Document ID: EPA-HQ-ORD-2006-0187-0018
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-23T05:00Z

Hydrogen
Cyanide/
PC
Code
045801
Subchronic
Oral
Study
(
Humans)
(
1982)/
Page
1
of
5
EPA
Reviewer:
William
Dykstra,
Ph.
D
Signature:
Reregistration
Branch
4,
Health
Effects
Division
(
7509C)
Date
EPA
Secondary
Reviewer:
Pramod
Terse,
PhD,
DVM
Signature:
Reregistration
Branch
4,
Health
Effects
Division
(
7509C)
Date
Template
version
11/
01Template
version
11/
01
TXR#:
none
DATA
EVALUATION
RECORD
STUDY
TYPE:
Subchronic
Oral
Study
(
Humans)

PC
CODE:
045801
TEST
MATERIAL
(
PURITY):
D­
mandelonitrile­
 ­
D­
glucosido­
6­
D­
glucoside;
Amygdalin
SYNONYMS:
Laetrile
CITATION:
Moertel,
CG
et
al
(
1982).
A
Clinical
Trial
of
Amygdalin
(
Laetrile)
in
the
Treatment
of
Human
Cancer.
New
England
Journal
of
Medicine,
Vol.
306,
No.
4:
201­
206,
MRID
#
46769602,
published.

Moertel,
CG
et
al
(
1981)
A
Pharmacologic
and
Toxicological
Study
of
Amygdalin.
JAMA,
Vol.
245,
No.
6:
591­
594,
MRID
#
46769601,
published.

SPONSOR:
National
Cancer
Institute,
USA.

EXECUTIVE
SUMMARY:
In
a
clinical
trial
of
Amygdalin,
one
hundred
seventy­
eight
cancer
patients
were
treated
with
amygdalin
(
Laetrile)
plus
a
"
metabolic
therapy"
consisting
of
diet,
enzymes
and
vitamins.
Amygdalin
was
administered
at
an
intravenous
dose
of
4.5
g/
m2
of
body
surface
area/
day
in
the
Standard
Dose
or
7
g/
m2
of
body
surface
area/
day
at
the
High
Dose
for
21
days.
Following
intravenous
treatment,
amygdalin
was
administered
orally
at
0.5
g
three
times
daily
at
the
Standard
Dose
Regimen
or
0.5
g
four
times
daily
at
the
High
Dose
Regimen
until
the
patient
had
definite
evidence
of
progressive
malignant
disease
or
until
severe
clinical
deterioration
occurred.
Amygdalin
releases
HCN
upon
enzymatic
action
of
$­
glucosidase
in
GI
tract
causing
high
blood
cyanide
level
and
producing
clinical
toxicity.
Clinical
signs
and
symptoms
consisting
of
nausea
(
30­
31%),
vomiting
(
17­
25%),
headaches
(
7­
8%),
dizziness
(
7­
10%),
mental
obtundation
(
4­
5%)
and
dermatitis
(
2%)
were
observed
on
occasion
following
a
single
0.5
g
oral
dose
of
amygdalin.
These
typical
symptoms
of
cyanide
toxicity
associated
with
elevated
blood
cyanide
levels
were
also
seen
when
two
0.5
g
oral
doses
were
taken
at
the
same
time,
or
shortly
apart,
to
compensate
for
a
missed
dose
or
when
consumed
raw
almonds
(
a
rich
source
of
$­
glucosidase)
following
oral
therapy.
Therefore,
the
single
dose
of
0.5
g
of
amygdalin
was
determined
to
be
a
minimally
toxic
dose,
whereas
the
double
dose
was
generally
regarded
as
frankly
toxic.
No
substantive
benefit
of
Amygdalin
therapy
was
observed
in
terms
of
cure,
improvement,
or
stabilization
of
cancer,
or
extension
of
life
span.
Thus,
amygdalin
(
laetrile)
is
a
toxic
drug
with
no
therapeutic
effect
on
cancer.
Hydrogen
Cyanide/
PC
Code
045801
Subchronic
Oral
Study
(
Humans)
(
1982)/
Page
2
of
5
The
study
is
acceptable/
non­
guideline
.

Materials
and
Methods:

1.
Patient
Selection:
Histologically
proved
one
hundred
seventy
eight
(
178)
cancer
patients
for
which
no
standard
treatment
was
known
to
be
curative
or
to
extend
life
expectancy
were
selected.
All
patients
had
no
surgery,
radiation
therapy,
or
chemotherapy
for
at
least
one
month
prior
to
being
selected
for
admission
to
the
trials.
Disabled
and
bedridden
patient
were
excluded
from
study.

