Page
1
of
57
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
June
9,
2006
MEMORANDUM
SUBJECT:
Benchmark
dose
analysis
of
cholinesterase
inhibition
data
in
neonatal
and
adult
rats
(
MRID
no.
46688914)
following
exposure
to
DDVP
PC
Code:
084001.
DP
Barcode
DP
328793.
TXR
No.
0054223
FROM:
Anna
Lowit
Toxicologist
Toxicology
Branch
Health
Effects
Division
(
7509C)

THRU:
Louis
Scarano
Branch
Chief
Toxicology
Branch
Health
Effects
Division
(
7509C)

TO:
Ray
Kent
Branch
Chief
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

The
purpose
of
the
current
memo
is
to
provide
BMD
estimates
calculated
by
the
Health
Effects
Division
for
the
acute
and
repeated
dosing
studies
in
adult
and
juvenile
rats
in
DDVP
(
MRID
nos.
45805703,
45842301,
46433201,
46153304).
The
results
of
this
memo
are
intended
to
inform
the
FQPA
10X
factor
for
dichlorvos
(
also
called
DDVP)
in
the
single
chemical
aggregate
and
cumulative
risk
assessments.
Page
2
of
57
Summary
This
memo
describes
a
benchmark
dose
analysis
for
red
blood
cell
(
RBC)
and
brain
cholinesterase
(
ChE)
inhibition
data
in
adult
and
juvenile
rats
exposed
orally
to
DDVP
(
MRID
nos.
45805703,
45842301,
46433201,
46153304).
This
analysis
was
developed
using
the
exponential
model
provided
in
EPA's
OPCum
Risk
software.
The
estimated
dose
to
result
in
10%
inhibition
(
BMD10)
and
the
lower
95%
confidence
limit
on
the
BMD10
(
BMDL10)
were
calculated.
For
acute
exposures,
the
calculated
BMDs10
range
from
approximately
1.3
mg/
kg
to
2.0
mg/
kg
for
each
compartment,
sex
and
age
group
(
young
adult
and
postnatal
day
8
[
PND8]
rats).
Regarding
repeated
exposures,
the
Agency
has
used
both
concurrent
and
historical
controls
to
estimate
RBC
and
brain
BMD10.
For
most
groups,
the
calculated
the
BMDs10
ranged
from
approximately
0.5
mg/
kg
to
1.2
mg/
kg
when
using
the
historical
or
concurrent
controls.
Overall,
for
the
repeated
exposure,
the
BMDs
are
similar
between
compartments,
sexes
and
age
groups.

Background
The
Agency's
draft
BMD
technical
guidance
indicates
that
the
BMD
approach
is
a
preferable
alternative
to
the
NOAEL/
LOAEL
approach
(
USEPA,
2000).
The
Office
of
Pesticide
Programs
is
increasing
its
use
of
BMD
techniques
in
its
hazard
assessments
and
risk
characterizations.
BMDs
are
preferred
over
the
NOAEL/
LOAEL
as
NOAELs/
LOAELs
are
highly
dependent
on
dose
selection
in
that
they
are
limited
to
the
doses
included
in
a
study.
Moreover,
the
NOAEL/
LOAEL
approach
does
not
account
for
the
uncertainty
in
the
estimate
of
the
dose­
response.
Benchmark
dose
analysis
attempts
to
model
the
doseresponse
relationship
with
a
dose­
response
curve
that
can
be
described
by
a
mathematical
function.
The
dose­
response
curve
that
is
estimated
based
on
the
experimental
observations
is
used
to
estimate
the
magnitude
of
the
response
for
any
dose
within
the
experimental
dose
range.
Various
mathematical
models
can
be
used
to
model
this
dose­
response
curve.
Once
a
BMD
model
has
been
selected,
the
dose
associated
with
a
specified
response
(
i.
e.
benchmark
response,
BMR)
is
determined.
For
cholinesterase
data,
the
BMR
is
typically
expressed
as
a
certain
percent
change
in
the
control
group
response
(
i.
e.,
background).
The
dose
resulting
in
the
specified
BMR
and
estimated
based
on
the
modeled
dose­
response
curve
is
termed
the
"
benchmark
dose."
Generally,
the
dose
resulting
in
a
BMR
of
X%
change
in
background
is
referred
to
as
the
BMDX.
The
corresponding
95%
lower
confidence
limit
on
the
BMDX
is
referred
to
as
the
BMDLX.
In
the
case
of
ChE
inhibition
for
DDVP,
EPA
has
used
a
BMR
of
10%
for
ChE
inhibition.
This
BMR
was
selected
based
on
both
statistical
and
toxicological
considerations.
The
reader
is
referred
to
the
Revised
Organophosphate
(
OP)
Cumulative
Assessment
which
provides
a
detailed
power
analysis
of
over
1000
measurements
of
brain
ChE
inhibition
which
indicates
that
10%
is
a
level
that
can
be
reliably
measured
in
the
majority
of
rat
toxicity
studies.
In
the
case
of
the
ChE
inhibiting
pesticides,
it
is
important
to
consider
the
degree
to
which
the
response
level
for
inhibition
of
ChE
is
protective
for
other
toxicities
which
may
result
from
pesticide
exposure.
The
Agency
believes
that
at
a
BMR
of
10%
for
brain
ChE
inhibition
is,
indeed,
protective
of
other
toxicities
whereas
higher
BMR
values
may
not
be.

Methods
Selected
Model
The
BMD
analysis
of
ChE
data
from
the
DDVP
oral
gavage
acute
and
repeated
comparative
sensitivity
toxicity
studies
was
performed
using
EPA's
OPCumRisk
program.
The
exponential
function
used
for
modeling
the
effect
of
DDVP
on
ChE
activity
was:

y
=
B
+
(
A
­
B)
e­
m
x
dose
Where
y
is
ChE
activity,
dose
is
the
dose
in
mg/
kg,
m
is
the
dose
scale
factor,
A
is
background
ChE
activity,
and
B
is
the
limiting
high­
dose
ChE
activity.
Both
y
(
ChE
activity)
and
dose
were
extracted
from
the
above
referenced
toxicity
study.
The
equation
for
the
exponential
model
reflects
the
observation
that
Page
3
of
57
ChE
activity
decreases
to
a
limiting
value
(
B)
as
dose
increases.
The
model
has
three
parameters
to
be
estimated:
m
(
dose
scale
factor),
A
(
background),
and
B
(
limiting
high­
dose
ChE
activity).

The
OPCumRisk
program
utilizes
the
same
dose­
response
model
(
i.
e.,
decreasing
exponential
model)
as
utilized
in
the
Preliminary
OP
Cumulative
Risk
Assessment
(
CRA;
USEPA,
2001).
The
OPCumRisk
program
can
be
obtained
at
www.
epa.
gov/
pesticides/
cumulative/
EPA_
approach_
methods.
htm.
These
dose­
response
models
and
the
respective
computer
code
are
publicly
available
for
download,
review,
and
use.
This
method
has
been
previously
evaluated
by
the
FIFRA
SAP
(
www.
epa.
gov/
scipoly/
sap/
2001/
index.
htm).
For
the
revised
OP
CRA
(
USEPA,
2002),
the
exponential
model
was
expanded
to
include
a
"
low
dose
shoulder."
The
low
dose
shoulder
corresponds
to
the
portion
of
the
dose­
response
curve
where
the
slope
at
the
low
end
of
the
dose­
response
curve
is
more
flat
compared
to
the
slope
at
higher
doses.
This
low
dose
shoulder
is
not
modeled
in
the
OPCumRisk
program.
For
DDVP
brain
and
RBC
ChE
data
in
the
comparative
ChE
study,
there
is
little
evidence
that
a
low
dose
shoulder
exists
and
as
such,
the
current
BMD
analysis
is
considered
adequate
and
supportable.
It
is
important
to
note
that
the
exponential
model
is
also
being
used
by
EPA
in
its
cumulative
risk
assessment
for
the
OP
common
mechanism
group
(
of
which
DDVP
is
a
member;
USEPA,
2002).

