History of Aspartame: article at http://www.dorway.com/enclosur.html
[ Mark D. Gold Aspartame Toxicity Information Center
www.HolisticMed.com/aspartame "Scientific Abuse in Aspartame Research"
at http://www.holisticmed.com/aspartame/abuse/methanol.html
mgold@... 35 Inman St., Cambridge, MA 02139 617-497-7843 ]
Before we discuss the other hazardous aspects of aspartame, it can be
helpful to understand the sordid history behind the approval of
aspartame.

From the article:

Numerous extensive, and very thorough, clinical investigations
have failed to reveal toxic side- effects of aspartame. A review
of over 100 animal and human studies by the Council on Scientific
Affairs of the American Medical Association (AMA) concluded that
'Consumption of aspartame by normal humans is safe and is not
associated with serious adverse health effects.' (AMA 1985)
Although the AMA frequently errs in its conclusions about
nutrition, medicine, and health in general, I believe they are
accurate in the case of aspartame."

This article, which was printed in the Journal of the American
Medical Association (JAMA), was basically a summary of information
provided by the FDA. After the heading, "Council Report," the article
degenerates into little more than a pro-aspartame fairy tale.
Unfortunately, this fairy tale has turned into a nightmare for
countless individuals. What follows is a short, but much more accurate
history of aspartame.

1964

The development of new pharmaceuticals was the focus of research at
the international pharmaceutical company, G.D. Searle and Company
(Farber 1989, page 29). A group working on an ulcer drug was formed
including Dr. Robert Mazer, James Schlatter, Arthur Goldkemp and
Imperial Chemical. In particular, they were looking for an inhibitor
of the gastrointestinal secretory hormone gastrin (Stegink 1984a, page
3).

1965

In 1965, while creating a bioassay, an intermediate chemical was
synthesized -- aspartylphenylalanine-methyl-ester (aspartame). In
December of 1965, while James Schlatter was recrystalling aspartame
from ethanol, the mixture spilled onto the outside of the flask. Some
of the powder got onto his fingers. Later, when he licked his fingers
to pick up a piece of paper, he noticed a very strong sweet taste. He
realized that the sweet taste might have been the aspartame. So,
believing that the dipeptide aspartame was not likely to be toxic, he
tasted a little bit and discovered its sweet taste (Stegink 1984a,
page 4). The discovery was reported in 1966, but there was no mention
of the sweetness (Furia 1972).

1969

The investigators first reported the discovery of the artificial
sweetener in the Journal of the American Chemical Society stating
(Mazur 1969):

"We wish to report another accidental discovery of an organic
compound with a profound sucrose (table sugar) like taste . . .
Prelminary tasting showed this compound to have a potency of
100-200 times sucrose depending on concentration and on what
other flavors are present and to be devoid of unpleasant
aftertaste."

In 1969, former Commissioner of the FDA, Dr. Herbert L. Ley was quoted
as follows (Griffin 1974):

"The thing that bugs me is that people think the Food and Drug
Administration (FDA) is protecting them -- it isn't. What the FDA
is doing and what the public thinks it's doing are as different
as night and day."

1970

The discovery of aspartame is reported in the well-known publication,
Science (Cloninger 1970).

G.D. Searle approached Dr. Harry Waisman, Biochemist, Professor of
Pediatrics, Director of the University of Wisconsin's Joseph P.
Kennedy Jr. Memorial Laboroatory of Mental Retardation Research and a
respected expert in phenylalanine toxicity, to conduct a study of the
effects of aspartame on primates. The study was initiated on January
15, 1970 and was terminated on or about April 25, 1971. Dr. Waisman
died unexpectedly in March, 1971.

Seven infant monkeys were given aspartame with milk. One died after
300 days. Five others (out of seven total) had grad mal seizures. The
actual results were hidden from the FDA when G.D. Searle submitted its
initial applications (Stoddard 1995a, page 6; Merrill 1977; Graves
1984, page S5506 of Congressional Record 1985a; Gross 1976b, page 333
of US Senate 1976b).

