The essay of food and science

The essay of food and science

Review

Artificial sweeteners—do they bear a carcinogenic risk?

M. R. Weihrauch* & V. Diehl

Department of Internal Medicine I of the University of Cologne, Cologne, Germany

Received 12 June 2003; accepted 6 January 2004

Artificial sweeteners are added to a wide variety of food, drinks, drugs and hygiene products. Since

their introduction, the mass media have reported about potential cancer risks, which has contributed

to undermine the public’s sense of security. It can be assumed that every citizen of Western

countries uses artificial sweeteners, knowingly or not. A cancer-inducing activity of one of these

substances would mean a health risk to an entire population. We performed several PubMed

searches of the National Library of Medicine for articles in English about artificial sweeteners.

These articles included ‘first generation’ sweeteners such as saccharin, cyclamate and aspartame, as

well as ‘new generation’ sweeteners such as acesulfame-K, sucralose, alitame and neotame. Epide-

miological studies in humans did not find the bladder cancer-inducing effects of saccharin and

cyclamate that had been reported from animal studies in rats. Despite some rather unscientific

assumptions, there is no evidence that aspartame is carcinogenic. Case–control studies showed an

elevated relative risk of 1.3 for heavy artificial sweetener use (no specific substances specified) of

>1.7 g/day. For new generation sweeteners, it is too early to establish any epidemiological evidence

about possible carcinogenic risks. As many artificial sweeteners are combined in today’s products,

the carcinogenic risk of a single substance is difficult to assess. However, according to the current

literature, the possible risk of artificial sweeteners to induce cancer seems to be negligible.

Key words: aspartame, cancer, cyclamate, saccharin, sweeteners

Introduction

The fondness of humans for sweet foods is inborn: studies

have proved a preference for sweet-tasting nutrition in new-

borns [1]. Therefore, mankind has always added sweet sub-

stances to their food. The first recorded sweetener was honey,

which was used in the ancient cultures of Greece and China

[2]. Honey was later replaced by saccharose, common sugar,

which was originally obtained from sugar cane. During the

World Wars, sugar beets were the major source of saccharose.

The first artificial sweetener was saccharin, which was syn-

thesized in 1879 by Remsen and Fahlberg. It was well

accepted during World Wars I and II because of its low

production costs and the shortcoming of regular sugar [2]. As

economies recovered and living standards increased after the

wars, sugar became affordable. With a growing candy and fast

food industry, obesity increased in the Western societies, as

we know today from our daily clinical practice. Since the

1950s, the reasons for using saccharin have shifted from cost

to calorie reduction. A profitable market for calorie-reduced

‘diet products’ evolved, in which sugar was substituted or

supplemented with artificial sweeteners. However, saccharin

was known not only for its extreme sweetness, but also for its

bitter aftertaste, so that there was a growing need for new

improved taste, calorie-reduced substances. A breakthrough in

the artificial sweetener industry was achieved with cyclamate

in the 1950s, which provided a better taste than saccharin. In

addition, it blended very well with saccharin. Both substances

were mixed together with other additives and were sold as

‘Sweet’n’Low’, which became a huge success in the USA.

Because of its characteristics, cyclamate was not only used in

tablet or liquid form (‘table top sweetener’), but also proved

suitable for sweetening soft drinks.

The first insecurity shook the artificial sweetener market in

1970, when the Food and Drug Administration (FDA) banned

cyclamate from all dietary foods and fruits in the USA. The

FDA had become suspicious of induced cancer in experimen-

tal animals [3]. In all other countries, cyclamate is still used

today, especially in combination with other sweeteners. The

next step in the development of artificial sweeteners was the

approval of aspartame in 1981 and its marketing as ‘Nutra-

Sweet’. For the first time, dairy products such as yogurts were

calorie-reduced and could be sold with the prefixes ‘diet’ or

‘light’ [4]. The first three substances, saccharin, cyclamate and

aspartame, are referred to as ‘first generation sweeteners’.

