1
OPP's
Policy
on
the
Use
Of
Cholinesterase
(
ChE)
Data
In
Human
Health
Risk
Assessment
And
N­
Methyl
Carbamate
Overview
Anna
Lowit,
Ph.
D.

Anna
Lowit,
Ph.
D.

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

OPP's
policy
for
using
cholinesterase
inhibition
data
in
human
health
risk
assessments
°
Organophosphates
(
OPs)
and
N­
methyl
carbamates
(
NMCs)


Overview
of
N­
methyl
carbamates
under
HSRB
review
3
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

Acetylcholinesterase
(
AChE)
inhibition
is
a
key
event
in
the
mode
of
action
leading
to
neurotoxicity
for
both:


OPs:
Phosphorylation
of
the
active
site

NMCs:
Carbamylation
of
the
active
site
leading
to
rapid
recovery
4
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

Types
of
endpoints
assessed

Physiological
and
functional
effects

Measures
of
AChE
inhibition
in
central
and
peripheral
nervous
systems

Measures
of
AChE
inhibition
in
blood
(
plasma
and
RBC)


Relationship
between
functional
effects
and
inhibition
of
AChE
inhibition
is
often
difficult
to
characterize
5
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

AChE
inhibition
in
the
central
nervous
system
(
CNS)
and
the
peripheral
nervous
systems
(
PNS)

provides
direct
evidence
of
adverse
effects
in
the
nervous
system
In
laboratory
animals:


Brain
ChE
(
data
are
most
often
submitted)


Peripheral
ChE
(
data
are
rarely
submitted)

 
e.
g.,
nerves
in
diaphragm,
muscles
6
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

Inhibition
of
blood
ChEs
is
not
an
adverse
effect,

but
may
indicate
the
potential
for
adverse
effects
on
the
nervous
system

Blood
ChE
inhibition
data
are
appropriate
surrogate
measures
of
potential
effects
for:


PNS
AChE
in
animals
when
such
data
are
lacking

CNS
AChE
in
animals
when
such
data
are
lacking

Both
PNS
and
CNS
AChE
data
in
humans
7
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

RBC
AChE
measures
are
generally
preferred
over
plasma
data.


Plasma
which
contain
both
butyrylcholinesterase
and
acetylcholinesterase
in
varying
ratios
depending
upon
the
species.


RBCs
contain
only
acetylcholinesterase

Potential
for
exerting
effects
on
neural
acetylcholinesterase
may
be
better
reflected
by
changes
in
RBC
AChE
than
by
changes
in
plasma
8
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

Results
should
be
assessed
in
context
to
both
statistical
and
biological
significance

No
fixed
percentage
of
change
is
predetermined
to
separate
adverse
from
non­
adverse
effects
9
OPP
OPP'
s
ChE
Policy
s
ChE
Policy

For
benchmark
analysis,
OPP
has
used
the
BMD
10
as
the
response
level

i.
e.,
the
dose
resulting
in
10%
inhibition
in
ChE
compared
to
control

10%
response
level
is
generally
at
or
near
the
limit
of
sensitivity
for
discerning
a
statistically
significant
decrease
in
ChE
activity
across
the
blood
and
brain
compartments
and
is
a
response
level
close
to
the
background
ChE.


Power
analysis
of
brain
ChE
data
available
for
more
than
30
OPs

Most
studies
in
rats
can
reliably
detect
10%
brain
ChE
inhibition.


Clinical
signs
and
behavioral
effects
have
not
been
shown
in
studies
at
or
near
10%
ChE
inhibition.
10
OPP
OPP'
s
ChE
s
ChE
Policy
Policy

Other
important
considerations:


Age­
related
differences
°
e.
g.,
potential
increased
sensitivity
of
young

Potential
sex
differences

Differences
between
animals
and
humans
°
Pharmacokinetics
°
Pharmacodyamics
11
Overview
Overview

Aggregate
risk:
single
chemical,

multi­
pathway

Each
OP
and
N­
methyl
carbamate
has
its
own
single
chemical
risk
assessment

Cumulative
risk:
multi­
chemical,

multi­
pathway

OPs

N­
methyl
carbamates
12
Common
Mechanism
Group:

Common
Mechanism
Group:

N­
methyl
Carbamate
Pesticides
methyl
Carbamate
Pesticides

Identified
based
on:


Structural
characteristics

AChE
inhibition
by
carbamylation
leading
to
rapid
recovery
(
minutes
to
hours):

°
Brain,
peripheral
nervous
system,
surrogate
measures
in
blood
(
RBC
or
plasma)

U.
S.
EPA
2001
Policy
Paper
13
N­
methyl
Carbamate
Common
methyl
Carbamate
Common
Assessment
Group
Assessment
Group
Aldicarb
Carbaryl
Carbofuran
Formetanate
HCl
Methiocarb
Methomyl
Oxamyl
Pirimicarb
Propoxur
Thiodicarb
14
Issues
for
HSRB
Issues
for
HSRB

Scientific
conduct/
study
design

Ethical
conduct

Aldicarb:


Single
chemical
and
cumulative
risk
assessment

Methomyl
and
Oxamyl

Cumulative
risk
assessment
