Page
1
of
14
Ha
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON
D.
C.,
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
March
21,
2006
MEMORANDUM
Subject:
Transmittal
of
Charge
Questions
for
the
April
2006
Meeting
of
the
Human
Studies
Review
Board.

To:
Paul
Lewis,
Ph.
D.
Designated
Federal
Official
Human
Studies
Review
Board
Office
of
Science
Advisor
(
8105R)

From:
Jack
E.
Housenger
Associate
Director
Health
Effects
Division
(
7509C)
Office
of
Pesticide
Programs
Through:
Tina
E.
Levine,
Ph.
D.
Director
Health
Effects
Division
(
7509C)
Office
of
Pesticide
Programs
The
first
public
meeting
of
EPA's
new
Human
Studies
Review
Board
(
HSRB
or
Board)
is
scheduled
for
April
4­
6,
2006.
This
meeting
will
address
scientific
and
ethical
issues
surrounding
toxicity
studies
involving
intentional
exposure
of
human
subjects
to
eight
pesticide
active
ingredients:
aldicarb,
amitraz,
azinphosmethyl
(
AZM),
dichlorvos
(
DDVP),
ethephon,
methomyl,
oxamyl,
and
sodium
cyanide.
This
memorandum
provides
the
Board
with
a
series
of
questions
that
the
Agency
is
seeking
comment
on
in
connection
with
OPP's
ethical
and
scientific
review
of
these
studies.
Page
2
of
14
CHARGE
AND
ISSUES
FOR
HSRB
The
Agency
is
asking
the
HSRB
to
review
a
number
of
completed
intentional
dosing,
human
toxicity
studies
and
to
provide
advice
to
EPA
on
the
degree
to
which
it
is
ethically
and
scientifically
appropriate
to
rely
on
the
results
of
these
studies
in
actions
under
the
pesticide
laws.

EPA's
decisions
about
whether
it
is
ethical
to
rely
on
a
particular
intentional
exposure
human
study
will
comply
with
the
provisions
of
the
recently
promulgated
regulation
in
40
CFR
Part
26,
"
Protections
for
Subjects
in
Human
Research."
71
Fed.
Reg.
6138
(
February
6,
2006).
This
rulemaking
takes
effect
on
April
7,
2006,
and
will
thus
apply
to
all
decisions
under
discussion
during
the
HSRB's
meeting.
The
Agency,
however,
recognizes
that
application
of
the
standards
in
the
new
regulation
will
involve
the
exercise
of
judgment.
Therefore,
the
Agency
has
posed
specific
questions
about
how
to
apply
the
new
rule
when
assessing
the
ethical
conduct
of
each
study
under
review.

EPA's
evaluation
of
the
scientific
strengths
and
weaknesses
of
these
studies
is
not
limited
by
statutory
or
regulatory
standards,
and
therefore
EPA
has
considerable
discretion
about
whether
(
and
if
so,
how)
to
rely
on
a
particular
study.
The
Agency
recognizes
that
the
quality
of
the
different
studies
presented
for
the
Board's
review
varies
considerably
 
with
the
studies
showing
differences
in,
for
example,
the
numbers
of
subjects,
gender
representation,
numbers
of
treatment
groups,
the
rigor
of
observation
of
potential
adverse
events,
and
the
degree
of
control
for
confounders.
The
Agency
also
thinks
that
the
scientific
value
of
a
particular
human
study
will
depend,
in
part,
on
the
quality
of
the
rest
of
the
toxicity
data
base
available
for
the
test
compound.
Therefore,
EPA
believes
that
the
decisions
about
how
to
use
the
results
of
human
studies
must
be
made
on
a
case­
by­
case
basis,
taking
all
of
these
different
factors
into
account.
The
Agency's
Weight
of
the
Evidence
(
WOE)
documents
for
each
chemical
provide
the
Agency's
conclusions
about
how
to
use
(
or
not)
the
human
studies
in
human
health
risk
assessment
.
The
Agency
has
focused
its
questions
for
the
Board
on
the
scientific
evidence
that
supports
these
conclusions.

The
Agency's
primary
goal
for
the
first
HSRB
meeting
is
to
get
comment
and
advice
regarding
the
various
human
toxicity
studies
available
for
the
eight
chemicals
under
review.
However,
the
Agency
recognizes
that
because
we
are
at
a
very
early
stage
of
interpreting
and
applying
the
new
rule,
the
Board's
advice
will
help
to
inform
future
assessments
of
other
studies.
Page
3
of
14
Part
1.
N­
Methyl
Carbamate
Pesticides
A.
Aldicarb
Aldicarb
is
a
N­
methyl
carbamate
(
NMC)
pesticide
whose
primary
toxic
effect
is
neurotoxicity
caused
by
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
carbamylation
followed
by
rapid
recovery.
Aldicarb
can,
at
sufficiently
high
doses,
lead
to
a
variety
of
clinical
signs.
The
Agency
is
conducting
an
acute,
aggregate
(
single
chemical,
multiroute
risk
assessment
of
aldicarb.
In
addition,
aldicarb
is
a
member
of
the
N­
methyl
carbamate
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
NMCs.

