The aspartame story: a model for the clinical

testing of a food additive”2

Lewis D Stegink, PhD

ABSTRACT Toxicology is based on the premise that all compounds are toxic at some dose.
Thus, it is not surprising that very large doses of aspartame (or its components-aspartate,

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
phenylalanine, and methanol) produce deleterious effects in sensitive animal species. The critical
question is whether aspartame ingestion is potentially harmful to humans at normal use and
potential abuse levels. This paper reviews clinical studies testing the effects of various doses of
aspartame upon blood levels of aspartate, phenylalanine, and methanol. These studies dern-
onstrate that blood levels of these compounds are well below levels associated with adverse
effects in sensitive animal species. Am J C/in Nutr l987;46:204-15.

KEY WORDS Aspartame, aspartate, phenylalanine, methanol, formate

This symposium honors Dr U Filer Jr for his many On July 26, 1974, the FDA approved Searle’s petition
contributions to studies ofthe safety and efficacy of food and issued a regulation authorizing the use of aspartame
additives. This paper reviews the studies carried out by in certain foods and for certain technologic purposes (5,
the Iowa research group to test aspartame safety. The as- 6). As permitted by law, two parties formally objected to
partame story illustrates the value of clinical studies and the regulation and requested a formal evidentiary hearing.
demonstrates how such studies were helpful in gaining The objections filed jointly by Olney and by Turner of
approval of aspartame. In the future these experiments Turner and Label, mc, questioned the safety of the as-
may well serve as a model for the type oftesting required partate and phenylalanine moieties of aspartame. Later
of food additives. these parties waived their right to a formal evidentiary
hearing conditioned upon the establishment of a Public
Historical background Board oflnquiry (PBOI) composed ofthree qualified sci-
entists from outside the FDA to review and evaluate the
Aspartame may well turn out to be the most thoroughly issue of safety.
studied food additive ever approved by the US Food and Before a PBOI could be convened the FDA formally
Drug Administration (FDA) in terms oftotal numbers of stayed the regulation authorizing the marketing of aspar-
studies conducted before approval. Safety studies of as- tame (7) pending an additional review of certain animal
partame were started in the late l960s when only the more studies. During this interval, Searle asked our assistance
classical toxicologic testing was required for food additives. in the design and execution ofcinical and animal studies
These studies, however, extended into the 1970s as more to address the questions raised by Olney and Turner.
rigorous tests were required by both regulatory agencies In January 1980, the PBOI was convened and heard
and consumer groups. During these two decades, aspar- three full days of testimony on aspartame, including a
tame faced and passed a number of regulatory reviews large amount of new clinical data generated by the Iowa
(1,2). research group. After considerable deliberation, the PBOI
The sweet taste
ofaspartame was discovered serendipi- agreed with Searle and the FDA that the aspartate and
tously in 1965 by Mazar and Schlatter working at GD phenylalanine content of aspartame did not constitute a
Searle (3). Searle recognized the potential of the com- risk when the additive was used according to the petition.
pound and conducted animal and clinical studies in the However, the PBOI agreed with Olney that available data
late l960s and early l970s with aspartame and its dike-
topiperazine decomposition product. In 1973 Searle pe-
I From the Departments ofPediatrics & Biochemistiy, The University
titioned the FDA for approval to market aspartame as a oflowa, Iowa City, IA.
sweetening agent for certain foods (4). Searle submitted 2 Address reprint requests to Lewis D Stegink, PhD, Departments of
a large amount of data in support of its claims of the Pediatrics and Biochemistry, 5385 Hospital School, The University of
safety of aspartame. Iowa, Iowa City, IA 52242.

204 Am J C/in Nutr 1987;46:204-15. Printed in USA. © 1987 American Society for Clinical Nutrition
 ASPARTAME METABOLISM 205

did not rule out the possibility that aspartame or its di- INTESTINAL LUMEN MUCOSAL CELL PORTAL BLOOD

ketopiperazine caused brain tumors in rats. Accordingly,

ASPARTATE )ASPARTATE
the PBOI withdrew approval of the aspartame food ad-
ASP-PHE .ASP-PHE--)
ditive petition and, after vacating the stay on the aspar-
tame regulation, revoked the regulation in its entirety. PHENYLALANINE -I-)PHENYLALANINE

