Neurosctenceand BaobehavloralReviews,Vol. 17, pp. 313-345, 1993 0149-7634/93$6 00 + .

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Sweeteners: State of Knowledge Review

S. S. S C H I F F M A N j A N D C. A. G A T L I N

Departments o f Psychology and Psychiatry, D u k e University, Durham, N C 27706

(Received 15 F e b r u a r y 1993)

SCHIFFMAN, S. S. AND C. A. GATLIN. Sweeteners: State of knowledge review. NEUROSCI BIOBEHAV REV
17(3) 313-345, 1993.-Sweeteners are widely used in the food and pharmaceutical industry. The purpose of this paper is to
review our current knowledge of sweet taste from chemical, biochemical, electrophysiolog~cal,psychophysical,and psycholog-
ical points of view. The most common sweeteners likely to be used in food and pharmaceuttcals will be examined in
detail. First, the chemtcal structures of sweet compounds including saccharides, diterpene glycosides, polyols, amino acids,
dipept~des, and other nonsugars will be discussed. Second, biochemical approaches to understanding sweetener receptors will
be reviewed. Third, electrophysiological and behavioral approaches to understanding sweetener receptors will be discussed.
Fourth, psychophysical studies in humans will be shown to be consistent w~th biochemical and neurophysiolog~caldata. In
addition, the basic mechamsms of sweet taste revealed by psychophysical studies will be given, including the role of multiple
receptor s~tes, hydrogen bonding, and sodium transport. Finally, the factors that affect preference for sweet taste including
the psychological and physiological variables associated with sweet preference will be explored.

Sweetness Taste Biochemistry Neurophysiology Psychophysics

IN the natural environment, sweet taste is a cue for edibility
(185). For this reason, there is an innate tendency in many
animal species including humans, to prefer sweet taste. The
purpose of this paper is to review our current knowledge of
sweet taste from chemical, biochemical, electrophysiological,
psychophysical, and psychological points of view. Detailed
descriptions of those sweeteners most likely to be used in the
food and pharmaceutical industry will also be given.
CHEMICAL STRUCTUREOF SWEETENERS
The chemical structures of molecules that confer a sweet
taste are wide and varied, encompassing both sugars and
nonsugars (50,52,116,205,211,244). Table 1 displays a repre-
sentative sampling of compounds that taste sweet to humans
and gives their chemical structures along with other perti-
nent information. These compounds include saccharides, di-
terpene glycosides, polyols, proteins, dipeptides, and other
nonsugars.
Our understanding of the chemical properties of these com-
pounds that are responsible for sweet taste is limited. One
frequently cited hypothesis is that an essential condition for
sweet sensation is a pair of s!multaneous hydrogen bonds sep-
arated by approximately 3 A(211,212). This theory depends
upon a putative sweet receptor (or receptors) with an AH-B
structure, where A and B are electronegative atoms separated
by 2.5 to 4.0 .~, and H is a hydrogen atom and part of a
polarized system A-H. The assumption is that a complemen-
tary AH-B group in the stimulus molecule interacts with the
AH-B receptor site, thus forming two simultaneous hydrogen
bonds. For potent sweetness, a third lipophilic site has also
been suggested (58,125).
The proposition by Shallenberger and Acree (211) that in-
termolecular hydrogen bonding is an essential condition for
sweet taste is derived from Shallenberger's earlier (210) studies
demonstrating that sweetness potency is correlated to the in-
verse of the strength of intramolecular hydrogen bonding.
Unfortunately, while the AH-B theory has been helpful in
accounting post facto for some functions of the sweet mole-
cule, it has resulted in minimal predictive use for development
of new compounds with sweet taste. Despite the presence of
an AH-B system, a compound will not necessarily taste sweet.
Moreover, the universal application of Shallenberger and
Acree's theory has been called into question by Jakinovich
(117) in studies indicating that an AH-B system may not be
required to produce a sweet taste. Although most studies do
suggest that hydrogen bonding contributes to the binding of
most sweeteners to their receptors, the more specific AH-B
hypothesis has probably outlived its usefulness.
Due to the fact that the relationship between chemical
structure of molecules and the ability to initiate a sweet sensa-
tion is not well understood, it is not surprising that most com-
pounds with sweet taste have been discovered by trial and
error. The sweetness of sugars is age-old knowledge, but dis-
coveries of the sweet taste of many of the nonsugars such as
saccharin, cyclamate, acesulfame-K, and aspartame have been
accidental, some quite recent. Remsen and Fahlberg discov-
ered the sweetness of saccharin in 1879 (187) during investiga-
tions of the oxidation of o-toluene-sulfonamides. Similarly,
while studying the antipyretic properties of a sulfamic acid

To whom requests for reprints should be addressed.

