Page
1
of
8
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
APR
11,
2006
MEMORANDUM:
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
SUBJECT:
Initial
Ethical
Review
of
Hexavalent
Chromium
Human
Sensitization
Study
FROM:
John
M.
Carley
TO:
Timothy
McMahon,
AD
Timothy
Leighton,
AD
REF:
Nethercutt,
J.,
Paustenbach,
D.,
Adams,
R,
et
al.(
1994)
A
study
of
chromium
induced
allergic
contact
dermatitis
with
54
volunteers:
implications
for
environmental
risk
assessment.
Occup.
Environ
Med
1994;
51:
371­
380.
(
MRID
46803602)

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
clinical
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.
and
Canada
in
1992;
it
cites
no
standard
of
ethical
conduct.
I
have
assumed
that
the
standards
prevailing
when
the
research
was
conducted
were
45
CFR
Part
46
(
the
precursor
of
the
Common
Rule)
and
the
Declaration
of
Helsinki
(
1989).
Page
2
of
8
A.
Summary
Assessment
of
Ethical
Conduct
of
the
Research
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
is
a
careful
and
thorough
study,
designed
to
provide
a
solid
basis
for
environmental
risk
assessments
involving
Cr(
VI).
It
was
designed
to
address
directly
many
of
the
questions
raised
by
inconsistencies
among
earlier
studies.

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
selected
from
patient
files
by
the
six
participating
dermatologists.
Study
design
required
subjects
who
were
Cr(
VI)
sensitive.
Inclusion
and
exclusion
criteria
seem
sound.

4.
Risk­
Benefit
Ratio:
Risk
to
subjects
was
characterized
as
"
allergic
dermatitis
of
type
IV,
a
delayed
or
cell­
mediated
reaction
.
.
.
similar
to
a
"
poison
oak"
hypersensitive
reaction,
.
.
.
elicits
the
standard
symptoms
of
erythema,
oedema,
and
small
vesicles.
.
.
.
Reactions
are
most
often
not
life
threatening
and
their
effect
is
generally
limited
to
the
skin.
"
(
p.
371)
The
highest
dose
administered
was
described
as
that
normally
used
in
dermatologic
practice
to
diagnose
Cr(
VI)
sensitivity;
all
subsequent
testing
was
at
levels
from
5x
to
244x
below
this
level.
There
is
no
explicit
discussion
of
how
societal
benefits
were
weighed
against
risks
to
individual
subjects.

5.
Independent
Ethical
Review:
The
study
reports
only
that
"[
t]
he
physicians
received
approval
from
their
respective
human
use
committees."
All
five
US­
based
institutions
involved
in
the
clinical
phase
of
the
work
now
hold
Federal­
Wide
Assurances
from
OHRP;
their
status
in
1992
is
unknown.

6.
Informed
Consent:
The
report
asserts
that
written
consent
was
obtained
from
all
subjects,
but
does
not
describe
what
they
were
told,
or
by
whom,
and
does
not
acknowledge
the
potential
role
conflict
for
the
doctor/
investigators.
Since
volunteers
were
recruited
from
among
the
past
patients
of
the
investigators,
the
shift
in
role
from
personal
physician
to
investigator
(
and
each
volunteer's
own
change
from
patient
to
subject)
may
not
have
been
clear
to
them.
There
is
also
no
mention
of
how
additional
consent
may
have
been
obtained
from
the
thirteen
subjects
who
also
took
part
in
the
special
supplemental
studies.

