Document ID: EPA-HQ-ORD-2006-0310-0013
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-17T04:00Z

Page
1
of
8
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
APR
14,
2006
MEMORANDUM:
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
SUBJECT:
Initial
Ethical
Review
of
Carbofuran
Human
Dermal
Study
FROM:
John
M.
Carley
TO:
John
Liccione,
HED
REF:
Arnold,
J.
D.
(
1977)
Carbamate
(
Carbofuran)
Human
Dermal
Study.
Unpublished
study
prepared
by
Quincy
Research
Center.
36
p.
(
MRID
92827;
pp.
106­
141
in
CDL
Accession
241303.)

I
have
performed
an
initial
review
of
available
information
concerning
the
referenced
document.
This
review
characterizes
the
ethical
conduct
of
the
research
in
terms
of
both
current
ethical
standards
and
ethical
standards
prevailing
when
the
study
was
performed.
The
review
applies
the
"
Summary
Framework
for
Ethical
Assessment
Using
Seven
Criteria
of
Emanuel
et
al."
developed
by
the
EPA
Science
Policy
Committee's
Human
Studies
Work
Group.
The
completed
"
framework"
is
attached.
This
framework
was
derived
from
the
work
of
Emanuel,
et
al.
(
2000),
which
summarizes
seven
general
principles
for
ethical
treatment
of
human
subjects
in
scientific
research.
The
Emanuel
article
was
primarily
directed
at
those
who
consider
proposals
for
new
medical
research
and
decide
which
are
worthy
of
funding
or
approval.
These
are
very
different
decisions
from
those
we
in
EPA
must
make
when
we
determine
whether
we
can
ethically
consider
already­
completed
human
studies.

The
Emanuel
article
reflects
current
standards
for
ethical
research
prevailing
in
the
U.
S.
This
study
was
conducted
in
the
U.
S.
in
late
1976,
but
cites
no
standard
of
ethical
research
conduct.
I
have
applied
FIFRA
§
12(
a)(
2)(
P)
and
assumed
the
Declaration
of
Helsinki
(
1975)
to
have
prevailed
when
the
research
was
conducted.

A.
Summary
Assessment
of
Ethical
Conduct
of
the
Research
Page
2
of
8
Here
is
a
summary
of
my
observations
about
the
study
under
the
seven
headings
used
in
the
Emanuel
framework.
Supporting
details
are
in
the
attachment.

1.
Value
of
the
Research
to
Society:
This
research
has
never
been
published,
suggesting
its
purpose
was
not
mainly
to
advance
generalizable
knowledge.
Its
purpose
is
characterized
differently
for
different
audiences.
It
is
clear
from
the
protocol
that
the
scientific
purpose
was
to
define
a
LOAEL;
it
was
described
to
volunteers
in
terms
of
a
"
safe
dosage",
perhaps
to
make
them
more
likely
to
consent
to
participate.
The
study
may
provide
some
information
on
the
toxicity
of
carbofuran
to
humans
that
could
help
to
inform
EPA's
assessment
of
human
health
risks.

2.
Scientific
Validity
of
the
Research:
I
defer
to
others
for
a
full
review
of
the
scientific
validity
of
this
study.
If
it
were
determined
not
to
have
scientific
validity,
it
would
also
not
be
ethically
acceptable.

3.
Subject
Selection:
Subjects
were
18
healthy
adult
men.
Restriction
to
men
was
consistent
with
the
stated
intent
to
explore
occupational
exposure
patterns.
Based
on
documentation
in
MRID
92829,
the
pool
from
which
subjects
were
drawn
consisted
mainly
of
unemployed
semi­
skilled
workers.

4.
Risk­
Benefit
Ratio:
Potential
symptoms
were
accurately
listed
in
the
information
for
volunteers,
but
risks
were
not
minimized
by
the
study
design,
which
committed
to
dose
escalation
until
toxic
signs
were
observed.
Volunteers
were
also
told
plainly
that
they
would
not
benefit
from
participating.
How
the
potential
societal
benefit
of
improved
safety
for
production
workers
was
weighed
against
the
risks
to
subjects 
either
by
the
investigator
or
by
the
review
committee 
was
not
reported.

5.
Independent
Ethical
Review:
The
protocol
and
related
materials,
including
both
the
procedures
and
the
information
associated
with
informed
consent,
were
reported
to
have
been
approved
by
the
Community
Review
Committee,
Inc.,
of
Kansas
City,
MO.
The
critical
changes
to
the
protocol
to
raise
the
doses
in
phase
2
were
made
after
ethics
approval
was
obtained,
and
without
consulting
the
committee.

