Safety of Aspartame

Literature Review, 2017

59 Pages, Grade: 1


Table of Contents


2.1 History
2.2 Chemical Properties
2.3 Aspartame Usage Rules and Safety Assessment
2.4 Biochemistry and Metabolism
2.5 Toxicological Profile
2.5.1 Acute Toxicity
2.5.2 Sub-Chronic Toxicity
2.5.3 Chronic Toxicity
2.5.4 Genotoxicity
2.6 Other Studies Related to Aspartame




Sweeteners are the most discussed among the food additives. Those, used as alternatives to sucrose, are generally referred to as ''alternative sweeteners'' (Mortensen, 2006). The first registered sweetener was honey (Bright 1999; Weihrauch and Diehl 2004), but as time pasts the common sugar took its place. Artificial sweeteners came into use, because diabetes and obesity rate was increased due to use of common sugar. The first used artificial sweetener was saccharin (Bright 1999; Weihrauch and Diehl 2004). Aspartame and cyclamate were used following the saccharin.

They are produced to be used instead of sugar, have the same taste as sugar, are not considered as harmful to health, have low calorie and/or without calories (Position of the American Dietetic Association, 2004). Increasing with the prevalence of obesity, individuals wishing to reduce energy intake have talented particularly to energy-free sweeteners and low-calorie products (World Health Organization, 2008). The products made with sweeteners are equivalent to the product made with sugar being preferred by producers and consumers (Blackburn and et al., 1997). During the past two decades, worldwide low-calorie food consumption has considerably increased, thus leading to an increase in health concerns associated with high intake of synthetic sweeteners (Bergamo et al. 2011).

''Intense sweeteners'' are the sweeteners that produce the required effect in minute quantities, because of their intense sweetness. To emphasize that most of them are produced by chemical synthesis, some call them "artificial" sweeteners, whereas sucrose and other sugars naturally found in plants are considered "natural" (SCF, 1985). Also depending on being source of calories, they have been classified as nutritive and non-nutritive (Whitehouse et al. 2008). While xylitol, sorbitol, mannitol and erythritol are energy-containing artificial sweeteners, acesulfame potassium (asesulfame-K), aspartame, saccharin, cyclamate and sucralose are non-energy artificial sweeteners. The sugar alcohols xylitol, sorbitol and mannitol give an average energy of 2.4 kcal/1gram (Tüfekçi, 2014).

Worldwide, in the 90s it was found that the use of saccharin, cyclamate and aspartame accounted for 7.19%, it constituted 9.05% in 2000 and 9.60% in 2010 (MECAS, 2012). Of the artificial sweeteners, aspartame represents 62% of the sweetener market in terms of global consumption (Fry, 1999) In Turkey, the share of saccharin, cyclamate and aspartame in the entire sweetener market was 6% in 2006 and about 11% in 2013 (TC Sugar Corporation, 2015). The general characteristics of the non-energy artificial sweeteners and the amounts allowed for daily use (ADI) found in Turkey are given in Table 1 (Tufekci, 2014).

Table 1. General characteristics of artificial sweeteners and amounts allowed for daily use

Abbildung in dieser Leseprobe nicht enthalten

The persistence of artificial sweeteners on the agenda and the desire to work on new sweeteners is due to the desire to achieve a near-sweet taste. There are many popular foods available because artificial sweeteners are assumed to reduce sugar consumption and caloric intake considerably (Humphries et al., 2007) Although non-nutritive or artificial sweeteners are using instead of sucrose in foods, in order to increase flavor and reduce calories, their safety has been controversial (Whitehouse et al., 2008). More people of all ages are choosing to use these products, because the public health attention has turned to reversing the obesity epidemic in the world. These choices may be helpful, for the people who cannot tolerate sugar in their diets (e.g., diabetics). It is also becoming increasingly important as part of the nutritional guidelines for diabetes because of the increased incidence in developed countries as well as in developing countries (Humphries et al., 2007). However, even though sugar alcohols are not a problem for diabetic patients, excessive amounts may have a laxative effect. In the United States, the Food and Drug Administration (FDA) has approved to use four of the non-energy artificial sweeteners (saccharin, aspartame, acesulfame-K and sucralose) (FDA, 2015).

However, there are lots of contradictory studies about relation between sweeteners and diseases (Whitehouse et al., 2008). The companies that produce artificial sweeteners, have conducted many studies about these sweeteners and these are not generally available to consumers. However, artificial sweeteners have associated with health disorders such as hepatotoxicity (Negro et al., 1994), and cancers (Whitehouse et al., 2008), by the result of some independent research studies. However, there is still a vast debate concerning about this issue. The role of sweeteners in the risk of cancer, has been extensively controversied (Bosetti et al., 2009).

