1
of
34
June
1,
2006
Minutes
of
the
United
States
Environmental
Protection
Agency
(
EPA)
Human
Studies
Review
Board
(
HSRB)
May
2­
3,
2006
Public
Meeting
Docket
Number:
EPA­
HQ­
ORD­
2006­
0310
Committee
Members:
(
See
Roster
­
Attachment
A)

Dates
and
Times:
Tuesday,
May
2,
2006;
8:
30AM
 
5:
00
PM
Wednesday,
May
3,
2006
8:
30AM
 
12:
00PM
(
See
Federal
Register
Notice
 
Attachment
B)

Location:
Holiday
Inn
Hotel
and
Suites,
Alexandria­
Historic
District
625
First
Street,
Alexandria,
VA
22314,
703­
548­
6300
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.
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.
*
Recused
from
carbofuran
discussion
and
deliberation
Meeting
Summary:
Meeting
discussions
generally
followed
the
issues
and
general
timing
presented
in
the
Meeting
Agenda,
unless
noted
otherwise
in
these
minutes
(
Attachment
C).
2
of
34
Introductory
Remarks,
Meeting
Administrative
Procedures
and
Meeting
Process
Celia
Fisher,
Ph.
D.,
Human
Studies
Review
Board
(
HSRB)
Chair
opened
the
meeting
and
thanked
Board
members
for
their
contributions
and
beginning
preparations
of
the
report
from
their
April
4­
6,
2006
meeting.
William
Farland,
Ph.
D.
(
Chief
Scientist,
Office
of
the
Science
Advisor
[
OSA],
EPA)
said
that
the
April
meeting
had
a
challenging
agenda
with
eight
compounds
discussed.
He
thanked
the
Board
for
their
deliberations
during
the
April
meeting.
Following
Dr.
Farland's
comments,
Mr.
Jack
Housenger
(
Associate
Director,
Health
Effects
Division,
Office
of
Pesticide
Programs
[
OPP],
EPA)
provided
opening
comments
for
Mr.
Jim
Jones,
(
Director,
Office
of
Pesticide
Programs).
Mr.
Housenger
said
that
OPP
was
pleasantly
surprised
by
Board
comments
from
the
April
meeting.
The
first
meeting
was
most
difficult
covering
eight
compounds.
For
carbofuran,
the
Agency
vacillated
with
respect
to
the
principle
study
for
risk
assessment:
first
the
dog
study,
then
the
human
study,
back
to
the
dog
study,
and
now,
based
on
HSRB
discussion
for
amitraz
at
the
April,
2006
HSRB
meeting,
the
human
study
was
coming
forward
again.
OPP
was
also
seeking
the
Board's
advice
on
chromium
as
a
dermal
sensitizer
and
MITC
as
an
eye
irritant.
Next,
Paul
Lewis,
Ph.
D.
(
Designated
Federal
Officer,
HSRB
Staff,
OSA,
EPA)
commented
that
the
HSRB
provides
advice
and
recommendations,
decision­
making
remains
with
the
Agency.
Dr.
Lewis
explained
that
he
serves
as
a
liaison
between
the
Board
and
Agency
and
that
the
HSRB
is
subject
to
Federal
Advisory
Committee
Activity
(
FACA)
requirements,
including
open
meetings
and
availability
of
meeting
documents
through
the
ORD
docket.
All
materials
and
reports
will
be
available
on
the
ORD
docket.
Dr.
Lewis
also
welcomed
Dr.
Torkil
Menné
from
the
University
of
Copenhagen,
Denmark.
Dr.
Torkil
Menné
will
be
serving
as
a
consultant
to
the
HSRB
regarding
dermal
sensitization
from
chromium.
Dr.
Lewis
also
stated
that
Drs.
Brimijoin
and
Chambers
were
recused
from
all
discussions
and
deliberations
concerning
carbofuran.

Before
the
discussion
of
chromium
began,
Dr.
Fisher
reviewed
the
responsibilities
of
the
HSRB.
The
HSRB's
charge
was
to
comment
on
completed
research
with
human
subjects,
to
answer
questions
posed
by
EPA,
and
to
raise
significant
issues
not
raised
by
the
Agency.
She
reminded
the
Board
that
for
a
study
to
be
of
benefit,
it
must
be
scientifically
valid
and
have
been
conducted
in
an
ethical
fashion
using
the
criteria
set
by
the
Chair
at
the
April
4­
6,
2006
HSRB
meeting
for
"
fundamentally
unethical"
and
"
significantly
deficit
relative
to
the
ethical
standards
at
the
time
the
study
was
conducted."

Science
and
Ethics
of
the
Chromium
Human
Studies
A
presentation
on
dermal
sensitization
testing
of
CrVI
was
provided
by
Timothy
McMahon,
Ph.
D.
(
OPP,
EPA).
Dr.
McMahon
explained
that
CrVI
is
a
registered
pesticide
that
is
incorporated
into
an
article
to
protect
the
integrity
of
the
article
or
substance
itself.
Treated
articles,
such
as
wood,
do
not
bear
pesticide
labels
or
other
information
to
inform
the
public
about
potential
hazards,
including
dermal
sensitization
or
allergic
contact
dermatitis
(
ACD).

Dr.
McMahon
said
that
CrVI
was
evaluated
by
Nethercott
et.
al.
(
1994),
encompassing
113
possible
volunteers
selected
from
the
examination
of
6000
patient
files.
Ultimately,
102
participants
were
involved
in
the
study
(
78
men,
24
women).
All
study
participants
were
believed
to
be
CrVI
sensitive
based
on
previous
patch
tests
performed
by
their
physicians.
Test
3
of
34
concentrations
were
selected
based
on
a
review
of
the
open
literature
where
the
highest
dose
provided
100%
response
and
the
lowest
dose
elicited
less
than
10%
response.
Three
rounds
of
testing
were
conducted
using
TRUE­
test
patches
applied
to
the
upper
sides
of
the
back
7
cm
apart.
Patches
remained
in
place
for
48
hours.

This
study
used
an
occlusive
patch.
The
10%
maximum
elicitation
threshold
(
MET
10)
was
calculated
as
0.089
µ
g
Cr+
6/
cm2.
While
the
Agency
used
the
recommendations
from
the
May
4­
6,
2004
FIFRA
SAP
for
selection
of
the
MET
10,
it
did
not
apply
the
FIFRA
SAP
recommendation
of
an
uncertainty
factor
less
than
1
in
deriving
the
total
UF.
The
Agency
concluded
that
the
Nethercott
et
al.
study
contained
information
sufficient
for
assessing
human
risk
from
potential
dermal
exposure
to
chromium.

Following
Dr.
McMahon's
presentation,
the
Board
questioned
who
the
study
sponsor
was
and
the
source
of
funding.
Dr.
McMahon
remarked
that
the
Agency
had
found
the
study,
it
was
not
submitted
by
a
sponsor,
and
did
not
know
who
had
paid
for
the
research.
The
Board
also
asked
for
information
on
the
derived
sensitization
value,
the
MET
10.
Dr.
McMahon
said
that
use
of
the
MET
10
was
based
on
the
FIFRA
SAP
recommendation.
The
Agency
recognized
that
there
may
be
a
range
of
MET
values
with
repeat
exposures
but
it
was
interested
in
a
single,
albeit
conservative,
value
that
deals
with
interspecies
variability.
Thus,
that
was
the
basis
for
the
Agency
utilizing
the
MET
10
value.
Other
human
studies
had
been
considered
by
the
Agency
but
they
had
smaller
sample
sizes
and
larger
uncertainty
factors.
These
studies
were
outlined
in
the
Agency's
background
documents
but
Nethercott
et
al.
was
selected
as
the
principle
study
because
it
included
both
sexes,
had
a
high
sample
size,
and
a
good
study
design.

Mr.
John
Carley
(
OPP,
EPA)
provided
an
overview
of
EPA's
ethical
review
of
the
Nethercott
et
al.
dermal
sensitization
study
of
chromium.
The
study
of
chrome­
sensitized
subjects
was
conducted
by
six
dermatologists
to
resolve
uncertainties
resulting
from
prior
work.
The
study
contained
minimal
reporting
of
ethical
conduct.
Standards
for
inclusion
or
exclusion
were
based
on
the
scientific
goals
of
the
study
but
the
use
of
investigators'
patients
introduced
role
ambiguity
that
was
not
addressed.
Some
subjects
benefited
directly
by
learning
they
were
not
chromium­
sensitized.
The
study
authors
indicated
that
written
consent
was
received
from
all
subjects
but
consent
materials
were
unavailable.
Subject
privacy
was
not
compromised
and
11
potential
subjects
withdrew
before
testing
for
personal
reasons,
demonstrating
that
they
were
free
to
withdraw.
No
ethical
standard
of
conduct
was
cited
in
the
report
but
dermatologists
were
likely
to
be
familiar
with
HHS
(
45
CFR
Part
46
subpart
A)
and
the
Declaration
of
Helsinki
(
1989)
was
also
assumed
to
apply.
The
ethical
review
was
based
on
the
Summary
Framework
for
Ethical
Assessment
Using
Seven
Criteria
by
Emanuel
et
al.
Mr.
Carley
found
gaps
in
the
records,
but
the
gaps
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.
Mr.
Carley
found
no
clear
evidence
that
the
research
was
intended
to
harm
participants,
or
that
it
was
fundamentally
unethical
in
other
ways.
He
identified
several
deficiencies
relative
to
the
standards
of
the
Declaration
of
Helsinki
(
1989)
and
the
HHS
regulations
but
concluded
that
these
deficiencies
did
not
amount
to
clear
and
convincing
evidence
that
this
study
was
fundamentally
unethical.

