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THE BITTER TRUTH ABOUT ARTIFICIAL SWEETENERS Aspartame sugar substitutes cause worrying symptoms from memory loss

to brain tumours. But despite US FDA approval as a 'safe' food additive, aspartame is one of the most dangerous substances ever to be foisted upon an unsuspecting public. Extracted from Nexus Magazine, Volume 2, #28 (Oct-Nov '95) and Volume 3, #1 (Dec '95-Jan '96). PO Box 30, Mapleton Qld 4560 Australia. nexus@peg.apc.org Telephone: +61 (0)7 5442 9280; Fax: +61 (0)7 5442 9381 From our web page at: http://www.peg.apc.org/~nexus/ 1995 by Mark D. Gold, 35 Inman St, Cambridge, MA 02139, USA Phone: (617) 497 7843, E-mail: mgold@tiac.net Web page: http://www.tiac.net/mgold/ users/health.html Extracted with permission from Blazing Tattles, Vol. 4, Nos. 4, 5, 6, April-June 1995 PO Box 1073, Half Moon Bay, CA 94019 USA. Email: blazing@igc.apc.org www.concentric.net/~blazingt Aspartame is the technical name for the brand names, NutraSweet, Equal, Spoonful, and Equal-Measure. Aspartame was discovered by accident in 1965, when James Schlatter, a chemist of G.D. Searle Company was testing an anti-ulcer drug. Aspartame was approved for dry goods in 1981 and for carbonated beverages in 1983. It was originally approved for dry goods on July 26, 1974, but objections filed by neuroscience researcher Dr John W. Olney and Consumer attorney James Turner in August 1974 as well as investigations of G.D. Searle's research practices caused the US Food and Drug Administration (FDA) to put approval of aspartame on hold (December 5, 1974). In 1985, Monsanto purchased G.D. Searle and made Searle Pharmaceuticals and The NutraSweet Company separate subsidiaries. Aspartame is, by far, the most dangerous substance on the market

that is added to foods. Aspartame accounts for over 75 percent of the adverse reactions to food additives reported to the US Food and Drug Administration (FDA). Many of these reactions are very serious including seizures and death as recently disclosed in a February 1994 Department of Health and Human Services report.(1) A few of the 90 different documented symptoms listed in the report as being caused by aspartame include: Headaches/migraines, dizziness, seizures, nausea, numbness, muscle spasms, weight gain, rashes, depression, fatigue, irritability, tachycardia, insomnia, vision problems, hearing loss, heart palpitations, breathing difficulties, anxiety attacks, slurred speech, loss of taste, tinnitus, vertigo, memory loss, and joint pain. According to researchers and physicians studying the adverse effects of aspartame, the following chronic illnesses can be triggered or worsened by ingesting of aspartame:(2) Brain tumors, multiple sclerosis, epilepsy, chronic fatigue syndrome, parkinson's disease, alzheimer's, mental retardation, lymphoma, birth defects, fibromyalgia, and diabetes. Aspartame is made up of three chemicals: Aspartic acid, phenylalanine, and methanol. The book, Prescription for Nutritional Healing, by James and Phyllis Balch, lists aspartame under the category of "chemical poison." As you shall see, that is exactly what it is. ASPARTIC ACID (40% OF ASPARTAME) Dr Russell L. Blaylock, a professor of Neurosurgery at the Medical University of Mississippi, recently published a book thoroughly detailing the damage that is caused by the ingestion of excessive aspartic acid from aspartame. [Ninety nine percent of monosodium glutamate 9MSG) is glutamic acid. The damage it causes is also documented in Blaylock's book.] Blaylock makes use of almost 500 scientific references to show how excess free excitatory amino acids such as aspartic acid and glutamic acid in our food supply are causing serious chronic neurological disorders and a myriad of other acute symptoms.(3) SUMMARY OF HOW ASPARTATE (AND GLUTAMATE) CAUSE DAMAGE Aspartate and glutamate act as neurotransmitters in the brain by facilitating the transmittion of information from neuron to neuron. Too much aspartate or glutamate in the brain kills certain neurons by allowing the influx of too much calcium into the cells. This influx triggers excessive amounts of free radicals which kill the cells. The neural cell damage that can be caused by excessive aspartate and glutamate is why they are referred to as "excitotoxins." They "excite" or stimulate the neural cells to death. Aspartic acid is an amino acid. Taken in its free form (unbound to proteins) it significantly raises the blood plasma level of aspartate and glutamate. The excess aspartate and glutamate in the blood plasma shortly after ingesting aspartame or products with free glutamic acid (glutamate precursor) leads to a high level of those neurotransmitters in certain areas of the brain.

The blood brain barrier (BBB) which normally protects the brain from excess glutamate and aspartate as well as toxins 1) is not fully developed during childhood, 2) does not fully protect all areas of the brain, 3) is damaged by numerous chronic and acute conditions, and 4) allows seepage of excess glutamate and aspartate into the brain even when intact. The excess glutamate and aspartate slowly begin to destroy neurons. The large majority (75%+) of neural cells in a particular area of the brain are killed before any clinical symptoms of a chronic illness are noticed. A few of the many chronic illnesses that have been shown to be contributed to by long-term exposure excitatory amino acid damage include: Multiple sclerosis (MS), ALS, memory loss, hormonal problems, hearing loss, epilepsy, Alzheimer's disease, Parkinson's disease, hypoglycemia, AIDS dementia, brain lessions, and neuroendocrine disorders. The risk to infants, children, pregnant women, the elderly, and persons with certain chronic health problems from excitotoxins are great. Even the Federation of American Societies For Experimental Biology (FASEB), which usually understates problems and mimmicks the FDA party-line, recently stated in a review that "it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children. The Existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L-glutamic acid should be avoided by women of childbearing age and individuals with affective disorders."(4) Aspartic acid from aspartame has the same deleterious effects on the body as glutamic acid. The exact mechanism of acute reactions to excess free glutamate and aspartate is currently being debated. As reported to the FDA, those reactions include:(5) Headaches/migraines, nausea, abdominal pains, fatigue (blocks sufficient glucose entry into brain), sleep problems, vision problems, anxiety attacks, depression, and asthma/chest tightness. One common complaint of persons suffering from the effect of aspartame is memory loss. Ironically, in 1987, G.D. Searle, the manufacturer of aspartame, undertook a search for a drug to combat memory loss caused by excititory amino acid damage. Blaylock is one of many scientists and physicians who are concerned about excititory amino acid damage caused by ingestion of aspartame and MSG. A few of the many experts who have spoken out against the damage being caused by aspartate and glutamate include Adrienne Samuels, Ph.D., an experimental psychologist specializing in research design. Another is Olney, a professor in the department of psychiatry, School of Medicine, Washington University, a neuroscientist and researcher, and one of the world's foremost authorities on excitotoxins. (He informed Searle in 1971 that aspartic acid caused holes in the brain of mice.) Also included is Francis J. Waickman, M.D., a recipient of the Rinkel and Forman Awards, and Board certified in Pediatrics, Allergy, and Immunology. Other concerned scientists include: John R. Hain, M.D., Board Certified Forensic Pathologist, and H.J. Roberts, M.D., FACP, FCCP,

Diabetic Specialist, and selected by a national medical publication as "The Best Doctor in the US" John Samuels is concerned, also. He compiled a list of scientific research sufficient to show the dangers of ingesting excess free glutamic and aspartic acid. And there are many more who can be added to this long list. PHENYLALANINE (50% OF ASPARTAME) Phenylalanine is an amino acid normally found in the brain. Persons with the genetic disorder, phenylketonuria (PKU) cannot metabolize phenylalanine. This leads to dangerously high levels of phenylalanine in the brain (sometimes lethal). It has been shown that ingesting aspartame, especially along with carbohydrates can lead to excess levels of phenylalanine in the brain even in persons who do not have PKU. This is not just a theory, as many people who have eaten large amounts of aspartame over a long period of time and do not have PKU have been shown to have excessive levels of phenylalanine in the blood. Excessive levels of phenylalanine in the brain can cause the levels of seratonin in the brain to decrease, leading to emotional disorders such as depression. It was shown in human testing that phenylalanine levels of the blood were increased significantly in human subjects who chronically used aspartame.(6) Even a single use of aspartame raised the blood phenylalanine levels. In his testimony before the US Congress, Dr Louis J. Elsas showed that high blood phenylalanine can be concentrated in parts of the brain, and is especially dangerous for infants and fetuses. He also showed that phenylalanine is metabolised much more effeciently by rodents than by humans.(7) One account of a case of extremely high phenylalanine levels caused by aspartame was recently published the the "Wednesday Journal" in an article entitled "An Aspartame Nightmare." John Cook began drinking 6 to 8 diet drinks every day. His symptoms started out as memory loss and frequent headaches. He began to crave more aspartame-sweetened drinks. His condition deteriorated so much that he experienced wide mood swings and violent rages. Even though he did not suffer from PKU, a blood test revealed a phenylalanine level of 80 mg/dl. He also showed abnormal brain function and brain damage. After he kicked his aspartame habit, his symptoms improved dramatically.(8) As Blaylock points out in his book, early studies measuring phenylalanine buildup in the brain were flawed. Investigators who measured specific brain regions and not the average throughout the brain notice significant rises in phenylalanine levels. Specifically the hypothalamus, medulla oblongata, and corpus striatum areas of the brain had the largest increases in phenylalanine. Blaylock goes on to point out that excessive buildup of phenylalanine in the brain can cause schizophrenia or make one more susceptible to seizures. Therefore, long-term, excessive use of aspartame may provided a boost to sales of seratonin reuptake inhibitors such as Prozac and drugs to control schizophrenia and seizures. METHANOL (AKA WOOD ALCOHOL/POISON) (10% OF ASPARTAME) Methanol/wood alcohol is a deadly poison. Some people may

remember methanol as the poison that has caused some "skid row" alcoholics to end up blind or dead. Methanol is gradually released in the small intestine when the methyl group of aspartame encounter the enzyme chymotrypsin. The absorption of methanol into the body is sped up considerably when free methanol is ingested. Free methanol is created from aspartame when it is heated to above 86 Fahrenheit (30 Centigrade). This would occur when aspartame-containing product is improperly stored or when it is heated (e.g., as part of a "food" product such as Jello). Methanol breaks down into formic acid and formaldehyde in the body. Formaldehyde is a deadly neurotoxin. An EPA assessment of methanol states that methanol "is considered a cumulative poison due to the low rate of excretion once it is absorbed. In the body, methanol is oxidized to formaldehyde and formic acid; both of these metabolites are toxic." The recommend a limit of consumption of 7.8 mg/day. A one-liter (approx. 1 quart) aspartame-sweetened beverage contains about 56 mg of methanol. Heavy users of aspartame-containing products consume as much as 250 mg of methanol daily or 32 times the EPA limit.(9) Symptoms from methanol poisoning include headaches, ear buzzing, dizziness, nausea, gastrointestinal disturbances, weakness, vertigo, chills, memory lapses, numbness and shooting pains in the extremities, behavioral disturbances, and neuritis. The most well knowm problems from methanol poisoning are vision problems including misty vision, progressive contraction of visual fields, blurring of vision, obscuration of vision, retinal damage, and blindness. Formaldehye is a known carcinogen, causes retinal damage, interferes with DNA replication, causes birth defects.(10) Due to the lack of a couple of key enzymes, humans are many times more sensitive to the toxic effects of methanol than animals. Therefore, tests of aspartame or methanol on animals do not accurately reflect the danger for humans. As pointed out by Dr Woodrow C. Monte, Director of the Food Science and Nutrition Laboratory at Arizona State University, "There are no human or mammalian studies to evaluate the possible mutagenic, teratogenic, or carcinogenic effects of chronic administration of methyl alcohol."(11) He was so concerned about the unresolved safety issues that he filed suit with the FDA requesting a hearing to address these issues. He asked the FDA to "slow down on this soft drink issue long enough to answer some of the important questions. It's not fair that you are leaving the full burden of proof on the few of us who are concerned and have such limited resources. You must remember that you are the American public's last defense. Once you allow usage (of aspartame) there is literally nothing I or my colleagues can do to reverse the course. Aspartame will then join saccharin, the sulfiting agents, and God knows how many other questionable compounds enjoined to insult the human constitution with governmental approval."(10) Shortly thereafter, the Commissioner of the FDA, Arthur Hull Hayes, Jr., approved the use of aspartame in carbonated beverages, he then left for a position with G.D. Searle's Public Relations firm.(11) It has been pointed out that some fruit juices and alcoholic beverages contain small amounts of methanol. It is important to remember, however, that methanol never appears alone. In every case, ethanol is present, usually in much higher amounts. Ethanol is an

antidote for methanol toxicity in humans.(9) The troops of Desert Storm were "treated" to large amounts of aspartame-sweetened beverages which had been heated to over 86o F. in the Saudi Arabian sun. Many of them returned home with numerous disorders similar to what has been seen in persons who have been chemically poisoned by formaldehyde. The free methanol in the beverages may have been a contributing factor in these illnesses. Other breakdown products of aspartame such as DKP (discussed below) may also have been a factor. In a 1993 act that can only be described as "unconscionable," the FDA approved aspartame as an ingredient in numerous food items that would always be heated to above 86F (30C). DIKETOPIPERAZINE (DKP) DKP is a by-product of aspartame metabolism. DKP has been implicated in the occurance of brain tumors. Olney noticed that DKP, when nitrosated in the gut, produced a compound which was similar to N-nitrosourea, a powerful brain tumor causing chemical. Some authors have said that DKP is produced after aspartame ingestion. I am not sure if that is correct. It is definately true that DKP is formed in liquid aspartame-containing products during prolonged storage. G.D. Searle conducted animal experiments on the safety of DKP. The FDA found numerous experimental errors occured, including "clerical errors, mixed-up animals, animals not getting drugs they were supposed to get, pathological specimens lost because of improper handling," and many other errors.(12) These sloppy laboratory procedures may explain why both the test and control animals had sixteen times more brain tumors than would be expected in experiments of this length. In an ironic twist, shortly after these experimental errors were discovered, the FDA used guidelines recommened by G.D. Searle to devlop the Industry-wide FDA standards for Good Laboratory Practies.(11) DKP has also been implicated as a cause of uterine polyps and changes in blood cholesterol by FDA Toxicologist Dr Jacqueline Verrett in her testimony before the US Senate.(13) AILMENTS RESULTING FROM ASPARTAME The components of aspartame can lead to a wide variety of ailments. Some of these problems occur gradually, others are immediate, acute reactions. There is an enormous population of people who are suffering from symtpoms contributed to by aspartame, yet they have no idea why herbs or drugs are not helping relieve their problems. There are other users of aspartame who appear not to be suffering immediate reactions to aspartame. But even these individuals are susceptible to the long-term damage caused by excitatory amino acids, phenylalanine, methanol, and DKP. A few of the many disorders that are of particular concern to me include the following. Birth Defects. Dr Diana Dow Edwards, a researcher was funded by Monsanto to study possible birth defects caused by the ingestion of aspartame.

After preliminary data showed damaging information about aspartame, funding for the study was cut off. A Gentetic Pediatrician at Emory University has testified that aspartame is causing birth defects.7360-367. In the book, While Waiting: A Prenatal Guidebook by George R. Verrilli, M.D. and Anne Marie Mueser, it is stated that aspartame is suspected of causing brain damage in sensitive individuals. A fetus may be at risk for these effects. Some researchers have suggested that high doses of aspartame may be associated with problems ranging from dizziness and subtle brain changes to mental retardation. Cancer (Brain Cancer). In 1981, Satya Dubey, an FDA statistician, stated that the brain tumor data on aspartame was so "worrisome" that he could not recommend approval of NutraSweet.(14) In a two-year study conducted by the manufacturer of aspartame, twelve of the 320 rats fed a normal diet and aspartame developed brain tumors while none of the control rats had tumors. Five of the twelve tumors were in rats given a low dose of aspartame.(15) The approval of aspartame was a violation of the Delaney Amendment which was supposed to prevent cancer-causing substances such as methanol (formaldehye) and DKP from entering our food supply. The late Dr Adrian Gross, an FDA toxicologist, testified before the US Congress that aspartame was capable of producing brain tumors. This made it illegal for the FDA to set an allowable daily intake at any level. He stated in his testimony that Searle's studies were "to a large extent unreliable" and that "at least one of those studies has established beyond any reasonable doubt that aspartame is capable of inducing brain tumors in experimental animals...." He concluded his testimony by asking, "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? .... And if the FDA itself elects to violate the law, who is left to protect the health of the public?"(16) In the mid-1970s it was discovered that the manufacturer of aspartame falsified studies in several ways. One of the techniques used was to cut tumors out of test animals and put them back in the study. Another technique used to falsify the studies was to list animals that had actually died as surviving the study. Thus, the data on brain tumors was likely worse than discussed above. In addition, a former employee of the manufacturer of aspartame, Raymond Schroeder told the FDA on July 13, 1977 that the particles of DKP were so large that the rats could dicriminate between the DKP and their normal diet.(12) It is interesting to note that the incidence of brain tumors in persons over 65 years of age has increase 67% between the years 1973 and 1990. Brain tumors in all age groups has jumped 10%. The greatest increase has come during the years 1985-1987.(17) In his book, Aspartame (NutraSweet). Is it Safe?, Roberts gives evidence that aspartame can cause a particularly dangerous form of cancer - primary lymphoma of the brain. Diabetes. The American Diabetes Association (ADA) is actually recommending

this chemical poison to persons with diabetes. According to research conducted by H.J. Roberts, a diabetes specialist, a member of the ADA, and an authority on artificial sweetners, aspartame: 1) Leads to the precipitation of clinical diabetes. 2) Causes poorer diabetic control in diebetics on insulin or oral drugs. 3) Leads to the aggravation of diabetic complications such as retinopathy, cataracts, neuropathy and gastroparesis. 4) Causes convulsions. In a statement concerning the use of products containing aspartain by persons with diabetes and hypoglycemia, Roberts says: "Unfortunately, many patients in my practice, and others seen in consultation, developed serious metabolic, neurologic and other complications that could be specifically attributed to using aspartame products. This was evidenced by: "The loss of diabetic control, the intensification of hypoglycemia, the occurrence of presumed 'insulin reactions' (including convulsions) that proved to be aspartame reactions, and the precipitation, aggravation or simulation of diabetic complications (especially impaired vision and neuropathy) while using these products. "Dramatic improvement of such features after avoiding aspartame, and the prompt predictable recurrence of these problems when the patient resumed aspartame products, knowingly or inadvertently." Roberts goes on to say: "I regret the failure of other physicians and the American Diabetes Association (ADA) to sound appropriate warnings to patients and consumers based on these repeated findings which have been described in my corporate-neutral studies and publications." Blaylock stated that excitotoxins such as that found in aspartame can precipitate diabetes in persons who are genetically susceptible to the disease.(5) Emotional Disorders. A double blind study of the effects of aspartame on persons with mood disorders was recently conducted by Dr Ralph G. Walton. Since the study wasn't funded/controlled by the makers of aspartame, The NutraSweet Company refused to sell him the aspartame. Walton was forced to obtain and certify it from an outside source. The study showed a large increase in serious symptoms for persons taking aspartame. Since some of the symptoms were so serious, the Institutional Review Board had to stop the study. Three of the participants had said that they had been "poisoned" by aspartame. Walton concludes that "individuals with mood disorders are particularly sensitive to this artificial sweetener; its use in this population should be discouraged."(18) Aware that the experiment could not be repeated because of the danger to the test subjects, Walton was recently quoted as saying, "I know it causes seizures. I'm

convinced also that it definitely causes behavioral changes. I'm very angry that this substance is on the market. I personally question the reliability and validity of any studies funded by the NutraSweet Company."(19) There are numerous reported cases of low brain serotonin levels, depression and other emotional disorders that have been linked to aspartame and often are relieved by stopping the intake of aspartame. Researchers have pointed out that increasing in phenylalanine levels in the brain, which can and does occur in persons without PKU, leads to a decreased level of the neurotransmitter, serotonin, which leads to a variety of emotional disorders. Dr William M. Pardridge of UCLA testified before the US Senate that a youth drinking four 16-ounce bottles of diet soda per day leads to an enormous increase in the phenylalanine level. Epilepsy/Seizures. With the large and growing number of seizures caused by aspartame, it is sad to see that the Epilepsy Foundation is promoting the "safety" of aspartame. At Massachusetts Institute of Technology, 80 people who had suffered seizures after ingesting aspartame were surveyed. Community Nutrition Institute concluded the following about the survey: "These 80 cases meet the FDA's own definition of an imminent hazard to the public health, which requires the FDA to expeditiously remove a product from the market." Both the Air Force's magazine Flying Safety and the Navy's magazine, Navy Physiology published articles warning about the many dangers of aspartame including the cumlative deliterious effects of methanol and the greater likelihood of birth defects. The articles note that the ingestion of aspartame can make pilots more susceptible to seizures and vertigo. Twenty articles sounding warnings about ingesting aspartame while flying have also appeared in the National Business Aircraft Association Digest (NBAA Digest 1993), Aviation Medical Bulletin (1988), The Aviation Consumer (1988), Canadian General Aviation News (1990), Pacific Flyer (1988), General Aviation News (1989), Aviation Safety Digest (1989), and Plane & Pilot (1990) and a paper warning about aspartame was presented at the 57th Annual Meeting of the Aerospace Medical Association (Gaffney 1986). Recently, a hotline was set up for pilots suffering from acute reactions to aspartame ingestion. Over 600 pilots have reported symptoms including some who have reported suffering grand mal seizures in the cockpit due to aspartame.(21) One of the original studies on aspartame was performed in 1969 by an independent scientist, Dr Harry Waisman. He studied the effects of aspartame on infant primates. Out of the seven infant monkeys, one died after 300 days and five others had grand mal seizures. Of course, these negative findings were not submitted to the FDA during the approval process.(22) Why don't we hear about these things? The reason many people do not hear about serious reactions to aspartame is twofold:

1) Lack of awareness by the general population. Aspartame-caused diseases are not reported in the newspapers like plane crashes. This is because these incidents occur one at a time in thousands of different locations across the US. 2) Most people do not associate their symptoms with the long-term use of aspartame. For the people who have killed a significant percentage of the brain cells and thereby caused a chronic illness, there is no way that they would normally associate such an illness with aspartame consumption. How aspartame was approved is a lesson in how chemical and pharmaceutical companies can manipulate government agencies such as the FDA, "bribe" organizations such as the American Dietetic Association, and flood the scientific community with flawed and fraudulent industry-sponsored studies funded by the makers of aspartame. Erik Millstone, a researcher at the Science Policy Research Unit of Sussex University has compiled thousands of pages of evidence, some of which have been obtained using the freedom of information act 23, showing: 1. Laboratory tests were faked and dangers were concealed. 2. Tumors were removed from animals and animals that had died were "restored to life" in laboratory records. 3. False and misleading statements were made to the FDA. 4. The two US Attorneys given the task of bringing fraud charges against the aspartame manufacturer took positions with the manufacturer's law firm, letting the statute of limitations run out. 5. The Commissioner of the FDA overruled the objections of the FDA's own scientific board of inquiry. Shortly after that decision, he took a position with Burson-Marsteller, the firm in charge of public relations for G.D. Searle. A Public Board of Inquiry (PBOI) was conducted in 1980. There were three scientists who reviewed the objections of Olney and Turner to the approval of aspartame. They voted unanimously against aspartame's approval. The FDA Commissioner, Dr Arthur Hull Hayes, Jr. then created a 5-person Scientific Commission to review the PBOI findings. After it became clear that the Commission would uphold the PBOI's decision by a vote of 3 to 2, another person was added to the Commission, creating a deadlocked vote. This allowed the FDA Commissioner to break the deadlock and approve aspartame for dry goods in 1981. Dr Jacqueline Verrett, the Senior Scientist in an FDA Bureau of Foods review team created in August 1977 to review the Bressler Report (a report that detailed G.D. Searle's abuses during the pre-approval testing) said: "It was pretty obvious that somewhere along the line, the bureau officials were working up to a whitewash." In 1987, Verrett testified before the US Senate stating that the experiments conducted by Searle were a "disaster." She stated that her team was instructed not to comment on or be concerned with the overall validity of the studies. She stated that questions about birth defects have not been answered. She continued her testimony by discussing the fact that DKP has been

shown to increase uterine polyps and change blood cholesterol and that increasing the temperature of the product leads to an increase in production of DKP.(13) Revolving doors The FDA and the manufacturers of aspartame have had a rovolving door of employment for many years. In addition to the FDA Commissioner and two US Attorneys leaving to take positions with companies connected with G.D. Searle, four other FDA officials connected with the approval of aspartame took positions connected with the NutraSweet industry between 1979 and 1982 including the Deputy FDA Commissioner, the Special Assistant to the FDA Commissioner, the Associate Director of the Bureau of Foods and Toxicology and the Attorney involved with the Public Board of Inquiry.(24) It is important to realize that this type of revolving-door activity has been going on for decades. The Townsend Letter for Doctors (11/92) reported on a study revealing that 37 of 49 top FDA officials who left the FDA took positions with companies they had regulated. They also reported that over 150 FDA officials owned stock in drug companies they were assigned to manage. Many organizations and universities receive large sums of money from companies connected to the NutraSweet Association, a group of companies promoting the use of aspartame. In January 1993, the American Dietetic Association received a US$75,000 grant from the NutraSweet Company. The American Dietetic Association has stated that the NutraSweet Company writes their "Facts" sheets.(25) Many other "independent" organizations and researchers receive large sums of money from the manufacturers of aspartame. The American Diabetes Association has received a large amount of money from Nutrasweet, including money to run a cooking school in Chicago (presumably to teach diabetes how to use Nutrasweet in their cooking). A researcher in New England who has pointed out the dangers of aspartame in the past is now a Monsanto consultant. Another researcher in the Southeastern US had testified about the dangers of aspartame on fetuses. An investigative reporter has discovered that he was told to keep his mouth shut to avoid causing the loss of a large grant from a diet cola manufacturer in the NutraSweet Association. What is the FDA doing to protect the consumer from the dangers of aspartame? Less than nothing. In 1992, the FDA approved aspartame for use in malt beverages, breakfast cereals, and refrigerated puddings and fillings. In 1993 the FDA approved aspartame for use in hard and soft candies, non-alcoholic favored beverages, tea beverages, fruit juices and concentrates, baked goods and baking mixes, and frostings, toppings and fillings for baked goods. In 1991, the FDA banned the importation of stevia. The powder of the leaf has been used for hundreds of years as an alternative sweetner. It is used widely in Japan with no adverse effects.

Scientists involved in reviewing stevia have declared it to be safe for human consumption - something which has been well known in many parts of the world where it is not banned. Everyone that I have spoken with in regards to this issue believes that stevia was banned to keep the product from taking hold in the US and cutting into sales of aspartame.(26) What is the US Congress doing to protect the consumer from the dangers of aspartame? Nothing. What is the US Administration (President) doing to protect the consumer from the dangers of aspartame? Nothing. Aspartame consumption is not only a problem in the US. It is being sold in over 70 countries throughout the world. ASPARTAME CAN BE FOUND IN: - instant breakfasts - breath mints - cereals - sugar-free chewing gum - cocoa mixes - coffee beverages - frozen desserts - gelatin desserts - juice beverages - laxatives - multivitamins - milk drinks - pharmaceuticals and supplements - shake mixes - soft drinks - tabletop sweeteners - tea beverages - instant teas and coffees - topping mixes

- wine coolers - yogurt I have been told that aspartame has been found in products where it is not listed on the label. One must be particular careful of pharmaceuticals and supplements. I have been informed that even some supplements made by well-known supplement manufacturers such as Twinlabs contain aspartame. The information I have related above is just the tip of the iceberg as far as damaging information about aspartame. In order for the reader to find out more, I have included some resources below. BOOKS Blaylock, Russell L., Excitotoxins: The Taste That Kills (Health Press, Santa Fe, New Mexico, c1994). One of the best books available on excitotoxins. Well worth reading!

H. J. Roberts, M.D., Aspartame (NutraSweet), Is it Safe? Available from the Aspartame Consumer Safety Network.

Sweet'ner Dearest, Available from the Aspartame Consumer Safety Network

Mary Nash Stoddard, The Deadly Deception, Available from the Aspartame Consumer Safety Network.

Barbara Mullarkey, Editor, Bittersweet Aspartame - A Diet Delusion,

Available from the Aspartame Consumer Safety Network.

The Aspartame Consumer Safety Network, The Aspartame Consumer Safety Network Synopsis.

Dennis Remington, M.D. and Barbara Higa, R.D., The Bitter Truth About Artificial Sweetners, Available from the Aspartame Consumer Safety Network ASPARTAME CONSUMER SAFETY NETWORK

PO Box 780634 Dallas, Texas 75378, USA. Phone: (214) 352-4268 REFERENCES (1) Department of Health and Human Services, Report on All Adverse Reactions in the Adverse Reaction Monitoring System, (February 25 and 28, 1994). (2) Compiled by researchers, physicians, and artificial sweetner experts for Mission Possible, a group dedicated to warning consumers about aspartame. (3) Excitotoxins: The Taste That Kills, by Russell L. Blaylock, M.D. (4) Safety of Amino Acids, Life Sciences Research Office, FASEB, FDA Contract No. 223-88-2124, Task Order No. 8. (5) FDA Adverse Reaction Monitoring System. (6) Wurtman and Walker, "Dietary Phenylalanine and Brain Function," Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function., Washington, D.C., May 8, 1987. (7) Hearing Before the Committee On Labor and Human Resources United States Senate, First Session on Examing the Health and Safety Concerns of Nutrasweet (Aspartame). (8) Account of John Cook as published in Informed Consent Magazine. "How Safe Is Your Artificial Sweetner" by Barbara Mullarkey, September/October 1994. (9) Woodrow C. Monte, Ph.D., R.D., "Aspartame: Methanol and the Public Health," Journal of Applied Nutrition, 36 (1): 42-53. (10) US Court of Appeals for the District of Columbia Circuit, No. 84-1153 Community Nutrition Institute and Dr Woodrow Monte v. Dr Mark Novitch, Acting Commissioner, US FDA (9/24/85). (11) Aspartame Time Line by Barbara Mullarkey as published in Informed Consent Magazine, May/June 1994. (12) FDA Searle Investigation Task Force. "Final Report of Investigation of G.D. Searle Company." (March 24, 1976) (13) Testimony of Dr Jacqueline Verrett, FDA Toxicologist before the US Senate Committee on Labor and Human Resources, (November 3, 1987). (14) Internal FDA memorandum. (15) Analysis prepared by Dr John Olney as a statement before the Aspartame Board of Inquire of the FDA. Also Excitotoxins by Russell Blaylock, M.D.

(16) Congressional Record SID835: 131 (August 1, 1985) (17) National Cancer Institute SEER Program Data. (18) Walton, Ralph G., Robert Hudak, Ruth Green-Waite "Adverse Reactions to Aspartame: Double-Blind Challenge in Patients from a Vulnerable Population," Biological Psychiatry, 1993:34:13-17. (19) Barbara Mullarkey, "How Safe Is Your Artificial Sweetner," September/October 1994 issue of Informed Consent Magazine. (20) US Air Force. "Aspartame Alert." Flying Safety, 48 (5): 20-21 (May 1992). (21) Reported by the Aspartame Consumer Safety Network. (22) Barbara Mullarkey, Bittersweet Aspartame, A Diet Delusion. (23) Millstone, Eric "Sweet and Sour." The Ecologist, 25 (March/April 1994). (24) Mary Nash Stoddard, Editor, "The Deadly Deception," Aspartame Consumer Safety Network. (25) ADA Courier, January 1993, Volume 32, Number 1. (26) "FDA Rejects AHPA Stevia Petition" by Mark Blumenthal, Whole Foods, April 1994.

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ORDER FORM temperature of 110oF could reach temperatures of 38oC (101oF) to 39oC (103oF) (0.92-0.94 x 110oF). "Overall, the study, considered together with representative historical temperature data show that soft drinks will frequently be exposed to temperatures of 32oC (90oF) to 49oC (120oF). In some cases product temperatures as high as 66oC (151oF) (especially in the southwestern United

States) can be reached. "The effects of these high product temperatures on [aspartame] degradation and the formation of degradation products, and the effects of temperature variation (for example, soft drinks displayed at a service station may reach temperatures of 49oC (120oF) for most of the afternoon, drop in temperature overnight, and heat up again during the following day) cannot be determined from the data submitted by Searle to the FDA." When aspartame in liquid is subjected to high temperatures, the breakdown of aspartame and the formation of large amounts of DKP happens very quickly as shown by Prudel (1986). In addition, Boehm and Bada showed that high tempatures can cause racemization of the free amino acids leading to significant amounts of unnatural D-type amino acids--much more than is produced through cooking normal, healthy foods (Boehm 1984). Gaines (1987) also showed that racemization can occur in the breakdown products of aspartame. The health affects of large amounts of these Dtype amino acids are not well known. In a statement submitted to the U.S. Senate hearings on aspartame, Dr. Jeffrey Bada had this to say about aspartame decomposition (Bada 1987): "Aspartame, a dipeptide containing the amino acids phenylalanine and aspartic acid, is prone to a number of decomposition/alteration reactions. Dominant are cyclization to the cyclic dipeptide or diketopiperazine [DKP] and stereochemical (racemization) inversion producing the unnatural Dstereoisomers of the amino acids. . . In some instances, however, these reactions are very significant, and the reaction products which are produced are not well-studied as far as their nutritional/toxicological properties are concerned. Some examples where these reactions could be significant are in soft drinks exposed to warm temperatures for prolonged periods and in consumer misuse of aspartame such as in cooking or baking." In an article for the Wednesday Journal, Jeffrey Bada, Ph.D. discusses some of his concerns relating to the chemical rearrangement of aspartame (Mullarkey 1992, page 10): "The chemistry of aspartame is changed when Boiled," says Bada. "There is internal rearrangement of its structure. The L-isomers of phenylalanine and aspartic acid change to unnatural D-isomers which are metabolized differently. How it is metabolized is anybody's guess. "Searle people," Bada Continues, "tend to dismiss stereo chemical inversion as unimportant. Chris Tschanz, director of aspartame clinical research,

and Louis D. Stegnik, M.D. of the University of Iowa College of Medicine, visited me and admitted that nobody thought of looking at aspartame the way we did." In 1993, the FDA approved aspartame for use in tea beverages, baked goods and mixes, frostings and toppings (Mullarkey 1994a, page 51). There are many products on the market which contain aspartame and are heated to high temperatures. Therefore, Dr. Bada's comment of aspartame's "misuse" in cooking or baking no longer applies--it is now a condoned use of aspartame. Beta-aspartame is another breakdown product which has been found in aspartame-containing products which may contribute to health problems in some individuals (Lawrence 1987, Stamp 1989b). The fact that it occurs in small amounts does not necessarily mean that it is harmless. It has been shown that aspartame can react with other food additives to form chemicals of unknown health consequences. Hussein showed that aspartame reacts with aldehydes which are commonly found flavor compounds in sodas and chewing gum (Hussein 1984). Cha has shown that aspartame can react with vanillin used in foods (Cha 1988). These reactions are very important considerations. As an example of how additive reactions can cause the formation of toxic substances, researchers tested three different food additives individually on mice. None of the mice reacted negatively. When the three food additives were tested in pairs, the mice became ill. When all three food additives were tested at once, the mice died (Ershoff 1976). Aspartame In Solid Food Products -------------------------------Graves showed that in a dried and acidified state, aspartame that is heated to 230oF breaks down into its components as described above (Graves 1987). It was also shown that other, previously unknown degredation products are formed when the dried product is heated to high temperatures. This type of aspartame breakdown would occur in baking goods that contain aspartame. Conclusion ---------Aspartame-containing products which are ingested in the realworld are chemically very different than 98-100% aspartame which is given in laboratory experiments. The large amount of breakdown products such as DKP, free phenylalanine, methanol, and others may play an important role in aspartame's negative health affects. Aspartame's strong tendancy to react with other food ingredients to form unique chemical compounds and the tendancy of the free amino acids to racemize at high temperatures are also very important considerations regarding its toxicity. Please keep this in mind while you read the rest of this review. What people are ingesting in the real world IS NOT the same aspartame as it was originally put into the food, but a very different and possibly much more dangerous toxic

chemical soup.

2. Average Daily Intake of Aspartame The article states: "The replacement of all sweeteners with aspartame has been estimated to yield an intake of 867 mg of aspartame/day, which translates to only 87 mg of methanol." Before we can discuss aspartame toxicity, it is crucial to set the record straight regarding aspartame intake. The statement in the article has three problems: a. The increasing use of aspartame has not lead to a decreased use in caloric sweeteners. According to the U.S. Department of Agriculture, the per capita consumption of aspartame quadrupled between the years 1983 and 1988 (USDA 1988). Since that time, the use of aspartame has continued to increase. Dr. H.J. Roberts reported on Wall Street Journal articles which stated that "the diet beverage market was increasing at a rate of 20-25% annually" and that "consumers began drinking up to six times as many diet drinks as those using sugared sodas." (WSJ 1988, WSJ 1989) Gregory Gordon wrote in a UPI Investigation that "Roy Burry, an analyst with Kidder-Peabody, Inc., said the exploding diet market now accounts for 24 percent of soft drink sales, compared with 10 percent in the late 1970s, and is growing at 20 to 25 percent a year (Gordon 1987, page 484 of US Senate 1987). From 1982 to 1988, the per capita consumption of caloric sweeteners jumped from 123.2 pounds to 133.5 pounds per year. Therefore the increased use of aspartame has not decreased the use of caloric sweetener products in the United States (USDA 1988). b. Studies have shown that when their diet is not closely monitored, many people use artificial sweeteners in addition to sugar products and not instead of sugar products (Chen 1991, Stellman 1986). Therefore, an increased use of aspartame will not necessarily alter the sugar-craving feeding behavior of the majority of persons. If they consume a non-sugar, aspartamecontaining beverage at one point in the day, they will simply make up for the lack of sugar at some other point in the day. Some studies have shown an increased consumption of sugar due to aspartame (Blundell 1986). In fact, Stellman showed that outside the confines of the highly structured, supervised environment, the subjects he surveyed who choose to use artificial sweeteners actually gained weight. Roberts (1988) showed in his survey of people outside of the laboratory that 5% of the people reported adverse reactions had extreme weight loss when using aspartame and tended towards

anorexia. He also noted that 6% of the respondants had a unexplained weight gain which averaged 19 pounds! c. Since diet products with aspartame have few calories and since many people have been conned into believing that they are safe, a significant percentage of people would likely "throw caution to the wind," by drinking large quantities of diet soft drinks and eating large quantities of other products with aspartame. This is something that they would not be as likely to do with high-calorie, sugar-containing products. The NutraSweet Company has been trying to convince people that persons who ingesting aspartame regularly ingest only 1-3 mg/kg (of body weight)/day of aspartame (Butchko 1991, Abrams 1992). This is based on surveys and diaries of consumers. What these surveys do not mention is that aspartame-containing products are often ingested as part of snacks and that people often forget what snacks they've eaten. This was aptly described by Dr. Richard Wurtman of MIT in a meeting with FDA officials on April 21, 1986 (Lisa 1994, page 201): "[NutraSweet's estimates of current use] show, among other things, that people consume less aspartame in the summer than in other months, a finding which violates good sense and reason. (This probably reflects the fact -- affirmed in our laboratories at MIT -- that people have much more difficulty accurately remembering snack than meal intakes . . . and most of the aspartame in the American diet comes via cold beverages and other snack foods.)" Another set of similar surveys shows that persons living in Canada (7-day survey) have more than 2.5 times the daily intake of aspartame than persons living in the U.S. (at the 90th percentile level of consumption). This is ridiculous because aspartame ingestion (the bulk of which comes from cold diet beverages) in warm climates would almost certainly be much larger than in cold climates. In addition, it appears that it is mathematically impossible for Canada to have an equal per capita aspartame consumption let alone a much greater per capita consumption. Aspartame net sales outside the U.S. amounts to only 10% of all net sales (Monsanto 1994) Canada's population is 10.8% of the U.S. population (CIA 1994). Therefore, Canada's per capita intake of aspartame cannot possibly be even equal to that in the U.S., even in the extremely unlikely scenerio where all aspartame sold outside the U.S. is sold only to Canada. (According to figures provided by the NutraSweet Company, the percentage of regular aspartame users in the United States and Canada are approximately the same (Farber 1989, page 56, Butchko 1991). Another preposturous claim can be seen in a paper by Butchko (1991). In this paper aspartame consumption for 6-12 year old children was shown to decrease significantly from 1984 (the year after aspartame was approved for use in carbonated

beverages) to 1989 despite nearly tripling the sales of aspartame from the middle of 1984 to 1989. (USDA 1988, Monsanto 1990). By the time this survey began the percentage of regular aspartame eaters in this age category was approximately 25% (Abrams 1991) according to NutraSweet Company figures. The NutraSweet Company admits that the use of aspartame had not risen to over 50% of the U.S. population at that time (Farber 1989, page 56). Therefore, an increase in the percentage of regular aspartame users could not have possibly accounted for the bulk of the increase in sales. Who are they kidding!? It shows that these surveys cannot be trusted to show anything close to accurate figures. Perhaps another reason the average daily intake of aspartame from these surveys is so low is due to the way that the amount of aspartame ingested is calculated. For example, Abrams (1991) points out that what is recorded on these surveys is not the amount of aspartame ingested, but only "the number of times an APM [aspartame] containing item of food was eaten on that day by that person." This value is then multiplied by the "average number of grams per eating occasion of that food for a person of that age and sex group" to give the total number of milligrams of aspartame ingested. However, the "average number of grams per eating occasion of that food for a person of that age and sex group" is drawn from a 1977-1978 USDA National Food Consumption Survey. Therefore, the calculations for the total milligrams of aspartame ingested is based on an old survey which is probably equally inaccurate as far as snack food ingestion goes and is most likely out of date. For example, these calculations assume that the average person would ingest the exact same amount of soft drink or diet food per item 1977 as they would in 1994. With the skyrocketing popularity of one- and two-liter bottles of soft drinks and the marketing push for diet foods, this is a ridiculous assumption. By making this assumption, NutraSweet are skewing the per capita intake figures and are using this "information" to justify studies on very small amounts of aspartame. What the NutraSweet tries to show with flawed studies and surveys is often contradicted by other studies which they fund or by statements made by their representatives. In 1976, Frey showed that children who are 7 to 12 years old can have an aspartame intake anywhere from 35 mg/kg to 76 mg/kg per day when aspartame-containing snack food is notrestricted (Frey 1976) (Note: No aspartame capsules were administered to the 7-12 year-old children. Only the 13-21 year-old children received capsules.). Three studies on obese individuals showed that their aspartame intake averaged 20 mg/kg per day (ranging from 8 to 36 mg/kg per day) (Porikos 1984). The Frey study and the three studies by Porikos monitored aspartame intake much more closely than the surveys often quoted by NutraSweet researchers. Those surveys relied on the ability of people to remember their snacks. In an article from Science Times, Jane E. Brody states the following (Brody 1985):

"The drug agency has set an allowable daily intake of 50 milligrams of aspartame per kilogram of body weight, and the agency predicted that actual average use would run around eight to ten milligrams. According to Dr. Gaull of Searle, levels of use found in a national survey last spring showed that the average was then already twice that--19 milligrams--and the maximum level consumed by 'aspartame abusers' was 28 milligrams. A United States attorney representing the F.D.A. said in court last month that average consumption is now 30 milligrams and that many consumers are above the 50 milligrams maxiumum suggested." Farber gave an example of what a typical aspartame consumption may be for a child (Farber 1989, page 146): "An 8-year-old of 20 kg, might eat the following: Cereal Soda Milkshake Ice Pop Total 250.0 200.0 350.0 250.0 mg mg mg mg

1,050.0 mg of aspartame

"This would equal 52.5 mg/kg of aspartame consumption....' [Note that even for a 60 kg adult, the above-listed example would amount to over 17 mg/kg per day.] On a hot Summer day, the child may ingest the aspartame listed above and several more carbonated beverages. There may be many children who are ingesting a full 2-liter bottle of pop during an active Summer day (1100 mgs. of aspartame). On top of that ingestion, there may be Jello, cereal, gum, and many other aspartame-containing foods. It is important to note that all aspartame-containing products of the same type do not contain the same amount of aspartame. For example, a one liter bottle of diet cola averages aproximately 560 mg of aspartame. However, orange soda contains as much as 930 mg of aspartame per liter (Federal Register 1984). In addition, the Tsang (1985) study showed that there may be an addition 10% or more amount of aspartame in the product than what is claimed by the manufacturer. Neuroscience researcher and Professor of Medicine at the University of California, Dr. William Partridge testified about the intake of aspartame before the U.S. Senate (Pardrige 1987): "The first question is the dosage problem. We are led to believe by the FDA this morning that the typical consumer will have 2 to 4 milligrams per kilogram of aspartame per day; that the 99th percentile intake is 34 milligrams per kilograms per day; and that the advisable daily intake or

ADI is 50 milligrams per kilogram per day. "Now, the layperson sitting in the audience is really in no position to analyze these esoteric numbers. But if we put it in a different context and recognize that 50 milligrams per kilogram per day is equal to 5 servings of NutraSweet per 50pound body weight, we can see that children, owing to their reduced body weight, are at a great risk for overconsumption of NutraSweet. "All one has to do in t his room is look up at that chart and ask yourself if a 50-pound or 60pound 7 year-old is going to consume 5 or 6 servings of that per day. If they are, then they have consumed 50 milligrams per kilogram per day, or the advisable daily intake. "Now, an 11-year[-old] study in the literature has already shown this, that the average 7-to-12-yearold, when made freely available to products like that, consumes 5 servings per 50-pound body weight per day, and up to 77 milligrams per kilogram per day." In the National Soft Drink Association's draft objection to use of aspartame in carbonated beverages it was stated (NSDA 1983): "FDA relied upon an intake value of 34 mg/kg/day in assessing the possible risks of aspartame, describing that level as the '. . . highest obtained from any estimate of potential consumption and exceed[ing] the 99th percentile consumption (25 mg/kg) for all age groups . . .' 48 Fed. Reg. at 31377. For a 30 kg child, however, it would not be unualual for that level to be achieved or, in terms of the effect on plasma PHE (phenylalanine) levels, even exceeded. For example, if a 30 kg child consumed on a warm day after exercise approximately two-thirds of a twoliter bottle of soft drink sweetened soley with aspartame, that child would be consuming 700 mg of aspartame, or approximately 23 mg/kg. This alone roughly equals what FDA considered, the 99th percentile consumption level. If during the day this child consumed other aspartame-sweetened products, the exposure level could quickly [reach] FDA's so called 'loading dose' of 34 mg/kg. 48 Fed. Reg. at 31377." Had the child in the above example consumed two-thirds of a two-liter bottle of aspartame-sweetened orange soda, the values could be as high as 1240 mg of aspartame or 41.3 mg/kg/day for a 30 kg child. Another way to look at intakes is to look at what a child may ingest in a single sitting. At the popular convenience store chain, 7-11, the drinks, "Big Gulp" and "Super Big Gulp" are popular items for both children and adults. A 30kg

child purchasing a Big Gulp (32 ounces) of diet soda would ingest 510 mg to 846 mg of aspartame depending upon whether it was diet cola or diet orange. This works out to between 17 mg/kg or 28.2 mg/kg of aspartame in a single sitting! The same child purchasing a Super Big Gulp of diet soda would ingest 700 mg to 1162 mg of aspartame. This works out to 23.3 mg/kg or 38.7 mg/kg of aspartame in one sitting! As an adult who plays basketball outside in the warm whether, I know many people, including myself who can easily drink twice the amount of liquids as found in a Super Big Gulp in one sitting in order to prevent dehydration. What is generally agreed upon when discussing the intake amounts of aspartame is the following: The majority of aspartame users ingest much less than the FDA's Acceptible Daily Intake (ADI). When plotting milligrams per day of aspartame ingested against the percentage of U.S. population, a smaller percentage of the population will ingest the largest amounts. However, a regular, smaller dose of a neurotoxin such as aspartame is not necessarily safe and certainly not healthbuilding. Dr. Roberts found many serious adverse effects from ingestion of aspartame at levels many times lower than the FDA's ADI (Roberts 1990a, page 71-72). The use of aspartame for a lifetime at even very small levels is foolish in my opinion. Looking a studies I have seen in the literature as well as USDA figures for artificial sweetener usage, I would estimate that the average person in the U.S. who ingests aspartame regularly ingests approximately 8 mg/kg per day. This is based on the following estimates: - Approximately 35% of the U.S. population (81 million people -- CIA 1994) are regular aspartame "eaters." Heybach (1988) showed that in adult women (a population likely to have a higher percentage of regular aspartame users than the general population), only 25% ingested aspartame in the survey. Since the survey was only a single day, I will give the NutraSweet Company the benefit of the doubt and assume 35% regular usage for the general population. The FDA submitted an aspartame intake survey to the U.S. Senate which admited that approximately 35% of the survey participants were regular consumers of aspartame (FDA PMS 1987). I do not believe the contrived NutraSweet Company estimates that more than 50% of the U.S. population uses aspartame regularly. - The average weight of regular aspartame users I estimate to be 50kg. This includes many thin women, adolescents, children, and infants who would tend to bring the average way down. - The amount of aspartame used in the U.S. in 1995 I estimate is 28 million pounds. McNamara (1995) stated that 20 million pounds will be sold in the U.S. in 1995. The author probably got that figure from the NutraSweet

Company and does not realize that every "fact" spewed out by this company is suspect at best. Figures from the USDA (1988) showed that 7 million pounds were consumed in 1984 and approximately 17.1 million pounds were consumed in 1987 Given that aspartame is now in over 5,000 junk food products worldwide (Geha 1993, Trefz 1994) and was only in hundres of products in 1987, and given that diet beverage sales have increased tremendously in the last 8 years, an estimate of 28 million pounds is quite reasonable (This estimate is probably too low. The actual figure may be as high as 35 million pounds). It is possible to determine the average usage of aspartame in regular eaters using the following formula: (lbs * 1,000,000 mg/kg) / (2.2 kg/lbs. * days/year * # of eaters * kg/person) = 8.6 mg/kg/day for regular eaters. I realize that this is an estimate, but given how ridiculous the "results" of NutraSweet-connected surveys are, an estimate is better than nothing. I believe that at least 10 percent of regular aspartame users ingest at least 20 mg/kg per day. This may amount to over 8 million people in the U.S. I would estimate that nearly 1 percent of aspartame users ingest at least 50 mg/kg per day. This may amount to over 800,000 people. This group would most likely be mostly made up of children and young, adolescent girls due to their low body weight and high intake of junk foods. For many of these people, the warm and hot weather intake will far exceed their Winter intake, such that a person ingesting 20 mg/kg per day in the Winter may ingest 40 mg/kg per day in the hot Summer months. According to Dr. Woodrow Monte, Director of the Arizona State University Food Science and Nutrition Laboratory, a significant number of people in Arizona drink as much as two or three liters of diet soda every day during the Summer (Monte 1995). Even if we accept the FDA's projection that only 1% of the regular aspartame users will consume more than 34 mg/kg/day of aspartame, that still may amount to over 800,000 people. While the national average may be lower than 34 mg/kg/day of aspartame, there are undoubtedly several hundreds of thousands of people who are consuming well over 34 mg/kg/day of aspartame, especially on hot Summer days. NutraSweet researchers sometimes use the following ploy to try and convince gullible listeners that people cannot ingest over 20 mg/kg/day or approach a level of 50 mg/kg/day (despite their own studies which prove them wrong). They compare the amount of one single product that would need to be ingested by an adult male in order to reach these high levels (e.g., Rowen 1995). For exampe, they might say that it takes 100 packets of Equal or 19 cans of diet soda for a 70kg man to reach a dose of 50 mg/kg. First of all, not everyone is a 70kg man. Many people are

50kg women or 20-30kg children where the amount of aspartame required to reach a dose of 50 kg/mg is much less. Secondly, many people who put themselves at risk by ingesting aspartame do so using a wide variety of aspartame-containing "food" products such as soda, puddings, cereal, hot chocolate, coffee, tabletop sweeteners, gum toppings, supplements and pharmaceuticals, fruit drinks, etc. People abusing themselves with aspartame in this way can easily ingest hugh doses. Finally, even doses of only a few mg/kg/day is not safe in the long run. Some researchers try to argue that they can use much less than the current FDA Acceptable Daily Intake (ADI) in their experiments as long as they use a test dosage well above the average intake of aspartame as deterimined by these (flawed) surveys. Stegink states the following (Stegink 1989): "Initial consideration of these projected intakes might lead one to question their validity since 12 oz of aspartame-sweetened beverage ingested by a 27-kg 8-year-old child would account for 7.4 mg aspartame/kg body weight. However, when beverage intake data are examined, the projected aspartame intake values are consistent with these data. For example, Morgan et al reported that 7- to 8-yearold children ingest, on average 6.0 4.2 oz soft drink daily (mean SD; value includes both regular and diet beverage) (Morgan 1985). Thus, an average 27-kg 8-year-old child would ingest 3.7 mg aspartame/kg body weight daily if all 6 oz of beverage were sweetened with aspartame. A 27-kg child ingesting beverage at 2 SD above the mean (approximately 97% of expected values) would ingest 14.4 oz of beverage. This would provide 8.9 mg aspartame/kg body weight if all beverage consumed was sweetened with aspartame. Therefore, young children would have to drink unusually large quantities of beverage to ingest much larger quantities of aspartame." What Stegink neglects to mention is the following: 1. The study cited by Stegink (Morgan 1985), does not take into account that, as Dr. Wurtman stated, snacks are commonly forgotten in daily food surveys so that the average ingestion of soft drinks would likely be much greater. 2. The study cited by Stegink uses data from a three-day survey instead of the more accurate seven-day survey. 3. The study cited by Stegink was published in 1985. This study was an evaluation of data from the 1977-78 Nationalwide Food Consumption Survey. Thus, the data was over ten years old when Stegink cited it and is now over 16 years old! Anyone adult in the U.S. who was not in a coma for the last 16 years knows that soft drink consumption has increased tremendously since the late 1970s.

4. Stegink neglects to mention that there are thousands of products with aspartame and that 7- to 8-year-old children can be ingesting significant amounts from foods and beverages other than soft drinks. 5. While the average intake may be relatively low, although much higher than reported by Stegink and not necessary safe, there are undoubtedly a significant number of 7to 8-year old children who are ingesting large quantities of aspartame by their own choice or by the choice of their parents to avoid sugar. It is ridiculous to use the "average" (even if it was accurately determined) to judge test amounts of aspartame. Conclusion ---------NutraSweet-written survey summaries show a negligable increase in daily aspartame consumption since 1983. Aspartame sales has skyrocketed since 1983. Therefore, the numbers from these surveys which are flawed as described by Dr. Richard Wurtman above, do not make any sense and should be ignored until large, well-designed surveys are conducted separate from the influence of the NutraSweet Company. Until that time, estimates of average consumption for regular eaters at 8 mg/kg/day, 20 mg/kg/day at the 90% level, and over 50 mg/kg/day at the 99% level seem quite reasonable. The NutraSweet Company researchers have begun a concerted effort to convince scientists and laypersons that they are testing high doses of aspartame. This is based on consumer surveys. The reality is that a) the surveys are flawed; b) their own studies show subjects ingesting much higher intakes of aspartame than they use in tests; and c) they are often testing using doses significantly below the FDA's Allowable Daily Intake (ADI). Their efforts to test small doses is a big con job. Don't buy into it. What should be used in experiments is double the ADI of real world aspartame. Any argument for using less should be taken as an admission that the ADI is not a safe amount of aspartame.