Olney, Searle, and the FDA filed detailed exceptions to METHANOL

those portions of the PBOI decision with which they dis-

agreed. Turner also filed an exception, objecting to the
ASPARTAME METHANOL I )METHANOL
scope of evidence considered by the PBOI. As a result, ‘I

the FDA made

issue. After considerable
a detailed
review ofavailable
reevaluation
data, a process
ofthe brain tumor
METHANOL
1/
that also included examination of new data, the com- +

missioner determined that aspartame had been shown to ASPARTATE * ASPARTATE

be safe for its proposed uses as a food additive and ap-

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
proved the aspartame food additive petition (8, 9). As-
PHENYLALANINE ) PHENYLALANINE --+PHENYLALANINE
partame was later approved for use in beverages (10).
Other questions have been raised about aspartame since
FIG 2. Aspartame hydrolysis occurs in both the intestinal lumen and
its FDA approval for use in beverages. These include
in mucosal cells, releasing aspartate, phenylalanine, and methanol to the
questions of aspartame-related changes in brain neuro-
portal blood.
transmitter levels, behavioral effects, allergic reactions, ef-
fects on blood pressure, and on seizure threshold. At this
time available data regarding these questions are conifict-
ing and controversial. Because studies on these points The question of how to prove safety is complicated by
currently are underway, these questions will not be dis- the problem that evaluation of new food additives must
cussed here. deal with differing sensitivities of various species. Some
animal species are less sensitive than others to adverse
effects of a specific compound. Investigators must deal
The Iowa studies with conificting toxicity data obtained in different species
The science of toxicology is based on the premise that and determine how these data relate to potential toxicity
all compounds are toxic at some dose. Salt, water, sugar, in humans. This was particularly true for aspartame.
and even a mother’s love produce deleterious effects when When we started our studies ofaspartame in 1975, our
given in inappropriate amounts. Thus, it is not surprising goal was to evaluate aspartame safety for humans, in-
that very large doses ofaspartame or its component parts cluding specific populations at increased risk. These pop-
(Fig 1) (aspartate, phenylalamne, and methanol) produce ulations included phenylketonuric heterozygotes, infants,
deleterious effects in sensitive animal species. The critical pregnant and lactating women, and individuals reporting
question is whether aspartame is potentially harmful at symptoms ofthe Chinese restaurant syndrome. However,
normal and at abuse levels of use. before such studies could take place, animal studies as
well as studies in normal adult humans had to be car-
ried out.
Orally ingested aspartame is absorbed and metabolized
AS PARTAME in one of two ways (Fig 2). It may be hydrolyzed
intestinal lumen to aspartate, phenylalanine, and
in the
meth-
0 anol by proteolytic and hydrolytic enzymes (1 1-16). The
components are absorbed from the lumen and reach the
NH-CH- portal blood in a manner similar to that of amino acids
and methanol arising from dietary protein or polysaccha-
CH2 rides. Alternatively, aspartame may be demethylated in
the lumen to yield the dipeptide aspartyl-phenylalanine
and methanol (16). The aspartyl-phenylalanine is ab-
6- sorbed directly into mucosal cells by peptide transport
mechanisms (14, 15) with subsequent hydrolysis within
the enterocyte to aspartate and phenylalanine. In either
case, the ingestion of large doses of aspartame releases
aspartate, phenylalanine, and methanol to the portal blood
(16) and these components must be metabolized and/or
ASP PHE MET-OH excreted.
FIG 1. Chemical structure of aspartame. The dotted lines divide the Objections to the use of aspartame as a food additive
structure into its component parts: aspartate (ASP), phenylalamne (PHE), have been based on concerns about the potential toxicity
and methanol (MET-OH). ofeach ofits three components (aspartate, phenylalanine
206 STEGINK

and methanol). Olney ( 17-20) and Reif-Lehrer (2 1) ex- tion by humans of doses producing similar blood levels
pressed concern about the safety ofaspartame because of poses little risk.
its aspartate content. Administration of high doses of as- This paper reviews data obtained from the administra-
partame or aspartate to neonatal mice or rats results in tion oflarge doses ofaspartame to experimental animals,
elevated plasma aspartate concentrations and hypotha- normal adults, and populations at special risk. The first
lamic neuronal necrosis (22-24). However, aspartame section will discuss the effect of aspartame loading on
administration (2 g/kg body weight) to infant nonhuman blood methanol and formate concentrations, the second
primates, with or without added monosodium L-gluta- its effect on plasma aspartate concentration, and the third
mate (MSG) (1 g/kg body weight), did not produce neu- its effect on plasma phenylalanine concentration.
ronal necrosis, even though plasma aspartate and gluta- Before examining the experimental data, we need to
mate levels were greatly elevated (24, 25). Thus, we were determine what the potential ingestion levels of aspartame
forced to resolve the question ofwhich species is the most by the general population may be. This will provide a
suitable model to study dicarboxylic amino acid toxicity basis for comparison with levels used in animal and hu-
for humans. man safety studies. Projected levels ofaspartame ingestion

