Dichlorvos:
WOE
Comparison
of
Human
and
Animal
Studies
for
Single
Chemical
Assessment
and
OP
Cumulative
Assessment
Ray
Kent,
Ph.
D.

Ray
Kent,
Ph.
D.

U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
April
5,
2006
April
5,
2006
2
1.

1.
HS
in
Single
Chemical
Risk
HS
in
Single
Chemical
Risk
Assessment
Assessment
2.

2.
HS
in
Cumulative
OP
HS
in
Cumulative
OP
Assessment
Assessment
3.

3.
HS
in
WOE
Discussions
HS
in
WOE
Discussions
Outline
of
Dichlorvos
Presentation
Outline
of
Dichlorvos
Presentation
3
Dichlorvos
(
DDVP)

Dichlorvos
(
DDVP)


Mol
Wt
=
221

VP
=
0.032
mm
Hg

Liquid
at
room
temp

H
2
O
sol.
~
1.5%

O
P
O
O
O
Cl
Cl
4
Human
Studies
Considered
in
the
Single
Human
Studies
Considered
in
the
Single
Chemical
Assessment
Chemical
Assessment

Single
administration,
single
dose
level
study

Repeated
administration,
single
dose
level
study
5
DDVP
Acute
Human
Study
DDVP
Acute
Human
Study
­
Details
Details

Single
oral
dose
of
70
mg
to
6
adult
males

No
placebo
 
10
baseline
RBC
AChE
measurements
prior
to
dosing

RBC
AChE
activity
monitored
on
days
1,
3,

5/
6,
7
&
14
after
dosing

First
AChE
measurement
was
24
hr
after
dosing
6
Acute
DDVP
Human
Study
Acute
DDVP
Human
Study
­
Conclusions
Conclusions

Data
in
rats
indicate
that
peak
inhibition
of
RBC
AChE
occurs
1­
3
hours
after
oral
dosing

Failure
to
measure
RBC
AChE
in
humans
until
24
hr
post­
dosing
is
judged
to
be
a
critical
deficiency

Acute
human
study
is
not
being
relied
upon
to
either
establish
an
acute
RfD
or
to
decrease
the
interspecies
uncertainty
factor
7
DDVP
Repeated
Dosing
Study
DDVP
Repeated
Dosing
Study

Nine
adult
male
subjects
­
6
dosed
subjects
&
3
placebo

Dosed
subjects
received
7
mg
DDVP
each
day
for
21
days

RBC
AChE
measured
7x
before
dosing
&

9x
on
dosing
days
1
through
18
&
3x
postdosing
8
Dichlorvos
21­
Day
Human
Study
0
20
40
60
80
100
120
0
5
10
15
20
Days
of
Dosing
%

of
Predose
AChE
Treated
Control
9
Repeated
Dosing
Study
Repeated
Dosing
Study
­
Considerations
Considerations

Males
only,
but
no
clear
indication
of
gender
specificity
in
animal
studies

Limited
number
of
subjects,
but
study
exhibits
a
positive
response
(
16%
RBC
ChEI
at
18
days)


RBC
AChE
not
measured
until
24
hours,
but
there
is
a
clear
pattern
of
response
over
21­
days

Data
indicates
that
0.1
mg/
kg
is
a
LOAEL
in
humans.

Steady
state
not
attained
over
18
days
10
Repeated
Dosing
Study
Repeated
Dosing
Study
­
Conclusions
Conclusions

DDVP
HS
selected
to
assess
short
(<
30
days)
and
intermediate
(<
6
months)

exposure
durations
by
oral
and
dermal
routes

Data
from
animal
studies
7
day
­
1
year
support
selection
of
the
human
study.

NOAELs/
LOAELs
are
~
0.1
mg/
kg
11
OP
Cumulative
Risk
Assessment
OP
Cumulative
Risk
Assessment

Female
rat
brain
ChE
data
for
steady
state
(
28­
days
and
longer)
provide
the
relative
potency
factors
(
RPFs)
and
Points
of
Departure
in
the
Revised
OP
cumulative
risk
assessment
(
2002).