313
314
derivative, Sveda accidently discovered the sweet taste of cy-
clamate in 1937 (8). Clauss and Jensen's recognition of a sweet
taste in a product obtained by reacting butyne with fluorosul-
fonyl isocyanate (44) resulted in the development of acesul-
fame-K (formerly called acetosulfam). Tracing the sweetness
to 5,6-dimethyl dihydrooxathiazinone dioxide, Clanss and
Jensen (44) discovered that it possessed a ring system not pre-
viously synthesized. Further studies of structure activity with
dihydrooxathiazinone dioxides disclosed that the compound
with the best sweet taste was the potassium salt of 6-methyl-
3,4-dihydro- 1,2,3-oxathiazin-4-one-2,2-dioxide (acesuifame-
K). In 1965, the dipeptide L-aspartyl-L-phenylaianine methyl
ester (aspartame) was accidentally discovered to have sweet-
taste properties by J. Schlatter of G. D. Searle while synthesiz-
ing gastrin and its tetrapeptide analogs (148,149). Table 1
shows that three of these four sweeteners, acesulfame-K, sac-
charin, and cyclamate contain a sulfonamide group and a
lipophilic part. The dipeptide aspartame, however, is chemi-
cally unrelated to the other three.
Other sweeteners have been isolated or synthesized from
natural products. For example, stevioside and rebaudioside
are derived from the foliage of Stevia rebaudiana Bert., a
diminutive shrub which grows in Paraguay. Neohesperidin
dihydrochalcone is a product of alkaline hydrogenation of
bitter-tasting neohesperidin, a citrus flavanoid. In the 1980's
a sesquiterpene named hernandulcin was isolated from the
Mexican plant Lippia dulcis Trev (47). Monellin is a protein
made up of two dissimilar polypeptide chains found in the red
berries of the tropical creeper Dioscoreophyllum cumminsu
Diels, native to West Africa. Thaumatin I and II, both sweet-
tasting proteins, have been isolated from the fruit of the Afri-
can plant Thaumatoccus damelli Benth.
Despite the number of reportedly sweet compounds, de-
tailed investigation of their structure-activity relationships has
been limited. This may be due to the considerable expense of
synthesizing very complex compounds only to taste them. A
remarkable exception is the extensive synthesis of thousands
of analogs for L-aspartyl-L-phenylalanine methyl ester (aspar-
tame, APM) after its discovery.
A brief description of structure-activity studies for several
sweeteners and their effects on taste follows.
Aspartame
When modifications of aspartame were investigated, a con-
sistent simple pattern was clear: c~-amides of L-aspartic acid
(isoasparagine derivatives) are often sweet (150,152). This fun-
damental finding suggests that the sweetness quality and
sweetness potency are mediated primarily by the steric proper-
ties of the amide part of the molecule. Accordingly, L-phenyl-
aianine methyl ester is a complex amine.
Viewed both theoretically and practically, analogs similar
in potency to aspartame are not as interesting as analogs with
more sweetness potency. Pursuant to the finding that L-
phenylalanine could be replaced by D-alanine and other ali-
phatic D-amino acids in aspartame (151), a group at Pfizer
synthesized highly branched amides of L-aspartyl-D-alanine
and L-aspartyl-D-serine (28). The superior compounds ranged
in potencies 1000-2000 times greater than sucrose and exhib-
ited highly satisfactory taste profiles. The corresponding sim-
ple amides average around 100 times sweeter than sucrose
(218). The structure of the most acceptable L-aspartyl-D-
alanme analog is called alitame, and its structure is gwen in
Table 1.
The Takeda laboratories made the remarkable discovery
SCHIFFMAN AND GATLIN
that replacing phenylalanine with certain aminomalonic acid
diesters results in exceptionally potent sweet compounds (80).
A large branched group is required for the highest potencies,
similar to the Pfizer compounds. In Shanghai, investigators
at the Institute of Organic Chemistry synthesized all four com-
pounds derived from the four possible isomers of the terpene
alcohol, fenchol. According to this group, the most potent
was 50,000× sucrose (139). Molecular modeling explains
(after the fact) how such similar substances manifest sweetness
potencies of 1, 10, 100, 1000, or 10,000.
The early studies on aspartame led to the conclusion that a
free amino group on aspartic acid was required for sweetness,
but studies from the Wyeth laboratories and the chemists at
the Universit6 Claude Bernard have refuted this theory (201).
A possible explanation may be that aspartame receptors are
not the only receptors involved when an N-acylated aspartic
acid derivative is perceived as sweet. Consideration of multiple
receptors will be taken up later in this review.
One group reported sweetness of trifluoro- and trichloro-
acetylaspartic acid p-cyanoanilide as 3000 times more potent
than sucrose (134). Another found that the glutamic acid ana-
log is 3000 times more potent than sucrose (122). Numerous
sweet glutamic acid derivatives are described as sweet.
A major breakthrough in developing an aspartame recep-
tor model occurred in 1979 at Universite6 Claude Bernard.
Jean-Marie Tinti, a graduate student with Professor Claude
Nofre, found that a structural hybrid of aspartame and the
sweetener known as suosan (177) is approximately 50 times as
potent as aspartame and 20 times as potent as suosan (170,
227). Molecular modeling studies based on this finding led to
the discovery of the guanidine structural class of sweeteners
which presumably act at a common site. One sweetener from
this group, sucrononic acid, has a potency of 200,000 times
that of a 2% sucrose reference (171). These discoveries led to
the development of a model for the aspartame receptor (53)
by NutraSweet scientists which has been used to design a new
series of aryl urea high-potency sweeteners (164).
Saccharin and Acesulfame-K
There has been extensive research on structural analogs of
saccharin (91,105) including acesulfame-K (44), which is really
a structural analog of saccharin. Saccharin-like structures
have an underlying bitter taste which is somewhat masked by
a sweet component, according to one report (91).
Dihydrochalcones
Modification studies of dihydrochalcone analogs in the
carbohydrate (68) and the aglycone portion (63) have resulted
in several compounds with increased potency but with no dis-
cernible improvement in temporal effects. This group of
sweeteners are limited in usefulness due to their persistent
taste. Because of this, it has not been particularly useful to
develop them commercially.
Other Sweeteners and Limitations of Models
Other structure-activity work has been done with sucrose,
sulfamate sweeteners, and amino acids. The potency of su-
crose can be increased by replacing selected atoms with chlo-
rine (112,115) as exemplified by sucralose in Table 1. Struc-
ture-activity studies show delineated size and shape limitations
for sulfamate sweeteners (214). A proposed explanation for
the difference in taste between amino acid enantiomers is that
nonsweet amino acids are prevented from binding by steric
hindrance, in this case, a spatial barrier (211).
SWEETENERS: STATE OF KNOWLEDGE REVIEW
Finally, even though analogs of the parent compounds
have been synthesized and a number of models have been
proposed (5, 53,108, 113,122, 136,150, 186,220, 222,226,232,
233), it is questionable whether a single model can account
for the stereochemical properties of all or most compounds
that confer a sweet taste sensation. This deficiency in predict-
ive value for any geometric model in determining a priori
the components of molecules that render a sweet sensation
indicates the likelihood of multiple types of receptors, each
with unique stereochemical and physicochemical require-
ments.
B I O C H E M I C A L A P P R O A C H E S TO
UNDERSTANDING SWEET RECEPTORS
The search for taste receptors has not been as successful
as the pursuit of neurotransmitter and hormone receptors.
Isolation of taste receptors is limited by the low affinity of
tastants for receptors as well as the physiology of the gustatory
system. Although hormones show Kos in the range of 10-~t
M-10 -8 M, the apparent Kos for sweeteners such as sugars
are as high as 0.5 M. Moreover, it is difficult to separate
mammalian taste buds containing gustatory receptors from
the surrounding epithelium. Attempts to understand the na-
ture of sweet receptors continue undeterred by the intrinsic
difficulties in methodology. Most biochemical studies thus far
have been based on the assumption that sweet-tasting mole-
cules bind to receptor proteins in a reversible manner. The
first studies obtained a protein fraction from homogenates of
bovine tongue epithelium. In the presence of sugars, saccha-
rin, and sweet-tasting amino acids, these fractions exhibited
either refractive index changes or ultraviolet difference spec-
tral changes (54,55,180,181). Preparations from rat and mon-
key tongues have also exhibited spectral changes in the pres-
ence of sweeteners (101-103). Rationale for the hypothesis
that this protein is indeed a sweet receptor protein has been
offered by Price and DeSimone (181) and Shimazaki et al.
(213). Their arguments are:
1. The concentrations of sweeteners that interact with protein
fractions are similar to those concentrations found to be
effective in behavioral and neural studies.
2. Sweet-tasting amino acids are more interactive with the
protein fraction than bitter-tasting ones.
3. In rats, the interaction of sugars with the protein fractions
is independent of pH within the range of 5.4-8.6, which is
consistent with electrophysiological taste data reported by
Noma and Hiji (172).
4. The quantity of sweet-sensitive protein in the homogenate
is significantly lower when taste bud turnover is reduced by
colchicine or when the taste buds are denervated (101,103).
Nevertheless, uncertainties persist, and the conclusion that
the sweet-sensitive protein is a sweetener receptor is not yet
fully substantiated. One difficulty is that the protein fraction
is not homogeneous and has been shown to contain sugar-
metabolizing enzymes as contaminants (182). A second prob-
lem is that the protein fraction has been shown to complex
with molecules that are not sweet such as dimethyl sulfoxide
(169). The question is compounded by the fact that a nongus-
tatory protein, hemoglobin, exhibits optical properties similar
to those of the protein fraction when complexed with sugar
(169), and further obscured by the fact that if the protein were
localized strictly in the taste cells that constitute a relatively
small portion of the epithelium, the yields of sweet-sensitive
protein from the lingual epithelium would be expected to be
considerably lower than they are (182). Lastly, Ostretsova et
315
al. (176) could not demonstrate significant spectral changes in
tongue protein from bovine fungiform papillae, the structures
in the epithelium actually containing the taste buds. On the
other hand, utilizing equilibrium dialysis in the sedimentable
fraction instead of the protein fraction reported by Dastoli
and Price (55), they were able to demonstrate binding activity.
Rather than using whole lingual epithelium as described
above, further investigations have been carried out to study
binding of sweeteners both to taste papillae or isolated lingual
membranes. Cagan (38) demonstrated that t4C-labeled sugars
bound two or three times more to bovine fungiform and cir-
cumvallate papillae that contain taste buds than to filiform
papillae which lack buds. However, the binding proved weak
(KD~ 10-'-10 -3 M), which is consistent with the neurophysio-
logical data described in the next section. Other binding stud-
ies with bovine papillae (140) reported the same conclusion.
Cagan and Morris (39) found that binding of the potently
sweet protein monellin to human tongue tissues had a higher
affinity (KD~ 10 -5 M). Another study (176) reported ['4C]glu-
cose binding to plasma membrane fragments from bovine cir-
cumvallate and fungiform papillae using equilibrium dialysis,
and Lum and Henkin (144) concluded that binding of sugars
to fractions probably derived from plasma membranes of bo-
vine taste buds.
There have been attempts to understand sweetener recep-
tors using immunological approaches. Hough and Edwardson
(110) have raised antibodies against the sweet-tasting plant
protein thaumatin in New Zealand white rabbits and found
that a variety of other sweet compounds varying widely in
molecular size and strength cross-reacted with those antibod-
ies. The compounds included aspartame, calcium cyclamate,
sucrose, and monellin. It is interesting to note that there was
a high degree of correlation between the immunoreactivity
and sweetness potencies of those substances that cross-reacted
with the antisera. From this the authors inferred that the struc-
tural feature that constitutes the antigenic determinant may
be similar to this sweetener taste receptor.
Another approach to understanding taste receptors uses as
a model system the channel catfish Ictalurus punctatus. Cat-
fish barbels contain large numbers of taste buds, and their
binding affinities for ligands, especially amino acids, are usu-
ally higher than in mammals. Binding of L-alanine (which
tastes sweet to humans) in the sedimentable fraction from
catfish barbel has been demonstrated by Krueger and Cagan
(131). Goldstein and Cagan (87) reported production of mouse
hybridomas that synthesize monoclonal antibodies against L-
[3H]alanine-binding activity in a membrane fraction (fraction
P2) in channel catfish. Over time, use of monoclonal antibod-
ies to characterize taste receptor molecules may be helpful in
yielding specific antagonists.
Although the isolation of sweetener receptors has proven
difficult, current consensus is that the sweet taste response is
indeed mediated by taste cell surface receptors that utilize the
adenylate cyclase system as a second messenger system. The
adenylate cyclase system, which is also the cellular signalling
system for many hormones, involves the following cascade
of events. The agonist (e.g., sweetener molecule) binds to a
receptor which transmits a signal via the guanine nucleotide-
binding protein (G protein) resulting in activation of adenylate
cyclase. Adenylate cyclase then induces hydrolysis of ATP to
cAMP which leads to activation of the phosphorylating en-
zyme known as protein kinase A. The activated kinase then
phosphorylates an ion channel m the taste cell membrane lead-
ing to depolarization of the taste cell. Evidence that this cas-
cade is involved in sweet taste transduction comes from the
316
fact that cAMP is elevated in taste cells from rat, cow, and
pig after exposure to sucrose or saccharin (217). In addition,
saccharin blocks outward potassium currents in hamster taste
cells, and this effect is mimicked by perfusion of these cells
with cAMP (9).
ELECTROPHYSIOLOGICAL AND
BEHAVIORAL APPROACHES IN ANIMALS
The findings just described are consistent with electrophys-
iological and behavioral data in animals. For example, neuro-
physiological data indicate that the affinities of sugars for
their receptors are weak (16,178). Electrical recordings from
taste nerves also show that proteolytic enzymes selectively sup-
press the neural responses to sweet stimuli implying that the
sweet receptor is, in fact, a protein. A report in 1975 (100)
demonstrated that Pronase E (pH 7.0) and semialkaline prote-
ase (pH 8.0) either eliminated or significantly suppressed the
sweet responses of sucrose, glucose, fructose, sorbitol, saccha-
rin, glycine, and DL-alanine but had no effect on salty, bitter,
or sour stimuli.
There are other compounds which selectively modify taste
by suppressing the responses of taste receptor cells to sweeten-
ers. Examples are: extracts of the leaf of the Indian plant
Gymnema sylvestre (3,59,70,95,96,248) and ziziphins, which
are saponins found in the leaves of the Chinese jujuba tree
Ziziphus jujuba (123,124). A sweet-inducing protein called
miraculin has been isolated from berries of the West Africa
shrub Synsepalum dulcificum (miracle fruit); it elicits neural
responses to acids that resemble responses to sweeteners (29).
In monkeys, behavioral tests after miraculin treatments show
an increased intake of citric acid which suggests an improve-
ment in taste possibly to sweet (93,94). The precise way in
which these substances modify taste is not yet known.
Although extracts of Gymnema sylvestre and Ziziphus ju-
juba block responses to all sweeteners, suggesting a single
sweetener receptor type, most evidence drawn from animal
studies points to multiple types of sweet receptors. First, spe-
cies differ widely in sweetener responses (166,196). For exam-
ple rats, guinea pigs, and the new world monkey, Sagumus
midas tamarin, do not respond to monellin and thaumatin,
both potently sweet to humans; on the other hand, the green
monkey, Cercopithecus aethiops, exhibits electrophysiological
and behavioral responses to these sweeteners (30,84,94). Fur-
ther, the gerbil demonstrates greater response to sweeteners
than the rat, giving electrophysiological responses to 14 of 21
compounds known to taste sweet to man, although six of these
compounds did not yield the expected behavioral responses to
a sweetener (118). Extensive comparison of responses to
amino acids in rats and man has been described in experiments
by Pritchard and Scott (183,184), and both similarities and
differences have been reported. Other behavioral studies show
that dulcin, which is sweet to humans, is preferred by squirrel
monkeys but rejected by rats, whereas saccharin is refused by
squirrel monkeys and selected by rats (75b).
A second line of evidence for multiple types of sweetener
receptors has been demonstrated by Faurion et al. (71) and
Faurion and MacLeod (72). Recording responses from indi-
vidual taste fibers of the chorda tympani nerve, they observed
that among neurons the response spectra to a range of sweet
stimuli was not consistent; that is, although a single neuron
reacted strongly to one sweetener, less to a second, and only
weakly to another, this pattern did not necessarily obtain in a
different neuron.
A third basis for the probability of multiple receptor sites
for sweetness, is the discovery that alloxan selectively de-
S C H I F F M A N AND GATLIN
presses neural response to sugars but does not suppress neural
activity to artificial sweeteners such as sodium saccharin (250).
Although other methods for inhibiting neural responses to
sweeteners including receptor photolabeling studies (64) have
been found to block of all sweet responses, the alloxan selec-
tivity suggests multiple sweetener receptor sites.
All of this evidence suggests that there are multiple types
of sweetener receptors, possibly with multiple sensitivities
tuned to respond to more than one sweetener. For example, if
aspartame binds to several types of sweet receptors, a single
geometric shape for an "aspartame receptor" may describe the
interactions too restrictively. Extending from this rationale is
the likely inference that each receptor type would have differ-
ent physicochemical and stereochemical requirements.
PSYCHOPHYSICAL STUDIES IN HUMANS
Psychophysical studies in humans are consistent with bio-
chemical, neurophysiological, and animal data. These studies
further imply that the sweet taste itself has multidimensional
characteristics transduced by multiple sweet receptor mecha-
nisms.
Multiple Receptor Sites Mediate Sweetness
Human psychophysical data like animal studies imply that
more than one receptor mechanism mediates sweetness. The
first line of evidence derives from many experiments that point
to nonhomogeneous variability among sweeteners in individ-
ual subjects for thresholds, intensity ratings, and the effect of
Pronase E. In 1980, Faurion et al. (74) obtained threshold
values of seven sweeteners from 98 subjects and found that
the thresholds for sweeteners varied independently from sub-
ject to subject. This study disclosed that it was not possible to
predict the threshold of one compound for a given subject
using the knowledge of his/her threshold for another com-
pound. The inference from these threshold data is that there
are numerous receptor sites, varying in number from one indi-
vidual to another. The same interindividual variability was
found for intensity ratings at suprathreshold concentrations
(73,74). The findings of Faurion and colleagues conform to
those reported by Schiffman et al. (206). The relative reduc-
tion of sweetness by Pronase E in humans has been shown to
have a similar effect in that the individual profiles of inhibi-
tion for different sweeteners do not covary (71,72). If there
were only one receptor site type, there would be no possible
explanation for these data.
A second line of evidence indicating a multiplicity of sweet
receptor types has been derived from experimental data utiliz-
ing the method of cross-adaptation (197). Cross-adaptation
experiments are based on the assumption that two tastants
may share common receptor sites if prolonged exposure (ad-
aptation) to one results in a decreased response to another
054). Conversely, if a diminished sensation to one tastant
does not occur after adaptation to another, a possible implica-
tion is that a second subtype of cells with different sweetener
receptors is involved. In one protocol (197), subjects first
tasted sweet test solution A and estimated its intensity. They
then held a sweet-adapting solution B in their mouths until
the sweet taste vanished (30-60 s), swirling it around to ensure
complete adaptation. The subjects next retasted test solution
A and reestimated its sweetness. Using this model, the degree
to which the post adaptation intensity was greater than, equal
to, or less than the preadaptation intensity could be deline-
ated. The degree of cross adaptation varied depending on the
sweeteners that were tested. For example, sodium saccharin
SWEETENERS: STATE OF KNOWLEDGE REVIEW
and acesulfame-K cross-adapt with one another (i.e., sodium
saccharin is significantly reduced in intensity by adaptation to
acesulfame-K and vice versa). D-tryptophan and aspartame
also mutually cross-adapt unlike sodium saccharin and aspar-
tame which do not cross-adapt. The results suggest that mole-
cules with related pharmacophores cross-adapt most strongly.
Acesulfame-K and Na saccharin, strongly mutually cross-
adaptive, have equivalent RSO2NHCOR- pharmacophores
(197), Aspartame and o-tryptophan may similarly be related
through their COOH/NH2 moieties which may be isosterically
arranged in space. Adaptation to xylitol and glucose reduces
the intensity of all the sweeteners suggesting that these two
sweeteners activate all subsets of sweet-sensitive receptor cells.
A third line of evidence for multiple sweet receptors comes
from an experiment in which subjects were asked to discern
similarity in quality of 17 sweeteners varying widely in chemi-
cal structure (205). Multidimensional scaling (MDS), a com-
puter-based mathematical technique, was applied to the mea-
surements of similarity to arrange the sweeteners in a spatial
map. Sweeteners assessed as similar in taste were placed close
to one another in the map, and dissimilar ones further from
one another. A three-dimensional map was derived revealing
that sweetness is a multidimensional concept with differing
characteristic sweet qualities as well as different side tastes
and temporal properties. The experimental subjects continued
to report that the nature of sweet sensation among these sweet-
eners varied, and that "sweet" itself is not a unity or undiffer-
entiated property. In addition, subjects also commented that
the location of sweetness on the tongue also varied across
sweeteners. This finding was also reported by van der Wel and
Arvidson (235) who found that sweet-tasting proteins such as
thaumatin produce more intense sweetness at the edges of the
tongue while sucrose is more intense at the tip of the tongue.
In addition, the sweetness of thaumatin and monellin develops
more slowly and lasts longer than that for sucrose. These
findings suggest that multiple receptors must exist to produce
these differences in sensory characteristics.
A fourth line of evidence comes from the variability in
dose-response curves for different sweeteners (65). Dose-re-
sponse curves for a wide range of sweeteners were constructed
from suprathreshold intensity judgments made by a trained
taste panel. The panel assigned intensity values to a large num-
ber of concentrations of a given sweetener using six concentra-
tions of sucrose (2070, 5°7o, 7.5%, 9070, 12°/0, and 1607o) as
standards. The dose-response curves for sucrose, fructose,
and sugar alcohols continued to increase in intensity beyond
the equivalent sweetness of 1607o sucrose. The intensity of
aspartame and alitame never increase beyond the sweetness of
15-16°70 sucrose even at maximum solubility. Thaumatin
never became sweeter than a 907o sucrose equivalent.
A fifth line of evidence for multiple sweet receptors comes
from "magnitude estimation" experiments that characterize
dose-response relationships for suprathreshold sweeteners in
both old and young subjects (202). Loss in perceived sweetness
with age was not uniform across sweeteners; the greatest loss
in growth of perceived intensity with concentration was for
large molecules which have the greatest number of possible
AH-B systems, such as thaumatin, rebaudioside, and neohes-
peridin dihydrochalcone. This finding suggests that receptors
that are capable of concerted intermolecular hydrogen bond-
ing may be more affected by aging than receptors that can
bind only one AH-B type or pharmacophore. Another possi-
bility is that there is selective loss of some subtypes of sweet-
sensitive receptor ceils.
A sixth line of evidence comes from studies by Frankmann
317
and Green (78) who studied the effect of cooling the tongue
on perceived intensity of taste. They found that cooling the
tongue had differential effects on sweeteners. While glucose
and fructose had temperature sensitivities similar to sucrose,
saccharin did not.
Finally, studies of the effect of methyl xanthines on taste
further emphasize the multiplicity of sweet taste receptor
mechanisms. Schiffman et al. (200) found that caffeine en-
hances the taste of some sweeteners including acesulfame-K,
D-tryptophan, neohesperidin dihydrochalcone, sodium sac-
charin, stevioside, and thaumatin. However, it had no effect
on other sweeteners including aspartame, calcium cyclamate,
fructose, and sucrose. This work also suggests multiple trans-
duction pathways in different cell subtypes.
Correlations of Psychophysical Data With
Hydrogen Bonding
Because the presence of an AH-B group does not assure
that a stimulus molecule will confer a sweet taste, it has been
difficult to substantiate the AH-B hypothesis. Nevertheless,
acetylation of amino groups, eliminating the possibility of
forming two simultaneous hydrogen bonds, distinctly dimin-
ishes the sweetness of amino acids (204) as well as the proteins
monellin and thaumatin (234). Moreover, correlations between
