Document ID: EPA-HQ-ORD-2006-0187-0079
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

Aldicarb:
WOE
Comparison
of
Human
and
Animal
Studies
for
Single
Chemical
Assessment
and
NMC
Cumulative
Assessment
Linda
Taylor,
Ph.
D.

Linda
Taylor,
Ph.
D.

Elissa
Reaves,
Ph.
D.

Elissa
Reaves,
Ph.
D.

U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
April
4,
2006
April
4,
2006
2
1.

1.
HS
in
Single
Chemical
Risk
HS
in
Single
Chemical
Risk
Assessment
Assessment
Linda
Taylor,
Ph.
D.

Linda
Taylor,
Ph.
D.

HED,
USEPA
HED,
USEPA
2.

2.
HS
in
NMC
Cumulative
Risk
HS
in
NMC
Cumulative
Risk
Assessment
Assessment
Elissa
Reaves,
Ph.
D.

Elissa
Reaves,
Ph.
D.

HED,
USEPA
HED,
USEPA
Outline
of
Aldicarb
Presentations
Outline
of
Aldicarb
Presentations
3
Aldicarb
Human
Study
Details
Aldicarb
Human
Study
Details

1992
Human
study

Double
blind,
placebo
controlled

Single
oral
dose,
multiple
dose
levels

males
 
0.01,
0.025,
0.05,
0.075
mg/
kg

females
 
0.025,
0.05
mg/
kg

Both
sexes
[
38
men;
9
women]

ChE
activity
monitored
[
plasma
and
RBC],
hourly
for
first
6
hours/
24
hours
4
Table
1.
Study
Design
for
Table
1.
Study
Design
for
Aldicarb
Aldicarb
Human
Study
Human
Study
Phase/
Session
Placebo
0.01
mg/
kg
0.025
mg/
kg
0.05
mg/
kg
0.075
mg/
kg
a
3
 
4
1
 

I
males
b
5
 
 
3
4
c
4
2
2
2
 

d
1
3
1
 
 

II
males
e
3
3
1
2
 

f
1
 
1
1
 

g
2
 
1
1
 

III
females
h
3
 
2
2
 
5
Table
2.
Comparison
of
Strengths
and
Weaknesses
of
Table
2.
Comparison
of
Strengths
and
Weaknesses
of
the
Aldicarb
Human
Study
the
Aldicarb
Human
Study
Strengths
Weaknesses
Double
Blind
Study
­­

Multiple
Doses
Levels
(
males)

Dose­
Response
Information
­­

Both
Sexes
At
Mid
Dose
Levels
No
Females
At
Low
Dose
And
High
Dose
Blood
Sampling
At
Multiple
Time
Point
1st
Blood
Sample
At
1
Hour
­­
Improper
Ellman
Method
without
Detergent
6
Uncertainty
from
Uncertainty
from
Ellman
Ellman
Assay
of
HS
Assay
of
HS

Not
an
optimal
assay
for
RBC
ChE
1.
RBC
ChE
is
membrane
bound
2.
Lack
of
detergent
to
solubilize
the
ChE
3.
Sample
was
spun
to
form
pellet
4.
Sample
from
the
supernatant
only
provides
a
snapshot
of
the
total
ChE
activity

Uncertainty
remains
regarding
the
accuracy
of
the
ChE
measured
in
the
assay
7
Human
study
Subchronic
Rat
study
Acute
Rat
study
Screen
­
16
hours
and
­
3
hours
N/
A
N/
A
0
hours
Pre­
test
Pre­
test
Pre­
test
1,
2,
3,
4,
5,
6,
24
hours
post
dose
0.75
hour
post
dose
0.75
and
8
hours
post
dose
Table
3.
Comparison
of
ChE
Sampling
Events
from
Table
3.
Comparison
of
ChE
Sampling
Events
from
Available
Rat
and
Human
Data
Available
Rat
and
Human
Data
8
Timing
of
Timing
of
ChE
ChE
Measurement
Measurement

Aldicarb
HS:
ChE
measured
earliest
at
1
hour,
uncertainty
regarding
timing
of
peak
ChE
inhibition

Comparison
of
peak
inhibition
of
7
NMC's
indicate
peak
inhibition
ranges
from
40
minutes
to
1
hour

Human
studies
for
oxamyl
and
methomyl
indicate
peak
inhibition
from
45
minutes
to
75
minutes,
depending
on
dose
9
Species/
duration
0.01
mg/
kg
0.025
mg/
kg
0.05
mg/
kg
HUMAN
(
acute;
1
hr)

RBC
males
RBC
females
3.8%

­
12%
20%
29%
36%

RAT
(
acute;
0.75
hr)

RBC
males
RBC
females
­
­
­
­
­
10%

RAT
(
subchronic;
0.75
hr)

