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International Journal of Research and Review www.ijrrjournal.com E-ISSN: 2349-9788; P-ISSN: 2454-2237

Review Paper

Artificial Sweeteners

Anushkkaran Periyasamy

Department of Chemistry, Faculty of Science, University of Jaffna, Jaffna, Sri Lanka

ABSTRACT

Artificial Sweeteners provide the of natural without the calories and produce a low glycemic response. These sweeteners are used instead of (table sugar) to sweeten and beverages. Consumers and manufacturers have long been interested in dietary sweeteners to replace sucrose in foods. This article goes into a lot of details about the different types of sweeteners such as , acesulfame , , and , their uses, chemistry and their potential effects on health. These sweeteners form acute and chronic effects on human health.

Keywords: Artificial sweeteners; adverse effects; potential toxicity

1. INTRODUCTION These artificial sweeteners further classified Artificial sweeteners are many times as nutritive and non-nutritive sweeteners sweeter than table sugar, smaller amounts depending on whether they are a source of are needed to create the same level of calories. The nutritive sweeteners include sweeteners, and which are either not the monosaccharide polyols (e.g., , metabolized in the human body or do not mannitol, and ) and the disaccharide significantly contribute to the energy polyols (e.g., and ). The non- content of foods and beverages. Those nutritive sweeteners are better to known as provide the sweeteners of sugar without the artificial sweeteners. [1] calories and produce a low glycemic Artificial sweeteners have some response. [1] Glycemic response to food is ideal requirements. They should provide the effect that food has on blood sugar sweetness with no unpleasant aftertaste, levels after consumption. [2] Consumers and should have little or no calories, should be food manufacturers have long been economical to produce, should not be interested in dietary sweeteners to replace degraded by heat when cooked and should sucrose in foods. Because recently these not be carcinogenic or mutagenic. products have received increased attention Carcinogenic is having the potential to due to their effects on regulation. cause cancer, and mutagenic is a physical or These exceed the sweeteners of sucrose by a chemical agent that changes the genetic factor of 30-13,000 times because of these material of the organism. [3] include substances from several different The main reasons for using artificial chemical classes. [1] These sweeteners are sweeteners are weight lose, dental care, widely used in baked goods, carbonated mellitus, reactive hypoglycemia beverages, powdered drink mixtures, jams, and low cost. [1] Dental caries are also jellies and dairy products. [3] These are known as teeth decay or cavities. regulated by the Food and Drug Breakdown of teeth due to activities of Administration (FDA). bacteria. This occurs due to made from Sweeteners have been classified as sugar on the tooth surfaces. Simple in natural sweeteners and artificial sweeteners. foods are the primary energy source of these

International Journal of Research & Review (www.ijrrjournal.com) 120 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners bacteria. [4] Reactive hypoglycemia refers to carbohydrate based meals. [5] To reduce low blood sugar that occurs after a meal these activities, most of the people are using usually within 4 hours after eating. This can artificial sweeteners. occur in both people with and without The main five sugar substitutes for diabetes and is thought to be more common use in a variety of foods are saccharin, in overweight individuals. Reactive , aspartame, neotame hypoglycemia is known as the result of too and sucralose. Characteristic features of much insulin being produced and released these five artificial sweeteners are given in by the pancreas following a large sugar or the Table 1.

Table 1. Characteristic features of artificial sweeteners [1] Common Brand names Number of times kcal/g Common uses name sweetener than sucrose Saccharin Sweet’N Low 200-700 0 Soft drinks, Tabletop sweetener, Jams, Chewing gum, Baked Sweet Twin goods Necta Sweet Acesulfame Sunett 200 0 Tabletop sweeteners, Candies, Chewing gum, Dairy products K Sweet One Aspartame Nutra Sweet 180-200 4 Soft drinks, Yoghurt, Pharmaceuticals Natrataste Equal Neotame Neotame 7000-13000 0 Baked goods, Soft drinks, Chewing gum, Jams, Jellies, Puddings, Processed fruit and fruit juices Sucralose Splenda 600 0 Frozen deserts, Fruit juices, Chewing gum, gelatins