The
calculated
BMD
values
represent
the
dose
at
which
a
10%
reduction
in
background
ChE
activity
levels
is
expected
(
i.
e.
BMD10
values
were
calculated).
For
each
ChE
dataset,
parameters
were
initially
estimated
including
all
dose
groups.
The
OPCumRisk
program
utilizes
a
decision
algorithm
for
selecting
from
among
various
options
for
the
exponential
model.
Generally
the
model
is
fitted
until
an
adequate
pvalue
for
the
 2
goodness­
of­
fit
(
GoF)
statistic
is
obtained.
The
decision
algorithm
is
provided
below.

1.
If
the
p­
value
for
the
GoF
statistic
is
greater
than
0.05,
then
the
model's
fit
was
considered
adequate
and
the
initial
parameter
estimates
were
used.

2.
Otherwise
(
that
is,
if
the
p­
value
was
less
than
0.05,
or
no
estimates
resulted
because
the
model
did
not
converge),
the
horizontal
asymptote
was
set
to
zero
and
the
model
was
refit
to
the
data.

3.
If
the
p­
value
was
still
less
than
0.05,
or
there
was
no
model
fit
at
all,
then
the
highest
dose
was
dropped
and
the
model
was
refit
with
the
horizontal
asymptote
set
to
zero
until
either
the
pvalue
exceeded
0.05,
or
there
are
only
three
doses
remaining.

Although
the
user
can
specify
options
that
are
not
consistent
with
the
default
decision
algorithm
utilized
by
OPCumRisk,
all
BMD
values
provided
in
these
analyses
are
based
on
the
default
decision
algorithm.
The
decision
algorithm
and
technical
details
of
the
"
basic"
exponential
model
used
in
this
BMD
analysis
can
be
obtained
at
www.
epa.
gov/
scipoly/
sap/
2001/
september/
rpfappendix1.
pdf.

Results
BMD
values
(
both
BMD10
and
BMDL10)
were
calculated
for
the
brain
and
RBC
ChE
data
from
the
oral
gavage
acute
comparative
sensitivity
toxicity
study.
These
BMD
values
and
the
goodness
of
fit
information
from
the
OPCumRisk
model
runs
are
provided
in
Tables
1
and
2
for
acute
and
repeated
exposures,
respectively.
Details
of
this
analysis
can
be
found
below
in
Appendix
1
and
2.

Based
on
statistical
and/
or
visual
fit,
the
exponential
model
adequately
fit
the
RBC
and
brain
ChE
data
from
the
acute
exposures
to
adult
and
PND8
rats.
Moreover,
for
acute
exposures,
all
of
calculated
the
BMD10
range
from
approximately
1.3
mg/
kg
to
2.0
mg/
kg.
The
BMDs
are
similar
between
compartments,
sexes
and
age
groups.
It
is
also
notable
that
there
is
a
narrow
margin
between
the
BMD10
and
BMDL10
indicating
quality
data
and
quality
model
fit.

Table
1.
BMD
Summary
of
OPP's
Analysis
of
ChE
Data
from
the
DDVP
Oral
Acute
Gavage
Comparative
Sensitivity
Toxicity
Study
(
MRID
no.
45805703,
45842301)
Based
on
the
Exponential
Model
Page
4
of
57
Compartment
Sex
Subpopulation
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
GoF
p­
value
Adult
1.46
0.76
0.53
Male
Neonate
1.50
1.40
0.46
Adult
1.29
0.65
0.51
Brain
Female
Neonate
2.02
1.80
0.95
Adult
1.66
1.31
0.20
Male
Neonate
1.63
1.41
0.95
Adult
1.55
1.26
0.65
RBC
Female
Neonate
1.47
0.83
0.15
Based
on
statistical
and/
or
visual
fit,
the
exponential
model
adequately
fit
most
of
the
sex­
agecompartment
scenarios
for
the
RBC
and
brain
ChE
data
from
the
repeated
exposures
to
DDVP
(
Table
2).
As
described
in
the
Data
Evaluation
Record
(
DER),
the
ChE
activity
measurements
in
some
control
groups
are
unusually
high
for
the
laboratory
which
conducted
the
repeated
exposure
study.
The
registrant,
AMVAC,
provided
historical
control
values
for
brain
and
RBC
ChE
activity.
BMD
estimates
were
developed
using
both
the
concurrent
and
pooled
historical
control
values.
For
most
groups,
the
calculated
the
BMDs10
ranged
from
approximately
0.5
mg/
kg
to
1.2
mg/
kg
when
using
the
historical
or
concurrent
controls.
For
the
female
brain
ChE
from
juvenile
rats,
when
using
the
concurrent
controls,
the
statistical
fit
was
not
adequate
(
p
<
0.05);
however,
when
using
the
historical
controls,
the
fit
was
improved.
For
the
female
adult
RBC
ChE
data,
when
using
the
concurrent
controls,
the
BMDs
were
substantially
lower
than
values
calculated
for
the
other
groups;
when
the
historical
control
values
were
considered,
the
BMD
for
this
group
increased
to
be
consistent
with
the
remaining
groups.
Overall,
for
the
repeated
exposure,
the
BMDs
are
similar
between
compartments,
sexes
and
age
groups.
It
is
also
notable
that
the
BMD10
and
BMDL10
are
close
together
in
magnitude
indicating
quality
data
for
most
treatment
groups
and
quality
model
fit.
Page
5
of
57
Table
2.
BMD
Summary
of
OPP's
Analysis
of
ChE
Data
from
the
DDVP
Oral
Multi­
dosing
Gavage
Comparative
Sensitivity
Toxicity
Study
(
MRID
no.
46433201,
46153304)
Based
on
the
Exponential
Model
Compartmen
t
Sex
Subpopulati
on
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
GoF
p­
value
Adult
0.72
0.55
0.71
Male
Neonate
0.88
0.75
0.0081
Adult
0.88
0.71
0.84
Brain
(
concurrent
controls)
Female
Neonate
0.95
0.80
0.022
Adult
0.77
0.62
0.63
Male
Neonate
0.84
0.65
0.37
Adult
0.92
0.75
0.75
Brain
(
pooled
historical
controls)
Female
Neonate
0.85
0.62
0.39
Adult
0.71
0.45
0.11
Male
Neonate
0.50
0.35
0.41
Adult
0.09
0.054
0.66
RBC
(
concurrent
controls)
Female
Neonate
0.57
0.43
0.69
Adult
0.75
0.50
0.30
Male
Neonate
0.55
0.38
0.094
Adult
1.17
1.00
0.90
RBC
(
pooled
historical
controls)
Female
Neonate
0.61
0.46
0.50
Conclusions
The
BMD
analysis
described
here
provides
a
robust
consideration
of
the
brain
and
RBC
ChE
data
from
the
acute
and
repeated
exposure
studies
in
young
adult
and
juvenile
rats
exposed
to
DDVP
orally.
This
analysis
indicates
that
for
acute
and
repeated
exposures
that
young
adult
and
juvenile
rats
respond
similarly
to
oral
dosing
to
DDVP.
Page
6
of
57
References
USEPA,
2000.
"
Benchmark
Dose
Technical
Guidance
Document"
Draft
report.
Risk
Assessment
Forum,
Office
of
Research
and
Development,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
EPA/
630/
R­
00/
001
USEPA
(
2001).
Preliminary
Organophosphorus
Pesticide
Cumulative
Risk
Assessment.
Office
of
Pesticide
Programs,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
http://
www.
epa.
gov/
pesticides/
cumulative/
pra_
op/.

