(CANCER RESEARCH31, 1201—
1205, September19711
Acute Synergistic Toxicity and Hepatic Necrosis following
Oral Administration of Sodium Nitrite and Secondary Amines
to Mice'
Shogo Asahina, Marvin A. Friedman, Elsie Arnold, Gail N. Millar, Myra Mishkin, Yvonne Bishop, and
Samuel S. Epstein
Laboratories ofEnvironmental
ty.
Toxicology and Carcinogenesis [S. A., M. A. F., E. A., G. N. M., M. M., S. S. E./ and Laboratories of Biostatististics
B.J, Children ‘s
Cancer Research Foundation,
Inc.; Department
of Pathology, Harvard Medical School IS. S. E.J; and Department of
Biostatistics, HarvardSchool ofFublic Health fY. B.J, Boston, Massachusetts02115
SUMMARY
vegetables,
and
saprophytic
Combined
p.o.
dimethylamine
administration
of
or methylbenzylamine
sodium
nitrite
and
intake
acute synergistic toxicity, as evidenced by relative weight loss,
mortality,
and
liver necrosis.
Similar
administration
of sodium
nitrite
results
were
at intervals
up to 3 hr;
toxicity was, however, markedly reduced when sodium nitrite
was administered prior to dimethylamine. The incidence of
mortality
and liver necrosis was dependent
separating successive administrations
dimethylamine.
on the time interval
of sodium nitrite and
INTRODUCTION
Nitrosamines are a major candidate class of carcinogens
likely to be causally related to human cancer (12)
Nitrosamines act systemically and produce cancer in a wide
variety of organs of many species at the ppm dietary level (5,
13, 14); some nitrosamines are also mutagenic and teratogenic
of nitrite
Nitrosamines
obtained
was followed by single
by nitroreductases
present
in many
has been estimated
as 22 pmoles,
equivalent
to I.5 mg of NaNO2 (20); levels in excess of this have
produced acute methemoglobinemia in infants (12).
to male mice produced
when p.o. dosage of dimethylamine
water)
and parasitic bacteria. The average human daily
are formed
chemically
from the interaction
of
nitrites or oxides of nitrogen and secondary amines in acidic
conditions (17). Such reactions also occur in vitro at nearly
neutral pH in the presence of enteric bacteria (2 1), in vitro in
the gastric juice of various species including man (20), and in
vivo in the stomach of laboratory animals and man (23, 25).
Nitrosopiperidine
is formed in vivo in the small intestine
rat from piperidine and sodium nitrite (1 , 2).
of the
Combined p.o. administration
of sodium nitrite and
dimethylamine or methylbenzylamine produced inhibition of
mouse liver protein and nRNA synthesis (10) and alkylation of
guanine in liver RNA;2 these effects are characteristic of those
produced
by the corresponding
nitrosamines,
dimethylnitros
amine and methylbenzylnitrosamine . This communication
extends these studies and reports acute synergistic toxicity
(weight loss, mortality, and hepatic necrosis) following p.o.
administration
of single doses of sodium nitrite and
dimethylamine or methylbenzylamine.
(12).Although
practical
methods
fordetection
lackspecificity
and sensitivity, nitrosamines have been found in tobacco
smoke, grains, and alcoholic beverages in concentrations of<5
ppm (15 , 16, 18). Higher concentrations of nitrosamines,
particularly
dimethylnitrosamine,
have
been
found
nitrite-preserved
fish meals which were highly toxic
in
to
ruminants (7, 19); dimethylnitrosamine
is formed during
cooking of canned or smoked fish with nitrite (26). However,
even more widespread and of possibly greater significance than
nitrosamines per se are their precursors, nitrites and secondary
amines (12). Nitrite and methylbenzylamine or morpholine are
carcinogenic when fed simultaneously
to rats (22, 24);
however, these secondary amines are not naturally occurring.
