Document ID: EPA-HQ-ORD-2006-0187-0089
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

1
Azinphos
Methyl:
WOE
Comparison
of
Human
and
Animal
Studies
for
Single
Chemical
and
Organophosphate
Cumulative
Risk
Assessments
J.
Doherty,
Ph.
D.
(
Study
review
and
single
chemical
risk
assessment)

A.
Lowit,
Ph.
D.
(
Cumulative
risk
assessment)

USEPA/
OPP/
HED
April
5,
2006
2
Azinphos
Methyl
(
AZM)

An
organophosphate
(
OP)
cholinesterase
inhibitor.

Included
in
the
OP
cumulative
risk
assessment
group
Used
as
acaricide
since
1953.

S­(
3,4­
dihydro­
4­
oxobenzo[
d] 
1,2,3­
triazin­
3­

ylmethyl)
O,

Odimethyl
phosphordithioate.

N
N
O
N
C
H
2
S
P
O
O
S
CH
3
CH
3
3
AZM
Repeat
Dose
Human
Study
AZM
Repeat
Dose
Human
Study
­
Details
Details
 
Inveresk
Laboratory
(
Scotland)
 
1999
 
28
daily
doses
of
0.25
mg/
kg
(
mkd)
in
8
adult
males
orally
by
capsule
 
Lactose
 
placebo 
in
4
adult
males.

 
Objective
of
study
 
determine
the
no
effect
level
for
plasma
ChE
and
RBC
AChE
and
assess
for
possible
reactions
to
treatment.

 
8
prestudy
baseline
plasma
and
RBC
ChE
assessments.

 
Daily
ChE
assessments
4
hours
after
dosing.
On
some
days
both
predose
and
postdose
assessments.

 
Constant
monitoring
for
reactions
plus
ECG
and
blood
pressure
and
clinical
chemistry.
4
Clinical
Assessment
Clinical
Assessment
°
No
treatment
related
clinical
signs
noted.

°
Clinical
signs
(
i.
e.
"
headache"
etc)
were
same
in
both
control
and
AZM
treated
groups.

°
"
Viral
infection"
in
both
groups
treated
with
tylenol.
Not
considered
to
compromise
the
study.
5
Cholinesterase
Inhibition
Cholinesterase
Inhibition
AZM
did
not
inhibit
either
plasma
ChE
or
RBC
AChE
based
on
three
different
comparisons:

1.
against
"
placebo"
control
2.
daily
postdosing
against
same
group
prestudy
baseline
3.
predose
and
4
hour
postdose
data
6
Individual
Plasma
ChE
or
RBC
AChE
Variation
From
Individual
Plasma
ChE
or
RBC
AChE
Variation
From
Baseline
Throughout
the
Study
Baseline
Throughout
the
Study
Plasma
ChE.
Controls:
86%
to
110%

AZM:
83%
to
112%

RBC
AChE
Controls:
77%
to
129%

AZM:
76%
to
133%

Similar
variation
and
no
consistent
decrease
in
activity
in
successive
daily
samplings
to
support
a
case
for
inhibition
in
any
individual.

Therefore
study
is
a
 
NOEL­
only
study .
7
NAS
Recommendation
7
NAS
Recommendation
7­
4.*

4.*

*
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes
*
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes
 

Scientific
and
Ethical
Issues.

Scientific
and
Ethical
Issues.
NAS
2004.

NAS
2004.

 
EPA
should
reject
data
from
 
NOEL­
only 
studies
for
risk
assessment.

 
Such
studies
provide
no
assurance
that
they
were
adequate
to
detect
the
effect
of
interest.

However,
the
Inversek
laboratory
demonstrated
their
ability
to
detect
plasma
ChE
and
RBC
AChE
inhibition
in
studies
with
human
volunteers
aldicarb
­
carbamate
(
1992)

methomyl
­
carbamate
(
1998)

oxamyl
­
carbamate
(
1999)

oxydemeton
 
OP
(
1999)
8
Repeated
Dose
study
Repeated
Dose
study
­
Considerations
Considerations
°
Males
only
but
females
not
consistently
more
sensitive
than
males
in
animal
studies.

°
Limited
number
of
subjects
(
8)
but
studies
with
other
chemicals
at
this
lab
demonstrate
inhibition
for
a
sample
this
size.
Intraspecies
uncertainty
factor
accounts
for
persons
of
increased
sensitivity
to
OP
inhibition.

°
Animal
data
indicate
steady
state
by
week
4.
9
Repeated
Dosing
Study
Repeated
Dosing
Study
­
Conclusions
Conclusions
°
Study
is
technically
scientifically
acceptable.