In general, sweeteners are substances having a sweet taste. In the past, the Scientific Committee on Food was the scientific guarantor for the safety of food additives (including sweeteners) which are using within the European Union (EU). This responsibility belongs to the European Food Safety Authority, at present. The safety of all sweeteners which are allowed for using in food in the EU, has demonstrated in extensive scientific research. Their safety is documented by the results of tests in humans, several in vitro and in vivo animal studies, and in some cases epidemiological studies (Mortensen, 2006). Although the scientific evidence shows that the sweeteners which are allowed for using in food are safe, some individuals and organizations remain sceptical about long-term health risks because of their consumption (Mortensen, 2006). Undoubtedly, the most controversial artificial sweetener is aspartame, because of its potential toxicity (Whitehouse et al., 2008), and carcinogenicity (Soffritti et al., 2006), even at a dosage level approximating the ADI for humans (Whitehouse et al., 2008). In this study, you can find aspartame safety in every direction.


2.1 History

The body mass index has increased from 28.8% to 36.9% in men and from 29.8% to 38.0% in women between 1980 and 2013 in worldwide. It was reported that an action plan should be prepared by the World Health Organization (WHO) to stop the rising prevelance of obesity (Vandevijvere et al., 2015). People are beginning to demand energy-reduced products to reduce energy intakes. With this demand, the food industry has produced oil-reduced milk and dairy products, oil-reduced crackers, natural and artificial sweeteners without sugar. Two scientists from Johns Hopkins University discovered saccharine that was 300 times sweeter than non-nutritious sugar in 1879. Saccharin was used as a sweetener in canned foods until 1907 but later it was banned by the Food and Drug Administration (FDA) (Kalkhoff and Levin, 1978).

Cyclamate has been produced due to safety concerns of saccharin. Cyclamate was isolated in the laboratory of Abbott in 1937 by a student working on antipyretic drugs and was allowed by the FDA to use it in foods in 1951 (Bopp et al., 1986). Cyclamate is used in products such as canned foods, pastries, bacon, toothpaste, gargle products and cereals and consumption of diet sodas containing cyclamate has increased rapidly and has doubled in 1967. However, after studies showing bladder tumors in laboratory rats in high doses of cyclamate then it was banned in 1969 (Administration, 1980). For this reason, international pharmaceutical companies have begun to work to discover new sweeteners.

In 1965, a chemist at G. D. Searle who was studying new treatments for gastric ulcers used a tetrapeptide, which is normally produced in the stomach, to test new anti-ulcer drugs. While the chemist was making an intermediate, aspartyl-phenylalanine methyl ester, which is one of the steps of synthesizing tetrapeptide, a small amount of the compound accidentally landed on the his hand. Later, without noticing the compound on his hand, the chemist licked his finger and noticed a sweet taste. He realized the material was from the powder aspartyl-phenylalanine methyl ester and it would be safe to taste the material. So he tasted the intermediate again and discovered the sweetness was indeed from aspartame (Mazur, 1984). When aspartame was crystallized from ethanol, it was suggested that the sweet taste of the mixture came from aspartame (Furia, 1972).

It was reported for the first time in 1969 in the Journal of the American Chemical Society that aspartame is an artificial sweetener having 180-200 times more sweet tastes depending on the concentration of sugar (Mazur et al., 1969).

Searle performed two separate toxicity studies on rats on 78th week in 1970 and later examined the pathology and autopsy results of rats in 1972. When the results of the studies are examined, it has been determined that aspartame causes tumor development in the liver, testes and thyroids of rats. When the results of the study were analyzed in another laboratory, it was emphasized that the increase in thyroid and testicular tumors was statistically significant but the increase in liver tumors was not significant and it was approved by the FDA in 1973 (Sarett, 1973). At the end of the 1960s and early 1970s, the prohibition of saccharin and cyclamate led to the need for a new sweetener. Searle started to use aspartame as a flavoring agent in certain foods in 1973 when it received the patent of aspartame from the FDA (Randolph, 1973).

It was determined that aspartame was caused by genetic damage in 13 genetic studies after 15 months of FDA approval, but Alexander Schmidt, who is on the FDA committee, stated that it is appropriate to be used only in dry foods at an panel and provide strong support the current name of the Center for Food Safety and Applied Nutrition (CFSAN). However, due to the objections made, the approval was stopped and it was decided that further studies should be done.

In 1979, the Public Board of Inquiry of FDA set up a study to investigate the safety of aspartame decided that it should not be approved before further research conducted on animal brain tumors. (Smyth, 1983). Despite the contradictory conclusions of the studies and the different opinions of the authorities, the use of aspartame in dry food was reauthorized in 1981 (Public Health Service Food and Drug Administration, 1981)

In July 1983, the National Soft Drink Association (NSDA) stated that aspartame is very volatile in liquid form, and therefore, more works should be done before confirmation of aspartame use in gaseous beverages, but aspartame containing gaseous beverages were launched for consumers (Spingola, 2015).

