Document ID: EPA-HQ-ORD-2006-0187-0027
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-28T05:00Z

Page
1
of
19
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
March
21,
2006
SUBJECT:
Human
Studies
Review
Board:
OPP's
Approach
for
Incorporating
Human
Studies
in
Human
Health
Risk
Assessment.

FROM:
Ray
Kent,
Elissa
Reaves,
and
Louis
Scarano
Health
Effects
Division
(
7509C)

THRU:
Jack
Housenger,
Associate
Director
Health
Effects
Division
(
7509C)

TO:
Tina
Levine,
Ph.
D.,
Director
Health
Effects
Division
(
7509C)

This
background
document
is
in
support
of
the
first
public
meeting
of
the
Human
Studies
Review
Board
(
HSRB)
scheduled
for
April
4­
6,
2006.
This
document
provides
a
general
overview
of
the
approaches
used
by
EPA's
Office
of
Pesticide
Program
when
developing
human
health
risk
assessments
and
provides
an
overview
of
the
ways
in
which
human
data
may
be
used
to
support
human
health
risk
assessments
for
pesticide
chemicals.
A
summary
of
the
study
design
for
the
human
studies
being
reviewed
by
the
HSRB
also
is
presented.
Finally,
this
document
provides
the
HSRB
with
a
summary
of
the
eleven
intentional
exposure
human
studies
that
will
be
the
focus
of
this
first
meeting
of
the
HSRB.
Page
2
of
19
Purpose
The
first
public
meeting
of
EPA's
new
Human
Studies
Review
Board
(
HSRB
or
Board)
is
scheduled
for
April
4­
6,
2006.
The
inaugural
meeting
will
address
scientific
and
ethical
issues
surrounding
toxicity
studies
involving
intentional
exposure
of
human
subjects
to
eight
pesticide
active
ingredients:
aldicarb,
amitraz,
azinphos
methyl
(
AZM),
ethephon,
dichlorvos
(
DDVP),
methomyl,
oxamyl,
and
sodium
cyanide.
The
Agency
has
provided
the
Board
with
a
variety
of
materials
which
describe
the
ethical
and
scientific
conduct
of
the
studies.
The
Agency
has
also
provided
the
Board
with
some
background
documents
including
some
which
describe
EPA
policies
and/
or
regulations.
The
purpose
of
this
document
is
to
provide
a
general
overview
of
the
approaches
used
by
EPA's
Office
of
Pesticide
Program
(
OPP)
when
developing
human
health
risk
assessments
and
to
provide
an
overview
of
the
ways
in
which
human
data
may
be
used
to
support
human
health
risk
assessments
for
pesticide
chemicals.
A
summary
of
the
study
design
for
the
human
studies
being
reviewed
by
the
Board
also
is
presented.
The
last
section
of
this
document
provides
a
summary
of
the
eleven
intentional
exposure
human
studies
that
will
be
the
focus
of
the
first
HSRB
meeting.
In
this
document,
they
will
be
presented
in
the
order
they
will
be
discussed
at
the
meeting:
Session
1
 
aldicarb,
methomyl,
and
oxamyl
(
the
N­
methyl
carbamates);
Session
2
 
azinphosmethyl
and
DDVP,
(
organophosphates);
and
Session
3
 
ethephon,
amitraz,
and
hydrogen
cyanide
(
note:
as
a
result
of
its
use
as
a
fumigant,
sodium
cyanide
forms
hydrogen
cyanide;
which
will
be
the
focus
of
this
review).

Regulatory
Background
In
the
US,
pesticide
chemicals
are
registered
for
use
by
the
Environmental
Protection
Agency
(
EPA).
EPA
regulates
the
use
of
pesticides
under
the
authority
of
two
federal
statues:
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
and
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA).
FIFRA,
first
passed
in
1947,
requires
pesticide
registration
by
EPA
prior
to
the
manufacture,
transport,
or
sale
in
the
US.
FIFRA
also
provides
the
EPA
with
the
authority
to
require
data
for
the
pesticide
before
registration.
Under
FFDCA,
EPA
establishes
tolerances
(
maximum
allowable
pesticide
residue
levels)
for
pesticide
residues
in
foods
and
feeds.
More
recently
the
Food
Quality
Protection
Act
of
1996
(
FQPA)
amended
FIFRA
and
FFDCA,
significantly
changing
the
way
EPA
regulates
pesticides.
Some
key
changes
by
FQPA
include
the
requirement
to
consider
aggregate
exposure,
i.
e.,
exposure
to
a
single
chemical
by
multiple
pathways;
cumulative
assessment
of
multiple
pesticides
that
share
a
common
mechanism
of
toxicity;
and
the
application
of
the
FQPA
10X
factor
for
the
protection
of
infants
and
children.
FQPA
set
a
deadline
of
August
3,
2006
for
EPA
to
reassess
pesticide
tolerances.
EPA
is
currently
in
the
final
stages
of
completing
its
reassessment
of
more
than
nine
thousand
tolerances.
Page
3
of
19
OPP's
Approach
to
Human
Health
Risk
Assessment
Historically,
EPA
has
focused
on
single
pathways
of
exposure
(
e.
g.,
pesticide
residues
in
food,
water,
or
residential/
non­
occupational
uses)
for
individual
chemicals.
The
FQPA
amendments
to
the
FFDCA
directed
EPA­
OPP
to
consider
"
aggregate
exposure"
in
single
chemical
assessments.
"
Aggregate
risk"
is
defined
by
EPA­
OPP
as
the
sum
total
of
all
exposure
to
pesticides
through
inhalation,
dermal,
oral,
or
optic
contact
(
USEPA,
2001a).
Thus,
aggregate
risk
is
the
risk
to
a
single
pesticide
chemical
from
multiple
routes
and
pathways
of
exposure
(
e.
g.,
food
+
water
+
residential).
As
part
of
single
chemical
risk
assessments,
EPA
also
assesses
occupational
risks
resulting
from
a
variety
of
work
activities.

FQPA
also
required
EPA­
OPP
to
consider
"
available
evidence
concerning
the
cumulative
effects
on
infants
and
children
of
such
residues
and
other
substances
that
have
a
common
mechanism
of
toxicity."
Thus,
cumulative
risk
is
defined
as
the
risk
that
may
result
from
dietary,
residential,
or
other
non­
occupational
exposure
to
multiple
chemicals
that
have
a
common
mechanism
of
toxicity.
Cumulative
risk
assessments
include
multiple
pathways
and
multiple
chemicals.
EPA­
OPP
has
developed
a
guidance
document
for
developing
cumulative
risk
assessments
under
FQPA
(
USEPA,
2002).
EPA
is
currently
developing
cumulative
risk
assessments
for
4
groups
of
pesticides:
organophosphates,
N­
methyl
carbamates,
triazines,
and
chloroacetanilides.

