Document ID: EPA-HQ-ORD-2006-0310-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-17T04:00Z

Page
1
of
16
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
APR
13,
2006
MEMORANDUM:
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
SUBJECT:
Initial
Ethical
Review
of
MITC
Human
Odor
Threshold
and
Eye
Irritation
Studies
FROM:
John
M.
Carley
TO:
Anna
Lowit,
HED
REF:
MRID
44400401
Russell,
M.,
Rush,
T.
(
1996)
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation.
Unpublished
study
performed
by
Sensory
Testing
Laboratory,
School
of
Medicine,
Univ.
of
California,
Davis,
and
Zeneca
Ag
Products
Western
Research
Center,
Richmond
CA.
Project
numbers
MITC­
UCD­
1A­
1993
and
MITC­
UCD­
1B­
1994;
Report
no.
RR
96­
049B.
136
p.

MRID
46546601
AMVAC
(
2005)
Raw
Data
for
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Detection
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation:
Supplement
to
MRID
44400401.
Unpublished
document.
43
p.

MRID
46558201
Metam
Sodium
Task
Force
(
2005)
Raw
Data
for
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Detection
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation:
Second
Supplement
to
MRID
44400401.
Unpublished
document.
13
p.

MRID
46584901
University
of
California,
Davis,
Human
Subjects
Review
Committee
Records
of
HS
Protocol
89­
488,
90­
605R,
91­
665R,
94­
601R,
95­
553R,
96­
547R,
and
97­
324R.
Unpublished
documents.
39
p.

The
original
report
(
MRID
44400401)
combines
two
independent
studies 
one
to
establish
an
odor
threshold,
and
one
to
measure
eye
irritation 
in
a
single
report.
Because
the
two
studies
were
conducted
separately
and
raise
different
concerns,
this
review
deals
with
each
of
them
in
turn.
The
first
supplemental
report
(
MRID
46546601)
provides
additional
information
about
the
ethical
conduct
of
the
eye
irritation
study.
The
second
and
third
supplements
(
MRIDs
46558201
and
46584901)
address
the
ethical
conduct
of
the
odor
threshold
study.
Page
2
of
16
I
have
performed
an
initial
review
of
available
information
concerning
the
referenced
documents.
This
review
characterizes
the
ethical
conduct
of
the
research
in
terms
of
both
current
ethical
standards
and
ethical
standards
prevailing
when
the
studies
were
conducted.
Each
review
applies
the
"
Summary
Framework
for
Ethical
Assessment
Using
Seven
Criteria
of
Emanuel
et
al."
developed
by
the
EPA
Science
Policy
Committee's
Human
Studies
Work
Group.
The
completed
"
framework"
is
attached.
This
framework
was
derived
from
the
work
of
Emanuel,
et
al.
(
2000),
which
summarizes
seven
general
principles
for
ethical
treatment
of
human
subjects
in
clinical
research.
The
Emanuel
article
was
primarily
directed
at
those
who
consider
proposals
for
new
medical
research
and
decide
which
are
worthy
of
funding
or
approval.
These
are
very
different
decisions
from
those
we
in
EPA
must
make
when
we
determine
whether
we
can
ethically
consider
already­
completed
human
studies.

The
Emanuel
article
reflects
current
standards
for
ethical
research
prevailing
in
the
U.
S.
This
research
was
conducted
in
the
U.
S.
in
1992­
95
in
an
institution 
the
University
of
California
at
Davis 
holding
a
"
multi­
project
assurance"
from
HHS/
OPRR
promising
compliance
with
the
Common
Rule.
It
asserts
compliance
with
both
the
Common
Rule
and
the
Declaration
of
Helsinki.
I
have
considered
both
standards
to
have
prevailed
when
the
research
was
conducted.

I.
Ethics
Review
of
the
Odor
Threshold
Study
A.
Summary
Assessment
of
Ethical
Conduct
of
the
Research
Here
is
a
summary
of
my
observations
about
the
odor
threshold
study
under
the
seven
headings
used
in
the
Emanuel
framework.
Supporting
details
are
in
the
first
attachment.

1.
Value
of
the
Research
to
Society:
The
study
has
never
been
published,
suggesting
that
its
purpose
was
not
mainly
to
obtain
generalizable
knowledge.
The
study
may,
however,
provide
some
information
that
could
help
inform
EPA's
assessment
of
human
health
risks
of
MITC.
Its
stated
purpose
was
"
to
determine
the
human
olfactory
threshold
for
MITC."

2.
Scientific
Validity
of
the
Research:
I
defer
to
others
for
a
full
review
of
the
scientific
validity
of
this
study.
If
it
were
determined
not
to
have
scientific
validity,
it
would
also
not
be
ethically
acceptable.

3.
Subject
Selection:
Methods
of
recruitment
are
not
described.
Subjects
were
33
healthy
males
and
females
aging
from
18
to
34,
drawn
from
the
university
community
surrounding
the
testing
institution.
There
is
no
evidence
suggesting
bias
in
their
selection
or
that
any
subjects
were
from
an
especially
vulnerable
population.

4.
Risk­
Benefit
Ratio:
The
research
was
characterized
by
the
investigator
in
correspondence
with
the
IRB
at
different
times
as
of
both
"
no
risk"
and
"
minimal
risk."
The
investigator
did
not
change
this
characterization
when
MITC
was
Page
3
of
16
added
to
the
list
of
odorants
he
was
already
testing.
There
is
no
documentation
of
how
risks
were
characterized
to
subjects.
Benefits
to
society
are
not
reported.
There
is
no
documentation
of
how
risks
and
benefits
were
weighed
by
the
investigators
or
the
overseeing
IRB.
Participants
were
compensated
$
25
for
participating
in
the
study.

