ARTIFICIAL SWEETENERS: - University of Maryland

ARTIFICIAL SWEETENERS:
THEIR ORIGINS AND MECHANISMS.
Our pursuit to tackle one of our senses…a battle between desire and need.
HTTP://WWW.DIETRIFFIC.COM/
ERINA ELISE VAN HORN
SPECIAL TOPICS – SCHOLARLY PAPER SUBMISSION
DR. BRUCE JARVIS
LFSC 608
UNIVERSITY OF MARYLAND
MAY 2009

Animals love the taste of sweet. From humans with their “sweet tooth” down to the
smallest vole hunting for the garden bulbs, it has been said that this craving is due to our
natural instinct to search and find food. (1) Sweetness implies there are calories: calories
to sustain our body through various activities and environments. Most of those calories
come from carbohydrates and lipids (fats and oils). Proteins as well as carbohydrates
contain four calories per gram, whereas fats contain nine calories per gram. (2) The
reason why then we take in more calories from carbohydrates than proteins is due to the
fact that we consume much more in volume of those carbohydrates. Carbohydrates are
molecules that come in a variety of sizes and resulting function. “The smallest
carbohydrates are the simple sugars, also known as monosaccharides and disaccharides.”
(3) The commonly referred to sugar is table sugar, or sucrose, which is a disaccharide.
Sucrose consists of two monosaccharides: glucose and fructose.
Figure 1. Sucrose molecule (3)
Fructose can be found solo in fruits, and glucose will form polysaccharides (also referred
to as complex carbohydrates) e.g. starch found in potatoes, beans and other fibrous
vegetables. (4) Glucose is very important in our diet, as it is the starting block of nearly
all energy derivation/mechanism in mammals.

SUCROSE TO GLUCOSE FOR ENERGY:
Gylcolysis is the breakdown sequence of glucose. This sequence of reactions leads to the
transformation of the simple sugars into smaller molecular building blocks, specifically
pyruvate and ATP 1 (adenosine triphosphate). For higher organisms, pyruvate is further
metabolized in the presence of oxygen to produce carbon dioxide, water and a significant
amount of additional ATP.
Figure 2. Net reaction of glycolysis (Wiki)
In order for glycolysis to operate effectively there must be the driving force to process the
glucose, meaning there must be an imbalance in the glucose concentration of the
bloodstream. Signals from the pancreas secrete glucagon, which draws glycogen out of
storage. Glycogen is a branched polymerized form of glucose that allows for stable
storage of glucose in the liver (predominantly) or the muscles. Once the glucose is
released from glycogen, it undergoes one further step prior to glycolysis. (2)
One might think that since glucose is our direct source of energy then the more glucose
we have the more energy we would have. For some this is true, however some
individuals must live with the disease diabetes mellitus. In general, diabetes occurs with
hyperglycemia, which is too much glucose in the blood. This is due to one of two factors
– there is not enough insulin to process the glucose or the insulin in the system is no
1 ATP is a powerful donor of phosphate groups to suitable acceptors because of the pyrophosphate nature of the bonds
between its three phosphate radicals during in the phosphorylation of glucose. ATP serves as the immediate source of
energy for the mechanical work performed by muscle. ATP serves as a link between sources of energy available to a
living system and the chemical and mechanical work that is associated with growth, reproduction, and maintenance of
living substance. McGraw-Hill Encyclopedia of Science and Technology. The McGraw-Hill Companies, Inc., 2005.
Answers.com 23 Apr. 2009. http://www.answers.com/topic/adenosine-triphosphate

longer effective to handle to the amount of glucose present. Diabetics use the glycemic
index to relate a numerical value to a carbohydrate-rich food, based on the average
increase in blood glucose levels occurring after the food is eaten. (5, 6) Glucose
intolerance is not the only sugar-related disease, as there are individuals that cannot
process fructose, but this is less common and treatment is usually similar to prescribed
treatment for diabetics. (7,8)
So, when a portion of the population suffers from a disease in which sucrose is the
initiating culprit, the treatment choices are to either eliminate the source of glucose or
add/regulate the amount of insulin available to the bloodstream. Most options are a
combination of both. As of 2007 almost 18 million people in the United States have been
diagnosed with the disease – over 5 million are estimated to be undiagnosed. (5)
Restricting the amount of glucose for some can be a daunting task. Americans consume
roughly 140 pounds of refined sugar per year; safe to say we consider ourselves as having
a sweet tooth. (10)
Figure 3. Chart on Sugar Consumption Trend (wiki)

