Live / Dead Status
Below are listed a selection of animals from G.D. Searle’s studies where
the researchers couldn’t even determine whether the animal was alive or
dead. This information comes from the original data observation sheets
as audited by the first FDA Task Force in 1975/1976. While not all of
this information applies to aspartame studies, it should serve to give
you a sense of the confusion that was rampant throughout the animal
observations (Schmidt 1976a, page 21 of US Senate 1976a).
J24HM Found dead 3/21/71
Alive 5/19/71
Dead 5/16/71
Alive 7/14/71
Dead 8/11/71
K18LF Alive 4/22/71
vanished (dead ?) 5/20/71
Alive 6/17/71
vanished (dead ?) 7/15/71
M25CF Found dead 3/6/71
Alive 6/18/71
Dead 7/16/71
Alive 9/10/71
Alive 10/8/71
Dead 11/5/71
H28MF Alive 7/13/71
vanished (dead ?) 8/10/71
H15CF Alive 7/13/71
vanished (dead ?) 8/10/71
G 2HM Found dead 3/10/71
Alive 8/9/71
A15MM Found dead 3/13/71
Alive 5/3/71
Dead 6/1/71
Alive 8/23/71
Dead 9/20/71
G16HM Found dead 3/9/71
Alive 8/9/71
Dead 9/7/71
A 6HM Found dead 2/25/71
Alive 5/3/71
Dead 6/1/71
Alive 8/23/71
Dead 9/20/71
G23HM Found dead 3/7/71
Alive 8/9/71
Dead 9/7/71
E15MM Found dead 1/21/72
Alive 2/25/72
G 8MM Found dead 9/3/71
Alive 11/29/71
Dead 12/27/71
B19HF Alive 6/29/71
vanished (dead ?) 7/27/71
Alive 8/24/71
vinished (dead ?) 9/21/71
Alive 10/19/71
vanished (dead ?) 11/16/71
Alive (?) 2/22/72
B21HF Found dead 2/25/71
Alive 8/24/71
Dead 9/21/71
Alive 10/19/71
Dead 11/16/71
Alive 2/22/72
B14MF Killed 7/30/71
Alive 10/19/71
Dead 11/16/71
Alive (?) 2/22/72
B12HF Found dead 9/2/71
Alive 10/19/71
Dead 11/16/71
Alive (?) 2/22/72
B 4CF Found dead 9/12/71
Alive 10/19/71
Dead 11/16/71
Alive (?) 2/22/72
D30LF Found dead 1/22/72
Alive 2/22/72
B15HF Found dead 1/25/72
Alive 2/22/72
C29LM Found dead 3/29/71
Alive 6/2/71
Dead 6/30/71
C12HM Found dead 8/10/71
Alive 10/20/71
Dead 11/17/71
There may have been numerous animals which were listed incorrectly as
alive and then dead. There would have been no way for the Task Force to
discover errors such as that. An animal’s alive or dead status is only
one of the variables which goes into the statistical analysis of an
experiment testing for cancer. Whether an animal has a tumor is another
important piece of information.
Tumor Status
There were many instances in which the FDA Task Forces discovered that
G.D. Searle had confused animals to such an extent, the tumor status was
not known. To give you a sample of the confusion that reigned during
this period of time in the G.D. Searle laboratories, here a sample from
just one cancer study of one of G.D. Searles drugs. The testimony is
that of FDA Toxicologist Dr. Addrienne Gross (Gross 1976b, page 44-49):
What may be added here is that the live/dead
status of the experimental animals is not the only
“careless” type of error present in the
Observation for Drug Effects. The following are
merely a few samples of the way entries are kept
on externally visible tissue masses in these
animals; most of such tissue masses turn out to be
benign or malignant mammary tumors.
1. Animal M21 (a control female), is said to have
developed a tissue mass in the left cervical
area; the mass is said to have been initially
detected on 6/18/71; at the next observation
period on 7/17/61 this animal is checked off
as having no tissue masses; however, the next
animal on the list (M22 – an exposed female)
is now listed as having its tissue mass
“larger” (presumably than at the previous
observation period); but this particular
animal had not been listed as having exhibited
any such masses at any time in the past; at
the next observation period on 8/13/71, the
tissue mass in the control animal is said to
be “larger” while the exposed animal is said
to have no tissue mass whatsoever.
2. Animal J16 is said on 2/23/72 under “Tissue
Masses – Lesions” to have an abscess in the
left inguinal region which is “larger”; no
mention of any such abscess is evident for any
prior observation.
3. Animal B26 is said on 12/14/71 under “Tissue
Masses – Lesions” that its mass is larger. But
no tissue mass in this animal is previously
reported. Four weeks later on 1/12/72 a tissue
mass is said to have been initially detected
on that day.
4. Animal B27 is said on 9/21/71 to have
developed a tissue mass initially detected on
that day; at the next observation period on
10/19/71 the mass is said to be unchanged; at
the next observation period on 11/16/71 the
mass is said to have regressed; at the next
two observation periods on 12/14/71 and
1/12/72 this animal is said to be free of
tissue masses; on 2/8/72, the next observation
period, the mass for this animal is said to be
the “same”(!)
5. Both animals A2 and A3 are said on 9/20/71 to
have developed tissue masses initially
detected on that day; at the next observation
period, on 10/8/71 both of these animals are
indicated to be free of any tissue masses; at
the next observation period on 11/5/71 it is
indicated that both of these masses regressed.
6. Animal E3 is said on 7/1/71 to have developed
a tissue mass initially detected on that day;
the following are the results of the six
subsequent examinations:
7/29/71 – animal is free of any masses
8/26/71 – mass is the same (as what?)
9/23/71 – mass is the same
10/21/71 – animal is free of any masses
11/08/71 – mass is the same
12/06/71 – mass regressed
7. Animal E9 is said on 9/23/71 to have developed
a tissue mass initially detected on that day;
the following are the results of the four
subsequent examinations:
10/21/71 – mass regressed
11/18/71 – animal is free of any masses
12/16/71 – mass regressed
1/13/72 – animal is free of any masses
8. Animal D29 is said on 7/1/71 to have developed
a tissue mass initially detected on that day;
the following are the results of the seven
subsequent examinations:
7/29/71 – animal is free of any masses
8/26/71 – animal is free of any masses
9/23/71 – mass is the same
10/21/71 – animal is free of any masses
11/18/71 – mass regressed
12/16/71 – mass is the same
1/13/72 – animal is free of any masses
9. Animals H26, D12, K25, D5, K17, and D19 each
are indicated to have developed more than on
tissue mass; in each case, however,
observations made subsequently fail to
distinguish to which tissue mass they apply.
10. Animal H19 is said on 11/2/71 to have
developed a tissue mass initially detected on
that date; the subsequent observation dated
11/30/71 indicates this animal to be free of
any tissue masses; at the next observation
made on 12/28/71 the mass in this animal is
said to be the “same.”
This list of 10 examples involving some 16 animals
could be extended further but it is sufficient to
make the point that records maintained at Searle
on the appearance, persistence or “regression” of
tissue masses do not give one much assurance on
their reliability.
One may ask can this sort of thing be shrugged
off as merely “careless” observations made by
those who were supposed to make such observations?
Or was this a situation that could be expected to
have occurred, given the policy and practice in
force in the Department of Pathology and
Toxicology at Searle?
A review of the names of the “observers” entered
on these sheets referring to “Observations for
Drug Effects” reveals different names for
subsequent observations. Question: If whoever
observed the animals on a given day and who
recorded such observation in his or her notebook,
is someone else than the one having observed them
at the previous observation period, who made
similar observations in some other notebook, how
can it be said that a certain tissue mass is the
“same” or “larger” or “unchanged”? After a certain
period in the experiment no names of any observers
appear on these records.
Searle maintains in their last communication (line
10, page 15) “In the truest sense, the errors
identified by the FDA (in these records) were
completely irrelevant to the scientific
conclusions of the study…” We note this
evaluation of “irrelevant” by Searle but we cannot
agree with it, and the reason for this is very
clear:
The title printed on these “Observation for Drug
Effects” is “Statistical Work Sheet”; this says
that it is reasonable to expect that these
“careless” entries must have formed the basis for
input for statistical operation which are crucial
to the “scientific conclusions of the study.” The
methodology used in these statistical operations
at Searle (the Horton and Sachs Life-Table
procedures) depend completely on the time a
certain tissue mass (tumor) is observed and on the
time the animals with the mass (and all other
animals in that group) died. Now, if the live/dead
status of each animals was “carelessly” entered on
these “Statistical Work Sheets” as conceded by
Searle and if its status as a tumor-bearer at any
time was largely in doubt (as demonstrated here)
of what value are any of the statistical
computations based on this kind of raw input data
and would this not affect the “scientific
conclusions of the study”?
Searle complains (line 2, page 14) that these
records “became a subject of considerable levity
at the hearing.” I believe, however, that the
members of the Subcommittee are sufficiently
knowledgeable in the ways of the world to realize
that animals seldom die more than once. However,
I
would tend to agree with Searle here, that the
state of their records on observations collected
during the course of this study is indeed no
laughing matter.
Given the lack of statistical power of NutraSweet’s animals experiments
and their inability to be certain whether their test animals are alive
or dead and whether they did or did not have tumors, how could any
unbiased individual rely on this information to make health policy
determinations that would effect an entire country? The items discussed
above combine to render the G.D. Searle experiments that tested for
cancer totally worthless as far as using them to prove safety. However,
these abuses were just the beginning of what was discovered.
Other Problems
The following testimony by Dr. Jacqueline Verrett, a former toxicologist
of the FDA, who was the Senior Scientist of the FDA Bureau of Foods Task
Force describing a few of the other problems with G.D. Searle’s cancer
studies (Verrett 1987):
1. There was no protocol written until the study
was well underway.
