Artificial sweeteners

Definition

Purpose

Description

Precautions

Interactions

Parental concerns

Resources

Definition

Artificial sweeteners, which are also called sugar substitutes, alternative sweeteners, or non-sugar sweeteners, are substances used to replace sugar in foods and beverages. They can be divided into two large groups: nutritive sweeteners, which add some energy value (calories) to food; and nonnutritive sweeteners, which are also called high-intensity sweeteners because they are used in very small quantities as well as adding no energy value to food. Nutritive sweeteners include the natural sugars—sucrose (table sugar; a compound of glucose and fructose), fructose (found in fruit as well as table sugar), and galactose (milk sugar)—as well as the polyols, which are a group of carbohydrate compounds that are not sugars but provide about half the calories of the natural sugars. The polyols are sometimes called sugar replacers,

Artificial sweeteners

source: Food and Drug Administration, U.S. Department of Health and Human Services.

(Illustration by GGS Information Services/Thomson Gale.)

sugar-free sweeteners, sugar alcohols, or novel sugars. Polyols occur naturally in plants but can also be produced commercially. They include such compounds as sorbitol, mannitol, xylitol, and hydrogenated starch hydrolysates.

Nonnutritive sweeteners are synthetic compounds that range between 160 and 13,000 times as sweet as sucrose, which is the standard for the measurement of sweetness. There are five nonnutritive sweeteners approved by the Food and Drug Administration (FDA) for use in the United States as of 2007. They are saccharin, aspartame, acesulfame potassium (or acesulfame-K), sucralose, and neotame. There are other nonnutritive sweeteners that have been approved for use elsewhere in the world by the Scientific Committee on Food (SCF) of the European Commission, the Joint Expert Committee of Food Additions (JECFA) of the United Nations Food and Agricultural Organization, and the World Health Organization (WHO) but have not been approved by the FDA. These substances are alitame, cyclamate, neohesperidine dihydrochalcone, stevia, and thaumatin. All of these will be described in further detail below.

The FDA uses two categories to classify both nutritive and nonnutritive sweeteners for regulatory purposes. Some are classified as food additives, which is a term that was introduced by the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938. This legislation was passed by Congress in response to a mass poisoning tragedy that took the lives of over a hundred people in 1937. A company in Tennessee that manufactured an antibacterial drug known as sulfanilamide, which had been used safely in powdered or pill form to treat childhood infections, dissolved the sulfanilamide in diethylene glycol—related to the active ingredient in automobile antifreeze—in order to market it as a liquid medicine. Diethylene glycol is highly

KEY TERMS

Acceptable daily intake level (ADI)— The level of a substance that a person can consume every day over a lifetime without risk. The ADIs for artificial sweeteners are very conservative measurements.

Carcinogen— A substance or other agent that causes cancer. Some artificial sweeteners have been banned in the United States on the grounds that they may be carcinogens.

Food additive— Defined by the Federal Food, Drug, and Cosmetic Act (FD&C) of 1938 as “any substance, the intended use of which results directly or indirectly, in its becoming a component or otherwise affecting the characteristics of food.”

Excipient— An inert substance, such as certain gums or starches, used to make drugs easier to take by allowing them to be formulated into tablets or liquids. Some artificial sweeteners are used as excipients.

Fructose— A simple sugar that occurs naturally in sucrose and fruit. It can be added in combination with sucrose in the form of high-fructose corn syrup (HFCS) to sweeten foods because it is sweeter than sucrose. Large amounts of fructose can cause diarrhea in infants and young children.

Generally recognized as safe (GRAS)— A phrase used bythefederal governmentto refer to exceptions to the FD&C Act of 1938 as modified by the Food Additives Amendment of 1958. Sweeteners that have a scientific consensus on their safety, based on either their use prior to 1958 or to well-known scientific information, may be given GRAS status.

Gulf war syndrome (GWS)—A disorder characterized by a wide range of symptoms, including skin rashes, migraine headaches, chronic fatigue, arthritis, and muscle cr amps, possibly related to military service in the Persian Gulf war of 1991. GWS was briefly attributed to the troops’ high consumption of beverages containing aspartame, but this explanation has been discredited.

High-intensity sweetener—Another term for nonnutritive sweetener, used because these substances add sweetness to food with very little volume.

Nonnutritive sweetener— Any sweetener that offers little or no energy value when added to food.

Nutritive sweetener— Any sweetener that adds some energy value to food.

Phenylketonuria (PKU)— A rare inherited metabolic disorder resulting in accumulation of phenylalanine, an amino acid, in the body. It can lead to mental retardation and seizures. People with PKU should not use products containing the artificial sweetener aspartame because it is broken down into phenylalanine (and other products) during digestion.

Sucrose— The natural sweetener commonly used as table sugar; sucrose is a compound of two simple sugars, glucose and fructose. It is used as the standard for measuring the sweetening power of high-intensity artificial sweeteners.

toxic to human beings and household pets, causing painful death from kidney failure. In 1937 there was no requirement for medications to be tested for toxicity before being placed on the market. The FD&C Act of 1938 thus included a legal definition of a food additive “any substance, the intended use of which results directly or indirectly, in its becoming a component or otherwise affecting the characteristics of food”

The FDA asks the following questions in evaluating a proposed new sweetener as a food additive:

• How is the sweetener made?
• What are its properties when it is added to foods or beverages?
• How much of the sweetener will be digested or otherwise absorbed by the body?
• Are certain groups of people likely to be more susceptible than others to the additive?
• Does the sweetener have any known toxic effects, including hereditary disorders or cancer?

Other sweeteners are classified as generally regarded as safe or GRAS, and are not defined for legal purposes as food additives. The GRAS category was created in 1958 when the FD&C Act was modified by the passage of the Food Additives Amendment. A sweetener, whether nutritive or nonnutritive, can be given GRAS status on the basis of “experience based on common use in food” or a scientific consensus represented by published studies. Sorbitol and a few other polyols have GRAS status along with the natural sugars. Most artificial sweeteners, however, are considered food additives by the FDA.

