Document ID: EPA-HQ-ORD-2006-0187-0137
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-05-17T04:00Z

1
May
15,
2006
Minutes
of
the
United
States
Environmental
Protection
Agency
(
EPA)
Human
Studies
Review
Board
(
HSRB)
April
4­
6,
2006
Public
Meeting
Docket
Number:
EPA­
HQ­
ORD­
2006­
0187
Committee
Members:
(
See
Roster
 
Attachment
A)

Dates
and
Times:
Tuesday,
April
4,
2006;
8:
30AM
 
6:
00
PM
Wednesday,
April
5,
2006;
8:
30AM
 
6:
00PM
Thursday,
April
6,
2006
8:
30
AM
 
1:
00PM
(
See
Federal
Register
Notice
Attachment
B)

Location:
Holiday
Inn
 
Rosslyn
at
Keybridge,
Arlington,
Virginia
Purpose:
The
EPA
Human
Studies
Review
Board
(
HSRB)
provides
advice,
information,
and
recommendations
on
issues
related
to
the
scientific
and
ethical
aspects
of
human
subject
research.

Attendees:
Chair:
Celia
B.
Fisher,
Ph.
D.
Vice
Chair:
William
S.
Brimijoin,
Ph.
D.

Board
Members:
David
C.
Bellinger
Ph.
D.
Gary
L.
Chadwick,
PharmD,
MPH,
CIP
Janice
Chambers,
Ph.
D.
D.
A.
B.
T.
Richard
Fenske,
Ph.
D.
MPH
Susan
S.
Fish,
PharmD,
MPH
Suzanne
C.
Fitzpatrick,
Ph.
D.
D.
A.
B.
T.
Kannan
Krishman,
Ph.
D.
KyungMann
Kim
Ph.
D.,
FCCP
Michael
D.
Lebowitz,
Ph.
D.
FCCP
Lois
D.
Lehman­
Mckeeman,
Ph.
D.
Jerry
A.
Menikoff,
M.
D.
Robert
Nelson,
M.
D.,
Ph.
D.
Sean
M.
Philpott,
Ph.
D.

Meeting
Summary:
Meeting
discussions
generally
followed
the
issues
and
general
timing
as
presented
in
the
meeting
Agenda,
unless
noted
otherwise
in
these
minutes
(
Attachment
C).

Introductory
Remarks,
Meeting
Administrative
Procedures
and
Meeting
Process
Celia
Fisher,
Ph.
D.
Human
Studies
Review
Board
(
HSRB)
Chair
opened
the
meeting
and
introduced
the
board
members.
George
Gray,
Ph.
D.
(
EPA
Science
Advisor)
2
welcomed
board
members
and
Susan
Hazen
(
Acting
Assistant
Administrator,
Office
of
Prevention,
Pesticides
and
Toxic
Substances,
EPA)
provided
opening
remarks.
Paul
Lewis,
Ph.
D.
(
Designated
Federal
Officer,
HSRB,
Office
of
the
Science
Advisor,
EPA)
explained
the
meeting
administrative
process
and
Celia
Fisher,
Ph.
D.
explained
the
responsibilities
of
the
board
as
outlined
in
the
HSRB
charter
She
explained
that
board
members
were
assigned
as
primary
and
secondary
discussants
to
answer
questions
posed
by
EPA
on
both
the
scientific
and
ethical
evaluation
of
specific
pesticides
under
review.
Dr.
Fisher
explained
that
the
Board
would
evaluate
the
science
of
each
study
first,
because
part
of
the
ethics
evaluation
depends
upon
the
risk­
benefit
calculus
and
if
a
human
dosing
study
does
not
have
scientific
validity
than
it
has
to
"
benefit."
Dr.
Fisher
then
provided
the
scientific
criteria
that
she
would
ask
the
Board
to
apply
to
each
study:
(
1)
Did
the
research
design
and
implementation
meet
scientific
standards?
(
2)
Do
the
data
generated
by
the
protocol
have
implications
for
the
Agency's
Weight
of
the
Evidence
(
WOE)
determination,
and
when
applicable,
aspects
of
the
risk
assessment.
The
Chair
concluded
with
the
criteria
that
she
would
ask
the
Board
to
apply
to
each
study:
(
1)
Did
the
study
fail
to
fully
meet
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted?
(
2)
Was
the
study
"
fundamentally
unethical"
(
There
was
clear
and
convincing
evidence
that
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent
cf.
Final
Rule
26.104)?
(
3)
Was
the
conduct
of
the
study
"
significantly
deficient"
relative
to
the
ethical
standards
prevailing
at
the
time:
Is
there
is
clear
and
convincing
evidence
that:
(
a)
The
deficiencies
identified
could
have
resulted
in
serious
harm
(
based
on
knowledge
available
at
the
time
the
study
was
conducted);
or
(
b)
The
information
provided
to
participants
could
seriously
impair
informed
consent?

Session
1:
Introduction
In
the
Session
1
Overview,
Mr.
William
Jordan
(
Office
of
Pesticide
Programs
[
OPP],
EPA)
explained
that
the
Food
Quality
Protection
Act
(
FQPA,
1996)
required
a
review
of
tolerance
limits
for
all
pesticides
currently
in
the
market
place.
The
FQPA
strengthened
and
expanded
review
of
human
studies
data.
The
HSRB
provides
scientific
and
ethical
review
of
human
studies
based
on
recommendations
by
the
National
Academy
of
Science
(
NAS)
report
"
Intentional
Human
Dosing
Studies
for
EPA
Regulatory
Purposes:
Scientific
and
Ethical
Issues".
EPA
strives
to
use
the
best
science
with
the
highest
ethical
qualities.
In
his
presentation,
"
Summary
of
EPA's
Requirements
for
Protections
for
Subjects
of
Human
Research",
Mr.
Jordan
provided
a
history
of
EPA
rulemaking
with
respect
to
Human
Studies
and
described
protections
for
the
subjects
of
human
studies
conducted
by
1st,
2nd
and
3rd
parties.
Mr.
Jordan
explained
that
EPA
is
required
to
document
its
scientific
and
ethical
assessments
of
completed,
intentional
human
dosing
research,
and
to
obtain
HSRB
review
for
certain
types
studies
on
which
EPA
intends
to
rely
under
the
pesticide
laws.
Ethical
deficiencies
must
be
established
by
clear
and
convincing
evidence
which
is
to
say
more
than
a
"
preponderance
of
the
evidence,"
but
less
than
"
beyond
a
reasonable
doubt".

Following
Mr.
Jordan's
presentations,
Mr.
Michael
Metzger
(
OPP,
EPA)
presented
EPA's
approach
to
assessing
human
health
risks
of
pesticides
using
data
from
3
human
studies.
Mr.
Metzger
provided
a
summary
of
toxicological
terminology
and
explained
that
EPA's
preferred
endpoint
for
cumulative
risk
assessment
is
the
benchmark
dose
(
BMD)
because
the
BMD
uses
all
the
data
points
from
one
or
more
toxicity
studies
to
statistically
derive
a
dose­
response
curve.
Mr.
Metzger
also
explained
OPP's
application
of
safety
factors
and
uncertainty
factors.
Safety
and
uncertainty
factors
are
generally
10­
fold
factors,
used
to
derive
the
RfD
and
RfC
from
experimental
data.
They
include:
1)
intraspecies
 
variability
among
humans;
2)
interspecies
 
extrapolating
animal
data
to
humans;
3)
extrapolating
from
less­
than­
lifetime
to
lifetime
exposures;
4)
LOAEL
to
NOAEL;
5)
incomplete
data
base
and;
6)
FQPA
for
protection
of
children.

OPP's
assessment
of
ethical
conduct
during
human
studies
was
provided
by
Mr.
John
Carley
(
OPPP,
EPA).
Mr.
Carley
explained
that
in
December
2001,
EPA
asked
the
NAS
for
advice
on
consideration
of
human
studies
and
announced
that
it
would
not
rely
on
third­
party
human
toxicity
studies
until
it
issued
regulations.
This
moratorium
was
challenged
by
CropLife
America,
and
others,
and
was
overturned
by
the
courts.
The
Agency
reverted
to
its
previous
practice
of
considering
third­
party
human
studies
on
a
case­
by­
case
basis,
applying
the
Common
Rule.
The
Agency's
Human
Studies
Working
Group
(
HSWG)
was
asked
to
develop
ethics
review
guidance
to
ensure
consistent
interpretation
and
implementation
of
the
CropLife
decision.
The
HSWG
focused
on
Emanuel
et
al.,
supplemented
with
an
article
by
Miller
"
Clinical
Research
with
Healthy
Volunteers:
An
Ethical
Framework".
EPA
did
not
rely
on
completed
research
if
there
is
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical,
or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted.
EPA
did
not
find
clear
and
convincing
evidence
to
suggest
that
any
of
the
research
presented
to
the
HSRB
for
this
week's
meeting
were
fundamentally
unethical.

Next,
Ray
Kent,
Ph.
D.
(
OPP,
EPA)
provided
an
assessment
of
the
type
and
scope
of
toxicity
studies
used
by
OPP
and
explained
which
human
studies
need
HSRB's
review.
Systemic
toxicity,
dermal
irritation
or
sensitization
and
eye
irritation
studies
need
HSRB
review.
Epidemiological
(
including
poisoning
or
incident
data)
and
In
vitro
studies
do
not
require
HSRB
review.
No
guidelines
exist
for
human
absorption,
distribution,
metabolism
and
excretion
(
ADME)
studies,
but
future
ADME
studies
may
be
subject
to
HSRB
review.
All
human
toxicity
studies
are
considered
for
their
relevance
to
the
overall
risk
assessment.
Relevant
studies
are
reviewed
for
scientific
quality
and
ethics.
The
role
of
a
study
in
a
risk
assessment
is
determined
in
a
weight
of
evidence
analysis
encompassing
the
whole
toxicity
database.

The
next
presentation
was
a
summary
of
the
human
studies
for
consideration
by
the
HSRB,
as
presented
by
Louis
Scarano,
Ph.
D.
(
OPP,
EPA).
Dr.
Scarano
said
that
the
Agency
will
provide
a
detailed
description
of
11
human
studies
that
are
being
considered
for
use
in
tolerance
setting
for
8
pesticides.
The
studies
are
proposed
for
use
in
single
chemical
and
cumulative
assessments.

Session
2:
Carbamate
Pesticides
4
Overview
Session
2
was
started
by
Anna
Lowit,
Ph.
D.
(
OPP,
EPA)
who
explained
that
organophosphate
pesticides
are
included
in
a
common
mechanism
group
based
on
inhibition
of
AChE
by
phosphorylation.
Effects
are
seen
in
the
brain,
peripheral
nervous
system
and
are
measured
using
surrogate
indicators
such
as
AChE
inhibition
in
RBC
and
plasma.
The
HSRB
was
asked
to
assess
scientific
conduct
and
study
design
as
well
as
ethical
conduct.

Dr.
Lowit
also
explained
OPP's
policy
on
the
use
of
cholinesterase
inhibition
data
for
the
risk
assessment
of
organophosphorous
(
OP)
and
carbamate
pesticides.
OP
and
carbamate
pesticides
constitute
common
mechanism
groups.
Both
classes
of
chemicals
inhibit
AChE
but
OPs
phosphorylate
the
active
site
while
carbamates
carbamylate
the
active
site.
Because
AChE
inhibition
is
a
key
event
in
the
mode
of
action
leading
to
neurotoxicity
for
both
common
mechanism
groups,
avoiding
AChE
inhibition
protects
subject
from
downstream
toxic
effects.
Inhibition
of
blood
AChEs
is
not
an
adverse
effect,
but
may
indicate
the
potential
for
adverse
effects
on
the
nervous
system.
Thus,
blood
AChE
inhibition
data
are
used
as
surrogate
measures
of
potential
toxic
effects
of
the
peripheral
and
central
nervous
systems.
RBC
AChE
results
are
preferred
over
plasma
results
but
both
should
be
assessed
in
context
to
both
statistical
and
biological
significance.
There
is
no
fixed
percentage
of
change
used
to
separate
adverse
from
nonadverse
effects.

Science
and
Ethics
of
the
Aldicarb
Human
Studies
Details
of
the
aldicarb
human
study
were
provided
by
Linda
Taylor,
Ph.
D.
(
OPP,
EPA)
and
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA).
The
aldicarb
human
study
was
conducted
in
1992.
Based
on
the
study
design,
the
Agency
proposed
to
apply
the
following
safety
factors:
 
LOAEL
to
NOAEL
factor:
an
additional
10x
uncertainty
factor
(
UF)
was
needed
to
account
for
extrapolating
from
a
LOAEL
to
NOAEL
 
FQPA
Factor:
a
Special
Hazard
Based
FQPA
safety
factor
was
not
needed
because
the
BMD
analysis
showed
that
the
young
are
approximately
2X
more
sensitive
than
adults.
However,
this
2X
sensitivity
was
accounted
for
in
the
point
of
departure
of
0.005
mg/
kg/
day.
 
A
total
uncertainty
factor
of
300
(
10X
for
intraspecies
variations,
3X
for
interspecies
differences,
and
10X
LOAEL
to
NOAEL)
was
recommended.

A
summary
of
the
EPA's
ethical
review
for
aldicarb
was
provided
by
John
Carley
(
OPP,
EPA).
The
aldicarb
human
study
was
conducted
in
the
United
Kingdom
in
1992
and
cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1989)
and
the
principles
of
good
clinical
practice.
Mr.
Carley
used
the
ethical
framework
to
evaluate
the
aldicarb
human
study
and
provided
a
comparison
to
relevant
principles
from
the
Declaration
of
Helsinki.
Mr.
Carley
concluded
that
because
of
the
supplemental
submissions,
more
is
known
about
this
study
than
most.
Although
some
gaps
remain,
these
gaps
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.
Some
5
deficiencies
were
apparent
relative
to
the
cited
1989
Declaration
of
Helsinki.

Science
and
Ethics
of
Methomyl
and
Oxamyl
Human
Studies
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA)
explained
that
methomyl
and
oxamyl
were
members
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
sharing
inhibition
of
AChE
as
the
common
mechanism
of
toxicity.
Rat
brain
ChE
data
provides
the
relative
potency
factor
(
RPF)
and
point
of
departure
(
POD)
for
the
cumulative
assessment.
The
methomyl
human
study
was
conducted
in
1998,
the
oxamyl
human
study
in
1999.

The
Agency's
weight
of
evidence
(
WOE)
documents
for
methomyl
and
oxamyl
described
the
study
design
and
results
of
the
human
studies
and
also
discussed
the
Agency's
conclusions
regarding
the
usefulness
of
the
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
methomyl,
the
Agency
concluded
that
the
human
toxicity
study
supports
a
10x
inter­
species
uncertainty
factor
for
methomyl
in
the
cumulative
risk
assessment
of
NMCs.
For
oxamyl,
the
Agency
concluded
that
the
human
toxicity
study
was
sufficiently
robust
for
reducing
the
10x
interspecies
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
cumulative
risk
assessment.