Single
chemical,
aggregate
assessments
differ
from
cumulative
risk
assessments
in
scope
and
purpose.
Regarding
hazard
assessment,
single
chemical
assessments
consider
all
potential
toxicities;
cumulative
risk
assessments
focus
on
the
common
toxic
effect
for
the
common
mechanism
group.
Specifically,
single
chemical
risk
assessments
consider
all
possible
toxicities
and
durations
(
e.
g.,
acute
to
chronic).
Cumulative
risk
assessments
focus
on
the
common
toxic
effect
and
duration
of
exposure
relevant
to
that
common
effect.
As
described
below,
there
are
a
variety
of
ways
in
which
human
data
can
be
incorporated
into
a
single
chemical
hazard
assessment.
Some
include
use
of
human
data
as
the
point
of
departure
for
risk
extrapolation
(
i.
e.,
NOAEL
or
benchmark
dose)
and
to
inform
the
interspecies
extrapolation
factor
when
animal
data
provide
the
point
of
departure
and/
or
the
intraspecies
extrapolation
factor.
An
important
step
in
cumulative
hazard
assessment
is
the
determination
of
relative
potency.
Determinations
of
relative
potency
should
be
made,
to
the
extent
possible,
using
a
uniform
measure
of
toxicity
with
a
single
species,
duration
of
exposure,
and
study
design.
To
ensure
that
potency
estimates
are
made
with
a
single
species,
the
Agency
expects
that
relative
potency
estimates
for
cumulative
risk
assessments
will
most
often
be
developed
using
laboratory
animal
data.
Page
4
of
19
For
those
groups
where
no
human
data
are
available,
the
Agency
will
likely
apply
the
default
10X
factor
for
interspecies
extrapolation1.
Thus
for
cumulative
risk
assessments,
human
data,
if
available,
may
be
used
to
inform
the
interspecies
factor(
s).

As
part
of
the
risk
assessment
process,
EPA
evaluates
many
toxicity
studies.
These
studies
are
submitted
to
the
Agency
for
a
wide
range
of
adverse
effects
and
durations
of
exposure,
from
eye
and
skin
irritation
to
cancer
and
developmental
toxicity
in
laboratory
animals.
The
studies
also
provide
information
regarding
toxicity
via
different
routes
of
exposure
(
e.
g.,
oral,
dermal,
and
inhalation).
EPA
may
also
consult
the
public
literature
or
other
sources
of
supporting
information
on
any
aspect
of
the
chemical.
The
majority
of
toxicity
studies
available
to
the
Agency
for
developing
hazard
assessments
are
conducted
on
laboratory
animals
(
rat,
mouse,
rabbit,
and
dog).
EPA
occasionally
receives
human
toxicity
studies.

EPA's
guidance
documents
for
developing
a
reference
dose
(
RfD)
and
reference
concentration
(
RfC)
and
performing
benchmark
dose
(
BMD)
analysis
(
USEPA
1994,
2000,
2002a)
provide
a
comprehensive
discussion
of
performing
dose­
response
analysis
for
risk
assessment
purposes.
Briefly
a
point
of
departure
(
PoD)
is
first
selected
to
be
protective
of
the
critical
effect
for
a
particular
pesticide.
This
approach
is
based,
in
part,
on
the
assumption
that
if
the
critical
toxic
effect
is
prevented,
then
other
toxicities
may
also
be
prevented.
A
PoD
can
be
a
benchmark
dose
estimate
(
USEPA,
2000),
no­
observed­
adverse­
effect­
level
(
NOAEL),
or
a
lowest­
observed­
adverse­
effectlevel
(
LOAEL).
Next,
uncertainty
and
extrapolation
factors
are
identified.
Historically,
EPA­
OPP
has
used
a
10X
factor
for
interspecies
extrapolation
(
i.
e.,
extrapolation
from
animal
to
human,
see
footnote
2)
and
a
10X
factor
for
intraspecies
extrapolation
to
account
for
human
variability.
Where
a
NOAEL
is
not
identified
in
the
critical
toxicity
study,
a
LOAEL
to
NOAEL
uncertainty
factor
may
be
applied.
A
database
uncertainty
factor
may
also
be
used
when
a
key
study
(
e.
g.,
developmental
toxicity)
is
not
available
in
the
pesticide's
toxicity
database.
Additionally,
FQPA
requires
that
EPA
apply
a
10X
factor
to
account
for
added
sensitivity
of
infants
and
children
unless
there
is
sufficient
data
to
reduce
this
factor.

Types
of
Human
Research
in
Pesticide
Risk
Assessment
OPP
utilizes
a
basic
risk
assessment
model
in
assessing
pesticide
risks
­
estimating
exposures
associated
with
pesticide
use,
estimating
delivered
doses
from
information
on
exposure
and
chemical
uptake,
and
comparing
estimates
of
delivered
dose
with
data
on
pesticide
toxicity.

For
hazard
assessment,
EPA's
human
health
risk
assessments
rely
primarily
on
1
Note:
As
of
February,
2006,
the
Agency
was
soliciting
public
comment
regarding
the
use
of
¾
body
weight
scaling
in
animal
to
human
extrapolations
for
non­
cancer
risk
assessment.
If
this
becomes
Agency­
wide
policy
in
the
future,
OPP's
cumulative
risk
assessment
will
appropriately
adopt
this
approach.
Page
5
of
19
toxicity­
related
information
derived
from
testing
with
laboratory
animals,
but
EPA
may
occasionally
receive
human
data
that
help
characterize
the
toxicity
or
kinetics
of
a
pesticide.
Regarding
exposure,
EPA
routinely
uses
data
from
human
research
in
estimating
potential
exposure
to
pesticides.
In
addition,
the
Agency
may
use
data
from
human
research
to
evaluate
the
efficacy
of
certain
types
of
pesticides.

The
range
of
types
of
human
research
on
pesticides
is
discussed
below,
followed
by
a
brief
discussion
of
the
role
of
human
toxicity
studies
in
pesticide
risk
assessment.

 
Systemic
toxicity
­
Ordinarily,
toxicity
studies
that
the
Agency
receives
in
support
of
pesticide
registrations
are
carried
out
in
rodents,
rabbits
or
dogs.
Occasionally,
human
toxicity
studies
are
submitted
to
support
pesticide
registration
or
reregistration,
but
such
studies
have
never
been
common,
and
OPP
has
never
developed
guidelines
for
the
conduct
of
human
systemic
toxicity
studies.
It
is
this
kind
of
study,
defined
as
a
study
to
define
or
quantify
an
adverse
response
in
human
subjects,
which
has
drawn
most
attention
from
those
who
have
criticized
the
Agency
for
the
use
of
human
data
in
pesticide
regulation.
All
human
systemic
toxicity
studies
of
pesticides
that
support
a
regulatory
decision
rendered
after
April
7,
2006
will
be
brought
to
the
HSRB
for
review
of
science
and
ethics,
even
studies
conducted
decades
ago.

 
Dermal
irritation
and
dermal
sensitization
­
These
studies,
typically
conducted
in
rabbits,
are
commonly
received
in
support
of
registration
of
all
pesticide
products.
Studies
performed
with
human
subjects
are
occasionally
submitted
in
support
of
pesticides,
particularly
for
antimicrobial
pesticides
intended
for
home
use.
For
conventional
pesticides,
data
of
this
sort
are
not
ordinarily
used
for
quantitative
risk
assessment,
but
can
influence
label
warnings
and
other
label
language.
These
types
of
human
studies
are
subject
to
HSRB
review.