Purpose

Artificial sweeteners are used in food products for several reasons: to lower the calorie content of soda pop and other sweet treats as part of weight reduction and weight maintenance diets; to assist patients with diabetes in controlling blood sugar levels more effectively; and to lower the risk of tooth decay. They are also added as excipients (inert substances used to make drugs easier to take in tablet or liquid form) to some prescription medications to disguise unpleasant tastes because they do not react with the active drug ingredients as natural sugars sometimes do. Sorbitol and mannitol are commonly added to toothpaste, mouthwash, breath mints, cough drops, cough syrups, sugarless gum, over-the-counter liquid antacids, and similar personal oral care products to add bulk to the product’s texture as well as minimize the risk of tooth decay.

In addition to adding a sweet flavor, artificial sweeteners are also used in the manufacture of baked goods, beverages, syrups, and other food products to improve texture, add bulk, retard spoilage, or as part of a fermentation process. The polyols in particular are used to retard spoilage because they do not support the growth of mold or bacteria to the same extent as natural sugars.

Description

Nutritive sweeteners

• Natural sugars. Natural sugars, which are also called primary sweeteners, include sucrose, a compound of glucose and fructose commonly used in crystalline form as table sugar; and fructose, which is a simple sugar found in sucrose and fruit, and is added to foods and beverages in combination with sucrose as high-fructose corn syrup or HFCS. These sweeteners provide about 4 calories per gram. Fructose is sweeter than sucrose; thus smaller amounts of it can be used to sweeten foods and drinks, which allows for some reduction in calories.
• Polyols. Polyols provide between 1.6 calories per gram (mannitol) and 3 calories per gram (hydrogenated starch hydrolysates). They are absorbed very slowly and incompletely during digestion, which is why they can be beneficial to patients with diabetes who want to avoid sudden or sharp increases in blood sugar levels.

Nonnutritive sweeteners approved by the FDA

There are five nonnutritive sweeteners approved by the FDA for use in the United States as of 2007:

• Acesulfame potassium (acesulfame-K). Acesulfame potassium is a high-intensity nonnutritive sweetener that is about 200 times sweeter than sucrose; 95% of it is excreted from the body unchanged. It was discovered by a German company, Hoechst AG, in 1967. It was first approved by the FDA for use in nonalcoholic beverages in 1998 and for general use in 2003. In addition to its usefulness in reducing the calorie content of foods, in diabetic diets, and in not promoting tooth decay, acesulfame potassium remains stable at the high temperatures used for cooking and baking, has a long shelf life, does not leave any bitter aftertaste, and combines well with other sweeteners. It is sold under the brand names ACK, Sunett, Sweet & Safe, and Sweet One.
• Aspartame. Aspartame, which is also about 200 times sweeter than sugar, was discovered in 1965 by a researcher at Searle Laboratories working on antiulcer medications. It is unusual among nonnutritive sweeteners in that it is completely broken down during digestion into its basic components—the amino acids aspartic acid and phenylalanine plus a small amount of methanol. Aspartame was approved by the FDA for tabletop use in 1981 and for use in carbonated beverages in 1983. As of the early 2000s, the United States uses 75% of the aspartame produced in the world, 70% of this amount consumed in diet beverages. Aspartame is the nonnutritive sweetener that has received the greatest amount of negative attention in the mass media because of a rumor that it caused Gulf War syndrome (GWS) in veterans of the Persian Gulf conflict of 1991, and because of a study done in Europe in 2005 that linked aspartame to two types of cancer (leukemia and lymphomas) in female laboratory rats. In response to the 2005 European study, the National Cancer Institute (NCI) conducted a study of half a million people in the United States in 2006 and found no connection between cancer rates and aspartame consumption. The details of this study can be found in a fact sheet available on the NCI website. Another study conducted by the National Toxicology Program (NTP) of the National Institute of Environmental Health Sciences (NIEHS) of aspartame as a possible carcinogen found no evidence that the sweetener causes cancer in humans. Aspartame is sold under the brand names NutraSweet, Equal, and Sugar Twin (blue box).
• Neotame. Neotame is similar chemically to aspartame but is between 7000 and 13,000 times sweeter than sugar. In July 2002, neotame was approved as a general-purpose sweetener by the FDA. Neotame is partially absorbed in the small intestine, the remainder excreted in urine and feces. It is not concentrated in any body organs and has not been identified as a cancer risk. Like acesulfame potassium, neotame has a clean taste with no bitter aftertaste, combines well with other sweeteners, and is stable when used in cooking and baking. It is also used to enhance the flavors of fruit and other ingredients in food. Neotame is manufactured in the United States by the NutraSweet Company of Mount Prospect, Illinois, but does not have a commercial or brand name as of early 2007.
• Saccharin. Saccharin is the oldest nonnutritive sweetener, having been discovered in 1879 by a chemist working at Johns Hopkins University. It is about 200 to 700 times as sweet as sugar. It was used extensively during World Wars I and II, when sugar was rationed in the United States as well as in Europe. It is still the least expensive high-intensity sweetener used around the world—about 65 million pounds per year in the late 1990s. Saccharin passes through the body essentially unchanged. It was so widely used in the United States that it was considered a GRAS substance when the Food Additives Amendment was passed in 1958, but it lost that status when studies performed on laboratory rats in the 1970s indicated that it might cause bladder cancer. At that point Congress mandated that all foods containing saccharin must carry a warning label that they might be hazardous to health. Later studies indicated that the bladder tumors in rats are caused by a mechanism that does not operate in humans, and that there is no evidence that saccharin is unsafe for humans. In 2000 the NTP took saccharin off its list of carcinogens and the saccharin-warning label was removed from food. Details of the controversy over saccharin and cancer can be found on the NCI website. Saccharin is presently sold under the trade names of Sweet ’N Low, Sweet Twin, and Necta Sweet.
• Sucralose. Sucralose is unusual in that it is the only nonnutritive sweetener made from sugar, but it is about 600 times as sweet as table sugar. Sucralose is manufactured from sugar by substituting three chlorine atoms for three hydroxyl groups in the sugar molecule. Only about 11 % of sucralose is absorbed during digestion; the remainder is excreted unchanged. The FDA approved sucralose in 1998 as a tabletop sweetener and in 1999 as a general-purpose sweetener. The acceptable daily intake (ADI) for sucralose is 5 mg per kilogram of body weight per day. Like acesulfame potassium, sucralose is highly heat-stable and works well in foods that must be baked or cooked. Sucralose is sold under the trade name Splenda for table use.