This translates not only in an increase of diabetes but an increase in obesity. Omitting
those sweet treats can be down right miserable to many. So, in lieu of ridding the diet of
sweet, science went looking for a sweet replacement.
SUGAR SUBSTITUTES – SWEETENERS
Sugar substitute is the broad term used to describe any substance that replaces sugar
(sucrose) as a sweetener in a product. A sugar substitute could either be from a natural
source or artificially derived. Reasons to replace sucrose vary from availability, product
formulation, cost/financial justifications, or a health/dietary choice. Two types of
alternative sweeteners are available: bulk and intense. Many bulk sweeteners have the
same caloric values as sucrose, but are chosen for financial reasons/motives. (9) Polyols,
or sugar alcohols, lead the list of most common sugar replacements, although many have
a fraction of the sweetness of sucrose, along with some other less desirable
characteristics; the leader being their laxative effects. (11)
Intense sweeteners are primarily made up of artificial sweeteners, synthesized from a
variety of starting materials. These sweeteners are intense due to their sweetness being
hundreds, sometimes thousands times sweeter than that of sucrose, and their mode of
action on the sweet taste bud are all similar. However, there are some clear distinctions
as to their mode of action within the body.
SWEET TASTE: IS THERE A DISTINCTION BETWEEN ARTIFICIAL OR NATURAL?
Sweetness is a perception. One of the five primary taste sensations, sweet is probably the
most beloved, and cursed, for its intensity. “The primary tastes gave early humans clues

about what food was good to eat and what was harmful. Sweet foods usually had calories.
Salty foods had important vitamins and minerals. Sour foods could be healthy, like
oranges, or spoiled, like rotten milk. Bitter tastes were often poisonous.”(12) Regardless
of the taste, the tongue functions in the same way. The tongue is covered with papillae -
within the papillae are the taste buds. The taste buds are actually small groups of
epithelial cells forming a complex interactive unit comprised of 50-150 neural receptors.
Figure 4. Tongue anatomy (12)
These receptors are sensitive to the electrophysiological characteristics of sweet
molecules; particularly the highly polar regions of the sugar molecule making for the
strong association between sugars and sweetness. Glucose specifically binds to the
heterodimeric receptors, T1R2 and T1R3, which recognize both natural and synthetic
sweeteners. (13,14) “After this binding there is a series of neural firings in the brain that
evokes memory retention about the sweetness. “A specific taste quality perception is
generated, which allows sugars to be differentiated from other compounds.” (1) It is these

same receptors that molecules of artificial sweeteners are triggering as well. They are
most effective at lower concentrations, which correspond well to packaging due to their
intense perception of sweetness. However, at higher concentrations some molecules can
also bind to another taste receptor, the TRPV1 receptor, which triggers the bitter and
sometimes metallic aftertaste associated with some of the artificial sweeteners. (15,16)
Figure 5. Human T1R2-T1R3 sweet receptor – Binding for most sweet ligands occurs on the
T1R2 unit. Sugars may interact with the large N termini of both T1R2 and T1R3. (17)
As further research developments are taken with these artificial, intense sweeteners the
conformation of these molecules are studied to determine which specific characteristics
are utilized in the distinction of sweetness. The first prominent theory dealing with
chemical reception for sweetness proposed that in order to be sweet, a compound must
contain a hydrogen bond donor (AH) and a Lewis base (B) separated by about 0.3
nanometers. “According to this theory, the AH-B unit of a sweetener binds with a
corresponding AH-B unit on the biological sweetness receptor to produce the sensation of
sweetness.”(13) This theory was further refined to include a third site that addressed the
variances in sweetness relative to concentration and how simply containing the functional
groups previously believed linked to sweetness was not enough. The interaction within

