Document ID: EPA-HQ-OPP-2003-0132-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-04-02T05:00Z

United
States
Science
Advisory
EPA­
SAB­
EC­
00­
017
Environmental
Board
(
1400A)
September
2000
Protection
Agency
Washington
DC
ww.
epa.
gov/
sab
COMMENTS
ON
THE
USE
OF
DATA
FROM
THE
TESTING
OF
HUMAN
SUBJECTS
A
REPORT
BY
THE
SCIENCE
ADVISORY
BOARD
AND
THE
FIFRA
SCIENTIFIC
ADVISORY
PANEL
September
11,
2000
EPA­
SAB­
EC­
00­
017
Honorable
Carol
Browner
Administrator
U.
S.
Environmental
Protection
Agency
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
Subject:
Consideration
of
issues
relating
to
EPA's
use
of
data
derived
from
the
testing
of
human
subjects
Dear
Ms.
Browner:

A
Joint
Subcommittee
of
the
Science
Advisory
Board
(
SAB)
and
the
Federal
Insecticide,
Fungicide
and
Rodenticide
Act
(
FIFRA)
Scientific
Advisory
Panel
(
SAP)
convened
in
a
public
meeting
on
December
10­
11,
1998.
The
purpose
of
the
meeting
was
to
provide
advice
and
comment
to
the
Environmental
Protection
Agency
(
EPA)
on
a
number
of
issues
related
to
data
derived
from
the
testing
of
human
subjects,
particularly
the
use
of
human
data
for
making
pesticide
registration
decisions.
Both
scientific
and
ethical
questions
have
been
raised
about
the
data,
to
include
the
manner
in
which
they
were
developed
and
how
or
whether
these
data
should
be
used
in
the
decision
making
process.
The
Charge
was
that
the
Subcommittee
address
the
value
of
human
studies;
identify
factors
for
consideration
when
(
a)
determining
what
constitutes
an
appropriate
human
study
for
use
in
environmental
decision­
making;
(
b)
when
making
a
judgment
on
what
constitutes
an
ethically
appropriate
human
study;
and
(
c)
when
determining
if
a
study
is
appropriate
(
or
inappropriate)
for
use.
It
asked
also
that
the
Subcommittee
discuss
the
risks
and
benefits
of
research
on
humans
for
both
subjects
and
society,
and
the
issues
relevant
to
determining
if
studies
are
in
compliance
with
accepted
guidelines
(
the
complete
Charge
will
be
found
in
section
2.2
of
the
enclosed
report).

A
draft
report
was
generated
based
on
the
presentations
and
discussions
at
this
meeting.
However,
a
significant
subset
of
the
Subcommittee
had
reservations
about
the
content
of
some
sections
of
the
report.
Therefore,
a
second
meeting
of
the
SAB/
SAP
Joint
Subcommittee
was
convened
on
November
30,
1999
to
permit
further
deliberations
for
the
purpose
of
resolving
and
bringing
to
closure
differences
of
opinion
within
the
Committee.

Section
3
of
the
report
addresses
each
element
of
the
Charge,
and
provides
many
specific
recommendations
to
the
EPA.
The
Subcommittee
found,
however,
that
its
most
significant
findings
2
could
be
best
expressed
outside
the
constraints
of
specific
Charge
issues.
First,
there
were
a
series
of
basic
findings
on
which
the
Subcommittee
was
unanimous.
These
are:

a)
Any
policy
adopted
by
the
Agency
should
reflect
the
highest
standards
of
respect
for
human
subjects
and
should
prohibit
research
protocols
that
override
the
interests
of
subjects
in
order
to
obtain
useful
data.

b)
If
it
can
be
justified
at
all
to
expose
human
subjects
intentionally
to
toxic
substances,
the
threshold
of
justification
for
such
action
should
be
very
high.
We
recommend,
therefore,
that
pesticide
exposure
to
human
subjects
be
approached
with
the
greatest
degree
of
caution.
The
risks
of
allowing
such
experimental
exposures
of
humans
include
the
possible
involvement
of
less
than
fully
informed
participants,
unanticipated
health
consequences,
the
exposure
of
large
numbers
of
subjects,
and
skewed
use
in
developing
countries.

c)
Bad
science
is
always
unethical;
research
protocols
that
are
fundamentally
flawed,
such
as
those
with
sample
sizes
inadequate
to
support
reasonable
inferences
about
the
matter
in
question,
are
unjustifiable.

d)
If
the
use
of
human
subjects
in
pesticide
testing
can
be
justified,
that
justification
cannot
be
to
facilitate
the
interests
of
industry
or
of
agriculture,
but
only
to
better
safeguard
the
public
health.

e)
Any
policy
adopted
by
the
Agency
must
reflect
a
special
concern
for
the
interests
of
vulnerable
populations,
such
as
fetuses,
children,
adolescents,
pregnant
women,
the
elderly,
and
those
with
fragile
health
due
to
compromised
respiratory
function
or
other
reasons.

f)
Unintended
exposures
provide
valuable
opportunities
for
research;
it
is
an
error
not
to
take
full
advantage
of
such
opportunities
to
gain
major
information
through
careful
incident
follow­
up.

g)
In
considering
research
protocols,
it
is
not
enough
to
determine
a
risk/
benefit
ratio;
it
is
important
also
to
consider
the
distribution
of
risks
and
of
benefits,
and
to
ensure
that
risks
are
not
imposed
on
one
population
for
the
sake
of
benefits
to
be
enjoyed
by
another.
It
is
also
important
to
be
sensitive
to
the
difference
between
a
reversible
risk
and
one
that
may
be
irreversible,
such
as
possible
interference
with
normal
neurological
development.

Addressing
the
issue
of
intentionally
dosing
human
subjects
with
pesticides,
all
but
two
of
the
Subcommittee
Members
could
envision
particular
circumstances
under
which
such
dosing
of
humans
3
could
be
scientifically
and
ethically
acceptable.
Defining
these
circumstances
generically,
however,
proved
to
be
very
difficult
and
were
the
source
of
prolonged
discussion
at
the
public
meeting
and
multiple
"
fine­
tuning"
during
preparation
of
the
report.
The
following
summary
presents
the
most
significant
findings
of
the
majority
of
the
Subcommittee
with
regard
to
both
the
institutional
guarantees
that
would
be
required
and
the
guidelines
that
could
be
used
to
determine
whether
or
not
intentional
dosing
of
humans
in
a
particular
study
is
scientifically
and
ethically
acceptable.
These
findings
are:

a)
All
research
involving
humans
should
require
prior
review
by
an
Institutional
Review
Board
(
IRB).
Standards
for
the
functioning
and
compositions
of
these
Boards
are
incorporated
in
the
"
Common
Rule,"
the
"
shorthand"
name
for
the
human
research
subject
protection
requirements
embodied
in
CFR
40
Part
26.
The
Rule,
adopted
by
17
Federal
Agencies,
describes
and
defines
in
detail
the
requirements
for
obtaining
and
documenting
informed
consent
from
subjects.

b)
The
structure,
function,
and
activities
of
both
the
Agency's
IRBs
and
external
IRBs
of
entities
submitting
data
should
be
under
active
and
aggressive
scrutiny
by
EPA,
with
adequate
staff
and
financial
resources
provided
to
carry
out
this
mission.
EPA
should
establish
an
internal
ethics
review
organization
to
perform
this
function,
staffed
by
fulltime
individuals
whose
duties
address
exclusively
compliance
oversight.
The
review
organization
should
also
provide
an
institutional
focus
for
continuous
close
liaison
on
ethical
matters
with
other
federal
agencies.

c)
The
intentional
administration
of
pesticides
to
human
subjects
testing
is
acceptable,
subject
to
limitations
described
as
ranging
from
"
rigorous"
to
"
severe."
The
information
sought
must
not
be
available
via
other
sources
(
e.
g.,
animal
studies
and
models,
or
the
study
of
incidental
exposures),
and
the
information
expected
to
be
gained
must
promise
reasonable
health
benefits
to
the
individual
or
society
at
large.
Studies
should
be
appropriately
designed
to
address
the
stated
objective,
and
have
sufficient
statistical
power
to
provide
an
unambiguous
answer
to
the
question
under
investigation.
In
addition,
some
ongoing
monitoring
of
the
subjects
involved
in
such
studies
is
essential
to
insure
that
they
do
not
subsequently
become
ill
or
suffer
other
adverse
effects.

d)
In
no
case
should
developing
humans
(
i.
e.,
the
fetus,
infant,
young
children,
or
adolescents)
be
exposed
to
neurotoxic
chemicals.
There
are
currently
too
many
unknown
dangers
to
justify
such
studies,
even
under
the
most
extraordinary
circumstances.

e)
The
EPA
should
take
whatever
administrative
action
is
necessary
to
extend
the
protections
of
40
CFR
Part
26
(
the
"
Common
Rule")
to
all
human
research
activities
whose
results
will
be
submitted
to
the
Agency.
4
f)
With
regard
to
data
derived
prior
to
enactment
of
Public
Law
92­
516
(
amendments
to
the
FIFRA),
the
Subcommittee
agreed
that
the
fact
that
research
was
done
unethically
does
not
alone
require
rejection
of
the
results
of
that
research.

g)
The
Subcommittee
identified
certain
situations
in
which
testing
would
or
would
not
be
appropriate:

1)
It
would
not
be
appropriate
to
conduct
such
testing
when
adequate
human
data
are
already
available.

2)
Human
studies
would
not
be
appropriate
for
pesticides
in
use
today
when
data
of
equal
quality
can
be
obtained
from
field
exposure
studies.

3)
Subject
to
the
other
limitations
discussed
in
this
report,
human
studies
could
be
appropriate
when
there
are
significant
data
gaps
and
such
studies
would
provide
a
more
accurate
risk
assessment.

4)
Subject
to
the
other
limitations
discussed
in
this
report,
human
studies
could
be
appropriate
for
pesticides
which
are
not
yet
on
the
market,
i.
e.
new
pesticides.

5)
Given
the
significance
of
statistical
considerations
in
regard
to
human
study
design,
the
Agency
ought
to
organize
a
workshop
to
deal
specifically
with
this
issue.

Finally,
we
wish
to
note
that
two
Members
of
the
Subcommittee,
Drs.
Needleman
and
Reigart,
do
not
concur
with
significant
portions
of
this
report
as
it
was
agreed
upon
by
the
remainder
of
the
Subcommittee.
At
the
suggestion
of
the
Co­
Chairs,
they
have
provided
a
minority
statement
which
is
incorporated
in
the
report
as
Appendix
C.
The
Executive
Committee
discussed
the
content
of
this
statement
during
their
review
of
this
report,
but
did
not
find
it
necessary
to
recommend
any
changes
to
the
report
as
a
result.

We
appreciate
the
opportunity
to
comment
on
these
issues,
and
look
forward
to
your
response.

Sincerely,

/
s/
Dr.
Morton
Lippmann,
Interim
Chair
Science
Advisory
Board
5
/
s/
/
s/
Dr.
Ronald
Kendall,
Co­
Chair
Dr.
Mark
Utell,
Co­
Chair
Data
from
the
Testing
of
Human
Subjects
Data
from
the
Testing
of
Human
Subjects
Subcommittee
Subcommittee
i
ERRATA
In
Appendix
C,
page
C­
1,
fourth
paragraph,
the
following
sentence
"
While
there
was
general
agreement
of
the
subcommittee
that
poor
science
is
per
se
unethical,
the
document
gives
little
credence
to
the
concerns
of
two
highly
qualified
statisticians
(
Needleman
and
Portier)."

should
be
changed
to
read
"
While
the
subcommittee
agreed
that
poor
science
is
per
se
unethical,
the
document
gives
little
credence
to
the
concerns
of
two
subcommittee
members
using
well
known
statistical
procedures
(
Needleman
and
Portier)."

10/
11/
2000
ii
NOTICE
This
report
has
been
written
as
part
of
the
activities
of
the
Science
Advisory
Board,
a
public
advisory
group
providing
extramural
scientific
information
and
advice
to
the
Administrator
and
other
officials
of
the
Environmental
Protection
Agency.
The
Board
is
structured
to
provide
balanced,
expert
assessment
of
scientific
matters
related
to
problems
facing
the
Agency.
This
report
has
not
been
reviewed
for
approval
by
the
Agency
and,
hence,
the
contents
of
this
report
do
not
necessarily
represent
the
views
and
policies
of
the
Environmental
Protection
Agency,
nor
of
other
agencies
in
the
Executive
Branch
of
the
Federal
government,
nor
does
mention
of
trade
names
or
commercial
products
constitute
a
recommendation
for
use.

Distribution
and
Availability:
This
Science
Advisory
Board
report
is
provided
to
the
EPA
Administrator,
senior
Agency
management,
appropriate
program
staff,
interested
members
of
the
iii
public,
and
is
posted
on
the
SAB
website
(
www.
epa.
gov/
sab).
Information
on
its
availability
is
also
provided
in
the
SAB's
monthly
newsletter
(
Happenings
at
the
Science
Advisory
Board).
Additional
copies
and
further
information
are
available
from
the
SAB
Staff.
iv
ABSTRACT
The
Joint
Science
Advisory
Board/
Scientific
Advisory
Panel
(
SAB/
SAP)
Data
from
Testing
on
Human
Subjects
Subcommittee
(
DTHSS)
first
met
on
December
10­
11,
1998,
in
Arlington
VA,
to
discuss
the
use
of
data
generated
by
testing
human
subjects.
The
Charge
addressed
a
wide
range
of
issues
on
the
ethics
and
efficacy
of
such
testing.
After
generating
a
series
of
drafts,
the
Subcommittee
met
a
second
time
in
Arlington,
VA
on
November
30,
1999
to
discuss
issues
on
which
consensus
had
not
been
reached.

The
most
significant
findings
are
best
expressed
outside
the
specific
Charge
issues.
The
findings
on
which
the
Subcommittee
was
unanimous
are:

a)
Any
policy
should
reflect
the
highest
standards
of
respect
for
human
subjects.

b)
The
threshold
of
justification
for
exposing
human
subjects
to
toxic
substances
should
be
very
high.

c)
Bad
science
is
always
unethical.

d)
The
only
justification
for
the
use
of
human
subjects
in
pesticide
testing
is
to
better
safeguard
public
health.

e)
Testing
policy
must
reflect
a
special
concern
for
vulnerable
populations
(
fetuses,
children,
adolescents,
pregnant
women,
the
elderly,
and
those
with
fragile
health).

f)
Unintended
exposures
provide
valuable
opportunities
for
research.

g)
EPA
must
consider
the
distribution
of
risks
and
of
benefits,
and
to
ensure
that
risks
are
not
imposed
on
one
population
to
provide
benefits
for
another.

All
but
two
of
the
Subcommittee
Members
agreed
on
circumstances
when
dosing
humans
with
toxic
agents
could
be
acceptable.
The
following
guidelines
were
cited
by
these
Members:

a)
All
research
involving
humans
should
require
prior
review
by
an
Institutional
Review
Board.

b)
The
structure/
function/
activities
of
IRBs
should
be
under
active
and
aggressive
scrutiny
c)
The
intentional
administration
of
pesticides
to
human
subjects
testing
is
acceptable,
subject
to
limitations
ranging
from
"
rigorous"
to
"
severe."
v
d)
Developing
humans
(
the
fetus,
infants,
young
children,
or
adolescents)
should
never
be
exposed
to
neurotoxic
chemicals.

e)
The
EPA
should
extend
the
protections
of
40
CFR
Part
26
to
all
human
research
activities
submitted
to
the
Agency.

f)
Research
done
unethically
should
not
be
rejected
automatically.

g)
Situations
in
which
such
testing
would
or
would
not
be
appropriate
include:

1)
No
such
testing
should
be
conducted
when
adequate
human
data
are
already
available.

2)
Testing
would
not
be
appropriate
when
data
of
equal
quality
is
available
from
field
exposure
studies.

3)
Human
studies
could
be
appropriate
when
there
are
significant
data
gaps.

4)
Human
studies
could
be
appropriate
for
pesticides
which
are
not
yet
on
the
market.

5)
EPA
should
organize
a
workshop
to
deal
with
the
statistical
considerations
in
human
study
design.