1.1 Structural requirements for sweetness artificial sweeteners is simple, as The generally accepted theory for the carbohydrates do not play any important phenomenon of sweetness was developed functional role in beverages. Other by Shallenberger and Acree. According to important applications are fruit flavored this theory, a molecular system of a proton dairy products and desserts. [7] donor and proton acceptor is necessary. 1.2.2 Tabletop sweeteners Changes in the distance between groups, as For household use, artificial sweeteners are well as changes in electronic structure formulated into table-top sweeteners, such influence the occurrence of the sweet as sweetener tablets, powders and spoon-by- and may change the general taste spoon products, and liquids. perception, sometimes eliminating 1.2.3 Pharmaceuticals sweetness totally, or changing it to Artificial sweeteners are used to mask bitterness. [6] undesired and of active pharmaceutical ingredients, e.g., bitterness, 1.2 General Uses whenever the pharmaceuticals are intended 1.2.1 Foods and Beverages for use by diabetics. Sweeteners are used in Foods and beverages are the most syrups, and soluble tablets and powders. important fields of application of artificial 1.2.4 Cosmetics sweeteners, with calorie reduction being the Several types of cosmetics, especially oral main goal. Single sweeteners or hygiene products, are sweetened to make combinations with other sweet substances. them more pleasant for consumers. For oral Artificial sweeteners can be used in diabetic hygiene products (e.g., toothpaste, foods and beverages; depending on the type , etc.), noncariogenic ingredients of product, either as single sweetening have to be used. The desired sweetness level agents or combined with bulk sugar is adjusted with an additional quantity of substitutes suitable for diabetic artificial sweetener. consumption. Beverage uses of artificial sweeteners account for more than 50% of 1.3 Saccharin human consumption; sugar replacement by

International Journal of Research & Review (www.ijrrjournal.com) 121 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners

Saccharin is the first and oldest artificial health hazard and that it was found to cause sweetener that has been used for over a cancer in laboratory animals. That label century to sweeten foods and beverages contains “use of this product may be without adding calories. Saccharin has been hazardous to your body”. In 2000, the approved by FDA for use in more than 100 National Toxicology Programme countries. [3] determined that saccharin should no longer 1.3.1 History be listed as a potential cancer-causing agent Saccharin was discovered by Fahlberg & because mechanistic studies have shown Remsen in 1879 at John Hopkins that these results apply only to rats. University. This was found after those Mechanistic studies that examine have a chemists were researching the oxidation substance work in a body. Human mechanisms of . They studies have shown no were working with coal-tar derivatives. consistent evidence that saccharin is During their research, a substance associated with incidence. accidentally splashed on Fahlberg’s finger Because the bladder tumors in the rats are and he noticed the substance had a sweet due to a mechanism not relevant to human taste, which he traced to the chemical and there is no clear evidence that saccharin commonly known as saccharin. Saccharin causes cancer in humans. Epidemiology enjoyed great commercial success in periods studies are that studies of patterns, causes of short sugar supply, e.g., during world and control of disease in groups of people. wars I and II. [8] In 2001, saccharin was officially declared In 1997, the FDA proposed a ban on safe and the ban was removed. [9] saccharin because of concerns about rats 1.3.2 Chemistry that developed bladder cancer after Saccharin is formed by an initial receiving high doses of saccharin. Foods reaction between toluene and chlorosulfonic containing saccharin were required to carry acid. Synthesis of saccharin is explained in a label warning that sweetener could be a Figure 1. [7]

Saccharin Figure 1. Synthesis of saccharin (Remsen-Fahlberg synthesis)

