.,
assign
only
one
treatment
to
a
subject
 
this
decreases
the
statistical
power!).
In
this
way,
each
treatment
would
be
evaluated
on
each
subject
(
i.
e.,
Latin
square
design);
for
instance,
6
subjects
are
required
for
6
treatments
 
where
a
"
treatment"
can
comprise
either
a
repellent
or
a
positive/
negative
control.

g.
Please
comment
on
whether
or
not
investigators
should
have
an
ethical
obligation
to
provide
subjects
of
repellent
efficacy
research
with
insurance
to
cover
possible
future
medical
costs
or
other
losses
that
result
from
injury
or
illness
experienced
by
the
subjects
as
a
consequence
of
their
participation
in
the
research.

Investigators
should
have
an
ethical
obligation
to
cover
any
medical
costs
for
situations
that
arise
while
a
subject
is
participating
in
a
trial.
It
is
the
ethical
obligation
of
the
investigator
to
inform
the
subject
of
all
possible
(=
conceivable)
risks,
injuries,
or
illness
that
the
subject
may
experience
while
participating
in
the
research.
Subjects
consent
to
participate
after
understanding
the
risks.
In
most
situations,
investigators
should
not
be
held
responsible
for
any
future
injury
or
illness
experienced
by
the
subjects
as
a
consequence
of
their
participation
in
the
research,
because
a
future
injury
or
illness
could
be
due
to
a
multitude
of
factors.
However,
responsibility
for
future
injury
or
illness
may
need
to
be
considered
if
field
trials
expose
subjects
to
vector­
borne
disease
(
malaria,
dengue,
etc.).
This
will
be
situational
dependent
and
any
risks
to
the
subject
and
future
responsibility
of
the
investigator
should
be
clearly
outlined
during
informed
consent.

h.
Please
comment
on
any
special
considerations
that
should
be
addressed
in
the
informed
consent
materials
provided
people
who
are
candidates
to
become
subjects
in
insect
repellent
efficacy
research.

(
1)
Verification
of
pregnancy
status
in
female
subjects
is
acceptable
as
determined
by
OTC
urine
dipstick
assay.
(
2)
Subjects
should
be
made
aware
that
the
repellent
being
tested
may
pose
different
hazards,
including
skin
exposure
and
inhalation.
(
3)
See
comment
to
Section
`
a'.

i.
Does
the
HSRB
recommend
that
the
draft
guideline
be
revised?
If
so,
please
explain
what
aspects
or
sections
might
improve
with
revision.

No
comment.