5.
Independent
Ethical
Review:
MRID
46584901
documents
IRB
approval
by
the
University
of
California,
Davis
Human
Subjects
Review
Committee,
initially
in
1989
and
in
annual
renewals
for
several
years
thereafter,
excluding,
however,
1992
and
1993,
when
the
MITC
odor
threshold
study
was
actually
conducted.
The
description
of
the
study
submitted
to
the
IRB
is
much
broader
than
the
MITC
study
reported
here,
and
it
is
not
clear
what
the
IRB
approved.
Neither
a
protocol
nor
any
informed
consent
material
concerning
the
MITC
testing
using
the
olfactometer
is
available.
The
IRB
did
not
waive
written
informed
consent,
or
respond
to
the
investigator's
request
for
a
waiver
of
written
informed
consent,
until
three
years
after
the
MITC
work
was
completed.

6.
Informed
Consent:
Orally
informed
oral
consent
is
asserted
(
MRID
46558201)
There
is
no
documentation
or
description
of
what
candidates
were
told
to
inform
their
consent,
or
of
the
process
by
which
consent
was
sought.
The
investigator
requested
from
the
IRB
a
waiver
from
the
standard
requirement
of
the
Common
Rule
for
written
consent;
the
IRB
did
not
respond
to
this
request
until
after
this
research
was
completed.

7.
Respect
for
Potential
and
Enrolled
Subjects:
The
privacy
of
subjects
was
not
compromised
in
the
report.
The
freedom
of
subjects
to
withdraw
from
the
research
was
not
addressed.

B.
Compliance
with
Ethical
Standard
Prevailing
when
the
Research
Was
Conducted
Numerous
ethical
deficiencies
are
apparent
when
this
study
is
reviewed
against
the
principles
of
the
Declaration
of
Helsinki
(
1989),
with
which
the
author
asserts
compliance,
and
the
Common
Rule,
which
the
IRB
was
obliged
to
apply
under
the
terms
of
the
Multi­
Project
Assurance
they
held
from
HSS/
OPRR
at
the
time
of
the
research:

 
Declaration
of
Helsinki
Basic
Principle
#
2:
"
The
design
and
performance
of
each
experimental
procedure
involving
human
subjects
should
be
clearly
formulated
in
an
experimental
protocol
which
should
be
transmitted
for
consideration,
comment
and
guidance
to
a
specially
appointed
committee
independent
of
the
investigator
and
the
sponsor
.
.
.
."

The
protocol
for
this
research 
especially
the
work
with
MITC
and
the
olfactometer 
was
not
clearly
formulated.
Based
on
the
records
of
the
IRB,
this
"
project"
began
with
mailing
11
million
"
scratch­
and­
sniff"
odor
surveys
by
the
National
Geographic
Society,
and
later
changed
into
testing
some
100­
150
people
a
year
in
the
university
community.
Page
4
of
16
The
MITC
work
was
an
aspect
of
this
later
phase,
and
MITC
was
one
of
several
chemicals
used
in
testing
for
olfactory
threshold.

 
Declaration
of
Helsinki
Basic
Principle
#
5:
"
Every
biomedical
research
project
involving
human
subjects
should
be
preceded
by
careful
assessment
of
predictable
risks
in
comparison
with
foreseeable
benefits
to
the
subject
or
to
others.
.
.
."

If
a
careful
assessment
of
risks
and
benefits
was
conducted,
it
was
not
reported.

 
Declaration
of
Helsinki
Basic
Principle
#
9:
"
In
any
research
on
human
beings,
each
potential
subject
must
be
adequately
informed
of
the
aims,
methods,
anticipated
benefits
and
potential
hazards
of
the
study
and
the
discomfort
it
may
entail.
He
or
she
should
be
informed
that
he
or
she
is
at
liberty
to
abstain
from
participation
in
the
study
and
that
he
or
she
is
free
to
withdraw
his
or
her
consent
to
participation
at
any
time.
The
physician
should
then
obtain
the
subject's
freely­
given
informed
consent,
preferably
in
writing.

The
primary
report
is
entirely
silent
about
consent,
and
the
information
provided
by
the
investigator
to
the
IRB
about
consent
was
irrelevant
to
the
research
with
MITC.
The
IRB
failed
to
notice
or
respond
to
the
investigator's
inappropriate
request
for
waiver
of
the
customary
requirement
for
written
informed
consent.

 
Declaration
of
Helsinki
Basic
Principle
#
12:
"
The
research
protocol
should
always
contain
a
statement
of
the
ethical
considerations
involved
and
should
indicate
that
the
principles
enunciated
in
the
present
Declaration
are
complied
with."

No
such
statement
appears
in
the
protocol.

 
Common
Rule
§
111(
a)(
2):
[
In
order
to
approve
research
covered
by
this
policy
the
IRB
shall
determine
that]
"
Risks
to
subjects
are
reasonable
in
relation
to
anticipated
benefits,
if
any,
to
subjects,
and
the
importance
of
the
knowledge
that
may
reasonably
be
expected
to
result."

IRB
records
do
not
evidence
any
discussion
of
either
risks
or
benefits
of
the
research.

 
Common
Rule
§
111(
a)(
4):
[
In
order
to
approve
research
covered
by
this
policy
the
IRB
shall
determine
that]
"
Informed
consent
will
be
sought
from
each
prospective
subject
.
.
."

IRB
records
do
not
evidence
any
discussion
of
informed
consent.

 
Common
Rule
§
111(
a)(
5):
[
In
order
to
approve
research
covered
by
this
policy
the
IRB
shall
determine
that]
"
Informed
consent
will
be
appropriately
documented,
in
accordance
with,
and
to
the
extent
required
by
Sec.
26.117."

IRB
records
do
not
provide
evidence
that
the
board
noticed
or
discussed
the
investigator's
request
for
waiver
of
written
informed
consent.