After ingestion, saccharin is not is often used with aspartame in diet absorbed or metabolized. Instead, it is carbonated soft drinks. [3] The form used as excreted, unchanged via the kidneys. [1] an artificial sweetener is and Slightly bitter taste and metallic taste and salt, especially by people restricting for this reason is sometimes combined with their dietary sodium intake. [1] other sweeteners. For an example, saccharin 1.3.3 Uses

International Journal of Research & Review (www.ijrrjournal.com) 122 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners

Important fields of application are used in baked products. It is used in over soft drinks, tabletop sweeteners, and 4000 products in approximately 90 desserts. For taste reasons, blends with other countries. The “K” refers to the mineral artificial sweeteners, or combinations with potassium, which is naturally found in our reduced sugar levels are preferred wherever bodies. [3] such blends are approved. In oral hygiene 1.4.1 History products, saccharin masks undesired tastes Acesulfame-K was discovered in of other ingredients. In starter feed for 1967 by chemist Karl Clauss and Jensen livestock, saccharin is used to avoid reduced during investigations on oxathiazinone feed intake after weaning. Besides its dioxides. The sweet taste was found by applications as an artificial sweetener, chance. Several other oxathiazinone saccharin is used in electrolytic nickel dioxides taste sweet but have less favorable deposition. Addition of saccharin to the characteristics. Acesulfame-K was approved nickel salt solutions increases the hardness in the United States in 1988 for specific and brightness of the nickel plate. This uses, including a tabletop sweetener. In effect is apparently specific to saccharin. [10] 1998, the FDA approved acesulfame-K to 1.3.4 Toxicology be use in beverages. In specially, it has been Saccharin causes a headache, breathing used to decrease the bitter aftertaste of difficulties, skin eruptions and diarrhea. aspartame. FDA continues to support the use of acesulfame-K in diabetic and low- 1.4 Acesulfame potassium calorie food. [1] This is a general purpose sweetener, 1.4.2 Chemistry white crystalline structure, high-intensity, Acesulfame-K is formed by an non-nutritive sweetener, non-carcinogenic initial reaction between 4-chlorophenol and and stable under high temperatures. So it sodium. Synthesis of acesulfame-K is does not break down in heat, therefore often explained in Figure 2.

Figure 2. Synthesis of acesulfame-K

Acesulfame-K is not metabolized by the consumed sweeteners basically ends up the body and is not stored in the body. It is excreted in the urine. [11] quickly absorbed and excreted in urine 1.4.3 Uses without undergoing any modification. Acesulfame K is used in all fields of Pharmacokinetic studies show that 95% of applications of artificial sweeteners. Common applications are table-top

International Journal of Research & Review (www.ijrrjournal.com) 123 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners sweeteners; beverages; foods, such as dairy some loss of sweeteners. It has been used in products, desserts, bakery products, over 6000 different types of products. [12] confectionery, chewing gum, pickles, and 1.5.1 History marinated fish; oral hygiene products and Aspartame was discovered in 1965 pharmaceuticals. Owing to its synergistic by G. D. Searle when he was studying new characteristics, acesulfame K is often used treatments for gastric ulcers. Tetrapeptide is in sweetener blends, and in combination normally produced in the stomach which with bulk sweeteners in products requiring was used by the biologist to test new anti- good stability, e.g., confectionery or bakery ulcer drugs. One of the most important steps products. in the process was to make an intermediate, 1.4.4 Toxicology aspartyl- methyl ester to Acesulfame-K contains methylene chloride synthesis tetrapeptide. When chemist was which is a known . Long-term synthesis this tetrapeptide, accidentally, a exposure to methylene chloride can cause a small amount of the compound landed on headache, depression, nausea, mental the chemist’s hand. Without noticing the confusion, liver and kidney effects. compound, the chemist licked his finger and Acesulfame-K’s breakdown in the body discovered a sweet taste. After realizing it forms the byproduct acetoacetamide, which was not likely to be toxic. is toxic at high doses and which has been It was first approved by the FDA in shown to cause tumor growth in the thyroid 1981 as a tabletop sweetener; in 1996, it gland in rats, rabbits and dogs. Only 1% was approved as a general-purpose acetoacetamide is accumulated for three sweetener in all foods and drinks. months. [3] Aspartame is sometimes blended with more stable sweetener saccharin. [13] 1.5 Aspartame 1.5.2 Chemistry One of the most debated sweeteners. Aspartame is made by joining L- Aspartame has a sugar-like taste. It can be phenylalanine or L-phenylalanine methyl safely heated to high temperatures with ester with L-. Synthesis of aspartame is explained in Figure 3.