3. Serious NutraSweet Research Flaws Before we discuss individual studies, it is important to list common and very serious flaws in all of the research funded by NutraSweet. This is by no means meant to be a comprehensive list of flaws -- simply the most common serious flaws. The flaws I will discuss in this section related to studies after aspartame was approved (postapproval). The pre-approval studies bordered on criminally fraudulent activity in my opinion and will be discussed in a later section. a. Test Material In most of the NutraSweet-funded studies, the test material used was fresh, encapsulated aspartame. This is

a major flaw for the following reasons: 1. The chemical makeup of the fresh aspartame used is almost 100% pure aspartame and differs significantly from what is being ingested by the general public. This is discussed thoroughly in the "By-Products and Breakdown constituents" section above. This means that DKP, beta-aspartame, free methanol, and other possible breakdown products are not being tested in these experiments. 2. In 1987, Stegink tested the effect of aspartame taken in liquid as opposed to capsules on plasma phenylalanine, phenylalanine/LNAA, tyrosine, and aspartate (Stegink 1987a). The difference was striking. The plasma phenylalanine and aspartate levels rose very quickly to extremely high levels when ingesting the liquid aspartame mixtures, but the plasma amino acid levels only rose moderately when ingesting encapsulated aspartame. While this experiment compared the effect of aspartame in liquid vs. capsules, it did not test real world liquid aspartame-containing products which would contain significant amounts of DKP, methanol, free amino acids, and other possibly dangerous chemicals. The rise in plasma amino acid levels may be even more striking and sudden with such products due to even faster absorbtion. 3. The experiment conducted by Stegink (1987a) showed that capsule administration of aspartame significantly delayed absorption of aspartic acid and phenylalanine. In fact, with liquid administration, the peak amino acid levels were reached within 32 minutes (average), yet capsule administration led to a gradual rise in amino acid levels and took approximately 2.5 times longer to reach much lower peak levels. Not only is the enormous difference in the plasma amino acid spikes important as discussed above, but the sudden spike that occurs in liquid administration that may also be very important. When a substance is gradually absorbed in a way that causes it to be slightly toxic, the body has a chance to adjust and mount a defense. Sudden absorption of single, potentially neurotoxic amino acids does not give the body a chance to mount a defense. It is also very important to note that delaying the absorption of methanol as would happen when ingesting encapsulated aspartame may reduce the methanol toxicity somewhat since food in the stomach, which also delays methanol absorption, seems to reduce methanol toxicity (Posner 1975). It is interesting to note that as early as 1973, the FDA told the manufacturer of aspartame that there is "No pharmacokinetic data . . . on absorption, excretion, metabolism, half-life; nor bioavailability of capsule vs. food additive administration" (Freeman 1973). It wasn't until 1987, 14 years later, that NutraSweet

finally got around to testing capsule administration as compared to liquid administration! There was a striking difference as described above. To this day, there has been no tests comparing the administration of various real-world, aspartame-containing products to capsule administration. The large difference in biochemical reactions produced when ingesting real world aspartame-containing products as opposed to capsules given in the laboratory totally negates the results from experiments which used such capsules and found no adverse effects. When using aspartame-containing capsules, 1) much less aspartame gets absorbed (Stegink 1987a), 2) the absorption is much slower causing the increase in blood levels of aspartame by-products to be much more gradual (Stegink 1987a), and 3) other by-products and breakdown constituents do not get absorbed as they do in real-world products (Tsang 1985). Had real-world, liquid products been used, the number and severity of negative reactions due to aspartame would likely have been much greater. b. Test Product Administration In order to test the effects of aspartame on health it is important to simulate the way the product is taken by the general public. Sometimes aspartame is ingested with full meals. More frequently, however, aspartame is ingested by itself (e.g., diet colas) or with a sugary snack. It is important to test both methods of administration. It is obvious that the biochemical effect of the three original components of aspartame, aspartic acid, phenylalanine, and methanol will be much greater when it is ingested separate from a full meal. (This will be discussed in more detail in later sections.) When taking aspartame with meals the following things occur: i) The aspartame will not be absorbed as quickly leading to less of a rise in plasma aspartate and phenylalanine levels; ii) The other amino acids absorbed from the food will keep the plasma aspartate and phenylalanine levels from rising as high as they would normally; iii) The plasma phenylalanine to large neutral amino acid (LNAA) ratio will not be as large due to the LNAA's in the food. (This will be discussed in detail in a later section.); iv) The food may serve as a protective factor reducing the methanol toxicity as will be discussed in the Methanol section. It is obvious that the acute and chronic effects of aspartame ingestion will be slightly less when it is ingested with full meals. All previous experiments that tested aspartame ingestion with full meals, tested the best-case scenerio and not what is most common in the real world. Therefore, all such research of aspartame

with full meals should be regarded as interesting, but not very useful. On the other hand, Yokogoshi (1984) has shown that aspartame ingestion with caloric sweeteners significantly raises to phenylalanine/LNAA ratio to even greater heights than by simply ingesting aspartame alone. Even a NutraSweet-funded, short study on healthy persons using a relatively small amount of aspartame showed a significant further increase in plasma phenylalanine/LNAA ratio when aspartame was ingested with a caloric sweetener (Wolf-Novak 1990). However, it is unclear whether the ingestion of carbohydrates along with aspartame renders the phenylalanine part of aspartame more dangerous. Carbohydrate ingestion lowers the levels of Large Neutral Amino Acids (LNAAs) and therefore the neutral amino acid trasport cites may become unsaturated causing a smaller change in brain chemistry than would otherwise happen with the phenylalanine alone. We will discuss this in more detail in a later section. Therefore, not only should more experiments be done using real-world aspartame products on persons not eating full meals, but experiments should be done on the combination of real-world liquid aspartame (at FDA ADI levels or greater) and caloric sweeteners. Only then will we begin to approach what happens in real-world aspartame ingestion. It is important to note, however, that the ingestion of aspartame with sugar reduces the possible negative effects from the aspartic acid part of aspartame (as will be discussed in the Aspartic Acid section). Such experiments (with caloric sweeteners plus aspartame are very useful, but lack of negative effects does not rule out possible negative effects from the aspartic acid or the aspartic acid plus another breakdown product (i.e., synergy). c. Short Experiments The majority of NutraSweet-funded experiments on humans tested aspartame for one day or less. Although there is a wide variation in when adverse reactions begin, it is usually several weeks or months after use begins before adverse reactions are noticed (Roberts 1990a, page 70). After the adverse reactions begin, regular aspartame use usually causes more frequent adverse reactions. Studies which are not funded by NutraSweet are usually much longer because the researchers are actually interested in testing aspartame. A quality study would be at least six months long, and preferably as long as one year or more. This way, the researchers will be testing adverse reactions that occur due to ongoing use of aspartame -- real world use. One to two year experiments would be ideal. James Scala, the former director of Health Sciences for General Foods Corporation said that most of the early

NutraSweet research consisted of short-term studies that ignored possible subtle, long-term effects. Pediatrician and Geneticist Dr. Reubon Matalon stated "Let us say cigarettes were invented today, and you give 20 people two packs a day and after six weeks, no one has cancer, would you say that it is safe? That's what they did with NutraSweet." (Gordon 1987, page 486 of US Senate 1987) All single day or single challenge tests, usually conducted by NutraSweet-connected researchers, should be disregarded. No one is claiming that a single ingestion of even real-world aspartame-containing products represents an imminent health hazard. A single dose of aspartic acid, phenylalanine, methanol, DKP, etc., from aspartame is not acutely toxic in the majority of cases. It is the regular use that represents a extreme hazard. These concerns are not addressed in one-day studies. No reputable researcher would try to extrapolate a lack of negative effects from aspartame in a one-day experiment to a declaration of safety for onging use throughout a lifetime. Unfortunately, this is commonly done by some NutraSweet-supported researchers. It should be noted that some very subtle adverse reactions may be noticed in a single day experiment, especially in vulnerable populations. While a much longer test is necessary, any significant adverse reactions after only a single day test should be a cause for extreme concern. On the other hand, lack of adverse reations after only a single day test does not prove anything. d. Small Test Population The smaller the test population, the more difficult it is to get a statistically significant difference in amino acid and methanol/formate levels in the blood and urine. NutraSweet-funded research usually has such a ridiculously small test population that it is virtually impossible to have a statistically significant difference in measurements. This is especially true when this flaw is combined with other flaws such as capsule administration of aspartame. Another way a small test population can be a problem is if a particular symptom (e.g., seizures) appears in a small percentage of aspartame users -- let's say one out of every 100 regular users, then experiments with small numbers of people would usually not have a seizure victim. This problem is called "lack of statistical power" of the studies and will be dealt with in more detail when the cancer issue is discussed. The technique of using ridiculously small test populations helps to guarantee that reactions that are occurring in the general population do not occur in the test population. e. Irrelevant or Faulty Tests There are numerous NutraSweet-funded research projects

which used irrelevant and faulty tests to draw their conclusions. An irrelevant or faulty test is useful only for press releases and convincing scientists who are not intimately familiar with the scientific issues surrounding aspartame ingestion. Performing many such irrelevant or faulty tests allows the researcher to proclaim, "Look! We tested aspartame, performed a whole battery of tests, and found no adverse effects!" When the protocol is examined closely, however, it becomes clear that many of these tests were meaningless or conducted improperly. Many of the improper testing methods appear to be deliberately created and used to avoid negative results. There are many cases of such irrelevant and faulty tests. I will discuss some of those when I get into the details of the research cited in the article. f. Dosage Tested In a number of NutraSweet-funded studies, the aspartame dosage used was much less than it should have been. As discussed in the previous section, NutraSweet's estimates of aspartame intake are obviously flawed. Frey (1976) showed that children can ingest as much as 76 mg/kg/day. In three studies on obese adults, Porikos (1984) showed that the average daily intake of aspartame varied from 8 to 36 mg/kg/day. The FDA's current Acceptable Daily Intake (ADI) is 50 mg/kg/day. NutraSweet researchers have made a significant effort to convince other researchers and the general population that it is okay to test small doses of aspartame. Much of their argument is based on average intake values presented in their ridiculous intake surveys. The fact is that hundreds of thousands of people are consuming amounts of aspartame approaching the FDA's Acceptable Daily Intake level. If the NutraSweet Company actually believes that the FDA's ADI is a safe amount of aspartame, then that is the minimum that should be tested. Either "put up, or shut up" so to speak. In order to have a safety margin, it is preferable to test at least double the ADI using read-world aspartamecontaining products in long-term experiments. If they do not want to test at levels at or above the FDA's ADI (using real-world aspartame of course), then we should 1) lower the ADI back to 20 mg/kg/day, 2) label the amount of aspartame on each "food" product that it is in, 3) put a warning on the label stating that no more than 20 mg/kg/day (9 mg/lbs./day) should be consumed, and 4) start proper safety testing in humans at 20 mg/kg/day (or more) using real-world aspartamecontaining products. g. Reaction Time Some research ignored certain adverse reactions if they did not occur soon after aspartame ingestion. This is one common way that food industry scientists

significantly reduce the number of adverse reactions recorded during the experiment. They simply imply that the suspected reactions are "allergic" (i.e., IgEmediated) and therefore must occur quickly after ingestion. The fact of the matter is that many food intolerance or toxicity reactions can occur as much as 48 hours after ingestion (Carroll 1992). This use of this flaw has occurred in several NutraSweet-funded experiments. The studies of MSG funded by the International Glutamate Association use this flaw quite often. Independent researchers usually design the experimental protocols to take into account the fact that people often experience delayed reactions. h. Average Values Shown In the publication of many NutraSweet-funded research projects only average values were shown in tables and plotted on graphs. This is fine in studies where there are a large number of participants and the substance being studied has similar biochemical effects on all people. However, most of these studies have very few subjects and it is well-known that there is a wide variation in the biochemical changes caused by methanol, phenylalanine, and aspartic acid. This may also be true with DKP and other breakdown products. If an experiment has six subjects, for example, and two of the subjects show biochemical changes that would be of concern, the significance of those changes would get lost in a listing of averages. Human studies of aspartame conducted by independent researchers often show measurements on an individual basis (not averages) so as not to obscure the possibility of individual susceptibilities (Koehler 1988, Matalon 1988, Van Den Eeden 1994, Walton 1993). Another related technique used by NutraSweet to help hide negative test results is to combine all of the subjects' measurements when they should not be combined. Suppose for a moment that we measure a blood plasma level of aspartate for the first 60 minutes after ingesting aspartame. Below are example values for five different subjects followed by the average values . 0 min Subject Subject Subject Subject Subject 1 2 3 4 5 6.0 5.0 7.0 5.0 6.0 15 min 38.0 14.0 8.0 23.0 9.0 18.4 30 min 32.0 28.0 12.0 41.0 24.0 27.4 45 min 16.0 51.0 41.0 21.0 37.0 33.2 60 min 9.0 50.0 12.0 19.0 53.0 28.6

Mean Values 5.8

In almost all NutraSweet funded experiments, all that would be shown in publication are the "Mean Values." Notice how the mean values only rise from 5.8 at 0

minutes to a maximum of 33.2 at 45 minutes. When going back to the actual data all of the rises in the subjects were much more extreme than what is apparent by looking only at the mean values. For example, the plasma aspartate level of Subject 2 rose from 5.0 to 51.0 at 45 minutes. Showing only the means values in a chart or a graph will obscure the true rise in blood plasma levels of the substance being measured. This is because some of the subjects reach their peak values at different times, so that when Subject 1 has a peak value of 38.0 at 15 minutes, Subject 3 has a value of only 8.0 at that time -- which brings the mean value at the 15 minutes time period down considerably. The appropriate thing to do would be to list all of measurements for each subject and list the mean starting values and mean peak values: Mean Starting Values = (6.0 + 5.0 + 7.0 + 5.0 + 6.0) / 5 = 5.8 Mean Peak Values = (38.0 + 51.0 + 41.0 + 41.0 + 53.0) / 5 = 44.8 If increases in certain measurements are only moderate, the NutraSweet Company researcher's use of mean values for each time period can sometimes enable the researcher to "prove" that the changes were not statistically significant. Therefore, NutraSweet-sponsored studies which show only mean values for each time period may be hiding some of the negative effects with their statistical games. i. Types of Volunteers Since serious health problems from aspartame seem to develop gradually in many people, it makes sense to conduct very long tests. The NutraSweet Company wants people to swallow this junk for their entire life. Experiments which last a lifetime are obviously impractical. Therefore, it is prudent to conduct relatively long experiments on susceptible populations first so as to get clues as to what will happen to healthy populations after years of use. Most of the studies funded by NutraSweet appears to have been conducted on healthy volunteers (for a very short test period). These experiments had numerous flaws. It seems that the experiments in which unhealthy volunteer were used, the number and seriousness of the experimental flaws increased significantly. The NutraSweet Company wants you to believe that out of the population that is currently allowed to consume aspartame, PKU Heterozygotes (persons who do not have phenylketonuria -- PKU, but have a single gene of PKU) would be the most susceptible to any possible negative effects from aspartame. While this population may be more susceptible than a healthy population, I submit that persons with the following illnesses will be much

more susceptible: Fibromyalgia Chronic Fatigue Syndrome (CFS) Chronic Depression Multiple Chemical Sensitivities Multiple Sclerosis

There are other possibilities, but this is a good start for legitimate tests on susceptible populations. Please note, however, that healthy persons are very susceptible to the damage that can be caused by aspartame, just not quite as susceptible, on average, as persons with the above-mentioned illnesses. j. Animal Tests All three main ingredients in aspartame, methanol, aspartic acid, and phenylalanine have been shown to have much greater toxic effects in humans than in rodents. Methanol and aspartic acid is much more toxic in humans than in monkeys. Methanol tests in rodents are worthless. Methanol tests in rheusus monkeys are also worthless or guesswork at best as discussed in the Methanol section below. Methanol is much more toxic in humans than any other species. Aspartic acid is 5 times more toxic in humans than in rodents and at least 20 times more toxic in humans than in monkeys as discussed in the Aspartic Acid section. Phenylalanine tests in rodents are guesswork at best and probably worthless as discussed in the Phenylalanine section below. Phenylalanine is much more dangerous in humans than in rodents. It is unknown whether DKP, beta-aspartame, or racemized amino acids have different effects in humans as opposed to laboratory animals. Therefore, aspartame tests in animals, especially those which tested for the effects of methanol and phenylalanine in rodents, or methanol and aspartic acid effects in monkeys should be ignored -- as the negative effect in humans would likely have been much greater. It is important to point out that these flaws are not news to the NutraSweet Company. Many people have been pointing out these flaws for years and pushing for legitimate experiments instead of press releases disguised as research. It is also important to note that NutraSweet can make the following claims about their research: "We "We "We "We have have have have studied studied studied studied aspartame aspartame aspartame aspartame in in in in healthy individuals." diabetics." persons with liver disease." adults."

"We have studied aspartame in children." "We have conducted acute-dosing tests." "We have conducted chronic use tests [a few weeks only]." etc., etc. However, each one of their experiments had multiple serious flaws, making it virtually useless for anything but a press release. For example, long-term studies often use capsules which were taken with meals and contained numerous irrelevant or poorly conducted tests. Given aspartame's history of what some people consider pre-approval fraud, it does not surprise me that the NutraSweet Company continues to flood the scientific community and the news services with results from badly flawed studies.

4. Methanol From the article: "The presence of small amounts of methanol in aspartame has generated a lot of undue concern. Although large amounts of methanol are harmful, the very small amounts of aspartame-derived methanol are easily handled by the body. "Methanol is a common component of the diet, and is found in many fruits, vegetables, and wines. Furthermore, the amount of methanol from foods far exceeds any contribution from aspartame (Lund 1981). Aspartame-sweetened soft drinks, for example, provide 60 mg of methanol per liter as compared to fruit juices which contain 140 mg of methanol per liter." The excerpt above contains so much NutraSweet Company propoganda, its hard to know where to begin. First, I will discuss how ingesting methanol from aspartame differs from ingesting methanol from alcohol, fruits and vegetables, and fruits and vegetable juices. Alcohol ------An exhaustive literature search by Monte (1984) showed that all natural products which contain tiny amounts of methanol also contain significant amounts of ethanol. Many alcoholic beverages contain over 200 times more ethanol than methanol. The large ethanol content of alcoholic beverages has served to protect humans from methanol poisoning throughout the ages. Despite the wishful thinking of NutraSweet Company spokespersons (Sturtevant 1985), researchers agree that ethanol serves as a protective factor (Leaf 1952, Liesivuori 1991, McMartin 1980, Posner 1975, Roe 1982). Ethanol protects from methanol poisoning by preventing the conversion of methanol to toxic formaldehyde and formic acid metabolites thus allowing methanol to be excreted through the lungs and urine (Roe 1982, Kruse 1992). Methanol poisoning is treated with ethanol (Kini 1961, Pamies 1993).

Leaf (1952) showed that co-administration of methanol with ethanol immediately stopped the conversion of methanol to its toxic metabolites. Fruits and Vegetables --------------------Fruits and vegetables do contain methyl ester as part of the pectin. However, human beings do not have digestive enzymes such as pectin esterase to release the methanol (Garrison 1990, page 16, Monte 1984). As Monte (1984) points out: "Fermentation in the gut may cause disappearance of pectin but the production of free methanol is not guaranteed by fermentation (Braverman 1957). In fact, bacteria in the colon probably reduce methanol directly to formic acid or carbon dioxide (Campbell 1978) (aspartame is completely absorbed before reaching the colon)." Microorganisms in the feces can contribute to the production of methanol from pectin, but methanol will not be released in significant amounts unless the pectin sits in the intestines for 72 hours (Siragusa 1988). A couple of grams of pectin (found in an apple, for example) will probably produce only a maximum of 20 mg of methanol provided it stays in the colon fermenting for at least 24 hours. Much of this small amount of methanol is probably used and converted to less harmful substances by intestinal bacteria (e.g., Wolin 1993). Extremely high doses of pectin (i.e., 120 grams over 2 days) by itself can lead to a significant increase in blood methanol (Gruner 1994), but it is not known whether protective factors are absorbed as well. Even if some of the methanol was absorbed and converted to formaldehyde, 120 grams of pectin would amount to eating over 50 small apples (Garrison 1990, page 16). Fruits and Vegetable Juices --------------------------When certain fruits and vegetables juices are extracted, the pectinmethylesterase enzymes demethylates some of the pectin and liberates methanol. However, the methanol content of most commonly ingested fruit juices do not average 140 mg per liter. The NutraSweet Company has been pushing this fallicy for years even though it has been disproven. The 140 mg/liter figure was obtained from a very old conference paper presented by Francot and Geoffroy (Francot 1956). The authors of this paper state that they did not perform many of the tests and give no original sources for the work except for grape juice and black current juice. No methodology was given although it is certain that in 1956 they did not use the more accurate techniques currently used. The methanol content of fresh juices is probably dependent upon the method used to extract the juice, the type of fruit used (including species), and the time harvested. Lund (1981) showed that the methanol content of fresh orange juice had a mean of 34 mg/liter. Fresh grapefruit juice

averaged 27 mg/liter in the Lund study. Sauri (1981) tested fresh orange juice and showed that it contained 33 mg/kg. Nisperos-Carriedo (1990) determined that their sample of fresh orange juice had a mean of 38 mg/liter. The methanol content of processed juices were much less than fresh juices. Lund (1981) showed that orange juice concentrates average about 6 mg/liter of methanol. Grapefruit concentrates average about 2 mg/liter. The reconstituted juices contained no detectible methanol. Nisperos-Carriedo (1990) showed that pasteurized orange juice contained 22 mg/liter and frozen-concentrated orange juice contained 3.4 mg/liter. White (1950) showed that 10.1 kg of apple essence contained 2000 mg of methanol. Since apple essence is a concentration of 150 times that of juice, 10.1 kg of juice contains 132 mg of methanol. However, the author points out that not all of the volatiles were extracted, but we can assume that the concentration in fresh juice is probably less than 200 mg/10.1 kg or 20mg/liter. The most popular freshly-made juices have about one-half (or less) of the concentration of methanol than aspartame. Processed juices contain many times less methanol than aspartame and reconstituted juices contain only trace amounts of methanol. The average juice product ingested in the U.S. probably contains much less than 10 mg/liter if all types of fruits and processing is included since fresh juice is consumed by only a small segment of the population and in relatively small quantities. Some juices have been shown to contain methanol at equal or greater levels than aspartame. Nelson (1969) showed that after extracting the tomato juice and heating it for 30 minutes at 212oF in when enclosed in tin or enamel that the methanol content varied from 127 to 560 mg/liter. However, heating can-sealed tomato juice to extremely high temperatures without inactivating the pectinmethylesterase enzyme would likely increase the creation of methanol tremendously. This is something that is unlikely to happen in commercial or home preparation. Kazeniac (1970) found that blended tomatoes had a methanol content of between 64 and 138 mg/liter depending upon the speed of the blendor and the time blended. The small amounts of methanol in fresh juices or the larger amounts in some fresh juices (such as tomato juice) are probably irrelevant since it is unlikely that the methanol from these natural substances is absorbed and metabolised the same way as methanol from aspartame. The following points lead me to conclude that methanol from natural foods is not absorbed and/or metabolised into formaldehyde and formic acid in significant amounts: a. Alcoholic beverages contain large amounts of ethanol which prevent the large amounts of methanol from being converted to formaldehyde and formic acid. This is a reference point. It proves that we cannot automatically

assume that a methanol-containing item will end up producing formaldehyde and formate after ingestion. b. If we can indulge NutraSweet's fantasy for a moment and pretend we find an "average" juice with 140 mg/l of methanol. Suppose that a person drinks 3 liters of this healthy juice per day. For a 50 kg adult woman that would amount to 8.4 mg/kg of methanol per day. Baumann (1979) showed that workers in a printing shop were exposed to methanol concentration in the air between 85 and 134 parts per million (111-174 mg/m3) for an 8-hour day. The total methanol intake of these workers at 60% absorption (twice resting respiration rate) was approximately 8 mg/kg (Kavet 1990). The average blood formate levels nearly doubled (3.2 mg/l to 7.9 mg/l) at this exposure. The urinary formate levels rose from 13.1 mg/l to 20.2 mg/l. Heinrich (1982) showed a similar blood and urinary formate increase for a single work day at a chemical plant at an exposure level of 92 ppm (120 mg/m3). Three liters of fruit juice, leading to a theoretical ingestion of 8 mg/kg of methanol has never been shown to spike urinary and blood formate levels as the experiments discussed above. Such a plasma formate level spike would be highly unlikely to say the least. I would challenge NutraSweet to find any independent research would shows such a spike in formate levels from fruit juice ingestion. c. Under the manufacturer's theory, someone "unfortunate" enough to drink two liters of one of the higher methanolcontaining juices such as black current juice (Monte 1984) would be getting about 1.3 grams of methanol (according to NutraSweet claims). The lowest recorded single lethal dose is 15 ml of 40% methanol. This equals 6 ml of methanol or 4.8 grams. (Bennett 1953). 1.3 grams (more than 25% of the minimum recorded lethal dose) of methanol would be an enormous quanity of methanol to ingest every day! God forbid this person would ingest tomatoes which NutraSweet claims is another source of large amounts of methanol (Butchko 1991). Methanol is also found in some cooked foods (Casey 1963). If NutraSweet actually believes its own theories about methanol absorption and metabolism from fruit, they should call for a ban on black currents, tomatoes, and juices with high amounts of methanol. A useful experiment would be to have an independent researcher test the equivalent methanol believed by NutraSweet to be found in 2 liters of black current juice plus a days worth of cooked foods and other methanol-containing foods -- say 1.8 grams per day. The test would be conducted on Monsanto and NutraSweet executives who would ingest 1.8 grams of methanol every day in a single dose with distilled water half way in between lunch and dinner. The experiment would be conducted for two years. Each day that alcohol is ingested would increase the experiment by a day for that subject. Regular blood and urine methanol and formate

levels would be tested to make sure that the subjects were getting proper doses. In this way, the company excecutives can see first-hand how "safe" methanol from juices is when taken without the rest of the juice. d. A growing number of people are extremely sensitive to methanol or formaldehyde exposure, hardly being able to tolerate a short exposure in a print shop or chemical plant, but easily being able to drink fresh juice. It would have been relatively easy for NutraSweet researchers to test tomato juice to see if it raises the blood methanol and urinary excretion of formate as does aspartame in the experiments discussed later in this section. Two to three liters of tomato juice given to a 30 kg child could contain the same amount of methanol as was shown in NutraSweet experiments to significantly increase blood methanol levels. Similar equivalent amounts could have been determined to correspond to the NutraSweet experiments which showed a significant increase in urinary formate levels. It's been almost two decades since tests relating to aspartame and methanol have been published and this obviously important experiment has not been conducted or has, more likely, been avoided. At this point, however, the experiment would have to be conducted and funded by corporate-neutral parties to have any validity. The simple fact is that methanol from natural products such as juices is almost certainly not absorbed or metabolised to formaldehyde and formic acid in signficant amounts. Researchers have not taken the time and effort to discover all of the protective factors in juices (similar to ethanol in alcoholic beverages). Juices contain a significant number of volatiles including ethanol, some of which may prevent absorption or metabolism of the methanol. Fructose has been shown to significantly slow methanol oxidation in some species when given in significant quantities (Bradford 1993). Whether this has an effect on humans ingesting small amounts of methanol with fruit juices is unknown. Certain intestinal bacteria have been shown to convert methanol or formaldehyde to acetate (Wolin 1993). It is possible that tiny amounts of methanol from fruit juices may be converted by bacteria in the human digestive tract before it can be absorbed. Some bacteria which convert methanol to acetate are known to do so many times faster in the presence of sodium (Na+) ions (Blaut 1992, Heise 1989). Sodium ions may be found more readily in natural juices than in junky diet sodas. Since methanol toxicity is blocked by ethanol in alcoholic beverages and since inhaled methanol has been shown to spike plasma formate (formic acid) levels, yet similar quantities of methanol from juices has not been shown to spike plasma formate levels, it seems rather ridiculous to automatically assume that methanol from juices would be absorbed and metabolized in the same way as methanol from an artificial sweetener. The high caloric content of fruit and vegetable juices as

well as their osmolarity places limits on the quanity of these products ingested on a regular basis (Monte 1984). Monte (1984) shows, using U.S. Department of Agriculture survey figures that the regular juice drinker probably ingests between 1 and 7 mg of methanol per day from these sources. Aspartame, on the other hand, has a low calorie content, leading to the possibility of ingesting large quantities. In fact, in hot whether, it is not uncommon for a person to drink anywhere from 1 to 3 liters of aspartamecontaing beverages every day (Monte 1995). Wurtman describes a case of a person who ingested 3.5 liters of diet Coke and a nearly equal amount of diet lemonade every day (Wurtman 1985a). This person was ingesting approximately 350 mg of methanol every day! I know several people who drink well over a liter (i.e., three 12-ounce cans) of diet beverage every day. A person ingesting two to three liters of diet orange soda on a daily basis, for example is ingesting 180 to 270 mg of methanol every day. Fresh juices contain vitamins and minerals which can help protect cells from damage caused by methanol. Folic acid, for example, is an important nutrient which helps break down and eliminate methanol metabolites. It is common that many chemicals in foods protect us from toxic substances in those foods. Remington (1987, page 88) gives a couple of examples of toxic substances causing more damage when not co-ingested with nutrients. In one example, rats which were fasted for six days died at 1/25th the dosage of a toxic substance as compared to rats which ate a normal diet. In the other example, it was shown that giving cabbage and brussels sprouts to rats increased the hydroxylase activity by 100 fold, protecting them from aflatoxin. Diet drinks and other aspartame-containing foods rarely contain significant amounts of nutrients that can protect against methanol damage and often contain other unnecessary and unhealthy chemical additives. In summary, juices usually contain much less methanol than aspartame. Due to the calorie content and osmolarity of juices, much less is ingested on a regular basis. Nutrients such as folic acid serve as protective factors against ingestion of methanol. And most important, it is very unlikely that methanol from juices is absorbed and metabolised in a similar way as methanol from aspartame. Most likely none or only trace amounts from natural juices are converted to formaldehyde. Therefore, NutraSweet's comparison of methanol from aspartame to methanol from natural products is flawed. Methanol Metabolism ------------------Methanol from aspartame is released in the small intestine when the methyl group of aspartame encounters the enzyme chymotrypsin (Stegink 1984, page 143). Free methanol rapidly forms in liquid aspartame-containing products at temperatures over 145oF (62oC) (Mullarkey 1992, page 9). Free methanol is absorbed and metabolised somewhat differently than methanol from freshly-prepared aspartame as pointed out by researchers for the NutraSweet industry (Stegink 1983a). Methanol is absorbed in the stomach and

more quickly when it is in its free form (Ranney 1976, Monte 1984, Stegink 1981a). There may be a greater toxicity for the quickly absorbed free methanol as discussed by Monte (Mullarkey 1992, page 9). Monte goes on to point out that when people are dieting or have not eaten for a while there is little gut fermentation producing the protective factor, ethanol. Whether absorbed quickly as free methanol or somewhat slower in the small intestine from fresh aspartame, the total amount of methanol absorbed will be approximately 10% of aspartame ingested. The absorbed methanol is then slowly converted to formaldehyde by alcohol dehydrogenase in the liver (DHHS 1993a, Liesivuori 1991). If methanol is co-ingested with a significant amount of ethanol, the methanol conversion is temporarily blocked since ethanol has nine times the affinity for alcohol dehydrogenase as does methanol (DHHS 1993a). This allows the body time to eliminate methanol via the lungs and urine before it gets converted to formaldehyde. The formaldehyde is then converted to formic acid by aldehyde dehydrogenase in the liver, by formaldehyde dehydrogenase in the blood, or through the tetrahydrofolic acid-dependent one-carbon pool (Liesivuori 1991). Methanol Dangers ---------------Methanol, also known as wood alcohol, is a deadly poison in small amounts. The toxic effects of methanol vary widely from person to person (Posner 1975, Roe 1982, Tephly 1984). As little as 6 ml (0.2 ounces) of methanol has killed a person (Bennett 1953) although it usually takes as much as 80 ml to 150 ml (2.8 oz. to 5.3 oz.) to cause fatalities in the average adult (EPA 1994). In extremely small amounts and taken without a protective factor (e.g., ethanol), methanol is a cumulative poison, despite the wishful thinking of the NutraSweet Company spokespersons (Sturtevant 1985). The U.S. Environmental Protection Agency published the following about methanol (Cleland 1977): "[Methanol] is considered a cumulative poison due to the low rate of excretion once it is absorbed." After studying workers exposed to formic acid, a toxic methanol metabolite, Liesivuori addressed the issue of it being a cumulative poison (Liesivuori 1986): "The data indicated that formic acid may have a long biological half-life possibly causing an accumulation of the acid in the body. This might constitute a hitherto unappreciated toxicological hazard, as the acid is an inhibitor of oxygen metabolism." Liesivuori later points out that formic acid can accumulate in the brain, kidneys, spinal fluid, and other organs because of the slow excretion from the body (Liesivuori 1991). He also described formic acid's effects at the cellular level: "Exposure to either methanol or formic acid leads

to accumulation of acid in the body. Formic acid inhibits cytochrome oxidase, causing decreased synthesis of ATP. This is followed by anaerobic glycolysis and lactic acidosis. At the same time, and also because of acidosis, the generation of superoxide anions and hydroxyl radicals is enhanced leading to membrane damage, lipid peroxidation and mitochondrial damage. This, and the decreased pH in acidosis, allows the influx of calcium into the cells. Although the mitochondrial dysfunction may be secondary to calcium overload in the mitochondria, the final consequence is cell death." While severe acidosis would obviously not likely by a consequence of small amounts of formic acid, the other damaging aspects of formic acid such as the inhibition of cytochrome oxidase and decreased production of ATP are still possible problems. Side Effects -----------The most well-known effect caused by acute or chronic poisoning of methyl alcohol is damage to the optic nerve fibers. However, there are many other symptoms and optic nerve damage is not always one of the symptoms which appear as pointed out by Monte (1984): "Many of the signs and symptoms of intoxication due to methanol ingestion are not specific to methyl alcohol. For example, headaches, ear buzzing, dizziness, nausea and unsteady gait (inebriation), gastrointestinal disturbances, weakness, vertigo, chills, memory lapses, numbness and shooting pains in the lower extremities hands and forearms, behavioral disturbances, and neuritis. The most characteristic signs and symptoms of methyl alcohol poisoning in humans are the various visual disturbances which can occur without acidosis although they unfortunately do not always appear. Some of these symptoms are the following: misty vision, progressive contraction of visual fields (vision tunneling), mist before the eyes, blurring of vision and obscuration of vision." "Chronic occupational exposure to methanol often produces human complaints of neuritis with paresthesia, numbing, prickling and shooting pains in the extremeties." "Methanol is one of the few etiologic factors associated with acute pancreatic inflammation." Many of these symptoms are common in persons ingesting aspartame for long periods of time (FDA 1993). Since the susceptibility of humans to methanol varies greatly and since aspartame provides no protective factors such as ethanol, it is not surprising that many people have experienced methanol poisoning-like symptoms after chronic,

long-term aspartame ingestion. The damage is often slow and silent. The following is a letter presented before the U.S. Senate hearings on NutraSweet. It was written by Dr. Margan B. Raiford, M.D., Ps, Msc Med. Ophthalmology (Raiford 1987): "I had the opportunity, in Atlanta, Ga., to see the effects of methyl alcohol toxicity in 19521953 which resulted in visual damage to the optic nerves and retina in over 300 cases and the deaths of over 30 persons. "I examined Shannon Roth on July 7, 1986, along with several other patients [65 cases as of July 10, 1986 (Roberts 1990a, page 136)]. I observed evidence of effects in her eye and the eyes of the other patients that were comparable to the effects observed in the patients who suffered methyl alcohol toxicity in 1952-1953. "There was damage in the central fibers, 225,000 of the total 137,000,000 optic nerve fibers (resulting in optic nerve atrophy) in her case, which would be comparable to that observed from patients suffering methyl alcohol toxicity. The extent of damage to these fibers would explain partial to total blindness. . . . . "But in the kind of chronic low dose exposure to methyl alcohol experienced by Shannon Roth (in NutraSweet consumption) and other NutraSweet consumers, it is likely that they would experience the impact on the optic nerve differently in each eye. "The important point is that the damage observed in Shannon Roth's eye was identical to the damage I observed repeatedly in the eyes of individuals whose eyes have been damaged by methyl alcohol toxicity." The large number of eye disturbances including cases of blindness that are being caused by aspartame led Dr. H.J. Roberts to dedicate an entire chapter to these problem and detail quite a few case histories (Roberts 1990a, page 128). Dr. Roberts surveyed 551 aspartame-reactors (Roberts 1988) and had this to say about eye problems (Roberts 1990a): "Decreased vision was a major complaint in 140 (25.4%), severe pain (one or both eyes) in 51 (9.3%), 'dry eyes' or trouble wearing contact lens in 46 (8.3%), and blindness (one or both eyes) in 14 (2.5%). . . . . "in most of these patients, there was no convincing evidence for underlying glaucoma, occlusion of a retinal vessel, toxic amblyopia (related to excessive alcohol or smoking), or optic neuritis due to multiple sclerosis and other

causes that might account for the symptoms. CT scans and MRI studies of the brain or optic nerves generally proved normal in these patients. "Furthermore, that patients had known cataracts, astigmatism, macular degeneration or diabetic retinopathy did not necessarily disprove the role of aspartame . . . especially when vision promptly improved after stopping aspartame products. . . . . "Ophthalmologists and other professionals have told me about dramatic improvement of vision in their patients after the cessation of aspartame products." Susceptibility -------------Folic acid is believed by most researchers to play a large role in protecting from methanol poisoning by increasing the conversion of formic acid to carbon dioxide and water (Roe 1982, Tephly 1984, DHHS 1993a). Persons who have a folic acid deficiency are likely to be much more susceptible to damage from chronic methanol ingestion. Other nutrients may play an important part in protecting from formic acid damage. As Tephly points out (Stegink 1984a, page 114): "Nutritional differences among individuals, such as folic acid deficiency, may play an iportant part in the ability of an individual to metabolize formate. Different degrees of nutritional deficiency may be observed in debilitated and inebriated persons who have not had an adequate diet. In monkeys we observed variability in the metabolism of methanol to formate and carbon dioxide when the animals were studied at different times. Some laboratories have been unable to duplicate results obtained by others. This failure may not be due to differences in experimental design or differences in the procedures of those individual laboratories. Instead, it is possible that animals maintained on the best nutritional regimens may be less susceptible to methanol poisoning, owing to a better hepatic capacity to metabolize methanol and formate to carbon dioxide." In addition to the protective factors of ethanol, folic acid, and possibly other nutrients, Posner (1975) pointed out that the presence of food in the stomach seems to lower the toxicity of methanol. The reason food slightly lowers the toxicity is probably because the food offers protective factors (as does alcohol and juices) and/or the food delays absorption (as does the administration of aspartame in capsules). This does not mean that aspartame in food is safe in long-term use, but probably slightly less toxic. Methanol ingestion may be even more dangerous for persons taking certain pharmaceuticals. The enzyme aldehyde dehydrogenase is believed to play a major role in methanol oxidation and elimination (DHHS 1993a, Liesivuori 1991). The

drug disulfiram (trade name Antabuse) inhibits the activity of aldehyde dehydrogenase (Merck 1992, page 2638). Animal experiments have shown a significant increase in toxicity of methanol and a slowing down of methanol elimination when disulfiram was given (Posner 1975). The results are likely to be similar in humans for this particular adverse effect. Antabuse is currently being taken by 400,000 persons in the U.S. and many more are taking generic brands of disulfiram (Roberts 1990a, page 43). Posner (1975) lists research on several pharmaceuticals which shows that ingesting aspartame while on these drugs may present an additional health hazard. Some of these include sulfonylureas (for diabetics), metronidazole (antibacterial), and allopurinol (reduces uric acid). There may be other pharmaceuticals which cause adverse reactions when taken with the methanol in aspartame, but few studies have been done. Pilots are another group which may be more susceptible to acute reactions from methanol ingestion. Dr. Phil Moskal, Professor of Microbiology, Biochemistry, and Pathology, Chairman of the Department of Pathology, Director of Public Health Laboratories, discussed one possibility of why pilots may be suffering from dangerous adverse reactions to methanol from aspartame in a letter to George Leighton (Moskal 1990): A. Military studies indicate that a smoking person at sea level is physiologically at 8,000 ft. MSL. Ref. Col. Mauriel Udol. C.O. Ellington AFB, Top Gun - William Tell 1980 B. One (1) ounce of (C2H5OH ) (Ethanol) at sea level doubles in its effects at 10,000 ft. MSL. Ref. AOPA C. (Methanol) (CH3OH) displaces binding sites on the Hemoglobin molecule the same way that Carbon Monoxide (CO) does, reducing O2 (Oxygen) binding sites as CH3OH is acting as a blocking agent to the Oxygen-O2. D. Methanol is metabolized to an aldehyde OHOO Methal - dehyde which is neuro-toxic (including respiratory, olfactory and ocular nerves. E. Physiology of the human body indicates that an average 170# person's liver metabolizes 1.0 oz. of alcohol/hours. F. Density altitude affects lung performance the same as it affects engine performance. We previously discussed and both know this through personal experience. The FAR's say that the pilot must use supplemental oxygen above 12,500 MSL beyond 30 minutes. As we painfully know, the lung (engine) does not

decipher MSL or pressure altitute, only density altitude. AOPA recommends supplemental O2 (oxygen) above 10,000 MSL. That makes sense. However, the FAA doesn't use that rule. Conclusion ---------A through F are additive and if you are 29,000 fee things begin to happen. Low Dosages ----------It is very important to understand that serious health problems can start on a microscopic scale. For example, cancer, atherosclerosis, multiple sclerosis, excitotoxic neural cell damage, and many other diseases can start on a very small scale and build very slowly over the years. Excitotoxic neural cell damage can happen gradually over a lifetime and symtpoms often do not appear until after a large percentage of neural cells in a particular area has died (Blaylock 1994, page 92). The damage caused by these diseases cannot usually be detected until they are much more widespread. By the same token, damage from formic acid and formadehyde, toxic methanol metabolites, may occur very slowly over a long period of time. Even the skeptics agree that laboratory-detectable changes in measurements do not preclude toxic damage. "It is not possible to completely elminate formaldehyde as a toxic intermediate because formaldehyde could be formed slowly within cells and interfere with normal cellular function without ever obtaining levels that are detectable in body fluids or tissues" (McMartin 1978). It is also very important to keep in mind that short, lowlevel exposure to methanol or its toxic metaboites (e.g., formaldehyde) does not cause laboratory-detectible changes even though longer exposures at those levels do lead to changes and can cause health problems over time. As an example, Schmid showed that persons exposed to a single dose of significant amounts of formaldehyde did not show a statistically significant increase in the excretion of formic acid through the urine (Schmid 1994). Triebig (1989) concurs that formic acid excretion is a "unspecific and insensitive biological indicator for monitoring low-dose formaldehyde exposure." After testing subjects exposed to formaldehyde, Heinzow (1992) stated: "Excretion [of formic acid] in the general population is determined by endogenous metabolism of amino acids, purine- and pyrimidine-bases rather than the uptake and metabolism of precursors like formaldehyde. Hence in contrast to recent recommendations in environmental medicine, formic acid in urine is not an appropriate parameter for biological-monitoring of low level exposure to formaldehyde."

A number of investigators have found that a very short, lowlevel methanol exposure at 200 parts per million (260 mg/m3), the current occupational exposure limit, does not significantly increase the urinary and plasma formic acid measures (average for all subjects) (d'Alessandro 1994, Franzblau 1992, Lee 1992). d'Alessandro found that one subject had a large jump in blood formate levels after exposure to methanol, but this large increase was lost when the average increases were presented (similar to the way the data is usually presented by NutraSweet industry researchers). Kingsley (1954-55) found that workers exposed to a methanol concentrations of 200 to 375 ppm (260-487 mg/m3) when using spirit duplicators experienced adverse reactions such as headaches. Frederick (1984) showed that spirit duplicator exposure caused adverse reactions such as headaches, dizziness, nausea, blurred vision, and behavior disturbances at levels from 365 to 3080 ppm (474-3704 mg/m3). What is important to understand is that most of these workers did not spend most of their day at the spirit duplicator and therefore were breathing in air with a much lower concentration of methanol most of the time. Many of these workers who experienced adverse reactions to intermittant exposures to methanol concentrations as low as 200 ppm (260 mg/m3) probably had been working at the job for a reletively short period of time as compared to a lifetime of methanol exposure from aspartame use. Cook (1991), in a double-blind study, found that after only a 75 minute exposure to 192 ppm (250 mg/m3) of methanol (below the exposure time and level that would lead to a significant change in urinary or plasma formate measurements), the overall results show no changes in some categories, but did show statistically significant changes in other, important measurements. The subjects showed: - slightly greater fatigue from workload - a slight impairment of concentration and memory - a slight change in brain wave patterns in response to light and sound. The amount of methanol absorbed was less than 2 liters of (non-orange) diet soda for a 60 kg adult or less than 1 liter for a 30 kg child. (This assumes 1.3 times resting respiration rate such that 250 mg/m3 * 60% absorption * .6m3/75 minutes = 90 mg of methanol.) One wonders what the results would be had the subjects had this exposure every day for one year, or five years or more, especially if the subjects are more susceptible to the toxic effects of methanol. Unfortunately, it is unlikely that this experiment will be repeated with more participants or for a longer period (e.g., 3 months of regular exposures) to confirm the findings as there is no longer an interest in methanol as a fuel (Cook 1995). Two Russian studies published eight years apart showed that very low levels of methanol exposure affect visual and peripheral olfactory receptors and produced changes in EEG

measurements (Kavet 1990). While the experimental protocols were not ideal, these studies seem to agree with Cook (1991) in that minor neurological changes were found for small, short exposures. While it is likely that formic acid is being eliminated when exposed to low levels for a short period of time (although some may accumulate in various organs as discussed earlier), the changes in laboratory measurements may not be statistically significant. However, that does not mean that low levels of formaldehye and formic acid are not causing damage. Getting back to our printing shop analogy, a child who ingests the highest daily amount of aspartame in the study conducted by Frey (1976) will be ingesting nearly 8 mg/kg per day of methanol. In other words, this developing child will be working full-time, 7-days per week in a methanolladen printing shop (or chemical plant) breathing in methanol fumes (at twice resting respiration rate). A 30 kg child who ingests a two-liter diet cola will be working more than half-days at the printing shop (unless, of course, the child ingests diet orange soda). Please remember that many people will ingest a variety of aspartame-containing "foods" that would be equivalent to 2 liters (or more) of diet soda. Equivalent Weekly Hours Worked at Printing Shop With 140 mg/m3 of Methanol in Air Compared to Aspartame Ingestion Weekly Intake -----------------------------------------------2 liters 2 liters six cans soda, cereal diet cola diet orange six Equal packets FDA ADI 30 kg child 26.1 43.4 37.3 33.0 50 kg adult 70 kg adult 15.7 11.2 26.0 18.6 22.4 16.0 33.0 33.0

The formula used to calculate methanol inhaled in the Baumann (1979) study was discussed by Kavet (1990): (140 mg/m3 * 6.67 m3/workday * 5 workdays * 60 absorption rate) / 70 kg = 40 mg/kg/week of methanol. The equivalent weekly hours is calculated with the following formula: ( (mg methanol * 7 days) / kg ) * (40 hours/workweek / 40.0 mg/kg/week) Now NutraSweet may try to make the following claims: a. That only 75% of the methanol gets absorbed from aspartame as discussed by Kavek (1990). This is not certain, but based on industry estimates. If it does turn out to be true then multiply the weekly

hours at the methanol-laden printing shop by 0.75. b. That 108 ppm (140 mg/m3) is within environmental exposure limits and therefore "safe." There are several problems with this claim. i. As we can see from the Baumann (1979) and Heinrich (1982) experiments detailed earlier, one would expect quite a significant change in blood chemistry (e.g., plasma methanol levels) in the course of regular, long-term aspartame ingestion. A single dose of aspartame has already been shown to increase urinary formate levels despite numerous experimental errors which would tend to negate the increase (Stegink 1981a). ii. It is quite common for long-term exposure to environmental toxins below the industry limits to cause adverse effects. (Ziem 1989) Occupational exposure limits were set long before chronic methanol testing was done and it had never been done until aspartame came on the market. iii. The toxic load of chemicals including methanol and formaldehyde (toxic methanol metabolite) has increased tremendously over the last 15 years. Methanol is used as a fuel on a small scale (EPA 1994). It is also used in paint strippers, duplicator fluid, model airplane fuel and dry gas. Formaldehyde can be found in carpeting, clothing, glues, adhesives, cements, paste, resins, urea-foam insulation, particle board, plywood, cellulose esters, paint, primer, paint stripping agents, paper, polishes, waxes, disinfectants, cleansers, fumigators, cosmetics, preservatives, medication, mouthwash, inks, sealers, and many other products (Remington 1987, page 89). With aspartame ingestion, we are adding tremendously to this toxic load. iv. As discussed earlier, short term exposures to methanol (i.e., 75 minutes) at levels which would not cause a statistically significant increase in average formate levels has been shown to cause subtle changes memory and concentration, slightly greater fatigue, and a slight change in brain wave patterns in response to light and sound (Cook 1991). v. In occupational exposure to methanol, we are only exposing the relatively healthy (to a large extent). With aspartame, we are exposing the healthy and the sick, the developing child and fetus, persons who may be susceptible to methanol such as persons with nutritional deficiencies and persons taking certain drugs which may increase the toxicity of methanol. A large part of the population has become NutraSweet lab rats for life-long exposure to methanol and its toxic metabolites. Some people, such as those with certain chronic immune system disorders, are more susceptible, of course. Some people may not

experience the symptoms from the slow, silent damage caused by regular exposure to methanol for 2 years, 5 years, 20 years, etc. vi. Aspartame's other breakdown products also effect some of the same areas of the brain that can be damaged by methanol exposure and may have a synergistic negative effect by potentiating the toxicity of the formaldehyde or formic acid. Formaldehyde -----------Repeated exposure to low doses of formaldehyde, a formic acid precursor and a methanol metabolite has been shown to cause a wide range of health problems (John 1994, Liu 1991, Molhave 1986, National Research Council 1981 page 175-220, Srivastava 1992). Srivastava (1992) stated the following at such low level exposure: "Complaints pertaining to gastrointestinal, musculoskeletal and carbiovascular systems were also more frequent in exposed subjects. In spite of formaldehyde concentrations being well within the prescribed ACGIH [American Conference of Governmental Industrial Hygienists] limits of 1 ppm, the high rates of sickness emphasise the need for detailed studies on formaldehye-exposed subjects...." While some of the damage from methanol and formaldehyde may be due to formic acid (since some of the formaldehyde appears to be converted to formic acid), it is not inconceivable for formadehyde itself to cause significant damage from repeated exposures over time. Formaldehyde appears to be much more toxic to the body in small amounts than formic acid. The National Research Council (1981, page 179) stated the following about formaldehyde: "Some adverse effects of formaldehyde may be related to its high reactivity with amines and formation of methylol adducts with nucleic acids, histones, proteins, and amino acids. The methylol adducts can react further to form methylene linkages among these reactants. "It appears that before formaldehyde reacts with amino groups in RNA, the hydrogen bonds forming the coiled RNA are broken. Formaldehyde reacts with DNA less frequently than with RNA, because the hydrogen bonds holding DNA in its double helix are more stable. "Reaction of formaldehyde with DNA has been observed, by spectrophotometry and electron microscopy, to result in irreversible denaturation. In reactions with transfer RNA, formaldehyde interferes with amino acid acceptance. The equilibrium reaction of formaldehyde with DNA involves thermally activated

opening and closing of hydrogen bonds between matching base pairs in the helix. If permanent cross links are formed between DNA reactive sites and formaldehyde, these links could interfere with the replication of DNA and may result in mutations." It is now thought by some researchers that persons with certain illnesses may be suffering from formaldehyde toxicity when excess methylamine and semicarbazide-sensitive amine oxidase (SSAO) react to form formaldehye (Yu 1993, Boor 1992). Yu states the following: "The cytoxicity seems, therefore, to be a consequence of the deamination of methylamine. Our findings suggest that formaldehyde, the deaminated product of methylamine, may be responsible for these toxic effects. Human serum, which also contains SSAO, was also capable of deaminating methylamine and cause cytotoxicity to cultured endothelial cells. Both methylamine and SSAO circulate in human blood, and their concentrations in the blood of normal healthy subjects are quite close to those required to induce cytotoxicity in tissue-cultured cells. Both SSAO activity and methylamine levels have been reported to be increased in the blood of diabetic individuals. ... It is possible, therefore, that an abnormal metabolism of methylamine may be involved in endothelial injury, and that it may subsequently induce atherosclerotic plaque formation and thus be involved in the cardiovascular disorders seen in diabetes." Therefore, regular ingestion of aspartame may be adding "formaldehyde fuel to the fire" so to speak. It would be especially worrisome to give aspartame to persons with abnormally high SSAO and methylamine levels such as some diabetics. Persons with chronic immune system disorders are often very sensitive to low level chemical exposure including formaldehye. As stated by the National Resource Council (1981, page 177): "In some persons not previously sensitized, repeated exposure to formaldehyde may result in the development of hypersensitivity." Fujimaki (1992) and Vojdani (1992) have shown immune system alteration from exposure to formaldehye. Dr. Sherry Rogers, an expert in environmental exposure and chemical sensitivity discusses how aldehydes, especially formadehyde can cause significant damage in the body (Rogers 1990). She lists the following symptoms found for persons exposed to urea foam formaldehyde insulation (UFFI) at levels of formaldehyde as low as 0.12 ppm: Depression

fatigue poor memory inability to concentrate can't think straight "like thinking in a fog" feel unreal headache dizzy or spacey flushing of face burning eyes or throat laryngitis chronic cough, asthma arthritis rashes heart palpitations and much more...... Dr. Rogers cites Main (1983) where adverse health effects to formaldehyde exposure were found at levels between 0.12-1.6 ppm. "One path the chemical may pass through in order for the body to get rid of it is called the ALDEHYDE PATHWAY. When the adehyde pathway, for example, becomes over burdened through inhaling many other chemicals, or through an undiscovered vitamin or mineral deficiency that is cruicial in that pathway, the body then shunts the chemistry to produce chloral hydrate, the old 'Mickey Finn' or 'knockout drops.' So, indeed, these people have a very good reason for the spacey, dizzy, inability to think and concentrate symptoms that they complain of." .... "But it's fairly easy for the aldehyde path to become overloaded. Breathing plastic fumes, formaldehyde-coated paper, carpet and fabric fumes, trichloroethylene from newly shampooed carpets or dry cleaned clothes, aldehydes from auto exhaust can all raise the blood level of aldehydes. So can being highly stressed, since most brain hormones or neurotransmitters also metabolize to aldehydes. Unfortunately, to make matters worse, sometimes the aldehyde pathway does not function well because of undiagnosed deficiencies." [Rogers 1990] Dr. Rogers goes on to discuss the important of zinc, molybdenum dependent enzymes, glutathion (GSH) and other nutrients which are crucial for the conversion of aldehydes (e.g., formaldehyde) to acids (e.g., formic acid). Many of these nutrients are often found lacking in typical American diet. Dr. Rogers' books should be required reading by medical practitioners. It may very well be that it is the formaldehyde metabolite of the methanol in aspartame that causes the most slow and silent damage, especially in combination with other breakdown products of aspartame. If this is the case the formic acid measurements may not tell us what we need to

know about the damage being done by the formaldehyde. Summary ------Given the following points, I believe it is definately premature for researchers to discount the role of methanol in aspartame side effects: 1. The amount of methanol ingested from aspartame is unprecidented in human history. Methanol from fruit juice ingestion does not even approach the quantity of methanol ingested from aspartame, especially in persons who ingest one to three liters (or more) of diet beverages every day. Unlike methanol from aspartame, methanol from natural products is probably not absorbed or converted to its toxic metabolites in significant amounts as discussed earlier. 2. Lack of laboratory-detectable changes in plasma formic acid and formaldehyde levels do not preclude damage being caused by these toxic metabolites. Laboratorydetectable changes in formate levels are often not found in short exposures to methanol. 3. Aspartame-containing products often provide little or no nutrients which may protect against chronic methanol poisoning and are often consumed in between meals. Persons who ingest aspartame-containing products are often dieting and more likely to have nutritional deficiencies than persons who take the time to make fresh juices. 4. Persons with certain health conditions or on certain drugs may be much more susceptible to chronic methanol poisoning. 5. Chronic diseases and side effects from slow poisons often build silently over a long period of time. Many chronic diseases which seem to appear suddenly have actually been building in the body over many years. 6. An increasing body of research is showing that many people are highly sensitive to low doses of formaldehyde in the environment. Environmental exposure to formaldehyde and ingestion of methanol (which converts to formaldehyde) from aspartame likely has a cumulative deleterious effect. 7. Formic acid has been shown to slowly accumulate in various parts of the body. Formic acid has been shown to inhibit oxygen metabolism. 8. The are a very large and growing number of persons are experiencing chronic health problems similar to the side effects of chronic methanol poisoning when ingesting aspartame-containing products for a significant length of time. This includes many cases of eye damage similar to the type of eye damage seen in methanol poisoning cases.

Research -------From the article: "This small amount [of methanol] is readily metabolized by the body. This fact is illustrated by clinical studies in which aspartame failed to increase the levels of methanol (or formate, a metabolite) in blood or urine." [Stegink 1984a, Roak-Foltz 1984] First of all, the author cites a whole 650-page compilation of 33 articles for his first reference (Stegink 1984a). It would have been helpful if he had just cited one or two articles rather than the whole book. The second reference cited by the author to back up the above-quoted statement (Roak-Foltz 1984) is nothing more than a NutraSweet estimate of projected aspartame intake and has nothing to do with methanol or formic acid in the blood or urine. Rather than belaboring the point, I will address the clinical studies in the cited reference (Stegink 1984a) which does measure methanol and formic acid after aspartame ingestion. I will also address the recent chronic dosing study (Leon 1989) which the author cited earlier in the article. a. Frey (1976), page 496 of book. This G.D. Searle (NutraSweet)-funded study tested aspartame on 61 healthy children and sucrose on 65 healthy children (ages 2 - 21) for 13 weeks. Methanol blood and urine measurements were obtained after an overnight fast on 22 aspartame-ingesting subjects at the end of week 7 and week 13. No changes in blood or urine methanol were noted. Flaws ----i. After an overnight fast, all of the ingested methanol would have either been eliminated or converted to formaldehyde and formic acid (DHHS 1993a, Liesivuori 1986, Stegink 1981a). It is ridiculous to test for methanol in the blood after an overnight fast. ii. Plasma phenylalanine measurements were also taken after the overnight fast. The fast allowed the plasma phenylalanine levels to return to normal or near normal levels. Another worthless test. iii. The subjects were all healthy. It is important to test healthy subjects, but the detrimental effects of methanol would likely be much greater in in subjects with particular health problems such as multiple chemical sensitivities, folic acid deficiency, or persons on pharmaceuticals that may increase the toxicity of methanol. iv. Test product was freshly prepared and not real-world aspartame products which would have a higher

percentage of DKP, beta-aspartame, and possibly other breakdown products such as free methanol. v. Test product was given with food more often than normal. This would significantly delay the absorbtion of methanol and cut down on its toxicity. (Posner 1975). Conclusion ---------A worthless methanol test and other major flaws in this industry-funded research project only proves that the researcher was completely unaware of how to properly test aspartame and its breakdown products. It is interesting to note that the eye complaints were limited to people ingesting aspartame as opposed to sucrose. b. Stegink (1981a), page 542 of book. While one may be able to imagine that the researcher in the Frey (1976) experiment didn't know how to properly take plasma methanol and amino acid measurements, this "experiment" contains so many ridiculous flaws that it seems to me to approach blatent dishonesty as opposed to a legitimate research project. This G.D. Searle (NutraSweet)-funded one-day experiment was performed with 30 healthy adults. Twelve subjects received a dose of 34 mg/kg of aspartame mixed in cold orange juice. The remaining 18 subjects were divided into three groups of six and received either 100, 150, or 200 mg/kg of aspartame. The blood methanol was measured for eight hours after ingestion. No significant blood methanol concentration increase was found at the 34 mg/kg dose. Significant increases in blood methanol concentrations were found in the 100, 150, and 200 mg/kg dose. The increases returned to near fasting levels eight hours after aspartame ingestion. Blood and urine formate concentrations were measured for the six subjects receiving 200 mg/kg of aspartame. The mean of the blood formate concentrations was listed for the first eight hours after aspartame ingestion. There were no statistically significant changes in the blood formate concentrations noted. There was a large, significant increase in urinary formate excretion during the first eight hours after aspartame ingestion. This increase was especially large (three times fasting levels) during the first four hours after aspartame ingestion. The authors claimed that "the rate of formate synthesis did not exceed the rate of format excretion, since blood formate levels were not elevated." Flaws ----i. The aspartame was given with orange juice. This major flaw, by itself, renders the entire experiment worthless. The researchers claim that the "methanol content of

fruit juices may range from 12 to 640 mg/l, with an average of 140 mg/l." Since the intent of the experiment was to measure methanol and formate levels, why in the world would they add what they claim to be a large amount of methanol in the form of fruit juice! By their own standards, this totally screws up their methanol and formate measurements. The important point to remember, though, is that the fruit juice almost certainly protects against methanol poisoning by keeping much of the methanol from being absorbed or converted to toxic metabolites such as formaldehyde and formic acid. Extremely high doses of aspartame such as 200 mg/kg will, of course, overwhelm the protective factors in orange juice. I believe that the researchers deliberately used fruit juice to lower the toxicity and skew methanol and formate measurements by changing its metabolism. They certainly didn't use it to add accuracy to their methanol and formate measurements. ii. The limit for methanol detection was 4 mg/l (or 0.4 mg/dl)! This very serious flaw renders their methanol tests completely worthless. Researchers who are actually interested in measuring methanol levels (as opposed to hiding negative results) from lowlevel exposure to methanol do not use tests that are incapable of measuring all but the largest spikes in plasma methanol levels. Cook (1991) used a test that was developed in 1981 that was capable of measuring plasma methanol levels lower than 0.26 mg/l. Cook showed that after exposure to methanol, the plasma levels rose in the subjects from a low of 0.26 mg/l to a high of 3.2 mg/l. (Averages increased from 0.57 mg/l to 1.88 mg/l.) Even the highest methanol spike in Cook's experiment would not show up using the worthless methanol test from this NutraSweetsponsored experiment! d'Alessandro (1994) measured methanol levels below 1 mg/l in test subjects exposed to methanol. Davoli (1986) showed that only 8 mg/kg of aspartame caused a statistically significant rise in plasma methanol levels. It is obvious that a 34 mg/kg dose of aspartame will increase plasma methanol levels substantially. It appears that these researchers deliberately used an outdated, worthless methanol testing procedure so that they could claim that "no increase in blood methanol concentration was detected...." While they were clear in the publication what the limits of the methanol detection was, most people would not know that they used a bad test. iii. It may take as much as 12 to 16 hours after exposure to methanol for plasma formate to reach its maximum levels (McMartin 1975, Liesivuori 1987). The researchers in this project tested formate at

intervals up to only 8 hours after exposure and then at the 24-hour mark. Therefore, it seems that they may have missed the period of time when plasma formate levels would be expected to spike to their highest level. iv. The average base blood formate concentration was 19.1 mg/l. This is an unusually high base blood formate level. This is more than twice as high as found by d'Alessandro (1994), Baumann (1979), and Heinrich (1982). Buttery (1988) measureed the plasma formate levels of 30 subjects and found that they ranged from approximately 4.8 to 11.2 mg/l. Osterloh (1986) noted an average value of 4 mg/l and an upper limit of 12 mg/l. While it is possible to find some people with that high a base formate level, for that to be an average seems a little bit ridiculous -- unless the subjects were breathing formaldehyde fumes before the test. As Kavet (1990) points out, the extremely high base formate levels and the variability in the formate measurements during this experiment would keep what might otherwise be a significant change in plasma formate levels from being noticed. It is also quite possible that there were errors in the plasma formate measurements or the assay itself may be faulty. Liesivuori (1986) mentions that analytical methods for measuring formic acid (including the method used in this industry experiment) are "notoriously inaccurate." v. The charts and numbers listed were averages for all the subjects for each time period. As discussed earlier, this technique tends to hide significant changes since following the administration of aspartame or methanol, each person's peak methanol and formate levels would likely occur at a different time. If Subject A's methanol level is sky-high at 2 hours, yet Subject B's level at two hours is still low and doesn't reach it's maximum until 4 hours, this would significantly bring down the average. In addition, any unusual increases in a small proportion of the subjects' measurements tend to not be seen in presentations of average values. vi. Each experimental group ingesting the higher doses of aspartame had a ridiculously small number of subjects, making statistical significance much more difficult to obtain. There were only 6 subjects in the group that had formate measurements taken. Given the wide variability in formate levels from one time period to the next and the tiny number of subjects in this group, obtaining statistical significance was highly unlikely. vii. This experiment was simply a one time ingestion of aspartame. As discussed earlier, short, single exposures to methanol or formaldehyde in the air often does not significantly raise formate levels.

However, regular or longer-term exposure does show an increase in formate levels. While it can be helpful to conduct a few quality acute dosing studies, such experiments prove very little as far as the "safety" of aspartame or methanol when ingested regularly or even when ingested from time-to-time. It is important to keep in mind that conducting hundreds of these acute dosing studies shows us very little about the affect of aspartame as it is used in the real world-regular, long-term ingestion. The very poor quality of these acute-dosing studies simply means that instead of showing us very little, they show us only that research on aspartame must be conducted independently in order to study the adverse health effects of aspartame. viii. The subjects were all healthy. It is important to test healthy subjects, but the detrimental effects of methanol would likely be much greater in subjects with particular health problems such as multiple chemical sensitivities, folic acid deficiency, or persons on pharmaceuticals that may increase the toxicity of methanol. ix. There were numerous useless tests for an experiment of this length. There was an ophthalmological examination before and after the aspartame ingestion. Eye damage occurs gradually after chronic methanol exposure, e.g., months or years after aspartame ingestion begins. There were blood tests for total protein, albumin, Ca, inorganic P, lactate dehydrogenase, total bilirubin, glutamic-oxaloacetic transaminase, Na, K, Cl, and CO2. All of these tests are worthless for such a short experiment which had so many experimental errors. Once again, the researchers measured the plasma amino acids levels after the subjects had fasted overnight. The plasma amino acid levels would return to normal or near normal after that length of time. Unfortunately, the large number of tests allow the researchers to claim that this proves the "safety" of aspartame. x. The aspartame given to the subjects was fresh aspartame and not nearly the same product that many unfortunate people are taking on a regular basis. The product sold at the stores have often degraded due to the length of time they have sat on the shelves and/or due to the exposure to high temperatures. Conclusion ---------This experiment appears to be quite deceptive. Giving aspartame with a product that you know will screw up your measurements it quite a mistake!