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
Turner objected to aspartame because of its phenylal- have been calculated by the FDA, the Market Research
anine content (26). He speculated that aspartame ingestion Corporation ofAmerica (MRCA), and our research group
would markedly elevate plasma phenylalanine concen- (34-37). Table 1 summarizes these data. The highest daily
tration. Grossly elevated plasma phenylalanine concen- aspartame ingestion, according to these calculations,
trations, such as those found in children with classic phe- ranges from 22 to 34 mg/kg body weight per day. This is
nylketonuria (PKU), are associated with mental retar- equivalent to ingesting 12-19 mg/kg body weight phe-
dation (27-30). Thus, the phenylalanine question also nylalanine, 9.8-15.2 mg/kg body weight aspartate, and
required us to consider the question ofrelative sensitivities 2.4-3.7 mg/kg body weight methanol. According to the
of animal species. It is impossible to produce a rodent MRCA (36, 37), an aspartame intake of 34 mg/kg body
model ofPKU by feeding excess phenylalamne alone (31). weight represents the 99th percentile of projected daily
However, Waisman and Harlow (32) reported that a ingestion.
monkey model of PKU could be produced by feeding
infant monkeys diets rich in phenylalanine. Thus, the in-
Methanol
fant primate again seemed the best animal model to test
the potential hazard of aspartame for the neonate. Aspartame is a dipeptide methyl ester and methanol is
Because aspartame is a methyl ester, its metabolism released during absorption and metabolism of the sweet-
releases methanol. Ingestion of large doses of methanol ener. The ingestion of large quantities of methanol pro-
is associated with adverse effects in sensitive species (33). duces elevated blood methanol and formate concentra-
Although no party objected to aspartame on the basis of tions and leads to a variety of adverse effects, including
its methanol content at the PBOI, we were concerned metabolic acidosis and blindness (33).
about the potential risk that might arise from aspartame’s Chronic feeding studies were carried out in infant non-
methanol content. Again the question of the appropriate human primates in collaboration with Dr WA Reynolds
animal species became important. It is difficult to develop of the University of Illinois. Animals were fed 1, 2, or 3
a rat model of methanol toxicity that includes the retinal g aspartame/kg body weight for the first 9 mo oflife. The
lesion because the rat metabolizes formate more rapidly animals grew well and showed no signs of seizures, met-
than humans. It is possible to produce methanol toxicity abolic acidosis, or blindness (38). Subsequent studies
in rodents if the oxidation of formate to carbon dioxide showed no sign oflearning deficits (39).
is blocked with drugs. However, we were fortunate that Methanol metabolism next was evaluated in normal
Tephly and colleagues (33) ofthe University oflowa Tox- human subjects administered aspartame at 34, 100, 150,
icology Center had developed a good model of methanol and 200 mg/kg body weight (40). When ingesting aspar-
toxicity in the nonhuman primate and had carried out tame at 34 mg/kg body weight, blood methanol concen-
several studies to determine precisely what caused meth- trations were below the limits of detection (0.4 mg/dL).
anol toxicity. The data from Tephly’s group were very Blood methanol concentrations in subjects administered
helpful in evaluating the potential toxicity of aspartame’s
methanol content.
Tests evaluating the potential toxicity of aspartate, TABLE 1
Summary of projections of aspartame intake
phenylalanine, and methanol in humans obviously must
be indirect. However, it is possible to examine in humans Aspartame totally
the effect of large doses of aspartame on blood concen- replaces mean
trations ofaspartate, phenylalanine, and methanol to de- Source sucrose sweetness Projected maximum
termine whether such doses produce the blood concen- mg/kg body weight mg/kg body weight
trations of these compounds associated with toxicity in
sensitive animal species. Our premise was that if aspar- FDA (35) not calculated 22-28
tame ingestion produced blood levels of its components MRCA(36,37) 3-11 25-34
Stegink, et al (34) 7-9 23-25
that are tolerated by sensitive animal species, then inges-
 ASPARTAME METABOLISM 207

aspartame at the higher doses are shown in Figure 3. Con- V

centrations increased significantly after aspartame inges-
E
tion, withpeak blood methanol concentrations propor-
Co
tional to the aspartame dose. -j
w
Studies by Tephly and colleagues (33) indicate that the
w
toxic effects of methanol ingestion reflect accumulation -j

of formate rather than formaldehyde or methanol. Ac- w

cordingly, blood and urine formate levels were determined
in subjects administered the highest dose of aspartame 0
(200 mg/kg body weight) (40). No significant change in I.
0
blood formate concentration was noted (Fig 4); however, 0
urinary formate excretion (Table 2) was increased signif- 0
-j

