Document ID: EPA-HQ-ORD-2006-0187-0092
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

1
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.
2
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.
3
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.
4
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.
5
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.
6
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;
7
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
8
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
9
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
10
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.