Using an outdated methanol test that can only measure very high levels of methanol is another particular serious mistake. Add to that, all of the other flaws: ridiculously high base formate levels, possible inappropriate times at which formate measurements were taken, use of average values for each time period, small numbers of subjects in each group, only a single ingestion of aspartame, healthy subjects, numerous useless tests, and fresh aspartame used. This experiment is a perfect example of just how bad "research" can get when G.D. Searle or the NutraSweet Company is connected in any way with the project. One wonders what good, if any, is the "peer review" process if a study like this can get published. The fact that a number of editors of this publication worked for G.D. Searle (the company that developed aspartame), may have something to do with how this study got published. It also may help explain why so many flawed industyconnected aspartame studies were published in this journal (Journal of Toxicology and Environmental Health). Even with all of its major flaws, this study contradicts the author's statement that "aspartame failed to increase the levels of methanol (or formate, a metabolite) in blood or urine." c. (Stegink 1983a), page of book. This General Foods Corporation-funded study was similar to the previous study, except that it was conducted on infants (8-14 months of age). Ten infants were given a single 34 mg/kg dose of aspartame mixed in a freshly-prepared, cherry-flavored beverage. Eight infants were given a dose of 50 mg/kg, and 6 received a dose of 100 mg/kg. Only the blood methanol concentrations were measured from the 1 ml of blood withdrawn at 4 different intervals within 3 hours following aspartame ingestion. Important measurements of blood formate and urinary excretion of formate were not done because, according to the researchers, there was too small an amount of blood available in the samples. The results of the blood methanol test were similar to that in the experiment discussed immediately above. Blood methanol concentrations showed no significant increase for infants ingesting the 34 mg/kg dose. Significant increases were seen in doses of 50 and 100 mg/kg. Flaws ----i. It is two years later and these researchers are still using the same outdated, worthless methanol testing

procedure that was used in the experiment discussed above. Therefore, any claim by the researchers that "no increase in blood methanol concentration was detected after administration of aspartame [34 mg/kg]..." is blatently deceptive. ii. Stegink's comparison of methanol from juices and methanol from aspartame seems particularly ridiculous. Stegink shows that a dose of 100 mg/kg of aspartame raises an infant's plasma methanol levels approximately 10 times above its base level. Stegink assumes that an infant weighs 10 kg. This means that they gave the infants approximately 1000 mg of aspartame. This is equivalent to 100 mg of methanol. The researchers cite the Francot (1956) study which claims that black current juice contains over 600 mg/l of methanol. One hundred milligrams (100 mg) of methanol (the equivalent amount to what the infants were given with aspartame) would be found in approximately six ounces of black current juice according to Francot's study. Stegink uses an example of an infant drinking six ounces of liquid and thus he must believe that this is a reasonable volume that an infant can ingest. Therefore, according to Stegink's reasoning, 6 ounces of black current juice given to an infant should raise that infant's blood methanol level by nearly 10-fold. I would love to see them try to show a 10-fold increase in blood methanol levels and a corresponding increase in blood formate levels after 6 ounces of black current juice were given to a 10kg infant. iii. This experiment did not test blood and urinary formate levels. Therefore, we do not know much about what happened to the methanol after it was absorbed into the bloodstream. iv. This experiment was simply a one time ingestion of aspartame. While it can be helpful to conduct a few quality acute dosing studies, such experiments prove very little as far as the "safety" of aspartame or methanol when ingested regularly or even when ingested from time-to-time. It is important to keep in mind that conducting hundreds of these acute dosing studies shows us very little about the affect of aspartame as it is used in the real world-regular, long-term ingestion. v. The aspartame given to the subjects was fresh aspartame and not nearly the same product that many unfortunate people are taking on a regular basis. The product sold at the stores have often degraded due to the length of time they have sat on the shelves and/or due to the exposure to high temperatures.

vi. The charts and numbers listed were averages for each time period. As discussed earlier, this technique tends to hide significant changes since following the administration of aspartame or methanol, each person's peak methanol and formate levels would likely occur at a different time. If Subject A's methanol level is sky-high at 2 hours, yet Subject B's level at two hours is still low and doesn't reach it's maximum until 4 hours, this would significantly bring down the average. In addition, any unusual increases in a small proportion of the subjects tend to not be seen in presentations of average values. Conclusion ---------These researchers are still using a worthless methanol testing procedure. One wonders how many years this same "test" will be used to "prove" that aspartame does not increase plasma methanol levels. We will find out later in this document. They also repeated many of the same mistakes they made in the previous experiment. Finally, this experiment was of less use since formate levels were not measured at all. Even with all of its major flaws, this study contradicts the author's statement that "aspartame failed to increase the levels of methanol (or formate, a metabolite) in blood or urine." d. Leon (1989). From the article: "Results of this study showed no significant differences between [experimental and placebo] groups with regard to urinary excretion of formate (a metabolite of methanol)." In this G.D. Searle (NutraSweet)-funded study, 108 subjects were divided into two groups. Fifty-three (53) subjects ingested capsules containing 75 mg/kg per day of aspartame in three equal doses along with meals. The 55 subjects in the placebo group ingested cellulose capsules along with meals. Each group took their doses for 6 months. A large number of laboratory tests were performed throughout the study. In addition, plasma amino acid tests were performed to test for phenylalanine and LNAA levels. (These tests will be discussed in later sections.) Blood methanol and blood formate measurements were taken at the start of the experiment and after weeks 6, 12, 18, and 24. Urinary formate measurements were taken at the start of the experiment and after weeks 6, 12, and 24.

Most of the blood methanol readings were below the detectable levels. Only at the week 18 test was there a much greater proportion of persons in the aspartame group with a detectable blood methanol level. No data was given, but the investigators stated that there was no significant difference in the measured blood formate, urinary formate excretion (or formate to creatinine excretion ratio) between the aspartame and the placebo group. Flaws ----i. The aspartame used was fresh, dry aspartame administered in capsules. Sixteen years after the FDA pointed out the lack of information on the difference in bioavailability between real-world aspartame and capsule administration (Freeman 1973), six years after the National Soft Drink Association pointed out the enormous chemical differences in real-world aspartame as compared to fresh aspartame (NSDA 1983), four years after Tsang published detailed data proving an enormous difference in the chemical composition between aspartame freshly prepared in capsules and realworld products, and two years after Stegink proved that aspartame dissolved in liquid has a much more extreme effect than capsule-enclosed aspartame (Stegink 1987a), these researchers had no legitimate excuse for using capsule administration of aspartame. One of the investigators on this project was from the University of Iowa and should have been intimately familiar with the work of Stegink (who is also from the University of Iowa), especially Stegink's (1987a) study showing the difference in bioavailability between liquid and encapsulated aspartame. This obvious mistake of using encapsulated aspartame completely invalidates much of this experiment. The plasma amino acid measurements are worthless. Capsule administration reduces the toxicity of aspartame significantly for the following reasons: - Fresh aspartame is used instead of the more toxic soup that is found in real-world products. - The plasma amino acid (i.e., phenylalanine and aspartate) spikes are considerably lessened with capsule administration of aspartame. - Methanol absorption is delayed. This may reduce the methanol toxicity as pointed out earlier. The researchers may claim that they needed to use capsules for a double-blind study. The answer to such a claim is as follows: 1) Even if it were a good excuse to use capsule administration, the lack of bioequivalence between capsule and real-world aspartame administration still invalidates much of

this experiment; 2) Most of the experiment was simply performing blood tests which do not need a double-blind protocol; 3) It may be possible to create a double-blind experiment using real-world, liquid aspartame-containing products as long as the taste is disguised. This has been done with MSG experiments in the past. ii. The aspartame capsules were ingested with full meals. This is one of many mistakes which combine to invalidate this experiment. The effects from the free amino acids would not be nearly pronounced when aspartame is taken with full meals. (I will go into more detail about this in a later section.) As Posner (1975) points out, taking methanol with meals slows its absorption and may affect its toxicity. The combination of this flaw plus the use of capsules would render formate and other measurements nearly useless. The chance of finding an adverse reactions to fresh, encapsulated aspartame, taken with full meals is tremendously reduced. One wonders if these researchers deliberately designed this experiment to produce negative results. iii. The blood methanol tests were taken after a 12-hour fast. Anyone who has done any reading on the subject of methanol would know that a blood test for methanol would be worthless after a 12-hour fast (as discussed earlier in this section). Had the investigator who conducted the blood methanol test in this experiment, Thomas Tephly, Ph.D., taken the time to read another paper that he coauthored (Stegink 1981a), he would have known that methanol gets converted to formic acid in the body causing the methanol concentration in the blood to return to normal levels within twelve hours after aspartame ingestion. On top of the worthlessness of taking the methanol test at the wrong time, these researchers used the same worthless blood methanol test that was used in the experiments discussed previously. This time, however, these researchers claimed that the blood methanol test had a limit of detection of 0.31 mmol/liter or, using the conversion factor presented in DHHS (1993a), approximately 1.0 mg/dl (10 mg/l). This is three times less sensitivity claimed than the previous experiments dicussed and as much as 45 times less sensitive than the methanol test used by Cook (1991)! One wonders how these researchers could possibly have found any of the methanol measurements over the limits of detection let alone 10 to 20 percent of the limits of detection. iv. The blood methanol and formate tests were taken on weeks 0, 6, 12, 18, and 24. The urine formate and creatinine tests were taken on weeks 0, 6, 12, and 24. What happened to week 18? Is it typical to skip

an important test for no particular reason? Is it possible that the test was done, but the data did not meet the researchers' expectations? This seems rather strange to say the least especially since this happens to be the week that blood methanol tests somehow showed the aspartame group well above the placebo group. v. The exclusion criteria stated, in part, that "All women included in the study were required at entry to be postmenopausal, to have been surgically sterilized, to be taking oral contraceptives, or to have had an intrauterine device in place for at least 6 months to prevent the possibility of pregnancy." The problem with this exclusion criteria is that women make of the majority of reported adverse reactions to aspartame (Mullarkey 1992, page 70, CDC 1984). It is not inconceivable that women who have certain hormonal fluctuations may be more susceptible to acute adverse effects from aspartame. Therefore, the researchers may have excluded a large percentage of the population who would have actually experienced adverse reactions (had the experiment not been so badly flawed). There appears to be no good reason for excluding this population of women. If these researchers insist on not studying anything but a perfectly healthy population, the least they could do is use a reasonable representation of a healthy population rather than further limiting it to whatever their whimsical desires call for. If, in the very unlikely occurrance, one of the women had become pregnant and experienced an adverse reaction, they could have simply noted that in their discussion. Instead, they chose to take an unrepresentative sample of subjects (healthy persons) and make it less representative by excluding women who may be more susceptible to acute adverse reactions.. vi. One subject with a history of bronchial asthma was dropped from the study due to symptoms of headaches, nausea, and malaise after aspartame capsule ingestion. The subject was rechallenged for a much shorter period of time (9 days as compared to 6 months), with a much smaller dosage (9 - 25 mg/kg capsules over a nine day period as compared to 75 mg/kg per day) with customized meals (which may have included foods to further offset the effects of methanol and amino acids). The subject experienced fewer reactions to aspartame under these conditions. The subject was rechallenged at least one more time (the paper does not mention under what conditions) and no aspartame reactions were found. This is an abuse of double-blind studies. The researchers cannot simply take results that they don't like such as a serious adverse reaction and then keep challenging the subject and changing the

protocol until the desired results are achieved. Why didn't the researchers change the protocol and rechallenge persons who did not experience reactions? vii. The subject that was dropped from the study had a history of bronchial asthma. The exclusion criteria stated that subjects should be excluded from the experiment if they had "any chronic disease detected by history, physical examination, or routine laboratory tests." What was this person doing in the experiment in the first place? He should have been excluded according to the protocol. If these researchers cannot even follow their own exclusion criteria, and change the protocol for rechallenges of this subject as described above, one wonders how many other times they deviated from the protocol and did not mention it in the publication. viii. Plasma phenylalanine and phenylalanine/LNAA measurements were taken after the overnight fast. The fast allowed the plasma phenylalanine levels to return to normal or near normal levels. Another worthless test. While fasting plasma phenylalanine levels in some persons may change over time and cause serious health problems after regular ingestion of aspartame (as per the example given near the start of this review), that would not have been seen here because the use of fresh, encapsulated aspartame taken with meals skewed the results so badly. ix. The formate test had only an 80% chance of detecting an average change of 0.13 mmol/L (5.2 mg/l) in blood levels. (Blood formate levels average approximately 0.1 mmol/l or 4 mg/l as discussed earlier.) Therefore, a significant increase could occur using this test without it being noticed. The blood formate measurements were not even presented. These values would have been much more relevant than the hematology values had the experiment not otherwise had so many major flaws. Even if the values had been presented, Liesivuori (1986) mentions that analytical methods for measuring formic acid (including the method used in this industry experiment are "notoriously inaccurate." x. Once again, the charts and numbers listed were averages for all subjects at each time period. As discussed earlier, this technique tends to hide significant changes since following the administration of aspartame or methanol, each person's peak methanol and formate levels would likely occur at a different time. If Subject A's methanol level is sky-high at 2 hours, yet Subject

B's level at two hours is still low and doesn't reach it's maximum until 4 hours, this would significantly bring down the average. In addition, any unusual increases in a small proportion of the subjects tend to not be seen in presentations of average values. xi. The quality of the study was monitored by an employee of the NutraSweet Company. This, in itself, I believe is a flaw due to the extreme corporate bias. Conclusion ---------Even with all of these major flaws, the aspartame group experienced approximately 50% more adverse reactions than the placebo group. This significant increase was played down in the text by breaking up the adverse reactions into categories such as "headaches." One wonders if the results would have even been more striking had the researchers used real-world aspartame products at a similar dose and not built so many other serious flaws into this experiment. A research project like this can make a person lose all faith in the scientific process. Only industry (e.g., NutraSweet) would fund and monitor a study this poorly designed. The study was presented at the 1988 Annual Meeting of the Federation of American Societies for Experimental Biology (FASEB). Such a presentation should have caused the audience to begin crying over the death of the scientific process. It boggles the mind that a peer-reviewed journal would accept this study for publication without addressing some of the serious questions raised above. It simply proves that the peerreview process does not prevent worthless, industrysponsored studies. I would prefer to say that the experiments discussed above are the worst research I have ever seen. Unfortunately, these are quite typical of industry-sponsored studies. Many of the pre-approval studies for aspartame which will be discussed later were much worse -- so bad that rolling dice would have been a more accurate method for determining the "safety" of aspartame. Yet, somehow, even the pre-approval studies met the FDA's "standards" for acceptable research upon which a safety determination could be made. NutraSweet/FDA Arguments -----------------------Animal Studies -------------Studies of methanol on rats and Rheusus monkeys cannot be extrapolated to humans. The differences between how these species handle methanol is described in detail by Roe (1982).

Sturtevant (1985) of G.D. Searle & Co. claims that MartinAmat (1978) created an animal model using Rhesus monkeys. However, Roe (1982) points out that, as other investigators have found, it is "very unlikely that in rhesus monkeys (blood pH about 7.2 (av.) and blood formate about 7.5 mmol/l) amaurosis and atrophy of the optic nerve can be caused by methanol." Roe also details the significant differences between methanol metabolism in rhesus monkeys and humans as well as the many times greater toxicity of methanol in humans. Finally, even if an animal model for acute methanol poisoning is created in the future, it is unlikely that the model will apply to low-level, chronic methanol poisoning since the mechanism is probably somewhat different (i.e., no severe acidosis) The NutraSweet Company's attempts to use the Rheusus monkey as a test animal for aspartame/methanol poisoning only proves that they do not understand or care about the researched differences of the effects of methanol between humans and that particular species of monkeys. Human Studies ------------Sometimes, as "proof" that low levels of methanol does not cause damage, the NutraSweet Company or the FDA cite several references. One study that is sometimes cited is a 1952 study published in the British Journal of Industrial Medicine (Leaf 1952). The FDA states (Federal Register 1984, page 6677): "In fact, studies in human subjects given oral dosages of methanol of 71 to 84 mg/kg body weight showed no toxic effects with blood levels of methanol reaching 47 to 76 mg per liter 2 to 3 hours afterwards." The reality is: 1. The study was performed on only five men given a dose of 2.5 to 7.0 ml (29-84 mg/kg) not 71 to 84 mg/kg. 2. It was a one-day, single-dose study of methanol and did not test chronic ingestion over months or years as happens with aspartame ingrestion. 3. There was no detailed discussion of reactions that may have been caused by the single dose of methanol in this experiment. 4. The first part of the study where methanol was given by itself showed that a large percentage of methanol was converted to formic acid. In the second part of the study where ethanol was taken concurrently with methanol, the ethanol blocked the conversion of methanol to formaldehyde and formic acid. (Remember, aspartame contains no protective ethanol.) 5. The investigators summarize as follows: "Owing to the slow rate of elimination of methanol

from the body, repeated exposure to the vapour or liquid may result in accumulation and under such conditions the use of methanol would constitute a toxic hazard. . . . The elimination of methanol after doses of 2.5 to 7.0 ml has been studied in five human subjects. At any time the rate of elimination was found to be proportional to the concentration of methanol in the body. The significance of this finding is discussed. Only a very small fraction of the ingested methanol (about 2%) was eliminated via the respiratory and urinary routes." 6. A significant portion of this publication addressed the important part ethanol plays in protecting against methanol poisoning. As was mentioned earlier, aspartame contains no ethanol or other protective factors. The FDA attempts to give further examples of the alleged lack of toxicity of methanol at low levels (Federal Register 1984, page 6677): "From estimates based on blood levels in methanol poisonings, it appears that the ingestion of methanol on the order of 200 to 500 mg/kg body weight is required to produce a significant accumulation of formate in the blood which may produce visual and central nervous system toxicity (Rowe 1982, Friedman 1980)." The references cited by the FDA are only discussing severe, acute toxicity (i.e., poisoning) and not long-term, chronic toxicity (i.e., slow poisoning). Unfortunately, this is the type of obfuscation that one can expect from the FDA and the NutraSweet Company -- keeping people busy chasing down references which are irrelevant, but which allow them to convince the uninformed scientist that aspartame is "safe." NutraSweet researchers will sometimes cite two more recent studies which they claim to show that methanol poisoning cannot occur from aspartame (Stegink 1989, Stegink 1990). Many of the same serious problems, bordering on outright deception, that were found in Stegink (1981a) are also found in these studies. Stegink (1989) tested six normal adult subjects ingesting eight 8-ounce servings of Kool-Aid each sweetened with 600 mg of aspartame. The servings were taken at one hour intervals. On another day, the subjects followed the same procedure, but the Kool-Aid was unsweetened (i.e., no aspartame). Stegink (1990) was nearly the same experiment, but the subjects were individuals heterozygous for Phenylketonuria (PKU). (PKU is a genetic disorder where the person lacks an enzyme necessary to metabolize the amino acid, phenylalanine. A PKU Heterozygote has a slightly impaired phenylalanine metabolism.) Both experiments showed a significant increase in plasma phenylalanine levels as well as plasma phenylalanine/LNAA ratios. (This will be discussed in more detail in the

Phenylalanine section.) No statistically significant difference was seen in the blood methanol levels, blood formate levels, or urinary formate levels on the day where aspartame was ingested compared to the day it was not ingested. Flaws ----i. These "researchers" are still using the same outdated (1969), non-sensitive, worthless methanol test that they were using in 1981! With all the money being poured into this lab from the NutraSweet Company, one would think that they could afford equipment for accurate and useful tests. Stegink (1990) took it one step beyond a mere deceptive, worthless methanol test. A graph was shown of blood methanol levels over 24 hours. The "apparent" aspartame day methanol levels were shown as the exact same as the Kool-Aid (alone) day. This is extremely deceptive for two reasons. The levels shown were more than three times below the detection limit of the methanol test used and therefore the figures on the graph were a wild guess (at best). Davoli (1986) had already shown a significant increase in blood methanol levels after a single dose of 500 mg of aspartame and therefore Stegink, et al. must have known that the methanol levels rose significantly and that the graph was complete nonsense. ii. It may take as much as 12 to 16 hours after exposure to methanol for plasma formate to reach its maximum levels (McMartin 1975, Liesivuori 1987). The researchers in this project tested formate at intervals up to only 8 hours after exposure and then at the 24-hour mark. Therefore, it seems that they may have missed the period of time when plasma formate levels would be expected to spike to their highest level. iii. The average base blood formate concentration was again ridiculously high -- 21.0 mg/l in Stegink (1990). This is two or three times higher than in almost any independent experiment (d'Alessandro 1994, Baumann 1979, Heinrich 1982, Buttery 1988, Osterloh 1986). While it is possible to find some people with that high a formate level, for that to be an average seems ridiculous -- unless the subjects were breathing formaldehyde fumes before the test. As Kavet (1990) points out, the extremely high base formate levels and the variability in the formate measurements during this experiment would keep what might otherwise be a significant change in plasma formate levels from being noticed. It is also quite possible that there were errors in the plasma formate measurements or the assay itself may be faulty. Liesivuori (1986) mentions that analytical methods for measuring formic acid (including the method used in this industry experiment are "notoriously inaccurate."

iv. The charts and numbers listed were averages for all the subjects for each time period. As discussed earlier, this technique tends to hide significant changes since following the administration of aspartame or methanol, each person's peak methanol and formate levels would likely occur at a different time. If Subject A's methanol level is sky-high at 2 hours, yet Subject B's level at two hours is still low and doesn't reach it's maximum until 4 hours, this would significantly bring down the average. In addition, any unusual increases in a small proportion of the subjects' measurements tend to not be seen in presentations of average values. v. Each experimental group ingesting the higher doses of aspartame had a ridiculously small number of subjects, making statistical significance much more difficult to obtain. There were only 6 subjects in the test groups. Given the wide variability in formate levels from one time period to the next and the tiny number of subjects in this group, obtaining statistical significance was highly unlikely.

vii. This experiment was simply a one day ingestion of aspartame. As discussed earlier, short, single exposures to methanol or formaldehyde in the air often does not significantly raise formate levels. However, regular or longer-term exposure does show an increase in formate levels. While it can be helpful to conduct a few quality acute dosing studies, such experiments prove very little as far as the "safety" of aspartame or methanol when ingested regularly or even when ingested from time-totime. It is important to keep in mind that conducting hundreds of these acute dosing studies shows us very little about the affect of aspartame as it is used in the real world--regular, long-term ingestion. The very poor quality of these acute-dosing studies simply means that instead of showing us very little, they show us only that research on aspartame must be conducted independently in order to study the adverse health effects of aspartame. viii The aspartame given to the subjects was fresh aspartame and not nearly the same product that many unfortunate people are taking on a regular basis. The product sold at the stores have often degraded due to the length of time they have sat on the shelves and/or due to the exposure to high temperatures. Conclusion ---------These two studies, while slightly better than the single dose experiments, were still only one day long. Numerous other flaws as well as deceptively faulty testing procedures make it impossible to draw any useful conclusion from the experiment. Sometimes NutraSweet researchers will try to argue that aspartame cannot possibly increase formate levels more than

9 mg/l (for 3 liters of diet cola) and is therefore within "normal" blood formate range -- meaning that it could not possibly be harmful. This argument was put forth by Shahangian (1984). The problem with this argument is that people have their own unique blood chemistry. To arbitrarily add a significant amount of formate to the blood and say that it is okay simply because they can find someone else in the world with that level of formate (meaning that the level is still "normal") does not make sense. An increase in formate of 9 mg/l would be considered by many health professionals to be a dangerous jump in formate levels if it occurred regularly. Chronic methanol poisoning does not necessarily mean that there are large jumps in the blood and urine methanol and formic acid levels. Small increases occurring regularly, over many months or years may be enough to cause damage a little bit at a time, especially in persons who 1) do not take the ethanol protective factor with aspartame ingestion, 2) have a folic acid or other nutrient deficiencies, 3) have a sensitivity to methanol or its toxic metabolites such as the growing number of persons with Multiple Chemical Sensititives (MCS), and 4) are taking pharmaceuticals which may react negatively with methanol ingestion. Finally, we have to keep in mind that the mechanism(s) for acute methanol toxicity and chronic methanol toxicity may be different in some ways and similar in others. Any highly technical argument by NutraSweet trying to convince readers that low levels of methanol is safe will have to address the following issues: a. Low levels of chronic methanol exposure in industry has caused adverse reactions after a relatively short period of time. The technical argument will have to show how and why low levels in industry cause adverse reactions, but levels not much lower than that from aspartame would somehow miraculously not cause any reactions even though it is proposed for a lifetime of use in even the most chemically sensitive individuals. b. Given that environmental researchers agree that there is a lack of data on long-term exposure to low-levels of methanol, how can NutraSweet, with any conscience, conduct a clinical trial of low levels of an extremely dangerous, human-specific poison on much of the population. This is especially true since prelimary experiments of short-term exposure to low levels of methanol show minor changes in brain function. Recent Case History Samples --------------------------1. I'm a 29 year old atheletic female victim of deadly NutraSweet poisoning. I began to use it in the spring of 1990, and soon afterwards my condition began to deteriorate. I never imagined my strange symtoms were from this chemical, after all its approved by the FDA and on restaurant tables.

My eyesight began to fade until I was almost blind in one eye. Next my hearing became dull and my legs, feet and torso lost sensation and became numb. I was dizzy most of the time, irritable and depressed and had constant terrible headaches. I became very clumsy, dropped and bumped into things. I used to skate but having lost my balance I had to give it up. My mind was affected and I thought I had a brain tumor. Reading comprehension and memory drastically decreased. I though I was dying. Two different doctors made the diagnosis of Multiple Sclerosis. One was an eye specialist I saw about my vision loss. This spring a friend explained to me that all my symptoms were coming from aspartame (NutraSweet) and that I had methanol toxicity which mimics Multiple Sclerosis. I was only drinking three Diet Cokes a day. I could hardly believe the horrible nightmare I was living was sold in 6 packs at the grocery store, but I would try anything so I stopped. Right away I began to feel better and today most of my symptoms have completely disappeared. My friend, Betty, was right, I was suffering from methanol toxicity. My hearing and vision have returned and so has my memory. I'm no longer clumsy and have regained my balance, and feeling has returned to my lower extremities. 2. I became a big drinker of Diet Coke, drinking more and more because I liked the taste. When I had vision disturbances my physician said it was optic migraines. There were silvery lines in my eyes and I would get dizzy. Sometimes I would have these optic migraines twice a day, and up to 6 times a week. One day I baked cookies with NutraSweet and really got worse. Never did I associate my problems with this substance. About six months ago I was given some information on aspartame (NutraSweet) and immediately stopped using it in any form. Within a week I realized I wasn't having any optic migraines or dizziness. In six months I've only had two small episodes, and feel they are related to having accidently consumed something with aspartame in it like the ice cream I had recently. I was not aware aspartame was in it until after I had eaten it. .... P.S. Since we've been notifying others of the dangers of aspartame they, too, have abstained, many with the disappearance of symptoms, including my husband, Bob. It turns out this is a very serious problems and the average person does not consider the association of this toxin with their medical problems. It is easily established this is the culprit when symptomatology does not return after elimination. Conclusion ---------Methanol ingestion by aspartame users is much greater than

what they would naturally ingest with fruit juices. The lack of natural ethanol protective factor makes methanol from aspartame even more dangerous. It is likely that toxic methanol metabolites are not produced in significant amounts after ingestion of food products as they are after ingestion of aspartame. Persons with certain health conditions or who are taking certain pharmaceuticals may be even more susceptible to chronic methanol poisoning. Clinical experience has shown that many persons who have ingested aspartame regularly for an extended period have suffered from symptoms which are common in methanol poisoning. NutraSweet-funded studies usually do not test chronic ingestion of aspartame, are usually hopelessly flawed, at best, and, in my opinion, represent a deliberate attempt to deceive. The question we have to ask ourselves is whether it is fair to sell a product which essentially provides the equivalent of part-time employment for much of the population, from the healthiest to the sickest, from children to pregnant women, at methanol-laden printing shops and chemical plants. Given that more and more people are becoming sensitive to chemical exposure and that an increasing number of people are developing chronic immunological and neurological problems, is it fair to significantly add to the toxic load without warning the consumers? Not only is it not fair to experiment with low levels of poison on the population, but contributing to the destruction of so many people's health simply to make money borders on criminality in my opinion.

5. History of Aspartame 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 sideeffects 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." The article, which was printed in the Journal of the American Medical Association (JAMA), was basically a summary of information provided by the FDA. Considering the fact that the author published an article in a book entitled "Stop the FDA" (Leibovitz 1992) and that the former Editor of JAMA, Dr. Robert Moser is a long-time consultant for the

NutraSweet Company (Moser 1994, Roberts 1992), I find it difficult to understand how the author could have taken the article seriously. 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 78week 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 claimed that Dr. Mauro's MBR report was not submitted because they did not like the terminology Dr. Mauro used in evaluating the thyroid slides. They claimed that her inaccurate terminology in this case showed that Dr. Mauro was unreliable as a pathologist. Yet, G.D. Searle never notified Dr. Mauro of any questions and on June 1, 1973, they wrote to MBR and stated that the report "looks just fine" (Merrill 1977). -------------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 mid1970'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 mid1970'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) FDA Toxicologist and Task Force member, Dr. Andrian Gross stated (Wilson 1985): "They [G.D. Searle] lied and they didn't submit the real nature of their observations because had they done that it is more than likely that a great number of these studies would have been rejected simply for adequacy. What Searle did, they took great pains to camouflage these shortcomings of the study. As I say filter and just present to the FDA what they wished the FDA to know and they did other terrible things for instance animals would develop tumors while they were under study. Well they would remove these tumors from the animals." FDA Lead Investigator and Task Force Team Leader, Phillip Brodsky described the 1975 FDA Task Force members as some of the most experienced drug investigators. He went on to state that he had never seen anything as bad as G.D. Searle's studies (Graves 1984, page S5499 of Congressional Record 1985a). The report quoted a letter written to G.D. Searle on July 15, 1975 from its consultant in reproduction and teratology, Dr. Gregory Palmer, in regards to a review of some of G.D. Searle's repreductive studies submitted to the FDA (Gross 1985, page S10838 of Congressional Record 1985b): "Even following the track you did, it seems to me

you have only confounded the issue by a series of studies most of which have severe design deficiencies or obvious lack of expertise in animal management. Because of these twin factors, all the careful and detailed examination of fetuses, all the writing, summarization and resummarization is of little avail because of the shaky foundation." G.D. Searle officials noted that Dr. Palmer did not look at all of the teratology studies (Searle 1976b, page 21). However, there is no credible evidence that would lead a reasonable person to believe that the studies which were not presented to Dr. Palmer were much better. In fact, the evidence shows that it is very likely that all of the studies were abyssmal. The FDA Commissioner at the time, Alexander Schmidt stated (Graves 1984, page S5497 of Congressional Record 1985a): "[Searle's studies were] incredibly sloppy science. What we discovered was reprehensible." Dr. Marvin Legator, professor and director of environmental toxicology at the University of Texas and the pioneer of mutagenicity testing at the FDA from 1962 to 1972 was asked by Common Cause Magazine to review the FDA investigation results of G.D. Searle's tests (Graves 1984, page S5498 of Congressional Record 1985a): "[All tests were] scientifically irresponsible [and] disgraceful. I'm just shocked that that kind of sloppy [work] would even be sent to FDA, and that the FDA administrators accepted it. There is no reason why these tests couldn't have been carried out correctly. It's not that we are talking about some great scientific breakthrough in methodology." Senator Edward Kennedy at the April 8, 1976 hearings before the Senate Subcommittee on Labor and Public Welfare stated (Kennedy 1976): "The extensive nature of the almost unbelievable range of abuses discovered by the FDA on several major Searle products is profoundly disturbing." -------------In January, 1976, G.D. Searle defended their results by claiming (Searle 1976a, page 5-6): "In all of the studies at Searle which have been examined by the FDA in its investigation, the scope of the material being considered included seven years of observation, from 1968 to date, in 57 studies involving more than 5,700 animals with over 228 million observations and calculations." However, their deliberate misconduct and "lies" (as put by

FDA Investigator, Dr. Adrian Gross) invalidated their experiments for the following reasons: 1. Many of the problems with the studies included horrendous experimental designs, questions regarding dosage given, loss of animal tissue and data, etc., etc., which invalidates entire experiments and causes what they claim to be 4 million observations and calculations per study (average) to become irrelevant. 2. Only the key aspartame studies were looked at. It is almost a certainty that the non-key aspartame studies were equally flawed. Therefore, this would invalidate the "hundreds of millions" of observations and calculations made during these studies. 3. The difference between a study showing no statistical difference and a significant statistical difference is often only a few observations or calculations. Therefore, had the myriad of other serious experimental errors not occurred (as detailed above), the observation and calculation mistakes in each experiment investigated would, by themselves, invalidate most of the key studies. 4. It is highly unlikely that the FDA Investigative teams found all of the problems with G.D. Searle's studies. G.D. Searle seemed so intent on covering up their misconduct, that it is quite likely that they were able to hide many of the problems from the FDA. -------------A series of poorly conceived, flawed studies funded by G.D. Searle were published in Volume 2 (1976) of the Journal of Toxicology and Environmental Health. An Associate Editor of this scientific journal was Robert G. McConnell, the Director of G.D. Searle's Department of Pathology and Toxicology (the department responsible for monitoring the quality of G.D. Searle's pre-approval tests investigated by the 1975 FDA Task Force). Mr. McConnell's story continues later in 1977. Another G.D. Searle employee, Carl R. Mackerer was an editor of the journal. Another editor of the journal was Thomas R. Tephly, the person responsible for conducting a series of badly flawed blood methanol and formate measurements in NutraSweet-funded studies over the last 15 years. -------------In July 1976, the FDA decided to investigate 15 key aspartame studies submited by G.D. Searle in which the 1975 FDA Task Force discovered problems. Three (3) of the studies were investigated at the FDA (E5, E77/78, E89) by a 5-member Task Force headed by FDA veteran Inspector, Jerome Bressler (Graves 1984, page S5499 of Congressional Record 1985a; Gordon 1987, page 497 of US Senate 1987; Farber 1989, page 110). --------------

On August 4, 1976, G.D. Searle representatives met with the FDA and convinced them to allow G.D. Searle to hire a private agency, University Associated for Education in Pathology (UAREP), and pay them $500,000 to "validate" the other 12 studies (Gordon 1987 page 498 of US Senate 1987) According the FDA Commissioner during the early 1980s, Arthur Hull Hayes, the UAREP investigation was to "make sure that the studies were actually conducted." As described by Florence Graves (1984, page S5500 of Congressional Record 1985a): "The pathologists were specifically told that they were not to make a judgment about aspartame's safety or to look at the designs of the tests. Why did the FDA choose to have pathologists conduct an investigation when even some FDA officials acknowledged at the time that UAREP had a limited task which would only partially shed light on the validity of Searle's testing? The answer is not clear. "Dr. Kenneth Endicott, Director of UAREP, said in an interview that the FDA had 'reasons to suspect' that Searle's tests 'were not entirely honest.' Because the FDA 'had doubts about [Searle's] veracity,' Edicott said, officials wanted UAREP 'to determine whether the reports were accurate.' "FDA scientist Dr. Adrian Gross, in a letter to an FDA official, said, 'speaking as a pathologist, it seemed questionable that the group could do the kind of comprehensive investigation that was required. He pointed in particular to a variety of issues that needed to be investigated. He said some of these would involved closely questioning administrators and lab technicians about their practices. Since many important issues that should be investigated 'have nothing to do with pathology,' he said, only trained FDA investigators were qualified to do a comprehensive evaluation of the testing. . . . "Meanwhile, an interview with Endicott indicates that Adrian Gross was right: the pathologists couldn't--and didn't--carry out a comprehensive review. . . . As former FDA Commissioner Alexander Schmidt put it in a recent interview, UAREP looked at the slides to determine whether they had been misrepresented, but didn't look at the conduct of the experiments in depth. The 1975 [FDA] task force investigation looked at the conduct of the experiments in depth, but did not look at the slides. . . . Endicott agreed . . . 'We could only look at what was there--the tissues.' The findings of this investigation where released in the Bessler Report in August 1977 (see below).

1977 ---Donald Rumsfeld, who was a former member of the U.S. Congress and the Chief of Staff in the Gerald Ford Administration, was hired as G.D. Searle's President. Attorney James Turner, Esq. alledged that G.D. Searle hired Rumsfeld to handle the aspartame approval difficulties as a "legal problem rather than a scientific problem." (Gordon 1987, page 497 of US Senate 1987). As layed out by Mary Nash Stoddard (Stoddard 1995a, page 11), Rumsfeld hired: John Robson as Executive Vice President. He was a former lawyer with Sidley and Austin, Searle's Law Firm and also served as chairman of the Civil Aeronautics Board, which was then connect to the Department of Transportation. Robert Shapiro as General Counsel. He is now head of Searle's NutraSweet Division. He had been Robson's Special Assistant at the Department of Transportation. William Greener, Jr., as Chief Spokesman. He was a former spokesman in the [Gerald] Ford White House. Donald Rumsfeld is now on the Board of Directors of the Chicago Tribune which recently wrote a glowing article about the NutraSweet Company (Millman 1995, Mullarkey 1995). -------------On January 10, 1977, FDA Chief Counsel Richard Merrill recommended to U.S. Attorney Sam Skinner in a 33-page letter detailing violations of the law that a grand jury be set up to investigate G.D. Searle. In the letter, Merrill stated (Merril 1977, page S10827 of Congressional Record 1985b): "We request that your office convene a Grand Jury investigation into apparent violations of the Federal Food, Drug, and Cosmetic Act, 21 U.S..C. 331(e), and the False Reports to the Government Act, 18 U.S.C. 1001, by G.D. Searle and Company and three of its responsible officers for their willful and knowing failure to make reports to the Food and Drug Administration required by the Act, 21 U.S.C. 355(i), and for conceailing material facts and making false statements in reports of animal studies conducted to establish the safety of the drug Aldactone and the food additive Aspartame." All of the G.D. Searle studies were abyssmal as discussed earlier. However, there were two studies where the violations of the law appeared to be especially flagrant. The two studies cited by Merrill were the 52-week toxicity study on infant monkeys performed by Dr. Waisman which G.D.

Searle withheld key information from the FDA and the 46-week toxicity study of hamsters where G.D. Searle had taken blood from healthy animals at the 26th week and claimed that the tests had actually been performed at the 38th week. Many of the animals from which G.D. Searle claimed had blood drawn from were actually dead at the 38th week. See earlier discussion for references. -------------On January 26, 1977, G.D. Searle's law firm, Sidley & Austin, requested a meeting with U.S. Attorney Samuel Skinner before a grand jury is convened (Gordon 1987 page 497 of US Senate 1987, Mullarkey 1994b, page 6-7). One representative of Sidley & Austin at that meeting was Newton Minow who is currently on the Board of Diretors at the Chicago Tribune (Gordon 1987, page 497 of US Senate 1987; Mullarkey 1995). -------------On March 8, 1977, in a confidential memo to aides, while he was supposed to be pushing for fraud indictments against G.D. Searle, U.S. Attorney Samuel Skinner stated that he had begun preliminary employment discussions with G.D. Searle's law firm Sidley & Austin (Gordon 1987, page 497 of US Senate 1987; Mullarkey 1994b, page 7). -------------On April 13, 1977, a U.S. Justice Department memo urged U.S. Attorney Samuel Skinner to proceed with grand jury investigations of G.D. Searle. The memo points out that the Statute of limitations on prosecution would run out shortly (October 10, 1977 for the Waisman monkey study and December 8, 1977 for the hamster study) (Mullarkey 1994b, page 7). -------------Samual Skinner withdrew from the G.D. Searle case and Assistant U.S. Attorney William Conlon was then assigned to the Grand Jury investigation (Gordon 1987, page 497 of US Senate 1987). -------------On July 1, 1977, U.S. Attorney Samuel Skinner left his job to work for the G.D. Searle law firm Sidley & Austin. Thomas Sullivan was appointed as Samuel Skinner's successor (Gordon 1987, page 497 of US Senate 1987). -------------Assistant U.S. Attorney William Conlon convened a grand jury, but he let the Statute of Limitations run out on the aspartame charges (Gordon 1987, page 497 of US Senate 1987). Fifteen months later, Conlon accepted a job with the law firm representing G.D. Searle, Sidley & Austin (Gordon 1987, page 497 of US Senate 1987).

-------------Robert McConnell was the Director of G.D. Searle's Department of Pathology and Toxicology which oversaw most of the aspartame research. Mr. McConnell was named in Richard Merrill's letter to U.S. Attorney Samuel Skinner. According to McConnell's attorney, his client was awarded a $15,000 bonus and asked to take a 3-year sabbatical (for which he received $60,000/year) because he was a "political liability." (Gordon 1987, page 496 of US Senate 1987) -------------Philip Brodsky, the Lead Investigator for the orginal FDA Task Force looking into G.D. Searles studies retired. He stated that his reason for retiring was the disclosure of the 1975 FDA Task Force findings before the U.S. Congress (Sen Kennedy hearings in 1976) had become "politicized." As Gregory Gordon put it in the UPI Investigative article (Gordon 1987, page 496 of US Senate 1987): "He said the main witnesses, Searle executives and top FDA officials uninvolved in the investigation gave 'the wrong answers to the wrong questions . . . They didn't even let the experts answer the questions.'" -------------In August 1977, the Bressler Report pertaining to three key aspartame studies, E5, E77/78 and E89, was released. Some of the findings from the three studies reviewed by the Bresslerled FDA Task Force include (Mullarkey 1994b, page 11, 48; Farber 1989, page 110-112; Verrett 1987, page 385 of US Senate 1987): a. In one study, 98 of the 196 animals died but were not autopsied until as much as one year later. Because of the delay, much of the animal tissue could not be used and at least 20 animals had to be excluded from postmortem examinations. b. The original pathology sheets and the pathology sheets submitted to the FDA showed differences for 30 animals. c. One animal was reported alive at week 88, dead from week 92 through week 104, alive at week 108, and finally dead at week 112. d. An outbreak of an infectious disease was not reported to the FDA. e. Tissue from some animals were noted to be unavailable for analysis on the pathology sheets, yet results from an analysis of this "unavailable" tissue was submitted to the FDA. f. There was evidence that the diet mix was not homogeneous allowing the animals to eat around the test substance.

This evidence included a picture and statements by a lab technician. g. Fifteen fetuses from animals in one experiment were missing. h. Sections from the animals were too thick for examination. i. There was no documentation on the age or source of the test animals. j. There was no protocol until one of the studies was well underway. k. Animals were not permanently tagged to prevent mixups. l. Some laboratory methods were changed during the study, but not documented. A G.D. Searle pathologist referring to the DKP study was quoted by investigators as saying (Graves 1984, page S5500 of Congressional Record 1985a): "You should have seen things when this study was run -- there were five studies being run at one time -- things were a mess!" The leader of the Task Force, Jerome Bressler, was quoted as saying (Gordon 1987, page 497 of US Senate 1987): "The question you have got to ask yourself is: Because of the importance of this study, why wasn't greater care taken? The study is highly questionable because of our findings. Why didn't Searle, with their scientists, closely evaluate this, knowing fully well that the whole society, from the youngest to the elderly, from the sick to the unsick . . . will have access to this product." -------------Immediately after the Bressler Report was released, H.R. Roberts, Director of the FDA's Bureau of Foods created a 5person task force to review the Bressler Report. The review was done by a team at the Center for Food Safety and Applied Nutrition (CFSAN report). H.R. Roberts would leave the FDA to become a vice president of the National Soft Drink Association in 1978. FDA Toxicologist, Jacqueline Verrett was appointed the Senior Scientist of the Bureau of Foods Task Force. On September 28, 1977, H.R. Roberts, Director of the FDA's Bureau of Foods received a report from a Bureau of Foods Task Force which claimed that G.D. Searle's studies they reviewed appeared to be authentic (meaning that they were actually conducted) (Mullarkey 1994b, page 8). For each of the major discrpancies found by the Bressler-led

Task Force -- those listed above and many others -- there was a comment in the FDA Bureau of Foods Report minimizing the problem. It seemed that no matter how serious the mistakes were, the FDA Bureau of Foods was determined to accept the studies by G.D. Searle. The experimental errors as described above were so bad that it proved difficult to minimize all of the major errors in these key studies. In some cases, the best that the CFSAN could do was to say that "The Task Force could find no evidence that this was a deliberate attempt to influence the study." or "It could not be determined if the results would have been altered...." (Farber 1989, page 111, GAO 1987, Appendix IV). The Senior Scientist of the FDA Bureau of Foods Task Force, Jacqueline Verrett had left the FDA when she openly discussed the Task Force with UPI Investigative Reporter, Gregory Gordon (Gordon 1987, page 497 of US Senate 1987): "Jacqueline Verrett, the senior scientist on the review team, said members were barred from stating opinions about the research quality. 'It seemed pretty obvious that somewhere along that line they (bureau officials) were working up to a whitewash,' she said. 'I seriously thought of just walking off of that task force.' Verrett, now a private consultant, said that she and other members wanted to 'just come out and say that this whole experiment was a disaster and should be disregarded.' In her testimony before the U.S. Senate, Dr. Verrett stated the following (Verrett 1987): "This authentication was hence intended to verify that the submitted data had not been altered; that it reflected the actual outcome of the study, and that it did not change substantially, particularly in a statistical sense, the various parameters from which the conclusion of safety had been derived. "Our analysis of the data in this manner revealed that in these three studies, there were really no substantial changes that resulted, although in numerous instances, a definitive answer could not be arrived at because of the basic inadequacies and improper procedures used in the execution of these studies. "I would like to emphasize the point that we were specifically instructed not to be concerned with, or to comment upon, the overall validity of the study. This was to be done in a subsequent review, carried out at a higher level. . . . . "It would appear that the safety of aspartame and its breakdown products has still not been

satisfactorily determined, since many of the flaws cited in these three studies were also present in all of the other studies submitted by Searle. . . . . "Well, they told us in no uncertain terms that we were not to comment on the validity of it. And I hoped, although having been there at that point for 19 years, I should have known better, that there really would be an objective evaluation of this beyond the evaluation that we did. "I do not feel that that was done, based on what I have read in the GAO report that I have looked at and so forth. They definately did not objectively evaluate these studies, and I really think it should have been thrown out from day one. "We were looking at a lot of little details and easy parameters in this study, when the foundation of the study, the diet and all of these other things, were worthless. We were talking about the jockey when we should have been talking about the horse, that he had weak legs. It is built on a foundation of sand." -------------The FDA general counsel wrote a letter to Consumer Attorney, James Turner, Esq. responding to Mr. Turner's concern about the quality and validity of G.D. Searle's experiments. The FDA stated, "The Public Board of Inquiry on aspartame should provide a vehicle for definitive resolution, at least for those studies about which you are most concerned." (Graves 1984, page S5498 of Congressional Record 1985a). As will be discussed later, Dr. John Olney and James Turner, Esq. were not allowed to have the quality and validity of the G.D. Searle studies considered at the Public Board of Inquiry. 1978 ---On December 13, 1978, UAREP submited its results of their analysis of 12 of G.D. Searle's aspartame studies. UAREP stated in their report that "no discrepancies in any of the sponsor's reports that were of sufficient magnitude or nature that would compromise that data originally submitted." (Farber 1989, page 33) Remember, the Director of UAREP pointed out in an interview that their pathologists did not conduct a comprehensive review of the studies, they only looked at the animal tissues (Graves 1984, page S5500 of Congressional Record 1985a). As it turns out, UAREP pathologists who examined the test results were discovered to have missed and withheld negative findings from the FDA (Gross 1987b, page 2-5). In some cases, they completely missed cancerous brain tumors when analyzing the slides. In addition, some of the slides that were to be examined by UAREP pathologists were missing even though they where supposed to have been kept under "FDA seal." (Olney 1987, page 6-7) FDA Toxicologist Adrian Gross

stated that the UAREP review "may well be interpreted as nothing short of a whitewash." (Farber 1989, page 114). Given that the UAREP review results was so biased in favor of G.D. Searle, one wonders why the FDA would allow a company being investigated for fraud to pay $500,000 and hire an outside entity to "validate" their studies. Even though the UAREP report was biased, there were numerous instances in that report which demonstrated that G.D. Searle had not submitted even marginally accurate findings to the FDA of their pre-approval aspartame tests. For example, in one study, twelve animals actually had cancerous brain tumors, yet UAREP reported to the FDA that only three animals had such tumors (Gross 1987b, page 3-4). 1979 ---In March of 1979, the FDA somehow concluded that G.D. Searle's aspartame studies could be accepted. They decide to convene the Public Board of Inquiry (PBOI) which was agreed to by Dr. John Olney and Attorney James Turner more than four years earlier (Federal Register 1979). -------------In April of 1979, the FDA outlined the specific questions which were to be addressed by the PBOI. The FDA limited the scope of the PBOI to (Federal Register 1981): a. Whether the ingestion of aspartame either alone or together with glutamate poses a risk of contributing to mental retardation, brain damage, or undesireable effects on neuroendocrine regulatory systems. b. Whether the ingestion of aspartame may induce brain neoplasms (tumors) in the rat. c. Based on answer to the above questions. (i) Should aspartame be allowed for use in foods, or, instead should approval of aspartame be withdrawn? (ii) If aspartame is allowed for use in foods, i.e., if its approval is not withdrawn, what conditions of use and labeling and label statements should be required, if any? Dr. John Olney, G.D. Searle, and the FDA's Bureau of Foods were allowed to nominate scientists for the 3-person PBOI panel (Farber 1989, page 34, Federal Register 1981, page 38286). It is important to note that the scope of the review was very limited in light of all of the various adverse reactions reported to the FDA. The PBOI also disallowed any discussion of the validity of the pre-approval experiments

because it accepted the word of certain FDA officials that these experiments had been "validated." Finally, the PBOI was told not to consider aspartame in beverages, only in dry goods. -------------In June of 1979, the acting FDA Commissioner, Sherwin Gardner selected the 3-person Public Board of Inquiry. The panelists were Peter J. Lampert, M.D., Professor and Chairman, Department of Pathology, University of California (San Diego), Vernon R. Young, Ph.D., University of Nutritional Biochemistry, M.I.T., and Walle Nauta, M.D., Ph.D., Institute Professor, Department of Psychology and Brain Science, M.I.T. Dr. John Olney strongly objected to the Commissioner's selection of one of the panelists, Dr. Vernon Young, on grounds of conflict of interest and lack of qualifications (Olney 1987, page 3). Dr. Young had written nonaspartamerelated articles in collaboration with G.D. Searle scientists (Brannigan 1983, page 196). In addition, Dr. Olney stated that the question of aspartic acid's neurotoxicity should be looked at by a neuropathologist and that Dr. Young was unqualified since his field was Nutrition and Metabolism. Dr. Olney's objections were overruled by acting FDA Commissioner Sherwin Gardner and the panelists who he objected to was assigned to study the issue of aspartic acid toxicity. One of the PBOI members, Dr. Walle Nauta stated (Graves 1984, page S5498 of Congressional Record 1985a): "It was a shocking story we were told [about Searle's animal testing] but, there was no way we could go after it. We had absolutely no way of knowing who was right. We had to take the FDA's word." Dr. Nauta stated that he would have "definately" considered other tests and factors if he had known that aspartame was planned for use in soft drinks (Graves 1984, page S5503 of Congressional Record 1985a). 1980 ---The Public Board Of Inquiry voted unanimously to reject the use of aspartame until additional studies on aspartame's potential to cause brain tumors could be done. The PBOI was particularly concerned about experiment E33/34 where 320 rats received aspartame and a much higher percentage of animals in the aspartame group developed tumors than in the control group (Brannigan 1983, page 196). In addition, the PBOI was concerned about experiment E70 where 80 rats received aspartame. Both the aspartame group and the control group had an unusually high number of tumors, leading one to suspect that both groups were actually given aspartame (Federal Register 1981). The PBOI did not believe that aspartic acid presented a

neurotoxic hazard. Yet, Dr. Olney pointed out that (Olney 1987, page 3): "[Dr. Young had a] lack of qualification" and that he "based his decision on a consideration of [aspartic acid] alone without regard to the real issue, i.e., is it safe to add [aspartic acid] to the large amounts of [glutamic acid/MSG] that are already adultering the food supply?" In addition, the "conservative" safety plasma level of aspartic acid used by Dr. Young was the level at which half the animals developed brain damage (Brannigan 1983, page 197). These errors by Dr. Young throw the question of safety of aspartic acid as part of aspartame into doubt. We will address this issue in more detail in a later section. 1981 ---On January 21, 1981, the day after Ronald Reagan takes office as U.S. President, G.D. Searle reapplied for the approval of aspartame. G.D. Searle submits several new studies along with their application. It was believed that Reagan would certainly replace Jere Goyan, the FDA Comissioner. G.D. Searle president, Donald Rumsfeld's connections to the Republican party were also thought to play a part in Searle's decision to reapply for aspartame's approval on the day after Ronald Reagan was inaugurated (Gordon 1987, page 499 of US Senate 1987). -------------According to a former G.D. Searle salesperson, Patty WoodAllott, G.D. Searle president, Donald Rumsfeld told his salesforce that, if necessary, "he would call in all his markers and that no matter what, he would see to it that aspartame would be approved that year." (Gordon 1987, page 499 of US Senate 1987) -------------In March of 1981, a 5-member panel of scientists was established by the FDA Commissioner Jere Goyan to review the issues raised by the PBOI (Gordon 1987, page 498 of US Senate 1987; Mullarkey 1994b, page 8). -------------In April 1981, Arthur Hull Hayes, Jr. was appointed FDA Commissioner by Ronald Reagan (Graves 1984, page S5502 of Congressional Record 1985a). -------------On May 18, panel sent discussing scientists Evaluation 1981, three of the scientists in the 5-member a letter to the panel lawyer, Joseph Levitt their concerns about aspartame. Those three were Satva Dubey (FDA Chief of Statistical Branch), Douglas Park (Staff Science Advisor),

and Robert Condon (Veterinary Medicine). Dubey thought that the brain tumor data was so "worrisome" in one study that he could not recommend approval of aspartame (Gordon 1987, page 495 of US Senate 1987). In another study, Dubey said that key data appeared to have been altered (Gordon 1987, page 499 of US Senate 1987). In his UPI Investigation, Gregory Gordon went on to describe the unusual events that followed (Gordon 1987, page 499 of US Senate 1987): "[Douglas] Park said that [panel lawyer Joseph] Levitt hurried the panel to decide the issue. 'They wanted to have the results yesterday,' he said. 'We really didn't have the time to do the indepth review we wanted to do.' "Park said Levitt met frequently with Hayes and 'was obviously getting the pressure to get a resolution and a decision made.' "With three of five scientists on the commissioner's team opposing approval, it was decided to bring in a toxicologist for his opinion on isolated issues [Barry N. Rosloff]. Goyan said if the decision were his, he never would have enlarged the team. While the panel did not vote, it ended up split 3-3. "Levitt, who normally would have been expected to draft an options paper spelling out scientific evidence on key issues, took an unusual tack. He circulated an approval recommendation and only backed off when Dubey, Park, and Condon objected, team members said. Levitt said he was not directed to draft the approval memo, but did so as a 'tactical' step to break the team's weeks-long impasse by forcing each scientist to state his views. 'It worked, didn't it?' said Levitt, who later was promoted to a post as an executive assistant to the FDA Commissioner." -------------On July 18, 1981 aspartame was approved for use dry foods by FDA Commissioner Arthur Hull Hayes, Jr. overruling the Public Board of Inquiry and ignoring the law, Section 409(c)(3) of the Food Drug and Cosmetic Act (21 U.S.C. 348), which says that a food additive should not be approved if tests are inconclusive (Federal Register 1981, Farber 1989, page 38). In an article in Common Cause Magazine, Florence Graves states that two FDA officials said that Arthur Hull Hayes, Jr. wanted to push aspartame approval through in order to signal reforms of the Reagan Administration. The "reasoning" behind the FDA Commissioner's decision will be discussed in a later section (Graves 1984, page S5497 of Congressional Record 1985a). 1982

---On October 15, 1982, G.D. Searle petitioned the FDA for approval to use aspartame in soft drinks and children's vitamins (Gordon 1987, page 499 of US Senate 1987; Farber 1989, page 38) -------------On October 1, 1982 an amendment was attached to the Orphan Drug Act (an act which encourages the development of drugs for rare diseases) which modified the U.S. Patent law (Congressional Record 1982). The amendment extended the patent on only one product -- aspartame -- by 5 years, 10 months and 17 days (Gordon 1987, page 504 of US Senate 1987). The amendment did not mention aspartame or G.D. Searle by name and there was no debate or discussion on the amendment. The amendment was proposed by Senator Howell Heflin, brought up for a vote by Senator Robert Byrd, and pushed through by Representative Henry Waxman and Orrin Hatch. G.D. Searle asked Senator Heflin to sponsor the amendment. Heflin received $9,000 in campaign donations shortly after this amendment was approved from G.D. Searle company executives and their wives. Senator Byrd had received a $1,000 campaign contribution from the CEO of G.D. Searle before the amendment was proposed. Representative Waxman received a $1,500 campaign contribution from the soft drink political action committee including $500 before the amendment was proposed. Senator Hatch received $2,500 from the soft drink political action committee prior to his reelection and $1,000 each from Daniel Searle, Wesley Dixon (Daniel Searle's brother-in-law), and William Searle (Gordon 1987, page 506 of US Senate 1987). Senator Hatch repeatedly blocked hearings looking into the safety of aspartame (Gordon 1987, page 506 of US Senate 1987). It could be argued that the amendment to extend G.D. Searle's patent of aspartame rectified the lost marketing time caused by the FDA investigations. However, it was G.D. Searle's horrendous pre-approval studies which led to the FDA investigations and the delays. Had they performed the studies with any competance, aspartame could have been approved quickly like any other FDA-approved food additive. (Actually, had the studies been done right, it is likely that aspartame would never been approved due to serious adverse reactions.) In addition, the amendment was applicable to one product and cannot be used similarly for other products. -------------Between 1979 and 1982, four FDA officials who took part in the aspartame approval process went through the FDA revolving door and took jobs in industries that are closely linked with the NutraSweet issue (Gordon 1987, page 498 of US Senate 1987): 1. Mike Taylor was an FDA lawyer who represented the FDA Bureau of Foods at the PBOI and was part of the team

that prevented the quality and validity of G.D. Searle's studies from being considered (Gordon 1987, page 498 of US Senate 1987). 2. Sherwin Gardner was the Deputy FDA Commissioner in 1979. In July, 1974, he had signed the initial approval for aspartame's use in dry foods. (This initial approval was later block by objections from James Turner, Esq. and Dr. John Olney.) In December, 1979, Sherwin Gardner became a Vice President of Grocery Manufacturers of America, Inc. (GAO 1986). While Mr. Garden claims that he did not discuss aspartame is his 4 meetings with the FDA within a year of leaving that agency or his 20 meetings with the FDA between 1980 and 1986, the organization he worked for does deal directly with aspartame products. It is unlikely that he would have been rewarded with the job had he called for another delay in approval and proposed that safety tests be conducted independantly in order to protect the public. 3. Stuart Pape was the Health and Human Services (HHS) Chief Counsel for Foods from October 1976 to March 1979. He served as special assistant to the FDA Commissioner from March 1979 to December 1979. He participated in meetings and discussions on aspartame as well as representing the FDA at the PBOI. In December 1979, Mr. Pape was given a job by the law firm of Patton, Boggs, and Blow. This law firm provided counself to the National Soft Drink Association (NSDA). Mr. Pape and Howard R. Roberts of the NSDA (who formerly fought for approval of aspartame at the FDA) met with the FDA twice in 1983 where aspartame was discussed. In 1983, the NSDA inexplicably withdrew their objection to aspartame in diet beverage (GAO 1986). 4. Albert Kolbye was the Associate Director of the FDA Bureau of Foods for toxicology. 1983 ---Acting FDA Commissioner, Mark Novitch approved aspartame for use in carbonated beverages and carbonated beverage syrup bases (Federal Register 1983). FDA Commissioner, Arthur Hull Hayes was out of town the day that the approval was signed, but he worked closely with Mark Novitch on this issue (Gordon 1987, page 499 of US Senate 1987). Ignoring the FDA's own safety standards, the more than doubled the Acceptable Daily Intake (ADI) of aspartame from 20 mg/kg to 50 mg/kg (Metzenbaum 1985). -------------Shortly after the FDA approval for aspartame in carbonated beverages, FDA Commissioner, Arthur Hull Hayes left the FDA under charges of improprieties, took a a position as the Dean of New York Medical Collage and was hired as an a

consultant ($1,000 per day) with G.D. Searle's public relations firm, Burston Marsteller (Gordon 1987, page 499 of US Senate 1987). -------------On July 8, 1983, Dr. Woodrow Monte, Director of the Science and Nutrition Laboratory at Arizona State University filed a petition objecting to the approval of aspartame based on possible serious adverse effects from the chronic intake of aspartame. Dr. Monte was especially concerned about the chronic intake of methanol (Federal Register 1984). Dr. Monte also filed a petition with the Arizona Department of Health Services to ban aspartame. -------------On July 8, 1983, James Turner, Esq. filed a peition with the FDA on behalf of himself and Community Nutrition Institute objecting to the approval of aspartame (Federal Register 1984). -------------Dr. Woodrow Monte, at the suggestion of his lawyer, invested $2,000 in G.D. Searle stock options in order to raise money for his costly legal battles against aspartame. He ended up losing $1,224. His purchasing of the "put options" caused some controversy. Dr. Monte was later accused of conflict-ofinterest by G.D. Searle. Dr. Monte's lawyer had told him that he "didn't think there was anything wrong" with purchasing the options. A move that Dr. Monte later called a mistake. (Gordon 1987, page 508 of US Senate 1987) -------------On November 23, 1983, the FDA denied a request to put the approval on hold "because public interest did not require it." (Federal Register 1984). 1984 ---On February 17, 1984, the FDA denied Dr. Woodrow Monte and James Turner the opportunity to hold a safety hearing on questions raised in their petition (Federal Register 1984). -------------G.D. Searle sent a number lobbyists to the State of Arizona including Andrew Herwitz, Arizona Governor Babbitt's former Chief of Staff, Charles Pine, a prominent Arizona lobbyist, Roger Thies, a G.D. Searle lawyer, and David West, a G.D. Searle official (Gordon 1987, page 507 of US Senate 1987; Stoddard 1995a, page 17). -------------The State of Arizona DHS completed studies showing that aspartame in carbonated beverages can break down into free

methanol (among other things) in 99oF temperatures. The amount of methanol which broke down concerned the DHS enough that a ban of aspartame was discussed (Gordon 1987, page 507 of US Senate 1987). -------------Between August 23, 1984 and September 21, 1984, G.D. Searle officials contributed to the campaign of Arizona House Majority Leader Burton Barr. The Committee to Reelect Barr then gave campaign contributions to a number of state representatives (Don Aldridge, Karen Miills, Jan Breuer) who all eventually voted of the side of G.D. Searle (Gordon 1987, page 507 of US Senate 1987). -------------Dr. Woodrow Monte's petition for a hearing regarding banning aspartame in Arizona was rejected (Gordon 1987, page 507 of US Senate 1987). -------------6,900,000 pounds of aspartame were consumed in the U.S. in 1984 (USDA 1988). 1985 ---Dr. Richard Wurtman of MIT is quoted as saying that Dr. Gerald Gaull, a G.D. Searle Vice President, came to his laboratory and threatened to veto his funding from the International Life Sciences Institute (ILSI) after Wurtman quit his job as a G.D. Searle consultant and became a NutraSweet opponent (Gordon 1987, page 503 of US Senate 1987). -------------Dr. Woodrow Monte filed for reconsideration of his petition for a hearing in Arizona. He was granted a hearing scheduled for April 1985 (Gordon 1987, page 507 of US Senate 1987). -------------In April 1985, in an unusual and secret maneuver, the Arizona legislature removed the text in a Toxic Waste Bill and used it to pass a bill which banned the regulation of FDA-approved food additives (Gordon 1987, page 508 of US Senate 1987). This bill scuttled the hearing that Dr. Monte had been promised. -------------On May 7, 1985, the U.S. Senate heard testimony relating to an amendment put forth by Senator Howard Metzenbaum requiring the quantity of aspartame to be labelled (Congressional Record 1985a). It is nearly impossible for a person to determine what quantity of aspartame they are ingesting unless it is labelled. Senator Orrin Hatch of Utah

led the fight (along with G.D. Searle) against the labelling ammendment. The ammendment was defeated. Those voting against the amendment included: Abdnor, Armstrong, Baucus, Bentsen, Biden, Bingaman, Boren, Boschwitz, Bradley, Bumpers, Cochran, Cohen, D'Amato, Danforth, DeConcini, Denton, Dixon, Dole, Domenici, Durenberger, Evans, Ford, Garn, Goldwater, Gore, Gorton, Gramm, Gassley, Hatch, Hawkins, Hecht, Heflin, Heinz, Helms, Hollings, Humphrey, Inouye, Kassebaum, Kasten, Laxalt, Leahy, Levin, Lugar, Mattingly, McClure, McConnell, Mitchell, Murkowski, Nickles, Nunn, Packwood, Pressler, Pryor, Quayle, Riegle, Roth, Rudman, Sasser, Simpson, Stafford, Stevens, Symms, Thurmond, Tribe, Wallop, Warner, Wilson, Zorinsky. Those voting for the amendment included: Burdick, Byrd, Chafee, Chiles, Cranston, Dodd, Eagleton, Glenn, Harkin, Hart, Hatfield, Johnston, Kennedy, Kerry, Lautenberg, Long, Mathias, Matsunaga, Melcher, Metzenbaum, Moynihan, Pell, Proxmire, Rockefeller, Sarbanes, Simon, Spector. -------------On August 1, 1985, Senator Howard Metzenbaum of Ohio introduced a bill entitled "Aspartame Safety Act of 1985" which required quantity labelling of aspartame on food items and mandated that there be a moratorium on new uses of aspartame until independent tests could be conducted under the auspices of the National Institutes of Health (Metzenbaum 1985). Testimony was submitted for the record. The bill was submitted to a Senate committee where it died. -------------After suffering a $28 million dollar loss in the previous year, selling off 30 subsidaries, and having a suit filed by 780 women claiming that G.D. Searle's intrauterine device caused them pelvic inflammatory disease, G.D. Searle sold out to the chemical company, Monsanto (Gordon 1987, page 509 of US Senate 1987). Monsanto then created the NutraSweet Company as a subsiderary separate from G.D. Searle. -------------14,400,000 pounds of aspartame were consumed in the U.S. in 1985 (USDA 1988). 1986 ---Community Nutrition Institute (CNI) filed suit against the FDA in District Court claiming that the FDA did not follow proper procedure in approving aspartame for beverages and that they should have held a public hearing before giving final approval (Farber 1989, page 39). After the District Court dismissed their suit and the D.C. Circuit Court of Appeals denied their request for a hearing stating that they

failed to "raise any material issues of fact that require the FDA to grant a hearing," CNI stated: ...where the holding of a public hearing is no longer a responsible part of the food additive process, the F.D.A. and the appeals court have increased the likelihood that unsafe food additives will reach the market. -------------In July 1986, the U.S. General Accounting Office (GAO) published the results of an investigation of five former government employees involved in the aspartame approval process who took jobs linked to the aspartame industry (GAO 1986). While these former employees' actions were not illegal, it is a good example of how the U.S. Government and especially the FDA "revolving door" helps certain powerful companies have near complete control over governmental actions. Government employees will give industry whatever it wants (and the public be damned). Then many of these employees will be rewarded with high-paying industry jobs. Some of those people will then end up back in government in order to do more favors for their industry friends -- even if it means destroying people's lives and health. The innercity gangs are not the only place where morally corrupt individuals operate with near impunity. -------------15,700,000 pounds of aspartame were consumed in the U.S. in 1986 (USDA 1988). 1987 ---The United Press reported on October 12, 1987 that more than 10 federal officials involved in the NutraSweet decision took jobs in the private sector linked to the aspartame industry (Gordon 1987, page 495 of US Senate 1987). -------------On November 3, 1987 a hearing was held in a U.S. Senate Committee to address the issue of aspartame safety and labelling (US Senate 1987). Senator Orin Hatch successfully block any labelling requirements. -------------In June 1987, the U.S. General Accounting Office (GAO) published the results of an investigation which looked into whether the FDA followed its required approval process (GAO 1987). The report concluded: "Because FDA followed its required approval process in approving aspartame and monitors adverse reactions and ongoing aspartame research, GAO is making no recommendations."