 
Eye
irritation
and
other
sensory
threshold
studies
 
Ordinarily,
eye
irritation
studies
are
performed
with
rabbits.
OPP
has
recently
received
a
two
eye
irritation
studies
on
fumigants
using
human
subjects.
Occasionally
the
eye
irritation
studies
are
associated
with
other
studies
such
as
odor
threshold
studies,
so
these
studies
may
have
originally
been
intended
to
ascertain
whether
a
product
has
adequate
warning
properties.
These
studies
are
subject
to
HSRB
review
and
examples
of
these
types
of
studies
may
be
presented
to
the
Board
in
2006.

 
Epidemiology
studies
­
Epidemiology
studies
are
not
common.
A
few
studies
have
been
submitted
by
registrants.
These
studies
are
not
considered
intentional
exposure
studies
and
normally
will
not
be
submitted
for
HSRB
review.

 
Poisoning/
incident
data
­
These
studies
or
reports
are
also
not
considered
intentional
exposure
data
and
normally
will
not
be
submitted
for
HSRB
review.
Incident
reports
may
serve
as
a
reality
check
on
the
risk
assessment.
Absence
of
Page
6
of
19
incident
reports
does
not
indicate
that
a
pesticide
is
without
risk,
but
positive
data
may
indicate
whether
the
risk
assessment
is
focused
on
the
key
effect.
Incident
reports
are
much
less
useful
quantitatively,
because
it
is
usually
difficult
to
associate
an
incident
with
a
measured
exposure.

 
In
vitro
studies
­
Genotoxicity
studies
with
human
lymphocytes
or
in
vitro
dermal
absorption
studies
with
human
cadaver
skin
are
examples
of
in
vitro
studies
of
human
cells
or
tissues
occasionally
submitted
to
OPP.
In
vitro
studies
on
human
cells
or
tissues
are
not
considered
to
be
"
human
research"
according
to
the
Human
Studies
Rule
and
normally
will
not
be
brought
to
the
HSRB
for
review.

 
Absorption,
distribution,
metabolism,
and
excretion
(
ADME)
studies.
These
studies
may
be
viewed
as
the
interface
between
toxicity
and
exposure
for
they
reveal
how
a
chemical
presented
to
a
human
subject
might
be
transported
to
the
target
tissue
and
transformed
to
more
toxic
forms
or
detoxified
to
less
active
forms.
Most
human
studies
submitted
in
this
category
(
ADME
studies)
are
dermal
absorption
studies.
As
is
the
case
with
toxicity
studies,
the
Agency
neither
requires
nor
encourages
the
generation
of
dermal
absorption
studies
in
humans
and
has
not
developed
guidelines
for
the
proper
conduct
of
such
studies.
These
studies
may
be
submitted
from
the
literature
or
may
have
been
generated
by
registrants
to
characterize
differences
in
absorption
between
humans
and
animals.
On
some
occasions,
the
Agency
has
received
comprehensive
human
ADME
data
on
pesticides,
particularly
pharmaceuticals.
These
studies
are
subject
to
HSRB
review.

Exposure
studies
 
Food
consumption
patterns
(
dietary
exposure
assessment).
OPP
dietary
exposure
assessments
rely
heavily
on
dietary
survey
data
collected
in
food
surveys,
such
as
USDA's
Continuing
Survey
of
Food
Intake
by
Individuals
(
CSFII).
As
a
survey,
this
sort
of
information
is
not
considered
to
be
research
involving
intentional
exposure
according
to
the
Human
Studies
Rule
and
normally
will
not
be
brought
to
the
HSRB
for
review.

 
Occupational/
residential
handler
(
mixer/
loader/
applicator)
studies.
Whereas
human
studies
are
relatively
uncommon
in
assessing
potential
risks
to
human
health,
human
studies
are
critical
to
the
assessment
of
occupational
and
residential
exposure,
and
nearly
every
occupational
or
residential
exposure
assessment
uses
human
data
either
directly
or
indirectly.
Human
studies
tend
to
focus
on
exposures
related
to
pesticide
application
(
i.
e.
mixer/
loader/
applicator
studies
or
pesticide
handler
studies),
or
post­
application
(
e.
g.
worker
reentry
studies).
The
Office
of
Pollution
Prevention
and
Toxics
has
published
test
guidelines
(
Series
875
­
Occupational
and
Residential
Exposure
Test
Guidelines)
that
outline
procedures
to
follow
in
developing
a
study
protocol.
Databases
of
exposure
studies
such
as
the
Pesticide
Handlers
Exposure
Database
(
PHED)
or
the
Outdoor
Residential
Page
7
of
19
Exposure
Task
Force
(
ORETF)
have
been
created
from
pools
of
exposure
studies
to
provide
generic
exposure
values
for
assessment
of
any
pesticide
whose
use
is
consistent
with
pesticides
in
the
databases.

Applicator
studies
have
typically
employed
patches
affixed
to
clothing
as
dosimeters
of
exposure
or
more
frequently
now,
use
whole
body
dosimeters.
Post­
application
studies
typically
measure
the
amount
of
pesticide
deposited
on
the
skin
in
human
subjects
performing
tasks,
such
as
plant
thinning
or
harvesting,
normally
carried
out
following
pesticide
application.
Another
type
of
exposure
study
that
is
being
submitted
with
increasing
frequency
to
OPP
is
the
biomonitoring
study.
The
internal
dose
is
determined
from
measured
levels
of
a
biomarker
in
urine
or
blood
coupled
with
knowledge
of
oral
and
dermal
pharmacokinetics
of
the
pesticide.
Review
of
biomonitoring
protocols
and
studies
requires
effective
collaboration
between
exposure
assessor
and
a
toxicologist
knowledgeable
about
pharmacokinetic
studies.

The
bulk
of
exposure
studies
already
submitted
to
the
Agency
is
interpreted
as
intentional
exposure
studies
because
the
study
investigators
are
considered
to
be
in
control
of
at
least
some
of
the
study
parameters
(
i.
e.
the
investigator
is
not
completely
passive
with
respect
to
the
conditions
of
exposure).
Intentional
exposure
studies
completed
in
the
past
normally
will
not
be
submitted
to
the
HSRB
for
their
review,
but
protocols
and
studies
to
be
carried
out
from
now
on
will
be
brought
to
the
HSRB
for
review
of
science
and
ethics.

Special
studies
 
Insect
repellent
efficacy
­
Submitted
in
support
of
the
registration
of
insect
repellents,
these
are
specialized
studies
to
determine
optimal
conditions
for
use
of
insect
repellents.
They
are
considered
intentional
exposure
studies
and
future
protocols
and
studies
will
be
submitted
to
the
HSRB.

Role
of
intentional
exposure
human
systemic
toxicity
studies
in
pesticide
risk
assessment.