icantly over preloading values in urine samples collected

0-4 h and 4-8 h after aspartame loading. Urinary formate

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
excretion returned to preloading values in samples oh- HOURS
mined 8-24 h after loading. Because the rate of formate
FIG 4. Mean (±SD) blood formate concentrations in normal adults
synthesis apparently did not exceed the rate of formate
administered aspartame at 200 mg/kg body weight. Reproduced with
metabolism and excretion, blood formate levels were not
permission from reference 41.
detectably elevated. Thus, there appears to be little risk
from aspartame’s methanol content at the doses studied.
One-year-old infants appear to handle aspartame’s methanol content offruit juice (140 mg/L). Other authors
methanol content as well as adults. Although limitations have reported similar levels of methanol in fruit juices
ofsample size prevented us from measuring blood formate (44-47).
concentration, blood methanol levels were measured in Monte (48) recently has suggested that aspartame-
l-y-old infants ingesting aspartame at 34, 50, and 100 sweetened beverages represent a special hazard in the
mg/kg body weight. These data (42) indicate that blood southern part ofthe United States. He was concerned that
methanol concentrations in infants are similar to those beverage storage in warmer climates would accelerate the
of adults ingesting the same doses of aspartame. conversion of the aspartame to its diketopiperazine and
Aspartame-sweetened beverages may provide less methanol. Because our studies (40) show that methanol
methanol than fruit juices. For example, the aspartame contained in aspartame is released, absorbed, and metab-
content ofan aspartame-sweetened beverage is ‘-555 mg/ olized without adverse effects when aspartame is ingested
L (or 55 mg/L of methanol), considerably less than the orally, there appears to be little basis for concern about
amount listed by Francot and Geoffroy (43) as the average small amounts of methanol released during storage of
aspartame-sweetened products. The total amount of ab-
sorbable methanol in a bottle ofdiet soda does not change
under these conditions because methanol is released and
absorbed during normal metabolism of aspartame itself.
E4 Monte’s other concerns (48) have been addressed by Stur-
0
0 tevant (49, 50).

0)
Aspartate

The dicarboxylic amino acids aspartate and glutamate

may exert toxic effects when administered at very high

TABLE 2
Urinary formate excretion in normal adults ingesting 200 mg/kg body
weight aspartame

Urine samplet Formate excreted

h cg/mg creatinine

-8toO 34±22t
01234567824 Oto4 10l±30
HOURS 4to8 8l±22
8to24 38±12
FIG 3. Mean (±SD) blood methanol concentrations in normal adults
administered aspartame at 100 (#{149}
- - - #{149}),
150 (0 - 0), or 200 mg/ S Data from (40). t Negative values are preloading times. Data are
kg body weight (A - - - A). Reproduced with permission from refer- expressed as the mean ± SD. § Differs statistically from baseline levels;
ence 40. p < 0.01.
 I 1I I I I -1---

208 STEGINK

methods of evaluating the potential neurotoxicity of

74 - GLUTAMINE : compounds
Neonatal
containing dicarboxylic
mice can ingest substantial
amino acids.
doses of aspartate,
70 aspartame, or MSG without developing neuronal necrosis.
Doses of aspartate or glutamate that produce plasma as-
66 partate concentrations < 1 10 imol/dL (20 times normal)
62 or plasma glutamate concentrations < 75 mol/dL do not

58

8
fft:’T1
: GLUTAMATE
produce
only when
ministered
52). These
lesions in the infant rodent (52). Lesions are noted

tions < 1 10 imol/dL

very
and plasma
large

data suggest
or plasma
doses

glutamate
of these
levels exceed
that plasma
concentrations
amino acids
the above levels (51,
aspartate concentra-
are ad-

6 flJ ! < 75 imol/dL

Further,
are not toxic to infant nonhuman
infant nonhuman primates
primates.
did not develop le-