USEPA,
2002.
Revised
Organophosphorous
Pesticide
Cumulative
Risk
Assessment;
June
10,
2002.
Office
of
Pesticide
Programs,
U.
S.
Environmental
Protection
Agency.
Washington,
D.
C.
Available:
http://
www.
epa.
gov/
pesticides/
cumulative/
rra­
op/
Page
7
of
57
Appendix
1:
Benchmark
dose
runs
for
the
acute
dosing
(
MRID
no.
45805703,
45842301)
DDVP:
Acute,
Brain,
Adult
Page
8
of
57
DDVP:
1­
D:
BRAIN:
F:
MAIN
Tue
Apr
25
16:
46:
22
2006
MRID:
ADULT
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
85.75863
89.74156
­
38.87931
Coefficients:
Value
Std.
Error
A
8.7164482
0.9536187
B
2.0810054
2.6396297
m
0.1093959
0.1071854
Correlation:
A
B
m
A
1.0000000
0.4940059
0.5941367
B
0.4940059
1.0000000
0.9731630
m
0.5941367
0.9731630
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
6.91981135
8.7164482
10.9795579
B
0.14322729
2.0810054
30.2357431
m
0.01384314
0.1093959
0.8645054
Residual
standard
error:
lower
est.
upper
2.063742
2.750235
4.122999
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.4272
with
1
degrees
of
freedom.
P
=
0.513
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
9.17
8.716448
2.19
2.637271
0.38455377
2
1
5
7.48
8.028853
2.19
2.409555
­
0.50933622
3
5
5
6.03
5.920903
2.25
1.741651
0.14006697
DDVP:
Acute,
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Adult
Page
9
of
57
4
15
5
3.36
3.366941
1.00
1.021351
­
0.01519591
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
1.287:
BMDL
=
0.6495
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1094
se:
0.1072
var=
se^
2:
0.01149
Per
cent.
of
background
at
unit
dose:
90
Per
cent.
of
background
at
the
highest
dose:
19
ED50
(
95%
CI):
6.336
(
0.9286
,
43.24
)

ln(
Potency)
­
2.213
se[
log(
Potency)]:
0.9798
se[
log(
Potency)]^
2:
0.96
DDVP:
Acute,
Brain,
Adult
Page
10
of
57
DDVP:
1­
D:
BRAIN:
M:
MAIN
Tue
Apr
25
16:
46:
28
2006
MRID:
ADULT
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
74.27587
78.25880
­
33.13793
Coefficients:
Value
Std.
Error
A
7.50616158
0.77906555
B
1.53331933
0.55183572
m
0.09231263
0.05727478
Correlation:
A
B
m
A
1.0000000
0.5155696
0.6408690
B
0.5155696
1.0000000
0.8990115
m
0.6408690
0.8990115
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
6.02999496
7.50616158
9.343700
B
0.71757370
1.53331933
3.276414
m
0.02493219
0.09231263
0.341792
Residual
standard
error:
lower
est.
upper
1.628137
2.169729
3.252736
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.3867
with
1
degrees
of
freedom.
P
=
0.534
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
7.14
7.506162
2.05
2.1838492
­
0.374916996
2
1
5
7.42
6.979477
1.81
2.0377088
0.483405815
3
5
5
5.22
5.297988
1.01
1.5652808
­
0.111408487
DDVP:
Acute,
Brain,
Adult
Page
11
of
57
4
35
5
1.77
1.769368
0.74
0.5147315
0.002747467
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
1.455:
BMDL
=
0.7623
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.09231
se:
0.05727
var=
se^
2:
0.00328
Per
cent.
of
background
at
unit
dose:
91
Per
cent.
of
background
at
the
highest
dose:
4
ED50
(
95%
CI):
7.509
(
2.226
,
25.33
)

ln(
Potency)
­
2.383
se[
log(
Potency)]:
0.6204
se[
log(
Potency)]^
2:
0.385
DDVP:
Acute,
RBC,
Adult
Page
12
of
57
DDVP:
1­
D:
RBC:
F:
MAIN
Tue
Apr
25
16:
46:
26
2006
MRID:
ADULT
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
Highest
1
doses
dropped
from
data
set.

The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
201.74977
203.87392
­
97.87489
Coefficients:
Value
Std.
Error
A
2.571638e+
03
71.521128484
m
6.799292e­
02
0.009431473
Correlation:
A
m
A
1.0000000
0.6800864
m
0.6800864
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2.421676e+
03
2.571638e+
03
2.730886e+
03
m
5.038701e­
02
6.799292e­
02
9.175059e­
02
Residual
standard
error:
lower
est.
upper
148.7009
205.1177
330.4533
Degrees
of
freedom:
15
total;
13
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.2042
with
1
degrees
of
freedom.
P
=
0.651
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
2597
2571.638
179
203.3146
0.27893149
2
1
5
2373
2402.597
264
189.8396
­
0.34861343
3
5
5
1835
1830.480
101
144.2978
0.07003547
DDVP:
Acute,
RBC,
Adult
Page
13
of
57
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
1.55:
BMDL
=
1.262
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.06799
se:
0.009431
var=
se^
2:
8.895e­
05
Per
cent.
of
background
at
unit
dose:
93
Per
cent.
of
background
at
the
highest
dose:
71
ED50
(
95%
CI):
10.19
(
7.768
,
13.38
)

ln(
Potency)
­
2.688
se[
log(
Potency)]:
0.1387
se[
log(
Potency)]^
2:
0.01924
DDVP:
Acute,
RBC,
Adult
Page
14
of
57
DDVP:
1­
D:
RBC:
M:
MAIN
Tue
Apr
25
16:
46:
32
2006
MRID:
ADULT
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
Highest
1
doses
dropped
from
data
set.