During
the
ethical
summary
for
methomyl,
Mr.
Carley
(
OPP,
EPA)
explained
that
the
human
study
was
a
randomized,
double­
blind,
ascending
oral
dose
study
used
to
establish
a
NOAEL.
The
unpublished
study
was
conducted
by
Inveresk
Clinical
Research
in
1998.
It
was
among
the
first
post­
FQPA
human
studies
of
ChE
inhibition
and
it
was
designed
as
a
6­
level
escalating­
dose
protocol,
with
no
further
escalation
after
greater
than
or
to
40%
ChE
inhibition.
One
subject
who
received
a
lead
dose
in
session
two
experienced
greater
than
40%
ChE
inhibition.
Investigators
proceeded
with
session
3,
omitting
the
lead
dose
and
later
amended
study
protocol
to
add
an
intermediate
(
lower)
dose.
The
methomyl
human
study
cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1996)
and
the
principles
of
good
clinical
practice.
Mr.
Carley
used
the
ethical
framework
to
evaluate
the
methomyl
human
study
and
provided
a
comparison
to
relevant
principles
from
the
Declaration
of
Helsinki.
Mr.
Carley
concluded
that
there
were
some
gaps
in
the
record,
but
the
gaps
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.
Some
deficiencies
were
apparent
relative
to
the
cited
1996
Declaration
of
Helsinki
For
oxamyl,
Mr.
Carley
stated
that
the
human
study
was
a
randomized,
doubleblind
ascending
oral
dose
study.
The
unpublished
study
was
conducted
by
Inveresk
Clinical
Research
in
1999.
The
study
followed
the
methomyl
human
study
and
was
designed
as
a
5­
level
escalating­
dose
protocol,
with
no
further
escalation
after
greater
than
or
equal
to
40%
ChEI
or
greater
than
or
equal
to
25%
at
two
successive
time­
points.
After
original
five
dose
levels
were
well
tolerated,
a
sixth
higher
dose
was
added.
Mr.
Carley
concluded
that
there
were
some
gaps
in
the
record,
but
the
gaps
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.
6
Public
Comments
Mr.
Angus
Cameron,
Regulatory
Affairs
Manager
at
Inveresk
Research
from
1985
to
Feb
2002.

Mr.
Cameron
stated
that
Inveresk
is
one
of
world's
largest,
full
service
contract
research
organization,
conducting
pre­
clinical
testing
in
animals
for
pharmaceuticals,
agrochemicals,
and
industrial
chemicals.
Inveresk
conducts
Phase
I
testing
of
new
and
established
molecules
conducted
on
healthy
volunteers
at
a
62
bed
clinical
unit
in
Edinburgh,
Scotland.
Inveresk's
Independent
Research
Ethics
Committee
was
established
in
1979
to
advise
Inveresk
Research
on
the
ethical
acceptability
of
clinical
research,
providing
written
standard
operating
procedures
which
are
reviewed
annually.
Inveresk
Research
procedures
are
designed
to
ensure
complete
safety
of
all
subjects
in
all
studies
and
to
ensure
that
the
highest
ethical
standards
are
met.

Neil
Carmichael,
Ph.
D.
Bayer
CropScience
Dr.
Carmichael
explained
that
the
objectives
of
the
aldicarb
human
study
were
to
characterize
the
dose
response
and
time
course
of
ChE
inhibition
following
administration
of
aldicarb
using
a
double
blind
design
and
to
demonstrate
the
relative
sensitivity
of
male
and
female
humans
compared
to
animals.
The
aldicarb
human
study
addressed
questions
raised
by
regulatory
authorities
about
aldicarb
toxicity
and
risks
to
humans
and
was
accepted
for
use
in
the
Agency's
risk
assessment
in
1993.
Bayer
CropScience
believed
the
human
study
represented
the
most
relevant
and
appropriate
data
for
setting
the
RfD
and
the
interspecies
safety
factor
for
aldicarb.
The
HSRB
was
charged
with
reviewing
the
ethical
and
scientific
considerations
pertaining
to
study
conduct,
including
the
scientific
justification
and
risk/
benefit
questions.
It
is
inappropriate
for
EPA
to
ask
the
HSRB
to
render
weight­
of­
evidence
(
WOE)
judgments
with
only
a
limited
sampling
and
summarization
of
the
available
information
and
data.

Jennifer
Sass,
Ph.
D.
Natural
Resources
Defense
Council
Dr.
Sass
stated
that
aldicarb
has
been
banned
in
seven
countries,
restricted
in
six
countries
and
is
listed
by
the
World
Health
Organization
(
WHO)
as
1a,
extremely
hazardous.
One
of
the
critical
issues
in
evaluating
the
scientific
validity
of
the
aldicarb
human
study
design
was
statistical
power.
A
study
with
inadequate
power
to
find
an
effect
is
by
definition
unethical.
There
are
roughly
19
million
children
in
the
United
States
less
than
or
equal
to
5
years
of
age.
If
a
toxicant
harmed
1
child
in
1,000,
that
would
place
19,000
children
at
risk
nationwide.
A
study
with
adequate
power
to
detect
an
increase
in
deficit
from
1%
to
2%
would
require
3,017
subjects
in
each
group
to
yield
a
power
of
0.8,
at
p=
0.05.
Studies
with
sample
sizes
<
50
have
about
a
3%
chance
of
finding
an
effect
if
it
were
present.
Dr.
Sass
summarized
NRDC's
position
on
human
studies:
1)
studies
should
only
be
considered
where
they
have
demonstrated
validity
of
study
design,
statistical
power,
and
sample
size;
2)
industry
sponsorship
may
bias
study
design,
data
analysis,
or
interpretation
(
this
also
applies
to
in­
house
IRBs);
3)
study
subjects
are
usually
limited
to
healthy
adults,
often
males,
and
are
not
representative
of
7
the
general
population;
and
4)
risks
accrue
to
subjects,
while
argued
benefits
accrue
to
society
(
pesticide
residue
in
food
have
no
known
health
benefits).

Aldicarb
Charge
To
The
Board
Aldicarb
is
a
N­
methyl
carbamate
(
NMC)
pesticide
whose
primary
toxic
effect
is
neurotoxicity
caused
by
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
carbamylation
followed
by
rapid
recovery.
Aldicarb
can,
at
sufficiently
high
doses,
lead
to
a
variety
of
clinical
signs.
The
Agency
is
conducting
an
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
aldicarb.
In
addition,
aldicarb
is
a
member
of
the
N­
methyl
carbamate
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
NMCs.

Scientific
considerations
The
Agency's
"
Weight
of
the
Evidence"
(
WOE)
document
and
Data
Evaluation
Records
(
DERs)
for
aldicarb
describe
the
study
design
and
results
of
the
aldicarb
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
acute,
aggregate,
single
chemical
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
NMCs.
Regarding
the
aldicarb
human
study,
the
Agency
has
concluded
that
the
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
aggregate
and
the
cumulative
risk
assessments.

Please
comment
on
the
scientific
evidence
that
supports
whether
the
aldicarb
human
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.
animal
to
human)
uncertainty
factor
in:

a.
single
chemical,
aggregate
risk
assessment
and
b.
cumulative
risk
assessment.

Board
Response
to
the
Charge
Drs.
Chambers
and
Dr.
Bellinger
highlighted
the
study
strengths
and
weaknesses.
During
Board
discussion
it
was
concluded
that
a
NOAEL
based
on
RBC
and
plasma
AChE
inhibition
and
clinical
signs
for
males
could
be
determined.
The
RBC
AChE
inhibition
was
dose
and
time
dependent
in
both
males
and
females.
For
the
single
chemical
aggregate
risk
assessment,
referring
to
the
Agency's
Data
Evaluation
Report,
the
Agency
concluded
that
the
NOAEL/
LOAEL
for
males
was
based
upon
sweating.
While
sweating
is
a
possible
clinical
sign
resulting
from
ChE
inhibition,
this
finding
was
not
consistently
dose
related
in
the
subjects.
The
WOE
concluded
that
whole
blood
ChE
inhibition
would
be
the
critical
endpoint.
Blood
ChE
was
probably
a
more
important
endpoint.
The
ChE
data,
while
probably
incomplete,
is
consistent
within
the
study.
The
measures
were
dose
and
time
dependent
in
both
sexes
and
were
expected.
8
For
the
cumulative
risk
assessment,
aldicarb
is
an
N­
methyl
carbamate.
Thus,
the
endpoint
had
to
be
ChE
inhibition.
The
dose
response
data
from
the
human
study
support
calculation
of
BMD10
and
BMDL10
because
there
were
a
number
of
doses
included.
Due
to
the
rapid
reactivation
of
carbamylated
ChE,
it
is
unclear
whether
accurate
ChE
inhibition
values
were
obtained
in
the
human
study
because
the
earliest
time
point
measured
was
one­
hour
after
dosing
and
the
assay
technique
was
incorrect.
The
WOE
document
stated
that
the
human
and
rat
ChE
inhibition
were
comparable.
However,
there
was
some
question
as
to
whether
they
were
recorded
at
the
same
time
along
with
the
recovery
patterns.
It
should
be
possible
to
extrapolate
this;
however
the
study
has
a
low
number
of
subjects.
Thus,
while
this
information
could
be
extrapolated,
the
low
number
of
subjects
makes
this
difficult.

Dr.
Fisher
summarized
the
Board's
scientific
considerations
for
aldicarb.
The
Board
raised
concerns
about
study
design.
The
study
had
weaknesses
but
was
still
useful.
The
Agency
should
use
the
data
with
caveats
for
study
weaknesses.
The
data
derived
was
sufficient
and
consistent
with
clinical
signs.
While
data
are
lacking
such
as
peak
inhibition,
the
same
information
is
limited
with
animal
studies.
Thus,
while
this
was
not
a
critical
flaw,
the
weaknesses
should
be
considered.
Missing
peak
data
was
not
critical
for
the
inter­
species
factor.
It
should
be
recognized
that
blood
analysis
was
not
conducted
correctly,
but
results
are
consistent
with
clinical
signs.
Both
Dr.
Chambers
and
Dr.
Bellinger
agreed
that
this
study
did
have
some
usefulness.
In
summary
the
human
study
appears
to
be
scientifically
valid
for
use
in
both
the
aggregate
and
cumulative
risk
assessment
Charge
to
the
Board
Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

In
light
of
the
ethics
committee's
instruction
that
the
lay
summary
be
"
greatly
expanded,"
and
the
fact
that
the
materials
used
to
obtain
informed
consent
listed
a
limited
range
of
symptoms
of
carbamate
toxicity
(
excluding
some
reported
as
adverse
effects
in
the
study),
included
multiple
references
to
the
test
material
as
a
drug,
and
failed
to
identify
dose
levels
to
be
administered
to
male
subjects,
whether,
the
materials
used
to
obtain
informed
consent
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted
Whether
the
absence
from
the
protocol
of
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1989
Declaration
of
Helsinki,
Principle
#
4,
with
which
the
research
asserted
compliance)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
9
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

°
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

°
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

Board
Response
to
the
Charge
Dr.
Nelson
lead
the
Board's
discussion
concluding
that
the
study
failed
to
fully
meet
the
specific
ethical
standards
prevalent
at
the
time
the
research
was
conducted.
These
deficiencies
were
primarily
in
the
area
of
informed
consent.
The
Board
also
recognized
that
having
the
stopping
rule
based
on
70%
AChE
inhibition
raised
the
possibility
of
exposing
subjects
to
inappropriate
risk.
However,
the
Board
acknowledged
that
data
existed
to
suggest
that
the
doses
used
in
the
study
would
likely
not
achieve
this
level.
The
Board
agreed
with
EPA's
assessment
that
there
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.
The
research
as
designed
and
conducted
was
not
intended
to
seriously
harm
participants
nor
failed
to
obtain
informed
consent.

The
Board
expressed
concern
that
the
informed
consent
process
may
also
have
been
deficient
but
lacked
direct
evidence.
Nevertheless,
the
Board
did
not
believe
that
these
deficiencies
could
have
resulted
in
serious
harm
based
on
the
knowledge
available
to
the
investigators
at
the
time,
nor
seriously
impaired
the
informed
consent
of
the
research
subjects.
Thus,
the
Board
concluded
that
there
was
no
ethical
objection
to
the
use
of
the
data
from
this
study,
given
the
absence
of
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical
or
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time.

Dr.
Menikoff
was
also
concerned
about
informed
consent.
Compared
to
consent
forms
used
for
other
studies
this
form
gave
very
little
information.
Other
consent
forms
comment
that
people
have
died
from
exposure
to
this
compound.
This
might
be
a
significant
deficiency
from
ethical
standard.
Dr.
Philpott
expressed
concern
about
the
reuse
of
female
subjects.
Recycled
subjects
knew
that
they
would
receive
aldicarb
in
the
second
dosing.
This
also
compromised
the
double­
blind
test
protocol.

Dr.
Fisher
summarized
the
HSRB
ethical
considerations
for
aldicarb.
The
Board
agreed
with
Mr.
Carley's
list
of
ethical
deficiencies.
However,
the
Board
did
not
believe
that
these
issues
were
serious
enough
to
rise
to
the
level
significantly
unethical.
As
for
informed
consent,
if
doses
in
the
study
were
not
near
the
lethal
limit,
stating
that
mortality
could
occur
was
not
needed.
Board
concerns
that
their
review
might
consider
the
study
as
significantly
deficient
would
include
the
lack
of
information
on
informed
10
consent
and
the
choice
of
70%
stopping
rule.
However,
there
were
mitigating
circumstances
so
the
Board
did
not
conclude
that
the
study
was
significantly
deficient.

Methomyl
Charge
to
the
Board
Scientific
considerations
The
Agency's
WOE
document
and
DER
for
methomyl
describe
the
study
design
and
results
of
the
methomyl
acute
oral,
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
methomyl,
the
Agency
has
concluded
that
the
human
toxicity
study
supports
a
10X
inter­
species
uncertainty
factor
for
methomyl
in
the
cumulative
risk
assessment
of
the
NMCs.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

Board
Response
to
the
Charge
Dr.
Lehman­
Mckeeman
listed
strengths
and
weaknesses
of
the
study
When
the
study
was
designed,
dose
escalation
was
planned
to
range
from
0.1­
0.5
mg,
with
40%
ChE
inhibition
as
the
stopping
point.
The
highest
dose
tested
was
0.3
mg/
kg.
When
a
subject
dosed
at
0.3
mg/
kg
exceeded
the
stopping
point
of
40%
ChE
inhibition
8
hours
after
dosing,
higher
exposures
were
dropped.
The
study
was
altered
when
this
finding
was
discovered.
A
subject
in
the
lowest
dose
group
exceeded
40%
inhibition
after
eight
hours.
This
was
considered
to
be
a
spurious
finding.
The
placebo
group
tested
at
20%
ChE
inhibition
at
eight
hours.
Overall
strengths
of
the
study
included
clear
dose­
response
findings
which
indicated
that
this
was
a
scientifically
valid
study
that
can
be
used
to
inform
selection
of
an
uncertainty
factor.
Dr.
Krishnan
added
that
the
results
at
eight
hours
were
probably
spurious
findings
since
placebo
assays
run
at
the
same
time
gave
comparable
numbers.
Dr.
Krishnan
had
no
major
concerns,
regarding
scientific
validity
of
findings.
With
appropriate
rat
studies,
this
study
can
be
informative
for
risk
assessment.