Nonnutritive sweeteners not approvedfor use in the United States

• Alitame. Alitame is a compound of aspartic acid, D-alanine, and an amide; it is 2000 times sweeter than sugar. In 1986 it was reviewed by the FDA, which found the application to be deficient. As of 2007, alitame is approved for use only in Australia, New Zealand, Mexico, Colombia, and China.
• Cyclamate. Cyclamate, which is about 30 times sweeter than sugar, was used as a nonnutritive sweetener in the United States until 1969, when it was shown to cause cancer in laboratory rats when combined with saccharin. Although cyclamate by itself was found by the National Academy of Sciences not to be a carcinogen in 1985 and is approved for use in over 50 countries, it has not been reinstated by the FDA for use in the United States as of 2007.
• Neohesperidine dihydrochalcone. Neohesperidine dihydrochalcone is a compound that is about 1500 times sweeter than sugar and adds a slight licorice flavor to foods and beverages. The FDA considers neohesperidone GRAS as a flavoring but not as a sweetener.
• Stevia. Stevia is a sweetener derived from a shrub native to South America. The FDA has not received sufficient scientific evidence to indicate that stevia is safe for use as a food additive.
• Thaumatin. Thaumatin is an intensely sweet mixture of proteins that also acts as a flavor enhancer. The FDA has given thaumatin GRAS status as a flavor adjunct but has not approved it as a sweetener as of 2007.

Precautions

Artificial sweeteners are generally regarded as safe when used appropriately. The official position of the American Dietetic Association is that nutritive and nonnutritive sweeteners are safe as long as one’s diet follows the current federation recommendations for nutrition.

The Institute of Medicine (IOM) maintains measurements of acceptable daily intake (ADI) levels for artificial sweeteners approved for use in the United States. The ADI is a regulatory definition that is often misunderstood. It is a very conservative estimate of the amount of a sweetener that can be safely consumed on a daily basis over the course of a person’s lifetime. The ADI is not intended to be used as a specific point at which safe use ends and health risks begin, as occasional use of an artificial sweetener over the ADI is not of concern. To use aspartame as an example, its ADI is 50 mg per kilogram of body weight per day. An adult weighing 150 pounds would have to drink 20 12-ounce containers of diet soft drink containing aspartame, eat 42 servings of gelatin, or use 97 packets of tabletop sweetener to reach the ADI.

Some specific artificial sweeteners must be used cautiously by certain groups of people:

• Polyols: Some polyols—most commonly mannitol and sorbitol—have a laxative effect in some people if they are consumed in large amounts (more than 50 g/day of sorbitol or 20 g/day of mannitol). Persons with diabetes may wish to limit their consumption of products containing polyols or increase their use gradually until they see how their bodies react to these sweeteners.
• Aspartame: Because aspartame is broken down in the body to the amino acid phenylalanine, foods or beverages containing aspartame should not be used by persons with phenylketonuria (PKU), a rare inherited disease that causes phenylalanine to accumulate in the body. The FDA requires all products containing aspartame sold in the United States to be labeled with the following warning: “Phenylketonurics: Contains Phenylalanine.” Although the breakdown products of neotame also include phenylalanine, the amount is so small that it does not affect people with PKU.

Interactions

There are no known interactions with prescription drugs caused by the use of nutritive or nonnutritive sweeteners. As was noted above, some nonnutritive sweeteners are considered useful excipients for medications precisely because they are chemically inert.

Parental concerns

There have been concerns expressed about the use of artificial sweeteners by children because children consume more sweeteners, both nutritive and nonnutritive, per pound of body weight on a daily basis than adults. The use of fruit juice and other sweet beverages by children has greatly increased since the 1980s; however, studies indicate that even children who drink large amounts of diet soda and other beverages usually remain well below the ADI levels for aspartame and other nonnutritive sweeteners. The chief risk to children’s digestive health is fructose, which is found in such popular children’s drinks as apple juice. Fructose is incompletely digested by children below the age of 18 months and may cause diarrhea in older children. Children diagnosed with nonspecific diarrhea maybenefit from being given smaller amounts of fruit juice to drink.

During the early 1990s, some researchers identified a possible connection between high levels of aspartame consumption and attention-deficit hyperactivity disorder (ADHD) in children. Two studies published in 1994 in Pediatrics and the New England Journal of Medicine respectively, however, found no connection between aspartame and ADHD, even when the children were given 10 times the normal daily amount of aspartame. Aspartame and other nonnutritive sweeteners, however, may have an additive effect on nerve cell development when they are combined with food colorings. This possibility was suggested by a 2006 study of laboratory mice in the United Kingdom, but the implications for humans are far from clear.

High intake of sweeteners added to food is of greatest concern during adolescence. As people age, they generally lower their intake of calories from added sugars. Fewer than 10% of adults over age 50 derive more than 25% of their daily calories from sugars, which is the maximal intake value established by the IOM. Nearly a third of adolescent females exceed this level, however, with almost a third of the extra sugar intake coming from carbonated beverages sweetened with high-fructose corn syrup. Although the rise in obesity in children and adolescents is a complex problem that cannot be attributed to a single factor, preliminary studies suggest that nonnutritive sweeteners may be useful in reducing adolescents’ consumption of drinks sweetened with HFCS.

Resources

BOOKS

Nabors, Lyn O’Brien, ed. Alternative Sweeteners, 3rd ed. New York: M. Dekker, 2001.

PERIODICALS

“Artificial Sweeteners: No Calories ... Sweet!” FDA Consumer 40 (July-August 2006). Available online at http://www.fda.gov/fdac/features/2006/406_sweeteners.html (accessed March 22, 2007).

Henkel, John. “Sugar Substitutes: Americans Opt for Sweetness and Lite.” FDA Consumer, February 2006. Available online at http://www.cfsan.fda.gov/—dms/fdsugar.html (accessed March 22, 2007).

Lau, K., W. G. McLean, D. P. Williams, and C. V. Howard. “Synergistic Interactions between Commonly Used Food Additives in a Developmental Neurotoxicity Test.” Toxicological Sciences 90 (March 2006): 178–187.

