Document ID: EPA-HQ-ORD-2006-0187-0084
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
Campbell,
J.
(
1984)
A
Comparison
of
the
metabolism
of
14­
C
Amitraz
in
rat,

mouse,
baboon
and
human.
Unpublished
study
performed
by
FBC
Ltd.,

Chesterford
Park
Research
Station,
UK,
under
project
number
Metab/
84/
01.
20
p.
MRID
00160964.

Campbell,
J.;
Needham,
D.
(
1984)
Urinary
Excretion
of
(
Carbon
14)­
Amitraz
by
Two
Humans
Following
a
Single
Oral
Dose
of
0.25
mg/
kg
Bodyweight:
M70.

Unpublished
study
performed
by
FBC
Ltd.,
Chesterford
Park
Research
Station,

UK,
under
project
number
Metab/
84/
10,
17L.
12
p.
MRID
46249601
2
Amitraz
84
Metabolism
Study
Amitraz
84
Metabolism
Study

Conducted
at
FBC
Ltd.,
Chesterford
Park
Research
Station
in
UK
in
1984

Component
of
multi­
species
study
of
comparative
metabolism
3
Amitraz
84
Amitraz
84
"
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
unknown
pool

Subjects
may
have
been
lab
employees
4
Amitraz
84
Amitraz
84
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

No
information
relevant
to
assessing
the
relation
of
research
risks
and
benefits
was
reported

Neither
risks
to
subjects
nor
their
minimization
was
discussed

The
rationale
for
dose
selection
at
1/
40
the
animal
dose
was
not
reported

Neither
societal
benefits
nor
their
relation
to
subject
risks
is
discussed
5
Amitraz
84
Amitraz
84
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

No
mention
of
ethics
oversight
or
independent
review

No
standard
of
ethical
conduct
cited
6.
Informed
Consent

"
Two
healthy
adult
human
males
volunteered
to
participate
in
the
experiment
and
consented
to
the
administration
of
the
radio­
active
dose."
6
Amitraz
84
Amitraz
84
"
Framework
Framework"
­­

­­
4
7.
Respect
for
Subjects

Subject
confidentiality
was
not
compromised
in
the
report.


No
mention
was
made
of
whether
they
were
free
to
withdraw.


The
failure
to
monitor
subjects
until
pulse
and
blood
pressure
returned
to
normal,
and
the
disturbing
report
of
adverse
effects
persisting
beyond
the
period
of
observation,
suggest
less
than
full
commitment
to
the
welfare
of
the
subjects.
7
Amitraz
84
Prevailing
Standard
Amitraz
84
Prevailing
Standard

Research
conducted
in
UK
in
1984

No
standard
of
ethical
conduct
cited

Declaration
of
Helsinki
(
1983)
assumed
to
have
prevailed
8
Comparison
to
Comparison
to
DoH
DoH

Basic
Principle
#
2:
"
The
design
and
performance
of
each
experimental
procedure
involving
human
subjects
should
be
clearly
formulated
in
an
experimental
protocol
which
should
be
transmitted
to
a
specially
appointed
independent
committee
for
consideration,

comment
and
guidance."

EPA
Comment:
The
protocol
is
not
available.
There
is
no
indication
that
it
was
transmitted
to
a
specially
appointed
independent
committee
for
review.
9
Comparison
to
Comparison
to
DoH
DoH
­­

­­
2

Basic
Principle
#
3:
"
The
responsibility
for
the
human
subject
must
always
rest
with
a
medically
qualified
person
and
never
rest
on
the
subject
of
the
research,
even
though
the
subject
has
given
his
or
her
consent."

EPA
Comment:
The
investigators'
failure
to
extend
the
period
of
observation
until
all
signs
of
effects
had
returned
to
normal,
and
their
report
of
effects
which
persisted
beyond
the
period
of
observation,
suggest
that
responsibility
was
inappropriately
placed
on
the
subjects
to
monitor
and
report
effects.
10
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.
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
4

Basic
Principle
#
9:
".
.
.
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
freely­
given
informed
consent,
preferably
in
writing."

EPA
Comment:
The
study
reports
that
the
subjects
volunteered
and
consented
to
receive
the
radio­
labeled
dose,

but
is
silent
with
respect
to
what
they
were
told
12
Comparison
to
Comparison
to
DoH
DoH
­­

­­
5

Basic
Principle
#
12:
"
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."

EPA
Comment:
No
protocol
was
included
in
the
report.
Neither
the
Declaration
nor
any
other
standard
was
cited,
nor
was
there
any
discussion
of
ethical
considerations
13
Amitraz
84
Summary
Amitraz
84
Summary

There
are
many
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
1964
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
14
Amitraz
Amitraz
Charge
to
the
HSRB
Charge
to
the
HSRB
Exposure
to
amitraz
can
result
in
neurotoxicity
as
evidenced
by
clinical
signs
such
as
ataxia,
ptosis,

emesis,
labored
respiration,
muscular
weakness,

tremors,
hypothermia
and
bradycardia.
The
Agency
is
conducting
an
aggregate
(
single
chemical,

multiroute
risk
assessment
of
amitraz.
15
Amitraz
Amitraz
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations:

The
Agency's
WOE
document
and
DERs
for
amitraz
describe
the
study
design
and
results
of
the
amitraz
acute
oral
and
dermal
toxicity
human
studies
and
the
human
metabolism
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
studies
in
the
single
chemical
risk
assessment
for
acute
and
chronic
oral
exposures
in
addition
to
dermal
and
inhalation
exposures
of
various
durations.
For
oral
exposure,
the
Agency
has
concluded
that
the
combined
results
from
the
single
oral
dose
study
and
human
metabolism
study
establishes
a
dose
response
relationship
in
human
subjects
and
that
the
single
oral
dose
study
is
appropriate
for
developing
a
point
of
departure
for
acute
and
chronic
dietary
risk,
short­
term
oral
exposure,
and
inhalation
exposures
of
various
durations.
16
Amitraz
Amitraz
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

The
Agency
has
further
concluded
that
the
human
dermal
study
is
appropriate
for
developing
a
point
of
departure
for
dermal
exposures
of
various
durations.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.
17
Amitraz
Amitraz
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

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


With
respect
to
the
Campbell
(
1984)
research,
whether
the
lack
of
medical
surveillance
of
subjects,
following
the
termination
of
dosing,
to
establish
that
subjects'
signs
of
adverse
effects
had
returned
to
normal
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
18
Amitraz
Amitraz
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

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


With
respect
to
the
Cass
(
1992)
and
the
Langford
(
1998)

studies,
whether
references
to
the
test
material
as
a
drug
and
other
statements
that
could
indicate
the
study
constituted
medical
research,
that
appear
in
the
materials
used
to
obtain
informed
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
19
Amitraz
Amitraz
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

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


OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.


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.