Following
Mr.
Carley's
presentation,
Dr.
Fisher
asked
whether
the
Agency
had
attempted
to
gain
informed
consent
documents
or
the
IRB­
approved
study
protocol.
Mr.
Carley
said
that
4
of
34
the
Agency
doesn't
usually
seek
backup
for
published
materials.
Dr.
Fisher
asked
that
for
future
submittals,
the
Agency
should
provide
a
clear
statement
of
risk,
symptoms,
and
whether
effects
were
acute
or
chronic.
For
clarification,
Mr.
Carley
said
that
for
the
Nethercott
et
al.
study
all
subjects
were
designated
as
chrome
sensitive
so
sensitization
was
not
a
risk
factor
for
the
study.
The
highest
dose
used
was
the
level
to
diagnose
chrome
sensitivity
and
could
be
administered
in
a
doctor's
office.
Thus
minimal
risk
was
anticipated.
There
was
additional
Board
discussion
regarding
study
funding
and
subject
selection.
Finally,
the
Board
mentioned
that
the
publication
indicated
informed
consent
and
IRB
approval.
However,
the
materials
were
not
provided
for
the
Board's
consideration.

Public
Comments
Jennifer
Sass,
Ph.
D.
of
the
Natural
Resource
Defense
Council
Dr.
Sass
said
that
the
NRDC
was
so
impressed
with
the
Board's
analysis
during
its
first
meeting
that
her
comments
were
focused
on
the
decision
regarding
when
a
study
was
fundamentally
unethical
or
significantly
deficient
relative
to
prevailing
ethical
standards.
Dr.
Sass'
three
principle
points
were:

1)
A
study
need
not
be
both
fundamentally
unethical
and
significantly
deficient
relative
to
prevailing
ethical
standards
to
be
rejected.

2)
The
HSRB
had
discretion
to
determine
that
a
study
should
be
rejected
as
"
fundamentally
unethical"
even
if
the
research
was
not
intended
to
seriously
harm
participants
and
did
not
lack
informed
consent
but
was
fundamentally
unethical
for
other
reasons.

3)
Because
the
Agency's
final
human
testing
rule
required
rejection
of
a
study
that
was
significantly
deficient
relative
to
ethical
standards
prevailing
at
the
time
the
research
was
conducted,
EPA
should
reject
as
unethical
those
studies
that
did
not
document
informed
consent
if
such
documentation
was
required
by
then
prevailing
ethical
standards.
Following
Dr.
Sass's
comments,
Dr.
Fisher
assured
her
that
the
HSRB
did
not
require
a
study
be
both
fundamentally
unethical
and
significantly
deficient
to
be
rejected.
Either
condition
was
considered
grounds
for
rejection.

Charge
to
the
Board
CrVI
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
CrVI
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
resulting
from
exposure
to
chromium.
See
www.
epa.
gov/
scipoly/
sap/
2004/
final.
doc
The
5
of
34
Agency
has
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
has
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,
"
CrVI
­
Finalization
of
Issues
related
to
Quantitation
of
Dermal
Risk
from
exposure
to
treated
wood
containing
CrVI,"
August
31,
2004.

Scientific
Considerations
EPA
has
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
has
concluded
that
the
study
contains
information
sufficient
for
assessing
human
risk
resulting
from
potential
dermal
exposure.

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

Board
Response
to
the
Charge
Torkil
Menné
MD
was
introduced
by
the
HSRB
Chair,
Dr.
Fisher,
as
a
consultant
to
the
Board.
Dr.
Menné
began
by
commenting
that
he
has
35
years
of
experience
in
dermatology
and
currently
serves
as
the
editor­
in­
chief
of
the
journal
Contact
Dermatitis.
Dr.
Menné
said
that
the
Nethercott
et
al.
study
was
conducted
in
1994
but
the
methods
used
are
still
considered
acceptable
by
today's
standards.
The
aim
of
the
study
was
clear
­
to
establish
a
MET
10.
The
three­
step
study
design
allowed
subjects
to
have
minimum
elicitation
before
moving
on
to
the
next
step.
The
method
used
to
recruit
study
subjects
is
still
used
today
and
is
the
only
practical
way
to
obtain
subjects.
Standard
reading
of
patch
test
results
is
used
internationally
and
is
still
generally
agreed
to
today.
Nethercott
et
al.
recruited
102
subjects
and
54
had
a
positive
reaction.
This
is
somewhat
low
since
researchers
typically
expect
between
60­
70%
elicitations.

Dr.
Menné
responded
to
Board
questions,
specifically
about
the
MET
10,
explaining
that
when
defining
the
threshold
to
protect
those
that
are
already
sensitized,
the
MET
10
is
also
protective
of
those
that
have
not
yet
been
sensitized.

There
was
also
a
need
to
consider
that
there
will
be
some
highly
reactive
individuals.
Dr.
McMahon
said
that
the
MET
10
was
derived
from
a
dose
response
curve
and
Dr.
Menné
indicated
that
Nethercott
et
al.
used
a
graded
response
scale
which
is
an
internationally
agreed
approach.
Dr.
Menné
commented
on
the
Hanson
(
2003)
study
concluding
that
it
should
not
be
used
as
the
principle
study
because
it
used
a
different
response
grading
scale
and
had
a
low
sample
size.
In
relation
to
the
TRUE
patch
in
the
Nethercott
et.
al.
study,
he
explained
that
dose
per
unit
area
is
a
critical
finding
and
that
in
some
situations
you
could
have
absorption
over
a
larger
area
resulting
in
contact
dermatitis.
Dr.
Menné
said
that
he
believes
the
Nethercott
et.
al.
study
was
scientifically
sound
for
determination
of
the
MET
10.
Mr.
Jordan
added
that
with
respect
to
the
Nethercott
et.
al.
study,
the
Agency
needed
to
know
whether
the
study
was
robust
6
of
34
enough
develop
a
MET
at
any
percent
response.
The
percent
MET
decision
is
a
risk
management
decision
for
the
Agency.

Dr.
Fenske
led
the
Board's
discussion
characterizing
the
Nethercott
et
al.
study
as
a
wellconducted
carefully
documented
study
using
appropriate
techniques.
EPA's
review
of
the
study
was
complete
and
did
not
need
interpretation.
The
study
did
raise
some
questions
regarding
transferring
diagnostic
data
into
the
risk
management
area.
For
CrVI,
the
Agency
only
focused
on
the
principle
study.
This
was
routine,
but
the
Hanson
(
2003)
study
was
more
recent,
wellconducted
and
found
a
lower
MET.
If
the
Agency
utilized
the
Nethercott
et
al.
study
and
excluded
the
Hansen
study,
the
basis
for
this
decision
needed
to
be
well
articulated.
This
was
a
single
exposure
study
because
once
a
subject
displayed
sensitization
at
a
particular
dose,
that
was
their
end
dose
for
the
study.
Since
we
are
protecting
for
induction
versus
elicitation,
the
MET
is
conservative
for
repeated
exposures.
Dr.
Fenske
added
that
skin
surface
area
needed
to
be
considered.
The
Nethercott
et
al.
study
was
appropriate
but
a
different
reaction
may
result
following
exposure
over
a
larger
skin
surface
area.
Finally,
Dr.
Fenske
commented
that
the
use
of
the
MET
10
is
a
scientific
as
well
as
a
regulatory
decision.
Below
10%
MET,
the
data
becomes
less
usable.
From
a
scientific
perspective
this
also
needs
to
be
explained
in
the
background
document.

Dr.
Fisher
questioned
if
a
MET
was
calculated
for
any
other
percent
response
whether
the
dose
levels
would
be
different.
Dr.
Fenske
did
not
think
so,
the
study
was
conducted
with
a
set
of
doses
to
achieve
a
range
of
effects
from
no
effect
up
to
some
effect.
Dr.
Lebowitz
added
that
the
standard
deviation
increased
as
the
number
of
subjects
declined.
Dr.
Lehman­
Mckeeman
said
she
thought
Nethercott
et.
al.
was
a
high
quality
study
where
the
researchers
determined
a
priori
the
number
of
subjects
they
needed
to
achieve
a
level
of
significance.
Dr.
Krishnan
believed
that
dosing
with
patches
were
appropriate
and
the
concentrations
were
selected
based
on
previous
studies
to
cover
a
range
of
effects.
Dr.
Krishnan
commented
that
the
exclusion
of
subjects
taking
immunosuppresive
or
steroidal
medications
was
also
appropriate
and
that
the
dose
response
curve
fits
the
data
nicely.
He
concluded
that
overall
the
study
appeared
to
be
useful
but
it
was
unclear
why
a
MET
10
was
selected.

Dr.
Fisher
summarized
the
Board
deliberations
indicating
that
the
Board
believed
the
Nethercott
et
al.
study
to
be
of
high
quality,
had
an
appropriate
sample
size,
appropriate
exclusion
criteria
and
good
effect
size
criteria.
Utilizing
clinical
data
for
Agency
decisionmaking
may
require
ethical
considerations.
There
was
Board
consensus
that
the
Hanson
study
should
be
considered
in
a
WOE.
A
limitation
of
the
Nethercott
et
al.
study
was
that
it
used
a
single
dose
and
small
skin
surface
area.
While
the
MET
10
was
a
generally
accepted
endpoint,
a
rationale
for
the
selection
of
this
limit
should
be
included.

Dr.
Menné
added
that
the
Nethercott
et.
al.
study
was
based
on
accumulated
information.
The
Nethercott
et.
al.
study
was
conducted
using
a
well­
defined
method
with
occluded
patch
testing.
This
may
compensate
for
a
lack
of
repeated
open
exposures.
While
a
larger
patch
could
result
in
a
higher
degree
of
response,
there
was
no
standard
for
testing
with
larger
patches.
Dr.
Fisher
concluded
by
saying
that
it
is
not
within
the
HSRB
charge
to
set
the
limit,
but
the
Board
asked
to
say
whether
the
study
was
appropriate.
The
HSRB
believed
that
the
Nethercott
et
al.
study
was
appropriate
taking
into
account
the
considerations
noted.
7
of
34
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
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
Dr.
Philpott
led
the
Board's
discussion
of
the
ethical
considerations
of
the
dermal
sensitization
study
of
chromium.
Dr.
Philpott
said
that
he
was
unclear
who
paid
for
the
study
but
the
six
key
investigators
were
academics
at
six
separate
institutions.
The
Common
Rule
would
apply
to
this
study
including
IRB
review,
informed
consent,
and
rules
governing
selection
of
subjects.
The
study
purports
to
comply
with
IRB
review
at
each
of
the
institutions.
However
neither
the
informed
consent
nor
IRB
protocol
were
provided.
If
the
Board
had
the
consent
documents,
the
Board
might
have
recommended
that
EPA
reject
the
study.
However,
the
fact
that
it
was
approved
at
six
institutions
does
lend
some
credence.
The
Board
strongly
recommended
that
the
Agency
make
every
effort
to
obtain
informed
consent
materials
and
other
documentation.
In
terms
of
equitable
risk,
the
three­
step
study
design
allowed
for
minimization
of
risk.
Since
11
subjects
did
withdraw,
it
would
appear
that
subjects
could
withdraw
at
any
time.
EPA
considered
this
study
minimal
risk
because
the
4.4
dose
level
was
used
to
screen
for
chromium
sensitization
but
the
subject
of
minimal
risk
was
not
well
defined.
Finally,
there
was
still
some
question
as
to
whether
the
Agency
can
use
clinical
studies
like
Nethercott
et.
al.
in
a
regulatory
setting.

