Artificial sweeteners

Artificial sweeteners GENERAL INFORMATION Acesulfame Acesulfame is an artificial sweetener derived from acetoacetic acid. It is used in a wide range of non-medicinal products [1].

Aspartame Aspartame is a dipeptide that is used as an artificial sweetener. It is completely hydrolysed in the gastrointestinal tract to methanol, aspartic acid, and phenylalanine [2]. Aspartame appears to be a safe sweetener, and despite numerous studies of its safety during the past three decades, the incidence of serious adverse effects has been difficult to determine in controlled studies. Since one of the metabolic products of aspartame is phenylalanine, excessive use of aspartame should be avoided by patients with phenylketonuria [3–5]. Toxicity of another possible metabolic product, methanol, is unlikely, even when aspartame is used in extraordinary amounts [6,7]. Aspartame has reportedly caused angioedema and urticaria [8].

Cyclamates Sodium cyclamate is a potent sweetening agent. It has been subjected to numerous safety and carcinogenicity studies. Animal data led to warning against excessive and indiscriminate use a long time ago, causing the World Health Organization in 1967 to adopt a safety limit of 50 mg/kg. However, in 1982 a joint FAO/WHO expert committee on food additives revised this recommendation to allow for a maximum daily intake of up to 11 mg/kg of sodium or calcium cyclamate (as cyclamic acid) [9]. Nevertheless, since in certain climates and populations the amount of cyclamates in soft drinks and other beverages can exceed these limits, more epidemiological data are needed to evaluate, for example, a possible association with cancer of the uropoietic system [10] and with histological and radiological abnormalities of the small intestine and malabsorption [11].

Saccharin Saccharin and its salts are potent sweeteners, about 300 times as sweet as sucrose. It is used to sweeten foods and beverages.

Sorbitol Sorbitol, a polyhydric alcohol, is used as a sweetening agent in many oral medicinal liquids. In addition to enhancing the palatability of these liquids, it improves solution stability and reduces crystallization of syrup vehicles [12]. It is used as a sweetener in many sugar-free food ã 2016 Elsevier B.V. All rights reserved.

products and confectioneries. Sorbitol-containing food products are often recommended for patients with diabetes, because sorbitol does not raise blood glucose concentrations or require insulin for its metabolism [13].

Stevioside Stevia species are members of the family of Asteraceae (qv). Stevia rebaudiana contains steviol glycosides, such as stevioside and rebaudioside A, used as artificial sweeteners and 100–300 times sweeter than sucrose [14,15]. Steviol glycosides have been reported to have mutagenic effects in some bacteria in vitro, but the results have been variable and are thought not to be relevant to daily use of stevioside as a sweetener [16]. In a multicenter, double-blind, randomized, placebocontrolled study, 106 Chinese subjects with hypertension aged 28–75 years were given stevioside 250 mg or placebo tds for 1 year [17]. After 3 months, the mean systolic and diastolic blood pressures in those who took stevioside fell significantly: systolic from 166 to 153 mmHg and diastolic from 105 to 90 mmHg, and the effect persisted for the whole year. There were no significant changes in lipids or glucose and no adverse reactions. In a similar 2-year study in 174 subjects by the same investigators, mean systolic pressure fell from 150 to 140 mmHg and diastolic pressure from 95 to 89 and there was a reduced incidence of left ventricular hypertrophy [18]. However, in a Brazilian randomized, placebo-controlled study in patients with previously untreated mild essential hypertension crude stevioside 3.75 mg/kg/day for 7 weeks, 7.5 mg/kg/day for 11 weeks, and 15 mg/kg/day for 6 weeks had no significant effect on blood pressure compared with placebo; there were no major adverse reactions during the trial [19]. In a randomized, double-blind, placebo-controlled, study in subjects with type 1 diabetes, subjects with type 2 diabetes, and subjects without diabetes and with normal/low normal blood pressures who were randomly allocated to stevioside 250 mg tds or placebo and were followed for 3 months, systolic and diastolic pressures, glucose, and glycated hemoglobin (HbA1c) were not altered; there were no adverse reactions [20]. In a randomized, double-blind, placebo-controlled study of the stevia glycoside rebaudioside A 1000 mg/day for 4 weeks in 100 individuals with normal and low-normal blood pressures aged 18–73 there was no change in blood pressure or heart rate [21].