Dr.
Fisher
summarized
the
Board's
scientific
considerations
for
methomyl.
The
study
did
provide
clear
dose­
response
and
time­
dependence
results.
While
the
study
captured
peak
of
inhibition,
it
had
a
small
sample
size
and
no
female
subjects.
The
baseline
ChE
inhibition
was
based
on
2
pre­
dose
measures.
More
pre­
dose
information
would
have
improved
the
estimate
of
baseline
ChE
inhibition.
The
decision
to
limit
the
protocol
to
0.3
mg/
kg
appears
appropriate.
Thus,
the
Board
concluded
that
the
study
was
scientifically
valid.
11
Charge
to
the
Board
Ethical
considerations
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

°
Whether
the
investigators'
decision
to
administer
a
dose
to
additional
subjects
in
session
3,
when
one
subject
receiving
that
dose
in
session
2
displayed
RBC
ChEI
greater
than
40%,
a
response
that
triggered
the
protocol's
anti­
escalation
provision,
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

°
Whether
the
timing
of
the
investigators'
report
to
the
ethics
committee
of
the
adverse
effects
observed
in
one
subject
during
session
2
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

°
Whether
the
failure
of
the
investigators
to
request
approval
from
the
ethics
committee
for
certain
amendments
to
the
approved
protocol,
as
required
by
the
protocol,
when
the
changes
were
administrative
and
had
no
effect
on
the
safety
of
the
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
°
Whether
the
absence
from
the
protocol
of
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

°
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

°
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted
Board
Response
to
the
Charge
Dr.
Menikoff
led
the
Board's
response
and
had
three
principle
concerns
with
the
study:
1)
when
were
the
results
for
the
subject
with
greater
than
40%
ChE
inhibition
available?
It
is
unclear
whether
this
result
was
available
before
moving
on
to
the
3rd
session;
2)
was
there
a
need
to
report
this
finding
to
IRB?
The
issue
of
this
being
a
spurious
finding
is
critical
because
if
it
was
not
they
couldn't
proceed;
and
3)
the
addition
12
of
the
lower
dose
group
of
0.2
mg/
kg/
dose
was
a
significant
change
to
the
study
protocol
that
could
have
resulted
in
serious
harm
and
should
have
been
brought
to
the
IRB
chair.
The
IRB
should
have
had
input
into
each
of
these
three
issues.
However,
while
Dr.
Menikoff
did
see
these
as
deficiencies,
there
was
not
clear
and
convincing
evidence
of
fundamentally
unethical
research
that
could
have
resulted
in
serious
harm.

Dr.
Fisher
summarized
the
HSRB
ethical
considerations
for
methomyl.
The
Board
agreed
with
the
first
three
points
made
by
Mr.
Carley.
The
study
was
deficient
because
it
did
not
have
a
report
of
risks
and
benefits
to
subjects.
Also,
it
was
deficient
in
not
seeking
a
response
from
the
IRB
regarding
the
addition
of
a
new
dosing
level.
The
Board
did
not
believe
that
these
deficiencies
were
significant
because
they
did
not
appear
to
seriously
compromise
participants'
rights
or
welfare.

Oxamyl
Charge
to
the
Board
Similar
to
aldicarb
and
methomyl,
oxamyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation
and
is
thus
included
in
the
NMC
cumulative
risk
assessment.
The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
oxamyl.
The
Agency
is
now
considering
the
use
of
the
oxamyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
in
the
cumulative
risk
assessment
of
the
NMCs.

Scientific
considerations
The
Agency's
WOE
document
and
DER
for
oxamyl
describe
the
study
design
and
results
of
the
oxamyl
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
oxamyl,
the
Agency
has
concluded
that
the
human
toxicity
study
is
sufficiently
robust
for
reducing
the
10X
inter­
species
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
cumulative
risk
assessment.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

Board
Response
to
the
Charge
Dr.
Fitzpatrick
enumerated
the
oxamyl
human
study
strengths
and
weaknesses
which
followed
almost
the
same
protocol
as
methomyl.
Dr
Fitzpatrick
listed
five
critical
factors
of
human
study
design
including:
1)
dose
selection
based
on
animal
data;
2)
purity
of
the
compound
tested;
3)
the
mode
of
compound
administration
 
oral,
would
have
been
most
relevant
to
exposure
via
food;
4)
comparable
methods
between
species
including
participants
of
both
genders
would
have
been
more
beneficial;
and
5)
the
study
should
include
a
statistical
method
to
justify
sample
size.
The
study
dosing
and
measurements
were
the
same
as
for
animal
studies
and
the
measurements
were
close
and
13
consistent.
The
study
reported
an
NOAEL
and
LOAEL
and
the
study
design
was
robust
enough
to
justify
estimation
of
a
safety
factor.
The
Board
could
not
comment
on
the
BMD10
estimate
because
animal
data
were
not
provided.
Dr.
Kim
added
that
false
positive
rates
and
study
power
operate
together.
In
a
drug
trial,
false
positives
are
good
for
drug
companies;
for
pesticides,
the
sponsor
would
like
to
show
no
differences.
Toxicity
studies
rarely
include
statistics
on
Type
1
error
because
they
do
not
want
to
show
difference.
There
was
an
incentive
on
the
part
of
a
sponsor
to
make
multiple
adjustments
because
this
lowers
the
power.
Of
all
the
studies
the
Board
had
reviewed
so
far,
this
study
was
the
most
robust.
Despite
the
lack
of
justification
for
sample
size,
this
study
does
well
to
support
determination
of
uncertainty
factors
and
the
lack
of
difference
in
genders.

Dr
Fisher
summarized
the
Board's
scientific
considerations
for
oxamyl.
The
study
was
useful
and
robust
with
multiple
dosages
and
multiple
exposure
times.
Dose
randomization
and
dosing
levels
were
chosen
appropriately
to
approximate
the
NOAEL
and
LOAEL.
In
terms
of
sample
size,
the
Board
requested
the
Agency
to
comment
on
Type
I
and
Type
II
error
bias
and
how
this
influences
EPA's
use
of
the
data
to
draw
statistical
conclusions.

Charge
to
the
Board
Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

°
Whether
inclusion
in
the
protocol
submitted
to
the
ethics
committee
of
a
factually
inaccurate
statement
regarding
unavailability
of
data
on
accidental
or
incidental
exposure
to
oxamyl
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

°
Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:

°
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.
°
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
14
Board
Response
to
the
Charge
Dr.
Philpott
initiated
the
Board's
response
raising
three
issues:
1)
applicable
ethical
and
regulatory
standards;
2)
informed
consent;
and
3)
study
design
to
minimize
the
risk
to
participants.
Dr.
Philpott
concluded
that
the
study
was
consistent
with
Declaration
of
Helsinki,
Common
Rule
and
21
CFR
but
had
concerns
about
whether
a
clear
discussion
of
risk
was
provided
to
subjects.
Existing
information
on
incidences
of
accidental
exposure
was
not
provided
to
the
subjects.
There
was
no
evidence
that
the
study
was
designed
in
a
fashion
to
cause
serious
or
unintended
injury.
Dr.
Menikoff
acknowledged
informed
consent
issues
but
concluded
that
based
on
the
knowledge
available
to
the
Board,
this
would
not
rise
to
the
level
of
unethical
Dr.
Fisher
summarized
the
Board's
ethical
considerations
for
oxamyl.
This
study
did
not
justify
human
exposure
and
informed
consent
documents
may
have
been
deceptive.
However,
the
Board
agreed
with
Mr.
Carley
and
did
not
believe
that
the
study
was
significantly
deficient.

Session
3:
Organophosphate
Pesticides
Session
3
began
with
an
overview
of
organophosphate
pesticide
toxicity
provided
by
Anna
Lowit,
Ph.
D.
(
OPP,
EPA).
Dr.
Lowit
explained
that
organophosphate
pesticides
are
members
of
a
common
mechanism
group.
Organophosphate
pesticides
inhibit
AChE
by
phosphorylation
affecting
brain
and
peripheral
nervous
system
(
e.
g.,
nerves
in
diaphragm,
muscles).
Blood
(
RBC,
plasma)
AChE
inhibition
is
used
as
a
surrogate
indicator
of
ChE
inhibition.

Science
and
Ethics
of
Azinphos
Methyl
(
AZM)
Human
Studies
John
Doherty,
Ph.
D.
(
OPP,
EPA)
provided
a
weight
of
evidence
(
WOE)
comparison
of
human
and
animal
studies
for
azinphos
methyl
(
AZM)
for
single
chemical
and
organophosphate
cumulative
risk
assessment.
Dr.
Doherty
provided
details
for
the
AZM
Repeat
Dose
Human
Study
conducted
at
Inveresk
Laboratory
(
Scotland)
in
1999.
The
study
included
28
daily
doses
of
0.25
mg/
kg
(
mkd)
AZM
in
8
adult
males
dosed
orally
by
capsule,
with
a
placebo
group
of
4
adult
males
dosed
orally
with
lactose
capsules.
The
objectives
of
the
study
were
to
determine
the
NOAEL
for
plasma
ChE
and
RBC
AChE
and
assess
for
possible
reactions
to
treatment.
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,
EPA
concluded
that
the
repeat
dose
human
study
was
technically
scientifically
acceptable.
The
NOAEL
of
0.25
mg/
kg/
dose
from
human
study
was
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
were
~
0.5
to
1
mg/
kg/
day,
and
the
10x
interspecies
uncertainty
factor
could
be
dropped.
Following
this
presentation,
the
Board
expressed
concerns
regarding
the
assumption
that
15
steady
state
had
been
achieved
and
how
the
NOAEL
was
determined.

A
summary
of
EPA's
ethical
review
of
the
AZM
28­
day
oral
study
was
provided
by
Mr.
John
Carley.
For
AZM,
Mr.
Carley
stated
that
the
study
was
conducted
at
Inveresk
Clinical
Research
in
1999.
The
subjects
were
residents
in
the
clinic
throughout
testing.
In
addition
they
were
provided
medical
supervision
throughout
testing
and
postdosing
until
they
returned
to
baseline
ChE
levels.
The
study
cites
and
asserts
compliance
with
Declaration
of
Helsinki
(
1996)
and
the
guidelines
for
good
clinical
practice.
Mr.
Carley
concluded
that
there
were
deficiencies
relative
to
the
cited
1996
Declaration
of
Helsinki
but
concluded
that
these
deficiencies
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.

Science
and
Ethics
of
Dichlorvos
(
DDVP)
Human
Studies
Ray
Kent,
Ph.
D.
(
OPP,
EPA)
reviewed
two
DDVP
human
studies
being
considered
for
use
in
the
single
chemical
assessment;
a
single
administration,
single
dose
study
and
a
repeat
administration,
single
dose
study.
The
first
study
involved
a
single
oral
dose
study
of
six
adult
males
dosed
with
of
70
mg
DDVP
and
measuring
AChE
24
hours
after
dosing.
Since
data
in
rats
indicated
that
peak
inhibition
of
RBC
AChE
occurred
1­
3
hours
after
oral
dosing
with
DDVP,
the
failure
to
measure
RBC
AChE
in
humans
until
24
hr
post­
dosing
was
judged
to
be
a
critical
deficiency.
The
acute
human
study
was
not
being
relied
upon
to
either
establish
an
acute
RfD
or
to
decrease
the
interspecies
uncertainty
factor.
The
repeated
dosing
study
included
nine
adult
male
subjects
­
6
dosed
subjects
and
3
placebo
subjects.
The
dosed
subjects
received
7
mg
DDVP
each
day
for
21
days.
RBC
AChE
was
measured
7
times
before
dosing
and
9
times
on
dosing
days
1
through
18
and
3
times
post
dosing.
Even
though
RBC
AChE
was
not
measured
until
24
hours
post
dosing,
there
was
a
clear
pattern
of
response
over
21
days.
The
data
indicated
that
0.1
mg/
kg
is
a
LOAEL
in
humans.
The
DDVP
repeat
dose
human
study
was
selected
to
assess
short
(
less
than
30
days)
and
intermediate
(
less
than
6
months)
exposure
durations
by
oral
and
dermal
routes.

Since
the
acute
human
study
was
not
being
relied
upon
to
either
establish
an
acute
RfD
or
to
decrease
the
interspecies
uncertainty
factor,
Mr.
Carley's
ethics
discussion
for
DDVP
were
limited
to
the
21­
day
oral
study.
This
study
was
conducted
at
Medeval
(
United
Kingdom)
in
1997
using
adult
males.
The
subjects
were
non­
resident,
unsupervised,
and
self­
reported
all
effects.
The
subjects'
ChE
levels
continued
to
decline
after
the
end
of
dosing
and
subjects
were
not
followed
back
to
baseline
ChE
levels.
The
study
cites
and
asserts
compliance
with
the
Declaration
of
Helsinki
(
1989).
In
summary,
Mr.
Carley
concluded
that
there
were
some
gaps
in
the
record,
but
the
gaps
were
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.
Some
deficiencies
were
apparent
relative
to
the
cited
1989
Declaration
of
Helsinki.

Public
Comments
Monty
Eberhardt,
Ph.
D.,
CIH
and
Dan
Van
Goethem,
M.
S.,
DABT
16
Bayer
CropScience
and
representing
Makteshim
Agan
of
North
America
Dr.
Eberhardt
and
Mr.
Van
Goethem
stated
that
they
respect
the
role
of
the
HSRB
in
providing
guidance
and
oversight
to
those
sponsoring
intentional
dosing
studies
for
submission
to
EPA
but
said
that
they
feel
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.
Dr.
Eberhardt
and
Mr.
Van
Goethem
said
that
the
safety
database
for
AZM
was
current
and
complete
and
includes
both
animal
studies
and
studies
in
human
volunteers.
The
animal
studies
demonstrated
that
AZM
wais
not
carcinogenic,
mutagenic,
teratogenic
or
a
reproductive
toxicant
and
that
inhibition
of
cholinesterase
is
the
most
sensitive
indicator
of
exposure.
The
human
studies
confirmed
that
humans
are
no
more,
and
perhaps
less,
sensitive
than
animals
to
AZM's
cholinesterase
inhibiting
effects.
The
knowledge
gained
from
these
studies
was
being
used
in
safety
assessments.
The
commenters
agreed
with
EPA's
interpretation
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
this
study
was
fundamentally
unethical.
However,
they
disagreed
with
EPA's
interpretation
that
the
study's
value
was
limited
to
establishing
a
human
ChE
NOAEL.
In
addition,
no
evidence
for
use
to
establish
RfDs,
REIs,
or
safe
levels
for
workers
existed.
They
also
disagreed
that
the
informed
consent
materials
were
insufficient
and
were
open
to
ideas
on
ways
to
improve
future
informed
consent
materials.
Dr.
Fisher
explained
that
the
charge
of
HSRB
was
not
to
evaluate
WOE
or
make
judgments
about
all
the
data
but
to
evaluate
the
studies
presented
to
them
for
scientific
validity
and
ethical
considerations.