the number of possible types of AH-B sites (or pharmaco-
phores) and sweet taste cross-adaptation are illustrated above.
Schiffman et al. (202) determined taste detection and rec-
ognition thresholds for 11 sweeteners whose chemical struc-
tures differed widely. A strong correlation between the num-
ber of possible types of systems for hydrogen bonding (i.e.,
AH-B systems) and mean detection thresholds was found.
Sweeteners with many possible types of AH-B systems (e.g.,
monellin) had the lowest thresholds whereas sweeteners with
only one type have the highest. A similar correlation between
number of AH-B groups and detection thresholds for elderly
subjects was found, although the thresholds for older individ-
uals were 2.72 times higher on average. While the recognition
thresholds for young subjects were 3.54 times higher on aver-
age than the detection thresholds, they were found to follow
the same pattern. Although the number of AH-B site types
and thresholds were correlated, this does not prove that the
AH-B system is the means by which sweetness is conferred.
Three-Dimensional Nature of Sweet Receptor Sites
Studies of taste characteristics of amino acids and dipep-
tides give some insight into the stereochemicai nature of sweet
receptors (198,200,202). Both D and L forms of amino acids
with short side chains taste sweet. However, as the side chain
increases, it appears that steric hindrance occurs for the L
forms preventing binding to sweet receptors.
The L- and D-enantiomers differ considerably in increase
of perceived intensity with concentration. When the logs of
the concentrations (C) of the amino acids were plotted against
the logs of the magnitude estimates of the intensity of their
sensations (S), a regression line could be fit to the data. In
most cases, the slopes for the regression lines for D- and L-
amino acids are different suggesting that enantiomers may not
occupy the same receptor sites.
The three-dimensional nature of receptors is also implied
by the fact that the taste of a dipeptide cannot be predicted
from the constituent amino acids (200) and that the sequence
of amino acids is critical in determining taste quality, For
seven pairs of dipeptides containing the same residues but in
reversed sequence, none had identical tastes. For example,
318
while glycyl-L-alanine is notably salty and bitter, L-alanylgly-
cine has little taste. Furthermore, dipeptides with two identical
constituent amino acids do not have the same taste as the
amino acid itself. While glycine alone is sweet, glycylglycine
tastes bitter.
Inhlbltton and Induction of Sweet Taste by Modtfiers
Studies show that compounds that inhibit neurophysiologi-
cal and behavioral responses to sweeteners in animals also
inhibit sweetness in humans. Pronase E inhibits the taste of
numerous sweeteners in humans to degrees varying with the
individual subjects (71,72). Ziziphins (90,123,157) and Gym-
nema sylvestre (13,156) also suppress sweet tastes. Lately, a
monosaccharide, methyl-4,6-dichloro-4,6-dideoxy-D-galactopyr-
anoside, has been demonstrated to specifically inhibit sweet taste
in both hamsters (115) and humans (207). Miracle fruit
(Synsepalum dulcificum) or the salts of chlorogenic acid and
cynarin found in artichoke (12) can elicit sweet taste.
Recently, two new sweet taste inhibitors have been de-
scribed in human studies. Lindley (137) found that substituted
phenoxyalkanoic acids are potent and immediate inhibitors of
sweetness. Unlike most sweetness inhibitors, pretreatment of
the tongue was not necessary to achieve the effect, and the
inhibition was rapidly reversible. Another sweetness inhibitor
derived by Muller et al. (164) from the synthetic sweetener
suosan has similar properties.
The Role of a Sodium Transport Pathway
That an amiloride-sensitive transport mechanism is in-
volved in the perception of sweetness in humans has been
suggested by Schiffman et al. (203). When amiloride (N-
amidino-3,5-diamino-6-chloropyrazine carboxamide), a po-
tassium-sparing diuretic and a potent inhibitor of sodium
transport in a wide variety of cellular and epithelial transport
systems, was applied to the human tongue, it reduced the
perceived taste intensity of Na+and Li + as well as sweeteners.
Application of 5 x 10 -4 M amiloride lowered the perceived
intensity of all the sweeteners tested; the range of percentage
inhibition was from 80.80/0 for stevioside to 44.2°7o for fruc-
tose. Amiloride also diminished the tastes of amino acid com-
pounds with a sweet or salty component. Amiloride had no
effect on the bitter- or sour-tasting compounds. Tennissen
(223) recently confirmed that amiloride blocked sweet taste in
human subjects.
The speculation that an amiloride-sensltive sodium channel
plays a role in sweet taste transduction is supported by studies
of lingual epithelium isolated from dogs. DeSimone et al. (56)
demonstrated that sodium ions are actively transported when
dog tongue epithelium is mounted between symmetrical Krebs-
Henseleit buffer solutions. When hyperosmotic NaCI was ap-
plied to the dorsal lingual surface, increased transepithelial
currents and potentials resulted. Application of glucose and
other sugars to the dorsal surface also gave a hyperosmotic
response. The inward current induced by sugars was signifi-
cantly blocked by amiloride.
These human psychophysical data and transepithelial po-
tential differences from isolated dog tongue epithelium sug-
gest, therefore, that a transduction step for sweet-tasting non-
electrolytes may involve a transcellular ion flow via an
amiloride-sensitive pathway. How this transcellular flow is
related to the adenylate cyclase system (217) or outward potas-
sium currents (9), which are both known to play a role in
sweet taste transduction, is not presently known.
SCHIFFMAN AND GATLIN
FACTORS THAT AFFECT PREFERENCE FOR SWEET TASTE
In humans and animals, preference for sweet taste is in-
nate. Distinct individual differences in adults are present,
however, attributable to early feeding experiences and genetic
differences in the ability to taste PROP (6-n-propylthiouracil).
Sweet taste preferences may also be influenced by physiologi-
cal state (208).
Although there is a preference for sweet taste, a number of
studies have demonstrated that appetite and food intake are
not stimulated by sweet sensations. Studies that use high-
potency sweeteners, such as aspartame, in place of sugar in
foods have shown that subjects do not necessarily compensate
for the caloric deficits created by the substitution of a high-
potency sweetener for sugar. Thus use of artificial sweeteners
may result in greater success at weight loss and long-term
weight maintenance (208).
The purpose of this section is to explore the psychological
and physiological variables associated with sweet preference.
The contribution of sweetness to satiety will be examined as
well.
Inborn Sweet Taste Preference in Humans and Animals
Humans are born with the capacity to distinguish between
the taste of sugars and other qualities of taste (138). Neonates
have been observed to ingest sugar water more vigorously
(174) and longer (51) than they did plain water. Preference for
sweet taste is also inferred from gustofacial responses (216),
although these responses are open to interpretation (49).
Rat studies have also revealed an innate preference for the
taste of sugars. Newborn rats display positive ingestive re-
sponses to oral infusions of sucrose solutions (1,89) and com-
plex carbohydrates (236). Twelve-day-old rats also respond
positively to Na saccharin (114,219).
Individual Differences for Preferencefor Intense Sweet
Stimuli in Adult Humans
In adults, there is considerable individual variability in he-
donic reactions to sweet stimuli (240). "Sweet likers" are peo-
ple who evaluate highly sweet sucrose solutions positively.
"Sweet dislikers" are those who respond to intense sucrose
concentrations negatively. Sweet liker/disliker status is con-
stant during fasted and fed states, although for sweet dislikers,
the unpleasantness of strongly sweet solutions lessens during
fasting (142). The sweet liker/disliker distinction is unchanged
when fructose or glucose are used as sweeteners (141).
Early feeding experiences (14) or genetic differences in 6-n-
propylthiouracil (PROP) taster status may account for indi-
vidual differences in sweet preference. Sweet likers tend to be
nontasters of PROP, while sweet dislikers tend to be PROP
tasters (143). PROP is a compound similar to phenylthiocar-
bamide (PTC) which has a bimodal threshold distribution
(243). Those who taste PROP detect its bitterness at low con-
centrations; nontasters detect the bitter taste only at high con-
centrations. Sweet likers experience a fairly complex taste sen-
sation with sucrose solutions; sweet dislikers report a purely
sweet gustatory experience (143).
Htgh-Potency Sweeteners: Effect on Appetite and Food
Intake m Humans
Two kinds of investigations have been employed for evalu-
ating the effect of high-potency sweeteners on appetite and
food intake. The first, the "additive" approach, tests the effect
SWEETENERS: STATE OF KNOWLEDGE REVIEW
that perception of a sweet taste has on subsequent responses;
responses to unsweetened foods are compared to responses to
nutritionally identical sweet foods. Aspartame, which gives a
sweet taste in calorically insignificant quantities, has been
most frequently used in additive studies to provide sweetness
without changing the nutritional value of the substance. For
example, noncaloric soft drinks have been compared with
mineral water (21), and a milkshake sweetened with aspartame
has been compared with one not sweetened (27).
The second, the "substitutive" approach, substitutes a high-
potency sweetener for a caloric sweetener in a food, producing
a food of equal sweetness but significantly fewer calories. As
the sensory properties of the meal are the same, the substitu-
tive study reveals the effect of nonsensory variables, such as
caloric density, on satiety.
Using these techniques, investigations usually have failed
to find any difference in appetite ratings following the sweet
and unsweet preloads (21a, 27,42,194). A few studies have
found that a sweet load was, in fact, more satiating, as in-
ferred from a greater decrease in subsequent hunger ratings
when compared to an unsweetened, nutritionally identical
meal (146,239).
There are three reports of enhancement of appetite follow-
ing ingestion o f aspartame-sweetened liquid (2 lb, 22,191 ). Ap-
petite ratings were obtained from subjects during the hour
following ingestion of plain water, and the results were com-
pared with appetite ratings after subjects drank aspartame-
sweetened water. Ratings of hunger and of desire to eat were
higher after ingestion of the aspartame-sweetened water.
These two studies (22,191), however, used a concentration of
aspartame (81 mg/100 ml) considered to be quite sweet, equal
to 9.5% sucrose (65). In a subsequent report from the labora-
tory (192), a sweeter solution of aspartame, 117.5 mg/100 ml,
produced no significant effect on appetite scores compared to
plain water. In evaluating these studies, it is important to note
that, although flavored or carbonated sweet beverages are ex-
perienced as pleasant, plain water is usually preferred over
purely sweet water (142). The results of these studies are ap-
parently confounded or at least inconclusive, because sweet
aqueous solutions may have been unpleasant or less pleasant
than plain water. Black et al. (21b) found an increase in appe-
tite after aspartame-sweetened mineral water but only when
280 ml were consumed; no increase in appetite was found
when 560 ml were consumed.
Even if these results are taken to indicate appetite stimula-
tion by sweetness, it must be borne in mind that the higher
appetite scores which occurred after consumption of aspar-
tame-sweetened water were not followed by increased food
intake. On the contrary, studies by Rogers et al. (191,192)
have demonstrated a marginally lowered food intake after
consumption of solutions of aspartame, consistent with
Mattes' (147) observation that correlation between hunger rat-
ings and food intake is poor. Many other investigations have
demonstrated no appreciable difference in food intake after
consumption of aspartame-sweetened or unsweetened bever-
ages (20,21a,21b,27,42,194,189). From these, it appears that
addition of sweetness to beverages does not affect subsequent
food intake.
The findings of an investigation utilizing saccharin to
sweeten yogurt (190) are at variance with the above aspartame
studies. Following ingestion of yogurt sweetened with saccha-
rin, subjects felt less satiated 30-60 min later than they did
after ingesting equicaloric unsweetened yogurt. Moreover,
their subsequent food intake increased after eating saccharin-
319
sweetened yogurt compared to the plain yogurt. Rogers and
Biundell (190) account for the increase as due to the sweetness
of saccharin, but this does not accord with their further find-
ings in the study that glucose-sweetened yogurt and equica-
loric, unsweetened yogurt had comparable effects on appetite
scores and subsequent food intake.
Another study evaluating the effects of aspartame-sweeten-
ed yogurt preloads on subsequent intake (162), which did not
include an unsweetened yogurt as a control, reported a nega-
tive relationship between yogurt preload sweetness intensity
and total 24-hour caloric intake.
Thus, the majority of studies do not support the contention
that sweetness per se stimulates appetite a n d / o r food intake.
On the contrary, the few researchers who have shown an in-
crease in subjective appetite scores following aspartame-
sweetened preloads have found contradictory results in their
own work. Further, consumption of aspartame-sweetened
preloads have never been shown to result in increased food
intake.
Using the "substitutive" protocol, foods of comparable
sweetness but different in caloric value are evaluated for their
effect on subsequent appetite and food intake. Gelatin des-
serts, puddings, and fruit-flavored drinks sweetened with
aspartame have been evaluated with respect to their sugar-
sweetened equivalents. Findings usually showed that ingestion
of preloads with equal sweetness but differing caloric content
resulted in similar effects on appetite ratings (2,42,193-195).
It can be inferred then, at least initially, that bulk and volume
of a substance have a greater effect on appetite than its caloric
content. Also expectations about caloric content of a food
influence appetite and satiety (23,224). These findings are not
consonant with those of Blundell and Hill (22) or Rogers et
al. (191) who found that appetite ratings rose significantly
after ingestion of aspartame-sweetened water, but fell with
glucose-sweetened water. No significant difference in subse-
quent food intake has been found after consumption of a low
calorie preload compared to the high calorie preload (2,42,
191,194). Findings from an investigation by Rogers and Blun-
dell (190) also showed that food intakes following preloads of
yogurt containing 131 Cals sweetened with saccharin did not
differ significantly from those after yogurt containing 295
Cals and sweetened with glucose.
These studies on short-term caloric compensation after pre-
loads of equal sweetness but differing caloric content imply
that caloric compensation is imperfect in the short term. It
must be emphasized that these studies use an entirely different
protocol from long-term studies of caloric compensation
(43,76,77) and should not be equated.
A recent report by Drewnowski et al. (61) combined the
additive and substitutive study designs. These studies utilized
four kinds of preloads with a base of soft white cheese: (A)
unsweetened, 300 Cais; (B) aspartame-sweetened, 300 Cals;
(C) sugar-sweetened, 700 Cals; and (D) aspartame-sweetened,
with maltodextrin, 700 Cals. Comparison of (A) vs. (B) re-
flects the additive effect, and comparison of (B) vs. (C) re-
flects the substitutive effect. Moreover, comparison of (C) vs.
(D) enables assessment of the unique effect of aspartame on
appetite and food intake under conditions where sweetness
and calories are controlled. The studies revealed no effect of
sweetness on subsequent intake: Food intake following (A)
was similar to that following (B). Nor was there caloric com-
pensation: Total daily caloric intake following (B) was ap-
proximately 400 Cals less than that after treatment (C), from
which it can be inferred that the subjects did not perceive the
320
400 calorie difference in preload (B) and increase subsequent
intake. Moreover, total caloric intake after treatments (C) and
(D) were similar, further supporting the conclusion that aspar-
tame does not stimulate food intake.
Effect o f Physiological State on Hedomc Response to
Sweet Taste
The pleasantness of sweet taste has a relationship to nutri-
tional state. During fasting, sucrose solutions are rated as
more pleasant than after nutritional satiety (35,69). Investiga-
tions using rodent models also reveal that sweet taste is more
appealing to starved animals (17,36,37). "Alliesthesia," or
shifts in the pleasantness of sweet taste as a function of nutri-
tional state (34), may be a component of food intake regula-
tion. When internal energy stores have been depleted and calo-
ric intake is important, perception of sweetness is highly
pleasant and increases the probability that a meal will be
eaten. If the gut has adequate energy supplies and is not,
therefore, in need of calories, the attractiveness of sweetness
lessens, thereby decreasing the probability of feeding.
Additional evidence for an integral relationship between
gustation and nutritional state are found in electrophysiologi-
cal studies. When internal metabolic conditions mimic reple-
tion, neural activity elicited by sugar on the tongue decreases.
Exogenous administration of glucose (82) and insulin (83) low-
ered neural activity evoked by the sweet taste of glucose, but
had negligible effect on responses to hydrochloric acid's sour
taste or quinine hydrochloride's bitterness. Similarly, stomach
distention without nutrient ingestion lowered neural responses
to sweet, but not to bitter taste (85).
Other investigations lend support to the hypothesis that
perceptual changes in the pleasantness of sweetness reflect
function. During the luteal phase of the menstrual cycle,
sweetness is experienced as more pleasant and intake of sweet
foods increases (26). Because metabolic rate rises during the
luteal phase (241), there is an increased palatability and intake
of sweet foods then would be compensatory for increased
energy expenditure. It has also been demonstrated that chil-
dren ranging from 9 to 15 yr of age preferred more intense
sweet taste than did adults (57). Because the adolescent gener-
ally has high activity levels and therefore high caloric needs,
elevated preference for sweetness may be due to an adaptive
response to physiological need.
Preference for Sweet Taste in Restrained Eaters and
Obese Persons
"Restrained eaters," a term for those who diet chronically
and preoccupy themselves with food and body weight (98),
characteristically ingest fewer calories per day than unre-
strained eaters (133). However, such caloric restraint is fol-
lowed by episodic consumption of large quantities of calories,
and these calories are often obtained by hinging on sweet
foods rather than nonsweet foods (229,238). It is possible that
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TABLE l
ACESULFAME-K
Physical and Chemwal
Chemical category: N-sulfonyl amide dihydrooxathiazi-
none dioxide (methyl derivative)
6-methyl-1,2,3-oxathiazine-4-(~H)-one-2,2-dioxide potassium
salt (237)
Molecular formula: C4H4KNO4S
Molecular weight: 201.2 (188)
Molecular structure:
O °
Solubility:
Acesuifame-K is readily soluble in water, N,N-di-
methylformamide, and dimethyl sulfoxide (31). The solubility
of acesulfame-K in water at 20°C is approximately 270 g/l; at
100°C the solubility increases sharply to more than I000 g/l.
The solubility of acesulfame-K in alcohol is 1 g/1 (237).
Stability (pH, heat):
The sweetness does not appear to be affected by baking or
pasteurization temperatures (40). The dry form has a very
good shelf life under dry conditions at room temperature,
independent of exposure to light; aqueous solutions with pH
above 2.5-3 show relatively good stability (7,242). However,
the hydrolytic stability of acesulfame-K is less than that of
saccharin (62). For example, in a cola system, 15070 is lost in
one year at room temperature. Decomposition occurs in ex-
treme conditions and the hydrolytic products are mainly ace-
tone, CO2, ammonium salts, sulfate, and amidosulfonate
(237).
Degradation route, in vivo:
Acesulfame-K is not metabolized, but is excreted by the
kidneys unchanged; therefore, has no caloric value (41,237).
Known incompatabilities:
Acesulfame-K shows variable compatibilities with flavor-
ings used in commercial food products (242). Bulking agents
such as polydextrose or polyalcohols are required for baking
applications because acesulfame-K does not have the bulking
properties of sugars (165).
SCHIFFMAN AND GATLIN
249. Ylikahri, R. H.; Pelkonen, R. Carbohydrate sweeteners in me-
tabolism and diseases. In: Kolvistoinen, P.; Hyvonen, L., eds.
Carbohydrate sweeteners in Foods and Nutrition. London: Aca-
demic Press; 1980:1-35.
250. Zawalich, W. S. Comparison of taste and pancreatic beta cell
receptor systems. In: Schneider, D., ed. Olfaction and taste IV.
Stuttgart: Wlss. Verlagsges.; 1972:280-286.
Sweetness
Potency: Pw2 = 204, Pw5 = 140, Pw~0 = 34 where Pw2,
Pws, and Pw~0 are the potencies in water equivalent to 2°70
sucrose, 5% sucrose, and 10% sucrose, respectively (65).
Typical concentration (range):
Acesulfame-K
15'
t~
I0"
e~
5"
500
- i
1000 150O
t
Concentration (ppm)
Response indicates sucrose sweetness equivalent in percent
(65).
Temporal properties:
The sweetness potency relative to sucrose decreases with
increasing concentration. The sweet taste of acesulfame K is
quickly perceptable and diminishes slowly, perhaps more so
than that of sucrose (242). The sweetness may be slightly en-
hanced in acidic solutions relative to neutral solutions (237).
Acesulfame-K is synergistic with many other high-potency
sweeteners, including aspartame and cyclamate. Blends of
acesulfame-K and aspartame (1 : 1 by weight) or acesulfame-K
and sodium cyclamate ( 1 : 5 by weight) have been recom-
mended (237). The sweetness quality of acesulfame-K is com-
patible with nutritive sweeteners including sorbitol, xylitol,
isomalt, and maltitol (237).
Acesulfame-K has a strong bitter taste to many persons,
especially at concentrations greater than 1000 ppm (205). It
also has a metallic component (62).
Limits of Use
Dose restrictions:
The Joint Expert Committee on Food Additives (JECFA)
of the F A O / W H O established an acceptable dally intake
(ADI) level for acesulfame-K of 9 mg/kg body weight in
1983. The FDA established an ADI of 15 mg/kg body
weight in 1988 (40,237). The ADI is the amount of a food
additive that can be taken dally in the diet over a lifetime
without risk.
The European Economic Community (EEC) has developed
SWEETENERS: STATE OF KNOWLEDGE REVIEW
a directive which specifies the acceptable maximum level of
sweeteners that may be used as food additives to give specific
foods a sweet taste. For acesulfame-K, label designation E950,
the food categories and levels are nonalcoholic drinks 350 mg/
l, desserts 350 mg/kg, breakfast cereals 350 mg/kg, various
fruit products 200-1000 mg/kg, confectioneries 500-2000 mg/
kg, bakery products 1000 mg/kg, specified alcoholic drinks
350 mg/l, sauces 350 mg/kg, and special dietary items 350
mg/kg (46).
Physiological and toxicological effects:
The oral toxicity of acesulfame-K is very low with an LDso
of 6.9-8.0 g/kg body weight. In a multigenerational study in
rats fed acesulfame-K at levels of 0, 0.3, 1.0, and 3.0070, no
adverse effects were reported in reproductive performance or
on teratologic examination (130). Extensive toxicological stud-
ies have found no potential carcinogenicity or mutagenicity
(175,237).
Current Use
Source(s): Synthetic
Dihydrooxathiazinone dioxides can be produced from ke-
tones, 15-diketones, derivatives of 15-oxocarbonic acids and al-
kynes which are reacted with halogen sulfonyl isocyanates.
Compounds resulting from this reaction are transformed into
N-halogen sulfonyl acetoacetic acid amide. In the presence of
potassium hydroxide this compound cyclizes to the dihydroox-
athiazinone ring system (237). Salts of the ring system are
formed because dihydrooxathiazinone dioxides are very acidic
(165).
Commercial products and concentration(s):
Acesulfame-K is suitable for low calorie and diabetic bever-
ages, jams and marmalade, confectionery items, sugarless
chewing gums, reduced-calorie baked goods, fruit-flavored
dairy products, oral hygiene products, pharmaceuticals, to-
bacco products and animal feedstuffs (237).
Frequency/advantages:
Internationally, acesulfame-K is available in 100 products
(165). It is heat stable (165) and synergistic with aspartame
and cyclamates (237).
Availability (manufacturers):
Diamin (Vitalia, UK) (188)
Sunette (Hoechst Celanese Corp, UK, US) (40,165,188)
Hermesetas Gold (Jenks Brokerage, UK)
Sweetex Plus (Crookes Healthcare, UK)
Regulatory status:
Acesulfame-K is approved for use in the US, UK, France,
Italy, Netherlands and Switzerland (46). In the US, acesulfa-
me-K is approved for use in chewing gum, dry mixes for bever-
ages, instant coffee, instant tea, gelatins, puddings, nondairy
creamers, and as a tabletop sweetener (165). A directive for
its use in countries in the EEC has been issued (46).
History
The sweetness of a dihydrooxathiazinone dioxide was acci-
dentally discovered in 1967 in Germany by K. Clauss and H.
Jensen at Hoechst AG while they were carrying out reactions
with butyne and fluorosulfonyl isocyanate (44,165). Analogs
of this chemical class were later synthesized and 6-methyl-
1,2,3-oxathiazine-4-(3H)-one-2,2-dioxide was found to have
the most favorable taste qualities (237). In 1988, the FDA
approved acesulfame-K as a food additive in the United
States, specifically as a sugar substitute (in small packages
and tablets), in chewing gum, and in dry bases for beverages,
327
instant coffee, instant tea, gelatins, puddings, pudding des-
serts and dairy product analogs (see 86 for review). US ap-
proval also includes confectionary products (hard and soft
candies). Subsequent petitions in the US submitted by Hoechst
Celanese have been for use in nonalcoholic beverages and
beverage bases and in baked hoods and baking mixes. Acesul-
fame-K has been approved in more than 50 countries, includ-
ing the United Kingdom, Switzerland, France, Italy, Belgium,
Australia, New Zealand, and South Africa (41,175). In coun-
tries other than the US, acesulfame-K is used in soft drinks,
candies, toothpastes, mouthwashes, and pharmaceutical prep-
arations (168).
ALITAME
Physical and Chemical
Chemical category: dipeptide