Figure 3. Synthesis of aspartame

International Journal of Research & Review (www.ijrrjournal.com) 124 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners

Aspartame breaks down into small vision, brain tumors, eye problems, memory amounts of , aspartic acid and loss and nausea. [15] phenylalanine during the digestion. The aspartame consists of aspartic Methanol is non-drinking alcohol, injecting acid which is a well-documented of that can lead to toxicity and death within excitotoxin. 3 amino such as a few hours. The body also breaks down this glutamate, aspartate and cysteine that excite methanol into which turns our neurons can be called as excitotoxin. into formic acid in the liver. Formaldehyde These neurotransmitters (amino acids) and formic acid both are toxic. excessively stimulate the nerve cells to Our body produces formaldehyde in either damage or kill. Excitotoxicity may be amounts thousands of times greater than we involved in spinal cord injury, stroke and get from the sweetener which is used by the hearing loss. [16] body to make important substances. Formic acid rarely builds up because the body uses 1.6 Neotame formaldehyde so quickly and if there were Neotame is the newest sweetener an excess, it would be eliminated through and a derivative of aspartame. A t-butyl urine or broken down into CO2 and water. group is added to the free group of Finally, the aspartame in diet produces so aspartic acid. This could be a super sweet little amount of ethanol. [14] deal for food and beverage manufacturers, 1.5.3 Uses all the sweetness of sugar without a metallic The sensory characteristics of after-taste plus at a fraction of the amount of aspartame allow its use in all common sweetener needed compared to other sugar sweetener applications. Limitations are substitutes. The neotame was approved in imposed by its susceptibility to hydrolytic 2002 as a general purpose sweetener, decomposition and limited temperature excluding in meat and poultry by FDA. [1] stability. 1.6.1 History 1.5.4 Toxicology After the success of aspartame in the FDA has mandated packaging bear a market, there were calls for developing a warning label to prevent individuals with novel sweetener possessing additional the rare genetic disorder qualities such as higher heat stability, fewer from ingesting the aspartame. restrictions and higher sweetener potency Phenylketonuria is an inborn error of which means less amount to achieve the that leads to attenuated same sweetness at a lower cost. Therefore metabolism of the amino acid scientists synthesized thousands of phenylalanine. Phenylketonuria can lead to compounds based on the simple structure of behaviour problems and mental disorders. aspartame. End of the research, neotame Individuals who suffer from this disease came up with the desirable qualities among have an insufficient amount of the enzyme those synthesized compounds. Neotame was phenylalanine hydroxylase which is approved by FDA for general use in 2002. required to breakdown the phenylalanine. [17] Without the presence of this enzyme, 1.6.2 Chemistry phenylalanine accumulates. When we add the t-butyl group to Due to the methanol, aspartic acid the free amine group of aspartic acid, it and phenylalanine which came from the leads to a second hydrophobic group and digestion of aspartame can cause the results in a product that is 30-60 times following symptoms: headache, blurred sweeter than aspartame. [18] Figure 4 shows the synthesis of neotame.