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
4 sions despite gross elevation of plasma glutamate and as-
partate concentrations (25).
2
: Having
glutamate
established
concentration
the threshold
producing
plasma
lesions
aspartate
in the mouse,
and
I I I I I I I I I
we examined the plasma aspartate concentrations in nor-
6 -iiJ & ASPARAGINE - -
mal humans ingesting aspartame. In our first study, nor-
-#{149}1cs I I
:TY‘T ±H:
4
mal subjects were administered aspartame at 34 mg/kg
body weight or aspartate at 13 mg/kg body weight in a
2
randomized crossover design (34). Plasma aspartate levels
_l I I I I I I I I
in these subjects, as well as levels of other amino acids
1.0
: ASPARTATE that might be derived metabolically from aspartate, are
Q5 shown in Figure 5. No significant differences were noted
in plasma aspartate, asparagine, glutamate, or glutamine
012345678 24 values from baseline values, indicating rapid metabolism
of the aspartate portion of aspartame.
HOURS
Plasma aspartate also remained unchanged in humans
FIG 5. Mean (±SD) plasma glutamine, glutamate, asparagine, and after aspartame dosing at 50 mg/kg body weight (58).
aspartate concentrations in normal adults administered 34 mg/kg body Thus, aspartame ingestion at 1.5 times the 99th percentile
weiglfl aspartame (#{149}
- #{149})
or 13 mg/kg body weight aspartate
level ofprojected intake failed to increase plasma aspartate
(0 - - - 0). Reproduced with permission from reference 34.
levels.
Table 3 shows mean peak plasma aspartate concentra-
tons in normal adults administered abuse doses (100,
doses although species susceptibility varies considerably. 1 50, or 200 mg/kg body weight) of aspartame (59). All
Neonatal rodents administered large doses of aspartame, plasma aspartate values were well below normal post-
aspartate, or glutamate develop hypothalamic neuronal prandial plasma aspartate levels observed in orally fed
necrosis (22-24, 5 1, 52). However, there is disagreement human infants and adults (60-62) and far below the levels
over the ability ofthe dicarboxylic amino acids to produce producing lesions in infant mice.
neuronal necrosis in the infant primate. Olney and col- These data demonstrate the rapid metabolism and
leagues (53, 54) originally reported that large doses of glu- clearance ofthe aspartate portion ofaspartame, even when
tamate given to neonatal nonhuman primates produced aspartame is administered at abuse levels. Because plasma
hypothalamic neuronal necrosis. However, scientists aspartate levels are not markedly elevated by such abuse
working in four other laboratories, in a series of studies
involving a large number of infant monkeys, were not
able to find lesions in animals given large doses of MSG, TABLE 3
aspartame, or aspartame plus MSG (24, 25, 55-57). Plasma aspartate concentrations (jimole/dL) in normal adults
The critical question, however, is how to interpret these administered aspartame at 100, 150, or 200 mg/kg body weight*
mouse and monkey data in relation to humans. The neo-
natal human probably resembles the neonatal monkey Plasma aspartat e concentrations
Aspartame
more than it resembles the infant mouse. Thus, the neg- dose Baseline Mean peak
ative findings noted in neonatal monkeys after adminis-
mg/kg
tration oflarge doses ofeither MSG, aspartame alone, or
aspartame plus MSG suggest that aspar-
(24, 25, 55-57) 100 0.16±0.05 0.43±0.23
tame is safe for human infants. However, the controversy 150 0.27±0.10 1.00±0.70
over the sensitivity of the nonhuman primate to large 200 0.22 ± 0.08 0.76 ± 0.57
doses of glutamate or aspartame led us to explore other * Data from (59).
 ASPARTAME METABOLISM 209

I I I_
doses of aspartame, it is difficult to conceive of a risk to
1.2 -‘ I I
humans of aspartate-induced neuronal damage. BEV ERAGE + ASPARTAME #{149}

Special population groups that may have increased 1.c - -

sensitivity
physiologic
conditions
to aspartame
state or genetic
included
ingestion

infancy,
on the basis ofan altered
defect also were studied.
pregnancy, lactation,
These
het- Ia E
erozygosity for the genetic defect of PKU, and suscepta- 0.6 -, -

bility to the Chinese restaurant syndrome. Studies of 0 -

pregnancy were limited to an investigation ofthe placental i 0.4 -

.(
transfer of aspartate in the nonhuman primate (63). -

.( (, - -
Phenylketonuric heterozygotes metabolize the phenyl- ‘,. UNSWEETENED BEVERAGE
U) - -
alanine portion of aspartame less rapidly than normal
subjects; however, our data indicate that such persons 0.0
- ?I . ? . .
metabolize the aspartate portion of the aspartame nor- I I I