the molecule itself and the binding sites were also needed to be involved for activation at
the receptor site. (14,15,17) It is evident that the molecule purported to be sweet must
contain a minimum of two binding sites for the receptor to recognize them as sweet.
RESEARCH, REGULATION AND THE FDA – CURRENT APPROVED ARTIFICIAL SWEETENERS:
How is an artificial sweetener regulated compared to crop-harvested sugar? The United
States Department of Agriculture, USDA, regulates all crops grown on US soil through
permits issued by the Animal and Plant Health Inspection Service, APHIS. APHIS
requires information on the plant, the origin of new genes, or gene product, and the
purpose for developing the crop. (10) The USDA also monitors imports/exports of crops
to international sites. In North America, sugar is predominately harvested from sugar
beets but also from sugar cane. (10) The Food and Drug Administration (FDA) regulates
artificial sweeteners as food additives and/or “foodstuffs”. The FDA came out of The
Pure Food and Drug Act of 1906, created to regulate foods and drugs meant for human
consumption. The main purpose of the act was to protect the consumer against
mislabeled or adulterated food. (18) In 1958 and 1960 the Food Additives and the Color
Additive Amendments required pre-market approval of new food ingredients and colors
used in foods respectively. The process for market approval is a four-step communication
between the FDA and the research company. These steps, laid out by The Federal, Food,
Drug and Cosmetic Act of 1938, which replaced the 1906 act, include: 1 st - a proposal,
2 nd - comments that are statements by any consumer or organization question/concern, 3 rd
- responses from the agency filing the proposal and 4 th - final rule from the FDA.
“Additives included are those specified in the regulations promulgated under the FD&C

Act, under Sections 401 (Food Standards), and 409 (Food Additives).” (18,19) This would
include artificial sweeteners as both food additives - alone or in combination - and
tabletop sweeteners.
Saccharin is the oldest artificial sweetener still in use today. (18) It has had a long
market life full of problems associated with its health safety. Discovered in 1879 by a
couple of scientists at John Hopkins University, it is manufactured from toluene in a
reaction initialized by sulfuric acid and phosphorus pentachloride to make the
sulfonamide, then esterfication closes the second ring to produce the final product.
Figure 6. Synthesis of Saccharin, Remsen and Fahlberg method (wiki)
Saccharin is 200-700X sweeter than sucrose and is seen in a multitude of applications. It
does tend to have a slightly bitter taste and metallic aftertaste, and for this reason is
sometimes combined with other sweeteners (both bulk and intense). Because its
discovery was well before the formation of the FDA, it was grandfathered in under
Federal Food & Drug Act of 1938 as GRAS (Generally Recognized as Safe). (19,20) It

continued to be tested, and although it was repeatedly shown to pass out of the body
unchanged, there were animal studies that a significant percentage of the rats used
developed bladder cancer when fed a diet with higher than normal limits of saccharin.
(21,22) Due to concern over cancer the FDA removed saccharin from GRAS status and
initiated a nationwide ban on the substance. At this time there was no other approved
artificial sweetener, so to protect its use in diabetic applications Congress passed the
“Saccharin Study & Labeling Act” in 1977 preventing it from being banned by the FDA.
As part of the act, any product that contained saccharin had to carry the warning label
that the product was known to cause cancer in lab animals. In 2001, saccharin was finally
recognized not to cause cancer in humans taking in normal limits, and the warning label
was removed. (18,22,23)
Aspartame was discovered in 1965 by a group of scientist working for G.D. Searle, that
later become a Monsanto company, to develop a new anti-ulcer drug based on a
tetrapeptide. (18,24)
+
Figure 7. Phenylalanine and Aspartic Acid to yield Aspartame (wiki)
The intermediate was a dipeptide made from the amino acids, aspartic acid and
phenylalanine that was found accidentally to be intensely sweet. On their own, the
individual amino acids have no sweetness, but when combined made a product 200 times
+H3N
H
N

sweeter that sucrose. In 1980 it was approved as a food additive alone or in combination
with other sweeteners, followed by in 1991 approval as a tabletop sweetener. Commercial
production of aspartame requires an initial fermentation process to produce the amino
acids using specific strains of bacteria. Aspartic acid is made from the bacteria
Brevibacterium flavum, while the phenylalanine is generated from Corynebacterium
glutamicum. (24) These two materials are combined through amidation to establish the
peptide bond. One of aspartames major health risk comes from the reverse of this process
in the body. Once ingested in the body it is metabolized to methanol and the two amino
acids. (18,25)
Figure 8. Metabolic processing of phenylalanine (wiki)
The extra addition of phenylalanine only bothers those with a specific disorder (a rare
genetic disorder phenylketonuria), which means they cannot handle certain
concentrations of phenylalanine (Phe). Individuals with PKU lack the oxidizing system,
specifically Phe-hydroxylase, that converts excess Phe into tyrosine (Tyr) through