G.D. Searle denied knowledge of or involvement with the initiation,
design or performance of the study. Yet, the false results were
submitted to the FDA like the rest of the 150 G.D. Searle studies (on
aspartame and other products), bearing a Searle Pathology-Toxicology
project number. Both Dr. Waisman and G.D. Searle were responsible for
the study design. A number of false statements were made by G.D.
Searle including that the animals were unavailable for purchase for
autopsy after the termination of the study.

Neuroscientist and researcher John W. Olney found that oral intake of
glutamate, aspartate and cysteine, all excitotoxic amino acids, cause
brain damage in mice (Olney 1970).

An internal G.D. Searle memo layed out the strategy for getting
aspartame approved (Helling 1970):

At this meeting [with FDA officials], the basic philospohy of our
approach to food and drugs should be to try to get them to say
"Yes," to rank the things that we are going to ask for so we are
putting first those questions we would like to get a "yes" to,
even if we have to throw some in that have no significance to us,
other than putting them in a yes saying habit.
We must create affirmative atmosphere in our dealing with them.
It would help if we can get them or get their people involved to
do us any such favors. This would also help bring them into
subconscious spirit of participation.

The FDA banned the sweetener cyclamate. Robert Scheuplein, who was the
acting Director of FDA's Toxicological Services Center for Food Safety
and Applied Nutrition was quoted as saying "the decision was more a
matter of politics than science." (Stoddard 1995a, page 7)

1971

Ann Reynolds, a researcher who was hired by G.D. Searle and who has
done research for the Glutamate (MSG) Association, confirmed
aspartame's neurotoxicity in infant mice (Reynolds 1971).

Dr. John W. Olney informed G.D. Searle that aspartic acid caused holes
in the brains of mice. G.D. Searle did not inform the FDA of this
study until after aspartame's approval. None of the tests submitted
by G.D. Searle to the FDA contradicted these findings (Olney 1970,
Gordon 1987, page 493 of US Senate 1987).

1972

FDA Toxicologist Dr. Adrian Gross came upon some irregularities in the
submitted tests of the G.D. Searle drug Flagyl. G.D. Searle did not
respond for another two years. Their response raised serious
questions about the validity of their tests (Gross 1975, page 35;
Schmidt 1976b, page 6).

1973

On March 5, 1973, G.D. Searle's petition to the FDA for approval to
market aspartame as a sweetening agent was published in the Federal
Register (1973).

On March 21, 1973 the MBR report was submitted to G.D. Searle.

Background In August of 1970, G.D. Searle conducted two 78- week
toxicity studies on rats for what was to become a best-selling
heart medication, Aldactone. One study was conducted at G.D.
Searle and one at Hazelton Laboratories. In March 1972, the rats
for autopsied and the pathology slides were analyzed. For
confirmation of the results, G.D. Searle sent the slides to
Biological Research, Ltd. where board certified pathologist, Dr.
Jacqueline Mauro examined the data. She discovered that the drug
appeared to induce tumors in the liver, testes, and thyroid of
the rats. The report submitted to G.D. Searle by Dr. Mauro was
known as the MBR Report.

These statistically significant findings were confirmed by G.D.
Searle's Mathematics- Statistics Departement. Instead of submitting
these alarming findings to the FDA, G.D. Searle contracted with
another pathologist, Dr. Donald A. Willigan. He was given 1,000 slides
to examine. The Willigan Report was more to G.D. Searle's liking
because it revealed a statistically significant increase in thyroid
and testes tumors, but not in liver tumors. Liver tumors are of much
more concern to the FDA. The Willigan Report was immediately submitted
to the FDA. G.D. Searle did not disclose the MBR Report to the FDA
until August 18, 1975, 27 months after it had been given to G.D.
Searle (Schmidt 1976b, page 14, Merrill 1977, page S10828-S10831).