In 1996, aspartame was approved to be used as a general-purpose artificial sweetener in any kind of food and drink (FDA, 2006).

Since then, aspartame has been widely used in more than 6,000 products, roughly 500 pharmaceutical products, including children’s medicines, and has been consumed by hundreds of millions of people in countries all around the world (Butchko & Stargel, 2001).

2.2 Chemical Properties

Aspartame (L-aspartic acid, L-phenylalanine methyl ester) is an artificial sweetener non-nourishing dipeptide which is not found naturally in foods and beverages. There are two forms of aspartame, an alpha and a beta form. The sweet one is only alpha, and when it doesn't specified, “aspartame” here will always refer to the alpha form (Magnuson et al., 2007). It is classified as a non-nutritive sweetener because of its intense sweetness and its ability to be used in very small quantities to sweeten the foods (FDA, 2007). Aspartame, by weight, provides the same calorie intake as sugar (i.e., 4 kcal/g), it can be added at almost 200 times lower levels and get the same sweetness, so providing a far lower net caloric intake. This feature has resulted in the use of aspartame as a low calorie or non-nutritive sweetener in foods and drinks worldwide (Magnuson et al., 2007).

Aspartame is not soluble in fats or oils, but it is slightly soluble in water and ethanol (Magnuson et al. 2007). It is not suitable for cooking or baking, because it is unstable at long-term high heat. But in dry form, it is very stable. It is also unstable in aqueous solutions which slowly return to diketopiperazine (DKP). This causes the sweet taste to be lost. The flavor of Aspartame is like sugar and it improves some tastes. The combinations of it with other intense sweeteners, e.g. saccharin and/or cyclamate, taste sweeter than expected from the sum of the individual sweeteners (Mortensen, 2006).Aspartame is used in cold beverage mixes, chewable multi-vitamins, breakfast cereals, chewing gum, puddings, carbonated drinks, iced drinks, yoghurt and in pharmacy. The European Food Safety Authority (EFSA) assessed the safety of aspartame and included in food additives with E951 code (SCF, 2002).

A large part of the studies related to aspartame was carried out to assess whether it is safe for humans. It is concerned that aspartame-forming compounds will pose a risk in phenylketonuria heterozygotes, newborns, pregnant and lactating mothers, and individuals with Chinese Restaurant Syndrome (Stegink, 1987).

The aspartame metabolite phenylalanine is an amino acid found naturally in the breast milk of mammals; however to those who born with phenylketonuria (PKU), a metabolic disorder caused by an hereditary mutation in the phenylalanine hydroxylase (PAH) gene that prevents the correct metabolization of phenylalanine, high levels of phenylalanine are a health danger. This results in a deleterious accumulation of the amino acid, which causes developmental defects, mental retardation and seizures (Blau et al, 2010). Normal mammalian plasma levels of phenylalanine are approx. 30–50 mM (0.5–0.8 mg/dL), however, 1 out of 50 individuals for the mutation in the phenylalanine hydroxylase gene, is heterozygous (Scriver et al, 1996), the fasting plasma phenylalanine levels were increased compared to the non-carriers (Griffin et al, 1973), with a decrease in the cholinergic ratio of phenylalanine after intravenous loading (Jagenburg et al, 1977). Repeated doses of 8 servings of aspartame-sweetened beverages by PAH heterozygous individuals led to plasma phenylalanine levels of up to 165 mM (Stegink et al, 1990), but remained below levels reported to cause neurotoxicity during acute administration in primates (Collison et al, 2012).

High doses of aspartame and its metabolites have been tested in humans and other animals. It has been proven that not only the metabolites of methanol but also methanol itself are toxic to the brain (Jeganathan & Namasivayam, 1998). Methanol is toxic to the brain because elevated blood levels of methanol can cause severe changes in brain monoamine levels. It is well known that the nervous system is highly sensitive to methanol intoxication (Jeganathan & Namasivayam, 1998). Consumption of aspartame may also cause brain damage, depending on the high levels of phenylalanine in the blood (Haschemeyer & Haschemeyer, 1973).

2.3 Aspartame Usage Rules and Safety Assessment

The debate on the safety of aspartame has existed since its ratification in the 1980s. There are a large number of people and website organizations presenting a large number of anecdote literature detailing consumer concerns, which include cancer (Zehetner & McLean, 1999) multiple sclerosis, seizures, loss of memory, depression, blindness, anxiety, obesity, birth defects and death, With both acute and chronic exposure concerns (Camfield et al., 1992; Watts, 1991; Van den Eeden, et al., 1994; Lean & Hankey, 2004).