“transamination with α-ketoglutarate to p-hydroxyphenylpyruvate” and then ultimately
into homogentisic acid. (26) Excess Phe accumulated in the blood can lead to “metabolic
acidosis” 2 , distortions of plasma concentrations of other amino acids which can affect
brain function due to lack of neurotransmitters, in particular serotonin. (26)
Even with the health risks associated with aspartame, it is used in a multitude of food
applications, including tabletop portions, with the exception of baked goods. Aspartame
degrades at temperatures above 90˚F; although there have been recent advances to
encapsulate it in order to protect it under heated conditions.
Acesulfame-K was discovered by accident by Germans Clauss and Jensen in 1967, (27)
while they were conducting research on then new cyclic group, dihydro-oxathiaxinone
dioxide. Approved by the FDA as a tabletop sweetener and food additive since 1988,
acesulfame is 200 times sweeter than sucrose. A major positive trait is its stability under
heat applications. This translates into longer shelf life, which makes it highly suitable in
packaged goods, as well as available for use in baking. (18)
Figure 9. Acesulfame K synthesis from chlorophenol (wikicommons)
Most applications have acesulfame salts in combination with another intense sweetener in
order to mask a minor fault (i.e. temperature degradation or slight metallic taste). (28)
2 Metabolic acidosis is an acid imbalance in the body that results in lack of bicarbonate in the blood to neutralize.

Acesulfame is not metabolized or stored in the body. The FDA continues to support the
use of acesulfame in diabetic and low-calorie foods.
Sucralose made it to the market with FDA approval in 1989. Like other artificial
sweeteners, it was discovered by accident in the laboratory in 1976. (18, 31) It is 600X
sweeter than sucrose and is considered non-caloric because it is not digested in the body.
Because it is such an intense sweetener, in order to formulate a tabletop delivery it is
packaged with bulking agents such as dextrose and malodextrin. This does affect its
performance in baked products. Dextrose and malodextrin are cornstarch derivatives that
do add some caloric value, but per serving it is less than 5 calories, which is the top limit
the FDA places on products that are considered calorie-free foods. (20)
Figure 10. From Sucrose to Sucralose (wiki)
Made from sucrose in a selective multi-step displacement reaction that starts with cane
sugar, three of the hydroxyl groups on the sugar molecule are replaced by three chlorine
atoms. (30) Tate and Lyle of Britain, developed and patented the original sucralose
manufacturing process to make Splenda. Splenda is the internationally recognized
brand of sucralose and is recognized by its trademark yellow packet. Since the end of the
patent term this year, several novel approaches to the production of sucralose have been
suggested. Once such method involves the production of intermediate “glucose-6-acetate

y fermentation of glucose using a strain of Bacillus megaterium followed by conversion
to sucrose-6-acetate as a kinetic product using a specially selected fructosyl transferase
produced by a newly isolated strain of Bacillus subtilis.” (32)
The product is then chlorinated and subsequently deacetylated to yield 4,1,6-trichlo-
4,1,6-trideoxy galactosucrose (sucralose). This process involves fewer steps than are
required for chemical synthesis using trityl chloride, acetic anhydride and methanol. That
process includes the final step using sodium methoxide to deacetylized the intermediate
ester. Sucralose is additionally attractive as a sweetener due to the fact that the body does
not metabolize it. The majority of the ingested amount is excreted unchanged from the
body. (30)
Neotame, N- [N- (3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester, is a
synthetic sweetener made by the NutraSweet Company. (34) It is similar to aspartame,
but has an extra branch that prevents its metabolism to produce phenylalanine that as
previously discussed can cause a tolerance problem in some people. This branch, a 3,3-
dimethylbutyl group, blocks the peptide enzyme from catalyzing the reaction, therefore
leaving the Neotame residue intact and generating a minor amount of methanol that the
body absorbs.

Figure 11. Metabolic (de-esterfication) of Neotame (wiki)
The residue is eliminated from the body without any concern for accumulation. For
marketing value, this means it does not require a safety-warning label and consumers can
feel better about the consuming the product. FDA approval was granted in 2002. Another
benefit over aspartame is that neotame does not degrade like aspartame at higher
temperatures, which means that it has a better shelf life. Neotame is used mainly in
manufactured goods and not solely as a tabletop sweetener; this is due to the fact that it is
so much more potent as a sweetener, 8000 times sweeter than sucrose. (34) The average
amount needed to sweeten a beverage is a fraction even of a normal marketed, e.g. only
6mg of neotame are needed to sweeten a 12oz beverage. NutraSweet has caused quite a
marketing uproar with its new “pink” sweetener: a combination of neotame and
acesulfame-K in a pink packet. Traditionally the pink packet has been exclusively
associated with saccharin. In a similar way, consumers associate blue packaging to
aspartame, and yellow to sucralose.

