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© by PSP Volume 37 – No 3. 2015 Advances in Food Sciences
138
SACCHARIN GENOTOXICITY
AND CARCINOGENICITY: A REVIEW
Aslı Uçar1 and Serkan Yilmaz*2
1 Ankara University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Aktaş Kavşağı Altındağ, 06340, Ankara, Turkey
2 Ankara University, Faculty of Health Sciences, Department of Midwifery, Aktaş Kavşağı Altındağ, 06340, Ankara, Turkey
ABSTRACT
In this study, it was aimed to review saccharine’s gen-
otoxicity and carcinogenicity. Saccharine is one of the
most common sweeteners like aspartame, acesulfame K,
and cyclamates. It is not metabolized in the gastrointestinal
(GI) tract and, therefore, does not affect blood insulin lev-
els. Saccharine -300 times sweeter than sucrose- is com-
monly used in many foods like soft drinks, baked goods,
jams, canned fruits, candy, salad dressings, dessert etc. Be-
cause saccharine is consumed by millions of people, in-
cluding children and even fetuses, it takes great public
health significance, and great of interest to the public about
its safety. Too many studies have been done for the safety
of saccharine. In this study, it was reviewed the all litera-
tures between 1975 and 2014 about saccharine’s safety.
According to the literature, genotoxicity and carcinogenic-
ity of saccharine is still confusing. So, consumers should
be careful to the consumption of this artificial sweetener.
KEYWORDS:
Saccharine, safety, genotoxicity, carcinogenicity, nutrition
1. INTRODUCTION
Artificial sweeteners are used as sugar substitutes in
called “zero” or “light”- beverages, foodstuffs, pharmaceu-
ticals and personnel care products [2]. They have been used
by consumers to achieve a sweet taste, for reasons of eco-
nomics, blood glucose control, or energy control [2]. The
most common sweeteners are aspartame, acesulfame K, sac-
charin, and cyclamates. The first generation of the sweetener
saccharin was produced in 1878 by Constantin Fahlberg [3].
Although saccharin was commercialized not long after its
discovery, it was not until sugar shortages during World
War I, that its use became widespread. Its popularity further
increased during the 1960s and 1970s, since saccharin is a
calorie-free sweetener [3]. Saccharin was originally listed
as GRAS. FDA proposed a ban on saccharin under the
Delaney Clause because of an association with bladder
cancer in laboratory animals in 1958 [2]. Not convinced of
saccharin's safety, because of the (inconsistent) evidence of
bladder tumors in saccharin-treated F1 male rats, the FDA
proposed a ban on its use as a food additive [4]. In 1996,
the ban was withdrawn and the zero-risk standard changed
to one of “reasonable certainty of no harm.” In 2000, sac-
charin was widely used, often in combination with other
sweeteners [2].
Saccharin (1,1-dioxo-1,2-benzothiazol-3-one) is
300 times sweeter than sucrose [5]. It is not metabolized in
the body and is heat-stable [6]. In the food industry, it is
commonly used in soft drinks, baked goods, jams, canned
fruit, candy, salad dressings, dessert toppings, and chewing
gum, in addition to being used as a tabletop sweetener. An
important characteristic of saccharin is that its sweetening
power is not reduced when heated, which makes it an ex-
cellent candidate as an additive in low-caloric and sugar-
free products. Saccharin is not metabolized in the gastroin-
testinal (GI) tract and, therefore, does not affect blood in-
sulin levels [7]. For the risk characterization of non-nutri-
tive sweeteners, the Joint Food and Agriculture Organiza-
tion/World Health Organization Expert Committee on Food
Additives (JECFA) had established an acceptable daily in-
take (ADI) of 5 mg/kg body weight for saccharin (SAC),
European Union, US FDA, Japan, France, China and Tai-
wan [8]. As per a 2010 report in Current Oncology, one
would have to drink about 800 twelve-ounce diet sodas
containing saccharin to reach doses that can induce carcin-
ogenesis [9].