At first, G.D. Searle claimed that they did not submit the MBR Report
to the FDA because of an "oversight." Later, they [sic]

The FDA Commissioner from 1972 to 1976, Alexander Schmidt, M.D. felt
that "Superficially, it seemed like, if there would ever be a safe
kind of product, that would be it. The idea that two
naturally-occurring amino acids could harm someone in relatively small
amounts...." (Mullarkey 1992, page 15)

In an FDA memorandum dated September 12, 1973, Martha M. Freeman, M.D.
of the FDA Division of Metabolic and Endocrine Drug Products addressed
the adequecy of the information submited by G.D. Searle in their
petition to approve aspartame (Freeman 1973):

"Although it was stated that studies were also performed with
diketopiperazine [DKP] an impurity which results from acid
hydrolysis of Aspartame, no data are provided on this product."

Commenting on one particular single dose study:

"It is not feasible to extrapolate results of such single dose
testing to the likely condition of use of Aspartame as an
artificial sweetener."

It is important to note that Dr. Freeman pointed out the inadequency
of single-dose tests of aspartame as early as 1973. Since then, the
NutraSweet Company has flooded the scientific community with
single-dose studies.

"Chemistry - No information is provided other than formulae for
Aspartame and its diketo-piperazine."

"Pharmacology - Reference is made to 2 year rat studies, but no
data are provided on acute or chronic toxicity."

"Clinical - No protocols nor curriculum vitae information are
provided for the 10 completed clinical studies. Results are
reported in narrative summary form, and tabulations of mean
average values only. No information is given as to the identity
of the reporting labs, methodology (except rarely), or normal
values. (Reported units for several parameters cannot be verified
at this time.)

"No pharmacokinetic data are provided on absorption, excretion,
metabolism, half-life; nor bioaviliability of capsule vs.
food-additive administration."

Dr. Freeman concludes:

"1. The administration of Aspartame, as reported in these
studies at high dosage levels for prolonged periods, constitutes
clinical investigational use of a new drug substance."

"2. The information submitted for our review is inadequate to
permit a scientific evaluation of clinical safety."

She went on to recommend that marketing of aspartame be contingent
upon proven clinical safety of aspartame. The FDA Bureau of Foods
rejected Dr. Freeman's recommendation (Graves 1984, page S5498 of
Congressional Record 1985a).

Construction of a large aspartame manufacturing plant in Augusta,
Georgia was halted. It was thought that aspartame's uncertain
regulatory future was the main reason for the stopping of
construction (Farber 1989, page 47). In the 1973 G.D. Searle Annual
Report, an executive stated that "commercial quanities of the
sweetener will be supplied from the enlarged facility of Ajinomoto."
Ajinomoto is the inventor and main producer of the food additive MSG.

1974

Ninety of the 113 aspartame studies which were submitted by G.D.
Searle to the FDA were conducted in the early to mid- 1970's. All of
the tests that were described by the FDA as "pivotal" were conducted
during this time. Eighty percent of these tests were conducted by
G.D. Searle or by their major contractor, Hazleton Laboratories, Inc.
(Graves 1984, page S5497 of Congressional Record 1985a).

Dr. J. Richard Crout, the acting director of the FDA Bureau of Drugs
stated that "The information submitted for our review was limited to
narrative clinical summaries and tabulated mean values of laboratory
studies. No protocols, manufacturing controls infromation or
preclinical data were provided. Such deficiencies in each area of
required infromation precluded a scientific evaluation of the clinical
safety of this product...." (Mullarkey 1992, page 23)

Dr. John Olney and Consumer Interest attorney, James Turner, Esq. met
with G.D. Searle to discuss the results of Olney's experiments. G.D.
Searle representatives claim that Olney's data raises no health
concerns (Stoddard 1995a, page 7).

The FDA approved aspartame for limited use on July 26, 1974. The
allowable uses included free-flowing sugar substitute, tablets for
sweetening hot beverages, cereals, gum, and dry bases (Farber 1989,
Federal Register 1974). It was not approved for baking goods,
cooking, or carbonated beverages. This approval came despite the fact
that FDA scientists found serious deficiencies in all of the 13 tests
related to genetic damage which were submitted by G.D. Searle.