 
Common
Rule
§
115:
IRB
Records
Page
5
of
16
IRB
records
of
this
research
fall
well
short
of
the
requirements
of
the
Common
Rule.

 
Common
Rule
§
116:
General
requirements
for
informed
consent
The
content
of
the
oral
informed
consent
process
is
not
documented.
It
cannot
be
determined
whether
it
was
consistent
with
these
requirements
of
the
Common
Rule.

 
Common
Rule
§
117:
Documentation
of
informed
consent.

(
a)
Except
as
provided
in
paragraph
(
c)
of
this
section,
informed
consent
shall
be
documented
by
the
use
of
a
written
consent
form
approved
by
the
IRB
and
signed
by
the
subject
or
the
subject's
legally
authorized
representative.
(
c)
An
IRB
may
waive
the
requirement
for
the
investigator
to
obtain
a
signed
consent
form
for
some
or
all
subjects
if
it
finds
either:
(
1)
That
the
only
record
linking
the
subject
and
the
research
would
be
the
consent
document
and
the
principal
risk
would
be
potential
harm
resulting
from
a
breach
of
confidentiality.
Each
subject
will
be
asked
whether
the
subject
wants
documentation
linking
the
subject
with
the
research,
and
the
subject's
wishes
will
govern;
or
(
2)
That
the
research
presents
no
more
than
minimal
risk
of
harm
to
subjects
and
involves
no
procedures
for
which
written
consent
is
normally
required
outside
of
the
research
context.
In
cases
in
which
the
documentation
requirement
is
waived,
the
IRB
may
require
the
investigator
to
provide
subjects
with
a
written
statement
regarding
the
research.

Informed
consent
is
not
documented
for
this
research.
The
failure
either
to
document
consent
or
to
waive
the
Common
Rule
requirement
to
document
consent
is
a
serious
shortcoming
in
the
conduct
of
this
odor
threshold
study.
Given
the
investigator's
assertion,
however,
that
informed
oral
consent
was
obtained,
this
lapse
does
not
in
my
judgment
amount
to
clear
and
convincing
evidence
that
this
study
was
fundamentally
unethical.

Available
documentation
suggests
that
the
IRB
noticed
neither
the
lack
of
any
consent
materials
nor
the
investigator's
request
for
waiver
of
written
consent
during
the
first
several
years
they
reviewed
this
research.
After
the
MITC
work
had
been
completed
they
waived
written
consent
based
on
an
argument
from
the
investigator
that
applied
only
to
the
mail­
out
survey
work
completed
years
earlier.

C.
Standards
for
Judging
Ethical
Acceptability
On
February
6,
2006,
EPA
published
a
final
rule,
"
Protections
for
Subjects
in
Human
Research,"
effective
on
April
7,
2006.
Section
26.1704
of
that
regulation
provides
in
pertinent
part:

EPA
shall
not
rely
on
data
from
any
research
initiated
before
[
April
7,
2006,
the
effective
date
of
the
final
rule]
if
there
is
clear
and
convincing
evidence
that
the
Page
6
of
16
conduct
of
the
research
was
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent),
or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted.

In
addition,
section
26.1703
of
the
final
rule
provides
in
pertinent
part:

EPA
shall
not
rely
on
data
from
any
research
involving
intentional
exposure
of
any
human
subject
who
is
a
pregnant
woman
(
and
therefore
her
fetus)
or
child.

I
have
applied
the
standards
in
sections
26.1704
and
26.1703
in
arriving
at
the
conclusions
below.

D.
Conclusions
All
subjects
were
at
least
18
years
old.
Female
subjects
said
they
were
not
pregnant;
this
was
a
requirement
to
participate
in
the
research.
Section
26.1703
does
not
prohibit
reliance
on
this
study.

Although
there
are
serious
gaps
in
the
documentation
of
the
ethical
conduct
of
this
study,
there
is
no
clear
evidence
that
the
research
was
intended
to
harm
participants,
or
that
it
was
fundamentally
unethical
in
other
ways.
Deficient
documentation
does
not
itself
constitute
evidence
that
the
ethical
conduct
of
this
study
was
deficient
relative
to
standards
prevailing
when
it
was
conducted.

From
the
documentation
available
I
have
identified
many
deficiencies
relative
to
the
standards
of
the
1989
Declaration
of
Helsinki
and
the
Common
Rule,
with
both
of
which
the
study
asserts
compliance.
These
ethical
deficiencies
do
not,
in
my
judgment,
amount
to
"
clear
and
convincing
evidence"
that
this
study
was
"
fundamentally
unethical."
This
review,
however,
does
not
take
a
position
on
either
the
persuasiveness
of
the
evidence
or
the
overall
significance
of
the
identified
deficiencies
relative
to
the
prevailing
ethical
standards.
This
decision
is
deferred
pending
review
of
the
research
by
the
Human
Studies
Review
Board
as
required
by
EPA
regulation
before
EPA
takes
an
action
relying
on
this
study.

II.
Ethics
Review
of
the
Eye
Irritation
Study
A.
Summary
Assessment
of
Ethical
Conduct
of
the
Research
Here
is
a
summary
of
my
observations
about
the
eye
irritation
study
under
the
seven
headings
used
in
the
Emanuel
framework.
Supporting
details
are
in
the
second
attachment.

1.
Value
of
the
Research
to
Society:
The
study
has
never
been
published,
suggesting
that
its
purpose
was
not
mainly
to
obtain
generalizable
knowledge.
The
study
Page
7
of
16
may,
however,
provide
some
information
that
could
help
inform
EPA's
assessment
of
human
health
risks
of
MITC.