When
a
human
toxicity
study
is
submitted
to
the
Agency,
it
is
assigned
to
a
toxicologist
familiar
with
the
active
ingredient.
Each
study
is
evaluated
according
to
standard
procedures2
which
details
the
factors
a
toxicologist
considers
in
reviewing
individual
human
studies
for
their
scientific
quality
and
in
preparing
a
weight
of
evidence
analysis.
Reviewers
focus
on
factors
such
as
study
design,
characterization
of
the
tested
material,
subject
selection,
adequacy
of
controls,
dose
selection,
clinical
observations
and
symptoms,
statistical
analysis,
etc.
For
human
studies
determined
to
be
scientifically
and
ethically
acceptable,
a
weight
of
evidence
analysis
is
undertaken
2
Included
in
the
data
package
for
the
first
HSRB
meeting
is
a
document
entitled
"
Interim
Guidance
for
Judging
the
Scientific
Quality
of
Intentional
Exposure
Human
Studies
Page
8
of
19
whereby
human
and
animal
studies
are
compared
with
respect
to
study
strengths
and
weaknesses
and
pattern
of
effects.
Since
the
OPP
toxicologist
is
familiar
with
the
whole
database
on
a
pesticide,
that
individual
is
well
suited
to
judge
how
human
data
fits
into
the
overall
database,
and
what
its
appropriate
role
in
the
risk
assessment
might
be.

Human
toxicity
data
could
be
used
in
any
of
the
following
ways:

 
Provide
an
endpoint
and
point
of
departure
for
risk
assessment.
If
a
human
study
is
scientifically
sound
and
the
pattern
of
observed
effects
is
consistent
with
that
observed
in
experimental
animals,
the
human
study
might
be
used
directly
to
establish
a
point
of
departure
such
as
a
NOAEL,
LOAEL
or
benchmark
dose.
For
some
toxicities,
the
effects
observed
in
human
studies
are
subjective
in
nature
and/
or
are
difficult
to
measure
in
laboratory
animals.
In
these
cases,
the
human
study
may
be
relevant
for
developing
points
of
departure.
There
may
be
cases
where
the
results
of
a
human
study
provide
a
more
sensitive
endpoint
than
any
observed
in
experimental
animals 
in
these
cases,
the
human
endpoint
may
be
used
for
risk
assessment.

 
Inform
the
interspecies
uncertainty
factor.
The
default
interspecies
uncertainty
factor
of
10X
assumes
that
the
average
adult
human
may
be
up
to
10
times
more
sensitive
than
the
most
sensitive
animal
species
for
a
particular
toxic
response.
This
default
10X
can
be
modified
if
quantitative,
scientifically
sound
data
comparing
the
response
in
humans
and
the
sensitive
species
are
provided
(
see
footnote
2).

 
Inform
the
intraspecies
uncertainty
factor.
The
default
intraspecies
uncertainty
factor
of
10X
assumes
that
sensitive
subpopulations
of
humans
may
be
up
to
10
times
more
sensitive
than
the
average
human.
This
assumption
can
be
modified
if
scientifically
sound
data
comparing
the
response
in
such
a
sensitive
subpopulation
with
average
adults
were
to
be
submitted.
The
challenge
in
this
case
is
to
rigorously
define
such
a
subpopulation
and
to
demonstrate
that
no
other
subpopulation
is
likely
to
be
more
sensitive.
This
use
of
human
data
is
expected
to
be
rare
for
this
case.

 
Evaluate
the
relevance
of
a
mechanism
or
mode
of
toxic
action.
Increasingly,
OPP
is
receiving
more
and
more
mechanistic
and
mode
of
action
data
on
pesticides.
It
is
conceivable
that
human
studies
could
be
performed
to
characterize
that
a
particular
mode
of
toxicity
shown
to
occur
in
animals
was
relevant
to
humans.

 
Develop
a
physiologically­
based
pharmacokinetic
(
PBPK)
or
biologically­
based
dose
response
(
BBDR)
model.
The
Agency
is
increasing
its
development
and
use
of
PBPK
and
BBDR
models.
These
models
may
contain
in
vivo
(
metabolism
or
toxicity)
or
in
vitro
data
from
humans.
Page
9
of
19
Summary
of
the
eleven
intentional
exposure
human
studies
to
be
reviewed
by
the
HSRB
at
its
April
4­
7,
2006
Meeting
There
are
eight
different
pesticides
for
which
human
data
are
being
presented
for
use
in
either
single
chemical
or
cumulative
risk
assessments
for
pesticide
reregistration.
In
all
cases,
these
assessments
are
required
under
the
FQPA
tolerance
reassessment
program
which
has
a
statutory
deadline
of
August
3,
2006.
Appendix
A
is
a
table
that
summarizes
important
details
of
each
of
11
studies
to
be
evaluated
in­
depth
by
the
HSRB:
aldicarb
(
one
study);
methomyl
(
one);
oxamyl
(
one);
azinphos­
methyl
(
one);
dichlorvos,
or
DDVP
(
one);
ethephon
(
two);
amitraz
(
three);
and
hydrogen
cyanide
(
one).
Tables
1
through
3
below
present
some
brief
summary
information
on
these
studies.
In
the
WOE
document
for
DDVP,
OPP
has
also
discussed
briefly
other
intentional
exposure
human
toxicity
studies
on
DDVP
on
which
OPP
is
not
relying.
OPP
has
determined
that
these
DDVP
studies
are
either
not
scientifically
useful
for
OPP's
human
health
risk
assessment
or
involved
intentional
exposure
of
children,
and
thus
are
not
studies
on
which
EPA
is
permitted
to
rely
on
under
the
final
rule.
OPP
has
made
available
to
the
Board
copies
of
each
of
these
studies.

Five
of
the
eight
pesticides
are
members
of
two
common
mechanism
groups:
N­
methyl
carbamates
(
aldicarb,
methomyl,
and
oxamyl),
and
organophosphates
(
azinphos­
methyl
and
DDVP).
In
mammals,
measurement
of
acetyl
cholinesterases
in
both
red
blood
cell
(
RBC)
and
brain
represent
biomarkers
of
exposure
to
these
chemicals.
Ethephon
appears
to
be
a
potent
inhibitor
of
butylcholinesterase
(
found
in
plasma
and
often
called
"
pseudocholinesterase"),
whereas
it
does
not
appear
to
interact
as
readily
with
RBC
or
brain
acetylcholinesterases.
The
HSRB
has
received
the
OPP/
HED
ChE
Policy
to
understand
how
we
use
such
data.
The
two
remaining
pesticides
(
amitraz
and
hydrogen
cyanide)
represent
other
chemical
classes
and
the
effects
monitored
or
observed
are
generally
measurable
clinical
signs
(
vital
signs,
pulse
rate,
EKG,
blood
pressure,
etc.)
or
symptoms
that
may
be
more
subjective
in
nature
(
headaches,
drowsiness,
etc.).