It is important to note that the author of the report specifically stated on the first page: "We did not evaluate the scientific issues raised concerning the studies used for aspartame's approval or FDA's resolution of these issues, nor did we determine aspartame's safety. We do not have such scientific expertise." The GAO seemed only interested in whether the FDA took the legally appropriate steps, not whether or not the FDA's decisions were based on the facts or made any sense. - They were not interested in the fact that CFSAN's evaluation of the Bressler report was a "whitewash" in the words of the head scientist of the CFSAN team. - They were not interested in the severe reactions suffered by many of the animals in the preapproval studies. - They were not interested in the countless, major flaws in the preapproval studies as described earlier. - They were not interested in the fact that the FDA Commissioner, who later consulted for the G.D. Searle Public Relations firm (at $1,000 per day), over-ruled the Public Board of Inquiry (PBOI) experts and overruled his own chosen scientific experts to approve aspartame. - They were not interested that the FDA decided to allow G.D. Searle to pay UAREP $500,000 to "validate" 15 of their studies. They were only interested in whether the legally required steps were taken. Even with the limited scope of the GAO investigation, they made numerous factual errors in their report, some of which are detailed in the letter from fromer FDA Investigator and Toxicologist Dr. Andrian Gross presented before the U.S. Senate in 1987 (Gross 1987b, page 11). Dr. Gross concludes: "Although in their report the GAO expresses the view that the FDA 'followed its required process in approving aspartame (for marketing)' I would sharply disagree with such evaluation. Although the FDA may have gone through the motions or it may have given the appearance of such a process being in place here, the people of this country expect and require a great deal more from that agency charged with protecting their public health:- in addition to mere facade or windowdressing on the part of the FDA, they require a thorough and scientifically based evaluation by the Agency on the safety of the products it regulates. "Unfortunately this has clearly not been the case here. And without this kind of assurance, any such

'process' or dance represents no more than a farce and a mockery of what is truly required." -------------An estimated 17,100,000 pounds of aspartame were consumed in the U.S. in 1987 (USDA 1988). NutraSweet stopped providing consumption data to the USDA after 1987. It is much easier for NutraSweet scientists to create inaccurate aspartame consumption figures when the total number of pounds sold is not publically available, or is inaccurate when it is given out publically. 1988 ---In August 1988, aspartame was approved for use in Brazil (Monsanto 1990). Thanks to a massive advertising campaign, at the end of 1990, 150 products were sweetened exclusively by aspartame. 1990 ---In May 1990, Nutrasweet opened a production facility in S o Jose dos Campos, Brazil (Monsanto 1990). There was no diet foods in Brazil in the 1980s. Unfortunately, part of NutraSweet's efforts "to build a diet segment from zero" in Brazil will likely lead to many people in Brazil obsessing about the weight and appearance which in turn often leads to eating disorders and other psychological problems. At the same time, NutraSweet is beginning to dose the population with their slow poison. 1991 ---NutraSweet joined with its long-time partner, Ajinomoto Co. Inc. of Japan to begin building an aspartame manufacturing plant in Gravelines, France (Monsanto 1991). -------------The NutraSweet Company began a project to develop a new artificial sweetener, called "Sweetener 2000" which is said to be approximately 10,000 times sweeter than sugar. The chemical composition of this sweetener was not detailed in Monsanto's Annual Report. NutraSweet's plan is to get this new sweetener to the market by the end of the decade (Monsanto 1991). 1992 ---NutraSweet signed agreements with the Coca-Cola Co. and PepsiCo Inc. "stipulating The NutraSweet Company as their preferred supplier of aspartame (Monsanto 1992). --------------

NutraSweet stated that one of their options for increases sales in the carbonated soft drink market is to prepare "higher-concentration formulations that use more aspartame" (Monsanto 1992). -------------The FDA approved the NutraSweet Company's application to market aspartame in bulk form. NutraSweet markets the product under the name "NutraSweet Spoonful" (Monsanto 1992). -------------The patent for aspartame expired on December 14, 1992 opening up the market to other companies such as Holland Sweetener Company (Monsanto 1992). 1993 ---In mid-1993, NutraSweet and long-time partner, Ajinomoto Co. of Japan began producing aspartame from the new production facility in Gravelines, France (Monsanto 1993). -------------NutraSweet began a joint venture with Nestle Mexico to bring aspartame to Mexico (Monsanto 1993). -------------NutraSweet began to explore other aspartame marketing opportunities in Mexico (Monsanto 1993). 1994 ---NutraSweet introduced tabletop aspartame products to Mexico, Hungary, Uganda, Ecuador, Romania, Uruguay, and Paraguay (Monsanto 1994). -------------Aspartame's net sales outside of the U.S. accounts for 10 percent of all net sales (Monsanto 1994). -------------NutraSweet announced plans to market aspartame tabletop sweeteners in 1995 throughout Southeast Asia. They plan to introduce aspartame to India and to test market an aspartame tabletop sweetener in China during 1995 (Monsanto 1994). 1995 ---In a June 12, 1995 article which appeared in Food Chemical News, Thomas Wilcox, the FDA epidemiology branch chief was quoted as saying, "FDA has no further plans to continue to

collect adverse reaction reports or monitor research periodically done on aspartame." (Food 1995) -------------Monsanto/NutraSweet is beginning to test market Equal in Shanghi, China. It is part of a plan to push their poison on 60 million Chinese in the coastal cities (Millman 1995).

6. Aspartylphenylalanine Diketopiperazine (DKP) The fact that Dr. Liebovitz did not even mention DKP, a chemical which can sometimes be more prevalent than aspartame itself, is rather distressing. At least one of the references he cites, AMA (1985) discusses DKP at length, so he must be aware of this breakdown product. Before aspartame was foisted upon the public, the amount of this particular DKP in the diet was essentially zero (Federal Register 1983). Therefore, no claim can automatically be made that DKP ingestion is safe. Several quality studies would have to be performed in order to conclude that DKP probably does not have a detrimental affect on humans. No such quality studies have ever been done. Most of the controversy surrounding DKP has involved the issue of brain tumors and uterine polyps. While I will limit my discussion in this section to cancer, there are two very important preliminary points that need to be made: a. Cancer is a very serious disease. However, there are countless other serious diseases and therefore no reason to limit the concern regarding DKP to cancer. The FDA and EPA have approved numerous drugs and chemicals that have unexpectedly caused or contributed to a wide range of serious adverse reactions other than cancer. There is no reason to believe that the possible detrimental effects of DKP are limited to cancer. Dioxin is an example of a chemical which was linked to cancer. Now it turns out that the biggest issue is that dioxin has an extremely deleterious effect on the immune system. b. When looking at the aspartame and cancer issue, DKP becomes a likely candidate for a possible cause. However, it is only one of several possibilities. Ingesting methanol or significant quantities of racemized amino acids could be another cause or contribuatory factor. Brain chemistry changes making one slightly more susceptible to brain tumors caused by longterm ingestion of aspartic acid and/or phenyalalnine might be another possibility as to how aspartame could contribute to brain cancer. We will discuss the studies that show aspartame caused cancer in laboratory animals later in this section. However, it should be understood that the pre-approval studies were so poorly designed and conducted that it would be impossible to conclude that aspartame is safe. Some of the flaws which

show that the FDA could not possibly have concluded that aspartame does not cause cancer are as follows: Lack of Statistical Power (simplified discussion of statistics) --------------------------------------------------------------Aspartame is being regularly consumed by over 70 million people in the U.S as discussed earlier. If aspartame was to cause cancerous tumors in 1% of the people who ingest it for several decades (as is what happens with cigarettes), 700,000 people would develop such aspartame-caused tumors in that time. A 5% tumor rate would lead to 3.5 million people developing tumors. etc. Let's say, for arguments sake that aspartame causes cancerous tumors in 2% of the people in their lifetime. That's 2% of 70 million people (in the U.S.) or 1.4 million people. If I wanted to see if this was really the case by testing aspartame in animals, I would feed aspartame to 70 million (test) animals. To another 70 million animals, I would give a normal diet. If the aspartame-ingesting animals had 1.4 million cancerous tumors more than the non-aspartameingesting (control) animals, the cancer rate of aspartame would be 2%. Of course, it would be impossible to conduct an experiment on this many animals. So, instead of 70 million test animals and 70 million control animals, I could use 1000 test animals and 1000 control animals. If the cancer rate was 2%, there would be, in theory, 20 more cancerous tumors in the test animals than in the control animals. If there was a 2% cancer rate for aspartame, the reality is that each time I conducted the experiment, an average of 20 more cancers in the test animals would appear than in the control animals. If I ran the experiment ten times I may get something like this: Number of Excess Tumors in Test Animals As Compared to Control Animals Run Run Run Run Run Run Run Run Run Run #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 24 14 18 22 28 19 13 20 22 20

As you can see, the numbers would vary, but the more times I conducted the experiment, the closer the average of all of the runs would be to 20. Instead of running the experiment on 1000 test animals and 1000 control animals, a researcher may choose to use only 100 test animals and 100 control animals. If there was a 2% cancer rate for aspartame, there would be an average of 2 more cancerous tumors for the test group as opposed to the control group. However, since there are variations for each experimental run, the results might look something like this

for 10 runs (on 100 test animals and 100 control animals): Test Group Run Run Run Run Run Run Run Run Run Run #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 2 4 0 3 4 0 5 3 5 0 Control Group 0 1 0 0 1 2 1 1 0 0

The average over 10 runs is a 2% more cancer rate in the test group, but there is a wide variations for each individual run. As you can see, the smaller the group of animals used, the wider the percentage variation for each run. Instead of 10 runs on 100 test animals and 100 control animals, had I simply done a single run, the results would likely be meaningless because there is such a wide variation for a particular run with this few amount of animals. For example, Run #9 shows 5 cancerous tumors in test animals and 0 in control animals. Whereas Run #6 shows 0 cancerous tumors in test animals and 2 cancerous tumors in control animals. Therefore, in order to more accurately investigate whether aspartame causes a 2% cancer rate (1.4 million in 70 million users), I would have to use many times more than 100 animals or make numerous test runs with 100 animals each. As you can see, if I was to use a small amount of animals, I could not accurately determine whether there was a 2% cancer rate of aspartame. I may be able to conclude that there is not a 20% cancer rate for aspartame use (or 14 million cancers). If I can say that aspartame does not cause 14 million cancers, that does not help me very much. It begs the question as to whether it causes a 5% cancer rate, a 2% cancer rate (1.4 million people) or a 0.2% cancer rate (140,000 people). G.D. Searle used such a small number of animals in their experiments relating to cancer that it would have been impossible to conclude that aspartame was safe even had the experiments been conducted properly and had there been no significant number of tumors found. FDA Chief of Statistical Evaluations Branch, Satya D. Dubey stated the following in a memo to the FDA Commissioner's office (Farber 1989, page 101): "From the design viewpoint, the probability of observing a statistically significant result at 5% significance level with 60 animals in the control group and 40 animals in the treatment group when the true difference in incidence rates of brain tumors is not more than 5% would be less than 27.9% . . . Even 27.9% of statistical power will generally be considered to be very low power. The

studies, E33/34 and E70, which I have statistically reviewed, thus possess very low power to detect true significant effect of the kind stated above. . . . Therefore, their results should not be considered confirmatory for decision purposes." What Dr. Dubey is saying is that there is only a 27.9% liklihood that a cancer rate of less than 5% would be found for the experiments discussed above. A 4.9% cancer rate still amounts to 3,430,000 cancers in 70 million aspartame users! E33/34 and E70 are two studies which showed that aspartame caused cancer in laboratory animals and will be discussed later. This is one of the tricks that is sometimes used in animals experiments. If the researcher uses a small amount of animals, the study may not find an increase in cancer rates for the test animal as opposed to the control animal, but the lack of statistical power caused by the use of a small number of animals made such a finding very unlikely. When a researcher does use a small number of animals, the condition of every single animal is very important. If even one animal's cancer is missed, the results of the experiment can be changed dramatically. Had the studies E33/34 and E70 been run perfectly, there would have been a 27.9% chance that the researchers would have found a 5% or more tumor rate. Since the experiments were so incredibly sloppy and the condition of the animals was really a guess, it is likely that a 10% cancer rate would have been missed. G.D. Searle employees attempted to increase the statistical power of the cancer studies by combining the results from different studies such as E33/34 and E70 (Cornell 1984). E70 studies the effects of aspartame on Charles River albino rat offspring by giving adding it to the mother's feed through the period of lactation and then the offspring's feed until death. The offspring were supposed to be examined at 104 weeks (or at death). E33/34 was a chronic dosing study of aspartame given in four different doses to rats for 104 weeks. However, FDA Senior Statistician, Dr. Satya Dubey stated in1981 in a memo to the FDA Commissioner's science advisory team on aspartame (Farber 1989, page 102): "Since the protocol of E70 study is different, its design is deficient, its data exhibit certain peculiar patterns, and the statistical conclusions derived from such data are much different from that of the E33/34 study (compare the statistical results of E33/34 and E70 studies), it does not appear proper to me to combine the results of these two studies." In his treatise on aspartame, Farber (1989, page 102) states in regards to combining E33/34 and E70: "I asked Myrto Lefkopoulou of the Harvard School

of Public Health, Biostatistics Department for her comments on the statistical aggregation of E70 and E33/34. She considered the aggregation of these studies inappropriate because the effect of an in utero study [E70] is different than a chronic feeding study [E33/34]. ...she stated that the in utero study is looking for a teratogenic effect, whereas the chronic feeding study was concerned with carcinogenicity -- did aspartame promote brain tumors?" Farber points out that even if the results of these studies are (improperly) combined, there is only a 67% chance that a 5% tumor rate could be discovered (Farber 1989, page 103). 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 Alive Dead Alive Dead K18LF Alive vanished (dead ?) Alive vanished (dead ?) M25CF Found dead Alive Dead Alive Alive Dead H28MF Alive vanished (dead ?) H15CF Alive vanished (dead ?) G 2HM Found dead Alive A15MM Found dead Alive Dead

3/21/71 5/19/71 5/16/71 7/14/71 8/11/71 4/22/71 5/20/71 6/17/71 7/15/71 3/6/71 6/18/71 7/16/71 9/10/71 10/8/71 11/5/71 7/13/71 8/10/71 7/13/71 8/10/71 3/10/71 8/9/71 3/13/71 5/3/71 6/1/71

Alive Dead G16HM Found dead Alive Dead A 6HM Found dead Alive Dead Alive Dead G23HM Found dead Alive Dead E15MM Found dead Alive G 8MM Found dead Alive Dead

8/23/71 9/20/71 3/9/71 8/9/71 9/7/71 2/25/71 5/3/71 6/1/71 8/23/71 9/20/71 3/7/71 8/9/71 9/7/71 1/21/72 2/25/72 9/3/71 11/29/71 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 Alive Dead Alive Dead Alive B14MF Killed Alive Dead Alive (?) B12HF Found dead Alive Dead Alive (?) B 4CF Found dead Alive Dead Alive (?) D30LF Found dead Alive B15HF Found dead Alive 2/25/71 8/24/71 9/21/71 10/19/71 11/16/71 2/22/72 7/30/71 10/19/71 11/16/71 2/22/72 9/2/71 10/19/71 11/16/71 2/22/72 9/12/71 10/19/71 11/16/71 2/22/72 1/22/72 2/22/72 1/25/72 2/22/72

C29LM Found dead Alive Dead C12HM Found dead Alive Dead

3/29/71 6/2/71 6/30/71 8/10/71 10/20/71 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 8/26/71 9/23/71 10/21/71 11/08/71 12/06/71 animal is free of any masses mass is the same (as what?) mass is the same animal is free of any masses mass is the same 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 11/18/71 12/16/71 1/13/72 mass regressed animal is free of any masses mass regressed 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 8/26/71 9/23/71 10/21/71 11/18/71 animal is free of any masses animal is free of any masses mass is the same animal is free of any masses 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

alive--almost 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 postmortem 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 1 1 1 1 2 3 3 3 3 3 4 4 Sex M M F F M M M M M F F F Animal # 83-651 83-745 83-769 83-766 83-837 83-919 83-888 83-892 83-895 83-934 84-010 84-019 Type of tumor Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Oligodendroglioma Astrocytoma Astrocytoma Astrocytoma Medulloblastoma 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 NutraSweetfed 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 the FDA;" 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 Control Control Control Control 1 1 1 2 Sex M M M F M M F M

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 doserelated 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 cancercausing 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 Group 1 1000 Group 2 2000 Group 3 4000 Group 4 6000-8000 In E70 the dosage was: Control Group Group 1 Group 2 0 mg/kg 2000 mg/kg 4000 mg/kg mg/kg mg/kg mg/kg mg/kg 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 bodysurface 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 Group 1 191.2 Group 2 382.4 Group 3 764.8 Group 4 1147.2-1529.6

mg/kg mg/kg mg/kg mg/kg mg/kg

In E70 the the body-surface adjusted dosages were: Control Group Group 1 Group 2 0 mg/kg 382.4 mg/kg 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 wellknown 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 SpragueDawley 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 wellconducted 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 preapproval 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 Group 1 Group 2 Group 3 Group 4 0 4 1 5 2 0 1000 2000 4000 6000-8000 mg/kg mg/kg mg/kg mg/kg 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 doseresponse 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 increases--and I think everybody agrees with that--of 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 precarcinogenic. 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 2liter 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 longtime 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 Nutrasweetfed 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 over well with bodybuilders Fitness - Health, the issue part of aspartame is not so sound. "safety" of amino acids may go reading Muscular Development of aspartic acid's "safety" as simple as Dr. Liebovitz makes it

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 acidforming 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 NutraSweetfunded 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 preapproval 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. Excitotoxins (Primate Studies) -----------------------------For many years, the food industry has been arguing that high levels of plasma glutamate or aspartate do not cause excitotoxic damage in primates (e.g., monkeys, humans), but

only in rodents. In order to see the lengths to which the food industry is willing to go to counter the findings of independent scientists that glutamate (MSG) and aspartate (from aspartame) can cause brain lesions in primates, here is an excerpt from Dr. John W. Olney's statement before the 1993 Federation of American Societies for Experimental Biology (FASEB) LSRO Committee Proceedings looking into the MSG issue (Olney 1993): Argument #5: Glutamate is a rat poison, but not a human poison. The paramount argument which has been the all-time favorite with the food industry and FDA is that glutamate is toxic only for subprimate species (e.g. rodents), but not for primates. In other words, glutamate is a rat poison but not a human poison. This issue has a long and sordid history. 1. When I reported in 1969-70 that glutamate destroys neurons in the hypothalamus when administered either subcutaneously or orally to immature mice (Olney 1969b, 1969c, 1970, 1971), a U.S. Senate Nutrition Committee was investigating infant nutrition and asked me to comment on the fact that glutamate was being added to baby foods (a fact that I was not aware of until they brought it to my attention). I asked how much was being added. At first, FDA and industry officials both claimed that only trace amounts were being added to foods. However, when pressed to provide details, they revealed that they were adding > 600 mg per 4-1/2 Oz jar (which translates into > 100 mg/kg body wt for the unwitting human baby, and is clearly in the same general dose range that destroys neurons in the infant animal brain). Under pressure from the Senate Committee, FDA arranged for a special "blue ribbon" committee to evaluate the safety of glutamate for babies. The committee investigated the matter and concluded that glutamate was safe, but the committee was then investigated (at my instigation) and most of its members were found to have close financial ties with the food industry (this was corroborated by U.S. Senators and written up in a news article that appeared in Science in 1972) (Gillette 1972). Of particular note, the Committee Chairman, Lloyd J. Filer, was found to be receiving monies from both the baby food industry and the glutamate industry while he chaired this committee. 2. When the Filer committee met in 1969-70, I was asked to present my findings to them. Inter alia, I advised the committee that I had demonstrated glutamate-induced brain damage in infant monkeys as well as rodents; the monkey

findings were not yet published, but I presented them to the Filer committee. Carefully thereafter, over a period of two years, I completed my monkey study and published the data in the world's leading neuropathology journal (Olney 1972). Hastily, on behalf of the glutamate and food industries, Filer assembled a group of nonneuroscientists (Reynolds, Filer et al) to study the issue. They hurriedly reported in Science in 1971 that infant monkeys are not susceptible to glutamate neurotoxicity (Reynolds 1971) and recommended that my findings be dismissed as fixation artefact. At this time, the glutamate and food industries had also hired several other non-neuroscience groups to study this brain damage issue. At first, they claimed that my findings could not be confirmed in any species, not even rodents (e.g., see Oser 1971), but later the industry consortium changed their story with respect to rodents and other subprimate species when numerous legitimate neuroscientists began reporting confirmation of my findings in these inexpensive species. However, the accuracy and authenticity of the industry findings in monkeys were never challenged, except by me, for a simple reason: no one outside the food/glutamate industry circle had either the motivation or funding to study monkeys. 3. In the 1970 era, I became alarmed at some apparent flaws in the findings of Reynolds et al. and began to challenge these authors. For example, they tube-fed very large doses (2-4 g/kg) of glutamate to infant monkeys, which led me to suspect that their infant monkeys probably vomited. This raised a crucial issue; if their infant monkeys vomited, they obviously lost dose control and this would render their data unreliable for establishing the safety of glutamate. I questioned Dr. Reynolds on this in public at a scientific meeting a few months before their Science paper appeared in print. In front of a large audience, she admitted that their monkeys vomited. However, a few months later when their Science paper appeared in print (Reynolds 1971), I was surprised to read the following description: "Each infant was maintained in an incubator with handling and cuddling at intervals for a 6 hour period. No unusual behavior was exhibited by the infants." No mention was made at all of vomiting. Therefore, I wrote a letter to Science pointing out that by the author's own acknowledgement at a public meeting, these infants had vomited. The letter was accepted for publication in Science and was sent to Dr. Reynolds for her response. To my astonishment,

in a letter signed by W.A. Reynolds which I have in my files, she responded with a denial that they had encountered problems with vomiting or with dose control. Therefore, I withdrew my letter and this exchange was never published. 4. Four years after the Science report, Reynolds and Filer together with Stegink, came out with another paper (Stegink 1975) which clearly pertained to the same experiment on the same group of monkeys. This time they admitted in print that their monkeys had vomited, which raises serious questions concerning: 1) Their failure to mention this obviously important point in their initial report, and 2) The signed letter denying vomiting. There were a number of other discrepancies between the first and second report which reflect poorly upon the reliability and credibility of these authors. For example, they identified individual monkeys as being of a certain species and receiving a certain dose of glutamate in the first report, then identified the same monkeys in the second report as being of another species and/or receiving a different dose of glutamate. 5. In addition, the 2nd report by Reynolds, Filer and colleagues (Stegink 1975), admitted for the first time that their monkeys were maintained under Sernylan (phencyclidine) anesthesia throughout the 6 hr experiment. Failure to divulge in their 1st report that their animals were anesthetized with phencyclidine is a particularly critical omission, since the use of phencyclidine thoroughly invalidates the entire study in the eyes of any knowledgable neuroscientist. Phencyclidine is one of the most potent antagonists of glutamate receptors known (Wang 1990, Olney 1990a, Olney 1986). Administration of phencyclidine or its various analogs, such as MK-801, totally prevents glutamate (even very high doses of glutamate) from damaging the hypothalamus (Wang 1990). Not only does the use of phencyclidine totally invalidate the primate non-susceptibility claims of Reynolds et al., their deliberate representation that "No unusual behavior was exhibited by the infants" when they clearly were aware that their infant monkeys had actually been drugged and anesthetized, raises additional grave questions. 6. I also criticized Reynolds et al for presenting nothing but spurious illustrations; while my findings showed that oral glutamate destroys neurons only in a very specific region of the hypothalamus, in their 1st paper

they published illustrations of a different and irrelevant hypothalamic region in support of their claim that glutamate is non toxic. In the following year, I invited Reynolds et al to send a member of their group to my laboratory to learn how to find glutamate damage in monkey brain. In May 1972, a member of their group (Dr. N. Lemkey-Johnston) did visit my laboratory and reviewed microscopic slides with me and she told me she was convinced that glutamate neuropathology was present in the hypothalamus of my monkeys. She also thanked me for pointing out specifically where to look in the hypothalamus to find these lesions. Although I do not know the details, it is my understanding that Dr. N. Lemkey-Johnston became ill shortly thereafter and ceased functioning as a scientist. Two years later, when Reynolds et al published their second paper (Stegink 1975), they stated that they had treated a few additional monkeys with glutamate and had serially sectioned the hypothalamus to provide definitive evidence of no damage. To my amazement, the illustration they showed was once again from the wrong region of the brain. In that same year (1975), I met with Dr. Reynolds and made it very clear to her that I considered it unethical for researchers to persistently make claims regarding non-susceptibility of monkeys to glutamate neurotoxicity, if they repeatedly presented nothing but spurious documentation of those claims. She apologized and promised to provide me with illustrations from the correct brain region, but no such illustrations were ever provided. Instead, as described in the next paragraph, she subsequently made additional claims in the medical literature and documented them even more spuriously. 7. In 1976, Reynolds et al attempted to convince the world definitively that glutamate is nontoxic for the infant primate by publishing a 3rd report (Reynolds 1976) in which new evidence is presented on an additional specie of monkey (fascicularis, a specie not documented in their first 2 reports). This report is illustrated with a brain section from a 7 day old fascicularis monkey that ingested glutamate 5 hrs earlier (Appendix, Exhibit # 2). Incredibly, the brain section used to illustrate the new finding is the same brain section used in their second report (Stegink 1975) to illustrate lack of brain damage in a 1 day old rhesus monkey dosed with glutamate 6 hrs earlier (Appendix, Exhibit #2). These illustrations are obviously spurious for two reasons: 1) They cannot possibly constitute evidence from two separate

monkeys or two separate species because they are one and the same photograph which has merely been cropped differently during photographic printer; 2) Regardless how this photograph is cropped, it does not authentically document lack of glutamate toxicity because it is selected from the caudal level of the hypothalamus which lies outside the zone that is subject to damage by orally administered glutamate. When Dr. Reynolds published this spurious photograph in her 3rd paper (Reynolds 1976), she had very good reason to know that it was from the wrong region of the brain, because not only had I instructed her colleague and co-author on this matter in 1972, but I met with Dr. Reynolds herself in 1975 and briefed her very carefully and pointedly on both the science and the ethics of this matter. This briefing was one year prior to the publication of her 3rd spuriously documented report. 8. Industry representatives will likely respond to this information by claiming that several other laboratories also studied this issue and reported that glutamate does not damage infant monkey brain. If this position is taken, some pointed questions should be asked: 1) Were all such studies funded by the glutamate or food industries, despite failure of the authors to disclose industry support in some of the published reports? 2) Was undisclosed vomiting and loss of dose control a problem in these studies, as it was in the Reynolds et al study? 3) Was phencyclidine anesthesia used, but not disclosed, as was the case in the Reynolds et al. study? 4) How can FDA or the scientific community know whether vomiting occurred, or phencyclidine anesthesia was used, if the authors of industry-funded studies do not disclose this kind of crucial information in their published reports? 5) Are records available from these laboratories for FDA inspection to obtain an objective answer to questions 1 through 4? 6) Did any of the authors of these studies have any demonstrated expertise in neuropathology research? 7) Were any of these studies published in a refereed neuropathology journal? 8) Did these groups report their findings in obscure journals editorially controlled either by themselves or their very close associates who have financial ties with the food industry? 9) Did they report their findings in obscure journals without even providing histological illustrations of the brain to document their claims? 10) Did these other studies pertain to only a small number of monkeys distributed over several laboratories, thereby providing multicenter evidence for the food industry and

FDA to cite as justification for keeping on the GRAS [generally recognized as safe] list for two additional decades after Olney et al (Olney 1972) published bona fide evidence for primate susceptibility to glutamate-induced brain damage in a highly reputable, rigorously refereed neuropathology journal? In summary, the record shows that FDA for two decades has been assuring the public that glutamate is safe, based largely on certain industry-generated monkey data which appear upon close scrutiny to be seriously flawed and spurious. However, even if these data were not flawed and spurious, it is obvious from industry's own findings, shown in Fig. 1 above, that the pharmacokinetics of gluatmate absorption and/or metabolism are so disparate between monkeys and man that monkeys, despite their phylogenetic closeness to humans, must be regarded as a singularly inappropriate animal model for evaluating oral gluatmate safety. Oral doses of glutamate that cause dramatic increases in blood glutamate concentrations in humans, cause no increase at all in monkeys. There are a couple of points that need to be made in regards to Dr. Olney's statement: 1. When Dr. Olney was referring to "the pharmacokinetics of gluatmate absorption and/or metabolism are so disparate between monkeys and man that monkeys, despite thier phylogenetic closeness to humans," he referenced a graph showing that humans concentrate glutamate 20 times more than monkeys when administered orally (Olney 1988, Stegink 1979a, page 90). This means that the dosage given to monkeys cannot be extrapolated to that of humans on a one-to-one basis. It also means that rodents may be a better animal model for testing glutamate than monkeys. 2. The Reynolds (1976) experiment (discussed by Dr. Olney above) was funded by G.D. Searle and tested both aspartame and MSG on neonatal primates. Therefore, the NutraSweet industry was involved in this fiasco as well. After learning about the sordid history behind both the NutraSweet industry's research and the Glutamate Association's-sponsored research and how key information was left out of published reports, I find it difficult to imagine how anyone could trust any of the "science" which is supported by those industries. As Dr. Olney mentions, there were a number of other studies which are used by the glutamate and aspartame industries to support their contention that glutamate and aspartate adversely affect only rodents despite the finding of an independent, experienced neuropathologist (Olney 1969a, Olney 1972). Reynolds (1980) administered aspartame at 2g/kg to eight

monkeys and aspartame (2 g/kg) plus MSG (1 g/kg) to six other monkeys. She did not find any brain lesions in the monkeys. Phencyclidine was given to the monkeys before the administration of aspartame and MSG. As Dr. Olney pointed out, this totally invalidates the experiment because phencyclidine is a powerful drug which prevents glutmate and aspartate from damaging brain cells. In addition, considering that humans concentrate glutamate in the plasma at least 20 times more than monkeys, the dose given was too small. Oser (1974) claimed to find no brain lesions in monkeys given MSG. This study can be discounted for the simple reason that he was unable to find brain lesion in infant mice and rats given a high dosage of MSG in the same experiment. He was unable to find brain lesions in rodents in an earlier experiment (Oser 1971). Since it is widely known that infant rodents develop brain lesions at the dosage used in his experiments, he must have had one or more major flaws in the protocols which did not allow him to find lesions. Therefore, the results in the monkeys should be discounted as should the results in the dogs from both the 1971 and 1974 publications. The study by Wen (1973) can be discounted by the same reason. In the same study as his monkey study, despite giving extremely large doses of MSG to rodents, he was unable to find any brain lesions. The lack of effects on rodents given such large doses of MSG would point to one or more flaws in his protocols. One major flaw in the protocol is that animals must be sacrificed within 8 hours of the MSG dose in order to find the brain lesions. If they are sacrificed any later, the massive influx of glial cells will obscure the lesions (Burde 1971, MSG 1994). The monkeys in this experiment were kept alive for days following the MSG dosing. The study by Newman (1973) can be discounted for the simple reason that it appears that the monkeys did not get even close to the stated dose of MSG (if they got any at all). Table I shows the plasma glutamate levels within 4 hours after MSG dosing. The levels are not significantly higher than the control animals. However, in Olney (1972) the plasma glutamate levels at 4 hours are four to five times the base level (for a similar dose). Reynolds (1980) shows similar increases in plasma glutamate levels at 4 hours. Therefore, there was likely a major flaw that caused the monkeys in the Newman experiment to have no rise in plasma glutamate. There are a number of possible reasons. It is possible that the monkeys did not get much MSG. Newman states that "the test solution was readily consumed voluntarily by all animals on all occasions throughout the study." However, the term "readily" is not very specific. The MSG was supplied by Ajinomoto Company of Japan, the company that makes it and a member of the Glutamate Association. It appears that the purity of the MSG was not tested by the investigators. Whatever the reason, it is obvious that something was done incorrectly to cause no rise in plasma glutamate.

In addition, Newman used older, less susceptible monkeys in the higher dose part of the experiment. Formalin was used for the brain tissue fixation. Burde (1971) points out that: "Infant rat brains perfused with formalin were extremely fragile. Tissue preservation was not satisfactory for photography, but the affected areas could not be identified and were in the periventricular arcuate area." Newman did not show any photos to back up his claim that there were no lesions. Finally, Newman did not list his funding source. In 1979, R. Heywood conducted an experiment on a single rhesus monkey (Heywood 1979). Heywood had been the coinvestigator on the Newman study mentioned above. In this study, Heywood admits that a dose of 4 g/kg of MSG caused vomitting at 43, 81 and 90 minutes after dosing. Heywood also states that the plasma glutamate level rose from 138 ug/ml to 333 ug/ml (unlike what happened in the Newman study). Among the more glaring problems with this report are: 1) the monkey vomitted and therefore did not get the full dose of MSG, 2) the investigators did not say what part of the hypothalamus was examined (as not all parts are vulnerable), 3) no photos were shown to back up the claim of no lesions, 4) the brain tissue was not examined with the electron microscope, and 5) formalin was used for brain tissue fixation. Several years after more detailed studies were conducted on infant monkeys, there seems to have been no reason to conduct such a small, sloppy, and poorly documented experiment. After discounting the above-mentioned industry-connected monkey studies for obvious mistakes and inconsistencies, we are left with: a) two studies showing brain lesions in monkeys from oral intake of MSG which were conducted by the reknowned neuropathologist, Dr. John W. Olney, who originally discovered brain lesions from excitatory amino acids such as glutamate (Olney 1969a, Olney 1972); and b) two studies by R. Abraham (Abraham 1971, Abraham 1975) showing no brain lesions in monkeys from oral intake of MSG. Abraham (1971) tested four monkeys with a dose of 4 g/kg of MSG. However, two of these monkeys were not sacrificed until 24 hours after the dose. This would cause the influx of glial cells to obscure the lesions as described earlier. In addition, damaged cells are removed from the area within 24 hours of glutmate or aspartate administration (Olney 1972). Therefore, these two particular monkeys can be discarded. One of the two remaining monkeys was given the MSG orally and one by subcutaneous injection. However, an oral dose of 4 g/kg of MSG often causes vomitting as discussed above and

admitted to by Stegink and Reynolds (Stegink 1975). This leaves us with one test monkey and one monkey strongly suspected to have vomitted in the Abraham (1971) study. In this experiment, Abraham found that only 60% of the infant mice he treated with a dose of 4 g/kg developed lesions. However, other laboratories have found that such extremely high doses of MSG in mice cause lesions in 100% of the mice (Olney 1970, Burde 1971, Daabees 1985, Lemkey-Johnston 1974). Even at a dose of 1 g/kg, Takasaki (1979) found that 75% of the mice develop lesions. Abraham (1971) claimed that only 60% of the mice which received 4 g/kg developed brain lesion and 43% of the mice receiving 1 g/kg developed lesions. This sugessts that Abraham had a major defect somewhere in his experiment which would prevent brain lesions from either a) developing and/or b) being discovered. This puts the results of his remaining monkey from this experiment (or "monkeys" if one included the monkey that likely vomitted up the MSG) into serious doubt. It is of note that Abraham (1971) supported his findings with only a single picture from the hypothlalmus of a monkey that was sacrificed after 24 hours after MSG administration and did not include pictures from the monkeys who were sacrified after 3 hours. At best, this study is highly suspect and probably should be discounted due to the inadequate sacrifice schedules, likely vomitting, and poor results in the mice part of the experiment. Like the earlier Abraham study, the Abraham (1975) study had only two monkeys which were given MSG and sacrificed before 24 hours had elapsed. It seems rather odd that Abraham would continue testing monkeys by sacrificing them after 24 hours after MSG administration since it had already been published in the scientific journals that the glial cells would obscure the brain damage and that the damaged cells would be removed when an inappropriate sacrifice schedule was used (Burde 1971, Olney 1972). In fact, Olney (1972), three years prior to this study (when critiquing the Abraham (1971) study), stated the following: However, beause of the remarkable efficiency with which degenerate elements are removed from the scene of an MSG-induced lesion (minimal lesions are cleared from the mouse brain within 12 to 18 hours), it is essential to examine the brain earlier than 24 hours. This is particularly true if, due to vomiting, the infant retained very little MSG and, therefore, sustained only a minimal lesion. One monkey was give 4 g/kg of MSG orally, the other was given the same dose subcutaneously. Once again, the monkey given an oral dose of 4 g/kg is likely to have vomitted. Abraham. It is also important to note that, as discussed earlier, plasma glutamate levels in monkeys after glutamate administration stay extremely high until at least 4 hours. Yet Abraham sacrificed these two monkeys after only three (3) hours. According to researchers at Dr. Olney's laboratory, a 3-hour sacrifice schedule is the minimum

needed to find any brain lesions (Samuels 1995a). If the earlier sacrifice schedule is combined with other minor or major experimental errors, no lesions would likely be found. Abraham (1975) stated that "The present investigation was undertaken in an attempt to resolve some aspects of this controversy." It appears that Abraham merely repeated most of the same flaws in his 1971 experiment and did not address Olney's direct criticisms. This study, therefore, should be discounted as well. Excitotoxins (Humans) --------------------Several discoveries have proven that ingested excitotoxins can cause adverse effects in human beings. In 1987, 150 Canadians got sick (4 died and 12 suffered permanent memory loss) after ingesting mussels whifch had high levels of domoic acid, a potent glutamate analog (Perl 1990). In parts of Asia and Africa, the chickling pea plant was eaten by some people during times of famine. It contains a naturally-occurring excitotoxin, -N-oxalylamino-L-alanine (BOAA), which has been shown to kill motor neurons (Spencer 1986). One of the more likely causes of the form of the ALS-like illness in the Chamorro population in Guam is the ingestion of improperly processed cycad flour which contains the excitotoxin, -N-methylamino-L-alanine (BMAA) (Spencer 1987, Choi 1992). The Chamorros ate a large amount of this seed during the famine following World War II. In the 1950s, the rate of the Guam ALS-Parkinson's-dementia complex was 50 to 100 times higher than in developed countries (Kurland 1988). The Chamorros no longer ingest much cycad flour (Chamuit, 1994). It was found that many people who ate the flour didn't come down with the disease until many years later, suggesting that the excitotoxic exposure plus age-related cell loss set the stage for the disease. As Choi (1992) states: "Such a model raises the possibility that nerve cell damage resulting from exposure to environmental excitotoxins could pave the way for other neurodegenerative diseases, such as Alzheimer's Parkinson's, or ALS, whose symptoms would become apparent only decades later. Garruto (1980) found that immigrants to the U.S. from high-risk areas in Guam had a high incidence of ALS even though they had not ingested cycad flour for over 30 years. Excitotoxins (Endocrine and Reproductive Disorders) --------------------------------------------------Aspartate and glutamate are also thought to have similar neuroendocrine effects. As recently discussed by Olney (1994): "Destruction of brain neurons is not the only mechanism by which Glu[tamate] can have adverse effects on children. As described above, whenever

elevated levels of Glu are present in the ciculating blood, Glu enters the endocrine hypothalamus (a CVO region which has no bloodbrain barriers) and interacts with EAA [excitatory amino acids] receptors on the surfaces of hypothalamic neurons. These neurons, when stimulated by Glu or related EAA, secrete hypophysiotrophic releasing factors into the portal blood which carries the releasing factors to the pituitary where they act to trigger release of pituitary hormones into the general circulation. This phenomenon was first domonstrated in the mid 1970s (Olney 1976, Price 1978), at which time it was pointed out that repetitive exposure of immature humans to Glu throughout critical stages of development entails potential risk, even if brain damage does not occur, that hormonal biorhythms may be disturbed with adverse effects on growth and development." Carlson (1989b) showed that by administering a dose of 150 mg/kg of glutamic acid (MSG) to healthy adults (an amount which can easily be ingested by children in one restaurant meal) there was a large increase in serum concentrations of the pituitary hormones prolactin and cortisol. Carlson (1989a) tested 534 mg of aspartame in a liquid medium and and 242 mg of aspartic acid in a capsule to see if it changed prolactin, cortisol, or growth hormones outputs. He found no such changes. Carlson (1989b) also tested 10 grams of aspartic acid in capsules and found no increase in prolactin or cortisol outputs. These results were a surprise to the researchers and definately a surprise to me. It is of note, however, that capsule administration was used for aspartic acid administration (but not for aspartame). In the Carlson (1989a) experiment where 534 mg of aspartame was given (in liquid), the plasma phenylalanine did not increase significantly. This seems strange since similar amounts of aspartame administered in other experiments do raise the plasma phenylalanine levels (Caballero 1986, Burns 1991). NutraSweet funded this experiment. One wonders if the aspartame and aspartic acid were provided by NutraSweet and, if so, did they provide the "type" of aspartame which has been shown to cause large spikes in plasma aspartate levels or the "type" that does not cause this spikes (as discussed earlier). In addition, the test substances in the Carlson experiments (1989a, 1989b) were mixed with 500ml-700ml of saline solution. The subjects were also given an infusion of 9 grams of saline/liter into the antecubital vein. This was presumably done to be consistent with a previous experiment which tested prolactin stimulation by meals (Carlson 1983). Since Carlson (1989b) admits that aspartic acid metabolism may be different than glutamic acid, how can he be sure that all of these saline solutions don't affect the results for aspartic acid? Carlson should have administered aspartame in a real world type of setting, i.e., without the saline

solution. What happens to prolactin and corisol measurements after meal intake is not necessarily relevant to aspartame intake because 1) the mechanism that cause excitotoxins to increase hormonal output may be different and more damaging than hormonal changes after a meal, and 2) a meal creates a number of biochemical changes and it is often the balance between these changes that prevent trouble from occurring (e.g., glucose and insulin balance), so that a single change in one parameter could be dangerous for aspartame because other key parameters are not changed. Finally, none of these studies measured levels of luteinizing hormone. Even if the hormonal levels do not change with the ingestion of aspartame (and this has yet to be confirmed with independently obtained and tested aspartame in a study without saline solution and without NutraSweet involvement), excess aspartate will likely over-excite (at least more than normal) cells in the hypothalamus and other areas of the brain not protected by the blood brain barrier. Who can say what a lifetime of such over-excitation will do to the body. Finally, it is crucial to remember that glutamic acid and aspartic acid effects are cumulative. The safety of either of these excitotoxic amino acids cannot be determined without looking at the cumulative effects. Recent animal experiments have shown that high levels of glutamate and aspartate stimulate the abrupt release of gonadotropin-releasing hormone and luteinizing hormone (Medhamurthy 1990, Goldsmith 1994). Plant (1989) and Gay (1988) have shown that an analog of glutamate, N-methyl aspartate induces the premature onset of puberty when given to monkeys repetitively. Other researchers have showed that subtoxic doses of excitatory amino acids change the sexual maturation of animals (Urbanski 1990, Lopez 1990). Subtoxic doses (i.e., less than required to cause brain lesions) of glutamate has been shown to cause a rapid elevation of leutenizing hormone in weanling and adult male rats (Olney 1976) and a depression of pulsatile output of growth hormone (Terry 1981). The dose tested in this experiment was only 25% of the toxic dose. Brann (1992) tested a dose of only 30 mg/kg of glutamate administered to female rats with low and high estrogen backgrounds. Female rats who were given estrogen showed a significant increase in the output of leutenizing hormone. Brann (1992) states: "There is a growing body of evidence which suggests that EAAs [Excitatory Amino Acids] are an integral component of the neurotransmission line that regulates gonadotropin secretion." Even the Federation of American Societies For Experimental Biology (FASEB), which usually understates problems and mimmicks the FDA party-line, recently stated in a review (FASEB 1992): "...it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women,

infants, and children. The Existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental Lglutamic acid should be avoided by women of childbearing age and individuals with affective disorders." Aspartic acid from aspartame has a cumulative harmful effect on the endocrine system and reproductive system. Since there are few safety studies on glutamic acid suppliments, FASEB used studies relating to MSG to make this determination. While it could be argued that MSG is ingested with food and therefore does not raise the plasma glutamate level as high as with suppliments, it appears that MSG is actually more dangerous than suppliments. I have already listed a number of experiments that show large spikes in plasma glutamate from real-world MSG products -- including with full meals. I have also listed a number of experiments showing a significant spike in plasma aspartame levels from aspartame ingestion. On the other hand, glutamic acid and aspartic acid suppliments may dissolve slowly (similar to encapsulated administration) leading to the conversion of more of the amino acid to alanine and definately lessening the plasma spike of the amino acid. Excitotoxins (Pregnancy Dangers) -------------------------------Several animal experiments have shown that excitotoxic amino acids can penetrate the placental barrier and cause damage to the fetus. Gao (1994) used a 3H-Glu tracer to show that low and higher doses of MSG injected into pregnant mice. The experiment showed that the memory and learning potential of the adult offspring was significantly affected. In addition, brain cell damage was found in both the arcuate nucleus and the ventromedial nucleus of the hypothamalmus. Fisher (1991) showed that perinatal MSG treatment of pregnant rats led to a variety of damage in the offspring including brain cell damage to the hypothalamic arcuate nucleus, parts of the circumventricular areas, parts of the visual system, and the dentate gyrus of the hippocampus. The authors stated: "The resulting hormonal dysfunction may be responsible for developmental anomalies of o rgan systems, obesity, and alterations in sensory/motor performance. We have shown that some behavioral indicators of MSG toxicity in rats can be masked by rearing them in enriched housing conditions. Here, we evaluated the impact of six housing conditions on MSG-induced alterations of organ systems and behavior. Perinatal MSG treatment reduced adrenal, heart and testes weights, as well as total white blood cell (WBC) counts, and increased tail flick latencies. .... Deficits in water maze performance were most evident following social and isolated single-case housing. We propose that deficits in water maze performance

following perinatal MSG may be attributable to hippocampal damage that can be alleviated by rearing the rats in stimulating environments." Toth (1987) found that MSG given to pregnant rats caused acute necrosis of the acetylcholinesterase-positive neurons in the area postrema. The authors noticed the same effet in the fetal rats except that the "embryonal neurons were more sensitive to glutamate...." Frieder (1984) showed that damage to the offspring can occur when pregnants rats are given MSG orally as opposed to subcutaneously. Frieder administered MSG in the drinking water during the second and third trimester of pregnancy. Administering MSG led to juvenile obesity, reduced general activity levels, and a learning disability. The dosage given to the pregnant rats was quite high. However, a recent survey showed that some restaurant meals can have as much as 9.9 grams of MSG in a single dish! (UNICEF 1986) An independent study using a smaller dose of orally administered MSG and/or aspartic acid would be useful. It is important to note however, that both orally and subcutaneously administered MSG and aspartame have been shown to cause brain lesions in animals at dosages that are not emensely different. Finally, glutamate has been shown to activate certain genes (Grayson 1990). As pointed out by neuroscientist, Dr. Russell Blaylock (Blaylock 1994, page 73, 235): "The gene activation occurs via a second messenger system, inositol triphosphate and diacylglycerol, which have been activated by phospholipase C. Modification of a preexisting transcription factor induces an early response in certain genes. .... Further, this capacity to activate genes may play an important part in the plasticity of the nervous system, that is, the ability of the nervous system to adapt and change in response to the stimuli of learning and observing the outside world. This is very important, not only in the initial development of the nervous system (while the baby is in the uterus) but also much later during childhood and adolescence. This is how the various mental and motor skills develop." It seems ridiculously reckless to allow women to ingest MSG or aspartame during pregnancy since there is a chance that it will adversely and irreversibly affect the child. Perhaps that is why the FASEB (1992) committee warned pregnant women to avoid glutamic acid. Excitotoxins (Other Disorders) -----------------------------The FASEB (1992) report, a detailed review by Nemeroff (1981), and a thoroughly-referenced analysis by Blaylock (1994) list studies which show test animals experiencing stunted growth, reproductive disfunction, changes in behavior and food intakes, obesity, reduced weights and

sizes of gonads, uteri, adrenals, thyroid, and pituitary glands, changes in insulin output, and various other disorders. As opposed to the single-dose experiments showing brain lesions and changes in hormonal output, some of these experiments were long-term studies. It is beyond the scope of this review to analyze what amounts to thousands of studies involving the health effects of excitotoxic amino acids. I strongly suggest reading the reviews mentioned above to get a good overview. In 1990, Dr. John Olney reviewed the strong connection between neuropsychiatric disorders and excitatory amino acids such as glutamate and aspartate (Olney 1990a). In 1993, Altamura (1993) conducted a study measuring the plasma level of glutamate in patients with psychiatric disorders. Plasma glutamate levels were significantly higher in the patients with mood disorders, schizophrenia and organic mental disorders than in the healthy controls. One would expect that the intake of large quantities of excitatory amino acids from aspartame or MSG would only add to the problems experienced by these patients, and may have caused or contributed to their illnesses. Excitotoxins (Intake) --------------------In the U.S., use of large amounts of free glutamic acid in the form of MSG, HVP, yeast extracts, etc. has increased tremendously over the past 15 years, especially with the advent of the low-fat craze that has swept the country (Samuels 1993). Glutamic acid is added (often in hidden forms) to low-fat foods in order to improve the taste. As much as 5,000 mg of MSG are often added to one restaurant dish. Twelve ounces of soup or broth can contain as much as 2,600 mg of MSG (Consumer Reports 1978) not counting other forms of glutamic acid added. The use of glutamic acid is increasing rapidly (Floreno 1995). It would be quite easy for a 30 kg child to ingest a restaurant meal (5,000 mg of MSG) plus 12 ounces of soup (2,600 mg of MSG) for a total intake of 7,600 mg of MSG or 253 mg/kg of MSG. The Glutamate Association tries to claim that intake of MSG in the U.S. averages only 0.5 g/day for each person. They do not account for the fact that glutamic acid intake has increased tremendously over the last 15 years and much of the intake is in "hidden" forms of MSG discussed below. Just three ounces of soup with some form of MSG would cause a person to ingest 0.5 grams of MSG. The current average is probably closer to 2 to 3 g/day and the intake at the 99 percentile is probably close to 12 to 15 g/day. Due to the public's concern about "MSG," free glutamic acid are being hidden (with the blessing of the U.S. FDA) in the labels in many ways. Common ingredients which, due to the processing technique can have a significant percentage of free glutamic acid or can have MSG directly added to them (without having to list it on the label) include (Samuels 1993): Monosodium glutamate

Hydrolyzed protein Autolyzed yeast Yeast extract Yeast nutrient Yeast food Hydrolyzed oat flour Textured protein Sodium caseinate (often, but not always hydrolyzed protein) Calcium caseinate (often, but not always hydrolyzed protein) Maltodextrim Malt extract Malt flavoring Some of the industry's new favorite synonyms for MSG include: Flavoring(s) Natural flavoring(s) Natural beef flavoring Natural chicken flavoring Natural pork flavoring "Seasonings" "Spices" Due to labeling law loopholes and FDA inaction on a petition to close those loopholes (Truth 1994, Samuels 1995a), it is almost impossible for even health-conscious individuals to know whether they are ingesting MSG. A recent survey at a national restaurant convention on May 27, 1995 revealed that a number of companies which provide soups to restaurants put labels on their soups which state "No MSG Added" and/or have literature with their soup which states that there is no MSG added even though their soups contain significant quantities of added free glutamic acid (MSG). Most of the salespeople were aware of what they were doing, i.e., that their soups really had a form of MSG in it. These soups are then distributed to restaurant owners who may innocently believe and tell restaurant patrons that they contain no MSG. Therefore, when you ask a restaurant for food without MSG, you may very well get MSG unless you look at the label of the packages for MSG synonyms. Claiming "No MSG Added" on the label, but including HVP in the food product has been found "false and deceptive" by the FDA, yet no one seems to be policing restaurant products (Oliver 1991). The intake of additional excitotoxins from aspartame was discussed in an earlier section. It is important to note that only since 1987 have large amounts of aspartame been ingested (USDA 1988). Cysteine, another excitoxic amino acid is currently being added to flour as a conditioner and it is being considered by the FDA for use on produce (Samuels 1995b). Excitotoxins (Food Insdustry Arguments) ---------------------------------------

The NutraSweet Company and the Glutamate Association have put together a number of arguments to try to convince FASEB, the FDA, researchers, and the general public of the "safety" of their products. Here is another excerpt from John Olney's presentation to FASEB (Olney 1993) addressing some of those arguments: Argument #1: Gutmate causes no apparent harm to children. One of the major arguments relied upon by the food industry and FDA is that immature humans do not wince or show overt signs of neurological injury when fed large amounts of glutamate as a food additive or drug. The evidence supporting this argument is that in the 1950s when glutamate was routinely fed in gram quantities to mental retardates with the mistaken believe that it might improve their IQ, these retarded children did not show obvious signs of neurological injury. Similarly "compelling" evidence was generated in an enormous, but totally uncontrolled, world-wide field experiment performed over a period of two decades by the food industry (and sanctioned by FDA) in which glutamate was routinely added to baby foods at ~ 600-800 mg per 4 1/2 Oz jar, the sole motivation being to make the baby food appealing to the maternal palate. Since hundreds of millions of immature humans thus exposed showed no obvious signs of injury, glutamate must be safe, so goes the illogic. As stated above (and I have personally witnessed this phenomenon many times), when immature animals are treated with doses of glutamate that unequivocally and irreversibly destroy neurons in the hypothalamus, they behave exactly like glutamate-fed human infants; they do not wince or show signs of discomfort or neurological injury during the acute 2-4 hour period while hypothalamic neurons are being destroyed. In some species, including primates, high doses cause emesis, but we have observed -- especially in infants -- that hypothalamic damage occurs from doses lower than those required to induce emesis. Later in life, the effects of the hypothalamic damage begin to manifest as subtle neuroendocrine deficits (obesity and disturbances in growth and sexual/reproductive function); but there is not warning of this in the behavior of the animals at the time the damage occurs. I do not comprehend how FDA and the food industry can be confident that exposure of infants and children to gluatmate in gram quantities (the practice FDA currently allows) does not silently destroy neurons in developing human hypothalamus. I know of no credible scientific evidence that could inspire confidence in that conclusion. Arguments #2 and #3: Glutamate is toxic only for

newborn, and only if force-fed. An argument sometimes embraced by FDA and food industry officials, is that glutamate is toxic only for the newborn immediately after birth. A related argument is that animals will not voluntarily ingest enough glutamate to cause brain damage. Both of these arguments are easily shown to be false by the enclosed journal article (Olney 1980) which demonstrates that if weanling mice are deprived of fluids overnight, and the next morning are offered a bottle of drinking water containing added glutamate, they avidly drink enough of the glutamate solution to destroy many neurons in the hypothalamus. While the neurons were being destroyed, the mice showed no clinical symptoms other than mild somnolence. A weanling mouse is roughly comparable in developmental age to a prepubescent human child. In view of this finding, which has been confirmed by others [in aspartame] (Takasaki 1981), I must reiterate that I do not comprehend how FDA and the food industry can, with good conscience, feel confident that the glutamate intentionally being added to foods fed to human infants and children does not ever destroy hypothalamic neurons. Other food industry arguments have included: a. The spike in the plasma glutamate and aspartate levels only lasts a short time (i.e., several hours) and returns to normal quickly and therefore does not keep the levels high for long enough to do damage. Animal research using glutamic acid labelled with radioactive tracers has shown that the levels of glutamate in the brain did not peak until two hours after the blood levels of glutamate returned to normal. It was also shown that glutamate remains in susceptible areas of the brain for as long as 24 hours after the original dosing (Inouye 1976, Paull 1975). Toth (1981) found that feeding liquid diets which contained aspartic acid or glutamic acid over a prolonged period of time increase the brain tissue levels of aspartate 61% and of glutamate 35%. This is a sign that prolonged exposure to high levels of aspartic acid from aspartame or glutamic acid (MSG) may significantly affect brain chemistry over time. b. Some food and breast milk contains free glutamic acid and free aspartic acid, therefore glutamic acid (MSG) and aspartic acid from aspartame are not dangerous. This is a very popular food industry argument attempting to justify adding large amounts of excitotoxins to the food supply. There are several reasons why this is not a legitimate argument. i. The amount of free glutamic acid and aspartic acid in foods is much less than what is often found in MSG and aspartame-containing foods. The IFIC (1995) "fact" sheet

lists tomatoes as containing 140 mg/100 grams of free glutamic acid. In a glutamate industry book, Giacometti (1979) also lists tomatoes as containing 140 mg/100 grams of free glutamic acid. Giacometti lists the free aspartic acid level at 35 mg/100 grams for tomatoes. These figures are based on a study by Stadtman (1972). Skurray (1988) found that fresh tomatoes contained 109 mg/100 grams of free glutamic acid. However, Skurray showed that beef soup contained 2,482 mg/100 grams of glutamic acid with MSG added. As you can see, it is very easy to ingest huge amounts of MSG from these processed junk foods. Human breast milk contains approximately 129 mg/liter of free glutamate (Giacometti 1979). This is many times less than the high concentration of gutamic acid found in MSG-containing products and much less than even the aspartic acid found in diet sodas. Despite the low body weight of infants and the corresponding high mg/kg of glutamic acid ingested per day from breast milk, the amount of glutamic acid ingested at each sitting is relatively small. Giving the regular doses of soup broth with as much as 7,000 mg/liter of glutamic acid is quite a bit different than giving the infant breast milk because the amount of MSG ingested with the soup would be dangerously high.. ii. The small amount of free glutamic acid and aspartic acid in foods is disbursed in the fiber. The food is digested gradually and the free gluatamic acid and aspartic acid are released gradually allowing these amino acids to be absorbed slowly. The food industry has been unable to show a significant glutamate or aspartate spike after the ingestion of real foods which sometimes contain small amounts of free glutamic acid or aspartic acid. A high protein meal does gradually raise plasma levels of amino acids (e.g, Stegink 1983c), but it is nothing like the plasma glutamate and aspartate spikes discussed earlier. This is key: If the free glutamic acid and aspartic acid in foods were really similar to MSG or aspartame ingestion, then these foods would cause enormous spikes in the plasma amino acid levels. Since these large spikes do not happen (Kenney 1972, Airoldi 1979), ingestion of free amino acids in foods cannot be compared to MSG or aspartame. iii. As will be discussed in the next section, persons who have regular, repeatable acute reactions to MSG (glutamic acid) generally do not react to free glutamic acid found in natural foods (Samuels 1993). c. The intake of MSG in some countries such as Thailand is very high and we do not see any health problems caused by glutamic acid in those countries. This is another popular glutamate industry claim. As pointed out by Science (1990), one cannot expect that every person in a country such as Thailand will suffer obvious adverse

effects from years of excess glutamic acid. There may very well be a vulnerable subset of the population. Furthermore, I am not aware of any epidemiological studies in Thailand (or any other country) which tests for the effects of longterm MSG usage. A research team would have to compare two populations one with a high MSG intake and one with little or no MSG intake, controlling for other variables such as diet, environment, heredity, etc., and then compare the incidence of certain diseases -- especially endocrine, neurological and reproductive disorders. The glutamate industry appears to be throwing this statement out without any corroborating evidence. One might wonder why the 307 males tested in Thailand had semen analysis values that were significantly below the standard for Caucasian males (Aribarg 1986). Was it racial or is it possible that glutamate was affecting FSH, LH and prolactin outputs? In a study of 137 Thai patients, 54% of the patients with secondary amenorrhea (cessation of menstration) had hypothalamic-pituitary dysfunction (Vutyavanich 1989). Almost 40% of those who discontinued oral contraceptive steroids still experienced amenorrhea. Might MSG play a factor in the children with stunted growth studied in North-East Thailand (Chusilp 1992)? According to Rajatanavin (1993), "available data indicate a seemingly high prevalence of central hypothyroidism due to postpartum pituitary necrosis in Thailand." Could constantly overstimulating the pituitary gland by ingesting large amounts of MSG contribute to this? Over the last 10 years there has been a significant increase in childhood obesity in Thailand (Suttapreyasri 1990, Mo-suwan 1993). One wonders if MSG, which has been shown to cause obesity in animals studies, could play a part in the increase in childhood obesity in Thailand. Fuller (1993) found that Thai women suffer from frequent reproductive system problems. Is this contributed to by long-term MSG ingestion? Animal studies found reproductive disorders in rats given glutamic acid. While this is obviously speculation, there is certainly some evidence that MSG may be contributing to illness in countries like Thailand. It is important to look closely at disease incidences before proclaiming safety. Conclusion ---------For the following reasons, I believe that the excitotoxic effect from aspartic acid in aspartame may be a major health problem in the general population and especially in children: a. In both human and animal study experiments, the plasma aspartate level has been shown to spike to high levels after liquid administration of aspartame. b. Animals experiments in a number of different species, including rodents and primates have shown a neurotoxic effect from a single dose of MSG or aspartame. The toxic dose required is especially low in infant animals. The industry tests are flawed and border on fraudulent behavior.

c. Humans are 5 times more susceptible to aspartic acid and glutamic acid than rodents and 20 times more susceptible than monkeys because they concentrate these excitatory amino acids in their blood plasma to much higher levels and for a longer period of time. Therefore, when the industry lists doses for susceptibility, dividing by 5 or 20 depending upon the species being compared is necessary. d. Single doses of aspartic acid or glutamic acid at much lower levels than that which can cause permenant brain damage has been shown to significantly affect the output of hormones in a number of difference species, including primates. Therefore, not only should one divide by 5 or 20 to determine human toxic dosage, but one should divide by at least 4 (as discussed above) to determine the single dose required to change hormonal outputs significantly in humans. Even if the dose of the excitotoxic amino acid is not high enough to cause irreversible brain lesions or excess hormonal output, regularly over-exciting unprotected brain cells day after day for months and years is a reckless practice at best, and very damaging at worst. e. In experiments conducted by independent investigators, long-term administration of glutamic acid to a variety of species have lead to obesity, stunted growth, neuroendocrine disorders, and other disorders. Despite the fact that the industry's studies have not turned up long-term danger, I am much more inclined to accept the independent studies. These repeated doses given to animals much more accurately reflects the repeated doses of excitotoxins that humans ingest. f. Excitotoxins in food have a cumulative effect. It does not make sense to consider only aspartame. Glutamic acid, aspartic acid, and possibly cysteine need to all be considered when looking at long-term safety -- or lack thereof. g. Some of the areas of the brain affected by spiked levels of aspartate and glutamate are not protected by the blood brain barrier (BBB). There are a number of conditions which can cause breaches in the BBB, leading to the possibility that other areas of the brain may be susceptible to damage or over-stimulation in certain population (e.g., old age -- see Olney (1990b)). h. I cannot see how daily spiking of the plasma glutamate and/or aspartate levels could be considered "normal" or "safe" when neuroendocrinologists are only just beginning to learn about the large role these excitatory amino acids play in the health and development of human beings. Since these excitotoxic amino acids can have such a devistating adverse effect on large populations many years after they are administered on a regular basis, adding aspartame to the food supply amounts to a very dangerous game. Once the damage is done, it will be too late and the repercussions will be felt for years

after we get the junk off the market. Acute Reactions --------------Since real-world aspartame products are such a witches' brew of small amounts of toxic and potentially toxic substances, it is difficult to be certain exactly what is causing the enormous number of acute reactions linked to aspartame. It may be a different breakdown product for different people. It may very well be a combination of two or more breakdown products acting together. Since many of the acute reactions to aspartame are the same as the acute reactions people have to MSG (glutamic acid) and since many MSG-sensitive people report the exact same reactions to aspartame (Samuels 1995a), it seems likely that the aspartic acid part of aspartame plays a role in causing these reactions. A recent comparison of a subset of MSG (glutamic acid) acute reactions with a subset of aspartame reactions revealed the following: Percent of all complaints for MSG** Aspartame* 21.0 18.4 8.7 6.5 4.6 4.4 3.2 2.6 2.8 2.2 2.7 3.8 1.6 1.1

Symptoms Headache Vomiting and nausea Abdominal pain and cramps Fatigue, weakness Sleep problems Change in vision Change in activity level *DHHS (1993b) **Tollefson (1988)

A significant number of independent studies have confirmed that MSG can cause acute reactions (Allen 1987, Ratner 1984, Rudin 1989, Monert-Vautrin 1987, Kenney 1972, Schaumburg 1969, Ghadimi 1970). If fact, Kenney (1972) stated: "The exhibition of quantities that might properly be regarded as bizarre in the culinary setting increases the possibility of symptom occurrence, in our experience to 30% of a test population at the 5-g level." Five grams of MSG is no longer considered "bizarre in the culinary setting." The Glutamate Association has spared no expense in trying to convince the world that the large and growing quantities of excitotoxins they are dumping into the food supply are safe. It is beyond the scope of this paper to go into all of the "techniques" they have used to "prove" safety. (A look at the "research," conflict of interest in FASEB reviews, etc. reveals enough problems to give any honest researcher indigestion.) You got a taste of those techniques when

looking at the excitotoxic amino acid and primate studies. I will provide an example of what they do in acute studies to hide adverse effects. But first, however, it is very important to understand that the MSG and aspartame issues are very closely tied together and therefore much of the industry hanky panky involving one of these issues is often applicable to both. Please note: a. A number of researchers are funded by both the MSG and aspartame industries and some have, not surprisingly, published glowing reviews about products. b. The glutamate industry book (Filer 1979) and the aspartame industry book (Stegink 1984a) were written by many of the same authors. c. NutraSweet is a long-time partner of MSG inventor and maker, Ajinomoto Co. of Japan. Together they are producing aspartame in France (Monsanto 1993). It is quite clear to any person but the most gullible that NutraSweet is aware of, if not an active participant, in the flawed glutamate industry experiments. The Tarasoff (1993) "study" is a typical example of glutamate industry "research." The "researchers" gave 71 healthy subjects MSG doses of 1.5, 3.0, and 3.15 grams/person over five days. The authors state that they used "a rigorous randomized double-blind crossover deisgn." They found no significant differences between the number of reactions for the MSG and the placebo. Flaws ----1. The "researchers" used aspartame in the beverage mixture that was given to both the test subjects and the controls. The use of aspartame (which will break down into aspartic acid among other things) has been shown to cause acute reactions similar to those caused by MSG and invalidates the entire experiment. It was revealed in a letter to FASEB from the Chairman of the International Glutamate Technical Committee (IGTC), Dr. Andrew G. Ebert, that the IGTC has been using aspartame in their beverage mixture since 1978! (Ebert 1991) Therefore, every "double-blind" experiment conducted by glutamate industry "researchers" since 1978 can be flushed down the toilet. It would take an absolute suspension of disbelief to believe that the IGTC was unaware of the similarities between glutamic acid and the aspartic acid from aspartame. In fact, on behalf of the glutamate industry, Dr. Alan Leviton testified to FASEB on April 8, 1993 that many MSG and aspartame reactions occur with similar frequencies (Samuels 1993). This deception has been going on for 13 years! Not once during that time did the "researchers" state in their publications that the beverage mixture contained aspartame!