Its
purpose
was
stated
in
the
study
report
as
"
to
determine
the
concentrations
of
MITC
vapor
that,
after
various
periods
of
exposure,
would
produce
no
observable
irritation
responses
in
the
eyes
of
normal,
human
volunteer
test
subjects."
In
the
informed
consent
materials
the
purpose
was
stated
as
"[
t]
he
State
of
California
wants
to
establish
eye
irritation
levels
for
.
.
.
MITC
as
a
potential
warning
signal
to
exposed
workers.
.
.
.
[
T]
his
study
is
designed
to
provide
these
data."

2.
Scientific
Validity
of
the
Research:
I
defer
to
others
for
a
full
review
of
the
scientific
validity
of
this
study.
If
it
were
determined
not
to
have
scientific
validity,
it
would
also
not
be
ethically
acceptable.

3.
Subject
Selection:
Subjects
were
healthy
males
and
females
aged
18
to
67,
drawn
from
the
community
of
the
testing
institution.
It
is
impossible
to
be
sure
how
many
subjects
actually
participated,
since
it
is
reported
that
many
of
them
took
part
in
more
than
one
phase
of
this
four­
phase
study
under
different
identifiers.
It
appears
likely
that
subjects
included
at
least
some
students
of
the
investigators,
and
perhaps
also
colleagues
or
employees
of
the
investigators.
This
could
lead
to
either
or
both
undue
influence
in
recruiting
or
bias
in
reporting
subjective
effects.
I
found
no
other
indication
that
subjects
were
members
of
particularly
vulnerable
populations.

4.
Risk­
Benefit
Ratio:
Risks
to
subjects
were
characterized
as
transient
eye
irritation
and
tearing.
The
study
report
does
not
address
steps
taken
to
minimize
risks
to
subjects,
or
possible
alternative
methods
to
obtain
similar
information.
Expected
societal
benefits
are
not
discussed
in
the
report,
or
in
the
documentation
of
the
ethics
committee's
review.
There
is
no
discussion
of
how
societal
benefits
were
balanced
against
the
risks
to
individual
subjects.
Participants
were
compensated
for
participating
in
each
phase
of
the
study,
$
60­
250
depending
on
its
duration.

5.
Independent
Ethical
Review:
Initial
approval
and
annual
renewals
with
protocol
revisions
were
provided
by
a
registered
IRB
and
are
documented.
There
is
no
documentation
of
IRB
discussion.
Documentation
of
risk
minimization
and
of
risk/
benefit
balancing
is
weak,
and
recruiting
of
students
or
employees
as
subjects
could
have
involved
undue
influence.

6.
Informed
Consent:
Consent
materials
are
brief
but
clear,
and
include
all
elements
required
by
the
Common
Rule.

7.
Respect
for
Potential
and
Enrolled
Subjects:
The
privacy
of
subjects
was
not
compromised.
They
were
free
to
withdraw
at
any
time,
although
compensation
would
have
been
reduced
for
early
withdrawal.

B.
Compliance
with
Ethical
Standard
Prevailing
when
the
Research
Was
Page
8
of
16
Conducted
Some
minor
deficiencies
are
apparent
when
this
study
is
reviewed
against
the
principles
of
the
Declaration
of
Helsinki
(
1989),
with
which
it
asserts
compliance,
and
the
Common
Rule,
which
the
IRB
was
obliged
to
apply
under
the
terms
of
the
Multi­
Project
Assurance
from
HHS/
OPRR
held
by
UC­
Davis
at
the
time
of
this
research.

Although
documentation
of
risk
reduction
and
societal
benefits
is
weak,
and
there
is
some
possibility
of
undue
influence
in
the
recruitment
as
subjects
of
students
of
the
investigators,
there
is
no
clear
evidence
that
the
conduct
of
this
research
fell
short
of
Common
Rule
standards.

C.
Standards
for
Judging
Ethical
Acceptability
On
February
6,
2006,
EPA
published
a
final
rule,
"
Protections
for
Subjects
in
Human
Research,"
effective
on
April
7,
2006.
Section
26.1704
of
that
regulation
provides
in
pertinent
part:

EPA
shall
not
rely
on
data
from
any
research
initiated
before
[
April
7,
2006,
the
effective
date
of
the
final
rule]
if
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical
(
e.
g.,
the
research
was
intended
to
seriously
harm
participants
or
failed
to
obtain
informed
consent),
or
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
at
the
time
the
research
was
conducted.

In
addition,
section
26.1703
of
the
final
rule
provides
in
pertinent
part:

EPA
shall
not
rely
on
data
from
any
research
involving
intentional
exposure
of
any
human
subject
who
is
a
pregnant
woman
(
and
therefore
her
fetus)
or
child.

I
have
applied
the
standards
in
sections
26.1704
and
26.1703
in
arriving
at
the
conclusions
below.

D.
Conclusions
All
subjects
were
at
least
18
years
old.
Female
subjects
said
they
were
not
pregnant;
this
was
a
requirement
to
participate
in
the
research.
Section
26.1703
does
not
prohibit
reliance
on
this
study.

Although
there
are
some
minor
gaps
in
the
documentation
of
the
ethical
conduct
of
this
study,
there
is
no
clear
evidence
that
the
research
was
intended
to
harm
participants,
or
that
it
was
fundamentally
unethical
in
other
ways.
Deficient
documentation
does
not
itself
constitute
evidence
that
the
ethical
conduct
of
this
study
was
deficient
relative
to
standards
prevailing
when
it
was
conducted.
Page
9
of
16
From
the
documentation
available
I
have
identified
only
minor
deficiencies
relative
to
the
standards
of
the
1989
Declaration
of
Helsinki,
with
which
the
study
asserts
compliance,
and
the
Common
Rule.
These
deficiencies
do
not,
in
my
judgment,
amount
to
"
clear
and
convincing
evidence"
that
this
study
was
"
fundamentally
unethical."
This
review,
however,
does
not
take
a
position
on
either
the
persuasiveness
of
the
evidence
or
the
overall
significance
of
the
identified
deficiencies
relative
to
the
prevailing
ethical
standards.
This
decision
is
deferred
pending
review
of
the
research
by
the
Human
Studies
Review
Board
as
required
by
EPA
regulation
before
EPA
takes
an
action
relying
on
this
study.