6.
Informed
Consent:
Both
the
information
for
subjects
and
the
consent
form
itself
were
remarkably
clear
and
complete
for
research
conducted
in
this
period.
Subjects
were
given
no
indication,
however,
that
the
design
of
the
research
required
dose
escalation
until
frank
toxic
signs
were
elicited.

7.
Respect
for
Potential
and
Enrolled
Subjects:
Subjects'
privacy
was
not
compromised.
They
were
free
to
withdraw
at
any
time.

B.
Compliance
with
Ethical
Standard
Prevailing
when
the
Research
Was
Conducted
No
standard
of
ethical
research
conduct
is
cited,
either
by
the
reviewing
ethics
committee
or
by
the
authors.
The
research
was
conducted
in
the
U.
S.
after
1972,
so
FIFRA
§
12(
a)(
2)(
P)
Page
3
of
8
applies.
In
addition,
as
clinical
research
this
falls
within
the
scope
of
the
Declaration
of
Helsinki.
I
have
applied
both
standards
in
assessing
the
conduct
of
this
study.

 
FIFRA
Sec.
12(
a)(
2)(
P)
states:
"
In
general,
[
i]
t
shall
be
unlawful
for
any
person
.
.
.
to
use
any
pesticide
in
tests
on
human
beings
unless
such
human
beings
(
i)
are
fully
informed
of
the
nature
and
purposes
of
the
test
and
of
any
physical
and
mental
health
consequences
which
are
reasonably
foreseeable
therefrom,
and
(
ii)
freely
volunteer
to
participate
in
the
test."

Although
the
information
provided
to
subjects
was
extraordinarily
complete
for
research
from
this
period,
subjects
were
not
told
that
the
design
of
the
study
required
dose
escalation
until
frank
toxic
effects
were
elicited.
Instead
they
were
told
that
"
The
purpose
of
the
testing
.
.
.
is
to
find
out
the
maximum
safe
dosage
when
applied
to
the
skin
.
.
.
.
The
nature
of
the
test
compound
.
.
.
is
such
that
we
do
not
expect
serious
complications
from
its
use."
This
falls
short
of
the
requirement
that
they
be
"
fully
informed
of
.
.
.
any
physical
.
.
.
consequences
which
are
reasonably
foreseeable."

 
Basic
Principle
#
5
of
the
Declaration
of
Helsinki
(
1975)
reads
"
Every
biomedical
research
project
involving
human
subjects
should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
to
foreseeable
benefits
to
the
subject
or
to
others.
Concern
for
the
interests
of
the
subject
must
always
prevail
over
the
interest
of
science
and
society."

Societal
benefits
are
not
explicitly
weighed
against
the
risks
to
subjects.
Comparable
benefit
could
probably
have
been
achieved
through
better
methods
of
measuring
ChE
inhibition,
without
proceeding
to
elicitation
of
frank
toxicity
requiring
administration
of
an
antidote.
The
decisions
to
raise
dose
levels
in
phase
2
does
not
show
that
the
interests
of
the
subjects
prevailed
over
other
interests.

 
Basic
Principle
#
12
of
the
Declaration
of
Helsinki
(
1975)
reads
"
The
research
protocol
should
always
contain
a
statement
of
the
ethical
considerations
involved
and
should
indicate
that
the
principles
enunciated
in
the
present
Declaration
are
complied
with."

No
discussion
of
substantive
ethical
considerations
appears
in
the
protocol.

C.
Standards
for
Judging
Ethical
Acceptability
On
February
6,
2006,
EPA
published
a
final
rule,
"
Protections
for
Subjects
in
Human
Research,"
effective
on
April
7,
2006.
Section
26.1704
of
that
regulation
provides
in
pertinent
part:

EPA
shall
not
rely
on
data
from
any
research
initiated
before
[
effective
date
of
the
final
rule]
if
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
research
Page
4
of
8
was
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent),
or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted.

In
addition,
section
26.1703
of
the
final
rule
provides
in
pertinent
part:

EPA
shall
not
rely
on
data
from
any
research
involving
intentional
exposure
of
any
human
subject
who
is
a
pregnant
woman
(
and
therefore
her
fetus)
or
child.

I
have
applied
the
standards
in
sections
26.1704
and
26.1703
in
arriving
at
the
conclusions
below.