KEYWORDS:
Human
studies;
ethics;
pesticides;
IRB;
Common
Rule;
NOAEL;
LOAEL
1Dr.
Reigart
participated
in
both
meetings
of
the
Subcommittee,
and
in
the
subsequent
report
preparation
process.
He
resigned
from
the
Subcommittee
on
June
7,
2000,
and
is
not
responsible
for
the
statements
and
recommendations
in
this
report.
He
has
submitted
a
statement,
which
is
displayed
in
Appendix
C.

vi
ROSTER
 
MEETING
1
SAB/
SAP
JOINT
SUBCOMMITTEE
ON
DATA
FROM
TESTING
HUMAN
SUBJECTS
DECEMBER
10­
11,
1998
CO­
CHAIRS
Dr.
Ernest
E.
McConnell,
ToxPath,
Raleigh,
North
Carolina
Dr.
Mark
Utell,
Professor
of
Medicine
and
Environmental
Medicine,
University
of
Rochester
Medical
Center,
Rochester,
NY
MEMBERS
AND
CONSULTANTS
Dr.
Nancy
Fiedler,
Environmental
and
Occupational
Health
Sciences
Institute,
Dept.
of
Environmental
&
Community
Medicine,
Piscataway,
NJ
Dr.
Samuel
Gorovitz,
Professor
of
Philosophy
and
of
Public
Administration,
Syracuse
University,
Syracuse,
NY
Dr.
Arthur
Caplan,
Director,
Center
for
Bioethics,
University
of
Pennsylvania,
Philadelphia
PA
Dr.
Jeffrey
P.
Kahn,
Center
for
Bioethics,
University
of
Minnesota,
Minneapolis
MN
Dr.
Ronald
J.
Kendall,
Director
and
Professor,
The
Institute
of
Environmental
and
Human
Health,
Texas
Tech
University
Health
Sciences
Center,
Lubbock,
TX
Dr.
Andre
Knottnerus,
Gezondheidsraad/
Health
Council
of
the
Netherlands,
The
Hague,
NL
Dr.
Herb
Needleman,
University
of
Pittsburgh,
School
of
Medicine,
Pittsburgh,
PA
Dr.
J.
Routt
Reigart,
Director,
General
Pediatrics,
Medical
University
of
South
Carolina,
Charleston
SC1
Dr.
Marinelle
Payton,
Instructor
in
Medicine
and
Occupational
Medicine,
Environmental
and
Occupational
Medicine,
Harvard
School
of
Public
Health,
Boston,
MA
vii
Dr.
Bernard
Weiss,
Professor
of
Environmental
Medicine
and
Pediatrics,
University
of
Rochester
School
of
Medicine
and
Dentistry,
Rochester,
NY
viii
FEDERAL
EXPERTS
Dr.
Gary
B.
Ellis,
Director,
Office
for
Protection
from
Research
Risks,
National
Institutes
of
Health,
Rockville,
MD
Dr.
Eric
M.
Meslin,
Executive
Director,
National
Bioethics
Advisory
Commission,
Rockville
MD
Dr.
Chris
Portier,
National
Institute
of
Environmental
Health
Sciences
Research
Triangle
Park,
NC
CO­
DESIGNATED
FEDERAL
OFFICIALS
Mr.
Larry
Dorsey
(
H7509C),
Executive
Secretary,
FIFRA
Scientific
Advisory
Panel,
Office
of
Pesticide
Programs,
Environmental
Protection
Agency,
Washington,
DC
Mr.
Samuel
Rondberg
(
1400A),
Designated
Federal
Official,
Science
Advisory
Board,
Environmental
Protection
Agency,
1200
Pennsylvania,
NW,
Washington,
DC
ix
ROSTER
 
MEETING
2
SAB/
SAP
JOINT
SUBCOMMITTEE
ON
DATA
FROM
TESTING
HUMAN
SUBJECTS
November
30,
1999
CO­
CHAIRS
Dr.
Ronald
J.
Kendall,
Director
and
Professor,
The
Institute
of
Environmental
and
Human
Health,
Texas
Tech
University/
Texas
Tech
Health
Sciences
Center,
Lubbock,
TX
Dr.
Mark
Utell,
Professor
of
Medicine
and
Environmental
Medicine,
University
of
Rochester
Medical
Center,
Rochester,
NY
MEMBERS
AND
CONSULTANTS
Dr.
Nancy
Fiedler,
Environmental
and
Occupational
Health
Sciences
Institute,
Dept.
of
Environmental
&
Community
Medicine,
Piscataway,
NJ
Dr.
Samuel
Gorovitz,
Professor
of
Philosophy
and
of
Public
Administration,
Syracuse
University,
Syracuse,
NY
Dr.
Jeffrey
P.
Kahn,
Director,
Center
for
Bioethics,
University
of
Minnesota,
Minneapolis
MN
Dr.
Ernest
E.
McConnell,
ToxPath,
Raleigh,
North
Carolina
Dr.
Herb
Needleman,
University
of
Pittsburgh,
School
of
Medicine,
Pittsburgh,
PA
Dr.
J.
Routt
Reigart,
Director,
General
Pediatrics,
Medical
University
of
South
Carolina,
Charleston
SC
Dr.
Bernard
Weiss,
Professor
of
Environmental
Medicine
and
Pediatrics,
University
of
Rochester
School
of
Medicine
and
Dentistry,
Rochester,
NY
FEDERAL
EXPERTS
Dr.
Joseph
J.
DeGeorge,
Associate
Director
for
Pharmacology
and
Toxicology,
Office
of
Review
Management,
Center
for
Drug
Evaluation
and
Research,
FDA,
Rockville,
MD
Dr.
Gary
B.
Ellis,
Director,
Office
for
Protection
from
Research
Risks,
National
Institutes
of
Health,
Rockville,
MD
Dr.
Eric
M.
Meslin,
Executive
Director,
National
Bioethics
Advisory
Commission,
Rockville
MD
x
Dr.
Chris
Portier,
National
Institute
of
Environmental
Health
Sciences,
Research
Triangle
Park,
NC
CO­
DESIGNATED
FEDERAL
OFFICIALS
Mr.
Larry
Dorsey
(
H7509C),
Executive
Secretary,
FIFRA
Scientific
Advisory
Panel,
Office
of
Pesticide
Programs,
Environmental
Protection
Agency,
Washington,
DC
Mr.
Samuel
Rondberg
(
1400A),
Designated
Federal
Official,
Science
Advisory
Board,
Environmental
Protection
Agency,
1200
Pennsylvania
Avenue,
NW,
Washington,
DC
xi
TABLE
OF
CONTENTS
1.
EXECUTIVE
SUMMARY
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1
2.
INTRODUCTION
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4
2.1
Background
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4
2.2
Charge
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7
3.
DETAILED
FINDINGS
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9
3.1
The
Value
of
Human
Studies
(
Issue
a)
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9
3.1.1
Information
Available
from
Studies
with
Human
Volunteers
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9
3.1.2
Limitations
of
Clinical
Studies
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10
3.1.3
Limitations
on
Establishing
NOELs
and
NOAELs
with
Human
Testing
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11
3.2
Factors
for
Consideration
in
Identifying
Ethically
Appropriate
Human
Studies
(
Issue
b)
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13
3.3
Risks
and
Benefits
to
Subjects
and
Society
(
Issue
c)
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19
3.3.1
The
Interrelationship
Between
Science
and
Ethics
and
the
Benefits
of
Research
Involving
Human
Subjects
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20
3.3.2
The
Impact
of
Remuneration
on
Benefits
to
Subjects
and
Society
.
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23
3.3.3
Distinctions
Between
Pesticides
and
Other
Environmental
Agents
.
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23
3.4
Application
to
Specific
Situations
(
Issue
d)
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24
3.4.1
Judgment
of
Current
and
Past
Studies
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24
3.4.2
Oral
Dosing
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27
3.5
Determining
Compliance
with
Ethical
Standards
(
Issue
e)
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28
3.5.1
Informed
Consent
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29
3.5.2
Voluntary
Participation
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30
3.5.3
Institutional
Review
Boards
(
IRB)
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30
4.
MAJOR
RECOMMENDATIONS
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32
APPENDIX
A
­
FACTORS
AFFECTING
STATISTICAL
POWER
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A­
1
APPENDIX
B
­
STATISTICAL
CONSIDERATIONS
IN
NO
OBSERVED
ADVERSE
EFFECTS
LEVEL
(
NOAEL)
STUDIES
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B­
1
APPENDIX
C
­
MINORITY
REPORT
FROM
DRS.
NEEDLEMAN
AND
REIGART
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C­
1
REFERENCES
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R­
1
xii
1
1.
EXECUTIVE
SUMMARY
The
Joint
Science
Advisory
Board/
Scientific
Advisory
Panel
(
SAB/
SAP)
Data
from
Testing
on
Human
Subjects
Subcommittee
(
DTHSS)
first
met
on
December
10­
11,
1998,
in
Arlington
VA,
to
consider
a
series
of
issues
raised
by
the
EPA
Office
of
Pesticides
Programs
concerning
the
acquisition
and
use
of
data
generated
by
testing
human
subjects.
The
Charge
was
that
the
Subcommittee
address
the
value
of
human
studies;
identify
factors
for
consideration
when
(
a)
determining
what
constitutes
an
appropriate
human
study
for
use
in
environmental
decision­
making;
(
b)
when
making
a
judgment
on
what
constitutes
an
ethically
appropriate
human
study;
and
(
c)
when
determining
if
a
study
is
appropriate
(
or
inappropriate)
for
use.
It
asked
also
that
the
Subcommittee
discuss
the
risks
and
benefits
of
research
on
humans
for
both
subjects
and
society,
and
the
issues
relevant
to
determining
if
studies
are
in
compliance
with
accepted
guidelines
(
the
complete
Charge
will
be
found
in
section
2.2
of
this
report).
After
generating
a
series
of
drafts,
the
Subcommittee
met
a
second
time
in
Arlington,
VA
on
November
30,
1999
to
discuss
various
issues
on
which
consensus
had
not
yet
been
reached.

Section
3
of
this
report
addresses
each
element
of
the
Charge,
and
provides
many
specific
recommendations
to
the
EPA.
The
Subcommittee
found,
however,
that
its
most
significant
findings
could
be
best
expressed
outside
the
constraints
of
specific
Charge
issues.
First,
there
were
a
series
of
basic
findings
on
which
the
Subcommittee
was
unanimous.
These
are:

a)
Any
policy
adopted
by
the
Agency
should
reflect
the
highest
standards
of
respect
for
human
subjects
and
should
prohibit
research
protocols
that
override
the
interests
of
subjects
in
order
to
obtain
useful
data.

b)
If
it
can
be
justified
at
all
to
expose
human
subjects
intentionally
to
toxic
substances,
the
threshold
of
justification
for
such
action
should
be
very
high.
We
recommend,
therefore,
that
pesticide
exposure
to
human
subjects
be
approached
with
the
greatest
degree
of
caution.
The
risks
of
allowing
such
experimental
exposures
of
humans
include
the
possible
involvement
of
less
than
fully
informed
participants,
unanticipated
health
consequences,
the
exposure
of
large
numbers
of
subjects,
and
skewed
use
in
developing
countries.

c)
Bad
science
is
always
unethical;
research
protocols
that
are
fundamentally
flawed,
such
as
those
with
sample
sizes
inadequate
to
support
reasonable
inferences
about
the
matter
in
question,
are
unjustifiable.

d)
If
the
use
of
human
subjects
in
pesticide
testing
can
be
justified,
that
justification
cannot
be
to
facilitate
the
interests
of
industry
or
of
agriculture,
but
only
to
better
safeguard
the
public
health.
2
e)
Any
policy
adopted
by
the
Agency
must
reflect
a
special
concern
for
the
interests
of
vulnerable
populations,
such
as
fetuses,
children,
adolescents,
pregnant
women,
the
elderly,
and
those
with
fragile
health
due
to
compromised
respiratory
function
or
other
reasons.

f)
Unintended
exposures
provide
valuable
opportunities
for
research;
it
is
an
error
not
to
take
full
advantage
of
such
opportunities
to
gain
major
information
through
careful
incident
follow­
up.

g)
In
considering
research
protocols,
it
is
not
enough
to
determine
a
risk/
benefit
ratio;
it
is
important
also
to
consider
the
distribution
of
risks
and
of
benefits,
and
to
ensure
that
risks
are
not
imposed
on
one
population
for
the
sake
of
benefits
to
be
enjoyed
by
another.
It
is
also
important
to
be
sensitive
to
the
difference
between
a
reversible
risk
and
one
that
may
be
irreversible,
such
as
possible
interference
with
normal
neurological
development.

Addressing
the
issue
of
intentionally
dosing
human
subjects
with
pesticides,
all
but
two
of
the
Subcommittee
Members
could
envision
particular
circumstances
under
which
such
dosing
of
humans
could
be
scientifically
and
ethically
acceptable.
Defining
these
circumstances
generically,
however,
proved
to
be
very
difficult
and
were
the
source
of
prolonged
discussion
at
the
public
meeting
and
multiple
"
fine­
tunning"
during
preparation
of
the
report.
The
following
summary
presents
the
most
significant
findings
of
the
majority
of
the
Subcommittee
with
regard
to
both
the
institutional
guarantees
that
would
be
required
and
the
guidelines
that
could
be
used
to
determine
whether
or
not
intentional
dosing
of
humans
in
a
particular
study
is
scientifically
and
ethically
acceptable.
These
findings
are:

a)
All
research
involving
humans
should
require
prior
review
by
an
Institutional
Review
Board.
Standards
for
the
functioning
and
compositions
of
these
Boards
are
incorporated
in
the
"
Common
Rule,"
the
"
shorthand"
name
for
the
human
research
subject
protection
requirements
embodied
in
CFR
40
Part
26.
The
Rule,
adopted
by
17
Federal
Agencies,
describes
and
defines
in
detail
the
requirements
for
obtaining
and
documenting
informed
consent
from
subjects.

b)
The
structure,
function,
and
activities
of
both
the
Agency's
IRBs
and
external
IRBs
of
entities
submitting
data
should
be
under
active
and
aggressive
scrutiny
by
EPA,
with
adequate
staff
and
financial
resources
provided
to
carry
out
this
mission.
EPA
should
establish
an
internal
ethics
review
organization
to
perform
this
function,
staffed
by
fulltime
individuals
whose
duties
address
exclusively
compliance
oversight.
The
review
organization
should
also
provide
an
institutional
focus
for
continuous
close
liaison
on
ethical
matters
with
other
federal
agencies.
3
c)
The
intentional
administration
of
pesticides
to
human
subjects
testing
is
acceptable,
subject
to
limitations
ranging
from
"
rigorous"
to
"
severe."
Those
supporting
such
testing
feel
that
the
information
sought
must
not
be
available
via
other
sources
(
e.
g.,
animal
studies
and
models
or
study
of
incidental
exposures),
and
the
information
expected
to
be
gained
must
promise
reasonable
health
benefits
to
the
individual
or
society
at
large.
Studies
should
be
appropriately
designed
to
address
the
stated
objective,
and
have
sufficient
statistical
power
to
provide
an
unambiguous
answer
to
the
question
under
investigation.
In
addition,
some
ongoing
monitoring
of
the
subjects
involved
in
such
studies
is
essential
to
insure
that
they
do
not
subsequently
become
ill
or
suffer
other
adverse
effects
d)
In
no
case
should
developing
humans
(
i.
e.,
the
fetus,
infant,
young
children,
or
adolescents)
be
exposed
to
neurotoxic
chemicals.
There
are
currently
too
many
unknown
dangers
to
justify
such
studies,
even
under
the
most
extraordinary
circumstances.

e)
The
EPA
should
take
whatever
administrative
action
is
necessary
to
extend
the
protections
of
40
CFR
Part
26
to
all
human
research
activities
whose
results
will
be
submitted
to
the
Agency.

f)
With
regard
to
data
derived
prior
to
enactment
of
Public
Law
92­
516
(
amendments
to
the
FIFRA),
the
Subcommittee
agreed
that
the
fact
that
research
was
done
unethically
does
not
alone
require
rejection
of
the
results
of
that
research.

g)
The
Subcommittee
identified
certain
situations
in
which
such
testing
would
or
would
not
be
appropriate:

1)
It
would
not
be
appropriate
to
conduct
such
testing
when
adequate
human
data
are
already
available.

2)
Human
studies
would
not
be
appropriate
for
pesticides
in
use
today
when
data
of
equal
quality
can
be
obtained
from
field
exposure
studies.

3)
Subject
to
the
other
limitations
discussed
in
this
report,
human
studies
could
be
appropriate
when
there
are
significant
data
gaps
and
such
studies
would
provide
a
more
accurate
risk
assessment.

4)
Subject
to
the
other
limitations
discussed
in
this
report,
human
studies
could
be
appropriate
for
pesticides,
which
are
not
yet
on
the
market,
i.
e.
new
pesticides.
4
5)
Given
the
significance
of
statistical
considerations
in
regard
to
human
study
design,
the
Agency
ought
to
organize
a
workshop
to
specifically
deal
with
this
issue.
5
2.
INTRODUCTION
2.1
Background
A
Joint
Subcommittee
of
the
Science
Advisory
Board
(
SAB)
and
the
Federal
Insecticide,
Fungicide
and
Rodenticide
Act
(
FIFRA)
Scientific
Advisory
Panel
(
SAP)
convened
in
a
public
meeting
on
December
10­
11,
1998.
The
purpose
of
the
meeting
was
to
provide
advice
and
comment
to
the
Environmental
Protection
Agency
(
EPA)
on
issues
related
to
data
derived
from
testing
on
human
subjects,
particularly
the
use
of
human
data
for
making
pesticide
registration
decisions.
Both
scientific
and
ethical
questions
have
been
raised
about
the
data
to
include
the
manner
in
which
they
were
developed
and
how
or
whether
these
data
should
be
used
in
the
decision
making
process.
A
draft
report
was
generated
based
on
the
presentations
and
discussions
at
this
meeting.
However,
a
significant
subset
of
the
Subcommittee
remained
concerned
about
the
content
of
the
report.
Therefore,
a
second
meeting
of
the
SAB/
SAP
Joint
Subcommittee
was
convened
on
November
30,
1999
to
permit
further
deliberations
for
the
purpose
of
resolving
and
bringing
to
closure
differences
of
opinion
within
the
Committee.

The
Office
of
Pesticide
Programs
has
received
a
growing
number
of
unsolicited
reports
of
research
with
humans
that
include
systemic
toxicity
studies
to
establish
a
human
No
Observable
Adverse
Effect
Level
(
NOAEL).
A
NOAEL
study
is
controversial
in
humans,
since
dosing
may
include
a
level
where
an
adverse
effect
occurs.
Therefore,
subjects
who
participate
in
these
studies
will
experience
adverse
effects
with
no
known
benefit
to
them
(
see
section
on
separation
of
risk
and
benefit).
Moreover,
the
exposure
levels
established
by
a
NOAEL
study
may
pertain
only
to
those
endpoints
measured
and
the
characteristics
of
the
subjects
who
participated.
Thus,
the
applicability
of
such
studies
will
be
constrained
by
these
limitations.
EPA
does
not
require
human
studies
to
establish
NOAELs
and
has
never
established
guidelines
for
the
conduct
of
such
studies
in
humans.
Since
July,
1998,
EPA
has
not
relied
on
the
submitted
human
NOAEL
pesticide
studies
to
support
decisions
under
the
Food
Quality
Protection
Act
(
FQPA).

The
FQPA
requires
EPA
to
reassess
all
food
residue
tolerances,
so
that
by
2006
over
9,000
current
pesticide
residue
tolerances
must
be
reassessed.
A
"
tolerance"
is
a
regulation
defining
the
allowable
amount
of
pesticide
in
or
on
a
food.
The
FQPA
requires
consideration
of
the
cumulative
risks
of
all
pesticides
with
a
common
mechanism
of
action.
This
is
in
contrast
to
the
previous
practice
of
assessing
exposure
to
one
pesticide
at
a
time.
An
additional
tenfold
safety
factor
must
be
included
by
EPA
in
risk
assessments
to
increase
protection
for
infants,
children,
and
adolescents,
unless
reliable
data
are
available
to
support
a
different
factor.
Finally,
the
FQPA
requires
that
EPA
address
the
"
worst
first"
pesticide.
That
is,
pesticides
regarded
as
the
riskiest,
such
as
the
organophosphates
and
carbamates,
are
being
reviewed
first.
Both
of
these
classes
are
cholinesterase
inhibitors
with
histories
of
human
testing.
The
first
third
of
these
tolerance
reassessment
decisions
were
completed
as
of
August,
1999
as
mandated
by
the
FQPA.
2The
Common
Rule
is
the
"
shorthand"
name
for
the
human
research
subject
protection
requirements
embodied
in
CFR
40
Part
26.
The
Rule,
adopted
by
17
Federal
Agencies,
describes
and
defines
in
detail
the
requirements
for
obtaining
and
documenting
informed
consent
from
subjects.
It
also
addresses
the
requirements
for,
the
functions
of,
and
the
composition
of,
Institutional
Review
Boards
(
IRB).
The
Rule
also
incorporates
procedures
for
prompt
reporting
of
any
unanticipated
adverse
events.