Table
1.
Characteristics
of
Eligible
Patients
Characteristic
Standard
Dose
Regimen
High
Dose
Regimen
Total
Patients
No.
of
patients
Sex
Male
Female
92
72
8
6
100
78
Age
(
yr)
Median
Range
57
18­
84
60
39­
73
57
18­
84
Primary
Tumor
Colorectal*
Lung+
Breast*
Melanoma
Sarcoma
Pancreas*
Stomach*
Kidney*
Lymphoma
Ovary*
Other
(
1
or
2
each)
44
30
21
15
10
8
7
6
5
4
14
14
­
­
­
­
­
­
­
­
­
­
58
30
21
15
10
8
7
6
5
4
14
Prior
radiation
therapy
Yes
no
72
92
0
14
72
106
Prior
chemotherapy
Yes
no
109
55
9
5
118
60
(
34)
Performance
status**
0­
1
2­
3
116
48
11
3
127
51
Hydrogen
Cyanide/
PC
Code
045801
Subchronic
Oral
Study
(
Humans)
(
1982)/
Page
3
of
5
Institution
U.
Arizona
UCLA
Mayo
Clinic
NY
Memorial
19
40
82
23
­
­
14
­
19
40
96
23
*
Adenocarcinoma
+
Non­
small­
cell
carcinoma
**
Eastern
Cooperative
Oncology
Group
Score:
0,
fully
active
to
4,
totally
disabled
2.
Treatment
Methods:
The
amygdalin
was
supplied
by
the
Pharmaceutical
Resources
Branch
of
the
NCI
in
vials
containing
3
g
of
lyophilized
RS­
amygdalin
(
racemic
mixture)
and
for
oral
use
in
tablets
containing
0.5
g
of
R­
amygdalin.
The
routes,
dosage,
and
schedule
of
amygdalin
treatment
were
chosen
to
be
consistent
with
current
Laetrile
practice.
"
All
patients
were
fully
informed
about
the
experimental
and
un­
orthodox
nature
of
the
treatment
program
as
well
as
any
possible
alternative
treatment
available
to
them.
A
signed
form
giving
informed
consent,
approved
by
the
Human
Subjects
Committee
at
each
of
the
four
participating
centers,
was
obtained
from
each
patient."

For
the
standard
regimen,
the
intravenous
doses
were
administered
in
21
daily
injections
at
a
daily
dose
of
4.5
g
per
square
meter
of
body­
surface
area.
The
intravenous
dose
was
given
either
on
consecutive
days
(
121
eligible
patients)
or
during
weekdays
only
(
57
patients).
After
completion
of
the
intravenous
phase
of
the
study,
oral
maintenance
therapy
was
initiated
at
a
dose
of
0.5
g
given
three
times
a
day.

In
the
high
dose
regimen,
the
intravenous
dose
the
intravenous
doses
were
administered
in
21
daily
injections
at
a
daily
dose
of
7.0
g
per
square
meter
of
body­
surface
area.
After
completion
of
the
intravenous
phase
of
the
study,
oral
maintenance
therapy
was
initiated
at
a
dose
of
0.5
g
given
four
times
a
day.
"
Metabolic
therapy"
of
large
doses
of
vitamins,
minerals,
and
pancreatic
enzymes
were
also
administered
to
patients
in
the
standard
and
high
dose
regimens.

Before
therapy,
a
pertinent
medical
history
was
obtained
from
patient
and
a
complete
physical
examination
was
given
including
a
chest
x­
ray
film,
blood
counts,
and
blood
chemistry
determinations.
The
evaluation
was
repeated
after
the
intravenous
course,
after
the
first
two
weeks
of
oral
treatment,
and
every
five
weeks
thereafter.
In
addition,
whole­
blood
cyanide
levels
were
determined
two
hours
after
the
first
morning
dose
of
oral
amygdalin
(
a
time
to
peak
cyanide
levels)
at
the
completion
of
intravenous
treatment,
48
hours
after
the
initiation
of
oral
treatment,
and
at
every
subsequent
reevaluation.
If
the
morning
blood
cyanide
level
was
between
2
to
3
Fg/
ml
at
48
hours
after
the
initiation
of
oral
therapy,
daily
blood
levels
of
cyanide
were
measured
until
they
had
stabilized
without
clinical
signs
of
toxicity.
If
the
blood
cyanide
level
was
found
to
be
3
Fg/
ml
or
greater
at
any
time,
therapy
was
permanently
discontinued.

Amygdalin
treatment
was
continued
until
the
patient
had
definite
evidence
of
progressive
malignant
disease
or
until
severe
clinical
deterioration.
Hydrogen
Cyanide/
PC
Code
045801
Subchronic
Oral
Study
(
Humans)
(
1982)/
Page
4
of
5
Results:

Mild
and
transient
adverse
clinical
signs
were
noticed
during
intravenous
and
oral
amygdalin
treatment
(
table
2).
Although
blood
cyanide
levels
after
intravenous
administration
were
"
negligible
or
not
detectable",
it
is
plausible
that
some
breakdown
of
amygdalin
with
cyanide
release
might
have
occurred.
In
the
previous
study
by
Moertel
et
al.,
1981
showed
that
amygdalin
given
intravenously
(
4.5
g/
sq
m/
day)
was
excreted
unchanged
in
the
urine
and
produced
no
clinical
or
laboratory
evidence
of
toxicity.
In
contrast,
a
few
patients
receiving
oral
amygdalin
had
a
syndrome
of
headache,
dizziness,
mental
obtundation,
nausea
and
vomiting.
These
symptoms
subsided
promptly
when
the
oral
amygdalin
treatment
was
discontinued.
These
clinical
signs
were
also
seen
in
the
previous
oral
study
by
Moertel
et
al.,
1981.