The
Board
commented
that
the
study
met
the
minimal
risk
standard.
Dr.
Nelson
added
that
documentation
was
not
available
and
standards
to
retain
records
varies.
How
the
research
was
presented
to
subjects
was
important
because
the
study
had
no
clinical
benefit
and
it
was
unclear
whether
the
subjects
were
patients
of
the
six
principle
researchers.

Dr.
Fisher
summarized
Board
deliberations
by
commenting
that
there
was
no
regulatory
or
legal
requirement
for
study
sponsors
to
provide
informed
consent
or
the
IRB
protocol
for
this
study.
However,
the
Agency
needs
to
make
an
effort
to
secure
the
records.
If
the
Board
did
receive
such
documents,
they
may
have
concluded
to
reject
the
study,
particularly
if
there
was
a
conflict
of
interest
with
practitioners
using
patients
in
a
study
with
no
clinical
benefits.
The
fact
that
11
people
dropped
out
of
the
study
suggested
that
recruitment
was
not
coercive.
Risk
minimization
standards
were
met
and
the
study
authors
stated
that
informed
consent
was
received.
The
study
was
not
likely
to
cause
serious
harm
to
participants
because
a
routine
8
of
34
screening
level
concentration
was
used
as
the
highest
dose.
Thus,
there
was
no
evidence
that,
even
with
documentation,
the
Board
would
recommend
that
the
Agency
reject
the
study.

Science
and
Ethics
of
the
Carbofuran
Human
Study
John
Liccione,
Ph.
D.
(
OPP,
EPA),
and
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA)
presented
a
WOE
report
on
the
study
designs,
methods,
and
results
of
three
different
human
studies
(
human
oral
study
[
1976],
human
dermal
study
[
1977]
and
human
dermal
study
[
1978]).
OPP
proposed
to
use
these
data
in
both
the
single
chemical
assessment
and
the
NMC
cumulative
assessments.
Dr.
Liccione
began
by
explaining
that
all
three
studies
were
conducted
by
the
Quincy
Research
Center,
in
Kansas
City,
Missouri
in
1976,
1977
and
1978.

The
human
oral
study
(
Arnold
1976)
was
designed
to
determine
the
threshold
toxicity
level
in
normal
male
volunteers
to
single
oral
doses
of
carbofuran.
The
Agency
performed
a
benchmark
(
BMD)
analysis
of
this
human
study
as
part
of
the
NMC
cumulative
assessment
and
calculated
a
BMDL10
of
0.026
mg/
kg
(
BMD10
of
0.039
mg/
kg).

The
human
dermal
study
(
Arnold
1977)
was
conducted
to
determine
the
threshold
toxicity
level
of
carbofuran
under
normal
and
elevated
temperature
and/
or
humidity.
The
Agency
believed
that
the
study
had
value
in
that
it
attempted
to
understand
dermal
absorption
and
possible
toxicity
to
carbofuran
under
high
heat
and
humidity
conditions
that
may
exist
in
certain
occupational
settings
(
e.
g.,
outdoor
agricultural
working
conditions).
Thus,
the
Agency
concluded
that
these
data
may
be
useful
in
a
hazard
assessment
as
a
point
of
departure.

The
second
human
dermal
study
(
Arnold
1978)
was
to
compare
the
effects
of
single
cutaneous
applications
of
two
different
carbofuran
formulations
in
workers
exposed
to
high
temperature
and
humidity.
The
study
designs
were
similar
between
the
two
dermal
studies,
with
the
major
difference
between
the
two
being
use
of
the
material
(
75%
carbofuran
in
Arnold
1977;
4%
carbofuran
in
Arnold
1978).
Together,
the
two
dermal
studies
suggested
a
dermal
LOAEL
of
0.5
mg/
kg
based
on
RBC
ChEI
at
the
expected
peak
time
(
3­
4
hours)
with
the
appropriate
recovery
over
the
next
six
hours.
Thus,
this
dose
may
be
used
as
a
point
of
departure
for
an
appropriate
occupational
dermal
exposure
scenario.

Elissa
Reaves
provided
a
brief
explanation
of
key
changes
to
the
approaches
used
by
EPA
to
assess
risks
to
pesticides
as
implemented
in
response
to
the
1996
Food
Quality
Protection
Act.
One
of
these
changes
was
the
requirement
to
consider
cumulative
risks
of
pesticides
which
act
by
a
common
mechanism
of
toxicity.
EPA
considered
the
n­
methyl
carbamate
(
NMC)
pesticides
as
a
common
mechanism
group
and
in
accordance
with
FQPA,
and
has
developed
a
preliminary
cumulative
risk
assessment
for
this
group
of
pesticides.
Carbofuran
is
a
member
of
the
NMC
common
mechanism
group.

Because
data
from
rat
studies
provide
the
basis
for
NMC
potency
determinations,
the
Agency
needed
to
consider
interspecies
extrapolation
(
i.
e.,
animal
to
human)
in
its
cumulative
risk
assessment
for
carbofuran.
Human
data
may
be
used
by
the
Agency
to
inform
the
pesticidespecific
interspecies
extrapolation.
9
of
34
Following
the
presentations
on
the
scientific
aspects
of
the
carbofuran
human
studies,
Dr.
Lehman­
Mckeeman
asked
whether
the
dermal
data
will
be
used
in
the
BMD
calculations
and
how
the
Agency
would
statistically
evaluate
a
study
with
a
sample
size
of
two.
Dr.
Fisher
asked
how
an
n=
2
could
be
scientifically
acceptable.
Dr.
Lowit
replied
that
the
BMD
analysis
was
still
in
draft
form
but
by
looking
at
all
the
data,
the
BMD
analysis
gains
robustness.
Dr.
Lehman­
Mckeeman
also
requested
clarification
on
the
dermal
absorption
of
carbofuran.
Dr.
Krishnan
noted
that
the
study
showed
10%
AChEI
in
the
control
group
and
asked
whether
this
was
accounted
for
in
the
BMD
analysis.
Dr.
Lowit
said
that
the
BMD
analysis
accounts
for
both
group
and
individual
AChEI.

Dr.
Fenske
expressed
the
Board's
concern
about
these
studies'
low
sample
size.
The
Board
received
no
information
about
lab
variability
with
respect
to
AChEI
measurements
and
with
a
small
control
group
this
was
important.
Dr.
Fenske
questioned
the
appropriate
level
of
loading
on
the
skin
(
mass
per
unit
area)
necessary
to
estimate
a
NOAEL/
LOAEL.

Mr.
Carley's
summary
of
EPA's
ethics
review
for
carbofuran
began
indicating
that
all
three
carbofuran
human
studies
were
overseen
and
approved
by
Community
Review
Committee,
Inc.
All
three
studies
had
explicit
informed
consent,
all
drew
from
a
pool
of
semi­
skilled
unemployed
workers
and
all
were
designed
to
continue
dose
escalation
until
toxic
signs
were
evident.
For
all
three
studies
there
were
some
gaps
in
the
record,
but
the
gaps
were
not
clear
and
convincing
evidence
of
ethical
deficiencies.
No
children
or
pregnant
female
subjects
were
used
and
there
was
no
evidence
that
the
research
was
fundamentally
unethical.
All
three
studies
had
inadequate
information
to
support
informed
consent
and
some
deficiencies
relative
to
the
Declaration
of
Helsinki
(
1975).

Dr.
Fisher
asked
if
there
had
been
any
voluntary
withdrawal
of
subjects.
Mr.
Carley
commented
that
five
subjects
received
atropine
but
none
withdrew
even
though
the
consent
form
said
a
subject
could
withdraw
at
any
time.

Public
Comments
Donald
Carson,
Ph.
D.
and
Ms.
Jane
McCarty
of
FMC
Corporation
Donald
Carlson,
Ph.
D.
presented
comments
in
support
of
the
conclusion
that
the
carbofuran
human
studies
met
scientific
and
ethical
standards
and
that
they
were
useful
as
a
point
of
departure
for
carbofuran
toxicity.
The
studies
were
conducted
to
improve
occupational
health
by
trying
to
emulate
worker
conditions
of
high
heat
and
humidity.
The
studies
were
reviewed
by
an
outside
group
with
no
financial
relationship
to
the
lab.
Subjects
were
notified
of
risks
and
were
monitored
throughout
the
study.
Ms.
McCarty
added
that
with
high
heat
and
humidity,
toxic
effects
were
noted
at
lower
doses
and
the
symptom
of
nausea
may
have
been
due
to
heat
exhaustion,
not
carbofuran
toxicity.
Ms.
McCarty
also
said
that
the
high
temperature
and
humidity
conditions
were
artificially
high,
and
that
moderate
conditions
were
considered
to
be
more
relevant.
She
concluded
that
the
studies
were
ethical
and
scientifically
valid
and
should
be
used.
10
of
34
Dr.
Lehman­
Mckeeman
questioned
Dr.
Carlson
on
small
sample
sizes.
Dr.
Carlson
responded
that
the
subject
numbers
were
lower
because
the
study
was
designed
to
reduce
worker
risk
in
a
manufacturing
environment.
Other
questions
raised
by
the
Board
included
prevalence
of
smokers
in
the
study
population,
determinations
of
atropine
use,
administration
and
relevance
of
high
temperature
and
humidity
to
actual
field
conditions.