Shaywitz, B. A., C. M. Sullivan, G. M. Anderson, et al. “Aspartame, Behavior, and Cognitive Function in Children with Attention Deficit Disorder. Pediatrics 93 (January 1994): 70–75.

Wax, Paul M. “Elixirs, Diluents, and the Passage of the 1938 Federal Food, Drug, and Cosmetic Act.” Annals of Internal Medicine 122 (March 15, 1995): 456–461. Available online at http://www.annals.org/cgi/content/full/122/6/456 (accessed March 23, 2007).

Wolraich, M. L., S. D. Lindgren, P. J. Stumbo, et al. “Effects of Diets High in Sucrose or Aspartame on the Behavior and Cognitive Performance of Children.” New England Journal of Medicine 330 (February 3, 1994): 301–307.

OTHER

American Dietetic Association (ADA). Position Statement on the Use of Nutritive and Nonnutritive Sweeteners Available online at http://www.eatright.org/cps/rde/xchg/ada/hs.xsl/home_3794_ENU_HTML.htm. This position paper was adopted by the ADA’s House of Delegates on October 18,1992; reaffirmed on September 6, 1996; and reaffirmed again on June 22, 2000. It will remain in effect until December 31, 2009.

National Cancer Institute (NCI) Fact Sheet. Artificial Sweeteners and Cancer: Questions and Answers Bethesda, MD: NCI, 2006. Available online at http://www.cancer.gov/cancertopics/factsheet/Risk/artificial-sweeteners.

National Cancer Institute (NCI) Fact Sheet. Aspartame and Cancer: Questions and Answers Bethesda, MD: NCI, 2006. Available online at http://www.cancer.gov/cancertopics/factsheet/AspartameQandA.

Office of Food Additive Safety. Guidance for Industry: Frequently Asked Questions about GRAS College Park, MD: Office of Food Additive Safety, 2004. Available online at http://www.cfsan.fda.gov/-dms/grasguid.html.

ORGANIZATIONS

American Dietetic Association (ADA). 120 South Riverside Plaza, Suite 2000, Chicago, IL 60606-6995. Telephone: (800): 877-1600. Website: http://www.eatright.org.

Dietitians of Canada/Les die´te´tistes du Canada (DC). 480 University Avenue, Suite 604, Toronto, Ontario, Canada M5G 1V2. Telephone: (416) 596-0857. Website: http://www.dietitians.ca.

Institute of Medicine (IOM). 500 Fifth Street NW, Washington, DC 20001. Telephone: (202) 334-2352. Website: http://www.iom.edu.

National Cancer Institute (NCI). NCI Public Inquiries Office, 6116 Executive Boulevard, Room 3036A, Bethesda, MD 20892-8322. Telephone: (800) 4-CANCER. Website: http://www.cancer.gov/.

National Toxicology Program (NTP). Report on Carcinogens. P.O. Box 12233, MD EC-14, Research Triangle Park, NC 27709. Telephone: (919) 541-4096. Website: http://ntp.niehs.nih.gov/ntpweb/index.cfm?objectid=7182FF48-BDB7-CEBA-F8980E5DD01A1E2D.

Office of Food Additive Safety, HFS-200, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. Telephone: (301) 436-1200. Website: http://www.cfsan.fda.gov/list.html.

U. S. Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. Telephone: (888) INFO-FDA. Website: http://www.fda.gov/default.htm.

Rebecca J. Frey, Ph.D.

Ascorbic acid seeVitamin C

Aspartame

Background

Aspartame is an artificial sweetener used in reduced calorie foods. It is derived primarily from two naturally occurring amino acids chemically combined and designated by the chemical name N-L-aaspartyl-L-phenylalanine-l-methyl ester (APM). Discovered inadvertently in 1965, it was later patented and is currently the most utilized artificial sweetener in the United States.

Aspartame is a white, odorless, crystalline powder. It is about 200 times sweeter than sugar and is readily dissolvable in water. It has a sweet taste without the bitter chemical or metallic aftertaste reported in other artificial sweeteners. These properties make it a good ingredient to use as a sugar replacement in many food recipes. However, aspartame does tend to interact with other food flavors, so it cannot perfectly replace sugar. Recipes for baked goods, candies, and other products must be modified if aspartame is utilized. Although aspartame can be used in microwave recipes, it is sensitive to extensive heating, which makes it unsuitable for baking.

The fact that aspartame provides sweetness and flavor without imparting other physical characteristics such as bulk or calories like other sweeteners makes it unique. Another useful trait is that it has a synergistic effect with other sweeteners, making it possible to use less total sweetener. In addition to sweetening foods, aspartame is used to reduce calories, and intensify and extend fruit flavors.

History

Humans have desired foods with a sweet taste for thousands of years. Ancient cave paintings at Arana in Spain show a neolithic man taking honey from a wild bee's nest. It has been suggested that early humans might have used the sweet taste of foods to tell them which ones would be safe to eat. It is even thought that the desire for sweet taste might be an innate human trait. Unfortunately, many of the foods that are naturally sweet contain relatively large amounts of calories and carbohydrates.

Alternative sweeteners were developed to provide the sweet taste without the unnecessary calories. They also provide the additional benefits of enhancing the palatability of pharmaceuticals, aiding in the management of diabetes, and providing a cost-effective source where sugar is not available. The first one, saccharin, was discovered in 1879 and has been used in products such as toothpaste, mouthwash, and sugarless gum.

The sugarlike taste of aspartame was discovered accidentally by James Schlatter, an American drug researcher at G.D. Searle and Co. in 1965. While working on an antiulcer drug, he inadvertently spilled some APM on his hand. Figuring that the material was not toxic, he went about his work without washing it off. He discovered APM's sweet taste when he licked his finger to pick up a piece of weighing paper. This initial breakthrough then led the company to screen hundreds of modified versions of APM. However, none of these materials offered all of the advantages found in the original compound, including economical manufacturing, excellent taste quality and potency, natural metabolic pathways for digestion, excellent stability, and very low toxicity. Consequently, the company pursued and was granted United States patent 3,492,131 and various international patents, and the initial discovery was commercialized. The U.S. patent expired in 1992, and the technology is now available to any company who wants to use it.