2. Animals were not permanently tagged to avoid
mixups over the course of the study.
3. Changes were introduced in some laboratory
methods during the study with inadequate
documentation.
4. There was either sporadic or inadequate
reporting and monitoring of both feed
consumption and animal weights.
5. In some cases, tumors were removed, and the
animals then returned to the study.
6. Animals were recorded as dead and then
subsequent records, after varying periods of
time, indicated the same animal was still
alivealmost a certain evidence of mixup.
7. Many animal tissues, a significant number,
were autolyzed, that is, decomposed, before
any post mortem examinations were performed.
8. And finally, of extreme importance is that in
the DKP study there was evidence, including
pictures found in notebooks at Searle, that
the diets were not homogeneous, and that the
animals could discriminate between feed and
the included particles of DKP. In other words,
they may or may not have been eating what it
was assumed they were eating.
Almost any single one of these aberrations would
suffice to negate a study designed to assess the
safety of a food additive, and most certainly, a
combination of many such improper practices would,
since the results are bound to be compromised.
Raymond Schoeder, a former G.D. Searle employee told the FDA that the
particles of DKP (in experiments to test DKP for cancer) were so large
that the rats could discriminate between the DKP and their normal diet
(Graves 1984, page S5500 of Congressional Record 1985a). After Raymond
Schroeder had made his original statements regarding the DKP study, FDA
Investigators went to interview him. He was then employed at a different
company. When the investigators got there, they noticed that a G.D.
Searle company employee had signed in immediately before them. During
the interview, Mr. Schroeder retracted his statements about the DKP
study (Olney 1987, page 8).
The evidence is very strong showing that the amount of DKP ingested was
much less than originally intended. This evidence includes the statement
by Mr. Schoeder as well as a picture of the large DKP particles. This is
a crucial issue as it shows that the uterine tumors and other problems
found in NutraSweet-fed rats in the DKP studies may have occurred at a
relatively low dose of DKP.
Dr. Adriene Gross describes problems with a 115-week study testing DKP
in rats (Gross 1987a, page 7):
1. Substitutions of some of the animals in that
study.
2. The presence of intercurrent disease amongst
the test animals and the administration of
drugs to combat this, neither of which were
completely reported to the FDA.
3. Incomplete examination of tissues from the
experimental animals.
4. Excision of tissue masses likely to be tumors
from live animals during the study.
5. Absence of batch records for the mixing of the
test substance into the diet of the test
animals.
6. Incomplete stability studies for the agent on
test.
7. Absence of homogeneity studies for the agent
on test.
8. Deficiencies in the methods of chemical assay
for the actual DKP that was mixed into the
diet of the experimental rats.
9. Problems with the dosage of the DKP that was
given to those rats.
10. Problems with the fixation-in-toto and
autolysis (decomposition of tissue).
11. Failure to report to the FDA all tissue
masses (likely to be tumors) which were found
in the experimental rats.
12. Failure to report to the FDA all internal
tumors present in the experimental rats, eg.,
polyps in the uterus (Animal K9MF), ovary
neoplasms (Animals H10CF, H19CF, and H7HF) as
well as other lesions (Animal D29CF).
13. Inconsistencies between different parts of
the report on this study submitted by GD
Searle & Co. to the FDA on the precise nature
of the lesions manifested by the test rats.
14. Numerous transcription errors in that report.
Brain Tumors
The pre-approval studies submitted to the FDA by G.D. Searle were so bad
that it would be impossible to determine safety of aspartame from them.
However, statistically significant increases in cancer rates in several
of the pre-approval experiments are an indication that aspartame may
cause cancer.
Two pre-approval studies showed an unusually large number of brain
tumors in the test animals. Those studies where called, E33/34 and E70.
Before discussing these studies in detail, it is useful to see how Dr.
Andrian Gross prefaced his discussion of brain tumors in G.D. Searle’s
pre-approval studies (Gross 1987b, page 1-2):
“However, having said all of this, let us assume
that in fact those studies were of an acceptable
quality; let us pretend that the test animals were
actually exposed qualitatively and quantitatively
to what G.D. Searle & Co. would have us believe
that they were exposed; that there was no post-
mortem autolysis [decay] of their carcasses
rendering vast numbers of their tissues to a state
unsuitable for pathology examination; that the
technicians involved in the conduct of those
studies were fully trained, competent, and
adequately supervised to make observations on
those animals prior to their death; that the same
was true with respect to the observations made
after their death; that in fact those technicians
actually made proper such observations; that the
proper samples of tissues with grossly observed
lesions were in fact collected for additional
microscopic examination; that the identity of such
tissue specimens corresponded (as they should) to
the identity of each animal that was their source,
etc. In short, let us make believe in a spirit of
Halloween that nothing which was uncovered for the
aspartame studies by the FDA investigations of
1975 and 1977 was actually true, i.e., that in
fact we are dealing here with studies of an
absolutely perfect quality or reliability. Of
course, such assumptions belong to the domain of
Fantasyland, but nevertheless, let us play this
little game for a while.”
“Under such highly speculative hypothetical
conditions, let us now ask again whether aspartame
can be viewed as being safe with “reasonable
certainty.”
E33/34
E33/34 was a 104-week study of Charles River CD rats. There were four
experimental groups each consisting of 80 rats. Each experiment group
was given a different dose of aspartame. The Control group had 119 rats.
Twelve brain tumors were found in the experimental rats and zero in the
control rats (Gross 1987b, page 2-3):
Group Sex Animal # Type of tumor
1 M 83-651 Astrocytoma
1 M 83-745 Astrocytoma
1 F 83-769 Astrocytoma
1 F 83-766 Astrocytoma
2 M 83-837 Astrocytoma
3 M 83-919 Astrocytoma
3 M 83-888 Oligodendroglioma
3 M 83-892 Astrocytoma
3 M 83-895 Astrocytoma
3 F 83-934 Astrocytoma
4 F 84-010 Medulloblastoma
4 F 84-019 Astrocytoma
The UAREP pathologists found only 11 brain tumors in the experimental
rats and 1 brain tumor in the control rat. Dr. John Olney had this to
say about that discrepancy (Olney 1987, page 6-7):
“There were other problematic aspects of the
brain
tumor data. In the pre-1975 records that I
reviewed, it was clear that several competent
pathologists had carefully examined the original
microscopic slides from the first study and agreed
that there were 12 brain tumors in the NutraSweet-
fed rats and zero brain tumors in the controls.
When the FDA conducted a task force investigation
of these laboratories in 1975, they singled out
these studies for further investigation and
ordered that all laboratory records, including
microscopic slides etc. be impounded under FDA
seal. Several years later when a group of
pathologists (UAREP) was sent to authenticate
these studies, they could not find the microscopic
slides. The UAREP pathologists were finally taken
to a laboratory where the slides were not supposed
to be and there they found some but not all of the
original slides. Clearly they had not been kept
under FDA seal and by mysterious coincidence the
slides that were finally presented to the UAREP
pathologists contained evidence for 11 brain
tumors in Nutrasweet-fed rats and 1 tumor in
contols. It is important to recognize that if
there are zero tumors in the controls, it is very
difficult to argue that the tumor incidence in the
control and Nutrasweet-fed rats is the same. But
if there is 1 tumor in the control group, it is
possible with statistical acrobatics to reach the
conclusion that the incidence is the same. And,
indeed, this is exactly the argument that the
manufacturer and the FDA Bureau of Foods pressed
at the Public Board of Inquiry. They accepted the
finding of 1 brain tumor among the controls even
though the authentic record showed zero brain
tumors in the controls, then they proceeded to
break down the animals into smaller and smaller
sub groups according to sex, dose level etc. and
finally the 1 brain tumor in one sub group of
control animals appeared to be not significantly
different from 2 or 3 tumors in each of the
experimental sub groups. I seriously doubt whether
this method of data analysis would stand the
scrutiny of competent disinterested statisticians.
Even more seriously I wonder why FDA allows
microscopic slides to disappear (while supposedly
impounded) and why they do not question the de
novo emergence of a brain tumor among the controls
when the slides reappear.”
In addition, the tumors that were found were large, leading one to
believe that they were not normal “spontaneous” tumors. As Dr. John
Olney stated (Olney 1987, page 7):
“Being a neuropathologist, I know that spontaneous
brain tumors in laboratory rats are extremely
rare. The archival literature documents an
incidence not exceeding 0.6%. Since the above
incidence in Nutrasweet-red rats is 3.75%, this
suggests that Nutrasweet may cause brain tumors
and certainly suggests the need for additional in
depth research to rule out that possibility.
….
“The PBOI panel member who was primarily
responsible for reviewing the brain tumor issue
was Peter Lampert, M.D., Neuropathologist and
chairman of the pathology department at Univ. of
Calif. San Diego. Dr. Lampert personally examined
the microscopic slides pertaining to the brain
tumor studies and told me a year or so after the
PBOI report was completed that he had been
surprised at the large size of the brain tumors in
the Nutrasweet-fed rats. This reinforced his
impression that they had been caused by some
tumorigenic agent since spontaneous brain tumors
are not only rare in laboratory rats but when they
do occur they are usually not so large. Dr.
Lampert is now deceased; he died in 1986 of
cancer. At the time he participated in the PBOI,
he was the President of the American Association
of Neuropathologists.”