Robert
J.
Levine,
MD,
Professor
of
Medicine
and
Co­
Director,
Yale
University's
Interdisciplinary
Bioethics
Center
representing
Amavac
Chemical
Corporation
Dr.
Levine
spoke
to
the
ethics
of
research
involving
children
as
subjects.
He
stated
that
there
was
an
ethical
requirement
to
use
all
historical
data.
Forbidding
research
involving
children
and
pregnant
women
virtually
guarantees
the
future
occurrence
of
Thalidomide­
like
disasters.
The
use
of
historical
data
puts
no
new
subjects
at
risk.
If
EPA
must
disqualify
data
from
children
and
pregnant
women,
it
should
not
disqualify
data
from
non­
pregnant
adults
involved
in
the
same
studies.
Dr.
Levine
stated
that
the
disqualification
of
any
historical
data
creates
ethical
problems
and
that
in
some
cases
the
data
from
disqualified
research
could
be
of
vital
importance
to
the
regulatory
decision.
It
would
be
unethical
to
repeat
the
research
under
otherwise
ethically
acceptable
conditions.
A
weight­
of­
evidence
approach
is
an
acceptable
method
of
developing
a
probative
data
set
from
multiple
studies
when
each
of
the
studies
is
 
for
one
reason
or
another
 
unsuitable
for
the
intended
purpose.
Public
exposure
of
errant
sponsors
and
investigators
is
usually
sufficient
to
deal
with
ethical
transgressions
for
academics.
The
NIH
might
bar
service
on
committees
or
their
eligibility
for
grants.
The
FDA
may
also
impose
criminal
sanctions,
fines
and/
or
imprisonment.

Mr.
Ian
Chart,
Amvac
Chemical
Corporation
Mr.
Chart
stated
that
all
DDVP
human
studies
were
commissioned
or
completed
before
1996
so
they
were
not
performed
in
response
to
FQPA.
The
DDVP
human
17
database
has
been
developed
by
many
organizations
(
WHO,
CDC
and
FDA)
over
many
years,
addresses
the
10X
default
interspecies
factor,
and
is
so
robust
that
it
can
also
address
the
intraspecies
factor.
Amvac
disagreed
with
EPA's
position
that
a
WOE
argument
is
only
as
robust
as
the
individual
studies.
DDVP
is
unique
as
it
has/
had
pharmaceutical,
veterinary,
and
public
health
pesticidal
uses.
There
are
hundreds
of
human
studies
on
DDVP
and
it
is
unlikely
that
such
a
vast
database
will
ever
be
developed
for
a
pesticide
again.
The
DDVP
human
database
is
unique
and
should
be
treated
in
totality.
Mr.
Chart
stated
that
weight
of
evidence
analysis
of
adult­
only
biomarker
data
should
not
be
disqualified
merely
because
some
of
the
data
in
the
full
database
are
available
on
children
and/
or
pregnant
women.
It
is
inappropriate
to
dismiss
individual
studies
without
considering
the
database
as
a
whole.
The
human
studies
considered
together
are
scientifically
relevant
and
ethically
valid.
The
DDVP
human
database
provides
more
than
sufficient
scientifically
sound
information
to
warrant
reduction
of
the
interspecies
uncertainty
factor.

Laura
Plunkett,
Ph.
D.
DABT,
Integrative
Biostrategies
representing
for
Amvac
Chemical
Corporation
Dr.
Plunkett
presented
the
findings
of
a
study
completed
in
March
2006
(
Plunkett
et
al.).
The
study
was
undertaken
to
examine
the
magnitude
of
interspecies
differences
in
adult
responses
to
DDVP
exposure.
The
DDVP
human
database
is
uniquely
large
and
robust,
with
studies
examining
a
variety
of
endpoints
and
issues.
The
large
human
database
(
more
than
300
studies)
was
reviewed,
along
with
a
robust
animal
database,
to
identify
information
useful
for
dose­
response
analyses.
Some
studies
dismissed
by
the
Agency
in
its
weight
of
evidence
and
used
in
this
analysis.
A
total
of
10
human
studies
and
9
animal
studies
were
used
to
construct
a
new
DDVP
interspecies
database.
Dr.
Plunkett
stated
that
all
of
the
studies
chosen
had
sufficient
documentation
to
ensure
that
the
research
was
conducted
in
a
way
to
produce
scientifically
reliable
data
on
RBC
cholinesterase
response
to
DDVP
exposure.

Thomas
Starr,
Ph.
D.
TBS
Associates
representing
Amvac
Chemical
Corporation
Dr.
Starr
stated
that
the
human
DDVP
data
do
provide
sufficient
scientifically
sound
information
to
warrant
reduction
of
the
10X
interspecies
factor.
This
conclusion
was
based
on
AMVAC's
analysis
for
non­
pregnant
adults
making
use
of
a
comprehensive
data
base,
not
just
one
study
or
one
dosing
study.
This
analysis
included
138
dose­
duration
data
points
for
animals
and
77
dose­
duration
data
points
for
humans.
The
conclusion
from
the
analysis
was
that
non­
pregnant
adult
humans
were
not
10X
more
sensitive
than
non­
pregnant
adult
animals
to
RBC
cholinesterase
inhibiting
effects
of
DDVP.
Humans
appear
to
be
no
more
sensitive
than
animals,
thus
a
1x
interspecies
factor
is
scientifically
warranted.
To
exclude
these
data
and
their
implications
from
full
and
fair
consideration
was
not
scientifically
defensible.
18
Jennifer
Sass,
Ph.
D.
Natural
Resource
Defense
Council
Dr.
Sass
began
with
general
comments
regarding
statistical
power
which
is
one
of
the
critical
issues
in
evaluating
the
scientific
validity
of
a
study.
A
study
with
inadequate
power
to
find
an
effect
is
by
definition
unethical.
Studies
with
sample
sizes
less
than
50
had
about
a
3%
chance
of
finding
an
effect
if
it
were
present.
For
DDVP,
EPA
determined
that
the
human
repeated
dose
study
was
well
supported
by
several
animal
studies
and
should
serve
as
the
basis
for
short­
and
intermediate­
term
risks.
NRDC
believed
that
there
was
no
value­
added
from
the
human
studies
that
were
not
already
available
from
well­
conducted
animal
studies,
epidemiological
and
biomonitoring
data.
The
human
study
data
are
often
limited
to
healthy
adults
and
do
not
capture
differences
across
the
population,
chronic
effects,
and
effects
from
early­
life
stage
exposures.
With
respect
to
AZM,
Dr.
Sass
cited
ethical
concerns
regarding
a
test
done
on
eight
volunteers
who
were
hospitalized
for
a
month,
were
dosed
with
a
known
poison,
took
repeated
blood
and
urine
tests,
and
gave
up
many
freedoms,
all
for
just
£
1500.
This
suggests
participants
were
economically
distressed.
Dr.
Sass
also
expressed
ethical
concerns
regarding
the
informed
consent
documents
used
for
this
study
and
the
adverse
effects
experienced
by
test
subjects.
By
their
own
retrospective
power
calculation,
the
AZM
study
had
no
statistical
power
to
detect
fluctuations
in
the
ranges
reported
in
the
study
(
i.
e.
within
15%
of
baseline).
NRDC
concluded
studies
should
only
be
considered
where
they
will
a
priori
have
demonstrated
validity
of
study
design,
statistical
power,
and
sample
size.

Ms.
Shelly
Davis,
Farmer
Worker
Justice
Fund
Ms.
Davis
commented
on
the
scientific
flaws
of
the
AZM
study
including
the
use
of
an
average
of
all
subjects
to
establish
the
baseline
used
to
determine
whether
AChE
occurred.
This
is
incorrect
because
there
is
great
variability
with
respect
to
this
measure
in
humans.
Each
individual
baseline
should
have
considered
the
control.
The
California
Department
of
Health
and
Environmental
Assessment
also
pointed
out
the
researchers
did
not
record
symptoms
of
the
test
subjects.
It
is
not
uncommon
for
people
to
have
clinical
signs.
Ms.
Davis
stated
that
these
are
fundamental
flaws
in
the
study
design
and
that
this
study
was
fundamentally
unethical
and
scientifically
flawed.

Azinphos
methyl
Charge
to
the
Board
Azinphos
methyl
(
AZM)
is
an
organophosphate
pesticide
(
OP).
Consistent
with
other
OPs,
AZM
elicits
neurotoxicity
through
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
At
sufficiently
high
doses,
exposure
to
AZM
can
lead
to
a
variety
of
clinical
signs.
The
Agency
is
developing
an
assessment
to
estimate
risk
to
workers
from
exposure
to
AZM.
In
addition,
AZM
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
risk
assessment
for
the
OPs.
19
Scientific
considerations
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,
the
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
risk
to
workers
exposed
to
AZM
via
the
dermal
and
inhalation
routes.
For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
because
no
cholinesterase
inhibition
was
seen
in
the
human
toxicity
study,
it
is
not
possible
to
evaluate
whether
steady
state
had
been
reached
in
humans
at
28
days
of
exposure.
Thus,
the
Agency
has
concluded
that
the
AZM
repeat
dose,
oral,
toxicity
study
is
not
sufficiently
robust
for
informing
the
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
a.
the
use
of
the
human
toxicity
study
to
develop
a
point
of
departure
for
extrapolation
of
risk
to
workers
in
the
worker
risk
assessment
and
b.
the
determination
that
the
human
toxicity
study
cannot
be
used
to
inform
the
inter­
species
factor
in
the
cumulative
risk
assessment.

Board
Response
to
the
Charge
Dr.
Bellinger
highlighted
the
strengths
of
the
study
including
double­
blind
protocol,
subjects
resided
in
a
clinic,
a
standardized
diet,
no
alcohol
or
cigarettes
and
plasma
and
RBC
values
analyzed.
Study
weaknesses
included
low
number
of
subjects,
the
use
of
a
modified
Elman's
method,
some
aspects
of
the
statistical
analysis
and
failure
to
acknowledge
intra­
individual
differences
by
lumping
pre­
dose
AChE
levels.
Dr.
Bellinger
expressed
limited
confidence
in
the
study
due
to
the
statistical
analysis
and
the
fact
that
it
was
a
single
dose
NOAEL
study.
Dr.
Fenske
added
that
registrants
should
be
discouraged
from
submitting
single
dose
NOAEL
studies.
There
were
some
adverse
effects
noted
during
the
study
and
a
grading
system
for
these
types
of
observations.
Nonetheless,
it
is
important
to
note
that
these
effects
were
attributed
to
a
viral
infection,
ward
conditions,
and
diet
based
on
judgments
of
a
clinical
team
rather
than
measured
observation.
Even
a
few
of
these
were
considered
adverse
effects,
this
may
have
altered
the
conclusions.
Dr.
Lebowitz
noted
that
if
recorded
symptoms
were
due
to
irritation
due
to
the
compound
or
to
some
other
cholinergic
effect,
the
standard
deviation
of
AChE
inhibition
was
20%.
Dr.
Lebowitz
expressed
serious
doubts
about
the
usefulness
of
the
study
even
with
animal
data.

After
further
discussion
by
the
Board,
Dr.
Fisher
summarized
the
Board's
findings
to
include
Dr.
Bellinger's
recommendation
that
an
additional
UF
be
included
to
account
for
study
weaknesses.
In
addition,
based
on
the
way
study
was
evaluated,
the
Board
did
not
believe
the
study
was
applicable
to
address
worker
risk.
20
Charge
to
the
Board
Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

Whether
the
informed
consent
materials
 
which
refer
to
"
the
company"
and
"
supervising
doctor",
without
further
identification,
and
contain
no
discussion
of
who
would
benefit
from
the
research
 
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and,

Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1996
Declaration
of
Helsinki,
Principle
#
5,
with
which
the
research
asserted
compliance)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:

OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

Board
Response
to
the
Charge
Dr.
Nelson
stated
that
if
the
science
lacked
validity
than
the
ethical
question
needs
to
be
revisited.
If
we
proceed
with
the
assumption
that
the
science
issues
could
have
informed
any
of
the
standards,
than
the
points
raised
by
Mr.
Carley
do
not
reach
the
level
of
significantly
deficient.
Dr.
Philpott
was
troubled
by
the
question
of
undue
inducement
of
this
financially
disadvantaged
group.
Dr.
Chadwick
expressed
concerns
regarding
amendments
to
the
study
protocol
submitted
to
IRB
chair.
Amendment
1
was
a
change
in
study
objectives
but
was
seen
as
having
no
ethical
consequence
and
did
not
need
prior
approval.

DDVP
Charge
to
the
Board
Like
AZM,
DDVP
is
an
organophosphate
pesticide
(
OP)
which
elicits
neurotoxicity
through
the
inhibition
of
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route,
21
multi­
duration)
risk
assessment
of
DDVP.
In
addition,
DDVP
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
OPs.

Scientific
considerations
a.
The
Agency's
WOE
document
and
DER
for
DDVP
describe
the
study
design
and
results
of
the
DDVP
repeat
dose,
oral
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
this
study
in
the
aggregate
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
OPs.
For
the
single
chemical
risk
assessment,
the
Agency
has
concluded
that
the
human
study
is
sufficiently
robust
for
developing
a
point
of
departure
for
estimating
dermal,
incidental
oral,
and
inhalation
risk
from
exposure
to
DDVP
in
the
single
chemical
risk
assessment.
For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
results
of
the
DDVP
multi­
dose
human
toxicity
study
do
not
support
reducing
the
default
10X
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
i.
the
Agency's
conclusions
for
use
of
the
human
study
for
developing
a
point
of
departure
for
estimating
risk
in
the
single
chemical,
aggregate
risk
assessment
and
ii.
the
Agency's
determination
that
the
human
study
cannot
be
used
to
reduce
the
interspecies
factor
in
the
cumulative
risk
assessment.

b.
The
Agency
has
concluded
that
other
human
studies
made
available
to
the
Board
do
not
provide
sufficient
scientifically
sound
information
to
warrant
any
reduction
in
the
10X
inter­
species
uncertainty
factor
used
to
derive
reference
dose
values
for
DDVP
based
on
animal
toxicity
endpoints.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.

Board
Response
to
the
Charge
Dr.
Lehman­
Mckeeman
stated
that
for
OPs,
the
disposition
of
the
compound,
kinetics,
pharmacodynamics,
and
reactivation
of
the
enzyme
were
all
important.
The
way
the
enzyme
recovers
is
based
on
RBC
turnover
so
OPs
are
different
from
carbamates.
For
the
repeated
dose
study,
the
strengths
were
placebo
control,
7
pre­
dose
measurements
of
AChE,
21­
day
dosing
administered
in
a
corn
oil
capsule,
with
RBC
AChE
as
the
primary
measurement.
Repeat
dosing
paradigm
was
good
for
OPs.
Each
subject
was
compared
to
a
pre­
dose
baseline
and
low
but
significant
inhibition
of
AChE
was
measured.
Study
weaknesses
were
are
single
dosage
levels
that
gave
no
perspective
on
dose­
response
relationship,
low
number
of
subjects
(
i.
e.
6
subjects,
3
controls),
and
single
sex
(
all
male
subjects)
were
used.
The
study
was
performed
for
21
days
but
final
sampling
data
was
conducted
on
day
18.
On
day
18,
AChE
inhibition
was
approaching
16%.
There
was
an
effect
on
day
18,
but
is
unclear
whether
a
steady
state
was
reached.
22
Follow­
up
testing
showed
2
subjects
had
22
and
24%
inhibition
following
secession
of
dosing.