ALTERNATIVE SWEETENERS:
Regardless of the studies provided to and provided by the FDA, artificial sweeteners
continue to receive negative press from a variety of public awareness groups. Many of
these groups recommend replacement sweeteners that have a more natural origin and are
not synthesized in chemical laboratories. (31,35) Sugar alcohols, or polyols, are a popular
substitute in baked goods as they are considered a bulk sugar – having similar volume
and texture as sucrose. Polyols are chemical derivatives of sugars that have an alcohol
group (-CH2OH) instead of the aldehyde group (-CHO). (36) Their caloric contribution
is about half that of a traditional carbohydrate and does not promote dental decay. Major
downsides of sugar alcohols stem from its major benefit – the body either slowly or
incompletely metabolizes the molecules. This means that diabetics tolerate sugar
alcohols because a glycemic response is not initiated, but also that the molecules pass out
through the small intestines causing gastric distress. (13,36)
Name Erythritol Glycerol Malitol Sorbitol Xylitol
Sweetness to
Sucrose
81% 60% 90% 60% 100%
Figure 12. Table of Common Sugar Alcohols Used as Food Additives (wiki)
“The laxative effect of sugar alcohols is due to its slow absorption rate. When the
number of small molecules sit in the small intestine for a very long time water is drawn

into the intestines. This increase in water directly increases the speed of evacuation of
that water.” (11)
FUTURE SWEETENERS:
As consumers continue to purchase prepared foods and food products, laboratory
research into artificial sweeteners and food additives continues to be a strong field of
study. A growing trend is towards organic 3 or more natural additives. One such interest is
in a sweetener collected and refined from the plant Stevia rebaudiana. Stevia usage has
been documented in a variety of crude forms in early “tribal” times in Paraguay and more
refined versions more recently in Japan, particularly after the Japanese ban on saccharin
in the 1970s. (37)
Figure 13. Stevioside (L) and Rebaudioside A (R) from Stevia rebaudiana (37)
3 “Organic”. In 1990, Congress passed the Federal Organic Foods Production Act, which called for national organic
food guidelines including certification of growers and standards for organic food production, monitoring crops for
chemical contamination and livestock for living conditions and screening organic imports. Under standards adopted by
the U.S. Agriculture Dept. (USDA) in 2000 and fully effective in 2002, synthetic fertilizers and pesticides and
antibiotics may not be used in raising organic foods, and the use of irradiation, biotechnology, and sewer-sludge
fertilizer is also banned.

The Stevia plant produces several steviol glycosides 4 , with stevioside (“stevia”) and
rebaudioside A (“rebiana”) in the highest percentage. Up until recently, the European
Union and the US FDA have not granted companies wishing to use stevia compounds as
a food additive permission, due to concerns that the chemical compounds may cause
mutagenic or reproductive difficulties. For this reason, stevia and rebiana containing
products started appearing in health food stores as “herbal supplements” – as the FDA
has no regulatory rule over these products as they do over food additives. (20) Concerns
over which glycosides were present in the food product and the manufacturing principles
of the supplier kept the FDA suspect of any product containing stevia as a primary
sweetener.
Figure 14. Steviol(37 )
Even though they each contain several glucose molecules, neither stevia nor rebiana are
absorbed into the blood stream and therefore do not affect blood glucose. (37) Both
4 "glycoside." A glycoside is a group of natural occurring molecules in which one or more glucose molecules are
attached The American Heritage® Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company,
2004. Answers.com 19 May. 2009. http://www.answers.com/topic/glycoside

hydrolyze to yield the aglycone steviol that is subsequently eliminated through the
kidneys.
Figure 15. Metabolism of Stevia and/or Rebiana to steviol. (37)
Up until recently, reports have been conflicting as to what exactly the affects of
consuming stevia leaves have been on reproductive and genetic health due to
inconsistency with data collection and administration of the tests. A 2008 study lead the
Joint Expert Committee on Food Additives (JECFA) of the FAO/WHO to support the
FDA on approving manufacturing guidelines of stevia and rebiana as a food additive.