The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
207.4049
209.5290
­
100.7024
Coefficients:
Value
Std.
Error
A
2.790461e+
03
85.30415667
m
6.358638e­
02
0.01043262
Correlation:
A
m
A
1.0000000
0.6773461
m
0.6773461
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2.612126e+
03
2.790461e+
03
2.980971e+
03
m
4.460953e­
02
6.358638e­
02
9.063597e­
02
Residual
standard
error:
lower
est.
upper
171.6033
236.7092
381.3486
Degrees
of
freedom:
15
total;
13
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
1.633
with
1
degrees
of
freedom.
P
=
0.201
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
2705
2790.461
343
242.2597
­
0.7888111
2
1
5
2719
2618.549
170
227.7068
0.9864189
3
5
5
2015
2030.486
94
177.7275
­
0.1948314
DDVP:
Acute,
RBC,
Adult
Page
15
of
57
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
1.657:
BMDL
=
1.305
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.06359
se:
0.01043
var=
se^
2:
0.0001088
Per
cent.
of
background
at
unit
dose:
94
Per
cent.
of
background
at
the
highest
dose:
73
ED50
(
95%
CI):
10.9
(
7.903
,
15.04
)

ln(
Potency)
­
2.755
se[
log(
Potency)]:
0.1641
se[
log(
Potency)]^
2:
0.02692
DDVP:
Acute,
Brain,
Pup
Page
16
of
57
DDVP:
1­
PND:
BRAIN:
F:
MAIN
Tue
Apr
25
16:
46:
45
2006
MRID:
PND8
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
4.4493049
7.4365018
0.7753475
Coefficients:
Value
Std.
Error
A
3.11393414
0.096228698
m
0.05220586
0.003914497
Correlation:
A
m
A
1.0000000
0.6615286
m
0.6615286
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2.91818820
3.11393414
3.32281030
m
0.04459687
0.05220586
0.06111309
Residual
standard
error:
lower
est.
upper
0.2410419
0.3190020
0.4717480
Degrees
of
freedom:
20
total;
18
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.1003
with
2
degrees
of
freedom.
P
=
0.951
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
3.08
3.113934
0.21
0.3220624
­
0.2356035
2
1
5
2.98
2.955539
0.23
0.3058005
0.1788627
3
5
5
2.41
2.398534
0.23
0.2485596
0.1031516
4
15
5
1.42
1.423045
0.24
0.1480511
­
0.0459906
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
DDVP:
Acute,
Brain,
Pup
Page
17
of
57
BMD
Computation
BMD
=
2.018:
BMDL
=
1.797
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.05221
se:
0.003914
var=
se^
2:
1.532e­
05
Per
cent.
of
background
at
unit
dose:
95
Per
cent.
of
background
at
the
highest
dose:
46
ED50
(
95%
CI):
13.28
(
11.46
,
15.38
)

ln(
Potency)
­
2.953
se[
log(
Potency)]:
0.07498
se[
log(
Potency)]^
2:
0.005622
DDVP:
Acute,
Brain,
Pup
Page
18
of
57
DDVP:
1­
PND:
BRAIN:
M:
MAIN
Tue
Apr
25
16:
46:
52
2006
MRID:
PND8
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
­
11.513330
­
8.526133
8.756665
Coefficients:
Value
Std.
Error
A
3.22799583
0.070577502
m
0.07048969
0.002815596
Correlation:
A
m
A
1.0000000
0.6557125
m
0.6557125
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3.08307201
3.22799583
3.37973197
m
0.06481574
0.07048969
0.07666033
Residual
standard
error:
lower
est.
upper
0.1743612
0.2307548
0.3412458
Degrees
of
freedom:
20
total;
18
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
1.551
with
2
degrees
of
freedom.
P
=
0.46
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
3.14
3.227996
0.20
0.23552098
­
0.8354443
2
1
5
3.04
3.008290
0.10
0.21999032
0.3223142
3
5
5
2.33
2.269167
0.24
0.16745554
0.8123092
4
15
5
1.11
1.121331
0.09
0.08465241
­
0.2992973
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
DDVP:
Acute,
Brain,
Pup
Page
19
of
57
BMD
Computation
BMD
=
1.495:
BMDL
=
1.403
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.07049
se:
0.002816
var=
se^
2:
7.928e­
06
Per
cent.
of
background
at
unit
dose:
93
Per
cent.
of
background
at
the
highest
dose:
35
ED50
(
95%
CI):
9.833
(
9.093
,
10.63
)

ln(
Potency)
­
2.652
se[
log(
Potency)]:
0.03994
se[
log(
Potency)]^
2:
0.001595
DDVP:
Acute,
RBC,
Pup
Page
20
of
57
DDVP:
1­
PND:
RBC:
F:
MAIN
Tue
Apr
25
16:
46:
50
2006
MRID:
PND8
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
311.3597
315.3426
­
151.6799
Coefficients:
Value
Std.
Error
A
3565.7686985
253.06695411
B
1304.7155991
653.72006213
m
0.1170090
0.08519761
Correlation:
A
B
m
A
1.0000000
0.4552855
0.5739303
B
0.4552855
1.0000000
0.9594333
m
0.5739303
0.9594333
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3069.8953381
3565.7686985
4141.7393788
B
453.3342457
1304.7155991
3755.0280190
m
0.0251796
0.1170090
0.5437383
Residual
standard
error:
lower
est.
upper
553.7944
738.0112
1106.3850
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
2.127
with
1
degrees
of
freedom.
P
=
0.145
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
3830
3565.769
733
696.0392
0.84885899
2
1
5
2991
3316.097
662
639.2002
­
1.13726262
3
5
5
2636
2564.305
315
480.8800
0.33337969
DDVP:
Acute,
RBC,
Pup
Page
21
of
57
4
15
5
1689
1695.615
349
331.6280
­
0.04460369
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
1.467:
BMDL
=
0.8317
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.117
se:
0.0852
var=
se^
2:
0.007259
Per
cent.
of
background
at
unit
dose:
89
Per
cent.
of
background
at
the
highest
dose:
17
ED50
(
95%
CI):
5.924
(
1.422
,
24.68
)

ln(
Potency)
­
2.146
se[
log(
Potency)]:
0.7281
se[
log(
Potency)]^
2:
0.5302
DDVP:
Acute,
RBC,
Pup
Page
22
of
57
DDVP:
1­
PND:
RBC:
M:
MAIN
Tue
Apr
25
16:
46:
56
2006
MRID:
PND8
Guideline:
81­
1
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
301.8481
304.8353
­
147.9240
Coefficients:
Value
Std.
Error
A
3.677296e+
03
1.737759e+
02
m
6.483032e­
02
6.020933e­
03
Correlation:
A
m
A
1.0000000
0.6594638
m
0.6594638
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3.329745e+
03
3.677296e+
03
4.061124e+
03
m
5.333839e­
02
6.483032e­
02
7.879824e­
02
Residual
standard
error:
lower
est.
upper
433.6720
573.9343
848.7482
Degrees
of
freedom:
20
total;
18
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.09684
with
2
degrees
of
freedom.
P
=
0.953
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0
5
3620
3677.296
276
580.9977
­
0.22051497
2
1
5
3473
3446.460
411
545.1029
0.10887159
3
5
5
2693
2659.202
442
422.3719
0.17892749
4
15
5
1384
1390.583
359
223.2216
­
0.06594177
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
DDVP:
Acute,
RBC,
Pup
Page
23
of
57
BMD
Computation
BMD
=
1.625:
BMDL
=
1.41
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.06483
se:
0.006021
var=
se^
2:
3.625e­
05
Per
cent.
of
background
at
unit
dose:
94
Per
cent.
of
background
at
the
highest
dose:
38
ED50
(
95%
CI):
10.69
(
8.912
,
12.83
)