In August 1974, before aspartame could go on the market, Dr. John
Olney, James Turner, and Label Inc. (Legal Action for Buyers'
Education and Labeling) filed a formal objection stating that they
believe aspartame could cause brain damage. They were particularly
worried about aspartame's effects on children (Graves 1984, page S5498
of Congressional Record 1985a; Federal Register 1975, Olney 1987, page
3).

G.D. Searle's responses to queries about the testing of their drug
Flagyl, serious and unexpected side effect from other drugs they
developed, and information from Dr. John Olney's studies started a
controversy within the FDA as to the quality and validity of G.D.
Searle's test of aspartame and pharmaceuticals (Graves 1984, page
S5498 of Congressional Record 1985a).

1975

In July 1975, the FDA Commissioner, Dr. Alexander Schmidt appointed a
special Task Force to look at 25 key studies for the drugs Flagyl,
Aldactone, Norpace, and the food additive aspartame. Eleven of the
pivotal studies examined involved aspartame. All of the studies
whether conducted at G.D. Searle or Hazleton Laboratories were the
responsibility of the Pathology-Toxicology Department at G.D. Searle.
(Gross 1987a, page 430 of US Senate 1987). The special Task Force was
headed by Philip Brodsky, FDA's Lead Investigator and assisted by FDA
Toxicologist, Dr. Adrian Gross. The Task Force was especially
interested in "pivotal" tests as described in an article from Common
Cause Magazine by Florence Graves (Graves 1984, page S5499 of
Congressional Record 1985a):

"Before the task force had completed its investigation in 1976,
Searle had submitted the vast majority of the more than 100 tests
it ultimately gave the FDA in an effort to get aspartame
approved.

These included all test ever described as 'pivotal' by the FDA.
About half the pivotal tests were done at Searle; about one-third
were done at Hazleton Laboratories. 'Pivotal' tests include
long-term (two-year) tests such as those done to determine
whether aspartame might cause cancer. Former FDA commissioner
Alexander Schmidt said in a recent interview that if a pivotal
test is found to be unreliable, it must be repeated 'Some studies
are more important than others, and they have to be done
impeccably,' Schmidt said."

G.D. Searle executives admited to "payments to employees of certain
foreign governments to obtain sales of their products." (Searle 1975)

On July 10, 1975, Senator Edward Kennedy chaired a hearing on
drug-related research before the Senate Subcommittee on Health of the
Committee on Labor and Public Welfare (US Senate 1975). Preliminary
reports of discrepancies discovered about G.D. Searle were discussed.
The findings of the FDA Task Force were later presented at further
hearings on January 20, 1976 (US Senate 1976a) and April 8, 1976 (US
Senate 1976b).

On December 5, 1975, Dr. John Olney and James Turner waived their
right to a hearing at the suggestion of the FDA General Counsel after
the FDA and G.D. Searle agreed to hold a Public Board Of Inquiry
(PBOI) (Federal Register 1975, page 286, Mullarkey 1994b, page 5-6).

On December 5, 1975, the FDA put a hold on the approval of aspartame
due to the preliminary findings of the FDA Task Force. The Public
Board of Inquiry is also put on hold (Mullarkey 1994b, page 5-6;
Federal Register 1975). The evidence of the aspartame pivotal studies
were protected under FDA seal on December 3, 1975 (Sharp 1975).

G.D. Searle had invested 19.7 million dollars in an incomplete
production facility and 9.2. million dollars in aspartame inventory.
On December 8, 1975, stockholders filed a class action lawsuit
alledging that G.D. Searle had concealed information from the public
regarding the nature and quality of animal research at G.D. Searle in
violation of the Securities and Exchange Act (Farber 1989, page 48).

1976

On January 7, 1976, G.D. Searle submited to the FDA their proposal for
the adoption of "Good Laboratory Practices" (Buzzard 1976b). G.D.
Searle's input was used in FDA's adoption of Good Laboratory
Practices.

In March 1976, the FDA Task Force completed a 500-page report with
15,000 pages of exhibits (80-page summary) to the FDA after completing
their investigation (Schmidt 1976c, page 4 of US Senate 1976b).