1.
Ethical
considerations:

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

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

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.
Page
4
of
14
 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted
2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
a.
single
chemical,
aggregate
risk
assessment
and
b.
cumulative
risk
assessment.

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

1.
Ethical
considerations:

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

 
Whether
the
investigators'
decision
to
administer
a
dose
to
additional
subjects
in
session
3,
when
one
subject
receiving
that
dose
in
session
2
displayed
RBC
ChEI
greater
than
40%,
a
response
that
triggered
the
protocol's
anti­
escalation
provision,
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
Page
5
of
14
 
Whether
the
timing
of
the
investigators'
report
to
the
ethics
committee
of
the
adverse
effects
observed
in
one
subject
during
session
2
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;

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

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

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted
2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
Page
6
of
14
C.
Oxamyl
Similar
to
aldicarb
and
methomyl,
oxamyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation
and
is
thus
included
in
the
NMC
cumulative
risk
assessment.
The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
oxamyl.
The
Agency
is
now
considering
the
use
of
the
oxamyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
in
the
cumulative
risk
assessment
of
the
NMCs.

1.
Ethical
considerations:

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

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

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

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

 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted
Page
7
of
14
2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.

D.
Azinphos
methyl
Azinphos
methyl
(
AZM)
is
an
organophosphate
pesticide
(
OP).
Consistent
with
other
OPs,
AZM
elicits
neurotoxicity
through
the
inhibition
of
the
enzyme,
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
At
sufficiently
high
doses,
exposure
to
AZM
can
lead
to
a
variety
of
clinical
signs.
The
Agency
is
developing
an
assessment
to
estimate
risk
to
workers
from
exposure
to
AZM.
In
addition,
AZM
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
risk
assessment
for
the
OPs.

1.
Ethical
considerations:

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

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

 
Whether
the
absence
from
the
protocol
of
any
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
1996
Declaration
of
Helsinki,
Principle
#
5,
with
which
the
research
asserted
compliance)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
Page
8
of
14
b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
[
this/
each]
study:

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

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

2.
Scientific
considerations:

The
Agency's
WOE
document
and
DER
for
AZM
describe
the
study
design
and
results
of
the
AZM
repeat
dose,
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
worker
risk
assessment
and
in
the
cumulative
risk
assessment
for
the
OPs.
For
AZM,
the
Agency
has
concluded
that
the
human
toxicity
study
is
appropriate
for
developing
a
point
of
departure
for
extrapolation
of
risk
to
workers
exposed
to
AZM
via
the
dermal
and
inhalation
routes.
For
the
cumulative
risk
assessment,
the
Agency
has
determined
that
because
no
cholinesterase
inhibition
was
seen
in
the
human
toxicity
study,
it
is
not
possible
to
evaluate
whether
steady
state
had
been
reached
in
humans
at
28
days
of
exposure.
Thus,
the
Agency
has
concluded
that
the
AZM
repeat
dose,
oral,
toxicity
study
is
not
sufficiently
robust
for
informing
the
inter­
species
factor
in
the
cumulative
risk
assessment
of
the
OPs.

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
a.
worker
risk
assessment
and
b.
cumulative
risk
assessment.
Page
9
of
14
E.
DDVP
Like
AZM,
DDVP
is
an
organophosphate
pesticide
(
OP)
which
elicits
neurotoxicity
through
the
inhibition
of
acetylcholinesterase,
via
phosphorylation
of
the
active
site.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route,
multi­
duration)
risk
assessment
of
DDVP.
In
addition,
DDVP
is
a
member
of
the
OP
common
mechanism
group
and
is
thus
included
in
the
cumulative
(
multi­
chemical,
multi­
route)
risk
assessment
for
the
OPs.

1.
Ethical
considerations:

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

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

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

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
Page
10
of
14
 
Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
Gledhill
repeat
dose
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.

2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
the
conclusions
for
the
i.
single
chemical,
aggregate
risk
assessment
and
ii.
cumulative
risk
assessment.

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

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.
Page
11
of
14
F.
Ethephon
Ethephon
is
an
organophosphorus
compound
that,
upon
absorption
into
plants,
forms
ethylene
gas
which
is
an
important
component
of
the
plant
hormone
complex.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
ethephon.

1.
Ethical
considerations:

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

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

2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
Page
12
of
14
G.
Amitraz
Exposure
to
amitraz
can
result
in
neurotoxicity
as
evidenced
by
clinical
signs
such
as
ataxia,
ptosis,
emesis,
labored
respiration,
muscular
weakness,
tremors,
hypothermia
and
bradycardia.
The
Agency
is
conducting
an
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
amitraz.

1.
Ethical
considerations
a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:

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

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

 
whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
Page
13
of
14
2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
these
conclusions.

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

1.
Ethical
considerations
In
its
ethics
review
of
this
research,
EPA
did
not
identify
any
deficiencies
with
respect
to
the
ethical
conduct
of
this
research.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:

 
OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical;
and
 
whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted.
Page
14
of
14
2.
Scientific
considerations:

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

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