Attachments
Cited
reference:

Emanuel,
E.;
Wender,
D.;
Grady,
C.
(
2000)
What
Makes
Clinical
Research
Ethical?
JAMA
283:
2701­
2711.
Page
10
of
16
Attachment
1:
Odor
Threshold
Framework
for
Ethical
Assessment
Using
Seven
Criteria
of
Emanuel
et
al.
1
April
13,
2006
MRID
44400401
Russell,
M.,
Rush,
T.
(
1996)
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation.
Unpublished
study
performed
by
Sensory
Testing
Laboratory,
School
of
Medicine,
Univ.
of
California,
Davis,
and
Zeneca
Ag
Products
Western
Research
Center,
Richmond
CA.
Project
numbers
MITC­
UCD­
1A­
1993
and
MITC­
UCD­
1B­
1994;
Report
no.
RR
96­
049B.
136
p.

MRID
46558201
Metam
Sodium
Task
Force
(
2005)
Raw
Data
for
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Detection
Threshold
And
Human
No
Observable
Effect
Level
for
Eye
Irritation:
Second
Supplement
to
MRID
44400401.
Unpublished
document.
13
p.

MRID
46584901
University
of
California,
Davis.
Human
Subjects
Review
Committee
records
of
HS
Protocols
89­
488,
90­
605R,
91­
665R,
94­
601R,
95­
553R,
96,547R,
and
97­
324R.
Unpublished
documents.
39
p.

1.
Value:
The
study
has
never
been
published,
suggesting
that
its
purpose
was
not
mainly
to
obtain
generalizable
knowledge.
The
study
may,
however,
provide
some
information
that
could
help
inform
EPA's
assessment
of
human
health
risks
of
MITC.
Its
stated
purpose
was
"
to
determine
the
human
olfactory
threshold
for
MITC."

a.
What
was
the
stated
purpose
of
the
research?
"
to
determine
the
human
olfactory
detection
threshold
for
MITC"
(
44400401
p.
12)

b.
Does
it
evaluate
a
diagnostic
or
therapeutic
intervention
that
could
lead
to
improvements
in
health
or
well­
being?
No.

c.
Does
it
test
a
hypothesis
that
can
generate
important
knowledge
about
structure
or
function
of
human
biological
systems,
with
or
without
immediate
practical
application?
No.

d.
Will
society
benefit
from
the
knowledge
gained
from
this
research?
Will
its
results
be
disseminated?
It
has
not
been
published.

e.
What
government,
organization,
company
and/
or
institution(
s)
funded
the
research?
Metam
Sodium
Task
Force
2.
Scientific
Validity:
I
defer
to
others
for
a
full
review
of
the
scientific
validity
of
this
study.
If
it
were
determined
not
to
have
scientific
validity,
it
would
also
not
be
ethically
acceptable.

a.
Did
the
research
have
a
clear
scientific
objective?
See
1(
a)
above.

b.
Was
the
research
designed
using
accepted
principles,
methods,
and
reliable
practices?
I
defer
to
the
science
reviewer.
The
equipment
is
reported
to
have
been
"
specifically
designed
and
constructed
for
this
project."
(
44400401,
p.
13)
Page
11
of
16
c.
In
what
way
were
human
subjects
intentionally
dosed
in
this
research,
and
what
were
the
endpoints
identified
or
quantified?
Subjects
were
exposed
to
an
airstream
capable
of
delivering
any
of
five
odorants
at
any
of
nine
concentrations.
Upon
each
exposure
they
reported
whether
they
could
detect
the
odorant.
No
other
endpoints
were
identified
or
quantified.

d.
Did
the
research
design
have
sufficient
power
to
definitively
test
the
objective?
I
defer
to
the
science
reviewer
e.
To
what
purpose
is
the
study
used,
or
proposed
for
use,
in
the
Agency?
To
inform
the
weight­
of­
evidence
assessment
of
MITC
for
reregistration/
tolerance
reassessment
3.
Fair
Subject
Selection:
Methods
of
recruitment
are
not
described.
Subjects
were
33
healthy
males
and
females
aging
from
18
to
34,
drawn
from
the
university
community
surrounding
the
testing
institution.
There
is
no
evidence
suggesting
bias
in
their
selection
or
that
any
subjects
were
from
an
especially
vulnerable
population.

a.
Were
the
groups
and
individuals
recruited
and
enrolled
determined
solely
on
the
basis
of
the
scientific
goals
of
the
study?
"
Thirty­
eight
human
volunteers
applied
to
be
test
subjects.
.
.
.
Applicants
were
excluded
if
they
scored
[
significantly]
below
the
mean
on
the
Smell
Identification
Test,
indicated
a
significant
history
of
smell
dysfunction,
evinced
current
symptoms
of
cold
or
allergy,
indicated
pregnancy,
or
failed
to
complete
an
initial
training
exercise
as
an
olfactometer
subject."
(
44400401
p.
12)

b.
Were
any
susceptible
groups
used
in
the
study,
such
as
children,
prisoners,
infirm,
or
impoverished?
Did
the
burden
of
participation
fall
disproportionately
on
a
particular
group?
All
subjects
were
adults;
females
said
they
were
not
pregnant.
There
is
no
indication
that
members
of
vulnerable
groups
were
recruited,
but
recruitment
methods
are
not
reported.

