Document ID: EPA-HQ-ORD-2006-0384-0091
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-27T04:00Z

1
of
104
July
25,
2006
Minutes
of
the
United
States
Environmental
Protection
Agency
(
EPA)
Human
Studies
Review
Board
(
HSRB)
June
27­
30,
2006
Public
Meeting
Docket
Number:
EPA­
HQ­
ORD­
2006­
0384
Committee
Members:
(
See
Roster
­
Attachment
A)

Dates
and
Times:
Tuesday,
June
27,
2006;
1:
00
PM
 
6:
00
PM
Wednesday,
June
28,
2006;
8:
30AM
 
5:
30
PM
Thursday,
June
29,
2006;
8:
30AM
 
5:
30
PM
Friday,
June
30,
2006;
8:
30AM
 
3:
00PM
(
See
Federal
Register
Notice
 
Attachment
B)

Location:
EPA,
One
Potomac
Yard
(
South
Building),
2777
Crystal
Drive,
Arlington,
VA
22202
Purpose:
The
EPA
Human
Studies
Review
Board
(
HSRB)
provides
advice,
information,
and
recommendations
on
issues
related
to
the
scientific
and
ethical
aspects
of
human
subject
research.

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

Board
Members:
David
C.
Bellinger
Ph.
D.
William
Brimijoin,
Ph.
D.
*
Alica
Carriquiry,
Ph.
D.
Gary
L.
Chadwick,
PharmD,
MPH,
CIP
Janice
Chambers,
Ph.
D.
D.
A.
B.
T.*
Richard
Fenske,
Ph.
D.
MPH
Susan
S.
Fish,
PharmD,
MPH
Suzanne
C.
Fitzpatrick,
Ph.
D.
D.
A.
B.
T.
Kannan
Krishnan,
Ph.
D.
Michael
D.
Lebowitz,
Ph.
D.
FCCP
Lois
D.
Lehman­
McKeeman,
Ph.
D.
Jerry
A.
Menikoff,
M.
D.
Robert
Nelson,
M.
D.,
Ph.
D.
Sean
M.
Philpott,
Ph.
D.

Consultants:
Col.
Raj
Gupta,
Ph.
D.
Daniel
Strickman,
Ph.
D.

*
Recused
from
carbofuran
discussion
and
deliberation
2
of
104
Meeting
Summary:
Meeting
discussions
generally
followed
the
issues
and
general
timing
presented
in
the
Meeting
Agenda,
unless
noted
otherwise
in
these
minutes
(
Attachment
C).
3
of
104
April
27,
2006
Introductory
Remarks
and
Meeting
Administrative
Procedures
Dr.
Celia
Fisher,
(
HSRB
Chair)
began
the
meeting
by
thanking
the
Board
members
for
their
hard
work
in
preparing
for
the
meeting
and
invited
them
to
introduce
themselves.
Following
Dr.
Fisher's
introduction,
Dr.
George
Gray,
(
Science
Advisor,
EPA)
thanked
the
Board
for
its
work
at
this
and
previous
meetings.
Dr.
Gray
commented
that
at
this
meeting,
the
Board
would
be
reviewing
both
completed
and
proposed
pesticide
human
exposure
studies.
In
addition,
the
Board
would
review
guidelines
for
the
efficacy
of
insect
repellents.
Dr.
Gray
remarked
that
Dr.
Peter
Preuss,
as
Director
of
the
National
Center
for
Environmental
Assessment,
also
served
as
the
Agency's
Human
Studies
Research
Review
Official
(
HSRRO).
However,
the
Agency
was
pleased
to
announce
that
it
had
selected
a
full
time
HSRRO.
That
person
would
be
joining
the
Agency
shortly.
Finally,
Dr.
Gray
thanked
his
EPA
colleagues
and
said
that
he
was
looking
forward
to
hearing
the
Board's
deliberations.

Next,
Mr.
Jim
Jones
(
Director,
Office
of
Pesticide
Programs
[
OPP],
EPA)
welcomed
the
Board
to
OPP's
new
facility
for
this
and
future
HSRB
meetings.
When
the
HSRB
was
formed,
EPA
faced
statutory
deadlines
set
by
the
Food
Quality
Protection
Act
(
FQPA).
The
Agency
asked
a
lot
of
the
HSRB
to
meet
this
deadline
and
was
now
confident
that
the
deadline
would
be
met,
largely
due
to
the
support
of
the
Board.
Mr.
Jones
said
the
Board's
advice
has
been
valuable
and
that
after
this
meeting,
would
establish
a
more
regular
schedule
for
meetings.

Dr.
Fisher
asked
Mr.
Jones
for
clarification
on
existing
Agency
time
pressures
since
there
are
statutory
deadlines,
seasonal
limitations
on
testing,
and
time
limits
set
by
applicant
submissions
for
license.
Mr.
Jones
responded
that
commonly,
new
registrations
had
time
limits.
In
addition,
OPP
expected
to
announce
the
HSRB
meeting
schedules
and
hoped
that
applicants
would
factor
this
into
their
protocol
review
cycle.
Dr.
Fisher
asked
Mr.
Jones
for
OPP
to
provide
all
background
documents
to
the
HSRB
at
least
three
weeks
before
a
meeting
in
addition
to
providing
a
summary
to
the
Board
regarding
prioritization
of
documents
for
Board
review.
For
the
April
meeting,
there
was
a
linking
for
review
documents.
This
type
of
linking
would
be
helpful
for
review
documents
for
future
meetings.
Dr.
Fisher
remarked
that
while
the
Board
would
deliberate
on
issues
at
an
HSRB
meeting,
and
the
Chair's
minutes
would
attempt
to
capture
points
raised
at
the
meeting,
the
Board
recommendations
are
not
final
until
the
Board
had
completed
and
approved
its
meeting
report.
Mr.
Jones
responded
that
he
agreed
with
Dr.
Fisher's
conclusion.

Dr.
Paul
Lewis,
(
Designated
Federal
Officer
[
DFO],
HSRB,
Office
of
the
Science
Advisor
[
OSA],
EPA)
thanked
the
Board
and
EPA
in
preparing
for
this
meeting.
He
explained
that
the
HSRB
is
a
federal
advisory
board
and
is
subject
to
the
Federal
Advisory
Committee
Act
(
FACA)
guidelines.
As
the
DFO,
he
said
that
he
serves
as
a
liaison
between
HSRB
and
EPA,
stating
that
HSRB
meetings
are
public
and
all
materials
were
available
at
the
public
docket.
Concerning
the
insect
repellent
efficacy
studies
and
protocols,
Drs.
Raj
Gupta
and
Daniel
Strickman
would
act
as
consultants
to
the
HSRB.
Drs.
Chambers
and
Brimijoin
were
recused
from
all
discussions
on
carbofuran.
The
informational
presentation
on
the
Proposed
Workshop
on
Best
Practices
for
EPA,
National
Exposure
Research
Laboratory
Observational
Human
4
of
104
Exposure
Measurement
Studies
by
Dr.
Roy
Fortmann
(
NERL,
Office
of
Research
and
Development,
EPA)
was
moved
to
Friday
morning
on
the
meeting
agenda.

Dr.
Fisher
asked
EPA
for
clarification
on
the
Board
process,
specifically
some
sense
of
the
time
pressures
EPA
is
under
with
respect
to
receipt
of
Board
recommendations.
The
Agency
understood
that
if
the
applicant
begins
studies
without
a
final
Agency
decision
on
the
protocol,
the
applicant
proceeds
at
its
own
risk
and
that
the
protocol
may
be
rejected.
Similarly
OPP
has
proceeded
with
risk
assessments
based
on
what
it
understood
the
Board's
recommendation
to
be 
prior
to
approval
of
the
final
report
by
the
Board.
OPP
took
into
consideration
that
it
was
proceeding
without
the
Board's
recommendations
as
outlined
in
its
report.

Mr.
John
Carley
(
OPP,
EPA)
gave
an
update
on
EPA
follow­
up
to
HSRB
recommendations.
Mr.
Carley
reported
that
action
had
been
taken
on
4
of
the
8
compounds
discussed
at
the
April
meeting.
All
actions
taken
were
consistent
with
Board
recommendations.
One
of
these
actions
included
a
follow­
up
on
the
study
conducted
on
hexavalent
chromium
by
Chemrisk.
Attempts
to
investigate,
in
more
detail,
the
conduct
of
the
study,
were
not
successful.
The
principle
investigator,
Dr.
Nethercutt,
was
deceased,
and
Chemrisk
had
declared
bankruptcy
in
2000,
being
reconstituted
as
Exponent.

Dr.
Fisher
reviewed
the
process
for
meeting
operations.
HSRB
review
would
begin
with
a
presentation
by
EPA
on
the
scientific
and
ethical
considerations
of
the
studies
under
review.
These
presentations
would
be
followed
by
public
comments
and
the
Board's
discussion
of
the
scientific
and
ethical
considerations
of
the
principle
studies.
Scientific
considerations
would
precede
ethical
considerations
because
if
a
study
wasn't
scientifically
sound,
ethical
deficiencies
within
the
study
would
be
raised.
Scientific
considerations
would
include
dose
selection,
endpoint
selection,
participant
selection,
methodology,
and
statistical
analyses.
At
previous
meetings,
the
Board
found
single
dose
level
studies
to
have
limited
utility
except
when
interpreted
in
the
context
of
other
studies
conducted
under
comparable
conditions
or
when
they
showed
evidence
of
toxicity
at
a
lower
dose
than
other
studies
conducted
under
comparable
conditions.
Dr.
Fisher
also
reviewed
the
dose
criteria
established
by
the
Board
at
its
May
meeting.
In
response
to
an
EPA
written
comment
on
the
Board's
draft
May
2006
meeting
report,
Dr.
Fisher
asked
the
Board
if
this
dose
criteria
were
applicable
to
all
studies
reviewed
and
to
be
reviewed
by
the
Board.
Members
agreed
that
it
did.
The
Board's
ethics
evaluation
from
completed
studies
would
include
an
assessment
of
whether
the
study
met
prevailing
ethical
standards.
If
it
did
not,
the
study
would
be
considered
fundamentally
unethical.

Science
and
Ethics
of
Chloropicrin
Human
Studies
Dr.
Elissa
Reaves
(
OPP,
EPA)
provided
a
summary
of
the
Agency's
analysis
of
the
chloropicrin
human
study.
Chloropicrin
is
a
non­
selective
soil
fumigant
whose
primary
toxic
effect
is
sensory
irritation.
Chloropicrin
is
a
unique
soil
fumigant,
in
that
it
is
also
used
as
an
indicator
chemical,
or
warning
agent.
The
Agency
is
developing
an
assessment
to
estimate
inhalation
risk
to
bystanders
and
workers
from
acute
exposures
to
chloropicrin.

Chloropicrin
is
one
of
several
soil
fumigants
currently
under
review.
It
has
a
variety
of
uses:
agricultural
settings,
on
telephone
poles,
and
empty
grain
and
potatoes
storage
facilities.
5
of
104
Dr.
Reaves
reported
a
robust
database
for
chloropicrin
inhalation
studies
but
limited
port
of
entry
details
from
acute
studies.
The
chloropicrin
human
study
was
a
3
phase
study
with
127
individuals.
Since
the
ability
to
detect
chloropicrin
induced
irritation
declines
with
age,
exposed
subjects
were
young
adults
(
ages
18­
35).
Odor
detection,
eye
feel
and
nasal
feel
were
assessed
following
brief
exposures.
During
Phase
1,
the
duration
of
exposure
for
odor
detection
was
1­
2
seconds,
eyes
were
exposed
for
25
seconds,
and
nose
irritation
exposures
lasted
7
seconds
in
one
nostril.
Some
subjects
could
not
detect
chloropicrin
at
the
levels
tested.
Overall
strengths
of
the
study
included
the
determination
of
pertinent
odor
and
eye
thresholds
with
similar
responses
among
males
and
females.
Phase
2
was
conducted
in
a
walk­
in
chamber.
Severity
of
feel
was
not
a
parameter
in
Phase
2.
Subjects
were
asked
to
make
a
confidence
of
response
judgment.
The
walk
in
chamber
was
considered
a
more
appropriate
exposure
scenario
for
acute
bystander
exposure.
For
all
phases,
the
doses
were
low
to
high
and
included
both
sexes.
For
Phases
1
and
2
there
were
no
severity
scores,
no
physiological
parameters,
and
the
durations
of
exposure
were
not
equal.
Phase
3
was
designed
for
occupational
exposure
and
was
also
conducted
in
the
walkin
chamber.
Exposure
duration
was
60
minutes/
day
for
4
days.
Phase
3
included
clinical
examination
of
the
eyes,
nose
and
throat,
before,
during
and
after
exposure.
Perceptual
effects,
the
time
required
to
feel
irritation,
decreased
with
increasing
concentration.
Study
strengths
included
subjective
and
objective
measures
and
repeated
dosing.
Study
weakness
included
lower
concentrations,
as
studied
in
Phase
2,
and
not
being
examined
(
i.
e.
100
ppb)
in
Phase
3.

Dr.
Reaves
concluded
that
Phase
3
provided
physiological
parameters
for
eye
irritation
and
was
used
as
the
point
of
departure
(
POD)
for
chloropicrin.
The
BMDL10
of
73
ppb
was
based
on
eye
irritation
noted
during
Phase
3.
The
Agency's
Weight
of
Evidence
(
WOE)
document
and
Data
Evaluation
Records
(
DER)
for
chloropicrin
described
the
study
design
of
the
acute
inhalation
human
toxicity
study.
In
addition,
the
Agency
had
concluded
that
the
human
toxicity
study
was
appropriate
for
developing
a
POD
for
extrapolation
of
inhalation
risk
to
bystanders
and
workers
exposed
to
chloropicrin.

The
Board
began
its
initial
discussion
questioning
the
lack
of
confidence
intervals.
Dr.
Reaves
said
that
OPP
also
had
trouble
interpreting
the
data
and
had
to
call
the
chloropicrin
study
director
and
requested
the
Excel
spreadsheets
of
the
data.
Dr.
Fenske
said
that
it
was
impossible
for
the
Board
to
assess
the
study
without
this
information.
The
study
report
indicated
an
estimate
of
central
tendency
but
gave
no
measure
of
variability.
Dr.
Fisher
asked
what
impact
the
human
study
had
on
limit
setting
and
whether
there
was
an
alternative
to
human
dosing.
Dr.
Reaves
responded
that
the
use
of
the
human
study
data
raised
the
POD
one
order
of
magnitude
because
a
10X
uncertainty
factor
was
eliminated.
In
terms
of
animal
studies,
rodent
odor
studies
were
not
useful.
While
animals
could
be
trained,
this
would
be
expensive
and
would
not
follow
Agency
guidelines.
However,
chloropicrin
does
have
a
solid
animal
toxicity
data
base.
Mr.
Jones
explained
that
a
decision
on
chloropicrin
was
needed
by
2008,
but
that
there
were
other
time
pressures,
including
an
international
interest
to
eliminate
methyl
bromide
(
a
fumigant),
and
an
EPA
commitment
to
move
through
decisions
on
all
soil
fumigants
quickly.
Historically,
chloropicrin
has
been
used
for
its
detection
properties,
but
pesticidal
use
is
on
the
rise
as
the
use
of
methyl
bromide
has
been
more
restricted.

Dr.
Fenske
asked
why
Phase
2
was
not
used
to
inform
the
POD
for
chloropicrin
since
Phase
3
was
designed
for
occupational
purposes.
The
Phase
3
assessment
included
a
benchmark
6
of
104
of
eye
irritation
to
be
protective
of
the
inhalation
exposure.
Dr.
Lowit
(
OPP,
EPA)
asked
the
Board
to
recall
the
MITC
eye­
irritation
study.
The
chloropicrin
study
was
a
stronger
study
because
it
utilized
a
walk­
in
chamber.
Dr.
Lowit
stressed
that
the
use
of
this
study
was
not
solely
to
reduce
the
POD
but
also
to
assess
physiological
parameters
and
reduce
risk
to
workers.
Dr.
Lebowitz
stressed
that
you
cannot
estimate
inhalation
risk
from
any
other
route
of
exposure
besides
inhalation
exposure.
Dr.
Fenske
followed
by
clarifying
that
in
Phase
2,
there
were
20­
30
minute
exposure
intervals.
He
was
concerned
that
a
lower
dose
was
not
included
in
Phase
3
given
the
results
of
Phase
2
at
the
lower
dose.
Dr.
Reaves
clarified
that
for
Phase
2,
there
was
no
measure
of
the
severity
of
effects.
Dr.
Brimijoin
asked
how
the
Agency
intended
to
address
acute
versus
chronic
effects
since
the
human
studies
all
dealt
with
short­
term
exposure.
Dr.
Reaves
said
that
the
animal
data
would
be
used
to
assess
chronic
effects
but
chronic
exposures
were
not
expected
given
chloropicrin's
use
as
a
soil
fumigant.

Mr.
John
Carley
(
OPP,
EPA)
provided
a
review
of
the
ethics
of
the
chloropicrin
human
study.
Mr.
Carley
explained
that
when
the
study
was
received,
it
did
not
include
sufficient
information
to
allow
for
an
ethics
review.
Supplemental
information
was
disorganized
and
did
not
address
key
ethical
considerations.
Mr.
Carley
summarized
the
framework
for
the
study
starting
with
the
study's
value.
The
study
explored
the
lower
threshold
of
human
sensitivity
to
chloropicrin
and
the
relationship
between
sensory
awareness
of
chloropicrin
and
potential
effects
of
exposure
to
the
pesticide.
As
such,
the
study
provided
information
of
potential
value
in
assessing
bystander
and
worker
risks
associated
with
chloropicrin
exposure.
Subject
screening
factors
were
well­
documented
and
consistent
with
the
scientific
goals
of
the
study.
The
racial
make­
up
of
the
subject
group
closely
matched
the
demographics
of
the
student
population
at
UCSan
Diego.
No
noteworthy
ethical
deficiencies
were
apparent
when
this
study
was
reviewed
against
the
standards
of
the
Common
Rule
or
the
requirements
of
FIFRA
§
12(
a)(
2)(
P).
Remaining
gaps
in
the
record
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.

Public
Comments
Dr.
Robert
Sielkin,
Jr.,
of
Sielkin
and
Associates
Inc.,
and
Dr.
John
Butala,
of
Toxicology
Consultants,
on
behalf
of
the
Chloropicrin
Manufacturers
Task
Force
Dr.
Sielkin
began
the
discussion
stating
that
prior
to
any
human
exposures,
a
statistical
analysis
of
the
proposed
human
sample
sizes
was
done
to
assure
that
the
study
had
sufficient
power.
This
analysis
was
done
to
determine
the
sample
size
such
that
the
sample
proportion
detecting
a
chloropicrin
concentration
was
sufficiently
close
to
a
true
population
proportion
that
would
detect
it.
Phase
3
had
80%
power
of
observing
at
least
one
respiratory
irritation
in
32
individuals.
The
study
design
did
involve
repeated
exposures
over
a
number
of
days.
Assuming
50%
correlation
between
first
day
and
each
subsequent
exposure
day,
the
Phase
3
study
had
80%
power
of
observing
at
least
one
respiratory
irritation
in
32
individuals.
It
was
assumed
that
each
individual's
probability
of
a
respiratory
irritation
following
an
exposure
session
at
0.1
ppm
chloropicrin
is
at
least
0.008
and
the
individual
probability
of
a
respiratory
irritation
following
an
exposure
session
at
0.15
ppm
is
1.5
times
that
at
0.10
ppm.
7
of
104
Dr.
Butala
commented
that
the
animal
data
base
for
inhalation
of
chloropicrin
is
fairly
extensive
and
follows
EPA
guidelines.
The
human
study
demonstrated
that
humans
could
detect
chloropicrin
at
levels
far
below
the
NOAEL
thresholds
based
on
human
studies.
Phases
1
and
2
informed
the
selection
of
dose
levels
for
Phase
3.
The
BMD
calculation
does
allow
for
the
derivation
of
a
threshold
below
the
lowest
dose
tested.
Dr.
Fenske
asked
how
one
could
account
for
subject
selection
that
excluded
subjects
with
eye
irritation
from
any
other
source.
Statistics
could
not
overcome
other
limitations
placed
on
the
subject
population.
Subject
selection
of
the
younger
adult
group
was
biased
to
find
sensitive
subjects.
The
public
commenter
indicated
that
the
concept
of
eliminating
people
with
previous
occupational
exposure
or
other
physiological
irritation
made
the
study
more
sensitive.

Dr.
Jennifer
Sass
of
the
Natural
Resources
Defense
Council
Dr.
Sass
stated
that
NRDC
had
concerns
that
the
chloropicrin
study
violated
several
ethical
standards.
The
study
report
did
not
admit
that
students
experienced
any
adverse
effects
beyond
slight
eye
or
nose
irritation.
In
addition,
there
was
no
medical
follow­
up.
Existing
studies
showed
effects
at
low
doses.
Thus
Dr.
Sass
wondered
how
this
study
was
beneficial
for
society.
Participants
must
be
fully
informed,
free
to
withdraw
and
receive
compensation
even
if
they
withdrew.
The
study
wasn't
scientifically
valid
and
did
not
have
sufficient
statistical
power.
Precise
adverse
effects
and
risk
were
not
disclosed.
Finally,
exposure
at
up
to
10x
the
occupational
limit
was
not
justified.

Charge
to
the
Board
Chloropicrin
is
a
non­
selective
soil
fumigant
whose
primary
toxic
effect
is
sensory
irritation
in
which
stimulated
free
nerve
endings
mediate
sensations
and
clinical
signs
in
the
nose,
eyes,
throat,
and
upper
respiratory
tract.
Chloropicrin
is
a
unique
soil
fumigant
in
that
it
is
also
used
as
an
indicator
chemical
or
warning
agent
(
2%
or
less
by
weight
in
formulations).
The
Agency
is
developing
an
assessment
to
estimate
inhalation
risk
to
bystanders
and
workers
from
acute
exposures
to
chloropicrin.

1.
Scientific
considerations
The
Agency's
"
Weight
of
Evidence"
(
WOE)
document
and
Data
Evaluation
Records
(
DER)
for
chloropicrin
describe
the
study
design
of
the
acute
inhalation,
human
toxicity
study.
The
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
inhalation
risk
to
bystanders
and
workers
exposed
to
chloropicrin.

Please
comment
on
whether
the
study
is
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
inhalation
exposure
to
chloropicrin.

Board
Response
to
the
Charge
Dr.
Lebowitz
began
Board
discussion
by
noting
that
Phase
1
considered
very
short­
term
exposures
discussed
in
terms
of
the
NIOSH
PEL.
The
methods
used
are
considered
state­
of­
the
art.
There
was
a
feeling
detected
in
the
eyes
of
subjects.
Phase
2
considered
20­
30
minute
8
of
104
exposures
in
a
chamber
and
included
repeated,
albeit
short
exposures.
Some
subjects
did
respond
at
the
lowest
dose
(
50ppb).
Phase
3
investigated
eye,
nose
and
throat
irritation
for
several
days.
One
limitation
was
no
lower
dose
level.
By
selecting
healthy
subjects,
subjects
with
existing
inflammation
were
excluded.
The
study
included
good
subjective
and
objective
measures
of
exposure
and
reasonable
statistical
analysis.
Consecutive
exposures
did
not
seem
to
matter
since
there
was
no
day­
to­
day
increase
in
response.
Most
of
the
standards
were
plus
or
minus
3%
of
the
measure
and
no
lower
airway
effects
were
noted.
The
nasal
passage
cytology
did
not
show
significant
irritation.
Dr.
Lebowitz
concluded
that
the
study
was
reasonably
sound
from
a
scientific
perspective
but
he
did
not
think
the
most
sensitive
subjects
were
included.

Dr.
Fenske
said
he
could
not
review
the
study
as
presented
because
the
data
were
not
presented
in
a
decipherable
fashion.
There
were
no
column
headings
and
the
Board
was
left
with
graphs
of
average
responses
over
time.
There
was
no
way
to
check
the
Agency's
analysis
because
the
data
were
not
available.
It
is
clear
that
certain
populations
were
excluded
because
those
with
eye
problems,
chemical
hypersensitivity,
or
previous
occupational
exposure
were
excluded.
Subject
selection
did
introduce
some
bias.
It
was
his
understanding
that
Phase
2
was
more
relevant
to
by­
stander
exposure.
Almost
25%
of
the
study
population
expressed
confidence
about
being
exposed
to
chloropicrin,
but
this
may
or
may
not
be
an
adverse
effect.
Phase
3
was
designed
to
address
occupational
exposure
but
he
did
not
understand
why
a
lower
dose
was
not
included.
The
investigators
focused
on
Phase
3
for
risk
assessment
which
included
30
minute
exposures
for
4
days.

Dr.
Chambers
said
that
the
study
was
well­
designed,
went
from
short­
term
to
longer
term
exposures,
and
identified
eye
irritation
as
the
most
sensitive
endpoint.
She
shared
concerns
that
a
lower
dose
was
not
included
in
Phase
3
and
felt
that
some
more
credence
might
be
given
to
Phase
2
for
limit
setting.

Dr.
Fisher
commented
that
the
study
might
be
well­
designed
but
did
not
provide
enough
supporting
data.
Board
discussion
noted
that
the
lack
of
chronic
data
was
considered
less
important
because
chronic
exposure
to
chloropicrin
was
not
expected.
There
are
custom
applicators
who
start
in
Florida
and
move
north
with
the
seasons
but
even
they
were
not
expected
to
be
exposed
for
180
days
per
year.
Soil
fumigants
are
typically
used
once
a
year.
The
human
study
is
only
being
used
to
inform
the
acute
threshold
limit
setting.
Given
the
selective
population
used
in
the
study,
some
additional
factor
might
be
needed
to
protect
for
bystander
populations.
Discussion
on
the
charge
to
the
Board
followed
and
Dr.
Fisher
asked
for
some
clarification
on
whether
a
human
study
was
required
to
answer
the
question
at
hand.
Dr.
Lebowitz
said
that
in
most
cases,
the
same
effects
at
the
same
doses
in
an
animal
study
would
not
be
seen.
Also,
subjective
responses
were
difficult
to
assess
with
animal
subjects.

Dr.
Fisher
summarized
the
Board
findings
as
follows:
the
study
was
well­
designed
and
provided
information
on
acute
exposure
and
interspecies
variability.
There
was
Board
concern
about
the
lack
of
one­
to­
one
correspondence
with
the
levels
used
in
Phase
2
and
Phase
3.
The
study
did
provide
useful
information
for
occupational
exposures.
The
study
may
be
used
for
bystander
populations
but
consideration
should
be
given
to
the
fact
that
bystander
populations
may
include
more
sensitive
individuals.
9
of
104
Charge
to
the
Board
2.
Ethical
considerations
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

a.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
Cain
study
was
fundamentally
unethical?

b.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Board
Response
to
the
Charge
Dr.
Menikoff
said
that
the
study
met
prevailing
ethical
standards,
exposed
subjects
to
relatively
low
risk
and
was
ethically
appropriate.
Informed
consent
for
Phase
3
may
have
been
deficient
because
it
characterized
side­
effects
as
minor.
Exposure
at
greater
amounts
was
characterized
as
completely
reversible.
A
publication,
"
Chemicals
in
War",
described
chloropicrin
as
a
lethal
compound
that
acts
primarily
as
a
lung
irritant.
It
was
the
major
toxic
gas
used
in
WWI
and
can
kill
people
at
high
levels.

Dr.
Nelson
stated
that
the
study
was
almost
contemporary
but
was
judged
as
a
retrospective
study.
In
terms
of
exculpatory
language
in
the
informed
consent
document,
the
language
was
more
exclusionary
than
what
is
typically
used.
Dr.
Nelson
did
not
believe
that
language
regarding
chloropicrin's
use
in
war
should
have
been
included
in
the
informed
consent
documents.
Dr.
Menikoff
said
that
if
there
were
screening
procedures,
subjects
should
have
been
asked
for
consent
before
screening.
During
screening
studies,
subjects
should
have
been
asked
to
complete
a
full
health
history.
If
consent
was
not
given
until
after
screening,
this
would
have
been
an
ethical
flaw.
Dr.
Fenske
commented
that
the
MSDS
for
chloropicrin
said
that
the
OSHA
limit
for
immediately
dangerous
to
life
and
health
was
2000
ppm.
The
TLV/
TWA
excursion
limits
were
never
exceeded
by
the
study.
While
there
was
momentary
exposure
at
1200
ppm
during
Phase
1,
this
was
a
graded
exposure.

Dr.
Fisher
summarized
the
Board's
conclusions
indicating
that
the
Board
would
have
appreciated
informed
consent
documents
to
include
additional
information
on
adverse
effects
at
higher
concentrations,
different
exculpatory
language,
and
more
information
on
whether
screening
subjects
were
given
informed
consent.
However,
there
was
no
clear
and
convincing
evidence
that
the
study
was
fundamentally
unethical
or
ethically
deficient.

Agency
Clarifying
Remarks
on
Chloropicrin
Mr.
Jones
provided
clarification
on
the
Agency's
intention
to
raise
or
lower
the
levels
of
protection
based
on
human
studies.
For
all
the
compounds
considered
under
the
FQPA,
the
Agency
was
raising
the
level
of
protection.
The
question
was,
how
much
more
protective
did
the
Agency
need
to
be.
All
the
compounds
presented
so
far
to
the
Board
were
older
compounds
that
had
been
in
use
for
many
years.
10
of
104
Insect
Repellent
Product
Performance
Testing
Guideline
Mr.
Jones'
comments
were
followed
by
a
presentation
of
the
science
and
ethics
of
insect
repellent
product
performance
testing
guidelines
by
Mr.
Kevin
Sweeney
(
OPP,
EPA),
Dr.
Clara
Fuentes
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA).
Mr.
Carley
explained
that
the
Agency
generally
only
published
guidelines
for
required
studies
and
was
committed
to
harmonization
with
other
offices
within
EPA
and
with
NAFTA
partners.
One
important
point
to
keep
in
mind
about
guidelines
was
that
they
were
not
rules.
Instead
they
are
advisory.
Deviations
from
guidelines
was
possible
but
needed
to
be
justified.
Likewise,
following
guidelines
was
no
guarantee
that
a
study
would
be
accepted.
The
context
for
the
repellants
could
be
found
in
OPPTS
Guidelines
810
3000,
3300,
3400,
3500
and
3700.
EPA
classifies
repellants
as
public
health
products,
therefore
product
safety
performance
data
are
required.
In
the
DEET
Reregistration
Eligibility
Decision
(
RED),
EPA
proposed
to
require
efficacy
data
for
each
registered
product
containing
DEET.
In
2001,
EPA
decided
to
postpone
further
work
on
guidelines
until
human
testing
issues
were
resolved.
In
2006,
the
final
human
subject
rule
was
published,
making
research
involving
intentional
exposure,
include
insect
repellent
efficacy
testing,
subject
to
HSRB
review.

Mr.
Sweeney
reviewed
key
issues
to
be
addressed
beginning
with
the
purpose
of
the
guideline
for
topically
applied
repellants.
There
were
no
alternative
hosts
and
no
good
substitutes
to
evaluate
efficacy
of
insect
repellants.
Thus,
human
subjects
were
needed.
Products
were
developed
for
use
on
human
subjects
to
prevent
disease
transmission.
Since
this
was
an
intentional
exposure,
ethical
requirements
covered
by
the
guidelines
included:
subject
selection,
risk
minimization,
independent
oversight,
voluntary
participation
and
fully
informed
consent.
Risks
included
allergic
reaction
to
the
repellent,
allergic
reaction
to
insect
bite,
and
disease
transmission.
Most
repellants
did
not
have
a
toxic
mode
of
action
and
are
of
low
toxicity.
The
primary
route
of
exposure
was
dermal.
Developing
an
effective
repellant
involves
complex
computerized
modeling
beginning
with
chemical
properties,
host
triggers
and
acute
toxicity
studies.
Full­
scale
efficacy
testing
would
likely
occur
only
late
in
the
development
cycle.
The
Agency
would
like
to
have
single
and
multiple
dose
human
toxicity
studies,
dermal
absorption
studies,
pharmacokinetics,
structure
activity
relationship
studies
and
lab
studies
with
disease
free
biting
arthropods
before
a
repellant
was
tested
in
the
field.

Dr.
Fuentes
discussed
advice
from
the
2000
Science
Advisory
Panel
(
SAP)
starting
with
the
recommendation
that
only
field
studies
be
used
to
determine
efficacy
of
skin­
applied
repellants.
She
said
that
tick
and
chigger
studies
were
hard
to
conduct.
In
addition,
exposure
to
tick
and
chigger
bites
was
hard
to
avoid
and
Rocky
Mountain
Spotted
Fever
and
Lyme
disease
were
risks
associated
with
tick
and
chigger
bites.
In
many
areas
of
the
U.
S.,
mosquitoes
transmit
West
Nile
Virus
and
it
was
difficult
to
differentiate
between
mosquito
vectors.
West
Nile
virus
is
wide
spread
and
has
moved
from
east
to
west,
Lyme
disease
is
more
focused
in
the
northeastern
US
while
Rocky
Mountain
Spotted
Fever
is
more
sporadic.
Dr.
Fuentes
provided
a
definition
of
terms
describing
arthropod
behavior.
11
of
104
Following
Dr.
Fuentes'
presentation,
Mr.
Sweeney
demonstrated
the
method
used
to
test
repellant
efficacy
in
laboratory
studies
as
described
in
the
Agency's
guidelines.
Mr.
Sweeney
was
assisted
by
Dr.
Robin
Todd
and
Mr.
Nick
Spero
of
Insect
Repellent
and
Control,
Inc.

The
Chair
adjourned
the
meeting
for
the
day.
12
of
104
April
28,
2006
The
Chair
reconvened
the
meeting
the
following
morning
beginning
with
comments
on
the
insect
repellent
product
performance
testing
guidelines.

Public
Comments
Dr.
Scott
P.
Carroll
on
behalf
of
Carroll­
Loye
Biological
Research
Dr.
Carroll
began
by
saying
that
he
is
a
proponent
of
insect
repellents,
including
DEET
alternatives.
Over
time
he
has
seen
less
new
product
development.
He
was
involved
with
the
Armed
Forces
Pest
Management
Board
tasked
with
searching
for
alternatives
to
DEET
and
he
had
previously
commented
on
the
insect
repellent
guidelines.
The
spread
of
West
Nile
Virus
had
made
public
interest
in
repellants
high
and
had
increased
the
military's
need
for
such
products.
Dr.
Carroll's
research
puts
emphasis
on
probes
and
landings
with
intent
to
bite
(
LIB).
The
Agency
should
consider
a
LIB
approach
compared
to
relative
protection
(
RP)
since
RP
could
result
in
an
overexposure
of
bites.
LIB
is
a
possible
alternative
to
reduce
subject
risk.
The
Agency
should
consider
six
as
the
minimum
number
of
subjects.
This
is
a
small
number
of
subjects
and
may
promote
excessive
exposure
to
fewer
subjects.
The
Agency's
guideline
asked
researchers
to
use
consumer
dosing
but
this
requires
dosimetry
data
which
may
require
additional
HSRB
review.

Following
his
public
comments,
the
Board
asked
Dr.
Carroll
about
how
field
studies
were
conducted.
Dr.
Carroll
said
that
field
studies
were
conducted
with
the
goal
of
zero
bites.
Dr.
Carroll
served
as
an
untreated
control.
Dr.
Carroll
was
asked
how
effective
trained
subjects
were
in
terms
of
getting
mosquitoes
before
they
bite.
Dr.
Carroll
said
that
there
was
little
data
to
quantify
this
but
that
in
his
field
studies,
after
a
few
exposure
periods,
subjects
tried
to
attract
mosquitoes.
Dr.
Brimijoin
asked
why
DEET
alternatives
were
needed.
Dr.
Carroll
explained
that
DEET
causes
rashes,
has
an
unpleasant
taste
and
odor
and
leaves
an
oily
residue.
Repellant
efficacy
varied
among
test
subjects
and
mosquito
species,
so
there
were
good
reasons
to
seek
alternatives.
Tests
were
conducted
in
areas
where
you
would
expect
one
bite
per
untreated
limb
per
minute.
Dr.
Lebowitz
asked
how
Dr.
Carroll's
metric
LIB
compares
to
EPA
metrics
and
whether
studies
had
been
conducted
under
a
variety
of
temperatures
and
humidities.
Dr.
Carroll
commented
that
his
testing
regime
would
not
work
in
tropical
environments
because
mosquito
behavior
is
different
in
these
environments.
Dr.
Carroll
said
that
they
had
not
attempted
night
time
work
and
that
most
studies
were
conducted
with
a
reliable
biting
rate
so
most
studies
were
conducted
at
between
80­
100
oF
with
high
humidity.
One
would
expect
repellant
failure
at
lower
temperatures
but
there
had
been
little
systematic
work
done
to
look
at
these
parameters.