ln(
Potency)
­
2.736
se[
log(
Potency)]:
0.09287
se[
log(
Potency)]^
2:
0.008625
Page
24
of
57
Appendix
2:
Benchmark
dose
runs
for
the
repeated
dosing
(
MRID
no.
46433201,
46153304)
DDVP:
Repeated,
Brain,
Adult,
Concurrent
controls
Page
25
of
57
DDVP:
7­
D:
BRAIN:
F:
WHOLE
Mon
Apr
24
21:
43:
34
2006
MRID:
MDAdconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
25.51746
29.50039
­
8.75873
Coefficients:
Value
Std.
Error
A
5.4680592
0.21623032
B
1.1331342
0.27076016
m
0.1529701
0.03053395
Correlation:
A
B
m
A
1.0000000
0.1901865
0.3377826
B
0.1901865
1.0000000
0.9369459
m
0.3377826
0.9369459
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.0303656
5.4680592
5.9438367
B
0.6844438
1.1331342
1.8759659
m
0.1003945
0.1529701
0.2330789
Residual
standard
error:
lower
est.
upper
0.5119114
0.6821960
1.0227101
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.03915
with
1
degrees
of
freedom.
P
=
0.843
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
5.51
5.468059
0.34
0.6770768
0.138510867
2
0.1
5
5.36
5.402252
0.25
0.6689085
­
0.141243990
3
7.5
5
2.51
2.509476
0.56
0.3104510
0.003776490
DDVP:
Repeated,
Brain,
Adult,
Concurrent
controls
Page
26
of
57
4
15.0
5
1.57
1.570124
0.15
0.1945313
­
0.001419862
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.8814:
BMDL
=
0.713
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.153
se:
0.03053
var=
se^
2:
0.0009323
Per
cent.
of
background
at
unit
dose:
86
Per
cent.
of
background
at
the
highest
dose:
10
ED50
(
95%
CI):
4.531
(
3.064
,
6.701
)

ln(
Potency)
­
1.878
se[
log(
Potency)]:
0.1996
se[
log(
Potency)]^
2:
0.03984
DDVP:
Repeated,
Brain,
Adult,
Concurrent
controls
Page
27
of
57
DDVP:
7­
D:
BRAIN:
M:
WHOLE
Mon
Apr
24
21:
43:
40
2006
MRID:
MDAdconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
38.65735
42.64027
­
15.32867
Coefficients:
Value
Std.
Error
A
5.7226764
0.31678214
B
1.2589525
0.25158074
m
0.1917306
0.04343782
Correlation:
A
B
m
A
1.0000000
0.1403111
0.3067966
B
0.1403111
1.0000000
0.8887349
m
0.3067966
0.8887349
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.0918770
5.7226764
6.4316216
B
0.8258587
1.2589525
1.9191677
m
0.1188781
0.1917306
0.3092295
Residual
standard
error:
lower
est.
upper
0.7591362
1.0116588
1.5166222
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.1429
with
1
degrees
of
freedom.
P
=
0.705
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
5.84
5.722676
0.40
0.9917110
0.264536182
2
0.1
5
5.52
5.637908
0.42
0.9768860
­
0.269889484
3
7.5
5
2.32
2.318672
0.68
0.4003437
0.007418733
DDVP:
Repeated,
Brain,
Adult,
Concurrent
controls
Page
28
of
57
4
15.0
5
1.51
1.510537
0.26
0.2624115
­
0.004578106
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.7156:
BMDL
=
0.551
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1917
se:
0.04344
var=
se^
2:
0.001887
Per
cent.
of
background
at
unit
dose:
83
Per
cent.
of
background
at
the
highest
dose:
5.6
ED50
(
95%
CI):
3.615
(
2.319
,
5.636
)

ln(
Potency)
­
1.652
se[
log(
Potency)]:
0.2266
se[
log(
Potency)]^
2:
0.05133
DDVP:
Repeated,
Brain,
Adult,
Historical
controls
Page
29
of
57
DDVP:
7­
D:
BRAIN:
F:
WHOLE
Mon
Apr
24
21:
43:
45
2006
MRID:
MDAdhist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
64.04178
70.79730
­
28.02089
Coefficients:
Value
Std.
Error
A
5.3368308
0.11905590
B
1.0997356
0.28281397
m
0.1465709
0.02915622
Correlation:
A
B
m
A
1.0000000
0.1150917
0.2036726
B
0.1150917
1.0000000
0.9481542
m
0.2036726
0.9481542
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.10097136
5.3368308
5.5835960
B
0.65311837
1.0997356
1.8517598
m
0.09794975
0.1465709
0.2193271
Residual
standard
error:
lower
est.
upper
0.5322331
0.6528354
0.8446040
Degrees
of
freedom:
40
total;
37
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.104
with
1
degrees
of
freedom.
P
=
0.747
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
25
5.32
5.336831
0.60
0.6499687
­
0.129474129
2
0.1
5
5.36
5.275180
0.25
0.6424933
0.295197982
3
7.5
5
2.51
2.511155
0.56
0.3062988
­
0.008433535
DDVP:
Repeated,
Brain,
Adult,
Historical
controls
Page
30
of
57
4
15.0
5
1.57
1.569894
0.15
0.1909515
0.001242926
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.9185:
BMDL
=
0.7518
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1466
se:
0.02916
var=
se^
2:
0.0008501
Per
cent.
of
background
at
unit
dose:
86
Per
cent.
of
background
at
the
highest
dose:
11
ED50
(
95%
CI):
4.729
(
3.202
,
6.984
)

ln(
Potency)
­
1.92
se[
log(
Potency)]:
0.1989
se[
log(
Potency)]^
2:
0.03957
DDVP:
Repeated,
Brain,
Adult,
Historical
controls
Page
31
of
57
DDVP:
7­
D:
BRAIN:
M:
WHOLE
Mon
Apr
24
21:
43:
52
2006
MRID:
MDAdhist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
78.62698
85.38250
­
35.31349
Coefficients:
Value
Std.
Error
A
5.4406635
0.14572755
B
1.2233684
0.23205212
m
0.1793503
0.03602974
Correlation:
A
B
m
A
1.00000000
0.08852252
0.1851917
B
0.08852252
1.00000000
0.9107214
m
0.18519170
0.91072141
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.1532609
5.4406635
5.7440950
B
0.8329963
1.2233684
1.7966830
m
0.1193784
0.1793503
0.2694501
Residual
standard
error:
lower
est.
upper
0.6580918
0.8072133
1.0443300
Degrees
of
freedom:
40
total;
37
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.2307
with
1
degrees
of
freedom.
P
=
0.631
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
25
5.41
5.440664
0.61
0.7954922
­
0.192733152
2
0.1
5
5.52
5.365700
0.42
0.7846436
0.439720961
3
7.5
5
2.32
2.322001
0.68
0.3407920
­
0.013132451
DDVP:
Repeated,
Brain,
Adult,
Historical
controls
Page
32
of
57
4
15.0
5
1.51
1.509570
0.26
0.2200316
0.004374445
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.7701:
BMDL
=
0.6168
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1794
se:
0.03603
var=
se^
2:
0.001298
Per
cent.
of
background
at
unit
dose:
84
Per
cent.
of
background
at
the
highest
dose:
6.8
ED50
(
95%
CI):
3.865
(
2.607
,
5.73
)