Concerns with regard to the safety of saccharin are of
great public health significance and of great interest to the
public, because saccharin is consumed by tens of millions
of people, including children and even fetuses. Any evi-
dence of carcinogenesis -- and there is ample such evidence
-- of such a widely used chemical should spur health offi-
cials to minimize human exposure to it [10]
There are lots of studies about saccharin effects on
health. Some studies found that use of saccharin is associ-
ated with an increased feeling of hunger [11-13]. A rat
study showed that their diets were sweetened with saccha-
rin for over 5 weeks, presented greater weight gain and ad-
iposity, as well as a decrease in the central body tempera-
ture, when compared to glucose supplementation [14]. In
another study, it was found that when taken together, the
use of aspartame, acesulfame, cyclamate and saccharin in
© by PSP Volume 37 – No 3. 2015 Advances in Food Sciences
139
foods may be considered as safe, with regard to no effects
on CYP1A1 induction and activation of AhR and GR re-
ceptors [15]. A few epidemiological studies also found
some relationships between saccharin and bladder cancer
risk in humans [16-19], but most – and the largest – studies
found no association [20-22]. In this study, we aimed to
review geno-toxic and carcinogenic effects of saccharine.
2. METHODS
This survey was conducted to gather available infor-
mation and providing an overall perspective on the geno-
toxicity and carcinogenicity of saccharin. A literature
search on genotoxicity and carcinogenicity of saccharin
was performed in the Pubmed, Scopus, Web of Science,
Science-Direct databases from year 1975 to 2014 (Octo-
ber). From the published literature, 11 genotoxicity studies
and 13 carcinogenicity studies were analyzed.
3. RESULTS
3.1 Genotoxicity
In reports of IARC [23, 24], Ashby [25], Tennant [26]
and Williams [27], saccharin was not active in in vitro
short-term and in vivo genotoxicity tests. However, it has
been found to induce SCE in human lymphocytes and plant
cells in vitro, at doses as high as 25–50 mM [28]. Jeffrey
and Williams [29] tested the geno-toxic activity of saccha-
rin in the rat hepatocyte DNA repair assay (from F344 and
Sprague-Dawley rats). Authors have reported that saccha-
rin was negative in this assay. Sasaki et al. [30] determined
the genotoxicity of sodium saccharin in male ddY mice us-
ing comet assay on the glandular stomach, colon, liver, kid-
ney, urinary bladder, lung, brain, and bone marrow, and
24 h after treatment. A hundred, 1000 and 2000 mg/kg doses
for 3-h treatment and 2000 mg/kg dose for 24-h treatment
were orally administered to male mice. Sodium saccharin
significantly increased the DNA damage in the glandular
stomach and colon. Bandyopadhyay et al. [31] evaluated
the mutagenicity of the saccharin in the Ames/Salmonella/
microsome test and their genotoxic potential by comet as-
say in the bone marrow cells of Swiss albino mice. Fifty,
100, and 200 mg/kg bw of saccharin was orally adminis-
tered. The comet parameters of DNA were increased in the
bone marrow cells due to the sweetener-induced DNA
strand breaks. However, none could act as a potential mu-
tagen in the Ames/Salmonella/microsome test. Icsel and
Yılmaz [32] reported the interactions of fish sperm DNA
(FS-DNA) with the sodium salt of sweetener saccharin,
and its copper and zinc complexes. They used UV–VIS ti-
tration, fluorometric competition, thermal denaturation,
viscosity and gel electrophoresis measurements. They have
reported that Na(sac) and its metal complexes showed a
moderate DNA binding affinity. Frenzilli et al. [33] inves-
tigated the in-vitro activity of saccharin using alkaline and
neutral comet assays in human leukocytes. Zero, 1, 5, 25
and 50 mM concentrations of saccharin were used for each
experiment. In the first experiment, no effects were ob-
served in alkaline conditions, whereas a significant in-
crease at the dose of 50 mM at pH 8 was detected. In the
second experiment, negative results were obtained under
both pH conditions. Authors have concluded that saccharin
is negative in the SGCE assay.