Some of the questions which arise out of this deception are: i. Were the subjects who were given the beverage mixture told that it contained aspartame so that they could give informed consent? If so, were they also told that approval to aspartame had been blocked due to the serious concern about brain cancer, uterine tumors, etc. Aspartame was not approved in liquid beverages until 1983. ii. Were persons with the genetic disorder PKU as well as pregnant PKU heterozygotes excluded from the study for their own safety? iii. Was the IGTC aware that they were using an unapproved substance in their "research"? iv. How could NutraSweet be unaware of what was going on since they must have provided the aspartame? Certainly, they knew that aspartame was not approved and its use would totally invalidate MSG experiments. v. Did the researchers know that the beverage mixture contained aspartame? I would find it difficult to beileve that they were unaware. vi. Given that this deception was not mentioned in a large number of publications, how can we believe any "research" connected with the glutamate industry? It takes an enormous amount of time to pick out all of the flaws detailed in these publications because some of them are so well hidden (e.g., monkey studies pictures discussed earlier). Knowing that some of the flaws are not even mentioned in publication after pubication makes it impossible to fully critique these articles. What future key information will be (or is being) left out of the glutamate industryassociated publications? vii. Given that this type of deception is occurring with alarming frequency (and I could cite many examples), why does it seem like the scientific community is not doing anything about it? A logical but perhaps impractical solution would be to ban all research associated with the glutamate industry or their researchers (related to MSG) and fund a series of completely corporate-neutral studies. Taking no agressive action is only encouraging more well-hidden (and some not-so-well-hidden) abuses. The glutamate industry will try to respond that they did not use much aspartame in the beverage mixture (Tarasoff 1995). Tarasoff compares the mg/kg of MSG with that of aspartame. The problem is that 1) aspartame reactions occur at much lower mg/kg doses than MSG, 2) the reactions are often similar causing there to be much less difference in placebo and test subjects, 3) many MSG-sensitive people are sensitive to aspartame and visa versa. The beverage mixture in the Tarasoff (1993) study

contained nearly enough aspartame for two-thirds of a can of soda. A person who is sensitive to MSG will often react to this amount of aspartame. We have no way of knowing how much aspartame was used in the beverage mixtures of earlier glutamate industry studies. It may have been more than was used in the Tarasoff (1993) study. 2. The "researchers" excluded all persons with pre-existing conditions including general allergy syndromes, asthma, and aspirin sensitivity. Persons with allergies and especially asthma tend to have more acute reactions to excess MSG. The "general allergy syndrome" exclusion would likely exclude persons who have food insensitivities (since many people call that "allergies"). Also excluded were persons on medications and those with "other" (unspecified) conditions. While the previous flaw would tend to equalize the number of reactions that occur in the test and the control populations, this flaw would significantly reduce the number of people who experienced reactions. 3. The patient interviews occurred only two hours after consuming the MSG or placebo. It has been known for many years that reactions to MSG often occur a long time after ingestion since they are probably not typical allergic (IgE-mediated) reactions. Allen (1987) showed that asthmic reactions occur as long as 12 hours after ingestion. Dr. Alfred Scopp (1991) of the California Headache Clinic requests that his patients record all food eaten within six hours of the onset of a headache be recorded. Settipane (1987) states that the development of late onset bronchospasm (after as long as 14 hours) may be related to MSG reactions. In a review of food sensitivies, Carroll (1992) states that food sensitivies can be delayed anywhere from 2 to 48 hours. While fewer subjects would experience MSG reactions after 24 hours, a protocol that calls for only a twohour followup is ridiculous. This would reduce the number of reactions experienced. 4. The meal given to both groups included "flavored" milk. Such products often contain a form of MSG (e.g., HVP). Why wasn't the issue of MSG in the meal addressed by the researchers? 5. Persons who experienced an aftertaste (13 people, 11 of whom took MSG, two took placebo) were excluded from the results. It is possible that persons who have more acute reactions from MSG also tend to experience an aftertaste. The aftertaste experienced may have been the result of the combination of aspartame (which often causes an aftertaste) and MSG. 6. The subjects were asked to fast before taking MSG or placebo. Fasting can sometimes precepitate a reaction caused by lowered blood sugar. Since these reactions would occur equally in the test and control groups, this would tend to reduce the significant difference between the two groups.

7. The "researchers" failed to space the test and placebo days far enough apart. This means that a person who experienced a delayed MSG reaction might do so after having switched to the control group. While Tarasoff may be able to come up with a excuses as to why their experiment (as well as other IGTC experiments) should be considered valid despite the flaws, their "research" was obviously designed to avoid finding reactions. One other common flaw in industry experiments of MSG is that they limit the kind of reactions to just a few symptoms such as those originally listed for the Chinese Restaurant Syndrome (Kwok 1968). While a few reactions were noted in 1968 by Kwok, the types of reactions that have been found to occur in people sensitive to MSG include a wide variety of reactions including neurological, respiratory, gastrointestinal, cardiac, and visual reactions (Samuels 1993). By limiting the reactions to burning, chest tightness and a couple of other reactions, researchers will often find fewer adverse reactions. The Glutamate Association is providing support for 7 or 8 new "studies" to try and prove the "safety" of MSG (Samuels 1995a). Since their deception with the use of aspartame was discovered and since the FASEB (1995) final draft report was rejected by the FDA until major modifications could be made, the IGTC was obviously trying to send as much (flawed) research to FASEB as possible before the final report was completed. This is not unlike what the glutamate industry did in the 1978-1980 FASEB "review." (Samuels 1993). FASEB is certainly in a precarious position. They recently used the MSG studies to warn a certain group of the population from the use of glutamic acid supplements (FASEB 1992). They will look extremely foolish if they now proclaim the "safety" of unrestricted use of MSG (and other excitotoxins) in the same population based on the same studies. As it turns out, FASEB (1995) foolishly did not warn susceptible individuals to avoid MSG as did FASEB (1992) even though they were aware of some of the potential dangers: "The Expert Panel concluded that the report by Carlson et al. (1989), while not definitive proof of a direct neuroendocrinological response to ingested MSG, does offer evidence for the potential for such a reaction. Consequently, this possibility must be considered plausible in the absence of contradictory evidence, particularly in light of the irrefutable evidence supplied by the animal studies of an effect of parenterally administered MSG on these hormones. The Expert Panel strongly recommends that future studies be designed to replicate and further explore this effect in humans." It is understandable that FASEB (1995) came to such a

different conclusion than FASEB (1992). At least four of the members of the FASEB (1995) committee appear to have proglutamate industry biases. Selection of such a biased committee taints the results. It is too bad that an honest effort was not made by FASEB to select a relatively unbiased committee. One member of the FASEB (1995) committee had been found many years earlier to have a conflict-of-interest in that he received money from companies who were, I believe, members of the Glutamate Association. This person also worked as a consultant to a government department which evaluated the usefulness of MSG-containing products (Rosenthal 1976). Another member of the committee had previously been offered as a spokesperson for the "safety" of MSG by the Glutamate Association to the television show "60 Minutes" (Samuels 1995). Another member of the committee frequently worked very closely on projects with a scientist who has publically testified that MSG cannot possibly represent a hazard and who has co-edited a book for the Glutamate Association. Finally, another member of the committee is a close associate of a researcher and spokesperson for the glutamate industry. While only the first of the four inappropriate appointees may have had an "official" conflict-of-interest, the appointing of four individuals who appear to have made up their mind before the review completely skewed the results of the review. It is now quite obvious that FASEB leadership (like the FDA) can no longer be trusted to create even a marginally unbiased committee. The FASEB (1995) committee was unable to completely ignore the independent research showing acute adverse reactions to MSG, especially after discovering the abuses in the industry research. Unfortunately, the committee inappropriately stated that reactions to MSG do not occur in amounts of less than 3 grams. They based this figure on a wild guess, certainly not the experience of the countless people who react to MSG when the level is below 3 grams. Acute Reaction Studies ---------------------Dr. Leibovitz states: "There is, at present, only one published, doubleblind study that reported harmful or toxic effects of aspartame ingestion." This statement is just plain wrong. While there are not many published, double-blind studies showing adverse reactions to aspartame that is simply because there is no money available for independent researchers who want to thoroughly test aspartame. I will discuss the lack of funds in a later section. The number of published, double-blind studies which show adverse reactions to aspartame is approximately equal to the number of published, double-blind studies which were not funded by NutraSweet or organizations connected to

NutraSweet. Here are a few published, double-blind studies showing adverse reactions: Camfield (1992), Van Den Eeden (1994), Walton (1993), Elsas (1988), Spiers (1988), and Koehler (1988). Kulczycki (1995) only had enough money (i.e., little funding) to study six subjects in a doubleblind fashion. He discussed the results in a Letter to the Editor. Dr. Leibovitz states: "[Sensitivities to aspartame were] tested in a double-blind crossover trial in which either aspartame (30 mg/kg body weight) or placebo (cellulose) was given to 40 subjects who reported having headaches after consuming products containing aspartame." [Schiffman 1987] [NOTE: 30 mg/kg translates to about 2,100 mg for an adult; this is a very large amount that could replace about 400 g of sugar. And that's almost a pound of sugar!] Capsules were used in order to circumvent aspartame's sweet taste. There were no significant differences between groups with respect to headache, dizziness, nausea, or a host of other symptoms assessed; in other words, subjects claiming to be 'sensitive' to aspartame were unable to distinguish it from placebo in a clinical setting. These findings cast serious doubt about whether 'aspartame-sensitive' individuals actually exist." It concerns me that Dr. Liebovitz decided to give any credance to this poorly designed, NutraSweet-funded study conducted by a former NutraSweet consultant. (Susan Schiffman performed her research at the "Searle Center" at Duke University. The Searle Center is under the guidance of William Anlyan, a former G.D. Searle director. Schiffman is a former General Foods and G.D. Searle consultant. The FDA helped design the study protocol. [Gordon 1987, page 500 of US Senate 1987; Shapiro 1987, page 403 of US Senate 1987].) Dr. Liebovitz did not even mention that two much better designed studies, Koehler (1988) and Van Den Eeden (1994), show a significant increase in headaches caused by aspartame (even though fresh, encapsulated aspartame was used). Flaws ----a. Fresh, encapsulated aspartame was used. At 30/mg/kg, encapsulating the aspartame significantly reduces the plasma amino acid spikes (Stegink 1987a) because the aspartame is absorbed gradually. b. Schiffman's study was a single day challenge while Koehler (1988), an independent investigator, conducted a thirteen-week trial. Van Den Eeden, another independent investigator, used a fairly short 7-day trial. c. Schiffman used an unspecified incentive to fly subjects to the experiment site, removing them from their normal surroundings. Since these subjects had a history of problems with aspartame, they were probably already

nervous about being in an aspartame trial. Then taking these subjects out of the environment they are comfortable with and flying them to a new and different hospital environment (with a new diet and having a number of tests performed) is bound to create an atmosphere where almost anything that makes the patient nervous would cause an adverse reaction. This may account for the large numbers of adverse reactions experienced by both the test and control group. d. Removing the subjects from their environment does not allow for the researchers to assess the interaction between the environment (including other dietary factors) and aspartame ingestion. Schiffman created an environment which doesn't exist in the real world. e. Schiffman did not monitor the baseline diet or headaches unlike Koehler and Van Den Eeden. f. Schiffman did not control for known dietary triggers of headaches. Since it was a new diet designed by a dietician, maybe caffeine withdrawl or some other unknown factor play a part in so many adverse reactions. g. The subjects studied were those who reported their adverse reactions to G.D. Searle. I don't mean to sound paranoid, but I just don't trust them to make a representative selection of subjects. h. Two of the three doses of encapsulated aspartame were given with meals, further reducing the speed with which the amino acids were absorbed. i. Schiffman's protocol chose subjects on the basis that they had experienced headaches or related neurological symptoms within 24 hours after aspartame ingestion. Yet, within 12 hours after the last dose of aspartame (or 16 hours after the first dose), it would have been midnight and the subject would likely have been asleep. If some of the subjects had experienced headaches the next morning (within 24 hours of aspartame ingestion), these headaches would not have been counted because it was the washout day. Dr. Leibovitz states: "There are other well-controlled trials of aspartame that have failed to find any negative effect of aspartame--even in people who believe themselves 'allergic to aspartame.'" (Garriga 1991) The real story is that there are no well-designed studies connected with the NutraSweet company. What they've done is to flood the research community with poorly designed studies guaranteed to show that aspartame is "safe." Almost all independent looks at aspartame's pre-approval studies have shown extreme concern and recommended against approval. Almost all independent post-approval studies have shown

problems with aspartame. Aspartame is a very serious problem. Anyone who has critically read the research and history of aspartame or who has taken the time to listen to some of the countless stories of severe reactions or worsening of health due to aspartame whether consumed knowingly or unknowingly would not be so quick to dismiss these adverse reactions. The Garriga study was funded by the International LIfe Sciences Institute (ILSI) which is essentially an industry annex as opposed to an independent organization as discussed in a later section. Garriga tested 12 individuals in a single blind fashion. The three positive responses were tested in a double-blind fashion and then with one diet soda. The nine negative responses were tested with one diet soda. One subject reacted twice to the diet soda, but not to the encapsulated aspartame. Flaws ----i. Only headaches which occurred within 1 hour of exposure were considered. This is far too short, and is only useful if headaches from aspartame are allergic reactions (e.g., IgE-mediated) and not food intolerance or toxicity reactions. ii. The researchers excluded legitamate candidates for the experiment -- patients with lupus, depression, seizures, thyroid disease. Do the researchers believe that these people somehow do not have access to aspartame and therefore do not need to be tested? iii. Subject recruitment appears to be poor, at best. The fact that after a couple of years of subject recruiting attempts, they were only able to come up with 12 testable subjects only shows that they didn't know what they were doing. They could have contacted any number of groups who could have helped provide many times more candidates than they found. After a television request for subjects in 1986, Kulzycki (1995) was contacted by 88 people. One wonders how big was the ad in the Washington Post which appeared in the Volunteer/Health ad section. Is it possible that many times fewer people would see the ad as opposed to the television appeal? Also, it is important to note that the study was initiated in 1986, not long after aspartame began to be sold in carbonated beverages. In 1987, there were 600 products with aspartame, now there are over 5000 products with aspartame. It would be much easier now to find such reactors. iv. A question that needs to be asked is, "Is it possible that persons who scan the Volunteer/Health ads in newspapers are more likely to sign up for the experiment for the compensation as opposed to the test itself?" An appeal directed at everyone such as Kulzycki's television appeal or contacting patient groups where

aspartame reactions are more common would be more likely to reduce this possibility. v. Three subjects had positive single-blind tests for aspartame reactions. The dosage for the double-blind test (encapsulated) was less than two-thirds the total received for the single-blind test. The dose of aspartame for the diet soda test was also too small.

vi. It appears that none of the subjects were suffering from serious hypersensitivity reactions near the time of the study. One theory is that repeated exposure to a substance can lead to hypersensitivity, much like exposure to formaldehyde for example. (Coincidentally, methanol from aspartame can break down into formaldehyde.) A single dose experiment would eliminate the chance of seeing hypersensitivity develop after chronic exposure to a substance over time. Conclusion ---------It is extremely important to understand that this study and other studies like it are only looking for hypersensitivity reactions and do not address the slow damage that can happen from long-term ingestion of aspartame. When conducting a single-dose hypersensitivity experiment, all parts of the experiment have to be conducted well -- subject recruitment, double-blind testing, proper defination of a "reaction," etc. in order to see a significant difference in reactions. It appears that the Garriga study had enough problems in those areas to significantly reduce the number of reactions that might have been found. Kulczycki (1995) was contacted by 88 individuals with hives who had seen an ad for subjects for aspartame research. Seventy-five of those subjects avoided aspartame for two weeks. Fifty of those subjects experienced a complete resolution of hives during that time. Twenty-two of these individuals who were willing to rechallenge themselves experienced skin reactions upon ingestion of aspartame. Kulczycki had only enough funding to conduct a double-blind challenge on six individuals with 50 mg. of aspartame. Four of these individuals had adverse reactions to aspartame and none had reactions to the placebo. One subject had a reaction after 3 hours, another had an immediate reaction and a delayed reaction after 12 hours, another had a reaction after 2.5 hours and delayed reactions after 9, 23, 30, and 43 hours, and the final reactor had a delayed reaction after 22 hours. These delayed reactions are not at all unusual. As pointed out earlier, Carroll (1992) states that food sensitivies can be delayed anywhere from 2 to 48 hours. Kulczycki states: "Allergists need to recognize that aspartameinduced hives can be acute, delayed, or chronic." Finally, Kulczycki pointed out a few of the flaws in another NutraSweet-sponsored study, Geha (1993). One of several

flaws that were not discussed was that the dosage was very small considering encapsulated aspartame was used. Novick (1985) presented that a 22-year-old patient who had numerous deep and large nodular lesions on her legs. The patient had been ingesting a saccharin-containing drink for six years previously. Ten weeks before being presented for evaluation, the manufacturer had switched to aspartame. Within four weeks after being taken off lesions "spontaneously resolved without after being rechallenged with 200 mg of capsules per day, nodules reappeared on After withdrawing aspartame once again, disappeared. aspartame all the residua." Ten days aspartame in the patient's legs. the nodules

Conclusion ---------It is becoming increasingly clear that the most important aspect of aspartame (and MSG) studies which test for acute reactions is the funding source or loyalties of the researchers. Almost any study conducted by independent researchers and which does not commit too many obvious experimental errors will find adverse reactions to aspartame. I believe that not one study linked to NutraSweet (from now until eternity) will ever find any adverse reactions to aspartame.

8. Phenylalanine The article states: "...the presence of phenylalanine, however, is a potential concern for persons suffering from phenylketornuia (PKU)--a rare genetic disease in which phenylalanine is improperly metabolized. .... But remember that PKU is extremely rare, and that phenylalanine is an important nutrient for the vast majority of people." It is unfortunate that Dr. Leibovitz glosses over such a crucial issue of phenylalanine intake. Everyone in the research community is well-aware of the fact that phenylalanine is an important amino acid and that it is commonly found in many foods. The issue revolves around the intake of a free amino acid that is very quickly absorbed without the presence of other amino acids that commonly make up protein. Never in the history of man has phenylalanine been ingested in free form without the presence of other amino acids on a long-term basis. 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. Phenylalanine Absorption -----------------------When phenylalanine is taken as part of aspartame, particularly in liquid form, the phenylalanine is absorbed very quickly and can spike the plasma phenylalanine to extremely high levels. The plasma level of the amino acid phenylalanine can rise more than as seven (7) times its average baseline (fasting) value after aspartame ingestion (in liquids such as carbonated beverages) (Stegink 1987a, Matalon 1988). The spike in the plasma phenylalanine level lasts about 2 hours (average). Even lower levels of aspartame cause spikes in the plasma phenylalanine levels (Caballero 1986, Burns 1991). Plasma phenylalanine levels gradually rise after a meal but the levels do not rise nearly as high (Stegink 1987b). Lactating women ingesting fresh aspartame in orange juice were found to have increased phenylalanine levels in their milk (Stegink 1979c). Plasma Phenylalanine/Large Neutral Amino Acids (LNAA) Ratio When a high protein meal is eaten, a number of amino acids gradually enter the bloodstream. Other Large Neutral Amino Acids (LNAAs) in addition to phenylalanine enter the bloodstream after the proteins from the foods are broken down. The other LNAAs are: valine leucine isoleucine tryptophan tyrosine histidine methionine These amino acids tend to be more abundant in foods than phenylalanine. When a protein food is eaten the plasma level of all the LNAAs (including phenylalanine) rises gradually.

However, since the other LNAAs are more abundant than phenylalanine, the Phenylalanine/(Other LNAA) ratio goes down (Fernstrom 1979, Maher 1984). In other words the plasma phenylalanine level gradually rises, but to a much less extent than the plasma level of the other LNAAs. Aspartame is the only "food" that contains phenylalanine and no other large neutral amino acids (LNAAs). Therefore, not only can the plasma phenylalanine level spike to high levels after aspartame ingestion, but the plasma phenylalanine/LNAA ratio also increases to very high levels after aspartame ingestion. In other words the phenylalanine level rises, and the other LNAA levels do not rise at all. Several studies have shown that ingestion of aspartame can spike the plasma phenylalanine levels and increase the phenylalanine/LNAA ratio tremendously (Stegink 1987a, Caballero 1986, Stegink 1989, Stegink 1990, Stegink 1979c). Ingestion of an aspartame-containing product along with a glucose or starch-containing product can increase the plasma phenylalanine/LNAA ratio much more than simply ingesting aspartame alone. Martin-Du Pan (1982) showed that doses of glucose as little as 6 grams can cause a drop in plasma LNAA levels by an average of 10%. Twenty-five (25) grams of glucose led to a 30% drop in plasma LNAA levels. Since these reductions in LNAA levels were caused by large decreases in the levels of most large neutral amino acids except phenylalanine which only had a small decrease, the plasma phenylalanine/LNAA ratio will be increased by administration of glucose or starch. Yokogoshi (1984) found this to be the case in studies on rats. Wolf-Novak (1990) confirmed this effect in humans. This large spike in plasma phenylalanine levels and the large increase in the phenylalanine/LNAA ratio after aspartame ingestion is one major difference between protein metabolism and aspartame metabolism. In fact, phenylalanine ingested as part of liquid aspartame-containing products produces a much more severe biochemical change then when phenylalanine is ingested in capsules or slow-dissolving tablets -- much like one would find it in a dietary supplement (Stegink 1987a, Burns 1990). In addition, many free amino acid supplements contain other LNAAs such that the plasma phenylalanine/LNAA ratio would not change significantly. NutraSweet researchers often try to argue that the peak level of the phenylalanine/LNAA ratio is not important, but only the "Area Under the Curve" (AUC) which is a combination of the level and the time the Phenylalanine/LNAA is above the baseline (i.e., fasting) level (Burns 1990). In this way, they try to claim that ingestion of phenylalanine in liquids which tends to spike the phenylalanine quickly and for a short period of time at high levels is the same as taking phenylalanine in capsules which spikes the plasma phenylalanine to a much less extent but for a longer time. One has to leave their brain at the door in order to buy into this argument. First of all, the whole argument falls apart when one

realizes that they are using averages of all of the subjects for each time period to calculate the AUCs. Comparing each individual's AUC for liquid aspartame ingestion and capsule aspartame ingestion would show a much larger difference for most people than inappropriately using averages for each time period. Second, even using average measurements for each time period, Stegink (1987a) showed a much greater AUC for liquid aspartame ingestion as opposed to capsule ingestion. Third, capsule ingestion of aspartame, while still different than ingesting a high-protein meal because there are not other LNAAs present, comes closer to what the body is used to as far as the more gradual rise in plasma phenylalanine levels. The human body has never experienced such a sudden and large influx of phenylalanine without other LNAAs present every day for a lifetime. Finally, by using capsules, NutraSweet researchers are testing a different product with a much lower spike on plasma phenylalanine and phenylalanine/LNAA levels. The metabolism is quite different in when ingested in liquid as opposed to capsules. NutraSweet researchers are guessing that this hugh difference doesn't matter. Considering all of the serious health problems being linked to aspartame ingestion, I do not think it is appropriate to base aspartame testing on the wild guesses and wishful thinking of NutraSweet researchers. If they insist upon studying aspartame in capsules, then aspartame should only be sold in freshly prepared capsules. Burns (1991) claims that ingestion of aspartame or sucrose produce similar Phenylalanine/LNAA ratios. First, Burns (1991) inappropriately used the groups' average values for each time period. Second, the phenylalanine levels actually goes down when the sucrose is administered. This is an enormous metabolic difference from the large phenylalanine spikes when aspartame is administered. It is possible that the neutral amino acid transport sites at the blood brain barrier which are normally saturated with phenylalanine and other amino acids become less saturated when sucrose is administered and do not have a similar change in brain chemistry as occurs with aspartame. (See Brain Uptake of Phenylalanine below for details.) Third, the change in the Phenylalanine/LNAA ratio is relatively small when sucrose is given, but extended over a longer period of time than when aspartame is given. Therefore, Burns (1991) had to use the Area Under the Curve (AUC) nonsense to try to prove that the changes are the same with both sucrose and aspartame. Even using this argument, there was a greater increase the phenylalanine/LNAA ratio when aspartame was administered. It is clear that the biochemical changes that occur when sucrose is administered is quite dissimilar to the changes which occurs when aspartame is administered. Finally, it is unclear whether the ingestion of carbohydrates along with aspartame renders the phenylalanine part of aspartame more dangerous. Carbohydrate ingestion lowers the levels of Large Neutral Amino Acids (LNAAs) and therefore the neutral amino acid trasport cites may become unsaturated causing a smaller

change in brain chemistry than would otherwise happen with the phenylalanine alone. Removal of Excess Phenylalanine ------------------------------Excess phenylalanine is converted in the liver to the amino acid tyrosine by the enzyme phenylalanine hydroxylase. Persons who have a genetic defect know as Phenylketonuria (PKU) have little or no phenylalanine hydroxylase activity and can therefore not convert excess phenylalanine in the blood to tyrosine. Excess phenylalanine in the cases of such genetic defects is converted to phenylpyruvic acid and acetyl-phenylalanine and eliminated through the urine (Caballero 1988). However, in cases of PKU, excess phenylalanine can be quite toxic and such persons, who are identified at birth, are told to limit their phenylalanine intake and warned to not ingest aspartame. Persons are considered to be "hyperphenylalaninemic" if they have only 5% to 15% of normal phenylalanine hydroxylase activity (Matalon 1988). PKU and hyperphenylalaninemia are rare conditions that are identified at birth, making up approximately 0.014% of the population (Guttler 1988). Persons who are the carriers of the PKU gene, "PKU heterozygotes," usually have anywhere from 15% to 40% of normal phenylalanine hydroxylase activity (Matalon 1988) and make up approximately 2% of the population (Caballero 1986). PKU heterozygotes are not identified at birth any many people do not know that they are carriers of the PKU gene. Finally, it has been shown that the elderly population tends to have a delayed plasma phenylalanine clearance (Rudman 1991). This would tend to increase their susceptibility to the long-term negative effects of spiking the phenyalalnine/LNAA ratio. Rodent Phenylalanine Metabolism ------------------------------It is important to understand that rodents metabolize phenylalanine much faster than humans. The conversion of phenylalanine to tyrosine occurs at a rate more than 12 times faster in rats than in humans (Caballero 1988). It takes 60 times the dose of aspartame in rats to produce a similar phenylalanine to tyrosine ratio (and therefore an equivalent change in the phenylalanine/LNAA ratio) as found when humans are given aspartame (Wurtman 1988). Therefore, a dose of aspartame of 1000 mg/kg given to a rat over its lifetime only approximates a dose of 17 mg/kg in humans as far as the phenylalanine part of aspartame is concerned. NutraSweet researchers have tried to claim that it only takes 2 to 6 times the amount of aspartame in mice and rats to cause an equivalent rise in plasma phenylalanine/LNAA ratio as is found in humans (Hjelle 1992). This experiment was conducted by NutraSweet Company and Hazelton Laboratory employees. The phenylalanine measurements in the rats and mice are so different than found by other researchers that they should be discounted. For example, a dose of 200 mg/kg of aspartame given to the rats was found to increase the

plasma phenylalanine from 73.6 nmol/ml to 295.0 nmol/ml -an increase of 4.0 times higher than the base value. The plasma tyrosine levels were found to increase from 91.6 nmol/ml to 212.0 nmol/ml -- a increase of 2.3 times higher than the base value. Wurtman (1983a) found that giving aspartame to rats at 200 mg/kg increased their plasma phenylalanine by only 1.92 times and increase their plasma tyrosine by 2.57 times. This shows that the tyrosine actually increased more than the phenylalanine. This makes sense since the rats convert phenylalanine to tyrosine much quicker than do humans. Yokogoshi (1984) showed similar results to Wurtman (1983a) after giving rats 200 mg/kg of aspartame. The plasma phenylalanine rose to 1.62 times its base value and the plasma tyrosine rose to 2.42 times its base value. Pinto (1988) tested 200 mg/kg of aspartame on mice. After one hour (half of the time alloted by the Wurtman and Yokogoshi experiments listed above), the plasma phenylalanine level was 1.26 times over its base value and the tyrosine was 1.48 times over its base value. The increases were less in this experiment than in Yokogoshi (1984) and Wurtman (1983a) because the measurements occurred at 1 hour, but the ratio of changes in phenylalanine to the changes in tyrosine are similar in all three experiments. For all three studies (Wurtman 1983a, Yokogoshi 1984, Pinto 1988), the plasma tyrosine rose 1.17 to 1.5 times more than the plasma phenylalanine. This is a relatively consistant result. In the NutraSweet-conducted experiment, the plasma phenylalanine rose 1.74 times more than the plasma tyrosine. This result is ridiculous. Even at the 500 mg/kg dosage there results in changes in plasma phenylalanine and tyrosine do not come close to matching any other researchers (Perego 1988, Pinto 1988). The rest of the discussion by Hjelle (1992) simply amounts to twisting of results from previous studies (which is something only someone intimately familiar with the research would be able to discover) and dredging up inaccurate information provided in previous NutraSweet-sponsored "research." The simple fact is that no one but NutraSweet researchers can seem to get rats to spike plasma phenylalanine and phenylalanine/LNAA levels similar to what happens in humans unless they give approximately 60 times the dosage typically tested in humans, i.e., over 1000 mg/kg. If they give less, the rats have increase tyrosine levels more than phenylalanine levels -- something which never occurs in humans with aspartame ingestion. Hjelle (1992) had the nerve to give the appearance that their results were similar to other studies: "The results at 200 mg/kg were similar to those of Yokogoshi (1984). We also obtained results similar to those of Fernstrom et al. (1983) who demonstrated that serum concentrations of PHE [phenylalanine] and tyrosine peaked in rats within

30-60 min. after an oral of 200 mg/kg of aspartame. The Cmaxs, Tmaxs and AUC for PHE and tyrosine at the 200 and 1,000 mg/kg doses of aspartame were generally the same as those calculated from data reported by Romano et al. (1990) who administered bolus doses of 250 and 1,000 mg/kg of aspartame to rats." I guess that since Hjelle (1992) decided to present such ridiculous phenylalanine and tyrosine measurements, it is not surprising that these researchers would go one step further in the insanity and imply that their results are similar to other studies. The plasma phenylalanine and tyrosine changes in Yogokoshi (1984), Fernstrom (1983), and Romano (1990) are enormously different than the changes shown in Hjelle (1992) as anyone who examines these studies can easily see. In fact, Hjelle (1992) goes on to admit at least one major difference: "However, at 1,000 mg/kg, Romano et al. (1990) reported plasma concentrations of PHE that were approximately one half of the current value and AUCs that were not directly proportional to the aspartame dose." Earlier Hjelle (1992) had said his data was "generally the same" as that of Romano (1990). But here he admits that his study had double the phenylalanine levels when 1,000 mg/kg was administered! Such obviously nonsensical results and such a deceptive presentation in this publication of the "research" performed by NutraSweet and Hazelton Laboratory personnel raises a very serious and important question: "If NutraSweet research cannot even honestly and accurately determine plasma phenylalanine and tyrosine levels in rats, how can we believe any study they have performed or will perform on any of their products"? Brain Uptake of Large Neutral Amino Acids (LNAAs) In humans, large neutral amino acids (LNAAs) compete for entry (at the neutral amino acid carrier sites) into the brain across the Blood Brain Barrier (BBB) (Pardridge 1988a). For example, when plasma phenylalanine levels are low, uptake of the LNAA methionine into the brain has been shown to increase. When plasma phenylalanine levels increase, uptake of the LNAA methionine into the brain has been shown to decrease (Comar 1981). Pardridge (1988a) points out that: "In experimental hyperphenylalaninemia, the impairment of brain protein synthesis can be normalized by the coadministration of other large neurtral amino acids that compete with phenylalanine at the neutral amino acid carrier sites within the brain capillary." A rise in the plasma phenylalanine/LNAA ratio leads to an

increased uptake of phenylalanine into the brain and a decreased uptake of other LNAAs into the brain (Pardridge 1983). The neutral amino acid carrier sites are normally saturated with neutral amino acids (Pardridge 1986, Smith 1991, Shulkin 1995). Since the affinity for phenylalanine at the neutral amino acid transport sites is high, an increase in the plasma phenylalanine levels without a corresponding increase in the levels of other large neutral amino acids (LNAAs) could saturate the transports sites with phenylalanine and block the availability of other amino acids (Pardrige 1988a). NutraSweet funded a study by Koeppe (1991) where seven subjects received 34 mg/kg of fresh aspartame in a beverage on one day and a placebo drink on another day. Before each ingestion, a positron emission tomography (PET) was performed using [11C]ACHC as a tracer to estimate neutral amino acid transport across the blood brain barrier at different sites. Forty-five (45) minutes after ingestion of the beverage, another PET was performed to determine any changes in transport of neutral amino acids. The authors conclude: "We observed an 11.5% decrease in the amino acid transport rate constant K1 and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET." Flaws ----i. The second PET scan was performed at 45 minutes. This is a major flaw. The researchers based their assumption that plasma phenylalanine levels would peak at 45 minutes on an old study by Stegink (1977) which only showed average values for all subjects at each time period. When individual values are shown such as in Stegink (1987a), one can see the following estimations for peak phenylalanine levels after ingestion: Estimated Time of Peak Subject No. Phenylalanine Level (min.) 1 15 2 15 3 45 4 30 5 30 6 15 7 45 8 30 9 60 10 30 Mean 31.5

As can easily be seen, many of the subjects had plasma phenylalanine peaks at a much earlier time than 45 minutes. One subject had a peak at near 60

minutes. The measured mean peak phenylalanine level from Koeppe 1991 was only 56% of that measured in Stegink (1987a). It is safe to assume that the measured mean peak phenylalanine level from Stegink (1987a) was below the actual mean peak level because measurements occurred only every 15 minutes. It is also a fairly safe assumption that the actual mean peak phenylalanine levels from Stegink (1987a) were approximately twice as high as that measured in this study (Koeppe 1991). Therefore, their average values from the PET scan after aspartame ingestion was closer to measuring amino acid transport after ingestion of 17 mg/kg of aspartame as opposed to 34 mg/kg of aspartame. ii. The researchers based their conclusion on the groups' average change in amino acid transport rate at a particular time. This flaw tends to dismiss the possibility that there can be a differences in phenylalanine transport rates from person to person. One can easily see individual differences in phenyalalnine metabolism by looking at the different levels of peak plasma phenyalalnine from Stegink (1987a). There is probably also differences in the changes in neutral amino acid transport rates from person to person at the same plasma phenylalanine level. iii. The authors tend to dismiss an 11.5% change in the amino acid transport rate constant and a 6% change in the ACHC tissue distribution volume at what really amounts to 17 mg/kg of aspartame. However, one of the major points of concern with ingesting large amounts of free phenylalanine without other LNAAs is that it could cause the brain chemistry to change very slowly, almost imperceptibly over a period of months or years. After a single dose, the researchers found a small, but measurable change. Can these researchers find a change in blockages of arteries after a single dose of a high-fat meal. Or can they find significant changes to lung tissue after smoking a single cigarette? In this case they did find a measurable change after a single dose. Drinking significant amounts of aspartame-containing product regularly may very well cause gradual changes in brain chemistry due to the phenylalanine (not to mention the damage from the other parts of aspartame) over many months or years depending upon a person's susceptibility. The large number of serious neurological adverse reactions reported from medium- and long-term use of aspartame tends to add weight to this argument. iv. These researchers seemed to simply cut-and-paste NutraSweet's nonsensical dosage arguments from other "studies." First of all, they claim that they tested a high dose of aspartame or 34 mg/kg. 34 mg/kg is only twothirds of the FDA Acceptable Daily Intake. Second, due to errors in timing of the PET scan, they were testing a value closer to 17 mg/kg of aspartame.

The researchers further claimed that 34 mg/kg amounts to ~5 liters of diet beverage for a 76.3 kg man. However, they base this figure on 500 mg of aspartame per liter. In reality, there is closer to 600 mg in a liter of aspartame (Tsang 1985). Also, not everyone is a 76.3 kg man. A 50 kg woman would have to drink 2.8 liters of aspartame-containing beverage (or a 2-liter bottle plus a few of aspartame-containing products) to reach 34 mg/kg. The equivalent of a "Super Big Gulp" would nearly reach 17 mg/kg of aspartame (the equivalent amount actually measured in this experiment) for a 50 kg woman. Two cans of diet soda would cause a 25 kg child to reach the 17 mg/kg level. If we discuss diet orange soda, the amounts needed to reach 17 mg/kg are much less. Conclusion ---------Even if a person ingested less aspartame than was ingested in this experiment, we get back to 1) the fact that there are individual susceptibilities and 2) it is the long-term ingestion that is the major concern as far as the phenylalanine goes, not a single ingestion. General Effects From Changes in Phenylalanine/LNAA Ratio It is nearly impossible to measure the very gradual changes that might occur in brain chemistry after months or years of ingesting phenylalanine from aspartame. We do, however, have some clues from animal studies as well as case histories. Yokogoshi (1984) found that aspartame given to rats significantly affected the brain levels of the amino acids tyrosine, valine, isoleucine, tryptophan, leucine, and phenyalalnine. Administration of aspartame and glucose increased these changes even more. Wurtman (1983a) found that the administration of aspartame plus glucose was shown to block the normal rise in brain 5hydroxyindole (5-HIAA -- a metabolite of the neurotransmitter serotonin) levels that occur after glucose administration. Who knows what the consequences of regularly blocking a normal change in brain chemistry might be. Coulombe (1986) tested doses of 13, 130, and 650 mg/kg of aspartame on mice. He found significant changes in norephinephrine (NE) in hypothalamus, medulla oblongata, and corpus striatum. He also found changes in dopamine (DA) and various catecholamine metabolistes VMA, HVA, and DOPAC in certain sections of the brain. Finally, no changes in 5-HIAA were found. However, unlike Wurtman (1983a), Coulombe (1986) did not co-administer glucose with aspartame. Coulombe concludes: "Such observed alterations in brain neurotransmitter concentrations may be responsible for the reported clinical and behavioral effects associated with ASM [aspartame] ingestion." During (1988) gave doses of 200, 500, and 1000 mg/kg to rats. When 200 mg/kg was given to rats, there was an

increase in basal dopamine (DA) of 59%. This was presumably because at such low doses in rats, the plasma tyrosine levels increase much more than the phenylalanine. At a dose which is more appropriate in mimicing what phenylalanine/tyrosine changes that occur in humans after aspartame administration -- 1000 mg/kg -- dopamine release was reduced by 26%. The authors conclude: "No corresponding changes were observed in the concentrations of DOPAC and HVA with any of the treatments, indicating that changes in brain phenylalanine and tyrosine levels may selectively affect production of the dopamine molecules that are preferentially released into synapses." .... Although the changes in dopamine release (the increase by 59% and the decrease by 26%) were small compared with the changes seen after a drug like amphetamine (2 mg/kg increasing release by 1600%), they may still be sufficient to cause behavioral effects, particularly in animals or humans with impaired nigrostriatal neurons." In addition to the consideration of humans with "impaired nigrostriatal neurons" one must consider the effects of a diminished dopamine release day after day for years. Reilly (1989) claims that aspartame does not alter levels of norephinephrine (NE) , serotonin (5-HT), dopamine (DA) in the rat. She administered 500 mg/kg per day to rats via their drinking water. Flaws ----i. The changes found in DA by Coulumbe (1986) were to a large extent in areas of the brain not looked at in this experiment. ii. The researchers claim that they were using 10 times the FDA Acceptable Daily Intake (ADI) in this experiment. In reality they gave a total of 500 mg/kg of aspartame to the rats throughout the day. Since it takes 60 times the amount of aspartame to be equivalent to human intake, they were really giving the equivalent of 8.3 mg/kg of aspartame per day. This is less than one-fifth the FDA ADI! iii. The experiment lasted for only 30 days. They gave the equivalent of 8.3 mg/kg to rats for 30 days. This is hardly a good way to measure long-term effect. iv. The brain measurements may not have been at a time when obvious changes would be expected. No details were provided on the timing of the tests. Coulumbe (1986) found changes three hours after a single aspartame dose (650 mg/kg or the equivalent of 11 mg/kg in humans). The brain chemistry may have returned to closer to normal since the animals were not given a significant dose within a few hours of sacrifice. Fernstrom (1983) found that a relatively small dose of

aspartame given to rats, 200 mg/kg caused changes in brain levels of phenylalanine and tyrosine. It is not surprising that the brain levels of tyrosine increased more than that of phenylalanine because at a dose of only 200 mg/kg the plasma tyrosine rises more than the plasma phenylalanine in a rat. At this dosage, it was no surprise that after a single administration there was no significant change in brain levels of 5-HT, DA, NE, or various metabolites of these neurotransmitters. Phenylalanine and Psychological/Psychiatry Problems --------------------------------------------------Medium- to long-term use of real-world aspartame-containing products may precipitate or worsen depression and other psychological conditions. Gradual changes in brain chemistry and function caused by the phenylalanine part of aspartame (and possibly other breakdown products) could easily produce a myriad of problems in susceptible individuals. It is believed by some researchers that excessive spiking of plasma phenylalanine levels can affect the levels of serotonin in the brain and possibly lead to neurological problems such as depression (Pardridge 1986). Since neurological problems including depression seem to be occurring in near epidemic proportions, any change that would further lead to brain chemistry imbalances in the population over a long period of time should be of enormous concern. The U.S. Department of Health and Human Services lists the following figures for persons reporting psychological problems caused by aspartame (DHHS 1993b): Health Problem Change in Mood quality or level Memory Loss "Other Neurological" [???] Sleep Problems Count 558 220 210 186

One has to bear in mind that it would be extremely difficult for many people to link their psychological problems to aspartame use because 1) aspartame-caused changes in brain chemistry often happeneds very slowly over a very long period of time, and 2) aspartame may not be the only causitive factor involved. In his survey of 551 aspartame reactors, Dr. H.J. Roberts found the following psychological health problems caused by aspartame consumption (Roberts 1988): # of people (%) - Severe depression 139 (25%) - "Extreme irritability" 125 (23%) - "Severe anixiety attacks" 105 (19%) - "Marked personality changes" 88 (16%) - Recent "severe insomnia" 76 (14%) - "Severe aggravation of phobias" 41 (7%) Dr. Leibovitz states:

"In that study [Walton (1993)], 13 subjects (8 patients and 5 non-patient volunteers) given 300 mg of aspartame showed increased 'number and severity of symptoms for patients with a history of depression.' The main concern about this study is that 5 (out of 8 patients) were on antidepressants (mainly Prozac) at the same time they were given aspartame." What Dr. Leibovitz did not mention was the following two points: a. The study protocol was written to test 40 subjects for 20 days, but the Institutional Review Board stopped the study due to adverse reactions as described by Dr. Walton: The severity of some of the reactions is noteworthy; three study participants spontaneously reported that they felt they had been "poisoned." One of the three to use this term felt that her symptoms were so severe that she had to discontinue the capsules -- after 3 days of her second week [aspartame]. One patient, a 42-yearold PhD psychologist with a history of recurrent major depression, reported pain in his left eye, followed by retinal detachment requiring emergency surgery. On the day of his surgery (day 4 of his second [placebo] week) he discontinued his capsules and symptoms reporting. Although this event occurred during the placebo week, 6 days after the aspartame had been discontinued, another individual -- one of the three to use the term "poisoned" -- experienced a conjunctival hemorrhage for the first time in her life during the aspartame week. These events led the Chairman of the IRB to halt the project. b. There was a clear statistically significant increase in the overall number of adverse reactions in the depressed group of subjects. Table 1 Headache Nervousness Dizziness Trouble remembering Binge eating Lower back pain Nausea Depression Insomnia Temper More energy Fatigue Malaise Placebo 63% 25% 13% 0% 13% 25% 25% 38% 38% 0% 0% 0% 0% Aspartame 88% 63% 25% 63% 13% 25% 100% 75% 50% 25% 25% 25% 38%

Weight loss 13% Pain in eye 13% Negative thoughts 0% Bad taste in mouth 0% Swollen lips 0% Facial numbness 0% Conjunctival hemorrhage 0% Weight gain 0% Irritability 0% Less sleep 0% Diarrhea 0% Nightmares 0% More sleep 0%

0% 0% 13% 13% 13% 13% 13% 13% 25% 0% 0% 0% 0%

This experiment conducted by Walton (1993) was intended to test vulnerable patients -- those with mood disorders who may or may not be on antidepressants. Given the enormous number of people in the U.S. with mood disorders and who are on antidepressants, it is very important for thorough independent aspartame research to be conducted on this population. Walton's study showed that the subjects with a history of depression had a clear increase in headaches, nervousness, memory loss, nausea, depression, malaise, and a possible increase in a number of other adverse symtpoms. What would years of aspartame do to such patients? The reason why the non-depressed subjects did not show a statistically significant change in adverse reactions may have been due to the fact that capsules were used and that the study lasted only 20 days -- a short time when compared to a lifetime of use. On the positive side: a. This study lasted 20 days, many times longer than most NutraSweet funded studies. b. It was conducted by a researcher not connected to NutraSweet. In fact, NutraSweet refused to sell Dr. Walton the aspartame because they could not control the outcome of the study. On the negative side: a. Capsules were used to administer the aspartame. Much worse reactions would likely have been encountered had aspartame been ingested in real-world products. b. Only 3/5 of the Acceptable Daily Intake (ADI) was given to the subjects. The absolute minimum that should be tested is the current 50 mg/kg/day ADI. c. The control group should have been similar to the test group in mood disorder and percentage of antidepressents taken. It is difficult to understand how Dr. Leibovitz could minimuze the serious reactions that occurred in the group ingesting aspartame. At the very least, these reactions are

a cause for great concern. How anyone could so easily recommend aspartame to the general population after reading this study is beyond me. It is necessary to correct some misunderstandings about the effects of phenylalanine on depression. A number of authors have suggested that phenylalanine can be taken to improve cognitive function and to treat depression. See Pearson (1982) for example. It is very important to understand that when phenylalanine supplements are taken, they are usually taken in capsule form and/or with other large neutral amino acids (LNAAs) (at least when taken on a long-term basis). This would, to some extent, offset negative effects. In addition, they are usually not taken recklessly (i.e., in liquid form and without other LNAAs) for a lifetime as is proposed for aspartame. There is some scientific evidence that phenylalanine can help some cases of depression when taken for a relatively short period of time (e.g., a few weeks). After that period, the evidence seems to indicate that the subjects become tolerant of the therapeutic effect. In a non-blinded study testing the efficacy of phenylalanine on depressed patients, Yaryura-Tobias (1974) gave 6 depressed patients 100 mg of d-l-phenylalanine or 100 mg of d-phenylalanine to 9 depressed patients. Earlier experiments had shown that urinary elimination of phenylethylamine (PEA), a metabolite of phenylalanine, is decreased in some cases of depression and therefore, Yaryura-Tobias believed that the administration of the phenylethylamine precursor, phenylalanine might improve cases of depression. The duration of the study was two weeks. Three of the six patients in the first group improved and seven of nine improved in the second group. One patient with depression and psycosis worsened. This study gives clues that shortterm phenylalanine administration may improve some cases of depression. It says nothing about administering high doses of phenylalanine in liquid form (without other LNAAs) for a lifetime. Spatz (1975) gave 11 subjects with depression (and a low urinary phenylethylamine output) a daily dose of 100 mg of dphenylalanine for five days, then 150 mg for five days, and finally 200 mg for five days. Most of the subjects had a significant improvement in their condition. The urinary phenylethylamine output increased after ten days of treatment and fell somewhat in most cases 20 days after treatment completed. This study, while not blinded, seems to show that short-term d-phenylalanine administration may improve some cases of depression. The authors hypothesize that a reduction in brain levels of phenylethylamine (the phenyalalnine metabolite) was one factor in causing the depression. Phenylethylamine has a very mild amphetaminelike effect. Beckmann (1977) administered to 20 depressed subjects 75-200 mg per day of d-l-phenylalanine for 20 days. Eighteen of the 20 patients had been treated in an outpatient setting with antidepressant drugs without any success. At the end of the

study, eight patients had a complete recovery and four others had a good response. Out of the remaining eight patients, four had a mild to moderate improvement, and four had no improvement at all. Again, this was not a blinded trial. However, it does provide compelling evidence that short-term administration of phenylalanine may significantly improve some cases of depression. Beckmann (1979) administered 150-200 mg/day of d-lphenylalanine to 20 depression patients and administered the antidepressant drug, imipramine, to 20 other depressed patients. At the end of 30 days there was a equally significant improvement in several parameters for both the phenylalanine and the imipramine patients. This is another study which provides evidence that the short-term administration of phenylalanine can improve depression in some cases. The authors hypothesized that cause of the improvement in the phenylalanine subjects was either increased brain levels of phenylethylamine or increased production of dopamine in the brain. (Phenylalanine --> Tyrosine --> Dopamine is one pathways for production of dopamine.) (Mann 1980) administered 200-600 mg/day of d-phenylalanine to 11 depressed patients for four weeks. There was a placebo week at the beginning of the trial. There were no significant improvements and two of the subjects had to drop out after becoming suicidal. The results in this experiment are quite different than previous experiments. There is not a clear reason why this result is different. Some of the earlier experiments used a hospital setting rather than an outpatient setting which would tend to change the results significantly. In addition, some of the earlier experiments used d-l-phenylalanine instead of just d-phenylalanine. Birkmayer (1984) administered 250 mg/day of l-phenylalanine and 5-10 mg/day of l-deprenyl to 155 unipolar depressed patients (102 outpatients and 53 inpatients). The dosages were given in the morning for 28 to 96 days. Ninety percent (90%) of the outpatients showed significant improvement and 80.5% of the inpatients showed significant improvement. Six percent (6%) of the outpatients did not improve and 4% had a worsening of their condition. Twelve percent (12%) of the inpatients did not improve and 7.5% dropped out. This nonblinded study provides compelling evidence that lphenylalanine plus l-deprenyl given to depressed patients for a relatively short period of time can significantly improve depression in many cases. Wood (1985) tested 600 mg/day of l-phenylalanine on nineteen patients with Attention Deficit Disorder (ADD) in a 2-week, double-blind, crossover trial. The results showed significant increases in the patients' mood and overall functioning, but no improvement in the ADD. The therapeutic effects were not observed until after 5-7 days of lphenylalanine administration. Mild sedation and fatigue were observed in doses over 600 mg. At the end of the two to three month initial testing period, all of the patients became tolerant of the therapeutic effects. Increasing dosage only resulted in increased sleepiness and fatigue.