It is also important to note that there may have been more brain tumors
in the E33/34 than reported. As Dr. Adrian Gross discovered (Gross
1987b, page 4-5):
“Furthermore, Appendix IV-20 on page 391 of that
same UAREP report reveals in the first row of the
table on that specific page that GD Searle & Co.
or their agents had provided to the subcontracting
EPL pathologists, i.e., to those whose report that
firm had originally submitted to the FDA:-
a) only 8 (or only 10%) of the brain sections for
the 80 animals in Group [1].
b) only 7 (or only less than 9%) of the brain
sections for the 80 animals in Group [2].
c) only 5 (or only less than 7%) of the brain
sections for the 80 animals in Group [3];
and the UAREP were provided with the brain
sections of 2 fewer animals than were provided to
the EPL. … This, quite by itself, is
sufficiently eloquent on just how G.D. Searle &
Co. saw fit to discharge their responsibilities in
reporting fully and completely their results of
the Two Year Rat Study with aspartame to theFDA;”
E70
E70 was a study of aspartame being fed to pregnant Charles River CD
rats. Aspartame was given to the offspring for 104 weeks. Two groups of
experimental animals were used, Group 1 was given a lower dose and had
78 rats, Group 2 was given a higher dose of aspartame and had 79 rats.
The control group had 115 rats.
The brain cancer which was found in E70 was as follows:
Group Sex
Control M
Control M
Control M
Control F
1 M
1 M
1 F
2 M
2 F
A total of nine brain tumors were reported, 4/115 rats in the control
group (3.48% incidence rate) and 5/157 rats in the experimental groups
(3.18%). Four of the nine brain tumors were reported as astrocytomas.
This seemed like an unusually high number of brain tumors in both the
experimental and control groups. As described by Dr. John Olney in his
testomony (Olney 1987, page 6):
“The manufacturer had done an additional study
[E70] and submitted it to FDA at the same time as
the former study [E33/34] was submitted. The
second study also showed a very high incidence of
brain tumors in Nutrasweet-fed rats but in this
study the control rats also had a similarly high
incidence. This did not make any sense, unless
both the control and experimental rats were
exposed to a tumor promoting agent. A subsequent
FDA investigation of the laboratories where these
studies were conducted revealed appearances that
the control and experimental animals may very well
have been fed one another’s chow in a sloppily
randomized manner so that, in essence, all animals
on the study may have been fed Nutrasweet during
portions of the study. The judges at the PBOI
agreed with me that the exceedingly high incidence
of brain tumors in the Nutrasweet-fed rats of the
first study and a similarly high incidence in all
rats of the second study was a “bizarre”
collection of data that could not be considered
evidence for the safety of Nutrasweet.”
FDA Toxicologist, Dr. Andriene Gross concluded, in part, the following
in his testimony before the US Senate (Gross 1985, page S10835-S10840 of
Congressional Record 1985b; Gross 1987b, page 453 of US Senate 1987):
Even if, contrary to the FDA’s view in 1976, the
quality of the conduct of those studies could be
relied upon by the same agency to even begin
making such a determination, at least one of those
studies had revealed a highly significantly dose-
related increase in the incidence of brain tumors
as a result of exposure to aspartame.
The full incidence of those brain tumors was not
disclosed by G.D. Searle & Co. to the FDA prior to
the initial approval for the marketing of
aspartame in 1974; moreover, the review of that
study in the FDA was so flawed that the Agency
apparently did not even realize at that time that
only a portion of the observations on brain tumors
had in fact been submitted by G.D. Searle & Co. in
their petition for that approval.
Quite aside from the remarkable significance of
the increased incidence with dose of those brain
tumors, the ADI [Acceptable Daily Intake] of 50
mgm/kgm body-weight recently set by the FDA for
the human consumption of aspartame is alarmingly
dangerous in that it involves an extremely high
and, therefore, a totally unacceptable upper limit
on the risk for those consuming aspartame: between
1/1,000 and 5/1,000 population to develop brain
tumors as a result of such exposure.
In view of all these indications that the cancer-
causing potential of aspartame is a matter that
had been established way beyond any reasonable
doubt, one can ask: What is the reason for the
apparent refusal by the FDA to invoke for this
food additive the so-called Delaney Amendment to
the Food, Drug, and Cosmetic Act? Is it not clear
beyond any shadow of a doubt that aspartame had
caused brain tumors or brain cancer in animals,
and is this not sufficient to satisfy the
provisions of that particular section of the law?
Given that this is so (and I cannot see any kind
of tenable argument opposing the view that
aspartame causes cancer) how would the FDA justify
its position that it views a certain amount of
aspartame (50 mg/mg body-weight) as constituting
an ADI (Allowable Daily Intake) or “safe” level of
it? Is that position in effect not equivalent to
setting a “tolerance” for this food additive and
thus a violation of that law? And if the FDA
itself elects to violate the law, who is left to
protect the health of the public?
In 1991, Dr. H.J. Roberts published an article in the Journal of
Advancement in Medicine (Roberts 1991), which showed a possible
correlation between the sudden, rising incidence of Primary Brain Cancer
and Primary Brain Lymphoma and the years soon after aspartame went on
the market. Dr. Roberts concludes with a recommendation for a closer
look at the relationship between aspartame and brain cancer:
The relationship between aspartame consumption and
the development of primary brain cancers in humans
requires careful analysis by corporate-neutral
investigators. In the event that such a
correlation is shown and brain cancer incidence
rates continue to rise, the FDA should declare
aspartame products an “imminent public health
hazard.”
It should be noted that it may take a generation or two of ingesting
aspartame before a significant increase in brain cancer incidence (due
to aspartame ingestion) is noticed. Hopefully, aspartame will be banned
long before that time.
Industry Arguments
1. Dosage
At first glace, the dosage of aspartame given in the E33/34 and E70
experiments seems absurdly high and based on that, it would not be
appropriate to extrapolate the results to human beings. However, upon
more careful consideration, the dosage given to the rats was not so high
after all.
The dosage given in experiment E33/34 was:
Control Group 0 mg/kg
Group 1 1000 mg/kg
Group 2 2000 mg/kg
Group 3 4000 mg/kg
Group 4 6000-8000 mg/kg
In E70 the dosage was:
Control Group 0 mg/kg
Group 1 2000 mg/kg
Group 2 4000 mg/kg
However, Dr. Adrian Gross points out that a very important adjustment in
the figures needs to take place in order to attempt to extrapolate
results in small rodents to what might occur in larger humans (Gross
1985, page S10840 of Congressional Record 1985b):
“The first item to be considered is that if one
wishes to extend safety data from small laboratory
rodents such as rats to much larger mammals such
as humans, the exposure rates expressed in grams
per body-weight must be modified or corrected by a
certain adjustment.
“The reason for this is that relatively small
animals have, per unit body-weight or mass, a much
larger body-surface. It is well known that most
metabolic functions are better related to body-
surface than they are to body-weight. For example,
if one were to provide general anesthesia, say,
for an elephant, and one were to select the same
dose in mgm/kgm body-weight of a general
anesthetic which is used in humans, chances are
excellent that the animal will promptly die due to
a drug-overdose, the reason for this is the same
for a given unit of body-weight, the elephant has
a much smaller total surface area than the human
and, therefore, a much lower tolerance for any
drug given on a basis of body-weight.”
On a body-weight basis, Dr. Gross points out that one average adult
human is worth 143.37 average rats or:
60,000 grams / 418.5 grams = 143.37 rats.
However, on a body surface basis, the average human is worth only 27.39
rats. Therefore, the dosages listed in E33/34 and E70 must be divided
by:
143.37 / 27.39 = 5.23
Therefore, the body-surface adjusted dosages given in experiment E33/34
were:
Control Group 0 mg/kg
Group 1 191.2 mg/kg
Group 2 382.4 mg/kg
Group 3 764.8 mg/kg
Group 4 1147.2-1529.6 mg/kg
In E70 the the body-surface adjusted dosages were:
Control Group 0 mg/kg
Group 1 382.4 mg/kg
Group 2 764.8 mg/kg
Even these adjusted doses seem much higher than the 50 mg/kg ADI
suggested for human beings. However, there are some well-known
differences in the toxicity of aspartame breakdown products which would
bring these adjusted dosages down considerably more.
For example,
- It has already been discussed that methanol is
relatively non-toxic in rodents compared to humans. In
fact it takes nearly 10 times more methanol to cause
death in rodents than it does in humans (Roe 1982). In
addition, the way relatively low doses of methanol
affects rats is not harmful and is completely dissimilar
to the dangerous ways low doses affect human beings. In
rats, there is no formate buildup, no metabolic
acidosis, and no optic nerve atrophy. It seems likely
that slow damage from low-level exposure to methanol
does not occur to any significant extent in rodents as
it does in humans.
- Wurtman (1988) used several published studies to show
that approximately 60 times more phenylalanine needs to
be given to rodents to cause the same effect as in
humans. This will be discussed in more detail in a later
section. For the phenylalanine part of aspartame, the
original doses in E33/34 and E70 should be divided by
60.
- In the Aspartic Acid section, we will see how the
negative effects from spikes in the aspartic acid levels
occur at five times lower doses in humans than in
rodents. Therefore, for the aspartic acid part of
aspartame, the original doses should be divided by five.
- It is unknown as to whether DKP is more toxic in humans
than in rodents. It should be noted that the fresh
aspartame given to rodents in E33/34 and E70 contained a
many times smaller percentage of DKP than is commonly
found in real world aspartame-containing products
ingested by humans.
Therefore, those seemingly high doses do not seem nearly so high when
one considers that several of the components of aspartame are many times
more toxic in humans than in rodents. The argument that the dosage was
too high has no basis in scientific reality. It might have been too high
to simulate what happens in humans. On the other hand, it might have
been too low. Finally, all of this assumes that the animals actually got
the dosage claimed a shakey assumption at best.