Dr.
Lehman­
McKeeman
said
that
dose
is
critical
to
the
interpretation
of
repellant
studies
and
asked
Dr.
Carroll
how
dose
was
determined.
Dr.
Carroll
said
that
based
on
the
history
of
repellant
use,
a
standard
dose
of
1ml/
600
cm2
was
used.
This
comes
from
military
studies
that
measured
an
area
of
the
forearm
in
many
subjects.
Dr.
Carroll
said
that
an
n=
20
would
be
nice
but
expensive,
an
n=
10
would
be
more
affordable.
Dr.
Carroll
said
that
EPA
was
not
requiring
field
studies
for
ticks
because
there
was
tremendous
variation
within
tick
populations.
Dr.
Fisher
inquired
about
the
risk
of
vector­
borne
disease
in
field
studies.
Dr.
Carroll
said
that
there
were
13
of
104
statistical
measures
for
evaluating
risk
in
a
given
area.
While
epidemiologists
could
study
the
risk
of
disease
in
a
population,
field
studies
should
specifically
avoid
areas
with
any
significant
West
Nile
Virus
and
was
assessed
using
sentinel
chicken
flocks.

Dr.
Fitzpatrick
asked
if
some
subjects
were
more
susceptible
to
bites
and
how
do
you
address
controls.
Dr.
Carroll
explained
that
he
acts
as
the
control
and
feels
he
is
average
with
respect
to
susceptibility
to
bites.
Dr.
Carriquiry
expressed
concerns
with
using
Dr.
Carroll
as
the
average
control.
Dr.
Carroll
explained
that
he
wanted
to
minimize
the
number
of
subjects
potentially
exposed
to
vector­
borne
diseases.
He
said
that
he
would
be
uncomfortable
with
a
high
number
of
untreated
controls.
Dr.
Carriquiry
said
that
the
appropriate
number
of
controls
needed
could
be
calculated.
Dr.
Carroll
said
that
this
was
easy
with
a
large
number
of
subjects,
but
in
the
field
it
was
more
difficult.
Dr.
Fisher
asked
about
statistical
power
and
said
that
the
methodological
framework
seemed
limited.
Dr.
Carroll
said
that
the
method
was
flexible
and
that
a
sample
size
of
six
is
more
common
than
an
n=
10
because
it
is
the
minimum
number
allowed
by
the
Agency's
draft
guidelines.
Dr.
Carriquiry
questioned
that
since
there
was
a
risk
to
subjects
from
vector­
borne
disease,
why
could
not
all
the
tests
be
conducted
in
the
laboratory?
This
would
enable
greater
flexibility
with
the
number
of
subjects.
Dr.
Carroll
responded
that
the
laboratory
model
might
be
appropriate
in
many
instances,
but
field
testing
still
needed
to
be
done.
He
commented
that
the
risk
of
vector­
borne
disease
transmission
is
lower
than
expected.
Dr.
Nelson
asked
what
the
scientific
objective
was
for
conducting
field
tests;
the
need
for
negative
controls
in
the
field
was
unclear
to
Dr.
Nelson.
Dr.
Carroll
said
that
negative
controls
were
used
to
assess
biting
pressure.
While
there
are
efficacy
data
from
the
laboratory,
the
behavior
of
wild
animals
was
being
observed
in
the
field.
Negative
controls
in
the
field
quantified
repellant
efficacy
over
time.

Consultants
to
the
Board
Dr.
Daniel
Strickman
Dr.
Strickman
began
his
remarks
by
indicating
that
the
purpose
of
such
discussion
should
focus
on
truth
in
labeling.
When
a
manufacturer
claims
eight
hours
protection
from
mosquitoes,
ticks
and
chiggers
we
want
to
know
whether
this
is
true.
There
are
huge
differences
between
the
4000
species
of
mosquitoes,
28
stable
flies,
etc.
In
addition,
considering
a
5­
10
fold
difference
between
individuals
and
label
claims
for
efficacy
can
be
subjective.
Variations
in
temperature
and
humidity
have
been
tested
in
the
laboratory
and
do
have
a
large
impact
on
efficacy;
repellant
efficacy
can
be
significantly
reduced.
Product
formulation
may
be
as
important
as
active
ingredient.
Experimental
repellants
with
liposomes
may
provide
24
hours
protection
by
binding
with
the
upper
layer
of
skin.
The
other
complication
in
dosing
is
just
how
much
faith
you
can
put
on
following
label
directions.
Dr.
Strickman
also
commented
on
the
laboratory
and
field
studies.
Comparing
field
studies
is
difficult
but
the
difference
between
the
laboratory
and
the
field
is
key.
A
repellant
is
intended
to
reduce
bites,
but
to
the
insect,
a
repellant
can
do
many
things.
The
insect
has
to
find
the
subject
using
multiple
chemical
signals.
Quantification
of
repellant
protection
can
be
represented
with
a
sigmoidal
curve.
We
are
up
at
the
top
where
the
curve
starts
to
flatten
out.
On
the
ends
of
the
curve,
precision
is
very
low
which
is
why
we
look
at
LD50s.
Dr.
Strickman
said
that
one
could
be
better
served
to
look
at
90%
repellency
rather
than
95%
acceptable
for
disease
control.
14
of
104
Dr.
Fisher
said
that
truth
in
labeling
is
important,
but
subject
protection
is
also
important.
Dr.
Nelson
said
that
rather
than
using
a
negative
control,
a
measure
of
biting
pressure
was
needed.
A
measure
of
efficacy
in
the
laboratory
needed
to
be
compared
to
a
measure
of
product
efficacy
in
the
field
under
varying
conditions.
The
first
step
for
IRB
review
was
to
minimize
risk.
The
PI
needed
to
explain
study
objectives
and
why
a
negative
control
was
needed.
Traps
might
be
adequate
to
assess
biting
pressure.
Dr.
Chadwick
asked
whether
some
repellants
were
stronger
than
others.
Dr.
Strickman
said
that
percent
active
ingredient
were
not
being
tested,
formulations
were
being
tested.

Col.
Raj
K.
Gupta,
Ph.
D.

Dr.
Gupta
stated
that
repellency
can
vary
both
day­
to­
day
and
by
the
time
of
day.
Feeding
behaviors
were
based
on
complex
chemical
signaling
so
product
registration
was
always
complex.
More
products
provide
consumers
with
more
choices,
but
required
consumers
to
be
more
educated.
Soldiers
had
been
the
target
population
for
many
studies
but
while
they
were
doing
research
and
development,
the
armed
services
followed
the
same
rules
as
commercial
product
sponsors.
Research
began
with
the
discovery
phase
to
answer
basic
science
questions.
Next,
the
concept
phase
asked
what
would
be
better
than
what
was
already
available.
During
the
exploratory
phase,
the
study
would
be
designed.
This
was
followed
by
the
laboratory
or
field
phase.
Field
studies
were
used
to
validate
laboratory
studies
and
should
simulate
actual
conditions
for
product
use.
The
studies
were
designed
to
address
concerns
or
meet
objectives.
Each
study
should
be
independently
designed
and
conducted.
The
average
person
used
repellant
products
differently
to
the
application
procedure
in
a
laboratory.
There
were
numerous
studies
that
provided
adequate
information
on
efficacy,
but
most
of
these
studies
were
done
from
a
pharmaceutical
perspective.

Meeting
Process
Dr.
Fisher
introduced
the
subject
of
the
amount
of
material
received
for
this
meeting,
10,000
pages
of
material
with
less
than
2
weeks
for
review.
Several
Board
members
expressed
concerns
about
being
a
deliberative
body
with
so
much
information
to
review
and
so
little
time.
Board
members
needed
advance
notice
of
what
to
expect
and
an
annotated
bibliography
so
that
materials
could
be
organized
and
accessible;
similarly
to
the
way
the
Board
materials
were
organized
for
the
April
2006
meeting.

Dr.
Fisher
made
some
comments
on
the
specifics
of
the
meeting.
This
included:
greater
time
needed
for
Board
discussion
of
their
draft
science
and
ethics
criteria
of
proposed
human
studies
research;
she
asked
for
clarification
from
OPP
for
the
need
for
the
urgency
of
the
chloropicrin
review
since
Agency
decisions
were
not
needed
until
2008,
and
the
need
for
the
EPA
NHEERL
presentation
since
no
background
materials
were
provided.
Dr.
Fisher
asked
that
unless
there
was
a
critical
reason
that
the
Board
hear
the
EPA
NHEERL
presentation,
that
it
be
removed
from
Friday's
agenda.
Dr.
Fisher
remarked
that
the
HSRB
Chair
sets
the
agenda
for
the
meeting,
in
consultation
with
the
Agency.
Several
other
Board
members
shared
Dr.
Fisher's
concern
regarding
the
primary
role
of
the
Chair
in
setting
the
agenda.
Dr.
Fisher
asked
for
15
of
104
clarification
of
OPP's
view
on
whether
the
Board,
with
the
leadership
of
the
Chair,
set
the
agenda
or
whether
OPP
set
the
agenda.

Mr.
Jones
responded
that
although
chloropicrin
is
not
subject
to
the
FQPA
deadline
of
August
30,
2006,
review
was
needed.
As
a
soil
fumigant,
decisions
on
chloropicrin
affect
methyl
bromide
and
there
is
global
interest
in
reducing
the
use
of
methyl
bromide.
In
terms
of
review
materials
and
time,
the
Agency
was
willing
to
work
with
the
Board
and
that
the
Board
sets
the
agenda.
Several
Board
members
asked
that
in
recognizing
that
the
Chair,
neither
EPA
nor
EPA/
OPP
set
the
agenda,
that
prior
to
the
Agency
organizing
materials
for
each
Board
meeting,
the
Chair
would
convene
a
discussion
about
the
agenda
with
HSRB
DFO,
EPA
OSA,
and
the
Agency
relevant
program
office
(
e.
g.
EPA/
OPP)
requesting
review
by
the
Board.
Mr.
Jones
agreed
that
there
needed
to
be
a
3­
way
dialog
on
the
agenda.
It
would
provide
the
tools
needed
to
make
reviews
easier.
Dr.
Fisher
said
that
EPA
needed
to
establish
priorities
for
each
meeting.
For
example,
it
would
have
been
helpful
for
OPP
to
provide
a
rationale
for
why
the
Board
was
asked
to
advise
on
insect
repellants
when
it
was
also
looking
at
protocols
for
agricultural
handlers?
Dr.
Lehman­
McKeeman
said
that
with
respect
to
the
May
report,
the
Board
was
told
that
OPP
was
doing
some
calculations
for
carbofuran.
The
Board
would
like
to
see
these
BMD
calculations
and
the
confidence
intervals
around
this
value.
EPA
agreed
to
deliver
the
materials
to
the
Board
during
the
meeting.
The
Board
wanted
to
know
why
they
were
issued
generic
protocols
for
insect
repellants
and
agricultural
handlers.
Mr.
Carley
explained
that
the
Board
needed
to
look
at
protocols
before
decisions
were
made.
The
generic
repellant
protocols
were
provided
for
specific
discussion
on
subject
selection
and
the
agricultural
handler
protocol
was
provided
as
a
blank
workbook.
This
should
have
been
explained.
The
Emanuel
approach
was
intended
for
protocol
review,
so
the
structure
fit
nicely
but
the
Agency
is
receptive
to
another
approach.
Dr.
Fisher
noted
that
the
Board
had
expressed
concern
at
previous
meetings
about
applying
the
Emanuel
approach
for
review
of
protocols,
it
may
not
be
appropriate
for
this
purpose.
Dr.
Fisher
suggested
the
Agency
consider
a
different
model;
especially
one
that
placed
greater
emphasis
on
evaluating
the
risks
and
benefits
of
the
research.
Finally,
Dr.
Fisher
expressed
concern
that
EPA
was
asking
the
Board
for
tacit
approval
of
the
generic
protocols,
when
the
Board
was
not
asked
to
specifically
advise
on
this.
She
added
that
the
Board
should
not
be
perceived
to
provide
review
of
generic
protocols.
Instead
its
charge
is
to
provide
advice
and
recommendations
on
specific
protocols,
the
focus
of
this
meeting.

Dr.
Fisher
asked
for
Board
discussion
on
the
meeting
agenda
moving
forward.
Dr.
Nelson
felt
that
the
guideline
discussion
should
go
first.
Dr.
Fish
seconded
this
order
and
said
that
it
would
be
wrong
to
look
prospectively.
Dr.
Preuss'
presentation
was
informational
regarding
protocol
review
so
this
presentation
may
be
premature.
Dr.
Preuss
might
present
later
at
the
meeting.
Mr.
Carley
said
there
has
been
an
Agency
order
in
place
since
1999
describing
the
policy
and
procedures
on
protection
of
human
subjects
in
EPA
conducted
or
supported
research,
including
the
role
of
the
HSRRO.
The
Agency
was
contemplating
a
revision
of
this
order,
including
further
defining
the
role
of
the
HSRRO.
The
Board
concluded
that
while
Dr.
Preuss'
presentation
might
be
helpful,
it
was
not
urgent.
The
Chair
they
requested
that
the
Board
begin
discussion
of
the
criteria
for
review
of
human
study
protocols.
This
discussion
began
with
a
brief
background
presentation
by
Mr.
John
Carley
on
human
studies
research
proposals.
16
of
104
EPA
Background
on
Human
Studies
Research
Proposals
Mr.
Carley
began
the
discussion
commenting
that
the
final
rule
for
testing
with
human
subjects,
which
were
effective
April
1,
2006,
expanded
Common
Rule
protections
to
third
party
research
and
forbid
EPA
from
using
data
that
was
collected
by
unethical
means.
Mr.
Carley
provided
a
brief
summary
of
the
subparts
of
the
rule.
One
of
the
challenges
of
conducting
intentional
exposure
studies
was
that
the
risk­
benefit
analysis
may
not
provide
benefits
to
the
subjects.
Intentional
exposure
studies
with
pesticides
were
not
designed
to
treat
disease,
so
risks
to
subjects
must
be
minimized
and
be
reasonable
in
relation
to
anticipated
benefits
and
the
importance
of
the
knowledge
gained.

Mr.
Carley
said
that
the
NAS
recommendations
for
human
studies
were
a
place
to
start
deliberations
but
not
an
ending
point.
Repellent
efficacy
studies
involved
intentional
exposure;
thus
IRB­
approved
protocols
and
supporting
materials
must
be
submitted
for
EPA
and
HSRB
review.
An
important
point
was
that
there
is
scientific
validity
of
human
studies
research;
studies
seeking
to
improve
the
accuracy
of
EPA
decisions.
Payment
for
participation
should
not
be
so
high
as
to
be
undue
influence
or
so
low
that
it
is
only
attractive
to
economically
distressed
subjects.
Human
studies
should
provide
compensation
for
research
related
injuries.
Mr.
Carley
then
presented
a
list
of
considerations
concerning
science
criteria
for
review
of
human
studies
protocols
for
HSRB
consideration.

Review
of
HSRB
Protocol
Criteria
Dr.
Fisher
stated
that
she
had
assigned
several
Board
members
to
either
an
ethics
or
science
workgroup
to
help
identify
issues
for
the
Board
to
discuss
with
respect
to
Ethics
and
Science
criteria
for
evaluating
protocols.

Ethical
Criteria
Dr.
Fisher
asked
the
Board
for
its
thoughts
on
a
guide
for
how
to
evaluate
new
studies
coming
to
the
Board.
Board
criteria
would
be
helpful
for
both
the
Agency
and
study
investigators
to
understand
the
Board's
approach
for
the
review
of
proposed
human
studies.
Dr.
Nelson
said
that
you
start
with
general
principles,
than
you
define
them
in
the
context
of
a
study.
The
Board
may
not
recommend
for
approval
a
study
that
does
not
comport
to
the
Agency's
final
human
studies
rule.
Dr.
Nelson
said
that
the
Board
needed
to
specify
what
information
needed
to
be
submitted
in
order
for
the
Board
to
make
a
decision
under
its
criteria.

Dr.
Fitzpatrick
said
that
the
roles
of
the
IRB
review
needed
to
be
separated
from
HSRB
review.
The
HSRB
could
have
additional
criteria.
Mr.
Carley
clarified
that
the
FDA
rules
were
identical
to
Subpart
K
of
the
Agency
final
human
studies
rule
and
as
noted
previously,
its
review
occurred
after
IRB
review.
The
Board
was
to
interpret
what
these
rules
meant
for
EPA
studies
and
needed
to
be
cognizant
of
the
difficulties
of
interpreting
these
rules.
Subpart
K
of
the
rule
describes
what
information
needs
to
be
submitted.
With
respect
to
the
insect
repellent
product
performance
testing
guidelines,
Mr.
Carley
said
that
the
document
was
submitted
by
Dr
Carroll.
EPA
took
the
IRB
records
and
compared
them
to
Subpart
K
requirements.
Pending
more
experience,
Dr.
Carroll's
summary
was
a
good
starting
place.
The
Agency
would
need
to
be
17
of
104
provided
guidance
on
how
the
materials
should
be
organized.
Dr.
Fisher
said
that
the
Board
appeared
to
be
in
agreement
about
what
was
expected
and
that
the
onus
was
on
the
investigator
to
present
the
information.
Mr.
Carley
felt
a
summary
document
might
be
helpful,
especially
with
respect
to
risk
minimization,
but
Dr.
Fisher
said
that
this
was
no
different
from
current
IRB
review.
Dr.
Fisher
introduced
Dr.
Peter
Preuss
as
the
Agency
HSRRO.

One
of
the
questions
that
emerged
during
Board
discussion
was
the
subject
of
payment.
This
was
not
considered
a
benefit
from
an
ethics
perspective.
Compensation
or
inducement
should
not
be
considered
in
the
benefits
analysis.
The
Board
would
be
looking
at
equity
in
terms
of
subject
payments.
In
addition
it
might
be
considered
coercive
if
workers
believed
they
obligated
to
perform
a
research
task
that
otherwise
would
not
be
asked
of
them.
In
such
circumstances
informed
consent
could
not
be
evaluated
as
voluntary.
Issues
related
to
employee
subjects
would
apply
to
insect
repellent
guidelines
and
the
agricultural
handler's
protocol.
There
was
also
a
need
for
monitoring
both
during
and
after
the
study,
and
to
assess
adverse
effects.
The
Board
decided
that
intentional
exposure
was
exposure
that
would
not
have
occurred
if
the
worker
or
participant
had
not
participated
in
the
research.
It
does
not
matter
if
the
exposure
is
to
a
product
that
the
worker
or
participant
may
be
ordinarily
exposed
to.
What
does
matter
is
if
the
timing,
extent
of
exposure,
and/
or
dosage
of
the
compound
is
in
addition
to
or
different
from
what
the
participant
would
have
been
exposed
to
on
the
day
of
the
testing.

Dr.
Lebowitz
said
that
improving
accuracy
was
not
a
valid
justification
for
a
human
study.
Human
studies
must
be
used
to
reduce
exposure
or
risk.
Dr.
Fish
commented
that
if
a
study
was
being
done
solely
to
improve
accuracy,
it
must
do
no
harm.
Dr.
Lebowitz
said
that
this
was
not
his
concern.
He
was
concerned
about
science
for
the
sake
of
science.
Dr.
Fenske
said
a
study
that
would
not
be
valuable
unless
it
reduced
exposure
would
be
wrong.
Dr.
Lehman­
McKeeman
said
that
improving
accuracy
was
a
frank
benefit
to
society
and
could
warrant
the
use
of
human
studies,
as
long
as
no­
one
was
at
risk.
Studies
that
improved
accuracy
should
not
be
excluded
but
research
for
basic
data
gathering
should
be
avoided.
If
there
was
risk,
the
researcher
should
have
a
sliding
scale
of
benefits.
Dr.
Lehman­
McKeeman
said
that
a
very
clear
statement
of
study
objectives
was
needed.
Dr.
Nelson
said
the
Board
was
calling
for
a
rationale
for
research,
not
saying
that
new
products
shouldn't
be
developed.
Researchers
need
to
explain
what
was
wrong
with
the
existing
products,
and
what
the
benefits
of
new
research
would
be.
Dr.
Philpott
noted
that
since
the
Final
Rule
required
exclusion
of
pregnant
women,
registrants
now
need
to
describe
in
the
ethics
section
and
IRB
proposal
how
pregnancy
would
be
identified
and
how
the
pregnancy
status
of
women
recruited
and
or
excluded
from
the
study
would
be
protected.

Dr.
Fitzpatrick
asked
whether
there
would
be
a
screening
procedure
for
what
the
Board
would
review
and
was
told
that
EPA
would
serve
as
the
gatekeeper
for
information
that
came
to
the
Board
and
also
the
final
decision­
maker
as
to
whether
the
Board's
recommendations
would
be
followed.

Summarizing
the
Board's
discussion,
Dr.
Fisher
listed
the
following
criteria
for
protocols:
18
of
104
1.
Provide
all
information
required
in
Agency
human
studies
rule
including
risks,
measures
to
minimize
risks,
benefits,
and
to
whom
they
accrue,
alternative
means
of
obtaining
data,
and
balance
of
risks
and
benefits.

2.
Describe
the
benefits
of
the
study
as
they
might
relate
for
example
to:
°
More
stringent
regulatory
standard
°
New
public
health
measure
adopted
°
New
product
that
protects
public
health
°
Improved
scientific
accuracy
of
risk
assessment
with
statement
of
the
potential
benefit
of
improved
accuracy.

3.
Incentives
or
remunerations
cannot
be
included
in
risk­
benefit
analysis.

4.
Informed
consent
must
include
all
information
required
in
Section
26.1116
of
the
Agency's
human
studies
rule.

5.
Provide
justification
that
subject
recruitment
and
incentives/
remunerations
are
not
unduly
coercive
or
could
result
in
a
retaliatory
response.

6.
Describe
the
rational
for
the
safety
monitoring
plan
during
and
post­
trial.

7.
Describe
procedures
to
reverse
experimentally
induced
harms.

Dr.
Fisher
added
if
a
researcher
had
difficulty
obtaining
IRB
records,
this
needed
to
be
explained.
Compensation
was
not
unethical,
but
should
not
be
considered
a
benefit
in
a
risk
benefit
analysis;
monitoring
after
research
was
required.
Dr.
Menikoff
commented
that
the
word
"
compensation"
should
not
be
used.
Instead
incentives
or
remuneration
were
more
appropriate.

Scientific
Criteria
Dr.
Fenske
said
that
there
was
overlap
between
scientific
and
ethical
considerations.
Empirical
evidence
supporting
estimations
of
risks
to
participants
should
be
provided.
The
researcher
needs
to
state
what
scientific
question
would
be
answered
by
the
study.
Study
benefits
should
be
clearly
defined.
Specific
objectives
or
hypotheses
should
be
identified.
The
following
questions
were
presented
as
science
criteria
for
review
of
human
studies
protocols:

1)
What
is
the
scientific
question
addressed
by
the
study?
2)
Are
existing
data
adequate
to
answer
the
scientific
question?
3)
Are
new
studies
involving
human
subjects
necessary
to
answer
the
question?
4)
What
are
the
potential
benefits
of
the
study?
5)
What
is
the
likelihood
that
the
benefits
will
be
realized?
6)
What
are
the
risks?
Are
they
serious
or
irreversible?
7)
Is
the
purpose
of
the
study
clearly
defined?
8)
What
are
the
potential
benefits
of
the
study?
What
is
the
likelihood
that
the
benefits
would
be
realized?
9)
Are
there
specific
objectives/
hypotheses?
19
of
104
10)
Can
the
study
as
described
achieve
these
objectives
or
test
these
hypotheses?
11)
What
is
the
sample
size
and
how
is
it
derived?
12)
What
is
the
basis
for
the
proposed
dose
levels
and
formulations
in
the
study?
13)
Is
there
a
plan
allocating
individuals
to
treatment?
14)
Can
the
findings
from
this
study
be
generalized
beyond
the
study
sample?
15)
Is
there
a
justification
for
the
selection
of
target
population?
16)
Are
participants
representative
of
the
population
of
concern?
If
not,
why
not?
17)
Are
the
inclusion/
exclusion
criteria
appropriate?
18)
Is
the
sample
a
vulnerable
group?
19)
Will
the
measurements
be
accurate
and
reliable?
20)
Are
measurements
appropriate
to
the
question
being
asked?
21)
Are
adequate
quality
assurance
procedures
described?
22)
Can
the
data
be
statistically
analyzed?
23)
Is
the
statistical
method
appropriate
to
answer
the
question?
24)
Point
estimates
must
be
accompanied
by
measures
of
uncertainty?
25)
Do
laboratory
conditions
simulate
real­
world
conditions?
26)
Are
field
conditions
representative
of
intended
use?
27)
Does
the
protocol
include
a
stop
rule
plan,
medical
management
plan,
and
a
safety
monitor?

The
Board
then
proceeded
to
respond
to
the
charge
for
the
insect
repellent
product
performance
test
guidelines.

Insect
Repellent
Product
Performance
Testing
Guideline
Charge
to
the
Board
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?

Board
Response
to
the
Charge
Dr.
Chambers
responded
that
repellant
efficacy
testing
can
only
be
done
with
human
subjects.
Because
repellants
would
be
used
at
relatively
high
doses
and
used
repeatedly,
toxicological
data
are
needed
including
the
possibility
of
a
developmental
toxicity
study.
Any
information
from
inadvertent
exposures
or
historical
use
should
be
gathered.
Laboratory
tests
should
precede
field
tests
with
disease­
free
insects.
Subjects
should
not
be
taking
any
drugs
that
may
result
in
adverse
interaction
during
exposure.
Formulations
should
be
the
same
as
that
proposed
for
use.
Laboratory
results
should
show
a
good
degree
of
repellency
before
going
out
to
the
field.
The
location
of
field
tests
should
have
a
low
frequency
of
disease
bearing
insects.
It
would
be
appropriate
to
empirically
define
areas
with
a
low
level
of
disease
bearing
insects.
Dr.
20
of
104
Gupta,
Consultant
to
the
HSRB,
commented
that
medical
monitoring
should
be
added
as
an
additional
step
to
reduce
risk.
Subjects
need
not
be
exposed
for
the
entire
test
duration
but
intermittently
throughout
the
period
of
warranty.
Dr.
Strickland,
Consultant
to
the
HSRB,
said
that
it
was
not
safe
to
assume
that
laboratory
populations
were
not
disease
vectors;
confirmatory
testing
would
be
needed.
Defining
allergic
reaction
to
bites
would
be
helpful.
There
should
be
a
medical
plan
to
respond
to
adverse
effects
such
as
anaphylaxis.
Dr.
Strickland
said
that
the
human
studies
should
exclude
populations
that
are
particularly
sensitive
to
vector­
borne
disease
such
as
West
Nile
Virus.
Dr.
Gupta
said
that
the
subject
population
should
be
from
the
local
area
because
local
populations
are
better
acclimated
to
local
insect
populations.
Dr.
Fisher
said
that
this
could
raise
some
ethical
issues.

Dr.
Fisher
summarized
some
of
the
additional
points
made
by
the
Board
in
order
to
document
an
evaluation
of
risk:

 
Overall
toxicity
of
the
test
material
in
the
database,
including
all
animal
and
reproductive
studies
should
be
considered.
 
Any
human
data
from
controlled
or
unintentional
exposures
or
usage
and
allergic
reactions.
 
Comparisons
to
comparable
database(
s).
 
Interactions
with
drugs
an
individual
might
be
taking
 
Lab
tests
prior
to
field
tests 
need
to
have
confidence
in
repellency
in
laboratory
studies
first.
 
In
vitro
models
when
appropriate.
 
Exclusion
of
subjects
who
are
sensitive
to
insect
bites,
allergens,
or
vulnerable
to
diseases
in
the
area.
 
Use
of
trained
personnel
for
adverse
events
and
medical
monitoring.
 
Selection
of
field
sites
with
documented
lowest
level
of
vector
borne
diseases.
 
Pilot
study
of
insect
to
empirically
define
vector
borne
disease
risk.
 
Continuous
testing
of
insects.
 
Lowest
number
of
control
subjects
to
ensure
statistical
power.

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

Board
Response
to
the
Charge
Dr.
Lehman­
McKeeman
began
the
discussion
by
recommending
that,
while
not
always
correct,
a
structural
analysis,
in
particular
computer
models
for
teratogenesis,
was
a
good
starting
point.
Acute
toxicology
studies
should
be
mandatory
and
dermal
exposure
would
be
critical.
Additional
studies
should
be
required
for
dermal
and
ocular
toxicology,
dermal
sensitization
and
dermal
absorption
including
modes
of
metabolism
and
excretion.
There
was
a
need
for
early
screening
for
mutagenesis
since
this
would
be
an
irreversible
effect,
and
also
an
in
vitro
analysis
of
clastogenicity.
It
would
be
ideal
to
have
some
assessment
of
repeat
dosing.
These
are
the
kinds
of
studies
that
would
be
essential,
but
there
should
be
a
tiering
of
information.
Subchronic
21
of
104
studies,
reproductive
toxicology
and
a
study
of
human
metabolism
as
it
compares
to
rodent
metabolism
studies
would
be
appropriate
given
the
high
rates
of
exposure.
Some
knowledge
of
what
the
human
dose
would
be
is
needed
to
assess
the
margin
of
safety
which
becomes
part
of
the
equation.
Dr.
Krishnan
added
that
the
section
on
dose
selection
should
be
based
on
how
the
product
would
be
used.
This
information
would
need
to
be
bridged
to
the
toxicology
studies.
The
dose
typically
used
is
1
ml/
600
cm2
which
equates
to
15mg/
kg.
Guidelines
should
include
some
relationship
between
the
dose
used
and
NOAEL/
LOAEL.

Mr.
Carley
responded
that
the
Agency
needed
to
know
if
the
Board
required
a
minimal
research
data
set
before
beginning
field
testing
on
human
subjects.
Dr.
Lehman­
McKeeman
believed
that
there
should
be
some
early
indication
of
whether
the
compound
had
teratogenic
potential.
This
could
be
a
quick
assessment
of
informed
structure
relationships
or
in
vitro
metabolism.
Dr.
Chadwick
said
repellant
studies
were
looking
for
no
toxicity
which
is
the
opposite
of
most
pesticide
testing.
Dr.
Lehman­
McKeeman
said
that
the
Board
was
looking
for
toxicity
as
a
hazard
identification
step.
Mr.
Carley
said
that
what
is
being
described
is
what
the
Agency
refers
to
as
acute
toxicity
testing.

Charge
to
the
Board
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?

Board
Response
to
the
Charge
Dr.
Fish
began
the
discussion
by
saying
that
she
could
think
of
no
situation
where
research
participation
would
be
an
ethical
requirement
for
employment.
Dr.
Chadwick
said
that
this
may
be
the
case
in
some
military
assignments.
Dr.
Gupta
said
that
the
military
was
no
different
than
the
commercial
sector,
and
that
all
human
subject
research
was
done
with
fullyinformed
subjects
who
have
given
consent.
Dr.
Fish
continued
that
untreated
controls
should
be
asked
to
sign
a
study­
specific
or
generic
consent
form
and
be
included
as
study
subjects,
not
as
non­
participants.
The
risk­
benefit
analysis
for
untreated
controls
could
be
removed
when
controls
are
described
as
non­
participants.
If
the
principle
investigator
(
PI)
enrolls
himself
into
a
study,
there
must
be
some
assurance
that
the
PI
can
be
determined
to
meet
all
inclusion
criteria,
without
exerting
undue
influence
on
a
co­
researcher.
The
book,
"
Who
Goes
First?",
describes
several
benefits
of
self­
participating
PI
research.
However,
study
oversight
would
have
to
be
assigned
to
someone
else.
PI
participation
would
be
acceptable
if
the
study
was
approved
by
the
IRB
prior
to
testing,
the
investigator
was
the
only
subject,
and
there
was
a
plan
for
safety,
integrity
and
oversight
should
the
PI
become
incapacitated.
Dr.
Carriquiry
stated
that
under
no
circumstances
can
we
have
a
single
control,
whether
this
is
the
PI
or
not,
unless
the
PI
can
prove
that
he/
she
was
randomly
drawn
from
the
study
population.
Repellant
research,
where
multiple
controls
are
exposed
to
multiple
bites,
may
be
more
acceptable.
A
single
source
for
biting
pressure
control
may
be
appropriate,
and
the
PI
may
be
best
at
knowing
the
intent
of
the
mosquito.
Dr.
Chadwick
believed
that
the
PI
research
opened
the
door
to
bias.
The
onus
was
on
22
of
104
the
investigator
to
demonstrate
that
bias
had
not
been
introduced.
PI
participation
in
research
was
not
a
priori
unethical
but
did
require
some
specific
guidelines.

Charge
to
the
Board
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.

Board
Response
to
the
Charge
Dr.
Chadwick
identified
risks
including
allergic
reaction
to
the
insect
bite
and
the
transmission
of
vector­
borne
disease.
Assuming
the
study
was
well
designed,
there
was
no
ethical
objection
to
the
use
of
negative
control
groups.
Dr.
Fenske
supported
this
and
said
that
evidence
of
insect
biting
pressure
was
needed,
which
most
likely
required
negative
controls.
Dr.
Fitzpatrick
added
that
informed
consents
for
negative
controls
were
essential,
along
with
a
stopping
rule
and
freedom
to
leave
the
study.
Dr.
Nelson
was
not
convinced
that
risks
to
the
negative
controls
would
be
trivial.
There
was
a
significant
burden
of
proof
for
sending
a
negative
control
out
into
the
field.
While
vaccines
for
vector­
borne
diseases
were
available,
there
was
an
associated
risk.
Dr.
Nelson
suggested
seeking
information
on
the
use
of
prophylactic
antibiotics.
The
Board
pointed
out
that
controls
were
needed
to
demonstrate
that
the
vectors
were
present
and
biting;
one
treated
and
one
control
could
be
used
for
this
purpose.
Trapping
was
also
effective
for
knowing
whether
mosquitoes
were
present.
Dr.
Fisher
said
that
there
might
be
situations
where
a
negative
control
would
be
needed.
In
these
situations
the
onus
would
be
on
the
investigator
to
demonstrate
that
alternative
means
of
investigation
were
not
suitable.
The
Board
had
some
mixed
opinions
on
what
the
threshold
for
using
a
negative
control
would
be.
The
guidelines
seem
to
assume
that
a
negative
control
will
be
used
in
field
studies.
Dr.
Strickland
said
that
generally,
a
negative
control
is
used
in
the
field.
These
are
parametric
studies:
yes
or
no,
the
subject
was
protected.
You
could
do
an
epidemiological
study,
find
an
area
without
a
high
disease
frequency,
treat
half
the
subjects
and
not
the
other
half.
This
has
been
done
but
it
is
expensive.
Dr.
Fisher
said
at
some
point,
the
Board
may
need
to
issue
a
statement
regarding
cost
and
ethics.
For
efficacy
testing
in
the
laboratory,
multiple
controls
are
needed;
in
the
field,
negative
controls
to
show
biting
pressure
may,
or
may
not
be
needed.
If
there
was
a
scientific
need
for
negative
controls,
this
should
be
included
in
the
guidelines.
The
Board
may
not
want
negative
controls
to
be
the
default.

Charge
to
the
Board
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).

Board
Response
to
the
Charge
Dr.
Nelson
led
the
discussion
by
saying
that
the
FIFRA
SAP
recommended
an
RP
method
based
on
95%
fewer
bites
in
treated
subjects
compared
with
controls.
This
method
23
of
104
exposed
subjects
to
many
bites.
The
proximity
of
a
treated
arm
to
the
untreated
arm
might
affect
mosquito
biting
behavior.
This
should
be
considered
in
an
experimental
design.
Aspirating
the
mosquitoes
before
they
bite
was
a
very
good
way
of
reducing
risks
to
subject.
Temperature
and
humidity
within
the
laboratory
should
be
examined
to
see
how
they
affect
efficacy.
Dr.
Lehman­
McKeeman
agreed
with
Dr
Nelson,
but
believed
that
the
FCB
and
RP
methods
provided
answers
to
different
questions.
TFCB
is
a
yes
or
no
whereas
the
RP
method
required
a
more
rigorous
statistical
analysis.
Dr.
Carriquiry
agreed
that
the
TFCB
and
RP
parameters
measured
different
things
and
said
that
RP
required
more
controls
than
TFCB.
Many
untreated
individuals
were
needed
in
the
field
to
calculate
the
second
metric.
Dr.
Gupta
differed,
stating
that
not
many
controls
were
needed,
and
that
for
statistical
design,
at
some
point,
there
was
a
diminishing
benefit
to
adding
additional
subjects.
Dr.
Carriquiry
said
that
because
mosquito
biting
was
variable,
a
well­
designed
study
needed
controls
for
integration
purposes.

The
Chair
adjourned
the
meeting
for
the
day
24
of
104
June
29,
2006
The
Chair
opened
the
meeting
with
the
Board
responding
to
question
F
of
the
insect
repellent
product
performance
test
guidelines.