After many years of toxicity testing, the FDA initially approved aspartame's use as a sweetener in 1980. However, a hallmark of synthetic chemicals used in food products is that their safety is under constant scrutiny. Aspartame is no exception and has been surrounded by some controversy concerning its safety since its introduction. Most of these concerns were put to rest in late 1984, when after investigating various aspartame-related complaints, the FDA and the Centers for Disease Control concluded that the substance is safe and does not represent a widespread health risk. This conclusion was further supported by the American Medical Association in 1985, and aspartame has been gaining market share ever since. In addition to its use in the United States, aspartame has also been approved for use in over 93 foreign countries.

Aspartame has been marketed since 1983 by Searle under the brand names NutraSweet' and Equal'. Currently, NutraSweet' is a very popular ingredient and is used in more than 4,000 products, including chewing gum, yogurt, diet soft drinks, fruit-juices, puddings, cereals, and powdered beverage mixes. In the U.S. alone, NutraSweet®'s sales topped $705 million in 1993, according to the company.

Raw Materials

Aspartame is primarily derived from compounds called amino acids. These are chemicals which are used by plants and animals to create proteins that are essential for life. Of the 20 naturally occurring amino acids, two of them, aspartic acid and phenylalanine, are used in the manufacture of aspartame.

All amino acids molecules have some common characteristics. They are composed of an amino group, a carboxyl group, and a side chain. The chemical nature of the side chain is what differentiates the various amino acids. Another characteristic of amino acids is the ability to form different molecular configurations known as isomers. These isomers are designated by the letters L and D. Aspartame is composed of only L, L isomers; none of the other isomer combinations taste sweet. The sweet taste of aspartame could not have been predicted by looking at the two amino acids that it is derived from. L-aspartic acid has a flat taste and L-phenylalanine tastes bitter. However, when the two compounds are chemically combined and the L-phenylalanine is slightly modified, a sweet taste is achieved.

Aspartic acid is one of five amino acids that have a "charged" side group. The charged side group on aspartic acid is (-CH₂-COOH). When put in water, this material ionizes and becomes negatively charged. Phenylalanine has a nonpolar, hydrophobic side group which is not compatible with water. It is made up of a six carbon ring and is attached to the main amino acid backbone via a methyl (-CH₂) group. Prior to synthesis into aspartame, it is reacted with methanol. This adds a methyl group which is linked to the molecule by an oxygen, and the compound is converted to a methyl ester. The methanol required for the synthesis of aspartame has the chemical structure (CH₃-OH). This is a very common material and is used extensively by organic chemists for various chemical syntheses.

The Manufacturing
Process

Although its components—aspartic acid, phenylalanine, and methanol—occur naturally in foods, aspartame itself does not and must be manufactured. NutraSweet' (aspartame) is made through fermentation and synthesis processes.

Fermentation

Direct fermentation produces the starting amino acids needed for the manufacture of aspartame. In this process, specific types of bacteria which have the ability to produce certain amino acids are raised in large quantities. Over the course of about three days, the amino acids are harvested and the bacteria are destroyed.

• 1 To start the fermentation process, a sample from a pure culture of bacteria is put into a test tube containing the nutrients necessary for its growth. After this initial inoculation the bacteria begin to multiply. When their population is large enough, they are transferred to a seed tank. The bacterial strains used to make L-aspartic acid and L-phenylalanine are B. flavum and C. glutamicum respectively.
• 2 The seed tank provides an ideal environment for growing more bacteria. It is filled with the things bacteria need to thrive, including warm water and carbohydrate foods like cane molasses, glucose, or sucrose. It also has carbon sources like acetic acid, alcohols or hydrocarbons, and nitrogen sources such as liquid ammonia or urea. These are required for the bacteria to synthesize large quantities of the desired amino acid. Other growth factors such as vitamins, amino acids, and minor nutrients round out seed tank contents. The seed tank is equipped with a mixer, which keeps the growth medium moving, and a pump, which delivers filtered, compressed air. When enough bacterial growth is present, the contents from the seed tank are pumped to the fermentation tank.
• 3 The fermentation tank is essentially a larger version of the seed tank. It is filled with the same growth media found in the seed tank and also provides a perfect environment for bacterial growth. Here the bacteria are allowed to grow and produce large quantities of amino acids. Since pH control is vital for optimal growth, ammonia water is added to the tank as necessary.
• 4 When enough amino acid is present, the contents of the fermentation tank are transferred out so isolation can begin. This process starts with a centrifugal separator, which isolates a large portion of the bacterial amino acids. The desired amino acid is further segregated and purified in an ion-exchange column. From this column, the amino acids are pumped to a crystallizing tank and then to a crystal separator. They are then dried and readied for the synthesis phase of aspartame production.

Synthesis

Aspartame can be made by various synthetic chemical pathways. In general, phenylalanine is modified by a reaction with methanol and then combined with a slightly modified aspartic acid which eventually forms aspartame.

• 5 The amino acids derived from the fermentation process are initially modified to produce aspartame. Phenylalanine is reacted with methanol resulting in a compound called L-phenylalanine methyl ester. Aspartic acid is also modified in such a way to shield various portions of the molecule from the effects of further reactions. One method is by reacting the aspartic acid with substances that result in added benzyl rings to protect these sites. This ensures that further chemical reactions will occur only on specific parts of the aspartic acid molecule.
• 6 After the amino acids are appropriately modified, they are pumped into a reactor tank, where they are allowed to mix at room temperature for 24 hours. The temperature is then increased to approximately 149°F (65 °C) and maintained for another 24 hours. The reaction is then cooled to room temperature. It is diluted with an appropriate solvent and cooled to about 0°F (-18°C), causing crystallization. The crystals are then isolated by filtration and dried. These crystals are an intermediate of aspartame which must be further modified.
• 7 The intermediate is converted to aspartame by reacting it with acetic acid. This reaction is performed in a large tank filled with an aqueous acid solution, a palladium metal catalyst, and hydrogen. It is thoroughly mixed and allowed to react for about 12 hours.

Purification

• 8 The metal catalyst is removed by filtration, and the solvent is distilled, leaving a solid residue. This residue is purified by dissolving it in an aqueous ethanol solution and recrystallizing. These crystals are filtered and dried to provide the finished, powder aspartame.