3.2 Carcinogenicity
There has been some controversy about the carcino-
genicity of saccharin in the past. Some feeding studies in-
dicated that saccharin at high dosage produced tumors;
however, several animal studies demonstrated no carcino-
genic effect of saccharin. Munro et al. [34] investigated the
carcinogenicity of saccharin in groups of 60 male and
60 female Charles River rats; 0, 90, 270, 810, or 2430 mg
saccharin/kg/day were administered to the animals for a pe-
riod of 26 months. Food consumption, body weight, and
clinical examinations were conducted weekly on all rats.
Four bladder tumors were found in the treated animals. The
tumors were transitional cell papillomata. However, sac-
charin administration was not accompanied by an increase
in tumor incidence, although high doses were associated
with reduced body weight in both sexes, and decreased
TABLE 1 - Sum of the genotoxicity of saccharin.
Test material Genotoxic end-point Results References
in vitro short-term and
in vivo genotoxicity tests
- IARC [23, 24], Ashby [25],
Tennant [26]and Williams [27]
Human lymphocytes Sister chromatid exchanges + Zhang et al. [28]
Plant Sister chromatid exchanges + Zhang et al. [28]
F344 and Sprague-Dawley rats Rat hepatocyte DNA repair assay - Jeffrey and Williams [29]
Male ddY mice glandular stomach, colon, liver, kidney,
urinary bladder, lung, brain, and bone mar-
row comet assay
+ (glandular stom-
ach and colon)
Sasaki et al. [30]
Salmonella typhimurium Ames - Bandyopadhyay et al. [31]
Swiss albino mice Comet assay + Bandyopadhyay et al. [31]
Fish sperm DNA DNA binding affinity +/- Icsel and Yılmaz [32]
Human leukocytes Alkaline and neutral comet assays - Frenzilli et al [33]
Footnote: + (Positive), - (Negative)
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140
TABLE 2 -Sum of the carcinogenicity of saccharin in animal models.
Test material Carcinogenicity model Results Reference
Male and female Charles River
rats
Bladder tumors - Munro et al. [34]
Bladder tumors + Howe et al. [16]
Rats and mice Bladder tumors + Reuber [37]
Bladder tumors - Risch et al. [35]
Bladder tumors - Morgan and Wong [36]
Rats Bladder tumors + Cohen et al. [39], Zurlo and
Squire [38], Andreetta et al.
[19]
Monkey Bladder tumors - Takayama et al. [40]
Footnote: + (Positive), - (Negative)
TABLE 3 - Sum of the carcinogenicity of saccharin in epidemiological studies.
Study design Carcinogenicity model Results Reference
Human Bladder - Armstrong and Doll [41]
Human Bladder - Jensen and Kamby [42]
1953 cases and 4154 controls Colorectum - Francheschi et al. [46]
254 bladder cancer patients and
254 Controls
Bladder + Yu et al. [43]
598 cases and 1491 controls Oral cavity and pharynx - Francheschi et al. [47]
304 cases and 743 controls Oesophagus - Bosetti et al. [48]
1031 cases and 2411 controls Ovary - Bosetti et al. [49]
460 cases and 1088 controls Larynx - Bosetti et al. [50]
2569 cases and 2588 controls Female breast - Tavani et al. [51]
1294 cases and 1451 controls Prostate - Bosetti et al. [52]
767 cases and 1534 controls Renal cell - Bravi et al. [53]
51 patients and 87 controls Urinary tract + Andreatta et al. [19]
230 patients and 547 controls, stomach - Bosetti et al. [54]
326 patients and 652 controls pancreas - Bosetti et al. [54]
454 patients and 908 controls endometrium - Bosetti et al. [54]
Footnote: + (Positive), - (Negative)
longevity in male rats. Howe et al. [16] reported a signifi-
cantly increased risk for bladder cancer among saccharin
consumers. However, the work of Risch et al. [35]) and
Morgan and Wong [36] did not confirm this finding. Reu-
ber [37] reported that saccharin is carcinogenic for the uri-
nary bladder in rats and mice, and most likely is carcino-
genic in human beings. The neoplasms of the urinary blad-
der are malignant, invade and metastasize. Male rats are
more susceptible to urinary bladder carcinogenesis than fe-
male rats. Even though carcinomas of the urinary bladder
are present in rats given the higher doses of saccharin, one
was observed in a female rat given 0.5%. Experimental
studies show also that sodium saccharin induces calcium
phosphate precipitates in rat urine, which causes irritation,
hyperplasia and, ultimately, tumors [19, 38, 39]. Takayama
et al. [40] investigated the sodium saccharin (25 mg/kg)
carcinogenicity on 20 monkeys, for up to 24 years. Authors
have reported that none of the animals developed bladder
cancer or urothelial proliferations.
