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-spartyl-L-phenylalanine methyl ester, is the methyl ester of a dipeptide. Acesulfame-K has the formula C5H6O3 NS. 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.
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. Artificial sweeteners, such as those in diet sodas, contain no calories and are used by dieters and diabetics. 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.
Toxicity is the capacity of a substance to poison. Swiss physician Paracelsus defined poison as: “What is there that is not a poison? All things are poison and nothing without poison. Solely the dose determines that thing is not a poison.” The toxicity of a substance is therefore not an inherent property but the detrimental manifestation of its biochemical effect in a living system. The severity of a substance’s toxicity is the function of its interaction with the physiology of a particular organism. For example, chocolate is moderately toxic to canines but minimally to other animals. Ingested in very large quantities, even vitamins can exhibit toxicity in humans.
The comparison of two substances in terms of their relative toxicity is difficult because every substance has its own mode of action and target organ(s). Hence, the short-term poisoning potential (acute toxicity) of a substance is measured by the amount needed to kill half the population of a test species, called the LD50 (lethal dose for 50 percent). The measurement is expressed as milligrams per kilogram of body weight (mg/kg). For example, administering to mice a substance with an LD50 for mice of 10 mg/kg would kill 50 percent of a population of mice. In environmental studies, the term used to measure toxicity in air or water is LC50 (lethal concentration for 50 percent), defined similarly to LD50 and expressed as parts per million, parts per billion, or milligrams per liter (mg/l).
The route of entry of a toxicant affects its LD50 value. Since the lethality of a substance is related to its ability to block vital cellular functions by interacting with specific biomolecules, the site of exposure, its dissemination speed, and the physiological importance of the target tissue all factor into its toxicity. For example, the common household pesticide dichlorovos has an LD50 for rats of 56 mg/kg if taken orally (through the mouth) and an LD50 of 15 mg/kg if injected intraperitoneally (into the abdominal cavity).
The toxicity of a chemical also varies from one animal to the next. The LD50 for the common insecticide Diazinon is 300 to 400 mg/kg in rats, while in birds it is 2.75 mg/kg. Theobromine, a chemical found in chocolate, is toxic to dogs but not to rodents. Although largely extrapolated from animal tests, a rating system for acute chemical toxicity for humans has been devised.
Chronic or cumulative toxicity is manifested as a result of continuous exposure to a chemical. A common example is the “genotoxicity” of benzene, a chemical present in car exhausts and cigarette smoke. The metabolism of benzene in the liver results in the formation of highly reactive free-radicals. These in turn may cause damage to the genetic material of a cell, in some cases leading to cancer.
LD50 is the amount of a hazardous substance that results in the death of 50 percent of the individuals exposed. LD50 is commonly measured by exposing rats or mice to increasing amounts of the toxic substance until a dosage is reached that kill half the exposed animals within a certain time period (usually fourteen days). Although traditional investigations into the toxicity of chemicals in the natural environment have focused on animals, the toxicity of agrichemical and environmental pollutants to plants (phytotoxicity) has gained interest. Despite being well documented in literature, phytotoxicity is measured in various ways by agronomists and
Dr. Badruddin Khan teaches Chemistry in the University of Kashmir, Srinagar, India.