Charge
to
the
Board
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.

Board
Response
to
the
Charge
Dr.
Carriquiry
said
that
the
guidelines
proposed
six
as
a
minimum
number
of
subjects.
However,
one
number
does
not
fit
all
studies.
Different
experimental
designs
required
different
sample
sizes,
depending
on
the
outcome
of
interest,
confounding
factors,
heterogeneity
of
the
sample
population
and
heterogeneity
of
the
environment
in
which
the
product
would
be
tested.
There
was
no
magic
number
but
there
were
procedures
that
should
be
followed.
Dr.
Bellinger
added
that
the
issue
of
replicates
needed
clarification.
Were
these
different
people
or
the
same
person
multiple
times?
If
the
same
data
were
repeatedly
collected
on
the
same
person
with
different
treatments,
power
calculations
were
needed
to
assess
variability
between
individuals.
The
lack
of
power
calculations
must
not
be
ignored.
Dr.
Strickman
said
that
there
was
a
4­
6
fold
variability
in
the
attractiveness
of
people
to
mosquitoes.
Biting
pressure
also
influenced
the
power
of
the
study.
Dr.
Carriquiry
commented
that
both
the
TFCB
and
RP
were
difficult
to
deal
with
when
calculating
confidence
intervals.
Dr.
Nelson
questioned
whether
inter­
personal
variability
affected
power
calculations.
Dr.
Carriquiry
responded
that
variability
among
test
subjects
meant
a
large
sample
size
was
needed
to
achieve
a
certain
power.

Charge
to
the
Board
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.

Board
Response
to
the
Charge
Dr.
Menikoff
said
that
historically
other
groups
had
looked
into
this
question
and
they
all
agreed
that
subjects
should
be
compensated
for
medical
costs
or
other
losses.
The
NAS
addressed
this
issue
and
said
justice,
fairness
and
gratitude
should
prevail
in
this
matter.
The
question
to
the
Board
suggested
that
insurance
be
provided
which
may
be
an
administrative
burden.
If
insurance
was
provided,
the
research
sponsor,
and
not
the
researcher,
should
pay
for
this.
Dr.
Nelson
agreed
with
Dr.
Menikoff
and
added
that
there
was
an
evidentiary
issue
that
may
at
times
be
controversial.
Dr.
Nelson
said
that
exculpatory
language
in
the
informed
consent
(
IC)
materials
should
be
examined
and
suggested
that
language
should
not
refer
to
compensation,
but
medical
care.
25
of
104
Charge
to
the
Board
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.

Board
Response
to
the
Charge
Dr.
Fitzpatrick
said
that
many
of
these
studies
were
performed
on
experienced
subjects
so
the
IC
materials
were
not
very
detailed.
This
is
not
what
is
expected
based
on
provisions
of
the
Common
Rule.
All
procedures
should
be
clear
and
it
might
help
to
have
photos
or
a
video
to
explain
experimental
procedures.
Aspirator
training
should
be
provided.
Subjects
should
be
given
an
estimate
of
the
number
of
bites
they
might
encounter
and
all
other
experimental
procedures.
The
consent
process
might
include
a
quiz
on
the
risks
of
vector­
borne
disease,
the
risk
of
being
bitten
and
sensitivity
reactions.
Subjects
need
to
understand
what
type
of
medical
support
would
be
provided.
They
need
to
know
the
stopping
rules
and
where
medical
personnel
would
be
available.
Confidentiality
of
records
and
the
element
of
undue
pressure
should
be
examined.
The
voluntary
nature
of
the
experiment
should
be
made
clear
and
compensation
for
time
provided.
Dr.
Menikoff
agreed
and
said
that
the
two
consent
forms
that
he
reviewed
were
not
sufficient.
EPA
may
want
to
develop
a
generic
consent
form
for
studies
of
this
type.
Dr.
Nelson
said
that
the
IC
form
should
be
clear,
short
and
simple.
Seasonality
of
risks
should
be
highlighted
but
a
quiz
for
comprehension
probably
was
not
needed.
Dr.
Fisher
suggested
that
the
IC
form
should
state
whether
the
product
was
experimental
or
approved.
Dr.
Gupta
added
that
the
IC
form
should
be
translated
into
the
subject's
native
language.

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

Board
Response
to
the
Charge
Dr.
Fisher
commended
the
Agency
on
the
first
draft
of
the
insect
repellent
product
performance
testing
guideline
but
said
that
revisions
were
needed.
Dr.
Nelson
said
that
historically
the
emphasis
seemed
to
be
on
field
testing
over
laboratory
testing,
but
the
Board's
discussions
seemed
to
put
more
emphasis
on
the
laboratory.
Dr.
Gupta
replied
that
laboratory
testing
would
be
helpful
and
may
replace
some
field
testing.
Protection
in
the
field
was
generally
longer
than
that
in
the
laboratory
and
most
exposures
to
mosquitoes
occurred
in
the
field.
Dr.
Chadwick
said
that
the
public
may
apply
the
product
more
often
than
was
needed
to
be
protected.
Dr.
Strickland
said
that
some
labels
do
limit
the
number
of
times
the
insect
repellent
could
be
applied.
Most
people
do
not
reapply
insect
repellent
by
the
time
elapsed,
but
by
when
they
start
to
be
bitten.
26
of
104
Research
on
the
Efficacy
of
Insect
Repellents
Protocol
CL­
001
Generic
Template
for
Repellant
Efficacy
Testing
Mr.
Carley
began
the
protocol
discussion
commenting
that
protocol
CL­
001
was
developed
to
submit
annually
to
the
California
Department
of
Pesticide
Regulation
and
is
intended
to
cover
both
laboratory
and
field
studies
of
repellent
performance
against
mosquitoes,
biting
flies,
fleas,
and
ticks.
CL­
001
contains
general
background
information,
especially
concerning
recruiting
practices.
It
is
not
a
template
for
executable
studies
and
cannot
support
full
review.
Because
of
the
attraction
of
biting
arthropods
to
humans
and
their
role
in
disease
transmission,
there
is
potential
societal
benefit
in
developing
additional
safe
and
effective
personal
repellents.
EPA
requires
testing
with
human
subjects
to
establish
repellant
efficacy.
CL­
001
includes
well
documented
methods
for
subject
selection
with
no
indication
that
subjects
would
be
subject
to
any
coercion
or
undue
influence,
or
be
recruited
or
enrolled
for
reasons
inconsistent
with
the
goals
of
the
research.
Exclusion
factors
ensure
exclusion
of
children
and
pregnant
or
lactating
women
and
students
of
investigators.
There
was
some
concern
evident
for
risk
reduction
since
a
risk­
benefit
assessment
cannot
be
performed
in
the
generic
case.
The
CL­
001
was
unanimously
approved
by
the
Florida­
based
IRB
"
as
a
template
for
future
research."
The
protocol
describes
adequate
procedures
for
IC
but
did
not
provide
a
generic
consent
form.
The
applicable
standards
for
this
protocol
are:
40
CFR
26,
Subparts
K
and
L,
FIFRA
§
12(
a)
(
2)
(
P),
and
if
conducted
in
California,
then
California
Code
of
Regulations
Title
3,
Section
6710.

Deficiencies
in
CL­
001
noted
included
a
statement
that
subjects
were
orally
informed
of
the
risks
of
disease
contraction.
The
risk
of
contracting
disease
and
treatment
available
should
have
been
discussed
in
writing
in
the
pre­
consent
information
package.
Section
4(
H)
stated
that
there
was
no
plan
for
compensation
for
injury
due
to
the
low
levels
of
risk
involved.
The
risk
of
contracting
an
arthropod­
borne
disease
through
participation
in
a
field
test
may
be
low,
but
it
is
not
zero.
Planning
for
the
possibility
that
subjects
may
be
bitten
by
a
disease­
carrying
insect
was
essential
both
to
risk
minimization
and
to
fully
informing
potential
subjects.
The
generic
protocol
should
have
acknowledged
the
applicable
standards
of
ethical
conduct
and
the
obligation
of
the
investigators
to
inform
the
IRB
of
any
amendments
to
or
deviations
from
the
approved
protocol.

Study
EMD­
003
from
Carroll­
Loye
Biological
Research
Mr.
John
Carley
began
the
Agency's
presentation
on
the
EMD­
003
by
stating
that
the
study
was
a
laboratory
assay
utilizing
human
subjects
to
evaluate
the
efficacy
against
ticks
of
three
skin­
applied
formulations
of
the
insect
repellent
IR­
3535.
The
protocol
was
similar
in
many
aspects
to
the
draft
EPA
guideline
for
tick
testing,
specifically
to
the
2000
version.
IR­
3535
has
been
registered
in
the
US
for
six
years
and
used
in
Europe
for
over
20
years.
Three
formulations
were
to
be
tested:
20%
lotion,
20%
aerosol
and
a
10%
pump­
spray
liquid.
Formulations
would
be
administered
by
pipette
to
the
limb
of
the
test
subject
as
a
liquid
at
the
rate
of
1
gram
of
formulation
per
600
cm2
of
skin
surface.
Five
treatments
groups
would
be
used,
including
a
DEET
positive
control
and
an
untreated
negative
control.
A
line
of
IR­
3535
is
drawn
across
the
wrist
of
each
subject
and
a
tick
is
placed
on
the
hand,
oriented
toward
the
wrist.
If
a
tick
crosses
the
line
in
3
minutes
it
is
not
repelled.
Only
one
species
of
tick
would
be
tested
even
though
the
guideline
recommended
testing
three
species
from
three
different
genera.
The
27
of
104
protocol
used
liquid
formulations
applied
by
pipette
when
the
guideline
called
for
testing
formulations
as
they
are
to
be
registered.
The
qualification
of
ticks
before
use,
handling
of
ticks
after
qualification,
and
disposition
of
ticks
after
use
were
inadequately
specified.

Mr.
Carley
reviewed
the
Emanuel
Framework
in
relation
to
the
protocol.
Mr.
Carley
said
that
the
purpose
of
the
study
was
poorly
described.
The
intention
was
to
gather
information
to
support
development
of
personal
repellents
for
future
commercial
marketing
which
do
have
a
potential
societal
benefit.
This
was
not
described
in
the
protocol.
Recruiting
methods
were
well
described
in
CL­
001
generic
protocol
and
there
was
no
indication
that
subjects
would
be
subjected
to
any
coercion
or
undue
influence,
or
be
recruited
or
enrolled
for
reasons
inconsistent
with
the
goals
of
the
research.
The
protocol
did
not
include
a
risk/
benefit
assessment.
The
Florida­
based
IRB
gave
unanimous
approval
of
the
protocol.
Written
consent
was
received
from
all
subjects
and
was
adequate
but
deficiencies
in
IC
materials
should
be
corrected.
The
applicable
standards
for
this
research
are:
40
CFR
26,
Subparts
K
and
L,
FIFRA
§
12(
a)
(
2)
(
P),
and
California
Code
of
Regulations
Title
3,
Section
6710.

Several
deficiencies
were
noted
for
IC
materials
including
a
statement
that
subjects
would
be
randomly
assigned
to
treated
or
control
groups
while
the
CL­
001
states
that
only
investigators
would
serve
as
controls.
Test
procedures
were
inadequately
described
to
subjects
in
IC
materials
and
there
was
vague
language
in
the
IC
regarding
how
far
ticks
would
be
allowed
to
travel
before
they
were
removed.
The
IC
form
also
needed
to
make
clear
that
the
ticks
used
in
this
test
are
captive­
bred
and
free
of
disease.
The
word
"
not"
is
missing
from
the
IC
discussion
of
"
Pregnancy
Risks"
which
should
read
".
.
.
it
is
important
that
you
do
not
participate
in
this
study
if
you
are,
or
think
you
may
be
pregnant."
The
IC
promised
to
cover
costs
of
"
treatment
required
for
injury
resulting
from
being
in
the
study,"
but
then
excluded
injuries
"
resulting
from
normal
work
activities",
and
then
further
excluded
compensation
for
"
such
things
as
lost
wages,
disability,
or
discomfort
due
to
injury."
This
is
unacceptable
exculpatory
language.
The
IC
materials
inappropriately
discussed
compensation
to
the
subjects
as
a
benefit,
but
did
not
discuss
expected
societal
benefits
and
how
they
were
weighed
against
risks
to
subjects.
The
California
Department
of
Pesticide
Regulation
should
be
added
to
the
list
of
parties
to
whom
personal
information
may
be
disclosed.
The
protocol
should
acknowledge
the
applicable
standards
of
ethical
conduct
and
the
obligation
of
the
investigators
to
inform
both
the
cognizant
IRB
and
the
California
Department
of
Pesticide
Regulation
of
any
amendments
or
deviations
from
the
approved
protocol
Mr.
Carley
concluded
by
saying
that
the
Agency
requested
some
additional
information
and
Dr.
Carroll
was
very
responsive
but
there
were
still
gaps.
Failure
to
get
the
requested
materials
from
the
IRB
was
unexpected.

Dr.
Nelson
asked
whether
the
Agency
interpreted
the
language
in
its
human
studies
rule
as
meaning
that
incomplete
protocols
for
HSRB
review
need
not
be
submitted
to
the
HSRB.
Mr.
Carley
said
that
the
initial
review
was
an
evaluation
for
the
completeness
of
the
documentation.
Then
the
protocol
was
reviewed
for
contents.
Dr.
Fisher
asked
if
the
Agency
felt
obligated
to
pass
onto
the
Board
protocols
it
believed
were
inadequate
or
incomplete.
Mr.
Carley
said
that
this
had
not
yet
been
addressed.
Dr.
Chadwick
said
that
these
protocols
should
not
have
been
advanced
to
the
Board
until
the
package
was
complete.
Mr.
Carley
acknowledged
that
this
would
be
strived
for
by
the
Agency.
Board
members
noted
that
it
was
no
always
necessary
or
a
good
use
of
Board
time
for
EPA
to
present
protocols
to
the
Board
that
the
EPA
judged
to
be
scientifically
or
ethically
inadequate.
28
of
104
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
Mr.
Carley
provided
background
on
this
protocol,
commenting
that
study
EMD­
004
is
a
field
test
with
human
subjects
designed
to
evaluate
the
efficacy
against
mosquitoes
of
three
skinapplied
formulations
of
the
insect
repellent
IR­
3535.
The
protocol
was
similar
in
many
aspects
to
the
draft
2000
version
of
the
EPA
guideline
for
mosquito
testing.
The
protocol
tests
three
formulations:
20%
lotion,
20%
aerosol
and
a
10%
pump­
spray
liquid.
Formulations
delivered
by
pipette
or
syringe
to
the
limb
of
the
test
subject
at
a
dose
rate
of
1
gram
of
formulation
per
600
cm2
of
skin
surface.
Tests
may
be
conducted
in
Central
California
or
the
Florida
Keys.
Exposure
of
treated
subjects
is
continuous
and
evaluation
intervals
differ
for
control
and
treated
subjects.
The
study
included
a
single
untreated
control
which
was
inconsistent
with
EPA
recommendations
and
compromises
RP
calculations.
Mosquitoes
were
aspirated
upon
landing
to
minimize
bites.
No
information
about
specimen
handling,
identification,
and
storage
were
provided.
Product
formulations
should
be
applied
and
tested
as
they
are
to
be
registered.
The
protocol
did
not
include
an
example
of
the
data
recording
sheet.

Protocol
EMD­
004
poorly
described
the
purpose
of
the
study
which
was
to
gather
information
to
support
development
of
personal
repellents
for
future
commercial
marketing.
Recruiting
methods
were
well
described
in
CL­
001
and
gave
no
indication
of
subject
coercion
or
undue
influence
or
recruitment
for
reasons
inconsistent
with
the
goals
of
the
research.
Materials
were
tested
for
acute
toxicity
and
candidates
sensitive
to
mosquito
bites
were
excluded.
The
aspiration
of
landing
mosquitoes
reduced
bites
and
risk
and
tests
would
be
conducted
where
disease­
carrying
mosquitoes
were
not
known
to
be
present.
The
protocol
was
unanimously
approved
by
the
Florida­
based
IRB.
The
procedures
for
IC
were
adequate
but
deficiencies
noted
in
the
IC
materials
should
be
corrected.
Subject
privacy
would
not
be
compromised
and
subjects
would
be
free
to
withdraw.
The
applicable
standards
for
this
protocol
are:
40
CFR
26,
Subparts
K
and
L,
FIFRA
§
12(
a)
(
2)
(
P),
and
California
Code
of
Regulations
Title
3,
Section
6710.

Deficiencies
noted
included
a
statement
in
the
IC
materials
telling
subjects
that
they
would
be
randomly
assigned
to
treated
or
control
groups
while
the
CL­
001
stated
that
only
investigators
would
serve
as
controls.
Separate
consent
documents
for
treated
and
control
subjects
may
be
needed.
IC
materials
should
be
clarified
to
better
explain
the
responsibility
of
the
subjects
to
aspirate
landing
mosquitoes
and
the
risks
of
being
bitten.
The
word
"
not"
is
missing
from
the
IC
discussion
of
pregnancy
risks.
Given
the
possibility
of
a
subject
contracting
a
serious
vector­
borne
disease,
the
IC
form
was
inadequate
and
unacceptably
exculpatory.
The
IC
materials
inappropriately
discussed
compensation
to
the
subjects
as
a
benefit,
but
did
not
discuss
expected
societal
benefits
and
how
they
were
weighed
against
risks
to
subjects.
The
California
Department
of
Pesticide
Regulation
should
be
added
to
the
list
of
parties
to
whom
personal
information
may
be
disclosed.
The
protocol
should
acknowledge
the
applicable
standards
of
ethical
conduct
and
the
obligation
of
the
investigators
to
inform
the
IRB
of
any
amendments
to
or
deviations
from
the
approved
protocol.
29
of
104
Board
Discussion
of
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
Scientific
Considerations
Dr.
Chambers
questioned
the
dose.
The
protocol
said
1
ml/
600
cm2
while
the
Agency
said
1
gram/
600
cm2.
This
would
be
clarified
with
Dr.
Carroll,
ml
was
probably
the
error.
Dr
Chambers
wondered,
since
this
protocol
had
been
used
for
years,
why
Board
review
was
needed.
Dr.
Philpott
asked
about
the
need
to
avoid
multiple
cycles
of
EPA
review
for
protocols.
Mr.
Carley
responded
that
presenting
this
protocol
to
the
Board
could
help
expedite
future
protocol
reviews.
Dr.
Fisher
questioned
why
the
Board
was
being
asked
to
evaluate
the
protocol
when
Mr.
Sweeney's
presentation
of
the
science
for
this
protocol,
the
previous
day,
was
negative?
Dr.
Chadwick
said
that
evaluating
the
protocol
could
be
very
informative,
particularly
in
the
early
days
of
protocol
review.
This
was
a
chance
to
apply
the
Board's
criteria
to
a
case
study.
Dr.
Fish
agreed,
and
said
that
this
may
take
more
than
one
meeting
and
more
than
one
protocol
but
the
Board
could
use
this
as
an
illustration.
Dr.
Krishnan
said
that
this
was
a
blind
study
but
that
the
control
may
know
whom
he
or
she
is.
Blinding
was
not
critical
to
the
study
design
but
was
important
for
IC.

Dr.
Lehman­
McKeeman
encouraged
EPA
to
interpret
the
protocol
literally
if
it
says
1
ml/
600
cm2
.
The
Board
should
not
be
spending
significant
amounts
of
time
reviewing
protocols
that
were
erroneous.
However,
the
Board
may
be
able
to
abridge
the
discussion
for
this
one
protocol.
Dr.
Fisher
replied
that
the
Board
did
not
need
to
see
bad
studies
but
that
its
goal
was
to
provide
advice
on
studies
that
the
Agency
believed
would
go
forward.
Dr.
Fish
said
that
in
the
biomedical
world,
the
control
would
have
been
treated
with
the
vehicle
without
the
active
ingredient.
Mr.
Sweeney
said
that
this
would
be
dependent
on
whether
the
vehicle
had
any
repellency
properties.
Dr.
Chambers
said
that
the
guidelines
were
not
mandatory
but
that
deviations
might
be
justified.
Dr.
Fisher
did
not
see
the
role
of
the
Board
as
giving
advice
for
protocol
improvement.
While
the
Board
was
advisory,
it
could
not,
in
good
faith,
approve
a
study
if
revisions
were
needed.
Mr.
Carley
said
to
bear
in
mind
that
these
protocols
had
already
been
approved
by
the
IRB.
If
the
HSRB
recommended
changes,
the
study
would
go
back
to
the
IRB.
Dr.
Fisher
said
that
Board
decisions
were
not
dictated
by
IRB
approval
and
that
the
onus
was
on
the
researcher
to
comply
with
the
rules.

Ethical
Considerations
The
Board
raised
general
issues
for
consideration.
All
of
the
counties
in
central
California
have
a
history
of
West
Nile
virus.
The
risk
of
vector­
borne
disease
was
assessed
based
on
sentinel
chicken
flocks.
The
IC
materials
said
subjects
would
be
randomly
assigned
when
untreated
controls
were
affiliates
of
the
research.
Procedures
needed
to
be
more
detailed.
The
word
"
not"
was
missing
from
the
IC
language
regarding
pregnancy.
The
language
related
to
normal
work
activities,
if
this
meant
that
the
study
would
cover
costs
not
covered
by
workman's
compensation,
this
needed
to
be
made
clearer.
Finally,
the
IC
discussed
compensation
as
a
benefit
but
did
not
discuss
societal
benefits.
30
of
104
Public
Comments
Dr.
Scott
Carroll
on
behalf
of
Carroll­
Loye
Biological
Research,
Inc
Dr.
Carroll
began
by
stating
that
he
sensed
that
the
protocols
were
viewed
by
the
Board
as
inadequate.
The
Agency
had
reviewed
past
protocols
as
a
courtesy
and
CalEPA
review
had
been
mandatory
since
1996.
These
protocols
were
narrative
and
were
accepted
and
CalEPA
personnel
had
acted
as
co­
principal
investigators
for
some
of
these
studies.
CalEPA
suggested
the
Florida
based
IRB
be
used
for
these
studies.
Supplemental
material
was
requested
by
EPA
and
was
provided
quickly.
The
protocols
and
supplemental
material
were
evaluated
by
Mr.
Sweeney
and
Dr.
Fuentes
of
EPA.
Dr.
Fuentes
said
that
the
materials
provided
met
the
requirements
with
minor
changes.
Mr.
Sweeney
provided
pages
of
criticism
which
had
been
responded
to
online.
The
revised
IC
document
was
five
pages
long
and
was
read
less
carefully
by
subjects.
The
major
point
that
Dr.
Carroll
was
concerned
with
was
that
we
were
getting
to
a
point
where
the
IC
could
be
improved
further,
but
would
be
15
pages
long
and
may
not
impact
relative
risk.

Dr.
Chadwick
wanted
to
know
whether
UC­
Davis
personnel
or
IRB
were
used.
Dr.
Carroll
said
that
other
faculty
had
participated
in
the
studies
but
there
was
no
official
UC­
Davis
involvement.
Dr.
Chambers
asked
about
clarification
of
dose.
Dr.
Carroll
said
the
standard
1
gram/
600
cm2
was
used.

Mr.
Nicketas
Spero
of
Insect
Control
and
Research
Inc.

Research
protocols
are
modeled
after
EPA
guidelines
for
product
registrations
with
considerations
going
into
the
field
for
the
species
present.
He
was
concerned
about
the
TFCB
method
and
two
negative
untreated
controls.
Tests
were
conducted
in
an
untreated
area,
counted
landings
and
removal
of
insect
with
a
pen.
Bites
were
minimized
but
there
was
an
active
population
of
mosquitoes
in
the
field.
The
95%
protection
was
a
concern
because
when
repellents
breakdown,
subjects
may
be
exposed
to
more
bites.
The
sole
purpose
of
testing
was
for
efficacy.
The
company
has
limited
research
until
the
guidelines
are
approved
by
the
Agency.

Mr.
Dan
Giambattisto
of
EDM
Chemicals,
Inc.

Mr.
Giambattisto
said
that
IR3535
is
a
registered
trademark
repellant
that
has
been
tested
against
a
wide
variety
of
mosquitoes
and
ticks.
IR3535
has
an
excellent
safety
and
efficacy
record
against
a
variety
of
arthropods.
IR3535
is
EPA
approved
and
WHO
recommended.
IR3535
is
the
best
selling
DEET
alternative
in
the
U.
S.
Sales
of
insect
repellent
products
are
seasonal
so
timely
approval
of
the
EMD
protocols
was
essential
for
products
to
be
on
the
market
in
2007.

Charge
to
the
Board
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
Scientific
Considerations
31
of
104
a.
Does
the
proposed
research
described
in
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
appear
likely
to
generate
scientifically
reliable
data,
useful
for
assessing
the
efficacy
of
a
test
substance
for
repellent
ticks?

Board
Response
to
the
Charge
Dr.
Chambers
began
the
discussion
by
saying
that
since
efficacy
had
already
been
established
in
the
laboratory,
perhaps
additional
human
studies
were
not
needed.
The
greatest
risk
would
be
disease
transmission.
Sample
size
was
derived
consistently
with
guidelines
but
dose
was
not
correctly
stated
and
this
was
a
clear
deficiency.
Study
findings
could
be
generalized
to
other
areas.
There
was
partial
justification
for
subject
selection.
Inclusion/
exclusion
criteria
were
adequate.
Measurements
would
be
adequate
and
the
LIB
approach
minimized
risk.
The
statistical
method
seemed
to
be
appropriate,
field
conditions
were
representative
of
real
world
conditions
and
there
was
a
stopping
rule
in
place.
Dr.
Brimijoin
added
that
there
seemed
to
be
a
variety
of
opinions
regarding
the
adequacy
of
a
single
untreated
control
and
viewed
this
as
a
weakness
of
the
protocol.
Dr.
Fitzpatrick
believed
that
the
protocol
needed
to
state
precisely
what
they
intended
to
accomplish
and
the
perceived
benefit.
Dr.
Bellinger
was
confused
about
the
statistical
methods;
this
needed
to
be
clarified
to
be
appropriate
for
a
continuous
variable.
Dr.
Carriquiry
said
that
the
protocols
needed
to
clarify
the
outcome:
TFCB
or
RP.
If
it
was
RP,
the
use
of
one
control
was
insufficient.
Dr.
Fish
asked
why
the
formulations
intended
for
public
use
were
not
tested;
especially
when
three
products
were
being
used.
There
might
be
substantial
differences
in
dose
with
these
three
methods
of
application.

In
summary,
Dr.
Fisher
said
that
there
were
some
strengths
in
the
study,
especially
incorporation
of
the
LIB
approach.
However,
problems
included
repellant
application,
identifying
the
number
of
subjects
and
the
use
of
a
single
untreated
control.
There
might
be
a
legitimate
justification
for
sample
size
but
it
wasn't
in
the
protocol.
Given
the
deficiencies
of
the
protocol,
as
presented,
the
Board
did
not
feel
that
the
study
was
likely
to
produce
useful
information.
Dr.
Chambers
said
that
there
were
deficiencies
but
no
fatal
flaws.
Dr.
Carriquiry
said
that
without
power
calculation
it
was
impossible
to
know
whether
or
not
the
study
would
generate
useful
information.
Dr.
Nelson
did
not
agree
that
relative
protection
was
an
appropriate
endpoint
for
this
study.
He
would
have
preferred
TFCB
with
a
single
untreated
control.
Dr.
Lehman­
McKeeman's
concern
was
that
another
researcher
could
not
duplicate
the
study
using
the
protocol
provided.
Product
formulations
were
a
critical
area
lacking
detail.
Dr.
Carriquiry
clarified
that
even
if
testing
TFCB,
power
calculations
were
required.
Dr.
Chadwick
remarked
that
this
discussion
was
exactly
why
this
type
of
protocol
should
not
be
reviewed
by
the
Board.
The
Board
should
not
be
discussing
the
details.
Instead
the
focus
should
be
on
whether
the
protocol
conformed
with
the
Agency's
human
studies
rule
 
a
yes
or
no
answer.
Dr.
Fisher
said
that
individuals
must
justify
why
they
are
not
using
a
preferred
method
and
asked
whether
there
was
a
consensus
on
whether
to
reject
this
protocol.
Dr.
Fenske
said
that
as
an
advisory
board,
it
should
keep
in
mind
that
the
protocol
was
developed
using
draft
guidelines.
If
the
Board
rejects
this
protocol
they
are
providing
EPA
with
recommendations
on
revisions
to
the
guidelines.
Dr.
Fisher
said
that
as
an
advisory
board,
it
could
not
approve
a
protocol
contingent
upon
revisions
being
made.
Dr.
Menikoff
agreed
with
Dr.
Fenske,
procedurally
the
Board
needed
to
understand
32
of
104
what
the
consequences
of
rejecting
the
protocol
were.
Dr.
Brimijoin
said
that
there
may
be
consensus
that
the
protocol,
as
submitted,
was
not
acceptable,
but
to
the
extent
that
we
can
make
recommendations
that
point
toward
a
solution
would
be
helpful.
The
Board
should
consider
that
approach.
Dr.
Brimijoin
would
not
approve
the
protocol
in
its
current
form
but
he
did
not
feel
that
the
flaws
were
unrecoverable.
Dr.
Fish
agreed
and
proposed
that
the
first
charge
question
could
not
be
answered.
Dr.
Fisher
recommended
that
the
Board
state
that
the
protocol
was
deficient.
If
the
deficiencies
were
met,
EPA
could
approve
the
protocol
without
returning
it
to
the
HSRB.
Dr.
Fisher
was
concerned
that
there
might
be
the
perception
that
researchers
could
send
anything
to
the
HSRB
and
the
Board
would
identify
and
solve
the
problems.
Dr.
Fish
said
that
the
Board
agreed
that
in
the
future
this
type
of
protocol
should
not
be
submitted
to
the
Board.

Charge
to
the
Board
Ethical
Considerations
b.
Does
the
proposed
research
described
in
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

Board
Response
to
the
Charge
Dr.
Nelson
stated
that
the
trouble
with
the
protocol
was
that
the
information
was
scattered
among
several
documents.
There
need
not
have
a
20
page
consent
form.
A
brief
IC
document
or
a
brief
film
could
be
constructed
that
will
facilitate
rather
than
impede
IC.
Dr.
Philpott
recommended
a
separate
consent
form
for
women
that
addresses
the
confidentiality
issues
pertaining
to
pregnancy.
If
a
woman
is
excluded
due
to
pregnancy,
and
this
is
uncovered
by
a
research
associate,
this
could
be
problematic.
It
is
important
to
know
what
the
affiliation
with
UC­
Davis
is
because
the
university
IRB
may
have
concerns.
It
would
be
helpful
to
see
what
the
IRB
said
regarding
the
IC
statement
about
treatment
provided
for
experimental
exposure
but
not
exposures
as
part
of
work.
Dr.
Nelson
again
said
that
the
IRB
contract
should
include
access
to
these
types
of
document.
If
IRB
minutes
were
not
available,
or
if
they
did
not
provide
them
when
requested
by
EPA,
this
made
the
IRB
deficient.
Dr.
Philpott
added
that
this
did
not
mean
that
the
protocol
was
deficient.
Dr.
Fisher
said
that
explanations
could
be
presented
orally
or
by
video,
but
that
risk
should
be
specified
in
writing.
Dr.
Fisher
also
stated
that
the
Board
has
concluded
that
the
protocol
did
not
comport
with
the
Agency's
human
studies
rule.

Charge
to
the
Board
Study
EMD­
003
from
Carroll­
Loye
Biological
Research
Scientific
Considerations
a.
Does
the
proposed
research
described
in
[
name
/
designation
of
the
protocol]
appear
likely
to
generate
scientifically
reliable
data,
[
useful
for
assessing
the
efficacy
of
the
repellent]
/
[
useful
33
of
104
(
together
with
other
data)
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
mixing,
loading
or
applying
a
pesticides]?

Board
Response
to
the
Charge
Dr.
Lehman­
McKeeman
evaluated
EMD­
003
for
ticks.
There
were
several
typos
but
the
compound
itself
had
been
approved
and
had
demonstrated
low
human
toxicity.
There
was
no
rationale
for
why
the
study
was
needed.
Another
deficiency
was
that
there
was
no
characterization
of
compound
stability.
Dr.
Bellinger
said
that
the
experimental
design
required
manual
dexterity
and
a
training
video
might
help
with
this.
Without
this,
experimental
data
might
be
subjective.
Dr.
Fish
added
that
all
relevant
comments
on
the
previous
protocol
should
be
applied
here.
There
was
no
clear
rationale
or
dose
justification,
no
measure
of
how
biting
pressure
would
be
assessed,
no
clear
explanation
of
negative
controls
and
some
concern
about
the
manipulation
of
subjects,
asking
them
to
aspire
mosquitoes.

Charge
to
the
Board
Ethical
Considerations
b.
Does
the
proposed
research
described
in
Study
EMD­
003
from
Carroll­
Loye
Biological
Research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

Board
Response
to
the
Charge
Dr.
Philpott
agreed
with
the
deficiencies
noted
by
Mr.
Carley
and
added
that
a
separate
consent
form
should
be
used
for
women.
Dr.
Philpott
stressed
that
compensation
should
never
be
listed
as
a
benefit.
Dr.
Menikoff
believed
that
the
consent
form
was
written
like
a
protocol.
A
brief
description
of
the
rationale
for
testing
this
product
and
of
the
study
design
would
be
helpful.
Major
risks
should
be
identified
in
the
IC
document.
Dr.
Fish
added
that
in
the
IC
documents,
study
duration
was
unclear
and
that
the
language
should
be
appropriate
for
the
reading
level
of
the
target
group.
Dr.
Fisher
said
that
the
relationship
of
the
subject
to
the
PI
needed
to
be
disclosed.
While
confidentiality
was
important,
and
conflicts
of
interest,
in
and
of
themselves
are
not
unethical,
these
need
to
be
disclosed
in
the
IC
documents.
This
was
not
a
new
requirement
but
may
be
new
to
repellent
testing.
The
Board
concluded
that
the
protocol
does
not
comport
to
the
Agency's
human
studies
rule.

Carbofuran:
BMD
Analysis
Dr.
Anna
Lowit
(
OPP,
EPA)
provided
the
Board
with
an
update
of
the
Agency's
BMD
calculation
for
carbofuran.
The
Agency
is
in
the
process
of
deciding
BMDs
for
AChE
inhibitors
and
there
are
10
compounds
in
this
common
endpoint
group.
Dr.
Lowit
noted
that
in
the
Board's
draft
May
2­
3,
2006
HSRB
meeting
report,
the
Board
had
some
issues
on
the
carbofuran
study
and
requested
supplemental
information
on
this
analysis.
For
carbamates,
rapid
recovery
makes
the
AChEI
analysis
confusing.
For
BMD
calculations,
all
the
data
points
were
used,
including
the
controls.
Dr.
Lowit
asked
Dr.
Rick
Reese
(
Exponent,
Inc.)
representing
FMC
Corp.
to
34
of
104
provide
additional
explanations
of
the
BMD
analysis.
Dr.
Lehman­
McKeeman
asked
about
changes
in
AChEI
in
controls.
Dr.
Lowit
explained
that
individual
changes
over
time
did
result
in
greater
variability
and
uncertainty
in
the
findings
and
the
materials
provided
to
the
Board
were
still
draft.
Dr.
Lehman­
McKeeman
said
that
the
question
was
how
robust
could
this
analysis
be
with
such
a
small
sample
size.
Dr.
Carriquiry
said
that
the
model
was
underestimating
at
one
end
of
the
curve,
but
with
such
a
small
sample
size,
it
was
difficult
to
know
which
end.
Dr.
Fisher
requested
that
Dr.
Lehman­
McKeeman
review
the
new
material
presented
by
the
Agency
and
provide
a
summary
of
her
analysis
during
the
Board's
final
review
of
its
May
2­
3,
2006
report,
occurring
at
this
week's
meeting.

Agricultural
Handler
Exposure
Monitoring
Studies
Scientific
Consideration
for
Agricultural
Handler
Protocols
Mr.
Jeff
Dawson
(
OPP,
EPA)
and
Mr.
Jeff
Evans
(
OPP,
EPA)
explained
that
the
Agricultural
Handlers
Exposure
Task
Force
(
AHETF)
had
submitted
five
protocols
for
pesticide
exposure
studies
that
are
part
of
a
larger
research
program
the
AHETF
is
conducting.
The
premise
of
the
AHETF
research
program
was
that
data
could
be
used
generically
by
various
stakeholders
(
e.
g.,
applicants,
registrants,
EPA,
and
others)
for
calculating
exposures
for
the
agricultural
handlers
of
pesticides.
The
scope
of
the
AHETF
research
program
was
very
broad
in
that
it
intended
to
address
exposures
related
to
many
job
functions
in
agriculture
and
also
to
assess
the
impacts
of
various
parameters
on
exposure
(
e.
g.,
how
do
changes
in
the
pounds
of
pesticide
handled
or
acres
treated
affect
exposure
levels?).
The
protocols
submitted
for
HSRB
review
described
studies
to
measure
exposures
for
five
specific
scenarios.