L~-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanin-
amide (31) composed of L-aspartic acid, D-alanine, and the
amide of the amine group 2,2,4,4-tetramethylthietanylamine
(215).
Molecular formula: CI4H25N3OaS
Molecular weight: 331.43
Molecular structure:
CH~
NH H,C~\
CO,H CH~
Solubility:
Alitame is very soluble in water (97,242). At 20°C, its solu-
bility ranges from 48.7% w/v at pH 2.0-24.907o w/v at pH
8.0.
Stability (pH, heat):
In the neutral pH range (5-8), alitame is stable at room
temperature for more than 1 yr. Stability is less, however, as
the pH is reduced to pH 2-4 (215). The half-life of alitame
solutions at pH 7.0 and 100°C is 13.4 h.
Degradation route, in vivo:
During metabolism the aspartic acid portion is hydrolyzed
off; the majority of the remainder is excreted as a mixture of
metabolites. Only a small percentage is excreted unaltered.
Known incompatabilities:
Alitame is incompatible with acidic food products includ-
ing cola under storage (Schiffman, personal observation),
high levels of reducing sugars, hydrogen peroxide, and sodium
bisulfite (97,242). A foul odor forms on storage of any acidic
product.
Sweetness
Potency: Pw2 = 4500, Pws = 3430, Pw~o = 1640, where
Pw2, Pws, and P,~o are the potencies in water at a sweetness
equivalent to 2070 sucrose, 5°'/0 sucrose, and 10070 sucrose, re-
spectively (65).
328
Typical concentration (range):
Alltame
15
lo
o
t~
~ 5
0 I00 200
Concentr'aUon (ppm}
Response indicates sucrose sweetness equivalent in percent
(65).
Temporal properties:
Alitame has a clean sweet taste which develops rapidly and
lingers slightly. It is synergistic with acesulfame-K and cycla-
mates (97,215)
Limtts of Use
Dose restrictions:
Alitame solutions exhibit taste saturation in which the
sweetness does not increase beyond 15070 sucrose equivalent
(65).
Physiological and toxicological effects:
The no effect level (NOEL) for alitame in animals is 100
mg/kg which is > 300 times the estimated mean chronic hu-
man exposure level. Animals treated with levels > 100 mg/kg
for 5 days to 2 yr had increased liver weights secondary to the
induction of hepatic microsomai metabolizing enzymes. In
man, no enzyme induction was observed over a 14-day period
at doses of 15 m g / k g / d a y (approximately 44 times the mean
chronic intake estimate). No carcinogenic, embryotoxic, te-
ratogenic, or mutagenic activity has been found (97). Alitame
contributes approximately 1.4 kcal/g or 0.0207o of calories of
replaced sucrose (165,215).
Current Use
Source(s):
Alitame is synthetically formed from the amino acids L-
aspartic acid and D-aianine with a novel C-terminal amide
moiety formed from 2,2,4,4-tetramethylthietanylamine.
Commercial products and concentration(s): Not available.
Frequency/advantages: Does not degrade with heat.
Availability (manufacturers): Manufactured by Pfizer.
Regulatory status:
The Food Additive Petition submitted to the US Food and
Drug Administration by Pfizer in 1986 was for the following
application categories: baked goods and baking mixes, pre-
sweetened ready-to-eat cereals, milk products, frozen desserts
and mixes, fruit and water ices and mixes, fruit drinks includ-
ing ales and mixes, confections and frosting, jams as well as
jellies, preserves, and sweet spreads, sweet sauces including
toppings and mixes, gelatins as well as puddings, custards,
filling, and mixes, nonalcoholic beverages and mixes, dairy
product analogs, sugar substitutes, sweetened coffee and tea
beverages, candy, and chewing gum. Permission for use in a
number of foreign countries has also been requested (97).
S C H I F F M A N AND GATLIN
History
After the accidental discovery of the potent sweet taste of
the dipeptide aspartame in 1965, Pfizer Central Research
started an intensive research program in the 1970's to system-
aticaily search for other-high potency sweeteners. They syn-
thesized a large number of dipeptides of diverse structural
types and ultimately patented alitame and structurally related
dipeptide sweeteners. It is not yet approved anywhere in the
world (97).
ASPARTAME
Physical and Chemical
Chemical category: dipeptide
N-L-c~-aspartyl-L-phenylaianine-1-methyl ester
3-amino-N-(ct-methoxycarbonylphenethyl) succinamic acid
Molecular formula: C~4HIeN20~ (188)
Molecular weight: 294.3 (188)
Molecular structure:
O
(o)- CH2"CH" N H ' C ' C H
" CH2 •
| " NH3
k
00CH 3 ,,
Solubility:
At pH 5.2, the isoelectric point, aspartame has a solubility
of 1°70 in water and 0.37070 in ethanol at 25°C (188,225) It is
more soluble in acidic solutions and hot water (188). It is not
soluble in fats and oils (106).
Stability (pH, heat):
Aspartame is most stable in solid form and should be
stored in an airtight container. Under certain moisture, tem-
perature and pH conditions, aspartame hydrolyzes to form
aspartylphenylaianine (AP) or is converted to its diketopipera-
zinc (DKP). DKP can convert to A P which can further convert
to individual amino acid components. Hydrolysis to free
amino acids tends to occur at pH 3.4 and lower; above pH
5.0 cyclization to diketopiperazine tends to occur. Hydrolysis
and cyclization result in loss of sweetness because neither A P
nor DKP are sweet (188, 225). In addition to DKP, there are
two other minor degradation products: L-aspartyl-L-phenyla-
lanine and fl-L-aspartyl-L-phenylalanine methyl ester; neither
of these exhibits off tastes (I 26).
The stability in aqueous solutions is dependent on concen-
tration, temperature, pH, buffer type and water activity (215).
Aspartame is most stable at pH 4.3 (7,188).
Aspartame can be used in High Temperature Short Time
(HTST) systems and ultra-high temperature (UHT) pasteurization
and aseptic systems where the product can be cooled quickly, or
when the aspartame is added aseptically after pasteurization.
While early studies showed that aspartame could not be used in
situations that required prolonged heating times such as in baking
(7,215,225), an FDA approval for a heat-stable form of aspartame
for baking was approved in 1993 (75a).
Degradation route, in vivo:
Metabolic studies indicate that aspartame is hydrolyzed
rapidly and completely in the gastrointestinal tract to its con-
 SWEETENERS: STATE OF KNOWLEDGE REVIEW
stituent amino acids, L-phenylalanine and L-aspartic acid, and
to methanol; it is not absorbed as an intact molecule (32,225).
Children metabolize aspartame as effectively as adults. Ad-
ministration of 34-200 mg aspartame/kg body weight (equiva-
lent to 4-24 liters of aspartame-sweetened beverage) produced
plasma concentrations of aspartic acid and phenylalanine well
below levels associated with toxicity. For example, a serving
of skim milk has approximately 13 times more aspartic acid
and 6 times more phenylalanine than an equal volume of bev-
erage sweetened with aspartame. Approximately 4 to 5 times
more methanol is obtained from a serving of tomato juice
than an equivalent volume of aspartame-sweetened beverage.
Acute doses of aspartame up to 100 mg/kg body weight are
also metabolized effectively by persons heterozygous for
phenylketonuria, a genetic disease characterized by a defi-
ciency in the ability to metabolize phenylalanine (32).
It provides 4 kcal/g; however, because its potency is as
much as 250 times that of sucrose, only very small amounts
are needed to sweeten foods. This leads to a dramatic reduc-
tion in total calories consumed in aspartame-containing prod-
ucts compared to an equally sweet sucrose-containing product
(215).
Known incompatabilities:
Aspartame has a normally reactive amino group and car-
boxyl group as well as an amide bond and a methyl ester.
Usually, foods do not contain large quantities of chemicals
that might spontaneously react with a carboxyl or amino func-
tion. An exception is cinnamon flavor which contains cinna-
maldehyde, an aldehyde which reacts readily with an unhin-
dered amino group. Consequently, it is difficult to formulate
cinnamon-flavored chewing gum with aspartame (153). This
may be a general limitation with flavors significantly depen-
dent on aldehydes (e.g. acetaldehyde, benzaldehyde, and va-
nillin).
Sweetness
Potency: Pw2 = 250, Pws = 196, Pw~0 = 107, where Pw2,
Pws, and Pw~oare the potencies in water at a sweetness equiva-
lent to 2% sucrose, 5% sucrose, and 10% sucrose, respectively
(65).
Aspartame sweetness potency in food products will vary
depending on the sweetener concentration and its application
to a particular formulation.
Aspartame is used in beverage and food products at typical
concentrations of 600 ppm in nonalcoholic beverages and 1000
ppm in desserts (173). Aspartame combined with other sweet-
eners provides an acceptable taste profile. Aspartame-xylitol
mixture (2.4:97.6) and blends of 5 0 : 5 0 with saccharin or
acesulfame-K have been used (7).
Typical concentration (range):
Aspartame
15'
r,
I0'
5'
0 Because aspartame, as a high-potency sweetener, does not
0 1000 2000 3000
Concentration [ppm)
329
Response indicates sucrose sweetness equivalent in percent
(65).
Temporal properties:
For most persons aspartame has a clean, sweet taste with-
out a bitter, chemical or metallic aftertaste (106,242). How-
ever, some persons report that it has an aftertaste character-
ized by lingering sweetness or bitter sweetness, predominantly
after repeated tasting (7). The sweetness develops more gradu-
ally and persists slightly longer than sucrose (106,242). The
AT (appearance time) for sweetness of aspartame is 5 s com-
pared to 4 s for sucrose; the ET (extinction time) is 19 s for
aspartame compared with 14 s for sucrose (126).
Limits of Use
Dose restrictions:
The Joint F A O / W H O Expert Committee on Food Addi-
tives approved aspartame with an ADI of up to 40 mg/kg
body weight/day in 1981 (7,188). The ADI of the diketopiper-
azine, a decompostion product of aspartame, is 7.5 mg/kg
(188). The US FDA established, in 1984, an ADI of 50 mg/kg
body weight/day with a request for a postmarket surveillance
system to monitor aspartame consumption (32,215). The re-
sults of postmarketing surveillance have demonstrated that
aspartame consumption by the general population (90th per-
centile) is only about 2.5-3 mg/kg/day, which is well below
the ADI (32).
Products containing aspartame must be labeled to alert
persons with phenylketonuria (PKU) of their need to restrict
intake of phenylalanine from all dietary sources (88). PKU is
a rare metabolic disease in which there is an absence of the
enzyme phenylalanine 4-monooxygenase which is involved in
the metabolism of phenylalanine. The phenylalanine content
from aspartame in aspartame-contalning products is far less
than would be found in meat, milk, and other protein foods.
The EEC has proposed a directive which specifies the ac-
ceptable maximum level of sweeteners that may be used as
food additives to give specific foods a sweet taste. For aspar-
tame, label designation E 951, these levels are 600 mg/I for
nonalcoholic drinks, 1000 mg/kg for desserts; I000 mg/kg for
breakfast cereals; 800 mg/kg for edible ices; 300 and 1000
mg/kg for fruits, depending on the product; I000-5500 mg/
kg for confectionery items, depending on the product; 1700
mg/kg for bakery products, 600 mg/l for alcoholic drinks;
300 mg/kg for fish products; 300 mg/kg for vegetables; 300
and 350 mg/kg for sauces; and 600-2000 mg/kg for special
dietary items (46).
Physiological and toxicological effects:
Toxicological studies have found no embryotoxic, terato-
genic or carcinogenic effects up to 2000-4000 mg aspartame/
kg body weight. The methanol obtained from aspartame me-
tabolism is oxidized in the body to formic acid and ultimately
to CO2 and H20; however, formic acid does not accumulate
from aspartame consumption, and the levels are far below
those where toxicity is observed. Intake of 200-500 mg metha-
nol/kg body weight is required to produce toxic levels of for-
mic acid; this is equivalent to a single dose of 240-600 liters
of aspartame-sweetened beverage. Consumption of aspartame
has no effect on neurologic function; it does not cause head-
aches or seizures nor does it alter mood, cognition or behavior
(33).
affect the blood glucose concentration in the diabetic person,
it is useful as a sugar substitute to reduce caloric intake in the
330
Type II diabetic individual for whom weight loss is a goal.
Aspartame provides the insulin-dependent diabetic with the
flexibility of an unscheduled snack and the ingestion of other-
wise substituted carbohydrates (175).
Aspartame is noncariogenic, and there is some evi-
dence that it may be anti-cariogenic by inhibition of bacterial-
growth a n d / o r reduction in plaque formation by Streptococ-
cus mutans, (175); however this has not been firmly estab-
lished.
Current Use
Source(s):
Aspartame is prepared by coupling the two constituent
amino acids, aspartic acid and phenylalanine, by two general
procedures, one enzymatic and the other chemical coupling.
In the enzymatic method, carbobenzoxy-L-aspartic acid (Z-
Asp) is coupled with L- or DL-phenylalanine methyl ester in
the presence of an enzyme under very special conditions. Be-
cause the enzyme is specific for the formation of protein-like
peptide bonds with L-amino acids, only the ~-carboxyl of Z-
Asp reacts and only with L-Phe-OMe. This gives cleanly Z-L-
Asp-L-Phe-OMe which can be catalytically hydrogenated to
aspartame. The classical chemical method activates a pro-
tected L-aspartic acid by conversion to the anhydride and reac-
tion of the latter with L-Phe or L-Phe-OMe. The Asp protect-
ing group is either formyl or carbobenzoxy. Final purification,
after deprotection, usually depends on the low water solubility
of aspartame hydrochloride which is then neutralized to yield
aspartame. The chemical synthesis method is less expensive
than the enzymatic process.
Commercial products and concentration(s):
Equal and NutraSweet (The NutraSweet Company, USA)
Canderel and Flix (Searle, UK) (188), (Ajinomoto,
Japan)
(Holland sweetener, Holland),
(Miwon, Korea)
Frequency/advantages:
Aspartame is available worldwide in over 5,000 products.
The largest single use is in carbonated soft drinks. The Nu-
traSweet brand is most readily available in the United States
and is used in soft drinks in an approximate concentration of
525 mg/l or ppm. This would give a product with sweetness
equivalent to 9°70 sucrose if the potency of aspartame at this
concentration is 180 times that of sucrose. The sweetness in-
tensity by a particular concentraion depends greatly on the
specific formulation.
Aspartame is also commonly used as a tabletop sweetener
with the quantity equivalent to two teaspoons of sucrose pack-
aged in a packet. This is typically 35 mg aspartame plus vari-
ous extenders such as glucose or maltodextrin.
Availability (manufacturers):
The NutraSweet Company, USA
Searle, UK
Ajinomoto, Japan
Holland Sweetener, Holland
Miwon, Korea
Regulatory status:
Aspartame is approved for use in over 90 countries, includ-
ing all major countries. The directive proposed by the EEC
will uniformly regulate its use in the twelve European Commu-
nity (EC) countries, and presumably those that would join the
EC in the future.
S C H I F F M A N AND GATLIN
History
In 1965, Jim Schlatter, working with Dr. Robert Mazur on
the synthesis of the C-terminal tetrapeptide of gastrin, discov-
ered the sweet taste of aspartylphenylalanine methyl ester
(aspartame). From 1965 to 1970 over 200 analogs of aspar-
tame were synthesized but none was more satisfactory than
aspartame itself (33,106). In 1974, the FDA approved aspar-
tame for use in dry products including cold breakfast cereals,
chewing gum, dry beverage mixes, instant tea and coffee, gela-
tins, puddings, fillings, dairy product analog toppings, and
tabletop sweeteners. However, the FDA stayed the regulation
and appointed a public board of inquiry to resolve safety
issues (155). In 1981, the marketing stay was lifted, and aspar-
tame was approved for dry uses, according to the 1974 ruling.
In 1983, aspartame was approved for use in carbonated bever-
ages. Since 1983, additional uses have been approved in the
US. However, it is estimated that at least 80070 of the US
market is carbonated soft drinks with a significant part of the
remainder being tabletop (packet) use (48). In addition to the
US, aspartame has been approved for use in foods, beverages,
and as a tabletop sweetener in over 90 countries (106).
CALCIUMCYCLAMATE
Physical and Chemical
Chemical category: sulfamate
Calcium cyclohexylsuifamate
Calcium cyclohexanesulfamate (31,188)
Molecular formula: Cj2H2 N206S2 Ca (24,188)
Molecular weight: 396.5 (24,188), 432.6 as dihydrate (188)
Molecular structure:
[
2
Solubility:
1 g/4 ml in water
1 g/60 ml in ethanol
1 g / l . 5 m l in propylene glycol (24,81)
Stability (pH, heat):
Solutions are stable to heat, light, and air throughout the
pH range 2-10 (24,188,242).
Degradation route, in vivo:
The breakdown of calcium cyclamate does not provide any
calories. Sodium and calcium cyclamate and cyclamic acid are
incompletely absorbed from the gastrointestinal tract; some
cyclamate is excreted in the urine. About 25% of a human
population may convert cyclamates to cyclohexylamine which
is then excreted in the urine. The conversion results from the
action of microflora on the nonabsorbed cyclamate in the
intestinal tract rather than metabolism by human cells (24).
The amount of cyclohexylamine converted varies greatly be-
tween individuals from < O.1070 to a maximum of 60070 (25,188).
SWEETENERS: STATE OF KNOWLEDGE REVIEW
Known incompatabilities:
Calcium cyclamate is incompatible with nitrites in acid solution
and exhibits limited comparability with potassium salts, carbon-
ates, citrates, phosphates, sulfates, and tartrates (188). Incompa-
tabilities with caramel and pectin have been reported (242).
Sweetness
Potency: Pw2 = 26, Pw5 = 32, Pw~5 = 18 where Pw2is the po-
tency in water at a sweetness equivalent to 2% sucrose, Pw5equiva-
lent to 5°7osucrose and Pw~5equivalent to 7.5°70 sucrose (65).
Typical concentration (range): (see sodium cyclamate)
Temporal properties:
When the concentration of calcium cyclamate approaches
0.507o in the formulation, a bitter taste becomes noticeable
(188). Sweetness of cyclamate builds more slowly to a maximal
level and persists longer than that of sucrose (24). The taste
of cyclamate is very compatible with fruit flavors (24). The
off-tastes for calcium cyclamate begin at a slightly lower con-
centration than for sodium cyclamate (24).
Limits of Use
Technical properties:
Advantages of calcium cyclamate in product formulation
are that it is nonhygroscopic and does not support mold or
bacterial growth. It also does not provide the bulk, body, or
texture that are characteristic of sugar (65).
Dose restrictions:
The following table shows the results of laboratory tests to
determine the LDso of calcium cyclamate when dosed by vari-
ous routes in various animals.
animal route LDs0 (25)
mouse oral 7.2 g/kg
mouse intravenous 0.57 g/kg
rat subcutaneous 0.1 g/kg
hamster oral 4.6 g/kg
rabbit intravenous 0.12 g/kg
Cyciohexylamine, a metabolic by-product of cyclamates,
has an oral LDs0 of 156-614 mg/kg in rats; this metabolite is
hence more toxic than cyclamates, and this toxcicity limits the
use of the sweetener (24,25).
The EEC has adopted a directive which specifies the ac-
ceptable maximum level of sweeteners that may be used as
food additives in ready-for-use commercial products to give
specific foods a sweet taste. For cyclamic acid and its sodium
and calcium salts, designated E 952 in this directive, the food
categories and levels are nonalcoholic drinks 400 mg/l, des-
serts 250 mg/kg, breakfast cereals 250 mg/kg, edible ices 400
mg/kg, fruit 1000 mg/kg, fruit preparations 250 mg/kg, con-
fectionery items 1000 mg/kg, sugar free chewing gum 3000
mg/kg, bakery products 1700 mg/kg, alcoholic drinks 350
mg/l, and special diet formulas/supplements 400 and 1000
mg/kg (46). The EEC designates a temporary ADI = 11.
Physiological and toxicological effects:
Calcium cyclamate is not cariogenic, but it also is not anti-
cariogenic as are some other high-potency sweeteners (24,25).
Softening of the stools and diarrhea are common side ef-
fects of cyclamate ingestion; this laxative action is due to a
change in the osmotic activity of the unabsorbed fraction of
cyclamate salts in the gastrointestinal tract (24,25).
Cyclohexylamine in the diet is known to produce testicular
331
atrophy, reduced body weight gain, and hyperactivity in rats
(25,45). It may also raise blood pressure in susceptible individ-
uals (24). A report issued by a National Academy of Sciences
National Research Council Committee concluded that cycla-
mate by itself is not carcinogenic; however, cyclamate may be
a co-carcinogen because cyclamate-saccharin mixtures in-
crease the risk of bladder cancer in animal models (24,86,167).
Also see section on sodium cyclamate.
Current Use
Source(s): Synthetic
Commercial products and concentration(s):
Sucaryl Calcium (Abbott, Canada), Cyclan
Frequency/advantages:
A mixture of cyclamate: saccharin in a ratio of 10 : 1 was
popular during the 1960s. Mixtures of cyclamate and saccha-
rin are synergistic and produce sweetness levels that are 20°7o
higher than would be expected based on the levels of the indi-
vidual components (24). Patents have recently been filed that
indicate cyclamate has potential in combination with other
sweeteners including aspartame and acesulfame-K (24).
Calcium cyclamate can be used to mask the bitterness and
unpalatable tastes of drugs, especially liquid formulations and
chewable tablets (24). Cyclamates have a low solid content at
a desirable sweetness level which makes a suspension more
fluid and reduces caking. Cyclamate disintegrates rapidly in
tablet form.
Availability (manufacturers):
Abbott Laboratories, USA
Numerous manufacturers in Korea
Regulatory status:
Calcium cyclamate is available as a table-top sweetener or
for use in foods and beverages in over 40 countries, including
Canada (24,25). It has been approved by the EEC Scientific
Committee for Food and by the JECFA of F A O / W H O . It
has been allocated a temporary ADI of 11 mg/kg body weight.
It is presently permitted for use in Australia, New Zealand,
Switzerland, Spain, and Germany. It may not be used in any
drugs, other than those with approved new drug applications,
or in any foods (including beverages) that are intended for use
in the United States (242).
History
Sodium cyclamate was synthesized in 1937 by Sveda, who
accidentally discovered that it has a sweet taste (8,25). Cycla-
mates were first introduced in tablet form as a table-top sweet-
ener for use by diabetics by Abbott Laboratories in the United
States in 1951 (24,25,45). After enactment of the Food Addi-
tive Amendment in 1958, sodium and calcium cyclamate were
classified as GRAS (Generally Regarded As Safe) by the US
FDA. Mixtures of cyclamate and saccharin (10: 1) subse-
quently became popular in the US during the 1960s (25). In
the UK, cyclamate was allowed in soft drinks under the 1964
Soft Drink Regulations (242).
In 1966 it was reported that cyclamates could be metabo-
lized by intestinal bacteria to cyclohexylamine (129). In 1968,
an interim report from the National Academy of Sciences
concluded from new animal studies that unrestricted use of
cyclamate was not warranted (86). Approval for its use was
withdrawn in the US when it was removed from the GRAS
list in 1969 (215). In 1970, a long-term study in rats was pub-
lished that reported an increased incidence of bladder tumors
332
compared to controls in animals fed mixtures of sodium cycla-
mate and sodium saccharin (10 : 1) and cyclohexylamine (179).
This finding led to the ban of cyclamates as a food additive in
many countries, including the United States. In 1982, Abbott
Laboratories repetitioned for approval for its use (215).
FRUCTOSE
Physical and Chemical
Chemical category: carbohydrate
Molecular formula: C6HI206(188)
Molecular weight: 180.2 (188)
Molecular structure:
CH2OH
:H2OH
H H
OH H
Solubility: 1 g/0.3 ml water, 1 g/15 ml alcohol
Stability (pH, heat):
May be sterilized by autoclaving; store in airtight container
at temperature not exceeding 25 °C.
Degradation route, in vivo:
Absorbed from the gastrointestinal tract but more slowly
than dextrose; metabolized more rapidly than dextrose,
mainly in the liver where it is phosphorylated and part is con-
verted to dextrose. Insulin is considered not to be necessary
for its metabolism. Fructose produces little effect upon the
blood-sugar concentration, except in diabetic patients, who
may metabolize it to dextrose to a greater extent than do
nondiabetic subjects; quantitative advantages are not great.
Known incompatabilities: chlortetracycline was incompati-
ble with solutions of levulose 10% in saline solution.
Sweetness
Potency: Pw2 = 1.3, Pw5 = 1.3, Pw,o = 1.3, where Pw2, Pws,
and Pw,0 are the potencies in water at a sweetness equivalent to
2%0 sucrose, 5% sucrose and 10% sucrose, respectively (65).
Relative:
The relative sweetness is dependent on temperature which af-
fects the mutarotational behavior of fructose. Sweetness is greater
at 20°C than 80°C. Pure crystals have maxiumum sweetness be-
cause they have not undergone mutarotation in solution.
Typical concentration (range):
Fructose
15"
i 10'
0
0 5 10
Concentration (%1
S C H I F F M A N AND GATLIN
Response indicates sucrose sweetness equivalent in percent
(65).
Current Use
Source(s):
Fructose is found naturally in many fruits and honey. How-
ever commercial fructose is synthesized from liquid dextrose.
GLYCYRRHIZIN OR GLYCYRRHIZICACID
Physical and Chemical
Chemical category: triterpenoid glycoside
20/3-carboxy-I l-oxo-30-norolean-12-en-3fl-yl-2-O-fl-D-gluco-
pyanuronosyl-c~-D-glucopyranosiduronic acid
Molecular formula: C42I-t620,6 (31)
Molecular weight: 822.92 (31)
Molecular structure:
aje..CNI
¢ ~
I gl I
t
glll I ~I
U U
Solubility:
Extracted from the plant as the K + and Ca ++ salts of
glycyrrhizic acid it is water soluble (145); conversion to ammo-
niated glycyrrhizin, the fully ammoniated salt, results in a
more water-soluble compound (127).
Stability (pH, heat):
Glycyrrhizin is reasonably stable at elevated temperatures
(127). Ammoniated glycyrrhizin precipitates at pH levels be-
low 4.5.
Degradation route, in vivo:
Glycyrrhizin is hydrolyzed by human intestinal flora to
glycyrrhetic acid which is absorbed from the small intestine in
that form (209). Glycyrrhetic acid binds to plasma protein,
enters the enterohepatic circulation, and is almost completely
metabolized (88). Both glycyrrhizin and glycyrrhetic acid have
mineralocorticoid and glucocorticoid properties because they
possess chemical structures that resemble steroids (209). Thus,
glycyrrhizin can affect electrolyte metabolism and result in
retention of sodium.
Sweetness
Potency: Pw2 -- 252, Pw5 = 109, Pw~ = 14, where Pw2,
Pw5, and Pw7 are the potencies in water at a sweetness equiva-
lent to 2% sucrose, 5%0 sucrose and 7% sucrose, respectively
(65).
Typical concentration (range):
Response indicates sucrose sweetness equivalent in percent
(65).
SWEETENERS: STATE OF KNOWLEDGE REVIEW 333