The
previous
section
described
the
various
ways
for
incorporating
human
toxicity
studies
into
human
health
risk
assessments.
For
five
of
the
eight
pesticides,
the
human
data
were
used
directly
to
derive
the
PoD
for
use
in
the
single
chemical
human
health
risk
assessment
(
azinphos­
methyl,
DDVP,
ethephon,
amitraz,
and
hydrogen
cyanide)
(
Table
1).
In
one
other
single
chemical
risk
assessment
case
(
aldicarb),
the
human
data
was
used
to
reduce
the
interspecies
UF.
In
the
remaining
two
cases
(
methomyl
and
oxamyl),
the
single
chemical
risk
assessments
have
already
been
completed
and
the
human
data
will
be
used
only
for
the
cumulative
assessment
for
interspecies
extrapolation
since
animal
data
were
used
to
develop
relative
potency
factors.
For
cumulative
risk
assessments,
the
human
data
for
methomyl
and
DDVP
supported
retaining
the
default
10X
interspecies
factors;
for
oxamyl
and
aldicarb
the
human
data
supported
reducing
the
interspecies
factor.
The
azinphos
methyl
human
data
are
not
being
used
in
the
cumulative
risk
assessment.
Page
10
of
19
Table
1:
Identification
of
Eight
Pesticides
and
the
Associated
Human
Studies
to
be
Considered
at
HSRB
(
April,
2006)

Pesticide
Chemical
Class
Effects
Monitored
Study
Duration
How
Used
in
OPP
RA
Aldicarb
N­
methyl
carbamate
Cholinesterase
inhibition
Acute
(
single
exposure)
Animal
data
used
as
PoD
1
for
single
chemical
and
relative
potency
value
used
for
cumulative.
Human
data
used
to
reduce
interspecies
UF
in
both
single
chemical
and
cumulative
risk
assessments
2
Methomyl
N­
methyl
carbamate
Cholinesterase
inhibition
Acute
(
single
exposure)
Single
chemical
assessment
previously
completed.
Animal
data
used
for
relative
potency
value.
Human
data
used
to
keep
interspecies
UF
of
10X
in
cumulative
risk
assessment
2
Oxamyl
N­
methyl
carbamate
Cholinesterase
inhibition
Acute
(
single
exposure)
Single
chemical
assessment
previously
completed.
Animal
data
used
for
relative
potency
value.
Human
data
used
to
reduce
interspecies
UF
of
10X
in
cumulative
risk
assessment
2
Azinphos
methyl
Organophosphate
Cholinesterase
inhibition
28­
Day
Study
Human
study
used
as
PoD
for
worker
assessment
for
up
to
60
days
in
single
chemical
assessment.
Animal
data
used
for
relative
potency
value
in
the
cumulative
risk
assessment
3
,
human
data
were
not
used
to
inform
the
interspecies
UF.

DDVP
Organophosphate
Cholinesterase
inhibition
21­
Day
Study
Human
study
used
as
PoD
for
short
and
intermediate­
term
dermal,
incidental
oral,
and
inhalation
exposure
scenarios
in
the
single
chemical
assessment.
Animal
data
were
used
for
relative
potency
in
the
cumulative
risk
assessment
3
,
human
data
used
to
keep
the
10X
interspecies
UF.

Ethephon
Organophosphorous
compound
Adverse
events
28­
Day
Study
Human
study
used
as
PoD
for
acute
and
chronic
dietary
exposure
scenarios.

Amitraz
Formamidine
Adverse
events
Three
acute
studies
Human
study
used
as
PoD
for
acute
and
chronic
dietary
exposures
and
for
non­
dietary
exposure
scenarios
of
various
durations.

Hydrogen
cyanide
4
Nitrile
Adverse
events
Multiple
days
of
oral
exposure
(
exact
number
not
specified)
Human
study
used
as
PoD
for
acute
dietary
exposure.

1
PoD
=
Point
of
Departure.
2
N­
methyl
carbamate
cumulative
risk
assessment.
3
Organophosphate
cumulative
risk
assessment.
4
Formed
during
use
of
sodium
cyanide
as
a
fumigant.
Page
11
of
19
Table
2
provides
information
about
study
design
for
each
of
the
11
studies.
Again,
Appendix
A
has
more
details.
Five
of
the
11
studies
were
performed
between
1997
and
1999;
with
the
remaining
six
being
run
from
1972
to
1992.
The
majority
of
the
studies
(
8/
11)
were
conducted
in
the
United
Kingdom,
with
the
remainder
occurring
in
the
U.
S.

The
total
number
of
human
volunteers
ranged
from
a
low
of
two
(
amitraz
metabolism
study)
to
a
high
of
178
(
cancer
patients
in
the
hydrogen
cyanide
study).
However,
the
nine
studies
between
these
extremes
ranged
from
having
six
to
47
volunteers.
In
addition
to
this
spread
in
the
number
of
human
volunteers
across
the
studies,
a
majority
(
7/
11)
used
male
volunteers
only.
In
three
of
the
four
cases
where
female
volunteers
were
used,
the
number
of
females
was
lower
than
the
number
of
males,
the
exception
being
the
1972
ethephon
study.

Table
2:
General
Information
on
Human
Volunteer
Studies
for
HSRB
(
April,
2006)
(
All
Studies
are
Via
the
Oral
Route
Unless
Otherwise
Noted)

Pesticide
Study
Year
No.
of
Males1
No.
of
Females1
Laboratory
Aldicarb
1992
38
9
Methomyl
1998
19
None
Oxamyl
1999
40
None
Azinphos
methyl
1999
12
None
Inveresk
(
Scotland)

DDVP
1997
9
None
Medeval,
(
UK)
1972
8
8
Ethephon
1977
16
14
Litton
(
US)

1998
2
8
1992
6
Simbec
(
UK)
Amitraz
1984
2
None
FBC
(
UK)

Hydrogen
cyanide
1982
100
78
Cancer
patients
from
four
different
cancer
centers
in
US.
1
Includes
control/
placebo
group.
2
Dermal
study.
Page
12
of
19
Most
of
the
studies
presented
(
10/
11)
involved
oral
exposure
(
Table
3).
In
most
of
these
cases
the
test
material
was
delivered
in
a
capsule
with
a
liquid
during
or
after
a
meal.
The
single
dermal
study
(
amitraz),
divided
the
total
intended
daily
dose
into
four
equal
parts
and
applied
them
to
the
forearm
of
male
volunteers
every
2.5
hours
for
10
hours
over
two
days.

Approximately
half
of
the
studies
(
six)
involved
acute
exposure
conditions
(
one
or
two
days
of
exposure),
four
used
repeated
dose
exposure
conditions
(
daily
oral
exposures
from
16
to
28
days),
and
in
one
(
hydrogen
cyanide)
case,
the
duration
of
exposure
via
the
oral
route
was
unclear.

The
methods
used
to
employ
placebo
groups
varied
among
the
11
studies
(
Table
3).
In
six
studies,
a
separate
group
of
volunteers
was
used
(
methomyl,
oxamyl,
azinphosmethyl
DDVP,
and
in
both
ethephon
studies).
Aldicarb
had
a
subset
of
volunteers
(
six
males
and
five
females)
that
received
both
a
placebo
and
treatment
capsule
as
part
of
the
study
design.
Two
of
the
three
amitraz
studies
(
the
acute
dermal
and
acute
oral
studies)
used
a
crossover
design
in
which
each
of
the
volunteers
on
study
were
given
a
placebo
and
each
treatment
exposure
over
the
course
of
the
study.
In
both
cases,
the
time
period
between
treatments
was
14
days.
The
third
amitraz
study
was
a
metabolism
study
in
which
radiolabeled
amitraz
was
given
orally
to
two
male
volunteers
and
there
was
no
placebo
group.
Finally,
the
hydrogen
cyanide
study
was
a
clinical
trial
without
a
placebo
group.
All
volunteers
were
given
amygdalin
(
Laetrile)
at
one
of
two
doses
and
monitored
for
an
unspecified
period
of
time.