Dr.
Fisher
summarized
the
Board
findings
on
the
scientific
considerations
for
DDVP.
Numerous
technical
limitations
to
the
study
design
and
execution
were
noted,
including
the
omission
of
plasma
cholinesterase
measurements.
This
greatly
limited
the
study
value.
Investigators
have
an
obligation
to
provide
appropriate
oversight
of
subjects
until
indications
of
the
effects
of
the
administered
dose
were
no
longer
present.
This
was
not
done.
The
Board
considered
continued
intentional
dosing
without
collection
of
blood
samples
for
cholinesterase
analysis
not
scientifically
defensible.
However,
the
observation
of
a
statistically
significant
change
in
RBC
cholinesterase
did
provide
evidence
to
support
the
conclusion
that
the
dosage
evaluated
in
the
repeat
human
dosing
study
can
be
used
as
a
LOAEL
for
the
single
chemical
aggregate
risk
assessment.
The
consensus
of
the
HSRB
was
that
the
scientific
limitations
of
the
study
design
did
not
justify
its
use
in
the
cumulative
risk
assessment
and
recommended
that
the
default
interspecies
uncertainty
factor
should
be
applied
for
the
cumulative
risk
assessment.

Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

Whether
references
to
the
test
material
as
a
drug
and
other
statements
that
could
indicate
the
study
constituted
medical
research,
that
appear
in
the
materials
used
to
obtain
informed
consent
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

Whether
the
administration
of
the
test
material
for
three
additional
days
without
monitoring
subjects'
cholinesterase
levels
following
the
detection
of
cholinesterase
inhibition
>
20
%
in
some
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
Whether
the
lack
of
medical
surveillance
of
subjects,
following
the
termination
of
dosing,
to
establish
the
subjects'
cholinesterase
levels
returned
to
normal
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
the
Gledhill
repeated
dose
study:

OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
Gledhill
repeat
dose
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
23
Board
Response
to
the
Charge
Dr.
Menikoff
stated
that
the
risks
in
this
study
were
not
different
with
what
the
Board
has
seen
in
other
studies
and
that
useful
information
did
result
from
this
study.
There
were
deficiencies
in
the
informed
consent
documents
with
respect
to
risk
of
cancer.
Continuing
to
dose
without
follow­
up
testing
was
consistent
with
ethical
standards
at
the
time.
The
lack
of
medical
monitoring
post­
dosing
is
consistent
with
ethical
standards
at
the
time.
Therefore,
the
study
was
not
fundamentally
unethical.
It
was
not
likely
that
subjects
would
have
been
seriously
harmed
so
there
was
no
clear
and
convincing
evidence
that
the
study
was
fundamentally
unethical.
Dr.
Nelson
agreed
but
questioned
the
scientific
findings
on
the
worth
of
the
study.
Since
the
study
never
reached
steady
state,
they
may
have
been
really
close,
but
this
is
a
serious
deficiency.
Dr.
Philpott
stated
that
a
lab
should
never
justify
use
of
word
"
drug"
for
a
pesticide
or
by
saying
that
a
"
generic
informed
consent
form"
was
used.

Dr.
Fisher
summarized
the
Board's
findings
concluding
that
the
study
could
have
been
improved.
However,
virtually
every
study
in
existence
could
be
improved
to
minimize
risk.
The
standard
of
clear
and
convincing
evidence
is
quite
high
and
places
burden
of
proof
on
the
HSRB,
not
on
the
study
sponsor.
There
was
a
conclusion
on
the
part
of
EPA
that
the
data,
although
limitations
were
evident,
were
robust
enough
to
be
used
in
the
risk
assessment.
There
was
a
need
to
know
if
the
study
yielded
information
worthy
of
the
risk
incurred
by
subjects.
The
Board's
report
should
reflect
tepid
endorsement
of
this
study
but
the
consensus
was
the
study
did
not
reach
the
threshold
of
significantly
deficient.

Session
4:
Other
Pesticides
The
Chair
modified
the
meeting
agenda
to
have
the
EPA
presentation,
public
comments
and
Board
discussion
for
each
pesticide
proceed
in
that
order.

Science
and
Ethics
of
Ethephon
Human
Studies
Abdallah
Khasawinah,
Ph.
D.
(
OPP,
EPA)
provided
an
overview
of
two
human
studies
with
ethephon.
Ethephon
human
studies
showed
clinical
signs
at
much
lower
doses.
Animal
studies
demonstrated
inhibition
of
blood
ChE
activity
without
concurrent
clinical
toxicity
and
no
increased
pre­
and/
or
post­
natal
toxicity
in
experimental
animals.
Effects
in
the
human
study
were
not
transient
and
reflect
the
toxicokinetics
of
ethephon.
Repeated
exposures
did
not
lead
to
cumulative
toxicity.
Ethephon
is
rapidly
absorbed,
metabolized
and
eliminated.
The
Agency's
WOE
document
and
DERs
for
ethephon
describe
the
study
design
and
results
of
the
ethephon
repeat
dose,
oral,
human
toxicity
studies.
The
Agency
had
concluded
that
the
28­
day
human
study
is
sufficiently
robust
to
establish
a
point
of
departure
for
extrapolating
acute
and
chronic
dietary
risk
Mr.
John
Carley
(
OPP,
EPA)
stated
that
the
28­
day
study
was
conducted
at
Litton
Bionetics
(
USA)
in
1971.
The
subjects
were
closely
observed
only
for
the
first
eight
hours
and
doses
were
self­
administered
on
weekends.
Effects
were
self­
reported.
No
24
standard
of
conduct
was
cited
so
the
Declaration
of
Helsinki
(
1964)
was
assumed
to
have
prevailed.
FIFRA
§
12(
a)
(
2)
(
p)
also
applied
because
the
research
was
conducted
in
the
United
States.
There
were
many
gaps
in
the
record,
but
the
gaps
were
not
clear
and
convincing
evidence.
The
informed
consent
materials
were
not
available,
but
the
report
stated
subjects
were
thoroughly
informed
and
signed
consent
forms.
There
is
no
evidence
that
the
research
was
fundamentally
unethical.
There
were
some
deficiencies
relative
to
the
cited
1964
Declaration
of
Helsinki.

Public
Comments
Neil
Carmichael
Ph.
D.,
Bayer
CropScience
Dr.
Carmichael
stated
that
Bayer
Crop
Sciences
(
BCS)'
s
position
on
human
volunteer
studies
with
ethephon
was
that
these
two
studies
date
from
another
era
(
i.
e.
1970s).
BCS
agreed
that
there
is
no
evidence
that
they
are
unethical
but
there
was
no
institutional
memory
of
these
studies
and
archives
are
not
traceable.
The
data
were
not
consistent
between
the
two
studies
and
BCS
can
not
defend
the
scientific
robustness
of
the
studies.
BCS
defers
to
EPA
in
the
use
of
these
studies.

Charge
to
the
Board
Ethephon
is
an
organophosphorus
compound
that,
upon
absorption
into
plants,
forms
ethylene
gas
which
is
an
important
component
of
the
plant
hormone
complex.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
ethephon.

Scientific
consideration
The
Agency's
WOE
document
and
DERs
for
ethephon
describe
the
study
design
and
results
of
the
ethephon
repeat
dose,
oral,
human
toxicity
studies.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
studies
in
the
aggregate,
single
chemical
risk
assessment.
The
Agency
has
concluded
that
the
28­
day
human
study
is
sufficiently
robust
to
establish
a
point
of
departure
for
extrapolating
acute
and
chronic
dietary
risk.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

Board
Response
to
the
Charge
Dr.
Leibowitz
believed
that
the
second
study
can
be
informative
about
the
first
study
even
though
it
was
a
single
dose
study.
With
respect
to
the
first
study,
the
28
day
study,
his
principle
concern
was
that
irritant
symptoms,
cholinergic
symptoms,
and
any
symptoms
other
than
those
associated
with
ChE
inhibition
were
important.
Two
of
the
controls
were
also
symptomatic
which
complicate
the
issue.
Some
test
and
control
subjects
had
irregular
erythrocytes
which
could
be
due
to
infections.
The
second
study
indicated
no
symptoms
were
reported
but
Dr.
Lebowitz
was
skeptical
about
statements
25
like
these
(
were
measures
negative
or
just
not
reported?).
Since
the
1977
study
included
only
one
dose
level,
the
NOAEL
was
based
on
this
dose.
No
higher
dose
was
given.
In
the
second
study,
no
symptoms
were
reported.
The
differences
in
plasma
and
RBC
AChE
inhibition
were
probably
a
problem
of
study
design
or
assay
techniques.
Thus,
Dr.
Lebowitz
agreed
that
both
studies
supported
the
LOAEL
selected
by
EPA.
Dr.
Krishnan
agreed
with
Dr.
Leibowitz
and
concluded
that
the
selection
of
NOAEL/
LOAEL
seems
reasonable
but
he
was
surprised
by
the
large
margin
between
animals
and
humans
with
no
mechanistic
explanations.
Dr.
Krishnan
was
concerned
about
ethylene
because
the
cancer
assessment
for
ethylene
showed
a
maximum
of
3000
ppm
with
no
evidence
of
carcinogenicity.
In
terms
of
the
high
dose
study,
Dr.
Krishnan
agreed
that
it
may
be
useful
for
validating
the
LOAEL.
For
most
studies
of
this
type,
each
subject
serves
as
their
own
control.
Thus,
the
baseline
was
the
average
of
measures
from
three
other
subjects.
However
this
doesn't
change
the
outcome
and
probably
was
an
appropriate
endpoint.
The
high
dose
study
seemed
to
be
a
reasonable
source
for
determining
LOAEL.

Dr.
Fisher
summarized
the
Board
conclusions
stating
the
Board's
report
will
show
consistent
reasoning
across
the
pesticides
studied.
While
the
two
studies
seem
to
converge
in
support
of
LOAEL,
the
Board
raised
some
concern
about
the
control
group
being
symptomatic.
The
study
provided
no
model
to
explain
differences
in
animal
and
human
data.
These
studies
do
have
usefulness
to
EPA
in
determining
a
LOAEL.

Ethical
considerations
Charge
to
the
Board
In
its
ethics
review
of
this
research,
EPA
documented
that
the
study
reports
contained
very
little
information
concerning
the
ethical
conduct
of
the
research
and
that
the
available
information
raised
no
ethical
concerns.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
each
study:

OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

Board
Response
to
the
Charge
Dr.
Philpott
described
the
study
as
a
28­
day
study
conducted
in
1971,
before
the
Common
Rule
and
FIFRA
12(
a)(
2)(
p).
Thus,
there
were
few
regulatory
statutes
by
which
to
judge
standards.
The
low
dose
study
(
1977)
occurred
after
FIFRA12
(
a)
(
2)
(
p),
so
FIFRA
does
apply.
Here
again
there
is
very
little
information
with
which
to
make
ethical
decisions.
In
the
high
dose
study,
the
only
statement
the
Board
had
was
that
all
26
subjects
were
thoroughly
briefed
about
the
nature
and
risks
of
the
compound.
The
low
dose
study
may
have
been
better
but
records
cannot
be
found.
The
Board
was
asked
to
determine
whether
there
was
clear
and
convincing
evidence
of
unethical
conduct.
Dr.
Philpott
had
serious
concerns
about
the
nature
of
voluntary
and
informed
consent.
Subjects
were
probably
lab
employees.
The
volunteers
experienced
unpleasant
clinical
effects
including
extreme
gastrointestinal
effects
(
e.
g.
explosive
diarrhea
and
abdominal
pain)
for
four
weeks,
yet
none
chose
to
withdraw.
This
was
suspicious.
The
low
dose
study
may
have
taken
clinical
measurements
but
they
weren't
reported.

Dr.
Fisher
summed
up
the
Board's
findings
by
stating
that
despite
clear
deficiencies
in
study
design,
the
Board
determined
that
there
was
not
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
Since
the
studies
show
greater
sensitivity
of
humans,
even
if
the
studies
were
fundamentally
unethical,
the
Board
may
reject
the
methodology,
but
still
recommend
their
use
by
the
Agency
because
its
use
would
increase
public
protection.

Science
and
Ethics
of
Hydrogen
Cyanide/
Amygdalin
Human
Studies
William
Dykstra,
Ph.
D.
(
OPP,
EPA)
provided
an
overview
of
the
scientific
consideration
of
human
studies
conducted
with
hydrogen
cyanide.
The
Agency's
WOE
document
described
a
lack
of
data
appropriate
for
developing
an
acute
dietary
risk
assessment
for
hydrogen
cyanide.
The
WOE
and
DER
present
the
results
from
a
clinical
trial
with
amygdalin
and
the
usefulness
of
this
clinical
trial
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.
The
Agency
had
concluded
that
the
clinical
trial
is
appropriate
for
establishing
a
point
of
departure
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.

The
EPA
ethics
review
for
the
amygdalin
clinical
trial
was
given
by
Mr.
John
Carley
(
OPP,
EPA).
Mr.
Carley
stated
that
two
articles
report
on
clinical
trial
of
Laetrile
for
advanced
human
cancers
conducted
at
four
centers
in
the
U.
S.
from
1980­
1981.
The
clinical
trial
was
conducted
under
FDA
application,
so
it
was
subject
to
21
CFR
parts
50
and
56.
Ethical
conditions
were
reported
much
more
completely
than
is
typical
of
published
articles
from
that
period.
No
noteworthy
deficiencies
relative
to
HHS
regulations
were
found.
There
was
no
evidence
that
the
research
was
fundamentally
unethical
or
significant
deficient
relative
to
prevailing
ethical
standards
at
the
time.
When
sodium
cyanide
was
used
as
a
fumigant,
hydrogen
cyanide
was
generated
by
acidification.
Because
residues
of
HCN
may
remain
on
fumigated
citrus,
the
Agency
is
conducting
an
acute
dietary
risk
assessment
of
hydrogen
cyanide.

Public
Comments
None
27
Charge
to
the
Board
When
sodium
cyanide
is
used
as
a
fumigant,
hydrogen
cyanide
is
generated
by
acidification.
Because
residues
of
HCN
may
remain
on
fumigated
citrus,
the
Agency
is
conducting
an
acute
dietary
risk
assessment
of
hydrogen
cyanide.

Scientific
considerations
The
Agency's
WOE
document
describes
a
lack
of
data
appropriate
for
developing
an
acute
dietary
risk
assessment
for
hydrogen
cyanide.
The
WOE
and
DER
present
the
results
from
a
clinical
trial
with
amygdalin
and
the
usefulness
of
this
clinical
trial
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.
The
Agency
has
concluded
that
the
clinical
trial
is
appropriate
for
establishing
a
point
of
departure
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

Board
Response
to
the
Charge
Dr.
Bellinger
provided
study
strengths
including
the
large
number
of
subjects,
serial
assessment
of
blood
cyanide
levels
and
good
clinical
definition
of
outcome
considered
as
tumor
progression.
Study
weaknesses
included
the
study
was
not
double
blind,
it
did
not
include
a
placebo
group
and
that
the
study
was
designed
to
assess
the
efficacy
of
amygdalin
as
a
cancer
treatment.
Thus,
such
information
on
toxic
effects
was
less
clinical,
more
antidotal.
Subjects
were
terminal
cancer
patients
and
may
represent
a
sensitive
subgroup.
Conclusions
regarding
toxicity
were
based
on
several
patients
who
developed
symptoms
related
to
cyanide
toxicity
that
subsided
when
the
dose
was
discontinued.
Oral
dosing
did
not
begin
until
patients
had
21
day
IV
treatment.
It
was
unlikely
that
this
introduced
any
bias
because
by
the
oral
route
amygdalin
excreted
in
urine
remain
unchanged.
Whole
blood
cyanide
levels
were
mostly
undetectable.
This
study
was
probably
the
best
we
will
ever
see
for
assessing
the
acute
endpoint
of
cyanide
toxicity.