Jennifer
Sass,
Ph.
D.
of
the
Natural
Resources
Defense
Council
Dr.
Sass
commented
that
the
use
of
the
oral
exposure
human
study
(
Arnold,
1976)
by
EPA
was
predicated
on
the
presumption
that
there
were
no
differences
in
response
between
sexes.
However,
EPA's
own
analysis
of
a
chronic
oral
dog
study,
used
by
the
Agency
in
its
September,
2005
human
health
assessment
to
establish
a
lowest­
effect
level,
established
the
male
as
more
sensitive
than
the
female.
The
Agency's
assessment
failed
to
mention
that
1
of
the
6
male
dogs
in
the
high
dose
group
(
500
ppm)
died
during
the
study
and
the
Agency's
Data
Evaluation
Record
reported
very
severe
effects
at
necropsy.
These
effects
deserve
discussion
and
consideration.
These
data
may
indicate
that
some
individuals
are
much
more
sensitive
to
carbofuran
toxicity
than
others,
and
that
males
are
more
sensitive
than
females.
Thus,
this
may
have
implications
for
human
sensitivity
patterns
not
captured
in
the
human
studies.

Charge
to
the
Board
Scientific
Considerations
The
Agency's
WOE
document
and
DERs
for
carbofuran
describe
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
are
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.

Board
Response
to
the
Charge
Dr.
Lehman­
Mckeeman
initiated
Board
deliberations
on
carbofuran
commenting
with
respect
to
using
the
oral
study
for
BMD
analysis,
the
low
sample
size
puts
a
greater
strain
on
the
data.
These
studies
have
a
single
baseline
reading,
highly
variable
AChEI
levels,
and
use
of
a
modified
Ellman
assay
with
a
different
substrate,
all
factors
further
reducing
the
confidence
with
the
data.
Dr.
Lehman­
Mckeeman
recommended
not
using
this
study.
The
two
dermal
studies
conducted
at
high
temperature
and
humidity
were
limited
but
could
be
used
qualitatively.
More
importantly,
as
a
review
board,
it
should
be
hesitant
to
conclude
that
any
study
with
a
sample
size
of
two
would
be
scientifically
valid.

Drs.
Fisher
and
Dr.
Lehman­
Mckeeman
discussed
whether
the
expected
comparison
between
oral
and
dermal
studies
could
be
used
as
a
validity
marker
and
if
the
effects
at
high
temperature
and
humidity
could
have
been
due
to
exercise
or
carbofuran
toxicity.
Dr.
Carriquiry
stated
that
in
addition
to
the
limitations
of
data,
there
was
a
lack
of
proper
statistical
11
of
34
analysis
and
an
appropriate
dose
response
curve
that
considered
the
compound
being
applied
under
a
variety
of
conditions.
Dr.
Lowit
stated
that
the
BMD
was
the
lower
bound
for
confidence
limits
but
Dr.
Carriquiry
felt
that
for
this
study,
the
error
bars
must
have
been
very
large.
Dr.
Lebowitz
questioned
use
of
a
statistical
analysis
that
takes
two
subjects
and
develops
a
number
with
some
measure
of
goodness
of
fit.
Dr.
Fenske
expressed
concerned
with
the
appropriateness
of
the
study
design
for
workplace
exposure
because
dermal
exposure
is
a
function
of
mass
per
unit
area
and
the
time
of
exposure.
The
flux
across
the
skin
would
increase
somewhat
as
a
function
of
concentration,
but
not
much.
Mass
per
unit
area
per
unit
of
time
is
what
counts.
If
you
spread
the
doses
out
over
a
larger
surface
area
(
i.
e.
area
of
the
hands)
your
potential
for
a
higher
dose
would
be
much
greater.

Dr.
Fisher
summarized
general
scientific
concerns
including
the
small
sample
size
which
was
insufficient
to
enable
statistical
analysis.
The
experimental
method
was
not
validated.
Dr.
Lowit
commented
on
the
low
sample
size
saying
that
if
a
response
was
not
noted,
you
have
to
ask
whether
the
sample
size
was
too
small.
If
you
do
see
a
response,
the
lower
bound
on
the
BMD
was
significantly
lower
than
the
NOEAL.
In
the
absence
of
the
BMD,
we
don't
have
these
confidence
limits
to
help
understand
the
toxicities
of
the
compound.
Mr.
Housenger
(
OPP,
EPA)
said
that
the
Agency
was
confused
because
for
the
HSRB's
review
of
amitraz
at
its
April
2006
meeting,
the
Board
approved
the
metabolism
study
that
had
an
n=
2.
Dr.
Fisher
explained
that
the
HSRB
did
not
determine
a
sample
size
that
was
acceptable
for
all
studies.
In
addition,
Dr.
Fisher
commented
she
recalled
that
the
Board
was
very
unhappy
with
the
n=
2.
Dr.
Fisher
added
that
the
Board
indicated
the
single
dose
oral
amitraz
study
did
not
support
the
determination
of
a
NOAEL.
The
Board's
report
was
not
completed
but
this
issue
will
be
clarified
in
its
final
report.
Dr.
Fisher
asked
Drs.
Fenske,
Lebowitz
and
Krishnan
to
look
over
Board
notes
and
draft
report
with
respect
to
the
amitraz
conclusions
in
relation
to
the
Board's
recommendations
on
the
carbofuran
studies.
Dr.
Lehman­
Mckeeman
provided
clarification
on
amitraz
explaining
that
the
metabolism
study
was
very
different
than
the
single
oral
dose
study.
There
was
a
larger
sample
size
at
lower
doses
and
it
was
controlled,
so
the
situations
were
fundamentally
different.

For
the
reasons
cited
above,
the
Board
reached
a
decision
that
quantitative
use
of
the
oral
carbofuran
study
was
poor
science.
From
a
qualitative
perspective,
it
may
be
helpful
as
a
point
of
departure
for
NOAEL/
LOEAL
determination.
Oral
and
dermal
comparisons
were
in
agreement
since
the
dermal
studies
were
more
consistent
than
the
oral
study.
Investigators
were
more
focused
on
high
end
rather
than
low
end
which
may
not
have
considered
the
mass
per
unit
area
effect
on
dermal
flux
rate.
Although
the
dermal
studies
were
conducted
under
different
conditions,
with
a
sample
size
of
two
and
highly
variable
AChEI
results,
there
was
no
support
for
the
scientific
usefulness
of
these
data.

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
any
of
the
human
studies
conducted
with
carbofuran
was
fundamentally
unethical?
12
of
34
b.
Is
there
clear
and
convincing
evidence
that
the
conduct
of
the
studies
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted?

Board
Response
to
the
Charge
Dr.
Nelson
led
the
Board's
discussion
for
ethical
considerations
of
carbofuran
human
studies.
The
following
comments
apply
to
all
three
studies.
The
fact
that
the
studies
were
not
published
does
not
imply
they
were
unethical.
Including
a
supervisory
physician,
requiring
abstinence
from
alcohol
and
cigarettes,
monitoring
for
24
hours,
and
treatment
with
atropine
are
all
risk
minimization
techniques.
The
fact
that
the
study
was
designed
to
determine
cholinergic
signs
was
not
unethical.
The
question
was
whether
the
risks
were
justified.
Informed
consent
materials
failed
to
describe
dose
escalation
study
design
and
a
description
of
symptoms.
For
the
dermal
study,
was
it
appropriate
to
expose
additional
subjects
to
a
LOAEL
level?
The
low
sample
size
in
the
previous
study
made
findings
questionable.
Information
was
not
provided
for
IRB
approval
of
dose
doubling
up
to
32.
Mention
was
made
for
the
administration
of
atropine
but
there
was
no
justification
for
the
delay
in
atropine
administration
for
1.5
to
2
hours
after
cholinergic
impacts.
For
the
oral
study,
there
was
no
clear
and
convincing
evidence
that
the
study
was
fundamentally
unethical
and
no
significant
deficiencies.
For
the
dermal
studies,
there
was
no
clear
and
convincing
evidence
that
the
study
was
fundamentally
unethical
in
that
it
intended
to
seriously
harm
participants
without
informed
consent.
The
delay
on
atropine
administration
for
the
amelioration
of
side
effects
was,
in
fact,
a
significant
deficiency
that
could
have
resulted
in
serious
harm.
Thus,
Dr.
Nelson
concluded
that
the
dermal
studies
should
not
be
used
from
an
ethical
perspective
based
on
the
criteria
provided.

Dr.
Philpott
agreed
with
Dr.
Nelson
that
the
oral
study
was
not
fundamentally
unethical
and
had
no
obvious
serious
deficiencies.
The
dermal
studies
raised
some
serious
questions.
For
the
1978
dermal
studies,
the
informed
consent
materials
diminished
risks
that
were
documented
by
the
1977
dermal
study.
It
seems
unreasonable
to
double
the
dose
from
2
mg/
kg
to
4
mg/
kg
dose
and
elicit
clinical
effects
severe
enough
to
require
treatment
with
atropine.
The
second
acute
dermal
study
was
fundamentally
unethical
because
of
the
downplaying
of
the
risks,
given
the
conclusions
of
the
1976
study,
along
with
doubling
the
dose
level.
The
informed
consent
materials
for
the
later
dermal
study
did
not
include
information
from
the
earlier
study
and
were
deceptive.
The
studies
were
designed
to
elicit
toxic
results
and
the
subjects
were
not
told
that
the
dose
would
escalate
until
a
toxic
effect
was
noted.