RBC
males
RBC
females
­
­
­
­
32%
24%

Table
4.
Comparison
of
ChE
Inhibition
from
Table
4.
Comparison
of
ChE
Inhibition
from
Available
Rat
and
Human
Data
Available
Rat
and
Human
Data
10
Aldicarb
HS
&
Single
Chemical
Approach
Aldicarb
HS
&
Single
Chemical
Approach

Animal
database
preferred
over
the
human
data
for
developing
the
point
of
departure
(
PoD)
for
assessment
of
acute
exposure
scenarios

Animals
of
both
sexes
were
tested
at
each
dose
level

Animal
data
comparing
young
and
adult
animals

Both
Ellman
and
radiometric
methods
used

Human
data

Less
than
optimal
Ellman
assay

ChE
measured
at
1
hour
increments

No
female
subjects
at
low
or
high
dose
11
Aldicarb
HS
&
Single
Chemical
Approach
Aldicarb
HS
&
Single
Chemical
Approach

Co­
critical
studies:
subchronic
neurotoxicity
study
(
rat)
with
non­
guideline
acute
study
(
rat,
adult
and
young)


Reversibility
of
ChEI
occurs
within
24
hours;
subchronic/
repeat
dosing
considered
a
series
of
acute
exposures

Propose
HS
for
Interspecies
Uncertainty
Factor
(
UF)

At
0.05
mg/
kg:

MALE
RBC:
FEMALE
RBC:

32%
(
rat)
24%
(
rat)

29%
(
human)
36%
(
human)

3X
refined
interspecies
factor:
appropriate
since
human
ChE
data
similar
to
rat
data,
lack
of
females
at
low
dose
of
human
study,
and
lack
of
brain
data
from
human
study
12
Aldicarb
HS
&
Risk
Assessment
Factors
Aldicarb
HS
&
Risk
Assessment
Factors

LOAEL
to
NOAEL
factor:
An
additional
10x
UF
needed
to
account
for
extrapolating
from
a
LOAEL
to
NOAEL

FQPA
factor:
A
Special
Hazard
Based
FQPA
safety
factor
is
not
needed

BMD
analysis
shows
that
young
are
approximately
2X
more
sensitive
than
adults
(
Moser).
However,
this
2X
sensitivity
is
accounted
for
in
the
point
of
departure
of
0.005
mg/
kg/
day

Total
uncertainty
factor
of
300
(
10X
for
intraspecies
variations,
3X
for
interspecies
differences,
and
10X
LOAEL
to
NOAEL)
13
Table
5.
Comparison
of
Endpoint
Selection
Possibilities
Parameter
Human
study
Rat
study
Rat
(
co­
critical)

(
recommended)
Human
BMDL10
LOAEL
0.01
mg/
kg
0.05
mg/
kg
0.05
mg/
kg
0.013
mg/
kg
UF
LOAEL­
to­

NOAEL
3X
10X
10X
1X
NOAEL
0.0033
mg/
kg
0.005
mg/
kg
0.005
mg/
kg
0.013
mg/
kg
UF
(
intraspecies)
10X
10X
10X
10X
UF
(
interspecies)
1X
10X
3X
(
human)
1X
FQPA
SF
2X
1X
1X
2X
acute
RfD
0.00033
mg/
kg
0.00005
mg/
kg
0.00017
mg/
kg
0.0013
mg/
kg
acute
PAD
0.00017
mg/
kg
0.00005
mg/
kg
0.00017
mg/
kg
0.00065
mg/
kg
endpoint
RBC/
plasma
ChEI
whole
blood/
brain
ChEI
whole
blood/
brain
ChEI
RBC
ChEI
14
1.

1.
HS
in
Single
Chemical
Assessment
HS
in
Single
Chemical
Assessment
Linda
Taylor,
Ph.
D.

Linda
Taylor,
Ph.
D.

HED,
USEPA
HED,
USEPA
Outline
of
Aldicarb
Presentations
Outline
of
Aldicarb
Presentations
2.

2.
HS
in
NMC
Cumulative
Risk
Assessment
HS
in
NMC
Cumulative
Risk
Assessment
Elissa
Reaves,
Ph.
D.

Elissa
Reaves,
Ph.
D.

HED,
USEPA
HED,
USEPA
15
NMC
Cumulative
Risk
Assessment
NMC
Cumulative
Risk
Assessment­
Aldicarb
Aldicarb

Aldicarb
is
a
member
of
the
multi­
chemical
NMC
CRA

Common
mechanism
of
toxicity
is
inhibition
of
acetylcholinesterase
(
AChE)

Appropriate
compartments
for
ChE
include
RBC
and
brain

Robust
database
for
the
rat
that
includes
brain
and
RBC
ChE,
from
both
sexes

Rat
data
indicate
peak
inhibition
by
1
hour
with
rapid
recovery
of
ChE
within
24
hours
16
NMC
Cumulative
Risk
Assessment
NMC
Cumulative
Risk
Assessment­
Aldicarb
Aldicarb

