Document ID: EPA-HQ-ORD-2006-0310-0032
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-05-01T04:00Z

1
Summary
of
Summary
of
EPA
Ethics
Reviews
EPA
Ethics
Reviews
Arnold,
J.
D.
(
1976)
Evaluation
of
the
Safe
Exposure
Levels
to
Carbamate,

Administered
Orally
to
Healthy
Adult
Normal
Male
Volunteers.
Unpublished
study
prepared
by
Quincy
Research
Center.
82
p.
MRID
92826.

Arnold,
J.
D.
(
1977)
Carbamate
(
Carbofuran)
Human
Dermal
Study.

Unpublished
study
prepared
by
Quincy
Research
Center.
36
p.
(
MRID
92827;

also
pp.
106­
141
in
CDL
Accession
241303.)

Arnold,
J.
D.
(
1978)
Comparison
of
Cholinesterase
Inhibition
and
Effects
of
Furadan
4F
and
FMC
35001
4EC.
Unpublished
study
prepared
by
Quincy
Research
Center.
92
p.
(
MRID
92829)
2
Carbofuran
Human
Studies
Carbofuran
Human
Studies

All
conducted
in
1976­
78
at
Quincy
Research
Center,
Kansas
City
MO

All
overseen
and
approved
by
"
Community
Review
Committee,
Inc."

All
with
explicit
informed
consent

All
drew
from
pool
of
semi­
skilled
unemployed
workers

All
designed
to
continue
dose
escalation
until
toxic
signs
were
evident
3
Carbofuran
(
76)
Oral
Carbofuran
(
76)
Oral
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports

Purpose
"
to
determine
.
.
.
the
minimum
dose
necessary
to
induce
toxic
effects.
.
."


Subjects
told
research
was
essential
to
determine
safe
levels
of
exposure
for
workers
2.
Scientific
Validity:
Defer
to
others
4
Carbofuran
Carbofuran
(
76)
Oral
(
76)
Oral
"
Framework
Framework"
­­

­­
2
3.
Subject
Selection

20
adult
male
volunteers
from
pool
at
laboratory
°
19­
58
years
old;
median
age
34
°
80%
white,
17%
black,
3%
other
races
°
52%
high­
school
grads;
16%
some
college
°
60%
semi­
skilled
workers
°
92%
not
steadily
employed

No
evidence
of
use
of
vulnerable
groups
5
Carbofuran
(
76)
Oral
Carbofuran
(
76)
Oral
"
Framework
Framework"­­

­­
3
4.
Risk­
Benefit
Ratio

Study
design
did
not
minimize
risk
to
subjects

Conducted
in
clinic
with
medical
supervision

Atropine
available
as
antidote

Subjects
told
of
possible
symptoms

Subjects
told
the
study
would
not
benefit
them
directly;
societal
benefits
not
addressed

Subjects
compensated;
amount
not
reported
6
Carbofuran
(
76)
Oral
Carbofuran
(
76)
Oral
"
Framework
Framework"­­

­­
4
5.
Independent
Ethics
Review

Protocol
and
IC
process
and
materials
asserted
to
have
been
approved
by
the
Community
Review
Committee,
Inc.


Committee
members
asserted
to
have
no
financial
or
professional
relationship
with
Quincy
Research

Committee
discussion
not
reported
7
Carbofuran
(
76)
Oral
Carbofuran
(
76)
Oral
"
Framework
Framework"­­

­­
5
6.
Informed
Consent

Consent
form
described
the
procedure
and
possible
physical
effects
adequately

Purpose
of
study
described
to
subjects
as
to
establish
"
maximum
safe
dosage"


Subjects
not
told
dose
escalation
would
continue
until
toxic
signs
induced

Consent
form
read
aloud,
verbatim,
before
subjects
were
asked
to
sign
8
Carbofuran
(
76)
Oral
Carbofuran
(
76)
Oral
"
Framework
Framework"­­

­­
6
7.
Respect
for
Subjects

Subjects'
privacy
was
not
compromised

Subjects
were
free
to
withdraw
without
penalty
9
Carbofuran
Oral
(
76)
Prevailing
Standard
Carbofuran
Oral
(
76)
Prevailing
Standard

Conducted
in
US
in
1976

Cited
no
standard
of
ethical
conduct

FIFRA
§
12(
a)(
2)(
P)
applicable

Declaration
of
Helsinki
(
1975)
assumed
to
have
prevailed
10
FIFRA
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

"
It
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."
11
FIFRA
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

Subjects
were
not
told
that
dose
would
escalate
until
toxic
signs
were
induced

Subjects
were
told
study
was
to
establish
"
maximum
safe
dose",
and
that
"
the
nature
of
the
test
compound
.
.
.
is
such
that
we
do
not
expect
serious
complications"

Subjects
were
not
fully
informed
of
"
any
physical
consequences
.
.
.
foreseeable."
12
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
5:
"
Every
.
.
.
project
.
.
.
should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
with
foreseeable
benefits
to
the
subject
or
to
others.
Concern
for
the
interests
of
the
subject
must
always
prevail
.
.
."