4.
Favorable
Risk­
Benefit
Ratio:
The
research
was
characterized
by
the
investigator
in
correspondence
with
the
IRB
at
different
times
as
of
both
"
no
risk"
and
"
minimal
risk"
(
MRID
46584901)
The
investigator
did
not
change
this
characterization
when
MITC
was
added
to
the
list
of
odorants
he
was
already
testing.
There
is
no
documentation
of
how
risks
were
characterized
to
subjects.
Benefits
to
society
are
not
reported.
There
is
no
documentation
of
how
risks
and
benefits
were
weighed
by
the
investigators
or
the
overseeing
IRB.
Participants
were
compensated
$
25
for
participating
in
the
study.

a.
Were
the
risks
to
individual
subjects
minimized?
Risks
to
subjects
are
not
identified.
The
original
protocol
sent
to
the
IRB
characterized
the
research
as
of
"
no
risk";
in
subsequent
renewal
applications
it
was
characterized
as
"
minimal
risk."
Under
the
Common
Rule
definition,
"
minimal
risk"
is
equivalent
to
the
risks
of
everyday
life.

b.
If
the
research
presents
no
health­
related
benefits
to
individual
subjects,
what
are
the
societal
benefits
in
terms
of
knowledge
from
the
study,
and
do
these
justify
the
excess
risk
to
individual
subjects?
There
is
no
discussion
of
benefits
to
society
or
others,
and
no
record
of
how
the
IRB
weighed
expected
societal
benefits
against
the
incremental
risks
to
subjects.

c.
What
compensation
was
paid
to
the
participants
in
the
study?
$
25.
Page
12
of
16
5.
Independent
Review:
MRID
46584901
documents
IRB
approval
by
the
University
of
California,
Davis
Human
Subjects
Review
Committee,
initially
in
1989
and
in
annual
renewals
for
several
years
thereafter,
excluding,
however,
1992
and
1993,
when
the
MITC
odor
threshold
study
was
actually
conducted.
The
description
of
the
study
submitted
to
the
IRB
is
much
broader
than
the
MITC
study
reported
here,
and
it
is
not
clear
what
the
IRB
approved.
Neither
a
protocol
nor
any
informed
consent
material
concerning
the
MITC
testing
using
the
olfactometer
is
available.
The
IRB
did
not
waive
written
informed
consent,
or
respond
to
the
investigator's
request
for
a
waiver
of
written
informed
consent,
until
three
years
after
the
MITC
work
was
completed.

a.
Was
the
research
asserted
to
have
been
overseen
by
an
ethics
review
body
(
ERB)?
What
ERB?
The
research
was
overseen
by
the
University
of
California,
Davis
Human
Subjects
Review
Committee.

b.
Was
the
research
subject
to
independent
review
by
individuals
unaffiliated
with
the
clinical
research?
Yes
c.
Was
the
research
conducted
in
compliance
with
the
Common
Rule?
The
research
was
initially
asserted
to
be
"
no­
risk",
and
in
subsequent
renewal
requests
as
"
minimal
risk".
The
investigator
requested
a
waiver
of
signed
consent,
but
this
was
not
acknowledged
or
approved
by
the
IRB.
A
note
to
the
file
dated
Dec
23,
1996,
and
included
in
MRID
46558201,
asserts
that
the
consent
process
was
entirely
oral.
In
the
absence
of
a
waiver
by
the
IRB
of
the
requirement
for
written
consent,
this
is
non­
compliant
with
the
Common
Rule.

d.
Does/
did
the
research
institution
(
or
any
institution
participating
in
the
research)
hold
a
Federal
Wide
Assurance
or,
previously,
Multi­
Project
Assurance
during
the
period
of
the
study?
UC­
Davis
held
a
Multi­
Project
Assurance
from
the
DHHS/
OHRP
at
the
time
of
this
research,
under
which
they
had
committed
to
comply
with
the
Common
Rule
in
all
research
with
human
subjects
conducted
at
their
institution,
without
regard
to
whether
it
was
supported
by
the
federal
government.

e.
Was
the
research
conducted
in
compliance
with
another
standard?
What
standard?
"
All
aspects
of
this
research
were
performed
in
accordance
with
the
Helsinki
Declaration
for
Testing
and
Protection
of
Human
Subjects
and
the
Human
Subject's
Bill
of
Rights."
(
44400401
p.
13)
This
assertion
is
not
supported
by
documentary
evidence.

6.
Informed
Consent:
Subjects
did
not
provide
written
consent.
Orally
informed
oral
consent
is
asserted.
There
is
no
documentation
of
the
information
provided
to
candidates
to
inform
their
consent
or
of
the
process
by
which
consent
was
sought.

a.
Does
the
research
assert
that
informed
consent
was
obtained
from
participants?
"[
T]
est
subjects
gave
consent
verbally,
rather
than
by
signing
a
document.
.
.
.
all
of
the
test
subjects
were
informed
verbally
of
the
risks
they
were
taking,
and
gave
consent
after
being
informed
of
the
risks.
They
were
not
exposed
to
any
odorants
until
they
had
given
informed
consent"
(
Supplement
p.
5)

b.
How
and
under
what
circumstances
was
informed
consent
obtained?
Methods
and
circumstances
are
not
reported,
nor
is
there
any
documentation
of
the
information
provided
to
candidates
to
inform
their
consent.