The
Agency
believed
that
these
studies
improved
EPA's
ability
to
assess
the
risks
of
using
pesticides
because
the
data
would
reflect
current
agricultural
practices,
equipment
and
techniques
leading
to
more
refined
exposure
estimates.
Further,
the
monitoring
techniques
to
be
used
for
these
studies
have
been
standardized
for
use
across
the
AHETF
research
program.
These
more
refined
and
reliable
data
would
allow
the
Agency
to
better
estimate
how
worker
exposure
levels
were
affected
by
changes
in
various
factors
such
as
the
amount
of
active
ingredient
handled,
type
of
application
equipment
used,
application
rate
used,
volumes
handled,
and
personal
protective
equipment
(
PPE).
It
should
be
noted,
however,
that
the
use
of
the
data
generated
in
this
study
by
the
U.
S.
EPA
and
other
stakeholders
would
depend
upon
the
nature
of
the
results.

There
are
limited
exposure
data
for
agricultural
workers
due
to
the
cost
and
variability
between
studies.
This
led
to
the
formation
of
AHETF
with
the
objective
of
evaluating
current
practices
and
factors
impacting
worker
exposure.
The
AHETF
includes
all
but
one
major
pesticide
manufacture.
The
data
generated
would
be
used
in
a
surrogate
fashion
and
has
been
a
4­
5
year,
iterative,
joint
process.
The
overall
goal
was
to
create
a
database
to
assess
handler
exposures
categorized
by
specific
tasks
performed.
The
AHETF
was
interested
in
evaluating
the
effectiveness
of
PPE
evaluating
trends
in
exposure,
and
what
caused
these
trends
to
change.
A
list
of
AHETF
protocols
were
summarized
to
date.
Replicates
are
exposure
events.
The
AHETF
used
a
multi­
faceted
approach
for
exposure
analysis.
There
were
two
basic
scenarios
for
dosimetry
­
pesticide
handlers
and
farm
labourer.
Exposure
scenarios
were
defined
by
job
35
of
104
function
and
other
factors
including:
(
1)
equipment
(
e.
g.
ground
boom,
aircraft);
(
2)
physical
nature
of
product,
(
e.
g.
liquid,
powder);
(
3)
packaging
(
open
bottle,
bag,
closed­
system);
(
4)
vehicle
type
(
tractor
with
cab
or
no
cab)
and;
(
5)
clothing
or
PPE
worn
(
e.
g.
long
pants,
coveralls,
respirator).
A
key
factor
was
that
handler
exposures
were
proportional
to
the
amount
of
pesticide
used,
not
the
identity
of
the
pesticide
ingredient.

Dr.
Fisher
asked
whether
participants
were
required
to
wear
PPE.
Mr.
Dawson
responded
that
if
their
clothing
did
not
meet
label
requirements,
they
were
not
allowed
to
participate
in
the
study.
If
compliant
clothing
was
not
routinely
worn,
was
the
AHETF
concerned
about
this?
Was
there
a
safety
factor
calculation
to
account
for
failure
to
wear
appropriate
clothing?
Mr.
Dawson
replied
that
the
AHETF
develops
risk
estimates
under
a
variety
of
exposure
scenarios.
Basic
inputs
to
calculations
included
application
rates
(
lbs
active
ingredient/
acre),
area
treated
(
acres)
and
unit
exposure
(
how
much
someone
gets
on
them
per
the
amount
that
they
handle).
The
margin
of
exposure
was
the
ratio
of
the
hazard
endpoint
to
daily
exposure.
Unit
exposure
estimates
were
to
be
obtained
from
proposed
AHETF
studies.
Mr.
Dawson
presented
a
list
of
EPA
guidelines
that
were
used
to
guide
study
design.
Whole
body
dosimetry
using
a
long
underwear
suit
would
be
used
to
monitor
deposition
on
the
skin.
Risks
would
be
calculated
assuming
100
percent
absorption.
The
hand
rinse
technique
estimated
residues
on
a
hand
using
a
solvent
rinse
but
he
acknowledged
that
this
technique
was
currently
under
review
for
suitability.
The
exposure
estimates
may
be
slightly
lower
than
anticipated
but
not
by
an
order
of
magnitude.
The
face
wipe
technique
would
be
used
to
assess
deposition
on
the
face.
A
personal
sampling
pump
was
used
to
estimate
inhalation
exposures
and
breakthrough
was
possible.
Dr.
Krishnan
asked
about
passive
dosimetry,
since
this
was
all
these
studies
evaluated.
Dr.
Fisher
asked
if
these
studies
were
to
be
done
to
update
the
agricultural
handlers
database,
and
if
so,
would
be
surprised
that
the
Agency
did
not
ask
for
preliminary
testing
of
the
collection
devices.
Mr.
Dawson
said
that
all
the
sampling
devices
had
limitations.
Mr.
Dawson
agreed
that
validation
would
be
nice
but
the
AHETF
methods
were
still
better
than
the
existing
1993
data.
More
quantitative
data
could
be
used
to
adjust
underestimation
or
variability.
Dr.
Carriquiry
said
that
it
must
be
difficult
to
collect
this
data,
and
asked
about
biomarkers.
Board
members
also
raised
questions
about
the
independence
of
the
AHETF
and
EPA
in
designing
and
evaluating
the
studies.

Mr.
Evans
then
reviewed
the
key
components
of
the
study.
Quality
assurance
was
based
on
good
laboratory
practice
requirements.
The
studies
were
done
on
individuals
that
would
routinely
be
doing
these
activities.
Scenario­
based
surrogate
design
had
to
do
with
the
data
generated.
Board
members
asked
if
the
exposure
events
would
be
done
on
the
job
or
if
this
would
be
an
additional
exposure
with
the
experimental
compound
at
experimentally
defined
levels.
If
so,
this
wasn't
strictly
an
observational
study.
There
were
three
possibilities
for
exposure:
1)
monitoring
existing
exposures
with
measurement
devices;
2)
monitoring
exposure
with
altered
compounds
or
concentrations;
or
3)
monitoring
additional
exposures
that
meet
the
requirements
of
the
study.
The
protocol
needed
to
define
this.
Mr.
Dawson
said
that
an
attempt
would
be
made
to
find
applicators
that
would
already
be
doing
this
nature
of
work.
The
exposure
scenarios
were
scripted
but
the
experimental
exposures
were
part
of
the
applicators'
routine
job
duties.
Application
may
need
to
be
altered
to
meet
the
needs
of
the
study
but
these
would
not
be
additional
exposure.
Thus,
the
Board
considered
this
protocol
an
intentional
exposure
study.
36
of
104
Mr.
Dawson
said
that
the
AHETF
is
collaboration
between
pesticide
manufacturers
and
EPA
that
coalesced
on
their
own
and
consults
with
EPA,
CalEPA,
and
Health
Canada.
There
was
a
process
of
working
with
the
task
force
to
make
sure
that
the
data
generated
were
generalizable
to
AHETF
purposes.
What
was
the
probability
that
a
worker
exposed
under
certain
conditions
would
exceed
a
given
threshold?
The
studies
tried
to
characterize
the
entire
distribution.
Dr.
Carriquiry
supported
the
Agency's
efforts
but
said
that
the
Agency
should
perform
replicate
sampling
on
a
different
day.
Mr.
Dawson
said
that
the
compounds
were
selected
with
a
broad
range
of
uses.
Mr.
Carley
added
that
these
compounds
were
already
in
use.
Mr.
Dawson
commented
that
the
existing
data
were
not
collected
in
a
uniform
fashion
and
did
not
allow
an
estimation
of
variability
and
distributions
of
exposure.
Dr.
Fenske
said
that
the
documents
provided
to
the
Board
did
not
make
it
clear
that
the
existing
data
were
inadequate.
Mr.
Dawson
commented
that
the
existing
data
were
not
fatally
flawed,
but
not
consistently
collected.
Existing
data
were
being
used
in
the
database
and
new
methods
would
be
used
to
advise
the
AHETF.
Dr.
Lebowitz
asked
and
Mr.
Dawson
responded
that
the
agricultural
handler
Standard
Operating
Procedures
(
SOPs)
were
final.

Ethical
Considerations
for
Agricultural
Handler
Protocols
Mr.
Carley
discussed
the
ethical
considerations
for
the
agricultural
handler
protocols.
Subjects
for
the
AHETF
studies
are
workers
with
specific
experience
in
the
tasks
to
be
performed.
The
IRB
asked
for
extra
care
to
avoid
undue
influence
in
subject
selection.
There
was
a
negligible
increase
in
pesticide
exposure
to
workers
because
pesticides
would
be
intercepted
by
the
sampling
device;
however,
there
was
increased
risk
due
to
heat
exposure.
There
was
IRB
review
and
the
protocols
promised
to
obtain
IC
in
the
subjects'
native
language.
Deviations
from
the
protocol
must
be
reported
to
the
IRB.
There
was
reference
to
excluding
subjects
with
conflicts
of
interest
but
this
was
unclear.
The
IC
materials
should
describe
pesticide
use
patterns
and
pesticide
labels
should
also
be
made
available.
The
Board
was
troubled
by
the
provisions
in
the
protocols
that
there
might
be
alteration
of
the
application
rates
to
meet
the
design
time
requirements
of
the
study.
The
protocols
failed
to
document
ethical
conduct
of
research
consistent
with
the
Agency's
human
studies
rule.
Subjects
should
have
been
told
the
exclusion
criteria.
Description
of
payment
to
participate
was
unclear.
Compensation
for
injuries
excluded
those
that
would
occur
as
part
of
routine
activities.
The
words
"
replicate"
and
"
worker"
were
used
interchangeably.
The
IC
form
was
not
provided
in
Spanish
and
was
not
signed.

Dr.
Fisher
said
that
she
understood
that
there
was
a
group
of
employers
that
encouraged
employees
to
participate.
What
did
the
employers
receive?
Mr.
Carley
could
not
answer
this
but
said
that
this
varied
greatly
across
the
country.
Dr.
Fish
did
not
see
IRB
minutes
as
part
of
the
submission,
but
noted
that
Western
Research
agreed
to
translate
the
IC
form
into
Spanish.
37
of
104
Public
Comments
Dr.
Elliot
Gordon
on
behalf
of
the
Agricultural
Handlers
Exposure
Task
Force,
Mr.
Curt
Lunchick
and
Dr.
Victor
Canez
of
Bayer
Crop
Science
on
behalf
of
the
Agricultural
Handlers
Exposure
Task
Force
and
Mr.
Larry
Smith
of
the
Agricultural
Handlers
Exposure
Task
Force
Dr.
Gordon
explained
that
there
are
several
defining
characteristics
of
the
AHETF
protocols.
They
monitor
workplace
exposure
under
normal
agricultural
product­
use
conditions,
in
contrast
to
clinical
toxicology
studies.
They
address
USEPA,
PMRA
and
Cal­
DPR
regulatory
data
requirements
and
utilize
consensus
derived
regulatory
exposure
monitoring
methods
and
standards
and
individual
studies
are
part
of
an
integrated
industry
task
force
effort.
AHETF
studies
monitor
professional
farm
workers
who
mix,
load,
and
apply
pesticides
during
their
normal
job
activities,
in
standard,
agricultural
settings
at
appropriate
times
during
the
year.
Products
handled
in
AHETF
studies
are
widely
used
USEPA­
registered
products.
The
study
participants
comply
with
all
product
label
requirements
and
the
USEPA
Worker
Protection
Standard
(
WPS).
An
IRB
reviews
and
approves
all
AHETF
protocols
prior
to
initiation
of
work
and
the
IC
document
is
issued
by
the
IRB.
AHETF
data
are
generic
rather
than
product­
specific.
AHETF
has
conducted
or
initiated
14
exposure
studies.
In
addition,
an
IRB
had
reviewed
and
approved
the
five
protocols
currently
before
the
HSRB.
Approximately
40
additional
studies
will
be
conducted
over
the
next
several
years.
North
American
regulatory
agencies
will
use
the
data
in
risk
assessments
applicable
to
crop
protection
products
and
uses.
AHETF
studies
conform
to
established
Agency
and
OECD
guideline
methods
and
procedures.
These
have
evolved
for
over
40
years
and
incorporate
advances
in
both
science
and
ethics.
Pesticides
can
be
mixed,
loaded
and
applied
in
numerous
ways
that
account
for
differences
in
equipment,
product
formulations,
crops
and
regions.
The
Task
Force
has
focused
on
33
use
scenarios
with
the
goal
of
developing
a
comprehensive,
integrated
database
rather
than
a
series
of
stand­
alone
studies,
which
pesticide
handlers
exposure
database
reflects.
To
summarize,
the
AHETF
study
schedules
are
time
sensitive
and
would
benefit
from
an
expedited
HSRB
review.
AHETF
is
interested
in
working
with
the
HSRB
and
USEPA
to
develop
ways
to
streamline
this
new
review
process.

Mr.
Lunchick
explained
that
the
recruitment
process
began
months
before
a
study
was
initiated.
Growers
notified
AHETF
as
to
when
they
were
ready
to
apply.
Applicators
did
have
access
to
the
label.
It
is
conceivable
that
an
applicator
may
be
asked
to
modify
application
rates
but
this
was
not
normally
done.
There
was
a
need
to
script
application
to
allow
for
meta­
analysis
conducted
across
scenarios.
The
Task
Force
was
looking
at
what
are
typically
maximum
label
application
rates.
The
AHETF
studies
were
being
designed
to
capture
variability
of
exposure
at
lower
application
rates.
In
the
existing
studies,
the
number
of
dosimeters
were
inconsistent
and
the
data
were
old.

Dr.
Philpott
asked
what
the
incentive
were
to
the
growers.
The
AHETF
supplied
free
pesticides.
Dr.
Canez
answered
questions
regarding
improper
handling
of
pesticides.
For
the
AHETF
studies,
application
rates
were
kept
at
label
limits,
and
one
person
assigned
to
each
handler
to
observe
techniques.
The
labels
have
not
been
made
available
in
Spanish
but
handlers
must
be
able
to
understand
the
applications
they
are
performing.
If
a
subject
wanted
to
withdraw,
they
could
still
receive
the
$
100
payment.
38
of
104
Dr.
Menikoff
asked
how
one
could
ensure
that
there
were
no
changes
in
application
rates
by
contacting
growers
ahead
of
time.
The
researchers
were
familiar
with
application
patterns
for
the
region
and
whether
the
grower
needed
this
product.
There
could
be
a
variety
of
products
that
would
suit
their
needs.
Most
applicators
objected
to
wearing
the
long
underwear
as
opposed
to
not
applying
the
product.
Dr.
Fisher
said
that
since
the
products
were
not
viewed
as
hazardous,
it
could
be
assumed
that
a
grower
was
more
likely
to
choose
the
experimental
product
since
it
was
provided
free.
The
Task
Force
said
they
were
monitoring
pesticide
applications
that
would
exist
and
that
the
free
pesticide
was
not
that
big
of
an
incentive.
Some
growers
believed
that
the
pesticides
did
not
meet
their
integrated
pest
management
(
IPM)
needs
so
they
would
not
participate.
There
was
a
local
site
coordinator
that
identified
growers
that
met
the
study
criteria.
After
growers
were
identified,
the
applicators
were
contacted
to
work
out
the
logistics
of
study
execution.
Applicators
were
allowed
to
drop
out
at
any
time
and
the
growers
were
not
told
why
a
subject
withdrew.
Dr.
Fenske
asked
that
since
there
were
no
biomarkers,
and
the
active
ingredient
did
not
make
a
difference,
why
not
do
the
studies
using
an
inert
ingredient?
Mr.
Lunchick
responded
that
it
was
easier
to
get
growers
to
agree
to
apply
a
compound
they
were
going
to
use
anyway.
None
of
the
products
tested
were
dermal
irritants
and
it
would
have
been
difficult
to
separate
product
formulations
from
toxic
ingredients.

There
has
been
some
replicate
testing
and
this
was
of
interest
from
the
perspective
of
intrapersonal
variability.
The
Task
Force
would
not
use
subjects
that
worked
for
member
companies
or
the
industry,
they
were
licensed
applicators
or
commercial
applicators
that
did
this
for
a
living.
All
materials
would
have
to
be
read
to
them.
Dr.
Lehman­
McKeeman
asked
how
the
AHETF
derived
the
subject
numbers.
AHETF
would
use
the
number
of
applicators
needed
to
apply
the
material.
AHETF
had
data
where
the
same
individual
was
tested
twice.
If
there
was
a
difference,
the
methods
would
be
modified
to
include
more
duplicate
testing
to
get
a
better
handle
on
the
intra­
variability.
Heat
illness
resulted
from
the
study
but
there
was
not
a
written
plan
for
a
response.
However,
the
study
director
was
aware
of
this
risk
and
would
address
this
concern.

Ms.
Shelly
Davis
of
the
Farm
Worker
Justice
Fund
Ms.
Davis
commented
that
in
the
scenarios
that
these
protocols
covered,
they
did
not
address
a
real
workday.
Workers
would
have
increased
exposure
because
the
grower
would
have
them
finish
the
job
after
the
study
was
completed.
The
products
were
toxic
and
these
exposures
are
cumulative.
Ms.
Davis
was
not
sure
whether
this
was
an
increase
over
what
they
would
normally
be
exposed
to
but
the
exposures
are
cumulative.
There
was
no
care
of
the
workers
in
the
protocols.
There
was
acknowledged
risk
due
to
heat
stress
and
lab
directors
said
that
they
would
respond
but
why
put
participants
at
risk
in
the
first
place?
The
IC
documents
did
not
include
health
risks
associated
with
the
products
they
were
applying.
Labels
were
available
but
they
were
not
in
Spanish.
Applicators
were
told
how
to
apply
the
products
but
they
did
not
know
the
health
risks
associated
with
the
products.
Health
risk
should
have
been
specified
in
a
language
the
subjects
understood
and
should
have
been
be
supplied
by
the
research
sponsors.
If
a
farm
hand
refused
to
participate,
they
would
be
sent
home
and
would
lose
a
day's
pay.
This
was
coercive.
The
small
number
of
replicates
raises
doubts
about
the
scientific
validity
of
the
studies.
If
this
cannot
be
done
in
an
ethical
and
scientifically
valid
manner
then
it
shouldn't
be
done.
Finally,
the
Farm
Worker
Justice
Fund
was
never
invited
to
comment
on
the
study
design.
39
of
104
The
Chair
adjourned
the
meeting
for
the
day.
40
of
104
June
30,
2006
The
Chair
opened
the
meeting
with
Board
discussion
of
the
agricultural
handler
protocol
change
questions.

Charge
to
the
Board
The
Agricultural
Handlers
Exposure
Task
Force
(
AHETF)
has
submitted
protocols
for
five
pesticide
exposure
studies
that
are
part
of
a
larger
research
program
the
AHETF
is
conducting.
The
premise
of
the
AHETF
research
program
is
that
data
can
be
used
generically
by
various
stakeholders
(
e.
g.,
applicants,
registrants,
EPA,
and
others)
for
calculating
exposures
for
the
occupational
handlers
of
pesticides.
The
scope
of
the
AHETF
research
program
is
very
broad
in
that
it
intends
to
address
exposures
related
to
many
job
functions
in
agriculture
and
also
to
assess
generally
the
impacts
of
various
parameters
on
exposure
(
e.
g.,
How
do
changes
in
the
pounds
of
pesticide
handled
or
acres
treated
affect
exposure
levels?).
The
protocols
submitted
for
HSRB
review
describe
studies
to
measure
exposures
for
five
specific
scenarios
(
i.
e.,
closed
or
open
system
mixing/
loading
,
airblast
applications
to
trellis
and
orchard
crops,
or
pilot
exposures
from
fixed
wing
agricultural
aircraft).

The
Agency
believes
these
studies
improve
EPA's
ability
to
assess
the
risks
of
using
pesticides
because
the
data
will
reflect
current
agricultural
practices,
equipment
and
techniques
and
will
allow
for
more
refined
exposure
estimates.
Further,
the
monitoring
techniques
to
be
used
for
these
studies
also
have
been
standardized
for
use
across
the
AHETF
research
program..
These
more
refined
and
reliable
data
will
allow
the
Agency
to
estimate
better
how
worker
exposure
levels
are
affected
by
changes
in
various
factors
such
as
the
amount
of
active
ingredient
handled,
type
of
application
equipment
used,
application
rate
used,
volumes
handled,
and
personal
protective
equipment
used.

It
should
be
noted,
however,
that
the
use
of
the
data
generated
in
this
study
by
the
U.
S.
EPA
and
other
stakeholders
will
depend
upon
the
nature
of
the
results.
For
example,
the
adequacy
of
the
field
or
laboratory
quality
control
data
may
dictate
that
correction
factors
are
applied
to
adjust
monitored
exposure
levels
to
account
for
losses
from
field
samplers
or
low
performing
analytical
methods.

1.
AHETF
Closed
System
Mixing/
Loading
of
Liquids
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE34
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
mixing,
loading
or
applying
a
liquid
pesticide
with
closed
systems?
[
Note:
In
a
few
cases,
corresponding
application
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE34
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?
41
of
104
2.
AHETF
Airblast
Application
to
Trellis
Crops
in
the
West
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE36
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
making
an
airblast
application
of
a
pesticide
to
a
trellis
crop
under
conditions
found
in
the
western
United
States?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE36
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

3.
AHETF
Airblast
Application
to
Trellis
Crops
in
the
East
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE37
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
making
an
airblast
application
of
a
pesticide
to
a
trellis
crop
under
conditions
found
in
the
eastern
United
States?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE37
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

4.
AHETF
Closed
Cab
Airblast
Application
to
Orchards
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE38
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
making
an
airblast
application
of
a
pesticide
to
orchard
crops?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE38
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?
42
of
104
5.
AHETF
Fixed­
Wing
Aerial
Application
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE42
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
making
an
aerial
application
of
a
pesticide
from
fixed­
wing
aircraft?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE42
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

Board
Response
to
the
Charge
Scientific
Considerations
Dr.
Fisher
began
the
Board's
discussion
reminding
the
Board
to
focus
on
similarities
between
each
protocol,
followed
by
the
consideration
of
specifics.
Dr.
Fisher
also
discussed
the
Board's
process
for
review
of
the
five
protocols
and
decided
that
due
to
the
previous
discussion
on
the
Agency's
presentation,
the
Board
would
discuss
the
protocols
together,
with
the
Board's
lead
discussants
for
each
protocol
serving
as
the
primary
respondents
for
all
five
protocols.

Dr.
Fenske
initiated
the
discussion
of
the
AHETF
protocols
with
comments
on
the
generic
database
design.
The
generic
database
is
a
valid
approach
and
has
the
advantage
of
allowing
focus
on
key
parameters
affecting
exposure.
Dr.
Fenske
believed
that
not
including
the
participation
of
labor
in
protocol
design
decisions
was
a
deficiency
because
independent
review
was
important
at
the
beginning
or
design
stage
of
the
project.
Dr.
Fenske
was
supportive
of
a
plan
to
present
the
guideline
to
the
FIFRA
SAP
first.
This
would
encourage
more
transparency
with
subsequent
joint
EPA
endeavors.
EPA
(
not
OPP)
should
be
providing
some
oversight
of
the
endeavor.
While
the
Agency
was
calling
this
a
third
party
study,
the
submitter
has
collaborated
with
the
Agency.
It
may
be
too
late
to
ask
whether
there
was
even
a
need
for
the
new
data
since
the
project
is
already
on­
going.
Dr.
Fenske
believed
not
including
farmworker
community
representation
into
the
taskforce
development
process
was
a
deficiency.
To
base
the
justification
of
the
study
on
outdated
software
was
not
convincing.
In
contrast,
stating
that
the
pesticide
handlers'
database
used
the
patch
technique,
which
gives
higher
estimates
of
exposure,
and
questioning
the
compatibility
of
the
two
databases
might
have
been
a
more
persuasive
argument
for
the
justification
of
the
study.
The
proposed
comparison
between
passive
dosimetry
and
biological
monitoring
might
allow
validation
of
results.
In
addition,
several
Board
members
raised
questions
on
how
the
term
replicate
was
used.
Dr.
Fenske
said
that
a
replicate
means
an
exact
copy,
which
is
not
what
this
was
so
the
word
replicate
should
not
have
been
used
to
describe
the
test
subjects.
The
same
person
doing
the
same
activity
two
times
are
repeated
measures.
Different
people
doing
the
same
job
are
test
subjects.
The
sample
sizes
for
subscenarios
were
small
and
the
lack
of
repeated
measures
could
overestimate
exposure.
Statistical
consultation
would
have
been
helpful.
The
methods
used
to
estimate
dermal
exposure
could
underestimate
exposure
and
could
allow
breakthrough.
Two
layers
of
the
cotton
garment
could
43
of
104
be
used
to
assess
quality
of
breakthrough
data.
The
face
and
neck
wipe
method
underestimates
exposure
and
is
not
a
standard
method.
Hand
washing
also
underestimates
exposure.
A
removal
efficiency
study
could
be
conducted
to
correct
for
this.
Dr.
Fenske
believed
that
the
4­
hour
exposure
duration
was
reasonable
and
allowed
investigators
the
time
they
needed
to
set
up
and
take
measurements.
Dr.
Fenske
also
raised
issues
on
over
and
underestimation
of
exposure,
based
on
the
study
design
and
estimates
of
exposure
from
hand
and
neck
wipes,
and
hand
rinsing.
The
Agency
could
develop
an
uncertainty
factor
(
UF)
to
account
for
underestimates
but
there
was
no
way
to
do
this
type
of
research
without
uncertainty.

Dr.
Lebowitz
added
that
the
characteristics
of
the
workers
were
insufficient
in
terms
of
representativeness
and
generalizability.
In
addition,
the
protocols
did
not
follow
SOPs
.
Since
there
were
problems
with
the
monitoring
of
exposures,
biomarkers
would
be
helpful
to
validate
measurements.
The
individuals
measured
used
pesticides
and
there
were
ways
to
use
PBPK
for
exposure
monitoring.

Dr.
Chambers
stated
that
exposure
data
were
always
the
weakest
part
of
any
risk
assessment.
Dr.
Chambers
was
impressed
with
the
efforts
taken
to
quantify
exposure
in
a
variety
of
settings
in
an
uncontrolled
field
environment.
She
objected
to
the
use
of
"
replicate"
and
believed
that
one
subject
was
insufficient.
With
dosimeters
taking
up
some
of
the
compound,
the
biomarker
approach
would
require
a
large
number
of
individuals
and
might
be
an
untenable
effort.
She
was
impressed
with
study
design
and
execution
and
stated
that
whole
body
sampling
data
is
better
than
patch
data.
She
concluded
that
it
was
unfair
to
criticize
the
lack
of
justification
because
the
criteria
were
just
developed.

Dr.
Bellinger
agreed
with
Dr.
Chambers
and
commended
the
study's
quality
assessment.
Statistical
methods
were
boilerplate
but
it
was
not
clear
how
the
data
would
ultimately
be
used.
Environmental
variables
such
as
wind
speed,
temperature,
etc.
were
recorded
but
it
wasn't
explained
how
this
data
would
be
combined
into
the
final
estimation.
This
was
also
true
for
hand
rinsing
and
individual
mixing
scenarios.
The
issue
of
sample
size
was
problematic.
Information
was
sought
from
three
handlers
under
a
variety
of
exposure
conditions
but
this
estimate
would
take
more
than
three
subjects.

Dr.
Brimijoin
was
more
critical
of
the
protocols.
He
believed
that
since
the
Agency
had
a
consultative
role
with
the
project,
they
should
have
been
aware
of
such
limitations
as
outlined
by
the
Board
in
relation
to
the
human
studies
rule.
Almost
all
the
studies
included
a
single
subject
under
some
specific
exposure
conditions
and
the
statistics
were
elementary.
Plans
to
group
the
data
were
not
described.

Dr.
Lehman­
McKeeman
believed
this
type
of
data
was
needed
but
struggled
with
the
study
design.
If
there
had
been
a
justification
of
the
study
this
would
affect
study
design.
One
replicate
was
not
adequate
for
inclusion.
She
could
see
how
this
data
could
be
used,
but
it
was
not
described
in
the
protocol.
The
Board
needed
to
understand
precisely
how
the
data
would
be
used.

Dr.
Krishnan
was
concerned
with
dose
selection.
Minimization
of
risk
could
not
be
achieved
without
this
understanding.
Using
the
maximum
application
rate
specified
on
the
label
44
of
104
was
problematic
in
the
context
of
multiple
and
aggregate
exposures.
The
study
needed
built
in
flexibility
with
application
rates
so
maximum
application
rates
specified
on
product
labels
were
not
exceeded.

Dr.
Fitzpatrick
saw
a
need
for
the
data
but
believed
it
would
have
been
nice
to
see
why
the
newer
estimate
of
exposure
would
be
more
reliable
than
other
methods
used
and
how
this
data
would
be
used.

Dr.
Fisher
summarized
Board
discussion
as
follows:
(
1)
there
were
advantages
to
having
a
generic
data
base
and
the
efforts
to
do
a
field
study
of
this
complexity
were
admirable;
(
2)
the
protocols
were
deficient
with
respect
to
compliance
with
Subpart
K
of
the
human
studies
rule
for
third
party
studies;
(
3)
not
enough
was
said
about
the
quality
of
existing
exposure
data
or
how
the
new
data
would
be
used
or
combined
with
old
data;
(
4)
the
term
subject
should
be
used
instead
of
replicate;
(
5)
more
information
was
needed
on
the
proposed
statistical
approach;
(
6)
worker
interests
needed
to
be
taken
into
account;
(
7)
sample
size
should
be
explained
and
when
there
were
single
subjects
this
needed
to
be
justified;
(
8)
accuracy
would
only
be
as
good
as
the
measurements
taken;
(
9)
clarification
needed
to
be
provided
on
agricultural
handler
work
hours
and
the
set
up
hours;
(
10)
there
was
concern
that
the
Agency's
SOPs
were
not
followed;
(
11)
the
generic
data
base
included
environmental
factors
but
the
study
design
did
not
describe
how
this
information
would
be
accounted
for;
(
12)
protocols
needed
to
clarify
who
the
subjects
were
and
their
level
of
authority;
(
13)
baseline
biomedical
and
biomarker
data
might
be
helpful
and;
(
14)
the
protocols
stated
that
label
instruction
would
be
followed
but
exposure
rates
were
not
detailed.
There
are
40
studies
planned
but
Dr.
Fisher
did
not
see
a
critical
health
need
to
have
these
data
immediately.
While
the
Board
discussed
the
draft
science
and
ethics
criteria
for
review
of
study
protocols
at
this
week's
meeting,
the
task
force
should
have
acknowledged
consideration
of
these
criteria,
at
least
as
part
of
their
oral
remarks.
She
felt
that
the
protocol
lacked
clear
articulation
of
the
study
justification.

Dr.
Lebowitz
stated
that
aggregate
exposure
and
biomarkers
are
critical.
The
database
would
be
given
to
EPA
statisticians
so
it
was
important
to
know
how
unusually
high
exposures
during
accidents
would
be
reported.
Dr.
Chadwick
said
that
the
protocols
were
all
done
over
3­
4
days
with
one
person
in
a
treatment
group
so
how
useful
was
this
database.
Dr.
Nelson
responded
that
the
purpose
of
exposure
scripting
was
to
allow
meta­
analysis
and
combination
of
studies
into
the
database.
Dr.
Lehman­
McKeeman
believed
that
these
data
could
be
very
useful
but
the
nature
of
the
overarching
purpose
and
execution
of
study
did
not
seem
to
come
through
study
execution.
Exposure
data
was
what
was
critical
and
collecting
biomarker
data
could
compromise
this
measure.
The
Board
should
take
biomarkers
off
the
table
and
focus
on
exposure
data.
Thus,
the
focus
should
be
on
exposure
data,
not
biomarkers.

Dr.
Fenske
said
that
it
would
not
be
practical
to
combine
biomonitoring
and
exposure
data.
Combining
exposure
data
collected
by
various
means
could
be
utilized
to
get
total
dermal
dose
but
there
was
a
lot
of
uncertainty
with
this.
Patch
studies
overestimated
exposure
but
the
methods
used
for
the
AHETF
protocol
included
a
systematic
bias
that
underestimated
exposure
because
absorbed
dose
was
lost.
There
was
no
data
analysis
plan
in
the
protocol
and
details
were
needed.
Fourteen
studies
have
already
been
initiated
but
it
was
not
explained
how
wind
speed
and
other
environmental
variables
would
be
incorporated
into
the
statistical
analysis.
It
was
up
45
of
104
to
EPA
to
take
the
lead
on
this
to
ensure
the
quality
of
the
database.
Meta­
analysis
refers
to
a
specific
method
for
data
across
studies.
If
there
are
different
scenarios
across
protocols,
we
may
not
be
able
to
combine
the
data
generated.
Dr.
Brimijoin
was
supportive
of
collecting
a
large
database
but
expressed
concern
about
integration
between
study
designs
and
the
use
of
a
metaanalysis

Dr.
Fisher
summarized
by
concluding
that
there
was
some
agreement
and
some
disagreement
about
the
use
of
biomarkers,
sampling
methods
and
the
study
justification
but
there
is
no
doubt
that
a
study
like
this
should
be
performed.
The
intent
to
do
meta­
analysis
was
good
but
with
so
many
variables
being
collected,
it
was
difficult
to
know
how
the
data
would
be
used.
Without
a
statistical
design
plan,
what
the
Board
would
be
approving
was
not
clear.
How
do
you
approve
five
studies
out
of
40
when
meta­
analysis
is
planned?
There
needed
to
be
discussion
whether
the
common
parts
of
protocol
should
move
forward,
then
see
whether
any
of
the
individual
studies
had
assets
or
deficiencies
and
whether
they
should
also
be
initiated.
Since
the
Board
had
concerns
about
use
of
the
data
moving
forward,
the
Board
needed
to
make
a
decision
as
to
whether
it
wanted
to
see
this
protocol
again.
What
the
Board
has
not
seen
is
the
overarching
study
and
analytical
plan
for
how
the
data
base
would
be
used.

Ethical
Considerations
Dr.
Philpott
began
the
Board's
discussion
indicating
that
he
was
not
supportive
of
the
protocol.
He
was
disappointed
with
the
lack
of
clear
validation
of
the
methods
and
failure
to
follow
some
of
the
NAS
recommendations.
Although
this
study
was
described
as
observational,
it
was
not
strictly
observational,
nor
a
clear
justification
for
why
the
data
was
needed.
Whether
or
not
there
truly
was
a
negligible
increase
in
risk,
given
the
scripted
protocols
for
application,
needed
to
be
evaluated.
Confidentiality
needed
to
be
examined
in
term
of
excluding
pregnant
women
and
illegal
immigrants
since
this
may
have
impacted
the
voluntariness
of
participation.
There
was
a
need
to
address
the
risks
of
pesticide
handling.
If
the
subjects
did
not
speak
English
as
their
primary
language,
ways
to
reduce
their
potential
exposure
needed
to
be
explained,
and
this
may
have
impacted
the
collection
of
exposure
data.
The
protection
of
subjects
was
primary
even
if
it
compromised
exposure
data.
The
risk
of
heat­
related
illness
also
needed
to
be
considered.
Heat
index
data
should
have
been
used
to
assess
this
condition
because
the
symptoms
of
heat
related
illnesses
are
vague
and
heat
stress
and
heat
stroke
can
have
sudden
onset.
The
growers
were
incentivized
with
free
pesticides.
Freedom
to
withdraw
needed
to
be
explicit.
The
fact
that
there
were
no
withdrawals
from
previous
studies
raised
a
concern
regarding
subjects'
perceptions
regarding
voluntary
withdrawal.
Defining
appropriate
compensation
for
time
without
getting
into
undue
influence
is
tricky.
Dr.
Philpott
recommended
that
additional
compensation
be
added
for
preparation
time.
Dr.
Philpott
expressed
concerns
about
language
in
the
IC
document,
the
reading
level,
and
possible
illiteracy
of
subjects.
The
IC
also
needed
to
describe
heat
related
illnesses.

Dr.
Nelson
started
with
minimization
of
risk.
The
scripted
nature
of
exposures
was
important
because
if
there
was
additional
exposure
to
pesticides,
this
would
be
unethical.
Even
if
the
duties
performed
were
the
worker's
routine
job
duties,
this
was
not
minimal
risk.
It
would
be
a
good
thing
if,
as
part
of
the
study,
the
workers
learned
better
ways
to
handle
pesticides
and
reduce
exposure.
Dr.
Nelson
would
be
inclined
to
share
the
data
with
workers
but
not
if
the
46
of
104
study
was
underestimating
exposure.
There
was
little
documentation
from
the
IRB,
but
the
IRB
appears
to
be
a
typical
biomedical
IRB.
The
IRB
did
not
include
an
expert
on
pesticide
application
so
this
may
not
be
the
right
group
of
people
to
use
for
the
IRB.