D.
Conclusion
All
subjects
were
adult
males.
Section
26.1703
therefore
does
not
prohibit
reliance
on
this
study.

Although
there
are
some
gaps
in
the
documentation
of
the
ethical
conduct
of
this
study,
it
is
extraordinarily
well
documented
for
research
from
this
period.
There
is
no
clear
evidence
that
the
research
was
intended
to
harm
participants,
or
that
it
was
fundamentally
unethical
in
other
ways.
Deficient
documentation
does
not
itself
constitute
evidence
that
the
ethical
conduct
of
this
study
was
deficient
relative
to
standards
prevailing
when
it
was
conducted.

From
the
documentation
available,
I
have
identified
some
deficiencies
relative
to
the
standards
of
FIFRA
§
12(
a)(
2)(
P)
and
the
1975
Declaration
of
Helsinki.
These
deficiencies
do
not,
in
my
judgment,
amount
to
"
clear
and
convincing
evidence"
that
this
study
was
"
fundamentally
unethical."
This
review,
however,
does
not
take
a
position
on
either
the
persuasiveness
of
the
evidence
or
the
overall
significance
of
the
identified
deficiencies
relative
to
the
prevailing
ethical
standards.
This
decision
is
deferred
pending
review
of
the
research
by
the
Human
Studies
Review
Board
as
required
by
EPA
regulation
before
EPA
takes
an
action
relying
on
this
study.

Attachment
Cited
reference:

Emanuel,
E.;
Wender,
D.;
Grady,
C.
(
2000)
What
Makes
Clinical
Research
Ethical?
JAMA
283:
2701­
2711.
Page
5
of
8
Framework
for
Ethical
Assessment
Using
Seven
Criteria
of
Emanuel
et
al.
1
April
14,
2006]

Arnold,
JD
(
1977)
Carbamate
(
Carbofuran)
Human
Dermal
Study.
Unpublished
study
prepared
by
Quincy
Research
Center.
36
p.
MRID
92827;
pp.
106­
141
in
CDL
Accession
241303.

1.
Value:
This
research
has
never
been
published,
suggesting
its
purpose
was
not
mainly
to
advance
generalizable
knowledge.
Its
purpose
is
characterized
differently
for
different
audiences.
It
is
clear
from
the
protocol
that
the
scientific
purpose
was
to
define
a
LOAEL;
it
was
described
to
volunteers
in
terms
of
a
"
safe
dosage",
perhaps
to
make
them
more
likely
to
consent
to
participate.
The
study
may
provide
some
information
on
the
toxicity
of
carbofuran
to
humans
that
could
help
to
inform
EPA's
assessment
of
human
health
risks.

a.
What
was
the
stated
purpose
of
the
research?
"
To
determine
the
threshold
toxicity
level
in
normal
male
volunteers
to
single
and
multiple
dermal
doses
of
carbamate
(
carbofuran)
under
normal
and
elevated
temperatures
and/
or
humidities."
(
p.
108)

"
To
find
out
the
maximum
safe
dosage
when
applied
to
the
skin
for
human
beings.
.
.
."
(
p.
120)

b.
Does
it
evaluate
a
diagnostic
or
therapeutic
intervention
that
could
lead
to
improvements
in
health
or
well­
being?
No
c.
Does
it
test
a
hypothesis
that
can
generate
important
knowledge
about
structure
or
function
of
human
biological
systems?
No
d.
Will
society
benefit
from
the
knowledge
gained
from
this
research?
Will
its
results
be
disseminated?
It
has
never
been
published.
Subjects
were
told
"
We
do
not
expect
you
to
derive
any
benefit
from
taking
the
test
compound;
however
it
is
essential
to
determine
the
levels
of
this
test
compound
that
are
safe
for
the
people
making
it
as
well
as
the
people
exposed
to
it
during
its
use."
(
p.
120)

e.
What
government,
organization,
company
and/
or
institution(
s)
funded
the
research?
FMC
2.
Scientific
Validity:
I
defer
to
others
for
a
full
review
of
the
scientific
validity
of
this
study.
If
it
were
determined
not
to
have
scientific
validity,
it
would
also
not
be
ethically
acceptable.

a.
Did
the
research
have
a
clear
scientific
objective?
See
item
1(
a)
above.
The
scientific
objective
was
to
establish
a
human
dermal
LOAEL.