ln(
Potency)
­
1.718
se[
log(
Potency)]:
0.2009
se[
log(
Potency)]^
2:
0.04036
DDVP:
Repeated,
RBC,
Adult,
Concurrent
controls
Page
33
of
57
DDVP:
7­
D:
RBC:
F:
WHOLE
Mon
Apr
24
21:
43:
38
2006
MRID:
MDAdconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
252.1003
256.0833
­
122.0502
Coefficients:
Value
Std.
Error
A
2727.000013
79.6172246
B
1258.499990
25.9812588
m
2.397083
0.8174793
Correlation:
A
B
m
A
1.000000e+
00
1.765012e­
06
0.66321810
B
1.765012e­
06
1.000000e+
00
0.05862781
m
6.632181e­
01
5.862781e­
02
1.00000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2564.091283
2727.000013
2900.259098
B
1204.860966
1258.499990
1314.526963
m
1.167355
2.397083
4.922246
Residual
standard
error:
lower
est.
upper
133.5911
178.0295
266.8919
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.1959
with
1
degrees
of
freedom.
P
=
0.658
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
2727
2727.0
150
178.02953
­
1.663420e­
07
2
0.1
5
2414
2414.0
158
157.59563
2.423883e­
07
3
7.5
5
1247
1258.5
109
82.15994
­
3.129848e­
01
DDVP:
Repeated,
RBC,
Adult,
Concurrent
controls
Page
34
of
57
4
15.0
5
1270
1258.5
70
82.15994
3.129847e­
01
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.0857:
BMDL
=
0.05385
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
2.397
se:
0.8175
var=
se^
2:
0.6683
Per
cent.
of
background
at
unit
dose:
9.1
Per
cent.
of
background
at
the
highest
dose:
2.4e­
14
ED50
(
95%
CI):
0.2892
(
0.1482
,
0.5642
)

ln(
Potency)
0.8743
se[
log(
Potency)]:
0.341
se[
log(
Potency)]^
2:
0.1163
DDVP:
Repeated,
RBC,
Adult,
Concurrent
controls
Page
35
of
57
DDVP:
7­
D:
RBC:
M:
WHOLE
Mon
Apr
24
21:
43:
43
2006
MRID:
MDAdconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
290.6427
294.6256
­
141.3214
Coefficients:
Value
Std.
Error
A
2681.7192647
145.3811253
B
1135.7992785
123.8320471
m
0.2702996
0.1094602
Correlation:
A
B
m
A
1.0000000
0.0618944
0.1785788
B
0.0618944
1.0000000
0.8143054
m
0.1785788
0.8143054
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2391.8831196
2681.7192647
3006.6762692
B
902.4076927
1135.7992785
1429.5534174
m
0.1150242
0.2702996
0.6351871
Residual
standard
error:
lower
est.
upper
368.1789
490.6517
735.5575
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
2.552
with
1
degrees
of
freedom.
P
=
0.110
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
2908
2681.719
610
453.8838
1.11477671
2
0.1
5
2413
2640.493
111
445.6730
­
1.14139604
3
7.5
5
1346
1339.393
236
220.5037
0.06699746
DDVP:
Repeated,
RBC,
Adult,
Concurrent
controls
Page
36
of
57
4
15.0
5
1159
1162.612
155
200.3797
­
0.04030813
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.7048:
BMDL
=
0.4481
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.2703
se:
0.1095
var=
se^
2:
0.01198
Per
cent.
of
background
at
unit
dose:
76
Per
cent.
of
background
at
the
highest
dose:
1.7
ED50
(
95%
CI):
2.564
(
1.16
,
5.671
)

ln(
Potency)
­
1.308
se[
log(
Potency)]:
0.405
se[
log(
Potency)]^
2:
0.164
DDVP:
Repeated,
RBC,
Adult,
Historical
controls
Page
37
of
57
DDVP:
7­
D:
RBC:
F:
WHOLE
Mon
Apr
24
21:
43:
50
2006
MRID:
MDAdhist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
Highest
1
doses
dropped
from
data
set.

The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
432.6351
436.8387
­
213.3175
Coefficients:
Value
Std.
Error
A
2.453625e+
03
68.975570904
m
9.025628e­
02
0.009178156
Correlation:
A
m
A
1.0000000
0.4137541
m
0.4137541
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2.316326e+
03
2.453625e+
03
2599.0618980
m
7.328462e­
02
9.025628e­
02
0.1111583
Residual
standard
error:
lower
est.
upper
273.4370
344.5616
466.0030
Degrees
of
freedom:
30
total;
28
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.01654
with
1
degrees
of
freedom.
P
=
0.898
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
20
2458
2453.625
399
343.9574
0.056889167
2
0.1
5
2414
2431.579
158
340.8656
­
0.115315893
3
7.5
5
1247
1246.880
109
174.7398
0.001538003
DDVP:
Repeated,
RBC,
Adult,
Historical
controls
Page
38
of
57
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
1.167:
BMDL
=
1
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.09026
se:
0.009178
var=
se^
2:
8.424e­
05
Per
cent.
of
background
at
unit
dose:
91
Per
cent.
of
background
at
the
highest
dose:
51
ED50
(
95%
CI):
7.68
(
6.292
,
9.374
)

ln(
Potency)
­
2.405
se[
log(
Potency)]:
0.1017
se[
log(
Potency)]^
2:
0.01034
DDVP:
Repeated,
RBC,
Adult,
Historical
controls
Page
39
of
57
DDVP:
7­
D:
RBC:
M:
WHOLE
Mon
Apr
24
21:
43:
56
2006
MRID:
MDAdhist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
506.1301
512.3515
­
249.0650
Coefficients:
Value
Std.
Error
A
2610.5056190
77.5940879
B
1131.7044406
110.4118748
m
0.2605430
0.0942001
Correlation:
A
B
m
A
1.00000000
0.04048633
0.1151000
B
0.04048633
1.00000000
0.8225566
m
0.11509996
0.82255665
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
2457.1412313
2610.5056190
2773.4423646
B
927.7403439
1131.7044406
1380.5101278
m
0.1247496
0.2605430
0.5441513
Residual
standard
error:
lower
est.
upper
314.8342
391.4927
517.8247
Degrees
of
freedom:
35
total;
32
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
1.095
with
1
degrees
of
freedom.
P
=
0.295
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
20
2650
2610.506
411
385.8967
0.45769820
2
0.1
5
2413
2572.474
111
379.8508
­
0.93877615
3
7.5
5
1346
1341.244
236
195.8061
0.05430863
DDVP:
Repeated,
RBC,
Adult,
Historical
controls
Page
40
of
57
4
15.0
5
1159
1161.395
155
173.2784
­
0.03091094
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.7455:
BMDL
=
0.4982
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.2605
se:
0.0942
var=
se^
2:
0.008874
Per
cent.
of
background
at
unit
dose:
77
Per
cent.
of
background
at
the
highest
dose:
2
ED50
(
95%
CI):
2.66
(
1.31
,
5.404
)

ln(
Potency)
­
1.345
se[
log(
Potency)]:
0.3616
se[
log(
Potency)]^
2:
0.1307
DDVP:
Repeated,
Brain,
Pup,
Concurrent
controls
Page
41
of
57
DDVP:
7­
D:
BRAIN:
F:
WHOLE
Mon
Apr
24
21:
43:
59
2006
MRID:
MDPupconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
Highest
1
doses
dropped
from
data
set.