Dr.
Fish
added
that
although
what
would
be
done
on
a
given
day
was
scripted,
it
would
be
one
of
the
usual
choices
of
what
the
worker
was
asked
to
do.
The
Board
appeared
to
be
struggling
with
the
research.
The
protocols
needed
statistical
consultation
and
the
IC
form
require
clarity
that
compensation
would
be
received
even
if
the
subject
withdrew.
Whatever
the
IRB­
approved
number
of
subjects
was,
this
should
have
been
followed.
The
IC
needed
to
be
changed
to
address
heat
stress.
If
the
worker's
day
was
extended
due
to
participation
in
the
research,
this
needed
to
be
made
clear.
Pregnancy
language
also
needed
to
be
clarified.

Dr.
Chadwick
confirmed
that
there
was
a
need
to
demonstrate
comprehension
of
IC
materials.
There
was
also
a
need
to
understand
whether
this
was
strictly
a
dosimetry
study
or
whether
exposures
would
be
altered.
Workers'
names
should
not
have
been
recorded
unless
it
was
needed
for
the
study
and
assistance
with
donning
cotton
garments
should
have
been
provided
by
a
same
sex
individual.
Amendments
to
the
protocol
are
permissible
but
require
approval
by
the
IRB,
not
just
the
study
director.
Boilerplate
language
should
have
been
removed
from
the
IC
form.
Use
of
the
word
sponsor
to
describe
Western
Research
may
be
misleading
since
the
task
force
was
the
sponsor.
The
protocol
needed
to
be
more
explicit
with
respect
to
safety.
The
IC
appeared
to
authorize
the
release
of
medical
records
which
did
not
respect
the
right
to
privacy.

Dr.
Fisher
said
that
the
risk
benefit
ratio
relies
on
the
science.
The
risks
were
only
acceptable
if
the
benefits
to
science
were
clear
and
the
Board
was
not
clear
as
to
what
the
risks
were.
If
the
pesticide
tested
was
no
more
toxic
than
what
it
is
being
substituted
for,
then
additional
risk
may
not
be
great.
Heat
exposure
was
a
critical
risk
that
was
not
adequately
addressed
with
respect
to
starting
rules,
IC,
or
medical
intervention.
If
the
compound
to
be
applied
was
different,
raising
concerns
regarding
participation,
the
impact
on
compensation
needed
to
be
clearly
stated.
Working
on
a
farm
as
a
pesticide
handler
but
not
wanting
to
participate
in
the
study
should
have
resulted
in
other
work
being
assigned.
The
study
designers
purposely
selected
lower
toxicity
compounds
so
that
if
two
insecticides
with
equal
toxicity
and
efficacy
were
used,
the
participants'
risk
would
be
no
greater
than
that
experienced
with
routine
work.
Heat
related
illness
was
a
more
critical
risk
but
the
study
team
commented
the
risk
should
be
manageable.

Dr.
Menikoff
said
that
it
is
not
about
increased
risk,
it
is
about
manipulating
exposure
without
fully
informed
consent.
This
may
not
be
coercive
but
the
consequences
of
withdrawing
from
the
study
needed
to
be
made
clear.
Dr.
Fisher
said
that
if
there
were
a
number
of
comparable
products,
the
grower
would
select
the
one
that
was
free
because
the
grower
would
always
select
the
product
they
could
get
the
most
cheaply.
The
grower
made
the
decision
about
which
pesticide
would
be
used.
The
individuals
in
the
research
needed
to
agree
to
apply
the
subject
pesticide
and
participate
in
research.
A
worker
advocate
might
be
helpful.
The
protocol
needed
to
address
medical
concerns
for
illegal
immigrants,
subject
names
should
be
coded
for
privacy
and
a
separate
consent
may
be
needed
if
pictures
are
taken.
Part
of
the
problem
with
heat
exhaustion
and
heat
stroke
were
sudden
onset.
This
needed
to
be
clarified
and
a
statement
47
of
104
that
all
medical
conditions
would
be
treated
needed
to
be
included.
The
protocol
lacked
adverse
event
planning.
Growers
should
not
have
been
penalized
if
a
worker
failed
to
participate.
The
protocols
should
have
included
an
explanation
of
the
$
100/
day
compensation.
A
field
study
with
this
degree
of
complexity
requires
a
long
day
for
staff.
The
protocols
needed
to
clarify
whether
extra
time
needed
for
subjects
to
participate
would
be
compensated.
Biomarkers
might
not
make
any
sense
based
on
the
compound
being
tested.
In
addition,
biomarkers
are
likely
to
give
an
underestimate
of
exposure.

Dr.
Fisher
asked
the
Board
whether
the
five
studies
should
proceed
given
the
inadequacies
noted.
Dr.
Brimijoin
responded
that
if
the
studies
were
to
proceed
they
would
do
so
at
the
risk
of
not
being
approved.
There
was
a
need
to
see
the
parent
protocol.
There
was
sufficient
uncertainty
about
the
science
and
the
purpose.
Thus
the
Board
could
not
respond
to
the
charge
question
positively.
Many
Board
members
indicated
agreement
with
Dr.
Brimijoin's
conclusion.

B
oard
Review
of
May
2­
3,
2006
HSRB
Meeting
Report
Dr.
Fisher
continued
the
meeting
by
leading
the
Board
in
review
of
the
draft
May
2­
3,
2006
meeting
report
and
opened
the
review
by
inviting
public
commenters
to
respond
to
the
report.

Public
Comments
Dr.
Donald
Carlson
and
Ms.
Jane
McCarty
of
FMC
Corp.
and
Dr.
Rick
Reiss
of
Exponent,
representing
FMC
Corp.

FMC
submitted
written
comments
on
the
scientific
and
ethical
issues
concerning
the
carbofuran
oral
study
and
procedural
issues.
Ethical
considerations
included:
no
evidence
that
the
study
failed
to
meet
ethical
standards
prevalent
at
the
time,
no
evidence
that
deficiencies
in
the
ethical
procedures
could
have
resulted
in
serious
harm,
nor
was
information
provided
that
impaired
their
informed
consent.
Procedural
issues
included
the
recusal
of
two
HSRB
members,
issues
covered
in
the
written
comments,
and
incomplete
BMD
analysis
available
for
the
HSRB
May
meeting.
FMC
appreciated
the
HSRB
interest
in
revisiting
BMD
analyses
and
wished
to
expand
the
Board's
June
29th
discussion.
Scientific
limitations
were
acknowledged
including
small
sample
size,
the
lack
of
control
subjects,
and
highly
variable
RBC
results.
Nevertheless,
FMC,
EPA,
and
prior
peer
reviewers
recommended
use
of
the
oral
study
for
BMD
modeling.
The
statistical
procedure
was
used
to
estimate
the
dosage
that
caused
a
specified
response
level
(
e.
g.,
10%
ChEI).
This
method
was
superior
to
NOAEL/
LOAEL
because
it
accounted
for
sample
size
and
variability
in
the
data.
EPA
typically
regulates
based
on
the
statistical
lower
limit
of
BMD
(
BMDL)
and
the
difference
between
BMD
and
BMDL
increases
with
greater
variability
and
fewer
samples.
The
BMD
fit
for
carbofuran
agreed
well
with
actual
data.
Use
of
human
data
to
inform
the
risk
assessment
for
carbofuran
reduced
uncertainty
in
interspecies
extrapolation.
The
rat
BMDL10
estimated
by
EPA
was
similar
to
human
values
so
EPA
could
use
the
BMDL10
from
the
human
data
for
risk
assessment.
In
addition,
it
had
the
discretion
to
add
a
database
uncertainty
factor
to
account
for
limitations
in
the
dataset.
In
conclusion,
the
FMC
human
oral
study
was
ethical,
enhanced
the
data
set
and
should
be
utilized.
Dr.
Lehman
48
of
104
McKeeman
questioned
that
when
the
study
was
initially
conducted,
it
was
done
to
characterize
exposure
symptoms.
This
was
confirmed
by
FMC.

Board
Discussion
Dr.
Fisher
led
the
review
of
the
May
2006
report
and
highlighted
comments
received,
specifically
from
EPA.
Concerning
hexavalent
chromium,
the
HSRB
concluded
that
the
1994
Nethercott
chromium
dermal
toxicity
study
was
sufficiently
sound
for
use
in
the
risk
assessment.
From
the
ethical
perspective,
the
HSRB
concluded
that
the
study
decision
was
hampered
by
a
lack
of
supporting
documentation
but
that
these
deficiencies
did
not
meet
the
threshold
of
fundamentally
unethical.
The
weaknesses
of
the
carbofuran
oral
studies
far
outweighed
their
strengths
so
the
HSRB
did
not
recommend
their
use
for
risk
assessment.
The
BMD
calculations
round
out
some
of
the
study
deficiencies
but
the
accuracy
and
reliability
of
these
calculations
were
limited
by
the
technical
shortcomings
noted
for
the
oral
study.
There
was
no
evidence
that
the
study
failed
to
meet
prevalent
ethical
standards
nor
was
the
study
fundamentally
unethical.
The
HSRB
found
deficiencies
in
both
dermal
toxicities
studies
with
respect
to
risk
minimization
and
the
administration
of
the
antidote.
For
MITC,
the
Board
concluded
that
the
eyes
were
a
sensitive
surrogate
endpoint
with
respect
to
respiratory
data.
The
HSRB
determined
that
there
were
minor
deficiencies
with
respect
to
ethical
standards
but
that
the
study
was
not
fundamentally
unethical.
Dr.
Krishnan
recommended
an
additional
modification
for
the
carbofuran
discussion.
Dr
Fisher
then
asked
the
Board
to
accept
the
May
meeting
report
with
EPA
comments.

Nelson
­
Accept
the
report
as
modified.
Chadwick­
Accept
the
report
as
modified.
Menikoff­
Accept
the
report
as
modified.
Lebowitz­
Accept
the
report
as
modified.
Menikoff­
Accept
the
report
as
modified.
Fitzpatrick­
Accept
the
report
as
modified.
Fish­
Accept
the
report
as
modified.
Fenske­
Accept
the
report
as
modified.
Lehman­
McKeeman­
Accept
the
report
as
modified.
Philpott­
Accept
the
report
as
modified.
Fisher­
Accept
the
report
as
modified.

Dr.
Lewis
announced
that
the
next
HSRB
meeting
is
tentatively
scheduled
to
occur
October
17­
20,
2006
at
One
Potomac
Yard,
South
Building.

The
meeting
was
adjourned
by
the
Chair.
49
of
104
Respectfully
submitted:

Paul
I.
Lewis,
Ph.
D.
Designated
Federal
Officer
Human
Studies
Review
Board
United
States
Environmental
Protection
Agency
Certified
to
be
true
by:

Celia
B.
Fisher,
Ph.
D.
Chair
Human
Studies
Review
Board
United
States
Environmental
Protection
Agency
NOTE
AND
DISCLAIMER:
The
minutes
of
this
public
meeting
reflect
diverse
ideas
and
suggestions
offered
by
Board
members
during
the
course
of
deliberations
within
the
meeting.
Such
ideas,
suggestions,
and
deliberations
do
not
necessarily
reflect
definitive
consensus
advice
for
the
Board
members.
The
reader
is
cautioned
to
not
rely
on
the
minutes
to
represent
final,
approved,
consensus
advice
and
recommendations
offered
to
the
Agency.
Such
advice
and
recommendations
may
be
found
in
the
final
report
prepared
and
transmitted
to
the
EPA
Science
Advisor
following
the
public
meeting.
50
of
104
Attachments
Attachment
A
HSRB
Members
and
Consultants
Attachment
B
Federal
Register
Notice
Announcing
Meeting
Attachment
C
Meeting
Agenda
Attachment
D
May
2­
3,
2006
Draft
HSRB
Meeting
Report
51
of
104
Attachment
A
EPA
HSRB
Members
and
Consultants
Chair
Celia
B.
Fisher,
Ph.
D.
Marie
Ward
Doty
Professor
of
Psychology
Director,
Center
for
Ethical
Education
Fordham
University,
Bronx,
NY
Vice
Chair
William
S.
Brimijoin,
Ph.
D.*
Chair
and
Professor,
Molecular
Pharmacology
and
experimental
Therapeutics
Mayo
Foundation,
Rochester,
MN
Members
David
C.
Bellinger
Ph.
D.
Professor
of
Neurology
Harvard
School
of
Medicine,
Boston,
MA.

Alicia
Carriquiry,
Ph.
D.
Professor,
Department
of
Statistics
Iowa
State
University,
Ames,
IA.

Gary
L.
Chadwick,
PharmD,
MPH,
CIP
Associate
Provost,
Director,
Office
for
Human
Subjects
Protection
University
of
Rochester,
Rochester,
NY
Janice
Chambers,
Ph.
D.
D.
A.
B.
T.*
Director,
Center
for
Environmental
Health
Sciences,
College
of
Veterinary
Medicine
Mississippi
State
University,
Mississippi
State,
MS
Richard
Fenske,
Ph.
D.
MPH
Professor,
Department
of
Environmental
and
Occupational
Health
Sciences
University
of
Washington,
Seattle,
WA
Susan
S.
Fish,
PharmD,
MPH
Professor,
Biostatistics
&
Epidemiology
Boston
University
School
of
Public
Health,
Boston,
MA
Suzanne
C.
Fitzpatrick,
Ph.
D.
D.
A.
B.
T.
Senior
Science
Policy
Analyst
U.
S.
Food
and
Drug
Administration,
Rockville,
MD.
52
of
104
Kannan
Krishnan,
Ph.
D.
Professor
Département
de
santé
environnementale
et
santé
au
travail
Faculté
de
médicine
Universite'
de
Montreal
Montreal,
Quebec,
Canada
KyungMann
Kim
Ph.
D.,
FCCP
**
Professor
and
Associate
Chair,
School
of
Medicine
and
Public
Health
University
of
Wisconsin­
Madison,
Madison,
WI
Michael
D.
Lebowitz,
Ph.
D.
FCCP
Professor
of
Public
Health
&
Medicine
University
of
Arizona,
Tucson,
AZ
Lois
D.
Lehman­
McKeeman,
Ph.
D.
Distinguished
Research
Fellow,
Discovery
Toxicology
Bristol­
Myers
Squibb
Company,
Princeton,
N.
J.

Jerry
A.
Menikoff,
M.
D.
Associate
Professor
of
Law,
Ethics
&
Medicine
Director
Institute
for
Bioethics,
Law
and
Public
Policy
University
of
Kansas,
Kansas
City,
KS
Robert
Nelson,
M.
D.,
Ph.
D.
Associate
Professor
of
Anesthesiology
University
of
Pennsylvania
School
of
Medicine,
Philadelphia,
PA.

Sean
Philpott,
PhD,
MS
Bioethics
Associate
Director
Alden
March
Bioethics
Institute
Albany
Medical
Center,
Albany,
NY
53
of
104
Consultants
to
the
Board
Col
Raj
K
Gupta,
Ph.
D.
BCE
Director,
Science,
Technology
and
Strategy
Headquarters,
Walter
Reed
Army
Institute
of
Research
Silver
Spring,
MD
Daniel
Strickman,
Ph.
D.
National
Program
Leader
Veterinary,
Medical,
and
Urban
Entomology
United
States
Department
of
Agriculture
Agricultural
Research
Service,
Beltsville,
MD
*
Recused
from
carbofuran
discussion
and
deliberation
**
Not
in
attendance
at
meeting
54
of
104
Attachment
B
Federal
Register
Notice
Announcing
Meeting
Human
Studies
Review
Board;
Notice
of
Public
Meeting
[
Federal
Register:
June
6,
2006
(
Volume
71,
Number
108)]
[
Notices]
[
Page
32536­
32538]
From
the
Federal
Register
Online
via
GPO
Access
[
wais.
access.
gpo.
gov]
[
DOCID:
fr06jn06­
53]

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

ENVIRONMENTAL
PROTECTION
AGENCY
[
EPA­
HQ­
ORD­
2006­
0384;
FRL­
8081­
6]

Human
Studies
Review
Board;
Notice
of
Public
Meeting
AGENCY:
Environmental
Protection
Agency
(
EPA).
ACTION:
Notice.

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

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

DATES:
The
public
meeting
will
be
held
June
28­
30,
2006
from
8:
30
a.
m.
to
approximately
5
p.
m.,
eastern
time.
Location:
One
Potomac
Yard,
2777
Crystal
Drive,
Arlington,
VA
22202.
Meeting
Access:
Seating
at
the
meeting
will
be
on
a
first­
come
basis.
Individuals
requiring
special
accommodations
at
this
meeting,
including
wheelchair
access
and
assistance
for
the
hearing
impaired,
should
contact
the
Designated
Federal
Officer
(
DFO)
at
least
10
business
days
prior
to
the
meeting
using
the
information
under
FOR
FURTHER
INFORMATION
CONTACT
so
that
appropriate
arrangements
can
be
made.

[[
Page
32537]]

Procedures
for
Providing
Public
Input:
Interested
members
of
the
public
may
submit
relevant
written
or
oral
comments
for
the
HSRB
to
consider
during
the
advisory
process.
Additional
information
concerning
submission
of
relevant
written
or
oral
comments
is
provided
in
Unit
I.
D.
of
this
notice.

FOR
FURTHER
INFORMATION
CONTACT:
Any
member
of
the
public
who
wishes
further
information
should
contact
Paul
I.
Lewis,
Designated
Federal
Officer
(
DFO),
EPA,
Office
of
the
Science
Advisor,
(
8105R),
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
55
of
104
Washington,
DC
20460;
telephone
number:
(
202)
564­
8381;
fax:
(
202)
564­
2070;
e­
mail
addresses:
lewis.
paul@
epa.
gov.

ADDRESSES:
Submit
your
written
comments,
identified
by
Docket
ID
No.
EPA­
HQ­
ORD­
2006­
0384,
by
one
of
the
following
methods:
http://
www.
regulations.
gov
:
Follow
the
on­
line
instructions
for
submitting
comments.
E­
mail:
ORD.
Docket@
epa.
gov.
Mail:
ORD
Docket,
Environmental
Protection
Agency,
Mailcode:
28221T,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460.
Hand
Delivery:
EPA
Docket
Center
(
EPA/
DC),
Room
B102,
EPA
West
Building,
1301
Constitution
Avenue,
NW.,
Washington,
DC
20460,
Attention
Docket
ID
No.
EPA­
HQ­
ORD­
2006­
0384.
Deliveries
are
only
accepted
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
Special
arrangements
should
be
made
for
deliveries
of
boxed
information.
Instructions:
Direct
your
comments
to
Docket
ID
No.
EPA­
HQ­
ORD­
2006­
0384.
EPA's
policy
is
that
all
comments
received
will
be
included
in
the
public
docket
without
change
and
may
be
made
available
online
at
http://
www.
regulations.
gov
,
including
any
personal
information
provided,
unless
the
comment
includes
information
claimed
to
be
Confidential
Business
Information
(
CBI)
or
other
information
whose
disclosure
is
restricted
by
statute.
Do
not
submit
information
that
you
consider
to
be
CBI
or
otherwise
protected
through
http://
www.
regulations.
gov
or
e­
mail.
The
http://
www.
regulations.
gov
Web
site
is
an
  
anonymous
access''
system,
which
means
EPA
will
not
know
your
identity
or
contact
information
unless
you
provide
it
in
the
body
of
your
comment.
If
you
send
an
e­
mail
comment
directly
to
EPA,
without
going
through
http://
www.
regulations.
gov
,
your
e­
mail
address
will
be
automatically
captured
and
included
as
part
of
the
comment
that
is
placed
in
the
public
docket
and
made
available
on
the
Internet.
If
you
submit
an
electronic
comment,
EPA
recommends
that
you
include
your
name
and
other
contact
information
in
the
body
of
your
comment
and
with
any
disk
or
CD­
ROM
you
submit.
If
EPA
cannot
read
your
comment
due
to
technical
difficulties
and
cannot
contact
you
for
clarification,
EPA
may
not
be
able
to
consider
your
comment.
Electronic
files
should
avoid
the
use
of
special
characters,
any
form
of
encryption,
and
be
free
of
any
defects
or
viruses.

SUPPLEMENTARY
INFORMATION:

I.
Public
Meeting
A.
Does
This
Action
Apply
to
Me?

This
action
is
directed
to
the
public
in
general.
This
action
may,
however,
be
of
interest
to
persons
who
conduct
or
assess
human
studies
on
substances
regulated
by
EPA
or
to
persons
who
are
or
may
be
required
to
conduct
testing
of
chemical
substances
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA)
or
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA).
Since
other
entities
may
also
be
interested,
the
Agency
has
not
attempted
to
describe
all
the
specific
entities
that
may
be
affected
by
this
action.
If
you
have
any
questions
regarding
the
applicability
of
this
action
to
a
particular
entity,
consult
the
person
listed
under
FOR
FURTHER
INFORMATION
CONTACT.
56
of
104
B.
How
Can
I
Access
Electronic
Copies
of
This
Document
and
Other
Related
Information?

In
addition
to
using
regulations.
gov,
you
may
access
this
Federal
Register
document
electronically
through
the
EPA
Internet
under
the
Federal
Register
listings
at
http://
www.
epa.
gov/
fedrgstr/
Docket:
All
documents
in
the
docket
are
listed
in
the
http://
www.
regulations.
gov
index.
Although
listed
in
the
index,
some
information
is
not
publicly
available,
e.
g.,
CBI
or
other
information
whose
disclosure
is
restricted
by
statute.
Certain
other
material,
such
as
copyrighted
material,
will
be
publicly
available
only
in
hard
copy.
Publicly
available
docket
materials
are
available
either
electronically
in
http://
www.
regulations.
gov
or
in
hard
copy
at
the
ORD
Docket,
EPA/
DC,
EPA
West,
Room
B102,
1301
Constitution
Ave.,
NW.,
Washington,
DC.
The
Public
Reading
Room
is
open
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
The
telephone
number
for
the
Public
Reading
Room
is
(
202)
566­
1744,
and
the
telephone
number
for
the
ORD
Docket
is
(
202)
566­
1752.
EPA's
position
paper(
s),
charge/
questions
to
the
HSRB,
and
the
meeting
agenda
will
be
available
by
mid
June
2006.
In
addition,
the
Agency
may
provide
additional
background
documents
as
the
materials
become
available.
You
may
obtain
electronic
copies
of
these
documents,
and
certain
other
related
documents
that
might
be
available
electronically,
from
the
regulations.
gov
website
and
the
HSRB
Internet
Home
Page
at
http://
www.
epa.
gov/
osa/
hsrb/.
For
questions
on
document
availability
or
if
you
do
not
have
access
to
the
Internet,
consult
the
person
listed
under
FOR
FURTHER
INFORMATION.

C.
What
Should
I
Consider
as
I
Prepare
My
Comments
for
EPA?

You
may
find
the
following
suggestions
helpful
for
preparing
your
comments:
a.
Explain
your
views
as
clearly
as
possible.
b.
Describe
any
assumptions
that
you
used.
c.
Provide
copies
of
any
technical
information
and/
or
data
you
used
that
support
your
views.
d.
Provide
specific
examples
to
illustrate
your
concerns.
e.
To
ensure
proper
receipt
by
EPA,
be
sure
to
identify
the
docket
ID
number
assigned
to
this
action
in
the
subject
line
on
the
first
page
of
your
response.
You
may
also
provide
the
name,
date,
and
Federal
Register
citation.

D.
How
May
I
Participate
in
This
Meeting?

You
may
participate
in
this
meeting
by
following
the
instructions
in
this
section.
To
ensure
proper
receipt
by
EPA,
it
is
imperative
that
you
identify
docket
ID
number
EPA­
HQ­
ORD­
2006­
0384
in
the
subject
line
on
the
first
page
of
your
request.
a.
Oral
comments.
Requests
to
present
oral
comments
will
be
accepted
up
to
June
21,
2006.
To
the
extent
that
time
permits,
interested
persons
who
have
not
pre­
registered
may
be
permitted
by
the
Chair
of
the
HSRB
to
present
oral
comments
at
the
meeting.
Each
individual
or
group
wishing
to
make
brief
oral
comments
to
the
HSRB
is
strongly
advised
to
submit
their
request
(
preferably
via
email)
to
the
DFO
listed
under
FOR
FURTHER
INFORMATION
CONTACT
no
later
than
noon,
eastern
time,
June
21,
2006,
in
order
to
be
included
on
the
meeting
57
of
104
agenda
and
to
provide
sufficient
time
for
the
HSRB
Chair
and
HSRB
DFO
to
review
the
agenda
to
provide
an
appropriate
public
comment
period.
The
request
should
identify
the
name
of
the
individual
making
the
presentation,
the
[[
Page
32538]]

organization
(
if
any)
the
individual
will
represent,
and
any
requirements
for
audiovisual
equipment
(
e.
g.,
overhead
projector,
LCD
projector,
chalkboard).
Oral
comments
before
the
HSRB
are
limited
to
5
minutes
per
individual
or
organization.
Please
note
that
this
limit
applies
to
the
cumulative
time
used
by
all
individuals
appearing
either
as
part
of,
or
on
behalf
of
an
organization.
While
it
is
our
intent
to
hear
a
full
range
of
oral
comments
on
the
science
and
ethics
issues
under
discussion,
it
is
not
our
intent
to
permit
organizations
to
expand
these
time
limitations
by
having
numerous
individuals
sign
up
separately
to
speak
on
their
behalf.
If
additional
time
is
available,
there
may
be
flexibility
in
time
for
public
comments.
Each
speaker
should
bring
25
copies
of
his
or
her
comments
and
presentation
slides
for
distribution
to
the
HSRB
at
the
meeting.
b.
Written
comments.
Although
you
may
submit
written
comments
at
any
time,
for
the
HSRB
to
have
the
best
opportunity
to
review
and
consider
your
comments
as
it
deliberates
on
its
report,
you
should
submit
your
comments
at
least
5
business
days
prior
to
the
beginning
of
the
meeting.
If
you
submit
comments
after
this
date,
those
comments
will
be
provided
to
the
Board
members,
but
you
should
recognize
that
the
Board
members
may
not
have
adequate
time
to
consider
those
comments
prior
to
making
a
decision.
Thus,
if
you
plan
to
submit
written
comments,
the
Agency
strongly
encourages
you
to
submit
such
comments
no
later
than
noon,
Eastern
Time,
June
21,
2006.
You
should
submit
your
comments
using
the
instructions
in
Unit
1.
C.
of
this
notice.
In
addition,
the
Agency
also
requests
that
person(
s)
submitting
comments
directly
to
the
docket
also
provide
a
copy
of
their
comments
to
the
DFO
listed
under
FOR
FURTHER
INFORMATION
CONTACT.
There
is
no
limit
on
the
length
of
written
comments
for
consideration
by
the
HSRB.

E.
Background
EPA
will
be
presenting
for
HSRB
review
the
results
of
a
completed
study
involving
intentional
exposure
of
human
subjects
to
the
pesticide
active
ingredient,
chloropicrin.
In
addition,
EPA
will
be
seeking
the
Board's
advice
on:
Draft
guidelines
for
conducting
research
on
the
efficacy
of
insect
repellent
products;
insect
repellent
human
studies
protocols
and
pesticide
agricultural
handler
human
studies
protocols.
EPA
will
also
be
providing
an
informational
presentation
of
its
proposed
workshop
on
Best
Practices
for
EPA,
National
Exposure
Research
Laboratory
Observational
Human
Exposure
Measurement
Studies.
Finally,
the
Board
may
be
reviewing
draft
HSRB
reports
for
subsequent
Board
approval.

Dated:
June
1,
2006.
George
Gray,
Science
Advisor.
[
FR
Doc.
E6­
8725
Filed
6­
5­
06;
8:
45
am]
BILLING
CODE
6560­
50­
P
Federal
Register:
June
12,
2006
(
Volume
71,
Number
112)]
[
Notices]
58
of
104
[
Page
33747]
From
the
Federal
Register
Online
via
GPO
Access
[
wais.
access.
gpo.
gov]
[
DOCID:
fr12jn06­
84]

=======================================================================
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

ENVIRONMENTAL
PROTECTION
AGENCY
[
EPA­
HQ­
ORD­
2006­
0384;
FRL­
8183­
4]

Human
Studies
Review
Board;
Notice
of
Public
Meeting
AGENCY:
Environmental
Protection
Agency
(
EPA).

ACTION:
Notice.

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

SUMMARY:
On
June
6,
2006
(
71
FR
32536),
the
U.
S.
Environmental
Protection
Agency's
(
EPA
or
Agency)
Office
of
the
Science
Advisor
(
OSA)
announced
a
public
meeting
of
the
Human
Studies
Review
Board
(
HSRB)
to
be
held
June
28­
30,
2006
from
8:
30
a.
m.
to
approximately
5
p.
m.,
Eastern
Time.
Please
be
advised
that
the
Board
will
also
be
meeting
on
June
27,
2006,
beginning
at
1
p.
m.
to
approximately
5
p.
m.,
Eastern
Time.
For
further
information
contact
Paul
I.
Lewis,
Designated
Federal
Officer
(
DFO),
EPA,
Office
of
the
Science
Advisor,
(
8105),
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460;
telephone
number:
(
202)
564­
8381;
fax:
(
202)
564
2070;
e­
mail
addresses:
lewis.
paul@
epa.
gov.

Dated:
June
6,
2006.
George
Gray,
EPA
Science
Advisor.
59
of
104
Attachment
C
June
27­
30,
2006
Meeting
of
the
HSRB
Meeting
Agenda
6/
26/
06
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
JUNE
27­
30,
2006
*
PUBLIC
MEETING
Tuesday,
June
27,
2006
One
Potomac
Yard
(
South
Building)
2777
Crystal
Drive
Arlington,
VA
22202
703­
305­
7090
HSRB
WEB
SITE
http://
www.
epa.
gov/
osa/
hsrb/
Docket
Telephone:
(
202)
566
1752
Docket
Number:
EPA­
HQ­
ORD­
2006­
0384
C
1:
00
PM
Introduction
and
Identification
of
Board
Members
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
1:
15
PM
Welcome
 
George
Gray,
Ph.
D.
(
EPA
Science
Advisor)

C
1:
25
PM
Opening
Remarks
 
Mr.
Jim
Jones
(
Director,
Office
of
Pesticide
Programs
[
OPP],
EPA)

C
1:
35
PM
Meeting
Administrative
Procedures
­
Paul
Lewis,
Ph.
D.
(
Designated
Federal
Officer
[
DFO],
HSRB,
OSA,
EPA)

C
1:
40
PM
Meeting
Process
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
1:
55
PM
Update
on
EPA
Follow­
up
of
HSRB
Recommendations
 
Mr.
John
Carley
(
EPA,
OPP)
Chloropicrin
C
2:
05
PM
Science
and
Ethics
of
Chloropicrin
Human
Studies
 
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)

C
3:
00
PM
Break
C
3:
15
PM
Public
Comments
C
3:
45
PM
Board
Discussion
Chloropicrin
is
a
non­
selective
soil
fumigant
whose
primary
toxic
effect
is
sensory
irritation
in
which
stimulated
free
nerve
endings
mediate
sensations
and
clinical
signs
in
the
nose,
eyes,
throat,
and
upper
respiratory
tract.
Chloropicrin
is
a
unique
soil
fumigant
in
that
it
is
also
used
as
an
indicator
chemical
or
warning
agent
(
2%
or
less
by
weight
in
formulations).
The
Agency
is
developing
an
assessment
to
estimate
inhalation
risk
to
bystanders
and
workers
from
acute
exposures
to
chloropicrin.
60
of
104
1.
Scientific
considerations:

The
Agency's
"
Weight
of
Evidence"
(
WOE)
document
and
Data
Evaluation
Records
(
DER)
for
chloropicrin
describe
the
study
design
of
the
acute
inhalation,
human
toxicity
study.
The
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
inhalation
risk
to
bystanders
and
workers
exposed
to
chloropicrin.

Please
comment
on
whether
the
study
is
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
inhalation
exposure
to
chloropicrin.

2.
Ethical
considerations:

The
Agency
requests
that
the
Board
provide
comment
on
the
following:

a.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
Cain
study
was
fundamentally
unethical?

b.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Insect
Repellent
Product
Performance
Testing
Guideline
C
4:
30
PM
Science
and
Ethics
of
Insect
Repellent
Efficacy
Guidelines
 
Mr.
Kevin
Sweeney
(
OPP,
EPA),
Clara
Fuentes,
Ph.
D.
(
OPP,
EPA),
Roger
Gardner,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)

C
6:
00
PM
Adjournment
61
of
104
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
JUNE
27­
30,
2006
*
PUBLIC
MEETING
Wednesday,
June
28,
2006
One
Potomac
Yard
(
South
Building)
2777
Crystal
Drive
Arlington,
VA
22202
703­
305­
7090
HSRB
WEB
SITE
http://
www.
epa.
gov/
osa/
hsrb/
Docket
Telephone:
(
202)
566
1752
Docket
Number:
EPA­
HQ­
ORD­
2006­
0384
C
8:
30
AM
Convene
Meeting
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
8:
40
AM
Follow­
up
From
Previous
Day's
Discussion
 
Mr.
John
Carley
(
OPP,
EPA)

Insect
Repellent
Product
Performance
Testing
Guideline
C
8:
50
AM
Public
Comments
C
9:
15
AM
Board
Discussion
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?

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

C
10:
15
AM
Break
C
10:
30
AM
Board
Discussion
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?
62
of
104
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.

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).

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.

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.

C
12:
30
PM
Lunch
C
1:
30
PM
Board
Discussion
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.

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

Human
Studies
Research
Protocols
C
2:
15
PM
Introduction
 
Peter
Preuss,
Ph.
D.
(
Director,
National
Center
for
Environmental
Assessment,
Office
of
Research
and
Development,
EPA)

HSRB
Review
of
Protocol
Criteria
C
2:
45
PM
HSRB
Science
and
Ethics
Criteria
of
Human
Studies
Protocols
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
3:
30
PM
Break
C
3:
45
PM
HSRB
Science
and
Ethics
Criteria
of
Human
Studies
Protocols
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)
63
of
104
Research
on
the
Efficacy
of
Insect
Repellents
C
4:
15
PM
Science
and
Ethics
of
Research
on
the
Efficacy
of
Insect
Repellents
 
Mr.
Kevin
Sweeney
(
OPP,
EPA),
Clara
Fuentes,
Ph.
D.
(
OPP,
EPA),
Roger
Gardner,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)

C
5:
15
PM
Adjournment
64
of
104
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
PUBLIC
MEETING
Thursday,
June
29,
2006
One
Potomac
Yard
(
South
Building)
2777
Crystal
Drive
Arlington,
VA
22202
703­
305­
7090
HSRB
WEB
SITE
http://
www.
epa.
gov/
osa/
hsrb/
Docket
Telephone:
(
202)
566
1752
Docket
Number:
EPA­
HQ­
ORD­
2006­
0310
C
8:
30
AM
Convene
Meeting
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
8:
40
AM
Follow­
up
From
Previous
Day's
Discussion
 
Mr.
John
Carley
(
OPP,
EPA)

Research
on
the
Efficacy
of
Insect
Repellents
C
8:
50
AM
Public
Comments
C
9:
20
AM
Board
Discussion
Study
EMD­
003
from
Carroll­
Loye
Biological
Research
a.
Does
the
proposed
research
described
in
[
name
/
designation
of
the
protocol]
appear
likely
to
generate
scientifically
reliable
data,
[
useful
for
assessing
the
efficacy
of
the
repellent]
/
[
useful
(
together
with
other
data)
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
mixing,
loading
or
applying
a
pesticides]?

b.
Does
the
proposed
research
described
in
Study
EMD­
003
from
Carroll­
Loye
Biological
Research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

C
10:
15
AM
Break
C
10:
30
AM
Board
Discussion
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
a.
Does
the
proposed
research
described
in
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
appear
likely
to
generate
scientifically
reliable
data,
useful
for
assessing
the
efficacy
of
a
test
substance
for
repellent
ticks?
65
of
104
b.
Does
the
proposed
research
described
in
Study
EMD­
004
from
Carroll­
Loye
Biological
Research
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

C
11:
45
AM
Lunch
Research
on
Agricultural
Handlers'
Exposure
to
Pesticides
C
12:
45
PM
Science
and
Ethics
of
Research
on
Agricultural
Handler's
Exposure
to
Pesticides
­
Mr.
Jeffrey
Dawson,
(
OPP,
EPA),
Mr.
Jeffrey
Evans
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)

C
1:
45
PM
Public
Comments
C
2:
15
PM
Board
Discussion
The
Agricultural
Handlers
Exposure
Task
Force
(
AHETF)
has
submitted
protocols
for
five
pesticide
exposure
studies
that
are
part
of
a
larger
research
program
the
AHETF
is
conducting.
The
premise
of
the
AHETF
research
program
is
that
data
can
be
used
generically
by
various
stakeholders
(
e.
g.,
applicants,
registrants,
EPA,
and
others)
for
calculating
exposures
for
the
occupational
handlers
of
pesticides.
The
scope
of
the
AHETF
research
program
is
very
broad
in
that
it
intends
to
address
exposures
related
to
many
job
functions
in
agriculture
and
also
to
assess
generally
the
impacts
of
various
parameters
on
exposure
(
e.
g.,
How
do
changes
in
the
pounds
of
pesticide
handled
or
acres
treated
affect
exposure
levels?).
The
protocols
submitted
for
HSRB
review
describe
studies
to
measure
exposures
for
five
specific
scenarios
(
i.
e.,
closed
or
open
system
mixing/
loading
,
airblast
applications
to
trellis
and
orchard
crops,
or
pilot
exposures
from
fixed
wing
agricultural
aircraft).