Brain
ChE
data
of
the
rat
chosen
for
use
in
NMC
CRA
(
supported
by
FIFRA
SAP,
2005)


Generate
the
BMD
10
for
relative
potency
factor
(
RPF)
and
BMDL
10
for
the
point
of
departure
(
PoD)
in
the
NMC
CRA

Because
rat
data
were
utilized
for
potency
in
the
NMC
CRA,

the
Agency
must
consider
interspecies
extrapolation
(
i.
e.,

animal
to
human)

Rat
ChE
data
indicated
no
difference
between
sex
or
compartment
(
brain,
RBC)

Compare
data
in
rat
RBC
to
human
RBC
17
Table
6.
Oral
BMD
Table
6.
Oral
BMD
10s
10s
and
BMDL
and
BMDL
10s
10s
Generated
from
Rat
ChE
(
RBC,
brain)

Generated
from
Rat
ChE
(
RBC,
brain)

and
Human
ChE
(
RBC)
Data
for
Aldicarb
and
Human
ChE
(
RBC)
Data
for
Aldicarb
Rat
Human
Brain
RBC
RBC
Chemical
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)

Aldicarb
F=
0.048
M=
0.056
F=
0.035
M=
0.035
0.031
0.020
0.016
0.013
BMD
estimates
are
presented
as
a
single
estimate
when
there
are
no
differences
between
sexes.
Human
RBC
data
obtained
from
MRID
42373001.
Rat
brain
and
RBC
data
obtained
from
MRIDs
43442302,
43442305,
43829601,
43829602,
45068601.
18
Approaches
for
Aldicarb
HS
in
NMC
CRA
Approaches
for
Aldicarb
HS
in
NMC
CRA
1.
Standard
Interspecies
Factor
of
10X
A.
Accounts
for
uncertainty
surrounding
lack
of
human
female
data
at
low
and
high
doses,
and
lack
of
brain
data
B.
May
be
conservative;
BMD
estimate
indicates
2X
2.
Ratio
of
RBC
BMD
10
Rat
vs.
Human
of
2X
A.
Refinement
of
standard
factor
based
on
human
data
B.
Supported
by
rat
ChE
data;
no
compartment
difference,
no
sex
difference
19
Aldicarb
Aldicarb
Charge
to
the
HSRB
Charge
to
the
HSRB
The
Agency s
 
Weight
of
the
Evidence 
(
WOE)
document
and
Data
Evaluation
Records
(
DERs)
for
aldicarb
describe
the
study
design
and
results
of
the
aldicarb
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency s
conclusions
regarding
the
usefulness
of
the
human
study
in
the
acute,
aggregate,
single
chemical
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
NMCs.
Regarding
the
aldicarb
human
study,
the
Agency
has
concluded
that
the
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
aggregate
and
the
cumulative
risk
assessments.

Please
comment
on
the
scientific
evidence
that
supports
whether
the
aldicarb
human
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.,
animal
to
human)
uncertainty
factor
in:

a.
Single
chemical,
aggregate
risk
assessment
and
b.
Cumulative
risk
assessment.
20
21
Oxamyl
Methomyl
Aldicarb
0.09
mg/
kg
0.15
mg/
kg
0.2
mg/
kg
0.3
mg/
kg
0.01
mg/
kg
0.025
mg/
kg
0.05
mg/
kg
Time
(
min)

Male
Male
Male
Male
Male
Male
Female
Male
Female
N=
N=
N=
N=
N=
8
N=
8
N=
4
N=
8
N=
4
+
1%
­
2%
­
1%
­
19%
­
­
­
­
­
15
­
7%
­
23%
­
12%
­
32%
­
­
­
­
­
30
+
0.2%
­
28%
­
20%
­
35%
­
­
­
­
­
45
­
27%
­
25%
­
28%
0­
10%
­
12%
­
20%
­
29%
­
36%
60
­
17%
­
28%
­
27%
­
­
­
­
­
75
­
16%
­
28%
­
23%
­
­
­
­
­
90
­
9%
­
16%
­
16%
­
­
­
­
­
120
4
subjects
with
maximum
RBC
inhibition:

­
34%
to
­
43%
at
45
to
60
minutes
3
subjects
with
maximum
RBC
inhibition:

41%­
43%
at
45
to
75
minutes
Range
0­
10%
Range
of
inhibition
M=
0­
21%

F=
14­
26%
Range
of
inhibition
M=
15­
31%

F=
22­
49%
22
­
0.1
0.0
0.1
0.2
0.3
0.4
0.5
P
e
r
c
e
n
t
C
h
E
I
n
h
i
b
i
t
i
o
n
Female
Male
Female
Male
Dose
0.025
mg/
kg
Dose
0.05
mg/
kg
Comparison
of
Variability
of
ChE
Inhibition
at
the
1
Hour
Sample
from
the
Aldicarb
Human
Study