7.
Respect
for
Potential
and
Enrolled
Subjects:
Subjects'
privacy
was
not
compromised.
Although
their
freedom
to
withdraw
was
not
discussed,
eleven
potential
subjects
are
reported
to
have
withdrawn
"
for
personal
reasons"
before
any
testing
began.
Page
3
of
8
B.
Compliance
with
Ethical
Standards
Prevailing
when
the
Research
Was
Conducted
Some
deficiencies
are
apparent
when
this
study
is
reviewed
against
the
principles
of
the
Declaration
of
Helsinki
(
1989),
assumed
to
have
prevailed
when
the
research
was
conducted:

 
General
principle
#
2
of
the
Declaration
reads
in
part
"
The
design
and
performance
of
each
experimental
procedure
involving
human
subjects
should
be
clearly
formulated
in
an
experimental
protocol
which
should
be
transmitted
for
consideration,
comment
and
guidance
to
a
specially
appointed
committee
independent
of
the
investigator
and
the
sponsor.
.
.
."
No
protocol
is
included
in
the
report;
the
reviewing
ethics
committees
are
inadequately
identified,
and
the
scope
of
their
review
is
undocumented.

 
General
principle
#
4
of
the
Declaration
reads
"
Biomedical
research
involving
human
subjects
cannot
legitimately
be
carried
out
unless
the
importance
of
the
objective
is
in
proportion
to
the
inherent
risk
to
the
subject."
The
study
report
is
silent
with
respect
to
the
nature
and
distribution
of
benefits
of
the
research,
and
how
they
were
weighed
against
risks
to
the
subjects.

 
General
principle
#
5
of
the
Declaration
reads
in
part
"
every
biomedical
research
project
involving
human
subjects
should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
with
foreseeable
benefits
to
the
subject
or
to
others."
If
such
a
careful
assessment
was
conducted
it
was
not
reported.

 
General
principle
#
9
of
the
Declaration
reads
"
in
any
research
on
human
beings,
each
potential
subject
must
be
adequately
informed
of
the
aims,
methods,
anticipated
benefits
and
potential
hazards
of
the
study
and
the
discomfort
it
may
entail.
He
or
she
should
be
informed
that
he
or
she
is
at
liberty
to
abstain
from
participation
in
the
study
and
that
he
or
she
is
free
to
withdraw
his
or
her
consent
to
participation
at
any
time.
The
physician
should
then
obtain
the
subject's
freelygiven
informed
consent,
preferably
in
writing."
Although
the
study
reports
obtaining
consent
from
all
subjects,
it
is
silent
with
respect
to
informing
the
subjects.

 
General
principle
#
10
of
the
Declaration
reads
"
when
obtaining
informed
consent
for
the
research
project
the
physician
should
be
particularly
cautious
if
the
subject
is
in
a
dependent
relationship
to
him
or
her
or
may
consent
under
duress.
In
that
case
the
informed
consent
should
be
obtained
by
a
physician
who
is
not
engaged
in
the
investigation
and
who
is
completely
independent
of
this
official
relationship."
Subjects
were
recruited
from
among
the
investigators'
patients.
The
role
shift
from
doctor
to
investigator,
and
from
patient
to
subject,
is
not
acknowledged.
The
specific
reference
to
"
volunteers"
providing
"
their
doctors"
with
written
consent
highlights
this
role
ambiguity.

 
General
principle
#
12
of
the
Declaration
reads
"
the
research
protocol
should
always
contain
a
statement
of
the
ethical
considerations
involved
and
should
Page
4
of
8
indicate
that
the
principles
enunciated
in
the
present
Declaration
are
complied
with."
The
study
report
is
silent
with
respect
to
ethical
considerations
involved.

 
Principle
#
6
for
"
Medical
Research
Combined
with
Professional
Care"
in
the
Declaration
reads
"
the
physician
can
combine
medical
research
with
professional
care,
the
objective
being
the
acquisition
of
new
medical
knowledge,
only
to
the
extent
that
medical
research
is
justified
by
its
potential
diagnostic
or
therapeutic
value
for
the
patient."
The
potential
diagnostic
or
therapeutic
value
for
the
subjects
of
this
research
is
not
addressed.

In
addition,
the
following
deficiencies
are
apparent
when
this
study
is
reviewed
against
the
requirements
of
45
CFR
Part
46:

 
Section
46.109(
b)
reads
in
part
"[
a]
n
IRB
shall
require
that
information
given
to
subjects
as
part
of
informed
consent
is
in
accordance
with
Sec.
46.116."
The
study
report
is
silent
with
respect
to
the
information
provided
to
subjects
as
part
of
informed
consent.