This study, once again, demonstrates that short-term administration of phenylalanine appears to improve mood significantly. However, it was clear that the effect wore off after a short time. This experiment is nothing like administering doses of liquid phenylalanine (from aspartame) without other LNAAs every day for months, years, or an entire lifetime. Sabelli (1986) gave 40 patients with major depression lphenylalanine in capsules for three or more weeks. The dosage started at 1000 mg (two 500 mg capsules per day) and increased until therapeutic effects or side effects were noticed (up to 14 g/day). The patients were also give 100 mg of decarboxylase cofactor pyridoxine. Some of the patients were kept on lithium. They were allowed to use diazepam or flurazepam for sleep. At the start of the study, the depressed patients had significantly lower blood and urine concentrations of phenylacetic acid (PAA), a metabolite of phenylethylamine (which is a metabolite of phenylalanine) as compared to the 48 control subjects. The phenylalanine supplements increased urinary output and plasma levels of phenylethylamine (PEA) and phenylacetic acid (PAA) in depressed patients. Twenty (20) of the 40 depressed patients had a partial mood elevation, and 11 had a complete recovery. Several patients reported insomnia and increased anxiety and a few transient adverse reactions were reported such as headaches, constipation, and nausea. The results provides more compelling evidence that short-term administration of phenylalanine to depressed patients can improve mood. All of these studies provide some strong evidence of the therapeutic use of phenylalanine in treating depressed patients and elevating mood. Some large, double-blinded trials would be useful as well. However, all of these studies are very short compared to months and years of phenylalanine use from aspartame. In addition, many of the studies used capsules which do not lead to the same type of spike in plasma phenylalanine levels as does liquid administration. The concern that medium- and long-term ingestion of large amounts of phenylalanine, especially in liquid form, and without any other LNAAs, would significantly change brain chemistry leading to health problems is not addressed by these short-term studies on depression. From the independent studies available and the growing number of serious adverse reactions to aspartame, it appears that the long-term effects are being felt in the most susceptible population. The less susceptible population may be in for an unpleasant surprise should they continue this dangerous experiment. It is of interest to researchers that many depressed patients have a blood and urinary deficit of phenylethylamaine (PEA) and phenylacetic acid (PAA). Matalon (1988) showed that subjects ingesting aspartame at the FDA ADI levels had large intermittent spikes in the urinary excretion of PEA. However, some patients with psychiatric disorders have an excess of these phenylalanine metabolites (Boulton 1991). Schizophrenic patients appear to have an excess of phenylethylamine, for example. Such patients might

not fare as well with long-term ingestion of real-world aspartame-containing products. Phenylalnine and Seizures ------------------------Seizures and convulsions make up a total of 7.88% of the total aspartame-related adverse reaction complaints reported to the FDA (DHHS 1993b). Not long after aspartame's approval in beverages in 1983, seizures became such a significant problem that Community Nutrition Institute (CNI) petitioned the FDA to ban aspartame. CNI stated the following regarding the 80 aspartame-related seizures which were reported to the Center for Brain Science and Metabolism at Massachusetts Institute of Technology (MIT) (Food 1986): "These 80 cases meet the FDA's own definition of an imminent hazard to the public health, which requires the FDA to expeditiously remove a product from the market." Some researchers believe that medium- or long-term ingestion of free phenylalanine without other LNAAs lowers the seizure threshhold and precipitates seizures in individuals who would otherwise not have them (Pardridge 1986, Wurtman 1985a). A large body of evidence shows that monoamines -norepinephrine, dopamine, and serotonin -- can modulate seizure activity and severity (Jobe 1988). It is thought by some researchers (Wurtman 1985a) that phenylalanine may gradually change the level of dopamine, norepinephrine, or serotonin and thus lower the seizure threshold in humans. A number of independent animal studies have shown that aspartame administered to rodents does lower the seizure theshold (Pinto 1986, Maher 1987, Garattini 1988, Kim 1988). The doses used were appeared quite high, i.e., 1000 mg/kg, but remember that one has to divide by 60 to get the equivalent effects of phenylalanine in humans. Still, the effects on animal experiments may be difficult to extrapolate to humans. It is very important to realize that phenylalanine may not be the only factor in the countless seizures linked to aspartame usage. Low-level methanol poisoning, regular ingestion of free aspartic acid in liquids, and regular ingestion of DKP may also play a part in the seizures. There is no consensus on all of the causitive factors, but phenylalanine seems to be one of the likely culprits. Elsas (1988) tested six adult phenylketonuria heterozygotes and one normal volunteer for two weeks in a double-blind, double-crossover study of four 2-week intervals. The amount of phenylalanine given was approximately equivalent to 34 mg/kg of aspartame per day. There was a wide range in the changes in phenylalanine levels. One subject who had a semifasting plasma phneylalanine concentration of 136 uM which rose to 539 uM on phenylalanine supplementation, compained of emotional changes during the phenylalanine supplementation and withdrew from further studies. Another

subject had several instances of forgetfulness during the testing phase. Elsas found that there was a slowing of the mean power frequency (MPF) (in the high-frequency alphaband) of the EEG measurement when the plasma phenylalanine increased, even for small changes in the phenylalanine levels. Walton (1988) presented eight sample case histories of persons suffering seizures from aspartame and stopping those seizures by stopping the intake of aspartame. Walton points out that the reports of seizures from aspartame as well as those of mania (Walton 1986), panic attacks (Wurtman 1983b), and weight gain (Blundell 1986) provide evidence that aspartame may be causing alteration in monoamine metabolism which then causes or contributes to these health problems. In 1992, an independent researcher, Camfield (1992), showed that children with a history of seizures who ingested a single dose of aspartame had abnormal EEG spike waves discharges. This was the first independent scientific test of aspartame and seizures since the Elsas (1988) study showing abnormal EEG measurements. Beyond the hundreds of reported case histories of seizures due to aspartame, it raised additional red flags. Monsanto/NutraSweet was quick to respond with a series of seriously flawed studies intended to "prove" that aspartame does not cause seizures. 1. Shaywitz (1994a) studied 9 children (ages 5-13) who had clinical evidence of seizure disorders for 7 days. He claimed that no seizures were noted nor were there unusual EEG measurements. Selected Flaws -------------a. Eight out of nine of the subjects were on antiepileptic medication at the time of the study. This definately helped prevent seizures and abnormal EEG readings. b. The aspartame was encapsuled which significantly lessens the plasma spikes of the amino acids. It's difficult to believe that the investigators were not aware of this fact. It also appears that the aspartame was taken near mealtime (breakfast) which would further cut down on the plasma amino acid spike and the methanol toxicity. c. The aspartame was fresh and did not include the numerous breakdown products found in real-world aspartame-containing products. d. The dosage was less than 1/2 the amount that Frey (1976) found that children of that age can ingest when aspartame products are freely available. It was less than 2/3 of the Acceptable Daily Intake (ADI) and less than 1/3 of what they should test (i.e., double the ADI). They base their reasoning on the laughable food survey results discussed earlier in this document. e. A 14-day study is hardly long enough to see seizures develop. Some people are on real-world aspartame

products for months or years before they get regular seizures. f. The blood sample was taken when the methanol would have long since been converted to formic acid. The investigator testing the blood samples was none other than Dr. Thomas Tephly. As discussed earlier in this document, urinary formate measures are worthless at low doses, even when those doses can cause health problems. Also, statistically significant changes in blood formate levels are not always present in exposure to low levels of methanol (especially when averages are used for each time period) as discussed earlier. 2. Rowen (1995) used a single dose of aspartame to test 15 adults and 2 children who had a claimed that aspartame caused seizures. He claimed that no clinical seizures were experienced nor were there any statistically significant differences in EEG measurements. Selected Flaws -------------a. Sixteen of the 17 subjects were on antiepileptic drugs which definately helped to prevent seizures or abnormal EEGs (especially since they hadn't taken aspartame 7 days before the study started and didn't take real-world aspartame on the study). b. This was a one day experiment! Much too short to determine anything. c. The aspartame was encapsuled which significantly lessens the plasma spikes of the amino acids. It's difficult to believe that the investigators were not aware of this fact. Two of the three aspartame doses were administered during meals which would further cut down on the plasma amino acid spike and the methanol toxicity. d. The aspartame was fresh and did not include the numerous breakdown products found in real-world aspartame-containing products. e. The investigators imply that their difficulty finding their goal of 60 subjects suggests that seizures linked to aspartame are rare. This is a ridiculous assumption as there are hundreds of cases registered with the FDA (1993) and countless others reported to independent parties (Stoddard 1995b). There are likely many times more than this that go unreported or undiagnosed. Their inability to find subjects is probably related to 1) inadequate recruitment methods as described by Kulczycki (1995); and 2) people being extremely unwilling to provoke seizures in the interest of "science." It is unlikley that Camfield's small, idependent study (Camfield 1992) showing abnormal spike waves in children who ingest aspartame and the hundreds of reported case histories of aspartame-caused seizures (and probably many more unreported cases) can hold up under the barrage of flawed NutraSweet-funded studies on seizures as shown above. Aspartame ingestion has lead to seizures (including grand

mal and petit mal) and convulsions in long-term users. Below is a copy of a case history from the Internet: "In Dec. 1990, I began having strange symptoms. I would awaken in the early morning hours, sometimes with a feeling of anxiety, and smell a strong odor of burning toast. The first time it happened, I went downstairs at 5:00 A.M. in the belief that one of my children was in the kitchen trying to fix breakfast. I was astonished to find no one there. My husband was unable to detect this odor. I had other olfactory hallucinations (simple seizures) for a period of a couple of months. Sometimes it was the odor of toast, sometime burning rubber, even men's cologne. I had one episode of strong deja vu, which is also considered a seizure indicator. I was otherwise in good physical and mental health. In January of 1991, I had a complex partial seizure while driving my car to work. This seizure was evidence by feeling the time was slowed down, that I could only move my foot from the accelerator to the brake by a strong act of will, and involuntary blinking of my eyes. I managed to pull off the road and waited for a while until I felt I could drive. When I got to work, I was told by my colleagues that my speech was slurred. I had trouble completing sentences. The slurring resolved in a couple of days, but the trouble completing sentences persisted for a while. I also experienced post-ictal "fog" for about a week. My memory for normal work and family activities was compromsied, and I had difficulties performing my customary duties. I underwent an EEG that day which showed slowing on one side of the brain. I later had another EEG (sleepdeprived) with the same results. I also had an MRI of my brain, which was normal. Dr. Don Smith, a neurologist in Englewood, Colorado, evaluated me, and asked me to keep track of any seizure activity. He restricted me from driving. After a few more olfactory hallucinations, he decided to put me on medication to control my seizures. He started me on a low dose of Tegretol, which I was instructed to increase over a period of a few weeks until I was at a therapeutic dose. I became ill before the therapeutic dose, with severe sore throat, swollen glands, fatigue and fever. Blood tests revealed that my bone marrow was depressed from the Tegretol. My WBC was 2.0. He told me to stop taking the Tegretol and recover from the illness, and that we would evaluate medication later. I spend the next two weeks in near seclusion waiting for my immune system to recover so I could go out in public without being abnormally vulnerable to disease. Meanwhile, my friend and colleague Kathy Goebel, who was Clinical Coordinator of the Epilepsy Center at Colorado Neurological Institute, told me about an article she had read in a neurological journal. The author stated that aspartame is a neuroexcitotoxin, and that it could lower a person's seizure threshold. At that time, I was using approximately four packets of Equal a day, in tea,

coffee and cereal, and also consuming NutraSweet in dessert products such as diet Jello and ice cream. Kathy suggested that I give up all products containing aspartame to see if it had an effect on my seizure activity. I did this immediately. My olfactory hallucinations stopped, and I was greatly relieved. Dr. Smith was skeptical at first and wanted to put me on another seizure medication. I convinced him to wait and see if I had more seizures. I never had another one until recently when I unknowingly ate a popsickle that had NutraSweet in it. I had an olfactory hallucination in the early morning hours. This happened recently, after I moved to Georgia, so Dr. Smith doesn't know about that one. Dr. Smith was convinced that my seizures had, in fact, been caused by aspartame. He testified to this effect during a trial concerning a later automobile accident. The seizures I experienced and the sequelae were terrifying for me. As a Clinical Research Associate at Colorado Neurological Institute, I was very aware of the implications of a diagnosis of epilepsy. I did, in fact, lose my job at CNI, although any connection to my seizure was denied. She was lucky to get off aspartame when she did. For some people, the silent damage becomes more severe and the symptoms get much worse over a long period of time before they notice the connection. Phenylalanine and Behavior -------------------------In a statement prevented to the U.S. Senate in 1985, research scientist, Dr. Richard Wurtman detailed his concerns about the effects of aspartame on brain chemistry and behavior (Wurtman 1985b): "1. When aspartame is consumed by laboratory rats in doses consonant with those sometimes ingested by people, it changes the chemical composition of the brain: It alters the brain's levels of some amino acids, and thereby affects the production and release of some of the neurotransmitters that the brain uses to carry signals from one nerve cell to another. These changes are enhanced when the aspartame is consumed along with a food that is rich in carbohydrate (as happens, for example, when someone eats a jelly sandwich or cookies or pasta along with diet soda). The changes in neurotransmitter release are likely to affect numerous brain functions (like the control of blood pressure, or the appetite) and aspects of behavior. "2. When normal human volunteers consume aspartame in doses that are high - but with the FDA's estimate of 90th percentile intakes - blood amino acid levels change in ways that almost certainly produce corresponding alterations in the

chemical composition of their brains (especially if the aspartame has been ingested along with carbohydrate-rich food). However the particular changes that occur in the human's brain are likely to be different from those occurring in the rat's. (This is because the rat's liver destroys the phenylalanine in aspartame very quickly, while the human's liver destroys the phenylalanine much more slowly. The predominant effect of aspartame on the human's brain is likely to be an increase in its phenylalanine levels; the predominant effect on the rat's brain has been shown to be an increase in its levels of tyrosine, another amino acid that is formed when the liver metabolizes phenylalanine.) Hence, while it seems likely that aspartame, in doses of sufficient size, will affect brain functions and behavior in people, the precise nature of its effects cannot necessarily be predicted using data from experiments on rats. It is necessary also to do functional and behavioral studies on people, - normal people; people with metabolic disorders that impair their ability to emtabolize phenyalalnine; and people with brain disorders that might sensitize them to whatever changes in brain chemistry the aspartame might produce." Dr. Leibovitz states: "More recently, a New England Journal of Medicine article reported that diets high in aspartame (38 mg/kg body weight) were without effect on children's behavior or cognitive function (Wolraich 1994). This dose translates to about 2,800 mg of aspartame -- a hugh amount!" There have been a number of experiments on aspartame and behavior and most of them have been abyssmal. This is in part because the researchers do not understand the science of aspartame well enough to know that it is the long-term effects that tend to be more pronounced and problematic. Wolraich (1994) tested the behavioral effects of three weeks of sucrose (sugar), three weeks of saccharine, and three weeks of aspartame (38 mg/kg) on 23 children (ages 6-10) who reportedly reacted adversely to sugar and 25 normal preschool children (ages 3-5). A dietician prepared the menus adding the sweeteners to the food. All of the diets were free of additives, artificial food coloring, and preservatives. There were no statisitcal difference in the majority of behavioral measurements in any of the groups (aspartame, sucrose, saccharine). Flaws ----i. Three weeks is hardy enough time to judge the behavioral effects from aspartame, especially if it is the slow changes in brain chemistry that cause those behavioral changes. As Dr. Roberts (1988) discovered, serious adverse reactions to aspartame do not occur immediately,

but usually take weeks or months of ingestion. For this reason alone, the aspartame part of the experiment is questionable, at best. It is my opinion that most, "normal" children would tend to be less susceptible than "normal" adults because they likely have not spent as many years slowly damaging their health by eating a poor diet, (i.e., high-fat, high-junkfood) and/or living an unhealthy lifestyle. Therefore, a longer testing period is required for children. The testing period in this experiment was not long enough for most subjects, especially those without a history of regularly ingesting aspartame. ii. Susceptible individuals were not used as test subjects. The fact that 23 of the test subjects reportedly react to sugar has no bearing on their susceptibility to aspartame. It is that susceptibility which would determine the length of time before health problems appear and would also determine the type and severity of those health problems. iii. All of the additives and preservatives were removed from the food and the children were provided with what may have been a more healthy diet other than the junky or dangerous sweeteners. If the sweeteners had any negative behavioral effects, they were likely offset by the significant change in the diet. Food additives, preservatives, and coloring can cause allergic and intolerance reactions and lead to behavioral changes as reported by Crook (1994) and Brenner (1994). This flaw raises significant doubts about the way this study was conducted. Kruesi (1987) tested aspartame in only a single-dose administration (30 mg/kg) before measuring behavioral parameters in non-susceptible children. This study is obviously much too short to determine much of anything. Saravis (1990) tested a single dose of aspartame (34 mg/kg) plus a carbohydrate (polycose) on the learning and behavior of children who were in good health and had not reported food allergies, learning, behavioral, or emotional disorders. Again, this length of experiment might be useful to measure the effects of amphetamines, but certainly not for testing the safety of aspartame. A number of other studies on aspartame and behavior also used extremely short testing periods and often used very low doses (Wolraich 1985, Ferguson 1986, Goldman 1984, Milich 1986, Lieberman 1988). On the other hand, Spiers (1988) found that by administering 50 mg/kg doses (the FDA Acceptable Daily Intake limit) to five subjects and placebos to five controls in a blinded pilot study for 12 days, that two of the aspartame-exposed subjects became irritable and anxious. None of the controls had this reaction. In addition, three of the five aspartameexposed subjects reported at least two of the following adverse effects: focal pains, autonomic symptoms, nausea,

lightheadedness, sleep disruption, frontal headaches, photophobia, and visual disturbances. Finally, there were significant differences between the placebo and aspartame group in the more active tests such as word reading and "Think Fast." This pilot study differed from the other studies in that it recruited subjects who had a history of ingesting at least two to three cans of diet soda per day. The study that Spiers (1988) had intended for more susceptible individuals has apparently never been performed. Eventually, he took part in a another short study on healthy subjects (which will be discussed later) that was presented at an industry conference (Spiers 1993b). A more recent industry study on aspartame and behavior, Shaywitz (1994), will also be discussed in a later section. Phenylalnine and Pregnancy -------------------------Given the fact that regular ingestion of aspartame can constantly spike the plasma phenylalanine and significantly increase the phenylalanine/LNAA ratio, I find it hard to understand how anyone can support its use during pregnancy. Methanol, aspartic acid, and DKP are also major concerns when discussing the intake of aspartame in pregnancy, but we will limit our discussion here to phenylalanine and pregnancy. The levels of phenylalanine in the brain of a developing fetus will be concentrated many times over that found in the mother's blood plasma. Here are the thoughts of two experts who testified before the U.S. Congress in 1987 (Elsas 1987; Pardridge 1987): Louis J. Elsas, II, M.D., Director, Division of Medical Genetics ---------------------------"I have no previous contact with this type of hearing. But that is probably appropriate because I am a pediatrician, a Professor of Pediatrics at Emory, and have spent 25 years in the biomedical sciences, trying to prevent mental retardation and birth defects caused by excess phenylalanine ..... "First of all, in the developing fetus -- a situation not considered previously -- the mother is supplying that fetus with nutrients. And if she were dieting, let's say, and increasing her blood phenylalanine uniquely by taking Crystal Lite or Kool Aid, or any of the various diet foods now, to maintain her weight, and increased her blood phenylalanine from its normal 50 to 150 umoles/liter by chronic ingestion at 35 milligrames of aspartame per kilo per day -- which everyone agrees could be reached -- the placenta will concentrate her blood phenylalanine two-fold. So the fetal blood circulation to her baby in utero, is now 300 umole per liter of phenylalanine. The fetal brain then, as Dr.

Pardridge will tell you, will increase further that concentration into the brain cells of that baby two- to four-fold. Those are neurotoxic levels in tissue culture and in many other circumstances. "This situation has not been studied in man. We have no research efforts in place to actively survey a cohort group, to find out whether chronic aspartame ingestion is adversely affecting our newborn population, either by producing microencephaly, mental retardation, or other birth defects that are associated with rises in blood phenylalanine. So that is one very worrisome area." His recommendations were as follows: "1) Immediate quantitative labeling of all aspartame-containing foods, so the consumer will know how much phenylalanine he/she is ingesting. 2) Declare an immediate moratorium on addition of aspartame to more foods and remove it from all low-protein beverages, foods,and children's medications. 3) Provide funds not controlled by industry to: a) Allow active surveillance for potential side-effects of aspartame on newborns whose mothers dieted with NutraSweet (Aspartame)-containing foods. b) Allow active evaluation of other users whose complaints cannot be adequately studied at present. c) Clarify the dose relationship and mechanisms by which L-phenylalanine affects human brain function. William M. Pardridge, M.D. Professor of Medicine --------------------"I am a Professor of Medicine at the University of California, a practicing endocrinologist, and I have been doing neuroscience research on the bloodbrain barrier transport of phenylalanine and other substances since 1970 ..... "...the third question that must now be addressed is, are there any untoward effects on the human brain that are associated with a four-fold increase in phenylalanine, bearing in mind that this molecule is a know neurotoxin? And three studies come to mind. One study shows that when blood phenylalanine in pregnant mothers is

increased five-fold [to ~250 umole/l], there is a 10-point drop inthe I.Q. of the baby born of that mother. "A second study shows that if you measure choice reaction time, a test of higher cognitive function in humans, that when their blood phenylalanine is increased six-fold, there is a 10 percent shift in your ability to make a key decision before a video screen. "And a more recent study by Dr. Elsas has shown that there are quantitative changes in the human electroencephalogram when the blood phenylalanine is raised three-fold [to ~150-200 umole/l] -something that clearly will happen in children who consume near 5 servings per 50-pound body weight." Levy (1994) found that plasma phenylalanine levels of around 400 umol/L in patients with mild hyperphenylalaninaemia were associated with a slightly lower birth measurements and offspring IQ than lower plasma phenylalanine measurements. However, Levy (1994) did not found any additional fetal loss, congenital heart disease or severe non-cardiac anomalies when compared to the control group. (Of course, these subjects were not ingesting methanol, aspartic acid, or DKP.) Smith (1995) pointed out that for every 100 umol/L rise in plasma phenylalanine levels, there is a clinically important change. Levy (1995) concurred that there is not a threshold level at 400 umol/L plasma phenylalanine. Given the lack of historical use of aspartame (unlike foods) and the lack of scientific information showing that constantly spiking the levels of plasma phenylalanine levels is okay for expectant mothers and developing fetuses, I would strongly recommend pregnant women stay away from aspartame. In addition, it is not clear what damage might occur from regular exposure to methanol, high levels of aspartic acid, and DKP. Phenylalnine and Other Conditions --------------------------------a. Parkinson's Disease Levodopa, a hypotensive agent used in treating Parkinson's Disease patients has a significantly reduced effect when coadministered with phenylalanine (Irwin 1992). Levodopa is an LNAA which has to compete for entry into the brain with other LNAAs such as phenylalanine. The dosage of phenylalanine in this experiment appears to be 100 mg/kg which is fairly high. Still, the changes caused by the short treatment of phenylalanine were large. Regular dosing of Parkinson's Disease patients with phenylalanine from aspartame is not a good idea. The adverse reaction reports I have received seem to indicate that aspartame increases Parkinson's tremors, significantly in many cases. An industry study (funded by ILSI), Karstaedt (1993) which claimed to show no negative effects from the ingestion of

aspartame on Parkinson's Disease patients was just a single dose study of fresh, encapsulated aspartame. Based on this single dose, the authors (unbelievably) recommended that aspartame need not be restricted in Parkinson's patients. ILSI seems to fund some of the most useless aspartame experiments I have ever seen. b. Melanoma A number of studies have found that phenylalanine-restricted diets limits the growth of melanoma in animals (Demopoulos 1966a, Jensen 1974) and in humans (Lorincz 1965, Demopoulos 1966b, Edmund 1974). However, a result which conflicts with previous human studies was found by Lawson (1985). Lawson (1985) restricted dietary phenylalanine levels to 8 mg/kg for 60 days in four advanced cancer (melanoma) patients. He did not find a positive effect. Since then, however, further animal studies have shown that limiting phenylalanine and tyrosine supresses the metastasis of melanoma (Elstad 1990). Since the ingestion of aspartame increases the plasma phenylalanine to very high levels in many cases, it would seem absurd to not recommend against the use of aspartame in melanoma patients. In addition, one wonders whether constantly spiking the plasma phenylalanine levels would, in some cases, cause the initial cancerous melanoma cells to metastasize more quickly such that melanoma might develop in cases where the immune system would normally have prevented it. Since 1983, not long after the approval of aspartame, there has been a significant and steady rise in in the ageadjusted incidence of melanoma in all susceptible age groups in the United States (Devesa 1995, Elder 1995). The melanoma incidence rates in whites (the most susceptible population group) rose from the 1973-1977 years to the 1983-1987 years 91% in Detroit, 63% in Utah, 55% in Iowa, 54% in New Mexico, 44% in Connecticut, 43% in Hawaii, 42% in San Francisco, 32% in Seattle, and 25% in Atlanta (Elder 1995). Conclusion ---------There has yet to be any quality, medium- or long-term tests (i.e., more than 3 months) on the negative effects of aspartame. The large majority of tests have been supported by NutraSweet or ILSI and appear to be deliberately designed to avoid finding negative effects. At least a couple of independent investigators have agreed that some people at NutraSweet and at least some (if not all) of their funded researchers have no interest in investigating aspartame's toxicity (Wurtman 1987, page 341 of US Senate 1987, Kulczycki 1995, Samuels 1995a). A good beginning to a quality experiment on the phenylalanine aspects of aspartame would have the following points: - Conducted independently of NutraSweet researchers. In other words, no input or involvment of their researchers.

- At least six months long, but preferably one or two years. - Start with tests on the most vulnerable such as those with behavioral problems, schizophrenia, psychosis, severe depression, etc. Negative effects in this population will likely show up sooner. - Use real-world aspartame products after creating a taste mask that in no way interferes with any of the aspartame metabolites. NutraSweet and their researchers should have no part in creating this taste mask and extensive biochemical tests should confirm no significant changes in the metabolism of aspartame when the taste mask is used. - The FDA Acceptable Daily Intake (ADI) level of aspartame should be use. - No other changes in diet such as removing additives and preservatives. - Biochemical measurements should be made on phenylalanine levels as well as other metabolites. Measurements of plasma, erythrocytes, and cerebrospinal fluid (CSF) for amino acids, amino acid metabolites, methanol, and methanol metabolites should be made. In other words, it is important to not just look at the plasma; CSF amino acid level changes seems to occur in some chronic illnesses and may be very important. Measurements should occur at the proper times as determined by independent pilot studies. This type of quality, common sense testing is absolutely essential before a potentially dangerous product such as aspartame is pushed on millions of people, especially considering all of the extremely serious chronic health problems that appear to be caused by its use.

9. Other Potentially Dangerous Chemicals The FDA's decision to allow the sale of aspartame in tea beverages and baked goods means that there is a much greater liklihood that racemized amino acids will form during the preparation (Boehm 1984, Bada 1987, Gaines 1987). The amount of racemized amino acids ingested by a person who regular eats these cooked products may far exceed that obtain from normal cooked foods (Boehm 1984, Man 1987a) While it is not expected that most aspartame ingesters will regularly heat aspartame products to high temperature, it is very possible that many people will do just that. The effects of ingesting significant quantities of D-aspartic acid for a lifetime are not well known. Man (1983) showed that D-Aspartic acid accumulates in the white matter of the brain as a person ages. Man (1987b) showed that the ratio between the levels of D-Aspartic acid in the grey matter and the white matter of the brain are

approximately the same in normal persons and patients with Parkinson's, MS, and Alzheimer's Disease. However, Fisher (1991) showed that the levels of free D-Aspartic acid in the white matter of Alheimer's patients are approximately twice the level found in healthy individuals. He also noted that Dalanine was found at approximately twice the normal level in the gray matter of Alzheimer's patients. Since Alzheimer's patients (and many others) can have damaged blood brain barriers, it is possible that a significant increase in dietary D-Aspartic acid could lead to an increase of free D-aspartic acid in the white matter of the brain. There may be significant adverse health consequences from the long-term ingestion of heated aspartame products due to the increase concentration of free D-aspartic acid. This may be especially worrisome for Alzheimer's patients. This is an area which has not been investigated.

10. Cumulative and Synergistic Reactions Monsanto/NutraSweet is fond of addressing the safety of each individual breakdown product separately from the other breakdown products. While it is important to consider the breakdown products separately, it is equally important to consider combinations of breakdown products that could damage a person's health when ingested over a long period of time. Three types of cumulative or synergistic situations need to be looked at very carefully when addressing the "safety" of aspartame: a. Breakdown products which, when acting together, have a much more damaging effect than the sum of the two effects when these breakdown products are taken separately. The experiment by Ershoff (1976) discussed earlier showed just how damaging certain chemicals can be when given in combination. One combination which may prove to be one of the significant problems with aspartame is methanol and aspartic acid. Methanol breaks down into formaldehyde. Aspartic acid is an excitatory amino acid. In animal experiments, formaldehyde solutions are used to induce tissue injury causing neurons with N-methyl-D-aspartate (NMDA) receptors to fire for a prolonged period (Haley 1990, Coderre 1992). The neural responses were enhanced in the Coderre (1992) experiment by the pretreatment with L-glutamic acid and L-aspartic acid. Therefore, it is possible that damage caused by formaldehyde or formic acid may cause neurons with NMDA receptors to fire for a prolonged period of time. This negative effect is enhanced by the administration of an excitatory amino acid. Also, neurons damaged by formaldehyde or formic acid may be much more susceptible to excitotory amino acid damage. b. Certain breakdown products may have a cumulative effect such that slight or moderate damage or biochemical

change caused by each breakdown product may add up to major damage over time. For example, methanol, aspartic acid, and phenylalanine have all been shown to cause vision damage in animals at some level. It is possible that methanol is not the only breakdown products from aspartame that is causing vision damage in some aspartame ingesters. It may be the cumulative damage caused by two or three of the breakdown products. c. Years of exposure to the damaging effects of aspartame breakdown products are very likely to cause one to become more susceptible to a variety of chronic illnesses. This is the cumulative negative effect from aspartame plus other non-aspartame causes. Years of very gradual damage to the unprotected areas of the brain by aspartic acid, very gradual changes in brain chemistry from phenylalanine, gradual damage to the immune system and the nervous system from methanol, and other possible damage from other breakdown products are bound to set a person up for a wide variety of chronic health problems five, 10, 20, or 50 years later. It would be almost impossible to trace these problems back to aspartame on an individual basis because a) the primary cause of the disease may not have been aspartame, and b) eliminating aspartame may not necessarily cure the illness because the internal damage is done and the aspartame was just the (or one of the) "set-ups" for the disease, but not the primary cause (at least for this example). Wellcontrolled, independent epidemiological studies of randomly-selected, long-term (5+ years) aspartame users (10 mg/kg/day or more) looking at all adverse reactions may be helpful.

11. Other Research Cited Dr. Leibovitz states: "Similarly, memory loss is unaffected by aspartame, as recently noted by Dr. Robert Moser at the University of New Mexico School of Medicine (Moser 1994). In his Journal of the American Medical Association letter, he stated that, 'Based on the results of these studies, there is no scientific basis to believe that aspartame causes adverse experiences, including neurobehavioral disorders and memory loss.'" What Dr. Leibovitz neglected to say was that Dr. Moser has been a consultant for NutraSweet for many years (Moser 1994) and was the former editor of the Journal of the American Medical Association (Roberts 1992). He spends much of his time defending aspartame for the NutraSweet Company. Memory loss would be caused by medium-term or long-term, regular use of aspartame in persons who are suceptible to that condition. Dr. Moser neglects to mention that almost all of NutraSweet's studies are so short (i.e., one day) that they can't possibly determine anything. Whether short

or long, they are hopelessly flawed as described throughout this document.

12. Scientific Research or Public Relations? The manufacturer of aspartame, Monsanto/NutraSweet, has literally flooded the scientific community with fatally flawed "scientific" studies. The number of studies are in the hundreds. Unfortunately, the trickle of a few independent studies per year gets lost in the NutraSweetpropogated "research." The company literally controls the "scientific" opinion of aspartame (much the same way the Glutmate Association controls scientific opinion on MSG and food-based excitotoxins) since it can afford to fund 10 flawed studies to "disprove" every single study by an independent researcher who finds problems with aspartame. There is almost no money available for independent researchers to perform studies despite researchers pleading to the U.S. Congress for money to study aspartame. Here's an excerpt that discusses this issue (Lisa 1994): Dr. Richard Wurtman, Director of the Clinical Research Center and Professor at Massachusetts Institute of Technology, in April 1988 urged the FDA to issue warnings to physicians that aspartame may be associated with a syndrome including severe headaches, and in some cases, grand mal seizures. Wurtman had received over 1,000 complaints at M.I.T. directly into his department . . . . . Wurtman tried for over a year to get support for his research [to study aspartame and seizures], to no avail. He said, "The present system, in which the companies that sell our synthetic foods--like NutraSweet--fund virtually all of the studies, FDAmandated or not...is too vulnerable to misuse...when outside investigators propose studies that might yield the 'wrong' answer, a large bag of 'dirty tricks' is available for derailing those studies." Looking at the NIH Current Research Information System (CRISP), one can see that in 1995, there are essentially no indenpendent studies on the health effects of aspartame. The chance of NIH funding an independent study on aspartame (or MSG) are almost zero. The chance of getting funding for a quality, long-term study (i.e., over one year) is zero. Therefore, based upon the horrendous quality of studies put out by industry researchers as discussed in this document and upon the lack of independent studies, we are at the mercy of whatever NutraSweet wants to convince us about aspartame. Researchers are continuing to put out badly flawed studies such as: 1. Stokes (1991) and Stokes (1994) published studies

purporting to show that aspartame had no effect on the cognitive performance of pilots. Selected Flaws -------------a. The 1991 study was only a single dose study. No one is suggesting that a single dose of aspartame in a lifetime is going to lead to major brain chemistry changes. Unfortunately, many industry experiments are worthless single-day studies when the major concern is the ingestion of aspartame for months and years. This is especially the case when considering the phenylalanine from aspartame since it is believed by some researchers to cause a gradual change in brain chemistry. The 1994 study was slightly better in this regard, but still only 9 days long. This can hardy be regarded as "chronic" aspartame dosing. I would not even consider it a medium length experiment. It is closer to an acute dosing study. On the other hand, if it didn't have all of the major flaws discussed below, it might be an acceptable acute dosing study. b. The aspartame was given in capsules. This was a particularly bad mistake. Stegink (1987a) showed the major differences between ingesting aspartame in liquid form and in capsules. The plasma phenylalanine spikes to extremely high levels when ingesting aspartame in liquids, but the spike is much lower when ingested in capsules. Since the hypothesis involved the concern for spiking the plasma phenylalanine levels, this mistake, by itself, renders this test questionable at best, and probably worthless. c. The tests given the pilots started 45 minutes after aspartame capsule ingestion. The Stegink (1987a) experiment cited above shows that plasma phenylalanine levels do not peak (using capsules) until 123 minutes (average) and it takes as much as 240 minutes until it peaks in some persons. In addition, simply because the plasma phenylalanine level has peaked, does not mean that enough time has passed for a) small changes in brain chemistry to take place and b) slight changes in neurotransmission (from the single dose of aspartame). d. Substances were given with aspartame that are likely to reduce any possible biochemical changes and toxicity from the aspartate and the methanol. The aspartame was mixed with orange juice which would help prevent any problems from low-level methanol effects such as that shown in Cook (1991). One hypothesis (discussed earlier in the Methanol section) presented by Dr. Phil Moskal is that the high altitude may potential the negative effects of methanol from aspartame, causing it to bind to hemoglobin (like carbon monoxide) and thereby inducing hypoxia (Moskal 1990, Stoddard 1994). A small amount of sweet product was given with the aspartame and orange juice, allegedly to increase the phenylalanine/LNAA ratio. The sweetener would likely

cause some or all of the aspartic acid to be converted to alanine before absorption. Therefore, two of the three major constituents of aspartame (methanol and aspartic acid) were not even being tested! e. Fresh aspartame was used, eliminating the possibility that DKP, beta-aspartame, or other breakdown products might cause or contribute to a degradation of pilot cognitive performance. Therefore, these protocol designs carefully eliminated any possibility of problems with aspartame's breakdown products. The protocols seemed to be designed to avoid finding problems with aspartame. f. The study was funded by two organizations that have had a history of turning their backs on the dangers of aspartame -- the FDA (see history section) and the Federal Aviation Administration (FAA) (Stoddard 1995a, page 19). In fact, the Transportation Secretary under the Bush Administration was none other than Samuel Skinner, the former U.S. Attorney who negotiated and took a job with G.D. Searle's law firm while he was supposed to be preparing to present fraud cases against G.D. Searle for their aspartame pre-approval studies. In addition, Harriet Butchko of the NutraSweet Company had some unknown role in support. I find it difficult to believe that protocols could have been this poorly designed without the imput of the NutraSweet Company. Conclusion ---------It is sad to see that the FDA and the FAA would ignore the seriousness of the aspartame problem for so long and then turn around and fund protocols this poorly designed. 2. Four studies were presented at the "Aspartame: Cognitive, Behavioral, and Electrophysiological Aspects Conference" (Spiers 1993a). While the introductory paragraph claimed that the studies were conducted by "independent" investigators, that was definately not the case. Three of the four studies (De Sonneville 1993, Benninger 1993a, and Shaywitz 1993) had researchers who have conducted flawed research funded by the NutraSweet Company (e.g., Trefz 1994, Shaywitz 1994b). The Trefz (1994) study involved the same exact set of investigators (Trefz, de Sonneville, Matthis, Benninger, Lanz-Englert, and Bickel), had the same protocol as the combination of the de Sonneville (1993) and Benninger (1993a) studies, and appeared to have been conducted around the same time period! The Trefz (1994) study was funded in part by the NutraSweet Company. How these researchers could be considered "independent" investigators is beyond me. The Shaywitz (1994b) study also involved the same exact investigators as their purportedly "independent" investigation presented at this conference, Shaywitz (1993) (B.A. Shaywitz, C. Sullivan, Anderson, Gillespie, B. Sullivan, S. Shaywitz). The protocol for boths studies appears to be the same. The Shaywitz (1994b)

study was funded by the NutraSweet Company. I suspect that the abstracts presented at this conference from "independent" researchers were from studies funded by the NutraSweet Company and published in full form at a later date. It seems clear that some researchers who get their money from the NutraSweet Company are attempting to convince people that they are "independent" researchers. Without going into detail about each study, which might be impossible anyhow since they were only published in abstract form, they seem to repeat many of the same standard aspartame industry experimental errors discussed throughout this document. It is very disappointing that Paul Spiers and Richard Wurtman conducted such a short study on relatively healthy individuals using what appears to be (as far as I can determine) capsule administration of fresh aspartame. It is even more disappointing that these individuals would pretend that the research presented at this conference was "independent" when, in fact, it was performed by industry-supported researchers. 3. Trefz (1994) published a study testing neuropsychological and biochemical responses to aspartame in heterozygotes for phenylketonuria. Fortyeight adult subjects were given either 15 or 45 mg/kg/day of aspartame or placebo for 12 weeks. The researchers found no difference in EEG analyses, urinary organic acid concentrations, or adverse experiences between the aspartame and placebo periods. Selected Flaws -------------a. The aspartame was given in capsules. Once again, as shown in Stegink (1987a), this significantly reduced the spikes on plasma amino acid levels. This is obviously one reason that the plasma phenylalanine measurements showed no change at 15 mg/kg/day and only a minor change at 45 mg/kg/day. It is hard to believe that these NutraSweet-funded investigators did not know of this fact. b. "Coincidentally," the aspartame doses mealtime (7 a.m, 1 p.m., and 7 p.m.). reduce the spikes in the plasma amino lessen the toxicity from the methanol protocol seemingly designed to reduce were given near This would further acid levels and (Posner 1975). A reactions.

c. Fresh aspartame was used. So much for testing breakdown products! d. The phenylalanine measurements were taken at 1 and 3 hours after dosing. Stegink (1987a) showed that while the time for phenylalanine to reach its peak varies considerably, the average time when aspartame was taken with capsules is 123 minutes or ~ 2 hours. Therefore, the investigators took the measurements at the wrong

time further contributing to an apparent lower spike in phenylalanine levels. e. Averages measurements for all of the subjects were presented a each time period. This is a common NutraSweet flaw discussed earlier in this document. f. The dosages given was very low in one group and barely passable in the other group (45 mg/kg/day). The researchers cite Butchko's ridiculous review of aspartame consumption surveys to claim that the study tested 20 times the average intake. g. The length of the study was only 12 weeks. Had the other major flaws not been part of the protocol (and real indepedent investigators conducted the study), 12 weeks may have just barely been long enough to notice significant neuropsychological effects from aspartame ingestion. 4. Shaywitz (1994b) conducted an experiment to test the effects of aspartame on children with Attention Deficit Disorder (ADD). Aspartame capsules containing approximately 34 mg/kg/day of aspartame were given to children each morning in either week 1 or 2 and week 3 or 4 of the study. No significant difference was found between the aspartame and placebo weeks except for a small difference in the activity category. Selected Flaws -------------a. The aspartame was given in capsules. Once again, as shown in Stegink (1987a), this significantly reduced the spikes on plasma amino acid levels. This is obviously one reason that the plasma phenylalanine measurements showed only a moderate change 1 hour after aspartame administration. b. "Coincidentally," the aspartame doses were given near mealtime (i.e., breakfast). This would further reduce the spikes in the plasma amino acid levels and lessen the toxicity from the methanol (Posner 1975). Another protocol seemingly designed to reduce reactions. c. Fresh aspartame was used. So much for testing breakdown products! d. The methanol testing was reprehensible at best. The outdated methanol test that was used had no possibility of finding changes in blood methanol levels. Researchers who are actually interested in looking for such changes (e.g., Cook 1991, d'Alessandro 1994) use proper tests that are sensitive enough to find such changes. e. The blood was drawn at improper times to test for high levels of formate -- 1 hour, 2 hours, and 24 hours after aspartame administration -- rather than 12 to 16 hours after administration. The timing of this formate test was far worse than the aspartame industry's earlier

studies. f. The phenylalanine measurement was taken at 1 hour after dosing. Stegink (1987a) showed that while the time for phenylalanine to reach its peak varies considerably, the average time when aspartame was taken with capsules is 123 minutes or ~ 2 hours. Therefore, the investigators took the measurements at the wrong time further contributing to an apparent lower spike in phenylalanine levels. g. Averages measurements for all of the subjects were presented a each time period. This is a common NutraSweet flaw discussed earlier in this document. h. The dosages given was too low considering that Frey (1976) showed that children, due to their low body weight, can ingest as much as 76 mg/kg/day of aspartame. The researchers cite Butchko's ridiculous review of aspartame consumption surveys to claim that the study tested 10 times the average intake. i. The length of the study was only 2 weeks (on aspartame). Had the other major flaws not been part of the protocol (and real indepedent investigators conducted the study), 2 weeks would probably still be much too short to notice major differences in the aspartame and placebo group. From time to time researchers for the NutraSweet Company will publish "reviews" of the scientific literature, always concluding by proclaiming the "safety" and "harmlessness" of aspartame. 1. Fernstrom (1994) published a review in the Journal of the American Dietetic Association where he discussed both the MSG and aspartame issue. Selected Flaws -------------a. Dr. Fernstrom did not divulge is strong ties to the aspartame and MSG industries thereby conning unsuspecting dieticians into believing that he was performing an unbiased review. b. Dr. Fernstrom had the nerve to cite the Reynolds (1976), Reynolds Stegink (1975), and Reynolds (1980) studies on the lack of effects of glutamate and aspartate on monkeys even though these studies were hopelessly flawed at best and bordered on fraud at worst as discussed in an earlier section of this document. He must have known the problems with these studies as 1) he participated in an MSG industry workshop three years earlier (MSG 1994) where some of the problems were discussed; and 2) Dr. Olney had submitted his statement to FASEB outlining these problems in 1993, one year before this publication (Olney 1993). c. Dr. Fernstrom neglected to point out that a couple

of industry studies have shown a significant increase in plasma aspartate after administration of aspartame (see Stegink 1987a, for example), but instead, pointed to a study which is likely flawed. d. Dr. Fernstrom neglected to point out that numerous industry studies have shown enormous increases in plasma glutamate levels when MSG was taken with water, broth, soup, or food. He simply cited a single study which did not find such an enormous increase most likely because of flaws. e. Dr. Fernstrom states that "aspartame ingestion has been found to produce no adverse effects" even though almost all independent research has shown that aspartame does produce adverse effects as discussed earlier. 1. Lajtha (1994) put together a work of art (NutraSweet PR) which would convince almost any uninformed scientist that aspartame is safe. Unfortunately, the whole review is based on flawed studies, half-truths and totally inaccurate information. Selected Flaws -------------a. Methanol i. Lajtha cites a NutraSweet study claiming that methanol is three times more prevelent in fruit juices than in aspartame even though he also cites Monte (1985) which points out the flaws in that argument and which lists more recent research showing several times less methanol in fruit juices.

ii. Lajtha tries to confuse the issue by comparing methanol doses required for severe acute poisoning to methanol from aspartame ingestion even though slow, chronic toxicity from methanol is the issue. Chronic toxicity from methanol, formaldehyde and formic acid has been discussed in the scientific literature, but this is rarely, if ever, mentioned by NutraSweet researchers. iii. Lajtha cites single-dose experiments to back up his claim that blood formate is not raised from aspartame ingestion. He neglects to mention that 1) a tiny number of subjects were tested, 2) average values at each time period were used, 3) formate measurements were not made at an appropriate time as discussed in Liesivouri (1986), 4) in many cases a single dose would not raise blood formate levels significantly, but regular doses would as seen in methanol and formadehyde experiments, 5) formic acid can accumulate in the organs, 6) the average base formate levels for the aspartame subjects was suspiciously high and probably helped prevent a significant increase from the single exposure, and 7) the aspartame was often given with gruit juice which may reduce the absorption of methanol and/or prevent

or delay the conversion of methanol to formaldehyde. iv. Lajtha cites four studies which he claims show no increase in plasma methanol levels at a dose of 2/3 the FDA Allowable Daily Intake. The methanol tests he cited represent incompetance at best (as discussed in the methanol section) or scientific fraud at worst, since an inappropriate testing procedure was used. v. Lajtha admits that as little as 8% of the FDA Allowable Daily Intake of aspartame led to a statistically significant increase in blood methanol. He passed it off as being with the "normal" range of individual variation. But one person's "normal" range may be dangerous to another person over time. It is difficult to understand how Lajtha can believe that small doses increase plasma methanol levels, yet larger doses cause no change.

vi. Lajtha claims that an extremely high blood methanol concentration is required for measurable formate formation even though single-dose experiments of aspartame have shown measurable formate formation (excreted through the urine) at blood methanol levels many times less than he claims. In addition, continuous environmental exposure to low levels of methanol or formaldehyde raises formate levels significantly as discussed in the Methanol section. He also neglects to consider that symptoms from chronic methanol exposure may be caused by different mechanisms than the severe acidosis which is present in acute poisoning. b. Aspartic Acid i. Lajtha mentions that the blood brain barrier (BBB) excludes excess aspartate, but neglects to focus the discussion on the areas of the brain unprotected by the BBB which are extremely sensitive to excitatory amino acids. He also neglects to mention that the BBB can be damaged in a number of diseases and that the infant BBB may not be fully formed.

ii. Lajtha mentions the dosages at which aspartic acid causes brain lesions in rodents. He neglects to mention that humans concentrate glutamate 5 times more than rodents in their blood and the same is expected with aspartate. This would decrease these values by a factor of five. He also neglects to mention that at 1/4 the toxic doses, significant changes in hormone output has been seen. Finally, he neglects to mention that these are single-dose studies and the regular ingestion of months or years -- constantly spiking the aspartic acid levels -- may be causing gradual damage, especially when one considers the cumulative effects of aspartic acid plus glutamic acid (MSG). iii. Lajtha uses a couple of experiments purporting to show the lack of increase in plasma glutamate and

aspartate after ingesting MSG or aspartame. He neglects to mention that there are a number of studies showing large increases in plasma glutamate after ingesting MSG with water, soup, or meals, and that there are several aspartame studies showing a significant increase in plasma aspartate. In particular, the Stegink (1987a) study showed an increase in plasma aspartate as much as 18 times that of the baseline measurement from a single dose. iv. The experiment conducted purporting to show that aspartic acid cannot cross the placental barrier was done in the third trimester when the barrier tends to be more impervious to free amino acids. Several studies have demonstrated that excitotoxic amino acids can cross the placental barrier as discussed in the Aspartic Acid section. d. Phenylalanine i. Lajtha confuses the issue of ingesting free phenylalanine in aspartame by using phenyalalnine in foods as a comparison. Phenyalalnine in aspartame spikes the plasma phenyalalnine to high levels, unlike when a high protein meal is ingested.

ii. Lajtha seems to be attempting to demonstrate the ability of the brain to tolerate higher concentrations of phenylalanine by pointing out that some areas of the brain have much higher concentrations than other areas. The problem is that areas of the brain have certain concentrations for a reason. Raising the concentration of phenylalanine in an area that is supposed to have a low concentration is not necessarily safe and almost certainly not health-building. iii. Lajtha cites studies where encapsulated aspartame was used (and where averages at each time period were the only values presented) to discuss plasma phenyalalnine. He ignored Stegink (1987a) and Matalon (1988) where realistic amounts of liquid aspartame spiked plasma phenylalanine to extremely high levels. This renders his whole discussion based on plasma phenylalanine and doses required to obtain these levels flawed and pointless. iv. Lajtha cites the absurd Hjelle (1992) NutraSweet study attempting to convince readers that it takes only two to six times the dose of phenylalanine in rats to obtain a similar effect as occurs in humans. The reality is that independent researchers have found that it takes at least 60 times the dose in rats to cause a similar change in plasma phenylalanine/LNAA ratio as occurs in humans. v. Lajtha cites the Koeppe (1991) study which showed a slight decrease in blood brain barrier amino acid transport rates after the administration of 34 mg/kg of aspartame. Lajtha states that there will be

"little measureable transport change" at levels "under average (50th percentile) dietary use." He neglects to mention that, in reality, the equivalent of approximately a dose of 17 mg/kg was tested (as discussed in the Phenyalalnine section). Also, it is a gradual change in brain chemistry which causes extreme concern. vi. Lajtha cites a number of low-dose studies in rats showing no effect of aspartame on monoamine levels of the brain. He neglected to mention that independent studies using a more appropriate dose and looking at certain specific brain areas found changes in levels of monoamines (Coulombe 1986, During 1988). e. DKP i. Lajtha states that DKP is metabolized in the gut to aspartic acid, but then later admits that 5% is excreted in the urine and the rest is "probably metabolized." It is clear that no one is sure what happens to the DKP and wishful speculation does not equate to food safety.

ii. Lajtha claims that the 90th percentile consumption of DKP is 0.6 mg/kg/day. However, it is clear that persons consumer the FDA Allowable Daily Intake of 50 mg/kg/day of aspartame can ingest 12 mg/kg/day of DKP or more based on the Tsang (1985) study discussed earlier. f. Aspartame Dosages i. Lajtha uses the same laughable "surveys" discussed in an earlier section to try to convince readers that a much lower dose of aspartame is being consumer than any sensible estimate would predict. He also cites a Canadian study saying that it measured "consumption in a single day," when Butchko (1994) clearly states that it was a 7-day survey. Are we to believe that Canadians went on a wild, seven-day binge of aspartame corresponding to this survey or, much more likely, the survey cited by NutraSweet researchers are flawed to the point of being worthless.

g. Pregnancy i. Lajtha points out that the maximum recommended level of plasma phenylalanine is 360 umole/liter, yet he uses flawed studies to show that aspartame doses do not raise the plasma phenylalanine to near these levels. The Stegink (1987a) and Matalon (1988) studies show that it is quite possible for even healthy women to approach this level of plasma phenylalanine. Women who are phenylketonuric heterozygoes may have even a higher risk of damaging their child. In addition, regular consumption of aspartame during pregnancy would spike the phenylalanine constantly, not just one time, causing the phenylalanine levels in the fetal brain to be

regularly spiked to extremely high levels. As discussed earlier in the Phenylalanine section, some researchers believe that smaller changes in the plasma phenylalanine levels during pregnancy have important clinical effects. ii. Lajtha obscures the concern about constantly spiking the phenylalanine level by discussing phenylalanine derived from food source. When ingesting food, the protein is broken down gradually, the phenylalanine is aborbed gradually and other Large Neutral Amino Acids (LNAAs) are absorbed along with the phenylalanine. h. Seizures i. Lajtha neglects to mention that one of the original studies on aspartame in monkeys showed that it caused seizures.

ii. Lajtha uses all of the NutraSweet-funded, flawed seizures studies (as discussed earlier) to back up the claim aspartame does not cause seizures. Independent examinations of the aspartame and seizure issue almost always show problems. Seizures are one of the most frequently reported reactions to aspartame. There are so many people who have gotten rid of their seizures by going off aspartame, that all that is lacking for final proof are real experiments from independent scientists. There are many other problems with the Lajtha review, but they are too numerous to mention here. Suffice it to say that the review is a masterful whitewash of the evidence of aspartame's danger. The food industry has formed organizations that fund flawed studies in order to convince government and private organization as well as scientists of the "safety" of their product. The International Glutamate Technical Committee (IGTC) is one such organization which funded "sutdies" that abused the scientific process as was discussed in the Aspartic Acid section. The International Life Sciences Institute (ILSI) is another such organization supported by food companies which has no interest in funding studies which have any possibility of finding problems with their supporter's products. ILSI consists of approximately 154 member companies and 12 to 14 technical committees, one of which is the Aspartame Committee (Dews 1987). The Aspartame Committee is made up of NutraSweet Company, Ajinomoto Co., Coca Cola Co., Pepsico, Inc., Royal Crown Co., Seven-Up, Inc., and six other manufacturers of aspartame-containing "food" products (Gordon 1987, page 488-489 of US Senate 1987). According to a investigation, the researcher NutraSweet and 1987 United Press International (UPI) the ILSI's Executive Director is Jack Filer, who has conducted numerous "studies" for who was found to have a conflict-of-interest

judging the "safety" of MSG while receiving money from the companies marketing the junk as discussed earlier in the Aspartic Acid section (Gordon 1987, page 486 of US Senate 1987). During the 1980s, ILSI denied funding to researchers who were independent at the time, Dr. Louis Elsas and Richard Wurtman and instead, funded researchers who had a long-standing relationship with industry groups (Elsas 1987; Gordon 1987, page 485-486, 488 of US Senate 1987). ILSIfunded studies are basically no different from the countless manufacturer-funded studies, except, judging from ILSI's aspartame studies, the protocol designs are actually worse! Industry Arguments -----------------Monsanto/NutraSweet or ILSI will fund these horribly flawed studies purporting to show the "safety" of aspartame. Soon after the study is published, a press release is pushed onto the unsuspecting media. The media then propogates the results from these flawed studies without critically examining the "information" and without discussing the design of the experiments with independent experts on the subject. As long as the study has an image of respectiability (i.e., conducted at a well-known university), the media can easily be manipulated by these big companies. The industry will argue that these studies are "peerreviewed," implying that they are examined closely by experts in the field and therefore properly conducted (Shapiro 1987, page 425-426 of US Senate 1987). First of all, almost all of the post-approval studies funded by Monsanto/NutraSweet discussed throughout this review were "peer-reviewed." These studies represent an abuse of the scientific method, yet they were still made it through "peer review" and were published. Secondly, many tobacco companies studies which also represented an abuse of science were peer reviewed. It is abundantly clear that the peer review system does not prevent deceptive and worthless studies from being published. Author Cynthia Crosen (Crossen 1994, page 178) had the following to say about the peer review system: "But the peer review system is stretched thin. The sheer volume of biomedical journals--some 15,000 journals publish about 250,000 articles a month-puts insupportable demands on the system. Peer reviewers are unpaid volunteers, and they can't take the time to scrutinize the raw data, let alone replicate the research. The specialization of medicine means the pool of people capable of doing any particular review is diminishing. Whatever the outcome of the peer review, the editor of the journal may decide to accept or reject the article for editorial or personal reasons. Scientists say that peer reviews are increasingly done by graduate students or postdoctoral fellows who do not have enough breadth of experience and that peer reviewers compete with teh authors for research money, possibly biasing their opinions. Critics also say

peer review is biased in favor of well-known professors from prestigious schools--the so-called halo effect-- and those who use 'current fashionable approaches.' And what scientist wants to break the news to another scientist that he or she has just wasted years on a poorly designed piece of research? "Even regular contributors to journals decry the state of the peer-review system. 'Despite this system, anyone who reads journals widely and critically is forced to realize that there are scarcely any bars to eventual publication,' wrote Drummond Rennie, professor of medicine at the University of California at San Francisco. 'There seems to be no study too fragmented, no hypothesis too trivial, no literature too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure and too contradictory, no analysis too self-serving, no argument to circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.'" Conclusion ---------"Corporate control of NutraSweet testing continues at Monsanto, torturing the ethics of academic medicine" (Constantine 1995). Much of the food safety research has become a no-rules, public relations playground for food companies. These companies help to fund and design hundreds of fatally flawed studies. Poorly-designed studies, guaranteed to put a particular product in a good light are certainly not limited to the aspartame and glutamate industries. These industries, however, seem to be capable of designing the most worthless and deceptive "research" which rivals some of the research done in the past by the tobacco companies.

13. The FDA Response -- Less Than Nothing The U.S. Food and Drug Administration (FDA) is the agency which is supposed to protect the country from health hazards in foods and drugs. How is it possible for the FDA to have less than no response at all to the significant health problems caused by aspartame? Had the FDA avoided the aspartame issue completely, the U.S. public and the rest of the world would have been much better off. Instead, the FDA has actively supressed information, fought against caution and independent research, banned alternatives, and generally acted like an unethical subsiderary of the Monsanto Chemical Company (owner of NutraSweet). After reading about the sordid history of aspartame (see earlier section) and the high-ranking FDA officials, U.S.

Attorneys, etc. who set aside all ethics and went to work in the aspartame industry, it is easy to see how the close relationships between these former government officials and current government officials (including those in the FDA) can lead to a situation where the FDA basically becomes and extension of industry. Shortly after the approval of aspartame, as adverse reactions began to pour in, the FDA took steps to reduce the public relations problem by trying to prevent adverse reaction reports from being submitted. We already saw how the FDA transferred victims to the AIDS hotline. In 1985, Rodney E. Leonard and James Turner, Esq. of the Community Nutrition Institute (CNI) wrote the FDA Commissioner, Dr. Frank E. Young, to report other major problems (CNI 1984): "When FDA approved in July 1983 the use of aspartame in liquids, the agency was aware of health concerns expressed both by scientists (particularly the instability of the substance in liquids) and consumers and said it would monitor complaints. "However, no monitoring program was established until February, some eight months later, after we specifically requested its July pledge. We proposed that the Centers for Disease Control be asked to make an epidemiological evaluation of the complaints, and we were subsequently informed that a monitoring program had been initiated--including a CDC evaluation. "We now have learned enough information to question whether an aspartame monitoring program ever has been, in fact, carried out by the FDA. The evidence suggests that FDA has sought to avoid the collection and analysis of complaints, and has instructed regional offices to withhold data from its Washington headquarters. "For example, FDA has informed us and others that it has received some 680 complaints that were forwarded to CDC, with the implied conclusion that this is the total number of complaints. However, in discussions with the staff in the Freedom of Information Office (FIO) at FDA, we now learn that those complaints were all received prior to February or March of this year, and do not include any complaints received subsequently. "In addition, the FIO office said that regional FDA offices had been told that only 'serious' complaints should be forwarded to FDA headquarters; and, for the guidance of regional office staff, a 'serious' complaint is one in which the illness is severe enough to require the attention of a physician. "Thus, no effort has been made since April to determine the actual extent of consumer reactions to NutraSweet, or to analyze and categorize the

complaints. In at least one regional office -located in Philadelphia -- we understand that NutraSweet complaints filed since June have not even been examined. "We also had requested FDA early this year to notify physicians the agency was monitoring complaints of adverse reactions to aspartame, or NutraSweet. We were told that FDA had no intention of inviting physicians to send in reports of complaints. This attitude now seems self-serving on the part of any agency that instructs its field offices to forward only those complaints which have been filed by individuals who sought the counsel of their physicians because of the severity of their reaction. "This also is a self-fulfilling argument for the basic FDA position that complaints about aspartame, or NutraSweet, have no pattern, and that all of them can be explained by the placebo effect--i.e., whenever any new product is introduced, it will be seized upon by the public as the source of their ailment. FDA has made no efforts to alert physicians to its need for information, but instead waits on consumers who seek medical advice about their complaints to make a special effort to alert FDA to the problem. Thus, FDA has consistently limited its knowledge as to whether a problem may or may not exist." Given that the FDA actively made an effort to limit reported adverse reactions, it becomes difficult to accept any figures that the FDA releases regarding adverse reactions to aspartame. Clearly, there has been and currently is too much conflict-of-interest for the FDA to be considered a reputable source of information about aspartame. A person might as well call up the Monsanto/NutraSweet Public Relations department and ask for information on adverse reactions! In 1984, the U.S. Centers for Disease Control (CDC) published an analysis of selected consumer adverse reaction reports to aspartame (CDC 1984). 517 cases were examined by the CDC, 199 of them were fully reviewed. The CDC found that the cases fell into four general categories: Neurological/Behavioral symptoms, Gastrointestinal symptoms, Allergy-like symptoms, and Menstrual symptoms. Most of the complaints were consumer-initiated, probably reflecting the FDA's refusal to request that physicians report adverse reactions as discussed earlier. In regards to the interpretation of the analysis, the CDC stated: "It was not anticipated that this investigation alone could definitively establish whether ingestion of aspartame-containing products did or did not cause the symptoms reported. .... Data from passive surveillance systems can, however,

indicate the possibility of an association." Twenty-eight percent (28%) of the cases that were fully reviewed showed that adverse reactions occurred on rechallenges of an aspartame-containing product. Forty-one percent (41%) of the cases had no history of attempted rechallenge. In 32% of the cases, a rechallenge did not reproduce symptoms or a physician stated that the symtpoms probably had a different etiology. Most of the cases examined in-depth occurred before aspartyame was available in carbonated beverages. What follows are a couple of sample cases from the CDC report: A 4-year-old white male had symptoms of insomnia, headache, aggressive behavior, and disorientation. His mother reported that he appeared "glassy eyed" and was "running around wildly...hitting his head against the wall," and that his speech was rapid and slurred. The symptoms first o ccurred whiled he was consuming 2-3 glasses of Kool Aid or Wyler's lemonade daily along with Halfsies cereal 3 times per week. His symptoms stopped approximately 24 hours after he stopped ingesting these products. Since this time, the child has participated in a double-blind, videotaped, observer-validated study. This study reportedly confirmed that the symptoms occur following aspartame ingestion. The symptoms have also consistently recurred on at least three occasions when the child was "accidentally" given three different foods with aspartame -- hot chocolate, bubble gum, and cookies. The child's private pediatrician, who feels that the child's symptoms are due to aspartame, reported that he has observed that the child's symptoms have become more prolonged with increased exposure to aspartame. Relevant Medical History: The child's mother reports that he is allergic to milk protein, but that he has no other allergies. --------------A 39-year-old white female complained of depression, memory loss, lethargy, irritability, dizziness, and headaches. The complainant's first use of aspartame-containing products was in March, 1983, when she began using approximately 8 packs of Equal per day. During the symptomatic interval, the complainant added other aspartamecontaining products to her diet, including Diet Coke and Kool Aid. The symptoms started in midApril and increased in number and intensity in subsequent months. The first symptom to occur was lethargy. Over the ensuing months, irritability, dizziness, depression, and memory loss occurred. She states that when she stopped using aspartame-

containing products in mid-September following a news report, the symptoms improved within 1 day and ceased within 1 week. The complainant subsequently rechallenged herself approximately 2 months later with Equal, consuming 4 packets per day for approximately 3 days. She stated that she became dizzy on the third day and that the episode was "very frightening." After these symptoms appeared she stated that she stopped consuming Equal, and approximately 24 hours later the symptoms subsided. The complainant consulted three physicians during this time. Only her family physician was available for interview, and he stated that he "had no reason to doubt the judgment of the complainant." Relevant Medical History: The patient has a past history of thyroid disease as well as a past history of migraine headaches for which she was on Valium and Cafergot at the time of the symptoms. Thyroid screen at the time of the symptoms was reported to be normal. The only other medical condition reported was an allergy to ampicillin and compazine. The CDC report concludes: "In summary, the quality and type of evidence obtained by a passive surveillance system based on consumer complaints precludes definitive determination of whether these complaints are or are not caused by the agent under question -- in this case, aspartame. .... The only way that these possibilities could be thoroughly evaluated would be through focused clinical studies." Although some of the rechallenge-confirmed adverse reactions discussed by the CDC report included seizures, cardiac arrest, severe mood swings, disorientation, extreme numbness, memory loss, liver impairment, suicidal tendancies, etc., the FDA proceeded to twist the conclusions of the CDC report, which was conducted shortly after aspartame appeared on the market, by stating (Mullarkey 1992, page 70): "In summary, currently available information, based on data with limitations as described in the report, indicated a wide variety of complaints that are generally of a mild nature. Although it may be that certain individuals have an unusual sensitivity to the product, these data do not provide evidence for the existence of serious, widespread, adverse health consequences to the use of aspartame." Beginning around 1987, FDA inspectors started visiting herb companies who were using a safe, natural, no-calorie sweetener called "stevia" and telling them to stop using it because it was an "unapproved food additive" (McCaleb 1995).

