Document ID: EPA-HQ-ORD-2006-0187-0088
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

1
Summary
of
Summary
of
EPA
Ethics
Review
EPA
Ethics
Review
McFarlane,
P.,
Freestone,
S.
(
1999)
A
Randomised
Double
Blind
Placebo
Controlled
Study
with
Azinphos­
Methyl
to
Determine
the
No­
Effect
Level
on
Plasma
and
RBC
Cholinesterase
Activity
after
Repeat
Doses.
Unpublished
study
prepared
by
Inveresk
Clinical
Research,
Ltd.,
Tranent,
UK;
Laboratory
Project
ID
013580.
634
p.
(
MRID
45476101)
2
AZM
28
AZM
28­
Day
Oral
Study
Day
Oral
Study

Conducted
at
Inveresk
Clinical
Research
in
1999

Subjects
resident
in
clinic
throughout
testing

Medical
supervision
throughout
testing

Post­
dose
follow­
up
until
return
to
baseline
3
AZM
AZM
"
Framework
Framework"

1.
Value

Not
published
or
disseminated

Societal
value
not
addressed
in
reports
2.
Scientific
Validity:
Defer
to
others
3.
Subject
Selection

Adult
male
volunteers
from
pool
at
laboratory

No
evidence
of
use
of
vulnerable
groups
4
AZM
AZM
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
adequately
described
to
subjects

Risk
minimization
not
discussed

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed

Subjects
compensated
£
1500
5
AZM
AZM
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

Protocol
approved
by
Inveresk
Independent
Ethics
Committee

Committee
members
named,
but
independence
from
investigators
and
freedom
from
conflicts
of
interest
not
addressed

Neither
the
protocol
amendment
restating
study
objectives
nor
reports
of
the
adverse
events
occurring
during
the
course
of
the
study
were
reported
to
the
ethics
committee
6
AZM
AZM
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Consent
was
obtained
from
all
subjects

Volunteer
information
covered
procedure
and
possible
physical
effects
adequately,
but
was
less
complete
on
other
topics,
especially
the
nature
and
distribution
of
benefits

potentially
confusing
references
to
the
"
supervising
doctor"
and
"
the
company",
neither
of
whom
was
identified
7
AZM
AZM
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Subjects'
privacy
was
protected

Subjects
were
free
to
withdraw
without
penalty
8
AZM
Prevailing
Standard
AZM
Prevailing
Standard

Conducted
in
the
UK
in
1999

Cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1996)

Protocol
promises
compliance
with
the
Guideline
for
Good
Clinical
Practice
(
CPMP/
ICH/
135/
95)
9
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
2:
"[
The]

experimental
protocol
.
.
.
should
be
transmitted
for
consideration,
comment
and
guidance
to
a
specially
appointed
committee
independent
of
the
investigator
and
the
sponsor.
.
.
."

EPA
Comment:
The
independence
of
the
reviewing
ethics
committee
is
inadequately
documented
10
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
Principle
#
4:
"
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."

EPA
Comment:
The
protocol
and
study
report
are
silent
with
respect
to
the
nature
and
distribution
of
benefits
of
the
research,

and
incomplete
in
describing
the
risks
to
the
subjects.
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

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."

EPA
Comment:
If
a
careful
assessment
was
conducted
it
was
not
reported.
12
Comparison
to
Comparison
to
DoH
DoH
­­

­­
4

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

EPA
Comment:
There
is
no
such
statement
in
the
protocol
13
AZM
Summary
AZM
Summary

There
are
some
gaps
in
the
record,
but
gaps
are
not
"
clear
and
convincing
evidence".

There
is
no
evidence
that
the
research
was
fundamentally
unethical.

Some
deficiencies
are
apparent
relative
to
the
cited
1996
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
14
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
Azinphos
methyl
(
AZM)
is
an
organophosphate
pesticide
(
OP).
Consistent
with
other
OPs,
AZM
elicits
neurotoxicity
through
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
At
sufficiently
high
doses,
exposure
to
AZM
can
lead
to
a
variety
of
clinical
signs.
The
Agency
is
developing
an
assessment
to
estimate
risk
to
workers
from
exposure
to
AZM.
In
addition,
AZM
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
risk
assessment
for
the
OPs.
15
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
WOE
document
and
DER
for
AZM
describe
the
study
design
and
results
of
the
AZM
repeat
dose,
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
worker
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
OPs.

For
AZM,
the
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
risk
to
workers
exposed
to
AZM
via
the
dermal
and
inhalation
routes.
16
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
because
no
cholinesterase
inhibition
was
seen
in
the
human
toxicity
study,
it
is
not
possible
to
evaluate
whether
steady
state
had
been
reached
in
humans
at
28
days
of
exposure.
Thus,
the
Agency
has
concluded
that
the
AZM
repeat
dose,
oral,
toxicity
study
is
not
sufficiently
robust
for
informing
the
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.
17
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

Please
comment
on
the
scientific
evidence
that
supports
the
Agency's
conclusions
for:

a.
the
use
of
the
human
toxicity
study
to
develop
a
point
of
departure
for
extrapolation
of
risk
to
workers
in
the
worker
risk
assessment,
and
b.
the
determination
that
the
human
toxicity
study
cannot
be
used
to
inform
the
inter­
species
factor
in
the
cumulative
risk
assessment.
18
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
2.
Ethical
considerations:

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


Whether
the
informed
consent
materials
 

which
refer
to
"
the
company"
and
"
supervising
doctor",
without
further
identification,
and
contain
no
discussion
of
who
would
benefit
from
the
research
 
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and,
19
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

a,
cont'd.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1996
Declaration
of
Helsinki,
Principle
#
5,
with
which
the
research
asserted
compliance)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
20
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
2.
Ethical
considerations:

b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:
provide
comment
on
the
following:


OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.
21
Azinphos
Azinphos
Methyl
Charge
to
the
HSRB
Methyl
Charge
to
the
HSRB
2.
Ethical
considerations:

b,
cont'd.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:
provide
comment
on
the
following:


Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.