 
Section
46.111
defines
criteria
for
IRB
approval
of
research.
There
is
no
documentation
of
the
IRB's
determination
that
all
these
requirements
were
satisfied.

 
Section
46.116
defines
general
requirements
for
informed
consent.
It
is
not
possible
to
determine
if
they
were
satisfied
by
this
study.

C.
Standard
for
Judging
Ethical
Acceptability
On
February
6,
2006,
EPA
published
a
final
rule
amending
40
CFR
Part
26,
"
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
April
7,
2006,
if
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent),
or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted.

This
research
was
conducted
before
the
effective
date
of
this
rule;
thus
this
criterion
is
applicable
for
judging
its
ethical
acceptability.

D.
Conclusion
Although
there
are
some
gaps
in
the
documentation
of
the
ethical
conduct
of
this
study,
there
is
no
clear
evidence
that
the
research
was
intended
to
harm
participants,
or
that
it
was
Page
5
of
8
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
several
deficiencies
relative
to
the
standards
of
the
1989
Declaration
of
Helsinki
and
the
HHS
regulations
(
45
CFR
Part
46,
subpart
A)
in
effect
when
this
research
was
conducted.
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
6
of
8
Framework
for
Ethical
Assessment
Using
Seven
Criteria
of
Emanuel
et
al.
1
April
10,
2006
Nethercutt,
J.,
Paustenbach,
D.,
Adams,
R,
et
al.(
1994)
A
study
of
chromium
induced
allergic
contact
dermatitis
with
54
volunteers:
implications
for
environmental
risk
assessment.
Occup.
Environ
Med
1994;
51:
371­
380.
(
MRID
46803602)

1.
Value:
This
is
a
careful
and
thorough
study,
designed
to
provide
a
solid
basis
for
environmental
risk
assessments
involving
Cr(
VI).
It
was
designed
to
address
directly
many
of
the
questions
raised
by
inconsistencies
among
earlier
studies.

a.
What
was
the
stated
purpose
of
the
research?
"
To
determine
the
area­
based
[
minimum
elicitation
threshold]
MET
(
ug
Cr/
Cm
2
skin)
of
solubilised
Cr(
VI)
and
Cr(
III)
that
will
elicit
allergic
contact
dermatitis
in
chromium­
sensitized
subjects."
(
p.
372)
A
secondary
purpose
was
to
replace
several
old
studies
with
poor
methods
and
inconsistent
results
with
better
data,
usable
for
risk
assessment.

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?
This
study
test
two
"
supplemental"
hypotheses:
(
1)
that
allergen
per
unit
area
of
skin
is
a
better
measure
of
dose
than
the
concentration
of
allergen
in
the
patch,
and
(
2)
that
sub­
MET
doses
over
a
larger
surface
area
might
elicit
a
response
at
lower
concentrations
than
the
METs
identified.

d.
Will
society
benefit
from
the
knowledge
gained
from
this
research?
Will
its
results
be
disseminated?
The
results
of
this
research
have
been
published,
to
the
benefit
of
society.

e.
What
government,
organization,
company
and/
or
institution(
s)
funded
the
research?
Not
reported
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
1(
a)
and
1(
c)
above.

b.
Was
the
research
designed
using
accepted
principles,
methods,
and
reliable
practices?
I
defer
to
science
reviewers.

c.
In
what
way
were
human
subjects
intentionally
dosed
in
this
research,
and
what
endpoints
were
identified
or
measured?
102
subjects
previously
diagnosed
as
Cr(
VI)­
sensitive
were
given
a
"
diagnostic
dose"
of
4.4
ug
Cr(
VI)/
cm
2
skin
to
confirm
sensitivity.
54
subjects
with
confirmed
sensitivity
at
this
dose
were
then
given
doses
of
0.018
and
0.088
ug/
cm
2
(
round
2)
and,
if
no
response,
additional
doses
of
0.18
and
0.88
ug/
cm
2
(
round
3).
Nine
subjects
also
participated
in
a
test
at
0.88
ug/
cm
2
comparing
concentration
of
allergen
per
unit
area
of
skin
and
concentration
of
allergen
per
unit
mass
of
patch
as
measures
of
dose,
and
four
subjects
who
had
shown
an
MET
at
0.88
ug/
cm
2
were
re­
tested
with
five
patches
at
0.18
ug/
cm
2
.
Endpoint
measured
was
allergic
contact
dermatitis.