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
mally (64-66). 0 1 2 3 4 5 6
Some individuals report an idiosyncratic response to HOURS
ingestion of large amounts of MSG (Chinese restaurant FIG 6. Mean plasma aspartate concentrations in normal adults in-
syndrome). Because ofthe structural similarities between gesting repeated servings of either unsweetened beverage (0 - 0) or
glutamate and aspartate, we investigated whether large beverage providing aspartame at 10 mg/kg body weight (#{149} #{149}). Re-
doses of aspartame would produce symptoms in such produced with permission from reference 41.
subjects. Six subjects reporting symptoms after ingestion
ofglutamate were given 34 mg/kg body weight aspartame
in orange juice. None of the subjects reported symp- (70), was not concentrated toward the fetal circulation.
toms (67). The data suggest that it is virtually impossible for women
Because aspartame is used as a sweetener of beverages, to ingest aspartame in quantities sufficient to increase
ingestion of several aspartame-sweetened beverages be- maternal plasma aspartate levels to an extent that would
tween meals is possible. Ifthe aspartate load is not cleared increase transfer of aspartate to the fetus.
completely and/or metabolized before ingestion of a sec- Olney suggested that infants are at greater risk from
ond dose of aspartame, a cumulative increase in plasma aspartame ingestion than adults (17, 20) because ofa pos-
aspartate concentration might occur with the ingestion of sible delay in the expression ofgenetic information coding
successive aspartame doses. To test this, we studied the for the enzymes metabolizing aspartate and phenylala-
effects of successive ingestion of three servings of aspar- nine. Our studies indicate that normal infants metabolize
tame-sweetened beverage upon plasma aspartate concen- the aspartate portion of aspartame as well as adults (71,
tration (68). The study was conducted in two stages in a 72) and thus refute Olney’s hypothesis.
standard crossover design. Subjects ingested three sue-
cessive 12-oz servings of beverage, with a 2-h interval be- Phenylalanine
tween servings. In one stage of the study, subjects drank
three servings of unsweetened beverage whereas in the Plasma phenylalanine levels increase after ingestion of
other stage the three servings of beverage each provided meals containing protein, with postprandial plasma phe-
aspartame at 10 mg/kg body weight. As shown in Figure nylalanine levels
reaching 9-12 tmol/dL (60-62). Grossly
6, the addition of aspartame to the beverage had no sig- elevated plasma
phenylalanine levels are associated with
nificant effect on plasma aspartate concentration. mental retardation in persons with PKU (27-30). In this
We also were concerned that aspartame ingestion by genetic disease, phenylalanine is not metabolized and ac-
lactating women might increase milk concentrations of cumulates in blood and tissues. In children with PKU
aspartate and phenylalamne. However,
in lactating studies plasma phenylalanine levels range from 120 to 600
women indicated that aspartame administration at 50 mg/ jzmol/dL.
kg body weight had only a minimal effect upon milk as- Concern has been expressed that aspartame’s phenyl-
partate and phenylalanine concentration (58). The small alanine portion might increase plasma phenylalanine val-
differences observed in the milk content of free amino ues to toxic levels especially in subjects who are hetero-
acids are not biologically important. zygous for PKU. The question is: at what plasma levels
In pregnancy, the placenta normally maintains a con- does phenylalanine become toxic? Studies in infant mon-
centration gradient of most amino acids in favor of the keys fed diets providing 1, 2, or 3 g aspartame/kg body
fetal circulation. Fetal plasma levels of most amino acids weight for the first 9 mo oflife indicate no obvious prob-
are approximately twice maternal levels. We asked lems despite marked elevation of plasma phenylalanine
whether maternal ingestion of abuse doses of aspartame concentrations (38, 39). However, we still are left with
would increase maternal plasma aspartate levels, and the problem of extrapolating these data to humans. In-
consequently fetal plasma aspartate concentration. formation obtained from studies of patients with PKU
Our studies in primates indicated that aspartate (63), can be used to evaluate aspartame safety in that they pro-
like glutamate (69), but unlike most other amino acids vide information regarding the degree of plasma phenyl-
2 10 STEGINK

alanine elevation necessary for neurologic damage to oc-

cur. Our premise was that iflarge quantities of aspartame
fail to elevate plasma phenylalanine to toxic levels, the Q I I I
risk of toxicity from aspartame ingestion is minimal. To 0
address this point, high doses of aspartame were admin-
Phenylala nine
istered to normal subjects; subsequently possible abuse ii) 20
doses were studied. Finally, the effects ofaspartame inges- 6)
tion on plasma phenylalanine concentration were eval- Q
uated in PKU heterozygotes. E
We first investigated the effect of aspartame loading at
34 mg/kg body weight on plasma phenylalanine levels in
normal adults (34). This dose represents the 99th percen- (I)
tile of projected ingestion of aspartame for an entire day 6) 10
when aspartame replaces dietary sucrose on a sweetness >

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
basis; in our study, it was ingested in a single dose. Control
subjects ingested an equimolar quantity of aspartate.
Figure 7 shows plasma phenylalanine and tyrosine fl 5
concentrations in these subjects. Plasma phenylalanine E
concentration increased significantly after ingestion ofas-
partame from a normal base line level of 5-6 imol/dL I
to concentrations normally seen postprandially in orally-
fed infants and adults (60-62). A small rise in plasma
0 1 2 34
tyrosine concentration, representing the conversion of H0 URS
phenylalanine to tyrosine, also was seen after aspartame 8. Comn ofplasma phenylalanine concentrations in normal
adult subjects administered lactose (#{149} #{149}),
34 mg/kg body weight
aspartame (c - - - G), or 50 mg/kg body weight aspartame (0 - - -0)
(data shown as the mean ± SEM). Reproduced with permission from
reference 41.

E loading. In contrast, a dose ofaspartate equivalent to that

0 provided by the aspartame load produced a small but sig-
nificant decrease in plasma phenylalamne
concentration.
0 Next, six subjects were given 50 mg/kg body weight of
L