2. Spontaneous Tumor Rate
The FDA Commissioner, Arthur Hull Hayes, and G.D. Searle argued that the
spontaneous brain tumor rate was really 2.2% in Charles River CD rats
(not 0.7% as determined by the Public Board of Inquiry (PBOI) experts)
and therefore it would not be unusual to see tumors rates of 3% to 4% in
G.D. Searle’s experiments on these rats (Federal Register 1981).
In order to determine if the brain tumor rate in E33/34 of 3.75% in the
experimental group and the rates of over 3% in the experimental and
control group of E70 was unusually high for the Charles River CD rats
used in those experiments, the Public Board of Inquiry (PBOI) needed to
find out what the “spontaneous” brain tumor rate is in those type of
rats. In order to do this, the PBOI looked at four different studies.
Mawdesly-Thomas (1974) found a spontaneous brain tumor rate of 0.09% (38
brain tumors in 41,000 rats). The researchers used both the experimental
groups and the control group and eliminated and tumors that were
suspected of being caused by the experimental substance. All of the rats
were the Sprague-Dawley strain used in G.D. Searle’s aspartame and DKP
studies, but not all of them came from the Charles River Laboratories.
One of the advantages of this study was that it used a large number of
rats so that the spontaneous rate could be determined more accurately.
However, that fact that the some brain tumors were eliminated because of
“suspicion” of being caused by the experimental substance and the fact
that not all of the rats were from Charles River Laboratories, caused
the PBOI to believe that the spontaneous rate of 0.09% found in this
study was too low.
MacKenzie (1973) found a brain tumor rate of 0.6% (3 brain tumors in 535
Charles River CD rats). This was a well-conducted study which was given
some weight by the PBOI. The FDA Commissioner criticized this study for
two reasons (Federal Register 1981, page 38297). First, both the
experimental groups (rats who received irradiated feed) and the control
groups were used. This is not a valid criticism because one would expect
that the group receiving the irradiated feed would have more brain
tumors, not less. Even if the irradiated feed somehow protected against
brain tumors, one would expect that there would be a statistically
significant difference between the tumors in the experimental and
control groups (i.e., many fewer brain tumors in the experimental
group), but this was not the case.
In addition, the FDA Commissioner pointed out that “the authors state
that ‘many small tumors’ found in other studies would not be called
neoplasms.” What the author actually states is:
“Gillman et al. (7) reported an incidence of
pheochromocytoma of 50% in females and 82% in
males in 18-month-old rats. Many small tumors
described in their study we would not have
considered neoplasms.”
Pheochromocytomas are adrenal tumors and were not found in E33/34 or
E70. Even if MacKenzie did discount small brain tumors, although he
certainly did not state that he did so, the FDA Commissioner’s argument
would still not make sense. As pointed out earlier, the PBOI judge,
Peter Lampert, M.D. who was the President of the American Association of
Neuropathologists, told Dr. John Olney that he was “surprised by the
large size of the brain tumors in Nutrasweet-fed rats.” MacKenzie
certainly did not discount large brain tumors.
Fitzgerald (1974) found a brain tumor rate of 0.7% (5 brain tumors in
650 rats). The FDA Commissioner criticized this study as he did for
MacKenzie (1974) stating that both the experimental and control groups
were used. The same argument applies, however, that the experimental
substance would not be expected to protect again brain tumors and that
there was no statistically significant difference in the brain tumor
rate between the experimental and control groups.
The FDA also made some legitimate criticisms of the study, stating that
the authors did not state at what intervals the animals were sacrificed.
Therefore, if some of the animals had been sacrificed early, some of the
brain tumors could have been missed. On the other hand, the authors
cited nine earlier studies showing that:
“This is especially true for albino rats, in which
spontaneous brain tumors are considered extremely
rare.”
One criticism of the Fitzgerald (1974) study by the FDA Commissioner was
that the authors did not say how many brain sections were examined and
did not go into enough detail about their methods. It is interesting to
note that the FDA Commissioner later used a study that did not say
anything at all about the methodology to claim that the spontaneous
brain tumor rate in Charles River CD rats is 2.2%. The PBOI gave the
Fitzgerald (1974) study some weight even though it had a few flaws.
Thompson (1963) found a brain tumor rate of 3.2% (4 brain tumors in 125
rats). This study was used by G.D. Searle at the Public Board of Inquiry
(PBOI) to claim that the spontaneous brain tumor rate of Charles River
CD rats was closer to 3.2%. However, the PBOI rightly put little weight
on this study because such a small number of rats were used. One might
expect some fluctuation in the brain tumors when such a small number of
animals are used. It is interesting to note that none of the brain
tumors found were astrocytomas. In addition, three of the four brain
tumors were found in the experimental group, although this may have been
due to chance and not due to the irradiated feed of the experimental
group causing the tumors.
The experts on the Public Board of Inquiry made a comprimise between the
two best studies it looked at, Fitzgerald (1974) and MacKenzie (1973)
and determined that the spontaneous brain tumor rate in Charles River CD
rats was approximately 0.7%. The PBOI did not put much weight on the two
other studies with more serious flaws, Mawdesly-Thomas (1974) and
Thompson (1963).
The FDA Commissioner took exception to this decision and put forth
another study, Gart (1979), which he claimed shows that the spontaneous
brain tumor rate in Charles River rats is 2.2% and therefore the E33/34
study which showed much higher rates of brain tumors (3.75%) in the
experimental group and the E70 study which showed rates of brain tumors
of over 3% were not much more than 2.2% found by Gart (1979).
Gart (1979) found a brain tumor rate of 2.2% (8 brain tumors in 368
Charles River CD rats). However, as Dr. John Olney points out, the study
states absolutely no methodology. In addition, a smaller number of rats
were used than in the Fitzgerald (1974) or MacKenzie (1973) studies.
While this study deserves some weight, it is unlikely that expert
neuropathologists (which the FDA Commissioner is not) would give it more
weight than the two better quality studies considered by the PBOI. If
the PBOI had reconvened to consider this study it is unlikely they would
have raised their estimated spontaneous brain tumor rate to over 1.0%.
The FDA Commissioner argued that the Gart (1979) study deserves more
weight because it is a “concurrent” spontaneous brain tumor study as
opposed to a “historic” spontaneous brain tumor study. A historic
spontaneous brain tumor study is where a lab other than the lab
conducting the experiment in question tried to determine the spontaneous
brain tumor rate. Gart (1979) acted as a “concurrent” spontaneous brain
tumor study because the experiment was conducted at the same laboratory
as E33/34 and E70 (Hazelton Laboratories). The FDA Commissioner argues
correctly that the thoroughness and methodology of discovering brain
tumors are specific to a particular laboratory and therefore since the
Gart (1979) study was conducted at the same laboratory, it would, upon
initial consideration, seem to act as a better control for the
spontaneous tumor rate in Charles River rats.
There is one major flaw in this argument, however. E33/34 and E70 were
conducted in the early 1970s at Hazelton Laboratory. Almost everyone
agrees that at that time the technicians were not fully trained or
competent. They were not adequately supervised. There was enormous
confusion in the lab. Much of the tissue was allowed to decay. There
were mixups in animals and animal feed, etc. In other words, the
Hazelton Laboratory was in near total disarray in the early 1970s. When
the Gart (1979) study was conducted, one would expect that after three
US Senate hearings in 1975 and 1976, the adoption of the FDA Good
Laboratory Practices, and assurances from the heads of the G.D. Searle
and Hazelton Laboratories on improving the quality of their work, that
the lab in which Gart (1979) was conducted in no way resembled what went
on when E33/34 and E70 were conducted. The enormous change in laboratory
practices would mean that the Gart (1979) cannot be thought of as a
“concurrent” spontaneous brain tumor rate study.
The best way to find a “concurrent” spontaneous brain tumor rate of
Charles River CD rats is to look at the brain tumor rates in rats from
E33/34, E70, and E77/78 (a 115-week study of DKP on rats) which were
definately part of the control group. The FDA Commissioner attempted to
do this by stating (Federal Register 1981, page 38297):
“If the controls from all three Searle studies are
combined, the resulting incidence rate is very
comparable to the NCI data [Gart (1979)] for
sample populations of nearly identical size: 2.0%
(7 [brain tumors]/356 [rats]) for combined Searle
control data and 2.2% (8/368) for NCI control
data.”
There are two problems with this statement by the FDA Commissioner.
First, the number of brain tumors found in the control groups of the
three G.D. Searle studies is 6 not 7. The FDA Commissioner, inaccurately
stated that one brain tumor was found in the control group of E33/34.
This would bring the control brain tumor rate down to 6/357 or 1.68%
(not 2.0%).
In addition, it is completely inappropriate to use the control brain
tumor rates from E70. This is because Dr. John Olney as well as the
Public Board of Inquiry was questioning whether the experimental group
and the control group received the same aspartame-containing feed (Olney
1987, page 6):
“A subsequent FDA investigation of the
laboratories where these studies were conducted
revealed appearances that the control and
experimental animals may very well have been fed
one another’s chow in a sloppily randomized manner
so that, in essence, all animals on the study may
have been fed Nutrasweet during portions of the
study.”
Other evidence which seems to show a mixup in the diets of E70 rats was
the biochemical measurements. In a memorandum from Richard Condon, one
of the FDA scientists who reviewed the PBOI decision, he stated (Farber
1989, page 104):
“In E70, liver PHE [phenylalanine] hydroxylase
activity was measured and found to be greater in
treated groups than in the control groups. The
attached reference indicates that PHE hydroxylase
is suppressed when excess PHE is added to the
diet. If PHE is being released from aspartame in
the gut and absorbed, what is the explanation for
the above results?”