These were followed by new generation or second genera-

tion sweeteners such as acesulfame-K, sucralose, alitame

*Correspondence to: Dr M. R. Weihrauch, Immunologisches Labor Haus 16, Uniklinik Koeln, Joseph-Stelzmann-Strasse 9, 50924 Koeln, Germany. Tel: +49-221-4784488; Fax: +49-221-4785912; E-mail: martin.weihrauch@uni-koeln.de

Annals of Oncology 15: 1460–1465, 2004

doi:10.1093/annonc/mdh256

q 2004 European Society for Medical Oncology

and neotame, which have quite different key market areas, as

shown in Table 1 (from Lindley [4]). However, even the new

sweeteners have similar limitations to the older ones. The

taste is often accompanied by a bitter and metallic aftertaste

and does not provide the ‘realistic’ and ‘voluminous’ mouth-

feel of regular sugar. The combination of many, synergic arti-

ficial sweeteners has led to an improvement of the quality of

sweetened products. In soft drinks, a combination of acesul-

fame-K, aspartame and others has found broad application (as

shown in Figure 1).

Today, many people have mixed feelings when using artifi-

cial sweeteners, because they associate news about possible

cancer risks with these substances. Particularly in the 1980s,

when many sweeteners were newly synthesized and intro-

duced to the food market, the public press reported on the

ostensible carcinogenic effects of sweeteners. News articles

frequently lacked a fundamental scientific background or were

inattentively investigated, and added to a public insecurity.

Even some of the scientific publications in reliable medical

journals, which caught media attention, were not well

researched, and ignored common statistical knowledge as

described later. During the last decade, the cancer-inducing

effect of artificial sweeteners has not been discussed as fre-

quently as in earlier years, although some of the long-term

studies about saccharin and cyclamate have recently been

completed and published.

Methods

Several PubMed searches of the National Library of Medicine were per-

formed. Relevant preclinical, clinical and epidemiological studies on artifi-

cial sweeteners and possible health risks were identified. All searches

focused on English language journals only, but were not limited to a cer-

tain period of time. Where appropriate, cited references of articles were

also reviewed. Key words for the PubMed search included ‘artificial

sweetener’, ‘cancer’ and ‘carcinogenic’, as well as all artificial sweetener

names. To present an overview, the studies were sorted by the investigated

artificial sweetener, and will be discussed separately.

Results

Saccharin

Saccharin is the oldest chemical sugar substitute and the best

researched of all sweeteners. More than 50 studies have been

published about saccharin in laboratory rats. Approximately

20 study groups analyzed the effect of saccharin in one gene-

ration of rats, which were exposed to high doses of saccharin

for at least 1.5 years. Usually, the doses administered included

a high concentration of 5% of the various forms of saccharin

in the diet, and in several cases, animals started the study at

6 weeks of age. Except for one study, none of the 20 groups

found significantly more neoplasias in the saccharin-fed ani-

mals than in controls. The positive study reported an increased

incidence of bladder cancers [5]. However, ACI rats were

used in this trial, which are frequently infected with the blad-

der parasite Trichosomoides crassicanda and are therefore sus-

ceptible to saccharin-induced bladder cell proliferation [6].

After many ‘one generation’ studies, ‘two generation’ stu-

dies were conducted feeding the parent (F0) and the following

Table 1. Current artificial sweeteners and their key market areas

(taken from Lindley [4])

Sweetener Key market areas

Acesulfame-K North America, Europe and Asia

Alitame Oceania, South/Central America

Aspartame North America, Europe and Asia

Cyclamate Europe and Asia

Neohesperidine DC Europe and Japan

Neotame USA

Saccharin Asia, Europe and USA

Stevioside Asia

Sucralose North America

Thaumatin Europe and Asia

Figure 1. Two product labels of a diet soda, taken from the USA (A) and Germany (B). In the USA, only aspartame is used in this soda, whereas the

same product is sold in Germany with an artificial sweetener combination of cyclamate, acesulfame-K and aspartame.