Temporal properties: Pure Glycyrrhiza Extract, USNF

15 M o n o a m m o n l u m Glycyrrhlztnate
0 Ammoniated glycyrrhizin is listed as GRAS (generally
0 -
0 I000 2000 3000
ConcentraUon Ippm]
Glycyrrhizin has a slow onset of sweetness and a long
aftertaste (127). The AT (appearance time) is 16 s compared
with AT = 4 s for sucrose. The ET (extinction time) is 69 s
compared to 14 s for sucrose. Ammoniated glycyrrhizin
has similar hedonic properties to glycyrrhizin. It has a very
slow onset of sweetness which subsequently lingers very
strongly (127).
Limits of Use
Dose restrictions:
The Ministry of Health in Japan has issued the caution
that glycyrrhizin use should be less than 200 mg/day when
used in drug formulations (127). The widespread use of glycyr-
rhizin and ammoniated glycyrrhizin by humans has been re-
lated to cases of pseudoaldosteronism with symptoms of hy-
pertension, edema, sodium retention, and mild potassium
diuresis (127).
Physiological and toxicological effects:
Glycyrrhizin and liquorice possess pharmacological prop-
erties including anti-inflammatory and anti-cariogenic effects.
Glycyrrhizin inhibits dental plaque formation by cariogenic
bacteria and protects enamel from demineralization due to its
antiglycolytic coating and buffering capacities (209). Glycyr-
rhizin and liquorice have also been used to treat oral ulcers,
herpetic lesions, bronchitis, and coughs (127,209). High intake
has been related to hypokalemia, hyperprolactinemia (209),
and pseudoaldosteronism manifested as hypertension, edema,
sodium retention, and potassium diuresis (127).
Current Use
Source(s):
Natural, extracted from the plant Glycyrrhiza glabra.
Commercial products and concentration(s):
In its natural form, glycyrrhizin is present in the plant in
yields of 6-1407o w/w as a mixture of various metallic salts
(127,145). Commercial extraction and purification follows es-
tablished procedures (127). In 1987 glycyrrhizin extract had
almost a 3007o share of the high-potency sweetener market in
Japan, being widely used for flavoring and sweetening food,
beverages, medicines, cosmetics and tobacco (127). Liquorice
is the British Adopted Name.
Frequency/advantages:
Ammoniated glycyrrhizin is used as a flavorant, flavor
modifier, and foaming agent in confectionery and dessert
items and in carbonated beverages with pH above 4.5. It is
used at a concentration of 30-300 ppm to enhance the flavor
of cocoa and chocolate-flavored products.
Availability (manufacturers):
Glycyrrhiza Fluidextract, USNF
Liquorice Liquid Extract, B.P.
Deglycyrrhizinised Liquorice Extract, B.P.
MagnaSweet (Wisconsin)
Ammoniated glycyrrhizin
Regulatory status:
regarded as safe) by the United States Food and Drug Ad-
ministration (FDA) when used as a natural flavoring agent
(127). It is not approved for use as a sugar substitute at
this time (215).
History
Glycyrrhizin (glycyrrhizic acid) is extracted from the rhi-
zomes and roots of the plant Glycyrrhlza glabra which means
"sweet root" in Greek. Glycyrrhtza glabra, better known as
liquorice, is a wild perennial herb that grows in deep sandy,
fertilized soil near water. Different varieties of Glycyrrhiza
glabra are grown in Southern Europe, North Africa, and West
and Central Asia. Both Glycyrrhiza glabra and glycyrrhizin
itself have been used for centuries as a crude drug (209).
MALTITOL
Physical and Chemical
Chemical category: carbohydrate
O-a-D-glucopyranosyl-(1-4)-sorbitol
Molecular formula: C~2H~O.
Molecular weight: 346.34
Molecular structure:
CH2OH CH2OH
H Jl~m=~O H H .L~~ O H
H OH H OH
Solubility:
"Very soluble" (66)
Stability (pH, heat):
Like the other polyalcohols, due to the absence of free
carbonyl groups, maltitol does not undergo Maillard reactions
to produce caramel-colored species in the presence of proteins
(66,163). Maltitol is more heat stable and more resistant to
microbial degradation than maltose. Maltitol is moderately
hygroscopic (66).
Degradation route, in vivo:
Mahitol is hydrolyzed by disaccharidases in the gastrointes-
tinal tract to yield free glucose and sorbitol. The glucose,
which digestibility studies show accounts for about 50°70 of an
ingested dose, (10,247) is slowly formed and rapidly absorbed,
as seen by a relatively fiat blood glucose curve and slow insulin
response (10,247). The sorbitol portion is incompletely ab-
sorbed; the absorbed portion being oxidized to fructose,
which is further metabolized as fructose-l-phosphate indepen-
dent of insulin (10).
334 SCHIFFMAN AND GATLIN

Sweetness Molecular structure:

Potency: Pw2 = 0.73, P.s = 0.72, P.75 = 0.71, where

Pw2, P~s, and P.7 5 are the potencies in water at a sweetness CH20H t
equivalent to 2070 sucrose, 5070 sucrose and 7.507o sucrose, re-
spectively (65). HO-C-H
Typical concentration (range):
HO-~.,-H
Maltltol H-(~-OH
H-C-OH

Solubility: 220 g/l in water (67)

O~ TI ~ T !
0 10 20
Concentration (%1
Response indicates sucrose sweetness equivalent in percent
(65).
Current Use
Source(s):
Maltitol is prepared commercially by hydrogenation of
corn syrup that has a high maltose content. This maltose is
the product of enzymatic hydrolysis of starch. Purification
and concentration of the hydrogenated syrup yields crystalline
maltitol in the proportion of 90-99% with the remainder being
small amounts of sorbitol and hydrogenated trisaccharides
(10). It is produced in substantial quantities only in Japan at
the present time (66).
Commercial products and concentration(s):
Hayashibara Biochemical Laboratories pioneered the pro-
cess of hydrogenation of maltose to produce maltitol and li-
censes the patent to Town Chemical Industry, Co., Ltd., an
affiliate of Mitsubishi, Tokyo, Japan and to ANIC and their
subsidiary Melida, Sp.A, Milan, Italy. Town produces and
markets crystalline maltitol and maltitol syrup under various
brand names and is limited to specific geographic regions,
which include Japan and the United States. The license re-
stricts ANIC to marketing in Europe (163).
Availability (manufacturers):
Malbit TM by ANIC/Melida
AmaltyTM and MabitTM by Towa Chemical Industry Co, Ltd.
Stability (pH, heat):
Moderately hygroscopic (188); more heat stable than corre-
sponding mono- and disaccharides (67); stable to sterilization
by autoclaving or filtration
Degradation route, in vivo:
Mannitol and sorbitol have common metabolic pathways;
both are slowly absorbed by passive diffusion through the
intestinal lumen. There are two different pathways for manni-
tol utilization: i) oxidation to D-fructose by the enzyme manni-
tol dehydrogenase in the liver, and ii) indirect metabolism
by intestinal flora via fermentative degradation (60,67). The
D-fructose is metabolized by the fructose-l-phosphate path-
way to pyruvate or to glucose and glycogen, depending on the
metabolic state of the individual (67).
Because mannitol is a poor substrate for enzymatic degra-
dation, a significant portion of the ingested dose is excreted
in the urine (60). Studies suggest that approximately 50°?0
of the ingested dose is utilized by the body, due to its incom-
plete metabolism and incomplete reabsorption by the kidney.
Mannitol has a caloric value of 2 cal/g, the majority of this
being secondary to the indirect metabolism by microbial fer-
mentation (60).
Sweetness
Potency: Pw2 = 0.55, Pw5 = 0.64, P~0 = 0.67, where P,2,
P~s, and P , J0are the potency in water at a sweetness equivalent to
2°70 sucrose, 5070sucrose, and 10% sucrose, respectively.
Typical concentration (range):
Mannitol
12"

Htstory 10"

8"
Maltitol was developed in Japan and has been used there c-
since about 1964 (163). o
6.
01
o