It is ridiculous to include data that is being questioned in a
calculation for the standard spontaneous brain tumor rate. Therefore,
the actual spontaneous brain tumor rate should use the two brain tumors
found in control group in the E77/78 experiment and the zero brain
tumors found in control group in the E33/34 experiment, or 2/242 =
0.83%. This rate is very close to the 0.7% determined by the PBOI to be
the spontaneous brain tumor rate in Charles River CD rats. The decision
by the FDA Commissioner, Arthur Hull Hayes (who would soon thereafter
consult for G.D. Searle’s public relations firm at $1,000/hour) to not
require additional studies, to play statistical games, and to use poorly
conducted studies as a basis for spontaneous brain tumor rates appears
to be reckless, at best.
Dr. Olney testified the following about the FDA Commissioner’s decision
in regards to the spontaneous rate of brain tumors (Olney 1987, page 9):
“In his written decision approving Nutrasweet, the
Commissioner of the FDA argued quite incorrectly
that the spontaneous incidence of brain tumors in
Sprague Dawley rats is much higher than 0.6%. In
spurious support of this conclusion he cited
several irrelevant and/or unreliable studies which
he considered more compelling than the appropriate
scientific evidence cited by the PBOI judges.”
NutraSweet-supported scientists sometimes cite Dagel (1979) as an
example of a study which shows that the types of spontaneous tumors
which were found in aspartame pre-approval studies appear in similar
proportions in this study (Koestner 1984). In other words, they claim
that because the proportion of astrocytomas to other brain tumors found
in aspartame studies is similar to what was found in Dagel (1979) that
the tumors found in the aspartame studies were probably spontaneous
brain tumors (i.e., unrelated to aspartame).
What they do not highlight is the fact that Dagel (1979) found a
spontaneous brain tumor incidence rate of only 1.2%, which is far below
the 3.75% found in E33/34 and below the 3%+ rates found in E70. The
Dagel (1979) study does not prove that the tumors in E33/34 and E70 were
spontaneous. On the contrary, it is another example of a spontaneous
tumor rate below what was claimed by G.D. Searle and the FDA
Commissioner. The fact that the proportions of the types of tumors in
each experiment had some similarity could be coincidence or could simply
mean that aspartame changes brain chemistry in such a way that the
likelihood of “spontaneous” brain tumors appearing increases
significantly.
3. Dose-related tumors?
G.D. Searle and the FDA Commissioner argued that there was not a dose-
related incidence of brain tumors in the E33/34 study. These arguments
are based on statistical games and more importantly, do not take into
account certain major flaws in the conduct of the study.
As stated earlier, the brain tumor incidence in E33/34 was:
Control Group 0 0 mg/kg
Group 1 4 1000 mg/kg
Group 2 1 2000 mg/kg
Group 3 5 4000 mg/kg
Group 4 2 6000-8000 mg/kg
At first glance this appears to be a random distribution of brain tumors
among the experimental groups. However, Group 4 should be dropped from
any determination of whether the incidence was dose-related. In a
memorandum from Richard Condon, one of the FDA scientists who reviewed
the PBOI decision, he stated (Farber 1989, page 104):
“Additionally there are some questions about the
conduct of E33/34. Why were the PHE
[phenylalanine] blood levels significantly (P<.05)
higher in control males than in high level treated
males?”
It appears from the phenylalanine level measurements that the males rats
in Group 4 did not even get any (or hardly any) aspartame. In Group 3,
there were 4 male rats with brain tumors and only one female rat with a
brain tumor. Therefore, had the male rats in Group 4 been given
aspartame, one might expect that there may be as many as 8 male rats
with brain tumors in that group. Since it seems that Group 4 male rats
did not receive aspartame and one cannot be certain how many cancers
would have occurred had they received aspartame, it is best to discard
the group altogether.
As discussed in his statistical analysis of E33/34, Dr. Adrian Gross
shows that the change in brain tumor incidence does show a statistically
significant dose related response to aspartame for the animals of both
sexes together (p=0.023) and for the male animals alone (p=0.021) even
though Group 2 results do not fit perfectly with the rest of the results
(Gross 1987b, page 5-6). The variation of brain tumor incidence in Group
2 could simply be due to chance or it could be a problem with decayed
tissue or the animals not receiving the correct diet.
It is also important to note that not all substances which contribute to
the formation of cancer do so on a linear dose-response curve. It may
very well be that above a certain dose level and in certain, susceptible
individuals (or rats), brain cancer will occur.
4. Fetal susceptibility
Koestner (1984) argued that fetuses are many times more sensitive to
certain compounds (e.g., 50-100 times more sensitive to N-nitroso
compounds) than adults. Therefore, he says, the study E70 (where the
pregnant mothers were exposed to aspartame) should have had a higher
tumor rate than E33/34. The incidence rate for aspartame-exposed groups
was 3.75% (12/360 rats) in E33/34 and 3.18% (4/157 rats) in E70.
There a couple of problems with Koestner’s theory:
1. If the feed was regularly mixed up between the
experimental group and the control group in E70 as
evidence seems to show, the experimental group may have
received much less aspartame than intended over the
course of the study. Had such regular mixups not
occurred, the aspartame-fed group may have had a much
larger tumor rate.
2. This theory assumes that whatever would cause the brain
tumors in aspartame-fed rats would a) cross the
placental barrier in the mothers and b) affect the fetal
brains the same way as the adult brain. Since we don’t
know what may be contributing to brain tumors in
aspartame-fed rats, it’s pure speculation that it would
affect the fetuses to increase the tumor rate.
Due to likely mixups in the feed and a lack of knowledge about the
aspartame metabolite(s) that might contribute to brain cancer in rats,
this theory remains wishful speculation on the part of NutraSweet.
5. Age of Tumor Appearance
Koestner (1984) claims that since the majority of the tumors in E33/34
and E70 did not appear at a younger age, aspartame therefore does not
meet the definition of a carcinogen. This is perhaps the most ridiculous
of NutraSweet’s arguments.
First of all, there is no way to be certain when the tumors appeared.
However, many of the tumors were not small as pointed out by Dr. Peter
Lampert after the PBOI (Olney 1987, page 7). In addition, the UAREP
pathologists also found that the tumors were much more remarkable than
the original G.D. Searle consulting pathologists (ESL) claimed (Gross
1987b, page 3-4). Therefore, despite what Koestner (1984) says, many of
those tumors may have appeared at a younger age.
Secondly, it surprises me that Koester is not familiar with cigarettes
and other substances that cause cancer after regular exposure over a
lifetime.
Finally, if aspartame sets up a condition in the brain of susceptible
rats (or humans) where cancer is more likely to occur, it may take long-
term exposure before the necessary brain chemistry changes take place.
This argument by Koestner (1984) is ridiculous and should be discounted.
Uterine Tumors
As discussed earlier, there was evidence that the rats in the 115-week
DKP study (E77/78) were able to avoid most of the DKP because the DKP
chunks were so large they would simply eat around them.
Florence Graves of Common Cause Magazine described the uterine tumor
situation (Graves 1984, page S5500 of Congressional Record 1985a):
“FDA officials and Searle defend the study, saying
that although there may have been problems, the
study was still valid. Both the FDA and Dr. Daniel
Azarnoff, president of Searle’s research and
development division, say one of several
indications that the rats ate the required amount
of DKP is the fact that a statistically
significant number of rats developed tumors in
their wombs (called ‘uterine polyps’).”
In testimony before the U.S. Congress, former FDA Toxicologist, Dr.
Jacqueline Verrett stated (Verrett 1987, page 388-389 of US Senate
1987):
“This (DKP) is the famous study with the uterine
polyps, and it is also the study in which there
were changes in serum cholesterol, significant
changes over the dose range.
“Now, we still are not sure exactly how much of
DKP each group of animals or any individual animal
got; they may not have gotten what would be
calculated on the basis of daily consumption had
the diet been homogeneous.
“The fact is, in spite of that, there were
significant increasesand I think everybody
agrees with thatof uterine polyps and also
changes in blood cholesterol.
“When that was then taken into consideration, they
said, oh, well, obviously, they must have gotten
the diet, because we have these changes. But then
they disregarded the changes as being significant-
-you know, uterine polyps were not pre-
carcinogenic. Well, I can rustle up 15 million
women by this afternoon who will disagree with
that.”
Even if the FDA is correct that the uterine polyps in the animal studies
were not cancerous, it is still a concern for women.
Research
I am not aware of any human research on the chronic ingestion of the
aspartylphenyalanine diketopiperazine (DKP) from aspartame.
a. Cho (1987)
In this study conducted in the early 1980s and published
in 1987 (Cho 1987), a single dose of aspartame with DKP
was ingested by six subjects. The urine and plasma
levels of DKP was measured at 0.25, 0.5, 0.75, 1, 1.5,
2, 3, 4, 5, 6, 7, 8, and 24 hours. Approximately 5% of
the DKP was excreted in the urine during the first 24
hours. No DKP was found in the blood.
Flaws
i. The dose of DKP used was only 2.2 mg/kg! This is an
exceptionally low dose. As seen in the Tsang (1985)
study, large amounts of DKP (e.g., 135 mg/liter)
within only six months after bottling at *room
temperature*. At higher temperatures the breakdown to
DKP would occur much faster. Since the minimum
testing dosage of aspartame should be double the
FDA’s ADI or 100 mg/kg, the minimum testing dosage of
DKP should be ~25 mg/kg. A 20 kg child drinking a 2-
liter orange soda in a day, stored in the garage for
a number of months could easily get 500 mg of DKP
(~2000 mg aspartame / 4 = 500 mg of DKP) or 25 mg/kg
(500 mg / 20 kg).
ii. The study was a single dose study. It is impossible
to extrapolate the results of a single dose of a
substance which never existed in the human diet to
the chronic ingestion of such a substance over a
lifetime.
iii. The authors speculated on what may have happened
to the other ~95% of the DKP that was consumed. It is
sad to see that we are basing the future health of
millions of people on the wishful thinking and
speculation of researchers funded by the aspartame
manufacturer. Blood tests for DKP are not necesarily
relevant as Olney’s original concern was that some
DKP was chemically changed in the gut (e.g.,
nitrosated) and then absorbed (Blaylock 1994, page
212).
iv. The authors try to convince readers of likely
safety by pointing out that there are other DKPs
which are natural. These are different chemicals and
likely have a different pharmacological effect.
v. The authors try to convince readers of likely safety
by citing pre-clinical studies conducted by G.D.