EPA
Comment:
If
a
careful
assessment
was
conducted
it
was
not
reported.
Exposure
of
additional
subjects
to
a
dose
already
shown
to
cause
illness
does
not
suggest
the
interests
of
the
subjects
prevailed
13
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
Principle
#
12:
"
The
research
protocol
should
always
contain
a
statement
of
the
ethical
considerations
involved
.
.
.
."

EPA
Comment:
There
is
no
substantive
discussion
of
ethical
considerations
in
the
protocol
14
Carbofuran
Oral
(
76)
Summary
Carbofuran
Oral
(
76)
Summary

Some
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence"

No
children;
no
pregnant
females;
no
evidence
that
the
research
was
fundamentally
unethical

Inadequate
information
to
support
consent

Some
deficiencies
relative
to
the
1975
Declaration
of
Helsinki

We
welcome
the
Board's
advice
on
the
significance
of
these
deficiencies
15
Carbofuran
(
77)
Dermal
Study
Carbofuran
(
77)
Dermal
Study

Conducted
in
1977
at
Quincy
Research

Reviewed
and
approved
by
Community
Review
Committee,
Inc.

18
healthy
adult
male
volunteers

Ascending
dose
design
in
phases
1
and
2

Single
dose,
repeat
exposure
in
phase
3

High
temp/
humidity
in
phases
1
and
3
16
Carbofuran
Dermal
(
77)

Carbofuran
Dermal
(
77)
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports

Subjects
told
research
was
essential
to
determine
safe
levels
of
exposure
for
workers

Purpose
"
to
determine
.
.
.
threshold
toxicity
level"

2.
Scientific
Validity:
Defer
to
others
17
Carbofuran
Dermal
(
77)

Carbofuran
Dermal
(
77)
"
Framework
Framework"
­­

­­
2
3.
Subject
Selection

Adult
male
volunteers
from
pool
at
laboratory 
mainly
semi­
skilled
workers
without
steady
employment

No
evidence
of
use
of
vulnerable
groups
18
Carbofuran
Dermal
(
77)

Carbofuran
Dermal
(
77)
"
Framework
Framework"
­­

­­
3
4.
Risk­
Benefit
Ratio

Study
design
did
not
minimize
risk
to
subjects

Conducted
in
clinic
with
medical
supervision

Atropine
available
as
antidote

Subjects
told
of
possible
symptoms

Subjects
told
the
study
would
not
benefit
them
directly;
societal
benefits
not
addressed

Subject
compensation
not
reported
19
Carbofuran
Dermal
(
77)

Carbofuran
Dermal
(
77)
"
Framework
Framework"
­­

­­
4
5.
Independent
Ethics
Review

Protocol
and
IC
process
and
materials
asserted
to
have
been
approved
by
the
Community
Review
Committee,
Inc.


Committee
discussion
not
reported

Changes
to
dose
levels
in
Phase
2
were
made
after
Committee
approval,
and
without
consulting
the
Committee
20
Carbofuran
Dermal
(
77)

Carbofuran
Dermal
(
77)
"
Framework
Framework"
­­

­­
5
6.
Informed
Consent

Consent
form
described
the
procedure
and
possible
physical
effects
adequately

Purpose
of
study
described
to
subjects
as
to
establish
"
maximum
safe
dosage"


Subjects
not
told
dose
escalation
would
continue
until
toxic
signs
induced

Consent
form
read
aloud,
verbatim,
before
subjects
were
asked
to
sign
21
Carbofuran
Dermal
(
77)

Carbofuran
Dermal
(
77)
"
Framework
Framework"
­­

­­
6
7.
Respect
for
Subjects

Subject
privacy
was
not
compromised

Subjects
were
free
to
withdraw
without
penalty
22
Carbofuran
Dermal
(
77)
Prevailing
Standard
Carbofuran
Dermal
(
77)
Prevailing
Standard

Conducted
in
US
in
1977

Cited
no
standard
of
ethical
conduct

FIFRA
§
12(
a)(
2)(
P)
applicable

Declaration
of
Helsinki
(
1975)
assumed
to
have
prevailed
23
FIFRA
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

"
It
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."
24
FIFRA
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

Subjects
were
not
told
that
dose
would
escalate
until
toxic
signs
were
induced

Subjects
were
told
study
was
to
establish
"
maximum
safe
dose",
and
that
"
the
nature
of
the
test
compound
.
.
.
is
such
that
we
do
not
expect
serious
complications"

Subjects
were
not
fully
informed
of
"
any
physical
consequences
.
.
.
foreseeable."
25
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
5:
"
Every
.
.
.
project
.
.
.
should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
with
foreseeable
benefits
to
the
subject
or
to
others.
Concern
for
the
interests
of
the
subject
must
always
prevail
.
.
."

EPA
Comment:
If
a
careful
assessment
was
conducted
it
was
not
reported.
Decision
to
raise
dose
levels
in
Phase
2
suggests
the
interests
of
the
subjects
may
not
have
prevailed
26
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
Principle
#
12:
"
The
research
protocol
should
always
contain
a
statement
of
the
ethical
considerations
involved
.
.
.
."