Dr.
Fisher
summarized
the
Board's
conclusions.
The
oral
study
was
not
fundamentally
unethical
nor
did
it
have
serious
deficiencies
that
would
cause
harm
or
impair
informed
consent.
The
Board
believed
that
the
dermal
studies
were
not
fundamentally
unethical
because
they
did
not
intend
to
cause
harm
and
they
did
obtain
informed
consent.
The
Board
noted
several
problems
with
the
dermal
studies
in
that
even
after
the
1977
study
identified
serious
side­
effects,
there
was
no
effort
to
minimize
these
risks
in
the
second
study.
The
increase
to
32
mg/
kg
dose,
and
not
following
the
protocol,
was
not
an
attempt
to
minimize
risk
but
could
have
caused
significant
harm.
There
was
a
delay
in
the
administration
of
atropine
which
was
a
serious
deficiency
and
could
have
harmed
subjects.
There
also
were
serious
deficiencies
with
informed
consent.
Irrespective
of
what
information
was
given,
when
they
are
called
risks
but
are
actually
13
of
34
known
effects,
the
subjects
should
be
told
of
the
consequences.
The
Board
believed
the
study
was
seriously
deficient
because
the
informed
consent
materials
described
potential
risks.
However
these
effects
were
to
occur
because
the
sponsor
was
studying
for
toxicity.
Dr.
Lebowitz
wanted
to
emphasize
that
when
you
cause
harm,
you
must
do
everything
in
your
power
to
reduce
it.
This
is
an
important
ethical
principle.
The
first
dermal
study
was
deficient
due
to
the
dose
escalation
and
delay
in
atropine,
the
second
dermal
study
was
deficient
with
respect
to
informed
consent.
Thus,
the
Board
was
unhappy
with
both
dermal
studies
for
different
reasons.
These
studies
were
not
conducted
with
sufficient
concern
and
monitoring.

HSRB
Science
Criteria
for
Intentional
Human
Dosing
Studies
Before
discussion
of
methyl
isothiocyanate,
Dr.
Fisher
led
the
Board
in
a
discussion
of
general
criteria
needed
to
be
applied
when
determining
whether
a
study
was
scientifically
credible.
Such
criteria
included
sample
size
and
inclusion/
exclusion
criteria.
Dr.
Nelson
added
that
if
there
were
available
surrogates
that
were
protective
of
downstream
effects,
surrogates
should
always
be
chosen
as
opposed
to
exposing
a
subject
to
toxic
effects.
With
small
sample
sizes,
the
lower
end
of
the
confidence
interval
could
be
used
to
describe
a
NOAEL
at
zero.
Dr.
Fisher
said
that
these
were
helpful
examples
but
that
the
criteria
won't
just
apply
to
pesticide
toxicity
studies.
The
use
of
a
RBC
AChEI
is
an
obvious
example
of
a
biomarker
or
surrogate
endpoint
that
could
be
used
rather
than
pushing
to
a
clinical
effect
that
may
pose
more
risk
to
human
subjects.
With
respect
to
endpoints,
Dr.
Lebowitz
stated
the
endpoint
needs
to
be
consistent
with
the
aim
of
research
and
that
route
and
pathway
of
exposure
also
needs
to
be
considered.
Dr.
Carriquiry
noted
that
some
of
these
issues
raised
by
the
Board
were
addressed
by
the
National
Academy
of
Science
(
NAS)
report
on
intentional
dosing
but
what
was
not
mentioned
by
the
Board
was
the
need
for
the
study
in
the
first
place.
Scientific
justification
must
be
provided
and
reduction
or
elimination
of
the
interspecies
uncertainty
factor
is
not
sufficient
justification
for
undertaking
an
intentional
human
dosing
study.

Dr.
Fisher
pointed
out
that
the
NAS
report
did
outline
some
key
scientific
criteria
for
human
studies
including:

1)
Endpoint
selection
described
in
relation
to
study
objectives;

2)
Dose
selection
to
allow
for
the
characterization
of
the
dose­
response
curve;

3)
Participant
selection
consistent
with
the
study
objectives
and
including
subjects
of
both
genders
when
possible;

4)
The
study
method
should
demonstrate
that
there
was
adequate
power
to
detect
relevant
changes
in
the
endpoint;

5)
Dosing
and
measurement
schedules
that
are
scientifically
supported
and
consistent
with
the
study
objectives
Dr.
Fenske
felt
that
the
NAS
list
of
scientific
issues
was
helpful
but
doesn't
address
single­
dose
studies
or
studies
with
women
and
children.
Dr.
Fisher
felt
that
the
list
was
helpful
14
of
34
but
for
retrospective
analysis
not
all
the
criteria
need
to
be
met.
For
example,
for
carbofuran
there
wasn't
a
single
fatal
flaw
but
many
deficiencies
overall.

Dr.
Carriquiry
could
not
determine
the
scenario
where
a
single
dose
study
could
be
helpful.
Dr.
Lebowitz
clarified
that
a
single
dose
study
was
one
with
a
single
dosing
level
but
that
dosing
may
occur
more
than
once.
He
stated
that
with
meta­
analysis,
the
single
dose
study
could
inform
a
point
of
departure.
Dr.
Fisher
added
that
if
a
prior,
single­
dose
study
indicated
that
what
was
thought
to
be
a
safe
level,
was,
in
fact,
unsafe,
we
should
use
this
information.
Dr.
Nelson
stated
that
the
carbofuran
study
illustrated
a
disconnect
of
objectives.
The
study
may
have
been
reasonable
from
an
industrial
hygiene
perspective,
but
not
for
the
questions
brought
before
the
Board.
Dr.
Fisher
said
the
question
was
whether
human
studies
are
being
used
to
insure
higher
tolerance
limits
or
are
they
needed
to
be
protective
of
a
human
population.
There
were
three
questions
for
consideration:
1)
Is
the
scientific
question
worthwhile;
2)
Are
human
subjects
required
to
answer
the
question;
and
3)
Has
the
probability
of
serious
harm
been
considered
and
is
it
reversible.
Study
methods
need
to
consider
such
factors
as
route
of
exposure
and
sample
size.
Dr.
Nelson
stated
that
not
all
of
these
criteria
can
be
applied
prospectively
and
Dr.
Carriquiry
felt
the
list
should
include
confounding
factors.
Dr.
Krishnan
believed
impurities
and
compound
formulation
should
be
included
under
methods.
Dr.
Fisher
added
that
these
criteria
can
be
judged
individually
or
together.

Dr.
Fisher
reviewed
the
Board's
discussion
of
general
criteria
that
need
to
be
applied
when
determining
whether
a
study
is
scientifically
credible.
There
were
several
ways
for
the
Board
to
approach
the
Agency's
charge
to
the
Board.
First,
the
Board
could
be
involved
in
how
the
calculations
were
made
but
this
is
probably
not
a
role
for
the
Board.
Second,
the
Board
would
make
a
recommendation
on
the
specific
question(
s)
for
consideration,
a
role
the
Board
would
continue.
On
the
overall
issue
of
going
beyond
the
charge
to
the
Board,
the
Board
would
take
the
liberty
of
making
recommendations
when
the
data
provided
to
the
Board
was
applicable.
While
the
Agency's
documents
have
been
clear,
the
Board
would
appreciate
more
information
on
the
goals
of
the
Agency
with
respect
to
how
the
Board's
recommendations
would
be
used.

A
related
question
was
whether
the
HSRB
was
setting
precedence
with
respect
to
the
validity
of
the
type
of
study
they
evaluate
(
e.
g.
a
single­
dose
study
with
two
subjects).
Dr.
Fisher
indicated
that
each
HSRB
decision
was
made
within
the
context
of
the
HSRB
Chair's
criteria
identified
previously
as
well
as
future
criteria
the
Board
may
develop.
However,
each
study
may
differ
in
terms
of
whether
it
does
or
does
not
meet
these
criteria
based
upon
a
complex
of
factors
including
the
particular
compound,
dosing,
and
power
calculation 
none
of
these
factors
can
be
judged
out
of
context.
Dr.
Fisher
noted
that
the
Agency
and
public
should
know
that
only
in
rare
incidences
would
the
Board
regard
low
sample
sizes
or
single
dose
studies
as
meaningful.

The
Board
provided
additional
clarification
concerning
its
review
of
amitraz.
First,
no
decision
is
made
by
the
Board
until
the
report
is
final.
An
initial
question
was
whether
the
studies
would
be
applicable
to
assessing
acute
dietary
risk.
In
this
regard,
the
two
subject
single
dose
study
was
not
considered
sufficient
to
answer
this
question.
The
second
study,
in
and
of
itself,
was
not
sufficient
to
provide
information
to
set
risk
levels.
The
first
study
showed
adverse
effects
at
the
highest
dose
level
while
the
second
study
showed
no
adverse
effects.
The
Board
would
not
normally
consider
the
no
effects
of
the
second
study
but
the
two
studies
together
were
15
of
34
valid
to
establish
an
acute
dietary
risk.
There
was
also
a
question
about
chronic
risk.
The
Board
will
insure
their
report
provide
clarity
in
their
response
to
this
question.

Mr.
Jordan
summarized
his
interpretation
of
the
Board's
conclusions
on
carbofuran.
He
also
said
the
Agency
required
clarity
about
alternative
means
of
using
the
carbofuran
data.
He
then
proceeded
to
provide
background
on
applicability
of
data
in
a
risk
assessment.
Mr.
Jordan
presented
four
different
points
of
how
the
data
could
be
used
in
risk
assessment:
1)
The
BMD
approach
used
all
the
data
points
and
appropriate
modeling
techniques
to
estimate
the
dose
level
at
which
a
percentage
of
a
population
would
respond
in
a
particular
fashion;
2)
establishing
a
NOAEL,
apply
UFs,
and
get
to
an
RfD;
3)
select
a
LOAEL
when
effects
were
noted
at
all
dose
levels,
apply
UFs
to
take
into
account
the
severity
of
effects
to
derive
an
RfD;
and
4)
human
data
could
be
used
to
make
an
adjustment
to
account
for
interspecies
sensitivity.
If
the
LOAEL/
NOAEL
from
animal
studies
was
selected,
appropriate
uncertainty
factors
are
applied
and
may
include
a
10X
interspecies
UF.
If
both
animal
and
human
data
are
applied,
the
human
data
may
allow
the
Agency
to
draw
a
conclusion
with
respect
to
the
relative
sensitivity
of
humans
compared
to
animals.
Thus,
a
different
interspecies
UF
may
be
applied
(
i.
e.
5X
or
3X
more
sensitive).