either aspartame or lactose in a randomized crossover

0.
design (58). As expected, plasma phenylalanine levels (Fig
C,) 8) increased significantly over baseline, reaching a mean
0 (±SD) peak value of 16.2 ± 4.9 jmol/dL after aspartame
E ingestion. Plasma phenylalanine levels were not affected
by lactose loading. Despite the large aspartame dose,
plasma phenylalanine concentrations were only slightly
higher than values found postprandially (12 ± 3 zmol/
-J
w dL) in orally fed infants (60, 6 1) or adults (62).
> Next, the effects ofabuse doses ofaspartame on plasma
hi phenylalanine concentrations were studied in normal
-J
adult volunteers (59). Aspartame doses of 100, 1 50, and
200 mg/kg body weight were studied. These doses rep-
resent intakes that would be ingested accidentally. The
highest dose studied (200 mg/kg body weight) was cal-
culated to be the potential dose received by a l-y-old child
-J
0 (10 kg) accidentally ingesting the entire contents ofa con-
tamer of aspartame coffee sweetener (100 tablets of 20
mg each). A similar level of ingestion was calculated as
being possible for a 50-kg soldier in the tropics ingesting
HOURS his entire water intake for the day (20 L maximum) as an
FIG 7. Mean (±SD) plasma phenylalanine and tyrosine concentra- aspartame-sweetened beverage in a single setting.
tions (imol/dL) in normal adults administered either 34 mg/kg body Normal fasted adults were administered aspartame
weight aspartame (#{149}
- #{149})
or 13 mg/kg body weight of aspartate doses of either 100, 150, or 200 mg/kg body weight dis-
(0 - - - 0). Reproduced with permission from reference 34. solved in 500 mL of orange juice. Figure 9 shows plasma
 ASPARTAME METABOLISM 211

TABLE 4
I ii I I I I I I I
Plasma phenylalanine levels under various conditions
60 - PHENYLALANINE

(mol/dL)
Normal subjects
50: Fasting 6±3
I \ 200 mg/kg Postprandial 12±3
Phenylalaninemia
II i
-J
0
U)
4O-/
-

\ Classic phenylketonuria
Questionable variants
120-600
60-120
w Benign variants 24-48
-J
0 After 34 mg/kg body weight aspartame
30 : Normal subjects 1 1 ±3
U) Phenylketonuric heterozygotes 16 ± 3

1I
z
0 After 100 mg/kg body weight aspartame
- 150 mg/kg Z
#{182}

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
I- Normal subjects 20±7
20
Phenylketonuric heterozygotes 42 ± 3
I-
z
w
C)
z 10 4I oog/g!’
!,..
0 body weight suggest that aspartame ingestion does not
0 akA represent a substantial toxicologic risk.
Individuals heterozygous for PKU will metabolize the
Co UI I I I I 1 I I I I
phenylalanine portion ofaspartame less well than normal
_1
0 15 - j-__j11-4L.... TYROSINE subjects. Thus, individuals heterozygous for PKU were
studied after aspartame administration at a dose of 34
10 - ‘ e(A mg/kg body weight (64). Figure 10 shows plasma phe-
5A nylalanine and tyrosine levels in PKU heterozygotes ad-
ministered 34 mg/kg body weight. Plasma phenylalanine
CI I I I I I I I I I levels increased significantly after aspartame loading in
0 1 2 3 4 5 6 7 8 24
both normal subjects and PKU heterozygotes. However,
HOURS

FIG 9. Mean (±SD) plasma phenylalanine and tyrosine concentrations

(imol/dL) in normal adults administered aspartame at 100 (#{149}),
150 (X),
or 200 mg/kg body weight (A). Reproduced with permission from ref-
erence 41. >

In
phenylalanine subjects. levels
Mean (±SD) peak
in these
0
plasma phenylalanine
levels were 20.2 ± 6.77, 35.1 >
± 1 1.3, and 48.7 ± 15.5 mol/dL after administration of
aspartame at 100, 150, and 200 mg/kg body weight, re- m
spectively.
Table 4 compares the plasma phenylalanine levels oh- L’) in
served in these subjects with plasma phenylalanine levels -J
hi In
in certain clinical situations. Normal fasting plasma phe-
nylalanine concentrations are “-4-6 tmol/dL, with post-
>
hi
prandial levels being 12 ± 3 jzmol/dL (60-62). Children -J
with classic PKU
have plasma phenylalanine levels rang-
ing from 120 to 600 .tmol/dL continually. These children
are mentally retarded. However, children with benign
variant forms of phenylalaninemia are not mentally re- LI)
tarded despite plasma phenylalanine levels ranging from
24 to 48 imol/dL continuously (28-30). Children with -J
0
classic PKU treated with diets low in phenylalanine are
permitted plasma phenylalanine levels of 24-48 tmol/ 012 34 5678
dL. Although the plasma phenylalanine levels noted after HOURS
administration of abuse doses of aspartame to normal FIG 10. Mean (±SEM) plasma phenylalanine and tyrosine con-
subjects are outside the usual postprandial range, the mean centrations in normal adults (#{149}
- #{149})
and PKU heterozygotes
maximal plasma phenylalanine levels of49 jmol/dL oh- (0 - - - 0) administered aspartame at 34 mg/kg body weight. Repro-
served after an abuse dose of aspartame of 200 mg/kg duced with permission from reference 64.
212 STEGINK

plasma phenylalanine levels in heterozygotes were signif-

icantly
broader
higher and the plasma
than that noted in normals.
concentration-time
This was expected
curve E
in view of the decreased level of liver phenylalanine hy-
0
0
droxylase present in the heterozygote (73). Maximal
plasma phenylalanine levels (mean ± SD) in PKU het- U)
erozygotes (16.0 ± 2.25 zmol/dL) were slightly above the ci)
normal postprandial range of 12 ± 3 mol/dL (60-62). 0
These data clearly indicate that PKU heterozygotes E
metabolize the phenylalanine portion ofaspartame slower
than normal subjects. However, peak phenylalanine val-
ues in heterozygous subjects were well below those asso- hi
ciated with toxic effects. Thus, the 99th percentile of pro- I
jected daily aspartame ingestion, given as a single dose to 0