A preliminary statement about the breadth of the investigation from
FDA Toxicologist and Task Force team member, Dr. Andrian Gross before
the US Senate (Gross 1987a, page 1-2):

"Practices that were noted in connection with any given such
study were quite likely to have been noted also for other studies
that were audited, and this was a situation which was in no way
unexpected: after all, the set of all such studies executed by
that firm from about 1968 to the mid- 1970's were conducted in
essentially the same facilities, by virtually the same
tehnicians, professional workers and supervisors, and the nature
of such studies does not differ much whether a food additive or a
drug product is being tested for safety in laboratory animals. It
is in this sense, therefore, that the overall conclusion
summarized at the beginning of the Searle Task Force Report have
relevance to all the studies audited in 1975 (whether they had
references to aspartame or to any of the six drug products of
Searle's) and, by extension, to the totality of experimental
studies carried out by that firm around that time -- 1968 to
1975."

A few of the conclusions of the FDA Task Force (Gross 1987a, page
2-3):

"At the heart of FDA's regulatory process is its ability to rely
upon the integrity of the basic safety data submitted by sponsors
of regulated products. Our investigation clearly demonstrates
that, in the (case of the) GD Searle Company, we have no basis
for such reliance now."

"We have noted that Searle has not submitted all the facts of
experiments to FDA, retaining unto itself the unpermitted option
of filtering, interpreting, and not submitting information which
we would consider material to the safety evaluation of the
product . . . Finally, we have found instances of irrelevant or
unproductive animal research where experiments have been poorly
conceived, carelessly executed, or inaccurately analyzed or
reported."

"Some of our findings suggest an attitude of disregard for FDA's
mission of protection of the public health by selectively
reporting the results of studies in a manner which allay the
concerns of questions of an FDA reviewer."

"Unreliability in Searle's animal research does not imply,
however, that its animal studies have provided no useful
information on the safety of its products. Poorly controlled
experiments containing random errors blur the differences between
treated and control animals and increase the difficulty of
discriminating between the two populations to detect a product
induced effect. A positive finding of toxicity in the test
animals in a poorly controlled study provides a reasonable lower
bound on the true toxicity of the substance. The agency must be
free to conclude that the results from such a study, while
admittedly imprecise as to incidence or severity of the untoward
effect, cannot be overlooked in arriving at a decision concerning
the toxic potential of the product."

A few of the relevant findings summarized from various documents
describing the FDA Task Force Report:

a. "Excising masses (tumors) from live animals, in some cases
without histologic examination of the masses, in others without
reporting them to the FDA." (Schmidt 1976c, page 4 of US Senate
1976b) Searle's representatives, when caught and questioned about
these actions, stated that "these masses were in the head and
neck areas and prevented the animals from feeding."
(Buzzard 1976a)

"Failure to report to the FDA all internal tumors present in
the experimental rats, e.g., polyps in the uterus, ovary
neoplasms as well as other lesions." (Gross 1987a, page 8).

b. G.D. Searle "stored animal tissues in formaldehyde for so long
that they deteriorated." (Gordon 1987, page 496 of US Senate
1987; US Schmidt 1976c, page 25, 27 of US Senate 1976b)

c. "Instead of performing autopsies on rhesus monkeys that
suffered seizures after being fed aspartame, the company had
financed a new monkey seizure study with a different methodology
that showed no problems." (Gordon 1987, page 496 of US Senate
1987)

d. "Reporting animals as unavailable for necropsy when, in fact,
records indicate that the animals were available but Searle
choose not to purchase them." (Schmidt 1976c, page 5 of US Senate