Summary
At
the
first
meeting
of
the
Human
Studies
Review
Board,
the
Office
of
Pesticides
Programs
is
soliciting
comments
from
the
Board
on
science
and
ethics
reviews
of
human
studies
involving
intentional
exposure
and
systemic
toxic
effects,
as
well
as
weight
of
evidence
documents
on
a
number
of
pesticides
for
which
registrants
have
submitted
human
studies.
The
risk
assessment
teams
for
the
pesticides
have
reviewed
the
human
and
animal
data
and
have
proposed
endpoints
for
risk
assessment
based
on
the
totality
of
the
data
for
each
pesticide.
In
some
instances,
the
risk
assessment
teams
have
proposed
using
human
studies
directly
with
interspecies
factors
reduced
to
1x.
In
other
instances,
the
human
studies
are
used
to
adjust
the
interspecies
factor
and
in
some
cases
the
human
studies
are
considered
not
to
be
useful
at
all
for
endpoint
selection.
An
ethical
review
has
also
been
conducted
on
each
of
the
human
studies
relied
upon
for
endpoint
selection.

The
HSRB
is
asked
to
comment
on
the
weight­
of­
evidence
discussions
for
each
of
the
pesticides
with
respect
to
the
quality
of
the
science
underlying
the
discussions
and
the
quality
of
the
ethics
reviews
which
have
been
prepared
for
each
of
the
human
studies
under
consideration.
Page
13
of
19
Table
3:
Study
Duration,
Number
of
Exposures,
and
Exposure
Method
for
Human
Volunteer
Studies
Considered
at
HSRB
(
April,
2006)
Pesticide
Study
Duration
No.
of
Exposures
Exposure
Method
Comments
Aldicarb
Oral,
single
exposure
Five
plus
placebo
(
males)
and
Two
plus
placebo
(
females)
In
orange
juice
with
breakfast
Six
males
and
five
females
participated
in
placebo
and
treatment
session.

Methomyl
Oral,
single
exposure
Three
plus
placebo
(
males
only)

Oxamyl
Oral,
single
exposure
Six
plus
placebo
(
males
only)
Double
blind,
ascending
dose
escalation
trial.

Azinphos
methyl
Oral,
repeated
exposure
(
28
days)
One
plus
placebo
(
males
only)
Gelatin
capsule
five
minutes
after
breakfast.

No
effects
observed.

DDVP
Oral,
repeated
exposure
(
21
days)
One
plus
placebo
(
males
only)
Capsule
taken
with
water
after
overnight
fast
No
comments.

Oral,
repeated
exposure
(
28
days)
No
comments.

Ethephon
Oral,
repeated
exposure
(
16
days)
One
plus
placebo
(
males
and
females)
Capsule
 
3X/
day;
first
two
after
a
meal
and
the
third
at
the
end
of
the
work
day
No
effects
observed.

Dermal,
acute
(
two
days)
Three
plus
placebo
(
males
only)
Four
equal
exposures
applied
dermally
every
2.5
hours
for
10
hours
for
two
days.

Oral,
single
exposure
Two
plus
placebo
(
males
only)
Capsule
taken
30
minutes
after
breakfast
with
water.
Randomized
crossover
design.
Each
person
received
all
doses
 
exposures
separated
by
14
days.
Amitraz
Oral,
single
exposure
One,
no
placebo
(
males
only)
Capsule;
possible
light
breakfast
eaten
two
hours
prior
to
exposure.
Metabolism
study
with
two
human
volunteers
­

Hydrogen
cyanide
Oral,
repeated
exposure
Two,
no
placebo
(
males
and
females)
Oral
exposure
given
either
three
or
four
times/
day
Exact
duration
of
exposure
difficult
to
determine.
Page
14
of
19
References:
Mileson,
B.
Chambers,
J.
E.,
Chen,
W.
L.,
Dettbarn,
W.,
Ehrich,
M.,
Eldefrawi,
A.
T.,
Gaylor,
D.
W.,
Hammernik,
K.,
Hodgson,
E.,
Karczmar,
A.
G.,
Padilla,
S.,
Pope,
C.
N.,
Richardson,
R.
J.,
Saunders,
D.
R.,
Sheets,
L.
P.,
Sultatos,
L.
G.,
and
Wallace,
K.
B.
1998.
Common
Mechanism
of
Toxicity:
a
case
of
organophosphorus
pesticides.
Toxicological
Sciences
41,
pp.
8­
20.

National
Research
Council
(
NRC).
1983.
Risk
Assessment
in
the
Federal
Government:
Managing
the
Process.
Washington,
DC.:
National
Academy
Press.

National
Research
Council
(
NRC).
2004.
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes:
Scientific
and
Ethical
Issues.
Washington,
DC.:
National
Academy
Press.

USEPA.
1994.
Methods
for
Derivation
of
Inhalation
Reference
Concentrations
and
Applications
of
Inhalation
Dosimetry.
EPA/
600/
8­
90/
066F.
Office
of
Research
and
Development,
Washington
DC.

USEPA,
1999a.
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity,
www.
epa.
gov/
fedrgstr/
EPA­
PEST/
1999/
Februrary/
Day­
05/
o­
p2781.
htm
USEPA,
1999b.
"
A
Science
Policy
on
a
Common
Mechanism
of
Toxicity:
The
Carbamate
Pesticides
and
the
Grouping
of
Carbamate
with
the
Organophosphorus
Pesticides;"
draft
document.
August
30,
1999.
http://
www.
epa.
gov/
scipoly/
sap/
1999/
september/
carbam.
pdf
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
USEPA
2001a.
"
General
Principles
for
Performing
Aggregate
Exposure
and
Risk
Assessments."
Final.
December
2,
2001.
Office
of
Pesticide
Programs,
Office
of
Prevention,
Pesticides,
and
Toxic
Substances,
US
Environmental
Protection
Agency.
Washington,
DC.
Available:
http://
www.
epa.
gov/
oppfead1/
trac/
science/

USEPA
2001b.
Memorandum
from
Marcia
Mulkey
to
Lois
Rossi.
"
Implementation
of
the
Determinations
of
a
Common
Mechanism
of
Toxicity
for
N­
Methyl
Carbamate
Pesticides
and
for
Certain
Chloroacentanilide
Pesticides."
July
12,
2001.
http://
www.
epa.
gov/
oppfead1/
cb/
cab_
page/
updates/
carbmate.
pdf
USEPA,
2002.
"
Guidance
on
Cumulative
Risk
Assessment
of
Pesticide
Chemicals
That
Have
a
Common
Mechanism
of
Toxicity."
January
14,
2002.
(
67
FR
2210;
January
16,
2002)
http://
www.
epa.
gov/
oppfead1/
trac/
science/#
common
USEPA
(
2002a)
A
Review
of
the
Reference
Dose
and
Reference
Concentration
Processes.
U.
S.
EPA,
Risk
Assessment
Forum,
Washington,
DC,
EPA/
630/
P­
02/
002F,
2002.
Page
15
of
19
APPENDIX
A:
SUMMARY
OF
ELEVEN
INTENTIONAL
EXPOSURE
HUMAN
STUDIES
FOR
HSRB
(
April,
2006)

Pesticide
and
MRID
No.
Study
Objective
Endpoint
Measured
&
Exp.

