Document ID: EPA-HQ-ORD-2006-0187-0095
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

A
Summary
of
Human
Studies
for
Consideration
by
the
HSRB
Louis
Scarano,
Ph.
D.

Louis
Scarano,
Ph.
D.

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

General
Information

The
Studies:


Effects
Monitored

Study
Design

How
the
Studies
Will
be
Used
in
OPP
Risk
Assessments
3
General
Information
General
Information

For
all
the
studies
to
be
discussed,
you
have
received
the
following
documents:


The
full
original
study

The
OPP
Data
Evaluation
Record
(
DER)
summarizing
OPP s
review
of
the
study

The
OPP
Weight­
of­
Evidence
(
WOE)
analysis
that
describes
how
OPP
proposes
to
use
the
study
in
a
risk
assessment

The
next
few
slides
provide
some
perspective
on
the
types
of
studies
you
will
be
discussing
over
the
next
two
days
4
General
Information
General
Information

Eight
pesticides
will
be
discussed

Aldicarb,
methomyl,
oxamyl,
azinphos­
methyl,
DDVP,
ethephon,

amitraz,
hydrogen
(
sodium)
cyanide

Eleven
studies
will
be
presented
in
detail*

10
of
11
are
oral
studies
(
one
is
a
dermal
study)

Six
involve
acute
exposures,
five
involve
repeated
dose
exposures
­­­­­­­­­­

*
In
one
case
(
DDVP),
numerous
studies
are
mentioned
in
the
WOE
analysis
but
are
not
relied
upon
5
General
Information
General
Information

For
six
pesticides,
one
human
study
is
presented

For
the
other
two
pesticides,
two
(
ethephon)

and
three
(
amitraz)
studies
are
presented

Importantly,
the
animal
and
human
data
are
considered
on
a
case­
by­
case
basis
6
Study
Design:
Effects
Monitored
Study
Design:
Effects
Monitored

Cholinesterase
inhibition
(
RBC/
Plasma)


N­
methyl
carbamates
(
aldicarb,
methomyl,

oxamyl)


Organophosphates
(
azinphos­
methyl,
DDVP)

Other
(
measurable
clinical
signs
and/
or
symptoms)


Ethephon,
amitraz,
hydrogen
cyanide
7
Study
Design:
Year,
No.
of
Subjects,
Location
Study
Design:
Year,
No.
of
Subjects,
Location
Table
1.
General
Information
on
Human
Exposure
Studies
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)

1
Includes
control/
placebo
group.
8
Study
Design:
Year,
No.
of
Subjects,
Location
Study
Design:
Year,
No.
of
Subjects,
Location
Table
1.
General
Information
on
Human
Exposure
Studies
Pesticide
Study
Year
No.
of
Males1
No.
of
Females1
Laboratory
1972
8
8
Ethephon
1977
16
14
Litton
(
US)

19982
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.
9
Study
Design:
Summary
of
No.
of
Subjects
Study
Design:
Summary
of
No.
of
Subjects

Range
of
number
of
volunteers
in
the
11
studies:
2
(
amitraz)
to
178
(
hydrogen
cyanide)


For
the
9
studies
between
2
and
178
­

(
representing
7
pesticides)
 
the
range
is
6
­
47

Range
of
number
of
volunteers
by
pesticide
(
9­

178)
 
thus
the
lowest
"
n"
is
9
(
DDVP)

7
of
11
studies
involved
male
volunteers
only
10
Study
Design:
Doses,
Exposure
Details
Study
Design:
Doses,
Exposure
Details
Table
2.
General
Information
on
Human
Exposure
Studies
Pesticide
Number
of
Doses
Exposure
Method
Study
Design
Aldicarb
5
plus
placebo
(
males)
and
2
plus
placebo
(
females)
In
orange
juice
with
breakfast
Double­
blind
Methomyl
3
plus
placebo
(
males
only)

Oxamyl
6
plus
placebo
(
males
only)
Double­
blind,
ascending
dose
schedule
Azinphos
methyl
1
plus
placebo
(
males
only)
Gelatin
capsule
five
minutes
after
breakfast.
Double­
blind
DDVP
1
plus
placebo
(
males
only)
Capsule
taken
with
water
after
overnight
fast
Single­
blind
11
Study
Design:
Doses,
Exposure
Details
Study
Design:
Doses,
Exposure
Details
Table
2.
General
Information
on
Human
Exposure
Studies
Pesticide
Number
of
Doses
Exposure
Method
Study
Design
Ethephon
1
plus
placebo
(
males
and
females)
Capsule
 
3X/
day;
first
two
after
a
meal.
Unclear
whether
investigators/
subjects
were
blinded
to
treatment
3
plus
placebo
(
males
only)
1
Four
equal
exposures
applied
dermally
every
2.5
hrs
for
10
hrs
for
two
days.
Randomized
crossover
(
double­
blind,
ascending
dose
schedule).
Each
person
received
all
doses
 
exposures
separated
by
7
days.

2
plus
placebo
(
males
only)
Capsule
taken
30
minutes
after
breakfast
with
water.
Randomized
crossover
(
double­
blind,
ascending
dose
schedule).
Each
person
received
all
doses
 
exposures
separated
by
14
days.

Amitraz
1,
no
placebo
(
males
only)
Capsule;
possible
light
breakfast
eaten
two
hrs
prior
to
exposure.
Metabolism
study
 
radiolabelled
material
used.

Hydrogen
cyanide
2,
no
placebo
(
males
and
females)
Oral
exposure
given
either
three
or
four
times/
day
Intravenous
dosing
for
21
days,
followed
by
oral
dosing
for
an
unspecified
period
of
time.

1
Dermal
study.
12
Study
Design:
Summary
of
Exposure
Details
Study
Design:
Summary
of
Exposure
Details

Range
of
doses
used
(
from
1­
6)


4
of
11
studies
used
only
one
dose

9
of
11
studies
had
placebo
groups
(
exceptions
 
hydrogen
cyanide
and
amitraz
metabolism
study)

6
of
11
studies
had
either
single­
or
doubleblind
study
design
13
How
are
the
studies
to
be
used
in
OPP
Risk
How
are
the
studies
to
be
used
in
OPP
Risk
Assessments?

Assessments?

Single
Chemical
Assessments:


Human
data
used
directly
as
the
point
of
departure
(
PoD)

for
five
pesticides
(
azinphos­
methyl,
DDVP,
ethephon,

amitraz,
and
hydrogen
cyanide)


For
methomyl
and
oxamyl,
the
single
chemical
risk
assessments
were
completed
before
the
human
data
were
submitted
and/
or
reviewed

For
aldicarb,
the
human
data
were
used
to
reduce
the
interspecies
UF
14
How
are
the
studies
to
be
used
in
OPP
Risk
How
are
the
studies
to
be
used
in
OPP
Risk
Assessments?

Assessments?

Cumulative
Assessments:


Organophosphate:

 
Azinphos­
methyl
(
keep
the
interspecies
UF
of
10)

 
DDVP
(
keep
the
interspecies
UF
of
10)


N­
methyl
carbamate:

 
Aldicarb
and
oxamyl
(
reduce
the
interspecies
UF
of
10)

 
Methomyl
(
keep
the
interspecies
UF
of
10)