4"
MANNITOL

2'
Phystcal and Chemical
0 2 4 S 8 10 12 14 16
Chemical category: carbohydrate Concentration (%)
Molecular formula: C6H~406 (188)
Molecular weight: 182.2 (188) Response indicates sucrose sweetness equivalent in percent.
SWEETENERS: STATE OF KNOWLEDGE REVIEW
Ltmits of Use
Dose restrictions:
Mannitol is permitted as a food additive pending further
study. Any food product containing mannitol that could con-
ceivably result in the ingestion of more than 20 g in one day is
required to be labeled with the statement "Excess consumption
may have a laxative effect" (60). In the United States it has
interim food additive status and use levels may not exceed the
following: Pressed mints 98o70, hard candies 5o70, cough drops
5%, chewing gum 31°/0, soft candies 40°70, confections and
frostings 8%, nonstandardized jams and jellies 15%, and oth-
ers 2.50/0 (67).
Physiological and toxicological effects:
Mannitol is only slowly fermented by oral microorganisms,
thus decreasing the acidification of plaque, making it signifi-
cantly less cariogenic than sucrose (60). Further study is neces-
sary to understand the mechanisms and significance of the
effect of enhanced mineral absorption by the polyols (60).
Current Use
Source(s): (natural, synthetic, both)
Mannitol is widely distributed in plants, including the exu-
date from the ash tree, seaweeds, and mushrooms. It is com-
mercially prepared by the hydrogenation of sugar, which
yields a mixture of sorbitol and mannitol from which the man-
nitol readily crystallizes due to its lower solubility and can
thus be separated (67).
Commercial products and concentration(s):
Mannitol is used as a dusting powder and anticaking agent
because of its nonhygroscopic nature. Manuitol is adminis-
tered intravenously as a 15-25% solution as an osmotic diure-
tic in acute renal failure, to reduce intracranial pressure, to
reduce intraocular pressure, and to promote excretion of toxic
substances (188).
Frequency/advantages:
Mannitol is widely used in food manufacture in the US.
In a recent survey of excipients in pharmaceutic antibiotic
preparations, mannitol was used in 7.7% of them, either alone
or in combination with sucrose a n d / o r saccharin (132). It is
used more commonly in chewable tablets than in liquid syrups
or suspensions. Information on the quantity of specific excipi-
ents is rarely provided by the drug manufacturer due to pro-
prietary exclusion, but surveys of sweetener use in pharmaceu-
ticals for pediatric use found mannitol used in the following
ratios in chewable antibiotic tablets: sucrose : mannitol : sac-
charin 215 : 169 : 1 and 6.25 : 73 : 1 and mannitol : saccharin
171 : 1 (104).
Regulatory status:
The regulations governing the use of mannitol vary in dif-
ferent countries, some listing it as sweetener and others only
as a food additive. The regulations as described by countries
include: South Africa and United States, permitted sweetener;
United Kingdom and Federal Republic of Germany, permitted
except where standard prohibits use but not listed as sweet-
ener; Belgium, Denmark, Australia, Greece, Spain, Sweden
and Switzerland, listed as sweetener and permitted in certain
food stuffs only; France, Canada, and Japan, listed as food
additive only; and Italy, Netherlands, Austria, Finland, Nor-
way, not described (67).
NEOHESPERIDIN DIHYDROCHALCONE
Physical and Chemical
Chemical category: dihydrochalcone glucoside
3,5-Dihydroxy-4- [3-(3-hydroxy-4-methoxyphenyl) propio-
335
nyl]phenyl 2-O- ( 6-deoxy-t~-L-rhamnopyranosyl)-/3-D-glucopy-
ranoside (188)
Molecular formula: C28H36OI5(188)
Molecular weight: 612.6 (188)
Molecular structure:
ONON
Solubility:
8.1 x 10 -4 M in distilled water at room temperature; 0.50
g/l increasing to approximately 653 g/1 at 80°C; sodium and
calcium salts of neohesperidin dihydrochalcone have a solubility
greater than 1 g/mi (109).
Stability (pH, heat):
Neohesperidin dihydrochalcone is resistant to hydrolysis at
pH values above 2. In aqueous solutions stored for years at
room temperature and exposed to light, there is little change in
sweetness although some yellowing may occur (109).
Degradation route, in vivo:
The metabolism of neohesperidin dihydrochalcone is similar
to that of other flavonoids and is brought about predominantly
by the intestinal microflora. During metabolism there is cleavage
between the substituted phloroglucinl A-ring and the adjacent
carbonyl group to yield a series of C3-C6 acids derived from the
B ring. The metabolic fate of the A ring is not well understood.
Thin-layer chromatograms suggest that the metabolites from
neohesperidin and neohesperidin dihydrochalcone are similar
(109).
Sweetness
Potency: Pw2 = 1470, Pw5 = 906, Pw75 = 434, where Pw2,
Pws, and Pw75 are the potencies in water at a.sweetness equivalent
to 2o70 sucrose, 5o70 sucrose, and 7.5% sucrose, respectively (65).
Relative:
Neohesperidin dihydrochalcone is approximately 1800 times
more potent than sucrose by weight at or near threshold. As the
concentration increases to the intensity of 8.5°70 sucrose, it is
only 200-340 times more potent than sucrose (109).
Typical concentration (range):
15- Neohcsperldin Dihydrochalcone
~ 10'
0 250 500 750 1000
Concentration (ppm)
Response indicates sucrose sweetness equivalent in percent
(65).
336 S C H I F F M A N AND GATLIN

Temporal properties: Molecular formula: C6I--II2NO3SNa (188)

Neohesperidin dihydrochalcone (NHDC) has a slow onset Molecular weight: 201.2 (188)
of sweetness with a lingering aftertaste which has been de- Molecular structure:
scribed as having a menthol or licorice-like quality. Mixture
of neohesperidin dihydrochalcone with/3-gluconolactone may
overcome some of the initial lag in sweetness perception (109).

Limits of Use

Dose restrictions:
The EEC has developed a directive that specifies the ac-
ceptable maximum level of sweeteners that may be used as
food additives in ready-for-use products to give specific foods
a sweet taste. For neohesperidin dihydrochalcone, designated
E 959 in the directive, the foods and levels include nonalco-
holic drinks 30 and 50 mg/l, desserts 50 mg/kg, edible ices 50
mg/kg, fruit 50 mg/kg, confectioneries 100 and 400 mg/kg,
and alcoholic drinks 10 and 20 mg/1 (46). NHDC has also
been recommended for use in pharmaceuticals, especially to
mask the bitter taste of the drugs. The Scientific Committee
for Food of the European Committee gave NHDC an ADI of
5 mg/kg body weight in 1987 (109). The ADI is the amount
of a food additive that can be taken dally in the diet over a
lifetime without risk.
Physiological and toxicological effects:
NHDC has an estimated caloric value of not more than 2
cal/g.
Rats kept on a 10% diet of NHDC for 11 mo exhibited
growth inhibition and increased testes weight relative to body
weight. A 5070 diet also showed reduced growth rate but no
carcinogenicity in rats. In dogs fed a diet of approximately 6070
NHDC, liver and thyroid weights were elevated and thyroid
hypertrophy and hyperplasia were found. Testicular atrophy
and degeneration also occurred in several of these animals
(109). Neohesperidin dihydrochalcone is not mutagenic ac-
cording to the Ames test.
Current Use
Source(s):
Flavanones, in the presence of alkali, undergo a ring-
opening reaction that produces chalcones. Catalytic reduction
of chalcones yields dihydrochalcones (109).
Regulatory status:
Neohesperidin dihydrochalcone has not been approved by
the FDA for use in the US because additional toxicological
tests are needed. Neohesperidin dihydrochalcone is approved
for use in chewing gum and some beverages in Belgium. Its
use throughout the European Community is currently pending
approval of the EC directive on sweeteners for use in food-
stuffs (109).
Na+
Solubility:
1 g/5 ml of water
1 g/250 ml of alcohol
1 g/25 ml of propylene glycol (188)
Stability (pH, heat):
Solutions are stable to heat, light and air throughout the
pH range of 2-10 (24,242).
Degradation route, in vivo:
The breakdown of sodium cyclamate does not provide any
calories. Sodium and calcium cyclamate and cyclamic acid are
incompletely absorbed from the gastrointestinal tract; some
cyclamate is excreted in the urine. About 25070 of a human
population may convert cyclamates to cyclohexylamine which
is then excreted in the urine. The conversion results from the
action of microflora on the nonabsorbed cyclamate in the
intestinal tract rather than metabolism by human cells (24).
The amount of cyclohexylamine converted varies greatly be-
tween individuals from <0.1°70 to a maximum of 60070
(25,188).
Known incompatabilities:
Sodium cyclamate is incompatible with nitrites in acid solu-
tion and has limited compatibility with potassium salts (188).
Sweetness
Potency: Pw2 = 26, Pw5 = 32, Pw~o = 18 where Pw2 is
the potency in water at a sweetness equivalent to 2070 sucrose,
P,,5 equivalent to 507o sucrose and Pwm equivalent to 10% su-
crose (65).
Typical concentration (range):
15'
Sodium Cyclamate
~ I0 ¸

History
The sweetening properties of dihydrochalcones were dis-
covered by Horowitz and Gentili over 30 years ago (109). Both 0 t t t
naringin and neohesperidin dihydrochalcone were synthesized 0 2500 5000 7500 I0000
from bitter citrus flavonones and found to have sweet tastes. Concentration {ppm|
Neohesperidin has been extracted from Seville oranges and
converted to neohesperidin dihydrochalcone (109).
Response indicates sucrose sweetness equivalent in percent
SODIUM CYCLAMATE
(65).
Temporal properties:
Physical and Chemical
A bitter taste becomes noticeable as the concentration of
Chemical category: sulfamate cyclamate in the formulation approaches 0.507o (188). Sweet-
sodium cyclohexylsulfamate (188) ness of cyclamate builds more slowly to a maximal level and
SWEETENERS: STATE OF KNOWLEDGE REVIEW
persists longer than does that of sucrose (24). The taste of
cyclamate is very compatible with fruit flavors (24). The off-
tastes begin at a slightly lower concentration for calcium cycla-
mate than for sodium cyclamate (24).
Limits of Use
Dose restrictions:
The Expert Committee of Food Additives of F A O / W H O
established an ADI of 11 mg/kg body weight in 1985 (7).
The following table shows the results of laboratory tests to
determine the LDs0 of sodium cyclamate when dosed by differ-
ent routes to different animals.
animal route LDs0 (25)
mouse oral 10-17 g/kg
mouse intraperitoneal 7.1-12 g/kg
mouse intravenous 4-4.8 g/kg
rat oral 12-17.5 g/kg
rat intraperitoneal 6 g/kg
rat intravenous 3.5 g/kg
hamster oral 10-12 gm/kg
Cyclohexylamine, a metabolic product of cyclamates, has
an oral LDs0 of 156-614 mg/kg in rats; this metabolite is hence
more toxic than cyclamates and this toxicity limits the use of
the sweetener (24).
The EEC has developed a directive which specifies the ac-
ceptable maximum level of sweeteners that may be used as
food additives in ready-for-use commercial products to give
specific foods a sweet taste. For cyclamic acid and its sodium
and calcium salts, designated E 952 in this directive, the food
categories and levels are nonalcoholic drinks 400 mg/l, des-
serts 250 mg/kg, breakfast cereals 250 mg/kg, edible ices 400
mg/kg, fruit 1000 mg/kg, fruit preparations 250 mg/kg, con-
fectionery items 1000 mg/kg, sugar-free chewing gum 3000
mg/kg, bakery products 1700 mg/kg, alcoholic drinks 350
mg/1, and special diet formulas/supplements 400 and 1000
mg/kg (24). The EEC has designated a temporary ADI of 11
for cyclamate.
Physiological and toxicological effects:
Photosensitive dermatitis has been reported. Softening of
the stools and diarrhea are common side effects of cyclamate
ingestion; this laxative action is due to a change in the osmotic
activity of the unabsorbed fraction of cyclamate salts in the
gastrointestinal tract (24,25). Cyclohexylamine in the diet is
known to produce testicular atrophy, reduced body weight
gain, and hyperactivity in rats (24,45). It may also raise blood
pressure in susceptible individuals (24). A report issued by
a National Academy of Sciences National Research Council
Committee in 1985 concluded that cyclamate by itself is not
carcinogenic; however, cyclamate may be a co-carcinogen be-
cause cyclamate-saccharin mixtures increase the risk of blad-
der cancer (24,86,167). Also see the section on calcium cycla-
mate.
Current Use
Source(s):
Sodium cyclamate is synthetic.
Commercial products and concentration(s):
Sucaryl Sodium, Sucrosa, Assugrin
Frequency/advantages:
Sodium cyclamate can be used to mask the bitterness and
unpalatable tastes of drugs, especially liquid formulations and
337
chewable tablets (24). Cyclamates have a low solid content at
a desirable sweetness level which makes a suspension more
fluid and reduces caking. Cyclamate disintegrates rapidly in
tablet form (24).
The actual relative sweetness varies with pH and product
type. A mixture of cyclamate: saccharin in a ratio of 10:1
was popular during the 1960s. Mixtures of cyclamate and sac-
charin are synergistic and produce sweetness levels that are
10-20°70 higher than would be expected based on the levels of
the individual components (24). Patents have recently been
filed that indicate cyclamate has potential in combination with
other sweeteners, including aspartame and acesulfame-K (24).
Availability (manufacturers):
Abbott Laboratories
Numerous manufacturers in Korea
Regulatory status:
Sodium cyclamate is available as a table-top sweetener or
for use in foods and beverages in over 40 countries, including
Canada (24,25). It has been approved by the EEC Scientific
Committee for Food and by the Joint Expert Committee on
Food Additives of F A O / W H O . It has been allocated a tempo-
rary ADI of 11 mg/kg body weight. It is presently permitted
for use in Australia, New Zealand, Switzerland, Spain, and
Germany. It may not be used in any drugs, other than those
with approved new drug applications, or in any foods (includ-
ing beverages) that are intended for use in the United States
(242).
History
Sodium cyclamate was synthesized in 1937 by Sveda who
accidentally discovered that it has a sweet taste (8,25). Cycla-
mates were first introduced in tablet form as a table-top sweet-
ener for use by diabetics by Abbott Laboratories in the United
States in 1951 (24,25,45). After enactment of the Food Addi-
tive Amendment in 1958, sodium and calcium cyclamate were
classified as GRAS (Generally Regarded As Safe) by the US
FDA. Mixtures of cyclamate and saccharin (10: 1) subse-
quently became popular in the US during the 1960s (25). In
the UK, cyclamate was allowed in soft drinks under the 1964
Soft Drink Regulations (242).
In 1966, it was reported that cyclamates could be metabo-
lized by intestinal bacteria to cyclohexylamine (129). In 1968,
an interim report from the National Academy of Sciences
concluded from new animal studies that unrestricted use of
cyclamate was not warranted (86). Approval for its use was
withdrawn in the US when it was removed from the GRAS
list in 1969 (215). In 1970, a long-term study in rats was pub-
fished that reported an increased incidence of bladder tumors
compared to controls in animals fed mixtures of sodium cycla-
mate and sodium saccharin (10 : 1) and cyclohexylamine (179).
This finding led to the ban of cyclamates as a food additive in
many countries, including the US. In 1982, Abbott Labora-
tories repetitioned for approval for its use (215).
SODIUMSACCHARIN
Physical and Chemical
Chemical category: N-sulfonyl amide
1,2-benzisothiazol-3(2H)-one- 1,1-dioxide, Na salt (31);
2,3-dihydro-3-oxobenzisosulfonazole, Na salt (31);
dihydrate of sodium salt of 1,2 benzisothiazolin-3-one-l, 1-
dioxide (188)
Molecular formula: C~H4NNaO3S; C~H4NNaO3S •2H20
Molecular weight: 241.2 (188)
338 SCHIFFMAN AND GATLIN

Molecular structure: Limits of Use

Dose restrictions:
O In the US the FDA has recommended that dally intake
should not exceed 1 g (188). The 28th Report of the Joint
F A O / W H O Expert Committee on Food Additives gave an
e eNa estimated temporary acceptable ADI for saccharin, including
its calcium, potassium and sodium salts, of up to 2.5 mg/kg
body weight. In 1969, the ADI had been 15 mg/kg.
2 The EEC has proposed a directive which specifies the ac-
ceptable maximum level of sweeteners that may be used as
food additives to give specific foods a sweet taste. For saccha-
Solubility: rin and its No, K, and Ca salts, label designation E 954, these
1 g / l . 2 ml water (31) foods and levels are nonalcoholic drinks 80 mg/1, desserts 100
1 g/50 ml alcohol (31) mg/kg, breakfast cereals 100mg/kg, edible ices 100 mg/kg,
Stability (pH, heat): fruit 100-200 mg/kg, confectionery items 200-1200 mg/kg,
Solutions of sodium saccharin are stable to pasteurization bakery products 170 mg/kg, fish 160 mg/kg, vegetables 160
but will undergo temperature-dependent, slow hydrolysis at mg/kg, alcoholic drinks 80 mg/l, sauces 100-320 mg/kg, and
low pH (242). The hydrolysis products are 2-sulfobenzoic acid special diet items 80-500mg/kg (46).
and 2-sul famoylbenzoic acid (161 ). Physiological and toxicological effects:
Degradation route, in vivo: Sodium saccharin has low acute toxicity: LDs0 (oral rat)
Saccharin is readily absorbed from the gastrointestinal = 14,200 mg/kg. High dose rat studies in a sensitive strain
tract with almost all being excreted unchanged in the urine have suggested adverse effects including bladder cancer. How-
within 24-48 h (188). Because it is not metabolized, it provides ever, a review panel which studied the safety issues related to
no calories. saccharin in 1983 concluded that the biochemical and physio-
Known incompatabilities: logical changes, including bladder tumors, which occur in rat
Saccharin is compatible with other soft-drink components at high doses do not occur in humans under normal patterns
(242). of use. A large bioassay conducted by the International Re-
search Development Corporation (IRDC) in Mattawan, MI
Sweetness found that in rat, the lowest statistically significant incidence
Potency: Pw2 = 510, Pw5 = 444, PwTs = 247 where Pw2, of bladder tumors was at 3070 of the rats diet (equivalent to
Pws, and Pw75 are the potencies in water at a sweetness equiva- 750 cans of soft drink per day over a lifetime). The tumors in
lent to 2070 sucrose, 5% sucrose, and 7.5070 sucrose, respec- rat appear to be species- and organ-specific (161). Epidemio-
ttvely (65). logic studies in diabetics support these findings. No increased
Typical concentration (range): risk of cancer (including bladder cancers) has been found in
diabetics who consumed saccharin for extended periods (161).
Sodium Saccharin Saccharin is noncariogenic (242).
15'
Current Use