Secondary amines, particularly dimethylamine, are found in
fish, fish meal, fish products, cereals, tea, flavoring agents,
crude liquors, tobacco, and tobacco smoke (12); various drugs
(piperazine,
thiocarbasone,
tolbutamide,
tryparsamide,
and
streptomycin) are also secondary amines. Inorganic nitrite is
produced from nitrate, in a wide variety of sources (plants,
MATERIALS AND METHODS
Solutions
of
dimethylamine
hydrochloride,
methylbenzylamine
hydrochloride, and sodium nitrite were
freshly prepared in distilled water and administered by gavage
to groups of adult male HaM/ICR mice (Charles River
Breeding Laboratory,
Wilmington, Mass.) maintained on
Purina chow and tap water ad libitum and housed 5 per
mesh-bottom hanging cage.
The dose-response effects of dimethylamine and sodium
nitrite
2 M.
1 Supported
by
NIH
Grants
C-65
16
and
FR-05526
and
Pollution Control Administration Contract CPA 70-17.
Received November 17, 1970; accepted April 28, 1971.
SEPTEMBER
National
Air
were
tested
by
their
combined
or
immediately
successive administration by gavage; combined dose-response
effects of methylbenzylamine and sodium nitrite were tested by
successive gavage of separate solutions. Sodium nitrite was
administered at doses of 100 and 150 mg/kg; dimethylamine
A.
Friedman,
G.
N.
Millar,
and
S.
S.
Epstein,
Acute
Inhibition
of
Liver Protein and Nuclear RNA Synthesis and Methylation of Guanine
following Oral Administration of Sodium Nitrite and Dimethylamine to
Mice, unpublished data.
1971
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I201
Asahina et aL
Table 1
Acute synergistic toxicity due to simultaneous p.o. administration ofsodium nitrite and dimethylamine hydrochloride to mice
Dose (mg/kg)Totalno.
(%)@—Dunethyl
miceSodium
weight
change
(g)Liver/body
miceSurviving
by 3 days (%)Body miceAll
ofmiceMortality
amineAll
with grossliver necrosis
weight
ratio (X 10 2)
for all miceMice
miceSurviving
Local
nitritehydro
chloride(repli cates)Mean
ized0070
S.D.―Mean
S.D.bMean
(2)0+1.3
(2)
30(2)0
(2)5
(2)18
0100
100500
50100200030100030
43100250030
25150070
1.48.5
1.68.5
1.98.5
1.98.4
1.98.2
0.80
0.80
0.90
1.00
0.80
00
00
00
00
00
1.39.0―
1.5
2.38.7
91d
1.68.6
2.18.6
0.70
0.7
5+1.3
10+0.5
1.3+1.3
1.5
2.3+1.2 +1.0
1.5+1.4
2.0‘-0.6
00
0
500
4050
2054
015050070(5)0+0.9
47150100070
(5)0+1.1
17—0.1
18—0.2
3—0.7
1.81-1.1
1.6+0.9
1.80.0
2.1÷0.2
1.3—1.5
1.88.3
1.67.9―
1.87@3(@
2.47.7―
1.375C
1.00
0.910
1@o51
0.977
49150200070
(5)19
(5)70
(2)77
24150250030
0+1.2
+1.0
7
1.20
0.953
1.357
Local
izedExten-sive
1.4+1.7
1.6+1.7
1.9+2.1
1.9+1.5
1.9+0.1
(5)0+1.7
(3)0+1.7
(3)0+2.1
(3)0+1.5
(3)0+0.1
0050040
00100040
00200040
00250040
0100030
SD.bExten-sive
S.D.bMean
0
7
00
4710
4042
967
786
0.887
14
a Variability between replicates.
b Variability
C A
5%
between
significance
d A 1% significance
mice,
all replicates
level
for
proportion
level
for proportion
combined.
of
points
of points
falling
on
falling
on one side of regression
one
side
of
Table 2
Acute synergistic toxicity due to simultaneous p.o. administration of
sodium nitrite and methylbenzylamine
hydrochloride to mice
Dose (mg/kg)No.
of
nitriteMethylbenzylamine
hydrochloride0
(%)Sodium
mice testedMortality
by 3 days
0
00
0100
800
160010
10
100
0
100
100
1000
800
1200
160010
10
10
100
10
40
90
regression
line
controls.
on controls.
minimum of 10 mice at each test dose level were replicated on
2 to 6 occasions.
