1
Sodium
Cyanide:
WOE
Comparison
Of
Human
And
Animal
Studies
WILLIAM
DYKSTRA,
PH.
D.

U.
S.
EPA
OFFICE
OF
PESTICIDE
PROGRAMS
APRIL
5,
2006
2
Registered
Product
Registered
Product

Sodium
Cyanide
(
NaCN)


Formulation
°
Granular
containing
98%
NaCN
as
the
active
ingredient
(
ai)


Application
°
Post­
harvest
fumigant
applied
to
citrus
3
Regulatory
Statute
Regulatory
Statute

Tolerances
are
established
in
the
40
CFR
180.130
for
hydrogen
Cyanide
(
HCN)
in/
on
citrus
at
50
ppm
(
50
mg
of
HCN
per
Kg
of
citrus)
4
Chronic
Reference
Dose
(

Chronic
Reference
Dose
(
RfD
RfD)


Chronic
reference
dose
(
RfD)
for
HCN

Located
in
the
agency's
Integrated
Risk
Information
System
(
IRIS)
database

Suitable
for
assessment
of
chronic
dietary
risks
°
Based
on
the
No­
Observed­
Adverse
Effect­
Level
(
NOAEL)

of
10
mg/
kg
bw/
day
in
a
2­
year
rat
feeding
study
°
Established
at
0.02
mg/
kg
bw/
day.
5
HCN
Dosage
HCN
Dosage

Extremely
and
acutely
toxic
to
humans
by
the
oral
route

Fatal
dose
in
humans

Estimated
to
be
1.0
mg/
kg
bw
(
FDA,
1956)


Lowest
fatal
dose
in
humans

Estimated
to
be
0.56
mg/
kg
bw
(
Gettler
and
Baine,

1938)


Subject
found
in
a
coma
6
Determination
of
Dietary
Risk
Determination
of
Dietary
Risk
70
kg
person
1
average
orange
(
160
g)
(
including
peel)

50
ppm
HCN
tolerance
level
Corresponding
dose
0.1
mg/
kg
bw
=

1/
10
of
a
fatal
dose
in
humans
7
Clinical
Trials
Clinical
Trials

The
HCN
team
was
not
able
to
identify
any
studies
in
laboratory
animals
suitable
for
assessment
of
acute
dietary
risks,
but
they
did
identify
the
potentially
useful
clinical
trial
on:


AMYGDALIN
(
Laetrile)
8
Laetrile
Human
Studies
Laetrile
Human
Studies

Cancer
treatments

National
Cancer
Institute
decided
to
conduct
a
large
definitive
study
of
Laetrile
9
Laetrile
Human
Studies
Laetrile
Human
Studies

Clinical
trial

178
cancer
patients
were
treated
with
Amygdalin
(
Laetrile)
plus
a
"
metabolic
therapy"
10
Details
of
the
Study
Details
of
the
Study

Intravenous
dose
for
21
days

Orally
at
a
dose
of
0.5
g
(
3X)
daily
at
the
standard
regimen
Or
Orally
at
0.5
g
(
4X)
times
daily
at
the
high
dose
regimen

Improvement
of
malignant
disease
Or
Severe
clinical
deterioration
11
Cyanide
Affects
Cyanide
Affects

Amygdalin
releases
HCN
upon
enzymatic
action
of
beta­
glucosidase
in
the
GI
tract

High
levels
of
blood
cyanide

Clinical
signs
and
symptoms
of
nausea,

vomiting,
headaches,
dizziness,
and
mental
obtundation.
12
Cyanide
Toxicity
Cyanide
Toxicity

Symptoms
of
cyanide
toxicity
seen
following
oral
exposure,
or
intravenous
therapy,
were
enhanced
when
two
0.5
g
oral
doses
were
taken
at
the
same
time,
or
shortly
apart,
to
compensate
for
a
missed
dose.