Searle and a study conducted by G.D. Searle’s long-
time partner, Ajinomoto Co. of Japan (MSG inventor)
(Ishii 1981). As seen earlier, the preclinical DKP
studies are laughable and show that aspartame may
have caused uterine tumors. Here is the testimony of
Dr. John Olney in regards to the Ajinomoto Co. study
(Ishii 1981) (Olney 1987, page 9):
“Although there is one study that has been reported
since the PBOI which claims to have demonstrated
that neither Nutrasweet nor DKP has tumorigenic
activity, I am not very impressed with this study.
It was conducted by the Ajinomoto Co. of Japan
which is one of the world’s largest manufacturers
of Monosodium glutamate and hydrolyzed vegetable
protein and a company which I believe has had a
contractual relationship with GD Searle to
manufacture Nutrasweet. This study, which was
reported sketchily in a journal of poor quality,
pertains to a different strain of rat than was used
in the GD Searle studies (Wistar instead of Sprague
Dawley) and therefore has not adequately addressed
the questions raised by the GD Searle studies.The
only way to address those questions is to conduct
studies that use the same strain of rat and
carefully control all experimental variables which
were not carefully controlled in the GD Searle
studies. One wants to know why Sprague Dawley rats
exposed to Nutrasweet had a 3.75% incidence of
brain tumors in the GD Searle study. Would another
study of Sprague Dawley rats, if properly
conducted, show the same thing or would it cleanse
the record and show that there is a very low
incidence of brain tumors in both the Nutrasweet-
fed and control rats? The record has not been set
straight by the Ajinomoto study on Wistar rats
briefly reported in a journal which is not
rigorously refereed (and whose editor is
finanacially dependent on the food industry). The
FDA Commissioner’s office stated at the time he
approved Nutrasweet that he was not relying on the
newly reported Ajinomoto study but rather was
satisfied with the original GD Searle data on
Nutrasweet and did not believe any further studies
are necessary. I am not satisfied with the original
GD Searle studies. The record shows them to be of
exceedingly poor quality and the only way to
overcome such a record is to have the key studies
repeated, preferably by an independent laboratory
of the highest possible integrity.”
In addition to Dr. Olney’s comments about this study
conducted by Ajinomoto Co. of Japan, it is important
to understand that studies by Ajinomoto Co. from that
era are highly suspect. As we will discuss in the
next section, Ajinomoto Co., through the Glutamate
Association and the International Glutamate Technical
Committee, funded studies during that era where key
information, which would have invalidated those
studies, was left out of the published reports and
only discovered years later.
7. Aspartic Acid
Dr. Liebovitz states:
“Aspartic acid is perfectly safe.”
While proclaimations of the “safety” of amino acids may go over well
with bodybuilders reading Muscular Development -Fitness – Health, the
issue of aspartic acid’s “safety” as part of aspartame is not so simple
as Dr. Liebovitz makes it sound.
Given Dr. Liebovitz’ strong beliefs in the absolute safety of all amino
acid supplements (Liebovitz 1993, Liebovitz 1994), I feel that my
disagreements in this section may fall on deaf ears. Nevertheless, I
will endeavor to present a scientific argument showing that aspartic
acid, as part of aspartame, is, at best, possibly dangerous for certain
populations, and, at worst, a contributing factor in a wide variety of
chronic neurological problems.
In order to show how the aspartic acid taken in aspartame differs from
aspartic acid which is one of the amino acids linked in protein as part
of food, it is necessary to trace and compare the digestion, absorption,
and metabolism of a high-protein food item and an aspartame-containing
beverage.
Protein Digestion & Metabolism
Proteins found in food are made up of building blocks called amino
acids. Proteins are in the form of chains of amino acids called
“peptides.” (Dipeptide = a chain of two amino acids; Tripeptide = a
chain of three amino acids; Polypeptide = a chain of four or more amino
acids.) Amino acids are rarely found in free form i.e., not bound in
amino acid chains known as protein molecules.
As summarized by Garrison (1990), the digestion of proteins begins when
a protein-containing food enters the stomach. Hydrochloric acid, pepsin,
and protease enzymes break specific protein links into polypeptides
(amino acid chains). When the food reaches the duodenum (part of the
small intestine), the enzyme trypsin in the pancreatic juice breaks the
polypeptides into dipeptides and tripeptides. As the amino acid chains
progress down the small intestine, several enzymes break the amino acid
chains into individual amino acids. The amino acids are then absorbed
through the intestinal wall and into the bloodstream. The whole process
is a long, slow process leading to a gradual absorption of amino acids
into the bloodstream. In addition, because proteins from food contains
many different amino acids, the ratios between the levels of amino acids
in the blood does not change significantly.
Aspartic Acid and Glutamic Acid Metabolism
Aspartic acid (also known as aspartate) and glutamic acid (also known as
glutamate) are acidic amino acids. Glutamic acid is directly converted
to alanine when it reacts with carbohydrate-derived glutamate pyruvate
transaminase (GPT) in the intestinal epithelia. (Pardridge 1986, page
206-207). In the presence of glutamate oxalacetate transaminase (GOT),
aspartatic acid is first converted to glutamic acid and then to alanine.
However, in the absence of carbohydrate-derived pyruvic acid, the
conversion of aspartic acid or glutamic acid to alanine is very slow. If
protein is ingested with food, non-carbohydrate sources of pyruvic acid
made in the body can convert the gradually-released glutamic acid and
aspartic acid to alanine.
When glutamic acid (in the form of monosodium glutamate -MSG) or
aspartic acid (as part of aspartame) is ingested in free form, there is
no gradual breakdown and absorption of proteins as there are only free
amino acids (e.g., aspartic acid and glutamic acid). These amino acids
are quickly absorbed. They are not converted to alanine unless they are
eaten with a significant amount of pyruvic acid-forming carbohydrade
such as a sugary snack. This leads to a significant spike in the blood
plasma level of aspartate or glutamate. Stegink showed that glutamic
acid ingested without a sugary snack spikes the plama levels of
glutamate significantly (Stegink 1983b). Many other industry-sponsored
experiments have shown large spikes in plasma glutamate levels after
ingesting real-world amounts of MSG with water, soup, and meals.
(Stegink 1979a, page 90, Stegink 1979b, pages 337-341, Stegink 1983c,
Stegink 1985, Stegink 1986) The plasma glutamate increases varied from
two to fourteen (14) times the increase when no glutamate was given with
the meal, soup, or water (up to an average level of 60 umoles/100 ml the
individual variation would probably put the level much higher for some
people). Bessman (1948) showed a nearly five-fold increase in plasma
glutamate when administering 100 mg/kg of unneutralized glutamic acid in
water. Himwich (1954) showed that when given a dose of approximately 200
mg/kg (15 grams) of glutamate to adults, the plasma glutamate spiked to
as much as fifteen times its fasting level. This dose can be expected in
some restaurant meals (i.e., 5 grams for a 25kg child). The same type of
spikes in plasma aspartate levels would be expected when ingesting
aspartic acid (or aspartame).
The large spikes in plasma glutamate levels after the ingestion of
glutamic acid (MSG) in food, soup, or water is not unexpected. After
all, a number of animal experiments with MSG showed large plasma
glutamate spikes as well (Daabees 1984, Airoldi 1980, Stegink 1979a).
Similarly, aspartic acid (40% of aspartame) has been shown to spike the
plasma aspartate levels in animals experiments (Reynolds 1980,
Applebaume 1984). This is no surprise since free aspartic acid is
absorbed and metabolized in a similar way to free glutamic acid
(Partridge 1986, page 206-207). It would seem obvious that plasma
aspartate levels in humans would be spiked to high levels after the
ingestion of aspartic acid (from aspartame), especially when ingested in
liquid form, so that absorption occurs quickly.
Unfortunately, what should have been a simple experiment measuring
plasma aspartate levels after the ingestion of aspartame has become
another embarrassment to science thanks to the involvement of
Monsanto/NutraSweet-funded “scientists.” In addition, the poor quality
of research in this area raises additional serious questions about the
honesty and accuracy of all Monsanto/NutraSweet-funded research.
Two key studies which show large increases in plasma aspartate from the
ingestion of aspartame were conducted by Stegink (1987a, 1987b). In the
first study (Stegink 1987a), ten subjects ingested aspartame in beverage
one day and one week later, the subjects ingested the same amount of
aspartame in capsule form. The dosage varied from 34.9 to 60 mg/kg of
aspartame. The following excerpt shows the large difference in the
levels of plasma aspartate when ingesting aspartame in beverages.