Dr.
Fisher
summarized
the
Board
comments
concluding
that
data
from
the
amygdalin
trial
could
be
used
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.
Despite
its
limitations,
this
study
provided
the
best
data
we
are
likely
to
ever
have
to
establish
a
POD
for
this
purpose.
Given
the
severity
of
the
effect,
the
steepness
of
the
dose­
response,
and
the
apparent
inter­
individual
differences
in
response
to
a
given
dose,
it
would
be
imprudent
to
undertake
an
intentional
dosing
study
of
healthy
humans
in
order
to
establish
a
LOAEL
and
NOAEL
for
hydrogen
cyanide.

Charge
to
the
Board
Ethical
considerations
28
In
its
ethics
review
of
this
research,
EPA
did
not
identify
any
deficiencies
with
respect
to
the
ethical
conduct
of
this
research.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

Board
Response
to
the
Charge
Dr.
Menikoff
believed
that
publication
of
the
study
demonstrates
support
for
the
Agency's
conclusion
of
compliance
with
existing
standards.
This
is
a
treatment
study
with
therapeutic
benefits
and
research
was
done
early
in
the
development
of
ethical
standards.
Dr.
Menikoff
was
comfortable
that
this
research
was
not
fundamentally
unethical.
He
also
believed
that
a
rule
for
when
to
pursue
supporting
documentation
was
needed.

Dr.
Fisher
summarized
Board
discussions
concluding
that
the
study
was
not
fundamentally
unethical
or
significantly
deficient
because
of
clinical
equipoise.
Dr.
Menikoff's
recommendation
regarding
supporting
documentation
was
noted.
The
Board
suggested
that
there
should
be
guidance
to
investigators
on
the
type
of
ethics
documentation
required.
The
Agency
could
provide
an
outline
of
this
policy,
possibly
in
the
fall.

Science
and
Ethics
of
Amitraz
Human
Studies
John
Liccione,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
presented
the
science
and
ethics
of
amitraz
human
studies,
respectively.
Dr.
Liccione
said
that
three
human
studies
of
amitraz
will
be
presented
including
a
single
oral
dose
study,
an
acute
dermal
dose
study,
and
an
oral
metabolism
study.
Numerous
animal
studies
were
also
available.
The
single
oral
dose
study
was
double
blind
with
frequent
monitoring
of
pulse,
respiration
rate,
blood
pressure,
temperature,
ECGs,
psychomotor
performance.
The
single
oral
dose
study
reported
no
treatment­
related
effects
and
a
NOAEL
=
0.125
mg/
kg.
The
acute
dermal
study
was
a
double
blind,
sequential
dosing
study.
Doses
were
given
as
aqueous
1:
1
slurry
every
2.5
hours
over
10
hours
according
to
random
schedule.
Monitoring
of
clinical
signs
included
ECG,
psychomotor
measurements,
hematology,
clinical
chemistry,
and
urinalysis.
The
dermal
study
also
reported
no
effects
and
supported
a
NOAEL
of
24
mg/
kg.
This
was
a
double
blind
study
with
adequate
monitoring
for
potential
neurotoxicity
but
had
a
limited
number
of
male
subjects.
A
metabolism
study
of
two
healthy
human
subjects
receiving
a
single
dose
(
0.25
mg/
kg)
of
14C­
amitraz
(>
95%
purity)
by
capsule
was
also
discussed.
This
study
had
no
control
group
and
no
statistical
analysis.
The
metabolism
study
reported
consistent
effects
in
both
subjects
which
are
also
consistent
with
animal
observations.
These
studies
show
29
clear
signs
of
neurotoxicity
which
was
consistent
with
animal
observations.
Humans
appear
to
be
the
most
sensitive
species.
The
Agency
proposed
to
use
these
human
studies
for
amitraz
tolerance
setting.

Mr.
Carley
stated
that
the
research
was
conducted
at
FBC
Ltd.,
Chesterford
Park
Research
Station
in
the
United
Kingdom
in
1984
as
part
of
a
multi­
species
study
of
comparative
metabolism.
No
standard
of
ethical
conduct
was
cited
so
the
Declaration
of
Helsinki
(
1983)
was
assumed
to
have
prevailed.
There
were
many
gaps
in
the
record,
but
the
gaps
were
not
clear
and
convincing
evidence
that
the
research
was
fundamentally
unethical.
Some
deficiencies
were
noted
relative
to
the
Declaration
of
Helsinki
(
1983).

Public
Comments
None
Charge
to
the
Board
Exposure
to
amitraz
can
result
in
neurotoxicity
as
evidenced
by
clinical
signs
such
as
ataxia,
ptosis,
emesis,
labored
respiration,
muscular
weakness,
tremors,
hypothermia
and
bradycardia.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
amitraz.

Scientific
considerations
The
Agency's
WOE
document
and
DERs
for
amitraz
describe
the
study
design
and
results
of
the
amitraz
acute
oral
and
dermal
toxicity
human
studies
and
the
human
metabolism
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
studies
in
the
single
chemical
risk
assessment
for
acute
and
chronic
oral
exposures
in
addition
to
dermal
and
inhalation
exposures
of
various
durations.
For
oral
exposure,
the
Agency
has
concluded
that
the
combined
results
from
the
single
oral
dose
study
and
human
metabolism
study
establishes
a
dose
response
relationship
in
human
subjects
and
that
the
single
oral
dose
study
is
appropriate
for
developing
a
point
of
departure
for
acute
and
chronic
dietary
risk,
short­
term
oral
exposure,
and
inhalation
exposures
of
various
durations.
The
Agency
has
further
concluded
that
the
human
dermal
study
is
appropriate
for
developing
a
point
of
departure
for
dermal
exposures
of
various
durations.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.

Board
Response
to
the
Charge
Dr.
Fenske
was
concerned
why
the
1984
metabolism
study
was
conducted
at
such
a
high
dose
level.
The
1992
study
reduced
the
dose
based
on
earlier
findings
but
lacked
a
critical
discussion
of
psychomotor
endpoints.
There
were
many
ways
to
measure
reaction
time
and
this
wasn't
described
in
the
study.
Some
subjects
had
increased
reaction
time
at
doses
above
placebo
that
were
found
to
be
statistically
30
insignificant.
The
dermal
study
was
also
based
on
reaction
time
data
but
the
apparatus
used
to
measure
reaction
time
wasn't
described.
For
the
dermal
study,
the
material
was
applied
to
small
areas
of
the
skin.
High
doses
applied
to
small
areas
do
not
always
result
in
high
internal
dose.
Once
the
skin
is
covered,
the
rest
of
the
material
isn't
available
for
absorption.
The
Agency
needs
to
re­
examine
oral
study
endpoints
to
determine
if
it
support
the
NOAEL.
Dr.
Fenske
would
not
support
using
the
dermal
study
for
support
of
the
NOAEL.
Dr.
Bellinger
agreed
with
Dr.
Fenske
on
the
utility
of
data.
With
seven
subjects,
there
was
no
chance
that
psychomotor
effects
could
be
seen,
especially
given
the
high
degree
of
variability
with
respect
to
psychomotor
effects.
Dr.
Bellinger
was
also
uncomfortable
with
the
dermal
study
because
no
LOAEL
was
demonstrated.

Charge
to
the
Board
Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

With
respect
to
the
Campbell
(
1984)
research,
whether
the
lack
of
medical
surveillance
of
subjects,
following
the
termination
of
dosing,
to
establish
that
subjects'
signs
of
adverse
effects
had
returned
to
normal
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
With
respect
to
the
Cass
(
1992)
and
the
Langford
(
1998)
studies,
whether
references
to
the
test
material
as
a
drug
and
other
statements
that
could
indicate
the
study
constituted
medical
research,
that
appear
in
the
materials
used
to
obtain
informed
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
each
study:

OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

Board
Response
to
the
Charge
Dr.
Nelson
discussed
the
studies
in
temporal
order
starting
with
the
metabolic
study.
Clearly
the
subjects
had
a
response
to
the
compound.
There
was
speculation
that
the
subjects
were
the
two
principal
investigators
so
there
was
doubt
that
they
had
good
medical
supervision.
For
the
oral
dosing
study,
the
risks
were
not
listed
in
the
informed
consent
form.
There
probably
wasn't
any
extreme
risk.
What
was
not
considered
for
the
dermal
study
is
the
choice
of
dose
and
dose
escalation
design.
Was
the
study
designed
in
31
a
way
so
they
could
anticipate
risk?
Dr.
Nelson
concluded
that
the
study
does
not
meet
the
standard
of
fundamentally
unethical
and
there
is
no
clear
and
convincing
evidence
of
unethical
design.

The
meeting
was
adjourned
by
the
Chair.

Respectfully
submitted:

Paul
I.
Lewis,
Ph.
D.
Designated
Federal
Officer
Human
Studies
Review
Board
United
States
Environmental
Protection
Agency
Certified
to
be
true
by:

Ceila
B.
Fisher,
Ph.
D.
Chair
Human
Studies
Review
Board
United
States
Environmental
Protection
Agency
NOTE
AND
DISCLAIMER:
The
minutes
of
this
public
meeting
reflect
diverse
ideas
and
suggestions
offered
by
Board
members
during
the
course
of
deliberations
within
the
meeting.
Such
ideas,
suggestions,
and
deliberations
do
not
necessarily
reflect
definitive
consensus
advice
for
the
Board
members.
The
reader
is
cautioned
to
not
rely
on
the
minutes
to
represent
final,
approved,
consensus
advice
and
recommendations
offered
to
the
Agency.
Such
advice
and
recommendations
my
be
found
in
the
final
report
prepared
and
transmitted
to
the
EPA
Science
Advisor
following
the
public
meeting.
32
Attachments
Attachment
A
HSRB
Members
Attachment
B
Federal
Register
Notice
Announcing
Meeting
Attachment
C
Meeting
Agenda
33
Attachment
A
EPA
HSRB
Members
Chair
Celia
B.
Fisher,
Ph.
D.
Marie
Ward
Doty
Professor
of
Psychology
Director,
Center
for
Ethical
Education
Fordham
University,
Bronx,
NY
Vice
Chair
William
S.
Brimijoin,
Ph.
D.
Chair
and
Professor,
Molecular
Pharmacology
and
experimental
Therapeutics
Mayo
Foundation,
Rochester,
MN
Members
David
C.
Bellinger
Ph.
D.
Professor
of
Neurology
Harvard
School
of
Medicine,
Boston,
MA.

Alicia
Carriquiry,
Ph.
D.
Statistics
Professor
Iowa
State
University,
Ames,
IA.

Gary
L.
Chadwick,
PharmD,
MPH,
CIP
Associate
Provost,
Director,
Office
for
Human
Subjects
Protection
University
of
Rochester,
Rochester,
NY
Janice
Chambers,
Ph.
D.
D.
A.
B.
T.
Director,
Center
for
Environmental
Health
Sciences,
College
of
Veterinary
Medicine
Mississippi
State
University,
Mississippi
State,
MS
Richard
Fenske,
Ph.
D.
MPH
Professor,
Dept.
of
Environmental
and
Occupational
Health
Sciences
University
of
Washington,
Seattle,
WA
Susan
S.
Fish,
PharmD,
MPH
Associate
Professor,
Biostatistics
&
Epidemiology
Boston
University
School
of
Public
Health,
Boston,
MA
Suzanne
C.
Fitzpatrick,
Ph.
D.
D.
A.
B.
T.
Senior
Science
Policy
Analyst
U.
S.
Food
and
Drug
Administration,
Rockville,
MD.
34
Kannan
Krishman,
Ph.
D.
Universite'
de
Montreal,
Montreal,
Quebec,
Canada
KyungMann
Kim
Ph.
D.,
FCCP
Professor
and
Associate
Chair,
School
of
Medicine
and
Public
Health
University
of
Wisconsin­
Madison,
Madison,
WI
Michael
D.
Lebowitz,
Ph.
D.
FCCP
Professor
of
Public
Health
&
Medicine
University
of
Arizona,
Tucson,
AZ
Lois
D.
Lehman­
Mckeeman,
Ph.
D.
Distinguished
Research
Fellow,
Discovery
Toxicology
Bristol­
Myers
Squibb
Company,
Princeton,
N.
J.

Jerry
A.
Menikoff,
M.
D.
Associate
Professor
of
Law,
Ethics
&
Medicine
Director
Institute
for
Bioethics,
Law
and
Public
Policy
University
of
Kansas,
Kansas
City,
KS
Robert
Nelson,
M.
D.,
Ph.
D.
Associate
Professor
of
Anesthesiology
University
of
Pennsylvania
School
of
Medicine,
Philadelphia,
PA.

Sean
M.
Philpott,
Ph.
D.
Research
Scientist
David
Axelrod
Institute
New
York
State
Department
of
Health,
Albany,
NY
35
Attachment
B
Federal
Register
Notice
Announcing
Meeting
Federal
Register:
March
9,
2006
(
Volume
71,
Number
46)]
[
Notices]
[
Page
12194­
12196]
From
the
Federal
Register
Online
via
GPO
Access
[
wais.
access.
gpo.
gov]
[
DOCID:
fr09mr06­
52]

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

ENVIRONMENTAL
PROTECTION
AGENCY
[
EPA­
HQ­
ORD­
2006­
0187;
FRL­
8042­
6]

Human
Studies
Review
Board;
Notice
of
Public
Meeting
and
Proposed
Candidates
for
Membership
to
the
Board
AGENCY:
Environmental
Protection
Agency
(
EPA).
ACTION:
Notice.

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

SUMMARY:
The
U.
S.
Environmental
Protection
Agency's
(
EPA
or
Agency)
Office
of
the
Science
Advisor
(
OSA)
announces
a
public
meeting
of
the
Human
Studies
Review
Board
(
HSRB)
to
advise
the
Agency
on
EPA's
scientific
and
ethical
reviews
of
human
subjects
research.
In
addition,
OSA
is
soliciting
public
comment
on
its
proposed
list
of
candidates
for
membership
to
the
HSRB.

DATES:
The
public
meeting
will
be
held
April
4­
6,
2006
from
8:
30
a.
m.
to
approximately
5
p.
m.,
eastern
time.
Location:
Holiday
Inn
Rosslyn
at
Key
Bridge,
1900
North
Fort
Myer
Drive,
Arlington,
VA
22209.
The
telephone
number
for
the
Holiday
Inn
Rosslyn
at
Key
Bridge
is
703­
807­
2000.
Requests
to
Present
Oral
Comments
and
Special
Accommodations:
To
submit
requests
for
special
accommodation
arrangements
or
requests
to
present
oral
comments,
notify
the
DFO
listed
under
FOR
FURTHER
INFORMATION
CONTACT.
To
ensure
proper
receipt
by
EPA,
your
request
must
identify
docket
ID
number
EPA­
HQ­
ORD­
2006­
0187
in
the
subject
line
on
the
first
page
of
your
response.
Additional
information
concerning
the
submission
of
requests
to
present
oral
comments
and
submission
of
written
comments
is
provided
in
Unit
I.
E.