7.
Respect
for
Potential
and
Enrolled
Subjects:
The
privacy
of
subjects
was
not
compromised.
The
freedom
of
subjects
to
withdraw
from
the
research
was
not
addressed.

a.
Was
information
about
individual
subjects
managed
so
as
to
ensure
their
privacy?
Yes.

b.
Were
subjects
free
to
withdraw
from
the
research
without
penalty?
Not
reported.
Page
13
of
16
1
Emanuel,
E;
Wender,
D;
Grady,
C
(
2000)
What
Makes
Clinical
Research
Ethical?
JAMA
283:
2701­
2711.
Page
14
of
16
Attachment
2:
Eye
Irritation
Framework
for
Ethical
Assessment
Using
Seven
Criteria
of
Emanuel
et
al.
1
April
13,
2006
MRID
44400401
Russell,
M.,
Rush,
T.
(
1996)
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation.
Unpublished
study
performed
by
Sensory
Testing
Laboratory,
School
of
Medicine,
Univ.
of
California,
Davis,
and
Zeneca
Ag
Products
Western
Research
Center,
Richmond
CA.
Project
numbers
MITC­
UCD­
1A­
1993
and
MITC­
UCD­
1B­
1994;
Report
no.
RR
96­
049B.
136
p.

MRID
46546601
AMVAC
(
2005)
Raw
Data
for
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Detection
Threshold
And
Human
No
Observable
Effect
Level
for
Eye
Irritation:
Supplement
to
MRID
44400401.
Unpublished
document.
43
p.

1.
Value:
The
study
has
not
been
published,
suggesting
that
its
purpose
was
not
mainly
to
obtain
generalizable
knowledge.
The
study
may,
however,
provide
some
information
that
could
help
inform
EPA's
assessment
of
human
health
risks
of
MITC.

a.
What
was
the
stated
purpose
of
the
research?
"[
T]
o
determine
the
concentrations
of
MITC
vapor
that,
after
various
periods
of
exposure,
would
produce
no
observable
irritation
responses
in
the
eyes
of
normal,
human
volunteer
test
subjects."
(
MRID
44400401,
p.
26).
In
the
informed
consent
materials
the
purpose
was
stated
as
"[
t]
he
State
of
California
wants
to
establish
eye
irritation
levels
for
.
.
.
MITC
as
a
potential
warning
signal
to
exposed
workers.
.
.
this
study
is
designed
to
provide
these
data."
(
MRID
46546601,
p.
11)

b.
Does
it
evaluate
a
diagnostic
or
therapeutic
intervention
that
could
lead
to
improvements
in
health
or
well­
being?
No.

c.
Does
it
test
a
hypothesis
that
can
generate
important
knowledge
about
structure
or
function
of
human
biological
systems,
with
or
without
immediate
practical
application?
No.

d.
Will
society
benefit
from
the
knowledge
gained
from
this
research?
Will
its
results
be
disseminated?
It
has
not
been
published.

e.
What
government,
organization,
company
and/
or
institution(
s)
funded
the
research?
Metam
Sodium
Task
Force
2.
Scientific
Validity:
I
defer
to
others
for
a
full
review
of
the
scientific
validity
of
this
study.
If
it
were
determined
not
to
have
scientific
validity,
it
would
also
not
be
ethically
acceptable.

a.
Did
the
research
have
a
clear
scientific
objective?
See
1(
a)
above.

b.
Was
the
research
designed
using
accepted
principles,
methods,
and
reliable
practices?
I
defer
to
the
science
reviewer.

c.
In
what
way
were
human
subjects
intentionally
dosed
in
this
research,
and
what
were
the
endpoints
identified
or
quantified?
Subjects
wore
goggles
into
which
air
with
measured
concentrations
of
MITC
was
routed,
and
exposure
continued
for
durations
from
a
few
minutes
to
8
hours.
Endpoints
measured
were
subjective
judgments
of
irritation,
blink
rate,
tearing,
and
visual
acuity.
Page
15
of
16
d.
Did
the
research
design
have
sufficient
power
to
definitively
test
the
objective?
I
defer
to
the
science
reviewer
e.
To
what
purpose
is
the
study
used,
or
proposed
for
use,
in
the
Agency?
To
inform
the
weight­
of­
evidence
assessment
of
MITC
for
reregistration/
tolerance
reassessment
3.
Fair
Subject
Selection:
It
is
impossible
to
tell
how
many
subjects
actually
participated,
since
it
is
acknowledged
that
many
of
them
took
part
in
more
than
one
phase
of
this
four­
phase
study
under
different
identifiers.
It
appears
likely
that
subjects
included
at
least
some
students
of
the
investigators,
and
perhaps
also
colleagues
or
employees
of
the
investigators.
This
could
lead
to
either
or
both
undue
influence
in
recruiting
or
bias
in
reporting
subjective
effects.
There
is
no
other
indication
that
subjects
came
from
particularly
vulnerable
populations.
All
were
over
18
and
said
they
were
not
pregnant.

a.
Were
the
groups
and
individuals
recruited
and
enrolled
determined
solely
on
the
basis
of
the
scientific
goals
of
the
study?
The
supplement
indicates
that
subjects
were
to
include
students
and
"
normal
adult
volunteers",
who
would
be
contacted
"
in
person:
home
or
work";
"
in
person:
public
place";
and
through
"
in­
class
announcement."
(
MRID
46546601,
p.
25)
"
Applicants
were
excluded
if
they
reported
any
abnormal
eye
irritability,
wearing
contact
lenses,
frequent
headaches,
recent
asthma
attacks,
or
pregnancy."
(
44400401p.
27)

b.
Were
any
susceptible
groups
used
in
the
study,
such
as
children,
prisoners,
infirm,
or
impoverished?
Did
the
burden
of
participation
fall
disproportionately
on
a
particular
group?
"
Volunteers
from
the
Sacramento
Metropolitan
area
applied
to
be
test
subjects.
.
.
.
Applicants
were
excluded
if
they
reported
any
abnormal
eye
irritability,
wearing
contact
lenses,
frequent
headaches,
recent
asthma
attacks,
or
pregnancy.
These
screening
procedures
resulted
in
a
subject
population
of
70
individuals
.
.
.
who
ranged
in
age
from
18
to
67
years.
.
.
Participants
in
the
previous
odor
threshold
study
were
invited
to
participate
in
this
study
as
well,
and
they
were
used
when
possible.
.
.
.
Many
of
the
subjects
participated
in
the
study
on
several
occasions
in
the
successive
trial
series
and
when
different
exposure
levels
were
offered,
taking
new
subject
identification
numbers
on
every
occasion."
Recruiting
in
person
at
subjects'
homes
or
workplaces,
and
through
in­
class
announcements,
could
involve
undue
influence,
especially
if
subjects
were
students
or
employees
of
the
investigators,
and
could
introduce
possible
bias
in
subjective
reporting
of
effects.