~ 10'

5'
Source(s): synthetic
Toluene is treated with chlorosulfonic acid which yields
the ortho- and para-toluenesulfonyl chlorides. Upon further
treatment with ammonia, the corresponding toluenesulfon-

0;"
..t! t amides are formed. The ortho form is separated from the para
0 250 500 750 1000
Concentration (ppm)
Response indicates sucrose sweetness equivalent in percent
(65).
Temporal properties:
A bitter, metallic, and astringent aftertaste is detectable by
about 25070 of the population in products with a saccharin
concentration over 0.01070. This aftertaste increases at higher
concentrations. This characteristic taste is inherent in the sac-
charin molecule and not attributable to impurities. Various
additives have been used in an attempt to mask this aftertaste,
including sucrose, lactose, and tartrates. Saccharin has been
combined most successfully with other high-potency sweeten-
ers and with sugar substitutes. Examples are saccharin with
cyclamate 1 : 10, saccharin with fructose 0.75 : 100, and sac-
charin with aspartame 1 : 1 (7,242). The temporal profile of
saccharin is similar to sucrose. The AT (appearance time) is 4
s and the ET (extinction time) is 14 s (126).
form and is oxidized to ortho-sulfamoylbenzoic acid which
cyclizes to saccharin when heated (161).
Commercial products and concentration(s):
Saccharin Sodium Tablets (U.S.P.)
Saccharin Sodium Oral Solution (U.S.P.)
Saccharin Solution (B.P.C. 1954)
Saccharin Tablets (B.P.C. 1973)
According to the EC guidelines of 1991, saccharin is per-
mitted for use in nonalcoholic beverages, desserts, breakfast
cereals, ice cream, fruits, confectioneries, bakery products,
and alcoholic beverages. Approved maximum limits are 50
ppm in nonalcoholic beverages comparable to a sweetness pro-
vided by 2°70 sucrose and 100 ppm in desserts to compare to
sweetness provided by 307o sucrose (173).
Frequency/advantages:
Sodium saccharin is most commonly used in soft drinks,
dessert mixes, yogurt, and as a table-top sweetener.
Availability (manufacturers):
Various brand names and manufacturers in France
Cumberland Packing Corp. (US)
PCM Spec (Ohio)
SWEETENERS: STATE OF KNOWLEDGE REVIEW
Regulatory status: see History.
History
Saccharin was accidentally synthesized by the American
chemist Constantine Fahlberg, and its potential as a sweeten-
ing agent was rapidly utilized commercially (see Ref. 160 for
a review of history).
Saccharin, as well as the sodium and calcium salts of sac-
charin, were first listed as GRAS in 1959; ammonium saccha-
rin was added in 1961. In 1972, the F D A removed saccharin
and its salts from the GRAS list based on questions of safety
raised by the Wisconsin Alumni Research Foundation (WARF)
study (228). However, continued food use was regulated under
an interim food additive regulation (see Ref. 86 for review.)
In 1977, the F D A proposed revocation of the interim food
additive regulation and recommended a ban on saccharin use
except as a nonprescription, single-ingredient drug, because
there was evidence that is was a weak carcinogen producing
bladder tumors in rats (6). The proposed ban was based on the
Delaney Anticancer Clause which specifies that a carcinogenic
food additive cannot be found as safe under the 1958 Food
Additives Amendment to the 1938 Federal Food, Drug, and
Cosmetic Act passed by Congress (see Ref. 25 for review).
Congress intervened and passed the Saccharin Study and La-
beling Act (SSLA) (231), which prohibited the FDA from ban-
ning saccharin for use in food, drugs, or cosmetics for 18 too.
SSLA directed further study of toxicity and carcinogenicity of
saccharin by the Secretary of the Department of Health and
Human Services (DHHS). In addition, it was stipulated that the
following warning statement must appear on the label of food
products: "USE OF THIS PRODUCT MAY BE HAZARD-
OUS TO YOUR HEALTH. THIS PRODUCT CONTAINS
SACCHARIN W H I C H HAS BEEN DETERMINED TO
CAUSE CANCER IN LABORATORY A N I M A L S . " The
SSLA has been extended four times since it was passed in
1977.
SORBITOL
Physical and Chemical
Chemical category: carbohydrate
Molecular formula: C6HI406 (188)
Molecular weight: 182.2 (188)
Molecular structure:
CH2OH
- -OH
HO--
- -OH
m-OH
CH2OH
Solubility: Sorbitol is very soluble in water:
235 g/100 g water at 25°C (67)
220 g/100 g water at 20°C (19)
It is more soluble than sucrose in water (1 I).
It is slightly soluble in acetic acid, alcohol and methylalco-
hol (188).
Stability (pH, heat):
Sorbitol is very hygroscopic. It is stable at high tempera-
339
tures with a melting point of 96-97°C (67). It is stable to
sterilization by autoclaving (188). Sorbitol is more heat stable
than the corresponding mono- and disaccharides and is more
resistant to microbial degradation than the sugars (67). It does
not caramelize due to the absence of free carbonyl groups
(67).
Degradation route, in vivo:
Sorbitol is slowly absorbed from the gastrointestinal tract
by passive diffusion. Part is oxidized, mainly in the liver, to
fructose, catalyzed by sorbitol dehydrogenase (67,188,245).
The fructose is then converted to fructose-l-phosphate, cata-
lyzed by fructokinase in a step that is not dependent on or
regulated by insulin. The fructose-l-phosphate is metabolized
in the liver to dihydroxyacetone phosphate and glyceralde-
hyde. The dihydroxyacetone phosphate is metabolized either
to pyruvate or to glucose and glycogen, depending on the
metabolic state of the person (67). Some sorbitol can undergo
direct conversion to glucose in the presence of the enzyme
aldose reductase (67,245). The portion that reaches the distal
intestine is partially or completely fermented by the intestinal
flora to short-chain volatile fatty acids which are then ab-
sorbed from the gut and metabolized (245). The presence of
sorbitol in the small intestine can result in osmotic diarrhea,
especially in large amounts.
Sweetness
Potency: P.5 = 0.82, P.1o = 0.53, where P.5, and P.1o are
the potencies in water at a sweetness equivalent to 3% sucrose,
5070 sucrose, and 10°7o sucrose, respectively.
Typical concentration (range):
Sorbitol is used as a vehicle for oral and topical liquids at
25-90070 and as a diluent for injectables below 10-25°70 (188).
In a recent survey of excipients in 91 pharmaceutic antibi-
otic preparations, sorbitol was found to be used in 7.7070. It
was present as the single sweetener or in combination with
sucrose a n d / o r saccharin in the liquid formulations of five
antibiotics. Information on quantities of sweeteners is not
readily available, but a search by Hill et al. (104) indicated use
of sorbitol in the following ratio: sucrose : sorbitol : saccharin
500 : 70 : 1 in sulfamethoxazole 200 mg-trimethoprim 40 mg/
5ml combination suspension (104). Sorbitol was also a sweet-
ener in liquid respiratory preparations, iron supplementation
liquids, and an H2-receptor antagonist liquid, either alone
or in combination with sucrose, saccharin, or invert sugar.
Quantity levels revealed diverse ratios: sorbitol:saccharin
400 : 1, 133 : 1,867 : 1, and 140 : 1; with sucrose : sorbitol the
ratios were 3.2 : 1, 1.2 : 1, and 8.6 : 1 with various drug entities
(104).
Sorbltol
18,
16 ~
14"
12"
10"
6
4
1o 20 3o ,'o
Concentration (%)
340
Response indicates sucrose sweetness equivalent in percent.
Limits of Use
Dose restrictions:
Sorbitol has a designation of GRAS, generally regarded as
safe, by the US FDA. If consumption of a sorbitol-containing
food is likely to result in daily ingestion of more than 50 g,
the label must contain the statement "Excess consumption
may have a laxative effect" (60).
Sorbitol may be used in food at levels not to exceed Good
Manufacturing Practices, which currently have the following
maximum levels: 99o7o for hard candy and cough drops, 75o70
for chewing gum, 980-/0 for soft candy, 300-/0 for jams and
jellies (nonstandardized), 170-/0 for baked goods and baking
mixes, and 120-/0for other foods (67).
The EEC has proposed a directive that specifies the accept-
able maximum level of sweeteners that may be used as food
additives to give specific foods a sweet taste. Sorbitol, desig-
nated E 420, may be used in all foodstuffs, excluding water-
based flavoured nonalcoholic drinks, at a maximum level of
quantum satis (46). It has become increasingly accepted that
sugar alcohols have a lower caloric value than sucrose and
glucose due to their incomplete absorption and metabolism.
A caloric value of 2.4 kcal/g was allocated for all sugar alco-
hols in a recent Directive of the Council of the European
Community (10).
Physiological and toxicological effects:
Studies show that sorbitol can increase the absorption of
minerals from the intestinal tract, specifically calcium and
iron. Mechanisms of action and clinical significance of such
effects require further study (60).
Sorbitol has been tested in multigenerational studies in
rats, mice, hamsters, and rabbits and no teratogenic or micro-
scopic abnormalities were found (245).
There is disagreement on the advisability of dietary substi-
tution of sorbitol for sucrose and other quickly absorbed car-
bohydrates in the diabetic patient. Opponents argue that sor-
bitol is capable of being converted to glucose and eventually
requires insulin for its metabolism. Also, the accumulation of
sorbitol intracellularly causes local edema and contributes to
the development of diabetic complications, such as cataracts
and polyneuritis. The proponents' research indicates that, al-
though glucose is produced in sorbitol metabolism, there is
such a delay that hyperglycemia is insignificant compared to
the metabolism of other carbohydrates (67).
Current Use
Source(s): natural
Sorbitol is found in significant amounts in many fruits
such as cherries and other stone fruits, (67,79) but it is not
economically feasible to extract sorbitol commercially.
Sorbitol is prepared commercially by hydrogenation of glu-
cose at high hydrogen pressure (70-140 atm) at 120-160°C
with Raney nickel as a catalyst (67). When sucrose is the raw
material, sorbitol (75°/o) and mannitol (250"/0) are produced
simultaneously by the hydrogenation of the invert sugar (67).
Commercial products and concentration(s):
Sorbitol Solution (U.S.P.) an aqueous solution containing
not less than 64070 w/w of sorbitol (188)
Sorbitol intravenous infusion (B.P.) Sorbitol injection. A
sterile solution of sorbitol for parenteral use in water for injec-
tion.
SCHIFFMAN AND GATLIN
Sorbitol Solution 70% (B.P.)
Frequency/advantages:
Sorbitol is used extensively in food, primarily baked goods,
frozen dairy products, soft candy and chewing gum as a bulk
sweetening agent and for its humectant properties as a sof-
tener and texturizer. It is used in combination with saccharin
to decrease the bitter taste of the latter. Sorbitol is a sugar
substitute in food items for diabetics (188).
Sorbitol is used as an excipient in pharmaceutical prepara-
tions for its unreactive nature (e.g., with amino acids), nonfer-
mentability, lower cariogenicity and viscosity (19).
There is interest in the use of sorbitol as a sweetener in
dentifrice products because it is much less cariogenic than
sucrose due to its slow fermentation by oral microorganisms.
This results in lower acidity of the plaque melieu that dissolves
dental enamel calcium and phosphate, which eventually re-
sults in cavities (19,60,245). There also may be decreased ad-
hesiveness of the microbial cells due to decreased formation
of insoluble glucans that contribute to the matrix of microor-
ganisms (60).
Availability (manufacturers):
Numerous international sources under proprietary names
Regulatory status:
Sorbitol has a designation of GRAS by the US FDA.
The Joint Expert Committee on Food Additives designated
an ADI of "not specified" in 1982 (10).
Sorbitol is permitted in various countries with some legisla-
tive or regulatory limitations. It is listed as a permitted sweet-
ener in Japan, South Africa, Sweden, and the United States.
It is not listed as a sweetener but is permitted, except when
standard prohibits use, in UK and Federal Republic of Ger-
many. It is listed as a sweetener but permitted only in certain
foodstuffs in Belgium, Denmark, Australia, Finland, Greece,
Norway, Spain, and Switzerland. It is listed as a food additive
only in France, Italy, Netherlands, Brazil, and Canada, and is
not described in Austria (67).
History
Sorbitol was first isolated in 1872 from the berries of the
mountain ash tree by French chemist Joseph Brussingault.
Sorbitol is widely distributed in nature (67). Originally listed
as GRAS in 1959, sorbitol was used at a maximum level of
7°-/0 in foods for special dietary use. In 1961 its category of
use was changed to nutrient and /or dietary supplement. It
was also regulated as a food additive for use as a stabilizer
and nutrient sweetener with a maximum of 15 g/serving or 40
g/day; labeling was required to warn of laxative effects at
higher intake (86). After comprehensive safety review by the
Select Committee on GRAS Substances in 1974, the FDA af-
firmed sorbitol as GRAS for a large number of technical ef-
fects and specified maximum levels in various foods (86).
STEVIOSIDE
Physical and Chem:cal
Chemical category: diterpene glycoside
13 - [(2 - O-/3 - D glucopyranosyl- c~- D- glucopyranosyl)oxy]
-
kaur- 16-en- 18-oic acid/3-D-glucopyranosyl ester (31)
Molecular formula: C38 H~o O~8
Molecular weight: 804.9
SWEETENERS: STATE OF KNOWLEDGE REVIEW 341

Molecular structure: similar to sucrose (4 s); however, the extinction time (ET) is
22 s which is far greater than the ET for sucrose which is 14 s
(126). Stevioside also exhibits some bitterness (128). Stevioside
is synergistic with glycyrrhizin, aspartame, calcium cyclamate,
and acesulfame-K (128),

Limits o f Use
Physiological and toxicological effects:
There has been a long history of exposure to Stevia rebau-
diana in Paraguay. However, a related compound, steviol, the

~ =CM~I
O~ ~,0
Solubility:
Sparingly soluble in water, 9300 ppm in water (72). Slightly
soluble in alcohol (31).
Stability (pH, heat):
Stevioside is stable at 100°C when maintained in solution
at pH ranging from 3 to 9. It decomposes at pH values of 10
and greater (128).
Degradation route, in vivo:
In rat, most of an orally administered dose of stevioside is
degraded by intestinal flora to steviol, steviobioside and glu-
cose which are then absorbed in the cecum. Glucose is then
metabolized and excreted as CO2 and water. Steviol is conju-
gated in the liver and excreted in the bile. Stevioside is also
excreted unchanged in the feces (128). Metabolism in humans
has not been investigated to date (128).
aglycone obtained on enzymatic hydrolysis of stevioside, has
raised safety concerns even though no data exists that steviol
is produced in vivo in humans. Steviol is an inhibitor of oxida-
tive phosphorylation and is mutagenic following activation
with liver microsomes (126). Steviol has been shown to be a
by-product of stevioside in metabolic studies in the rat (128).
Rodents dosed with Stevia rebaudiana extracts also exhibit
reduced spermatogenesis, medullary cell proliferation in the
adrenal glands, inflammatory lesions in the trachea and lungs,
and pigmentation and increased hematogenesis of the spleen
(128). It may also have hypotensive effects.
Current Use
Source(s): natural, extracted from the leaves of yerba
dulce, Stevia rebaudiana
SUCRALOSE
Physical and Chemical
Chemical category: carbohydrate
1,6-dichloro-1,6-dideoxy-/3-D-fructo fur anosyl-4-chloro-4-de-
oxy-(x-D-galactopyranoside(3 I)
l',4,6'-trichlorogalactosucrose (3 I)
Molecular formula: CI2I-IIgCI3Os(31)
Molecular weight: 397.64 (31)
Molecular structure:

Sweetness CH = OH
CH zCl O H
Potency: Pw2 = 193, P,5 = 120, P,75 = 59, where Pw2,
Pws, and P,75 are the potencies in water at a sweetness equiva-
lent to 2070 sucrose, 5°70 sucrose, and 7.5°70 sucrose, respec- I I O I ]
tively (65). H OH OH H
Typical concentration (range):
Solubility:
The solubility of sucralose in water ranges from 28.3 g/100
15"
Stevioslde rnl at 20°C to 66 g/100 ml at 60°C. Its solubility in ethanol
ranges from 9.5 g/100 ml at 2°C to 18.9 g/100 ml at 60°C (159).