The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
39.29316
41.41732
­
16.64658
Coefficients:
Value
Std.
Error
A
5.8381055
0.33369886
m
0.1111981
0.01312090
Correlation:
A
m
A
1.0000000
0.5883474
m
0.5883474
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.15992657
5.8381055
6.6054187
m
0.08617663
0.1111981
0.1434846
Residual
standard
error:
lower
est.
upper
0.8565106
1.1814689
1.9033966
Degrees
of
freedom:
15
total;
13
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
5.215
with
1
degrees
of
freedom.
P
=
0.0224
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
6.59
5.838105
0.59
1.0482540
1.60389304
2
0.1
5
5.02
5.773546
0.46
1.0365378
­
1.62558583
3
7.5
5
2.54
2.535575
0.54
0.4511931
0.02192763
DDVP:
Repeated,
Brain,
Pup,
Concurrent
controls
Page
42
of
57
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.9475:
BMDL
=
0.7935
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1112
se:
0.01312
var=
se^
2:
0.0001722
Per
cent.
of
background
at
unit
dose:
89
Per
cent.
of
background
at
the
highest
dose:
43
ED50
(
95%
CI):
6.233
(
4.946
,
7.855
)

ln(
Potency)
­
2.196
se[
log(
Potency)]:
0.118
se[
log(
Potency)]^
2:
0.01392
DDVP:
Repeated,
Brain,
Pup,
Concurrent
controls
Page
43
of
57
DDVP:
7­
D:
BRAIN:
M:
WHOLE
Mon
Apr
24
21:
44:
06
2006
MRID:
MDPupconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
Highest
1
doses
dropped
from
data
set.

The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
38.62180
40.74595
­
16.31090
Coefficients:
Value
Std.
Error
A
6.2176817
0.33406064
m
0.1201434
0.01231365
Correlation:
A
m
A
1.000000
0.589248
m
0.589248
1.000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.53629700
6.2176817
6.9829285
m
0.09628064
0.1201434
0.1499205
Residual
standard
error:
lower
est.
upper
0.8659536
1.1944947
1.9243816
Degrees
of
freedom:
15
total;
13
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
7.004
with
1
degrees
of
freedom.
P
=
0.00813
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
7.09
6.217682
0.64
1.0494073
1.85872816
2
0.1
5
5.27
6.143427
0.44
1.0367170
­
1.88387271
3
7.5
5
2.53
2.525203
0.41
0.4213597
0.02545729
DDVP:
Repeated,
Brain,
Pup,
Concurrent
controls
Page
44
of
57
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.877:
BMDL
=
0.7504
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1201
se:
0.01231
var=
se^
2:
0.0001516
Per
cent.
of
background
at
unit
dose:
89
Per
cent.
of
background
at
the
highest
dose:
41
ED50
(
95%
CI):
5.769
(
4.719
,
7.053
)

ln(
Potency)
­
2.119
se[
log(
Potency)]:
0.1025
se[
log(
Potency)]^
2:
0.0105
DDVP:
Repeated,
Brain,
Pup,
Historical
controls
Page
45
of
57
DDVP:
7­
D:
BRAIN:
F:
WHOLE
Mon
Apr
24
21:
44:
12
2006
MRID:
MDPuphist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
91.73904
98.07312
­
41.86952
Coefficients:
Value
Std.
Error
A
5.4535860
0.20843990
B
1.3874190
0.37759636
m
0.1686908
0.05235096
Correlation:
A
B
m
A
1.0000000
0.0969725
0.1952096
B
0.0969725
1.0000000
0.9213612
m
0.1952096
0.9213612
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.04558081
5.4535860
5.8945841
B
0.79750815
1.3874190
2.4136825
m
0.08971903
0.1686908
0.3171746
Residual
standard
error:
lower
est.
upper
0.867120
1.075062
1.415080
Degrees
of
freedom:
36
total;
33
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.7522
with
1
degrees
of
freedom.
P
=
0.386
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
21
5.54
5.453586
1.18
1.0587084
0.374039299
2
0.1
5
5.02
5.385569
0.46
1.0451764
­
0.782104088
3
7.5
5
2.54
2.534843
0.54
0.4881430
0.023622823
DDVP:
Repeated,
Brain,
Pup,
Historical
controls
Page
46
of
57
4
15.0
5
1.71
1.711208
0.22
0.3342521
­
0.008084159
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.8537:
BMDL
=
0.6228
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1687
se:
0.05235
var=
se^
2:
0.002741
Per
cent.
of
background
at
unit
dose:
84
Per
cent.
of
background
at
the
highest
dose:
8
ED50
(
95%
CI):
4.109
(
2.237
,
7.549
)

ln(
Potency)
­
1.78
se[
log(
Potency)]:
0.3103
se[
log(
Potency)]^
2:
0.09631
DDVP:
Repeated,
Brain,
Pup,
Historical
controls
Page
47
of
57
DDVP:
7­
D:
BRAIN:
M:
WHOLE
Mon
Apr
24
21:
44:
18
2006
MRID:
MDPuphist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
90.63050
97.28474
­
41.31525
Coefficients:
Value
Std.
Error
A
5.6883165
0.17732604
B
1.1782553
0.33427136
m
0.1610776
0.03905932
Correlation:
A
B
m
A
1.0000000
0.1065217
0.2028358
B
0.1065217
1.0000000
0.9324765
m
0.2028358
0.9324765
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
5.33981535
5.6883165
6.059562
B
0.66276419
1.1782553
2.094690
m
0.09850411
0.1610776
0.263400
Residual
standard
error:
lower
est.
upper
0.7834716
0.9634302
1.2514578
Degrees
of
freedom:
39
total;
36
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.8159
with
1
degrees
of
freedom.
P
=
0.366
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
24
5.76
5.688316
1.05
0.9517421
0.36898250
2
0.1
5
5.27
5.616251
0.44
0.9394402
­
0.82415231
3
7.5
5
2.53
2.525726
0.41
0.4194838
0.02278489
DDVP:
Repeated,
Brain,
Pup,
Historical
controls
Page
48
of
57
4
15.0
5
1.58
1.580839
0.21
0.2660983
­
0.00704853
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.837:
BMDL
=
0.6514
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.1611
se:
0.03906
var=
se^
2:
0.001526
Per
cent.
of
background
at
unit
dose:
85
Per
cent.
of
background
at
the
highest
dose:
8.9
ED50
(
95%
CI):
4.303
(
2.675
,
6.921
)

ln(
Potency)
­
1.826
se[
log(
Potency)]:
0.2425
se[
log(
Potency)]^
2:
0.0588
DDVP:
Repeated,
RBC,
Pup,
Concurrent
controls
Page
49
of
57
DDVP:
7­
D:
RBC:
F:
WHOLE
Mon
Apr
24
21:
44:
03
2006
MRID:
MDPupconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
282.2902
286.2732
­
137.1451
Coefficients:
Value
Std.
Error
A
3367.8252655
128.82707749
B
1182.3605015
84.42210176
m
0.2942281
0.06693016
Correlation:
A
B
m
A
1.00000000
0.05726548
0.1789545
B
0.05726548
1.00000000
0.7844004
m
0.17895453
0.78440045
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3106.7025997
3367.8252655
3650.8956538
B
1017.0123351
1182.3605015
1374.5913469
m
0.1820754
0.2942281
0.4754635
Residual
standard
error:
lower
est.
upper
305.9931
407.7801
611.3211
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.1602
with
1
degrees
of
freedom.
P
=
0.689
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
3418
3367.825
470
401.9922
0.27909526
2
0.1
5
3254
3304.460
257
394.2670
­
0.28617896
3
7.5
5
1424
1422.897
201
169.0092
0.01459009
DDVP:
Repeated,
RBC,
Pup,
Concurrent
controls
Page
50
of
57
4
15.0
5
1208
1208.834
145
144.7334
­
0.01289216
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.5688:
BMDL
=
0.427
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.2942
se:
0.06693
var=
se^
2:
0.00448
Per
cent.
of
background
at
unit
dose:
75
Per
cent.
of
background
at
the
highest
dose:
1.2
ED50
(
95%
CI):
2.356
(
1.508
,
3.679
)