According to the Herb Research Foundation: "In one case FDA's inspector reportedly told a company president they were trying to get people to stop using stevia 'because NutraSweet complained to FDA.'" The FDA refused to supply to the Herb Research Foundation the name of the company that complained to the FDA despite a Freedom of Information Act request (McCaleb 1995). In May of 1991, the FDA banned the importation of stevia into the U.S. and began warning companies that it was an illegal herb (Import 1991). This act violated laws allowing the use of products with an extensive history of safe use. But since the FDA often has no one to answer to, it can essentially make up the rules as it sees fit, and in this case it saw fit to protect what could be called its "parent company," Monsanto/NutraSweet from competing against a safe, natural product. Stevia has been used extensively in South America for hundreds of years without any reports of adverse reactions (AHPA 1991, HRF 1993, Kinghorn 1985, Kinghorn 1992). It has been used commercially in Japan, South Korea, and other countries without any reports of adverse reactions. In fact, if has already been used for the past 20 years in Japan and has captured over 40% of the Japanese sweetener market (McCaleb 1995). Stevia is safe for all populations, and is particularly recommended by diabetics because it appears to help stabalize blood sugar levels (Kinghorn 1992). Even though Stevia has been proven safe through an extensive history of use, there have been a large number of animal studies on stevia and stevia extracts which also prove it to be extremely safe (Kinghorn 1992, AHPA 1991). Two old animal studies raised questions about stevia's safety, but since that time other studies as well as survey's have more than answered those questions (Kinghorn 1992). Despite an extensive, peer-reviewed analysis of the literature performed by plant-based sweetener expert , Dr. Douglas A. Kinghorn (Professor of Pharmacognosy and Medicinal Chemistry at the University of Illinois College of Pharmacy in Chicago) (Kinghorn 1992) proving stevia's safety, an extensive history of safe use including not a single report of an adverse reaction, a petition submitted to the FDA by the American Herbal Products Association (AHPA 1991) detailing the safety of stevia, a supplement to the AHPA petition further demonstrating stevia's safety, and the law requiring products with a history of safe use before 1958 to be automatically approved, the FDA refused to allow the importation of stevia. After rejecting the AHPA's initial petition, the FDA stated that it needed more information. When asked "how much more?" by Timothy Moley of the AHPA, the FDA responded (Blumenthal 1994): "Well, this may sound flippant, but we'll know it when we see it." On September 18, 1995, the FDA revised their import ban on

stevia to allow for the importation only in cases where it is clearly to be used as, or in a "dietary suppliment" (Import 1995). The FDA specifically disallowed stevia's use as a sweetener. This allows the FDA to avoid violating the recently-passed dietary supplement law and still allows them to protect their "client," Monsanto/NutraSweet by severely limiting the use of stevia. Food companies will not begin to use stevia in their products on a large-scale basis until they can be certain that the products will not be seized by the FDA. The enormous positive response by food companies to an article in Food Processing magazine shows that stevia would become widely used if the FDA would stop violating the law by banning its use as a sweetener (Food 1990, Johnson 1990). In 1992, scientists from the FDA Center for Food Safety and Applied Nutrition (CFSAN), performed an analysis of seizures linked to aspartame which had been reported to the FDA (Tollefson 1992). It was a blatantly skewed analysis. The author created several categories for adverse reaction reports. Group A referred to persons whose symtpoms occurred after being rechallenged by different aspartame-containing products. Group B referred to persons whose symptoms occurred after being rechallenged by the same aspartamecontaining product. Group C referred to complaints where the person did not rechallenge himself/herself. Group D referred to adverse reactions that were "highly unlikely that the reported symtpoms are associated with" aspartame. After analyzing the cases, the authors concluded: "The findings from FDA's ARMS [Adverse Reaction Monitoring System], however, do not merit a scientific study on the association between seizures in human beings and aspartame ingestion." Flaws ----i. The authors inappropriately classified subjects as "Group D" if they refused to release their medical reports. This refusal does not mean that the link to aspartame is "highly unlikely." It may mean that in these cases the link is "unknown." Therefore, any conclusions drawn from the number of cases in Group D ("highly unlikely" link to aspartame) is worthless. ii. The authors inappropriately classified subjects as "Group D" if there was any other possible contribuatory factor to the seizures. This simply means that aspartame may have caused the seizures or something else may have caused the seizures or a combination of things. If the person rechallenged themself with aspartame and still experienced seizures despite other possible causes, a categorization of Group D ("highly unlikely" link to aspartame) becomes absurd. iii. The authors made a number of other inappropriate determinations that the cases were not likely linked to aspartame. For example, occurrence of seizures months or years after stopping aspartame was categorized as Group D. However, if aspartame changes brain chemistry and

lowers the seizure threshold, it is quite possible for seizures to occur long after aspartame consumption has ceased, especially in the more severe cases. iv. The authors inappropriately declared ineligable, 35% of the non-Group D seizure victims because the seizures occured more than 13 hours after ingestion of aspartame. This is absurd because 1) it is thought that aspartame may lower the seizure threshold and therefore, aspartamecaused seizures could occur long after phenylalanine levels return to normal, 2) aspartic acid can accumulate in areas of the brain not protected by the blood brain barrier and remain there for as much as 24 hours (Inouye 1976), 3) methanol is converted to formaldehyde and formate very slowly and can remain in the blood for more than 16 hours, 4) an article immediately following this lousy analysis, Carroll (1992), points out that food reactions can be delayed up to 48 hours after ingestion. v. The authors claim that only 251 cases of seizures due to aspartame ingestion have been reported to the FDA. In reality, the FDA splits the categories into: "Seizures and Convulsions," "Grand Mal," "Petit Mal," "Complex Partial Seizures," and "Simple Partial Seizures." The 251 cases quoted by the authors referred only to the "Seizures and convulsions" category as of 1992. There have been over 500 seizures reported to the FDA (DHHS 1995) at probably a reporting rate of approximately 1%.

vi. The dicussion section listed only industry-funded research. No mention was made of the several independent studies showing adverse reactions to aspartame. For example, the poorly-conducted Schiffman (1987) headache study was cited, but the much better-conducted Koehler (1988) study was not mentioned. Summary ------The fact that so many cases were inappropriately categorized as "highly unlikely" that they were linked to aspartame, when many of them should have been categorized as "unknown" or "likely" points to the fact that the authors did not know how to properly conduct an analysis. This is frightening considering that one author is a representative of the FDA. Other inappropriate categorizations as well as citing only poorly-conducted industry research proves that this was an extremely biased analysis of the aspartame and seizure issue. This article was published in the Journal of the American Dietetic Association where, apparently, any proaspartame article can be published, no matter how absurd its reasoning. On June 12, 1995, an FDA representative was quoted as saying (Food 1995): "FDA has no further plans to continue to collect adverse reaction reports or monitor research periodically done on aspartame."

Conclusion ---------When it comes to the subject of aspartame, the FDA regularly releases inaccurate and extremely biased information to the press and the general public. The news media, foreign government agencies, and a number of organizations (many which are well-meaning), take this information, which amounts to little more than Monsanto/NutraSweet Public Relations, and passes it on to the unsuspecting public. Any statement about aspartame from the FDA should be followed with the question: "And what's the real story?" It has always appeared that the FDA wishes that all of the countless adverse reaction reports submitted by irate citizens would just go away. The FDA made considerable effort to convince the medical community and the general population that aspartame is safe. Despite this effort, there is growing evidence from independent researchers that aspartame is dangerous, especially for long-term use. The reports of very serious health problems caused or contributed to by aspartame which are being received by independent organizations are beginning to confirm this danger. These reports will not go away even if the FDA chooses to try and ignore them.

14. Public Relations Much like the tobacco companies did in the past, Monsanto/NutraSweet has not let honesty or ethics get in the way of its attempts to convince the world that a dangerous neurotoxin, aspartame, is "safe." They have spared no expense in their public relations campaign. What follows is a list of the most common public relations techniques used by Monsanto to buy public opinion. A. "Scientific" Studies --> Press Releases This technique was discussed in a previous section. I have no doubt that Monsanto/NutraSweet is preparing to release additional press releases in the guise of "scientific" studies. They know that by flooding the scientific community with deceptive and mostly irrelevant studies (much as the tobacco companies did) that they can convince the scientific community and the general public of just about anything. It is likely that Monsanto/NutraSweet will do everything in their power to create the appearance of an independent, quality study in order to offset the bad publicity from previous unethical practices and the growing number of serious adverse reactions. In order to help prevent continued abuses in this area, I have created what I feel to be the minimally acceptable protocol for research into the affects of aspartame in the next chapter. B. "Scientific" Reviews This technique was discussed in a previous section. Editors who accept these "scientific" reviews by extremely biased researchers are only promoting the abuse of the scientific

method. An enormous number of people are giving up on medical science, at least in part, because of these abuses. Many people are finding solutions to their problems by giving up aspartame and other "scientifically" accepted toxic substances and pursuing a more holistic-oriented healing approach. Medical science can play an important part in the discovery of useful healing tools and regimens in the future. But by promoting toxic products such as aspartame, the medical community is only succeeding in hastening the alienating of educated individuals and causing them to lose all faith in medical science. C. Statements from the FDA This technique was discussed in a previous section. The promotion of aspartame by the FDA gives me mixed feelings. On the one hand, the officials who are doing such promotion are responsible for the continuing development of serious health problems amongst tens of thousands of persons in the United States as well as countless thousands of people worldwide who actually believe what the FDA says is something more than Monsanto/NutraSweet PR. In addition, the FDA is responsible for the continuing the abuse of science by ignoring research abuses which, in my personal opinion, amount to scientific fraud. They are also continuing to abuse the laws of the United States by banning stevia use as a sweetener without any reasonable cause. On the other hand, by promoting toxic products such as aspartame and banning safe products, a growing number of people are realizing that the FDA, with its revolving door employment policy, is in many cases, simply a mouthpiece for industry and will do what it takes to serve its industry clients. This is causing many people to realize that accurate and helpful information can and should be found in sources other than the FDA and industry public relations departments. D. Industry Public Relations Groups The International Food Information Council (IFIC) is the Public Relations organization for the dangerous food and the junk-food industry. According to IFIC's World Wide Web homepage (as of 12/1/95) (IFIC 1995): "Formed in 1985, IFIC's programs and activities are supported by a number of leading food and beverage companies." IFIC's function is to propogate inaccurate information about dangerous and generally unhealthy food and agriculture products to healthcare professionals, reporters, educators, parents, and consumers. The information is generally based on inadequate, or often times, severely flawed "scientific" studies. Since the articles put out by IFIC sound authoritative, most individuals and even some scientists take what they say to be factual. Unfortunately, these articles are usually no more factual than articles about the "safety" of cigarettes put out by the Tobacco Institute. After all, IFIC is a group of chemical and junk-food

companies which funds their own flawed studies and tries to pass them off as "science" just like the tobacco companies did. IFIC promotes aspartame, MSG, food additives and coloring, caffeine, refined sugar, recombinant bovine growth hormone (rBGH), pesticides, and other unhealthy and dangerous products. Much of the information provided by IFIC is simply industry public relations. Some information provided is a mixture of fact and fiction. If a person really wants to eat a healthy diet, he/she would be wise to avoid the junk food promoted by IFIC and gradually move towards a natural foods diet such as described by well-known and well-respected authors such as Colbin (1979, 1986) and Ornish (1990). If a person then wants to take the healthy ideas presented in these books and add a little more meat or naturally-made snacks (from natural food stores), that would be perfectly acceptable. But the junk promoted by IFIC is simply not healthy food even if IFIC can find some scientist, somewhere in the world, to say it is. E. Throwing Large Sums of Money at Organizations Monsanto/NutraSweet gives large sums of money to organizations so that those organizations will help promote the "safety" of aspartame. In January 1993, the American Dietetic Association (ADA) Courrier published a notice that NutraSweet gave the ADA a $75,000 grant (ADA 1993). The notice went on to say that NutraSweet helps write the ADA "Fact" sheets. Monsanto/NutraSweet funds a number of organizations such as the ADA which then reciprocate by proclaiming the "safety" of aspartame despite the evidence of harm. While individual Registered Dieticians can do quality work, any information they receive from the American Dietetic Association often comes by way of a junk food company. The ADA receives funds from numerous junk food companies and then turns around and promotes these companies' products (Burros 1995). Monsanto/NutraSweet funds the American Diabetes Association (Monsanto 1995a, Martini 1995, Stoddard 1995b), the Juvinile Diabetes Association (Mosanto 1995a), and other organizations. These financiallydependent organizations then "review" the flawed research performed by Monsanto/NutraSweet and proclaim the "safety" of aspartame, adding the appearance of credibility to NutraSweet's safety arguments. F. Sponsoring Events Sometimes NutraSweet sponsors sporting events. I find nothing wrong with a company sponsoring a sporting event. However, it is extremely disappointing that an event organizer would let the maker of a neurotoxin sponsor their event. Monsanto/NutraSweet sponsored the 1994 London Marathon. I will never understand why a health-promoting sport such as marathoning would help promote a slow poison, aspartame, by letting Monsanto/NutraSweet sponsor their event. They sponsored the professional figure skating competition in Landover, Maryland on December 9, 1995. On December 14, 1995

NutraSweet sponsored the "[NutraPoison] World Challenge of Champions" figure skating event in London, England. It will be rebroadcast on ABC on January 13, March 9, and May 11, 1996. It is disheartening that such a beautiful sport would be supported by such a dangerous "food" product. Monsanto also sponsors golf and tennis tournaments (Monsanto 1995a). While some of the tournaments raise money for worthy causes, the sale of this neurotoxin does far more damage to people than their sponsorship money could ever help. In addition, since their sponsorship encourages people to ingest aspartame, it perpetuates the damage done to these people. G. Other Companies Other companies such as the soft drink manufacturers, the junk food industry, and even some suppliment manufacturers (e.g., Twin Laboratories) promote aspartame by promoting the "safety" of their product. Soft drink manufacturers are particularly amoral when it comes to addressing the major health problems caused by aspartame in food products. In 1983 the National Soft Drink Association (NSDA) drafted a document which detailed some of the dangers and potential dangers of aspartame (NSDA 1983). People have written to soft drink manufacturers detailing the terrible health damage caused by long-term ingestion of aspartame (e.g., Fitchpatrick 1995). Yet, these companies still push aspartame in the United States and are now expanding the health damage to the rest of the world. When people talk about the lack of morality in society, it is crucial to look at some business leaders who are poisoning people's health with aspartame and a wide range of dangerous and unhealthy food and environmental products. One or two "Mea culpa's" or a quick prayer in their place of worship every week cannot make up for the pain and suffering that they cause. Twin Laboratories, Inc. is a popular supplement manufacturer. Like the soft drink manufacturers, this company has received extensive documentation as to the health problems caused by aspartame (Martini 1995b). It is extremely disappointing that a company which creates an image that it sells healthy products is continuing to push aspartame even though a) it knows of the dangers, and b) there are alternatives that are available (Mayerhoff 1995). H. Government "Contributions" As was discussed in the history section, G.D. Searle, the original manufacturer of aspartame (now owned by Monsanto) was caught making "payments to employees of certain foreign governments to obtain sales of their products." (Searle 1975). Recently, a Monsanto official was caught offering one to two million dollars to Health Canada's Bureau of Veterinary Drugs on the condition that rBGH (a dangerous synthetic hormone given to cows) be approved without any further testing (Lloyd 1995). It appears that paying off government officials may be another way to "promote" the sales and "safety" of a

dangerous product. One wonders how many payoffs might have happened in various foreign countries without Monsanto/NutraSweet getting caught. In addition to possible illegal payoffs, G.D. Searle, company owners (and their wives, family members, etc.) contributed significant amounts to the campaign coffers of Congressional Representatives that helped G.D. Searle. I would be shocked if Monsanto/NutraSweet did not do the very same thing in the United States and all other countries that they are pushng their poison. Monsanto/NutraSweet representatives will often state: "The safety of aspartame is recognized not only by the FDA, but also by the regulatory agencies of more than 80 other nations (Moser 1990)." According to Dr. H.J. Roberts (Roberts 1990b): "To the best of my knowledge, neither the FDA, the WHO [World Health Organization], nor the regulatory agencies of 80 countries that Dr. Moser continually cites have conducted independent animal and human studies to confirm the earlier report, especially about toxicity and brain tumors. Most merely rubber-stamp the previous literature and bibliography." I. Attacking Critics As an example of how Monsanto (owner of NutraSweet) can attack critics, the following is an excerpt from an article about studies done by independent scientist, Rosiland Anderson, Ph.D. which showed that air passed over carpeting and breathed by animals produced nervous system damage (Duehring 1994): "p. 2 -- 'Erode the credibility of the Anderson study ...' [ellipses in memorandum] -- This kind of statement written down in a document is dangerous from a public relations viewpoint. It is possible that this document could fall into the wrong hands or be subpoenaed. There are several references like this throughout the document that could be phrased better. It would be better to say something like: 'Determine the validity of Anderson's research and educate the public concerning its scientific credibility.' "p. 4 -- Last paragraph, last sentence -- 'The key is to discredit her methodology, results and motives.' We need to be careful with this tactic. It may be necessary to publicly discredit and disgrace her but this is a risky endeavor. Even if we can prove she is incompetent, consumer advocates generally are difficult to discredit and we would run the risk of turning her into a martyr. That's not to say it shouldn't be done, but we should be on very strong foodting if we go this route." (1)

"Attorney Kevin McIvers of Santo Barbara, California, responds, 'That's atrocious because what they're implying is that they're not trying to objectively look at the validity of her work. They're out to destroy it. I view her as a very honorable person doing her humble best in her little laboratory to share her information with people who are in a position to do something about it, and their response is to personally discredit and disgrace her rather than take what she has to offer." 1. Monsanto memorandum from Dallas A. Meneely to T.G. Iversen, L.J. O'Neill, C.B. Beckmann, V.L. Rhodes, L.W. Wassell, and B.A. Vanderbeck, regarding "Fleishman Hillard IAQ Proposal.' (November 11, 1992). I am confident that Monsanto/NutraSweet will attack this review if it becomes public. There is nothing wrong with them responding. It is my hope that they will not act in an underhanded sort of way as they did with Dr. Anderson and begin "eroding my credibility" rather than addressing the important points raised in this document.

15. Minimum Requirements For High Quality Research One of Monsanto/NutraSweet's first steps in counteracting criticism of the horrendous quality of research they funded is to fund additional poor quality research. As Dr. Wurtman pointed out, they use their influence to derail funding for truely independent research. Most scientists I have talked to about the possibility of conducting independent studies will not consider proposing a study on aspartame because a) full, independent funding for quality research is highly unlikely, and b) it is considered professional suicide in the sense that should the research find adverse reactions to aspartame (as it inevitably does with quality, independent research), Monsanto/NutraSweet will do everything in its power to make the researcher(s) and the results look foolish. Therefore, Monsanto/NutraSweet can now conduct one flawed research project after another virtually unincumbered by the inconvenience of independent researchers obtaining results that conflict with industry "research." In previous chapters we saw how researchers of industryfunded studies prevent their studies from being invalidated by not publishing crucial information and keeping it hidden from the scientific community for years. We also saw how industry researchers were trying to be passed off as "independent" researchers at an aspartame conference. Considering the absurd results from the plasma aspartate measurements, the fact that NutraSweet has refused to provide an independent researcher with their standard aspartame capsules, and the fact that almost all independent research has found problems with aspartame, the question of what was really in those "aspartame-containing" capsules in

NutraSweet- and ILSI-funded studies is a major concern. Given all of the years of constant abuses on the scientific method by the aspartame and glutamate industries, it would be ridiculous to, all of a sudden, begin trusting their research even if their was slightly more oversight. With the above-mentioned points in mind, what follows are my suggestions for minimum requirements for high quality research on aspartame. A. Funding & Oversight Given the abuse of science that has occurred since the late 1960s, any involvement of Monsanto/NutraSweet or organizations closely linked to this company (e.g., FDA, American Dietetics Association, American Diabetes Association, Epilepsy Institute, ILSI, IFIC, etc., etc.) automatically disqualifies the research as quality work. Normally, industry involvement does not automatically mean that the research is of poor quality, but in this case, since the abuses were so severe and so frequent, it is clear that the aspartame industry is incapable of conducting research without several well-hidden or not-so-well-hidden flaws. Ideally, funding should come from the U.S. National Institutes of Health (NIH). The amount of funding must be large enough to conduct a quality research project. The NIH should not have any say in the protocol design, however, a truly independent team of experts must be chosen at the NIH to conduct occasional site visits to make sure that the study is being conducted appropriately. B. Researchers One of the most important keys to a quality study will be to have a researcher who has proven his/her independence and knowledge in the area oversee the experiment and protocol design. Dr. John Olney comes to mind as one of the best qualified to provide independence and expertise. The researchers must have demonstrated a complete independence from Monsanto/NutraSweet and related organizations (see above). Close colleagues of researchers with extreme industry bias as was seen in the FASEB (1995) team of experts need not apply. Of course, a background check is not necessary, just common sense in choosing indenpendent experts. The research team must include individuals who have expertise in methanol/formic acid issues, excitotoxic amino acids, phenylalanine, and general knowledge of the sordid history of aspartame research. C. Protocol Design The researchers should accept no input on protocol design from any person or organization linked to the aspartame industry. As long as the researchers are willing to really put aspartame to the test as opposed to continuing Monsanto/NutraSweet's abuse of science, there is no need for

them to rely primarily on input from outside organizations. D. Test Product & Administration i. Capsules or Real-World The strong preference is to use real-world, aspartamecontaining products. If the experiment is simply to test biochemical changes over time, a double-blind protocol may not be necessary. In that case, capsules should not be used. In order to use real-world products in a doubleblind experiment, a taste mask must be created. This means that preliminary biochemical experiments need to be conducted to be absolutely certain that the taste mask has no significant effect on the biochemical measurements (e.g., methanol, formate, aspartate, phenylalanine/LNAA, DKP, prolactin, luteinizing hormone, etc.) which might occur after real-world aspartame product administration. Any taste mask that is recommended by industry should be immediately suspect, but not automatically discarded. ii. Dosage If real-world products are used, they should be given to the subject at a level of approximately the current FDA Acceptable Daily Intake limit of 50 mg/kg/day. If capsules are used, they should be given to the subject at a dosage of 100 mg/kg/day since the capsules will reduce the biochemical changes significantly. iii. Administration The test product should not be given with meals except for in experiments which allow the subject to ingest real-world products at any time they wish throughout the day. Experiments focusing on aspartame administration with carbohydrate-containing products in order to add to the effect of the phenylalanine part of aspartame or with MSG to enhance the excitotoxic effects can and should be conducted at a later date. iv. Obtaining Test Product If real-world products are used, the researchers should try to use a wide variety of products, focusing primarily on liquid, aspartame-containing products such as diet sodas that have been stored at room temperature or above for at least two months. Also, baked goods and heated mixtures should be used as well. The products should be purchased from retailers and ideally at different locations around the region and then kept in storage at or above room temperature. Spot testing of test products using quality HPLC techniques should be done. If encapsulated aspartame products are used, it would be preferable to add 10 mg/kg of DKP and a small amount of beta-aspartame to the powder. The encapsulated substance should ideally be obtain from an independent source as

opposed to from NutraSweet. If it is obtained from NutraSweet, it should be obtained as powder, not in capsules, and every batch of aspartame, DKP, and betaaspartame should be very carefully checked using HPLC for anyunexpected chemicals. If the aspartame, DKP, and beta-aspartame are obtain independently, spot checks should be performed using HPLC to assure purity. Capsule material must be obtained independently and should be spot-checked for purity using HPLC. The capsules should be of a variety that quickly dissolves once in the stomach. The test products should be kept in a very secure location to prevent tampering. E. Length of Test Ideally, a double-blind test for adverse reactions caused by aspartame should be at least one year long, preferably two years long. Since we are expecting that aspartame will be used for a lifetime, it is not unreasonable to test for at least a year. Even a test of cigarette smoking for a year would not likely turn up many cases of lung cancer. A six month test would be the absolute minimum required for a reasonable quality test of aspartame. But we have to understand that it is very unlikely that many of the more serious adverse reactions to aspartame would occur within six months of the initial ingestion of aspartame. F. Subjects Since it is nearly impossible to conduct a study which is long enough to produce the very serious adverse reactions that are often seen in the general population upon regular, long-term consumption of aspartame-containing products, initial, high-quality tests should be first done on vulnerable populations. As discussed earlier, PKU heterozygotes are not an extremely vulnerable population. It would be appropriate to first conduct the test on persons with Chronic Fatigue Syndrome, Fibromyalgia, Chronic Depression, and Mutiple Chemical Sensitivities. There are, of course, many vulnerable populations, but these four vulnerable populations would be a good start. Inappropriate exclusion criteria which is quite common in industry studies should not be used in a high-quality, independent study. A representative sample of the test population should be used. Since all people except persons with PKU are told that aspartame is "safe" for them, persons with histories of serious illnesses should not be excluded. Women of childbearing age should also not be excluded, obviously. The larger the test group, the better. Eightly subjects would be ideal, but forty would also be acceptable. G. Biochemical Tests In an independent study, the researchers should actively

look for biochemical changes that may cause or contribute to adverse reactions from short-term and/or long-term use. Not only does this mean taking standard measurements (e.g., aspartate, phenylalanine/LNAA, methanol, formaldehyde, formate, prolactin, luteinizing hormone, DKP) at appropriate times using appropriate, accurate and sensitive measuring techniques, but also looking in places that are not obvious such as CSF measurements for various biochemical changes (shortly after aspartame administration and long-term changes), effects on glutamate receptors (if possible) both in the hypothalamus and peripheral glutamate receptors, changes in others amino acid levels, changes in immune system response or other changes which may occur from formaldehyde exposure, and any other possible changes that the experienced researchers might think could lead to adverse health consequences. H. Location Research should be conducted at laboratories or universities that are not influenced by Monsanto/NutraSweet or International Technical Glutamate Committee (ITGC) funding, funding from food companies using aspartame or MSG, or funding from organizations which receive money from Monsanto/NutraSweet or the ITGC. Common sites for NutraSweetfunded "research" should not be used under any circumstances. I. Preliminary Results It would be preferable if preliminary data was forwarded to an independent accounting organization, the Aspartame Consumer Safety Network, the funding organization, and the NutraSweet Company every few months. In this way, should the experiment or the publication of the results get sidetracked (due to political pressure, for example), at least some data will have been obtained by the concerned organizations. J. Publication It is important that as many individual measurements be shown as possible in the publication. In addition, the display of data should be sensible (e.g., not based on averages for each time period), and appropriate statistical techniques should be used (e.g., not splitting adverse reactions up into 50 different categories to avoid statistical significance). The results of the research should be published in a timely manner and the slant of the text should not be unduly influenced by the journal editor.

16. Conclusion Dr. Leibovitz concludes the article by stating: "Aspartame is a potent sweetener that -- at the

very least -- can be safely used by virtually the entire population. The choice between sugar and aspartame is a 'no-brainer' if ever there was one." If by "no-brainer" Dr. Leibovitz is refering to the fact that aspartame will destroy brain cells over time, I wholeheartedly agree!

References Abraham, R., et al., 1971. "The Response of the Hypothalamus to High Doses of Monosodium Glutamate in Mice and Monkeys," Experimental and Molecular Pathology, Volume 15, page 43-60. Abraham, R., et al., 1975. "Electron Microscopic Observations of Hypothalami in Neonatal Rhesus Monkeys (Macaca mulatta) After Administration of Monosodium-LGlutamate," Experimental and Molecular Pathology, Volume 23, page 203-213. Abrams, I.J., 1992. "Using the Menu Census Survey To Estimate Dietary Intake: Postmarket Surveillance of Aspartame," in Food Safety Assessment edited by JW Finley, SF Robinson, and DJ Armstrong, ACS Symposium Series 484, American Chemical Society, Washington, DC, page 201-213. ADA 1993. "ADAF Receives Grant to Support NCND," ADA Courier, Volume 32, January, 1993. AHPA 1991. "GRAS Affirmation Petition Number 2G0390: Stevia rebaudiana Bertoni," Petition to the FDA for the marketing of food products containing Stevia Rebaudiana Bertoni, hand-delivered to David A. Kessler, M.D., Commissioner of Food and Drugs, Food and Drug Administration, October 21, 1991. Airoldi, L., et al., 1979. "Attempts To Establish the Safety Margin for Neurotoxicity of Monosodium Glutamate," In Filer L.J. Jr., Garattini, S., Dare MR, Reynolds WA, Wurtman RJ (eds): Glutamic Acid: Advances in Biochemistry and Physiology, Raven Press, New York 1979, pages 321331. Airoldi, L. et al., 1980. "Effect of Oral Monosodium Glutamate on Glutamic Acid Levels in the Nucleas Arcuatus of the Hypothalamus and on Serum Osmolarity of Adult and Infant Mice," Toxicology Letters, Volume 7, page 107-111. Alafuzoff, I. et al., "Albumin and Immunoglobulin in Plasma and Cerebrospinal Fluid, and the Blood-Cerebrospinal Fluid Barrier Function in Patients with Dementia of Alzheimer-Type and Multi-Infarct Dementia," Journal of the Neurological Sciences, Volume 60, page 465-472.

Alafuzoff, I., et al., 1987. "Blood-Brain Barrier in Alzheimer Dementia and in Non-Demented Elderly. An Immunocytochemical Study," Acta Neuropathologica, Volume 73, No. 2, page 160-166. Altamura, Carlo A., et al., 1993, "Plasma and Platelet Excitatory Amino Acids in Psychiatric Disorders," American Journal of Psychiatry, Volume 150, No. 11, page 1731-1733. Allen, David H., Gary Baker, 1987. "Monosodium-Induced Asthma," Journal of Allergy & Clinical Immunology, Volume 80, No. 4, page 530-537. AMA 1985. "Aspartame: Review of Safety Issues," Journal of the American Medical Association, Volume 254, No. 3, page 400-402. Applebaum, Arnold E., et al., 1984. "Aspartate-Induced Neurotoxicity in Infant Mice," IN Stegink, L., Filer L., 1984. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y., page 349-362. Aribarg, A., et al., 1986. "Testicular Volume, Semen Profile and Serum Hormone Levels in Fertile Thai Males," International Journal of Andrology, Volume 9, No. 3, page 170-180. Aviation Medical Bulletin 1988. "Pilots and Aspartame," October 1988. Aviation Safety Digest 1989. "Aspartame -- not for the dieting pilot?" Aviation Safety Digest, ASD 142, Spring 1989 (Australia - 062/5841111). Bada, Jeffrey 1987. Letter from Dr. Jeffrey Bada to the Office of Senator Howard Metzenbaum. The statement was put in the record before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 456-458. Baker, George L., L.J. Filer Jr., Lewis D. Stegink, 1976. "Plasma, Red Cell and Breast Milk Free Amino Acid Levels in Lactating Women Administered Aspartame or Lactose at 50 mg per kg Body Weight," Journal of Nutrition, Volume 106, July, xxxiii. Balon, R., T.W., et al., 1994. "Dietary Magnesium Prevents Fructose-Induced Insulin Insensitivity in Rats," Hypertension, Volume 23, part 2, page 1036-1039. Banks, W.A., A.J. Kastin, "Peptides and the SEnescent BloodBrain Barrier," Neurobiology of Aging, Volume 9, page 4849. Baumann, K., J. Angerer, 1979. "Occupational Chronic Exposure to Organic Solvents. VI. Formic Acid Concentration in Blood and Urine as an Indicator of Methanol Exposure," International Archives of

Occupational and Environmental Health, Volume 42, page 241. Beckmann, H., M.A. Strauss, E. Ludolph, 1977. "DLPhenylalanine in Depressed Patients: An Open Study," Journal of Neural Transmission, Volume 41, page 123-134. Beckmann, Helmut, et al., 1979. "DL-Phenylalanine Versus Imipramine: A Double-Blind Control Study," Archiv fur Psychiatrie und Nervenkrankheiten (Archives of Psychiatry and Neurological Dciences), Volume 227, page 49-58. Bennett, I.L., et al., 1953. "Acute Methyl Alcohol Poisoning: A Review Based on Experiences in an Outbreak of 323 Cases," Medicine, Volume 32, page 431-463. Bennett, S., et al., 1995. "Periodic Acid-Schiff (PAS)Positive Deposits in Brain Following Kainic Acid-Induced Siezures: Relationshs to Fos Induction, Neuronal Necrosis, Reactive Gliosis, and Blood-Brain Barrier Breakdown," Acta Neuropathologica, Volume 89, No. 2, page 126-138. Benninger, C., P. Matthis, L.M.J. de Sonneville, et al. 1993a. "Chronic High-Dose Aspartame Ingestion Does Not Affect Electro-Encephalogram (EEG) Spectral Parameters in Phenylketonuric Heterozygotes," Journal of Clinical and Experimental Neuropsychology, Volume 15, page 407 Benninger, C., et al., 1993b. "Electroencephalographic Evaluation of Chronic Aspartame Ingestion in Phenylketonuric Heterozygoes (PKUH)," Electroencephalography and Clinical Neurolophysiology, Volume 87, page S58. Bessman, S.P., et al., 1948. "The Absorption of Glutamic Acid and Glutamine," Journal of Biological Chemistry, Volume 175, page 817-823. Birkmayer, W., P. Riederer, W. Linauer, J. Knoll, 1984. "LDeprenyl Plus L-Phenylalanine in the Treatment of Depression," Journal of Neural Transmission, Volume 59, page 81-87. Blaut, M., et al., 1992. "Energetics of Methanogenesis Studied in Vesicular Systems," Journal of Bioenergetics and Biomembranes, Volume 24, No. 6, page 529-546. Blaylock, Russell L., 1994. "Excitotoxins: The Taste That Kills," Health Press, Santa Fe, New Mexico, c1994. Blumenthal, Mark, 1994. "FDA Rejects AHPA Stevia Petition," Whole Foods, April 1994, page 61-63. Blundell, J.E., A.J. Hill, 1986. "Paradoxical effects of an intense sweetener (aspartame) on appetite" The Lancet, Volume 1, page 1092-1093. Boehm, Marcus F., Jeffrey L. Bada, 1984. "Racemization of aspartic acid and phenylalanine in the sweetener

aspartame at 100 C. Proceeding of the National Academy of Sciences, Volume 81. pp. 5263-5266, August 1984. Boor, P.J., et al., 1992. "Methylamine Metabolism to Formaldehyde by Vascular Semicarbazide-Sensitive Amine Oxidase," Toxicology, Volume 73, No. 3, page 251-258. Boulton, Alan A., "Phenylethylaminergic Modulation of Catecholaminergic Neurotransmission," Progress in NeuroPsychopharmacology & Biological Psychiatry, Volume 15, page 139-156. Bradford, Blair U., et al., 1993. "Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate," Archives of Biochemistry and Biophysics, Volume 303, No. 1, page 172-176. Brann, Darrell, Virendra Mahesh, 1992. "Excitatory Amino Acid Regulation of Gonadotropin Secretion: Modulation by Steroid Hormones," Journal of Steroid Biochemistry and Molecular Biology, Volume 41, No. 3-8, page 847-850. Brannigan, Vincent, 1983. "The First FDA Board of Inquiry: The Aspartame Case," IN "Law and Science in Collaboration," edited by J.D. Nyhart and Milton M. Carrow, Lexington Books, D.C. Heath and Company, Lexington, Massachusetts, c1983, page 181-210 Braverman, J.B.S., A. Lifshitz, 1957. "Pectin Hydrolysis in Certain Fruits During Alcoholic Fermentation," Food Technology, July 1957, page 356-358. Brenner, Arnold, 1994. "Sugar and Children's Behavior" Correspondance, New England Journal of Medicine, Volume 330, No. 26, page 1902. Brody, Jane E., 1985, "Sweetener Worries Some Scientists," Science Times, February 5, 1985, Reprinted in Congressional Record (1985a, page S5493-S5494). Burde, R.M., et al., 1971. "Monosodium Glutamate: Acute Effect of Oral and Subcutaneous Administration on the Arcuate Nucleus of the Hypothalamus in Mice and Rats," Nature, Volume 233, page 58. Burns, Thomas S., et al., 1990. "Bioavailability of Phenylalanine and Aspartate From Aspartame (20 mg/kg) in Capsules and Solution," Metabolism, Volume 39, No. 11, page 1200-1203. Burns, Thomas S., et al., 1991. "Aspartame and Sucrose Produce a Similar Increase in the Plasma Phenylalanine to Large Nuetral Amino Acid Ratio in Healthy Subjects," Pharmacology, Volume 43, page 210-219. Burros, Marian, 1995. "Additives In Advice On Food," New York Times, November 15, 1995, page C1, C4. Butchko, Harriett H., Frank N. Kotsonis 1991. "Acceptable

Daily Intake vs Actual Intake: The Aspartame Example," Journal of the American College of Nutrition, Volume 10, No. 3, page 258-266. Buttery, J.E., B.R. Chamberlain, 1988. "A Simple Enzymatic Method for the Measurement of Abnormal Levels of Formate in Plasma," Journal of Analytical Toxicology, Volume 12, page 292-294. Butchko, Harriett H., Frank N. Kotsonis 1994. "Postmarketing Surveillance in the Food Industry: The Aspartame Case Study," in Nutritional Toxicology, edited by Frank N. Kotsonis, Maureen Macky and Jerry Hjelle, Raven Press, Ltd., New York, c1994. Buzzard, James A., 1976a. Testimony of James A. Buzzard, G.D. Searle, before the U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 168. Buzzard, James A., 1976b. Letter from James A. Buzzard of G.D. Searle to Dr. Alexander M. Schmidt, Commissioner, U.S. Food and Drug Administration, January 7, 1976, "Good Laboratory Practices" proposal enclosure, Reprinted in U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 185-213. CAA General Aviation (1989). Safety Information Leaflet, April 1989, Great Britain. Caballero, Benjamin, et al., 1986. "Plasma Amino Acid Levels After Single-Dose Aspartame COnsumption in Phenylketonuria, Milk Hyperphenylalaninemai, and Heterozygous State for Phenylketonuria," Journal of Pediatrics, Volume 190, No. 4, page 668-671. Caballero, Benjamin, Richard J. Wurtman, 1988. "Control of Plasma Phenylalanine Levels," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 3-12. Camfield, PR, et al., 1992. "Aspartame exacerbates EEG spikewave discharge in children with generalized absence epilepsy: a double-blind controlled study." Neurology, Volume 42, page 1000-1003.

Campbell, L.A., G.H. Palmer, 1978. "Pectin in Topics in Dietary Fiber Research," Edited by G.A. Spiller and R.J. Amen, Plenum Press, NY, c1978. Canadian General Aviation News 1990. "Fit to fly" Canadian General Aviation News, March 1990, page 28. Carlson, H.E., et. al., 1989a. "Aspartame and its Constituent Amino Acids: Effects on Prolactin, Cortisol, Growth Hormone, Insulin, and Glucose in Normal Humans," American Journal of Clinical Nutrition, Volume 49, No. 3, page 427-432. Carlson, H.E., et. al., 1989b. "Stimulation of Pituitary Hormone Secretion by Neurotransmitter Amino Acids in Humans," Metabolism, Volume 38, No. 12, page 1179-1182. Carroll, Polly, Kelsy Caplinger, Gene France, 1992. "Guidelines for Counseling Parents of Young Children with Food Sensitivities," Journal of the American Dietetic Association, Volume 92, No. 5, page 602-603. Casey, J.C., R. Self, T. Swain, 1963. "Origin of Methanol and Dimethyl Sulphide from Cooked Foods," Nature, Volume 200, page 885. CDC 1984. "Evaluation of Consumer Complaints Related to Aspartame Use," Division of Nutrition, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, GA 30333, November 1984. Cha, Alice Shen, Chi-Tang Ho, 1988. "Studies of the Interaction between Aspartame and Flavor Vanillin by High Performance Liquid Chromatography," Journal of Food Science, Volume 53, No. 2, page 562-564. Chambron, J., et al., "Magnetic Resonance Imaging Study of the Role of the Blood-Brain Barrier in the Pathogenesis of Experimental Allergic Encephalomyelitis: Application to Multiple Sclerosis," Bulletin de l'Academie nationale de medecine, Volume 178, No. 9, page 1647-1663. Chamuit, Stephen, 1994. Electronic mail from Chamuit@aol.com (from Guam) to Mark D. Gold on December 25, 1994. Chaturvedi, U.C., et al., "Breakdown of the Blood-Brain Barrier During Dengue Virus Infection of Mice," Journal of General Virology, Volume 72, Part 4, page 859-866. Chen, L.N.A., E.S. Parham, 1991. "College Students' Use of High-Intensity Sweeteners is Not Consistently Associated With Sugar Consumption," Journal of the American Dietetic Association, Volume 91, page 686-690. Cho, E.S., J.D. Coon, L.D. Stegink, 1987. "Plasma and Urine Diketopiperazine Concentrations in Normal Adults Ingesting Large Quantities of Aspartame," Food and Chemical Toxicology, Volume 25, No. 7, page 499-504. Choi, Dennis W., 1992. "Amyotrophic Lateral Sclerosis and

Glutamate -- Too Much of a Good Thing," Science, Volume 326, No. 22, page 1493-1495. Chusilp, K., et al., 1992. "Observations on the Development of Stunting Children of the Khon Kaen Region of Thailand," European Journal of Clinical Nutrition, Volume 46, No. 7, page 475-487 (Erratum Volume 46, No. 11, page 841). CIA 1994. The World Fact Book 1994, U.S. Central Intelligence Agency, World Wide Web address: http://www.odci.gov/cia. Cleland, J.G., G.L. Kingsbury, 1977. "Multimedia Goals for Environmental Assessment, U.S. Environmental Protection Agency: EPA-600/7-77-136b, November 1977. Cloninger, M.R., R.E. Balwin 1970. "Aspartylphenylalanine methyl ester: a low calorie sweetener," Science, Volume 170, page 81. CNI 1984. Letter from Rodney E. Leonard and James S. Turner of Community Nutrition Institute (CNI) to Dr. Frank E. Young, Commissioner, Food and Drug Administration, Reprinted in Congressional Record 1985b, page S10841. Coderre, T.J., R. Melzack, 1992. "The Contribution of Excitatory Amino Acids to Central Sensitization and Persistent Nociception After Formalin-induced Tissue Injury," Journal of Neuroscience, Volume 12, No. 9, page 3665-3670. Colbin, Annamarie, 1979. "The Book of Whole Meals," Ballantine Books, c1979. Colbin, Annamarie, 1986. "Food and Healing," Ballantine Books, c1986, ISBN 0-345-30385-7. Comer, D., et al., 1981. "Brain Uptake of 11C-methionine in Phenylketonuria," European Journal of Pediatrics, Volume 136, page 13-19. Congressional Record 1982. "Orphan Drug Act," Congressional Record, December 14, 1982, page 30445. Congressional Record 1985a. "Saccharin Study and Labeling Act Amendments of 1985," Congressional Record, Volume 131, No. 58, May 7, 1985, page S5489-S5519. Congressional Record 1985b. "Aspartame Safety Act," Congressional Record, Volume 131, No. 106, August 1, 1985, page S10820-10847. Constantine, Alex, 1995. "NutraSweet, the NutraPoison," Prevailing Winds Magazine (P.O. Box 23511, Santa Barbara, CA 93121), Premier Issue, No. 1, page 40-49. Consumer Reports 1978. "Dried Soup Mixes (This Is Soup?)," Consumer Reports, November 1978, page 615-619.

Cook, M.R., F.J. Bergman, et al., 1991. "Effects of Methanol Vapor on Human Neurobehavioral Measures," Research Report No. 42, Health Effects Institute, 141 Portland Street, Suite 7300, Cambridge, MA 02139, (617) 621-0266, August 1991. Cook, M.R., 1995. Conversation between Mary R. Cook and Mark Gold, June 1995. Cornell, Richard G., Robert A. Wolfe, Paul G. Sanders, 1984. "Aspartame and Brain Tumors: Statistical Issues," IN Stegink, L., Filer L., 1984. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y., page 459-479. Coulombe, Jr., Roger A., Raghubir P. Sharma, 1986. "Neurobiochemical Alterations Induced by the Artificial Sweetener Aspartame (NutraSweet)," Toxicology and Applied Pharmacology, Volume 83, page 79-85. Crook, William G., 1994. "Sugar and Children's Behavior" Correspondance, New England Journal of Medicine, Volume 330, No. 26, page 1901-1902. Crossen, Cynthia, 1994. "Tainted Truth: The Manipulation of Fact in America," Simon & Schuster, New York, c1994. d'Alessandro, Alessandra, et al., 1994, "Formate in Serum and Urine after Controlled Methanol Exposure at the Threshold Limit Value," Environmental Health Perspectives, Volume 102, No. 2, February, 1994, page 178181. Daabees, T.T., D.W. Anderson, W.L. Zike, L.J. Filer, L.D. Stegink, 1984. "Effect of Meal Components on Peripheral and Portal Plasma Glutamate Levels in Young Pigs Administered Large Doses of Monosodium-L-Glutamate," Metabolism, Volume 33, page 58-67. Daabees, T.T., M.W. Finkelstein, L.D. Stegink, and A.E. Applebaum, 1985. "Correlation of Glutamate Plus Aspartate Dose, Plasma Amino Acid Concentration and Neuronal Necrosis in Infant Mice," Food and Chemical Toxicology, Volume 23, No. 10, page 887-893. Dagel, G.E., et al., 1979. "Morphology of Spontaneous Tumors in the Rat," Vetinary Pathology, Volume 16, page 318-324. Davoli, E., et al., 1986. "Serum Methanol Concentrations in Rats and in Men After a Single Dose of Aspartame," Food and Chemical Toxicology, Volume 24, No. 3, page 187-189. de Sonneville, L.M.J., B. Lanz-Engert, F.K. Trefz, C. Benninger, et al., 1993. "Aspartame (APM) has No Effect on Cognitive Function in Phenylketonuric Heterozygotes (PKUH)," Journal of Clinical and Experimental Neuropsychology, Volume 15, page 407. Demopoulos, H.B., 1966a. "Effects of Low PhenylalanineTyrosine Diets on S91 Mouse Melanomas," Journal of the National Cancer Institute, Volume 37, page 185-190.

Demopoulos, H.B., 1966b. "Effects of Reducing the Phenylalanine-Tyrosine Intake of Patients with Advanced Malignant Melanoma, Cancer, Volume 19, page 657-664. Devesa, Susan S., et al., 1995. "Recent Cancer Trends in the United States," Journal of the National Cancer Institute, Volume 87, No. 3, page 175-182. Dews, Peter B., 1987. Testimony of Peter B. Dews, Professor of Psychology and Psychobiology, Harvard Medical School, before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 376. DHHS 1993a. "Methanol Toxicity," American Family Physician, Volume 71(1):163-171, January 1993. Adapted from Case Studies in Environmental Medicine published by the Agency For Toxic Substances and Disease Registry, U.S. Department of Helath and Human Services. DHHS 1993b. "Adverse Reactions Associated With Aspartame Consumption," Department of Health & Human Services Memorandum, April 1, 1993, Reprinted in Mullarkey (1992, preface). DHHS 1994. Department of Health and Human Services. "Report on All Adverse Reactions in the Adverse Reaction Monitoring System." (February 25 and 28, 1994). DHHS 1995. Department of Health and Human Services. "Report on All Adverse Reactions in the Adverse Reaction Monitoring System." (April 20, 1995). Duehring, Cindy, 1994. "Carpet Update: Industry Strategizing Memorandum Comes to Light," Informed Consent, Volume 1, No. 5, September/October 1994. Available from Cindy Duehring, Director of Research, Environmental Access Research Network (EARN), P.O. Box 426, Williston, ND 58802, (701) 859-6363 During, Mathew J., Ian N. Acworth, Richard J. Wurtman, 1988. "An In Vivo Study of Dopamine Release in Striatum: The Effects of Phenylalanine," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 81-86. Ebert, Andrew G., 1991. Letter to Sue Ann Anderson, R.D., Ph.D., Senior Staff Scientist, Life Sciences Research Office, Federation of American Societies for Experimental Biology (FASEB), March 22, 1991. FDA Docket No. 90N-0379 (Item CR2). Edmund, J., O.A. Jensen, J. Egeberg., 1974. "Reduced Intake

of Phenylalanine and Tyrosine as Treatment of Choroidal Malignant Melanoma," Modern Problems in Ophthalmology, Volume 12, page 504-509. EHSA 1994, "Environmental, Health & Social Alternatives" April 1994, P.O. Box 56682, Atlanta, Georgia 30356 (404) 303-1873 Elder, David E., 1995. "Skin Cancer: Melanoma and Other Specific Nonmelanoma Skin Cancers," Cancer, Supplement, Volume 75, No. 1 page 245-256. Elsas, Louis J., 1987. Testimony and Statement of Dr. Louis J. Elsas, II, Director, Division of Medical Genetics, Emory University School of Medicine, before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 360-367. Elsas, Louis J., James F. Trotter, 1988. "Changes in Physiological Concentrations of Blood Phenylalanine Produces Changes in Sensitive Parameters of Human Brain Function," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 187-195. Elstad, C.A., G.G. Meadows, R.M. Abdallah, 1990. "Specificity of the Suppression of Metastatic Phenotype by Tyrosine and Phenylalanine Restriction," Clinical and Experimental Metastasis, Volume 8, No. 5, page 393-416. EPA 1994. "Methanol Basics," Fact Sheet OMS-7. EPA 400-F-92009. Ershoff, Benjamin H., 1976. "Synergistic Toxicity of Food Additives in Rats Fed a Diet Low in Dietary Fiber," Journal of Food Science, Volume 41, page 949-951. Farber, Steven A. 1989. "Aspartame and the Regulation of Food Additives: A Study of FDA Decision-Making and a Proposal for Change," Master of Science in Technology and Public Policy Thesis at Massachusetts Institute of Technology, Cambridge, MA 02139. FASEB 1992. "Safety of Amino Acids Use as Dietary Suppliments," Life Sciences Research Office, Federation of American Societies for Experimental Biology, 9650 Rockville Pike, Bethesda, Maryland 20814-3998, (301) 5307000, FDA Contract No. 223-88-2124, Task Order No. 8, page 166. FASEB 1995. "Analysis of Adverse Reactions to Monosodium Glutamate (MSG)," Life Sciences Research Office, Federation of American Societies for Experimental Biology, 9650 Rockville Pike, Bethesda, Maryland 20814-

3998, (301) 530-7000, FDA Contract No. 223-92-2185, Task Orders 1 and 7. FDA PMS 1987. "Post-Marketing Survey (PSM) of Aspartame Intake," Submission for the Record by the U.S. Food and Drug Administration, U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 229-238. FDA 1993. "Symptoms For Aspartame," from Freedom of Information Request by Barbara Mullarkey. See reference: Mullarkey 1992, page: Introduction. Federal Register 1973. Notice of Filing of Food Additive Petition, G.D.Searle & Company. Federal Register, Volume 38, page 5,921. Federal Register 1974. Volume 39, page 27137. Federal Register 1975. Volume 40, page 56907, December 5, 1975. Federal Register 1979. "Ruling on Objections and Notice of Hearing Before a Public Board of Inquiry; Aspartame," Federal Register, Volume 44, page 31,717. Federal Register 1981. "Aspartame: Commissioner's Final Decision," Federal Register, Volume 46, page 38284-38308. Federal Register 1983. "Food Additives Permitted for Direct Addition to Food: Aspartame," 48(July 8): 31376-31382. Federal Register 1984. "Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame," Volume 49, No. 36, February 22, 1984, page 6672-6682. Ferguson, H.B., C. Stoddart, J.G. Simeon, 1986. "Double Blinded Challenge Studies of Behavioral and Cognitive Effects of Sucrose-Aspartame Ingestion in Normal Children," Nutrition Reviews, Volume 44, page 144-150. Fernstrom, John D., 1979. "Diurnal Variations in Plasma Concentrations of Tryptophan, Tyrosine, and Other Neutral Amino Acids: Effects of Dietary Protein Intake," American Journal of Clinical Nutrition, Volume 32, page 1912-1922. Fernstrom, John, D., Madelyn H. Fernstrom, Marcia A. Gillis, 1983. "Acute Effects of Aspartame on Large Neutral Amino Acids and Monoamines in Rat Brain," Life Sciences, Volume 32, page 1651-1658. Fernstrom, John D., 1994. "Dietary Amino Acids and Brain Function," Journal of the American Dietetic Association, Volume 94, No. 1, page 71-77. Filer, L.J., Jr., et al., 1979. "Glutamic Acid: Advances in Biochemistry and Physiology," Raven Press, c1979. Fisher, G.H., et al., 1991. "Free D-Aspartate and D-Alanine

in Normal and Alzheimer Brain," Brain Research Bulletin, Volume 26, No. 6, page 983-985. Fisher, K.N., et al., 1991. "The Postweaning Housing Environment Determines Expression of Learning Deficit Associated With Neonatal Monosodium Glutamate (M.S.G.)," Neurotoxicology & Teratology, Volume 13, No. 5, page 507513. Fitchpatrick, Elaine, 1995. Letter from Elaine Fitchpatrick to Karlyn Kauffmann, Consumer Affairs Specialist, The Coca-Cola Company dated August 22, 1995. Fitzgerald, J.E., et al., 1974. "Spontaneous Tumors of the Nervous System in Albino Rats," Journal of the National Cancer Institute, Volume 52, page 265-273. Floreno, Anthony, 1995. "Ajinomoto Mulls New MSG As World Supply Tightens," Chemical Marketing Reporter, May 29, 1995, page 16. Food 1986. Food Chemical News, July 28, 1986, page 44. Food 1990. "Foods of Tomorrow," Food Processing, August 1990. Food 1995. "Aspartame Adverse Reaction Reports Down in 1994 From 1985 Peak: FDA," Food Chemical News, June 12, 1995, page 27. Francot, P., P. Geoffroy, 1956. "Le Methanol dans les jus de fruits, les boissons, fermentees, les alcools et spiritueux." Rev. Ferment. Inc. Aliment., Volume 11, page 279-287, 1956. Franzblau, A., et al., 1992. "Use of Urinary Formic Acid as aBiologic Exposure Index of Methanol Exposure," Appl of Occupational Environmental Hygiene, Volume 7, page 467471. Frederick, Linda J., et al., 1984. "Investigation and Control of Occupational Hazards Associated with the Use of Spirit Duplicators," American Industrial Hygiene Association Journal, Volume 45, No. 1, page 51-55. Freeman, Martha, 1973. Memorandum from Martha A. Freeman, Supervisory Medical Officer, FDA Division of Metabolic and Endocrine Drug Products to Dr. C.J. Kokosi, FDA Division of Toxicology, September 12, 1973, Reprinted in US Senate 1987, page 326-336. Frey, Gunther H., 1976. "Use of Aspartame By Apparently Healthy Children and Adolescents," Journal of Toxicology and Environmental Health, Volume 2, page 401-415. Frieder, Brina, Veronika Grimm, 1984. "Prenatal Monosodium Glutamate (MSG) Treatment Given Through the Mother's Diet Causes Behavioral Deficits in Rat Offspring," International Journal of Neuroscience, Volume 23, page 117-126.

Friedman, P.A., 1980. "Common Poisons," in "Harrison's Principles of Internal Medicine," Ninth Edition, McGrawHill, Inc., New York. Fujimaki, H., et al., 1992. "Mast Cell Response to Formadehyde," International Archives of Allergy & Immunology, Volume 98, No. 4, page 324-331. Fuller, T.D., et al., 1993. "Gender and Health: Some Asian Evidence," Journal of Health and Social Behavior, Volume 34, No. 3, page 252-271. Furia, T.E. 1972. CRC Handbook of Food Additives. 2nd ed., Cleveland, Ohio: CRC Press, pp. 193. Gaffney, C., 1986. "Aspartame in Aviation," Armed Forces Institute of Pathology. Paper presented at the 57th Annual Meeting of the Aerospace Medical Association, April 1986. Gaines, Susan M., Jeffrey L. Bada 1987. "Reversed-Phase HighPerformance Liquid Chromatographic Separation of Aspartame Diastereomeric Decomposition Products," Journal of Chromatography, Volume 389, page 219-225. GAO 1986. "Six Former HHS Employees' Involvement in Aspartame's Approval," United States General Accounting Office, GAO/HRD-86-109BR, July 1986. GAO 1987. "Food Additive Approval Process Followed for Aspartame," United States General Accounting Office, GAO/HRD-87-46, June 1987. Gao, J., et al., 1994. "Transplacental Neurotoxic Effects of Monosodium Glutmate on Structures and Functions of Specific Brain Areas of Filial Mice," Sheng Li Hsueh Pao -- Acta Physiologica Sinica, Volume 46, No. 1, page 44-51. Garrattini, Silvo, et al., 1988. "Studies on the Susceptibility to Convulsions in Animals Receiving Abuse Doses of Aspartame," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 131-143. Garriga, Margarita M., et al., 1991. "A Combined SingleBlind, Double-Blind, Placebo-Controlled Study to Determine the Reproducibility of Hypersensitivity Reactions to Aspartame," Journal of Allergy and Clinical Immunology, Volume 87, No. 4, page 821-827. Garrison, Robert H., Elizabeth Somer, 1990. "The Nutrition Desk Reference," Keats Publishing, Inc., New Canaan, Connecticut.

Garruto, R.M., et al., 1980. "Amyotrophic Lateral Sclerosis Among Chamorro Migrants From Guam," Annuls of Neurology, Volume 8, page 1540-1542. Gart, J.J., et al., 1979. "Statistical Issues in Interpretation of Chronic Bioassay Tests for Carcinogenicity," Journal of the National Cancer Institute," Volume 62, page 957-984. Gay, VL, TM Plant, 1988. "Sustained Intermittent Release of Gonadotropin-Releasing Hormone in the Prepubertal Male Rhesus Monkey Induced by N-methyl-DL-Aspartic Acid," Neuroendocrinology, Volume 48, page 147. Geha, Raif, et al., 1993. "Aspartame is No More Likely Than Placebo to Cause Urticaria/Angioedema: Results of a multicenter, Randomized, Double-Blind, PlaceboControlled, Crossover Study," Journal of Allergy and Clinical Immunology, Volume 92, page 513-520. General Aviation News 1989. "NutraSweet...too good to be true?" by Megan Hicks, General Aviation News, July 31, 1989. Ghadimi, H., S. Kumar, F. Abaci, 1971. "Studies on Monosodium Glutamate Ingestion," Biochemical Medicine, Volume 5, page 447-456. Giacometti, T., 1979. "Free and Bound Glutamate in Natural Products," IN "Glutamic Acid: Advances in Biochemistry and Physiology," edited by L.J. Filer, Jr., et al., Raven Press, c1979, pages 25-34. Gillette, R. 1972. "Academic Food Committees: New Criticism of Industry Ties," Science, Volume 177, page 1172-1174. Goldman, J.A., et al., 1984. "Behavioral effects of sucrose on preschool children," Journal of Abnormal Child Psychology, Volume 14, No. 4, page 565-577. Goldsmith, Paul C., et al., 1994. "Glutamate-Immunoreactive Neurons and Their Gonadotropin-Releasing Hormone-Neuronal Interactions in the Monkey Hypothalamus," Endocrinology, Volume 134, No. 2, page 858-868. Gordon, Gregory, 1987. "NutraSweet: Questions Swirl," UPI Investigative Report, 10/12/87. Reprinted in US Senate (1987, page 483-510). Graves, Florence, 1984. "How Safe is Your Diet Soft Drink," Common Cause Magazine, July/August 1984. Reprinted in Congressional Record (1985a, pages S5497-S5506) Graves, Donald J., Siquan Luo, 1987. "Decomposition of Aspartame Caused by Heat in the Acidified and Dried State," Journal of Agriculture and Food Chemistry, Vol. 35, No. 3, page 439-442. Grayson, D.R., A.M. Szekely, E. Coas, 1990. "GlutamateInduced Gene Expression in Primary Cerebellar Neurons,"

In Neurotoxicity of Excitatory Amino Acids, edited by A. Guidotti, Raven Press, Ltd., New York, c1990. Griffin, G. Edward, 1974. "World Without Cancer," America Media, Westlake Village, California, ISBN 0-912986-09-3, c1974, page 395. Quote from "Autopsy On The A.M.A.," San Francisco Chronicle, January 2, 1970, page 42. Gross, Adrian, 1975. Memorandum from Mr. Adrian Gross, Scientific Investigations Staff to Mr. Carlton Sharp, Chairman, Searle Investigation Task Force, September 29, 1975, Reprinted in U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1975, Part 1," No. Y4.L11/2:P49/2/975, CIS# S541-16, page 440+. Gross, Adrian, 1976b. Memorandum from Mr. Adrian Gross, Scientific Investigations Staff to Mr. Carlton Sharp, Chairman, Searle Investigation Task Force, March 15, 1976, Reprinted in U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 3," No. Y4.L11/2:P49/2/976/pt.3, CIS# S541-12, page 310-376. Gross, Adrian, 1985. Statement from Dr. Andrian Gross, Former FDA Investigator and Scientist, "Aspartame Safety Act," Congressional Record, Volume 131, No. 106, August 1, 1985, page S10835-S10840. Gross, Adrian, 1987a. Letter from Dr. Andrian Gross, Former FDA Investigator and Scientist to Senator Howard Metzenbaum regarding pre-approval tests by G.D. Searle, October 30, 1987, Reprinted in US Senate 1987, page 430439. Gross, Adrian, 1987b. Letter from Dr. Andrian Gross, Former FDA Investigator and Scientist to Senator Howard Metzenbaum regarding pre-approval tests by G.D. Searle, November 3, 1987, Reprinted in US Senate 1987, page 443453. Gruner, O., et al., 1994. "Methanol Formation in vitro and in vivo (Methanol Formation After Pectin Administration," Blutalkohol, Volume 31, No. 4, page 228-232. Guttler, Flemming, 1988. "Epidemiology and Natural History of Phenylketonuria and Other Phyperphenylalininemias," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 810, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 213-

227. Haley, Jane, et al., 1990. "Evidence for Spinal N-methyl-Daspartate Receptor Involvement in Prolonged Chemical Nociception in the Rat," Brain Research, Volume 518, page 218-226. Heinrich, R., J. Angerer, 1982. "Occupational Chronic Exposure to Organic Solvents. X. Biological Monitoring Parameters for Methanol Exposure," International Archives of Occupational and Environmental Health, Volume 50, page 341. Heinzow, B., T. Ellrott 1992. "Formic Acid in Urine -- A Significant Parameter in Environmental Diagnosis?" Zentralbl Hyg Umweltmed, Volume 192, No. 5, page 455-461. Heise, Reno, et al., 1989. "Sodium Dependence of Acetate Formation by the Acetogenic Bacterium Acetobacterium woodii," Journal of Bacteriology, Volume 171, No. 10, pages 5473-5478. Helling, Herbert, 1970. Memorandum from Herbert Helling, G.D. Searle Official to several G.D. Searle Officials, regarding Food and Drug Sweetener Strategy, December 28, 1970, Reprinted in U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 16-19. Heybach, J.P., J.L. Smith, 1988. "Intake of Aspartame in 1950 Year-Old Women From the USDA Continuing Survey of Food Intakes by Individuals," (CSFII 85), FASEB Journal, Volume 2, page A1615. Heywood, R., R.W. James, 1979. "An Attempt to Induce Neurotoxicity in an Infant Rhesus Monkey with Monosodium Glutamate," Toxicology Letters, Volume 4, page 285-286. Himwich, Williamina A., et al., 1954. "Ingested Sodium Glutamate and Plasma Levels of Glutamic Acid," Journal of Applied Physiology, Volume 7, page 196-199. Hjelle, Jerry J., et al., 1992. "Plasma Concentrations and Pharmacokinetics of Phenylalanine in Rats and Mice Administered Aspartame," Pharmacology, Volume 44, page 4860. HRF 1993. "Supplement to GRAS Affirmation Petition Number 2G0390: Stevia rebaudiana Bertoni," prepared by the Herb Research Foundation, September 28, 1993. Hussein, M.M., et al., 1984. "Determination of Reactivity of Aspartame with Flavor Aldehydes by Gas Chromatography, HPLC and GPC," Journal of Food Science, Volume 49, page 520-524.