Table
2.
Toxicity
of
Amygdalin
Therapy
Toxic
Reaction
Route
Intravenous
Oral
%
of
178
patients
%
of
132
patients
Nausea
31
30
Vomiting
25
17
Headache
7
8
Dizziness
7
10
Mental
obtundation
4
5
Dermatitis
2
2
Discussion:

Hydrogen
cyanide
(
HCN)
is
extremely
acutely
toxic
by
the
oral
route
with
a
fatal
dose
in
humans
estimated
to
be
50­
90
mg
total
or
1
mg/
kg
BW
(
FDA,
1956).
The
lowest
fatal
dose
reported
in
humans
was
estimated
as
0.56
mg/
kg
BW
cyanide
(
form
not
specified)
(
Gettler
and
Baine,
1938).
However,
these
data
were
obtained
from
the
case
history;
furthermore,
analytical
measurements
of
the
time
lack
the
precision
of
current
technology.
Similarly,
both
sodium
and
potassium
cyanide
have
lethal
doses
(
calculated
as
HCN)
given
as
200
mg
total,
representing
81
and
110
mg
HCN,
respectively,
which
also
fall
within
the
range
for
HCN
given
above
(
FDA,
1956).

In
the
Moertel
et
al
studies
(
1981,
1982),
amygdalin
was
administered
at
an
intravenous
dose
of
4.5
g/
m2
of
body
surface
area/
day
for
21
days
in
the
Standard
Dose
or
7
g/
m2
of
body
surface
area/
day
for
21
days
at
the
High
Dose.
Following
intravenous
treatment,
amygdalin
was
administered
orally
at
0.5
g,
three
times
daily
at
the
Standard
Dose
Regimen
or
0.5
g,
four
times
daily
at
the
High
Dose
Regimen.
Clinical
signs
and
symptoms
consisting
of
nausea,
vomiting,
headaches,
dizziness,
metal
obtundation
and
on
a
few
occasions,
dermatitis
occurred
in
some
patients
on
occasion
following
a
single
0.5
g
oral
dose
of
amygdalin
or
when
two
0.5
g
doses
were
administered
at
the
same
time,
or
shortly
apart,
to
compensate
for
a
missed
dose
and
in
one
Hydrogen
Cyanide/
PC
Code
045801
Subchronic
Oral
Study
(
Humans)
(
1982)/
Page
5
of
5
patient
who
consumed
raw
almonds
following
oral
therapy.
Blood
levels
of
cyanide
rose
when
the
single
0.5
g
dose
was
doubled
to
two
0.5
g
doses
at
an
administration.
These
increased
blood
levels
were
associated
with
an
increase
in
the
incidence
and
severity
of
some
of
the
toxic
signs
and
symptoms
due
to
the
release
of
HCN
from
amygdalin
by
the
enzymatic
action
of
 ­
glucosidase,
an
intestinal
enzyme.
Therefore,
the
single
dose
of
0.5
g
of
amygdalin
was
determined
to
be
a
minimally
toxic
dose,
whereas
the
double
dose
was
generally
regarded
as
toxic.
In
the
Standard
Dose
study,
a
single
dose
0.5
g
of
amygdalin
results
in
29.4
mg
of
HCN
(
500
mg/
17.1
mw
of
laetrile/
hydrogen
cyanide
=
29.4
mg
of
HCN).
When
the
HCN
content
is
divided
by
the
approximate
BW
of
70
kg,
the
result
is
0.4
mg/
kg
BW/
day.

This
single
oral
dose
level
(
0.4
mg/
kg
BW)
for
HCN
has
been
identified
as
a
LOAEL
by
Moertel
et
al
(
1982)
in
comparison
to
the
human
NOAEL
of
0.2
mg/
kg
BW
for
thiocyanate
determinations
in
human
saliva
(
FDA,
1956)
and
the
LOAEL
for
cyanide
mortality
of
0.56
­
1.0
mg/
kg
BW.

References:

Gettler
AO,
Baine
JO
(
1938)
The
toxicology
of
cyanide.
Am
J
Med
Sci
195:
182­
198.

Food
and
Drug
Administration
(
FDA,
1956)
Association
of
Food
and
Drug
Officials:
Quarterly
Report
to
the
Editor
on
Topics
of
Current
Interest:
Hydrogen
Cyanide
and
Amygdalin.
AJ
Lehman,
Ph.
D.,
M.
D.,
Editor