Mice were observed and weighed daily up to 3 days;
survivors were killed with ether. Postmortem examination was
carried out on all animals, and the liver and both kidneys were
weighed. Livers from 10 to 20% of mice per dose group were
fixed in Tellyesniczky's solution for 24 hr; tissues were stained
with hematoxylin and eosin.
No
nitrite
nitrite
both
mortality
or either
produced
doses of
dimethylamine
of 0, 15, 30, 60, or 120 mm; second, dimethylamine
was administered and followed by sodium nitrite at intervals
of 0, 15, 30, 120, or 180 mm (Table 3). Tests based on a
1202
on
RESULTS
was administered at doses of 500, 1000, 2000, and 2500
mg/kg (Table 1); and methylbenzylamine was administered at
doses of 800, 1200, and 1600 mg/kg (Table 2). Mice given
water, dimethylamine, methylbenzylamine, and sodium nitrite
alone served as concurrent controls. Mice were tested in groups
of 10 to 15; tests with dimethylamine were more extensive
and were replicated on 2 to 5 occasions.
The effects of sequential administration of dimethylamine
(2500 mg/kg) and sodium nitrite (150 mg/kg) were
determined as follows. First, sodium nitrite was administered
and followed by a single dose of dimethylamine at subsequent
intervals
based
line based
occurred following administration of sodium
secondary amine alone. Single doses of sodium
temporary inertia; weight gain was reduced at
sodium nitrite and at the highest dose of
alone (Table
1). Combined
administration
of
sodium nitrite and dimethylamine produced acute toxicity, as
evidenced by progressive inertia, anorexia, ascites, relative
weight loss, and mortality; relative weight loss and mortality
were both clearly dose dependent (Table 1). Mortality was
similar irrespective of whether dimethylamine and sodium
nitrite
were
administered
singly
in combined
solution
or
successively in separate solutions. Dose-dependent mortality
was also seen following combined administration of sodium
nitrite and methylbenzylamine (Table 2). In general, the onset
of mortality was more rapid when sodium nitrite was
administered in combination with methylbenzylamine
rather
than with dimethylamine.
The median lethal dose of
dimethylamine,
in combination
with 150 mg/kg sodium
nitrite, was 1600 mg/kg; the median lethal dose of
CANCER RESEARCH VOL. 31
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Synergistic Toxicity from Sodium Nitrite and Amines
Table 3
Synergistic toxicity in mice due to p.o. administration ofdimethylamine
hydrochloride and sodium nitrite at timed intervals
Liver/bodyDose
(mg/kg)Interval
weight (X 10 2)
Total no.
between
of mice
hydrochlorideSodiumnitriteExtensive
doses (min)Mortality
(replicates)
S.D.@00040(4)
by 3 days (%)
(%)Dimethylamine
00150015
025000015
0No
nitrite2500150080(6)
Mean
S.D.a
0
0
0
(3)
(3)
for all mice
Mean
0
0
0
no. of mice
with
with liver necrosisMiceliver necrosis
S.D.@'Overall
7.7
8.0
8.0
0.80
0.80
0.90
LocalizedMean
00
00
00
interval between dimethylamine and
9Nitrite
dimethylamine25001501520
43
22
7@3C@ 0.859
1390
before
(2)
15
(2)
5
(2)
0
14Dimethylamine
(2)
0
1025001503020
725001506020
7250015012020
nitrite25001501565
7
7
0
0
74d
7.6
7.6
7.7
0.81
0.60
0.60
0.80
740
735
15
420
before
1725001503050(5)
252500
(6)
2500150
15060
21250015018039(4)
12080(6)
32
30
26
20
13
50 (5)
13
20
24
16
14
7•3C@ o@934
7.1―
0.921
7.4―
0.8
73d
0.826
72C
0.814
13
1981
1266
28
1468
856
23
54
13
a Variability between replicates.
b Variability
C A
1%
between
significance
mice,
level
d A 5% significance
for
all replicates
proportion
level for proportion
combined.
of
points
of points
falling
on
falling
on one side of regression
one
side
of
regression
line
based
line based
on
controls.
on controls.