1976b)

e. Animals which had died were sometimes recorded as being alive
and vica versa. "These include approximately 20 instances of
animals reported as dead and then reported as having vital signs
normal again at subsequent observation periods." (Gross 1985,
page S10835)

f. "Selecting statistical procedures which used a total number of
animals as the denominator when only a portion of the animals
were examined, thus reducing the significance of adverse
effects." (Schmidt 1976c, page 4 of US Senate 1976b)

g. G.D. Searle told the FDA that 12 lots of DKP were
manufacturered and tested in one study, yet only seven batches
were actually made. (Gross 1985, page S10835)

h. "Significant deviations from the protocols of several studies
were noted which may have compromised the value of these studies
. . . In at least one study, the Aspartame 52 weeks monkey study,
the protocol was written after the study had been initiated."
(Gross 1985, page S10835)

i. "It is significant to note that the Searle employee
responsible for reviewing most of the reproduction studies had
only one year of prior experience, working on population dynamics
of cotton tail rabbits while employed by Illinois Wildlife
Service. In order to prepare him for this title of 'Senior
Research Assistant in Teratology' (fetal damage) Searle bought
him books to read on the subject and also sent him to a meeting of
the Teratology Society. This qualified him to submit 18 of the
initial tests to the FDA, in addition to training an assistant
and 2 technicians. He certainly must have kept them busy because
Searle claimed that 329 teratology examinations were conducted in
just 2 days. He estimated that he himself examined about 30
fetuses a day, but officials for the Center for Food and Applied
Nutrition could never determine how that was possible." (Stoddard
1995a, page 9; Graves 1984, page S5500 of Congressional Record
1985a)

j. "In each study investigated, poor practices, inaccuracies, and
discrepancies were noted in the antemortem phases which could
compromise the study." (Gross 1985, page S10836 of Congressional
Record 1985b)

k. "Presenting information to FDA in a manner likely to obscure
problems, such as editing the report of a consulting pathologist
. . . Reporting one pathology report while failing to submit, or
make reference to another usually more adverse pathology report
on the same slide." (Schmidt 1976c, page 4-5 of US Senate 1976b)

l. Animals were not removed from the room during the twice per
month exterminator sprayings. (Gross 1985, page S10836 of
Congressional Record 1985b)

m. Often the substance being tested which was given to the
animals was not analyzed or tested for homogeneity. "No records
were found to indicate that any treatment mixtures used in the
studies were ever tested or assayed for pesticide content . . .
Running inventory records for either treatment mixtures or the
test compounds used in treatment mixtures are not maintained."
(Gross 1985, page S10836 of Congressional Record 1985b)

n. In the Aspartame (DKP) 115 week rat study the written
observations of the pathology report was changed by the
supervising pathologist, Dr. Rudolph Stejskal even though he was
not physically present during the autopsies and could not have
verified the observations of the pathologist who did perform
the autopsies. The pathologist who did perform some of the
autopsies had no formal training for such procedures. (Gross
1985, page S10837 of Congressional Record 1985b)

o. "Contrary to protocol, slides were not prepared of this
[unusual lesions from the Aspartame (DKP) study) tissue for
microscopic examinstions . . . ." (Gross 1985, page S10837 of
Congressional Record 1985b)

p. "In the Aspartame 46 weeks hamster study, blood samples
reported in the submission to FDA as 26 week values (for certain
specified animals) were found by our investigators as being, in
fact, values for different animals which were bled at the 38th
week. Many of the animals for which these values were reported
(to the FDA) were dead at the 38th week." (Gross 1985, page
S10838 of Congressional Record 1985b)

"It is apparent from the report, that the Appendix portion
contains all the individual (animal) values of clinical lab
data available from the raw data file. A selected portion of
these values appears to have been used in computing group
means (which were reported to the FDA). It is not clear what
criteria may have been used for selecting a portion of the
data or for deleting the others in computing the means
(reported to the FDA)." (Gross 1985, page S10838 of
Congressional Record 1985b)

q. "Searle technical personnel failed to adhere to protocols,
make accurate observations, sign and date records, and accurately
administer the product under test and proper lab procedures."
(Farber 1989, page 109)

r. [There were] "clerical or arithmetic errors which resulted in
reports of fewer tumors." (Schmidt 1976c, page 27 of US Senate
1976b)

s. [G.D. Searle] "delayed the reporting of alarming findings."
(Schmidt 1976c, page 27 of US Senate 1976b)