6
Prior
to
registration,
a
pesticide
must
undergo
many
tests
in
animals
to
evaluate
toxicity
and
to
extrapolate
these
animal
study
results
to
judge
the
potential
toxicity
for
humans.
These
study
requirements,
as
outlined
in
40
CFR
Ch
1
158­
202
(
e)
Hazard
to
humans
and
domestic
animals,
call
for
data
derived
from
a
variety
of
acute
studies
and
from
subchronic
and
chronic
toxicity
tests.
Exposure
data
are
also
required
by
40
CFR
Ch
1
258­
202
(
d)
Environmental
fate
and
include
general
studies
involving
the
fate
of
chosen
agents,
as
well
as
studies
of
degradation,
metabolism,
mobility,
dissipation,
and
accumulation.
A
reference
dose
(
RfD)
for
a
pesticide,
which
is
considered
the
"
safe"
daily
dose,
is
then
calculated
by
dividing
the
NOAEL
derived
usually
from
the
most
sensitive
study
in
the
most
sensitive
species
by
applying
a
series
of
uncertainty/
safety
factors.
If,
as
in
most
cases,
the
study
is
an
animal
study,
then
a
tenfold
uncertainty
factor
is
applied
to
accommodate
variability
between
animals
and
humans.
A
second
tenfold
factor
is
applied
to
account
for
variability
within
humans,
and
finally
the
FQPA
requires
consideration
of
an
additional
tenfold
safety
factor
to
protect
children
and
adolescents.
If,
however,
human
data
are
available,
the
interspecies
factor
of
ten
can
be
dropped.
Furthermore,
when
human
data
have
been
available
and
used
it
has
generally
raised
the
"
safe
dose."
A
higher
"
safe
dose"
allows
greater
use
of
a
pesticide.
Thus,
the
FQPA
may
have
inadvertently
created
an
incentive
to
test
pesticides
in
humans.
In
fact,
since
passage
of
the
FQPA,
the
Office
of
Pesticide
Programs
has
received
14
human
NOAEL
studies,
which
represents
a
significant
increase
in
the
submission
of
such
data
from
the
previous
ten
years.

For
many
years,
EPA
has
performed,
supported
and
made
use
of
human
studies
on
various
agents
of
environmental
concern,
including
pesticides,
in
compliance
with
the
Common
Rule2.
For
example,
EPA
has
required
studies
to
determine
exposure
levels
among
pesticide
applicators,
mixers,
and
loaders
of
pesticides
as
well
as
field
workers
and
others
re­
entering
pesticide
treated
areas.
EPA's
requirements
for
exposure
data
are
documented
in
Subdivisions
U
and
K
of
its
Pesticide
Assessment
Guidelines
of
1984.
However,
with
the
increased
submission
of
human
experimental
studies
that
involve
intentional
pesticide
exposures,
new
concerns
are
raised
regarding
EPA
policy
for
evaluating
the
science
and
ethics
of
these
studies.
Therefore,
EPA
convened
the
Joint
Subcommittee
of
the
SAB/
SAP
for
the
purpose
of
gathering
advice
to
aid
in
establishing
such
a
policy.

Through
the
establishment
of
"
test
guidelines,"
EPA
has
the
authority
to
specify
the
tests
required
and
the
manner
in
which
these
tests
are
performed.
These
guidelines
are
established
in
collaboration
with
other
regulatory
agencies,
both
in
the
U.
S.
and
abroad,
and
are
subjected
to
rigorous
peer
review.
EPA
wants
to
develop
a
policy
that
applies
protections,
such
as
those
in
the
Common
Rule,
consistently
to
all
human
research
considered
or
supported
by
the
Agency.
This
policy
must
be
7
subjected
to
peer
review
and
public
comment.
This
policy
should
address
the
wide
range
of
human
research
to
include:
a)
incident
follow­
up
and
epidemiologic
studies
of
humans
performing
usual
activities;
b)
human
experimental
studies
of
intentional
exposure
such
as
patch
tests
for
irritancy
or
sensitization,
studies
of
pharmacodynamics
or
metabolism,
and
testing
to
establish
a
NOAEL.
When
the
criteria
for
acceptability
of
these
two
classes
of
studies
vary,
EPA
is
requesting
that
the
distinctions
be
specified.
Moreover,
EPA
is
requesting
guidance
in
applying
contemporary
scientific
and
ethical
standards
to
older
data
or
to
studies
from
other
countries.

In
its
initial
deliberations,
the
Joint
Subcommittee
reached
ready
agreement
on
several
basic
and
preliminary
points.
These
include:

a)
Any
policy
adopted
by
the
Agency
should
reflect
the
highest
standards
of
respect
for
human
subjects
and
should
prohibit
research
protocols
that
override
the
interests
of
subjects
in
order
to
obtain
useful
data.

b)
If
it
can
be
justified
at
all
to
expose
human
subjects
intentionally
to
toxic
substances,
the
threshold
of
justification
for
such
action
should
be
very
high.

c)
Bad
science
is
always
unethical;
research
protocols
that
are
fundamentally
flawed,
such
as
those
with
sample
sizes
inadequate
to
support
reasonable
inferences
about
the
matter
in
question,
are
unjustifiable.

d)
If
the
use
of
human
subjects
in
pesticide
testing
can
be
justified,
that
justification
cannot
be
to
facilitate
the
interests
of
industry
or
of
agriculture,
but
only
to
better
safeguard
the
public
health.

e)
Any
policy
adopted
by
the
Agency
must
reflect
a
special
concern
for
the
interests
of
vulnerable
populations,
such
as
fetuses,
children,
adolescents,
pregnant
women,
the
elderly,
and
those
with
fragile
health
due
to
compromised
respiratory
function
or
other
reasons.

f)
Unintended
exposures
provide
valuable
opportunities
for
research;
it
is
an
error
not
to
take
full
advantage
of
such
opportunities
to
gain
major
information
through
careful
incident
follow­
up.

g)
In
considering
research
protocols,
it
is
not
enough
to
determine
a
risk/
benefit
ratio;
it
is
important
also
to
consider
the
distribution
of
risks
and
of
benefits,
and
to
ensure
that
risks
are
not
imposed
on
one
population
for
the
sake
of
benefits
to
be
enjoyed
by
another.
It
is
also
important
to
be
sensitive
to
the
difference
between
a
reversible
risk
and
one
that
may
be
irreversible,
such
as
possible
interference
with
normal
neurological
development.
3
Two
Members
suggested
revisions
to
the
Charge
to
clarify
the
general
language
and
to
eliminate
wording
which
could
be
interpreted
as
advocating
exposing
a
human
subject
to
damage
if
the
potential
societal
benefits
were
great
enough.
The
Charge
conveys
the
questions
asked
by
the
Agency,
and
is
the
starting
point
and
framework
for
the
Public
Meeting
and
subsequent
report.
In
order
to
maintain
the
historical
record
and
process,
the
Charge
is
not
changed
once
a
meeting
is
completed.

8
Having
agreed
to
these
points
as
providing
the
underlying
values
that
should
inform
the
development
of
actual
policy
recommendations,
the
Joint
Subcommittee
then
faced
the
challenge
of
providing
greater
operational
clarity
regarding
the
boundaries
of
what
should
and
what
should
not
be
allowed.
A
second
meeting
on
November
30,
1999
­­
and
a
subsequent
process
of
exchanging
views
on
a
developing
draft
of
this
report
­­
led
to
the
conclusions
and
recommendations
contained
herein.

2.2
Charge
In
pursuit
of
these
objectives,
the
Joint
Subcommittee
was
charged
as
follows:
3
a)
The
Value
of
Human
Studies
­
Human
studies
provide
a
special
type
of
information
that
may
contribute
to
the
decision­
making
process.
The
Agency
seeks
advice
on
the
role
that
such
data
can
play
in
evaluating
a
toxicological
data
base
for
purposes
of
regulatory
decision­
making.
Specifically,
what
are
the
general
arguments
for
the
proper
role
of
human
studies
in
supplementing
animal
studies
in
making
regulatory
decisions
about
various
environmental
agents;
e.
g.,
water
pollutants,
air
emissions,
and
pesticides?

b)
Factors
for
Consideration
­
The
Agency
is
confronted
with
the
question
of
how
to
determine
what
constitutes
an
appropriate
human
study
for
use
in
environmental
decision­
making.
There
are
similarities
and
differences
between
the
use
of
such
studies
in
reaching
decisions
in
other
areas;
e.
g.,
drug
licensing.
In
all
cases,
the
Agency
recognizes
that
the
scientific
benefits
must
at
least
be
commensurate
with
the
risks
involved.

1)
What
factors
are
relevant
to
consider
when
reaching
a
judgment
on
what
constitutes
an
ethically
appropriate
human
study?

2)
How
can
these
factors
be
used
to
make
decisions
in
such
cases?
Please
give
some
examples.

3)
In
using
these
factors,
are
there
"
benchmarks"
that
emerge
that
would
clearly
make
a
study
appropriate
(
or
inappropriate)
for
use?
Please
give
some
examples.
9
c)
The
Risks
and
Benefits
to
Subjects
and
Society
­
The
Agency
is
concerned
that
the
best
scientific
information
be
brought
to
bear
in
making
its
decisions.
At
the
same
time,
the
Agency
is
concerned
that
the
studies
they
require/
rely
on
to
make
those
decisions
should
meet
rigorous
ethical
standards.
Specifically,
the
risks
to
the
study
subjects
should
be
outweighed
by
the
benefits
for
them
personally
or
for
society
as
a
whole.

1)
What
are
the
benefits
to
subjects
and
to
society
from
human
participation
in
research
studies;
e.
g.,
those
supporting
pesticide
registration?

2)
What
is
the
impact
of
remuneration
on
this
question
of
benefits
to
subjects
and
society?

3)
Are
there
differences
or
distinctions
that
should
be
made
for
studies
involving
pesticides
versus
those
involving
other
environmental
chemicals?

d)
Application
to
specific
situations
­
The
Agency
must
make
judgments
on
a
wide
variety
of
studies
involving
humans.
Such
studies
include
controlled
ingestion
(
as
well
as
exposure
by
other
routes)
of
test
compounds
by
test
subjects,
accident
reports,
and
monitoring
of
exposure
during
routine
activities.
It
would
be
helpful
to
have
advice
on
how
the
guiding
principles
on
human
subject
research
and
testing
(
i.
e.,
the
Common
Rule
and
Declaration
of
Helsinki)
might
be
applied
across
this
broad
range
of
studies,
particularly
as
they
might
apply
in
the
case
of
studies
submitted
in
support
of
a
pesticide
registration:

1)
How
can/
should
this
guidance
be
applied
to
(
i)
Studies
conducted
in
the
past,
prior
to
the
adoption
of
the
Common
Rule
(
1991),
but
which
may
(
or
may
not)
have
adhered
to
another
ethical
standard
of
another
day?

(
ii)
Studies
gathered
from
the
open
literature
for
use
by
the
Agency?

2)
Is
it
ethical
to
engage
in
the
oral
dosing
of
human
subjects
with
environmental
toxicants
or
infectious
agents
of
interest
(
e.
g.,
cryptosporidium
in
drinking
water
or
organophosphates
(
OPs))
in
order
to
establish
a
No
Observed
Adverse
Effects
Level
(
NOAEL)?

e)
Compliance
­
Even
if
the
Agency
has
appropriate
ethical
standards
in
place,
there
is
the
question
of
determining
compliance
with
those
standards.
How
can
the
Agency
10
determine
whether
and
to
what
extent
its
ethical
standards
have
been
met
in
a
particular
test
with
respect
to
the
following
aspects:

1)
Informed
consent
2)
Voluntary
participation
3)
Institutional
Review
Board
(
IRB)
approval
11
3.
DETAILED
FINDINGS
3.1
The
Value
of
Human
Studies
(
Issue
a)

Human
studies
provide
a
special
type
of
information
that
may
contribute
to
the
decision­
making
process.
Specifically,
this
element
of
the
Charge
asked
the
Subcommittee
to
address
and
enumerate
the
general
arguments
for
the
proper
role
of
human
studies
in
supplementing
animal
studies
in
making
regulatory
decisions,
particularly
concerning
various
environmental
agents:
e.
g.,
water
pollutants,
air
emissions,
and
pesticides.

3.1.1
Information
Available
from
Studies
with
Human
Volunteers
Contemporary
human
research
in
toxicology
proceeds
from
the
assumption
that,
in
most
situations,
we
already
have
a
considerable
amount
of
information
about
the
toxic
properties
of
a
given
agent
(
derived
primarily
from
animal
research
and
fortuitous
epidemiological
studies)
before
we
deliberately
expose
human
subjects.
However,
with
new
pesticides
(
prior
to
registration)
there
are
no
epidemiological
or
exposure
data
available
to
provide
a
context
for
prediction
or
extrapolation.
Both
researchers
and
regulators
support
the
use
of
epidemiological
and
exposure
data
as
important
to
the
evaluation
of
potential
environmental
risks.
A
majority
of
the
Subcommittee
supported
allowing
human
clinical
trials
with
pesticides,
but
called
for
cautious
approaches
(
i.
e.,
that
exposures
must
be
done
only
under
the
strict
ethical
and
safety
guidelines
discussed
below);
several
other
Members
called
for
severe
restriction
on,
or
outright
prohibition
of,
such
research,
particularly
when
neurotoxicants
were
involved.
One
additional
caveat
concerning
such
intentional
exposure
is
important
­­
the
Subcommittee,
in
general,
would
not
support
human
experimentation
primarily
to
determine
a
No
Observed
Adverse
Effects
Level
(
NOAEL).
Although
a
No
Observed
Effects
Level
(
NOEL)
or
NOAEL
may
be
defined
in
the
absence
of
a
documented
toxicological
response
(
in
which
case
it
does
not
have
strong
scientific
standing
or
support),
such
data
are
of
value
in
the
clinical
and
regulatory
arena
for
setting
exposure
limits,
etc.
The
likelihood
of
mechanistic
insights
improves
with
the
inclusion
of
dosage
level
inducing
some
discernible
sign
of
toxicity.
Generating
such
data
pose
ethical
concerns,
however,
as
discussed
below
in
section
3.1.2.

The
Subcommittee
believes
that
pharmaceutical
industry
practices
offer
useful
models
for
human
pesticides
research.
When
a
new
drug
is
released,
the
manufacturer
performs
post­
marketing
surveillance,
mainly
to
gather
information
about
adverse
effects.
Similar,
properly
designed
observational
studies
of
humans
accidentally
or
occupationally
exposed
to
pesticides
should
be
encouraged
over
intentional
exposure
studies
with
paid
and
un­
paid
volunteers.
These
observational
studies
can
address
the
nature
and
incidence
of
adverse
effects
in
a
much
more
diverse
group
than
that
represented
by
the
experimental
volunteers
and,
as
such,
should
have
greater
value
for
risk
assessment.
12
However,
such
studies
lose
some
degree
of
control
over
exposures
and
timing
of
observation
that
could
make
them
very
difficult
to
implement.

Perhaps
the
greatest
potential
value
to
be
derived
from
experimental
studies
in
paid
and
un­
paid
volunteers
is
the
opportunity
to
place
the
results
into
a
structured
hierarchical
information
base
incorporating
and
integrating
both
animal
experiments
and
human
research
(
particularly
addressing
indices
of
neurobehavioral
function
in
the
case
of
insecticides)
addressing
short­
term
exposures.

Such
a
structured
information
system
would
provide
a
clearer
purpose
for
human
data.
It
would
help
overcome
several
of
the
ethical
issues
inherent
in
experiments
with
paid
and
un­
paid
volunteers
by
providing
better
insights
as
to
"
safe"
levels"
and
expected
reactions.
Perhaps
most
crucial,
within
such
a
decision
system,
human
experimental
data
would
serve
as
a
valuable
transition
to
further
research
on
both
exposure
assessment
and
toxic
mechanisms.
In
such
a
role,
human
experiments
would
pose
fewer
of
the
ethical
quandaries
that
arise
when
they
are
used
simply
to
establish
a
NOAEL
that
lacks
cogent
scientific
value
and
whose
purpose
can
be
interpreted
as
simply
an
argument
for
higher
permissible
exposure
levels.
Strategically
designed
studies
with
focused
efforts
and
clear
decision
systems
in
place
to
acquire
information
can
be
defensible
both
scientifically
and
ethically.

3.1.2
Limitations
of
Clinical
Studies
Controlled
experiments
with
human
paid
and
un­
paid
volunteers
are
framed
to
answer
a
limited
range
of
questions
about
the
risk
potential
of
a
substance.
To
conform
to
accepted
ethical
standards,
they
are
typically
confined
to
low
or
moderate
doses
of
limited
duration
and
constructed
as
carefully
as
possible
to
avoid
producing
a
serious
effect,
either
acute
or
long­
term.
Ethical
guidelines
take
account
of
both
the
usefulness
and
shortcomings
of
such
studies,
and
their
applicability
to
questions
about
other
agents
and
other
populations.
There
are
several
factors,
discussed
below,
which
these
guidelines
must
take
into
account.

First,
paid
and
un­
paid
volunteers
generally
are
recruited
from
a
healthy
adult
population
(
although
participation
by
pregnant
women
is
not
precluded
by
current
federal
policy,
we
believe
that
they
should
be
excluded
from
clinical
studies
with
pesticides,
as
should
all
other
sensitive
subpopulations
such
as
the
elderly,
those
with
already
compromised
health,
children,
and
adolescents).
Like
the
"
Healthy
Worker
Effect"
recognized
by
epidemiologists,
such
a
selective
process
limits
the
generality
of
the
findings.
In
addition
to
the
"
healthy
worker
effect,"
findings
may
be
affected
by
the
fact
that
some
groups
in
society
are
less
likely
to
volunteer.

Second,
although
volunteer
experiments
typically
involve
brief
exposures,
many
real
world
questions
about
safety
involve
chronic
exposures.
This
is
particularly
relevant
with
pesticide
exposures.
In
one
case
from
the
insecticide
literature,
investigators
studying
a
sample
of
farmers
exposed
while
13
treating
sheep
with
organophosphates
(
OPs)
reported
that
the
chronic
effects
of
exposure,
primarily
neurobehavioral
in
character,
are
not
predicted
by
sensitivity
to
any
acute
warning
signs
(
Stevens
et
al.,
1996).
Although
this
difference
in
exposure
patterns
can
be
a
complicating
factor
and
is
certainly
a
limitation,
it
can
often
be
addressed
by
careful
experimental
design,
as
has
been
demonstrated
in
human
studies
of
ozone
and
carbon
monoxide,
which
also
had
to
deal
with
the
issue
of
brief
versus
chronic
exposures.
One
Member
disagreed,
noting
that
chronic
effects,
such
as
the
neurobehavioral
changes
seen
for
the
OP's,
would
be
very
difficult
,
possibly
impossible,
to
detect
in
acute
studies
regardless
of
the
design.