Fig. 1. Centrilobular necrosis and congestion
in portal veins in a mouse which died 3 days
after p.o. administration
of 2000 mg/kg
dimethylamine in combination with 150 mg/kg
sodium nitrite. X 100.
SEPTEMBER
1971
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1203
Asahina
et aL
methylbenzylamine,
in combination with 100 mg/kg sodium
nitrite, was 1300 mg/kg.
At autopsy, no significant abnormalities were seen in mice
treated
with
sodium
nitrite,
dimethylamine,
or
methylbenzylamine alone. However, ascites and congestion of
the kidney and spleen were generally seen in surviving mice
and in those dying within 3 days of administration of sodium
nitrite and dimethylamine; such changes were minimal in
combination
groups
methylbenzylamine.
transparent,
although
involving
sodium
nitrite
and
The ascitic fluid was generally clear and
occasionally
it was hemorrhagic.
Males
dying within 24 hr after treatment had distended and
food-free stomachs which, in some cases, revealed submucosal
hemorrhages;
no free blood was found in the gastrointestinal
tract. The ratio of kidney to body weight was comparable in
all dimethylamine test and control groups; the ratio of liver to
body weight was, however, reduced in mice simultaneously
treated with high doses of dimethylamine and sodium nitrite
(Table 1).
Livers in animals from high-dosage combined treatment
groups were generally swollen and mottled and, in some cases,
hemorrhagic,
friable, and necrotic. Macroscopically, the
hepatic lesions were either extensive, involving 1 or several
lobes, or localized, involving only a discrete area in 1 or more
lobes. No necrotic liver lesions or hemorrhage was seen in any
mice treated with dimethylamine,
methylbenzylamine,
or
sodium nitrite alone.
Microscopic
examination
of livers
of mice
treated
with
sodium nitrite and dimethylamine
revealed widespread
centrilobular
and midzonal parenchymal
liver necrosis,
sinusoidal and portal congestion, and hemorrhage. In some
cases, necrosis was extensive and diffuse and included all but
immediately periportal areas (Fig. 1); the incidence and
severity
of liver necrosis
were clearly
dose related
(Table
1).
Hepatic changes were similar in mice receiving high doses of
methylbenzylamine
and sodium nitrite, except that the
necrosis
was largely
accompanied
parenchymal
by
periportal.
Necrosis
leukocytic
regeneration
was
infiltration
in surviving
reduced
and
and
minimal
mice of all combined
treatment groups. No proliferative endothelial changes were
observed in central or portal veins nor in the sinusoids; no
epithelial changes were noted in bile ducts.
In studies on sequential administration of dimethylamine
and sodium nitrite, mortality and hepatic necrosis were highest
following simultaneous administration of dimethylamine and
sodium nitrite (Chart 1; Table 3). Mortality and hepatic
necrosis were reduced in groups receiving sodium nitrite 15 or
30 mm before dimethylamine; no deaths occurred when this
interval exceeded 30 mm. Mortality and extensive hepatic
necrosis occurred in all groups receiving dimethylamine
before
sodium nitrite; the mean percentage of mortality decreased
with increasing intervals between doses.