Plasma Aspartate Levels
(umol/liter) Average
Subject Solution Capsules Pre-Dose Level
1 28.5 14.5 3.2 ± 1.1
2 13.3 10.4 3.2 ± 1.1
3 46.4 14.0 3.2 ± 1.1
4 56.4 13.4 3.2 ± 1.1
5 17.0 13.9 3.2 ± 1.1
6 23.2 13.4 3.2 ± 1.1
7 30.7 14.5 3.2 ± 1.1
8 23.0 28.1 3.2 ± 1.1
9 8.8 17.3 3.2 ± 1.1
10 36.9 12.5 3.2 ± 1.1
Mean 28.4 15.2
“Aspartame ingested in solution significantly
increased the mean plasma aspartate concentration
from a baseline value of 3.2 ± 1.1 umol/L to a
high mean value of 26.2 ± 16.3 umold/L at 30
minutes after dosing. … When aspartame was
ingested in capsules, the higher mean plasma
aspartate concentration was significantly smaller
(10.4 ± 5.0 umol/L) and occurred later (1.5
hours).”
As you can see, some of the subjects had an extremely large and rapid
increase in plasma aspatate when ingesting aspartame in solution. One
subject (#4) spiked their plasma aspartate levels by over 18 times the
pre-dose level. Regular, long-term consumption of aspartame-containing
beverages which constantly spike the levels blood aspartate as shown
above would be very unwise.
These results were an embarrassment to Monsanto/NutraSweet. For years,
NutraSweet had been trying to claim that aspartic acid from aspartame
did not, for some strange reason, spike the plasma aspartate levels in
humans (Stegink 1984b). The results from Stegink (1987a) show that
plasma aspartate levels can be spiked to extremely high levels after the
ingestion of aspartame.
The Department of Clinical Research at NutraSweet conducted and funded a
similar study challenging some of Stegink’s results presented above
(Burns 1990). This is know as “damage control.” Not only did this
“study” show no difference in the plasma aspartate levels when the
subjects ingested aspartame in beverage as compared to aspartame in
capsules, but the NutraSweet researchers had the nerve to claim that the
plasma aspartate levels do not increase at all after the ingestion of
aspartame in liquid. It would be interesting to see how the NutraSweet
company can explain the enormous difference in the plasma aspartate
levels in the two experiments.
Despite the fact that Burns intended to compare his results directly to
the Stegink (1987a) study, he neglected to mention the almost
unbelievable difference in plasma aspartate levels between the
experiments! I find it difficult to believe that a researcher would
simply not notice or forget to mention this enormous difference. It
makes one wonder if they were trying to avoid drawing attention to the
Stegink (1987a) aspartic acid test results.
One partial explaination may be that the Burns (1990) study presented
the high mean values of the plasma aspartate levels as opposed to each
individual’s peak levels. Since individuals reach a peak aspartate level
at different times, the mean level of all the participants together at a
particular time will be much lower. What is important is each
individual’s peak aspartate level and how long they stay at dangerously
high levels. Whether subject A has neurotoxic levels of plasma aspartate
has nothing to do with what subject B’s plasma aspartate levels are at
that particular time. Yet Burns (1990) presented data as if they are
related.
Another possible explanation is that Burns used a lithium citrate buffer
instead of a sodium citrate buffer. According to Stegink (1985),
aspartate “co-elutes with reduced glutathione when lithium citrate
buffers are used” giving inaccurate measurements. From the description
in the published protocol, it appears this may have been done. One
wonders how many times this mistake may have “inadvertantly” occurred.
One final explanation is that the subjects in the Burns study may have
been given a significant amount of carbohydrate (e.g., sugar) with the
aspartame causing the aspartate to be converted to alanine as discussed
earlier. As you will see later, secretely adding substances to the
testing protocol and not mentioning that fact in the published protocol
has happened quite a few times in MSG and aspartame-related “research.”
This possibility raises grave concerns about the formulation of the
substance being testing in not only this experiment but all other
NutraSweet-funded experiments and in independently-conducted experiments
where the test substance was obtained from NutraSweet but not analyzed
independently.
In the second experiment (Stegink 1987b), 12 subjects ingested 50 mg/kg
of monosodium glutamate (MSG) in soup with and then without 34 mg/kg of
aspartame dissolved in a beverage. The average peak plasma aspartate
level almost doubled when the aspartame was ingested with the soup.
“Plasma aspartate levels were not significantly
affected by ingestion of the soup/beverage meal
without added MSG of aspartame. The addition of 50
mg MSG/kg body weight to the meal resulted in a
significant increase (P < .05) in plasma aspartate
concentration; values increased from a fasting
mean of 0.83 ± 0.64 umol/dL to a high mean value
of 2.69 ± 1.16 umol/dL 30 minutes after loading.
Plasma aspartate concentration descreased rapidly
thereafter and returned to baseline 120 minutes
after loading. The addition of aspartame and MSG
to the soup/beverage meal resulted in plasma
aspartate concentration above values noted after
ingestion of the meal providing MSG alone. The
high mean (± SD) peak plasma aspartate
concentration reached 5.01 ± 2.43 umol/dL at 30
minutes and returned to baseline 150 minutes after
dosing.”
On the other hand, Stegink (1987c) purported to show no increase in
plasma aspartate levels after the ingestion of 34 mg/kg of aspartame.
NutraSweet researchers will have us believe that we can trust their
testing procedures. Stegink (1987a) showed huge spikes in plasma
aspartate levels after ingesting aspartame. Stegink (1987c) showed no
increase in plasma aspartate levels from a similar amount of aspartame.
Stegink (1987b) showed a large increase in plasma aspartate levels. Yet
(Burns 1990) showed no increase in these levels after aspartame
ingestion.
In another acute-dosing study, Stegink (1977) showed that healthy
volunteers ingesting aspartame caused a statistically significant
increase in plasma glutamate levels with 1 hour. Remember, when aspartic
acid is metabolized, some of it can get converted to glutamic acid and
then 1) quickly absorbed, or 2) converted to alanine if from proteins
(which are digested slowly) or ingested with sugar.
One other experiment tested the milk of lactating women after the
administration of 34 mg/kg of aspartame as compared to 50 mg/kg of
lactose (Stegink 1979c). When ingesting the aspartame, the mean
glutamate levels of the milk increased from 1.09 to 1.20 umol/100 ml and
the aspartate levels increased from 2.3 to 4.8 umol/100 ml (more than
doubling). The lactose “placebo” also increased the aspartate and
glutamate in the milk, although not as much as the aspartame but who
cares no one said that taking a dose of 50 mg/kg of lactose is healthy
and it is certainly not an appropriate placebo for human studies. Baker
(1976) also found a significant increase in breast milk aspartate
levels, from 2.25 umoles/dL to 5.59 umoles/dL 12 hours after
administration of 50 mg/kg of aspartame. Note: Only average values for
each time period were presented. Also, ingesting the aspartame in cold
orange juice may cause some of the aspartic acid to be converted to
alanine.
However, several other Monsanto/NutraSweet-funded experiments purport to
show that aspartame does not spike the plasma aspartate levels after
ingestion. I find that some of the studies funded by NutraSweet which
show no increase in plasma aspartate levels to be extremely suspicious.
The most likely flaws are mixing aspartame with a form of sugar to
reduce spikes in the plasma aspartate levels and/or using a aspartate
measurement procedure that is flawed as described earlier. The studies
showing no change in aspartate levels are invariably the only studies
cited by NutraSweet scientists when reviewing aspartame. Given what some
people consider to be fraud in the pre-approval studies of aspartame and
the possible fraud of aspartic acid- and glutamic acid-related studies
as discussed later in this section, the results of some NutraSweet-
funded studies showing no increase in plasma aspartate levels should not
be accepted unless corroborated by several independent research teams.
It seems clear from the Stegink (1987a), Stegink (1987b), and other
studies mentioned above that aspartame (especially in liquids) can cause
enormous spikes in the plasma aspartate levels under some circumstances.
These experiments need to be repeated by truely independent researchers.
Glutamate is readily converted to the amino acid glutamine (FASEB 1995,
page 32). Other by-products of glutamate and aspartate metabolism
include glucose, ornithine, proline, urea, ammonia, and fatty acids
(Stegink 1984c, FASEB 1995, page 22). Vitamin B6 plays an important role
in this metabolism (FASEB 1995, page 36).
Other Biochemical Tests and Susceptibility
The blood plasma and erythrocyte levels of glutamate and aspartate are,
of course, very important measurements. However, these are not the only
places with levels of amino acids. For example, it has been shown that
during migraine attacks, neuroexcitatory amino acids (glutamic acid and
aspartic acid) rise significantly in the cerebrospinal fluid (CSF) and
are actually lower in the plasma (Martinez 1993a). CSF levels of the
amino acid taurine have also found to be significantly higher in persons
suffering a migraine (Martinez 1993b). Interestingly, Plaitakis (1983)
found that the oral administration of glutamic acid (MSG) increases
plasma levels of taurine significantly. Is it possible that MSG and
aspartame increase the levels of CSF neuroexcitatory amino acids and/or
taurine in persons who experience headaches or migraine after their
ingestion? Westlund (1992) has shown that glutamate can have an potent
excitatory effects on spinal cord neurons. It seems important to measure
CSF levels of amino acids at various times after aspartame
administration. Of course, the CSF levels of amino acids or methanol
metabolites may or may not be affected by aspartame or MSG
administration. Or they may only be affected in a subset of individuals
(i.e., migraine sufferers from aspartame).
There are peripheral glutamate (and aspartate) receptors in the body
which may be effected by the ingestion of aspartic acid or glutamic
acid. For example, Said (1994) recently discovered excitatory amino acid
(e.g., glutamic and aspartic acid) receptors in the lungs which may
become overexcited and contribute to the asthmatic reaction that is
sometimes experienced after MSG or aspartame administration.
Measurements to determine the effects of MSG and aspartame on these
receptors should be devised by independent investigators.
As mentioned earlier, Plaitakis (1983) showed that the administration of
glutamic acid (MSG) increases the plasma levels of taurine
significantly. Bessman (1948) showed that the administration of glutamic
acid decreased the plasma levels of the amino acid glutamine
significantly within 15 minutes. After 30 minutes the levels of
glutamine rose substantially over the fasting level. The rise in
glutamine levels after its initial drop may have been due to the fact
that glutamate is converted to glutamine in an attempt to keep the
plasma glutamate from becoming excessive.