Quality Control

The quality of the compounds is checked regularly during the manufacturing process. Of particular importance are frequent checks of the bacterial culture during fermentation. Also, various physical and chemical properties of the finished product are checked, such as pH level, melting point, and moisture content.

The Future

Currently, there are only three alternative sweeteners in the United States that can be used in food products. While aspartame is perhaps one of the best available, scientists are looking for new ways to make these sweeteners taste as much like sugar as possible. Their research has been focused in three areas, including finding new derivatives, blending sweeteners, and enhancing the efficiency of aspartame.

Most of the chemical derivative work has centered on finding compounds which will fit into the taste bud receptors better than traditional aspartame. Using aspartame as the model, researchers believe they will be able to improve various characteristics by making slight modifications. For example, they have found that when L-aspartic acid alone is modified in a certain way, it gives products that have a sweet taste. Future research will likely focus on these kinds of derivatives.

Another area of research focuses on improving the heat stability of aspartame. Using encapsulation technology, aspartame has been developed which can be used in baked goods and baking mixes. Initial test results are positive, and FDA approval has been granted for bakery applications.

Since only three synthetic sugar substitutes are currently approved for use in food in the U.S., combining artificial sweeteners in products is becoming an important technological advance. Here, scientists combine two or three sweeteners in an effort to make the product taste more sugarlike.

Where to Learn More

Books

Nabors, Lyn, and Robert Gelardi. Alternative Sweeteners. Marcel Dekker, Inc., 1986.

Periodicals

Best, Daniel and Lisa Nelson. "Low-calorie foods and sweeteners." Prepared Foods, June 1993, p. 47.

Tomasula, Dean. "Sweet as sugar: artificial sweetener producers are blending products, in search of a market winning combination." Chemical Marketing Reporter, June 27, 1994, p. S22.

—PerryRomanowski

Artificial Sweeteners

Artificial sweeteners may assist in weight management, prevention of dental caries , and control of blood glucose for diabetics. It has also been suggested that low-calorie sweeteners may stimulate the appetite, but the bulk of evidence does not support this hypothesis. Conclusive research demonstrates that artificial sweeteners have no effect on carbohydrate metabolism , short- or long-term blood glucose control, or insulin secretion, and they are thus an excellent sugar alternative for diabetics. There have been a number of health concerns related with these products, though the Food and Drug Administration (FDA) approval process for artificial sweeteners involves a comprehensive analysis of scientific data to satisfy safety requirements. All "generally recognized as safe" (GRAS) sweeteners have undergone extensive safety testing and have been carefully reviewed by the FDA.

Five FDA-Approved (GRAS) Artificial Sweeteners

Acesulfame potassium (Acesulfame-K) was discovered in 1967 and approved for use in the United States in 1988. Its trade name is Sunette. Two hundred times sweeter than sucrose , this sweetener is stable when heated, making it suitable for cooking. However, when used in large amounts it has a bitter aftertaste. It is not broken down by the body, and it does not provide any calories. Over ninety scientific studies have been conducted by the FDA, and the World Health Organization's Joint Expert Committee on Food Additives (JECFA) has also endorsed Acesulfame K's safety.

Aspartame was discovered in 1969 and approved for use in the United States in 1981. Its trade name is NutraSweet. Also two hundred times sweeter than sugar, aspartame is not suitable in applications that require high temperatures, as it loses its sweetness when heated. It contains four calories per gram, but, because of its intense sweetness, the amount of energy derived from it is negligible. It is synthesized from aspartic acid and phenylalanine, two essential amino acids . Persons with the rare hereditary metabolic disorder phenylketonuria (PKU), an inborn error of metabolism, must control their intake of phenylalanine from all sources, including aspartame, and therefore all U.S. products containing aspartame are labeled "This product contains phenylalanine." Because it is impossible to know if an unborn child has PKU, it is recommended that pregnant women not use aspartame. The FDA states that aspartame is the most thoroughly tested food additive ever submitted to the agency.

Neotame was discovered in 1990 and was approved for use in the United States in 2002. Eight thousand times sweeter than sugar, this analog of aspartame can be used in both cooking and baking applications. Although neotame is a derivative of aspartame, it is not metabolized to phenylalanine, and no special PKU labeling is required. The FDA reviewed more than 113 human and animal studies before ruling on neotame.

Saccharin was discovered in 1879 and approved for use in the United States in 1879. Its trade name is Sweet'n Low. Three hundred to five hundred times sweeter than table sugar, saccharin provides no energy, as it is not metabolized by human beings. It has a bitter and somewhat metallic aftertaste. The largest population study to date, involving nine thousand individuals, showed that saccharin does not increase the risk of cancer , and on December 15, 2000, the U.S. Congress passed legislation to remove the warning label that had been required on foods and beverages containing saccharin since 1977 (warning labels were required because of findings that saccharin caused bladder tumors in mice when they were given high doses of the sweetener). Saccharin is approved in more than one hundred countries around the world and has been reviewed and determined safe by the Joint Expert Committee on Food Additives of the World Health Organization and the Scientific Committee for Food of the European Union.

Sucralose was discovered in 1976 and approved for use in the United States in 1988. Its trade name is Splenda. Six hundred times sweeter than sugar, sucralose is not absorbed from the digestive tract, so it adds no calories to consumed food. It is made from rearranged sugar molecules that substitute three atoms of chlorine for three hydroxyl groups on the sugar molecule. Sucralose has been tested in more than one hundred studies.

Sugar Alcohols (GRAS)

Sugar alcohols are not technically artificial sweeteners. Examples include sorbitol, xylitol, lactitol, mannitol, isomalt, and maltitol, which are used to sweeten "sugar-free" foods such as candy, cookies, and chewing gum. The alcohols have fewer calories than sugar, do not promote tooth decay, and do not cause a sudden increase in blood glucose because the bloodstream does not easily absorb them. They may cause, however, effects similar to a laxative if consumed in excess. Products containing large amounts of sugar alcohols must be labeled with the warning: "Excess consumption may have a laxative effect."

Artificial Sweeteners Pending FDA Approval

Alitame is two thousand times sweeter than sugar. An FDA petition was filed in 1986. Like neotame, alitame is a derivative of aspartame. It is approved for use in a variety of food and beverage products in Australia, New Zealand, Mexico, Colombia, Indonesia, and the People's Republic of China.