The
single
dose
of
0.5
g
of
Amygdalin
was
determined
to
be
a
"
minimally
toxic"
dose

The
double
dose
was
generally
regarded
as
"
toxic"

(
Moertel
et
al,
1982)
13
Mode
of
Action
Mode
of
Action

Cyanide
competitively
inhibits
the
enzyme
cytochrome
oxidase
in
the
electron
transport
system
of
the
mitochondria
and
prevents
utilization
of
cellular
oxygen
14
Laetrile
Study
Laetrile
Study

Oral
dose
of
Amygdalin

0.5
g
(
500
mg)
administered
3
or
4
times
daily

The
single
dose
of
500
mg
of
Amygdalin
has
the
potential
to
release
30
mg
of
HCN
or
0.4
mg
HCN/
kg
bw
for
a
70
kg
person
15
Additional
Human
Data
Additional
Human
Data

The
Quarterly
Report
of
the
Association
of
Food
and
Drug
Officials
by
A.
J.
Lehman
(
FDA,
1956).


Total
oral
dose
of
20
to
30
mg
sodium
cyanide
or
0.2
mg
HCN/
kg
bw
administered
to
demonstrate
thiocyanate
in
saliva
without
apparent
adverse
effect

Lack
of
data
16
Selection
of
Selection
of
RfD
RfD

Comparison
of
the
acute
LD50
studies
in
animals

Range
from
2­
8
mg
CN/
kg
bw
(
ATSDR,
2004)


Chronic
study
NOAEL
of
10
mg/
kg
bw/
day

Cyanide
is
much
more
hazardous
when
administered
all
at
once
rather
than
throughout
the
day
due
to
metabolism
to
thiocyanate
17
Comparison
to
Animal
Studies
Comparison
to
Animal
Studies

Comparing
the
animal
LD50s
of
2­
8
mg
CN/
kg
bw
with
fatal
human
doses
of
1
mg/
kg
bw,


The
cyanide
review
(
WHO,
2004)
suggests
that
humans
may
be
less
able
than
rodents
to
detoxify
cyanide
because
of
lower
concentrations
of
sulfur
donors
in
humans.
18
Dose
Selection
Dose
Selection

Limitations
of
the
clinical
study
on
amygdalin

OPP's
HCN
risk
assessment
team
concluded:

°
Oral
administration
of
500
mg
of
amygdalin,

equivalent
to
30
mg
of
HCN
or
approximately
0.4
mg/
kg
bw
HCN
provided
a
reasonable
basis
to
assess
acute
dietary
risks
from
ingestion
of
citrus
containing
residues
of
HCN.
19
Team
Recommendations
Team
Recommendations

The
equivalent
lowest­
observed­

adverseeffect
level
(
LOAEL)
of
0.4
mg
HCN/
kg
bw
with
uncertainty
factors
of
10x
for
intraspecies
variations

A
second
factor
of
10x
to
account
for:


Severity
of
effect,
steepness
of
dose­
response

500
mg
amygdalin
per
administration
was
a
minimal
effect
level
and
not
a
NOAEL.
20
Comparison
to
Endpoints
Comparison
to
Endpoints

The
acute
RfD
is
0.4
mg/
kg
bw
÷
100
=
0.004
mg/
kg
bw

The
acute
RfD
is
1/
5
that
of
the
chronic
RfD
in
IRIS

The
acute
RfD
is
250x
less
than
the
reported
fatal
dose
in
humans
of
approximately
1
mg/
kg
bw
(
FDA,
1956)


140x
less
than
the
lowest
fatal
dose
in
humans
of
0.56
mg/
kg
bw
(
Gettler
and
Baine,
1938)


50x
less
than
the
unsubstantiated
NOAEL
for
CN
in
humans
of
0.2
mg/
kg
bw
(
FDA,
1956).


HED
scientists
believe
that
use
of
the
acute
RfD
is
appropriate
whenever
cyanide
exposure
is
expected
to
occur
all
at
once.
21
HCN
Charge
to
the
HSRB
HCN
Charge
to
the
HSRB

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.