Figure 16. Elimination of Steviol. (37)
On December 17, 2008 the FDA granted GRAS status to manufacturers Cargill and
Merisant to produce rebauside A according to specified purity guidelines. (38,39) This
allows these companies to use rebiana as a food additive in accordance to FDA ruling.
There has always been an interest in a sugar alternative for persons living with diabetes,
and secondary benefit to an alternative would be for those looking to reduce their caloric
intake. Although, glucose is still necessary for energy production in the body, there is
sufficient quantity achieved through other carbohydrate means. Those that are considered
diabetic sugars are listed as such because they do not activate insulin production from the
pancreas. Not all are a benefit over the simple sugar molecule, and must be evaluated for
their benefits over their detriments. Whether the choice of an artificial sweetener over a
natural/harvest crop sugar is due to medicinal reasons or dietary restriction, there are
good options to support any decision. Artificial sweeteners are proven to be a safe
alternative to sucrose, and a person is given a variety to choose from depending upon the

level of desired sweetness. Products that use artificial sweeteners usually contain more
than one because “certain sweeteners amplify one another”. (13)
The looming question that about most artificial sweeteners is: should we modify our
foods or should our behavior be modified? Can we not just moderate our consumption of
crop sugar? This has becoming increasingly more difficult with more and more pre-
made, pre-packaged food products that have made their way into our homes. Food
manufacturers look for inexpensive ways to bring products to market that consumers will
enjoy. Both bulk and intense sweeteners have filled this job effectively. Our job as
consumers is, and will forever remain, to read the labels and understand what we are
putting into our bodies.

References:
(1) McCaughy, Stuart A.. "The taste of sugars". Neuroscience and Biobehavioral Reviews Vol.
32, April 10, 2008: 1024-1043
(2) Campbell, Mary K., and Shawn O. Farrell. Biochemistry 6th Edition. Belmont, CA:
Brooks/Cole, 2009.
(3) "Sugar Science". Canadian Sugar Institute. April 2009.
(4) Harper, A. (1999). "Defining the Essentiality of Nutrients." In Modern Nutrition in Health and
Disease, 9th edition, ed. M. E. Shills, et al. Baltimore, MD: Williams and Wilkins.
http://www.faqs.org/nutrition/Met-Obe/Nutrients.html
(5) diabetics – NIH http://diabetes.niddk.nih.gov/DM/pubs/statistics/index.htm
(6) nutritional disease." Encyclopædia Britannica. 2009. Encyclopædia Britannica Online.
18 May 2009 http://www.search.eb.com.proxy-um.researchport.umd.edu/eb/article-247890.
(7) Food-Info.net, "Fructose Intolerance". Wageningen Univeristy. April 2009 .
(8) "fructose." Wikipedia. Wikipedia, 2008. Answers.com 09 May. 2009.
http://www.answers.com/topic/fructose
(9) "food additive." Encyclopædia Britannica. 2009. Encyclopædia Britannica Online.
18 May 2009 09 May 2009.
(13) DuBois, Grant E.. "Unraveling the biochemistry of sweet and umami tastes". PNAS
September 2004 vol. 101 no 39: 13972-13973.
(14) Xu, Hong. L. Staszewski, H.Tang, E. Adler, M. Zoller, and X. Li. "Different functional roles
of T1R subunits in the heteromeric taste receptors". PNAS September 2004 vol. 101 no 39:
14258-14263.
(15)“Human receptors for sweet and umami taste” Li, Staszewski, Hong Xu, Kyle Durick†, Mark
Zoller, and Elliot Adler PNAS April 2, 2002 vol. 99 no. 7 4692-4696
http://www.pnas.org/content/99/7/4692.abstract#aff-1

