Document ID: EPA-HQ-ORD-2006-0187-0093
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
Gledhill,
A.
J.
(
1997)
Dichorvos:
A
Single­
Blind,
Placebo
Controlled,
Randomised
Study
to
Investigate
the
Effects
of
Multiple
Oral
Dosing
on
Erythrocyte
Cholinesterase
Inhibition
in
Healthy
Male
Volunteers.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Laboratory
and
Medeval
Ltd.
52
p.
(
MRID
44248801)

Jairath,
M.
(
1996)
Final
Protocol:
A
Single­
Blind,
Placebo
Controlled,
Randomised
Study
to
Investigate
the
Effect
of
Multiple
Oral
Dosing
of
Dichlorvos
on
Erythrocyte
Cholinesterase
Inhibition
in
Healthy
Male
Volunteers.
Unpublished
protocol
dated
24
Sept
1996,
prepared
by
Medeval
Ltd.,
Manchester,
UK,
under
Medeval
Code
No:

ME0370
and
Sponsor
Code
No:
XH6063.
Unpaginated.
Included
as
Appendix
A­
8
in
MRID
46774601.
2
DDVP
21
DDVP
21­
Day
Oral
Study
Day
Oral
Study

Conducted
at
Medeval
(
UK)
in
1997

Subjects
non­
resident,
unsupervised;

self­
reported
effects

Subjects'
ChE
continued
to
decline
after
end
of
dosing

Subjects
not
followed
until
ChE
returned
to
baseline
3
DDVP
DDVP
"
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

Volunteers
required
to
be
of
same
race

No
evidence
of
use
of
vulnerable
groups
4
DDVP
DDVP
"
Framework
Framework"
­­

­­
2
4.
Risk­
Benefit
Ratio

Risks
to
subjects
not
described
in
report

Risk
minimization
not
discussed

Societal
or
other
benefits
not
addressed

Weighing
of
societal
benefits
against
risks
to
subjects
not
addressed

Subjects
compensated
£
330
5
DDVP
DDVP
"
Framework
Framework"
­­

­­
3
5.
Independent
Ethics
Review

Protocol
approved
by
Medeval
Independent
Ethics
Committee

Committee
members
names
redacted
in
supplemental
submission

Independence
from
investigators
inadequately
documented

Freedom
from
conflicts
of
interest
not
addressed
6
DDVP
DDVP
"
Framework
Framework"
­­

­­
4
6.
Informed
Consent

Consent
was
obtained
from
all
subjects

Volunteer
information
covered
procedure
adequately,
but
was
less
complete
on
other
topics,
especially
the
nature
and
distribution
of
benefits

Many
potentially
confusing
references
to
drugs
and
drug
regulation
7
DDVP
DDVP
"
Framework
Framework"
­­

­­
5
7.
Respect
for
Subjects

Subjects'
privacy
was
protected

Subjects
were
free
to
withdraw

Delay
in
ChE
testing
of
subjects
with
>
20%
ChEI
made
stopping
criterion
non­
protective

3
subjects
had
lowest
ChE
in
final
post­
test
exam

No
treated
subjects
followed
until
return
to
baseline
ChE
8
DDVP
Prevailing
Standard
DDVP
Prevailing
Standard

Conducted
in
the
UK
in
1996­
7

Cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1989)
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
#
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
over
the
interests
of
science
and
society."

EPA
Comment:
If
a
careful
assessment
of
risks
and
benefits
was
conducted,
it
was
not
reported.
Failure
to
follow
the
subjects
medically
until
their
ChE
activity
returned
to
pre­
test
baseline
levels
suggests
that
the
interests
of
the
subjects
may
not
have
prevailed
11
Comparison
to
Comparison
to
DoH
DoH
­­

­­
3

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
12
Comparison
to
Comparison
to
DoH
DoH
­­

­­
4

Non­
Therapeutic
Principle
#
3.
"
The
investigator
or
the
investigating
team
should
discontinue
the
research
if
in
his/
her
or
their
judgment
it
may,
if
continued,
be
harmful
to
the
individual."