Route
Doses
Used
No.
of
Males
(
By
Dose)
No.
of
Females
(
By
Dose)
Exposure
Method
Timing
of
observation
&/
or
blood
draw
Adverse
events
noted?
NOAEL,
LOAEL
&
Benchmark
Dose
(
BMD,
if
calculated)

Aldicarb
42373001
"
1.
Determine
the
general
tolerance
of
human
volunteers
(
both
males
and
females)
to
a
range
of
doses
of
aldicarb.

2.
Provide
cholinesterase
determination
on
red
blood
cells
and
separated
plasma."
ChE
inhibition
(
RBC,
plasma)
and
clinical
signs.

Oral,
single
exposure
Males:
0,
0.01,

0.025,
0.05,

0.06,
0.075
mg/
kg.
Females:
0,

0.025,
0.05
mg/
kg.
Total:
38
(
16
placebo,

and
8,
8,
8,

1,
5
for
low
to
high
dose
groups)
Total:
9
(
6
placebo
and
4/
dose)
In
orange
juice
with
breakfast
At
post­
exposure
times
of
1,
2,
3,
4,
5,

6,
24
hours
Sweating
observed
in
males
at
0.025
mg/
kg.
No
overall
NOAEL
identified
(
see
WOE).

Male
NOAEL
=
0.01
mg/
kg
Male
LOAEL
=

0.025
mg/
kg
[
plasma
36%;
RBC
12%];

Female
NOAEL
=
not
est.
Female
LOAEL
=
0.025
mg/
kg,

plasma
ChEI
50%;

RBC
20%]

(
BMD10
 
0.02
mg/
kg;

BMDL10
=
0.01
mg/
kg).

Methomyl
44721401
" 
to
determine
the
no
 
observableadverse
effect
level
(
NOAEL)
for
methomyl
in
humans
after
oral
administration
ChE
inhibition
(
RBC,
plasma)
and
clinical
signs.

Oral,
single
exposure
0,
0.1,
0.2,
0.3
mg/
kg
(
0.5
mg/
kg
dropped)
Total:
19
(
4
placebo
and
5/
dose)
None
Gelatin
capsule
five
minutes
after
"
stand­
ard"

breakfast
Screening,
­
16
hrs,

­
30
mins.,
every
15
mins
to
2
hrs,
hourly
to
8
hrs,
24
hrs,
7
days
Physiol.
Parameters:
pulse,

resp.
rate,

salivation,
pupillary
responses.
One
male
(
0.3)
­
transient
head­
ache,

early
inc.
in
salivation
NOAEL
=
not
est.

LOAEL=
0.1
mg/
kg,

decreased
peak
RBC
ChE
activity
(
19%)

(
BMD10
 
0.035
mg/
kg;
BMDLL10=

0.015
mg/
kg).
Page
16
of
19
Pesticide
and
MRID
No.
Study
Objective
Endpoint
Measured
&
Exp.

Route
Doses
Used
No.
of
Males
(
By
Dose)
No.
of
Females
(
By
Dose)
Exposure
Method
Timing
of
observation
&/
or
blood
draw
Adverse
events
noted?
NOAEL,
LOAEL
&
Benchmark
Dose
(
BMD,
if
calculated)

Oxamyl
44912301
" 
to
determine
the
no
 
observableadverse
effect
level
(
NOAEL)
for
oxamyl
in
humans
after
oral
administration."
ChE
inhibition
(
RBC,
plasma)

Oral,
single
exposure
0,
0.005,
0.015,

0.03,
0.06,
0.09,

0.15
mg/
kg
Total:
40
(
10
placebo
and
5/
dose)
None
Gelatin
capsule
five
minutes
after
"
standard"

breakfast
ChE
assays
­

Screening,
­

2days,
­
16hrs,
­

­
30mins,
every
15
mins
to
2hrs,
3hrs,

4,
6,
8,
12,
24hrs,
7
days
Physiol.
Parameters:
pulse,

resp.
rate,

salivation,
pupillary
responses.
No
treatment
related
clinical
signs
NOAEL
=
0.06
mg/
kg
7­
12%
decreased
plasma
&
RBC
ChE
@
0.09
mg/
kg
(
BMD10
 
0.083
mg/
kg;
BMDL10
=

0.069
mg/
kg).

Azinphos
methyl
45476101
"
To
determine
the
no
effect
level
for
plasma
and
RBC
cholinesterase
after
repeated
exposure
and
to
compare
the
human
and
animal
sensitivities
at
no
effect
levels."
ChE
inhibition
(
RBC,
plasma)

Oral,
repeated
exposure
(
daily
for
28
days)
0,
and
0.25
mg/
kg/
day
Total:
12
(
4
placebo
and
8
treated)
None
Gelatin
capsule
five
minutes
after
"
standard"

breakfast
ChE
assays
­

Screening,
­

14,
­
12,
­
10,
­
8,
­
6,
­

4,
and
­
1
days.

Then
daily
after
exposure
for
28
days
(
on
12
of
these
days,
two
blood
samples
taken
 

before
exposure
and
4hours
post
exposure).

Clin
obs
and
selfreporting
of
symptoms.
None
observed.
NOAEL
set
at
0.25
mg/
kg/
day
but
since
no
effects
on
ChE,
no
LOAEL
established.
Page
17
of
19
Pesticide
and
MRID
No.
Study
Objective
Endpoint
Measured
&
Exp.

Route
Doses
Used
No.
of
Males
(
By
Dose)
No.
of
Females
(
By
Dose)
Exposure
Method
Timing
of
observation
&/
or
blood
draw
Adverse
events
noted?
NOAEL,
LOAEL
&
Benchmark
Dose
(
BMD,
if
calculated)

DDVP
44248801
" 
assess
inhibition
of
erythrocyte
cholinesterase
following
multiple
oral
doses
of
dichlorvos."
RBC
ChE
inhibition
Oral,
repeated
exposure
(
daily
for
21
days)
0
and
7
mg/
adult
male
(
0.1
mg/
kg/
day)
Total:
9
(
3
placebo,

6
treated)
None
Dissolved
in
corn
oil,
put
in
capsule
and
taken
with
150
mL
water
after
overnight
fast.
ChE
assays
­

Screening,
­

14,
­
12,
­
10,
­
7,
­
5,
­

3
days
and
immed.

pre­
dose.
Then
on
days
2,
4,
7,
9,
11,

14,
16,
18
just
before
exposure
for
21
days
(
and
day
25
and
28
postexposure

Self­
reported
symptoms
None
considered
treatment
related
LOAEL
=
0.1
mg/
kg/
day
(
up
to
16%
RBC
ChEI)

Ethephon
36510
"
Evaluation
of
compound
effect
on
cholinesterase
activity
in
human
plasma
and
red
blood
cells
following
repeated
daily
doses."
RBC/
Plasma
ChEI,
clin.

chem.
,
and
urinal.