ln(
Potency)
­
1.223
se[
log(
Potency)]:
0.2275
se[
log(
Potency)]^
2:
0.05175
DDVP:
Repeated,
RBC,
Pup,
Concurrent
controls
Page
51
of
57
DDVP:
7­
D:
RBC:
M:
WHOLE
Mon
Apr
24
21:
44:
10
2006
MRID:
MDPupconc
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
284.3103
288.2933
­
138.1552
Coefficients:
Value
Std.
Error
A
3405.8244474
134.5531824
B
1265.5873297
82.6795659
m
0.3447276
0.0992573
Correlation:
A
B
m
A
1.00000000
0.05821642
0.1595949
B
0.05821642
1.00000000
0.7517474
m
0.15959491
0.75174742
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3133.4511572
3405.8244474
3701.8736162
B
1102.6365176
1265.5873297
1452.6194839
m
0.1877810
0.3447276
0.6328497
Residual
standard
error:
lower
est.
upper
317.7069
423.3904
634.7231
Degrees
of
freedom:
20
total;
17
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.6739
with
1
degrees
of
freedom.
P
=
0.412
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
5
3299
3405.824
353
418.5584
­
0.57068917
2
0.1
5
3441
3333.302
484
410.1457
0.58715849
DDVP:
Repeated,
RBC,
Pup,
Concurrent
controls
Page
52
of
57
3
7.5
5
1423
1426.879
186
177.3018
­
0.04892138
4
15.0
5
1280
1277.743
146
155.8875
0.03238133
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.5028:
BMDL
=
0.3509
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.3447
se:
0.09926
var=
se^
2:
0.009852
Per
cent.
of
background
at
unit
dose:
71
Per
cent.
of
background
at
the
highest
dose:
0.57
ED50
(
95%
CI):
2.011
(
1.144
,
3.535
)

ln(
Potency)
­
1.065
se[
log(
Potency)]:
0.2879
se[
log(
Potency)]^
2:
0.0829
DDVP:
Repeated,
RBC,
Pup,
Historical
controls
Page
53
of
57
DDVP:
7­
D:
RBC:
F:
WHOLE
Mon
Apr
24
21:
44:
16
2006
MRID:
MDPuphist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
471.1821
477.1681
­
231.5910
Coefficients:
Value
Std.
Error
A
3212.0118304
78.13348301
B
1175.9601007
84.40054910
m
0.2793221
0.06360987
Correlation:
A
B
m
A
1.00000000
0.03961674
0.1212268
B
0.03961674
1.00000000
0.7972136
m
0.12122680
0.79721362
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3056.3407841
3212.0118304
3375.6117944
B
1015.6286087
1175.9601007
1361.6022102
m
0.1754370
0.2793221
0.4447228
Residual
standard
error:
lower
est.
upper
301.6668
377.5026
504.5976
Degrees
of
freedom:
33
total;
30
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
0.4548
with
1
degrees
of
freedom.
P
=
0.5
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
18
3185
3212.012
377
372.5099
­
0.30764682
2
0.1
5
3254
3155.927
257
366.1959
0.59885197
3
7.5
5
1424
1426.559
201
166.5420
­
0.03435202
DDVP:
Repeated,
RBC,
Pup,
Historical
controls
Page
54
of
57
4
15.0
5
1208
1206.804
145
139.2642
0.01920492
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.6147:
BMDL
=
0.4647
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.2793
se:
0.06361
var=
se^
2:
0.004046
Per
cent.
of
background
at
unit
dose:
76
Per
cent.
of
background
at
the
highest
dose:
1.5
ED50
(
95%
CI):
2.482
(
1.588
,
3.878
)

ln(
Potency)
­
1.275
se[
log(
Potency)]:
0.2277
se[
log(
Potency)]^
2:
0.05186
DDVP:
Repeated,
RBC,
Pup,
Historical
controls
Page
55
of
57
DDVP:
7­
D:
RBC:
M:
WHOLE
Mon
Apr
24
21:
44:
21
2006
MRID:
MDPuphist
Guideline:
NONGUIDELINE
Continuous
Exponential
Model
(
Decreasing)
Formula:
chei
=
B
+
(
A­
B)*
exp(­(
m*
dose)^
g)

Variance
Function:
power
The
BMD
corresponds
to
a
dose
that
results
in
a
10%
reduction
in
the
response
relative
to
the
control
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Summary
of
Model
Fitting
Results
AIC
BIC
logLik
508.6161
514.8375
­
250.3081
Coefficients:
Value
Std.
Error
A
3229.7438903
83.54133448
B
1259.4597968
88.49275967
m
0.3240709
0.09828153
Correlation:
A
B
m
A
1.00000000
0.03616319
0.1024154
B
0.03616319
1.00000000
0.7630263
m
0.10241540
0.76302628
1.0000000
Approximate
95%
confidence
intervals
Coefficients:
lower
est.
upper
A
3063.9809484
3229.7438903
3404.4746923
B
1091.5109432
1259.4597968
1453.2506428
m
0.1747259
0.3240709
0.6010671
Residual
standard
error:
lower
est.
upper
355.8975
442.5545
585.3637
Degrees
of
freedom:
35
total;
32
residual
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Goodness
of
Fit
The
chi­
squared
goodness­
of­
fit
values
should
be
taken
as
general
indications
of
fit
only.
P­
values
are
likely
to
be
inaccurate
to
some
degree
Pearson
Chi­
Square
Statistic:
2.812
with
1
degrees
of
freedom.
P
=
0.0936
dose
n
chei
Expected
sd
Exp.
SD
X2
Resid.
1
0.0
20
3162
3229.744
385
415.0112
­
0.7300042
2
0.1
5
3441
3166.916
484
407.7138
1.5031865
3
7.5
5
1423
1432.825
186
187.6611
­
0.1170705
DDVP:
Repeated,
RBC,
Pup,
Historical
controls
Page
56
of
57
4
15.0
5
1280
1274.714
146
161.4604
0.0732030
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
BMD
Computation
BMD
=
0.5525:
BMDL
=
0.3825
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Potency
Measures
A
unit
dose
(
1
mg/
kg)
would
result
in
100*
exp(­
Potency)%
of
background
activity
Potency:
0.3241
se:
0.09828
var=
se^
2:
0.009659
Per
cent.
of
background
at
unit
dose:
72
Per
cent.
of
background
at
the
highest
dose:
0.77
ED50
(
95%
CI):
2.139
(
1.18
,
3.876
)

ln(
Potency)
­
1.127
se[
log(
Potency)]:
0.3033
se[
log(
Potency)]^
2:
0.09197
DDVP:
Repeated,
RBC,
Pup,
Historical
controls
Page
57
of
57