3.1.3
Limitations
on
Establishing
NOELs
and
NOAELs
with
Human
Testing
Given
the
above,
we
must
recognize
that
the
ability
of
short­
term
human
experiments
to
provide
a
scientifically
meaningful
NOEL
or
NOAEL
is
circumscribed,
as
detailed
below:

Although
establishment
of
a
NOEL,
NOAEL,
or
Lowest
Observed
Adverse
Effects
Level
(
LOAEL)
can
provide
data
of
value
in
the
clinical
and
regulatory
arena,
there
are
also
ethical
considerations
about
the
research
needed
to
establish
them.
The
benefits
of
obtaining
a
LOAEL
are
discussed
above.
However,
generating
a
LOAEL
requires
a
level
of
exposure
inducing
some
identifiable
effect
or
symptom.
To
obtain
such
data
raises
a
particular
ethical
problem,
because
it
will
require
human
volunteers
to
experience
some
toxicity­
induced
symptoms
if
the
dosing
levels
approach
critical
thresholds,
with
no
prospect
of
any
direct
therapeutic
effect.
This
is
at
variance
with
most
biomedical
research
where
exposure
to
a
known
risk
(
e.
g.,
a
new
chemotherapy
agent)
is
balanced
against
the
potential
health
benefits.
In
addition,
research
at
the
National
Cancer
Institute
(
Mantel
and
Bryan,
1961),
and
later
at
the
National
Center
for
Toxicological
Research
(
Gaylor,
1992)
showed
that
even
NOELs,
which
are
statistically
derived,
actually
correspond
to
some
finite
incidence
of
adverse
effects.
That
is,
for
both
paid
and
un­
paid
volunteers,
research
to
identify
a
NOEL
may
not
be
free
of
risk
Testing
insecticides
presents
unique
challenges
because
their
adverse
effects
are
often
neurobehavioral
in
character.
If,
as
some
reports
suggest
(
Steenland
et
al.,
1994),
such
effects
are
more
sensitive
than
other
measures
of
toxicity,
the
use
of
these
neurobehavioral
measures
might
generate
LOAELs
at
lower
dose
levels.

In
addition,
short­
term
volunteer
experiments
have
yet
to
mimic
the
most
common
exposure
pattern,
consisting
of
repeated,
intermittent,
acute
elevations
in
dose,
typically
to
the
combination
of
agents
seen
in
most
pesticide
formulations
rather
than
to
a
single
agent.
The
degree
to
which
intermittent
or
even
single
doses
of
insecticides
might
induce
central
nervous
system
sensitization
to
OP
insecticides
possessing
proconvulsant
properties
is
not
known.
Also,
the
scope
of
OP
interactions
with
certain
classes
of
proconvulsant
medications,
such
as
the
popular
selective
serotonin
re­
uptake
inhibitors,
is
unknown.
Volunteers
presumably
would
not
be
used
to
assay
such
a
possibility.
Whether
14
or
not
conventional
uncertainty
factors
(
UF)
account
for
the
effects
of
such
medications
should
be
further
investigated
in
animals
and
in
humans
exposed
occupationally
to
insecticides.

Additional
obstacles
arise
when
attempting
to
extrapolate
findings
to
children,
particularly
in
addressing
the
most
troublesome
question
in
human
research:
the
consequences
of
exposure
during
early
development.
Current
human
volunteer
studies
are
not
designed
to
yield
a
reference
dose
for
children,
but
rather
(
as
noted
before)
to
place
some
portion
of
the
animal
data
into
human
context.
The
biology
of
the
child
diverges
markedly
from
that
of
the
adult.
This
difference
is
probably
best
seen
in
the
central
nervous
system.
Before,
and
for
a
number
of
years
after
birth,
the
child's
nervous
system
develops
at
an
extremely
rapid
rate.
Nerve
cells
are
laid
down
and
migrate
to
their
final
destination;
connections
are
built;
synapses
are
formed;
and
neuron
populations
are
pruned.
Perturbations
to
the
nervous
system
at
this
time
may
produce
persistent
changes
in
brain
architecture.
The
particular
sensitivity
of
the
developing
organism
to
insult
has
been
shown
for
so
many
noxious
agents
that
it
has
achieved
the
status
of
a
general
principle.
Among
the
exemplars
are
the
effects
of
oxygen
on
the
premature
infant
eye
and
the
effects
of
prostaglandin
antagonists
on
closure
of
the
ductus
arteriosu.
These,
and
the
effects
of
lead,
mercury,
alcohol,
dilantin,
bilirubin,
and
cocaine
on
the
infant
brain
establish
this
principle
(
Needleman
and
Bellinger,
1994).
Dosing
healthy
adults
provides
extremely
limited
(
if
any)
insight
into
the
risks
for
the
developing
brain.

Such
a
distortion
of
the
response
profiles
may
not
be
fully
accounted
for
by
the
imposition
of
traditional
UF
when
results
are
extrapolated
to
the
general
population.
The
conventional
UF
of
10
for
inter­
individual
variation
dates
from
the
1950s,
and
is
not
an
instrument
devised
to
reflect
contemporary
molecular
toxicology.

The
magnitude
of
an
intraspecies
UF
based
on
rodents
also
has
limited
bearing
on
the
appropriate
UF
for
children.
Furthermore,
neurotoxic
insecticides
induce
many
effects
on
the
body
and
nervous
system.
Each
is
characterized
by
its
own
dose­
response
function.
Attempts
to
establish
a
NOAEL
on
the
basis
of
a
single
outcome,
such
as
peripheral
acetyl
cholinesterase
(
AChE)
levels,
may
mask
a
substantial
Type
II
error.
That
is
a
type
of
error
causing
the
null
hypothesis
to
be
improperly
accepted,
so
that
an
effect
which
is
actually
present
is
not
identified
(
e.
g.,
a
neurotoxic
effect
of
an
OP
that
occurs
at
a
lower
dose
level
than
would
cause
a
statistically
significant
change
in
a
measure
such
as
peripheral
AChE
levels).
For
example,
although
cholinesterase
inhibition
by
carbamates
is
rapidly
reversible,
the
symptoms
of
toxicity
may
linger,
so
that
cholinesterase
assays
in
this
instance
may
provide
an
erroneous
diagnosis.

Further
deterrents
to
extrapolation
from
volunteer
studies
to
children
are
posed
by
two
additional
factors
that
have
led
EPA
to
conduct
targeted
exposure
assays:

a)
Young
children
occupy
a
different
spatial
ecology
than
adults.
They
often
experience
elevated
exposures
simply
because
their
environment
lies
close
to
floor
level.
With
metallic
mercury,
for
example,
vapor
concentrations
at
floor
level
may
be
10­
20
times
15
higher
than
concentrations
at
an
adult's
waist
level.
Dust
stirred
up
by
activities
such
as
crawling
causes
increased
inhalation
of
lead
dust
and
pesticides
residues
by
children.

b)
As
a
result
of
the
spatial
niche
they
occupy,
young
children
have
a
propensity
(
as
a
function
of
their
close
proximity
to
the
floor
or
ground
and/
or
behavior
in
crawling)
to
either
pick
up
or
be
exposed
to
objects
or
substances
on
the
ground.
They
tend
to
explore
their
world
by
hand­
to­
mouth
sampling,
which
increases
their
exposures
considerably.
Such
behaviors
help
explain
why
children
living
adjacent
to
agricultural
sites
tend
to
experience
elevated
pesticide
exposures.
Adult
NOAELs,
obtained
under
highly
controlled
conditions,
have
to
be
modified
to
account
for
such
exposure
sources.
This
problem
is
recognized
by
the
FQPA
in
its
requirement
to
aggregate
total
exposure
from
all
sources,
which
may
diminish
the
usefulness
of
volunteer
data.

In
any
study
involving
potential
harm
to
the
study
participants,
whether
humans
or
animals,
there
is
an
ethical
necessity
to
be
certain
that
the
study
has
sufficient
statistical
power
and
is
appropriately
designed
to
address
the
objective
of
the
study.
Many
Institutional
Review
Boards
(
IRBs),
in
fact,
now
require
documentation
that
the
proposed
study
possesses
adequate
statistical
power.
This
is
a
multifaceted
issue
requiring
consideration
of
a
number
of
factors,
which
are
detailed
in
Appendix
A.

The
most
serious
problem
of
those
identified
above
is
that
of
generating
data
applicable
to
the
developing
child
(
or
fetus).
There
seems
little
probability
that
high
quality
data
relevant
to
children
can
be
derived
from
studies
on
adults
at
this
time,
or
in
the
foreseeable
future.
The
Subcommittee
rules
out
the
only
alternative,
the
testing
of
children
and
adolescents,
as
being
ethically
unacceptable.
There
are
too
many
unknown
dangers
to
justify
the
effort,
even
under
the
most
extraordinary
circumstances.

Despite
the
constraints,
uncertainties,
and
risks
noted
above,
experiments
with
human
paid
and
un­
paid
volunteers
can
still
provide
helpful
information.
With
radioactive
isotopes,
they
can
help
trace
the
distribution
pattern
of
a
chemical
and
its
persistence
in
certain
organs,
as
with
mercury.
They
can
help
determine
if
specific
subpopulations
are
predisposed
to
adverse
effects
from
acute
exposures,
as
with
the
response
of
asthmatics
to
air
pollutants.
They
can
help
determine
the
relationship
between
exposures
and
exposure
biomarkers,
as
with
the
correlation
between
specified
doses
of
organophosphate
insecticides
and
cholinesterase
levels
in
blood.
Volunteer
experiments
with
pesticides
can
be
useful
as
guides
to
additional
laboratory
research
with
animals
and
the
formulation
of
more
specific
animal
models.

3.2
Factors
for
Consideration
in
Identifying
Ethically
Appropriate
Human
Studies
(
Issue
b)

The
original
Charge
posed
three
specific
questions:
16
a)
What
factors
are
relevant
to
consider
when
reaching
a
judgment
on
what
constitutes
an
ethically
appropriate
study?

b)
How
can
these
factors
be
used
to
make
decisions
in
such
cases?

c)
In
using
these
factors,
are
there
benchmarks
that
emerge
that
would
clearly
make
a
study
appropriate
(
or
inappropriate)
for
use?

Because
these
questions
are
closely
intertwined,
the
Subcommittee
has
chosen
to
address
them
collectively,
focusing
on
the
following
factors.

Study
Design:
The
Subcommittee
unanimously
supports
the
principle
that
any
study
that
does
not
have
a
clearly
defined
hypothesis
and
proper
study
design
to
test
that
hypothesis
is
per
se
unethical.

The
EPA
relies
on
the
determination
of
a
no­
adverse­
effects
level
(
NOAEL)
and/
or
a
lowestobserved
adverse­
effects
level
(
LOAEL)
in
setting
reference
doses
for
toxicants.
This
procedure
raises
serious
concerns
about
the
ethical
use
of
human
data
in
the
evaluation
of
health
risks
of
environmental
hazards.
An
experiment
that
does
not
have
a
chance
of
achieving
its
goal,
in
this
case
estimating
the
effect
it
seeks,
is
per
se
unethical.

Considering
the
other
problems
associated
with
the
use
of
NOAEL/
LOAEL's
(
e.
g.
design
dependency,
not
an
estimated
value
but
the
result
of
a
test),
the
Subcommittee
does
not
believe
human
studies
should
be
used
to
directly
estimate
these
quantities.
However,
a
properly
designed
human
study
with
sufficient
sample
sizes
could
aid
in
understanding
differences
in
metabolism
and
help
to
guide
the
species
extrapolation.
Appendix
B
presents
a
detailed
discussion
of
how
sample
size
affects
the
ability
of
a
study
to
detect
small
changes
and
effects.

The
Subcommittee
believes
that
issues
of
age,
gender,
and
ethnicity
should
receive
consideration
in
designing
studies
and
assessing
their
relevance
for
regulatory
purposes.
Though
the
Subcommittee
opposes
the
use
of
children
and
adolescents
as
experimental
subjects
particularly
in
relation
to
intentional
exposure
to
toxic
agents,
it
also
supports
the
concept
that
the
relevance
of
studies
to
assessing
the
risk
to
children
should
be
specifically
addressed.
Special
concerns
were
expressed
that
risks
to
developing
organ
systems
might
be
less
reversible
than
to
mature
systems
and
that
the
risk
to
children
is
unacceptable.
This
concern
also
would
affect
the
potential
ability
to
generalize
from
adult
subjects
to
children.
Likewise,
studies
performed
in
male
subjects
must
be
examined
to
determine
their
relevance
to
female
subjects.
Ethnic
variation
in
response
must
also
be
considered.

Overall
Considerations:
Existing
federal
standards,
noted
below,
can
serve
as
an
initial
guide
to
discussing
the
Charge
questions.
These
standards,
however,
basically
apply
to
drug
development
protocols.
In
this
model,
research
is
guided
by
the
premise
that
its
eventual
goal
is
either
to
benefit
the
subject
directly
or
to
benefit
patients
with
a
specific
disease.
Because
it
presumes
the
possibility
of
17
benefit,
it
weighs
the
risk
of
possible
harm
against
potential
benefit.
The
ultimate
aims
of
volunteer
testing
for
drug
development
and
for
pesticide
exposure
standards
diverge
because
of
the
benefit
component
of
the
risk­
benefit
equation.
That
is,
both
drug
and
pesticides
testing
have
financial
goals
and
both
use
healthy
paid
and
un­
paid
volunteers
who
do
not
stand
to
benefit
personally.
Thus,
the
risk
and
benefit
are
split.
They
diverge
in
that
drug
studies
can
be
easily
justified
because
they
benefit
others
with
a
disease
or
condition,
which
cannot
be
said
for
pesticides.
However,
protection
of
the
food
supply
has
a
societal
benefit
that
we
do
not
see
for
drugs.
In
the
course
of
marketing,
drugs
are
targeted
to
a
specific
population
in
need
and
their
effects
are
monitored
by
physicians.
However,
in
the
case
of
pesticides,
a
broader
population
is
potentially
exposed
and
not
monitored
for
health
effects.
This
situation
is
a
powerful
argument
for
the
conduct
of
controlled
exposure
studies
to
better
understand
the
effects
of
low
level
exposures.
Otherwise,
all
segments
of
the
populace
participate
in
an
exposure
study.

The
intention
variable:
A
core
question
for
ethical
review
of
a
proposed
or
submitted
study
is
intent.
Although
intent
might
be
argued
as
beyond
the
purview
of
an
ethical
review,
and
is
difficult
to
interpret,
the
Subcommittee
views
it
as
a
critical
issue,
in
part
because
it
helps
define
the
scientific
value
of
a
study.
For
that
reason,
it
maintains
that
the
intent
of
a
proposed
study
should
be
defined
clearly
at
the
outset.
It
agreed
that,
generally,
human
dosing
experiments
are
not
appropriate
if
the
primary
intent
of
the
study
is
to
determine
or
revise
a
NOEL
or
NOAEL
so
as
to
eliminate
the
interspecies
uncertainty
factor.
Studies
designed
to
advance
scientific
understanding,
for
example,
to
clarify
mechanistic
questions,
may
be
ethically
defensible.
A
cogent
model
for
such
experiments
would
be
the
studies
of
mercury
vapor
conducted
by
Cherian
et
al
(
1978).
These
investigators
had
subjects
inhale
trace
amounts
of
203Hg,
then
followed
the
time
course
of
its
distribution
in
various
tissues
and
fluids.
The
experiment
was
not
designed
to
provide
any
direct
information
about
toxicity.
The
use
of
observational
or
epidemiological
studies
to
test
hypotheses
that
are
appropriately
addressed
by
such
studies
often
present
only
very
limited
ethical
concern.
A
test
of
intent
for
ethical
"
acceptability"
resides
in
the
scientific
value
of
a
study,
i.
e.,
its
potential
to
provide
useful
information.
Although
rigid
rules
should
not
be
imposed,
a
weight­
of­
evidence
approach
should
prove
useful.
For
instance,
as
discussed
elsewhere
in
this
report,
does
the
study
have
sufficient
statistical
power?
Is
more
than
one
dose
included?
Are
sensitive
and
comprehensive
response
indices
described?
Do
they
extend
beyond
conventional
clinical
observations?
Could
the
results
be
extrapolated
to
the
population
at
large,
considering
its
age,
genetic,
gender,
and
ethnic
diversity?
The
enormous
breadth
of
such
variation,
which
contrasts
sharply
with
the
typical
volunteer
pool,
presents
difficult
problems
for
extrapolation,
as
discussed
elsewhere
in
the
Subcommittee
report.
Would
the
research
be
acceptable
in
a
recognized
peer­
reviewed
journal?

Standards
for
risk
review:
The
discussion
below
amplifies
the
Subcommittee's
application
of
existing
Federal
guidelines
for
human
subjects
research.
It
might
be
framed
as
a
set
of
questions
to
an
IRB:
18
a)
Have
risks
to
subjects
been
minimized?
­
IRB
reviews
must
devote
considerable
care
and
attention
to
items
such
as
medical
exams
(
including
histories)
to
determine
the
health
status
of
the
subjects,
identifying
medications
taken
by
the
subject
and
alcohol
use.
The
review
should
also
examine
the
doses
or
concentrations
to
which
subjects
will
be
exposed
and
determine
how
these
relate
to
our
existing
knowledge
of
the
agent's
effects.
In
addition,
there
should
be
consideration
of
the
possibility
that
subjects
may
have
been
previously
exposed
to
toxic
substances;
previous
exposure
could
both
jeopardize
the
subject's
well
being
and
distort
the
study's
findings.
The
review
must
also
examine
the
plans
for
dealing
with
any
unexpected
response
to
the
agent
administered.
The
IRB
needs
concrete
details,
and
should
assure
itself
that
these
have
been
provided
in
sufficient
depth.
19
b)
Are
risks
to
subjects
reasonable
in
relation
to
anticipated
benefits?
­

1)
Is
there
an
important
research
question
being
asked,
one
which
could
not
be
addressed
with
animal
data?
2)
Are
the
design
instruments
and
methods,
and
the
competence
of
the
researcher,
appropriate
to
answer
the
question?
3)
How
will
the
research
findings
be
used?
4)
Have
designs
that
could
pose
less
serious
ethical
issues
been
considered
(
and
if
rejected,
why)?
5)
Is
there
a
need
to
use
human
subjects?
6)
Have
stopping
rules
been
described?