Both Stegink 1979 and Stegink 1980 show an obvious decrease in plasma
glutamine levels for at least four hours after the administration of
aspartame to a group of PKU heterozygotes (persons with reduced ability
to process the amino acid phenyalalnine). However, these obvious trends
were not statistically significant because the groups’ average glutamine
levels were used at each time period. It would have been useful to look
at individual measurements at each time period. The normal subjects in
Stegink (1980) appeared to have an increase in the plasma levels of the
amino acid, asparagine for a couple of hours after aspartame
administration. But these results were not statistically significant
because only six subjects were used and only the average values for each
time period were presented.
Plaitakis (1982) and Plaitakis (1983) found that the oral administration
of glutamic acid (MSG) increased the plasma glutamate and aspartate
levels substantially above controls in persons who have a deficiency of
the glutamate metabolizing enzyme, glutamate dehydrogenase (GDH) such as
patients with the genetic neurological disorder, olivopontocerebellar
atrophy (OPCA). Such patients are good candidates for the long-term
testing of real-world aspartame and MSG products by independent
investigators if they don’t mind being slowly poisoned, that is.
NutraSweet researchers avoid looking at possible reasons for the
suffering that their product has caused because they are simply not
interested in trying to discover anything; they are trying to protect a
dangerous product. If forced to do a test that might discover a problem
with the product, they will simply perform the test improperly and hide
those improprieties amidst a morass of half-truths. Asking such
“researchers” to perform (or participate in any way in) a test on CSF
amino acid levels, the effect on peripheral glutamate receptors, or
anything else that might reveal a problem with the dangerous product, is
an enormous waste of time and money.
Before looking at exactly what the damage may be from excess aspartic
acid and/or glutamic acid, it can be helpful to consider the following
question:
Given that physicians and researchers know so little
about what causes many diseases and given that many
things that researchers thought were healthy yesterday
are disease-causing today, do we really want to tell
people that since we cannot prove beyond any doubt
whatsoever that regular aspartic acid (from aspartame)
ingestion causes damage, it is okay to regularly and
haphazardly wreak havoc with the amino acid levels in
various parts of the body? It is reminiscent of telling
people that smoking cigarettes is safe.
There are two main health concerns with ingesting significant quantities
of aspartic acid from aspartame. The first is acute reactions. The
second is long term damage also known as excitatory amino acid damage.
In order to discuss the effects of aspartic acid on health it will be
necessary to discuss the well-studied effects of glutamic acid (MSG) on
health. Most neuroscientists and health professionals agree that these
two amino acids have similar effects in many cases as they both
stimulate the same types of cells in the same way. In addition, many
people who are sensitive to MSG experience similar acute reactions from
aspartame.
Excitotoxins (Summary)
Excitotoxins are defined as amino acids such as aspartic acid and
glutamic acid which, when applied to certain types of neurons (brain
cells) at certain concentrations will cause them to become
overstimulated and die (Blaylock 1994, Glossary). What follows is a
summary of how excitotoxins cause cell death or overstimulation from
Blaylock (1994), Lipton (1994), and Nicholls (1990).
Aspartate and glutamate are important neurotransmitters,
a chemical which allows neurons (brain cells) in the
brain to communicate between each other. Normally, excess
aspartate and glutamate is pumped back in the the glial
cells surrounding the neurons. However, when particular
types of neurons are exposed to excessive amount of
aspartate and glutamate, these neural cells are
overstimulated and, at a certain level of aspartate
and/or glutamate, the cells die.
Aspartate and glutamate can open the calcium channel in
the neurons so that calcium can move into the cell. A
number of chemical reactions occur within the cell which
eventually leads to the release of chemicals which
stimulate connected neurons. One of the products of this
chemical reaction in the neuron is arachidonic acid.
Arachidonic acid then reacts with two different enzymes
causing the production of free radicals such as the
hydroxyl radical. The hydroxyl radical, left unchecked
can kill brain cells. Fortunately, the potentially
destructive free radicals are absorbed by antioxidant
vitamins such as C, E, and beta carotene. Magnesium,
chromium, zinc and selinium are all very important
protectors of neural cells.
Magnesium normally blocks the calcium channel from
opening. Aspartate and glutamate can remove this block
and open the calcium channel a normal reaction.
However, when the glutamate or aspartate levels become
excessive, the calcium channels in some neural cells can
get stuck open, leading to the overstimulation or
destruction of those cells and adjacent cells. Not every
nearby brain cell is affected only the cells with
glutamate receptors.
The pumping action to remove excess glutamate back into
the glial cells takes an enormous amount of energy in the
form of the chemical ATP (adenosine triphosphate). In
addition, it is important that there is adequate
magnesium, and vitamins C, E, and beta carotene in order
to prevent cell damage. If brain energy or any of the
proper vitamins or minerals are lacking, neural cell
death can occur. In severe cases of lack of brain energy
or vitamins or minerals, a normal glutamate level can
lead to cell death.
Normally, there is a blood brain barrier to prevent
excessive glutamate levels from entering the brain.The
blood-brain barrier is a system in the walls of the
capillaries within the brain that is used to keep toxic
substances from entering the brain. However, there are
areas of the brain which are not protected by this
barrier including the hypothalamus (a part of the brain
which controls the release of hormones from the pituitary
gland), the circumventricular organs (a part of the brain
stem), and the pineal gland (a gland which controls the
production of the hormone melatonin and stops the release
of the luteinizing hormone (LH) which plays a part in sex
hormone control estrogen (females) and testosterone
(males)).
It has been shown experimentally in animals that
prolonged high levels of glutamate in the blood plasma
cause glutamate to seep through the blood brain barrier
(Toth 1981). This might occur if a person were ingesting
amounts of glutamic acid and aspartic acid that are not
normally found in a healthy diet say from MSG and
aspartame. In addition, the blood brain barrier appears
not to be fully developed during infancy and childhood
possibly allowing excess glutamate to be delivered to the
brain (Wakai 1978, Olney 1988, Risau 1991).
Finally, there are a number of conditions which can
damage the bloodbrain barrier to some extent and allow
excess glutamate to seepl into the brain:
- head injuries (Tanno 1992, Shapira 1993)
- certain diseases (e.g., diabetes, alzheimer’s, MS, ALS,
etc.) (Alafuzoff 1987, Scheibel 1988, Chambron 1994,
Bennett 1995)
- hypertension (Alafuzoff 1987)
- exposure to certain chemicals (Stewart 1988, Velaj 1985)
- exposure to radiation (Krueck 1994)
- infections (Chaturvedi 1991, Mathur 1992)
- brain tumors (Lohle 1992)
- strokes or mini-strokes which happen frequently in the
elderly (Banks 1988, Alafuzoff 1983)
- aging may cause a partial breakdown especially if there
is poor health (Pardridge 1988b, Banks 1988, Alafuzoff
1987)
Excitotoxins (Rodent Studies)
There is no question that glutamate and aspartate administered
subcutaneously or orally to mice or rats cause cell death to neural
cells in certain areas of the brain. Both independent scientists and
industry scientists agree on this point (Olney 1969b, 1969c, 1980, MSG
1994, Burde 1971, Okaniwa 1979). At first, the food industry challenged
these findings and even claimed that the destruction of the arcuate
nucleas in the hypothalamus was of no importance (Olney 1988).
The destruction of circumventricular organ neurons in infant mice have
been shown to occur at low doses of glutamate and aspartate. Independent
researchers such as Okaniwa (1979) and Olney (1970) have shown the cell
death to begin at a dose of 0.5 g/kg body weight. Other researchers
found the minimum dosage to be between 0.5 and 0.7 g/kg body weight
(Takasaki 1979, Applebaum 1984, Daabees (1985). Both Applebaum (1984)
and Daabees (1985) showed that the effect of glutamate and aspartate is
cumulative such that 0.25 g/kg aspartate + 0.25 g/kg glutamate caused
brain lesions.
The dosage in the rodent experiments above may, at first glance, seem
rather high 0.5 g/kg = 500 mg/kg. However, humans concentrate glutamate
(and probably aspartate) in the plasma at five (5) times that of rodents
(Olney 1988, Stegink 1979a, page 90). This translates to a dose of 100
mg/kg for human infants. Since it is not uncommon to find as much as
5,000 mg of MSG added to restaurant dishes (Olney 1984) and many soups
and broths contain as much as 2,600 mg of MSG per 12 ounces (Consumer
Reports 1978), humans are already being dosed with large amounts of free
glutamate. Even for a 50 kg (110 lbs.) person, 5000 mg of glutamate
works out to a dose of 100 mg/kg (or 250 mg/kg for a 20kg child!).
Both Daabees (1985) and Olney (1988) are in agreement that the plasma
glutamate of infant rodents must reach approximately 75 umoles/100 ml to
cause excitotoxic cell death. This value is several times less than the
value of 200 umoles/100 ml used by Pardridge (1986) to discount the
danger of aspartate. The 75 umole/100 ml plasma glutamate levels can
easily be obtained in infants and children by eating canned soup (or
broth) with MSG or restaurant meals.
Now that aspartame is on the market, humans have an additional source of
significant amounts of exicitotoxins, which as described above, have a
cumulative effect with MSG (Olney 1988, Applebaum 1984). While MSG can
raise the glutamate level significantly more than aspartame raises the
aspartate (and glutamate) levels, the combination of the two could
easily raise the level of plasma glutamate plus aspartate in infants to
a level that has been shown in animals experiments to cause brain
lesions.
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