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generation (F1) with saccharin. In these studies, an increased

risk for bladder cancer could be consistently proven for the F1 generation. Taylor et al. [7] showed that especially male rats

developed bladder tumors in up to 30% of all animals at a dose

of 7.5% saccharin of their diet. Later trials, the largest with

2500 F1 generation rats [8], found that the risk for bladder can-

cers increases with a saccharin concentration of 4%. Because

of these results, saccharin was prohibited in Canada. In the

USA, since 1981, saccharin-containing products have had to be

labeled with a warning that saccharin can cause cancer in lab-

oratory animals. However, the National Institute for Environ-

mental Health Sciences, which issues a biannual report,

removed saccharin as a potential cancer-causing agent, because

it could be shown that the cancer-inducing mechanisms in rats

do not apply in humans. Ascorbic acid (vitamin C), when fed in

similar doses as saccharin, could also cause bladder cancer in

rats; this could be prevented by adding prophylactic ammonium

chloride. Rodents have a high urine osmolarity, which

enhances the precipitation of calcium phosphate-containing

crystals, which are cytotoxic to the superficial layer of the

bladder epithelium, leading to regenerative hyperplasia and

tumors [9].

Takayama et al. [10] in 1998 published a long-term study

on 20 monkeys, of three species, that were treated with

sodium saccharin (25 mg in the diet/kg daily for 5 days a

week) for up to 24 years. Sixteen monkeys served as controls.

None of the animals developed bladder cancer or urothelial

proliferations. The study was criticized for the small number

of monkeys and for the relatively low dosage of saccharin,

which corresponds to a daily diet-soda consumption of 1.5 l in

a 70-kg person [11]. The first studies about the cancerogenous

risk of saccharin in humans were only of descriptive design.

In the UK, a longitudinal study did not show an increase in

bladder cancer incidence during World War II, when saccharin

consumption was high [12]. The same authors analyzed

19 709 death certificates from the UK between 1966 and 1972

and compared the bladder cancer mortality between diabetics,

who used artificial sweeteners more frequently, and non-

diabetics. They did not find any significant differences

between the groups [13]. A Danish study could not detect an

increase of bladder cancer mortality in people aged up to

30 years old, who were born between 1941 and 1945, when

saccharin use was higher than in the years before and after

[14]. The authors concluded that an exposition to saccharin

in utero does not increase bladder cancer incidence during the

first three decades of life. A case–control study from China

published in 1997 analyzed different risk factors in 254

bladder cancer patients and 254 controls [15]. They reported

an odd ratio of 3.9 for bladder cancer in patients with frequent

saccharin use of at least 19 consumptions per year for at least

15 years. However, this study has to be critically assessed as

to its worth, because it was unable to identify the elevated risk

of bladder cancer in smokers, which was proven by other

large trials [16–18]. There are many case–control studies

from the USA and Europe about bladder cancer risk factors,

which not only investigate saccharin as a possible cause, but

also the use of artificial sweeteners in general. Therefore, they

will be discussed later in this review.

Cyclamate

Sodium cyclamate entered the US market after its FDA

approval in 1951 [19]. Owing to a study by Wagner in 1970

[20], which found an increased incidence of bladder carci-

nomas in rats, the use of cyclamate was prohibited in several

countries, including the USA and UK. Further evaluations by

the Cancer Assessment Committee of the Center for Food

Safety and Applied Nutrition of the FDA, by the Scientific

Committee for Foods of the European Union and by the WHO

concluded that cyclamate is not a carcinogen, and readmitted

it to the food market [21].

Cyclamate is converted to a metabolite, cyclohexylamine,

which has been reported to be rather toxic [22]. In experi-

ments with rats and dogs, cyclohexylamine caused testicu-

lar atrophy and impairment of spermatogenesis [23–26].

