EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
1
Mahktesheim
Agan
(
MANA)

and
Comments
on
Azinphos­
methyl
Monty
Eberhart,
Ph.
D.,
CIH
Dan
Van
Goethem,
M.
S.,
DABT
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
2
General
Comments

BCS
and
MANA
respect
the
role
of
the
HSRB
in
providing
guidance
and
oversight
to
those
sponsoring
intentional
dosing
studies
for
submission
to
EPA.


HSRB's
focus
should
be
on
the
ethical
and
scientific
considerations
pertaining
to
study
conduct
including
the
scientific
justification
and
risk/
benefit
questions.


It
is
unfair
to
ask
the
HSRB
to
render
WOE
judgments
about
these
studies
in
a
much
broader
regulatory
context
with
only
a
small
sampling
of
the
available
information
and
data.


We
appreciate
the
opportunity
to
provide
some
context
on
the
AZM
human
volunteer
studies
and
EPA's
ethical
and
scientific
opinions
and
questions.
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
3
Background
on
Azinphos­
methyl
(
AZM)


It
is
OP
insecticide
first
registered
in
1959
and
still
widely
used
in
tree
fruit
where
crop
production
activities
involve
high
potential
for
worker
exposures.


The
safety
database
for
AZM
is
current
and
complete,
and
includes
both
animal
studies
and
studies
in
human
volunteers.


The
animal
studies
demonstrate
that
AZM
is
not
carcinogenic,

mutagenic,
teratogenic
or
a
reproductive
toxicant
and
that
inhibition
of
cholinesterase
(
ChE)
is
the
most
sensitive
indicator
of
exposure.


The
human
studies
confirm
that
humans
are
no
more,
and
perhaps
less,
sensitive
than
animals
to
AZM's
cholinesterase
inhibiting
effects.
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
4
Rationale
for
Conducting
Human
Volunteer
Studies

what
activity­
specific
exposure
values
to
use
in
deriving
MOE
estimates

what
dermal
absorption
factor
to
use
in
extrapolating
the
worker's
dermal
exposure
to
a
systemic
dose


whether
humans
were
more
sensitive
than
animals
to
the
anti­
cholinesterase
properties
of
AZM


the
appropriate
AZM
cholinesterase
NOAEL(
s)
to
use
in
deriving
margin
of
exposure
(
MOE)
estimates
Dietary
Safety
Worker
Safety
Regulatory
Safety
Questions
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
5
Human
Volunteer
Studies
with
AZM
(
1998­
1999)


Absorption,
Excretion,
Balance
and
Pharmacokinetics
of
14­
C
Radioactivity
after
Single
Dose
Dermal
Application
of
Three
Dose
Levels
of
14­
C
Labeled
Guthion
to
Healthy
Volunteers.


A
Randomised
Double
Blind
Ascending
Single
Oral
Dose
Study
with
Azinphos­
Methyl
to
Determine
the
No­
Effect­
Level
on
Plasma
and
RBC
Cholinesterase
Activity.


A
Randomised
Double
Blind
Placebo
Controlled
Study
with
Azinphos­

Methyl
to
Determine
the
No
Effect
Level
on
Plasma
and
RBC
Cholinesterase
Activity
After
Repeated
Doses.
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
6
Human
Volunteer
Studies
 
Summary
of
Results

Dermal
absorption
and
PK
study
demonstrated
that

88%
of
a
dermally
absorbed
dose
is
excreted
in
urine
over
4.5
days,
and
MSMB
is
a
stable
metabolite
for
biological
monitoring
of
workers.


mean
dermal
absorption
of
WP
formulation
was
21.9%
(
similar
to
the
value
of
16%
obtained
by
Feldman
and
Maibach,
1974).


Single
dose
oral
study
demonstrated
that

A
single
dose
of
1.0
and
0.75
mg/
kg/
day
had
no
effect
on
plasma
or
erythrocyte
ChE
activity
in
male
and
female
volunteers,
respectively
(
rat
NOAEL
<
1.0
mg/
kg/
day).