Supported
by
the
FIFRA
Scientific
Advisory
Panel

Uncertainties:


21­
day
human
study
did
not
reach
steady
state

Extrapolating
information
across
compartments
(
RBC
to
brain)


Extrapolating
information
across
sexes
(
male
subjects
to
female
rat)


16%
in
human
compared
10%
in
rat
Male
only
Male
and
Female
Brain
ChE
RBC
ChE
Rat
Data
Not
available
RBC
ChE
DDVP
21­

Day
Human
Study
OP
Cumulative
Risk
Assessment
OP
Cumulative
Risk
Assessment
BMD
10
=
2.35
BMDL
10
=
1.61
BMD
10
=
0.65
mkd
BMDL
10
=
0.45
 
0.54
mkd
Rat
(
female)
BMD
10
=
1.71
BMDL
10
=
0.08
BMD
10
=
0.57­
0.60
mkd
BMDL
10
=
0.41
 
0.49
mkd
Rat
(
male)
NA
16%
Inhibition
at
0.1
mkd
on
Day
18
Human
(
male)
Brain
RBC
Species
&
Sex
Human/
Rat
=
~
6X
Given
uncertainties,
apply
10X
inter­
species
in
the
cumulative
risk
assessment
13
Comparison
of
Concern
Levels
Comparison
of
Concern
Levels
Rat
Human
Step
in
Risk
Assessment
0.004
0.003
Concern
level
(
mg/
kg/
day)
10x
10x
Intraspecies
factor
10x
1x
Interspecies
factor
NA
3x
LOAEL
to
NOAEL
0.4
0.1
PoD
(
mg/
kg/
day)

Note:
FQPA
Safety
Factor
not
provided
here
but
included
in
aggregate
risk
assessment
14
Interspecies
Factor
Weight
of
Evidence
Interspecies
Factor
Weight
of
Evidence

MacGregor
et
al.
(
2005).
Humans
appear
no
more
sensitive
than
laboratory
animals
to
the
inhibition
of
red
blood
cell
cholinesterase
by
dichlorvos.
Regulatory
Toxicology
and
Pharmacology
43
150 
167

Comparison
of
human
and
animal
data
demonstrates
interspecies
factor
should
be
1x

11
Human
studies
identified
for
quantitative
comparison
15
Interspecies
Factor
Interspecies
Factor
 
Oral
Studies
Oral
Studies

Gledhill
1997a
 
discussed
in
the
WOE
 

missed
peak
effect

Gledhill
1997b
 
acute
study
+
16d
study
 

(
not
in
HSRB
list)


Gledhill
1997c
 
21­
day
study
 
used
in
single
chemical
risk
assessment

Slomka
&
Hine,
1981
 
plastic
bead
formulation
 
bioavailability
unknown
16
Interspecies
Factor
Interspecies
Factor
­
Inhalation
Inhalation

Funckes
et
al,
1963.
Children
exposed

Johnston
et
al,
2002.
Children
exposed
(
not
in
HSRB
list)


Shell
Chemical,
1970.
Children
exposed
(
not
in
HSRB
list)


Smith
et
al,
1972.
1
hour
acute
exposure
 

not
relevant
to
current
use
17
Interspecies
Factor
Interspecies
Factor
­
Inhalation
Inhalation

Stein,
et
al,
1966.
Exposure
levels
to
individuals
highly
uncertain

Ueda
&
Nishimura,
1967.
Limited
use
 

4
subjects
exposed
2
days
to
high
conc
(
not
in
HSRB
list)


Witter,
et
al,
1961.
1­
2
hours
exposure
not
relevant
to
current
use
18
Weight
of
Evidence
Conclusions
Weight
of
Evidence
Conclusions

All
relevant
human
data
have
been
and
will
be
considered
in
the
DDVP
RA

A
weight
of
evidence
argument
is
only
as
robust
as
the
underlying
data

A
WOE
comparison
of
human
and
animal
ChEI
must
use
matching
study
parameters
19
Charge
Questions
to
the
Panel
Charge
Questions
to
the
Panel
a.
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.
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.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
i.
single
chemical,
aggregate
risk
assessment
and
ii.
cumulative
risk
assessment.
20
Charge
Questions
to
the
Panel
Charge
Questions
to
the
Panel
­
continued
continued
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.