The
carbofuran
study
did
show
clear
treatment
related
signs
at
the
high
end
dose
level
that
were
consistent
with
findings
from
the
animal
studies.
Therefore,
the
Agency's
believed
there
was
clear
evidence
that
the
clinical
signs
were
treatment
related.
The
Agency
requested
the
Board's
advice
on
whether
it
was
appropriate
to
consider
clinical
signs
from
carbofuran
to
inform
an
interspecies
UF.
Dr.
Lowit
added
that
the
risk
assessment
process
can
be
divided
into
risk
management
and
risk
mitigation.
The
risk
assessment
is
a
calculation
of
risk
and
to
help
risk
managers
understand
risk.
In
the
case
of
carbofuran,
the
Agency
can
rely
heavily
on
the
animal
data
base,
or
can
use
human
data
to
look
at
the
clinical
signs
from
the
human
data
as
a
LOAEL
or
NOAEL
and
describe
the
relative
confidence
we
have
in
these
values.
Conversely,
the
Agency
could
look
at
what
the
AChEI
data
was
indicating.
The
BMD
analysis
accounts
for
low
sample
sizes
and
low
number
of
doses.
The
Agency
wants
a
number
that
would
protect
a
large
portion
of
the
population.
By
looking
at
the
error
bars
on
the
BMD
for
the
carbofuran
study,
the
Agency
expects
them
to
be
very
large
and
the
lower
limit
to
be
low.

Dr.
Lehman­
Mckeeman
commented
that
it
was
clear
the
carbofuran
study
was
done
specifically
to
determine
effects
and
how
to
treat
subjects
in
the
industrial
setting.
Given
how
the
study
was
designed,
we
may
be
trying
to
force
fit
these
data
into
a
model
where
they
were
not
applicable.
The
relation
of
RBC
AchEI
was
not
established
by
the
study.
The
oral
study
did
show
a
steep
dose
response
curve
creating
additional
uncertainty.
The
strength
of
the
BMD
modeling
was
using
all
the
data
points.
The
Board
did
not
see
the
calculations
but
would
have
considerable
uncertainty
about
this
analysis.
The
carbofuran
study
doesn't
help
identify
LOAEL/
NOAEL
with
any
real
assurance.
Dr.
Carriquiry
felt
there
was
a
serious
lack
of
information
at
the
lower
dose
levels
and
that
there
simply
wasn't
enough
power
in
the
data.
While
Dr.
Fitzpatrick
believed
that
the
data
may
have
some
qualitative
value,
Dr.
Fenske
said
that
the
BMD
approach
lays
out
a
different
question
than
the
NOAEL/
LOAEL
approach.
Part
of
the
science
needed
is
to
see
how
the
BMD
methodology
works.
Dr.
Fisher
stated
that
the
statistics
required
for
confidence
intervals
suggested
this
was
of
little
importance.
She
added
16
of
34
that
the
data
was
incredibly
limited
and,
as
agreed
by
the
Board,
of
poor
quality.
The
Board
suggested
the
Agency
use
much
caution
regarding
the
scientific
validity
of
this
data.

Science
and
Ethics
of
Methyl
Isothiocyanate
(
MITC)
Human
Studies
Dr.
Lowit
provided
the
WOE
presentation
for
MITC.
MITC
can
be
used
as
a
pesticide
directly
to
treat
wood
poles
and
is
also
a
key
degradate
of
several
fumigant
pesticides
(
i.
e.,
metam
sodium,
metam
potassium
and
dazomet).
It
is
believed
that
MITC
provides
the
fumigating
properties
of
the
parent
active
ingredients.
Acute
inhalation
exposures
to
bystanders
and
workers
appear
to
present
the
greatest
risk
concern.
The
Agency's
risk
assessments
for
metam
sodium,
metam
potassium,
dazomet,
and
MITC
have
relied
on
the
MITC
eye
irritation
study
as
the
basis
for
the
point
of
departure
for
acute
inhalation
exposures
to
by­
standers
and
occupational
workers
from
off­
gassing
of
MITC.
In
accordance
with
the
human
studies
rule,
the
Agency
is
asking
the
HSRB
to
review
the
scientific
conduct
and
design
of
the
eye
irritation
study
and
its
potential
utility
in
assessing
human
health
risk.

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.
The
majority
of
animal
studies
available
for
metam
sodium/
potassium,
dazomet,
and
MITC
are
for
oral
exposure
and
are
not
considered
relevant
for
assessing
acute
inhalation
exposure
for
MITC.
At
the
present
time,
the
data
base
of
acceptable
animal
inhalation
toxicology
studies
for
MITC
is
very
limited.
There
are
no
studies
with
laboratory
animals
available.
In
order
to
evaluate
the
human
odor
threshold
and
eye
irritation
produced
by
MITC
vapors,
human
volunteers
were
exposed
to
air
concentrations
of
MITC
in
a
laboratory
setting.

Due
to
the
limitations
in
the
existing
inhalation
toxicology
database
for
MITC,
the
degree
to
which
eye
irritation
predicts
more
serious
outcomes
was
unclear.
However,
given
that
humans
exposed
to
MITC
complain
of
symptoms
such
as
itchy
and
burning
eyes
in
addition
to
rash
and
burning
skin,
nausea,
scratchy
throat,
salivation,
coughing,
and
shortness
of
breath,
in
the
absence
of
more
robust
dose­
response
data
from
acute
exposures,
eye
irritation
can
be
considered
as
a
biomarker
and
surrogate
for
potential
respiratory
effects.
The
results
of
the
odor
threshold
study
indicated
that
the
eyes
were
likely
to
become
irritated
prior
to
detecting
the
odor;
thus
the
odor
threshold
study
was
not
be
used
to
derive
the
point
of
departure.
The
human
eye
study
provided
a
dose
and
time­
related
response
to
MITC
for
the
subjective
scale
and
the
blinking
rate.
Thus,
the
Agency
selected
the
human
eye
irritation
study
as
the
basis
for
the
point
of
departure
in
acute
risk
assessment
to
MITC
in
air.

Following
the
presentation,
Dr.
Lebowitz
asked
for
clarification
on
the
Agency's
objection
to
the
study
design
using
goggles.
Dr.
Lowit
explained
that
the
study
design
did
not
inform
relative
sensitivity
for
other
endpoints,
such
as
throat
irritation.
Even
though
the
acetic
acid
positive
control
data
weren't
considered
reliable,
the
data
should
have
been
reported.
The
Board
did
not
know
which
subjects
were
used
twice
and
no
information
was
available
on
whether
one
gender
or
age
group
was
more
sensitive.
The
Agency
agreed
that
they
should
seek
the
raw
data
for
the
eye
irritation
study.
Dr.
Philpott
asked
how
evidence
that
MITC
was
a
17
of
34
dermal
sensitizer
was
factored
into
the
Agency's
analysis
of
the
study
results.
Dr.
Lowit
said
that
dermal
sensitization
would
be
addressed
through
labeling
instructions
but
not
in
the
risk
assessment.
The
risk
assessment
does
not
consider
dermal
sensitization.

John
Carley
(
OPP,
EPA)
provided
a
summary
the
Agency's
ethical
review.
The
review
characterized
the
ethical
conduct
of
the
research
in
terms
of
both
current
ethical
standards
and
ethical
standards
prevailing
when
the
studies
were
conducted.
Mr.
Carley
also
applied
the
Summary
Framework
for
Ethical
Assessment
Using
Seven
Criteria
(
Emanuel
et
al.)
to
complete
a
summary
assessment
of
the
ethical
conduct
of
both
the
odor
threshold
and
the
eye
irritation
study.

The
Agency
was
not
proposing
to
use
the
odor
threshold
study
but
background
was
provided
because
some
supplemental
material
applied
to
the
eye
irritation
study.
The
odor
threshold
study
followed
a
spill
of
MITC
into
the
Sacramento
River
in
1990
and
the
mailing
of
a
scratch­
and­
sniff
survey
conducted
by
National
Geographic.
There
was
no
documentation
of
the
IRB­
approved
protocol
or
informed
consent
for
the
olfactometer
study.
The
study
was
a
binary
response
study
(
i.
e.
positive
or
negative
response
for
the
presence
of
smell).
The
eye
irritation
study
was
better
documented.
Informed
consent
materials
for
the
eye
irritation
study
were
brief,
but
clear.

Mr.
Carley
reviewed
the
risk
matrix
for
the
eye
irritation
study
and
the
odor
threshold
study.
For
the
odor
threshold
study,
Mr.
Carley
noted
numerous
ethical
deficiencies
with
respect
to
the
principles
of
the
Declaration
of
Helsinki
(
1989),
with
which
the
author
asserted
compliance
and
the
Common
Rule.
For
the
eye
irritation
study,
Mr.
Carley
identified
only
minor
deficiencies
relative
to
the
standards
of
the
1989
Declaration
of
Helsinki
and
the
Common
Rule.
One
of
the
central
issues
was
whether
the
subjects
were
adequately
informed.
This
was
not
known
since
the
Agency
did
not
have
informed
consent
documents.
In
Mr.
Carley's
judgment,
the
deficiencies
noted
do
not
amount
to
clear
and
convincing
evidence
that
the
studies
were
fundamentally
unethical.

Following
Mr.
Carley's
presentation,
there
was
limited
Board
discussion
regarding
the
adequacy
and
availability
of
study
documents.