Noting
other
issues
that
arise
when
one
considers
the
scientific
merits
of
an
experiment
may
help
to
illustrate
further
the
issues
raised
by
the
Charge.
There
may
be
a
difference
between
the
scientific
assessment
(
today)
of
a
study,
involving
the
evaluation
and
use
of
existing
data
(
e.
g.,
a
retrospective
review
of
previous
exposures,
where
consent
had
not
been
obtained),
and
prospective
studies
proposing
intentional
exposure
of
human
subjects
to
a
test
agent.
How
should
IRBs
judge
current
studies
using
different
and
more
rigorous
standards
than
applied
to
the
acceptance
of
studies
conducted
in
the
past
under
somewhat
different
ethical
guidelines.
How
should
they
evaluate
retrospective
studies,
consistent
with
40
CFR
26.119
(
the
"
Common
Rule)?

Should
IRBs
require
those
who
use
historical
data
to
specify
the
data's
origins,
methods,
and
limitations,
especially
where
concerns
about
the
validity
of
those
studies
exist?

c)
Is
the
selection
of
human
subjects
necessary
and
appropriate?
­
Does
the
question
asked
require
human
testing?
Before
undertaking
human
experiments,
one
should
carefully
decide
whether
the
information
one
plans
to
obtain
can
be
derived
from
animal
studies.
This
is
particularly
true
with
"
new"
unregistered
pesticides
because
human
exposure
information
will
not
be
available,
and
estimates
of
risks
to
humans
will
have
to
be
calculated
on
the
basis
of
animal
studies.
Even
if
the
estimates
from
animals
are
highly
uncertain,
calculations
of
these
values
are
critical
to
the
proper
design
of
the
human
investigation.
These
provide
target
estimates
for
the
measures
of
interest
and
valuable
guidance
as
to
what
might
be
expected
in
the
human
studies.

d)
Have
less
ethically
questionable
studies
been
considered?
­
Controlled
exposure
studies
in
humans
are
problematic
in
that
they
raise
ethical
questions.
In
some
cases,
epidemiological
studies
or
studies
of
exposed
populations
may
be
able
to
obtain/
provide
virtually
the
same
information,
or
at
only
a
modest
cost
in
the
significance
20
of
the
information.
However,
for
"
new"
pesticides,
epidemiological
information
will
not
be
available.

e)
Is
the
informed
consent
process
properly
designed,
with
the
opportunity
for
potential
subjects
to
think
through
the
relevant
issues,
including
possible
compensation
for
harm?

Related
issues:
Some
aspects
of
risk
assessment
that
bear
on
the
ethics
of
human
testing
were
not
addressed
by
the
charge
nor
are
they
properly
addressed
by
prevailing
Federal
guidelines.
They
are
pertinent
to
the
Subcommittee's
task,
however.

a)
Ethical
questions
pertaining
to
human
testing
range
beyond
conventional
risk
assessment
evaluations.
It
would
be
advisable
to
include
contemporary
risk
characterization
issues
such
as
individual
and
community
risk
perceptions
and
acceptability
(
Stern
and
Fineberg,
1996).
The
role
of
the
community
in
research
involving
human
subjects
is
now
generating
considerable
interest
in
the
clinical
trials
world.
In
response
to
community
concerns,
potential
subjects
may
be
invited
to
participate
in
the
design
of
studies;
or,
community
input
may
be
sought,
directly
or
indirectly,
about
the
use
of
research
data.
Also,
community
concerns
about
potential
benefit
and
harm
may
be
surveyed.
EPA
,
in
fact,
is
increasingly
attentive
to
this
broader
context
of
risk
characterization.
This
is
true
with
genetic
studies
to
determine
susceptibility,
but
it
is
also
true
as
we
begin
to
explore
the
connections
between
genetic
and
environmental
factors
in
the
etiology
of
human
disease.

The
Subcommittee
recognizes
that
such
an
expansion
of
ethical
dimensions
may
present
difficulties
arising
from
risk
perceptions
in
a
particular
community.
For
example,
the
public
historically
has
been
more
concerned
about
cancer
than
other
potential
risks,
and
judges
its
adverse
effects
to
exceed
those
associated
with
other
potential
risks.
Both
investigators
and
IRB
members
need
to
be
sensitive
to
public
perceptions,
however,
to
acknowledge
them
in
informed
consent
documents,
and
to
guard
against
the
intrusion
of
their
own
values
and
perceptions
into
their
evaluations.

b)
The
Common
Rule
has
a
specified
and
very
helpful
list
of
required
considerations
concerning
informed
consent.
Because
of
questions
raised
by
past
studies
on
pesticides,
the
Subcommittee
notes
that
a
useful
way
of
determining
whether
a
potential
subject
grasps
the
information
in
the
consent
form
is
to
administer
a
brief
multiplechoice
test
based
on
the
form's
content.
Such
a
test
provides
a
measure
of
how
well
the
subject
grasps
the
contents
of
the
consent
form.

c)
Other
issues
that
may
be
of
particular
relevance
to
both
environmental
agents
and
pesticide
testing
include:
21
1)
Although
subjects
should
have
the
undisputed
right
to
withdraw
from
a
study
at
any
time,
exercise
of
this
right
could
make
it
difficult
for
researchers
conducting
environmental
exposure
studies,
particularly
longitudinal,
epidemiological
studies,
to
complete
their
protocols.
This
right
must,
however,
be
described
unambiguously.

2)
Subjects
should
have
rights
to
compensation
if
they
are
injured
as
a
result
of
the
experiment.
Since
injury
may
only
become
evident
long
after
the
experiment,
such
compensation
issues
need
to
be
addressed
at
the
inception
of
the
study.
As
part
of
their
reviews
of
experimental
protocols,
IRBs
should
request
the
investigator's
plans
for
ascertaining
the
subjects'
health
status
for
some
period
after
the
end
of
the
experiment,
and
ensure
that
each
subject
is
given
clear
information
about
how
to
deal
with
problems
that
might
emerge
later.

3)
General
issues
related
to
privacy
rights
and
confidentiality
are
already
described
in
existing
regulations.
Additionally,
there
are
specific
concerns
about
the
use
of
confidential
information
obtained
from
a
subject's
participation
in
a
study.
For
example,
the
use
of
data
relating
to
susceptibility
to
certain
diseases
that
have
an
environmental
component
(
e.
g.,
paroxonase
levels)
may
place
individuals
at
risk
of
discrimination
(
health
care,
life
insurance,
employment).
These
issues
would
need
to
be
addressed
in
the
consent
process
and
protections
built
into
the
protocol.

4)
University­
based
research
has
been
displaced
in
many
instances
by
contract
organizations
dependent
on
relationships
with
industry
clients.
These
relationships
may
arouse
skepticism
about
the
assumption
that
the
experimenters
are
neutral
parties.
Moreover,
such
relationships
also
provoke
concerns
about
the
IRBs
appointed
to
review
study
protocols.
These
include
the
criteria
for
membership
on
an
IRB
(
inclusion
of
public
members,
advocacy
groups,
etc.);
criteria
for
approval
(
consensus
vs.
voting);
and
public
disclosure
of
reasons
for
decisions.

5)
When
the
results
of
volunteer
studies
are
submitted
for
publication
in
scientific
journals,
it
is
essential
that
the
sources
of
research
support
be
disclosed
unambiguously.
Several
prominent
medical
journals
have
encountered
possibly
deceptive
statements
about
such
support.

6)
Independent
review
is
especially
crucial,
but
an
increasing
number
of
private
IRBs
are
now
operated
by
commercial,
"
for
profit"
entities
­­
an
environment
that
may
pose
problems
when
attempting
to
conduct
a
truly
independent
review,
and
that
calls
for
close
scrutiny.
At
the
same
time,
it
should
be
22
recognized
that
the
number
of
privately
operated
IRBs
has
increased
because
of
the
financial
and
operational
efficiencies
they
offer.
In
addition
many
academic
institutions
may
lack
the
resources
to
conduct
the
appropriate
reviews
and
to
fulfill
administrative
requirements
imposed
by
the
federal
government
and
other
oversight
authorities.
Monetary
compensation
for
members
of
private
IRBs,
however,
should
be
described
in
any
submission
to
EPA.

In
view
of
the
complexity
and
interrelationships
of
the
manifold
questions
presented
by
volunteer
studies,
the
Subcommittee
agreed
that
no
specific
benchmark,
algorithm,
or
unambiguous
dividing
line
could
be
applied
universally
to
categorize
research
as
either
unethical
or
ethical.
Such
judgments
require
the
weighing
of
multiple
factors
in
two
categories:
technical
and
scientific
issues
(
e.
g.,
sample
size,
experimental
design,
and
the
nature
of
the
agent
under
study),
and
subject
welfare
issues
(
e.
g.,
provision
of
informed
consent,
lack
of
coercion
of
any
type,
and
compensation
for
any
harm
done
in
the
course
of
the
experiment).

Because
of
the
lack
of
fixed
landmarks,
except
perhaps
at
the
extremes,
the
Subcommittee
proposes
that
the
Agency
offer
guidance
in
the
form
of
examples.
One
extreme
at
the
innocuous
end
of
the
scale
might
be
exemplified
by
a
skin
irritation
study
with
glyphosphate
in
adult
males.
The
other
extreme
might
be
exemplified
by
a
study
designed
to
obtain
a
NOAEL
for
neurotoxicity
with
a
highly
potent
organophosphate.
The
territory
between
these
extremes
is
where
the
Agency
needs
to
provide
guidance
both
for
its
own
policies
and
for
parties
contemplating
the
submission
of
human
data
from
paid
and
un­
paid
volunteers.
Appropriate
questions
which
could
be
asked
include:

a)
Who
would
be
acceptable
volunteers?
Under
what
conditions,
if
any,
are
the
aged,
and
female
subjects
acceptable?

b)
What
is
the
hypothesis?
What
would
be
the
intent
of
the
study,
e.
g.,
kinetics,
determining
LOAELs,
etc?
Under
what
conditions
are
these
studies
appropriate/
acceptable?

c)
Given
the
intent,
how
would
reasonable
sample
sizes
be
determined?

d)
What
level
of
dosing
is
appropriate,
acceptable?
Are
there
conditions
under
which
dosing
to
measurable/
observed
toxicity
is
appropriate?

e)
If
dosing
can
be
administered
at
a
level
that
produces
toxicity,
what
organ
system
toxicities
are
acceptable?
Can
neurologic
toxicity
ever
be
accepted?
Can
or
should
biochemical
alterations
be
used
as
surrogates
for
clinical
toxicity?
Do
these
surrogates
allow/
promote
protection
of
subjects?
23
3.3
Risks
and
Benefits
to
Subjects
and
Society
(
Issue
c)

Issue
(
c)
of
the
Charge
posed
three
separate,
but
interrelated,
questions
concerning
both
the
risks
and
benefits
associated
with
human
experimentation.
Each
of
these
questions,
and
the
Subcommittee's
responses,
is
addressed
below.
24
3.3.1
The
Interrelationship
Between
Science
and
Ethics
and
the
Benefits
of
Research
Involving
Human
Subjects
Interrelationship
between
science
and
ethics:
The
design
and
conduct
of
research
involving
human
subjects
involves
two
types
of
considerations:
First,
research
must
have
scientific
merit
­­
it
must
ask
important
and
relevant
research
questions
that
have
not
already
been
adequately
answered,
and
must
do
so
based
on
a
rigorous
methodology
that
can
answer
the
research
questions.
Second,
for
research
to
be
ethically
acceptable,
it
must
be
based
on
a
set
of
ethical
considerations
that
provide
assurance
that
the
rights
and
interests
of
subjects
will
be
protected
and
that
valuable
and
important
research
will
be
conducted.

It
should
follow
that
there
is
an
interrelationship
between
science
and
ethics
­­
a
research
design
that
does
not
deal
with
a
novel,
important
and
relevant
question,
or
is
not
based
on
rigorous
scientific
methodology
(
or
both)
cannot
be
considered
good
from
either
a
scientific
or
an
ethical
perspective.
Indeed
it
has
been
said
that
good
science
is
a
prerequisite
for
good
ethics.
This
is
more
than
just
a
statement
of
intent
or
of
aspiration.
The
separation
of
science
and
ethics­
as
occurs
when
scientific
peer
review
precedes
the
evaluation
of
a
study
by
an
Institutional
Review
Board
(
IRB)
­­
may
be
procedurally
necessary,
but
it
is
a
separation
that
is
arbitrary
and
difficult
to
defend.

For
almost
all
scientific
considerations
in
the
design
and
conduct
of
a
study
there
are
ethical
counterparts,
and
vice
versa.
For
example,
the
scientific
requirement
that
a
study
is
well
defined,
asks
novel
questions,
or
can
obtain
measurable
outcomes
can
also
be
seen
through
an
ethics
lens:
is
the
study
necessary?
Is
the
research
question
important?
Are
the
needs
of
potential
subjects
and/
or
society
being
met?
Both
sets
of
considerations
relate
to
the
importance
of
the
research
question.
Similarly,
the
questions
one
would
ask
from
the
ethical
perspective
(
Is
the
study
feasible
as
designed?
Has
there
been
fairness
in
the
recruitment/
retention
of
subjects?
Are
appropriate
safety
procedures
in
place
to
minimize
potential
harm
to
subjects?)
are
relevant
to
the
scientific
requirements
that
a
study
be
well
designed,
that
the
study
architecture
is
appropriate
(
e.
g.,
a
case­
control
study,
and
randomized
trial),
that
methods
have
been
introduced
to
reduce
bias
by
investigators,
and
that
the
methods
of
monitoring
procedures
in
the
case
of
toxicity,
drop
out
by
subjects
or
discontinuation
are
appropriate.

Attention
to
the
interrelationship
between
science
and
ethics
in
research
involving
human
subjects
need
not
involve
simultaneously
assessing
both;
rather,
it
requires
only
an
appreciation
that
scientific
merit
and
ethical
acceptability
are
jointly
necessary
conditions
to
be
satisfied
prior
to
enrolling
human
beings
in
research.
Investigators,
IRBs,
and
regulatory
agencies
should
not
lose
sight
of
this
crucial
principle.

The
benefits
of
research
involving
human
subjects,
e.
g.
those
supporting
pesticide
registration:
The
question
of
benefits
to
human
subjects
needs
to
be
considered
as
part
of
the
assessment
of
risk
in
relation
to
potential
benefits
(
sometimes
referred
to
as
the
"
risk­
benefit
ratio)
posed
by
human
subject
research.
Human
research
subject
protection
policies
evolved
out
of
25
experiences
in
which
research
subjects
were
exploited,
such
as
in
the
Tuskegee
Syphilis
Study.
In
addition
to
the
outright
deception
it
involved,
the
Syphilis
Study
further
exploited
research
subjects
in
that
all
the
burdens
of
research
were
borne
by
the
subjects,
and
all
the
(
future)
benefits
of
the
research
were
realized
by
others.
This
splitting
apart
of
risks
and
benefits
is
not
necessarily
unethical,
but
raises
the
potential
for
exploitation
and
thus
argues
that
ethically
acceptable
levels
of
risk
ought
to
be
lower
when
there
are
no
offsetting
potential
benefits
to
subjects.
In
addition,
subjects
involved
in
such
studies
should
be
compensated
for
the
cost
of
caring
for
all
research­
derived
harms
and
injuries.
This
means
more
than
asking
the
researcher
for
a
plan,
but
for
the
assumption
of
the
duty
to
cover
any
research
related
health
care
a
subject
requires.

Research
in
which
risk
and
benefit
are
separated
in
this
way
was
historically
known
as
"
non­
therapeutic,"
and
is
now
referred
to
as
'
research
without
prospect
of
direct
medical
benefits
to
the
subject.'
It
is
therefore
important
to
enumerate
and
understand
the
potential
benefits
to
subjects
of
research
supporting
pesticide
registration,
since
identification
of
potential
benefits
to
the
subject,
if
any,
will
influence
assessments
of
the
ethically
acceptable
levels
of
risk
imposed
by
such
research.

This
section
examines
the
risks
and
potential
benefits
to
be
realized
by
subjects
in
research
that
supports
pesticide
registration.
Given
that
human
dosing
studies
using
pesticides
expose
research
subjects
to
risk
in
an
effort
to
gain
information
in
support
of
pesticide
registration,
it
is
important
to
identify
whatever
potential
benefits
might
accrue
to
subjects
as
part
of
making
an
appropriate
risk­
benefit
assessment.

a)
Research
with
potential
medical/
health
benefits
to
the
subject:
Some
research
in
support
of
pesticide
registration
may
have
direct
medical
benefits
to
research
subjects.
This
includes
studies
in
which
the
subjects
have
been
exposed
to
pesticides
for
purposes
other
than
research,
such
as
in
occupational
settings,
and
accidental
or
environmental
exposures.
The
potential
benefits
may
accrue
to
both
the
individual
subjects,
their
families,
co­
workers
and
the
groups
and
communities
to
which
they
belong.
Research
subjects
themselves
may
benefit
through
increased
health
monitoring,
safer
work
environment,
and
improved
protections
(
protective
clothing,
respirators,
etc.).
It
is,
however,
important
to
distinguish
between
direct
benefits
(
those
benefits
that
are
the
direct
result
of
the
intervention
itself)
and
indirect
benefits
(
those
that
arise
as
a
later
consequence
of
the
intervention.
As
noted
below,
many
of
the
potential
benefits
from
pesticide
testing
for
purposes
of
registration
may
be
of
the
latter
type.

In
addition
to
whatever
benefits
may
be
realized
by
subjects
themselves,
there
are
potential
benefits
to
those
with
close
relationships
to
the
subjects
that
must
also
be
taken
into
account.
The
family
of
research
subjects
may
benefit
in
cases
where
family
members
live
near
the
workplace
and
are
exposed
to
similar
hazards
as
the
individual
26
(
e.
g.,
farm
workers).
The
benefits
to
family
members
may
include
health
monitoring,
safer
living
conditions,
and
improved
protections.

b)
Research
with
potential
direct
medical
or
health
benefits
to
groups
to
which
subjects
belong,
but
not
to
the
subjects
themselves:
Some
research
offers
no
prospect
of
direct
medical
or
health
benefits
to
the
subjects
themselves,
but
may
benefit
groups
to
which
the
subjects
belong.
Potential
benefits
may
accrue
to
groups
that
may
be
at
increased
susceptibility
due
to
genetic
variation,
e.
g.,
an
ethnic
group
to
which
the
subject
belongs,
but
for
whom
the
research
will
not
have
a
personal
impact.
The
benefits
of
research
may
accrue
to
future
workers
in
similar
occupational
settings
to
the
subject,
e.
g.,
fellow
pesticide
workers/
loaders,
even
if
the
research
will
not
have
a
direct
impact
on
the
research
subject.
And
the
benefits
of
research
may
accrue
to
the
members
of
a
geographical
community
that
has
been
exposed,
and
whose
members
will
benefit
from
a
safer
environment
in
the
future,
even
if
the
research
will
not
have
a
direct
impact
on
the
research
subjects
themselves.