Oral,
repeated
exposure
(
daily
for
28
days)
0
and
1.8
mg/
kg/
day
(
ave.

dose
for
males
and
females)
for
28
consecutive
days
Total:
8
(
3
placebo,

5
treated).
Total:
8
(
3
placebo,

5
treated)
Orally
by
capsule
and
divided
into
three
doses
each
day
 
the
first
two
after
a
meal
and
the
third
at
end
of
work
day.
Hematology,
clinical
chem.,
urinalysis
on
Day
1,
7,
14,
21,
28
and
two
weeks
after
last
exposure.

ChE
anal.
used
modified
Michel
method.
Gastrointestinal
distress
(
incl.

diarrhea)
and
inc.
urgency
and
freq.
of
urination
LOAEL
=
1.8
mg/
kg/
day;
One
dose
tested
Ethephon
66931
" 
to
further
evaluate
the
bioeffects
of
Ethephon
on
human
volunteers
with
regard
to
plasma
and
red
blood
cell
cholinesterase
activity
,
other
biochemical
parameters
and
subjective
clinical
observations."
RBC/
Plasma
ChEI,
clin.

chem.
,
and
urinalysis
Oral,
repeated
exposure
(
daily
for
16
days)
0
and
0.5
mg/
kg/
day
for
16
days,
followed
by
29
day
recovery
period.

Daily
dose
given
in
three
periods
in
the
morning
and
evening
Total:
16
(
6
placebo,

10
treated).
Total:
14
(
4
placebo,

10
treated).
Orally
by
capsule
and
divided
into
three
doses
each
day
 
the
first
two
after
a
meal
and
the
third
at
end
of
work
day.
Hematology,
clinical
chem.,
urinalysis
on
Day
4,
8,
12,
16
during
exposure
period
and
Days
15
and
29
after
last
exposure.

ChE
anal.
used
modified
Michel
method.
No
symptoms
reported;
questionable
ChEI
results
Not
determined.

Considered
contrary
to
1972
findings
Page
18
of
19
Pesticide
and
MRID
No.
Study
Objective
Endpoint
Measured
&
Exp.

Route
Doses
Used
No.
of
Males
(
By
Dose)
No.
of
Females
(
By
Dose)
Exposure
Method
Timing
of
observation
&/
or
blood
draw
Adverse
events
noted?
NOAEL,
LOAEL
&
Benchmark
Dose
(
BMD,
if
calculated)

Amitraz
44639401
" 
to
determine
the
tolerance
in
human
volunteers
and
establish
a
no
effect
dose
level
for
acute
pharmacological
effects
following
administration
of
repeated
dermal
doses
of
Amitraz "
Adverse
events,
psychomotor
activity,
vital
signs,
clin.

chem.
Dermal,
eight
doses
over
two
days
Total
dose
of
0,

8,
16
or
24
mg/
kg
Total:
8
(
Each
person
received
placebo
and
each
dose
for
two
days 
applications
were
separated
by
seven
days.)
None
Aqueous
1:
1
slurry;
placebo:
starch
(
1:
1)
water.

Each
person
rec'd
4
equal
doses
over
10
hrs.
for
two
days.
Vital
signs:
predose
­
1,
­
0.5
hrs;

postdose:
3,
6,
12,

24,
36
hrs;
ECG:

predose:
­
1;

postdose:
3,
6,
12,

24,
36
hrs.
Psychomotor:

predose
 
0.5
hr;

post­
dose
 
5
and
10
hr.
Hemato/
clin
chem./
urin
 
36
hr
after
first
dose
No
treatment
related
events
NOAEL:
24
mg/
kg/
day;
LOAEL:

not
established
Amitraz
43283101
" 
to
determine
the
general
tolerance
of
male
volunteers
to
two
single
doses
of
amitraz
spaced
2­
3
weeks
apart
and
to
determine
the
noeffect
level
(
NOEL)."
Vital
signs,

pupil
response,
psychomotor
performance

Oral,
single
exposure
0,
0.625,
0.125
mg/
kg
Total:
6
Each
person
received
placebo
and
each
dose.
Doses
separated
by
14
days.
None
In
capsule
with
lactose
taken
30
minutes
after
breakfast
with
water.
Vital
signs:
­
1,
­
0.5,

1,
3,
6,
12,
24,
&
36
hrs
ECGs:
­
1,
1,
3,
6,

12,
24
&
36
Pupil
response
psychometric
performance:

predose
&
2.5
&
8
hrs
No
treatment
related
events
NOAEL:
0.125
mg/
kg/
day;
LOAEL:

not
established
Page
19
of
19
Pesticide
and
MRID
No.
Study
Objective
Endpoint
Measured
&
Exp.

Route
Doses
Used
No.
of
Males
(
By
Dose)
No.
of
Females
(
By
Dose)
Exposure
Method
Timing
of
observation
&/
or
blood
draw
Adverse
events
noted?
NOAEL,
LOAEL
&
Benchmark
Dose
(
BMD,
if
calculated)

Amitraz
00160964;

46249601
00160964
 
" 
the
metabolism
of
amitraz
in
rats,
mice,

baboons,
and
humans."
46249601
 
" 
an
investigation
of
the
urinary
excretion
of
[
14C]­
amitraz
by
male
human
volunteers."
Clinical
signs.

(
Purpose
of
study
was
to
assess
metabolism)

Oral,
single
exposure
(
radiolabeled)
0.25
mg/
kg
14Camitraz
Total:
2
(
No
placebo
group)
None
Crystalline
amitraz
in
gelatin
capsules
Volunteers
were
"
instructed"
to
eat
a
light
breakfast
two
hours
prior
to
exposure.
Vital
signs
and
observation
up
to
12
hrs;
urinalysis
up
to
72
hours.
Dry
mouth,
drowsiness,
disorientation,

decreased
temperature,

bradycardia,

slightly
pale
appearance
in
both
volunteers
for
up
to
several
hours
postexposure
LOAEL:
0.25
mg/
kg;

no
NOAEL
established
Hydrogen
Cyanide
(
HCN)
46769602
" 
a
clinical
trial
of
amygdalin
for
the
treatment
of
advanced
cancer."
Possible
cancer
therapeutic
agent.

I
ntravenous
and
oral
doses
of
amygdalin;

oral
doses
evaluated
(
duration
not
specified).
Standard
 
4.5
g/
m2
x
21
days
iv
followed
by
0.5
g
orally
three
times/
day.

High
 
7
g/
m2
x
21
days
iv
followed
by
0.5
g
orally
four
times/
day
NOTE:
Each
oral
dose
of
amygdalin
(
0.5
g)
is
equivalent
to
~
0.4
mg/
kg/
d
HCN.
Total:
100
(
92
standard
and
8
high
dose)
Total:
78
(
72
standard
and
6
high
dose)
Intravenous
dose
given
for
21
days
and
then
oral
tablets
given
until
cancer
progression
worsened
Blood
drawn
for
CN
analysis:
after
iv
course,
48
hrs.
after
first
oral
dose,
and
then
two
hours
after
first
oral
daily
dose.
Headache,

dizziness,

nausea,
vomiting,
loss
of
mental
acuity.
(
After
one
or
two
oral
doses;

especially
if
taken
together
to
compensate
for
a
missed
dose.
Standard
oral
dose
considered
a
NOAEL
(
0.4
mg/
kg).