The
Agency
believes
these
studies
improve
EPA's
ability
to
assess
the
risks
of
using
pesticides
because
the
data
will
reflect
current
agricultural
practices,
equipment
and
techniques
and
will
allow
for
more
refined
exposure
estimates.
Further,
the
monitoring
techniques
to
be
used
for
these
studies
also
have
been
standardized
for
use
across
the
AHETF
research
program..
These
more
refined
and
reliable
data
will
allow
the
Agency
to
estimate
better
how
worker
exposure
levels
are
affected
by
changes
in
various
factors
such
as
the
amount
of
active
ingredient
handled,
type
of
application
equipment
used,
application
rate
used,
volumes
handled,
and
personal
protective
equipment
used.

It
should
be
noted,
however,
that
the
use
of
the
data
generated
in
this
study
by
the
U.
S.
EPA
and
other
stakeholders
will
depend
upon
the
nature
of
the
results.
For
example,
the
adequacy
of
the
field
or
laboratory
quality
control
data
may
dictate
that
correction
factors
are
applied
to
adjust
monitored
exposure
levels
to
account
for
losses
from
field
samplers
or
low
performing
analytical
methods.

1.
AHETF
Closed
System
Mixing/
Loading
of
Liquids
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE34
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
66
of
104
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
mixing,
loading
or
applying
a
liquid
pesticide
with
closed
systems?
[
Note:
In
a
few
cases,
corresponding
application
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE34
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

C
3:
15
PM
Break
C
3:
15
PM
Board
Discussion
2.
AHETF
Airblast
Application
to
Trellis
Crops
in
the
West
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE36
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
making
an
airblast
application
of
a
pesticide
to
a
trellis
crop
under
conditions
found
in
the
western
United
States?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE36
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

3.
AHETF
Airblast
Application
to
Trellis
Crops
in
the
East
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE37
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
making
an
airblast
application
of
a
pesticide
to
a
trellis
crop
under
conditions
found
in
the
eastern
United
States?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE37
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

C
5:
00
PM
Adjournment
67
of
104
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
PUBLIC
MEETING
Friday,
June
30,
2006
One
Potomac
Yard
2777
Crystal
Drive
Arlington,
VA
22202
703­
305­
7090
C
8:
30
AM
Convene
Meeting
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
8:
40
AM
Follow­
up
From
Previous
Day's
Discussion
 
Mr.
John
Carley
(
OPP,
EPA)

Research
on
Agricultural
Handlers'
Exposure
to
Pesticides
C
9:
00
AM
Board
Discussion
4.
AHETF
Closed
Cab
Airblast
Application
to
Orchards
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE38
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
when
making
an
airblast
application
of
a
pesticide
to
orchard
crops?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE38
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?

5.
AHETF
Fixed­
Wing
Aerial
Application
Protocol
a.
Does
the
proposed
research
described
in
Study
No.
AHE42
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
likely
to
generate
scientifically
reliable
data,
which
will
be
useful,
together
with
other
data,
for
assessing
the
potential
levels
of
pesticide
exposure
received
by
people
making
an
aerial
application
of
a
pesticide
from
fixed­
wing
aircraft?
[
Note:
In
a
few
cases,
corresponding
mixing/
loading
events
are
also
to
be
monitored;
the
same
question
applies
to
those
elements
of
the
study.]

b.
Does
the
proposed
research
described
in
Study
No.
AHE42
from
the
Agricultural
Handlers
Exposure
Task
Force
appear
to
comport
with
the
applicable
requirements
of
40
CFR
part
26,
subparts
K
and
L?
68
of
104
C
10:
30
AM
Break
Proposed
Workshop
on
Best
Practices
for
EPA,
National
Exposure
Research
Laboratory
Observational
Human
Exposure
Measurement
Studies
C
10:
45
PM
Informational
Presentation
of
Proposed
Workshop
on
Best
Practices
for
EPA,
National
Exposure
Research
Laboratory
Observational
Human
Exposure
Measurement
Studies
­
Roy
Fortmann,
Ph.
D.
(
NERL,
Office
of
Research
and
Development,
EPA)

C
11:
30
AM
Lunch
May
2­
3,
2006
HSRB
Meeting
Report
C
12:
30
PM
HSRB
Review
of
May
2­
3,
2006
HRSB
Meeting
Report
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
12:
45
PM
Public
Comments
C
1:
15
PM
Board
Discussion
and
Decision
on
Report
Chromium
Methyl
Isothiocyanate
Carbofuran
C
2:
45
PM
Summary
and
Next
Steps
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)
and
Paul
Lewis,
Ph.
D.
(
HSRB
DFO)

C
3:
00
PM
Adjournment
*
Agenda
dates
and
times
are
approximate
For
further
information,
please
contact
the
Designated
Federal
Officer
for
this
meeting,
Paul
Lewis,
via
telephone:
(
202)
564­
8381
or
email:
lewis.
paul@
epa.
gov
69
of
104
Attachment
D
May
2­
3,
2006
Draft
HSRB
Meeting
Report
EPA­
HSRB­
06­
02
George
Gray,
Ph.
D.
Science
Advisor
Office
of
the
Science
Advisor
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
Subject:
May
2­
3,
2006
EPA
Human
Studies
Review
Board
Meeting
Report
Dear
Dr.
Gray:

The
United
States
Environmental
Protection
Agency
(
EPA
or
Agency)
requested
the
Human
Studies
Review
Board
(
HSRB)
to
review
scientific
and
ethics
reviews
of
chromium,
carbofuran
and
methyl
isothiocyanate.
The
enclosed
HSRB
report
addresses
the
Board's
response
to
EPA
charge
questions
for
the
Board's
consideration
at
its
May
2­
3,
2006
meeting.

A
summary
of
the
Board's
conclusions
on
the
scientific
and
ethical
considerations
of
the
human
toxicity
studies
for
the
three
pesticides
are
provided
below.

Chromium
Scientific
Considerations
 
The
Board
concluded
that
the
1994
Nethercott
et
al.
dermal
sensitization
study
was
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
dermal
exposure
to
hexavalent
chromium.

 
The
study
was
properly
designed,
well­
conducted,
and
employed
appropriate
scientific
and
clinical
methods
to
determine
a
minimum
elicitation
threshold
for
dermal
sensitization
due
to
hexavalent
chromium.
The
MET10
reported
in
the
study
provided
a
reasonable
point
of
departure
for
risk
assessment.

Ethical
Considerations
 
The
HSRB
concluded
there
was
insufficient
information
to
determine
whether
the
study
failed
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted.

 
The
Board
concurred
with
the
assessment
of
the
Agency
that
there
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
in
that
the
deficiencies
did
not
result
in
serious
harm,
nor
seriously
impair
the
informed
consent
of
the
research
subjects
and;
70
of
104
 
The
Board
determined
that
there
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

Carbofuran
Scientific
Considerations
 
The
HSRB
concluded
that
there
were
numerous
technical
issues
regarding
the
conduct
of
the
oral
and
dermal
studies
with
carbofuran
and
that
overall,
the
weakness
of
the
studies
far
outweigh
the
strengths.
Accordingly,
the
HSRB
did
not
recommend
any
of
the
oral
or
dermal
studies
conducted
with
carbofuran
in
human
subjects
for
the
single
chemical
assessment
or
in
informing
the
interspecies
uncertainty
factor
for
the
cumulative
assessment.

Ethical
Considerations
 
For
the
oral
study,
there
was
no
evidence
that
the
study
failed
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted.

 
For
the
oral
human
toxicity
study,
there
was
no
clear
and
convincing
evidence
of
significant
deficiencies
in
the
ethical
procedures
that
could
have
resulted
in
serious
harm
(
based
on
the
knowledge
available
at
the
time
the
study
was
conducted)
nor
that
information
provided
to
participants
seriously
impaired
their
informed
consent.

 
For
the
oral
study
there
was
no
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical
(
e.
g.,
intended
to
seriously
harm
participants
or
that
informed
consent
was
not
obtained).

 
The
HSRB
found
deficiencies
in
both
dermal
human
toxicity
studies
relative
to
specific
ethical
standards
prevalent
at
the
time
the
study
was
conducted.

 
For
both
dermal
human
toxicity
studies,
there
was
clear
and
convincing
evidence
of
significant
deficiencies
in
the
ethical
procedures
for
minimizing
risk
that
could
have
resulted
in
serious
harm
(
based
on
the
knowledge
available
at
the
time
the
study
was
conducted).
The
first
dermal
toxicity
study
was
significantly
deficient
given
the
delay
in
the
administration
of
atropine
to
more
than
one
subject
experiencing
the
signs
and
symptoms
of
carbamate
toxicity.
The
second
dermal
toxicity
study
was
considered
significantly
deficient
in
that
the
lack
of
information
provided
about
the
results
from
the
initial
dermal
toxicity
study
seriously
impaired
their
informed
consent.

 
However,
for
both
dermal
human
toxicity
studies,
there
was
no
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical
(
e.
g.,
intended
to
seriously
harm
participants
or
that
informed
consent
was
not
obtained).

Methyl
Isothiocyanate
71
of
104
Scientific
Considerations
 
The
Board
concluded
that
air
concentrations
of
methyl
isothiocyanate
sufficient
to
produce
eye
irritation
would
lead
to
a
conservative
and
prudent
point
of
departure
for
inhalation
risk
(
i.
e.,
eyes
were
a
sensitive
endpoint
in
relation
to
the
respiratory
system).
The
Board
reached
it
decision
based
on
eye
irritation
LOAELs
are
often
lower
than
respiratory
irritation
LOAELs
for
irritant
gases.
While
the
use
of
eye
irritation
data
as
a
surrogate
for
respiratory
data
is
reasonable
in
this
situation,
one
must
be
cautious
as
only
appropriate
controlled
human
studies
of
the
respiratory
system
can
provide
a
final
and
definitive
respiratory
point
of
departure,
if
ever
determined.

Ethical
Considerations
 
The
HSRB
determined
there
were
minor
deficiencies
in
the
ethical
procedures
relative
to
those
prevalent
at
the
time,
however:

 
There
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent)
and;

 
There
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

The
Board
also
provided
commentary
of
its
scientific
criteria
for
review
of
human
dosing
studies.
The
Board's
criteria
encompassed
the
following:
(
1)
justification;
(
2)
dose
selection;
(
3)
endpoint
selection;
(
4)
participants;
(
5)
method;
and
(
6)
statistical
analyses.
In
addition,
the
Board
established
criteria
for
evaluating
the
utility
of
single
dose
level
studies.

In
conclusion,
the
EPA
HSRB
appreciated
the
opportunity
to
advise
the
Agency
on
the
scientific
and
ethical
aspects
of
human
subjects
research
and
looks
forward
to
future
opportunities
to
continue
advising
the
Agency
in
this
endeavor.

Sincerely,

Celia
Fisher,
Ph.
D.
Chair
EPA
Human
Studies
Review
Board
72
of
104
NOTICE
This
report
has
been
written
as
part
of
the
activities
of
the
EPA
Human
Studies
Review
Board,
a
Federal
advisory
committee
providing
advice,
information
and
recommendations
on
issues
related
to
scientific
and
ethical
aspects
of
human
subjects
research.
This
report
has
not
been
reviewed
for
approval
by
the
Agency
and,
hence,
the
contents
of
this
report
do
not
necessarily
represent
the
view
and
policies
of
the
Environmental
Protection
Agency,
nor
of
other
agencies
in
the
Executive
Branch
of
the
Federal
government,
nor
does
mention
of
trade
names
or
commercial
product
constitute
a
recommendation
for
use.
Further
information
about
the
EPA
Human
Studies
Review
Board
can
be
obtained
from
its
website
at
http://
www.
epa.
gov/
osa/
hsrb/.
Interested
persons
are
invited
to
contact
Paul
Lewis,
Designated
Federal
Officer,
via
e­
mail
at
lewis.
paul@
epa.
gov.

In
preparing
this
document,
the
Board
carefully
considered
all
information
provided
and
presented
by
the
Agency
presenters,
as
well
as
information
presented
by
public
commenters.
This
document
addresses
the
information
provided
and
presented
within
the
structure
of
the
charge
by
the
Agency.
73
of
104
United
States
Environmental
Protection
Agency
Human
Studies
Review
Board
Chair
Celia
B.
Fisher,
Ph.
D.
Marie
Ward
Doty
Professor
of
Psychology,
Director,
Center
for
Ethics
Education,
Fordham
University,
Department
of
Psychology,
Bronx,
NY
Vice
Chair
William
S.
Brimijoin,
Ph.
D.,
Chair
and
Professor,
Molecular
Pharmacology
and
Experimental
Therapeutics,
Mayo
Foundation,
Rochester,
MN
*
**

Members
David
C.
Bellinger,
Ph.
D.,
Professor
of
Neurology,
Harvard
Medical
School
Professor
in
the
Department
of
Environmental
Health,
Harvard
School
of
Public
Health
Children's
Hospital,
Boston,
MA
Alicia
Carriquiry,
Ph.
D.,
Professor,
Department
of
Statistics,
Iowa
State
University
Snedecor
Hall,
Ames,
IA
Gary
L.
Chadwick,
PharmD,
MPH,
CIP,
Associate
Provost,
Director,
Office
for
Human
Subjects
Protection,
University
of
Rochester,
Rochester,
NY
Janice
Chambers,
Ph.
D.,
D.
A.
B.
T.,
William
L.
Giles
Distinguished
Professor,
Director,
Center
for
Environmental
Health
Sciences,
College
of
Veterinary
Medicine,
Mississippi
State
University,
Wise
Center,
Mississippi
State,
MS
*

Richard
Fenske,
Ph.
D.,
MPH,
Professor,
Department
of
Environmental
and
Occupational
Health
Sciences,
University
of
Washington,
Seattle
WA
Susan
S.
Fish,
PharmD,
MPH,
Professor,
Biostatistics
&
Epidemiology,
Boston
University
School
of
Public
Health,
Co­
Director,
MA
in
Clinical
Investigation
Boston
University
School
of
Medicine,
Boston,
MA
Suzanne
C.
Fitzpatrick,
Ph.
D.,
DABT,
Senior
Science
Policy
Analyst,
Office
of
the
Commissioner,
Office
of
Science
and
Health
Coordination,
U.
S.
Food
and
Drug
Administration,
Rockville,
MD
Kannan
Krishnan,
Ph.
D.,
Professor,
Département
de
santé
environnementale
et
santé
au
travail,
Faculté
de
medicine,
Université
de
Montréal,
Montréal,
Canada
KyungMann
Kim,
Ph.
D.,
CCRP,
Professor
&
Associate
Chair,
Department
of
Biostatistics
&
Medical
Informatics,
School
of
Medicine
and
Public
Health,
University
of
Wisconsin­
Madison,
Madison,
WI
**
74
of
104
Michael
D.
Lebowitz,
Ph.
D.,
FCCP,
Professor
of
Public
Health
&
Medicine.
University
of
Arizona,
Tucson,
AZ
Lois
D.
Lehman­
Mckeeman,
Ph.
D.,
Distinguished
Research
Fellow,
Discovery
Toxicology,
Bristol­
Myers
Squibb
Company,
Princeton,
NJ
Jerry
A.
Menikoff,
M.
D.,
Associate
Professor
of
Law,
Ethics
&
Medicine,
Director
of
the
Institute
for
Bioethics,
Law
and
Public
Policy,
University
of
Kansas
Medical
Center,
Kansas
City,
KS
Robert
Nelson,
M.
D.,
Ph.
D.,
Associate
Professor
of
Anesthesiology
and
Critical
Care,
Department
of
Anesthesiology
and
Critical
Care,
University
of
Pennsylvania
School
of
Medicine,
The
Children's
Hospital
of
Philadelphia,
Philadelphia,
PA
19104
Sean
M.
Philpott,
Ph.
D.,
Research
Scientist,
David
Axelrod
Institute,
Wadsworth
Center
for
Laboratories
and
Research,
New
York
State
Department
of
Health,
Albany,
NY
Human
Studies
Review
Board
Staff
Paul
I.
Lewis,
Ph.
D.,
Designated
Federal
Officer,
United
States
Environmental
Protection
Agency,
Washington,
DC
*
Recused
from
carbofuran
discussion
and
deliberation
**
Not
in
attendance
at
May
2­
3,
2006
Public
Meeting
75
of
104
TABLE
OF
CONTENTS
INTRODUCTION....................................................................................................................
76
REVIEW
PROCESS.................................................................................................................
77
CHARGE
TO
THE
BOARD
AND
BOARD
RESPONSE.........................................................
78
1.
Chromium.........................................................................................................................
78
2.
Carbofuran
.......................................................................................................................
84
3.
Methyl
Isothiocyanate
.......................................................................................................
94
COMMENTARY
ON
SCIENTIFIC
STANDARDS
FOR
HUMAN
DOSING
STUDIES.......
101
REFERENCES.......................................................................................................................
103
76
of
104
INTRODUCTION
On
May
2­
3,
2006,
the
United
States
Environmental
Protection
Agency's
(
EPA
or
Agency)
Human
Studies
Review
Board
(
HSRB)
met
to
review
scientific
and
ethical
issues
concerning
human
toxicity
studies
involving
two
pesticide
active
ingredients,
carbofuran
and
methyl
isothiocyanate
(
MITC),
and
chromium,
a
constituent
of
wood
preservative
products
(
wood
preservatives
are
regulated
as
pesticides
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act).

The
Pesticide
Registration
Improvement
Act
(
PRIA)
requires
that
EPA
complete
its
decision­
making
process
on
certain
types
of
applications
to
register
a
pesticide
product
within
specified
amounts
of
time
after
receiving
the
application
for
registration.
In
addition,
PRIA
established
deadlines
for
EPA
to
complete
"
reregistration"
of
pesticide
active
ingredients
that
are
contained
in
pesticide
products
initially
registered
before
1984.
Reregistration
involves
the
systematic
reexamination
of
older
pesticides,
applying
contemporary
scientific
and
regulatory
standards.
When
a
pesticide
active
ingredient
is
approved
for
use
on
food,
EPA
combines
reregistration
with
the
tolerance
reassessment
process
mandated
by
the
Food
Quality
Protection
Act
of
1996
(
FQPA).

Both
MITC
and
carbofuran
are
undergoing
reevaluation
in
the
reregistration
process.
EPA
is
considering
the
human
health
risks
of
chromium
both
in
its
reregistration
program
and
as
part
of
its
review
of
an
application
for
registration
pending
under
FIFRA
and
PRIA.

For
each
of
the
human
studies
under
consideration,
the
Agency
provided
the
Board
with
the
complete
study
report
and
any
supplements
available
to
the
Agency.
Each
of
these
studies
was
assigned
a
unique
identifier,
the
Master
Record
Identifier
or
MRID,
which
the
EPA,
Office
of
Pesticide
Programs
(
OPP)
uses
to
manage
documents
in
its
archive.
When
a
company
submits
multiple
documents
pertaining
to
a
single
study,
each
document
is
assigned
a
unique
MRID
as
it
is
received
and
catalogued.
Thus
a
study
with
several
supplements,
such
as
the
MITC
study
discussed
at
the
meeting,
may
be
associated
with
several
MRIDs.

For
each
study,
the
Agency
had
provided
a
review
of
the
ethical
conduct
of
the
study.
Each
ethics
review
identified
any
deficiencies
noted
in
the
conduct
of
the
specific
study
compared
to
both
current
ethical
standards
and
the
ethical
standards
prevailing
at
the
time
the
research
was
performed.
EPA
has
intentionally
deferred
making
a
final
determination
of
whether
an
individual
study
satisfies
the
ethical
standards
for
acceptability
in
40
CFR
sections
26.1704
 
26.1706,
pending
the
advice
of
the
Board.

For
most
studies,
the
Agency
develops
documents,
called
Data
Evaluation
Records
(
DERs),
containing
a
scientific
review
of
the
study;
the
Board
was
provided
with
one
or
more
DERs
for
carbofuran
and
MITC.
DERs
contain
summaries
of
the
study
design,
methods
and
results,
describe
potential
deficiencies,
and
provides
conclusions
about
the
usefulness
of
the
study
in
risk
assessment.

In
addition
to
the
DERs,
the
Agency
had
prepared
a
Weight
of
Evidence
(
WOE)
memorandum
for
carbofuran
and
MITC
discussing
the
differences
and
similarities
between
the
77
of
104
human
and
animal
responses
to
each
chemical
and
characterizing
the
usefulness
of
the
human
toxicity
studies
for
human
health
risk
assessment.
The
WOE
memos
expressed
the
Agency's
current
scientific
conclusions
on
which
the
Agency
was
soliciting
the
Board's
comments.
To
maintain
the
historical
record
of
review,
the
Agency
may,
in
some
cases,
include
a
DER
for
a
study
that
expressed
scientific
conclusions
differing
from
those
in
the
WOE
document.

For
chromium,
the
Agency
provided
a
set
of
documents
which
contained
similar
information
to
DERs
and
WOEs,
but
which
had
a
slightly
different
format
and
presentation,
due
to
the
procedural
history
of
the
EPA's
review
of
this
chemical.
As
noted
above,
chromium
is
a
constituent
in
wood
preservative
products.
The
Agency
has
concern
about
the
potential
for
chromium
to
elicit
an
allergic
response
in
sensitized
individuals
who
come
in
contact
with
residues
remaining
in
products
made
from
wood
that
has
been
treated
with
chromium­
containing
wood
preservatives.
To
assess
the
risk
of
potential
dermal
exposure,
the
Agency
reviewed,
among
other
information,
a
study
involving
intentional
exposure
of
sensitized
subjects
to
different
levels
of
chromium,
(
Nethercott
et
al.
1994).
This
assessment
was
one
of
the
first
assessments
of
this
kind
performed
by
the
Agency,
and
it
raised
significant
scientific
issues.
Accordingly,
the
Agency
prepared
a
background
document
for
its
independent,
peer
review
advisory
committee,
the
FIFRA
Scientific
Advisory
Panel
(
SAP).
The
SAP
is
a
federally
chartered
advisory
committee
of
scientific
experts
who
provide
advice
to
the
Agency
on
pesticides
and
pesticide­
related
issues
as
to
their
impact
on
human
health
and
the
environment
of
regulatory
actions.
The
Agency
provided
a
copy
of
the
materials
given
to
the
SAP
for
its
review,
as
well
as
a
copy
of
the
SAP's
final
report.
After
receiving
the
SAP's
recommendations,
the
Agency
sought
review
and
comment
from
other
Agency
scientists
through
the
steering
committee
of
the
Agency's
internal
Science
Policy
Council
(
SPC)
to
ensure
consistency
across
programs
in
the
approach
to
regulating
substances
that
are
skin
sensitizers.
Using
the
advice
of
the
SAP
and
the
steering
committee
of
the
SPC,
the
Agency
developed
a
memorandum
describing
how
it
intended
to
use
the
results
of
the
Nethercott
study
to
derive
a
sensitization
Reference
Dose.

The
HSRB
has
reviewed
studies
on
which
the
Agency
proposes
to
rely
in
actions
under
the
pesticide
laws
and
studies
that
the
Agency
has
decided
not
to
use
in
its
risk
assessments,
either
for
scientific
reasons
or
because
they
do
not
meet
the
standards
in
EPA's
final
human
studies
rule,
40
CFR
Part
26.
The
Agency
asked
the
HSRB
to
advise
the
Agency
on
a
range
of
scientific
and
ethics
issues
and
on
how
the
studies
should
be
assessed
against
the
provisions
in
40
CFR
sections
26.1701
 
26.1704
of
EPA's
final
human
studies
rule.
This
report
transmits
the
HSRB's
comments
and
recommendations
from
its
May
2­
3,
2006
meeting.

REVIEW
PROCESS
On
May
2­
3,
2006
the
Board
had
a
public
face­
to­
face
meeting
in
Arlington,
Virginia.
Advance
notice
of
the
meeting
was
published
in
the
Federal
Register
"
Human
Studies
Review
Board:
Notice
of
Public
Meeting
(
71
Federal
Register
19725).
At
the
public
meeting,
following
welcoming
remarks
from
Agency
officials,
Celia
B.
Fisher,
HRSB
Chair,
proposed
a
set
of
scientific
and
ethics
criteria
consistent
with
the
language
of
71
Federal
Register
6137
to
guide
Board
evaluation
of
each
protocol.
The
Chair's
scientific
criteria
asked
the
Board
to
consider
the
following
two
questions:
(
1)
did
the
research
design
and
implementation
meet
scientific
78
of
104
standards
and
(
2)
Did
the
data
generated
by
the
study
have
implications
for
the
Agency's
Weight
of
the
Evidence
(
WOE)
review
and
when
applicable
aspects
of
the
risk
assessment?
The
Chair's
ethics
criteria
asked
the
Board
to
consider
three
questions:
(
1)
did
the
study
fail
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted;
(
2)
was
the
conduct
of
the
study
fundamentally
unethical
(
i.
e.,
specifically
was
there
clear
and
convincing
evidence
that
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent);
and
(
3)
was
the
conduct
of
the
study
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
(
i.
e.,
was
there
clear
and
convincing
evidence
that
identified
deficiencies
identified
could
have
resulted
in
serious
harm
based
on
knowledge
available
at
the
time
the
study
was
conducted
or
the
information
provided
to
participants
could
seriously
impair
informed
consent).
The
Board
then
heard
presentations
from
the
Agency
on
the
following
topics:
science
and
ethics
of
chromium
human
studies,
science
and
ethics
of
carbofuran
human
studies
and
science
and
ethics
of
methyl
isothiocyanate
human
studies.
The
Board
heard
oral
public
comments
from
the
following
individuals:

Chromium
Jennifer
Sass,
Ph.
D.
representing
the
Natural
Resources
Defense
Council
Carbofuran
Donald
Carson,
Ph.
D.
and
Ms.
Jane
McCarty
on
behalf
of
FMC
Corporation
Jennifer
Sass,
Ph.
D.
representing
the
Natural
Resources
Defense
Council
In
addition,
the
Board
received
written
public
comments
from
CRLA
Foundation,
FMC
Corporation,
and
the
Natural
Resources
Defense
Council.
Following
Agency
presentations
and
public
comments,
the
Board
deliberated
on
the
charge
questions.
For
their
deliberations,
the
Board
considered
the
materials
presented
at
the
meeting,
written
public
comments
and
Agency
background
documents
on
each
individual
pesticide
(
i.
e.,
pesticide
human
study,
Agency
data
evaluation
record
(
DER)
of
the
pesticide
human
study,
weight
of
evidence
review,
risk
assessment
and
ethics
review).

CHARGE
TO
THE
BOARD
AND
BOARD
RESPONSE
1.
Chromium
Charge
to
the
Board
Hexavalent
chromium
is
a
component
of
a
pesticide
product
intended
to
be
used
as
a
wood
preservative.
Members
of
the
general
public
may
experience
dermal
exposure
to
residues
of
hexavalent
chromium
remaining
on
wood
treated
with
a
wood
preservative.
Because
chromium
has
caused
allergic
contact
dermatitis
(
ACD)
in
occupational
settings,
EPA
has
determined
that
it
should
assess
the
potential
for
ACD
in
the
general
public
resulting
from
the
use
of
wood
preservatives
containing
chromium.

In
a
meeting
of
the
FIFRA
Scientific
Advisory
Panel
(
SAP)
in
May
2004,
EPA
obtained
independent
peer
review
of
scientific
issues
related
to
the
assessment
of
the
potential
dermal
risk
79
of
104
resulting
from
exposure
to
chromium.
See
www.
epa.
gov/
scipoly/
sap/
2004/
final.
doc
The
Agency
had
carefully
considered
the
report
of
the
SAP,
as
well
as
the
advice
of
EPA
scientists
through
the
steering
committee
of
the
Agency's
Science
Policy
Council.
Taking
all
of
this
into
account,
EPA
had
derived
a
"
sensitization
reference
dose"
(
RfD)
based
on
the
10%
Minimum
Elicitation
Threshold
(
MET
10)
and
use
of
a
10­
fold
uncertainty
factor
for
potential
variability
within
the
human
population
and
other
uncertainties.
See
ADTC
Memorandum,
"
Hexavalent
Chromium
­
Finalization
of
Issues
related
to
Quantitation
of
Dermal
Risk
from
exposure
to
treated
wood
containing
hexavalent
chromium,"
August
31,
2004.

Scientific
considerations
EPA
had
identified
a
study
performed
with
subjects
who
had
documented
sensitivity
to
chromium
(
Nethercott,
et
al.,
1994).
The
study
was
conducted
to
identify
a
level
of
exposure
to
chromium
below
which
dermal
exposure
did
not
appear
to
elicit
an
ACD
response.
Regarding
the
Nethercott
human
study,
the
Agency
had
concluded
that
the
study
contains
information
sufficient
for
assessing
human
risk
resulting
from
potential
dermal
exposure.

Please
comment
on
whether
the
Nethercott
study
was
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
dermal
exposure
to
hexavalent
chromium.

Board
Response
to
the
Charge
Introduction
Hexavalent
chromium
(
CrVI)
is
known
to
cause
allergic
contact
dermatitis
(
ACD).
CrVI
is
a
component
of
a
pesticide
product
used
as
a
wood
preservative,
and
members
of
the
general
public
may
be
exposed
through
contact
with
treated
wood.
ACD
is
a
delayed,
immunologically
mediated,
inflammatory
skin
disease
consisting
of
various
degrees
of
erythema,
edema,
and
vesiculation.
ACD
is
typically
characterized
by
two
phases,
termed
induction
and
elicitation.
Induction
occurs
when
there
was
an
exposure
of
sufficient
magnitude
and/
or
duration
to
activate
specific
immune
mechanisms
resulting
in
the
acquisition
of
sensitization,
while
elicitation
occurs
from
a
subsequent
exposure
to
the
same
chemical
allergen.
In
general,
the
amount
of
allergen
exposure
needed
to
produce
induction
is
greater
than
that
needed
to
produce
elicitation
in
previously
sensitized
individuals.
Thus,
the
study
of
elicitation
can
provide
an
appropriate
critical
endpoint
for
risk
assessments.
One
approach
to
estimate
an
acceptable
area
dose
for
protection
against
elicitation
is
the
determination
of
a
minimum
elicitation
threshold,
or
MET.
The
concept
behind
the
MET
is
that
there
was
an
elicitation
threshold
below
which
no
sensitization
reaction
is
expected.

The
EPA
FIFRA
Scientific
Advisory
Panel
met
in
May
2004
to
review
human
and
animal
studies
related
to
CrVI
(
SAP,
2004).
In
August,
2004
the
Agency's
Antimicrobials
Division
Toxicity
Endpoint
Selection
Committee
issued
a
memorandum
that
summarized
its
assessment
of
dermal
risk
from
CrVI
(
ADTC,
2004).
The
Agency
identified
a
study
performed
with
human
subjects
who
had
documented
sensitivity
to
chromium
(
Nethercott
et
al.,
1994).
The
study
was
conducted
to
identify
a
level
of
exposure
to
chromium
below
which
dermal
exposure
did
not
appear
to
elicit
an
ACD
response.
Regarding
the
Nethercott
et
al.
study,
the
Agency
had
80
of
104
concluded
that
the
study
contained
information
sufficient
for
assessing
human
risk
resulting
from
potential
dermal
exposure.
The
Agency
had
asked
the
HSRB
to
comment
on
whether
this
study
was
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
dermal
exposure
to
hexavalent
chromium.

Critique
of
the
1994
Nethercott
et
al.
Study
The
purpose
of
the
study
was
to
determine
the
MET
as
mass
of
allergen
per
skin
surface
area
for
CrVI
by
a
patch
testing
technique.
The
study
also
included
response
to
CRIII,
but
these
data
were
not
discussed
here.
Five
concentration
levels
of
CrVI
(
4.4,
0.88,
0.18,
0.088,
0.018
µ
g/
cm2)
was
used
in
the
patch
test,
and
"
TRUE­
Test"
patches
were
manufactured
specifically
for
use
in
the
study
to
reduce
the
variability
inherent
in
earlier
patch
preparation
methods.
The
highest
concentration
(
4.4
µ
g/
cm2)
were
used
as
a
screening
concentration
to
identify
those
who
were
sensitized
to
CrVI.
This
first
round
of
testing
involved
102
volunteers
(
78
men
and
24
women)
previously
shown
to
be
sensitive
to
developing
allergic
contact
dermatitis
(
ACD)
in
response
to
an
allergen.
CrVI
elicited
ACD
in
54
(
39
men
and
15
women)
of
these
102
subjects.
Two
lower
concentrations
(
0.018
and
0.088
µ
g/
cm2)
were
tested
in
these
54
volunteers
in
round
two.
Those
who
had
no
ACD
response
during
round
two
were
tested
with
the
next
two
higher
concentrations
(
0.18
and
0.88
µ
g/
cm2)
in
round
three.
These
concentrations
were
chosen
to
provide
a
maximal
ACD
response.
The
study
was
double
blind
as
to
concentration,
and
each
concentration
was
matched
with
a
control
(
placebo)
concentration
within
each
volunteer.
Patch
concentrations
were
validated
analytically
and
found
to
be
within
Contract
Laboratory
Procedure
criteria
for
acceptability.
The
serial
escalation
of
patch
concentration
level
permitted
the
authors
to
determine
a
dose­
response
relationship
and
to
calculate
MET
values.
The
authors
calculated
a
10%
minimum
elicitation
threshold
(
MET10)
of
0.089
µ
g/
cm2.

This
study
had
a
number
of
strengths.
It
involved
both
sexes,
the
study
concentrations
were
selected
carefully
based
on
previous
studies,
and
the
investigators
determined
a
priori
what
sample
size
and
dosing
group
size
were
needed
to
establish
statistical
accuracy
for
the
MET10.
Many
elements
of
the
experimental
protocol
(
e.
g.,
employment
of
the
control
patch,
serial
increase
of
the
concentration
until
manifestation
of
ACD,
double
blinding
of
patch
concentration
levels)
were
thoughtfully
developed.
The
study
was
designed
in
accordance
with
current
scientific
standards
to
address
a
clearly
defined
research
question,
included
representative
study
populations
for
the
endpoint
in
question,
and
met
requirements
for
adequate
statistical
power.
It
appears
to
have
been
conducted
in
accordance
with
recognized
good
clinical
practices,
including
appropriate
monitoring
for
safety.
Finally,
the
study
authors
reported
the
design,
conduct
and
analysis
very
comprehensively.