In a work of MRCA Information Service evaluated in the USA between the years of 1984-1992 aspartame consumption of about 2,000 households have been followed (Abrams, 1986; Butchko et al, 1996). In the 14-day-long questionnaire, all foods that individuals eat at home and outside were recorded and aspartame consumption by age groups was calculated in mg/kg. According to the results of the questionnaire, aspartame consumption was recorded as 1.6-3.0 mg/kg/day even in children, diabetics who were thought to be consuming aspartame the most. In addition, consumption of aspartame was gradually increased in the general population (1984-1985: 1.6 mg / kg / day, 1991-1992: 3.0 mg / kg / day). Another study of 1,500 women in the US regarding aspartame consumption reported that aspartame consumption of more than 90% of women was less than 5 mg / kg / day (Heybach and Smith, 1988).

Renwick's study of recent consumption of artificial sweeteners reported that aspartame consumption was 5.16 mg / kg / day for men and 4.64 mg / kg / day for women. In the general population, aspartame consumption in excess dose was found to be 13.29 mg / kg / day on average (Renwick, 2006).

A study conducted in Norway reports that the aspartame intakes of beverage consumers are below the ADI and range from 6.1 to 10.2 mg/kg bw, but the estimated intake might increase to levels above ADI if the contribution of other food categories is considered (Husøy et al., 2008). The daily intakes of aspartame by children and adolescents are estimated to be below the ADI (Butchko & Kotsonis, 1991).

When other works investigated in other countries, aspartame consumption per person in the general population in Australia was found to be 3 mg / kg / day (National Food Authority Australia, 1995). In a study of changes in nutrient intake, it was reported that Australians reduced consumption of artificial sweeteners significantly. However, the average daily consumption amount was not quantified (Rangan et al., 2011). In Brazil, it was reported that the general population consumed about 1.2 mg / kg / day, about 1.0 mg / kg / day for diabetic individuals and about 1.2 mg / kg / day for individuals who were on weight loss diet (Toledo and Ioshi, 1995). This amount was 1.1 mg / kg / day in Finland (Virtanen et al. 1988), 2.4 mg / kg / day in France (Garnier-Sagne et al. Biermann, 1992), 0.3 mg / kg / day in Italy (Leclercq et al. 1999), 1.9 mg / kg / day in the Netherlands (Hulshof and Bouman, 1992) and 0.9-3.4 mg / kg / day in Norway (Bergsten, 1993).

Aspartame usage has been regulated in more than 100 countries in accordance with health-based guidance values defined by the key regulatory authorities around the world, including the US Food and Drug Administration (FDA, 1984), and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (JECFA, 1980). In Europe, the following scientific organizations were responsible for advising on the safety of sweeteners: the Scientific Committee for Food (SCF from 1974 until April 2003), the EFSA Panel on Food Additives, Flavorings, Processing Aids and Materials in Contact with Food (from 2003 to 2008), and currently the EFSA Panel on Food Additives and Nutrient Sources Added to Food (ANS, from 2008 to present).

The first safety assessment guidelines for food additives were issued by SCF in 1980 (SCF, 1980). Later, SCF adopted its new guideline in 2001 (SCF, 2001). JECFA, which started its work in 1956, offers its results of evaluations to the member governments of the United Nations, in an informal manner. JECFA issued guidelines for safety assessment of food additives in 1987 (WHO, 1987).

These organizations and authorities have independently set different ADIs for aspartame of 50 mg/kg/day in the U.S. (FDA, 1984), 0–40 mg/kg bw (JECFA, 1980), and 0–40 mg/kg bw in European Union based on long-term rat studies using the NOAEL of 4 g/kg bw/day (SCF, 1985). Later on in 1988, 1997, 2002, SCF (SCF, 1989, 1997, 2002) and more recently EFSA (2005, 2006, 2009, 2011) performed additional reviews of aspartame data. Diketopiperazine (DKP), a minor cyclic dipeptide derivative of aspartame which is formed in some aqueous solutions, was also regulated by an ADI of 7.5 mg/kg bw/day (JECFA, 1980; SCF, 1985).

Food and beverages containing aspartame must include a label on their packaging indicating that the product contains phenylalanine. Individuals suffering from hereditary disease phenylketonuria, must strictly limit their intake of this amino acid; hence this label will be beneficial for people suffering from PKU disorder. Contrary, normal and healthy individuals do not need to restrict their phenylalanine intake (Mortensen, 2006).


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Safety of Aspartame
Ankara University  (Faculty of Health Sciences)
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Aslı Ucar (Author)Mustafa Özgür (Author)Serkan Yilmaz (Author), 2017, Safety of Aspartame, Munich, GRIN Verlag,


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