3.3 Epidemiological works
Armstrong and Doll [41] analyzed 19 709 deaths in
view of the bladder cancer mortality in the UK, between
1966 and 1972. They compared between artificial sweet-
ener users and non-users. Authors reported that there were
no significant differences between the groups. Jensen and
Kamby [42] studied the cancer mortality in people who
were born between 1941 and 1945. There was no significant
increase in bladder cancer. Yu et al. [43] conducted a case–
control study in 254 bladder cancer patients and 254 controls
in China. They reported that, compared with non-users, by
the use of saccharine for more than 19 times per year, and
for more than 15 years, significant associations were found.
Statistically significant associations were also found for
diseases related to the urinary system. Goodman et al. [44]
reported that there was no association for saccharin con-
sumption and renal cell carcinoma in 267 patients. Gallus
et al. [45] analysed artificial sweeteners (including saccha-
rin) and cancer incidence works conducted in Italy between
1991 and 2004, with 1953 colorectum cancer cases and
4154 controls {45, 46], 598 oral cavity and pharynx cancer
cases and 1491 controls [45, 47], 304 oesophagus cancer
cases and 743 controls [45, 48], 1031 ovary cancer cases
and 2411 controls [45, 49], 460 larynx cancer cases and
1088 controls [45, 50], 2569 female breast cancer cases and
2588 controls [45, 51], 1294 prostate cancer cases and
1451 controls [45, 52], and 767 renal cell carcinoma cases
and 1534 controls [45, 53]. Authors have reported that
there is no evidence about the increased risk of cancer and
saccharin consumption at several common sites in humans.
© by PSP Volume 37 – No 3. 2015 Advances in Food Sciences
141
Andreatta et al. [19] studied the correlation between
the urinary tract tumors (UTT) and artificial sweetener use.
51 UTT patients and 87 controls used artificial sweeteners
(including saccharin). Authors have reported that the risk
of UTT was significantly increased in long-term (≥10
years) artificial sweetener users, compared with none- arti-
ficial sweetener users. Bosetti et al. [54] investigated a case
control study with 230 patients, histologically confirmed
cancers of the stomach and 547 corresponding controls,
326 of the pancreas and 652 controls, and 454 of the endo-
metrium and 908 controls. The authors reported that sac-
charin consumption is not associated with the risk of cancer
of the stomach, pancreas, and endometrium.
4. CONCLUSION
In conclusion, according to the literature on genotoxi-
city and carcinogenity of saccharine is still confusing. So,
consumers should be careful to the consumption of this ar-
tificial sweetener.
The authors have declared no conflict of interest.
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Received: January 27, 2015
Accepted: February 24, 2015
CORRESPONDING AUTHOR
Serkan Yilmaz
Ankara University
Faculty of Health Sciences
Department of Midwifery
Aktaş Kavşağı Altındağ
Ankara, 06340
TURKEY
E-mail: syilmaz@health.ankara.edu.tr
AFS/ Vol 37/ No 3/ 2015 – pages 138 - 142