There
are
several
questions
that
can
be
raised
regarding
the
scientific
validity
of
this
study.
First,
the
authors
developed
a
cumulative
response
curve
that
included
subjects
who
did
not
respond
to
any
of
the
doses
presented
in
rounds
two
and
three.
These
subjects
were
assigned
a
minimum
elicitation
threshold
value
of
4.4
µ
g/
cm2,
although
none
were
tested
at
doses
between
0.88
and
4.4
µ
g/
cm2.
The
assignment
of
this
MET
value
appeared
arbitrary,
and
potentially
distorts
the
shape
of
the
cumulative
response
curve.
However,
this
use
of
the
high
MET
value
does
not
affect
the
calculation
of
the
MET10,
and
so
it
was
of
no
consequence
to
the
study's
primary
conclusion.
Second,
a
recent
study
by
Hansen
et
al.
(
2003)
reported
a
MET10
of
0.03
81
of
104
ug/
cm2
for
18
subjects,
a
value
substantially
lower
than
that
reported
by
Nethercott
et
al.
However,
these
two
studies
differed
with
respect
to
the
reading
scale
employed.
The
reading
of
the
tests
in
the
Nethercott
et
al.
study
followed
rules
adopted
for
the
diagnostic
patch
test;
that
is
to
say,
the
definition
of
a
positive
reaction
was
the
appearance
of
erythema
infiltration
and
papules.
This
approach
was
consistent
with
current
international
clinical
standards.
For
the
Hansen
et
al.
study,
the
investigators
used
the
same
reading
scale
for
diagnostic
patch
testing,
but
for
definition
of
thresholds
they
used
any
degree
of
reaction,
including
erythematous
and
follicular
reactions.
The
logic
for
this
approach
was
that
at
very
low
concentrations
irritation
was
not
an
issue,
so
that
the
question
of
threshold
was
not
a
diagnostic
decision.
This
more
sensitive
reading
approach,
which
at
present
was
considered
experimental,
accounts
for
the
difference
in
MET10
values
reported
in
these
two
studies.
Third,
Nethercott
et
al.
(
1994)
used
patches
that
covered
a
very
small
area
of
skin
(
0.81
cm2).
Workers,
and
presumably
members
of
the
public,
would
typically
be
exposed
over
a
much
larger
skin
surface
area
than
that
used
in
this
study.
In
their
article
Nethercott
et
al.
discussed
the
potential
importance
of
patch
surface
area,
and
described
an
additional
experiment
with
four
of
the
study
subjects
who
had
exhibited
MET
values
at
0.88
µ
g/
cm2.
In
this
experiment
five
patches
were
used
for
each
subject,
and
the
exposure
level
of
CrVI
was
reduced
to
0.18
µ
g/
cm2
for
each
patch.
The
data
that
resulted
from
this
experiment
were
not
presented,
but
the
authors
stated
that
"
sub­
MET
concentrations
of
CrVI
applied
over
a
larger
skin
surface
area
did
not
elicit
the
positive
responses
seen
when
the
MET
concentration
was
applied
in
the
standard
patch."
Current
evidence
indicated
that
the
dose
per
unit
area
was
the
most
important
parameter
for
studies
of
this
kind.
But
there
was
no
doubt
that
if
an
extended
area
was
exposed,
such
as
the
full
arm,
there
may
be
an
effect
from
absorption
of
an
ACD­
producing
compound.
This
type
of
exposure
could
lead
to
a
systemic
contact
dermatitis
reaction
with
spreading
of
the
dermatitis
to
a
vesicular
palmar
eczema,
and
eventually
flexural
eczema.
Such
systemic
spreads
are
well
known
in
relation
to
major
contact
dermatitis
reactions,
as
occur
in
occupational
exposures.
The
Nethercott
et
al.
study,
where
relatively
small
skin
surface
areas
were
exposed,
does
not
exclude
that
such
effects
could
happen
if
larger
areas
were
exposed.

HSRB
Consensus
and
Rationale
The
Board
concluded
that
the
1994
Nethercott
et
al.
dermal
sensitization
study
was
sufficiently
sound,
from
a
scientific
perspective,
to
be
used
to
estimate
a
safe
level
of
dermal
exposure
to
hexavalent
chromium.

The
1994
Nethercott
et
al.
study
was
properly
designed,
well­
conducted,
and
employed
appropriate
scientific
and
clinical
methods
to
determine
a
minimum
elicitation
threshold
for
dermal
sensitization
due
to
hexavalent
chromium.
The
MET10
reported
in
the
study
provided
a
reasonable
point
of
departure
for
risk
assessment.

Charge
to
the
Board
Ethical
considerations
The
Agency
requested
that
the
Board
provide
comment
on
the
following:
82
of
104
a.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
Nethercott
study
was
fundamentally
unethical?

b.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Board
Response
to
the
Charge
Brief
Overview
of
the
Study
A
previously­
published
study
involving
dermal
exposure
of
102
healthy
volunteers
to
increasing
doses
of
CrVI
was
evaluated,
hereinafter
referred
to
as
Nethercott
et
al.
1994.
he
study
sponsor
was
unknown,
but
is
likely
to
be
either
the
Chem
Risk
Division
of
McLaren/
Hart
Environmental
Engineering,
Alameda
CA,
or
a
client
of
McLaren/
Hart.
The
study
was
conducted
in
1992
at
five
U.
S.
and
one
Canadian
academic
institution:
the
Cleveland
Clinic
Foundation
(
Cleveland,
OH),
Johns
Hopkins
University
(
Baltimore,
MD),
Pennsylvania
State
University
(
Hershey,
PA),
Stanford
University
(
Palo
Alto,
CA),
the
University
of
British
Columbia
(
Vancouver,
BC),
and
the
University
of
Louisville
(
Louisville,
KY).
The
study
was
conducted
after
the
promulgation
of
federal
protections
for
the
protection
of
human
participants
in
research
(
i.
e.
Common
Rule)
(
§
45CFR46;
adopted
by
the
EPA
in
1991
and
published
at
§
40CFR26),
so
the
regulatory
requirements
of
the
Common
Rule
were
applicable.
Furthermore,
all
five
US
academic
institutions
participating
had
a
valid
Multiple
Project
Assurance
of
Compliance
with
U.
S.
Department
of
Health
and
Human
Services
(
DHHS)
Regulations
for
Protection
of
Human
Research
Subjects
at
the
time
the
study
was
performed.
The
University
of
British
Columbia,
in
contrast,
held
a
Cooperative
Project
Assurance
at
that
time,
allowing
its
participation
in
DHHS­
recognized
research
programs
and
documenting
the
University
of
British
Columbia's
commitment
to
the
protection
of
human
research
subjects
in
accordance
with
§
45CFR46.

Critique
of
Study
The
Board
concurred
with
the
factual
observations
of
the
strengths
and
weaknesses
of
the
study,
as
detailed
in
USEPA
(
2006a).
However,
further
comments
were
raised
regarding:
1)
whether
the
documentation
and
process
of
study
subject
enrollment
was
sufficient
to
meet
prevailing
standards
of
voluntary
informed
consent
and
2)
whether
the
repeat
high­
dose
oralexposure
protocols
used
were
designed
to
minimize
risks
to
study
participants.

1)
Voluntary
Informed
Consent
The
Common
Rule
provides
a
comprehensive
framework
for
initial
and
continuing
review
of
research
involving
human
subjects.
In
order
to
ensure
that
a
study
like
Nethercott
et
al.
was
performed
ethically,
the
Common
Rule
requires
that:
1)
people
who
participate
as
subjects
in
research
are
selected
equitably
and
give
informed
and
voluntary
written
consent;
and
2)
research
involving
human
subjects
be
reviewed
and
approved
by
an
independent
oversight
group
such
as
an
Institutional
Review
Board
(
IRB).
As
published,
however,
the
Nethercott
et
al.
study
did
not
contain
sufficient
information
for
the
Board
to
adequately
determine
whether
or
not
the
83
of
104
informed
consent
process
used
to
enrolled
study
participants
met
the
standards
outlined
in
§
45CFR46.
All
that
is
known
about
the
informed
consent
process
is
that
"
all
volunteers
provided
their
doctors
with
written
consent
to
participate
in
the
study"
(
Nethercott
et
al.
1994).

Given
the
paucity
of
documentation,
the
Board
concluded
there
was
no
evidence
that
the
voluntary
informed
consent
process
used
failed
to
meet
the
regulatory
and
ethical
standards
applicable
to
research
conducted
in
the
United
States
and
Canada
in
1992.
All
six
academic
institutions
participating
in
this
study
had
an
assurance
of
compliance
with
DHHS
Regulations
for
Protection
of
Human
Research
Subjects
at
the
time,
requiring
independent
review
of
the
research
protocol
and
consent
documents
by
IRBs.
These
review
boards
were
expected
to
approve
a
study
involving
human
subjects
only
if:
1)
the
risks
to
subjects
were
minimized
by
using
procedures
which
were
consistent
with
sound
research
design
and
which
do
not
unnecessarily
expose
subjects
to
risk;
and
2)
the
risks
to
subjects
were
reasonable
in
relation
to
anticipated
benefits
to
subjects,
if
any,
and
the
importance
of
the
knowledge
that
may
reasonably
be
expected
to
result
(
see,
e.
g.,
§
45CFR46.111).
The
HSRB
believed
that
it
was
unlikely
that
all
six
of
these
IRBs
would
overlook
deficiencies
in
the
consent
process
that
would
seriously
impair
the
voluntary
informed
consent
of
the
research
subjects.

2)
Minimization
of
Risks
to
Study
Participants
The
Nethercott
et
al.
study
employed
a
three­
step
exposure
protocol.
Initially,
102
volunteers
were
screened
for
hexavalent
chromium
sensitivity
by
dermal
exposure
using
a
chromium
concentration
equivalent
to
the
standard
dose
used
in
patch
testing
for
skin
allergies
(
4.4
µ
g
Cr(
VI)/
cm2).
Pregnant
women,
individuals
receiving
immunosuppressive
or
steroid
medications,
and
patients
with
recent
or
concurrent
dermatological
conditions
were
excluded
from
study
participation.
54
chromium­
sensitive
subjects
were
identified
by
Nethercott
et
al.
These
chromium­
sensitive
subjects
then
participated
in
up
to
two
rounds
of
additional
testing.
In
the
first
round,
subjects
were
exposed
to
0.018
and
0.088
µ
g
CrVI/
cm2
using
a
skin
patch
approach.
Five
subjects
developed
allergic
contact
dermatitis
to
one
or
both
of
these
lower
doses;
these
subjects
were
excluded
from
further
testing.
Subjects
who
failed
to
respond
to
either
the
0.018
or
0.088
µ
g
dose,
however,
were
subsequently
exposed
to
ten­
fold
higher
doses
(
0.18
or
0.88
µ
g
Cr(
VI)/
cm2.
27
subjects
developed
allergic
contact
dermatitis
to
one
or
both
of
these
higher
doses.

In
sensitized
individuals,
chromium
exposure
elicits
an
allergic
contact
dermatitis
similar
to
a
poison
oak
or
poison
ivy
rash.
The
result
typically
is
an
itching,
red
rash
with
bumps
or
blisters;
these
transient
symptoms
usually
are
mild
and
can
be
treated
with
calamine
lotion
and
hydrocortisone
cream.
The
use
of
patch
testing,
even
when
it
knowingly
results
in
allergic
contact
dermatitis,
thus
meets
the
generally
accepted
definition
of
minimal
risk.
Furthermore,
Dr.
Torkil
Menne,
a
consultant
to
the
HSRB,
commented
that
most
studies
designed
to
determine
the
minimum
elicitation
threshold
to
a
dermal
sensitizing
agent
like
chromium
have
used
a
singlestep
protocol
in
which
study
subjects
were
exposed
to
the
entire
range
of
dermal
concentrations
in
a
single
round
of
testing.
The
study
exclusion
criteria
and
the
use
of
a
three­
step
exposure
protocol,
involving
initial
screening
of
subjects
for
chromium
sensitivity
followed
by
additional
rounds
of
testing,
using
doses
significantly
smaller
than
those
routinely
employed
for
allergy
testing
and
excluding
reactive
study
participants
from
further
exposure,
seems
designed
84
of
104
specifically
to
minimize
the
risk
of
serious
harm
to
research
participants.
Thus,
the
Board
believed
that
there
was
not
was
clear
and
convincing
evidence
that
these
studies
could
have
resulted
in
serious
harm
based
on
the
knowledge
available
to
the
investigators
at
the
time.

HSRB
Consensus
and
Rationale
The
Board
concurred
with
the
assessment
of
the
Agency
that
there
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
in
that
the
deficiencies
did
not
result
in
serious
harm,
nor
seriously
impair
the
informed
consent
of
the
research
subjects.

The
Board
determined
that
there
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

The
Board
based
these
two
determinations
on
its
conclusion
that
this
study
appeared
to
have
not
deviated
significantly
from
the
ethical
standards
prevailing
when
the
study
was
conducted.
However,
this
conclusion
was
based,
in
part,
on
a
process
that
was
hampered
by
a
lack
of
supporting
documentation
concerning
independent
ethical
review
by
the
study
investigators'
home
institutions.
The
Board
strongly
recommended
that
for
all
studies
submitted
to
the
HSRB,
the
Agency
make
a
good
faith
effort
to
obtain
such
documentation
in
the
future.

2.
Carbofuran
Charge
to
the
Board
Carbofuran
is
an
N­
methyl
carbamate
(
NMC)
pesticide
whose
primary
toxic
effect
is
neurotoxicity
caused
by
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
carbamylation
followed
by
rapid
recovery.
Carbofuran
can,
at
sufficiently
high
doses,
lead
to
a
variety
of
clinical
signs.
The
Agency
is
conducting
acute,
aggregate
(
single
chemical,
multi­
route)
and
worker
risk
assessments
of
carbofuran.
In
addition,
carbofuran
is
a
member
of
the
N­
methyl
carbamate
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
NMCs.

Scientific
considerations:

The
Agency's
WOE
document
and
DERs
for
carbofuran
described
the
study
design
and
results
of
a
carbofuran
human
oral
study
and
two
human
dermal
toxicity
studies.
The
WOE
document
also
discusses
the
Agency's
conclusions
that
these
studies
were
useful
in
establishing
points
of
departure,
both
oral
and
dermal,
for
the
single
chemical
assessment
and
in
informing
the
interspecies
uncertainty
factor
for
the
cumulative
assessment.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.
85
of
104
Board
Response
to
the
Charge
Study
Overview
Three
separate
studies
(
one
oral,
two
dermal)
were
carried
out
with
carbofuran
in
human
subjects.
The
study
details
are
described
separately
below.

Overview
of
Oral
Study
The
oral
study
conducted
with
carbofuran
was
carried
out
in
nine
healthy
male
volunteers
using
an
ascending
dose
schedule
and
single
doses
of
0.05,
0.1
and
0.25
mg/
kg
(
1976).
The
goal
of
this
study
was
to
determine
the
threshold
for
toxicity
following
a
single
oral
dose.
Initially,
the
study
was
conducted
in
an
open
design
(
subject
and
investigator
knew
that
carbofuran
was
ingested)
until
a
dose
level
produced
symptoms
determined
to
be
intolerable
(
described
below).
Once
the
intolerable
dose
was
achieved
(
0.25
mg/
kg),
the
study
was
completed
in
a
randomized,
double
blind
manner.
Carbofuran
was
administered
as
a
single
dose
in
a
capsule
immediately
following
breakfast,
after
which
subjects
remained
under
observation
for
24
hours.
Blood
samples
were
collected
for
analysis
of
plasma
and
RBC
cholinesterase
activity
at
0.5,
1,
2,
3,
6
and
24
hours
after
dosing.
The
baseline
level
of
RBC
cholinesterase
activity
was
established
from
a
predose
sample
collected
immediately
prior
to
dosing.
For
each
subject,
additional
physiological
parameters
including
ECG,
blood
pressure,
pupil
size
and
accommodation
and
the
Fukuda
step
test
were
collected,
and
subjects
were
monitored
continuously
for
additional
symptoms
of
toxicity,
including
sweating,
salivation,
headaches
and
nausea
and
vomiting
throughout
the
24­
hour
post­
dosing
period.
A
complete
clinical
chemistry
profile
was
performed
predose
and
at
24
hours.
The
next
highest
dose
was
not
initiated
until
data
from
the
24­
hour
post­
treatment
period
were
evaluated.
Plasma
and
RBC
cholinesterase
levels
were
determined
using
a
modification
of
the
Ellman
colorimetric
method
with
propionylthiocholine
as
substrate.
Subjects
were
allowed
to
smoke
during
the
24­
hour
sample
collection
period.

After
administration
of
the
0.05
mg/
kg
dose
(
2
subjects),
no
symptoms
were
noted
and
RBC
cholinesterase
activity
was
decreased
by
11
or
22%
from
baseline
(
plasma
cholinesterase
was
decreased
by
32
and
36%,
respectively).
Accordingly,
the
dose
was
escalated
to
0.1
mg/
kg
(
2
subjects).
In
this
leg
of
the
study,
one
subject
exhibited
an
abnormal
vestibular
mechanism
prior
to
dosing
and
showed
further
deterioration
after
exposure
to
carbofuran.
This
subject
also
showed
changes
in
cardiovascular
parameters
including
sinus
bradycardia
and
sinus
arrhythmia.
Two
subjects
presented
with
mild
symptoms
including
headache
(
1
subject)
or
lightheadedness
(
the
other
subject).
RBC
cholinesterase
activity
decreased
33
and
31%,
respectively,
whereas
plasma
cholinesterase
activity
was
more
variable
(
decreased
56
and
35%,
respectively).
Based
on
these
results,
the
dose
was
escalated
to
0.25
mg/
kg
(
2
subjects)
where
marked
symptoms,
including
drowsiness,
nausea,
vomiting,
headache,
salivation,
and
sinus
bradycardia
were
noted.
Accordingly,
this
dose
level
was
considered
to
have
achieved
the
level
of
intolerable
symptoms,
and
an
additional
2
subjects
were
exposed
to
this
level
along
with
one
control
subject
in
a
double
blinded
manner.
At
this
dose
level,
RBC
cholinesterase
inhibition
ranged
from
46­
63%
and
plasma
cholinesterase
inhibition
ranged
from
33­
100%.

Overview
of
Dermal
Studies
86
of
104
The
dermal
studies
conducted
with
carbofuran
(
1977
and
1978)
involved
application
of
the
compound
to
the
backs
of
subjects
for
4
hours.
The
two
studies
were
similar
in
design,
but
differed
with
respect
to
the
commercial
formulations
tested
and
the
mass
applied
per
unit
area
of
skin.

The
1977
dermal
study
(
i.
e.,
first
dermal
study)
was
carried
out
as
a
single,
ascending
dose
study
and
was
designed
to
determine
the
threshold
for
toxicity
under
conditions
of
normal
and
elevated
temperatures.
Carbofuran
was
provided
in
labeled
capsules
containing
75.4%
carbamate
powder
or
placebo.
This
powder
was
applied
to
the
backs
of
each
subject
over
an
area
described
by
a
paper
template
and
was
then
mixed
with
either
water,
an
artificial
sweat
medium,
or
normal
saline
to
insure
adhesion.
Under
normal
temperature
conditions
(
approximately
70
°
F
and
35%
humidity),
the
doses
evaluated
were
2,
4,
8
and
32
mg/
kg
(
2
subjects
per
dose
level),
whereas
under
elevated
temperature
conditions
(
approximately
90
°
F
and
68­
89%
humidity),
the
doses
evaluated
were
0.5,
1
and
2
mg/
kg
(
2
subjects
per
dose
level).
A
control
group
(
2
subjects)
was
included
in
the
high
temperature
leg
of
this
study.
For
the
high
temperature
conditions,
subjects
were
also
made
to
exercise
by
riding
a
stationary
bicycle
(
5
minutes
of
exercise
followed
by
15
minutes
of
rest)
throughout
the
entire
4­
hour
exposure
period.
The
parameters
outlined
above
under
the
overview
of
the
oral
study
were
performed
on
all
subjects
in
this
study.

Under
normal
temperature
conditions,
no
symptoms
were
noted
at
any
dose
level,
and
changes
in
RBC
and
plasma
cholinesterase
were
variable.
RBC
cholinesterase
inhibition
did
not
exceed
24%
(
observed
at
32
mg/
kg).
Plasma
cholinesterase
activity
was
highly
variable,
with
a
maximal
inhibition
of
33%
noted
at
the
4
mg/
kg
dose,
whereas
only
0
or
2
%
inhibition
was
reported
in
the
2
subjects
dosed
with
32
mg/
kg.

Under
conditions
of
high
temperature
and
humidity,
symptoms
were
observed
in
the
two
subjects
dosed
at
2
mg
carbofuran/
kg.
One
subject
at
this
level
exhibited
severe
symptoms
(
including
hazy
vision,
vomiting,
defecation
with
muscle
cramps
and
chills)
and
required
atropine
(
at
3
separate
times)
to
ameliorate
symptoms.
Maximal
inhibition
of
RBC
cholinesterase
activity
at
this
dose
level
was
45
and
65%
in
the
2
subjects
(
4
hours),
whereas
plasma
cholinesterase
inhibition
was
maximal
at
24
hours
(
12
and
16
%,
respectively).

The
1978
dermal
study
(
i.
e.,
second
dermal
study)
was
carried
out
as
a
single,
ascending
dose
study
and
was
conducted
under
conditions
of
elevated
temperature
and
humidity
as
described
above.
The
carbofuran
used
in
this
study
was
a
formulation
containing
44%
active
ingredient
and
was
applied
at
a
concentration
of
approximately
0.5
mg/
cm2
using
a
50%
dilution
of
the
formulation.
The
doses
evaluated
were
0.5,
1,
2
and
4
mg/
kg
(
2
subjects
per
dose
level).
There
was
no
control
group.
The
same
parameters
outlined
above
under
the
overview
of
the
oral
study
were
performed
on
all
subjects
in
this
study.

One
subject
dosed
at
0.5
mg/
kg
reported
nausea
after
treatment
and
the
other
subject
noted
burning
at
the
application
site.
In
contrast,
neither
subject
dosed
with
1
or
2
mg/
kg
experienced
any
symptoms.
A
dose
of
4
mg/
kg
resulted
in
symptoms
of
nausea,
dizziness
and
weakness
in
both
subjects,
and
atropine
was
administered
to
these
subjects.
Inhibition
of
RBC
cholinesterase
activity
showed
some
evidence
of
dose­
dependence
but
was
variable,
ranging
87
of
104
from
22
and
7%
to
61
and
49%
in
the
2
subjects
treated
with
0.5
and
4
mg/
kg,
respectively.
Plasma
cholinesterase
levels
were
highly
variable,
with
33
and
46%
inhibition
observed
at
0.5
mg/
kg
and
6
and
9%
at
4
mg/
kg,
respectively.

Critique
of
the
Oral
and
Dermal
Studies
Conducted
with
Carbofuran
In
the
three
studies
described
above,
the
major
strength
of
the
work
was
that
the
experimental
design
included
the
evaluation
of
at
least
three
dose
levels
from
which
dose
response
relationships
could
be
evaluated.
Furthermore,
the
study
outcomes
were
generally
consistent
with
fundamental
principles
of
xenobiotic
disposition
including
observations
that
exposure
from
the
oral
route
likely
exceeded
that
from
the
dermal
route
(
reflected
by
the
observation
of
toxicity
at
much
lower
oral
doses)
and
that
dermal
exposure
was
increased
in
an
environment
of
increased
temperature
and
humidity.
However,
in
evaluating
all
of
the
studies,
numerous
weaknesses
were
noted
by
the
HSRB.
These
weaknesses
included:

1)
There
was
no
justification
or
rationale
for
the
selection
of
doses
used
in
any
of
the
three
studies.

2)
The
sample
size
was
very
small
(
typically
two
subjects
per
dose
or
condition)
with
few
or
no
controls
(
no
more
than
two
control
subjects
in
any
study).
Such
a
design
prevented
evaluation
of
statistical
significance
for
any
parameter
measured
in
the
studies.

3)
The
values
obtained
for
RBC
and
plasma
cholinesterase
levels
were
highly
variable.
Factors
that
contributed
to
this
variability
included
the
small
sample
size,
the
inclusion
of
only
a
single
baseline
sample
collected
immediately
prior
to
dosing
used
to
compare
all
post­
dosing
samples,
the
small
number
of
control
subjects,
and
an
uncommon
method
for
analytical
determination
of
cholinesterase
activities.
The
contribution
of
potential
laboratory
error
cannot
be
ruled
out.

4)
Plasma
cholinesterase
levels
were
highly
variable
in
all
studies
so
as
to
preclude
any
useful
interpretation.
In
general,
plasma
cholinesterase
levels
were
not
consistent
with
changes
in
RBC
cholinesterase
activities.

5)
One
subject
who
presented
with
abnormal
vestibular
mechanisms
in
the
pre­
dose
evaluation
was
used
in
the
oral
study
and
showed
serious
symptoms
after
treatment.

6)
Subjects
were
allowed
to
smoke
during
the
study
period.

While
the
oral
and
dermal
studies
shared
these
common
weaknesses,
there
were
also
serious
limitations
regarding
the
application
of
carbofuran
in
the
conduct
of
the
dermal
studies.
In
particular,
it
is
known
that
dermal
absorption
is
influenced
by
the
concentration
of
compound
applied
per
unit
surface
area
of
skin,
and
it
was
clear
that
the
studies
were
extremely
different
in
this
regard.
For
example,
as
shown
in
the
Table
1
below
in
the
first
dermal
study
(
high
temperature/
humidity),
the
mass
loading
range
was
6,000
to
12,000
µ
g
carbofuran/
cm2.
These
extremely
high
loading
levels
were
not
appropriate
for
evaluating
potential
dermal
absorption
from
occupational
or
environmental
exposure
to
carbofuran.
In
the
first
dermal
study,
the
88
of
104
greatest
skin
surface
area
treated
in
the
normal
temperature
leg
of
this
study
was
40
cm2;
a
mass
of
3,264
mg
was
applied
to
this
area,
equivalent
to
a
loading
of
81,600
µ
g
carbofuran/
cm2.
In
contrast,
mass
loading
was
controlled
to
achieve
approximately
500
µ
g
carbofuran/
cm2
at
all
dose
levels
in
the
second
dermal
study.

Table
1.
Calculation
Of
Loading
Levels
For
Carbofuran
For
Subjects
In
The
First
Dermal
Study
(
High
temperature/
humidity
conditions)

Subject
Dose
Body
Wt
Mass
Template
Loading
(
mg/
kg)
(
kg)
(
mg)
(
cm2)
(
ug/
cm2)

1
0
63
0
2
0
65
0
3
0.5
72
36
6
6,000
4
0.5
66
33
5.72
5,769
5
1
74
74
8.55
8,655
6
1
64
64
7.94
8,060
7
2
74
148
12.16
12,171
8
2
78
156
12.49
12,490
A
primary
deficiency
of
the
first
dermal
study
was
that
it
did
not
provide
a
realistic
worker
exposure
scenario;
that
is,
the
exposures
of
the
subjects
in
these
experiments
did
not
correspond
to
exposures
likely
to
be
seen
among
workers.
Large
amounts
of
carbofuran
(
up
to
3,000
mg)
were
applied
to
a
relatively
small
skin
surface
area
(
6­
40
cm2)
in
the
experiments,
whereas
we
typically
see
much
larger
skin
surface
areas
exposed
to
smaller
amounts
among
workers
(
e.
g.,
1­
10
µ
g/
cm2).
For
example,
the
hands,
a
skin
surface
commonly
exposed
to
pesticides,
have
a
total
surface
area
of
990
cm2
(
EPA
Exposure
Factors
Handbook,
1997).
Dermal
dosing
studies
require
careful
consideration
of
three
factors:
mass
applied
to
the
skin,
surface
area
treated,
and
the
duration
of
exposure.
Therefore,
the
skin
loadings
and
skin
surface
areas
exposed
in
both
carbofuran
dermal
studies
were
not
appropriate
for
determination
of
a
NOAEL
or
a
LOAEL
for
risk
assessment
purposes.

HSRB
Consensus
and
Rationale
The
EPA
concluded
that
the
oral
and
dermal
studies
conducted
with
carbofuran
in
human
subjects
were
useful
in
establishing
points
of
departure,
both
oral
and
dermal,
for
the
single
chemical
assessment
and
in
informing
the
interspecies
uncertainty
factor
for
the
cumulative
assessment.

However,
while
these
studies
were
informative,
the
HSRB
concluded
that
there
were
numerous
technical
issues
regarding
the
conduct
of
the
oral
and
dermal
studies
with
carbofuran
and
that
overall,
the
weakness
of
the
studies
far
outweigh
the
strengths.
The
weaknesses
included
the
small
sample
size,
the
lack
of
control
subjects,
the
highly
variable
results
for
RBC
cholinesterase
activity
and
the
inappropriate
application
methods
used
in
the
dermal
studies.
Accordingly,
the
HSRB
did
not
recommend
any
of
the
oral
or
dermal
studies
conducted
with
89
of
104
carbofuran
in
human
subjects
for
the
single
chemical
assessment
or
in
informing
the
interspecies
uncertainty
factor
for
the
cumulative
assessment.

Additional
Considerations:
Potential
For
The
Carbofuran
Human
Studies
Data
The
Board
provided
additional
analysis
in
response
to
the
Agency's
charge
to
the
Board
concerning
the
potential
for
the
data
in
human
subjects
for
carbofuran
to
be
applied
to:
(
1)
the
calculation
of
a
benchmark
dose
(
BMD10)
and
identification
of
the
BMD10L
(
lower
confidence
limit);
(
2)
the
identification
of
a
NOAEL
or
LOAEL
for
effects
or
(
3)
the
comparison
to
other
species
for
possible
adjustments
to
uncertainty
factor
for
the
cumulative
assessment.

The
HSRB
provided
the
following
additional
perspective
relative
to
the
Agency's
question:

The
utility
of
the
human
studies
with
carbofuran
was
limited
by
the
very
small
sample
size
used
in
all
of
the
studies.
The
Agency
proposed
to
use
the
RBC
cholinesterase
data
for
determination
of
the
BMD10L.
However,
under
conditions
where
the
group
size
was
only
two,
it
would
be
imperative
to
have
highly
accurate,
valid,
reliable
and
consistent
measures
of
RBC
cholinesterase
activity
in
both
control
and
carbofuran­
treated
subjects.
This
rigor
was
simply
not
achieved
in
the
human
studies.
Rather,
RBC
cholinesterase
activities
were
compared
to
a
single
baseline
value,
were
highly
variable
across
subjects,
including
controls,
and
did
not
show
any
consistency
with
plasma
cholinesterase
levels.
As
such,
although
a
BMD10L
could
be
calculated,
the
magnitude
of
the
error
in
the
derived
values
would
preclude
a
reliable,
meaningful
assessment.
Therefore,
the
HSRB
reiterated
its
recommendation
that
the
human
data
should
not
be
used
for
calculation
of
the
BMD10.

In
a
similar
manner,
the
small
sample
size,
compounded
by
the
lack
of
consistent
changes
in
cholinesterase
activities
in
all
studies,
the
inappropriate
methods
used
for
dermal
application
of
the
compound
in
the
dermal
studies
and
the
inclusion
of
at
least
one
subject
who
presented
with
abnormal
vestibular
function
in
a
pre­
dose
assessments
limited
the
general
utility
of
the
data.
Collectively,
the
weaknesses
in
the
carbofuran
human
studies
conduct
and
outcomes
cast
doubt
on
the
utility
of
the
data
for
identifying
a
NOAEL
or
LOAEL
or
for
comparing
across
species
in
consideration
of
the
interspecies
uncertainty
factor
for
the
cumulative
risk
assessment.
Thus
the
HSRB
recommended
that
the
human
data
should
not
be
used
for
these
evaluations.

Charge
to
the
Board
Ethical
Considerations
The
Agency
requested
that
the
Board
provide
comment
on
the
following:

Oral
Toxicity
Study:
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
human
oral
study
conducted
with
carbofuran
was
fundamentally
unethical?
90
of
104
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
oral
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Dermal
Toxicity
Studies:
Is
there
clear
and
convincing
evidence
that
the
conduct
of
either
of
the
human
dermal
studies
conducted
with
carbofuran
was
fundamentally
unethical?

Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
dermal
studies
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Board
Response
to
the
Charge
Study
Overview
There
were
three
studies
involving
either
oral
or
dermal
administration
of
carbofuran:
an
oral
toxicity
study
performed
in
1976
(
IRB
Review
dated
March
31,
1976;
Final
Report
dated
September
17,
1976);
a
dermal
toxicity
study
performed
in
late
1976
and
early
1977
(
IRB
Review
dated
August
25,
1976;
Final
Report
dated
March
18,
1977);
and
a
second
dermal
toxicity
study
conducted
in
late
1977
(
REC
Review
date
unknown;
Final
Report
dated
February
15,
1978).

The
location
for
the
research
was
the
Quincy
Research
Center
in
Kansas
City,
Missouri.
All
three
studies
were
under
the
direction
of
a
single
principal
investigator,
John
D.
Arnold,
MD.
The
research
appeared
to
have
been
performed
under
contract
to
the
Midwest
Research
Institute,
also
located
in
Kansas
City.
The
responsible
institutional
review
board
was
the
Community
Review
Committee,
Inc.,
again
located
in
Kansas
City.
The
research
sponsor
was
FMC
Corporation,
located
in
Philadelphia,
Pennsylvania
with
the
manufacturing
facility
apparently
located
in
Middleport,
New
York.

No
ethical
or
regulatory
standards
were
mentioned
in
any
of
the
study
documents.
Given
the
dates
of
the
research
studies,
Section
12
of
FIFRA
applied
to
the
research.
In
addition,
the
1975
version
of
the
Declaration
of
Helsinki
was
available
at
the
time.

Critique
of
Studies
The
following
comments
apply
to
all
three
studies.

1)
The
fact
that
these
studies
have
never
been
published
should
not
be
used
as
the
sole
criterion
to
determine
whether
the
purpose
of
the
research
was
to
obtain
generalizable
knowledge.
Publication
is
neither
a
necessary
nor
sufficient
criterion
of
whether
or
not
the
research
was
designed
to
allow
for
either
a
descriptive
or
causal
inference.

2)
The
risks
were
minimized
by
the
study
design
(
setting
aside
the
actual
conduct),
assuming
that
there
was
a
valid
scientific
purpose
in
escalating
the
dose
until
achieving
a
"
lowest
observable
adverse
effect
level"
(
LOAEL).
Examples
of
the
procedures
that
were
incorporated
to
91
of
104
minimize
risk
included
the
presence
of
a
supervising
physician
who
was
readily
available
for
24
hours
after
dosing,
confinement
of
the
subjects
for
24
hours,
abstinence
from
alcohol
during
the
study,
the
exclusion
of
other
drugs
within
two
weeks
of
performing
the
study,
the
availability
and
administration
of
atropine
(
discussed
further
below),
and
a
delay
in
dose
escalation
(
at
least
in
the
oral
toxicity
study)
until
the
24
hour
clinical
data
was
available.
In
addition,
subjects
only
received
the
active
compound
once
during
each
research
study.

3)
Measurements
of
RBC
cholinesterase
inhibition
should
serve
as
an
adequate
surrogate
measure
of
toxicity,
obviating
the
need
to
induce
clinical
signs
and
symptoms
of
cholinergic
toxicity.
The
question
however
in
judging
these
three
studies
was
whether
this
standard
was
either
appreciated
or
applicable
in
1976
and
1977.
The
fact
that
the
research
was
designed
to
cause
clinical
signs
and
symptoms
of
cholinergic
toxicity
as
the
study
endpoint
does
not,
in
and
of
itself,
establish
that
the
interests
of
the
subjects
did
not
prevail
over
other
interests.
The
Common
Rule
allows
for
the
balancing
of
the
risks
of
research
against
the
knowledge
that
may
reasonably
be
obtained.
The
central
question
then
was
whether
the
risks
were
reasonable,
not
whether
the
research
was
designed
to
elicit
clinical
toxicity.

4)
With
respect
to
informed
consent,
the
list
of
signs
and
symptoms
of
cholinergic
toxicity
found
in
the
consent
documents
was
fairly
complete.
The
consent
documents
were
fairly
straightforward
about
the
fact
that
the
testing
involved
a
pesticide
and
that
the
research
would
be
of
no
benefit
to
the
subject.
The
freedom
to
withdraw
was
emphasized,
along
with
the
fact
that
additional
testing
to
ensure
the
safety
of
subjects
would
be
requested
by
the
supervising
physician.
In
spite
of
these
strengths,
the
consent
documents
failed
to
provide
a
description
of
the
study
design
(
i.
e.,
dose
escalation)
and
the
anticipated
endpoint
of
clinical
toxicity.
The
phrase
"
we
do
not
expect
any
serious
complications"
is
clearly
open
to
interpretation.
Some
would
and
some
would
not
consider
the
clinical
signs
and
symptoms
of
cholinergic
stimulation
"
serious."
Regardless,
the
phrase
does
introduce
a
framing
of
these
stated
risks
as
"
non­
serious."
Given
the
research
design,
the
consent
documents
would
have
been
improved
if
they
had
been
explicit
about
the
dose
escalation,
the
place
of
the
specific
subject
within
that
dose
escalation,
and
the
fact
that
someone
would
eventually
have
a
100%
chance
of
experiencing
clinical
toxicity.
Although
these
changes
are
an
admirable
standard
going
forward,
the
consent
documents
used
for
the
oral
and
first
dermal
toxicity
study
met
(
and
some
might
argue
exceeded)
the
standards
prevalent
in
1976
and
1977.
However,
as
discussed
below,
the
consent
document
for
the
second
dermal
toxicity
study
was
seriously
deficient.

The
Board
had
specific
comments
about
the
conduct
of
each
of
the
studies
that
can
be
addressed
under
the
general
topic
of
the
reasonableness
of
the
risks
(
and
the
efforts
to
reduce
those
risks)
that
the
subjects
experienced
in
the
conduct
of
this
research.