b.
Was
the
research
designed
using
accepted
principles,
methods,
and
reliable
practices?
I
defer
to
the
science
reviewer.
Page
6
of
8
c.
In
what
way
were
human
subjects
intentionally
dosed
in
this
research,
and
what
endpoints
were
identified
or
measured?
Testing
took
place
in
three
phases.
In
phase
1,
subjects
entered
the
clinic
the
evening
before
dosing.
After
eating
a
standard
breakfast,
two
subjects
at
a
time
entered
a
controlled
environment
with
high
temperature
and
humidity.
They
were
pre­
tested
for
ChE
and
neurovegetative
signs
immediately
before
administration
of
the
dose,
and
repeatedly
from
15
minutes
to
6
h.
post­
dose.
For
four
hours
post­
dose
subjects
alternated
5
minutes
on
an
exercise
bicycle
with
15
minutes
of
rest,
all
the
time
in
the
chamber
with
elevated
temperature
and
humidity.
After
a
first
pass
with
only
the
vehicle
as
a
control,
the
initial
dose
was
0.5
mg/
kg;
after
evaluation
of
symptoms
and
data
at
each
dose
level,
doses
escalated
by
doubling.
Escalation
was
discontinued
at
2.0
mg/
kg
because
of
frank
toxic
signs
in
both
subjects.

In
phase
2
subjects
similarly
were
dosed
after
breakfast
and
then
alternated
exercise
and
rest
for
four
hours,
but
at
lower
temperature
and
humidity.
In
this
phase
dosing
began
at
2.0
mg/
kg
(
although
the
protocol
originally
specified
it
should
begin
at
half
the
LOAEL
from
phase
1,
or
1.0
mg/
kg)
and
doubled
each
time
to
4.0
mg/
kg,
then
to
8.0
mg/
kg,
and
then
the
planned
dose
of
16
mg/
kg
was
skipped
in
favor
of
32
mg/
kg.

In
phase
3
two
additional
subjects
received
a
dose
of
1.0
mg/
kg
under
high
temperature
and
humidity
each
day
for
three
consecutive
days.

Subjects
remained
in
the
clinic
for
24
hours
post­
dose.
Measures
included
RBC
and
plasma
ChEI,
pulse,
blood
pressure,
pupil
size,
eye
accommodation,
Fukuda
step
test,
and
ECG.

d.
Did
the
research
design
have
sufficient
power
to
definitively
test
the
objective?
I
defer
to
the
science
reviewer
e.
To
what
purpose
is
the
study
used,
or
proposed
for
use,
in
the
Agency?
To
inform
the
WOE
for
reassessment
of
carbofuran
3.
Fair
Subject
Selection:
Subjects
were
18
healthy
adult
men.
Restriction
to
men
was
consistent
with
the
stated
intent
to
explore
occupational
exposure
patterns.
Based
on
documentation
in
MRID
92829,
the
pool
from
which
subjects
were
drawn
consisted
mainly
of
unemployed
semi­
skilled
workers.

a.
Were
the
groups
and
individuals
recruited
and
enrolled
determined
solely
on
the
basis
of
the
scientific
goals
of
the
study?
Eighteen
healthy
adult
men
participated
in
the
research.
Limitation
to
adult
men
was
consistent
with
the
stated
intent
to
explore
occupational
exposure
patterns.
Exclusion
factors
included
organic
disease,
use
of
medications
before
or
during
the
study,
or
use
of
alcohol
during
the
study.
The
protocol
states
"
special
attention
will
be
paid
to
the
use
of
tobacco",
but
does
not
indicate
that
it
was
controlled.

b.
Were
any
susceptible
groups
used
in
the
study,
such
as
children,
prisoners,
infirm,
or
impoverished?
Did
the
burden
of
participation
fall
disproportionately
on
a
particular
group?
The
pool
from
which
volunteers
were
drawn
was
described
in
these
terms:
"[
V]
olunteers
were
19
to
58
year
old
men
with
60%
between
20
and
40
and
a
median
age
of
34.
Seventeen
percent
were
black,
80%
were
white,
and
3%
were
from
other
ethnic
groups.
Fifty­
two
percent
had
completed
the
twelfth
grade,
and
16
percent
had
attended
college.
Sixty
percent
were
semi­
skilled
workers
and
8%
were
steadily
employed."
[
MRID
92829,
p.
85]