(16) Cui, Meng. "The Heterodimeric Sweet Taste Receptor has Multiple Potential Ligand
Binding Sites". Current Pharmaceutical Design December 2006, Vol.12 Issue 35: 4591-4600.
(17) Palmer, R. Kyle. "The Pharmacology and Signaling of Bitter, Sweet, and Umami Taste
Sensing". Molecular Interventions 7:2007: 87-98.
http://molinterv.aspetjournals.org/cgi/content/full/7/2/87#F2
(18) Food and Drug Administration, "Artificial Sweeteners: No Calories...Sweet!". FDA
Consumer Magazine July-August 2006:
http://www.fda.gov/fdac/features/2006/406_sweeteners.html.
(19) US Government, "FDA Milestons". Food and Drug Administration. May 2009
http://www.fda.gov/fdac/features/2006/106_milestones.html
(20) CFSAN, Office of Food Additive Safety. "Food Additive Status List". Food and Drug
Administration. March 10, 2009. http://www.cfsan.fda.gov/~dms/opa-appa.html#ftnA .
(21)“saccharin”. Encyclopædia Brittanica. 2009. Encyclopædia Brittanica Online. 20 April 2009
(22) Oser, B.L.. "Highlights in the History of Saccharin Toxicology". Food Chemical Toxicology
April-May 1985 (23:4-5): 535-542
(23) History of Saccharin, 24 April 2009. http://www.saccharin.org/history.html
(24) "aspartame." How Products are Made. The Gale Group, Inc, 2002. Answers.com 13 Apr.
2009. http://www.answers.com/topic/aspartame
(25) Hodgin, Greg. "The History, Synthesis, Metabolism, and Uses of Artificial Sweeteners."
http://monsanto.unveiled.info/products/aspartme.htm
(26) Stegink, Lewis D., and Filer Lloyd J.. Aspartame: Physiology and Biochemistry. New York
City: CRC Press, 1984.
http://books.google.com/books?id=yTH1iI9ybl4C&printsec=frontcover
(27) “Acesulfame K.” O'Brien Nabors, Lyn, Gert-Wolfhard von Ryman Lipinkski, and Lisa Y.
Hanger. Alternative Sweeteners. New York City: CRC Press, 2001.
(28) International Food Information Council, "Acesulfame K". IFIC Foundation. May 2009
http://www.ific.org/publications/brochures/acekbroch.cfm
(29) Food and Drug Administration, "Sugar Substitutes: Americans Opt for Sweetness and Lite”
FDA Consumer Magazine November-December 1999; Rev.Dec 2004/Feb 2006
(30) Grice, H.C.. "Sucralose - An Overview of the Toxicity Data". Food Chemical Toxicology
2000: Supplement 1-6.
(31) Selim, Jocelyn. “Hitting the Sweet Spot.” Discover 26.8 (August 2005): 18-19.

(32) Jones, Joan D., A.J. Hacking, P.S.J. Cheetham. "Biological method for protection of 6position
of sucrose and its use in synthesis of disaccharide". Biotechnology & Bioengineering
November 1990. Vol.39 Issue 2: 203-210.
(33) Bennett, Christopher., J.S. Dordick, A.J. Hacking, P.S.J. Cheetham. "Biocatalytic synthesis
of disaccharide high-intensity sweeterner sucralose via a tetrachlororaffinose intermediate".
Biotechnology & Bioengineering November 1990. Vol.39 Issue 2: 211-217.
(34) Neotame: A Scientific Overview. Chicago, IL: The Nutrasweet Company, 2002.
(35) Schardt, David. "Sweet Nothings: not all sweeteners are Equal". NUTRITION ACTION
HEALTHLETTER May 2004: 9-11.
(36) "Sugar alcohol." McGraw-Hill Dictionary of Scientific and Technical Terms. McGraw-Hill
Companies, Inc., 2003. Answers.com 20 May. 2009. http://www.answers.com/topic/sugaralcohol
(37) Carakostas, M.C.. "Overview: The history, technical function and safety of rebaudioside A, a
naturally occurring steviol glycoside, for use in food and beverages". Food and Chemical
Toxicology 46 (2009): S1-S10.
(38) Tarantino, Laura M.. "Agency Response Letter GRAS Notice 252". Food and Drug
Administration December 17, 2008: http://www.cfsan.fda.gov/~rdb/opa-g252.html
(39) Tarantino, Laura M.. "Agency Response Letter GRAS Notice 253". Food and Drug
Administration December 17, 2008: http://www.cfsan.fda.gov/~rdb/opa-g253.html
* Associated Press, "FDA Approves 2 New Sweeteners". New York Times December 18, 2008:
http://www.nytimes.com/2008/12/18/business/18sweet.html?_r=2.
* Leban, Ivan et al.. "Structures of artificial sweeteners - clylamic acid and sodium cyclamate
with other cyclamates". Acta Crystallographica (2007) B63: 418-425
* “Low-calorie Sweeteners and Other Sugar Substitutes: A Review of the Safety Issues”.
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