EPA
Comment:
There
is
no
substantive
discussion
of
ethical
considerations
in
the
protocol
27
Carbofuran
Dermal
(
77)
Summary
Carbofuran
Dermal
(
77)
Summary

Some
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence"

No
children;
no
pregnant
females;
no
evidence
that
the
research
was
fundamentally
unethical

Inadequate
information
provided
to
support
consent

Some
deficiencies
relative
to
the
1975
Declaration
of
Helsinki

We
welcome
the
Board's
advice
on
the
significance
of
these
deficiencies
28
Carbofuran
Dermal
(
78)
Study
Carbofuran
Dermal
(
78)
Study

Conducted
in
1978
at
Quincy
Research

Reviewed
and
approved
by
Community
Review
Committee,
Inc.

20
healthy
adult
male
volunteers

Comparison
of
effects
from
two
different
formulations

High
temperature
and
humidity
29
Carbofuran
Dermal
(
78)

Carbofuran
Dermal
(
78)
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports

Subjects
told
research
was
essential
to
determine
safe
levels
of
exposure
for
workers

Purpose
"
to
compare
effects
of
single
cutaneous
applications
of
[
2
formulations]"

2.
Scientific
Validity:
Defer
to
others
30
Carbofuran
Dermal
(
78)

Carbofuran
Dermal
(
78)
"
Framework
Framework"
­­

­­
2
3.
Subject
Selection

Adult
male
volunteers
from
pool
at
laboratory 

mainly
semi­
skilled
workers
without
steady
employment

Demographics
of
pool
described
in
unusual
detail

No
evidence
of
use
of
vulnerable
groups
31
Carbofuran
Dermal
(
78)

Carbofuran
Dermal
(
78)
"
Framework
Framework"
­­

­­
3
4.
Risk­
Benefit
Ratio

Study
design
did
not
minimize
risk
to
subjects

Conducted
in
clinic
with
medical
supervision

Atropine
available
as
antidote

Subjects
told
of
possible
symptoms

Subjects
told
the
study
would
not
benefit
them
directly;
societal
benefits
not
addressed

Subject
compensation
not
reported
32
Carbofuran
Dermal
(
78)

Carbofuran
Dermal
(
78)
"
Framework
Framework"
­­

­­
4
5.
Independent
Ethics
Review

Protocol
and
IC
process
and
materials
asserted
to
have
been
approved
by
the
Community
Review
Committee,
Inc.


Committee
discussion
not
reported

Unusually
complete
information
provided
about
the
review
committee
33
Carbofuran
Dermal
(
78)

Carbofuran
Dermal
(
78)
"
Framework
Framework"
­­

­­
5
6.
Informed
Consent

Consent
form
described
the
procedure
and
possible
physical
effects
adequately

Purpose
of
study
described
to
subjects
as
to
establish
"
maximum
safe
dosage"


Subjects
not
told
dose
escalation
would
continue
until
toxic
signs
induced

"
Purposes,
procedures,
and
risks"
explained
before
subjects
were
asked
to
sign
consent
34
Carbofuran
Dermal
(
78)

Carbofuran
Dermal
(
78)
"
Framework
Framework"
­­

­­
6
7.
Respect
for
Subjects

Subject
privacy
was
not
compromised

Subjects
were
free
to
withdraw
without
penalty
35
Carbofuran
Dermal
(
78)
Prevailing
Standard
Carbofuran
Dermal
(
78)
Prevailing
Standard

Conducted
in
US
in
1978

Cited
no
standard
of
ethical
conduct

FIFRA
§
12(
a)(
2)(
P)
applicable

Declaration
of
Helsinki
(
1975)
assumed
to
have
prevailed
36
FIFRA
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

"
It
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."
37
FIFRA
FIFRA
§
12(
a)(
2)(
P)

12(
a)(
2)(
P)

Subjects
were
not
told
that
dose
would
escalate
until
toxic
signs
were
induced

Subjects
were
told
study
was
to
establish
"
maximum
safe
dose",
and
that
"
the
nature
of
the
test
compound
.
.
.
is
such
that
we
do
not
expect
serious
complications"

Subjects
were
not
fully
informed
of
"
any
physical
consequences
.
.
.
foreseeable."
38
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
2:
"
The
design
.
.
.
of
each
experimental
procedure
involving
human
subjects
should
be
clearly
formulated
in
an
experimental
protocol"

EPA
Comment:
Protocol
not
included
in
report
39
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
Principle
#
5:
"
Every
.
.
.
project
.
.
.

should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
with
foreseeable
benefits
to
the
subject
or
to
others.
Concern
for
the
interests
of
the
subject
must
always
prevail
.
.
."

EPA
Comment:
If
a
careful
assessment
was
conducted
it
was
not
reported.
40
Carbofuran
Dermal
(
78)
Summary
Carbofuran
Dermal
(
78)
Summary

Some
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence"

No
children;
no
pregnant
females;
no
evidence
that
the
research
was
fundamentally
unethical

Inadequate
information
provided
to
support
consent

Some
deficiencies
relative
to
the
1975
Declaration
of
Helsinki

We
welcome
the
Board's
advice
on
the
significance
of
these
deficiencies