Public
Comments
None
Charge
to
the
Board
Scientific
Considerations
for
MITC
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
has
concluded
that
the
odor
threshold
study
is
less
useful
than
the
eye
irritation
study
for
18
of
34
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
has
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
Dr.
Lebowitz
initiated
discussion
for
the
Board
saying
that
the
Agency's
WOE
presentation
discussed
the
Agency's
conclusion
that
the
eye
irritation
study
was
useful
for
assessing
the
effects
of
short­
term
exposures
to
MITC,
yet
the
mode
of
toxic
action
for
MITC
was
not
known.
The
experimental
design
for
the
eye
irritation
study
was
excellent.
Data
were
sufficient
to
estimate
LOAELs/
NOAELs
and
comparisons
were
made
to
air
control
and
zerotime
control.
The
study
excluded
people
with
eye
irritation
but
not
those
with
environmental
eye
irritation.
The
LOAEL
for
eye
irritation
would
not
protect
for
inhalation
response.
Dr.
Fish
added
that
the
study
had
more
than
two
subjects,
but
how
the
number
of
subjects
was
selected
was
unclear.
The
study
included
no
power
calculations
so
the
NOAEL
may
be
uninformative
null.
Had
a
repeated
measures
analysis
been
done,
subjects
reaching
the
threshold
of
sensitivity
may
not
have
been
positive.
Dr.
Fenske
asked
if
we
can
assume
eyes
are
more
sensitive
than
pulmonary
irritation.
Dr.
Lebowitz
explained
that
if
the
subjects
included
sensitive
subgroups
(
i.
e.
asthmatics),
this
population
may
display
respiratory
effects
before
those
seen
in
the
eye
irritation
study.
The
eye
irritation
study
did
not
specifically
include
these
sensitive
subgroups
so
they
were
not
protected.
In
addition,
one
cannot
predict
inhalation
irritation
from
an
eye
study.
Dr.
Fenske
believed
that
information
regarding
why
oral
studies
were
not
applicable
needed
to
be
included
in
the
Agency's
background
document.
He
also
asked
why
this
type
of
extrapolation
(
i.
e.
applicable
for
oral
studies)
was
appropriate
for
some
OPs
(
i.
e.
such
as
amitraz)
but
not
for
MITC.
Dr.
Lowit
said
that
route­
to­
route
extrapolation
was
always
difficult
but
for
the
OPs,
systemic
effects
were
being
considered.
In
the
case
of
MITC,
point­
of­
entry
effects
drive
toxic
responses.
Finally,
oral
studies
may
also
be
used
if
they
provide
a
more
conservative
point
of
departure.

Dr.
Bellinger
believed
that
the
eye
irritation
study
was
a
fine
study
and
he
endorsed
the
Agency's
use
of
the
data.
Statistically,
some
type
of
non­
parametric
analysis
would
have
been
helpful.
The
researchers
were
rigid
in
their
interpretation
of
the
p
statistic
and
didn't
provide
the
rationale
for
sample
size
selection.
Dr.
Fisher
summarized
the
Board
deliberations
concluding
that
the
MITC
eye
irritation
study
should
be
used;
it
had
an
excellent
design
with
both
subjective
and
objective
measures.
Exclusion
criteria
were
good
but
they
didn't
test
for
eye
allergies
and
30­
40%
of
subjects
could
have
eye
allergies.
The
study
had
both
positive
and
negative
controls.
Statistical
measures
could
have
been
improved
(
e.
g.
non­
parametric,
repeated
subject
analysis).
Dr.
Carriquiry
and
Dr.
Bellinger
clarified
that
it
is
unknown
whether
there
was
an
adequate
number
of
subjects
in
the
cells
and
the
greater
number
of
subjects
in
the
low
dose
cells
was
a
study
strength,
not
a
weakness.

Charge
to
the
Board
Ethical
Considerations
19
of
34
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
Dr.
Menikoff
led
the
Board's
discussion
that
the
olfactory
study
raised
some
issues
in
terms
of
how
the
IRB
was
operating.
The
eye
irritation
study
appeared
to
be
ethical.
There
was
adequate
written
informed
consent
and
adequate
documentation
that
indicated
IRB
approval.
Changes
in
the
study
protocol
were
submitted
for
IRB
approval.
Amendments
to
the
protocol
were
handled
by
attaching
a
memo
to
the
protocol.
One
of
these
amendments
was
that
the
principle
investigators
exposed
themselves
to
MITC,
a
deviation
from
the
protocol
without
IRB
approval.
Dr.
Philpott
noted
that
some
of
the
protocol
changes
made
reference
to
a
1993
study
with
2­
minute
exposures
and
20­
minute
breaks.
This
study
was
referenced
but
not
provided
to
the
HSRB.
The
protocol
did
not
include
specific
criteria
for
stopping.
Dr.
Nelson
noted
that
some
might
consider
self­
testing
a
virtue.
Dr.
Fisher
concluded
that
the
Board
considered
that
the
eye
irritation
study
was
ethical.

HSRB
Discussion
of
Single
Dose
Level
Study
Discussion
Dr.
Fisher
began
a
discussion
of
single­
dose
studies
and
when
they
might
be
useful
to
add
clarity
to
the
HSRB
recommendations.
Dr.
Carriquiry
explained
that
single
dose
studies
are
of
limited
value
and
cannot
be
used
to
establish
a
NOAEL.
While
they
could
be
used
with
other
findings,
a
single
dose
in
isolation
is
useless.
This
may
be
confusing
because
at
the
April
2006
meeting,
the
Board
actually
did
recommend
that
the
results
of
one
single
dose
study
be
used.
Dr.
Lebowitz
indicated
that
clarification
was
needed
with
respect
to
how
we
define
a
single­
dose
study.
He
believed
that
a
single
dose
study
is
one
that
uses
one
dose
level.
Dr.
Fenske
added
that
the
study
may
have
multiple
dosing
but
all
doses
were
given
at
a
single
dose
level.
He
said
single
oral
dose
is
an
ambiguous
term.
Some
human
subjects
receive
a
single
dose
but
others
continue
28­
days
with
a
single
dose
administered
daily.
To
remove
this
ambiguity,
there
is
a
need
to
call
these
single
oral
dose
level
studies.
Dr.
Fisher
clarified
that
a
single
dose
study
is
an
individual
study
that
uses
one
dose
level
irrespective
of
the
number
of
subjects
or
frequency
of
dosing.
Dr.
Nelson
added
if
you
give
this
dose
to
numerous
people
and
until
you
have
a
fairly
tight
confidence
limit,
these
data
could
be
used
to
develop
a
safe
level.
Dr.
Lehman­
Mckeeman
responded
that
the
Board
holds
the
dose­
response
curve
of
critical
importance
and
agreed
with
Dr.
Nelson
that
there
are
conditions
where
a
single
dose
study
could
be
useful.
Dr.
Bellinger
added
that
what
was
lacking
was
a
measure
of
the
sensitivity
of
the
test
system.
Without
a
demonstration
at
a
higher
dose,
it
was
not
known
whether
the
endpoint
was
quantifiable.
Dr.
Lebowitz
added
that
there
is
an
issue
of
control
­
the
more
data
available,
the
more
likely
we
are
to
accept
a
single
dose
study.
Dr.
Nelson
said
that
for
the
ethical
discussion
of
carbofuran,
there
was
concern
about
pushing
to
a
level
of
clinical
toxicity.
If
a
small
sample
size
is
present
and
a
20
of
34
limited
response
occurs,
then
we
are
left
with
the
uncertainty
that
we
may
have
missed
something
that
would
have
been
evident
with
a
larger
sample
size.

Dr.
Fenske
said
the
problem
is
a
single
dose
level
study
where
no
result
occurs.
If
we
don't
see
a
result
we
have
to
draw
on
supplementary
information
to
hypothesize
a
conclusion.
On
the
other
hand
if
we
do
see
an
effect,
how
do
we
know
that
this
was
the
lowest
level
where
an
effect
was
likely
to
occur.
If
we
combine
data
using
meta­
analysis,
again
we
need
supplemental
information.
If
we
have
a
single
dose
level
study
and
have
to
bring
in
all
kinds
of
supplementary
data,
this
increases
uncertainty.
Dr.
Lehman­
Mckeeman
added
that
if
we
have
a
single
dose
level
study
and
nothing
happens,
then
one
has
much
uncertainty
with
respect
to
how
to
interpret
the
finding.
If,
on
the
other
hand,
an
effect
occurs
with
a
single
dose
study,
then
it's
a
value
judgment
about
severity
of
effect
and
robustness
of
the
study.
If
we
know
the
mode
of
action
and
have
a
surrogate
marker
that
is
relevant
to
the
effect
with
limits
recognized
as
biochemically
related
to
the
effect
without
eliciting
severe
effects,
this
is
a
situation
where
a
single
dose
study
could
be
used.
It
starts
with
and
comes
back
to
robustness
of
study
design
and
what
the
study
hopes
to
demonstrate.

Dr.
Fisher
summarized
the
Board's
conclusions.
The
Board
defined
a
single
dose
study
as
an
individual
study
that
uses
one
dose
level
irrespective
of
the
number
of
subjects,
frequency
of
dosing,
or
number
of
controls
or
placebos.
The
Board
agreed
there
was
limited
utility
in
a
single
dose
level
study,
especially
if
the
study
exhibited
no
effects
in
which
case
we
have
a
finding
with
severely
limited
interpretation.
In
some
very
limited
circumstances
the
data
may
be
useful.
With
meta­
analysis,
a
single
dose
level
study
may
shed
light
on
other
findings
and
can
thus
be
used
to
inform
the
other
findings.
Depending
on
the
rigor
of
the
study,
there
may
be
some
utility
of
single
dose
level
study.

Dr.
Lewis
asked
the
Board
for
comments
on
the
April
report.
He
will
be
modifying
the
report
and
sending
the
revised
report
to
the
Chair
before
forwarding
it
on
to
the
Board.
Lead
Discussant
write­
ups
for
the
May
meeting
are
due
to
Dr.
Lewis
by
next
Wednesday.
Mr.
Jordan
explained
that
the
late
HSRB
meeting
will
include
a
discussion
of
seven
experimental
protocols
but
the
material
just
arrived
at
the
Agency
so
the
Agency
needs
to
review
these
materials
before
they
can
be
distributed
to
the
Board.
This
meeting
may
be
moved
to
July
to
give
the
Agency
some
more
time
to
prepare.
The
Agency
does
not,
at
this
time,
have
other
pesticide
topics
for
the
Board
consideration
after
the
June
meeting
The
protocol
discussion
cannot
be
postponed
further
because
there
are
specific
times
of
the
year
that
this
type
of
study
can
be
conducted.
Dr.
Fisher
commented
that
registrants
should
not
assume
that
the
HSRB
can
meet
whenever
they
need
to
begin
a
study.
The
schedule
will
be
late
June
for
protocol
evaluation
with
information
provided
regarding
the
urgency
of
evaluation
for
additional
studies.
Dr.
Fenske
felt
that
complete
documentation
is
essential
for
Board
review.
To
avoid
tabling
protocol
discussion,
Dr.
Nelson
added
that
perhaps
one
scientific
and
one
ethics
Board
member
be
assigned
to
ensure
that
documentation
was
adequate.
Dr.
Fisher
said
that
the
burden
is
on
the
registrant
to
provide
sufficient
documentation
with
protocols.