In
the
case
of
testing
of
pesticides,
particularly
those
used
in
human
food
production,
there
is
potential
for
the
volunteer
to
benefit,
as
a
member
of
the
general
population,
from
participating
in
such
a
study
because
of
that
person's
potential
for
being
exposed
to
the
pesticide
in
his/
her
food.
However,
in
the
case
of
pesticides,
a
broader
population
is
potentially
exposed
and
not
monitored
for
health
effects.
As
noted
earlier,
this
situation
is
a
powerful
argument
for
the
conduct
of
controlled
exposure
studies
to
better
understand
the
effects
of
low
level
exposures.
Otherwise,
the
populace
is
the
exposed
cohort.

c)
Research
with
potential
medical
or
health
benefit
only
to
the
population
at
large:
Some
research
offers
benefits
to
subjects
in
only
the
most
removed
sense,
through
benefits
to
the
population
at
large.
The
general
population
may
realize
benefit
from
increased
safety
information
and
a
safer
environment
due
to
the
information
yielded
by
human
testing
of
toxicants.
But
research
that
yields
benefits
to
the
population
at
the
expense
of
risk
to
the
subjects
of
research
is
ripe
for
exploitation,
and
may
arguably
be
inherently
exploitative.
In
this
vein,
the
Subcommittee
would
not
support
human
dosing
that
intended
bring
about
increased
allowable
residue
levels.
Moreover,
unlike
the
potential
benefits
described
above,
benefits
to
the
population
at
large
may
only
accrue
at
a
future
time.

Further,
the
economic
benefits
of
pesticide
registration
should
not
be
considered
in
the
risk­
benefit
ratio
of
pesticide
testing
on
humans,
any
more
than
the
economic
benefits
of
pharmaceutical
development
ought
to
be
considered
in
the
risk­
benefit
ratio
of
new
drug
testing.
Lastly,
payment
or
other
remuneration
for
participation
in
research
should
not
be
considered
as
a
benefit
of
research
to
be
weighed
in
offsetting
the
risk
posed.
27
As
discussed
below,
the
level
of
remuneration
should
never
be
so
great
as
to
encourage
overlooking
the
risk
imposed
by
the
research,
or
to
compensate
for
it.

Potential
benefits
are,
like
risk,
often
difficult
to
predict
with
accuracy,
especially
for
individuals.
28
3.3.2
The
Impact
of
Remuneration
on
Benefits
to
Subjects
and
Society
Element
(
c)(
2)
asked
the
Committee
to
identify
and
discuss
the
impact
of
remuneration
on
this
question
of
benefits
to
subjects
and
society.

Remuneration
for
volunteer
studies
arouses
debate
because
it
can
be
a
form
of
undue
inducement.
IRBs
confront
this
issue
repeatedly,
even
when
paid
and
un­
paid
volunteers
face
minimal
risks.
Many
IRBs
are
reluctant
to
permit
large
sums
to
be
offered
under
these
circumstances.
There
is
no
fixed
standard,
however,
and
prescribing
such
a
standard
for
remuneration
is
not
feasible,
given
the
varying
situations
in
which
subjects
are
recruited.
For
IRBs,
a
review
of
the
remuneration
to
be
offered
to
subjects
is
partly
subjective,
and
partly
governed
by
community
standards.
Similarly,
the
degree
to
which
remuneration
becomes
unethical
will
depend
upon
both
community
standards
and
individual
situations.
Local
IRBs
will
have
to
make
such
judgments,
perhaps
applying
various
decision
analysis
techniques
to
determine
non­
exploitive
levels
of
remuneration.

3.3.3
Distinctions
Between
Pesticides
and
Other
Environmental
Agents
The
third
element
of
issue
(
c)
asked
the
Subcommittee
to
consider
if
differences
or
distinctions
should
be
made
for
studies
involving
pesticides
versus
those
involving
other
environmental
chemicals.

This
discussion
focuses
on
the
use
of
intentional,
controlled,
human
exposures
to
gather
data
(
e.
g.,
pharmacokinetic
information)
on
the
agent(
s)
under
study.
Pesticides
do
not
stand
alone
as
environmental
chemicals
that
have
been
intentionally
administered
to
humans
to
determine
the
dose
at
which
health
effects
occur.
For
example,
an
extensive
literature
documents
controlled
inhalation
studies
in
which
humans
have
been
exposed
to
organic
solvents
from
minutes
to
hours,
under
sedentary
or
exercise
conditions,
at
varying
doses
during
which
uptake,
metabolism,
subjective
symptoms,
physical
symptoms,
neurologic
signs,
and
behavioral
performance
have
been
measured
(
Iregren,
1996).

It
is
important
to
understand
what
a
pesticide
is
and
how
it
compares
with
other
environmental
chemicals.
Chemically,
there
is
nothing
unique
about
a
pesticide;
what
makes
a
chemical/
compound
a
pesticide
is
its
use.
Pesticides
do
not
all
share
the
same
chemistry,
toxicity,
use,
mode
of
action,
or
measurable
health
effect.
Therefore,
it
is
not
accurate
to
discuss
pesticides
as
one
class
of
chemicals.
In
addition,
the
same
chemical
can
be
a
pesticide
in
one
case,
an
"
inert"
ingredient
for
a
different
pesticide
in
another
case,
and
even
a
food
additive
in
other
cases.
It
should
be
noted
however,
that
pesticides
are,
as
a
class,
applied
in
many
ways,
including
as
a
spray
by
planes
and
as
fogs
dispersed
at
ground
level.
Pesticides
not
only
cover
the
target
area,
but,
to
a
large
degree,
drift
from
it,
exposing
unintended
targets
such
as
individuals
and
wildlife.
Therefore,
pesticides
are,
in
this
sense,
unique.
Both
target
populations
and
non­
targeted
populations
may
receive
a
dose.
These
agents,
liberated
around
homes,
cities,
agricultural
fields,
etc.,
have
unique
relevance
when
both
target
and
non­
target
systems
are
involved
and
often
impacted.
29
As
for
any
study,
the
risks
must
be
weighed
against
the
possible
benefits.
If
it
was
relatively
clear
that
no
specific
benefits
would
accrue
for
the
individual
subject
exposed
to
pesticides
in
a
controlled
experiment,
the
motivation
to
participate
in
such
a
study
could
arise
purely
from
the
desire
to
benefit
humankind
(
although
in
a
coercive
environment
the
motivation
could
be
of
many
sorts
apart
from
altruism,
especially
in
a
context
of
implicit
coercion
(
e.
g.,
the
desire
to
avoid
reprisals
for
being
uncooperative
in
the
context
of
a
subject's
employment)).

Is
it
possible
to
conceptualize
what
can
be
learned
from
controlled
exposures
to
pesticides
as
a
benefit
to
humankind?
If
such
studies
were
part
of
a
program
of
research
in
which
the
controlled
human
exposure
was
built
on
extensive
animal
data
and
the
purpose
was
to
administer
the
lowest
dose
possible
to
humans
for
perhaps
the
purpose
of
validating
a
subtle
neurobehavioral
health
effect,
then
a
benefit
could
be
construed.
Moreover,
if
the
detection
of
such
a
health
effect
led
to
reduced
use
of
pesticides,
then
the
benefit
of
less
pesticide
in
the
environment
could
be
realized.
While
food
producers
may
not
regard
this
as
a
benefit,
it
seems
likely
that
society
as
a
whole,
given
the
concern
for
an
environment
and
a
food
supply
with
fewer
environmental
pollutants
and
chemicals,
would
construe
this
as
a
benefit.
However,
if
the
purpose
is
primarily
to
support
the
monetary
gain
of
a
company
marketing
a
product
with
no
ability
to
rationalize
the
exposure
in
terms
of
general
benefits
to
society,
then
the
risk
to
individuals
does
not
support
this
benefit.

Based
on
these
considerations,
the
overall
conclusion
appears
to
be
that
there
are
no
specific
toxicological
grounds
on
which
to
differentiate
pesticides
from
other
environmental
chemicals.
However,
pesticides
may
be
differentiated
from
other
agents
in
that
the
whole
population
is
potentially
exposed
through
ingestion
of
residues
in
food
and
many
inadvertent
sources
such
as
those
arising
from
spraying,
deposition
in
household
dust,
and
drinking
water.
In
addition,
we
typically
attempt
to
limit
exposures
to
all
other
environmental
chemicals,
whereas
with
pesticides
there
is
a
constant
tension
between
the
desire
to
obtain
enhanced
toxic
effect
on
target
pests
(
and
possibly
to
increase
profits
to
the
manufacturer),
and
efforts
to
limit
exposure
to
non­
target
organisms.
The
major
motivation
for
such
testing
is
usually
to
bring
a
product
to
market
or
to
address
a
specific
regulation.
Thus,
we
are
left
with
weighing
the
risks
to
individuals
of
a
particular
exposure
against
the
benefits
to
society
and
the
environment
as
a
whole
to
decide
whether
an
individual
controlled
exposure
is
ethically
justified.
Some
Subcommittee
Members
contend
that,
unlike
drug
testing,
no
personal
benefit
can
accrue
to
a
subject
intentionally
exposed
to
pesticides
or
other
environmental
toxicants;
others
disagree
,
noting
that
there
can
be
benefits,
e.
g.,
reduction
in
future
exposures.

3.4
Application
to
Specific
Situations
(
Issue
d)

3.4.1
Judgment
of
Current
and
Past
Studies
The
first
element
of
Charge
issue
(
d)(
1)
asked
the
Subcommittee
to
advise
the
Agency
on
how
to
apply
ethics
guidance
to
a)
human
studies
conducted
in
the
past,
prior
to
the
adoption
of
the
30
Common
Rule
(
1991)
but
which
may
(
or
may
not)
have
adhered
to
the
ethical
standard
of
the
time,
and
b)
to
studies
gathered
from
the
open
literature
for
use
by
the
Agency.

For
the
Environmental
Protection
Agency,
the
concept
of
the
"
ethical
standard
of
the
time"
is
anchored
by
language
in
Public
Law
92­
516,
the
October
21,
1972
amendments
to
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA).
The
1972
statute
makes
it
unlawful
for
any
person
to
use
any
pesticide
in
tests
on
human
beings
unless
such
human
beings
a)
are
fully
informed
of
the
nature
and
purposes
of
the
test
and
of
any
physical
and
mental
health
consequences
which
are
reasonably
foreseeable
therefrom,
and
b)
freely
volunteer
to
participate
in
the
test.
The
impact
of
this
statute
is
to
specifically
prohibit,
from
1972
on,
use
by
the
Agency
of
test
data
derived
from
human
studies,
unless
any
human
test
subject
voluntarily
exercised
his
or
her
informed
choice.
On
the
other
hand,
the
1972
statute
must
also
be
viewed
as
permitting
use
by
the
Agency
of
test
data
derived
from
human
studies,
when
the
law's
strictures
are
met.

With
regard
to
data
derived
prior
to
enactment
of
Public
Law
92­
516,
the
Subcommittee
agreed
that
the
fact
that
research
was
done
unethically
does
not
alone
require
rejection
of
the
results
of
that
research.

Some
useful
starting
presumptions
as
we
consider
this
issue
of
possibly
unethical
research
are:

a)
Useful
data
may,
and
often
should,
be
used
when
they
have
been
collected
in
compliance
with
any
applicable
law
or
regulation.

b)
We
ought
assiduously
to
protect
the
public
health
and
the
environment.

c)
We
must
condemn
unethical
research
and
seek
to
prevent
it.

d)
Poorly
designed
and/
or
executed
research
on
human
subjects
is
unethical
science,
regardless
of
other
"
traditional"
ethical
considerations.

In
addition,
it
is
at
best
imprudent
to
ignore
the
data
yielded
by
accidents
and
catastrophes.
We
have
learned
much
from
mass
chemical
disasters,
e.
g.,
the
epidemic
of
methyl
mercury
poisoning
in
Iraq
in
the
winter
of
1971­
72,
which
led
to
the
discovery
of
the
sensitivity
of
the
fetal
brain
to
this
chemical.
This
incident
spurred
developmental
research.
Considerable
information
has
also
been
gained
as
a
result
of
studying
the
survivors
of
the
World
War
Two
atomic
bombings.

"
Incident
reports,"
accidents,
and
unanticipated
problems
involving
risks
to
people
should
be
documented
rigorously,
and
victims
should
be
monitored
afterward
for
some
time.
This
documentation
and
monitoring
is
especially
important
where
children
are
involved..
Such
monitoring
should
be
the
responsibility
of
the
manufacturer
of
the
toxicant,
but
it
is
unrealistic
to
expect
that
this
responsibility
will
be
consistently
met
on
a
voluntary
basis,
so
some
manner
of
government
requirement
is
essential.
Also,
31
in
comparing
deliberate
with
adventitious
exposures,
note
that
the
Common
Rule
implies
that
the
former
prescribe
a
much
greater
degree
of
scientific
rigor.
With
adventitious
exposures,
we
are
quite
aware
of
the
flaws
in
the
data.
With
experimental
data,
the
flaws
may
be
subtle
and
not
conveyed
directly
in
reports,
so
that
EPA
has
to
be
more
alert
to
them.

When
we
consider
research
results
that
have
been
obtained
in
a
manner
inconsistent
with
accepted
ethical
standards,
it
is
important
to
ask
several
questions,
including:

a)
How
serious
was
the
ethical
violation?
There
are
varying
degrees
of
ethical
deficiency.
Research
that
conscientiously
adhered
to
then
acceptable
ethical
standards
might
not
be
acceptable
today
under
more
stringent,
current
standards,
but
it
is
not
equivalent
in
its
violation
of
ethical
principles
to
research
that
callously
disregarded
the
ethical
standards
of
its
time
(
Caplan,
1992,
1993,
and
1998,
discusses
this
topic
in
detail).

b)
What
is
at
stake?
Is
the
use
of
the
results
of
substantial
benefit
to
the
public
health,
or
is
the
benefit
simply
commercial?
If
the
intended
benefit
of
the
use
is
protective,
it
is
far
easier
to
justify
that
use
than
if
the
intended
use
is
to
support
the
release
or
approval
of
a
product.

c)
Are
there
alternative
sources
of
or
routes
to
equivalent
information?
If
ethical
animal
studies
or
other
human
subjects
research
can
serve
the
same
purposes,
then
there
is
no
need
to
rely
on
ethically
tainted
data.

If
the
answers
support
using
the
results,
additional
considerations
come
into
play.
The
users
of
the
research
should
issue
a
clearly
articulated
statement,
explaining
why
the
use
is
justified
and
unambiguously
condemning
the
ethical
violations
associated
with
the
research.
In
this
way,
the
use
of
the
data
can
be
made
into
an
opportunity
to
teach
and
to
reinforce
the
ethical
standards
that
must
be
observed
by
future
research.

When
subjects
of
the
research
are
still
accessible,
it
is
best
to
consult
with
them
about
the
intended
use
of
the
research.
This
may
open
the
door
to
compensation
issues,
as
in
the
case
of
the
human
radiation
inquiry
(
ACHRE,
1995),
but
is
also
an
important
affirmation
of
the
respect
for
human
subjects
that
is
at
the
core
of
ethical
research.

In
addition
to
considering
what
is
to
be
done
with
the
data
and
compensating
(
if
possible)
the
subjects
via
remuneration
and/
or
medical­
follow
up
(
the
need
for
which
may
not
have
been
known
prior
to
discovery
of
the
unethical
research),
we
must
ask
also
what
to
do
about
the
fact
that
the
research
was
done.
It
might
be
appropriate,
or
necessary,
to
identify
and
sanction
the
researchers
(
with
criminal,
civil,
or
professional
penalties
­­
fines,
barriers
to
or
bans
on
future
funding),
the
institutions
where
the
research
was
done,
or
the
financial
supporters
of
the
research.
And
of
course,
the
discovery
of
unethical
research
can
always
raise
questions
of
a
need
for
revision
of
policy
and
or
32
directives.
There
are
some
very
clear
rules
that
EPA
should
follow
if
it
ever
does
utilize
or
sanctions
the
use
of
data
known
to
be
acquired
in
an
unethical
manner.
It
must:
(
a)
acknowledge
what
it
is
doing,
(
b)
give
a
rationale
why
the
decision
is
justified,
(
c)
only
refer
to
the
unethical
research
in
a
way
that
gives
no
credit
or
vindication
to
the
researchers
who
engaged
in
unethical
conduct;
and
(
d)
make
sure
that
it
is
clear
that
such
research
will
not
be
tolerated
in
the
future.

Some
journals
demand
convincing
evidence
that
research
results
submitted
to
them
have
been
obtained
in
ethically
appropriate
ways.
When
they
reject
manuscripts
for
inadequate
documentation
that
ethical
standards
have
been
met,
they
play
an
educative
role
that
helps
sustain
the
integrity
of
research.
But
this
cannot
be
assumed
of
all
journals,
nor
even
of
all
that
have
respectable
standards
of
scientific
quality.
So
each
study
must
be
evaluated
on
its
own
merits
before
a
conclusion
about
its
ethical
propriety
can
be
warranted.

No
algorithm
can
exist
for
making
the
decisions
raised
by
this
question.
One
can
draw
a
temporal
"
bright
line"
benchmark,
affirming
that
from
a
certain
date,
all
research
must
meet
certain
ethical
standards
to
be
accepted
by
the
Agency
­­
no
matter
who
has
done
it,
where
it
was
done,
or
how
it
was
financed.
But
for
prior
research,
as
well
as
incidents
(
e.
g.,
the
methyl
mercury
poisoning
in
Iraq),
there
is
an
unavoidable
need
to
rely
on
judgment.
For
this
reason,
it
is
crucial
that
there
be
an
on­
going
capacity
in
the
Agency
both
for
providing
supportive
advice
and
guidance
to
researchers
and
for
scrutiny
and
oversight
of
research
activities.

Some
ethical
violations
may
also
signal
methodological
flaws.
If
the
executives
of
a
corporation,
or
in
a
research
community,
are
invited
to
volunteer
to
participate
as
research
subjects,
they
may
agree
because
of
subtle
contextual
coercion
­­
a
sense
that
they
are
disloyal
to
their
employer
if
they
decline,
or
that
they
will
forgo
good
favor
that
may
matter
to
their
future.
Recruiting
them
as
subjects
is
therefore
ethically
objectionable.
For
parallel
reasons,
they
may
be
less
likely
to
report
adverse
outcomes
than
subjects
who
have
no
other
connection
with
the
research
enterprise,
and
the
results
of
such
research
are
thus
methodologically
tainted
as
well
as
ethically
flawed.