DISCUSSION
The acute synergistic toxicity induced by combined
administration
of high doses of sodium nitrite and
dimethylamine or sodium nitrite and methylbenzylamine is
consistent with in vivo biosynthesis of nitrosamines from
amine and nitrite precursors. Liver lesions in mice treated
simultaneously with dimethylamine and sodium nitrite or
methylbenzylamine and sodium nitrite were morphologically
identical with those in mice receiving the corresponding
n it rosamine ,
dimethylnit
rosamine
or
methyl
benzylnitrosamine,
respectively (3, 4, 11). Similar liver
changes
were
induced
even
when
sodium
nitrite
and
dimethylamine
were administered
on closely separate
occasions. Toxicity, mortality, and necrosis were reduced with
increasing
w
NECROSIS
U
(EXTENSIVE
and LOCALIZED)
intervals
100% of administered
w
I4
between
successive
administrations;
nitrite
is absorbed
within
30 mm (9,
24). However, marked mortality and extensive necrosis were
observed when sodium nitrite was given as long as 3 hr after
dimethylamine,
suggesting that dimethylamine is absorbed
relatively slowly and is thus available over prolonged periods
for reaction with subsequently ingested nitrates and nitrites to
yield endogenous nitrosamines. Similarly, there was no
inhibition of mouse liver nRNA synthesis when sodium nitrite
was administered 30 mm prior to dimethylamine; however,
there was significant inhibition when dimethylamine was
administered 1 hr before sodium nitrite.2
Zonal hepatic necrosis may be induced by shock (6).
Lii
Li.
0
I-.
Lii
U
Lii
0.
20
60
0
60
120
—
NITRITE
80
@-
BEFORE DIMETHYLAMINE
DIMETHYLAMINE
BEFORE NITRITE
MINUTES BETWEEN SUCCESSIVE DOSES OF COMPOUNDS
Chart 1. Synergistic toxicity and hepatic necrosis in mice following
successive p.o. administration of dimethylamine and sodium nitrite at
timed intervals.
1204
time
such time dependency was particularly marked when sodium
nitrite was given before dimethylamine. Sodium nitrite is
absorbed very rapidly from the stomach of the mouse; 70 to
However,
were
observed
no significant
in
animals
necrotic
receiving
lesions in these experiments
sodium
nitrite
or
high
doses
of secondary
amines alone, although these produced
temporary inertia in some mice; similar results were seen
following parenteral administration (S. Asahina and S. S.
Epstein, unpublished data). Synergistic toxicity (mortality and
hepatic necrosis) resulting from combined dosage with sodium
CANCER RESEARCH
VOL. 31
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Synergistic Toxicity from Sodium Nitrite and Amines
nitrite
and
either
of 2 secondary
amines,
in the
present
experiments, is consistent with previous data on synergistic
inhibition of mouse liver protein and nRNA synthesis by
sodium nitrite and dimethylamine or methylbenzylamine (10).
The use of such toxicological and biochemical markers as
indirect indices of in vivo biosynthesis of dimethylnitrosamine,
rather than its chemical
identification,
is necessary
due to the
rapid absorption and metabolism of this particular nitrosamine
(14);however,
7-methylguanine
hasbeen
isolated
fromliver
RNA following combined administration of dimethylamine
and sodium nitrite.2 These studies further extend data on in
vivo biosynthesis of nitrosamines (1 , 2, 23—25)and are of
particular practical relevance in view of the widespread dietary
occurrence of dimethylamine (12). Synergistic carcinogenicity
has been demonstrated following combined feeding of rats
with sodium nitrite and morpholine or methylbenzylamine
(22), but neither of these amines occur naturally.
The relevance of these findings to in vivo biosynthesis of
nitrosamines in man, particularly at normal dietary levels of
nitrites and secondary amines, requires further consideration.
Critical attention should be directed to the use of secondary
amines as food-flavoring agents as well as their use as drugs, to
the drinking of water with elevated nitrate levels, and to the
propriety of continued use of nitrates and nitrites as food
additives
in
concentrations
meat
and
fish
at
presently
permissible
of500 and 200 ppm, respectively (8).
ACKNOWLEDGMENTS
We thank Dr. W. Lijinsky, Dr. S. Preussman, and Dr. B. S. Alam for
their comments.
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SEPTEMBER
1971
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I205
Acute Synergistic Toxicity and Hepatic Necrosis following Oral
Administration of Sodium Nitrite and Secondary Amines to Mice
Shogo Asahina, Marvin A. Friedman, Elsie Arnold, et al.
Cancer Res 1971;31:1201-1205.
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