Takayama et al. [21] conducted a long-term toxicity study

with cyclamate in non-human primates, as described before

for saccharin. Twenty-one monkeys were fed either 100 or

500 mg/kg cyclamate per day over 24 years, and compared

with 16 controls. A dose of 500 mg/kg corresponds to � 30 calorie-reduced drinks. In 1994, after 24 years, the remaining

14 cyclamate and 16 control monkeys were killed and

autopsied. In the cyclamate group, three animals showed

malignancies, whereas none were found in the controls. The

tumor stages and histologies of the cancers were a metastatic

adenocarcinoma of the colon (500 mg/kg), a metastatic hepa-

tocellular carcinoma (500 mg/kg) and a local well-differen-

tiated papillary adenocarcinoma of the prostate (100 mg/kg).

In addition, three benign tumors were found in the treatment

group, an adenoma of the thyroid gland and two leiomyoma

of the uterus, whereas the control group remained free of

tumors. The authors concluded that there is no evidence for

carcinogenicity of sodium cyclamate, because the tumors in

the treatment groups were of different histologies and the

tumors occurred at a rate frequently observed in monkeys. In

particular, no bladder carcinomas were reported as in the rat

study, which had led to the ban of cyclamates. The trial of

Takayama et al. [21] was critcized for the small number of

animals, which was too low to reach any significance or to

confirm a negative result [27]. In addition, the critics claimed

that the tumor incidence in the treatment group (33%) was

higher than the spontaneous neoplasia rate in respective

monkey strains, and unlikely to be a chance occurrence. There

are no descriptive or case–control studies of cyclamate in

humans, because it was approved after saccharin, and products

contained mixtures of both artificial sweeteners. It has to be

assumed that most consumers have used both saccharin and

cyclamate since the introduction of cyclamate.

Aspartame

Aspartame entered the market in 1981 as the third artificial

sweetener, and was free of any suspicions regarding

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carcinogenicity. Animal studies showed that aspartame does

not have any cancer-inducing effects, even in very high doses

[28, 29]. DNA repair assays for the evaluation of genotoxicity

of substances did not show any DNA-damaging properties for

aspartame, cyclamate, saccharin, acesulfame-K or sucralose

[30]. Fifteen years after the approval of aspartame, the Journal

of Neuropathology and Experimental Neurology published an

article by Olney et al. [31] with the title ‘Increasing brain

tumor rates: Is there a link to aspartame?’, which received tre-

mendous attention from the mass media, as well as the scienti-

fic community. The authors hypothesized that the increasing

rate of brain tumors in humans since 1980 could possibly be

explained by the introduction of aspartame. They supported

their hypothesis with an FDA trial in 320 Sprague–Dawley

rats. Twelve rats developed malignant brain tumors after

receiving an aspartame-containing feed for 2 years [32]. They

argued that another trial had shown that the aspartame

molecule acquires mutagenic activity when nitrosated [33].

The publication of Olney et al. [31] led to heavy criticism of

the scientific community, whereas the laymen press suggested

abstaining from aspartame-sweetened products [34]. In an

editorial, Ross [35] demonstrated the weaknesses of the Olney

study. He explained that Olney et al. [31] linked two events

that incidentally occurred during roughly the same time

period: the increase of brain tumors and the introduction of

aspartame. This correlation is not admissible in epidemiology,

and is called ‘ecological fallacy’. There was no information

available regarding whether the individuals who developed

brain tumors consumed aspartame. As Ross states, one might

also invoke home computers, VCR usage or the depletion of

the ozone layer to argue trends in brain tumors. In addition,

the introduction of aspartame and the rising brain tumor rate

occurred almost simultaneously. For the development of brain

tumors, a certain latency would have been required. The study

that showed an increased brain tumor incidence in aspartame-

fed rats, which gave rise to the argument of Olney et al.,

could not be confirmed by later trials [36]. Ross [35]

suggested evaluating the link between aspartame exposure and

brain tumors in a case–control or cohort study.