The
point
of
raising
such
concerns
is
not
to
eliminate
research
or
even
to
impede
it
unduly,
but
to
prevent
the
abuse
that
occurs
when
subjects
(
even
if
they
are
not
harmed
physically)
are
induced
to
participate
in
research
in
the
face
of
risks
they
do
not
properly
understand.

There
will,
of
course,
be
transitional
issues
even
if
the
Agency
takes
an
unambiguously
clear
position
for
the
future.
Some
studies
may
already
be
well
underway
that
fail,
perhaps
narrowly,
to
satisfy
strict
ethical
standards.
And
it
will
take
time,
effort,
and
investment
to
convey
to
all
relevant
constituencies
just
what
it
takes
to
conduct
research
with
sufficient
ethical
sensitivity
to
meet
the
highest
standards.

3.4.2
Oral
Dosing
33
The
second
element
of
Charge
(
d)
asked
the
Subcommittee
to
comment
on
the
ethical
issues
attendant
to
the
oral
dosing
of
paid
and
un­
paid
human
volunteers
with
environmental
toxicants
or
infectious
agents
found
in
the
environment
(
e.
g.,
cryptosporidium
in
drinking
water,
or
organophosphates
(
OPs))
in
order
to
establish
a
NOAEL.
Since
the
Agency
must
make
judgments
on
a
wide
variety
of
studies
involving
humans,
it
would
be
helpful
to
have
advice
on
how
the
guiding
principles
on
human
subject
research
and
testing
(
i.
e.,
the
Common
Rule
and
Declaration
of
Helsinki)
might
be
applied
to
a
given
study
particularly
as
they
might
apply
in
the
case
of
studies
submitted
in
support
of
a
pesticide
registration.

Comparing
oral
dosing
as
a
route
of
human
exposure
for
environmental
toxicants
with
other
routes,
it
seems
apparent
that,
from
a
toxicological
standpoint,
it
is
inappropriate
to
consider
oral
dosing
any
differently
from
the
other
two
possible
routes
of
human
exposure
to
pesticides,
e.
g.,
inhalation
or
dermal
exposure.
It
is
clearly
pointed
out
in
the
Agency's
guidelines
that,
when
testing
xenobiotics
in
animals,
the
route
that
most
closely
mimics
the
route
of
human
exposure
of
concern
should
be
used.
In
that
regard
it
would
normally
be
appropriate
to
use
inhalation
as
the
route
for
estimating
the
hazard
to
an
applicator
of
the
pesticide
or
person
downwind
from
a
spraying
operation.
Similarly,
it
would
be
more
appropriate
to
use
dermal
exposure
for
the
same
pesticide
if
one
is
interested
in
the
hazard
from
working
in
a
field
at
some
point
after
that
same
spray
operation.
Following
this
example
to
its
logical
conclusion,
the
most
appropriate
route
of
exposure
for
ascertaining
the
toxic
potential
of
that
same
pesticide
as
a
residue
on
food
would
be
to
use
an
oral
exposure.

One
could
appropriately
design
a
study
to
evaluate
the
absorption,
distribution,
metabolism,
excretion
and
pharmacokinetic
behavior
of
a
given
chemical
in
humans
with
some
assurance
that
exposures
were
below
the
NOAEL.
Such
an
exposure
(
one
would
not
need
to
use
multiple
doses)
would
automatically
become
the
NOEL
in
this
context.
Obviously,
one
would
not
know
if
the
NOEL
was
potentially
higher
but
one
could
say
with
certainty
that
a
given
dose,
by
definition
of
the
term,
was
a
NOEL.

The
Subcommittee's
discussion
at
the
public
meeting
centered
on
pesticides,
and
did
not
address
infectious
pathogens,
(
e.
g.,
Crytosporidia,
as
called
out
in
the
Charge).
It
was
recognized
during
the
development
of
this
report,
however,
that
studies
of
infectious
pathogens
also
must
be
carefully
considered
in
terms
of
their
potential
hazard
to
the
volunteer
as
contrasted
to
the
potential
benefit
to
society
at
large.
Such
a
study
would
require
a
very
high
justification.
The
basic
difference
between
this
type
of
study
and
one
of
a
chemical
nature
in
terms
of
"
dose"
is
that
a
study
of
an
infectious
agent
provides
only
two
endpoints:
infection
(
disease)
or
no
infection
(
no
disease).
If
the
former
result
is
encountered,
that
particular
individual
can
become
just
as
ill
as
if
the
disease
were
contracted
under
"
real
world"
exposure
conditions,
although
it
is
assumed
that
therapeutic
countermeasures
would
be
initiated
as
soon
as
infection
was
recognized.
Data
from
such
studies
would
also
have
to
be
considered
in
terms
of
inter­
individual
susceptibility.

3.5
Determining
Compliance
with
Ethical
Standards
(
Issue
e)
34
Even
if
the
Agency
has
ethical
standards
in
place,
there
is
the
question
of
determining
compliance
with
those
standards.
There
is
an
imperative
to
actively
oversee
compliance
with
these
standards
on
a
continuing
basis.
This
element
of
the
Charge
asks
how
the
Agency
can
determine
whether
and
to
what
extent
its
ethical
standards
have
been
met
in
a
particular
test
with
respect
to
a)
informed
consent,
b)
voluntary
participation,
and
c)
Institutional
Review
Boards.

Specifically,
the
Agency's
"
having
standards
in
place"
means
precisely
the
following:
a)
there
is
a
policy
describing
the
requirements
for
review
and
approval;
and
b)
there
is
a
mechanism
for
assuring
compliance.

Attentive
Agency
oversight
of
compliance
with
its
procedures
for
protection
of
human
subjects
requires
written
compliance
oversight
procedures.
The
procedures
should
be
in
sufficient
detail
so
that
researchers
know
what
to
expect,
and,
to
that
end,
Agency
procedures
should
be
publicly
promulgated
and
freely
available.
The
Agency
can
expect,
and
should
be
prepared,
to
revise
its
compliance
oversight
procedures,
as
needed,
to
keep
pace
with
evolving
thinking
and
practice.

To
pursue
the
goal
of
compliance
oversight
properly,
the
Agency
will
require
staff
with
the
authority
to
carry
out
compliance
oversight
and
to
make
formal
determinations
regarding
noncompliance.
As
a
matter
of
best
practice,
compliance
oversight
staff
should
be
full­
time
individuals
whose
duties
exclusively
address
compliance
oversight.
Individuals
who
are
advocates
for
the
rights
and
welfare
of
human
subjects,
who
are
committed
to
thoroughness,
and
who
are
unencumbered
in
their
formulating
and
asking
of
pertinent
questions
should
be
selected
for
such
a
review
staff.

Agency
staff
dedicated
to
compliance
oversight
should
not
be
responsible
for
day­
to­
day
education
and
interpretation
of
Agency
standards
regarding
human­
subject
protection.
It
is
critical
to
preserve
an
easy
avenue
for
asking
the
Agency
questions
in
a
non­
threatening
atmosphere,
and
having
those
questions
answered
by
Agency
staff
without
nominal
responsibility
for
"
compliance
oversight."

The
following
sections
of
this
report
discuss
means
by
which
the
Agency
can
determine
whether
and
to
what
extent
its
ethical
standards
have
been
met
in
a
particular
test,
in
the
context
of
informed
consent,
voluntary
participation,
and
IRBs.

3.5.1
Informed
Consent
In
reviewing
proposed
or
submitted
human
studies,
Agency
staff
should
examine
informed
consent
documents
and
informational
brochures
or
allied
materials,
including
advertisements
intended
to
recruit
subjects.
"
Advertisements"
include
electronic
items
posted
on
the
World
Wide
Web.
Agency
staff
should
seek
answers
to
the
following
questions
of
the
informed
consent
document
and
process:

a)
Are
the
required
elements
of
information
present?
35
b)
Is
the
language
understandable
to
the
prospective
subject?

c)
Who
actually
seeks
the
consent
of
the
subject?
36
3.5.2
Voluntary
Participation
Agency
staff
should
ask
the
following
questions
concerning
the
research
under
scrutiny:

a)
What
steps
have
been
taken
to
minimize
the
possibility
of
coercion
or
undue
influence?

b)
How
will
the
prospective
subject
be
provided
with
sufficient
opportunity
to
consider
whether
or
not
to
participate?

c)
What
instruction
is
provided
to
research
staff
who
will
be
recruiting
subjects?

d)
How
many
prospective
subjects
decline
participation?

e)
How
many
subjects
withdraw
from
the
research
effort?

f)
Is
the
design
of
the
experiment
valid?
Has
it
sufficient
power?
Does
it
use
the
appropriate
response
measures?

3.5.3
Institutional
Review
Boards
(
IRB)

As
a
matter
of
routine
compliance
oversight,
Agency
staff
should
a)
validate
membership
of
Institutional
Review
Boards,
b)
evaluate
IRB
policies
and
procedures,
and
c)
review
minutes
of
selected
IRB
meetings.
All
IRB
records
must
be
accessible
for
inspection
and
copying
by
authorized
representatives
of
the
Agency
at
reasonable
times
and
in
a
reasonable
manner
(
see
40
CFR
Part
26.115(
b)).
These
records
must
capture
the
identity
of
persons
recruited
for
experimentation,
including
the
total
numbers,
sex,
ethnicity,
and
age.
Given
differing
cultural
and
political
systems,
as
well
as
the
simple
fact
of
distance,
it
is
very
difficult
to
maintain
this
level
of
scrutiny
of
foreign
research
activities.
The
Agency
should
consider
it
imperative
to
provide
needed
staff
and
financial
resources
to
make
it
possible
to
provide
the
same
level
of
monitoring
of
foreign
research
whose
results
are
presented
to
the
Agency
as
it
does
with
domestic
research.

Agency
staff
should
evaluate
the
IRB's
receipt
of
reports
of
unanticipated
problems
involving
risks
to
subjects
or
others.
Agency
staff
should
ask
of
the
IRB,
"
What
additional
safeguards
does
the
IRB
require
to
protect
the
rights
and
welfare
of
subjects
who
are
likely
to
be
vulnerable
to
coercion
or
undue
influence?"

There
is
no
substitute
for
site
visits
in
evaluating
IRB
compliance.
The
Agency
should
exercise,
on
occasion,
authority
to
carry
out
"
not­
for­
cause"
on­
site
inspections
and
audits.
Common
knowledge
of
this
Agency
practice,
despite
the
infrequency
of
such
site
visits,
has
a
remarkable
deterrent
value
(
This
approach
is
similar
in
principle
to
the
Internal
Revenue
Service
random
audit
and
its
impact
on
37
compliance
with
income
tax
code.).
The
publicity
that
attends
this
Agency
practice
(
i.
e.,
the
telling
and
retelling
of
stories
of
noncompliance)
has
broad
positive
impact
for
human
research
subjects.

Agency
audits
of
the
IRBs
under
its
purview
should
include
performance
measures
­­
and
not
just
the
paper
trail.
The
Agency
should
make
certain
that
IRBs
under
its
purview
have
sufficient
provisions
for
meeting
space
and
sufficient
staff
to
support
the
IRB's
review
and
record­
keeping
duties
(
see
40
CFR
Part
26.103(
b)(
2)).

In
short,
compliance
oversight
requires
an
ongoing
commitment
on
behalf
of
the
Agency
and
its
staff
in
the
dynamic
and
evolving
field
of
research
ethics.
This
commitment
must
include
the
provision
of
sufficient
staff
and
budget
to
maintain
this
oversight.
Moreover,
the
Agency's
effort
would
be
well­
served
by
creating
an
internal
evaluation
organization
to
facilitate
oversight
and
maintain
regular
communication
with
other
federal
departments
and
agencies.
38
4.
MAJOR
RECOMMENDATIONS
In
the
body
of
this
of
this
report,
the
Subcommittee
has
provided
(
within
the
context
of
the
Charge)
many
recommendations
and
cautions
to
the
EPA.
This
section
"
looks
across"
the
Charge
and
highlights
the
Subcommittee's
major
findings
and
advice
to
the
Agency.
First,
there
were
a
series
of
basic
findings
on
which
the
Subcommittee
was
unanimous.
These
are:

a)
Any
policy
adopted
by
the
Agency
should
reflect
the
highest
standards
of
respect
for
human
subjects
and
should
prohibit
research
protocols
that
override
the
interests
of
subjects
in
order
to
obtain
useful
data.

b)
If
it
can
be
justified
at
all
to
expose
human
subjects
intentionally
to
toxic
substances,
the
threshold
of
justification
for
such
action
should
be
very
high.
We
recommend,
therefore,
that
pesticide
exposure
to
human
subjects
be
approached
with
the
greatest
degree
caution.
The
risks
of
allowing
such
experimental
exposures
of
humans
include
the
possible
involvement
of
less
than
fully
informed
participants,
unanticipated
health
consequences,
the
exposure
of
large
numbers
of
subjects,
and
skewed
use
in
developing
countries.

c)
Bad
science
is
always
unethical;
research
protocols
that
are
fundamentally
flawed,
such
as
those
with
sample
sizes
inadequate
to
support
reasonable
inferences
about
the
matter
in
question,
are
unjustifiable.

d)
If
the
use
of
human
subjects
in
pesticide
testing
can
be
justified,
that
justification
cannot
be
to
facilitate
the
interests
of
industry
or
of
agriculture,
but
only
to
better
safeguard
the
public
health.

e)
Any
policy
adopted
by
the
Agency
must
reflect
a
special
concern
for
the
interests
of
vulnerable
populations,
such
as
fetuses,
children,
adolescents,
pregnant
women,
the
elderly,
and
those
with
fragile
health
due
to
compromised
respiratory
function
or
other
reasons.

f)
Unintended
exposures
provide
valuable
opportunities
for
research;
it
is
an
error
not
to
take
full
advantage
of
such
opportunities
to
gain
major
information
through
careful
incident
follow­
up.

g)
In
considering
research
protocols,
it
is
not
enough
to
determine
a
risk/
benefit
ratio;
it
is
important
also
to
consider
the
distribution
of
risks
and
of
benefits,
and
to
ensure
that
risks
are
not
imposed
on
one
population
for
the
sake
of
benefits
to
be
enjoyed
by
another.
It
is
also
important
to
be
sensitive
to
the
difference
between
a
reversible
risk
39
and
one
that
may
be
irreversible,
such
as
possible
interference
with
normal
neurological
development.

Addressing
the
issue
of
intentionally
dosing
human
subjects
with
pesticides,
all
but
two
of
the
Subcommittee
Members
could
envision
particular
circumstances
under
which
such
dosing
of
humans
could
be
scientifically
and
ethically
acceptable.
Defining
these
circumstances
generically,
however,
proved
to
be
very
difficult
and
were
the
source
of
prolonged
discussion
at
the
public
meeting
and
multiple
"
fine­
tunning"
during
preparation
of
the
report.
The
following
summary
presents
the
most
significant
findings
of
the
majority
of
the
Subcommittee
with
regard
to
both
the
institutional
guarantees
that
would
be
required
and
the
guidelines
that
could
be
used
to
determine
whether
or
not
intentional
dosing
of
humans
in
a
particular
study
is
scientifically
and
ethically
acceptable.
These
findings
are:

a)
All
research
involving
humans
should
require
prior
review
by
an
Institutional
Review
Board.

b)
The
structure,
function,
and
activities
of
both
the
Agency's
IRBs
and
external
IRBs
of
entities
submitting
data
should
be
under
active
and
aggressive
scrutiny
by
EPA,
with
adequate
staff
and
financial
resources
provided
to
carry
out
this
mission.
EPA
should
establish
an
internal
ethics
review
organization
to
perform
this
function,
staffed
by
fulltime
individuals
whose
duties
address
exclusively
compliance
oversight.
The
review
organization
should
also
provide
an
institutional
focus
for
continuous
close
liaison
on
ethical
matters
with
other
federal
agencies.

c)
The
intentional
administration
of
pesticides
to
human
subjects
testing
is
acceptable,
subject
to
limitations
ranging
from
"
rigorous"
to
"
severe."
The
information
sought
must
not
be
available
via
other
sources
(
e.
g.,
animal
studies
and
models
or
study
of
incidental
exposures),
and
the
information
expected
to
be
gained
must
promise
reasonable
health
benefits
to
the
individual
or
society
at
large.
Studies
should
be
appropriately
designed
to
address
the
stated
objective,
and
have
sufficient
statistical
power
to
provide
an
unambiguous
answer
to
the
question
under
investigation.
In
addition,
some
ongoing
monitoring
of
the
subjects
involved
in
such
studies
is
essential
to
insure
that
they
do
not
subsequently
become
ill
or
suffer
other
adverse
effects
d)
In
no
case
should
developing
humans
(
i.
e.,
the
fetus,
infant,
young
children
or
adolescents)
be
exposed
to
neurotoxic
chemicals.
There
are
currently
too
many
unknown
dangers
to
justify
such
studies,
even
under
the
most
extraordinary
circumstances.

e)
The
EPA
should
take
whatever
administrative
action
is
necessary
to
extend
the
protections
of
40
CFR
Part
26
to
all
human
research
activities
whose
results
will
be
submitted
to
the
Agency.
40
f)
With
regard
to
data
derived
prior
to
enactment
of
Public
Law
92­
516
(
amendments
to
the
FIFRA),
the
Subcommittee
agreed
that
the
fact
that
research
was
done
unethically
does
not
alone
require
rejection
of
the
results
of
that
research.

g)
Some
of
the
Subcommittee
Members
that
accepted
the
use
of
paid
and
un­
paid
human
volunteer
testing
of
pesticides
identified
certain
situations
in
which
such
testing
would
or
would
not
be
appropriate:

1)
It
would
not
be
appropriate
to
conduct
such
testing
when
adequate
human
data
are
already
available.

2)
Such
studies
would
not
be
appropriate
for
pesticides
in
use
today
when
data
of
equal
quality
can
be
obtained
from
field
exposure
studies.

3)
Subject
to
the
other
limitations
discussed
in
this
report,
human
studies
could
be
appropriate
when
there
are
significant
data
gaps
and
such
studies
would
provide
a
more
accurate
risk
assessment.

4)
Subject
to
the
other
limitations
discussed
in
this
report,
human
studies
could
be
appropriate
for
pesticides,
which
are
not
yet
on
the
market,
i.
e.
new
pesticides.