d.
Did
the
research
design
have
sufficient
power
to
definitively
test
the
objective?
An
extensive
discussion
of
statistical
issues
in
defining
sample
size
appears
on
p.
374
Page
7
of
8
e.
To
what
purpose
is
the
study
used,
or
proposed
for
use,
in
the
Agency?
Risk
assessment
for
pesticide
registration
of
ACC
as
wood
preservative
3.
Fair
Subject
Selection:
Subjects
were
selected
from
patient
files
by
the
six
participating
dermatologist/
investigators.
Study
design
required
subjects
who
were
Cr(
VI)­
sensitive.
Inclusion
and
exclusion
criteria
seem
sound.
There
is
no
indication
that
any
subjects
came
from
particularly
vulnerable
groups,
but
all
were
recruited
from
among
the
participating
dermatologists'
patients.
No
mention
is
made
of
the
potential
for
role
ambiguity
as
doctors
became
investigators
and
invited
their
patients
to
become
research
subjects.

a.
Were
the
groups
and
individuals
recruited
and
enrolled
determined
solely
on
the
basis
of
the
scientific
goals
of
the
study?
6000
patient
files
were
screened;
113
potential
subjects
were
found;
11
dropped
out
for
personal
reasons.
102
subjects
participated
in
round
1
to
confirm
Cr(
VI)
sensitivity;
54
participated
in
later
rounds.

b.
Were
any
susceptible
groups
used
in
the
study,
such
as
children,
prisoners,
infirm,
or
impoverished;
or
did
the
burden
of
participation
fall
disproportionately
on
a
particular
group?
All
subjects
were
over
18.
None
were
pregnant.
All
but
five
were
employed;
those
five
were
described
as
retired.
There
is
no
indication
that
any
subjects
came
from
particularly
vulnerable
groups,
but
all
were
recruited
from
among
the
participating
dermatologists'
patients.
No
mention
is
made
of
the
potential
for
role
ambiguity
as
doctors
became
investigators
and
invited
their
patients
to
become
research
subjects.

4.
Favorable
Risk­
Benefit
Ratio:
Risk
to
subjects
was
characterized
as
"
allergic
dermatitis
of
type
IV,
a
delayed
or
cell­
mediated
reaction
.
.
.
similar
to
a
"
poison
oak"
hypersensitive
reaction,
.
.
.
elicits
the
standard
symptoms
of
erythema,
oedema,
and
small
vesicles.
...
Reactions
are
most
often
not
life
threatening
and
their
effect
is
generally
limited
to
the
skin.
"
(
p.
371)
The
highest
dose
administered
was
described
as
that
normally
used
in
dermatologic
practice
to
diagnose
Cr(
VI)
sensitivity;
all
subsequent
testing
was
at
levels
from
5x
to
244x
below
this
level.
There
is
no
explicit
discussion
of
how
societal
benefits
were
weighed
against
risks
to
individual
subjects.

a.
How
were
the
risks
to
individual
subjects
minimized?
Risk
to
subjects
was
characterized
as
"
allergic
dermatitis
of
type
IV,
a
delayed
or
cell­
mediated
reaction
.
.
.
similar
to
a
"
poison
oak"
hypersensitive
reaction,
.
.
.
elicits
the
standard
symptoms
of
erythema,
oedema,
and
small
vesicles.
...
Reactions
are
most
often
not
life
threatening
and
their
effect
is
generally
limited
to
the
skin.
"
(
p.
371)
The
highest
dose
administered
was
described
as
that
normally
used
in
dermatologic
practice
to
diagnose
Cr(
VI)
sensitivity;
all
subsequent
testing
was
at
levels
from
5x
to
244x
below
this
level.