International Journal of Research & Review (www.ijrrjournal.com) 125 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners

Figure 4. Synthesis of neotame

Neotame is rapidly metabolized by 1.6.3 Toxicology of the methyl ester via esterase Neotame causes some of the toxic present throughout the body. It forms a effects in the human such as it to reveal minor amount of methanol that the body changes in body weight and food absorbs. This process yields de-esterified consumption, headache and hepatotoxicity neotame. Neotame and de-esterified at high dosages. neotame are rapidly clear from the plasma, which is completely eliminated from the 1.7 Sucralose body with recovery in urine and feces Sucralose is a sucrose molecule in which within 72 hours. It is safe for who suffer three of the hydroxyl groups have been from phenylketonuria because t-butyl group replaced by Cl atoms. Sucralose is also heat is added to the free amine group of aspartic stable which quality makes it a superb acid. This t-butyl group typically break the sweetener for cooking and baking. It retains peptide bond between the aspartic acid and its sweeteners significantly longer than phenylalanine, thus reduce the availability aspartame. Figure 5 shows structures of of phenylalanine which is responsible for sucrose and sucralose. phenylketonuria. [19]

Figure 5. Structures of sucrose and sucralose

1.7.1 History states out as cane sugar but ends up 600 Sucralose was accidentally times sweeter than table sugar. It came on discovered by Tate & Lyle in 1976, was the scene in 1976 and was approved by the looking for ways to use sucrose as a FDA in 1999 for use in 15 food categories. chemical intermediate. Ironically, sucralose After some laboratory experiments which

International Journal of Research & Review (www.ijrrjournal.com) 126 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners changes the sugar molecule, its structure 1.7.2 Chemistry now prevents it from being absorbed by the Synthesis of sucralose is shown in the figure body. [20] 6.

Figure 6. Synthesis of sucralose TrCl = triphenylmethyl chloride; DMAP = 4-dimethylaminopyridine

Sucralose is poorly absorbed in the human 3. ADVERSE EFFCTS OF ARTIFICIAL and the majority of ingested sucralose SWEETENERS excreted unchanged in the feces. Saccharin, acesulfame-K and aspartame induced DNA damage in human 1.7.3 Toxicology peripheral lymphocytes. Sucralose has been Sucralose is responsible for the well-tried through scientific shrunken thymus glands with diets of 5% experimentation to cause a decrease in sucralose, and also it causes diarrhea and beneficial micro-organisms. Under acidic dizziness. conditions, acesulfame-K formed minute quantities of acetoacetamide and 2. HEALTH BENEFITS OF acetoacetamide-N-sulfonic acid. While ARTIFICIAL SWEETENERS under basic conditions, acetoacetic acid and Artificial sweeteners are not acetoacetamide-N-sulfonic acid are formed. carbohydrates. So generally they don’t raise These degradation products may cause blood sugar levels and cause diabetes. They DNA strand breaks. [3] have no calories. In distinction, every gram Toxic potential of artificial sweeteners for of normal table sugar contains four calories. the human body are shown in the Table 2. They are suitable for obesity. They do not promote dental caries. [1]

Table 2. Toxic potential of artificial sweeteners [1] Common Known metabolites ADI Acute Chronic name (mg/kg) Saccharin O-sulfamoylbenzoic acid 5 Nausea, vomiting, diarrhea Low birth weight, bladder cancer, hepatotoxicity Acesulfame- Acetoacetamide 15 Headache Thyroid tumors K Aspartame Methanol, aspartic acid, 50 Headache, dizziness, nausea, vomiting, Lymphomas phenylalanine thrombocytopenia Neotame Methanol, de-esterified 2 Headache, hepatotoxic at high doses Lower birth rate, weight loss neotame Sucralose 5 Diarrhea, dizziness, stomach pain Thymus shrinkage ADI - Annual daily intake

International Journal of Research & Review (www.ijrrjournal.com) 127 Vol.6; Issue: 1; January 2019 Anushkkaran Periyasamy. Artificial Sweeteners

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How to cite this article: Periyasamy A. Artificial sweeteners. International Journal of Research and Review. 2019; 6(1):120-128.

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International Journal of Research & Review (www.ijrrjournal.com) 128 Vol.6; Issue: 1; January 2019