5)
Given
the
significance
of
statistical
considerations
in
regard
to
human
study
design,
the
Agency
ought
to
organize
a
workshop
to
specifically
deal
with
this
issue.
A­
1
APPENDIX
A
­
FACTORS
AFFECTING
STATISTICAL
POWER
Major
factors
are:

a)
Clinical
trials
for
pharmaceuticals
fall
into
two
basic
areas:
evaluation
of
dose
ranges
for
proper
delivery
of
the
agent,
and
larger
studies
aimed
at
product
efficacy.
With
pesticides,
controlled
experimental
exposures
are
aimed
at
similar
issues,
comprising
absorption,
distribution,
metabolism,
and
elimination
(
ADME)
studies
and
studies
aimed
at
finding
exposures
intended
(
and
expected)
to
produce
some
trivial,
non­
toxic
effect
in
the
study
subjects
(
NOAEL).
For
ADME
studies,
one
is
attempting
to
estimate
pharmacokinetic­
pharmacodynamic
parameters.
The
precision
required
for
the
estimation
of
these
parameters
is
determined
by
knowledge
of
the
variability
in
the
general
population
and
by
a
decision
about
the
size
of
the
standard
error
relative
to
the
mean
value
of
the
population.
Generally,
the
ratio
of
the
standard
error
to
the
mean
should
be
smaller
than
1.0,
preferentially
much
smaller
than
1.0.
In
attempting
to
find
a
dose
that
produces
effects
no
larger
than
a
specified
value,
the
probability
that
the
effect
is
greater
than
the
specified
value
should
be
fairly
small,
typically
less
than
0.2
or
0.1.
Different
designs
can
satisfy
these
requirements
and
care
should
be
taken
to
have
the
design
match
the
needs.
Similar
concepts
apply
to
human
epidemiology
studies
and
human
studies
of
biomarkers
in
worker
or
environmentally
exposed
populations.

b)
Questions
about
the
precision
of
estimates
and
the
probability
of
exceedance
should
also
be
addressed.
Have
statistical
criteria
been
established
to
allow
for
continuous
monitoring
of
the
responses
in
such
a
way
that,
if
the
question
can
be
answered
earlier
than
projected,
the
study
is
terminated?
Statistical
methods
exist
for
evaluating
these
issues
without
affecting
the
final
probability
of
making
an
error.
Sequential
decision
designs,
such
as
those
now
recommended
for
LD50
calculations,
could
also
serve
such
a
purpose.
In
fact,
they
could
also
be
applied
in
short­
term
experiments.

Several
Members
of
the
Subcommittee
expressed
serious
reservations
concerning
the
overall
issue
of
statistical
considerations
in
regard
to
human
study
design.
Some
of
these
Members
felt
that
this
issue
was
of
such
import
that
it
deserved
separate
consideration.
Therefore,
we
encourage
the
Agency
to
organize
a
workshop
to
specifically
deal
with
this
issue.
4The
alpha
level
is
generally
specified
in
advance
of
the
study.
The
beta
error,
and
therefore
the
power
of
a
study,
is
determined
by
three
factors:
the
alpha
level
initially
set,
the
size
of
the
effect
looked
for,
and
the
number
of
subjects
studied.
If
any
three
parameters
are
established,
the
fourth
is
fixed
and
readily
determined.
If
the
effect
size
sought,
the
alpha
level
and
the
power
desired
are
known,
the
number
of
subjects
can
easily
be
calculated.
If
the
alpha
level,
effect
size
and
number
of
subjects
are
known,
the
power
can
be
determined.

B­
1
APPENDIX
B
­
STATISTICAL
CONSIDERATIONS
IN
NO
OBSERVED
ADVERSE
EFFECTS
LEVEL
(
NOAEL)
STUDIES
Two
critical
statistical
measures
determine
the
ability
of
a
study
to
meet
its
objectives:
the
probability
of
detecting
an
effect
when
no
effect
exists
(
Type
I
or
alpha
error);
and
the
probability
of
missing
an
effect
that
is
real
(
Type
II
or
beta
error).
The
probability
of
detecting
a
true
effect
is
generally
referred
to
as
the
power
and
is
defined
as
1
minus
beta.
The
NOAEL
is
partially
defined
by
rejection
of
the
null
hypothesis
(
i.
e.,
that
no
effect
exists).
4
The
choice
of
an
effect
size
to
look
for
in
a
study
of
a
neurotoxic
pesticide
is
somewhat
arbitrary
and
entails
value
judgments.
For
example,
what
effect
size
should
be
sought
in
a
study
of
dietary
pesticides?
The
number
of
exposed
American
children
argues
for
conducting
studies
that
will
find
small
effect
sizes.
In
this
context
the
word
"
small"
does
not
mean
negligible;
it
means
difficult
to
measure.
There
are
18.9
million
children
under
five
years
of
age
in
the
United
States.
If
a
pesticide
in
their
diet
and
environment
were
to
cause
a
1%
increase
in
the
rate
of
neurobehavioral
toxicity,
that
would
be
189,000
affected
cases.
Assuming
a
base
rate
of
deficit
of
1%,
we
can
ask
how
many
subjects
would
be
needed
to
find
an
increase
from
1%
to
2%,
or
from
3%
to
4%.
The
proportion
of
children
3­
5
with
disabilities
is
approximately
4%.
We
also
calculate
(
in
Table
1)
the
number
of
subjects
required
to
find
an
increase
from
4
to
5%
with
an
80%
power.

Table
1
Alpha
level
.05
.05
.05
.05
proportion
in
unexposed
group
.01
.02
.03
.04
proportion
in
exposed
group
.02
.03
.04
.05
number
of
cases
in
each
group
3017
5071
7062
6725
POWER
.90
.90
.90
.80
It
can
be
readily
seen
that
large
numbers
of
subjects
(
between
6000
and
14,000)
are
needed
to
make
a
dependable
no­
effect
assertion
for
a
small
effect
with
80%
confidence.
Conversely,
with
the
number
of
subjects
employed
by
registrants
in
past
studies
submitted
to
EPA,
there
was
little
chance
of
finding
an
effect
if
it
were
present.
A
power
of
0.04
is
one
chance
in
25.
It
is
as
if
there
were
4
black
B­
2
balls
representing
a
toxic
effect
and
96
white
balls
representing
no
toxic
effect
placed
in
a
jar.
Asserting
that
no
toxicity
was
seen
in
a
study
of
50
subjects
is
no
different
that
reaching
into
the
jar,
pulling
out
a
white
ball,
and
stating
that
only
white
balls
were
in
the
jar.

So,
what
is
the
probability
of
missing
a
real
effect
for
a
given
sample
size
and
a
given
true
effect?
To
be
able
to
study
this
issue,
one
must
know
the
distribution
of
the
target
measurement
in
the
study
population
and
have
some
idea
of
how
changes
in
this
value
will
affect
this
distribution.

Entering
the
number
of
subjects
commonly
used
in
past
human
studies
made
available
to
the
EPA
enables
us
to
measure
the
power
to
find
an
adverse
pesticide
effect
(
Table
2).

Table
2
Alpha
level
.05
.05
.05
proportion
in
unexposed
group
.04
.04
.04
proportion
in
exposed
group
.05
.05
.05
number
of
cases
in
each
group
10
20
50
POWER
.03
.04
.04
To
illustrate
the
value
of
power
for
continuous
alternatives,
consider
the
levels
of
acetylcholinesterase
in
humans.
Singh
et
al.
(
1987)
measured
acetylcholinesterase
(
nmol/
mg
HB/
min)
in
the
red
blood
cells
of
193
individuals
in
India
who
were
"
unexposed"
to
organophosphates.
They
estimated
a
mean
of
35
and
a
standard
deviation
of
13.7.
Assuming
the
variance
acetylcholinesterase
(
AchE)
in
this
population
is
due
to
two
independent
sources
of
variation,
variation
across
individuals
(
50%)
and
variation
within
individuals
(
50%),
and
assuming
the
reduction
in
AchE
is
still
subject
to
interindividual
variation
and
a
small
additional
variation
due
to
variation
in
response
to
the
organophosphate,
one
can
estimate
the
power
for
detecting
a
real
effect
for
various
reductions
in
AchE
levels
and
various
sample
sizes
(
see
code
below
for
the
parameters
used
to
make
these
calculations).
Table
3
presents
the
power
of
the
signed­
rank
test
for
AchE
reduction
in
the
case
where
individuals
are
used
as
their
own
controls
and
comparisons
are
made
between
a
targeted
time
point
with
the
specified
reduction
and
the
AchE
level
prior
to
exposure.
It
is
clear
that,
if
the
sample
size
is
greater
than
10,
it
is
possible
to
detect
a
25%
or
greater
reduction
in
AChE
with
high
power.
However,
for
a
10%
reduction,
at
least
20
samples
must
be
taken,
for
a
10%
reduction,
at
least
100
samples
must
be
taken
and
for
a
1%
reduction,
at
least
1000
samples
must
be
taken.

It
is
possible
to
argue
that
since
we
have
used
NOAEL's
from
animal
studies
as
a
general
rule
for
setting
standards,
then
the
power
for
the
animal
study
should
equal
the
power
of
the
human
study
in
detecting
a
NOAEL.
All
else
equal,
this
would
mean
equivalent
samples.
If
there
B­
3
TABLE
3:
Power
(
in
%)
for
detecting
specified
changes
in
AchE
levels
based
upon
distributions
and
assumptions
given
in
MatLab
code
following
the
table
Sample
Size
Reduction
In
AchE
(
AchE
in
nmol/
mg
HB/
min
50%
25%
10%
5%
1%

10
1
99.6
56.2
15.2
5.0
20
1
1
89.6
35.8
7.6
50
1
1
99.8
76.2
8.2
100
1
1
1
96.6
11.6
200
1
1
1
99.8
18.8
500
1
1
1
1
41.0
1000
1
1
1
1
69.8
2000
1
1
1
1
94.0
are
differences
in
variation
between
the
species,
the
sample
sizes
would
have
to
be
adjusted.
Even
if
the
powers
for
detecting
a
NOAEL
are
equivalent,
it
should
be
noted
that
the
human
study
will
provide
less
protection
against
a
possible
adverse
effect
since
the
10­
fold
interspecies
extrapolation
uncertainty
factor
will
not
be
applied.

The
proper
way
to
design
a
human
study
would
be
to
decide
upon
a
change
in
AchE
levels
which
would
be
of
no
clinical
significance
taking
into
account
sensitive
individuals
and
possible
effects
of
longer
exposures
in
the
environment
as
compared
to
the
laboratory.
Then
choose
exposures
which
are
unlikely
to
yield
this
level
of
response
and
choose
a
sample
size
such
that,
if
this
response
were
true,
you
would
have
sufficient
power
to
detect
it.
Even
this
approach
carries
some
risk
since
some
members
of
the
study
population
could
be
somewhat
sensitive
to
the
exposure.
In
general,
the
targeted
reduction
should
be
fairly
low
to
insure
safety
(
say
less
than
5%
or
less
than
1%).
This
would
require
sample
sizes
much
larger
than
those
generally
used
in
these
types
of
trials.
5
Received
in
June,
2000
6
Dr.
Gorovitz
wished
to
state
that,
in
signing
the
subject
letter,
he
was
supporting
only
the
request
for
a
second
meeting
of
the
Subcommittee.

C­
1
APPENDIX
C
­
MINORITY
REPORT
FROM
DRS.
NEEDLEMAN
AND
REIGART5
We
have
read
the
Final
Draft
of
the
Subcommittee
on
Human
Testing,
and
submit
this
minority
report
to
be
made
part
of
the
Report.
We
are
compelled
to
take
this
step
because
the
Final
Draft
is
a
distorted
and
diluted
version
of
the
public
proceedings
of
the
Subcommittee.
It
is
a
disservice
to
the
efforts
of
the
members,
and
in
the
final
analysis,
to
the
truth.
If
accepted,
it
will
serve
to
increase
the
health
risks
of
children
from
pesticide
exposure.
This
is
precisely
the
opposite
of
the
subcommittee's
pronounced
purpose.
As
pediatricians
whose
careers
have
been
dedicated
to
the
prevention
of
childhood
disease,
we
cannot
allow
this
report
to
be
issued
without
registering
our
emphatic
dissent.

The
authors
of
the
draft,
by
hindering
free
access
to
the
record
and
to
communication
among
members
of
the
subcommittee,
permitted
this
misleading
report
to
be
written.
At
the
first
subcommittee
meeting
in
December
of
1998,
strong
doubts
about
both
the
ethics
and
scientific
validity
of
exposing
humans
to
organophosphate
pesticides
were
expressed
by
most
of
the
members.
But
the
first
drafts
of
the
proceedings
did
not
reflect
this
consensus.
Although
a
transcript
of
the
proceedings
was
promised
within
30
days
of
the
meeting,
it
was
not
made
available
until
June
1,
1999.
As
a
result,
there
were
no
means
for
members
to
refresh
their
memories
and
test
the
accuracy
of
the
draft
report.
Comparing
the
transcript
with
the
draft
reports
revealed
many
misrepresentations
of
the
statements
of
members.

In
June
of
1999,
four
members
of
the
committee
signed
a
minority
report
(
Kendall,
Needleman,
Reigart,
Kahn).
That
minority
report
stated
that
" 
the
five
draft
reports
of
the
subcommittee
do
not
accurately
reflect
the
statements
made,
or
the
sentiments
expressed
in
that
meeting.
These
members
of
the
Subcommittee
expressed
many
doubts
about
the
acceptability
or
utility
of
human
testing
of
pesticides."
Four
other
members,
(
Caplan,
Meslin,
Ellis
and
Gorovitz6),
signed
a
letter
of
support
for
the
minority
statement.
Including
the
chairmen,
there
were
13
members
of
the
Subcommittee.

The
final
draft
differs
in
no
substantial
way
from
earlier
flawed
versions.
It
minimizes
the
risks
to
humans
from
intentional
experimental
dosing,
and
de­
emphasizes
the
salient
issue:
that
no
limited
human
study
will
provide
information
about
safe
levels
of
intake
of
pesticides
by
humans,
especially
children.
While
there
was
general
agreement
of
the
subcommittee
that
poor
science
is
per
se
unethical,
the
document
gives
little
credence
to
the
concerns
of
two
highly
qualified
statisticians
(
Needleman
and
Portier).
The
report
gives
lip
service
to
the
need
for
large
numbers
of
subjects
to
achieve
adequate
statistical
power
to
find
a
small
effect.
Calculations
of
statistical
power
were
submitted
at
the
request
of
C­
2
the
subcommittee.
These
provided
strong
documentation
that
the
human
studies
done
by
the
pesticide
manufacturers
were
scientifically
invalid.
They
showed
that
to
find
a
small
effect,
at
least
2500
subjects
in
each
group
were
necessary.
They
also
showed
that
the
sample
sizes
used
by
the
manufacturers,
(
7
to
50
subjects)
to
report
no
effect,
had
a
3%
to
4%
chance
to
find
an
effect.
This
was
initially
placed
in
the
body
of
the
draft,
then
removed
and
buried
in
the
appendix,
despite
the
repeated
protest
of
members
of
the
committee.

The
Draft
paid
considerable
attention
to
identifying
a
rationale
for
using
human
adult
subjects.
It
reaches
so
far
as
to
say
that
a
subject
given
a
pesticide
is
a
potential
beneficiary
since
he
or
she
will
encounter
the
pesticide
in
the
diet.
It
strains
to
rationalize
the
experimental
exposure
to
humans
saying:
"
the
overall
conclusion
appears
to
be
that
there
are
no
specific
toxicological
grounds
on
which
to
differentiate
pesticides
form
other
environmental
chemicals."
This
is
a
common
assertion
of
the
pesticide
industry
and
its
spokesmen.
Only
one
member
of
the
committee
advocated
this
position,
but
the
Draft
portrays
it
as
a
majority
opinion.
To
make
this
statement
the
writer
was
forced
to
ignore
the
provenance
of
those
pesticides
that
the
SAP
was
asked
to
examine
first:
organophosphate
pesticides.
These
compounds
originated
as
military
weapons
designed
to
kill
people.

The
rationale
for
metabolic
studies
of
pesticides
in
humans
is
a
pesticidal
Trojan
Horse:
It
provides
a
ready
mechanism
for
dosing
humans
under
the
guise
of
studying
metabolic
pathways,
and
then
arguing
to
no
effect
levels.
This
intention
to
use
studies
with
other
professed
purposes
to
establish
a
NOAEL
is
embodied
in
this
statement
in
the
report
"
It
is
agreed
that,
generally,
human
dosing
experiments
are
not
appropriate
if
the
primary
intent
of
the
study
is
to
determine
or
revise
a
NOEL
or
NOAEL
so
as
to
eliminate
the
interspecies
uncertainty
factor"
(
emphasis
added).
The
words
"
generally"
and
"
primary"
provide
a
loophole
that
is
sufficient
to
justify
any
use
of
research
to
establish
an
NOAEL.
This
clear
loophole
was
inserted
in
the
document
despite
agreement
of
the
committee
that
there
was
no
desire
to
include
such
inclusions
of
research
which
lead
to
a
NOAEL
by
human
dosing.

The
inclusion
in
the
"
Major
Recommendations"
of
situations
under
which
testing
would
be
appropriate
could
potentially
provide
justification
for
any
and
all
research
on
humans,
as
long
as
IRB
approval
could
be
obtained.
With
the
growth
of
commercial
IRB's
and
extensive
opportunities
for
overseas
research
such
IRB
approval
is
no
barrier
at
all.
This
recommendation
lays
the
groundwork
for
a
flood
of
submissions
of
data
from
research
which
should
not
be
conducted
and
should
not
be
accepted
by
USEPA
for
regulatory
purposes.

The
applicability
of
adult
studies
to
children's
safety
is
nowhere
mentioned
in
the
draft.
The
Draft
acknowledges
the
enhanced
vulnerability
of
children
as
a
reason
to
exclude
them
from
dosing.
If
children
are
different,
then
what
information
can
adult
dosing
provide
that
is
of
use
to
set
FQPA
standards
for
protecting
children?

These
are
a
few
of
the
many
objections
that
we
have
to
this
Report.
The
others
are
recorded
in
our
many
letters
to
the
DFO.
We
have
worked
hard
to
be
heard,
and
to
make
the
report
congruent
C­
3
with
the
beliefs
of
the
committee
as
recorded
in
the
two
transcripts.
The
highest
goal
of
pediatric
medicine
is
prevention
of
illness.
This
Report
does
nothing
to
accomplish
this.
To
the
contrary,
children
will
be
placed
at
higher
risk
of
exposure
to
neurotoxic
pesticides
if
this
is
allowed
to
become
part
of
EPA's
pesticide
policy.
R­
1
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1993.
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1992.
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