Indeed, a case–control study on aspartame consumption was

conducted in children with brain tumors [37]. The study group

compared 56 patients with 94 controls in terms of aspartame

use and other known and suspected risk factors, such as

maternal vitamin consumption, cured meat intake, passive

smoke exposure, X-ray exposure and family history of brain

cancer. They observed no elevated brain tumor risk to the child

from maternal consumption of aspartame during pregnany, nor

did they find elevated risks during any trimester of pregnancy

or during breast-feeding. After the questionable study of Olney

et al. [31], Schwartz [38] wrote a letter to the Western Journal

of Medicine, which was published in 1999. Schwartz hypoth-

esized a link between aspartame and the increase of breast

cancer. He argued that aspartame is partly metabolized to

methanol, which itself is converted to formaldehyde, which

accumulates within cells and induces cancer [39]. In the same

issue of the journal, Tichopoulos [40] responded to the letter.

He explained that the increase of the breast cancer rate

occurred before the introduction of aspartame, and has been

declining during the last few years [39, 41]. He concluded that

Schwartz also succumbed to an ecological fallacy.

New generation sweeteners

Except for the toxicological animal data required for FDA

approval, there are no larger studies that investigate the poten-

tially hazardous effects of second generation sweeteners. None

of the substances such as acesulfame-K, neohisperidine,

alitame or sucralose has been suspected to cause cancer or to

be genotoxic.

Epidemiological studies in humans

After cyclamate and aspartame had entered the food market,

diseases such as bladder cancer could not be linked to the

consumption of saccharin alone, because most consumers used

different artificial sweeteners. Also, substances were mixed in

food products to improve the taste. Therefore, most epidemio-

logical studies in humans relate to sweetener consumption in

general, and not to single substances. The most important pub-

lications in this field are case–control studies. Many of these

trials were conducted with small patient groups of up to 350

bladder cancer patients in the years 1965–1986 [42–46].

None of them showed a significantly increased risk of bladder

carcinoma for artificial sweetener use. A study from the UK

[47] included 622 existing and 219 new cases of bladder can-

cer, and matched them to hospital-based controls for age and

sex. The study group found an increased relative risk (RR) for

non-smoking males [RR 2.2; 95% confidence interval (CI)

1.3–3.8] and non-smoking females (RR 1.6; 95% CI 0.8–

3.2), but not for smokers. Sweetener use was defined as regu-

lar use for over 1 year at least 5 years prior to diagnosis.

The most recent case–control study was published by

Sturgeon et al. [48] with 1860 bladder cancer patients and

3934 controls. They examined different factors, among which

were smoking, urinary tract infection, coffee consumption, his-

tory of cystolithiasis and genetic predisposition for the risk of

inducing bladder cancer. Artificial sweetener consumption was

classified as ‘low’ (<1680 mg per day) or ‘heavy’ (>1680 mg

per day). The risk of bladder cancer was not associated with

low sweetener use in 966 patients and 3410 controls. Heavy

sweetener consumption (31 patients, 78 controls) led to a sig-

nificantly increased RR of 1.3 (95% CI 0.9–2.1). Also, high

coffee consumption of >50 cups per week was associated with

an RR of 1.4, and therefore was comparable to heavy artificial

sweetener use or the history of one to two urinary tract infec-

tions (RR 1.3). The authors scrutinized the bladder cancer

histologies. Heavy artificial sweetener use was associated with

higher grade, poorly differentiated tumors.

Conclusions

Owing to the existing studies, the following statements can be

made about the carcinogenic potential of artificial sweeteners.

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Saccharin induces bladder cancer in rats, when fed in high

doses. However, rodents react to most sodium salts, such as

sodium ascorbate, with urothel proliferation and neoplasia of

the bladder.

Heavy artificial sweetener use (>1680 mg per day) leads to

an increased relative risk of 1.3 for bladder cancer in humans.

A more precise determination of the exact agents is not

possible, because many artificial sweeteners are combined in

current food products.

Despite unscientific articles in the mass media and scientific

press, there is no evidence that the artificial sweetener aspar-

tame bears a carcinogenic risk.

The approvals of new generation sweeteners (acesulfame-K,

sucralose, alitame and neotame) are too recent to establish any

epidemiological evidence about possible carcinogenic risks.

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