FOR
FURTHER
INFORMATION
CONTACT:
Any
member
of
the
public
who
wishes
further
information
should
contact
Paul
I.
Lewis,
Designated
Federal
Official
(
DFO),
EPA,
Office
of
the
Science
Advisor,
(
8105),
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460;
telephone
number:
(
202)
564­
8381;
fax:
(
202)
564
2070;
e­
mail
addresses:
lewis.
paul@
epa.
gov.
36
ADDRESSES:
Submit
your
written
comments,
identified
by
Docket
ID
No.
EPA­
HQORD
2006­
018,
by
one
of
the
following
methods:

http://
www.
regulations.
gov:
Follow
the
on­
line
instructions
for
submitting
comments.
E­
mail:
ORD.
Docket@
epa.
gov.
Mail:
ORD
Docket,
Environmental
Protection
Agency,
Mailcode:
28221T,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460.
Hand
Delivery:
EPA
Docket
Center
(
EPA/
DC),
Room
B102,
EPA
West
Building,
1301
Constitution
Avenue,
NW.,
Washington,
DC
20460,
Attention
Docket
ID
No.
EPA­
HQ­
ORD­
2006­
0187.
Deliveries
are
only
accepted
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
Special
arrangements
should
be
made
for
deliveries
of
boxed
information.
Instructions:
Direct
your
comments
to
Docket
ID
No.
EPA­
HQ­
ORD­
2006­
0187.
EPA's
policy
is
that
all
comments
received
will
be
included
in
the
public
docket
without
change
and
may
be
made
available
online
at
http://
www.
regulations.
gov,
including
any
personal
information
provided,
unless
the
comment
includes
information
claimed
to
be
Confidential
Business
Information
(
CBI)
or
other
information
whose
disclosure
is
restricted
by
statute.
Do
not
submit
information
that
you
consider
to
be
CBI
or
otherwise
protected
through
http://
www.
regulations.
gov
or
e­
mail.
The
http://
www.
regulations.
gov
Web
site
is
an
  
anonymous
access''
system,
which
means
EPA
will
not
know
your
identity
or
contact
information
unless
you
provide
it
in
the
body
of
your
comment.
If
you
send
an
e­
mail
comment
directly
to
EPA,
without
going
through
http://
www.
regulations.
gov,
your
e­
mail
address
will
be
automatically
captured
and
included
as
part
of
the
comment
that
is
placed
in
the
public
docket
and
made
available
on
the
Internet.
If
you
submit
an
electronic
comment,
EPA
recommends
that
you
include
your
name
and
other
contact
information
in
the
body
of
your
comment
and
with
any
disk
or
CD­
ROM
you
submit.
If
EPA
cannot
read
your
comment
due
to
technical
difficulties
and
cannot
contact
you
for
clarification,
EPA
may
not
be
able
to
consider
your
comment.
Electronic
files
should
avoid
the
use
of
special
characters,
any
form
of
encryption,
and
be
free
of
any
defects
or
viruses.

I.
Public
Meeting
A.
Does
This
Action
Apply
to
Me?

This
action
is
directed
to
the
public
in
general.
This
action
may,
however,
be
of
interest
to
persons
who
conduct
or
assess
human
studies
on
substances
regulated
by
EPA
or
to
persons
who
are
or
may
be
required
to
conduct
testing
of
chemical
substances
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA)
or
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA).
Since
other
entities
may
also
be
interested,
the
Agency
has
not
attempted
to
describe
all
the
specific
entities
that
may
be
affected
by
this
action.
If
you
have
any
questions
regarding
the
applicability
of
this
action
to
a
particular
entity,
consult
the
person
listed
under
FOR
FURTHER
INFORMATION
CONTACT.

B.
How
Can
I
Access
Electronic
Copies
of
This
Document
and
Other
Related
Information?
37
In
addition
to
using
regulations.
gov,
you
may
access
this
Federal
Register
document
electronically
through
the
EPA
Internet
under
the
  
Federal
Register''
listings
at
http://
www.
epa.
gov/
fedrgstr/.
A
frequently
updated
electronic
version
of
the
Code
of
Federal
Regulations
(
CFR)
is
available
at
http://
www.
gpoaccess.
gov/
ecfr/
Docket:
All
documents
in
the
docket
are
listed
in
the
http://
www.
regulations.
gov
index.
Although
listed
in
the
index,
some
information
is
not
publicly
available,
e.
g.,
CBI
or
other
information
whose
disclosure
is
restricted
by
statute.
Certain
other
material,
such
as
copyrighted
material,
will
be
publicly
available
only
in
hard
copy.
Publicly
available
docket
materials
are
available
either
electronically
in
http://
www.
regulations.
gov
or
in
hard
copy
at
the
ORD
Docket,
EPA/
DC,
EPA
West,
Room
B102,
1301
Constitution
Ave.,
NW.,
Washington,
DC.
The
Public
Reading
Room
is
open
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
The
telephone
number
for
the
Public
Reading
Room
is
(
202)
566­
1744,
and
the
telephone
number
for
the
ORD
Docket
is
(
202)
566­
1752.
EPA's
position
paper,
charge/
questions
to
the
HSRB,
HSRB
composition
and
the
meeting
agenda
will
be
available
by
mid
March
2006.
In
addition,
the
Agency
may
provide
additional
background
documents
as
the
materials
become
available.
You
may
obtain
electronic
copies
of
these
documents,
and
certain
other
related
documents
that
might
be
available
electronically,
from
the
regulations.
gov
Web
site
and
the
HSRB
Internet
Home
Page
at
http://
www.
epa.
gov/
osa/
hsrb/.

C.
What
Should
I
Consider
as
I
Prepare
My
Comments
for
EPA?

You
may
find
the
following
suggestions
helpful
for
preparing
your
comments:
1.
Explain
your
views
as
clearly
as
possible.
2.
Describe
any
assumptions
that
you
used.
3.
Provide
copies
of
any
technical
information
and/
or
data
you
used
that
support
your
views.
4.
Provide
specific
examples
to
illustrate
your
concerns.
5.
To
ensure
proper
receipt
by
EPA,
be
sure
to
identify
the
docket
ID
number
assigned
to
this
action
in
the
subject
line
on
the
first
page
of
your
response.
You
may
also
provide
the
name,
date,
and
Federal
Register
citation.

E.
How
May
I
Participate
in
This
Meeting?

You
may
participate
in
this
meeting
by
following
the
instructions
in
this
unit.
To
ensure
proper
receipt
by
EPA,
it
is
imperative
that
you
identify
docket
ID
number
EPAHQ
ORD­
2006­
0187
in
the
subject
line
on
the
first
page
of
your
request.
1.
Oral
comments.
Oral
comments
presented
at
the
meetings
should
not
be
repetitive
of
previously
submitted
oral
or
written
comments.
Although
requests
to
present
oral
comments
are
accepted
until
the
date
of
the
meeting
(
unless
otherwise
stated),
to
the
extent
that
time
permits,
interested
persons
may
be
permitted
by
the
Chair
of
the
HSRB
to
present
oral
comments
at
the
meeting.
Each
individual
or
group
wishing
to
make
brief
oral
comments
to
the
HSRB
is
strongly
advised
to
submit
their
request
(
preferably
via
email)
to
the
DFO
listed
under
FOR
FURTHER
INFORMATION
CONTACT
no
later
38
than
noon,
eastern
time,
March
29,
2006,
in
order
to
be
included
on
the
meeting
agenda.
The
request
should
identify
the
name
of
the
individual
making
the
presentation,
the
organization
(
if
any)
the
individual
will
represent,
and
any
requirements
for
audiovisual
equipment
(
e.
g.,
overhead
projector,
35
mm
projector,
chalkboard).
Oral
comments
before
the
HSRB
are
limited
to
approximately
5
minutes
unless
prior
arrangements
have
been
made.
In
addition,
each
speaker
should
bring
30
copies
of
his
or
her
comments
and
presentation
slides
for
distribution
to
the
HSRB
at
the
meeting.
2.
Written
comments.
Although
written
comments
will
be
accepted
until
the
date
of
the
meeting
(
unless
otherwise
stated),
the
Agency
strongly
encourages
that
written
comments
be
submitted,
using
the
instructions
in
Unit
1.
C.
no
later
than
noon,
eastern
time,
March
29,
2006
to
provide
the
HSRB
the
time
necessary
to
consider
and
review
the
written
comments.
It
is
requested
that
persons
submitting
comments
directly
to
the
docket
also
notify
the
DFO
listed
under
FOR
FURTHER
INFORMATION
CONTACT.
There
is
no
limit
on
the
extent
of
written
comments
for
consideration
by
the
HSRB.
3.
Seating
at
the
meeting.
Seating
at
the
meeting
will
be
on
a
first­
come
basis.
Individuals
requiring
special
accommodations
at
this
meeting,
including
wheelchair
access
and
assistance
for
the
hearing
impaired,
should
contact
the
DFO
at
least
10
business
days
prior
to
the
meeting
using
the
information
under
FOR
FURTHER
INFORMATION
CONTACT
so
that
appropriate
arrangements
can
be
made.

F.
Background
At
the
inaugural
meeting
of
the
HSRB,
EPA
will
provide
a
broad
overview
of
the
Agency's
approach
to
the
assessment
of
the
potential
risk
to
human
health
from
the
use
of
pesticides
and
how
EPA
uses
data
from
human
studies
in
such
risk
assessments.
The
Agency
will
then
present
to
the
HSRB
its
scientific
and
ethics
reviews
of
approximately
two
dozen
completed
human
studies
concerning
the
following
pesticide
active
ingredients:
aldicarb,
amitraz,
azinphos­
methyl,
dichlorovos
(
DDVP),
ethephon,
methomyl,
oxamyl,
and
sodium
cyanide.
The
studies
being
reviewed
at
this
meeting
will
include
both
studies
on
which
the
Agency
proposes
to
rely
in
actions
under
the
pesticide
laws
and
studies
that
the
Agency
has
decided
not
to
use
in
its
risk
assessments,
either
for
ethical
or
scientific
reasons.
The
Agency
will
ask
the
HSRB
to
advise
the
Agency
on
a
range
of
scientific
issues
and
on
how
the
studies
should
be
assessed
against
the
provisions
in
sections
26.1701­
26.1704
of
EPA's
final
human
studies
rule.

II.
Proposed
Candidates
for
Membership
to
the
Board
On
January
3,
2006,
the
EPA,
OSA
announced
a
request
for
nominations
of
qualified
individuals
to
serve
on
the
HSRB
(
Federal
Register
71
116).
Per
the
Federal
Register
notice,
the
OSA
requested
nominees
who
are
nationallyrecognized
experts
in
one
or
more
of
the
following
disciplines:
(
a)
Biostatistics.
Expertise
in
statistical
design
and
analysis
of
human
subjects
research
studies.
(
b)
Human
toxicology.
Expertise
in
pharmacokinetic
and
toxicokinetic
studies,
clinical
trials,
and
toxicology
of
cholinesterase
inhibitors
and
other
classes
of
environmental
substances.
39
(
c)
Bioethics.
Expertise
in
the
ethics
of
research
on
human
subjects;
research
ethics.
(
d)
Human
health
risk
assessment.
EPA
carefully
considered
the
qualifications
of
nominees
who
agreed
to
be
further
considered
and
has
identified
candidates
from
whom
EPA
expects
to
select
members
to
serve
on
the
HSRB.
EPA
now
invites
comments
from
members
of
the
public
for
relevant
information
or
other
documentation
that
the
OSA
should
consider
in
the
selection
of
HSRB
members.
The
names
of
the
candidates,
together
with
a
short
biographical
description
of
their
qualifications,
appear
on
the
Agency's
Web
site
at
http://
www.
epa.
gov/
osa/
hsrb/.
Please
e­
mail
your
comments
no
later
than
noon,
eastern
time,
March
14,
2006,
listed
under
FOR
FURTHER
INFORMATION
CONTACT.
Any
information
furnished
by
the
public
in
response
to
this
Web
site
posting
will
be
combined
with
information
already
provided
by
the
candidates,
and
gathered
independently
by
the
OSA.
Prior
to
final
selection
of
HSRB
members,
the
combined
information
will
be
reviewed
and
evaluated
for
any
possible
financial
conflict
of
interest
or
a
possible
appearance
of
a
lack
of
impartiality.
The
information
will
also
be
used
to
ensure
appropriate
balance
and
breadth
of
expertise
needed
to
address
the
charge
to
the
Board.
The
EPA
Science
Advisor
will
make
the
final
decision
concerning
who
will
serve
on
the
HSRB.

Dated:
March
2,
2006.
George
Gray,
EPA
Science
Advisor.
40
Attachment
C
April
2006
Meeting
of
the
HSRB
Meeting
Agenda
HOLIDAY
INN
 
ROSSLYN
AT
KEY
BRIDGE
ARLINGTON,
VA
HSRB
WEB
SITE
http://
www.
epa.
gov/
osa/
hsrb/
Docket
Telephone:
(
202)
566
1752
Docket
Number:
EPA­
HQ­
ORD­
2006­
0187
Tuesday,
April
4,
2006
8:
30
a.
m.
Introduction
and
Identification
of
Board
Members
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)
8:
45
a.
m.
Welcome
George
Gray,
Ph.
D.
(
EPA
Science
Advisor)
9:
00
a.
m.
Opening
Remarks
Ms.
Susan
Hazen
(
Acting
Assistant
Administrator,
Office
of
Prevention,
Pesticides
and
Toxic
Substances,
EPA)
9:
15
a.
m.
Meeting
Administrative
Procedures
Paul
Lewis,
Ph.
D.
(
Designated
Federal
Officer,
HSRB,
EPA)
9:
20
a.
m.
Meeting
Process
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)

Session
1:
Introduction
9:
30
a.
m.
Session
1
Overview
Mr.
William
Jordan
(
Office
of
Pesticide
Programs
[
OPP],
EPA)
9:
35
a.
m.
Summary
of
EPA's
Protections
for
Subjects
of
Human
Research
Mr.
William
Jordan
(
OPP,
EPA)
10:
05
a.
m.
Break
10:
20
a.
m.
EPA,
OPP
Approach
to
Assessing
Human
Health
Risks
of
Pesticides
Using
Data
From
Human
Studies
Mr.
Michael
Metzger
(
OPP,
EPA)
10:
45
a.
m.
EPA,
OPP
Assessment
of
Ethical
Conduct
of
Human
Studies
Mr.
John
Carley
(
OPP,
EPA)
11:
15
a.
m.
EPA,
OPP
Assessment
of
Individual
Human
Studies
Ray
Kent,
Ph.
D.
(
OPP,
EPA)
11:
40
a.
m.
A
Summary
of
Human
Studies
for
Consideration
by
the
Human
Studies
Review
Board
Louis
Scarano,
Ph.
D.
(
OPP,
EPA)
11:
50
a.
m.
Lunch
41
Session
2:
Carbamate
Pesticides
1:
00
p.
m.
Session
2
Overview
Anna
Lowit,
Ph.
D.
(
OPP,
EPA)
1:
05
p.
m.
EPA,
OPP
Policy
on
"
The
Use
of
Data
on
Cholinesterase
Inhibition
for
Risk
Assessment
of
Organophosphorous
and
Carbamate
Pesticides"
Anna
Lowit,
Ph.
D.
(
OPP,
EPA)
1:
20
p.
m.
Science
and
Ethics
of
Aldicarb
Human
Studies
Linda
Taylor,
Ph.
D.
(
OPP,
EPA),
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
1:
50
p.
m.
Science
and
Ethics
of
Methomyl
Human
Studies
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
2:
20
p.
m.
Science
and
Ethics
of
Oxamyl
Human
Studies
Elissa
Reaves,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
3:
00
p.
m.
Break
3:
15
p.
m.
Public
Comments
on
Session
2
4:
15
p.
m.
Board
Discussion
and
Writing
Session
A.
Aldicarb
Aldicarb
is
a
N­
methyl
carbamate
(
NMC)
pesticide
whose
primary
toxic
effect
is
neurotoxicity
caused
by
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
carbamylation
followed
by
rapid
recovery.
Aldicarb
can,
at
sufficiently
high
doses,
lead
to
a
variety
of
clinical
signs.
The
Agency
is
conducting
an
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
aldicarb.
In
addition,
aldicarb
is
a
member
of
the
N­
methyl
carbamate
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
NMCs.