~ 10"

5'
Stability (pH, heat):
Sucralose is stable in aqueous solutions with no measurable
loss after one year of storage at pH 4.0, 6.0, and 7.5. At pH
3.0, there is less than 4°70 loss of sucralose after one year of
storage. Sucrnlose is not susceptible to enzymatic hydrolysis
(215). Sucralose is more stable to heat and acid than sugar, and
0 does not break down under high heat conditions used for baked
0 500 I000 xs'oo goods (107).
Concentration Ippm) Degradalion route, in vivo:
Sucralose does not hydrolyze or dechlorinate following inges-
tion in human, rat, mouse, dog, or rabbit (159). It does not
Response indicates sucrose sweetness equivalent in percent provide any calories (18).
(65). Known ineompatabilities:
Temporal properties: Sucralose has a good compatibility prof'de (242). The reactiv-
The AT (appearance time) for stevioside is 6 s which is ity of sucralose as a 1.0070 solution was evaluated with 0.1070
342
concentrations of niacinamide, monosodium glutamate, hydro-
gen peroxide, sodium metabisulfite, acetaldehyde, ethyl acet-
oacetate, or ferric chloride. The resulting data demonstrate that
sucralose is relatively inactive chemically. Interactions between
sucralose and any other food components are unlikely (159).
Sweetness
Potency: Pw2 = 614, P,5 = 636, P , t0 = 385 where Pw2, Pws,
and Pwt0 are the potencies in water at a sweetness equivalent to
2070 sucrose, 50/0 sucrose, and 10°70 sucrose, respectively (65).
Typical concentration (range)
Typical use levels range from 50 to 2000 ppm.
Sucralose
157
g pings, and syrups (155).
I0
5 Availability (manufacturers):
0 ---- -'" =1
I
- .
&
-
0 250 500 750 1000
Coneealtrat/on (ppm)
Response indicates sucrose sweetness equivalent in percent
(65).
Temporal properties:
Sucralose has a good quality sweetness with no unpleasant
aftertaste (8,242). The sweetness time/intensity profile indicates
that sucralose has a slower rate of sweetness decay than sucrose
(159). The temporal properties of sweetness, onset, and lingering
are similar to those of aspartame (158).
Limits of Use
Dose restrictions: not yet determined
Taste saturation: The sweetness of sucralose does not increase
beyond 16070 sucrose (65).
Physiological and toxicological effects:
Sucralose is not acutely toxic, with an LDso > 16 g/kg in
mice and > 10 g/kg in the rat. It has no known mutagenic,
teratogenic, carcinogenic, or neurotoxic activity and has no
known effect on reproductive performance. No adverse effects
applicable to man were observed in long-term sucralose studies
in the mouse, the rat, and the dog at dose levels which are 700
(rat) and 400 (dog) times, respectively, the projected maximal
mean dally human consumption of sucralose. However, under
slow breakdown which can occur especially at low pH (4070 per
year), two monosaccharides are produced. One (l,6-dichloro-
1,6-dideoxyfructose) is mutagenic in in vitro assays and cova-
lently attaches to tissue macromolecules including DNA. The
projected maximal mean daily human intake of sucralose is 100
mg or 2.3 mg/kg at the 90th percentile of projected intake level
(92). Sucralose is also noncariogeuic (159).
The WHO JECFA recommended a temporary ADI level of
0-15 mg/kg/day in June 1990 (88).
Current Use
Source(s):
Sucralose is synthesized from sucrose by replacement of three
hydroxyl groups with chlorine atoms at the 4-,1 '- and 6 ' - posi-
tions (the 4-position on the galactose moiety and the 1- and 6-
S C H I F F M A N AND GATLIN
position on the fructose moiety) (159). This is achieved as fol-
lows: First, the primary alcohols of sucrose are blocked with
trityl chloride and the remaining alcohol groups are protected
with acetate. Next, the trityl protecting groups are removed and
an acetate group is caused to migrate from the 4-position to the
6-position. Then the exposed alcohol groups are chlorinated.
Finally, synthesis of sucralose is achieved by removal of the
acetate groups (158).
Commercial products and concentration(s):
The Food Additive Petition submitted to the US FDA by
McNeil Specialty Products Co. in 1987 was for the following
application categories: baked goods and baking mixes, beverages
and beverage bases, chewing gum, coffee and tea, confections
and frostings, dairy products analogs, fats and oils (salad dress-
ings), frozen dairy desserts and mixes, fruits and water ices,
gelatins and puddings, jams and jellies, milk products, processed
fruits and fruit juices, sugar substitutes, and sweet sauces, top-
Frequency/advantages:
Sucralose is not currently approved in the US. It is approved
in Canada and is used as a table-top sweetener.
Redpath Specialty Products, Toronto, Canada
McNeil Specialty Products, Inc. a subsidiary of Johnson &
Johnson, New Brunswick, New Jersey, USA Vending approval
in the US and currently marketed as Splenda 'M in Canada)
Tate and Lyle PLC, London, UK (pending approval)
Regulatory status:
Sucralose is currently not approved by the FDA, but the Food
Additive Petition was filed in 1987. The F A O / W H O JECFA
granted an ADI of 15 mg/kg/day in June 1990 (88). Sucralose
was approved by the Health Protection Branch in Canada with
permission for use in 13 categories as of September 1991. The EEC
lists sucralose as not toxicologicallyacceptable (159).
History
During the 1970s, a program to develop new chemical enti-
ties from sugar was established at T a t e & Lyle. During this
program, it was found that selective halogenation of sucrose
greatly enhanced sweetness potency (110). Of the halogenated
sugars, sucralose (1,6 - dichioro - 1 , 6 - dideoxy-/3- D - fructofur-
anosyl-4-chloro-4-deoxy-t~-D-galactopyranoside)was ultimately
selected for development and commercialization.
SUCROSE
Physical and Chemical
Chemical category: carbohydrate
Molecular formula: C,2H2201~
Molecular weight: 342.3 (31)
Molecular structure:
c oH
2OH
I-I OH OHi-I
Solubility:
1 g/0.5 ml water at 25°C (31,188)
Can be prepared as unsaturated, saturated and supersatu-
rated solutions
SWEETENERS: STATE OF KNOWLEDGE REVIEW 343

Stability (pH, heat): Current Use

Sucrose has good stability at room temperature and moder-
ate relative humidity. It absorbs up to 1070 moisture which
makes its subject to microbial attack. Sucrose has a melting
point of 186°C. Dry sugar melts when heated above 160°C,
resulting in caramelization.
Degradation route, in vivo:
Sucrose is hydrolyzed in the small intestine by sucrase to
glucose and fructose, which are then absorbed; sucrose is ex-
creted unchanged in the urine when given intravenously (188).
Known incompatabilities:
Potential contaminant trace heavy metals are incompatibile
with ascorbic acid; contamination with sulfite can cause color
changes in coated tablets when the sucrose is used as an excip-
ient.
Sweetness
Typical concentration (range):
Cola-type beverages are sweetened to approximately 10070
sucrose (242). The response curve is linear by definition within
the concentration limit of 15070(65).
Sucrose
15'
I0' ~o
ig
5'
0 is strongly dependent on concentration, pH, and temperature (99).
0 5 I0 15
Concentration (%)
Response indicates sucrose sweetness equivalent in percent
(65).
Temporal properties:
Sucrose is used as the comparison standard for expert taste
panels. Sucrose is described as having a pure, clean sweetness
with few perceived secondary attributes, such as bitterness and
astringency. Its sweetness time-intensity profile indicates a
quick perception of sweetness and a sharp cut-off, (230) with
an appearance time (AT) of 4 s and an extinction time (ET) of
14 s (126).
Limits of Use
Source(s): natural
For commercial quantities, sucrose is extracted from sugar
cane and sugar beets. It is used as a sweetening agent and
demulcent, lozenge base, tablet coating, and for syrup solu-
tions.
Commercial products and concentration(s):
Syrup (U.S.N.F.) sucrose 85070 w/v in water
THAUMATIN
Physical and Chemical
Chemical category: several distinct proteins
Molecular formula: protein
Molecular weight: T~ = 22,209 (99), T2 = 22,293
Molecular structure: protein
Solubility:
Thaumatin is extremely soluble in water. It has good solu-
bility in aqueous alcohols, propylene glycol and in higher alco-
hols such as sorbitol (99).
Stability (pH, heat):
The Talin protein (thaumatin) molecule is most stable to
heat between pH 2.7 and 6.0, with an optimum around 2.8-
3.0. At higher pH values, Talin protein becomes less stable to
heat but at ambient temperatures is stable at pH up to 8-9.
It can be pasteurized or sterilized at ultrahigh temperatures.
Because Talin protein stability is enhanced at lower pH levels,
it can be heated at 100 ° for several hours without sweetness
loss, thus making it suitable for typical soft drinks, which
have pH2.8 -3.5 (99).
Known incompatabilities: The thaumatin molecule has an
overall positive ionic charge that allows it to form salts or polymers
with suitably shaped, negatively charged ingredients such as food
gums and synthetic colors. This interaction can result in molecular
aggregation, dimerization, polymerization, reduction in sweet
taste or actual precipitation. The thaumatin molecule can ionically
bond to synthetic colors having sulfonate groups; the interaction
Research efforts to make thaumatin more compatible have re-
sulted in co-drying thaumatin with 6-20 parts of gum arabic or
other weakly acidic polymer. The resulting bulkier product also
has the added advantage of being denser and more easily handled
and mixed (99).
Sweetness
Potency: Pw2 = 22,500, Pw5 = 14,200, Pw75 = 278 where
Pw2 is the potency in water at a sweetness equivalent to 2070
sucrose, Pw5 equivalent to 5070 sucrose and Pw75 equivalent to
7.5070 sucrose (65).
Typical concentration (range):
Thaumatln
15"

Dose restrictions:
Sucrose must be administered with care to diabetics. The
~ I0" X

I
_

primary health concerns with the ingestion of sucrose are ex-

cessive calories and tooth decay. Sucrose is also contraindi-
cated in patients with fructose intolerance, glucose-galactose
malabsorption syndrome, or sucrase-isomaltase deficiency.
Physiological and toxicological effects:
0
0
n** I.
20
I
4O 6O
t
LDs0 is 35 + 7 g/kg males and 29.7 g/kg in females Concentration {ppm)
344 S C H I F F M A N AND GATLIN

Response indicates sucrose sweetness equivalent in percent seeds inside the fruit was known by natives for many centu-
(65). ries; it was used before sugar cane was introduced into West
Temporal properties: Africa (99).
Talin's flavor profile indicates a delay in perceiving the
XYLITOL
sweetness, a slow buildup to maximum intensity, and a long,
lingering sweet aftertaste without any unpleasant aftertaste
Physical and Chemical
(99).
Chemical category: carbohydrate
Limits of Use
Molecular formula: C5I-II205
Dose restrictions: Thaumatin was assigned an ADI of "not Molecular weight: 152.15 (31)
specified" in the 29th Report of the Joint F A O / W H O Expert
Molecular structure:
Committee on Food Additives in 1986.
CH2OH
Current Use

Source(s):
Thaumatin is a natural product from the fruit of Thauma-
tococcus daniellii, a plant that grows abundantly in the rain
forest belt of West Africa, primarily in Ghana, Ivory Coast,
Togo, and Sierra Leone. After the fruit is collected, the arils
are removed, frozen and transported to the UK for processing.
The details of the extraction and purification process are pro-
prietary, but basically, a solely aqueous extraction process
using filtration and ultrafiltration are used (99).
The Unilever Research Laboratorium of The Netherlands
has undertaken to produce Talin protein or its constituent
proteins through genetic engineering. They have two patents
for the recombinant DNA production of thaumatin and pre-
prothaumatin. This technology is not yet applicable to pro-
duction quantities (99).
Commercial products and concentration(s): Used in chew-
ing gum in the US and Europe.
Availability (manufacturers): Trade name: Talin
Regulatory status:
Talin has been permitted as a natural protein in Japan since
1979, with recommended codes of practice and specification/
analysis published by the Japanese Food Additive Federation.
A petition for its use in medicines is under consideration.
In the UK, the Talin protein has been listed as a safe excipi-
ent in medicines when accompanied by the appropriate prod-
uct license as determined by the UK Committee on the Safety
of Medicines in 1981. In 1982 the Food Additive and Contami-
nants Committee agreed to regulate Talin protein as a sweet-
ener. The Sweeteners in Food Regulations took effect in 1983
permitting the use of Talin protein in foods, drinks, and di-
etary products with the sole exception of baby foods (99). In
the United States the Flavor Extract Manufacturers Associa-
tion (FEMA) has designated Talin protein as GRAS (generally
regarded as safe) as a flavor adjunct in chewing gum (99).
The F A O / W H O JECFA set specifications in 1983; in 1985
they agreed it was safe for food use and designated at ADI of
"not specified" in its 29th Report. Petitions are pending in
various other countries for use of Talin protein as a flavor
enhancer and sweetener.
History
The sweetness of the red, pyramid-shaped fruit of the trop-
ical plant was first described in the literature by British physi-
cian-amateur botanist W.F. Daniell in 1855. John Joseph Ben-
nett, F.R.S. first classified the plant as from the species
Phrynium danielli but it was later classified as Thaumatococ-
cus. No doubt the extreme sweetness of the fleshy top to the
----Oil
HO---
- -- OH
CH2OH
Solubility:
169 g/100 g water (11)
1.2 g/100 g ethanol solution (31)
Less soluble than sucrose (11).
Stability (pH, heat):
Stable at 120 ° and under normal food processing condi-
tions with no caramelization, caramelization occurs if heated
for several minutes near boiling point of 216°C (760 mmHg)
(11).
Degradation route, in vivo:
Xylitol, like other polyols, is slowly absorbed from the
intestine because there is no specific transport system for facil-
itated transport. After ingestion, approximately one-third of
the ingested portion of xylitol is absorbed and enters the liver,
where it is metabolized via the glucuronate-pentose phosphate
cycle. The remainder of xylitol reaches the distal gut where it
undergoes indirect metabolism via extensive fermentation by
intestinal flora, yielding gas (H2, CH4, and COz) plus short-
chain volatile fatty acids which are subsequently absorbed
from the gut. In the liver, xylitol is converted to D-xylulose
and then to fructose-6-phosphate without requiring insulin;
insulin is necessary for utilization and storage of the glucose
formed from further metabolism (11,188).
Known incompatabilities:
Xylitol cannot be used in products requiring yeast as a
leavening agent because it inhibits growth and fermentative
properties of yeast (1 I).
Sweetness
Potency: Pw5 = 0.97, PwJo = 0.77, where Pws, and Pw~0are
the potencies in water at a sweetness equivalent to 507o sucrose,
and 10°7o sucrose, respectively.
Relative:
Xylitol is considered to he isosweet with sucrose (11). All
other sugar alcohols are less sweet than sucrose.
Typical concentration (range):
SWEETENERS: STATE OF KNOWLEDGE REVIEW
Xylitol has been used in an aspartame:xylitol mixture
2.4 : 97.6 to provide a taste more like that of sucrose and to
improve the stability of aspartame (7).
Xylitol
18'
16,
14,
12'
10,
8 ely such as chewing gum, candies, chocolate and gum drops,
6
4 tablets, cough syrup, and toothpaste (1 I).
2 Eutrit, Klinit, and Kylit all are products in Japan.
0
o 5 i"0 I~ 20 25
Concentration (%)
Response indicates sucrose sweetness equivalent in percent.
Temporal properties:
There is a cooling effect when crystalline xylitol is dissolved
in the mouth because there is loss of heat when sugar alcohols
are dissolved in water. This cooling effect is not perceived in
products in which xylitol is already dissolved (11). Xylitol has
a lower viscosity than maltitol (11).
Limits of Use
Dose restrictions:
Doses larger than 50 g can cause osmotic diarrhea (249).
Physiological and toxicological effects:
There is the suggestion that sugar alcohols have a lower
caloric value than sucrose and glucose due to their incomplete
absorption and metabolism. A caloric value of 2.4 kcal/g was
allocated for all sugar alcohols in a recent Directive of the
Council of the European Community (l 0).
Xylitol is not fermented by most oral microorganisms and
plaque pH is not reduced upon exposure to xylitol (11). Xylitol
is generally considered noncariogenic and may be anticario-
genic. Under certain conditions, it reduces the cariogenic po-
tential of sucrose (60). The possible anticariogenic effects are
produced by several processes, including inhibition of acid
formation from glucose by Steptococcus mutans (I 1).
Xylitol taken orally does not increase blood glucose or insulin
levels, probably because conversion of xylitol to glucose is very
slow (11). It may effect mineral absorption and utilization (60).
Xylitol has been found to have low acute toxicity by all
routes of administration. It is not embryotoxic, teratogenic,
mutagenic, or clastogenic (11).
345
Current Use
Source(s):
Xylitol is produced synthetically by chemical conversion of
xylan which has been extracted from birchwood, almond
shells, straw, corn cobs, or wastes from the pulp and paper
industries. Xylan is first hydrolyzed to xylose which is then
hydrogenated to xylitol in the presence of a nickel catalyst
(11).
Commercial products and concentration(s):
Xylitol is used as a sweetener in noncariogenic confection-
and in foods for diabetics. It is also used in pharmaceutical
preparations, including tablets, throat lozenges, multivitamin
Frequency/advantages:
Xylitol is more chemically inert than sucrose and thus phar-
maceutical preparations made with xylitol have good shelf life
because they neither ferment nor mold. Xylitol is a good car-
rier for tablets because of its low melting point (92-96°C).
Solid dispersions of some drugs with xylitol showed a faster
release than micronized drugs. Xylitol is also used in paren-
teral nutrition because it has little effect on insulin and thus
does not suppress lipolysis (11).
Availability (manufacturers):
Xylitol Injection (Jap.P) a sterile solution of xylitol in Wa-
ter for Injection
Xylotin Company
Regulatory status:
The JECFA assigned an ADI of "not specified" in its 27th
report in 1983. This is a favorable designation. The proposed
directive from the EEC specifies acceptable maximum levels
of sweeteners that may be used as food additives to give spe-
cific foods a sweet taste. For xylitol, label designation E 967,
the proposed level is quantum satis (46). In the United States,
it is approved as a food additive for special dietary or nutri-
tional uses as long as the amount used does not exceed that
needed to produce the intended effect (60). It is approved
for pharmaceutical use in many countries, including Austria,
Canada, Denmark, Germany, Italy, Norway, Portugal,
Spain, Japan, and Switzerland. However, it is not approved
for pharmaceutical use in the US or UK (11).
History
Xylitol is found naturally in small amounts in a variety
of fruits and vegetables. It is also formed naturally in the
body as an intermediate in glucose metabolism through the
glucuronate cycle in the liver (11,31). It was first syn-
thesized and described by Emil Fischer and his associates in
1891 (11).