4.
Favorable
Risk­
Benefit
Ratio:
The
study
report
does
not
address
steps
taken
to
minimize
risks
to
subjects,
or
possible
alternative
methods
to
obtain
similar
information.
Expected
societal
benefits
are
not
discussed
in
the
report,
or
in
the
documentation
of
the
ethics
committee's
review.
Participants
were
compensated
$
60­
250,
depending
on
the
duration
of
each
phase
of
the
study.

a.
Were
the
risks
to
individual
subjects
minimized?
Risk
minimization
is
not
directly
discussed.
Materials
submitted
to
the
IRB
emphasized
that
doses
were
low
compared
to
animal
NOAELs.
(
MRID
46546601)
The
informed
consent
materials
told
potential
subjects
"[
t]
here
is
no
known
long­
term
risk
though
you
may
experience
irritation
and
tearing
of
the
eyes
that
quickly
goes
away
at
the
end
of
exposure.
The
maximum
exposure
level
is
well
below
any
known
health
risk."
(
MRID
46546601
p.
11)

b.
If
the
research
presents
no
health­
related
benefits
to
individual
subjects,
what
are
the
societal
benefits
in
terms
of
knowledge
from
the
study,
and
do
these
justify
the
excess
risk
to
subjects?
Indirect
reference
is
made
to
the
potential
for
this
study
to
establish
threshold
levels
for
eye
irritation
that
would
help
regulatory
authorities
to
determine
safe
exposures
for
workers.
It
is
acknowledged
there
is
no
direct
benefit
to
the
subjects.
There
is
no
direct
discussion
of
benefits
to
society
or
others,
and
there
is
no
record
of
how
the
IRB
weighed
expected
societal
benefits
against
the
incremental
risks
to
subjects.
Page
16
of
16
c.
What
compensation
was
paid
to
the
participants
in
the
study?
$
60
for
a
single,
acute
exposure;
$
75
for
one­
hour
exposure;
$
150
for
four­
hour
exposure;
$
250
for
eight­
hour
exposure;
all
prorated
in
case
of
early
withdrawal.

5.
Independent
Review:
Initial
approval
and
annual
renewals
with
protocol
revisions
were
provided
by
a
registered
IRB
and
are
documented.
There
is
no
documentation
of
IRB
discussion.

a.
Was
the
research
asserted
to
have
been
overseen
by
an
ethics
review
body
(
ERB)?
What
ERB?
The
research
was
reviewed
and
approved
by
the
University
of
California,
Davis
Human
Subjects
Review
Committee.
The
IRB
required
annual
renewal
of
approval,
and
received
progress
reports
and
protocol
revisions.

b.
Was
the
research
subject
to
independent
review
by
individuals
unaffiliated
with
the
clinical
research?
Yes
c.
Was
the
research
conducted
in
compliance
with
the
Common
Rule?
UC
Davis
held
a
Multi­
Project
Assurance
from
HHS/
OPRR
at
this
time
of
this
research,
under
which
they
committed
to
comply
with
the
Common
Rule
in
all
research
they
conducted
with
human
subjects.
The
study
report
does
not
assert
compliance
with
the
Common
Rule.

d.
Does/
did
the
research
institution
(
or
any
institution
participating
in
the
research)
hold
a
Federal
Wide
Assurance
or,
previously,
Multi­
Project
Assurance
during
the
period
of
the
study?
UC­
Davis
held
a
Multi­
Project
Assurance
from
the
DHHS/
OHRP
at
the
time
of
this
research
e.
Was
the
research
conducted
in
compliance
with
another
standard?
What
standard?
"[
T]
his
study
was
conducted
in
accordance
with
the
Helsinki
Declaration
.
.
.
and
the
Human
Subject's
Bill
of
Rights."
(
p.
27)

6.
Informed
Consent:
Consent
materials
are
brief,
but
clear,
and
include
all
elements
required
by
the
Common
Rule.

a.
Does
the
research
assert
that
informed
consent
was
obtained
from
participants?
"
Each
subject
was
informed
as
to
the
nature
of
the
study
and
gave
written
consent
to
participate."
(
MRID
44400401,
p.
27).
Informed
consent
materials
were
included
in
the
supplemental
report
(
MRID
46546601.)

b.
How
and
under
what
circumstances
was
informed
consent
obtained?
Methods
and
circumstances
are
not
reported.
The
IC
materials
are
clear
that
the
subject
can
expect
no
benefit
from
participation,
and
is
free
to
withdraw
at
any
time.

7.
Respect
for
Potential
and
Enrolled
Subjects:
The
privacy
of
subjects
was
not
compromised.
They
were
free
to
withdraw
at
any
time,
although
compensation
would
have
been
reduced
for
early
withdrawal.

a.
Was
information
about
individual
subjects
managed
so
as
to
ensure
their
privacy?
Yes.

b.
Were
subjects
free
to
withdraw
from
the
research
without
penalty?
Yes,
although
compensation
would
have
been
reduced
for
early
withdrawal.
No
early
withdrawals
were
reported.

1
Emanuel,
E;
Wender,
D;
Grady,
C
(
2000)
What
Makes
Clinical
Research
Ethical?
JAMA
283:
2701­
2711.