ORGANS AND SYSTEMS Cardiovascular Two patients with Raynaud’s phenomenon [22] and one man with fibromyalgia had all used aspartame 6–15 g/day (0.12–0.16 mg/kg/day) as well as a dietary drink containing aspartame, and no other risk factors were identified. All three described regular keyboarding to the extent of 30 hours per week but had used wrist rests, “stretch breaks,” and other steps to optimize their work practices. Complete resolution of symptoms occurred over 2 weeks after they had eliminated aspartame from the diet, despite no

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Artificial sweeteners

Psychological, psychiatric

also have a higher consumption of sorbitol-containing dietary foods. Patients on chronic hemodialysis can be predisposed to sorbitol intolerance as a result of carbohydrate malabsorption [34]. Kayexalate (sodium polystyrene sulfonate) in sorbitol is commonly used to treat hyperkalemia in patients with renal insufficiency. Case reports have documented intestinal necrosis after the administration of kayexalate in sorbitol [35,36]. In one study, there was an incidence of 1.8%, and the authors concluded that sorbitol-associated complications may not be uncommon postoperatively [37]. Furthermore, it has been suggested that some cases of idiopathic colonic ulcers in patients with renal failure are due to the effects of sorbitol. While kayexalate crystals, which are purple, irregular, and jagged, can be an incidental finding and are not known to cause injury, they are a helpful histological clue to the possibility that sorbitol has been administered [38]. Five cases of extensive mucosal necrosis and transmural infarction of the colon have been reported after the use of kayexalate and sorbitol enemas to treat hyperkalemia in uremic patients [39]. The authors also studied the effects of kayexalate sorbitol enemas in normal and uremic rats and concluded that sorbitol was responsible for colonic damage and that the injury was potentiated in uremic rats. When sorbitol alone or kayexalate sorbitol were given, extensive transmural necrosis developed in 80% of normal rats and in all the uremic rats. Following reports of colonic necrosis, the Pharmaceutical Affairs Bureau of Japan has revised the product information for enemas of polystyrene sulfonate cation exchange resin suspension in sorbitol solution for potassium removal [40]. Although a causal relation has not been established definitively, the Bureau has decided that sorbitol solution should not be used for enemas of sodium polystyrene sulfonate cation exchange resins.

Aspartame has been associated with mood disturbances, but only anecdotally [20].

Immunologic

changes in the intensity of keyboarding or other work practices. Nerve conduction velocities had been within normal limits before the withdrawal of aspartame and were not repeated.

Nervous system Headaches can follow aspartame ingestion [23]. Up to July 1991 the FDA had received over 5000 reports of adverse effects in a passive surveillance program; in this and other studies the main complaints were of neurological symptoms, and headaches accounted for 18–45% of cases [24]. It appears that some people are particularly susceptible to headaches caused by aspartame and may want to limit their consumption [25]. In a double-blind, crossover study using volunteers with self-identified headaches after aspartame, some were particularly susceptible, and their headaches were attributed to aspartame [26]. Aspartame can alter brain wave activity in epileptic children [27]. It has been associated with seizures, but only anecdotally [28]. In three non-obese individuals (two women and one man), it was suspected that heavy use of aspartame was causally related to symptoms of carpal tunnel syndrome [29]. All three reported moderate pain and tingling in the hands, especially at night, using a self-administered questionnaire for the assessment of severity of symptoms and functional status [30]. Given the ubiquity of aspartame— one manufacturer has stated that it is used in 5000 products—physicians may want to inquire about its use in patients who report symptoms of carpal tunnel syndrome.