The
meeting
was
adjourned
by
the
Chair.
21
of
34
Respectfully
submitted:

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

Ceila
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.
22
of
34
Attachments
Attachment
A
HSRB
Members
Attachment
B
Federal
Register
Notice
Announcing
Meeting
Attachment
C
Meeting
Agenda
23
of
34
Attachment
A
EPA
HSRB
Members
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.
Statistics
Professor
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,
Dept.
of
Environmental
and
Occupational
Health
Sciences
University
of
Washington,
Seattle,
WA
Susan
S.
Fish,
PharmD,
MPH
Associate
Professor,
Biostatistics
&
Epidemiology
Boston
University
School
of
Public
Health,
Boston,
MA
Suzanne
C.
Fitzpatrick,
Ph.
D.
D.
A.
B.
T.
Senior
Science
Policy
Analyst
U.
S.
Food
and
Drug
Administration,
Rockville,
MD.
24
of
34
Kannan
Krishman,
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
M.
Philpott,
Ph.
D.
Research
Scientist
David
Axelrod
Institute
New
York
State
Department
of
Health,
Albany,
NY
*
Recused
from
carbofuran
discussion
and
deliberation
25
of
34
Attachment
B
Federal
Register
Notice
Announcing
Meeting
[
Federal
Register:
April
17,
2006
(
Volume
71,
Number
73)]
[
Notices]
[
Page
19725­
19727]
From
the
Federal
Register
Online
via
GPO
Access
[
wais.
access.
gpo.
gov]
[
DOCID:
fr17ap06­
61]

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

ENVIRONMENTAL
PROTECTION
AGENCY
[
EPA­
HQ­
ORD­
2006­
0316;
FRL­
8158­
8]

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
May
2­
4,
2006
from
8:
30
a.
m.
to
approximately
5
p.
m.,
eastern
time
(
However,
the
third
day
may
not
be
needed).
Location:
Holiday
Inn
Hotel
&
Suites,
Alexandria­
Historic
District,
625
First
Street,
Alexandria,
VA
22314.
The
telephone
number
for
the
Holiday
Inn
Hotel
&
Suites,
Alexandria­
Historic
District
is
(
703)
548­
6300.
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
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.
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.
E.
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,
(
8105),
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460;
telephone
number:
(
202)
564­
8381;
fax:
(
202)
564­
2070;
e­
mail
address:
lewis.
paul@
epa.
gov.
26
of
34
ADDRESSES:
Submit
your
written
comments,
identified
by
Docket
ID
No.
EPA­
HQ­
ORD­
2006­
0316,
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
0316.
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
0316.
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
[[
Page
19726]]

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
27
of
34
Rodenticide
Act
(
FIFRA).
Since
other
entities
may
also
be
interested,
the
Agency
has
not
attempted
to
describe
all
the
specific
entities
that
may
be
affected
by
this
action.
If
you
have
any
questions
regarding
the
applicability
of
this
action
to
a
particular
entity,
consult
the
person
listed
under
FOR
FURTHER
INFORMATION
CONTACT.

B.
How
Can
I
Access
Electronic
Copies
of
This
Document
and
Other
Related
Information?

In
addition
to
using
regulations.
gov,
you
may
access
this
Federal
Register
document
electronically
through
the
EPA
Internet
under
the
  
Federal
Register''
listings
at
http://
www.
epa.
gov/
fedrgstr/.
A
frequently
updated
electronic
version
of
the
Code
of
Federal
Regulations
(
CFR)
is
available
at
http://
www.
gpoaccess.
gov/
ecfr/
Docket:
All
documents
in
the
docket
are
listed
in
the
http://.

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
to
late
April
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
Web
site
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
CONTACT.

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

You
may
find
the
following
suggestions
helpful
for
preparing
your
comments:
1.
Explain
your
views
as
clearly
as
possible.
2.
Describe
any
assumptions
that
you
used.
3.
Provide
copies
of
any
technical
information
and/
or
data
you
used
that
support
your
views.
4.
Provide
specific
examples
to
illustrate
your
concerns.
5.
To
ensure
proper
receipt
by
EPA,
be
sure
to
identify
the
docket
ID
number
assigned
to
this
action
in
the
subject
line
on
the
first
page
of
your
response.
You
may
also
provide
the
name,
date,
and
Federal
Register
citation.

E.
How
May
I
Participate
in
This
Meeting?
28
of
34
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
0316
in
the
subject
line
on
the
first
page
of
your
request.
1.
Oral
comments.
Requests
to
present
oral
comments
will
be
accepted
up
to
April
26,
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
e­
mail)
to
the
DFO
listed
under
FOR
FURTHER
INFORMATION
CONTACT
no
later
than
noon,
eastern
time,
April
26,
2006,
in
order
to
be
included
on
the
meeting
agenda.
The
request
should
identify
the
name
of
the
individual
making
the
presentation,
the
organization
(
if
any)
the
individual
will
represent,
and
any
requirements
for
audiovisual
equipment
(
e.
g.,
overhead
projector,
35
mm
projector,
chalkboard).
Oral
comments
before
the
HSRB
are
limited
to
5
minutes
per
individual
or
organization.
Please
note
that
this
includes
all
individuals
appearing
either
as
part
of,
or
on
behalf
of
an
organization.
While
it
is
our
intent
to
hear
a
full
range
of
oral
comments
on
the
science
and
ethics
issues
under
discussion,
it
is
not
our
intent
to
permit
organizations
to
expand
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
being
25
copies
of
his
or
her
comments
and
presentation
slides
for
distribution
to
the
HSRB
at
the
meeting.
2.
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
the
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,
April
26,
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.

F.
Background
The
HSRB
will
meet
to
consider
and
review
EPA's
scientific
and
ethics
analyses
of
six
completed
human
toxicity
studies
concerning
three
different
compounds,
including:
Hexavalent
chromium,
a
constituent
of
a
wood
preservative;
and
the
following
pesticide
active
ingredients­­
carbofuran
and
methyl
isothiocyanate
(
MITC).
The
studies
being
considered
at
this
meeting
will
include
both
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
will
ask
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
26.1701­
26.1704
of
EPA's
final
human
studies
rule.
In
addition,
the
29
of
34
Board
may
be
reviewing
draft
HSRB
reports
for
subsequent
Board
approval.

[[
Page
19727]]

Dated:
April
11,
2006.
William
H.
Farland,
Acting
EPA
Science
Advisor.
[
FR
Doc.
06­
3635
Filed
4­
14­
06;
8:
45
am]
BILLING
CODE
6960­
50­
M
30
of
34
Attachment
C
May
2­
3,
2006
Meeting
of
the
HSRB
Meeting
Agenda
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
MAY
2­
3,
2006
PUBLIC
MEETING
Tuesday,
May
2,
2006
Holiday
Inn
Hotel
and
Suites
Alexandria­
Historic
District
625
First
Street
Alexandria,
VA
22314
703­
548­
6300
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
Introduction
and
Identification
of
Board
Members
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
8:
45
AM
Welcome
 
William
Farland,
Ph.
D.
(
Chief
Scientist,
Office
of
the
Science
Advisor
[
OSA],
EPA)

C
8:
55
AM
Opening
Remarks
 
Mr.
Jack
Housenger
(
Associate
Director,
Health
Effects
Division,
Office
of
Pesticide
Programs
[
OPP],
EPA)

C
9:
05
AM
Meeting
Administrative
Procedures
­
Paul
Lewis,
Ph.
D.
(
Designated
Federal
Officer,
HSRB
Staff,
OSA,
EPA)

C
9:
10
AM
Meeting
Process
 
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

C
9:
30
PM
Science
and
Ethics
of
Chromium
Human
Studies
­
Timothy
McMahon,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)

C
10:
30
AM
Break
C
10:
45
AM
Public
Comments
C
11:
45
AM
Lunch
C
12:
45
PM
Board
Discussion
Hexavalent
chromiumis
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
resulting
from
exposure
to
chromium.
See
www.
epa.
gov/
scipoly/
sap/
2004/
final.
doc
The
31
of
34
Agency
has
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
has
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.

1.
Scientific
considerations
EPA
has
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
has
concluded
that
the
study
contains
information
sufficient
for
assessing
human
risk
resulting
from
potential
dermal
exposure.

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

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
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?

C
2:
30
PM
Science
and
Ethics
of
Carbofuran
Human
Studies
 
John
Liccione,
Ph.
D.
(
OPP,
EPA),
Elissa
Reaves,
Ph.
D.
and
Mr.
John
Carley
(
OPP,
EPA)

C
3:
30
PM
Break
C
3:
45
PM
Public
Comments
C
4:
30
PM
Board
Discussion
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.

1.
Scientific
considerations
32
of
34
The
Agency's
WOE
document
and
DERs
for
carbofuran
describe
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
are
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.

C
5:
30
PM
Adjournment
33
of
34
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
HUMAN
STUDIES
REVIEW
BOARD
(
HSRB)
PUBLIC
MEETING
Wednesday,
May
3,
2006
Holiday
Inn
Hotel
and
Suites
Alexandria­
Historic
District
62
First
Street
Alexandria,
VA
22314
703­
548­
6300
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
Welcome
 
Mr.
Jim
Jones
(
Director,
OPP,
EPA)

C
8:
50
AM
Follow­
up
From
Previous
Day's
Discussion
 
Mr.
William
Jordan
(
OPP,
EPA)

C
9:
00
AM
Board
Discussion
(
continued)

Carbofuran
(
continued)

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
any
of
the
human
studies
conducted
with
carbofuran
was
fundamentally
unethical?

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

C
9:
30
AM
Science
and
Ethics
of
Methyl
Isothiocyanate
(
MITC)
 
Anna
Lowit,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)

C
10:
30
AM
Break
C
10:
45
AM
Public
Comments
C
11:
30
AM
Lunch
C
12:
30
PM
Board
Discussion
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,
34
of
34
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.

1.
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
has
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
has
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.

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
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?

C
2:
30
PM
Board
Writing
Session
C
3:
30
PM
Adjournment
Please
be
advised
that
agenda
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