Downloaded from www.ajcn.org at Universidade Federal de São Paulo on January 10, 2010
the PKU heterozygote, poses no significant risk.
Next, the effects ofa potential abuse dose of aspartame
on plasma phenylalanine levels was investigated in PKU
heterozygotes (65). PKU heterozygotes were administered LI)
100 mg/kg body weight loads ofaspartame dissolved in
orange juice.
Figure 1 1 shows plasma phenylalanine and tyrosine a-
levels in these subjects. Metabolism ofthe phenylalanine 012 345 678
portion ofaspartame was slower in heterozygous subjects
than in normal subjects. Peak plasma phenylalanine levels HOURS
after aspartame loading in heterozygotes were significantly FIG 12. Mean (±SD) plasma
phenylalanine concentrations in normal
higher than values in normal subjects and the area under adults (#{149}
- #{149})
administered aspartame at 200 mg/kg body weight
and PKU heterozygotes (0 - - - 0) administered aspartame at 100 mg/
kg body weight. Reproduced with permission from reference 65.

the plasma concentration-time curve greater. The maxi-

mal mean (±SD) plasma phenylalanine level in PKU het-
erozygotes after aspartame loading at 100 mg/kg body
weight (41.7 ± 2.33 tmol/dL) was approximately two
times greater than the mean peak value (20.2 ± 6.77 imol/
E
dL) noted in normal subjects.
0
0 Based upon the observation that the plasma concen-
tration-time curve of heterozygotes administered aspar-
U, tame at 34 mg/kg body weight was similar
of nor- to that
a) mal subjects administered aspartame at 50 mg/kg body
0
E weight, we concluded that heterozygotes metabolized the
phenylalanine portion of aspartame approximately one-
half as well as normal subjects. The possibility existed,
(1) however, that an aspartame dose of 34 mg/kg body weight
-J
hi represents the maximal quantity readily handled by the
> heterozygote. However, peak plasma phenylalamne con-
hi
-J centrations and the area under the plasma phenylalanine
concentration-time curves indicate that PKU heterozy-
gotes ingesting aspartame at 100 mg/kg body weight me-
(I)
tabolize the phenylalanine portion of aspartame at least
as rapidly as normal adults metabolize and clear aspar-
-J tame doses of 200 mg/kg body weight (Fig 12). Thus, it
IL
appears that potential abuse dose ofaspartame would not
overwhelm the metabolism-clearance mechanisms for
HOURS phenylalanine in the PKU heterozygote.
FIG 1 1. Mean (±SD) plasma phenylalanine and tyrosine concentra- All these studies represent the response to a single acute
tions in normal adults (#{149}
- ) and PKU heterozygotes (0 - - -0) dose in which large amounts of aspartame were admin-
administered aspartame at 100 mg/kg body weight. Reproduced with istered to normal human subjects or PKU heterozygotes.
permission from reference 65. These studies did not evaluate the effect of successive
 ASPARTAME METABOLISM 213

smaller doses of aspartame on plasma phenylalanine sweetened beverage without appreciably increasing plasma
levels. phenylalanine levels.
If the phenylalanine load produced by aspartame In summary, our data indicate little risk associated with
ingestion is not completely cleared before ingestion of the aspartame ingestion at projected intake levels. Blood for-
next load of aspartame, a cumulative increase in plasma mate concentrations as well as plasma aspartate and phe-
phenylalanine concentration might occur. The population nylalanine concentrations remained within the normal
group ofgreatest concern are children. Morgan and Stults postprandial range after aspartame ingestion and were far
(74) have reported that 5-y-old children ingest an average below concentrations ofthese compounds associated with
of 1 1 .4 oz ofnoncarbonated sweetened beverage and 10.8 adverse effects.
oz ofcarbonated soft drinks daily. Thus, it is possible that
some children will ingest three 12-oz beverage servings
between meals. A 20-kg 4-y-old child drinking 12 oz of References
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>- ‘#{149}‘ \._..#{149}‘
6 16. Burgert SL, Merrick RH, Coon JD, Takeuchi H, Stegink LD. In-
0
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HOURS
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214 STEGINK

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 ASPARTAME METABOLISM 215

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