Cyclamate was discovered in 1937, banned in 1969, and a petition for approval was refiled in 1982. After being banned by the FDA in 1969, due to findings that high doses cause bladder tumors in mice, cyclamate has been approved for use in more than fifty countries. The sweetener is a derivative of cyclohexylsulfamic acid and is thirty times sweeter than sucrose. In May 2003, the European Union reduced the recommended average daily intake of this sweetener in soft drinks, juice, and milk-based drinks, based on evidence that the conversion rate of cyclamate in the body is higher than previously thought.

Stevioside (stevia) is obtained from the leaves of a South American shrub. Though it can impart a sweet taste to foods, it cannot be sold as a sweetener because the FDA considers it an unapproved food additive. Stevioside is a high-intensity low-calorie sweetener three hundred times sweeter than sucrose. It is approved in Japan, South Korea, Brazil, Paraguay, and Argentina. However, the World Health Organization (WHO) has determined that the data is insufficient to label it as a sweetener.

Artificial sweeteners taste sweet like sugar without the added calories. They do not promote tooth decay, and they are an acceptable alternative for people with diabetes or those wishing to decrease their use of sucrose. Artificial sweeteners, and their metabolic by-products and components, are not considered harmful to human beings at the levels normally used. When used in the context of a healthful diet , artificial sweeteners are generally safe for consumption.

see also Generally Recognized as Safe; Inborn Errors of Metabolism; Phenylketonuria.

Kyle Shadix

Bibliography

American Dietetic Association (1998). "Position of the American Dietetic Association: Use of Nutritive and Nonnutritive Sweeteners." Journal of the American Dietetic Association 98:580–587.

Drewnoski, A. (1995). "Intense Sweeteners and Control of Appetite." Nutrition Review 53:1–7.

Joint FAO/WHO Expert Committee on Food Additives (1993–2003). "Evaluation of Certain Food Additives and Contaminants." Geneva, Switzerland: World Health Organization.

Nabors, Lyn (2001). Alternative Sweeteners, 3rd edition. New York: Marcel Dekker.

Stegink, Lewis, and Filer, L. (1984). Aspartame: Physiology and Biochemistry. New York: Marcel Dekker.

Artificial Sweeteners

There are presently four artificial, or synthetic, sweeteners that have been approved by the U.S. Food and Drug Administration (FDA): saccharin, aspartame, acesulfame-K, and sucralose. People use artificial sweeteners because they suffer from diseases such as diabetes mellitus, because they are concerned about dental caries and periodontal disease, or because they wish to lose or to avoid gaining weight. Artificial sweeteners in very small quantities give foods sweetness, and most are not metabolized, meaning that the artificial sweeteners themselves furnish zero dietary calories.

Sweetener Molecules and Sweetness

Sucrose and most artificial sweeteners are chemically quite dissimilar. Sucrose (C₁₂H₂₂O₁₁), the most common "natural" sweetener, is a disaccharide composed of the monosaccharides glucose and fructose. Saccharin has the formula C₇H₅O₃NS. Aspartame (C₁₃H₁₈O₅N₂), L-aspartyl-L-phenylalanine methyl ester , is the methyl ester of a dipeptide. Acesulfame-K has the formula C₅H₆O₃NS. Sucralose (C₁₁H₁₉O₈Cl₃) is prepared from sucrose via the substitution of three chloride groups for three hydroxyl groups. The molecular structures of sucrose, saccharin, aspartame, acesulfame-K, and sucralose are shown in Figure 1.

A sweetener must be soluble in water and the molecule must bind readily to a specific kind of receptor molecule at the surface of the tongue. The receptor is coupled to a G-protein, which dissociates when the sweetener binds to the receptor, activating a nearby enzyme, and triggering a sequence of events resulting in signals that are carried to and interpreted by the brain. The sweetness "signal" depends on this interaction between receptor and sweetener. The importance of molecular shape to sweetness is illustrated by the case of aspartame, as its stereo isomer , L-aspartyl-D-phenylalanine methyl ester, has a bitter, not a sweet, taste.

Discovery, Sweetness, and Metabolic Products

Saccharin was the first artificial sweetener, discovered in 1879 by Constantin Fahlberg at Johns Hopkins University. The Monsanto Chemical Works was incorporated in 1901 to produce saccharin in the United States. Saccharin is easy to make, stable when heated, and is approximately 300 times sweeter than sucrose when equal quantities are compared. One common saccharin product is Sweet and Low.

Saccharin does not accumulate in body tissues. Controversy over the use of saccharin has existed for over a century. In the 1960s and early 1970s saccharin and/or its impurities were shown to cause bladder cancer in rats.

In 1977 a Canadian study concluded that saccharin was the causative agent. Saccharin was banned in Canada. At about the same time the FDA proposed to limit the use of saccharin, but public outcry was so great that the U.S. Congress placed a moratorium on bans of saccharin until further studies were completed. The original moratorium was in effect for two years but has been continually extended to the present day.

Aspartame was discovered in 1965 by James Schlatter at G.D. Searle & Company. Aspartame is relatively easy to make and is approximately 200 times sweeter than sucrose. It is most commonly sold as Nutra Sweet and Equal. It is less stable than saccharin and breaks down above 29.44°C (85°F). In the body, aspartame is broken down into/absorbed as products that include aspartate, phenylalanine, and methanol. Phenylalanine is toxic to individuals who are homozygous (having identical genes in homologous chromosomes) for phenylketonuria, a genetic disease wherein individuals cannot catabolize phenylalanine. Phenylketonuria causes mental retardation. Products containing aspartame must therefore be labeled for phenylalanine. The FDA considers aspartame to be one of the most thoroughly studied and tested food additives and has judged it to be safe. Controversy still lingers with respect to the effects of aspartame's breakdown products—phenylalanine and aspartate, as well as methanol and its breakdown products formaldehyde and formate.

Acesulfame-K was discovered in 1967 by scientists working at Hoechst AG. It is also called Sunett. It is approximately 200 times sweeter than sugar. It has a long shelf life and does not break down in foods that are cooked or

baked. Over ninety studies have been completed that have concluded that acesulfame-K is safe.