°
The
NOAEL
of
0.25
mkd
from
human
study
is
selected
as
the
endpoint
for
short
(
1­
30
days)
and
intermediate
(
1­
6
months)
term
occupational
exposure
risk
assessments.

°
Data
from
animal
studies
support
selection
of
the
human
study.
Animal
NOAELs
and
LOAELs
are
~
0.5
to
1
mg/
kg/
day.

°
The
10
X
interspecies
uncertainty
factor
can
be
dropped.
10
Sample
Impact
of
Removing
the
10
X
Sample
Impact
of
Removing
the
10
X
Interspecies
Uncertainty
factor
for
Dermal
Interspecies
Uncertainty
factor
for
Dermal
Single
Chemical
Exposure
Single
Chemical
Exposure
>
10
Acceptable
60
0.01
mkd
0.60
mkd
0.25
mkd
Human
Oral
Study
>
100
Not
Acceptable
36
0.01
mkd
0.36
mkd
0.149
Mkd
Dog
Oral
Study
Acceptable
MOE
Calculated
MOE
Hypothetical
Exposure
Adjusted
for
42%
Absorption
NOAEL
Source
11
OP
Cumulative
Risk
Assessment
OP
Cumulative
Risk
Assessment
°
Female
rat
brain
ChE
data
for
steady
state
(
21
to
28
days
and
longer)
provide
the
relative
potency
factors
(
RPF)
for
AZM
in
the
Revised
OP
cumulative
risk
assessment
(
2002).

 
Supported
by
the
FIFRA
Scientific
Advisory
Panel
°
Human
data
may
be
considered
for
the
inter­
species
factor
12
OP
Cumulative
Risk
Assessment
OP
Cumulative
Risk
Assessment
°
28­
day
AZM
human
study
does
not
show
any
ChE
inhibition
 
Can
not
evaluate
whether
or
not
steady
state
was
reached
°
Bayer
CropScience
provided
additional
data
to
EPA
 
Concentration
of
key
metabolite
in
urine
of
human
subjects
that
indicates
steady
state
for
metabolite
at
approximately
4­
5
days
of
exposure
 
Oral
exposure
study
in
rats
where
whole
blood
ChE
inhibition
was
measured
at
durations
ranging
from
3
days
up
to
9
weeks
of
exposure
 
Steady
state
reached
in
whole
blood
ChE
inhibition
by
14
days.
13
OP
Cumulative
Risk
Assessment
OP
Cumulative
Risk
Assessment
°
Additional
uncertainties
 
28­
day
AZM
human
study
does
not
show
any
inhibition
°
No
data
to
compare
relative
sensitivity
between
humans
and
rats
 
Extrapolating
information
across
compartments
(
RBC
to
brain)

 
Extrapolating
information
across
sexes
(
male
subjects
to
female
rat)
14
OP
Cumulative
Risk
Assessment
OP
Cumulative
Risk
Assessment
°
Only
a
NOAEL
dose
°
Where
is
this
dose
on
the
human
doseresponse
curve?

°
Human
to
rat
comparison
is
unknown.
NOAEL
Response
(%)
mg/
kg/
day
X
X
X
X
X
BMD10
The
inter­
species
factor
for
AZM
in
the
OP
CRA:

10X
15
Charge
(
Scientific)
to
the
HSRB
Charge
(
Scientific)
to
the
HSRB
°
The
Agency's
WOE
document
and
DER
for
AZM
describe
the
study
design
and
results
of
the
AZM
repeat
dose,
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
worker
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
OPs.

For
AZM,

 
Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
worker
risk
assessment
cumulative
risk
assessment
16
°
Backpocket
slides
for
AZM
17
Inveresk
Inveresk'
s
procedures
do
detect
plasma
ChE
s
procedures
do
detect
plasma
ChE
and
RBC
AChE
inhibition
in
humans.

and
RBC
AChE
inhibition
in
humans.

*
statistically
significant.

*
statistically
significant.
11326
±
895
(­
1%)

7120
±
1268
(­
36%)*

7605
±
1043
(­
29%)*

8499
±
1072
(­
23%)*

11409
±
478
11174
±
1014
10686
±
1644
11054
±
641
RBC
AChE
Azinphos
methyl­ 
99
Methomyl­ 
98
Oxamyl­
 
99
Oxydemeton­ 
99
5560
±
888
(+
5%)

4459
±
388
(­
21%)*

2758
±
739
(­
43%)*

3463
±
715
(­
24%)*

5307
±
1048
5665
±
534
4871
±
777
4542
±
900
Plasma
ChE
Azinphos
methyl­ 
99
Methomyl­ 
98
Oxamyl­ 
99
Oxydemeton­ 
99
Postdosing
mean
IU/
mL
Predosing
mean
IU/
mL
Study­
year