Document ID: EPA-HQ-ORD-2006-0187-0123
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-06T04:00Z

DDVP
Human
Studies
 
Charge
Question
1.
b.

Laura
M.
Plunkett,
Ph.
D,
DABT
Integrative
Biostrategies,
LLC
Houston,
Texas
March
2006
Interspecies
Analysis
(
Plunkett
et
al.)

Research
Undertaken
to
Examine
the
Magnitude
of
Interspecies
Differences
in
Adult
Responses
to
DDVP
Exposure
Response
=
Red
Blood
Cell
(
RBC)
Cholinesterase
Inhibition
(
ChEI)

DDVP
Human
Database
is
Uniquely
Large
and
Robust,
With
Studies
Examining
a
Variety
of
Endpoints
and
Issues
 
Pharmaceutical
uses
(
anti­
worming
drug,
geriatric
dementias)

 
Insect
vector
control
(
public
health
studies,
e.
g.,
WHO,
CDC,
FAA)

 
Occupational
exposure
studies
(
regulatory
bodies,
academics,
industry)

 
Product
safety
assessment
(
Amvac
Chemical
Corp.,
Shell
Chemical)

 
Metabolism/
kinetics
 
Data
on
1000 
s
of
people
exposed
to
DDVP
Integrative
Biostrategies,
LLC
science
for
decision­
making
Methods
Used
Very
Large
Available
Human
Database
(
More
than
300
Studies)
Reviewed,
with
Robust
Animal
Database,
to
Identify
Information
Useful
for
Dose­
Response
Analysis
Data/
Study
Inclusion
Criteria
 
Quantifiable
exposure
(
mg
DDVP/
kg/
day)

 
Adequate
description
of
analytical
methods
 
Consistency
of
analytical
method
 
Data
reporting
in
a
quantitative
form
 
No
evidence
of
non­
ethical
study
conduct
 
Data
only
for
adult
(
non­
pregnant)
humans
and
animals
Integrative
Biostrategies,
LLC
science
for
decision­
making
Methods
Used
(
cont'd)

Main
Reasons
Studies
Not
Included
in
this
Analysis
 
Qualitative
statements
of
no
significant
effect,
but
without
quantitative
measurements
necessary
for
this
analysis
 
Studies
of
pro­
drug
form,
making
dose
assessment
problematic
for
this
analysis
 
Studies
on
populations
other
than
non­
pregnant
adults
 
Studies
not
included
provide
valuable
information
on
other
analyses
relevant
to
DDVP
assessment
­
­
e.
g.,
issues
addressing
intraspecies
differences,
pharmacokinetics,

exposure
Exclusion
of
studies
does
not
diminish
their
value
as
part
of
the
whole
human
database
and
for
other
analyses
Comments
on
Studies
Dismissed
by
EPA
in
WOE
and
Used
in
this
Analysis
Gledhill
1997a,
1997b:
EPA
analysis
incorrect
for
failing
to
consider
published
human
and
animal
data
demonstrating
that
cholinesterase
peak
inhibition
in
RBC
with
DDVP
exposure
does
NOT
recover
to
any
significant
extent
within
24
hours
(
Ueda
and
Nishimura
1967;

Nordgren
et
al.
1980;
Plestina
et
al.
1972;
Dingemanse
et
al.
1999)

Slomka
and
Hine
1981:
EPA
comment
incorrect
as
authors
report
a
bioavailability
factor.

Funckes
et
al
1963:
Study
not
used
in
this
analysis.

Johnston
et
al.
2002:
Study
not
used
in
this
analysis.

Shell
Chemical
1970:
Data
used
only
from
adults
(
non­
pregnant).

Smith
et
al.
1972;
Ueda
and
Nishimura
1967;
Witter
et
al.
1961:
EPA
incorrect
because
all
data
points,
regardless
of
exposure
duration,
provide
relevant
information
for
a
weight
of
the
evidence
interspecies
assessment.

Stein
et
al.
1966:
EPA
comment
incorrect
as
data
used
were
for
a
handler
population
where
exposure
data
were
well
described
and
reliable.
Other
Comments
on
Studies
Dismissed
by
EPA
and
Used
in
the
MacGregor
2005
Analysis
or
in
this
Analysis
Johnston
et
al.
2002:
EPA
used
this
study
in
the
June
2005
risk
assessment
for
DDVP
to
determine
an
NOAEL
for
chronic
inhalation
exposure.

Youngren
et
al.
2006:
This
new
study
addresses
only
data
from
non­
pregnant
adults
and
provides
information
on
the
same
endpoints
as
Johnston
et
al.
2002.
Integrative
Biostrategies,
LLC
science
for
decision­
making
Results
A
New
DDVP
Interspecies
Database
Was
Constructed
from
10
Human
Studies
and
9
Animal
Studies
 
96
human
subjects
(
adult,
non­
pregnant)

 
4
animal
species
(
rats,
mice,
dogs,
monkeys)

 
Male
and
female
humans
and
animals
 
Durations
of
exposure
from
1
day
to
6
months
in
humans
and
1
day
to
2
years
in
animals
 
Routes
of
exposure
were
oral
and
inhalation
 
Studies
performed
around
the
world
 
All
studies
chosen
had
sufficient
documentation
to
ensure
that
studies
were
conducted
in
a
way
to
produce
scientifically
reliable
data
on
RBC
cholinesterase
responses
to
DDVP
exposure
Integrative
Biostrategies,
LLC
science
for
decision­
making
Integrative
Biostrategies,
LLC
science
for
decision­
making
Integrative
Biostrategies,
LLC
science
for
decision­
making