4.
Favorable
Risk­
Benefit
Ratio:
Potential
symptoms
were
accurately
listed
in
the
information
for
volunteers,
but
risks
were
not
minimized
by
the
study
design,
which
committed
to
dose
escalation
until
toxic
signs
were
observed.
Volunteers
were
also
told
plainly
that
they
would
not
benefit
from
participating.
How
the
potential
societal
benefit
of
improved
safety
for
production
workers
was
weighed
against
the
risks
to
subjects 
either
by
the
investigator
or
by
the
review
committee 
was
not
reported.
Page
7
of
8
a.
How
were
the
risks
to
individual
subjects
minimized?
Research
was
conducted
in
a
clinic
under
medical
supervision.
Subjects
were
told
what
kinds
of
symptoms
they
might
experience,
and
encouraged
to
report
any
complaints.
Atropine
was
available
in
the
clinic,
and
was
administered
intravenously
to
the
two
subjects
who
received
the
2
mg/
kg
dose
at
high
temperature
and
humidity.
A
study
design
with
a
more
robust
baseline
and
better
methods
for
analyzing
ChE
inhibition
could
probably
have
generated
similar
knowledge
without
exposing
the
subjects
to
doses
producing
frank
toxic
signs
requiring
administration
of
an
antidote.
The
decision
to
change
the
protocol
for
phase
2
to
raise
the
starting
dose
level
and
the
subsequent
decision
to
quadruple
the
NOAEL
level
of
8
mg/
kg
did
not
show
a
commitment
to
risk
minimization.

b.
If
the
research
presents
no
health­
related
benefits
to
individual
subjects,
what
are
the
societal
benefits
in
terms
of
knowledge
from
the
study,
and
do
these
justify
the
excess
risk
to
individual
subjects?
The
results
of
this
research
may
have
been
used
to
improve
safety
of
Furadan
production
workers.

c.
What
compensation
was
paid
to
the
participants
in
the
study?
Not
reported
5.
Independent
Review:
The
protocol
and
related
materials,
including
both
the
procedures
and
the
information
associated
with
informed
consent,
were
reported
to
have
been
approved
by
the
Community
Review
Committee,
Inc.,
of
Kansas
City,
MO.
The
critical
changes
to
the
protocol
to
raise
the
doses
in
phase
2
were
made
after
ethics
approval
was
obtained,
and
without
consulting
the
committee.

a.
Was
the
research
asserted
to
have
been
overseen
by
an
ethics
review
body?
Yes,
the
protocol
and
informed
consent
materials
were
reportedly
reviewed
and
approved
by
the
Community
Review
Committee,
Inc.,
of
Kansas
City,
MO.

b.
Was
the
research
subject
to
independent
review
by
individuals
unaffiliated
with
the
clinical
research?
Yes.

c.
Was
the
research
conducted
in
compliance
with
the
Common
Rule?
It
pre­
dates
the
Common
Rule
d.
Does/
did
the
research
institution
(
or
any
institution
participating
in
the
research)
hold
a
Federal
Wide
Assurance
or
Multi­
Project
Assurance
during
the
period
of
the
study?
n/
a
e.
Was
the
research
conducted
in
compliance
with
another
standard?
What
standard?
No
ethical
standard
was
cited.
FIFRA
§
12(
a)(
2)(
P)
applies,
as
does
the
Declaration
of
Helsinki
(
1975).

6.
Informed
Consent:
Both
the
information
for
subjects
and
the
consent
form
itself
were
remarkably
clear
and
complete
for
research
conducted
in
this
period.
Subjects
were
given
no
indication,
however,
that
the
design
of
the
research
required
dose
escalation
until
frank
toxic
signs
were
elicited.

a.
Does
the
research
assert
that
informed
consent
was
obtained
from
participants?
Yes
b.
How
and
under
what
circumstances
was
informed
consent
obtained?
The
"
Volunteer
agreement
and
informed
consent"
was
read
aloud,
verbatim,
and
then
the
subjects
were
asked
to
sign
the
consent
form.

7.
Respect
for
Potential
and
Enrolled
Subjects:
Subjects'
privacy
was
not
compromised.
They
were
free
to
withdraw
at
any
time.
Page
8
of
8
a.
Was
information
about
individual
subjects
managed
so
as
to
ensure
their
privacy?
"
The
collection
and
submission
of
the
medical
information
from
this
study
will
be
accomplished
with
strict
adherence
to
professional
standards
of
confidentiality."

b.
Were
subjects
free
to
withdraw
from
the
research
without
penalty?
"
As
a
volunteer,
I
understand
that
I
am
free
to
withdraw
and
discontinue
my
participation
at
any
time
upon
my
request.
Both
participation
in
the
study
as
well
as
possible
withdrawal
are
at
my
own
free
will
without
coercion,
duress,
or
intimidation
of
any
sort."

1
Emanuel,
E;
Wender,
D;
Grady,
C
(
2000)
What
Makes
Clinical
Research
Ethical?
JAMA
283:
2701­
2711.