1.
Scientific
considerations:

The
Agency's
"
Weight
of
the
Evidence"
(
WOE)
document
and
Data
Evaluation
Records
(
DERs)
for
aldicarb
describe
the
study
design
and
results
of
the
aldicarb
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
acute,
aggregate,
single
chemical
risk
assessment
and
in
the
42
cumulative
risk
assessment
for
the
NMCs.
Regarding
the
aldicarb
human
study,
the
Agency
has
concluded
that
the
study
is
sufficiently
robust
for
reducing
the
inter­
species
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
aggregate
and
the
cumulative
risk
assessments.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
a.
Single
chemical,
aggregate
risk
assessment
and
b.
Cumulative
risk
assessment
2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

 
In
light
of
the
ethics
committee's
instruction
that
the
lay
summary
be
"
greatly
expanded,"
and
the
fact
that
the
materials
used
to
obtain
informed
consent
listed
a
limited
range
of
symptoms
of
carbamate
toxicity
(
excluding
some
reported
as
adverse
effects
in
the
study),
included
multiple
references
to
the
test
material
as
a
drug,
and
failed
to
identify
dose
levels
to
be
administered
to
male
subjects,
whether,
the
materials
used
to
obtain
informed
consent
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

 
Whether
the
absence
from
the
protocol
of
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1989
Declaration
of
Helsinki,
Principle
#
4,
with
which
the
research
asserted
compliance)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

B.
Methomyl
Methomyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation.
The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
43
of
methomyl.
At
the
present
time,
the
Agency
is
considering
the
use
of
the
methomyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
used
in
the
cumulative
risk
assessment
of
the
NMCs.

1.
Scientific
considerations:

The
Agency's
WOE
document
and
DER
for
methomyl
describe
the
study
design
and
results
of
the
methomyl
acute
oral,
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
methomyl,
the
Agency
has
concluded
that
the
human
toxicity
study
supports
a
10X
inter­
species
uncertainty
factor
for
methomyl
in
the
cumulative
risk
assessment
of
the
NMCs.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

 
Whether
the
investigators'
decision
to
administer
a
dose
to
additional
subjects
in
session
3,
when
one
subject
receiving
that
dose
in
session
2
displayed
RBC
ChEI
greater
than
40%,
a
response
that
triggered
the
protocol's
anti­
escalation
provision,
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

 
Whether
the
timing
of
the
investigators'
report
to
the
ethics
committee
of
the
adverse
effects
observed
in
one
subject
during
session
2
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

 
Whether
the
failure
of
the
investigators
to
request
approval
from
the
ethics
committee
for
certain
amendments
to
the
approved
protocol,
as
required
by
the
protocol,
when
the
changes
were
administrative
and
had
no
effect
on
the
safety
of
the
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
 
Whether
the
absence
from
the
protocol
of
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
44
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

C.
Oxamyl
Similar
to
aldicarb
and
methomyl,
oxamyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation
and
is
thus
included
in
the
NMC
cumulative
risk
assessment.
The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
oxamyl.
The
Agency
is
now
considering
the
use
of
the
oxamyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
in
the
cumulative
risk
assessment
of
the
NMCs.

1.
Scientific
considerations:

The
Agency's
WOE
document
and
DER
for
oxamyl
describe
the
study
design
and
results
of
the
oxamyl
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
oxamyl,
the
Agency
has
concluded
that
the
human
toxicity
study
is
sufficiently
robust
for
reducing
the
10X
inter­
species
(
ie,
animal
to
human)
uncertainty
factor
in
the
cumulative
risk
assessment.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

 
Whether
inclusion
in
the
protocol
submitted
to
the
ethics
committee
of
a
factually
inaccurate
statement
regarding
unavailability
of
data
on
accidental
or
incidental
exposure
to
oxamyl
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

 
Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
45
proposed
research
(
as
required
by
the
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

5:
00
p.
m.
Adjourn
Wednesday,
April
5,
2006
8:
30
a.
m.
Convene
Meeting
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)
8:
40
a.
m.
Follow­
up
From
Previous
Day's
Discussion
Mr.
William
Jordan
(
OPP,
EPA)
8:
50
a.
m.
Board
Discussion
and
Writing
Session
(
continued)
10:
15
a.
m.
Break
Session
3:
Organophosphate
Pesticides
10:
30
a.
m.
Session
3
Overview
Anna
Lowit,
Ph.
D.
(
OPP,
EPA)
10:
35
a.
m.
Science
and
Ethics
of
Azinphos
Methyl
Human
Studies
John
Doherty,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
11:
00
a.
m.
Science
and
Ethics
of
DDVP
Human
Studies
Ray
Kent,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
11:
45
a.
m.
Lunch
12:
45
p.
m.
Public
Comments
on
Session
3
2:
00
p.
m.
Board
Discussion
and
Writing
Session
D.
Azinphos
methyl
Azinphos
methyl
(
AZM)
is
an
organophosphate
pesticide
(
OP).
Consistent
with
other
OPs,
AZM
elicits
neurotoxicity
through
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
At
sufficiently
high
doses,
exposure
to
AZM
can
lead
to
a
variety
of
clinical
signs.
The
Agency
is
developing
an
46
assessment
to
estimate
risk
to
workers
from
exposure
to
AZM.
In
addition,
AZM
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
risk
assessment
for
the
OPs.

1.
Scientific
considerations:

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,
the
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
risk
to
workers
exposed
to
AZM
via
the
dermal
and
inhalation
routes.

For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
because
no
cholinesterase
inhibition
was
seen
in
the
human
toxicity
study,
it
is
not
possible
to
evaluate
whether
steady
state
had
been
reached
in
humans
at
28
days
of
exposure.
Thus,
the
Agency
has
concluded
that
the
AZM
repeat
dose,
oral,
toxicity
study
is
not
sufficiently
robust
for
informing
the
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
a.
Worker
risk
assessment
and
b.
Cumulative
risk
assessment
2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

 
Whether
the
informed
consent
materials
 
which
refer
to
"
the
company"
and
"
supervising
doctor,"
without
further
identification,
and
contain
no
discussion
of
who
would
benefit
from
the
research
 
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and,

 
Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1996
Declaration
of
Helsinki,
Principle
#
5,
with
which
the
research
asserted
compliance)
should
be
considered
47
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

E.
DDVP
Like
AZM,
DDVP
is
an
organophosphate
pesticide
(
OP)
which
elicits
neurotoxicity
through
the
inhibition
of
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route,
multi­
duration)
risk
assessment
of
DDVP.
In
addition,
DDVP
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
OPs.

1.
Scientific
considerations:

a.
The
Agency's
WOE
document
and
DER
for
DDVP
describe
the
study
design
and
results
of
the
DDVP
repeat
dose,
oral
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
this
study
in
the
aggregate
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
OPs.
For
the
single
chemical
risk
assessment,
the
Agency
has
concluded
that
the
human
study
is
sufficiently
robust
for
developing
a
point
of
departure
for
estimating
dermal,
incidental
oral,
and
inhalation
risk
from
exposure
to
DDVP
in
the
single
chemical
risk
assessment.
For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
results
of
the
DDVP
multi­
dose
human
toxicity
study
do
not
support
reducing
the
default
10X
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
i.
Single
chemical,
aggregate
risk
assessment
and
ii.
Cumulative
risk
assessment
48
b.
The
Agency
has
concluded
that
other
human
studies
made
available
to
the
Board
do
not
provide
sufficient
scientifically
sound
information
to
warrant
any
reduction
in
the
10X
inter­
species
uncertainty
factor
used
to
derive
reference
dose
values
for
DDVP
based
on
animal
toxicity
endpoints.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.

2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

 
Whether
references
to
the
test
material
as
a
drug
and
other
statements
that
could
indicate
the
study
constituted
medical
research,
that
appear
in
the
materials
used
to
obtain
informed
consent
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

 
Whether
the
administration
of
the
test
material
for
three
additional
days
without
monitoring
subjects'
cholinesterase
levels
following
the
detection
of
cholinesterase
inhibition
>
20
%
in
some
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
 
Whether
the
lack
of
medical
surveillance
of
subjects,
following
the
termination
of
dosing,
to
establish
the
subjects'
cholinesterase
levels
returned
to
normal
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
the
Gledhill
repeated
dose
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
Gledhill
repeat
dose
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

3:
15
p.
m.
Break
Session
4:
Other
Pesticides
49
3:
30
p.
m.
Session
Overview
Ray
Kent,
Ph.
D.
(
OPP,
EPA)
3:
35
p.
m.
Science
and
Ethics
of
Ethephon
Abdallah
Khasawinah,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
4:
00
p.
m.
Science
and
Ethics
of
Sodium
Cyanide
Human
Studies
William
Dykstra,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
4:
30
p.
m.
Science
and
Ethics
of
Amitraz
Human
Studies
John
Liccione,
Ph.
D.
(
OPP,
EPA)
and
Mr.
John
Carley
(
OPP,
EPA)
5:
00
p.
m.
Adjournment
Thursday,
April
6,
2006
8:
30
a.
m.
Convene
Meeting
Celia
Fisher,
Ph.
D.
(
HSRB
Chair)
8:
45
a.
m.
Follow­
up
From
Previous
Day's
Discussion
Mr.
William
Jordan
(
OPP,
EPA)
9:
30
a.
m.
Public
Comments
on
Session
4
10:
30
a.
m.
Break
10:
45
a.
m.
Board
Discussion
and
Writing
Session
F.
Ethephon
Ethephon
is
an
organophosphorus
compound
that,
upon
absorption
into
plants,
forms
ethylene
gas
which
is
an
important
component
of
the
plant
hormone
complex.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
ethephon.

1.
Scientific
considerations:

The
Agency's
WOE
document
and
DERs
for
ethephon
describe
the
study
design
and
results
of
the
ethephon
repeat
dose,
oral,
human
toxicity
studies.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
studies
in
the
aggregate,
single
chemical
risk
assessment.
The
Agency
has
concluded
that
the
28­
day
human
study
is
sufficiently
robust
to
establish
a
point
of
departure
for
extrapolating
acute
and
chronic
dietary
risk.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

2.
Ethical
considerations:
50
In
its
ethics
review
of
this
research,
EPA
documented
that
the
study
reports
contained
very
little
information
concerning
the
ethical
conduct
of
the
research
and
that
the
available
information
raised
no
ethical
concerns.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
each
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

G.
Hydrogen
Cyanide
/
Amygdalin
When
sodium
cyanide
is
used
as
a
fumigant,
hydrogen
cyanide
is
generated
by
acidification.
Because
residues
of
HCN
may
remain
on
fumigated
citrus,
the
Agency
is
conducting
an
acute
dietary
risk
assessment
of
hydrogen
cyanide.

1.
Scientific
considerations:

The
Agency's
WOE
document
describes
a
lack
of
data
appropriate
for
developing
an
acute
dietary
risk
assessment
for
hydrogen
cyanide.
The
WOE
and
DER
present
the
results
from
a
clinical
trial
with
amygdalin
and
the
usefulness
of
this
clinical
trial
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.
The
Agency
has
concluded
that
the
clinical
trial
is
appropriate
for
establishing
a
point
of
departure
in
the
acute
dietary
risk
assessment
for
hydrogen
cyanide.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

2.
Ethical
considerations
In
its
ethics
review
of
this
research,
EPA
did
not
identify
any
deficiencies
with
respect
to
the
ethical
conduct
of
this
research.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
51
H.
Amitraz
Exposure
to
amitraz
can
result
in
neurotoxicity
as
evidenced
by
clinical
signs
such
as
ataxia,
ptosis,
emesis,
labored
respiration,
muscular
weakness,
tremors,
hypothermia
and
bradycardia.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
amitraz.

1.
Scientific
considerations:

The
Agency's
WOE
document
and
DERs
for
amitraz
describe
the
study
design
and
results
of
the
amitraz
acute
oral
and
dermal
toxicity
human
studies
and
the
human
metabolism
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
studies
in
the
single
chemical
risk
assessment
for
acute
and
chronic
oral
exposures
in
addition
to
dermal
and
inhalation
exposures
of
various
durations.
For
oral
exposure,
the
Agency
has
concluded
that
the
combined
results
from
the
single
oral
dose
study
and
human
metabolism
study
establishes
a
dose
response
relationship
in
human
subjects
and
that
the
single
oral
dose
study
is
appropriate
for
developing
a
point
of
departure
for
acute
and
chronic
dietary
risk,
short­
term
oral
exposure,
and
inhalation
exposures
of
various
durations.
The
Agency
has
further
concluded
that
the
human
dermal
study
is
appropriate
for
developing
a
point
of
departure
for
dermal
exposures
of
various
durations.

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.

2.
Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

 
With
respect
to
the
Campbell
(
1984)
research,
whether
the
lack
of
medical
surveillance
of
subjects,
following
the
termination
of
dosing,
to
establish
that
subjects'
signs
of
adverse
effects
had
returned
to
normal
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
 
With
respect
to
the
Cass
(
1992)
and
the
Langford
(
1998)
studies,
whether
references
to
the
test
material
as
a
drug
and
other
statements
that
could
indicate
the
study
constituted
medical
research,
that
appear
in
the
materials
used
to
obtain
informed
should
be
considered
52
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
.
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
each
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

12:
00
p.
m.
Lunch
1:
00
p.
m.
Board
Discussion
and
Writing
Session
(
continued)
4:
30
p.
m.
Adjournment
Please
be
advised
that
agenda
times
are
approximate.
For
further
information,
please
contact
the
Designated
Federal
Officer
for
this
meeting,
Paul
Lewis
via
telephone:
(
202)
564­
8381
or
email:
lewis.
paul@
epa.
gov