1)
Was
it
appropriate
to
expose
additional
subjects,
in
the
oral
toxicity
study,
to
a
dose
which
had
already
been
shown
to
cause
clinical
toxicity
if
the
scientific
purpose
was
to
establish
a
LOAEL?
Given
the
criticism
of
attempting
to
determine
a
"
no
observable
adverse
effect
level"
(
NOAEL)
using
a
small
sample
size,
the
design
chosen
in
these
three
studies
to
elicit
a
LOAEL
may
be
more
reliable.
However
the
small
sample
size,
when
combined
with
the
variability
and
unreliability
of
the
RBC
cholinesterase
measurements,
undermine
confidence
that
the
study
was
designed
to
establish
the
real
LOAEL.
The
repeat
administration
of
the
test
substance
absent
92
of
104
dose
escalation
was
used
in
other
cholinesterase
inhibitor
studies,
but
the
endpoint
driving
the
decision
to
not
escalate
dosing
was
the
more
sensitive
endpoint
of
the
degree
of
RBC
cholinesterase
inhibition.

2)
There
was
documentation
(
in
a
letter
dated
October
26,
1976)
of
the
decision
to
start
at
the
2.0
mg/
kg
dose
in
the
low­
temperature
and
low­
humidity
phase
of
the
first
dermal
toxicity
study.
Although
the
responsible
IRB
was
not
consulted
(
for
which
there
were
no
procedural
guidelines
in
1976),
was
the
decision
to
bypass
the
16
mg/
kg
dose
in
favor
of
a
32
mg/
kg
dose
in
the
low
temperature
and
humidity
phase
of
the
dermal
toxicity
study
reasonable?
If
the
doseresponse
relationship
based
on
the
percent
RBC
acetyl
cholinesterase
inhibition
was
linear,
yet
the
onset
of
clinical
signs
and
symptoms
reflects
a
threshold
response,
this
decision
could
have
placed
the
subjects
given
the
higher
dose
at
greater
risk
even
though,
in
retrospect,
the
32
mg/
kg
dose
was
well
tolerated.

3)
The
administration
of
atropine
as
an
antidote
to
cholinergic
toxicity
may
have
been
delayed
for
one
or
more
of
the
subjects
in
the
high­
temperature
and
high­
humidity
phase
of
both
dermal
toxicity
studies.
Although
mention
was
made
of
written
instructions
for
the
administration
of
atropine,
these
instructions
were
not
included
in
the
submitted
documentation.
The
question
then
was
whether
there
could
be
any
justification
for
the
delay
in
the
administration
of
atropine.
Two
possible
justifications
might
be:
(
1)
the
signs
and
symptoms
were
from
nonmuscarinic
cholinergic
receptors
and
thus
would
not
be
responsive
to
atropine
(
which
was
not
the
case);
or
(
2)
the
supervising
physician
was
concerned
that
any
resulting
tachycardia
or
other
side­
effects
from
the
administration
of
atropine
would
be
of
greater
risk
(
highly
unlikely).
After
considerable
reflection,
the
Board
could
find
no
scientific
or
clinical
reason
to
delay
the
administration
of
atropine.

4)
Study
participants
were
not
fully
informed
of
the
risks
of
the
study.
It
should
have
been
clear
to
study
investigators
that
the
escalating
dose
design
used
was
likely
to
result
in
serious
harm
to
some
research
subjects.
For
example,
several
participants
who
received
a
2.0
mg/
kg
dose
of
carbofuran
during
the
high­
temperature
and
high­
humidity
phase
of
the
first
dermal
toxicity
study
exhibited
clear
clinical
signs
and
symptoms
of
carbamate
poisoning,
requiring
administration
of
atropine
as
an
antidote.
Plasma
and
red
cell
cholinesterase
inhibition
data
also
was
obtained
from
these
individuals,
with
participants
demonstrating
46%
and
65%
peak
red
cell
inhibition
respectively.
In
the
subsequent
second
dermal
toxicity
study,
however,
the
data
from
the
first
dermal
toxicity
study
were
not
used
either
to
develop
clear
stopping
criteria
or
to
modify
the
dosing
protocol,
thus
exposing
study
participants
to
an
unacceptable
level
of
risk.
The
two
participants
in
the
high­
temperature
and
high­
humidity
second
dermal
toxicity
study
who
received
a
2.0
mg/
kg
dose
of
carbofuran
did
not
exhibit
any
clinical
symptoms
of
carbamate
poisoning.
These
individuals
did,
however,
exhibit
peak
red
cell
cholinesterase
inhibition
of
40%
and
42%
respectively,
similar
to
the
level
of
inhibition
seen
in
one
of
the
symptomatic
participants
in
the
first
dermal
toxicity
study.
These
data
suggest
that
the
LOAEL
for
carbofuran
was
at
or
near
2.0
mg/
kg.
Nevertheless,
the
decision
was
made
to
expose
two
subjects
to
a
dose
of
4.0
mg/
kg
carbofuran,
once
again
resulting
in
severe
clinical
symptoms
indicative
of
carbamate
poisoning
and
requiring
administration
of
atropine
as
an
antidote.
In
light
of
the
clinical
and
biomarker
data
obtained
from
the
first
dermal
toxicity
study,
it
should
have
93
of
104
been
obvious
to
study
investigators
that
exposure
of
additional
research
subjects
to
a
dose
of
4.0
mg/
kg
carbofuran
was
likely
to
have
resulted
in
serious
harm
to
these
two
study
participants.

This
conclusion,
coupled
with
the
observation
that
the
consent
documents
from
the
second
dermal
toxicity
study
explicitly
stated
study
investigators
"[
did]
not
expect
a
serious
complications"
raises
serious
questions
about
the
informed
consent
process.
At
least
some
study
participants
were
likely
to
experience
clinical
signs
indicative
of
carbamate
toxicity.
To
imply
otherwise
in
the
informed
consent
documents
suggests
that
the
consent
process
was
severely
flawed.
Study
participants
were
denied
access
to
information
that
might
have
influenced
their
decision
to
voluntarily
enroll
in
the
second
dermal
toxicity
study.

HSRB
Consensus
and
Rationale
Oral
Toxicity
Study
For
the
oral
study,
there
was
no
evidence
that
the
study
failed
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted.

There
was
no
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical
(
e.
g.,
intended
to
seriously
harm
participants
or
that
informed
consent
was
not
obtained).

There
was
no
clear
and
convincing
evidence
of
significant
deficiencies
in
the
ethical
procedures
that
could
have
resulted
in
serious
harm
(
based
on
the
knowledge
available
at
the
time
the
study
was
conducted)
nor
that
information
provided
to
participants
seriously
impaired
their
informed
consent.

Dermal
Toxicity
Studies
The
HSRB
found
deficiencies
in
both
dermal
human
toxicity
studies
relative
to
specific
ethical
standards
prevalent
at
the
time
the
study
was
conducted.

The
majority
of
the
Board
concluded
there
was
no
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical
(
e.
g.,
intended
to
seriously
harm
participants
or
that
informed
consent
was
not
obtained).
In
light
of
the
results
obtained
from
the
first
dermal
toxicity
study,
one
Board
member
concluded
that
the
second
dermal
toxicity
study
was
fundamentally
unethical
in
design.
The
Board
member
believed
that
this
study
was
neither
designed
to
minimize
the
risk
of
serious
harm
to
participants
nor
to
ensure
an
adequate
informed
consent.

For
both
dermal
toxicity
studies,
there
was
clear
and
convincing
evidence
of
significant
deficiencies
in
the
ethical
procedures
for
minimizing
risk
that
could
have
resulted
in
serious
harm
(
based
on
the
knowledge
available
at
the
time
the
study
was
conducted).
The
first
dermal
toxicity
study
was
significantly
deficient
given
the
delay
in
the
administration
of
atropine
to
more
than
one
subject
experiencing
the
signs
and
symptoms
of
carbamate
toxicity.
The
second
dermal
toxicity
study
was
considered
significantly
deficient
by
a
majority
of
Board
members
in
94
of
104
that
the
lack
of
information
provided
about
the
results
from
the
initial
dermal
toxicity
study
seriously
impaired
their
informed
consent.

3.
Methyl
Isothiocyanate
(
MITC)

Charge
to
the
Board
MITC
is
an
irritating
compound
that
has
a
limited
animal
database
for
toxicity
via
inhalation,
the
key
route
of
exposure.
MITC
can
be
used
as
a
pesticide
directly
to
treat
wood
poles,
but
the
major
pathway
of
exposure
to
MITC
is
from
degradation
of
several
fumigant
pesticides
(
i.
e.,
metam
sodium,
metam
potassium,
and
dazomet).
Due
to
its
volatility,
MITC
has
the
potential
to
move
off­
site,
which
can
result
in
exposure
to
bystanders
near
treated
areas
and,
through
ambient
air,
to
people
far
away
from
treated
areas.
Use
of
the
soil
fumigants
also
results
in
exposure
to
those
handling
the
pesticides
or
working
in
treated
fields.

Scientific
considerations
The
Agency's
WOE
document
and
DER
for
MITC
describe
the
study
design
and
results
of
the
MITC
odor
threshold
and
eye
irritation
human
studies.
The
WOE
document
also
discusses
the
Agency's
conclusions
that
the
eye
irritation
study
is
useful
for
the
assessment
of
potential
effects
on
bystanders
and
workers
from
exposures
to
MITC
during
acute
(
1­
day)
intervals.
The
Agency
had
concluded
that
the
odor
threshold
study
is
less
useful
than
the
eye
irritation
study
for
assessing
the
human
health
effects
of
MITC,
since
the
odor
detection
threshold
for
humans
is
higher
than
the
level
that
causes
eye
irritation.
The
Agency
had
decided,
however,
to
use
the
results
of
the
eye
irritation
study
for
assessing
the
inhalation
exposure
of
MITC.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

Board
Response
to
the
Charge
Introduction
MITC
is
the
primary
and
key
degradate
of
these
fumigant
pesticides
(
i.
e.,
metam
sodium,
metam
potassium
and
dazomet).
As
a
gas
injected
into
soil,
it
can
kill
soil­
borne
pests,
such
as
insects,
microorganisms,
weeds,
and
nematodes.
The
fumigant
dissipates
from
the
soil
in
a
few
days
to
a
couple
of
weeks.

According
to
the
EPA
Weight
of
Evidence
(
WOE)
document
(
USEPA
2006b)
"
The
mode
of
toxic
action
for
MITC
is
not
known
at
this
time.
MITC
is
primarily
an
irritating
compound
that
produces
non­
specific
systemic
effects
in
oral
toxicity
studies
such
as
changes
in
body
weight,
food
consumption,
and
hematological
parameters.
Following
air
exposures
to
MITC,
consistent
effects
are
observed
in
rats
and
humans.
For
example,
clinical
signs
and
pathological
changes
of
the
respiratory
tract
consistent
with
an
irritant
have
been
observed
in
laboratory
studies
in
rat.
Humans
exposed
to
MITC
complain
of
symptoms
such
as
itchy
and
burning
eyes,
rash
and
burning
skin,
nausea,
scratchy
throat,
salivation,
coughing,
and
shortness
95
of
104
of
breath.
In
acute
toxicity
testing
with
animals,
MITC
is
considered
Acute
Toxicity
Category
I
(
corrosive)
for
skin
and
eye
irritation."
Since
the
animal
studies
were
either
long­
term
inhalation
or
oral
studies,
they
were
not
considered
for
a
point
of
departure
and
therefore
would
be
less
protective
of
human
health.
Thus,
the
Board
recommended
the
eye
irritation
LOAL
as
a
point
of
departure.

Brief
Overview
of
Study
The
EPA
WOE
extracted
a
description
of
the
odor
and
eye
irritation
study
(
Russell
and
Rush
1996)
directly
from
the
Risk
Characterization
Document
for
MITC
of
the
Department
of
Pesticide
Regulation,
Cal
EPA
(
July
25,
2003,
pp
53­
59),
which
was
considered
accurate
and
quoted
herein.

"
In
order
to
determine
the
NOEL
for
human
eye
irritation
produced
by
MITC
vapors,
as
well
as
its
odor
threshold,
human
volunteers
were
exposed
to
air
concentrations
of
MITC
in
a
laboratory
setting
(
Russell
and
Rush,
1996).
The
study
specifically
focused
on
assessing
these
parameters
at
different
times
of
exposure.
An
olfactometer
was
used
which
permitted
the
operator
to
dispense
the
test
material
through
a
manifold
system.
The
test
material
could
thus
be
diluted
over
a
100­
fold
concentration
range.
The
material
was
dispensed
by
diffusion
from
a
glass
vessel
which
could
be
maintained
at
any
temperature
±
0.1
°
C
over
a
range
of
30
to
70
°
C.
A
Total
Hydrocarbon
Analyzer
(
THA)
was
used
to
monitor
the
flow
of
test
material
during
the
exposure
period.
In
addition,
carbon
tube
samples
were
drawn
once
the
system
was
equilibrated
prior
to
exposure,
and
at
the
end
of
the
exposure.
The
test
material
was
desorbed
from
the
carbon
and
analyzed
by
gas
chromatography.
Every
effort
was
undertaken
to
minimize
the
reaction
of
the
test
material
with
the
tubing
and
other
equipment
used
in
the
delivery
system".

"
In
the
olfactory
threshold
study,
33
individuals
(
16
males,
17
females)
with
a
mean
age
of
25
years
(
range,
18
to
34
years)
were
tested.
They
were
exposed
to
three
positive
control
odorants,
pyridine,
acetic
acid,
and
n­
butyl
alcohol
as
well
as
to
MITC.
The
technician
chose
the
odorant
and
concentration
level.
The
odorant
was
dispensed
in
double
blind
fashion
from
one
of
three
presentation
ports.
The
subject
was
responsible
for
identifying
from
which
of
the
presentation
ports
the
odorant
was
dispersed.
A
30­
second
rest
period
between
exposures
was
permitted
in
order
to
allow
the
subject
to
recover
prior
to
the
next
exposure.
The
operator
tested
each
subject
over
the
range
of
concentrations
for
each
odorant
until
he
was
assured
that
the
threshold
had
been
adequately
ascertained.
A
standard
procedure
was
employed
in
order
to
make
this
determination."

"
In
the
NOEL
determination
for
eye
irritation,
the
olfactometer
was
modified
by
attaching
goggles
to
the
presentation
line.
This
permitted
the
test
material
to
be
directed
only
to
the
eyes.
Five
parameters
were
used
to
ascertain
an
irritation
response:
1.
the
subjects'
subjective
estimation
of
irritation
(
using
the
"
Likert"
scale);
2.
photographs
of
the
subjects'
eyes
prior
to
and
after
exposure;
3.
blink
rate
as
measured
by
electromyography;
4.
effect
upon
visual
acuity;
5.
tear
production.
Both
a
positive
control
(
acetic
acid)
and
a
negative
control
(
air)
were
employed.
Baseline
responses
for
each
of
the
assessment
parameters
were
determined
under
preexposure
conditions
("
zero­
time
controls")
and
upon
exposure
to
the
negative
control
("
air­
only
controls")
for
the
prescribed
period.
A
positive
irritation
response
was
based
on
three
criteria:
1.
96
of
104
the
average
response
must
be
quantitatively
greater
than
the
pre­
exposure
response;
2.
the
average
response
must
be
greater
than
pre­
exposure
and
greater
than
could
be
expected
statistically
from
individual
to
individual
differences
within
the
group;
3.
the
average
treated
response
must
be
greater
than
the
air­
only
group's
response
and
greater
than
could
be
expected
from
individual
differences
observed
within
the
group.
Seventy
individuals
(
38
males,
32
females)
with
a
mean
age
of
32
years
(
range,
18­
67
years;
median
age,
28
years)
were
exposed
to
air,
MITC,
and/
or
acetic
acid.
Between
9
and
16
subjects
were
examined
under
each
dose/
time
period
combination.
Three
exposure
periods,
14
minutes,
4
hours
and
8
hours
were
used.
In
the
eight
hour
test,
subjective
responses,
blink
rates
and
tearing
were
assessed
at
0,
1.5,
3,
3.5,
6
and
8
hours
(
tearing
was
not
measured
at
3.5
hours).
Two
15­
minute
rest
breaks
and
a
30­
minute
lunch
break
were
permitted
during
the
8­
hour
period.
In
the
four
hour
test,
these
same
parameters
were
assessed
at
0,
1,
2,
3
and
4
hours
(
tearing
was
not
measured
at
0,
2
and
3
hours).
In
the
14­
minute
exposure
protocol,
subjective
responses
and
blink
rates
were
measured
at
0,
1,
4
and
14
minutes
after
the
start
of
exposure.
Tearing
was
measured
at
14
minutes
only.
Visual
acuity
and
ocular
morphology
were
assessed
at
the
beginning
and
end
of
each
exposure
period.
All
analyses
were
performed
in
a
double­
blind
manner."
T­
tests
were
used
to
compare
responses
at
each
computed
concentration
level
for
each
time
period
to
both
air
control
results
and
zero­
time
results.
Both
were
significant
and
positive
but
responses
to
the
control
substance
were
not
as
dramatic.

Critique
of
the
Study
Introduction
Table
2
shows
what
the
investigators
called
the
NOEL,
which
the
Agency's
Data
Evaluation
Record
and
WOE
call
the
NOAEL
and
LOEL
respectively
(
EPA's
RfC
methodology
document
included
eye,
nasal,
and
throat
irritation
in
its
list
of
adverse
effects).
97
of
104
Table
2.
Summary
Of
MITC
Eye
Irritation
Effects
From
Human
Subjects
Exposure
time
NOAEL
(
ppm)
LOAEL
(
ppm)
Source
of
observed
Effect
1
minute
3.3
­
­
4
minutes
0.6
1.9
Subjective
eye
irritation
14
minutes
0.6
1.9
Subjective
eye
irritation
1
hour
0.23
a
0.8
Subjective
eye
irritation
1.5
hours
0.22
a
­
­

2
hours
0.23
a
0.8
Subjective
eye
irritation
and
blink
rate
3
hours
0.23
a
0.8
Subjective
eye
irritation
and
blink
rate
3.5
hours
0.22
a
­
­

4
hours
0.23
a
0.8
Subjective
eye
irritation
6
hours
0.22
a
­
­

8
hours
0.22
a
­
­

a
The
slightly
different
values
obtained
at
the
low
dose
NOAEL
level
(
0.22
and
0.23
ppm)
reflected
the
fact
that
they
were
derived
from
tests
performed
on
different
days.

As
the
WOE
stated
"
Exposure
to
0.8
ppm
(
800
ppb)
MITC
resulted
in
a
statistically
significant
positive
response
based
on
averaging
the
subjective
assessments
by
the
subjects
using
the
Likert
scale
methodology.
As
many
as
8
out
of
9
subjects
showed
a
positive
response
at
1
and
2
hours,
the
first
two
time
points
examined
[
and
also
at
3
&
4
hours].
Shorter
exposures
to
0.6
ppm
did
not
result
in
statistically
significant
Likert
scale
changes,
though
1
of
9
individuals
appeared
to
respond
at
4
and
14
minutes.
Exposure
to
1.9
ppm
or
3.3
ppm
MITC
for
4
or
14
minutes
resulted
in
positive
subjective
responses
at
4
and
14
minutes.
At
1
minute
of
exposure,
levels
as
high
as
3.3
ppm
did
not
evoke
a
statistically
significant
positive
response."

"
Mean
blink
rate
determinations
at
0.8
ppm
were
statistically
significantly
increased
at
the
2­
and
3­
hour
time
points
compared
both
to
air­
only
and
zero­
time
controls.
Statistical
significance
was
not
achieved
at
1
and
4
hours,
though
a
positive
response
was
indicated
in
several
individuals.
The
blink
response
to
0.6
ppm
and
1.9
ppm
at
1,
4
and
14
minutes
did
not
show
a
positive
response.
At
3.3
ppm,
statistical
significance
was
achieved
at
4
and
14
minutes.
"
The
Board
agreed
with
the
Agency's
conclusion
that
"
A
strong
suggestion
of
a
response
was
also
present
at
1
minute,
though
it
was
not
statistically
significant."
In
addition,
the
subjective
(
Likert
scale)
responses
were
the
most
sensitive
and
most
variable.
The
eye
blink
rate
was
the
next
most
sensitive.
The
other
tests
were
not
as
sensitive
and
usually
were
not
significant.

The
Board
agreed
with
the
Agency
conclusions
as
noted
in
their
DER:
98
of
104
"°
For
a
one­
minute
exposure,
the
NOAEL
for
eye
irritation
is
3.3
ppm
due
to
a
lack
of
response
in
any
parameter
tested."

"°
For
exposures
4­
14
minutes,
the
NOAEL
for
eye
irritation
is
0.6
ppm
based
on
responses
on
the
Likert
subjective
scale
at
1.9
ppm.
"

"°
For
exposures
of
1­
8
hours,
based
on
the
statistically
significant
subjective
(
Likert
scale)
responses
at
0.8
ppm
MITC
at
1­
4
hours
and
the
statistically
significant
eyeblink
responses
at
2
and
3
hours,
0.22
ppm
was
designated
as
the
NOAEL
for
this
study.
The
NOAEL
for
eye
irritation
was
consistent
for
the
1­
8
hour
measurements.
It
is
reasonable
to
assume
that
exposures
up
to
24
hours
would
likely
yield
a
similar
response."

Finally,
in
terms
of
the
olfactory
threshold
study,
the
Board
agreed
with
the
Agency's
conclusion
that
"
The
observed
odor
threshold
for
MITC
ranged
from
0.2
to
8
ppm
with
a
geometric
mean
of
1.7
ppm."

Strengths
of
the
study
The
studies
were
well­
designed,
equipped,
carefully
controlled
and
performed
by
experienced
investigators
at
a
respected
institute.
The
lowest
concentration
tested
was
the
largest
sample
size.
Exclusion
criteria
were
appropriate:
abnormal
irritation,
contacts,
frequent
headaches,
recent
asthma
attacks,
and
pregnancy.

Weaknesses
of
the
study
The
eye
irritation
studies
did
not
have
a
sufficient
number
of
subjects
in
each
of
the
experiments
and
phases.
In
addition
there
was
no
information
on
the
susceptibility
status
of
individuals
tested
nor
information
on
within
subject
variation.
Another
shortcoming
is
that
eye
irritation
does
not
predict
dermal
nor
respiratory
effects.
Thus,
there
may
be
lower
NOAELs
for
these
latter
effects.

Two­
tailed
t­
tests
were
used
to
compare
the
responses
of
subjects
receiving
different
doses
of
MITC
despite
the
presence
of
substantial
skew
in
the
data
of
some
groups,
with
some
standard
deviations
exceeding
the
corresponding
means.
This
was
most
common
among
the
subjects
receiving
the
lower
doses,
an
issue
of
particular
concern
insofar
as
the
goal
of
the
study
was
to
identify
a
NOAEL.
A
nonparametric
test
would
have
been
a
more
appropriate
choice.
In
addition,
because
responses
were
measured
repeatedly
on
the
same
subjects
over
time,
a
statistical
approach
that
took
this
into
account
would
also
have
been
more
appropriate
than
the
series
of
independent
t­
tests
that
were
carried
out.

The
investigators
were
rather
rigid
in
their
approach
to
the
interpretation
of
p­
values.
For
instance,
a
group
difference
for
which
the
p­
value
was
0.052
was
not
considered
evidence
of
an
effect.
On
the
other
hand,
the
investigators
clearly
stated
their
criteria
for
interpretation
and
applied
these
rules
consistently.
Moreover,
inspection
of
the
tables
indicated
that
the
conclusions
reached
would
not
have
differed
even
if
a
somewhat
more
liberal
criterion
of
statistical
significance
had
been
applied.
99
of
104
This
issue
does
raise
a
more
general
concern
relating
to
the
size
of
the
study
sample.
The
investigators
provided
no
rationale
for
the
sample
size
that
was
used
nor
power
calculations,
despite
the
important
influence
that
sample
size
has
on
whether
a
group
difference
reaches
some
level
of
statistical
significance.
The
inclusion
of
a
small
number
of
additional
subjects
in
the
different
groups
could
well
have
caused
some
of
the
borderline
p­
values
to
fall
to
a
level
that
would
have
met
the
investigators'
criteria
for
significance
and,
potentially,
change
the
inferences
drawn,
as
demonstrable
by
re­
calculations
of
significance.
Thus
it
is
important
that
one
could
be
confident
that
the
sample
size
was
adequate
for
the
assessment
of
the
study
hypotheses.
Ideally,
the
investigators
should
have
begun
by
specifying
the
magnitude
of
the
response
that
they
consider
meaningful
and
want
to
be
able
to
detect,
should
it
exist
(
e.
g.,
a
50%
increase
in
the
response,
a
doubling
of
the
response,
etc).
Then,
after
making
additional
assumptions,
they
could
calculate
the
number
of
subjects
that
would
be
necessary.
As
stated,
this
was
not
done.

HSRB
Consensus
and
Rationale
The
Board
concluded
that
air
concentrations
of
methyl
isothiocyanate
sufficient
to
produce
eye
irritation
would
lead
to
a
conservative
and
prudent
point
of
departure
for
inhalation
risk
(
i.
e.,
eyes
were
a
sensitive
endpoint
in
relation
to
the
respiratory
system).
The
Board
reached
its
decision
based
on
eye
irritation
LOAELs
are
often
lower
than
respiratory
irritation
LOAELs
for
irritant
gases
(
WHO
1979ab,
NRC
1986;
WHO/
EURO
1986).
While
the
use
of
eye
irritation
date
as
a
surrogate
for
respiratory
data
is
reasonable
in
this
situation,
one
must
be
cautious
as
only
appropriate
controlled
human
studies
of
the
respiratory
system
can
provide
a
final
and
definitive
respiratory
point
of
departure,
if
ever
determined
(
NAS
1975).

Charge
to
the
Board
Ethical
considerations
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

a.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
human
eye
irritation
study
with
MITC
was
fundamentally
unethical?

b.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
this
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Board
Response
to
the
Charge
Brief
Overview
of
the
Study
The
human
eye
irritation
study
was
conducted
in
1993
through
1995.
The
study
was
performed
in
Davis,
California
by
researchers
at
the
Sensory
Testing
Laboratory,
School
of
Medicine,
University
of
California,
Davis,
together
with
the
Western
Research
Center
of
Zeneca
Ag
Products,
Richmond,
California.
The
study
sponsor
was
the
Metam
Sodium
Task
Force
(
representing
chemical
manufacturers),
whose
mailing
address
is
in
care
of
Zeneca
Ag
Products
100
of
104
of
Wilmington,
Delaware.
The
documents
provided
by
the
sponsor
specifically
state
that
the
research
was
conducted
in
compliance
with
the
Declaration
of
Helsinki
(
presumably
the
1989
version,
though
no
date
is
specified)
and
the
Human
Subject's
Bill
of
Rights
(
a
provision
of
California
law).
The
study
was
reviewed
and
approved
by
the
Human
Subjects
Review
Committee
at
the
University
of
California,
Davis,
an
institution
which
held
a
Multiple
Project
Assurance
with
the
U.
S.
Department
of
Health
and
Human
Services.
The
documentation
provided
by
that
Committee
indicated
that
it
reviewed
this
study
pursuant
to
the
standards
of
the
Common
Rule
(
45
C.
F.
R.
Part
46,
Subpart
A)
and
determined
it
to
be
in
compliance
with
that
Rule.

The
Board's
comments
only
relate
to
the
human
eye
irritation
study,
and
not
to
the
human
odor
threshold
study
conducted
by
the
same
group
of
investigators.
Consistent
with
the
charge
presented
to
the
Board
by
the
EPA,
the
Board
made
no
comments
with
regard
to
the
human
odor
threshold
study.

Critique
of
Study
The
Board
concurred
with
the
factual
observations
of
the
strengths
and
weaknesses
of
the
human
eye
irritation
study,
as
detailed
in
USEPA
(
2006c).
The
Board
concurred
with
the
Agency's
conclusion
that
although
there
were
deficiencies
with
regard
to
the
applicable
ethical
standards
prevailing
at
the
time
this
study
was
conducted,
those
deficiencies
were
relatively
minor.
In
addition
to
the
deficiencies
specified
in
USEPA
(
2006c),
the
Board
wanted
to
comment
on
two
additional
aspects
of
the
study:

1.
The
Human
Subjects
Review
Committee
asked
the
investigators
to
add
a
provision
to
the
protocol
and
the
consent
form
indicating
that
"
if
significant
irritation
is
experienced,
no
higher
dose
will
be
administered."
The
revised
protocol
never
provided
any
specific
criteria
for
determining
how
it
would
be
determined
whether
a
subject
was
experiencing
significant
irritation.
It
was
appropriate
that
such
stopping
rules
be
relatively
specific,
if
possible.

2.
The
original
protocol
for
the
eye
irritation
study
involved
exposing
subjects
to
MITC
for
a
series
of
two­
minute
periods,
with
twenty­
minute
breaks
between
each
exposure.
In
the
study
investigator's
memorandum
to
the
IRB
dated
August
17,
1994,
requesting
renewal
of
the
protocol,
the
investigator
indicated
that
he
had
apparently
finished
conducting
at
least
part
of
the
study
as
initially
described,
and
that
it
was
"
going
well
without
any
ill
effects."
He
submitted
a
protocol
amendment
so
that
he
might
study
the
effects
of
longer
exposure
to
MITC
(
up
to
eight
hours
at
a
time).
In
the
document
submitted
to
the
EPA
describing
the
results
of
this
series
of
studies,
however,
no
data
were
provided
as
to
the
results
of
the
short­
term
study.
On
page
26
of
the
submitted
documents,
which
outlines
when
subjects
were
exposed
to
this
agent
and
for
what
periods
of
time,
there
was
mention
only
of
the
8­
hour,
4­
hour,
and
14­
minute
exposure
periods.
The
tables
accompanying
the
report
only
gave
details
of
the
results
of
those
longer
exposure
periods.
Since
the
longer
exposures
were
premised
on
the
favorable
results
from
the
short­
term
exposures,
it
would
have
been
appropriate
for
the
report
to
have
also
included
details
relating
to
the
results
from
the
short­
term
(
two­
minute)
trials.
The
absence
of
such
details
makes
it
difficult
to
determine
any
ethical
irregularities
that
might
have
been
revealed
by
such
additional
information.
101
of
104
HSRB
Consensus
and
Rationale
The
Board
concluded
that:

There
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent).

There
was
no
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

The
Board
based
these
two
determinations
on
its
conclusion
that
this
study,
based
on
the
evidence
presented,
appeared
to
have
had
only
relatively
minor
deviations
from
the
ethical
standards
prevailing
when
the
study
was
conducted.

COMMENTARY
ON
SCIENTIFIC
STANDARDS
FOR
HUMAN
DOSING
STUDIES
The
Chair
asked
the
Board
to
articulate
the
set
of
scientific
standards
that
has
and
will
continue
to
guide
Board
decision­
making
for
human
dosing
studies.
Following
Board
deliberation,
scientific
standards
for
human
dosing
studies
in
general
and
for
single
dose
studies
in
particular
were
adopted.

Scientific
Standards
for
Human
Dosing
Studies
1.
Justification
 
Is
the
scientific
question
worthwhile?
 
Are
human
subjects
necessary
to
answer
the
question?
 
Is
potential
risk
serious
or
irreversible?

2.
Dose
Selection
 
Sufficient
to
test
the
question?
(
single
dose
in
most
cases
is
not
sufficient
to
determine
NOAEL
and
LOAEL)
 
Based
on
appropriate
data
(
e.
g.
preclinical;
previous
studies)

3.
Endpoint
Selection
 
Consistent
with
the
aim
of
the
study?
 
Appropriate
to
answer
questions
about
human
responses
(
e.
g.,
sensitivity,
accuracy,
validity,
replicability)?
 
Measured
accurately
and
reliably
with
good
quality
assurance?
 
Participants
 
Characteristics
generalizable
to
question
asked?
102
of
104
 
Appropriate
inclusion/
exclusion
criteria?
 
Are
measurements
taken
at
appropriate
times
to
answer
the
study
question?

4.
Method
 
Is
the
sample
size
sufficient?
 
Is
selection
of
control
and
experimental
groups
appropriate?
 
Is
the
staging
of
dose
intervals,
dose
amounts,
and
type
of
exposure
sufficient
to
answer
the
question?
 
Is
there
quality
assurance
for
observations,
instruments
and
data?

5.
Statistical
Analyses
 
Can
data
be
statistically
analyzed?
 
Is
the
statistical
method
appropriate
to
answer
the
question?

Scientific
Standards
for
Single
Dose
Level
Study
Board
definition
of
single
dose
level
study
­
individual
study
that
uses
one
dose
level
irrespective
of
the
number
of
subjects,
frequency
of
dosing
or
inclusion
of
a
control
or
placebo.

1.
In
general,
single
dose
level
studies
have
limited
utility
 
Such
studies
cannot
be
used
in
isolation
to
establish
a
NOAEL
or
LOAEL
 
In
rare
instances
they
may
have
utility
if
interpreted
within
the
context
of
one
or
more
supplementary
studies
that
provide
information
at
other
dose
levels
under
analogous
conditions.

2.
Single
dose
level
studies
may
be
able
to
answer
a
very
focused
question
 
However
in
such
instances
its
utility
will
depend
upon
the
robustness
of
study
design,
the
rationale
for
the
study
and
whether
the
study
design
was
consistent
with
the
rationale.
 
Evaluation
of
robustness
will
include
questions
of:
control,
relevant
endpoints,
evidence
that
measures
can
identify
an
adverse
effect
or
detect
a
change,
use
of
a
surrogate
marker
that
is
quantifiable
and
recognized
as
an
established
function
of
the
compound
and
other
criteria
for
scientific
validity.

3.
A
single
dose
level
study
may
have
utility
if
it
provides
evidence
of
adverse
effects
observed
at
lower
levels
than
other
studies
have
indicated.
103
of
104
REFERENCES
ADTC.
2004.
Memorandum:
Hexavalent
Chromium
­
Finalization
of
Issues
related
to
Quantitation
of
Dermal
Risk
from
exposure
to
treated
wood
containing
hexavalent
chromium,
Antimicrobials
Division
Toxicity
Endpoint
Selection
Committee,
August
31.

Hansen
MB.
Johansen
JD.
Menné
T.
2003.
Chromium
allergy:
significance
of
both
CR(
III)
and
Cr(
VI).
Contact
Dermatitis
49:
206­
212.

National
Academy
of
Sciences.
1975.
Principles
for
Evaluating
Chemicals
in
the
Environment.

Nethercott
J.
Paustenbach
D.
Adams
R.
Fowler
J.
Marks
J.
Morton
C.
Taylor
J.
Horowitz
S.
Finley
B.
1994.
A
study
of
chromium
induced
allergic
contact
dermatitis
with
54
volunteers;
implications
for
environmental
risk
assessment.
Occup
Environ
Med
51:
371­
380.

NRC.
1986
ETS.
Environmental
tobacco
smoke:
measuring
exposures
and
assessing
health
effects.
National
Research
Council
(
U.
S.).
Committee
on
Passive
Smoking.
National
Academy
Press,
1986.
http://
darwin.
nap.
edu/
books/
0309037301/
html/
13.
html
Russell
MJ
and
Rush
TI.
(
1996)
Methyl
Isothiocyanate:
Determination
of
human
olfactory
detection
threshold
and
human
no
observable
effect
level
for
eye
irritation.
Sensory
Testing
Laboratory,
University
of
California
at
Davis.
Report
No.
RR
96­
049B.
September
10,
1996
MRID
44400401.

SAP.
2004.
Transmittal
of
Minutes
of
the
FIFRA
Scientific
Advisory
Panel
Meeting
Held
May
4­
6,
2004:
A
Consultation
On
Dermal
Sensitization
Issues
For
Exposures
To
Pesticides.
July
1.

United
States
Environmental
Protection
Agency.
Data
Evaluation
Review.
Methyl
Isothiocyanate.
Special
Study;
Human
Eye
Irritation
and
Odor
Threshold.

USEPA.
2006a.
EPA's
Initial
Ethical
Review
of
Hexavalent
Chromium
Human
Sensitization
Study.
April
11,
2006.

USEPA.
2006b.
United
States
Environmental
Protection
Agency.
Weight
of
Evidence
Discussion
for
Methyl
Isothiocyanate.
April
13,
2006.

USEPA.
2006c.
EPA's
Initial
Ethical
Review
of
MITC
Human
Odor
Threshold
and
Eye
Irritation
Studies,
dated
April
13,
2006.

WHO
1986.
EHO/
EURO
EH
13.

WHO
1979a.
EHC
7.
Environmental
Health
Criteria
7:
Photochemical
oxidants.
World
Health
Organization,
1979.
http://
www.
inchem.
org/
documents/
ehc/
ehc/
ehc007.
htm
104
of
104
WHO
1979b
.
EHC
8
Environmental
Health
Criteria
8:
SULFUR
OXIDES
AND
SUSPENDED
PARTICULATE
MATTER.
World
Health
Organization,
1979.
http://
www.
inchem.
org/
documents/
ehc/
ehc/
ehc008.
htm