Non­
Therapeutic
Principle
#
4.
"
In
research
on
man,
the
interest
of
science
and
society
should
never
take
precedence
over
considerations
related
to
the
well­
being
of
the
subject."
13
Comparison
to
Comparison
to
DoH
DoH
­­

­­
5

EPA
Comment:
Continued
dosing
and
ten­
day
delay
in
re­
testing
subjects
with
>
20%
ChEI
on
day
18,
and
failure
to
follow
all
subjects
until
return
to
pretest
ChE
levels,
suggest
the
interests
of
subjects
may
not
have
prevailed.

In
addition,
releasing
subjects
each
day
after
dosing
placed
primary
responsibility
on
the
subjects
for
monitoring
their
safety.
14
DDVP
Summary
DDVP
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
1989
Declaration
of
Helsinki.

We
welcome
the
Board's
advice
on
the
significance
of
those
deficiencies.
15
DDVP
Methyl
Charge
to
the
HSRB
DDVP
Methyl
Charge
to
the
HSRB
Like
AZM,
DDVP
is
an
organophosphate
pesticide
(
OP)
which
elicits
neurotoxicity
through
the
inhibition
of
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route,
multi­
duration)
risk
assessment
of
DDVP.
In
addition,
DDVP
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,

multi­
route)
risk
assessment
for
the
OPs.
16
DDVP
Charge
to
the
HSRB
DDVP
Charge
to
the
HSRB
1.
Scientific
considerations:

a.
The
Agency's
WOE
document
and
DER
for
DDVP
describe
the
study
design
and
results
of
the
DDVP
repeat
dose,
oral
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
this
study
in
the
aggregate
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
OPs.
For
the
single
chemical
risk
assessment,
the
Agency
has
concluded
that
the
human
study
is
sufficiently
robust
for
developing
a
point
of
departure
for
estimating
dermal,
incidental
oral,
and
inhalation
risk
from
exposure
to
DDVP
in
the
single
chemical
risk
assessment.
17
DDVP
Charge
to
the
HSRB
DDVP
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

a.
For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
results
of
the
DDVP
multi­
dose
human
toxicity
study
do
not
support
reducing
the
default
10X
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.
18
DDVP
Charge
to
the
HSRB
DDVP
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

Please
comment
on
the
scientific
evidence
that
supports:

i.
the
Agency's
conclusions
for
use
of
the
human
study
for
developing
a
point
of
departure
for
estimating
risk
in
the
single
chemical,
aggregate
risk
assessment
and,

ii.
the
Agency's
determination
that
the
human
study
cannot
be
used
to
reduce
the
interspecies
factor
in
the
cumulative
risk
assessment.
19
DDVP
Charge
to
the
HSRB
DDVP
Charge
to
the
HSRB
1.
Scientific
considerations,
cont'd:

b.
The
Agency
has
concluded
that
other
human
studies
made
available
to
the
Board
do
not
provide
sufficient
scientifically
sound
information
to
warrant
any
reduction
in
the
10X
inter­
species
uncertainty
factor
used
to
derive
reference
dose
values
for
DDVP
based
on
animal
toxicity
endpoints.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.
20
DDVP
Charge
to
the
HSRB
DDVP
Charge
to
the
HSRB
2.
Ethical
considerations:

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


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
consent
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
21
DDVP
Charge
to
the
HSRB
DDVP
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
administration
of
the
test
material
for
three
additional
days
without
monitoring
subjects'
cholinesterase
levels
following
the
detection
of
cholinesterase
inhibition
>
20
%
in
some
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
22
DDVP
Charge
to
the
HSRB
DDVP
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
lack
of
medical
surveillance
of
subjects,
following
the
termination
of
dosing,
to
establish
the
subjects'
cholinesterase
levels
returned
to
normal
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
23
DDVP
Charge
to
the
HSRB
DDVP
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
the
Gledhill
repeated
dose
study:


OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
24
DDVP
Charge
to
the
HSRB
DDVP
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
Gledhill
repeat
dose
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.