Sucralose was discovered in 1976 by researchers at Tate & Lyle PLC. It is also called Splenda. Sucralose is approximately 600 times sweeter than sugar and is stable at high temperatures. It was approved by the FDA in 1998–1999, and it is supported by a safety database of more than 110 studies. Concerns persist, including concerns over possible side effects associated with breakdown products (which include chlorine and 1,6-dichlorofructose), shrunken thymus glands (and their impacts on the immune system), and unanticipated effects that may not have manifested during the short time that sucralose has been used.

see also Toxicity.

Vivienne A. Whitworth

Bibliography

Henkel, John (1999). "Sugar Substitutes: Americans Opt for Sweetness and Lite." FDA Consumer Magazine 33(6):12–16.

Kretchmer, Norman, and Hollenbeck, Claire B., eds. (1991). Sugars and Sweeteners. Boca Raton, FL: CRC Press.

Smith, David V., and Margolskee, Robert F. (2001). "Making Sense of Taste." Scientific American 284(3):32–39.

Internet Resources

Hodgin, Greg. "The History, Synthesis, Metabolism, and Uses of Artificial Sweeteners." Available from <http://www.ecit.emory.edu/ecit>.

Kitts, David D. "Sweetness Chemistry." Available from <http://www.agsci.ubc.ca/courses>.

Lok, Corie. "Sweet Tooth Gene Found." Available from <http://www.nature.com/nsu/>.

Tate & Lyle PLC. "Sucralose—Technical Information." Available from <http://www.officialsucralosesite.com>.

Aspartame

Definition

Aspartame, an artificial sweetener that is used as a substitute for sugar in many foods and beverages, is considered by some scientists to be a neurotoxin, a substance that is detrimental to the nervous system. This allegation remains controversial.

Description

Aspartame was introduced as an artificial sweetener by the Monsanto Company in the 1970s. For much of the intervening time, individuals and special interest groups have maintained that aspartame damages the nervous system. Given the number and popularity of the items that are sweetened using aspartame (i.e., yogurts, soft drinks), the special interest groups assert that the general population is at risk for neurological damage caused by the ingestion of aspartame.

Alleged harmful effects of aspartame ingestion include seizures and a change in the level of dopamine, a brain neurotransmitter. Symptoms associated with lupus , multiple sclerosis , and Alzheimer's disease have been claimed to result from an excess intake of aspartame. As well, aspartame consumption is claimed to increase the difficulty of diet-dependent diabetics in regulating their blood glucose level.

One peer-reviewed scientific study has documented an improvement in fibromyalgia symptoms (pain in the muscles, ligaments, and tendons) following the elimination of monosodium glutamate and aspartame from the diet. The influence of aspartame alone, however, was not assessed. Studies conducted prior to the marketing of aspartame and following its introduction have failed to demonstrate these claimed negative effects. The U.S. Food and Drug Administration (FDA) maintains that aspartame is not a health threat to the general population, although individuals who are sensitive to the compound can develop headaches and feel fatigued. Currently, there is no evidence directly linking aspartame with diseases such as lupus, multiple sclerosis, and Alzheimer's.

Demographics

As the association of aspartame with neurological disorders is not proven, statistics relating to how often and how many individuals suffer ill effects from aspartame are unavailable. If the claim of a general population effect is true, and that the effect is cumulative (builds up over time), then aspartame would affect older people more than younger people. There has been no evidence or suggestion of any gender, race, or cultural predilection to negative effects from aspartame.

If, however, only certain people are predisposed to be more sensitive to the presence of aspartame, then the demographics would include this subpopulation. The characteristics of such a group have not been defined.

Causes and symptoms

At elevated temperatures of about 90° Fahrenheit, a component of aspartame can convert to formaldehyde. High concentrations of formaldehyde can kill cells and tissues. Furthermore, formaldehyde can, in turn, be converted to formic acid, which can cause metabolic acidosis. Whether these changes are detrimental to the nervous system is not known.

One research paper published in 2001 reported one patient in whom aspartame exacerbated an ongoing migraine attack. Whether this occurrence is more widespread among the general public is unknown.

Diagnosis

Currently, any symptoms that are directly attributable to aspartame excess have not been conclusively identified. The suspected symptoms such as fibromyalgia and changes in dopamine levels are associated with other maladies including lupus, multiple sclerosis, or Alzheimer's disease. Factors that may trigger migraine headache vary among individuals, and physicians may suggest that those suffering from migraine lower their consumption of aspartame.

Treatment

Symptoms may disappear when the use of aspartame is discontinued.

Special concerns

Aspartame poisoning is a contentious issue. Scientific peer-reviewed papers have reported on research performed at companies that have a vested interest in sales of aspartame. While the quality of the scientific data contained in these studies may be sound, other scientists criticize that the evidence presented is difficult to evaluate in light of possible conflicting interests. By the same token, the claims made by special interest groups concerning the dangers of aspartame should be viewed cautiously, as little or no data is presented to support their claims.

Resources

BOOKS

Blaylock, R. L. Excitotoxins. Santa Fe, NM: Health Press. 1996.

Roberts, H. J. Aspartame (Nutrasweet): Is It Safe? Philadelphia: The Charles Press, 1992.

PERIODICALS

Butchko, H. H., et al. "Aspartame: Review of Safety." Regulatory Toxicology and Pharmacology (April 2002): S1–93.

Newman, L. C., and R. B. Lipton. "Migraine MLT-down: An Unusual Presentation of Migraine in Patients with Aspartame-triggered Headaches." Headache (October 2001): 899–901.

Smith, J. D., C. M. Terpening, S. O. Schmidt, and J. G. Gums. "Relief of Fibromyalgia Symptoms following Discontinuation of Dietary Excitotoxins." Annals of Pharmacotherapy (June 2001): 702–706.

OTHER

"Aspartame Information Page." National Institute of Neurological Disorders and Stroke. January 21, 2004 (May 17, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/aspartame.htm>.

ORGANIZATIONS

Food and Drug Administration. 5600 Fishers Lane, CDER

HFD-210, Rockville, MD 20857. (301) 827-4573 or (888) 463-6332. <http://www.fda.gov>.

Brian Douglas Hoyle, PhD