Repeat
dose
oral
study
demonstrated
that

28­
day
repeated
doses
of
0.25
mg/
kg/
day
had
no
effect
on
plasma
or
erythrocyte
ChE
activity
in
male
volunteers
(
similar
to
the
30­
day
NOAEL
of
0.29
mg/
kg/
day
obtained
by
Rider
et
al.,
1972).
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
7
Human
Volunteer
Studies
 
Use
of
Data

Knowledge
gained
from
these
studies
was
used
to:


Design
and
conduct
an
extensive
AZM­
specific
biological
monitoring
program
for
workers
(
required
by
EPA),


Confirm
that
1.0
and
0.25
mg/
kg/
day
are
single
and
28­
day
NOAELS
in
humans
as
expected
based
on
existing
animal
and
human
data,
and

Further
increase
confidence
that
humans
are
not
more
sensitive
to
the
ChE
inhibiting
properties
of
AZM
than
animals.


Regulatory
authorities
using
these
data
in
regulatory
decisions
include:


California
Department
of
Pesticide
Regulation
(
CDPR)


Australian
Pesticides
and
Veterinary
Medicine
Authority

European
Union
(
proposed
by
Rapporteur
Member
State)
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
8
Ethical
Considerations
Before
the
HSRB

BCS
and
MANA
strongly
believe
that
all
three
AZM
human
volunteer
studies
were
conducted
in
an
ethical
manner.


With
respect
to
the
28­
day
oral
study
being
reviewed
by
HSRB:


we
agree
with
EPA's
interpretation
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
this
study
was
fundamentally
unethical

we
disagree
with
EPA's
interpretation
that
the
study's
value
was
limited
to
establishing
a
human
ChE
NOAEL,
and
that
no
evidence
of
use
to
establish
RfDs,
REIs,
or
safe
levels
for
workers
exists

we
disagree
the
informed
consent
materials
did
not
identify
the
supervising
doctor
or
contain
a
discussion
of
who
would
benefit
from
the
study,
or
that
the
protocol
did
not
contain
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society

We
are
open
to
ideas
on
ways
to
improve
future
informed
consent
materials.
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
9
Scientific
Issues
Before
the
HSRB

BCS
and
MANA
agree
with
the
EPA
that:


the
0.25
mg/
kg/
day
NOAEL
from
the
28­
day
oral
volunteer
study
is
appropriate
for
evaluating
worker
safety,
and

that
interspecies
and
gender
differences
with
respect
to
ChE
inhibition
would
not
be
expected
at
these
dose
levels.


BCS
and
MANA
do
not
agree
with
the
EPA
that:


rat
rather
than
human
dermal
absorption
data
should
be
used
for
route­

toroute
extrapolations
when
evaluating
worker
safety,
and

the
28­
day
human
volunteer
study
is
not
sufficiently
robust
to
inform
the
interspecies
uncertainty
factor
for
cumulative
risk.
Exposure
Assessment
Approaches
A.
Passive
Dosimetry
­
Lower
Tier
B.
Biological
Monitoring
­
Higher
Tier
Inhalation
Exposure
Dermal
Exposure
Systemic
Dose
Feces
Urine
100%
absorption
assumed
dermal
absorption
factor
(
rat)

Inhalation
Exposure
Dermal
Exposure
Systemic
Dose
Feces
Urine
100%
absorption
assumed
dermal
absorption
factor
(
human)

Generic
Data
Compound­
Specific
Data
modified
from:
Eberhart,
D.
C.,
Methods
of
Pesticide
Exposure
Assessment.
Plenum
Press,
New
York,
1995
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
11
AZM
Lower
vs
Higher
Tier
Exposure
Assessment
Dermal
Exposure
(
µ
g/
lb
AI)
Dermal
Absorption
(%)
Absorbed
Dose
(
µ
g/
kg/
day)

Passive
Dosimetry
(
lower
tier)

Biological
Monitoring
(
higher
tier)
25.7
22.5
19.0
19.0
1.40
1.22
Human
Dermal
Absorption
Data
Passive
Dosimetry
(
lower
tier)

Biological
Monitoring
(
higher
tier)
25.7
10.2
41.7
41.7
3.06
1.22
Rat
Dermal
Absorption
Data
EPA
Human
Subjects
Review
Board
Meeting
°
April
5,
2006
°
Slide
12
Urinary
Metabolites
of
Molinate*
in
Mammals
Species
Rat
Mouse
Rabbit
Dog
Monkey
Human
C­
oxidation
32%
50%
63%
36%
43%
39%
S­
oxidation
29%
21%

7%
33%
19%

1%
Th­
cleavage
33%
23%

5%
28%

1%

ND
Primary
biotransformation
pathways
from:
Wickramaratne
et
al.,
Reg.
Tox.
Pharm.
27,
112­
18
(
1998)

*
molinate
is
a
thiocarbamate
herbicide