Gastrointestinal Sorbitol is slowly absorbed by passive diffusion in the small intestine. After oral administration, it increases osmotic pressure in the bowel by drawing in water, and is thus an osmotic laxative, sometimes leading to diarrhea [31]. Bacterial fermentation of sorbitol in the large bowel is associated with increased flatulence and abdominal cramping. Sorbitol 10 g can cause flatulence and bloating, and 20 g abdominal cramps and diarrhea. Many healthy individuals are intolerant of sorbitol, and develop abdominal cramping and diarrhea with less than the usual laxative dose [32]. It has been suggested that more than 30% of healthy adults, irrespective of ethnic origin, cannot tolerate 10 g of sorbitol [33]. Certain other patients are especially sensitive to the gastrointestinal effects of sorbitol; for example, diabetics can be prone to sorbitol intolerance, because of altered gastrointestinal transit time and motility. Some of them

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The role of aspartame in hypersensitivity reactions is controversial, although there have been case reports [41]. In a multicenter, randomized, double-blind, placebo-controlled, crossover study, aspartame was more likely than placebo to cause urticaria or angioedema [42]. Aspartame can cause granulomatous septal panniculitis [43]. Lobular panniculitis has been described in a 57-year-old diabetic man who ingested large amounts of aspartame as a sweetener, in soft drinks and other products. He stopped taking aspartame and the tender subcutaneous nodules disappeared [44].

LONG-TERM EFFECTS Tumorigenicity Attempts have been made to determine the role of habitual use of the most common artificial sweeteners in the devel-

Artificial sweeteners 715 opment of urinary tract tumors in 197 patients with histologically confirmed transitional tumors and 397 controls with acute, non-neoplastic, and non-urinary tract disease admitted to a hospital between 1999 and 2006 [45]. All were interviewed about their use of artificial sweeteners and exposure to other known or suspected risk factors for urinary tract tumors. Artificial sweeteners had been used by 51 patients with urinary tract tumors (26%) and 87 controls (22%). The risk of urinary tract tumors was significantly increased in those who had used artificial sweeteners for more than 10 years compared with non-users. The OR (95% CI) for long-term consumers was 2.18 (1.22, 3.89) and for short-term users 1.10 (0.61, 2.00) after adjustment for age, sex, BMI, social status, and years of tobacco use.

Acesulfame The studies on the basis of which acesulfame gained approval showed no evidence in animals of mutagenicity, teratogenicity, or adverse reproductive effects; a 2-year toxicology study in beagles showed no untoward adverse effects. The incidence of lymphocytic leukemia was slightly increased in high-dosed female mice, but not beyond the spontaneous variation with this strain. No other evidence of potential carcinogenicity was obtained, and it has been concluded that at the estimated level of exposure, acesulfame and its metabolites are not a health hazard [46].

Aspartame It has been suggested that aspartame may be linked to the increase in incidence of brain tumors. Brain tumor incidence increases in the USA occurred in two distinct phases, an early modest increase that may have primarily reflected improved diagnostic technology, and a latersustained increase in the incidence and shift toward greater malignancy that must be explained by some other factor(s) [47]. Evidence potentially implicating aspartame includes an early animal study that showed an exceedingly high incidence of brain tumors in aspartamefed rats compared with no brain tumors in concurrent controls, the finding that aspartame has mutagenic potential, and the close temporal association (aspartame was introduced into US food and beverage markets several years prior to the sharp increase in brain tumor incidence and malignancy). The authors concluded that the carcinogenic potential of aspartame needs to be reassessed.

Saccharin Saccharin has been considered to be a possible human carcinogen on the basis of animal experiments. This suspicion has now been discredited. There is no evidence that people with diabetes, who consume larger quantities of saccharin than non-diabetics, are at greater risk of developing bladder cancer [48] or other malignancies. However, in the USA, saccharin-containing medicines are required to carry the following warning: “Use of this prod-

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uct may be hazardous to your health. This product contains saccharin which has been determined to cause cancer in laboratory animals” [49].

SUSCEPTIBILITY FACTORS Individuals with mood disorders are thought to be particularly sensitive to aspartame, and it has been suggested that its use in such patients should be discouraged [50].

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