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?
Nearly
half
the
subjects
in
round
1
(
48/
102)
benefited
directly
by
learning
that
they
were
not,
after
all,
sensitive
to
Cr(
VI).
In
addition,
the
study
provides
a
basis
for
rigorous
risk
assessment
of
Cr(
VI)
in
the
environment.
There
is
no
explicit
discussion
of
how
societal
benefits
were
weighed
against
risks
to
individual
subjects.

c.
What
compensation
was
paid
to
the
participants
in
the
study?
Not
reported.

5.
Independent
Review:
The
study
reports
only
that
"[
t]
he
physicians
received
approval
from
their
respective
human
use
committees
as
appropriate."
All
five
US­
based
institutions
involved
in
the
clinical
phase
of
the
work
(
Johns
Hopkins
Univ.,
Stanford
Univ.,
Univ
of
Louisville,
Pennsylvania
State
Univ.,
and
Cleveland
Clinic
Foundation)
now
hold
FWAs
from
OHRP;
their
status
in
1992
is
unknown.
Page
8
of
8
a.
Was
the
research
asserted
to
have
been
overseen
by
an
ethics
review
body?
Yes.

b.
Was
the
research
subject
to
independent
review
by
individuals
unaffiliated
with
the
clinical
research?
The
report
says
only
that
"[
t]
he
physicians
received
approval
from
their
respective
human
use
committees
as
appropriate."
(
p.
374)

c.
Was
the
research
conducted
in
compliance
with
the
Common
Rule?
The
research
was
conducted
very
soon
after
promulgation
of
the
Common
Rule,
but
as
practicing
dermatologists
the
investigators
were
likely
familiar
with
the
earlier
DHEW
rules
at
45
CFR
Part
46.

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?
All
five
US­
based
institutions
involved
in
the
clinical
phase
of
the
work
(
Johns
Hopkins
Univ.,
Stanford
Univ.,
Univ
of
Louisville,
Pennsylvania
State
Univ.,
and
Cleveland
Clinic
Foundation)
now
hold
FWAs
from
OHRP;
their
status
in
1992
is
unknown.

e.
Was
the
research
conducted
in
compliance
with
another
standard?
What
standard?
n/
a
6.
Informed
Consent:
The
report
asserts
that
written
consent
was
obtained
from
all
subjects,
but
does
not
describe
what
they
were
told,
or
by
whom,
and
does
not
acknowledge
the
potential
role
conflict
for
the
doctor/
investigators.
Since
volunteers
were
recruited
from
among
the
past
patients
of
the
investigators,
the
shift
in
role
from
personal
physician
to
investigator
(
and
each
volunteer's
own
change
from
patient
to
subject)
may
not
have
been
clear
to
them.
The
report
is
silent
about
whether
or
how
separate
consent
may
have
been
obtained
from
the
thirteen
subjects
who
participated
in
follow­
up
testing.

a.
Does
the
research
assert
that
informed
consent
was
obtained
from
participants?
Yes
b.
How
and
under
what
circumstances
was
informed
consent
obtained?
"
All
volunteers
provided
their
doctors
with
written
consent
to
participate
in
the
study".
(
p.
374)
What
potential
subjects
were
told,
and
by
whom,
is
not
reported.

7.
Respect
for
Potential
and
Enrolled
Subjects:
Subjects'
privacy
was
not
compromised.
Although
their
freedom
to
withdraw
was
not
discussed,
eleven
potential
subjects
are
reported
to
have
withdrawn
"
for
personal
reasons"
before
any
testing
began.

a.
Was
information
about
individual
subjects
managed
so
as
to
ensure
their
privacy?
Yes.

b.
Were
subjects
free
to
withdraw
from
the
research
without
penalty?
Not
reported.
Eleven
potential
subjects
were
reported
to
have
withdrawn
"
for
personal
reasons"
from
the
original
group
of
113
former
patients
screened
for
Cr(
VI)
sensitivity.

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