ICAS 1995. "Aspartame Side Effects: Fact or Fiction?" International Council of Air Shows, February 1995. IFIC 1995. "IFIC Review of Monosodium Glutamate: Examining the Myths," International Food Information Council, May 1994. World Wide Web page: http://ificinfo.health.org/ificinfo.htm Import 1991. "Automatic Detention of Stevia Leaves, Extract of Stevia Leaves, and Foods Containing Stevia," FDA Import Alert #45-06, May 17, 1991. Import 1995. "Automatic Detention of Stevia Leaves, Extract of Stevia Leaves, and Foods Containing Stevia," Revised FDA Import Alert #45-06, September 18, 1995. Inouye, M., 1976. "Selective Distribution of Radioactivity in the Neonatal Mouse Brain Following Subcutaneous Administration of 14 C-Labeled Monosodium Glutamate," Congenital Anomolies (Journal Serial # 0914-3505, Japan), Volume 16, page 79-84. Irwin, Robert P., et al., "Pharmacodynamics of the Hypotensive Effect of Levodopa in Parkinsonian Patients," Clinical Neuropharmacology, Volume 15, No. 5, page 365374. Ishii, H., 1981. "Toxicity of Aspartame and Its Diketopiperazine for Wistar Rats by Dietary Administration for 104 Weeks," Toxicology, Volume 21, page 91. Jensen, O.A., J. Egeberg, J. Edmund, 1974. "The Influence of Phenylalanine- and Tyrosine-low Diet on the Growth and Structure of Transplantable Malignant Melanomas of the Syrian Golden Hamster (Mesocricetus auratus)," Modern Problems in Ophthalmology, Volume 12, page 510-516. Jobe, Phillip C., John W. Dailey, 1988. "Role of Monoamines in Seizure Predisposition in the Genetically EpilepsyProne Rat," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 111-121. John, E.M., et al., 1994. "Spontaneous Abortion Among Cosmetologists," Epidemiology, Volume 5, No. 2, page 147155. Johnson, R. Elton, 1990. "Stevioside, 'NATURALLY'!" A Special Presentation To: The Calorie Control Council, 23rd Annual Meeting, Tucson, Arizona, November 4-7, 1990, Prepared by Dr. R. Elton Johnson, Jr., P.O. Box 1356, Fayetteville, Georgia 30214. Karstaedt, Patricia J., Jonathan H. Pincus, 1993. "Aspartame

Use in Parkinson's Disease," Neurology, Volume 43, page 611-613. Kavet, Robert, Kathleen M. Nauss, 1990. "The Toxicity of Inhaled Methanol Vapors," Critical Reviews in Toxicology, Volume 21, Issue 1, page 21-50. Kazeniac, S.J., R.M. Hall, 1970. "Flavor Chemistry of Tomato Volatiles," Journal of Food Science, Volume 35, page 519530. Kennedy, Edward M., 1976. Testimony of U.S. Senator Edward M. Kennedy at the U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 3," No. Y4.L11/2:P49/2/976/pt.3, CIS# S541-12. Kenney, R.A., C.S. Tidball, 1972. "Human Susceptibility to Oral Monosodium L-Glutamate," American Journal of Clinical Nutrition, Volume 25, page 140-146. Kessler, David A. 1993, "Introducing MEDWatch: A New Approach to Reporting Medication and Device Adverse Effects and Product Problems" Journal of the American Medical Association 269:2765-68. Kim, K.C., M.D. Tasch, S.H. Kim, 1988. "The Effect of Aspartame on 50% Convulsion Doses of Lidocaine," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 810, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 127130. Kinghorn, Douglas A., Djaja D. Soejarto, 1985. "Current Status of Stevioside as a Sweetening Agent for Human Use," Economic and Medicinal Plant Research (published by Academic Press Inc., London), Volume 1, page 1-52. Kinghorn, Douglas A., 1992. "Food Ingredient Safety Review: Stevia rebaudiana leaves," prepared for Herb Research Foundation, unpublished -- submitted to the FDA, March 16, 1992. Kingsley, W.H., F.G. Hirsch, 1954-1955. "Toxicological Considerations in Direct Process Spirit Duplication Machines," Compen. Medicine, Volume 40, page 7-8. Kini, M.M., J.R. Cooper, 1961. "Biochemistry of Methanol Poisoning-III," Biochemical Pharmacology, Volume 8, page 207-215. Knoop, R.H., 1976. "Effects of Aspartame in Young Persons During Weight Reduction" Journal of Toxicology and

Environmental Health, Volume 2, page 417-428. Koehler, SM, A. Glaros, 1988. "The Effect of Aspartame on Migraine Headache," Headache, Volume 28, page 10-14. Koeppe, Robert A., et al., 1991. "Effect of AspartameDerived Phenylalanine on Neutral Amino Acid Update in Human Brain: A Positron Emission Tomography Study," Journal of Neurochemistry, Volume 56, No. 5, page 1526-1535. Koestner, Adalbert, 1984. "Aspartame and Brain Tumors: Pathology Issues," IN Stegink, L., Filer L., 1984. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y., page 447-457. Krueck, W.G., et al., 1994. "MR Assessment of RadiationInduced Blood-Brain Barrier Permeability Changes in Rat Glioma Model," AJNR, American Journal of Neuroradiology, Volume 15, No. 4, page 625-632. Kruesi, Markus J.P., et al., 1987. "Effects of Sugar and Aspartame on Aggression and Activity in Children," American Journal of Psychiatry, Volume 144, page 14871490. Kruse, JA, 1992. "Methanol Poisoning," Intensive Care Medicine, Volume 18, No. 7, page 391-397. Kulczycki Jr., Anthony, 1995, "Aspartame-induced hives," Journal of Allergy & Clinical Immunology, February 1995, page 639-640. Kurland, L.T., "Amyotrophic Lateral Sclerosis and Parkinson's Disease Complex on Guam Linked to an Environmental Neurotoxin," Trends in Neuroscience, Volume 11, page 51-54. Lajtha, Abel, Margaret Reilly, David Dunlop, 1994. "Aspartame Consumption: Lack of Effects on Neural Function," Journal of Nutritional Biochemistry, Volume 5, page 266-283. Lawrence, J.F., J.R. Iyengar, 1987. "Liquid Chromatographic Determination of Beta-Aspartame in Diet Soft Drinks, Beverage Powders and Pudding Mixes," Journal of Chromatography, Volume 404, page 261-266. Lawson, David H., et al., 1985. "The Effect of a Phenylalanine and Tyrosine Restricted Diet on Elemental Balance Studies and Plasma Aminograms of Patients with Disseminated Malignant Melanoma," American Journal of Clinical Nutrition, Volume 41, page 73-84. Leaf, G., L.J. Zatman 1952, "A Study of the conditions Under Which Methanol May Exert a Toxic Hazard in Industry," British Journal ofIndustrial Medicine, Volume 9, page 1931. Lee, E.W., et al., 1992. "Lack of Blood Formate Accumulation

in Humans Following Exposure to Methanol Vapor at the Current Permissible Exposure Limit of 200 ppm," American Industrial Hygiene Association Journal, Volume 53, page 99-104. Leibovitz, B. 1992. "Nutrition: At the Crossroads" by Brian Leibovitz, Ph.D. Reprinted in the book "Stop The FDA" edited by John Morgenthaler & Steven Wm. Fowkes, Health Freedom Publications, Menlo Park, CA, c1992 Leibovitz, B., 1993. "Safety of Amino Acids Used as Dietary Supplements," American Journal of Clinical Nutrition, Volume 57, page 944-948. Lemkey-Johnston, N., W.A. Reynolds, 1974. "Nature and Extent of Brain Lesions in Mice Related to Ingestion of Monosodium Glutamate," Journal of Neuropathology and Experimental Neurology, Volume 33, page 74-97. Leon, Arthur S., et al., 1989. "Safety of Long-Term Large Doses of Aspartame," Archives of Internal Medicine, Volume 149, page 2318-2324. Levy, Harvey L., et al., 1994. "Maternal Mild Hyperphenylalaninaemia: An International Survey of Offspring Outcome," The Lancet, Volume 344, page 15891593. Levy, Harvey L., et al., 1995. "Outcome in Offspring of Women With Mild Hyperphenylalaninaemia," The Lancet, Volume 345, page 386. Liberman, Harris R., Benjamin Caballero, et al., 1988. "The Effects of Aspartame on Human Mood, Performance, and Plasma Amino Acid Levels," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 196-200. Liesivuori, Jyrik, 1986. "Slow Urinary Elimination of Formic Acid in Occupationally Exposed Farmers," Annals of Occupational Hygiene, Volume 30, No. 3, page 329-333. Liesivuori, Jyrik, H. Savolainen, 1987. "Urinary Formic Acid as an Indicator of Occupational Exposure to Formic Acid and Methanol," American Industrial Hygiene Association Journal, Volume 48, page 32-34. Liesivuori, Jyrki, Heikki Savolainen, 1991. "Methanol and Formic Acid Toxicity: Biochemical Mechanisms," Pharmacology & Toxicology, Volume 69, page 157-163. Lipton, Stuart A., Paul A. Rosenberg, 1994. "Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders," New England Journal of Medicine, Volume 300, No. 9, page 613-622.

Lisa, P. Joseph 1994. "The Assault on Medical Freedom" by P. Joseph Lisa, Hampton Roads Publishing, c1994, page 200. Liu, Kai-Shen, et al., "Irritant Effects of Formaldehyde Exposure in Mobile Homes," Environmental Health Perspectives, Volume 94, page 91-94. Lloyd, Richard, 1995. "Milk Hormone Issue Bloows Up," Alive: Canadian Journal of Health and Nutrition, No. 151, April 1995, page 14-16, 604-435-1919. Lohle, P.N., et al., 1992. "The Pathogenesis of Cerebral Gliomatous Cysts," Neurosurgery, Volume 30, No. 2, page 180-185. Lopez, FJ, et al., 1990. "Endogenous Excitatory Amino Acid Neurotransmission Regulates the Estradiol-Induced LH Surge in Ovariectomized Rats," Endocrinology, Volume 126, No. 3, page 1771-1773. Lund, Eric D., et al., 1981. "Methanol, Ethanol, and Acetaldehyde Contents of Citrus Products," Journal of Agriculture and Food Chemistry, Volume 29, page 361-366. MacKenzie, W.F., F.M. Garner, 1973. "Comparison of Neoplasms in Six Sources of Rats," Journal of the National Cancer Institute, Volume 50, page 1243-1257. Maher, Tomothy J., B.S. Glaeser, Richard J. Wurtman, 1984. "Diurnal Variations in Plasma Concentrations of Basic and Neutral Amino Acids in Red Cell Cencentrations of Aspartate and Glutamate: Effects of Dietary Protein Intake," American Journal of Clinical Nutrition, Volume 39, page 722-729. Maher, Tomothy J., Richard Wurtman, 1987. "Possible Neurologic Effects of Aspartame, a Widely Used Food Additive," Environmental Health Perspectives, Volume 75, page 53-57. Main, D.M., T.J. Hogan, 1983. "Health Effect of Low-Level Exposure to Formaldehyde," Journal of Occupational Medicine, Volume 25, page 896-900. Man, Eugene H., et al., 1983. "Accumulation of D-Aspartic Acid with Age in Human Brain," Science, Volume 220, page 1407-1408. Man, Eugene H., Jeffrey L. Bada, 1987a. "Dietary D-Amino Acids," Annual Review of Nutrition, Volume 7, page 209225, Man, Eugene H., et al., 1987b. "D-Aspartate in Human Brain," Journal of Neurochemistry, Volume 48, page 510-515. Mann, John, et al., 1980. "D-Phenylalanine in Endogenous Depression," American Journal of Psychiatry, Volume 137, page 1611-1612.

Martin-Amat, G., K.E. McMartin, S.S. Hayreh, M.S. Hayreh, Thomas Tephly, 1978. "Methanol Poisoning. Ocular Toxicity Produced By Formate," Toxicology and Applied Pharmacology, Volume 45, page 201. Martin-Du Pan, R., et al., 1982. "Effect of Various Oral Glucose Doses on Plasma Neutral Amino Acid Levels," Metabolism, Volume 31, No. 9, page 937-943. Martinez, F. J. Castillo, et al., 1993a. "Neuroexcitatory Amino Acid Levels in Plasma and Cerebrospinal Fluid During Migraine Attacks," Cephalagia, Volume 13, No. 2, page 89-93. Martinez, F., Castillo, et al., 1993b. "Taurine Levels in Plasma and Cerebrospinal Fluid in Migraine Patients," Headache, Volume 33, No. 6, page 324-327. Martini, Betty, 1995a. Conversations between Betty Martini of Mission Possible and Mark D. Gold. Martini, Betty, 1995b. Letter and documentation from Betty Martini of Mission Possible to Ms. B. Glassner of Twin Laboratories, Inc. dated September 7, 1995. Matalon, Reuben, et al., 1988. "Aspartame Consumption in Normal Individuals and Carriers for Phenylketonuria (PKU)," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 41-52. Mathur, A., N. Khanna, U.C. Chaturvedi, 1992. "Breakdown of Blood-Brain Barrier By Virus-Induced Cytokine During Japanese Encephalitis Virus Infection, International Journal of Experimental Pathology, Volume 73, No. 5, page 603-611. Mawdesley- Thomas, L.E., A.J. Newman, 1974. "Some Observations on Spontaneously Occurring Tumors of the Central Nervous System of Sprague-Dawley Derived Rats," Journal of Pathology, Volume 112, page 107-116. Mayerhoff, Adina, 1995. Letter from Adina Mayerhoff, Product Information Director, Twin Laboratories, Inc. to Betty Martini dated October 25, 1995. Mazur, Robert, James Schlatter, Arthur Goldkemp 1969. "The Structure-Taste Relationship of Some Dipeptides," Journal of the Americna Chemical Society, Volume 91, No. 2, page 684. McCaleb, Rob, 1995. "Stevia Leaf - Too Good To Be Legal?" Herb Research Foundation additional to the Medicinal Herb Frequently Asked Questions (FAQ) for the Internet HERB mailing list. Available by FTP at sunsite.unc.edu in the

directory pub/academic/medicine/alternativehealthcare/herbs/faqs/ Also available at http://sunsite.unc.edu/herbmed by World Wide Web (WWW). McMartin, Kenneth E., et al., 1975. "Methanol Poisoning: I. The Role of Formic Acid in the Development of Metabolic Acidosis in the Monkey and Reversal by 4-Methylpyrazole," Biochemical Medicine, Volume 13, page 319-333. McMartin, Kenneth E., et al., 1978. "Lack of a Role for Formaldehyde in Methanol Poisoning in the Monkey," Biochemical Pharmacology, Volume 28, page 645-649. McMartin, Kenneth E., et al., 1980. "Methanol Poisoning in Human Subjects," The American Journal of Medicine, Volume 68, page 414-418. McNamara, Damian, 1995. "Sweeteners Plateau," Chemical Marketing Reporter, Volume 247, No. 22, May 29, 1995, page SR16-SR18. Medhamurthy, R., et al., 1990. "Stimulation of Gonadotropin Secretion in Prepubertal Monkeys After Hypothalamic Excitation with Aspartate and Glutamate," Journal of Clinical Endocrinology and Metabolism, Volume 71, No. 5, page 1390. Merck 1992. "The Merck Manual" 16th Edition, Merck Research Laboratory, Merck & Co. Inc., Rahway, N.J. Merrill, Richard, A., 1977. Memorandum from Richard A. Merrill, Chief Counsel, Food and Drug Administration to U.S. Attorney, Samuel K. Skinner, January 10, 1977, Reprinted in Congressional Record 1985b, page S10827S10835. Metzenbaum, Senator Howard, 1985. Testimony of U.S. Senator Howard Metzenbaum of Ohio at "Aspartame Safety Act," Congressional Record, Volume 131, No. 106, August 1, 1985, page S10821. Milich, R., W.E. Pelham, 1986. "The Effects of Sugar Ingestion on the Classroom and Playgroup Behavior of Attention Deficit Disordered Boys," Journal of Consulting and Clinical Psychology, Volume 54, page 714-718. Millman, Nancy, 1995. "King of the Tabletop," Chicago Tribune, Sunday, September 17, 1995, page C1. Mission Possible 1994. Compiled by researchers, physicians, and artificial sweetner experts for Mission Possible, a group dedicated to warning consumers about aspartame. Available from the Aspartame Consumer Safety Network, P.O. Box 780634, Dallas, Texas 75378, (214/352-4268). Molhave, L., et al., 1986. "Dose-Response Relation of Volitile Organic Compounds in the Sick Building Syndrome," Clinical Ecology, Volume 4, No. 2, page 52-56.

Moneret-Vautrin, D.A., 1987. "Monosodium Glutamate Induced Asthma: A Potential Risk of 30 Asthmatics and a Review of the Literature," Allergy and Immunology, Volume 19, page 29-35. Monsanto 1990. "Monsanto Annual Report," 1990. Monsanto 1991. "Monsanto Annual Report," 1991. Monsanto 1992. "Monsanto Annual Report," 1992. Monsanto 1993. "Monsanto Annual Report," 1993. Monsanto 1994. "Monsanto Annual Report," 1994. Monsanto 1995a. "MonsantoFund: Monsanto's Charitable Contributions," World Wide Web page: http://www.monsanto.com:80/phil/. Monte, Woodrow C., 1984. "Aspartame: Methanol and the Public Health," Journal of Applied Nutrition, Volume 36, No. 1, page 42-54. Monte, Woodrow C., 1995. Telephone conversation between Mark D. Gold and Dr. Woodrow Monte, April 21, 1995. Morgan KJ, et al., 1985. "Soft drink consumption patterns of the U.S. population," Journal of the American Dietetic Association, Volume 85, page 352-354. Moser, Robert H., 1990. "NutraSweet Response: 'Our Products Are Safe,'" Wednesday Journal, April 11, 1990, Reprinted in Mullarkey (1992). Moser, Robert H., 1994, "Aspartame and Memory Loss," Journal of the American Medical Association, Volume 272, No. 19, page 1543. Moskal, Phil, 1990. Letter from Dr. Phil Moskal to George Leighton, June 19, 1990, Reprinted in Stoddard (1995a). Mo-Suwan, L., et al., 1993. "Increasing Obesity in School Children in a Transitional Society and the Effect of the Weight Control Program," Southeast Asian Journal of Tropical Medicine and Public Health, Volume 24, No. 3, page 590-594. MSG 1994. "A Report of the Proceedings of an MSG Workshop Held August 1991," Organized by L.J. Filer, Critical Reviews in Food Science and Nutrition, Volume 34, No. 2, page 159-174. Mullarkey, Barbara, 1992. "Bittersweet Aspartame: A Diet Delusion" by Barbara Alexander Mullarkey, NutriVoice, P.O. Box 946, Oak Park, Illinois 60303, (708) 848-0116. Mullarkey, Barbara, 1994a. "How Safe Is Your Artificial Sweetner" by Barbara Mullarkey, May/June 1994. Available from Informed Consent Magazine, P.O. Box 935, Williston, ND 58802-0935, 701/859-3002. Available from NutriVoice,

P.O. Box 946, Oak Park, Illinois 60303, (708) 848-0116. Mullarkey, Barbara, 1994b. Account of John Cook as published in Informed Consent Magazine. "How Safe Is Your Artificial Sweetner" by Barbara Mullarkey, September/October 1994. Available from Informed Consent Magazine, P.O. Box 935, Williston, ND 58802-0935, 701/8593002. Available from NutriVoice, P.O. Box 946, Oak Park, Illinois 60303, (708) 848-0116. Mullarkey, Barbara, 1995. Conversations between Mark D. Gold and Barbara Mullarkey in 1995. National Research Council 1981. "Formaldehyde and Other Aldehydes," National Research Council, National Academy Press, Washington, D.C., c1981. NBAA Digest 1993. "OperationallySpeaking" by G. Dennis Wright, Vice President of Operations. NBAA Digest, Volume 6, Number 6, June 1993. Available from National Business Aircraft Association, Inc., 1200 Eighteenth St., NW, Suite 200, Washington, DC 20036-2506, (202) 783-9000. Nelson, P.E., J.E. Hoff, 1969. "Tomato Volatiles: Effect of Variety, Processing and Storage Time," Journal of Food Science, Volume 34, page 53-57. Nemeroff, Charles B., 1981. "Monosodium Glutamate-Induced Neurotoxicity: Review of the Literature and Call for Further Research," IN "Nutrition & Behavior," Edited by Sanford A. Miller, The Franklin Institute Press, c1981, page 177-211. Newman, A.J., R. Heywood, et al., 1973. "The Administration of Monosodium L-Glutamate to Neonatal and Pregnant Rhesus Monkeys," Toxicology, Volume 1, page 197-204. Nicholls, David, and David Attwell, 1990. "The Release and Uptake of Excitatory Amino Acids," Trends in Pharmacological Sciences, Volume 11, No. 11, page 462468. Nisperos-Carriedo, M.D., P.E. Shaw, 1989. "Comparison of volatile flavor component in fresh and processed orange juices" Presented at Annual Meeting, Institute of Food Technology, Chicago, June 25-29, 1989. Nisperos-Carriedo, Myrna O., Philip E. Shaw, 1990. "Comparison of Volatile Flavor Components in Fresh and Processed Orange Juices,"Journal of Agriculture & Food Chemistry, Volume 38, page 1048-1052. Novick, Nelson Lee, 1985. "Aspartame-Induced Granulomatous Panniculitis," Annals of Internal Medicine, Volume 102, No. 2, page 206-207. NSDA 1983. "Objections of the National Soft Drink Association to a Final Rule Permitting the Use of Aspartame in Carbonated Beverages and Carbonated Beverage Syrup Bases and a Request for a Hearing on the

Objections," Docket No. 82F-0305, Draft, July 28, 1983. Transcript of objections appeared in Congressional Record, Volume 131, No. 58, May 7, 1985, 5507-5511. Okaniwa, A., 1979. "Histopathological Study of Effects of Potassium Aspartate on the Hypothalamus of Rats," Journal ofToxicological Sciences, Volume 4, page 31-46. Oliver, Janice F., 1991. Letter from Janice F. Oliver, Director, Office of Regulatory Guidance, Center for Food Safety and Applied Nutrition, Food and Drug Administration to Jack L. Samuels in December 1991. Olney, John W., Lawrence G. Sharpe, 1969a. "Brain Lesions in an Infant Rhesus Monkey Treated with Monosodium Glutamate," Science, Volume 166, page 386-388. Olney, John W., 1969b. "Brain Lesions, Obesity and Other Disturbances in Mice Treated With Monosodium Glutamate," Science, Volume 164, page 719-721. Olney, John W., 1969c. "Glutamate-induced Retinal Degeneration in Neonatal Mice. Electron Microscopy of the Acutely Evolving Lesion," Journal of Neuropathology and Experimental Neurology, Volume 28, page 455-474. Olney, John W., et al., 1970. "Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine," Nature, Volume 227, page 609-610. Olney, John W., et al., 1971. "Glutamate-Induced Neuronal Necrosis in the Infant Mouse Hypothalamus: An Electron Microscopic Study," Journal of Neuropathology and Experimental Neurology, Volume 30, page 75-90. Olney, John W., et al., 1972. "Glutamate-Induced Brain Damage of Infant Primates," Journal of Neuropathology and Experimental Neurology, Volume 31, page 464-488. Olney, John W., et al., 1976. "Acute Glutamate-Induced Elevations in Serum Testosterone and Leuteinizing Hormone," Brain Research, Volume 112, page 420-424. Olney, John W., et al., 1980. "Brain Damage in Mice From Voluntary Ingestion of Glutamate and Aspartate," Neurobehavioral Toxicology and Teratology, Volume 2, page 125-129. Olney, John W., 1984. "Excitotoxic Food Additives--Relevance of Animal Studies to Human Safety," Neurobehavioral Toxicology and Teratology, Volume 6, page 455-462. Olney, John W., et al., 1986. "The Anti-Excitotoxic Effects of Certain Anesthetics, Analgesics and SedativeHypnotics," Neuroscience Letters, Volume 68, page 29-34. Olney, John W. 1987. Letter from Dr. John W. Olney, Neuropathologis, Washington University School of Medicine, to Senator Howard M. Metzenbaum, December 8, 1987, Presented in the record before the U.S. Senate

Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 468-476. Olney, John W., 1988. "Excitotoxic Food Additives: Functional Teratological Aspects," In Progress in Brain Research, Volume 73 -- Biochemical Basis of Functional Neuroteratology: Permanent Effects of Chemicals on the Developing Brain, Edited by Boer, G.J., et al., Elsevier, New York, c1988. Olney, John W., 1990a. "Excitotoxic Amino Acids and Neuropsychiatric Disorders," IN "Annual Review of Pharmacology and Toxicology," Volume 30, R. George, AK Cho and TF Blaschke (Eds), Annu Rev Inc., Palo Alto, CA, c1990, page 47-71. Olney, John W., 1990b. "Excitotoxin-Mediated Neuron Death in Youth and Old Age," Progress in Brain Research, Volume 86, page 37-51. Olney, John W., 1993. "Prepared Statement for the Public Meeting (April 1993) Pertaining to Adverse Reactions to Monosodium Glutamate (MSG)," statement submited to the 1993 Federation of American Societies for Experimental Biology (FASEB) LSRO Committee Proceedings, FDA Dockets Management Branch, FDA Docket No. 92N-0391. Olney, John W., 1994. "Excitotoxins in Foods," NeuroToxicology, Volume 15, Number 3, page 535-544. Ornish, Dean, 1990. "Dr. Dean Ornish's Program For Reversing Heart Disease," Ballantine Books, c1990, ISBN 0-345-373537. Oser, B.L., et al., 1971. "Oral and Subcutaneous Administration of MSG to Infant Rodents and Dogs," Nature, Volume 229, page 411-413. Oser, B.L., et al., 1974. "Monosodium Glutamate Studies in Four Species of Neonatal and Infant Animals," Food and Chemical Toxicology, Volume 13, page 7-14. Osterloh, J., 1986. "The Utility of Tetrabromophenophthalein Methyl Ester (TBPME) Spot Test for the Identification of Drug Positive Urines," Journal of Analytical Toxicology, Volume 10, page 255. Pacific Flyer 1988. "This Could Save Your Life" Pacific Flyer Aviation News, November 1988, 3355 Mission Ave., Oceanside, CA 92054. Pamies, R.J., et al., 1993. "Methanol Intoxication. "How to Help Patients Who Have Been Exposed to Toxic Solvents," Postgraduate Medicine, Volume 93, No. 8, page 183-194. Pardridge, William M., 1983. "Brain Metabolism: A Perspective From the Blood Brain Barrier," Physiological Reviews, Volume 63, page 1481-1532.

Pardridge, William M., 1986. "Potential Effects of the Dipeptide Sweetener Aspartame on the Brain," In "Nutrition and the Brain, Volume 7," Edited by R.J. Wurtman and J.J. Wurtman, Raven Press, New York, c1986, page 199-241. Pardridge, William M., 1987. Testimony and Statement of William M. Pardridge, Neuroscientist and Endocrinologist, University of California before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 367-373. Pardridge, William M., 1988a. "Phenylalalnine Trasports at the Human Blood Brain Barrier," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 55-62. Pardridge, William M., 1988b. "Does the Brain's Gatekeeper Falter in Aging," Neurobiology of Aging, Volume 9, page 144-146. Pauli, George, 1995. FDA Center for Food Safety and Applied Nutrition (CFSAN). Radio broadcast: "Aspartame," The Derek McGinty Show, WAMU Radio (88.5 FM), Brandywine Building, The American University, Washington, DC 200168082, (202) 885-1200, August 29, 1995. Paull, W.K., 1975. "An Autoradiographic Analysis of Arcuate Neuron Sensitivity to Monosodium Glutamate," Anatomical Record, Volume 181, page 445. Pearson, Dirk, Sandy Shaw, 1982. "Life Extension: A Practical Scientific Approach," Warner Books, New York, c1982. Perego, C., et al., 1988. "Aspartame and the Rat Brain Monoaminergic System," Toxicology Letters, Volume 44, page 331-339. Perl, T.M., et al., 1990. "An Outbreak of Toxic Encephalopathy Caused By Eating Mussels Contaminated With Domoic Acid," New England Journal of Medicine, Volume 322, page 1775-1780. Pinto, Judith M.B., Timothy J. Maher, 1986. "High Dose Aspartame Lowers the Seizure Threshold to Subcutaneous Pentylenetetrazol in Mice," The Pharmacologist, Volume 28, page 155. Pinto, Judith M.B., Timmothy J. Maher, 1988. "Administration of Aspartame Potentiates Pentylenetetrazole- and Fluorothyl-Induced Seizures in Mice," Neuropharmacology, Volume 27, No. 1, page 51-55.

Plaitakis, Andreas, Soll Berl, Melvin D. Yahr, 1982. "Abnormal Glutamate Metabolism in an Adult-Onset Degenerative Neurological Disorder," Science, Volume 216, page 193-196. Plaitakis, Andreas, Soll Berl, 1983. "Oral Glutamate Loading in Disorders with Spinocerebellar and Extrapyramidal Involvement: Effect on Plasma Glutamate, Aspartate and Taurine," Journal of Neural Transmission, Suppl. 19, page 65-74. Plane & Pilot 1990. "Getting High" Plane & Pilot, January 1990, page 36-37. Plant, TM, VL Gay, et al., 1989. "Puberty in Monkeys is Triggered by Chemical Stimulation of the Hypothalamus," Proceedings of the National Academy of Sciences, Volume 86, page 2506. Plapp, Bryce V., 1975. "Rate-Limiting Steps in Ethanol Metabolism and Approaches to Changing These Rates Biochemically," In "Biochemical Pharmacology of Ethanol," (Advances in Experimental Medicine and Biology, Volume 56), Edited by Edward Majchrowicz, Plenum Press, New York, c1975, pages 79-109. Porikos, Katherine P., Theodore B. Van Italie, 1984. "Efficacy of Low-Calorie Sweeteners in Reducing Food Intake: Studies with Aspartame" IN Stegink, L., Filer L., 1984. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y., page 273-286. Posner, Herbert S., 1975. "Biohazards of Methanol in Proposed New Uses," Journal of Toxicology and Environmental Helath, Volume 1, page 153-171. Price, Madelon, John W. Olney, TJ Cicero, 1978. "Acute Elevations of Serum Luteinizing Hormone Induced by Kainic Acid, N-methylaspartic acid or homocysteic acid," Neuroendocrinology, Volume 26, page 352-358. Prudel, M., et al., 1986. "Kinnetics of Decomposition of Aspartame Hydrochloride (Usal) in Aqueous Solutions," Journal of Food Science, Volume 51, No. 6, page 1393-1397. Rajatanavin, R., 1993. "Postpartum Thyroid Dysfunction: A Viewpoint From Thailand," Ann Acad Med Singapore, Volume 22, No. 4, page 587-592. Raiford, Morgan B., 1987. Letter from Dr. Morgan B. Raiford to the Office of Senator Howard Metzenbaum. The statement was put in the record before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 517-518. Ranney, R.E., et al., 1976. "Comparative Metabolism of Aspartame in Experimental Animals and Humans," Journal of Toxicology and Environmental Health, Volume 2, page 441451.

Ratner, David, Elyakim Eshel, Ehud Shoshani, 1984. "Adverse Effects of Monosodium Glutamate: A Diagnostic Problem," Israel Journal of Medicine, Volume 20, page 252-253. Reilly, Margaret A., Edmund A. Debler, Arthur Fleischer, Abel Lajtha, 1989. "Lack of Effect of Chronic Aspartame Ingestion on Aminergic Receptors in Rat Brain," Volume 38, No. 23, page 4339-4341. Remington, Dennis W., Barbara W. Higa, 1987. "The Bitter Truth About Artificial Sweeteners," Published by Vitality House International, Inc., 3707 North Canyon Road #8-C, Provo, Utah 84604, (801) 224-9214. Reynolds, W. Ann, N. Lemkey-Johnston, L.J. Filer, Jr., R.M. Pitkin, 1971. "Monosodium Glutamate: Absence of Hypothalamic Lesions After Ingestion by Newborn Primates," Science, Volume 172, page 1342-1344. Reynolds, W. Ann, et al., 1976. "Hypothalamic Morphology Following Ingestion of Aspartame or MSG in the Neonatal Rodent and Primate: A Priliminary Report," Journal of Toxicology and Environmental Health, Volume 2, page 471480. Reynolds, W. Ann, Lewis D. Stegink, L.J. Filer, Jr., et al., 1980. "Aspartame Administration to the Infant Monkey: Hypothalamic Morphology and Plasma Amino Acid Levels," Anatomic Record, Volume 198, page 73-85. Risau, W., H. Wolburg, Letter to the Editor, Trends in Neuroscience, Volume 14, page 15. Roak-Foltz, R., Leveille, G., 1984. "Projected Aspartame Intake: Daily Ingestion of Aspartic Acid, Phenylalanine, and Methanol," in Stegink, L., Filer L., 1984. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y. Roberts, H.J., 1988. "Reactions Attributed to AspartameContaining Products: 551 Cases," Journal of Applied Nutrition, Volume 40, page 85-94. Roberts, H.J., 1990a. "Aspartame (NutraSweet):Is It Safe?" by H.J. Roberts, M.D. The Charles Press Publishers, Philadelphia, PA, c1990. Excerpt from page 91. Roberts, H.J., 1990b. "Letters to the Editor," The Expert Witness Journal, Volume 2, No. 4, April 1990, page 14-18, Reprinted in Stoddard (1995a). Roberts, H.J., 1991. "Does Aspartame Cause Human Brain Cancer?" Journal of Advancement in Medicine, Volume 4, No. 4, Winter 1991, page 231-241. Roberts, H.J. 1992. "Sweet'ner Dearest" by H.J. Roberts, M.D., The Sunshine Sentinel Press, Inc., PO Box 8697, West Palm Beach, FL 33407, (407) 832-2409, c1992, page 85.

Roberts, H.J. 1994. Statement of H.J. Roberts, M.D., Concerning the Use of Products Containing Aspartame (NutraSweet) by Persons with Diabetes and Hypoglycemia. Available from Dr. H.J. Roberts, M.D., 300 27th Street, West Palm Beach, Florida 33407-5299 (404/832-2408). Roe, O., 1982. "Species Differences in Mehtanol Poisoning," CRC Critical Reviews In Toxicology, October 1982, page 275-286. Rogers, Sherry, 1990. "Tired or Toxic?," Pulished by Prestige Publishers, Syracuse, NY, c1990, ISBN: 0-96188212-3. Rolla, Arturo R., Book Review: "Aspartame (NutraSweet): Is It Safe," New England Journal of Medicine, Volume 323, No. 1., page 1495-1496. Romano, M., et al., 1990. "Plasma and Brain Kinetics of Large Neutral Amino Acids and of Striatum Monoamines in Rats Given Aspartame," Food and Chemical Toxicology, Volume 28, No. 5, page 317-321. Rosenthal, Benjamin, Michael Jacobson, Marcy Bohm, 1976. "Feeding at The Company Trough," Study by Senator Benjamin Rosenthal in conjuction with the Center for Science in the Public Interest (CSPI), reported in "Feeding at the Company Trough," Congressional Record, August 24, 1976, page 27526-27531. Rowe, V.K., S.B. McCollister, 1982. "Alcohols," in "Patty's Industrial Hygiene and Toxicology," Third Edition, John Wiley and Sons, New York. Rowen, A. James, Bennett A. Shaywitz, et al., 1995. "Aspartame and Seizure Susceptibility: Results of a Clinical Study in Reportedly Sensitive Individuals," Epilepsia, Volume 36, No. 3, page 270-275. Rudin, O., et al., 1989. "Glutamins ure-Gruppeinintoxikation Sogenanntes China-Restaurant-Syndrom," Beitrag Gericht Med., Volume 47, page 69-71. Rudman, Daniel, et al., 1991. "Delayed Plasma Clearance of Phenylalanine and Tyrosine in Elderly Men," Journal of the American Geriatrics Society, Volume 39, page 33-38. Ryan-Harshman, M., et al., 1987. "Phenylalanine and Aspartame Fail to Alter Feeding Behavior, Mood and Arousal in Men" Physiology and Behavior, Volume 39, page 247-253. Sabelli, H.C., et al., 1986. "Clinical Studies on the Phenylethylamine Hypothesis of Affective Disorder: Urine and Blood Phenylacetic Acid and Phenylalanine Dietary Supplements," Journal of Clinical Psychiatry, Volume 47, page 66-70. Said, S. I., et al., 1994. "NMDA Receptors in the Lung:

Activation Triggers Acute Injury That is Prevented by No Synthase Inhibitor and by VIP," Society for Neuroscience Abstracts, Volume 20, page 649. Samuels, Jack, Adrienne Samuels, 1993. "MSG: The Truth & Consequences," Search For Health, Report Number 18, September/October 1993, P.O. Box 11089, Naples, Florida 33941, (813) 263-4101. Samuels, Jack, Adrienne Samuels, 1995a. Conversations between Mark D. Gold and Jack and Adrienne Samuels in 1995. Samuels, Adrienne, 1995b. "Excitatory Amino Acids in Neurologic Disorders," (letter), New England Journal of Medicine, Volume 331, No. 4, page 274-275. Saravis, Susan, et al., 1990. "Aspartame: Effects on Learning, Behavior, and Mood," Pediatrics, Volume 86, No. 1, page 75-82. Sauri, E., et al., 1981. "Rev. Agroquim Tecnol. Aliment. (Inst. Agroquim. Tecnol. Alimentos, CSIC, Valencia, Spain 10), Volume 21, No. 2, page 276-280. Scheibel, A.B., T. Duong, "On the Possible Relationship of Cortical Microvascular Pathology to Blood-Brain Barrier Changes in Alzheimer's Disease," Neurobiology of Aging, Volume 9, page 41-42. Schaumburg, Herbert H., et al., 1969. "Monosodium LGlutamate: Its Pharmacology and Role in the Chinese Restaurant Syndrome," Science, Volume 163, page 826-828. Schiffman, Susan S., et al., 1987. "Aspartame and Susceptibility to Headache," The New England Journal of Medicine, Volume 317, No. 19, page 1181-1185. Schmid, K., et al., 1994. "The Importance of Formic Acid Excretion in the Urine for Environmental and Occupational Medicine Questions," Zentralbl Hyg Umweltmed, Volume 196, No. 2, page 139-152. Schmidt, Alexander M., 1976a. Testimony of Alexander M. Schmidt, Commissioner, U.S. Food and Drug Administration before the U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 4-49. Schmidt, Alexander M., 1976b. Statement by Alexander M. Schmidt, Commissioner, U.S. Food and Drug Administration before the U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical

Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 50-110. Schmidt, Alexander M., 1976b. Statement by Alexander M. Schmidt, Commissioner, U.S. Food and Drug Administration before the U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 3," No. Y4.L11/2:P49/2/976/pt.3, CIS# S541-12, page 3-56. Science, 1990. "Amino Acids: How Much Excitement Is Too Much," Science, Volume 247, page 20-23. Scopp, Alfred L., 1991. "MSG and Hydrolyzed Vegetable Protein Induced Headache: Review and Case Studies," Headache, Volume 31, No. 2, page 107-110. Searle 1975. "G.D. Searle Annual Report," 1975. Searle, Daniel C. 1976b. Statement of Daniel C. Searle, Chief Executive Officer, G.D. Searle & Co. before the U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 173-184. Searle, Daniel C. 1976b. Letter from Daniel C. Searle, Chief Executive Officer, G.D. Searle & Co., to U.S. Senator Edward M. Kennedy, February 13, 1976, Reprinted in U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 279-311. Settipane, G.A., 1987. "The Restaurant Syndromes," New England Regional (Society of) Allergy Proceedings, Volume 8, No. 1, page 39-46. Shahangian, Shahram, et al., "Aspartame Not a Source of Formate Toxicity," Clinical Chemistry, Volume 30, No. 7, 1984. Shapira, Y., et al., 1993. "Blood-Brain Barrier Permeability, Cerebral Edema, and Neurologic Function After Closed Head Injury in Rats," Anesthesia and Analgesia, Volume 77, No. 1, page 141-148. Shapiro, Robert, 1987. Statement of Robert Shapiro, Chief Executive Officer, NutraSweet Company, before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 400-427.

Sharp, Carlton, 1975. Memorandum from Carlton Sharp and Searle Investigation Task Force to the Searle Investigation Steering Committee, December 8, 1975, Reprinted in U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82, page 24-28. Shaywitz, B.A., et al., 1993. "Evaluation of Aspartame on Behavior and Cognitive Function in Children With Attention Deficit Disorder (ADD)," Journal of Clinical and Experimental Neuropsychology, Volume 15, page 407 Shaywitz, B.A., et al., 1994a, "Aspartame Has No Effect on Seizures or Epileptiform Discharges in Epileptic Children," Annuls of Neurology, Volume 35, page 98-103. Shaywitz, Bennett A., et al., 1994b. "Aspartame, Behavior, and Cognitive Function in Children With Attention Deficit Disorder," Pediatrics, Volume 93, page 70-75. Shulkin, Barry L., et al., 1995. "Inhibition of Neutral Amino Acid Transport Across the Human Blood-Brain Barrier by Phenylalanine," Journal of Neurochemistry, Volume 64, page 1252-1257. Siragusa, Roy J., et al., 1988. "Methanol Production From the Degradation of Pectin by Human Colonic Bacteria," American Journal of Clinical Nutrition, Volume 47, page 848-851. Skurray, George R., Nicholas Pucar, 1988. "L-Glutamic Acid of Fresh and Processed Foods," Food Chemistry, Volume 27, page 177-180. Smith, Isabel, Sarah Tillotson, 1995. "Outcome in Offspring of Women With Mild Hyperphenylalaninaemia," The Lancet, Volume 345, page 385-386. Smith, Q. R., 1991. "The Blood-Brain Barrier and the Regulation of Amino Acid Uptake and Availability to Brain," Advances in Experimental Medicine and Biology, Volume 291, page 55-71. Spatz, H., B. Heller, M. Nachon, E. Fischer, 1975. "Effects of D-Phenylalanine on Clinical Picture and Phenethylaminuria in Depression," Biological Psychiatry, Volume 10, No. 2, page 235-239. Spencer, P.S., et al., 1986. "Lathyrism: Evidence For Role of the Neuroexcitatory Amino Acid BOAA," Lancet, Volume 2, page 1066-1067. Spencer, P.S., et al., 1987. "Guam Amyotrophic Lateral Sclerosic-Parkinsonism-Dementia Linked to a Plant Excitant Neurotoxin," Science, Volume 237, page 517-522.

Spiers, P.A., Donald Schomer, LuAnn Sabounjian, Harris Lieberman, Richard Wurtman, John Duguid, Riley McCarten, Michele Lyden, 1988. "Aspartame and Human Behavior: Cognitive and Behavioral Observations," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 810, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 169178. Spiers, P.A., 1993a. Aspartame: Cognitive, Behavioral and Electrophysiological Aspects Conference, P.A. Spiers, Organizer and Chair, Journal of Clinical and Experimental Neuropsychology, Volume 15, page 406-407. Spiers, P.A., D.L. Schomer, R.J. Wurtman, et al., 1993b. "Lack of Neuropsychological Effects From Chronic or Acute Aspartame (NutraSweet) and Sucrose Consumption," Journal of Clinical and Experimental Neuropsychology, Volume 15, page 407. Srivastava, A.K., et al., 1992. "Clinical studies of employees in a sheet-forming process at a paper mill," Veterinary and Human Toxicology, Volume 34, No. 6, page 525-527. Stadtman, Flloyd H., 1972. "Free Amino Acids in Raw and Processed Tomato Juices by Ion Exchange Chromatography With a Lithiu Citrate Column for Separation of Glutamine and Asparagine From Threonine and Serine," Journal of Food Science, Volume 37, page 944-951. Stamp, Jeffrey A., Theodore P. Labuza, 1989a. "An Ion-Pair High Performance Liquid Chromatographic Method for the Determination of Aspartame and its Decomposition Products," Journal of Food Science, Volume 54, No. 4, pg. 1043-1046. Stamp, Jeffrey A., Theodore P. Labuza, 1989b. "Mass Spectrometric Determination of Aspartame Decomposition Products. Evidence for B-isomer Formation in Solution," Food Additives and Contaminants, Volume 6, page 397-414. Stegink, Lewis D., W. Ann Reynolds, L.J. Filer, Jr., et al., 1975. "Monosodium Glutamate Metabolism in the Neonatal Monkey," American Jounral of Physiology, Volume 229, No. 1, page 246-250. Stegink, Lewis D., et al., 1977. "Effect of Aspartame and Aspartate Loading Upon Plasma and Erythrocyte Free Amino Acid Levels in Normal Adult Volunteers," Journal of Nutrition, Volume 107, page 1837-1845. Stegink, Lewis D., W.A. Reynolds, L.J. Filer, et al. 1979a. "Comparative Metabolism of Glutamate in the Mouse and Man," In Filer L.J. Jr., Garattini, S., Dare MR, Reynolds

WA, Wurtman RJ (eds): "Glutamic Acid: Advances in Biochemistry and Physiology," Raven Press, New York 1979, pages 85-102. Stegink, Lewis D., et al. 1979b. "Factors Affecting Plasma Glutamate Levels in Normal Adult Subjects," In Filer L.J. Jr., Garattini, S., Dare MR, Reynolds WA, Wurtman RJ (eds): "Glutamic Acid: Advances in Biochemistry and Physiology," Raven Press, New York 1979, pages Stegink, Lewis D., L.J. Filer Jr., George L. Baker, 1979c. "Plasma, Erythrocyte and Human Milk Levels of Free Amino Acids in Lactating Women Administered Aspartame or Lactose," Journal of Nutrition, Volume 109, page 21732181. Stegink, Lewis D., L.J. Filer, Jr., George L. Baker, Jean E. McDonnell, 1979d. "Effect of Aspartame Loading Upon Plasma and Erythrocyte Levels of Amino Acids in Phenylketonuric Heterozygous and Normal Subjects," Journal of Nutrition, Volume 109, page 708-717. Stegink, Lewis D., L.J. Filer, Jr., George L. Baker, Jean E. McDonnell, 1980. "Effect of an Abuse Dose of Aspartame Upon Plasma and Erythrocyte Levels of Amino Acids in Phenylketonuric Heterozygous and Normal Adults," Journal of Nutrition, Volume 110, page 2216-2224. Stegink, Lewis D., et al., 1981a. "Blood Methanol Concentrations in Normal Adult Subject Administered Abuse Doses of Aspartame," Journal of Toxicology and Environmental Health, Volume 7, page 281-290. Stegink, Lewis D., et al., 1981b. "Plasma and Erythrocyte Concentrations of Free Amino Acids in Adult Humans Administered Abuse Doses of Aspartame," Journal of Toxicology and Environmental Health, Volume 7, page 291305. Stegink, Lewis D., L. Filer, G.L. Baker, 1983a. "Blood Methanol Concentrations in One-Year-Old Infants Administered Graded Doses of Aspartame," Journal of Nutrition, Volume 113, page 1600-1606. Stegink, Lewis D., L.J. Filer, G.L. Baker, 1983b. "Effect of Carbohydrate on Plasma and Erythrocyte Glutamate Levels in Humans Ingesting Large Doses of Monosodium L-Glutamate in Water," American Journal of Clinical Nutrition, Volume 37, page 961-968. Stegink, Lewis D., L.J. Filer, G.L. Baker, 1983c. "Plasma Amino Acid Concentrations in Normal Adults Fed Meals With Added Monosodium L-Glutamate and Aspartame," Journal of Nutrition, Volume 113, page 1851-1860. Stegink, Lewis D., Filer L., 1984a. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y. Stegink, Lewis D., 1984b. "Aspartame Metabolism in Humans: Acute Dosing Studies," IN Stegink, L., Filer L., 1984.

"Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y., page 509-553. Stegink, Lewis D., 1984c. "Aspartate and Glutamate Metabolism," IN Stegink, L., Filer L., 1984. "Aspartame: Physiology and Biochemistry," Marcel Dekker, Inc., N.Y., page 47-76. Stegink, Lewis D., L.J. Filer, G.L. Baker, 1985. "Plasma Glutamate Concentrations in Adult Subjects Ingesting Monosodium L-Glutamate in Consomme," American Journal of Clinical Nutrition, Volume 42, page 220-225. Stegink, Lewis D., L.J. Filer, G.L. Baker, Edward Bell, 1986. "Effect of Sucrose Ingestion on Plasma Glutamate Concentrations in Humans Administered Monosodium LGlutmate," American Journal of Clinical Nutrition, Volume 43, page 510-515. Stegink, Lewis D., et al. 1987a. "Plasma Amino Acid Concentrations in Normal Adults Administered Aspartame in Capsules or Solution: Lack of Bioequivalence," Metabolism, Volume 36, No. 5, page 507-512. Stegink, Lewis D., et al., 1987b. "Plasma Amino Acid Concentrations in Normal Adults Ingesting Aspartame and Monosodium L-Glutamate as Part of a Soup/Beverage Meal," Metabolism, Volumn 36, No. 11, page 1073-1079. Stegink, Lewis D., et al., 1987c. "Aspartame-Sweetened Beverage: Effect on Plasma Amino Acid Concentrations in Normal Adults and Adults Heterozygous for Phenylketonuria," Journal of Nutrition, Volume 117, page 1989-1995. Stegink, Lewis D., et al., 1989. "Effect of Repeated Ingestion of Aspartame-Sweetened Beverage on Plasma Amino Acid, Blood Methanol, and Blood Formate Concentrations in Normal Adults," Metabolism, Volume 38, No. 4, page 357363. Stegink, Lews D., et al., 1990. "Repeated Ingestion of Aspartame-Sweetended Beverages: Further Observations in Individuals Heterozygous for Phenylketonuria," Metabolism, Volume 39, No. 10, page 1076-1081. Stellman, S.D., L. Garfinkel, 1986. "Artificial Sweetener Use and One-Year Weight Change Among Women," Preventative Medicine, Volume 15, page 195-202. Stewart, P.A., et al., 1988. "Ethanol and Pentobarbital in Combination Increase Blood-Brain Barrier Permeability to Horseradish Peroxidase," Brain Research, Volume 443, page 12-20. Stoddard, Mary Nash, George Leighton, 1994. "Aspartame and Flying...The Untold Story," Natural Food & Farming, May/June 1994, Reprinted in Stoddard (1995a). Stoddard, Mary Nash, 1995a. "The Deadly Deception" Compiled

by the Aspartame Consumer Safety Network for volumes of available published information, ACSN, P.O. Box 780634, Dallas, Texas 75378, (800) 969-6050. Stoddard, Mary Nash, 1995b. Conversations between Mary Nash Stoddard of the Aspartame Consumer Safety Network and Mark D. Gold. Stokes, Alan F., et al., 1991. "Effects of Acute Aspartame and Acute Alcohol Ingestion Upon the Cognitive Performance of Pilots," Aviation, Space, and Environmental Medicine, Volume 62, page 648-653. Stokes, Alan F., et al., 1993. "Effects of Alcohol and Chronic Aspartame Ingestion Upon Performance in Aviation Relevant Cognitive Tasks," Aviation, Space, and Environmental Medicine, Volume 65, page 7-15. Sturtevant, F., 1985. "Does Aspartame Cause Methanol Toxicity" (Letter To The Editor), Food and Chemical Toxicology, Volume 23, No. 10, page 961, 1985. Suttapreyasri, D., et al., 1990. "Weight-Control TrainingModels for Obese Pupils in Bangkok," Journal of the Medical Association of Thailand, Volume 73, No. 7, page 394-400. Takasaki, Yutaka, et al., 1979. "Toxicological Studies on Monosodium L-Glutamate in Rodents: Relationship Between Routes of Administration and Neurotoxicity," IN Filer L.J. Jr., Garattini, S., Dare MR, Reynolds WA, Wurtman RJ (eds): "Glutamic Acid: Advances in Biochemistry and Physiology," Raven Press, New York 1979, pages 255-275. Takasaki, Y, et. al., 1981. "Drinking Behavior and the Development of Hypothalamic Lesions From Aspartame Ingestion in Water-Restricted Weanling Mice," Journal of Neural Transmission, Volume 50, page 283-295. Tanno, H., et al., 1992. "Breakdown of the Blood-Brain Barrier After Fluid Percussion Brain Injury in the Rat: Part 2: Effect of Hypoxia on Permeability to Plasma Proteins," Journal of Neurotrama, Volume 9, No. 4, page 335-347. Tarasoff, L., M.F. Kelly, 1993. "Monosodium L-Glutamate: A Double-Blind Study and Review," Food and Chemical Toxicology, Volume 31, No. 2, page 1019-1035. Tarasoff, L., M.F. Kelly, 1995. "Letter to the Editor -Monosodium L-Glutamate: A Double-Blind Study and Review," Food and Chemical Toxicology, Volume 33, No. 1, page 6978. Tephly, Thomas R., Kenneth E. McMartin, 1984. "Methanol Metabolism and Toxicity," From the book"Aspartame: Physiology and Biochemistry" Marcel Dekker, Inc., NY, 1984. Terry, L.C., et al., 1981. "Monosodium Glutamate: Acute and

Chronic Effects on Rhythmic Growth Hormone and Prolactin Secretion, and Somatostatin in the Undisturbed Male Rat," Brain Research, Volume 273, page 179-182. The Aviation Consumer 1988. "SafeGuard" The Aviation Consumer, June 15, 1988. Thompson, S.W., R.D. Hunt, 1963. "Spontaneous Tumors in the Sprague-Dawley Rat: Incidence Rates of Some Types of Neoplasms as Determined by Serial Section Versus Single Section Technics," Annuals of the N.Y. Academy of Science, Volume 108, page 832-845. Tollefson, Linda, 1988. "Monitoring Adverse Reactions to Food Additives in the US Food and Drug Administration," Regulatory toxicology and pharmacology, Volume 8, page 438-446. Tollefson, Linda, Robert J. Barnard,1992. "An Analysis of FDA Passive Surveillance Reports of Seizures Associated With Consumption of Aspartame," Journal of the American Dietetic Association, Volume 92, No. 5, page 598-601. Toth, E., Abel Lajtha, 1981. "Elevation of Cerebral Levels on onessential Amino Acids In Vivo by Administration of Large Doses," Neurochemistry Research, Volume 6, page 1309-1317. Toth, L. et al., 1987. "Neurotoxicity of Monosodium-LGlutamate in Pregnant and Fetal Rats," Acta Neuropatholigica, Volume 75, page 16-22. Trefz, Friedrich, Leo de Sonneville, Peter Matthis, Christian Benninger, Brigitte Lanz-Englert, Horst Bickel, 1994. "Neuropsychological and Biochemical Investigations in Heterozygotes for Phenylketonuria During Ingestion of High Dose Aspartame (A Sweetener Containing Phenylalanine)," Human Genetics, Volume 93, page 369-374. Triebig, G., et al., 1989. "Formaldehyde exposure at various workplaces," Science of the Total Envirnment, Volume 79, No. 2, page 191-195. Truth in Labeling Campaign 1994. Citizen Petition filed by Truth in Labeling Campaign with the U.S. Food and Drug Administration on December 13, 1994. Truth In Labeling Campaign, P.O. Box 2532, Darien, IL 60561. Tsang, Wing-Sum, et al., 1985. "Determination of Aspartame and Its Breakdown Products in Soft Drinks by ReversePhase Chromatography with UV Detection," Journal Agriculture and Food Chemistry, Vol. 33, No. 4, page 734738. Turner, James, 1987. Testimony of James Turner, Esq., Community Nutrition Institute before the U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 316.

UNICEF 1986. "Citizens Alliance for Consumer Protection of Korea," United National Childrens Fund (UNICEF), page 1-9. Urbanski, H.F., S.R. Ojeda, 1990. "A Role for N-methyl-Daspartate (NMDA) Receptors in the Control of LH Secretion and Initiation of Female Puberty," Endocrinology, Volume 126, No. 3, page 1774-1776. US Air Force 1992. "Aspartame Alert." Flying Safety 48(5): 20-21 (May 1992). USDA 1988. "1988 United States Department of Agriculture Situation and Outlook Report; Sugar and Sweeteners." Washington, DC: U.S. Government Printing Office, pp. 51. US Senate 1975. U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1975, Part 1," No. Y4.L11/2:P49/2/975, CIS# S541-16. US Senate 1976a. U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 2," No. Y4.L11/2:P49/2/976/pt2, CIS# S541-82. US Senate 1976b. U.S. Senate Joint Hearings before the Subcommittee on Health of the Committee on Labor and Public Welfare and the Subcommittee on Administrative Practice and Procedure of the Committee on the Judiciary, "Preclinical and Clinical Testing by the Pharmaceutical Industry, 1976, Part 3," No. Y4.L11/2:P49/2/976/pt.3, CIS# S541-12. US Senate 1985. "U.S. Senate Hearing Before the Committee on Labor and Human Resources, "Saccharin Study and Labeling Act Amendments of 1985," April 2, 1985. US Senate 1987. U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100. Van Den Eeden, SK, et al., 1994. "Aspartame Ingestion and Headaches," Neurology, Volume 44, page 1787-1793. Velaj, R., et al., 1985. "Comparative Neurotoxicity of Angiographic Contrast Media," Neurology, Volume 35, No. 9, page 1290-1298. Verrett, Jacqueline, 1987. Statement of Dr. Jacqueline Verrett, Former Toxicologist, U.S. Food and Drug Administration before U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 383-390.

Vojdani, A., 1992. "Immune Alteration Associated With Exposure to Toxic Chemicals," Toxicol Ind Health, Volume 8, No. 5, page 239-254. Vutyavanich, T., et al., 1989. "Secondary Amenorrhea at Maharaj Nakhon Chiang Mai Hospital," Journal of the Medical Association of Thailand, Volume 72, No. 3, page 160-166. Wakai, S., N. Hirokawa, 1978. Cell Tissue Research, Volume 195, page 195-203. WSJ 1988. The Wall Street Journal, June 27, 1988, page 20. WSJ 1989. The Wall Street Journal, January 24, 1989, page B1. Walton, Ralph G., 1986. "Seizure and Mania After High Intake of Aspartame," Psychosomatics, Volume 27, page 218-220. Walton, Ralph G., 1988. "The Possible Role of Aspartame in Seizure Induction," Presented at "Dietary Phenylalanine and Brain Function." Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA, page 159-162. Walton, Ralph G., et al., 1993. "Adverse Reactionbs to Aspartame: Double-Blind Challenge in Patients From a Vulnerable Population," Biological Psychiatry, Volume 34, page 13-17. Wang, G.J., et al., 1990. "Extreme Sensitivity of Infant Animals to Glutamate Toxicity: Role of NMDA Receptors," Neuroscience Abstracts, Volume 16, page 198. Wen, Chi-Pang, et al., 1973. "Effects of Dietary Supplementation of Monosodium Glutamate on Infant Monkeys, Weanling Rats, and Suckling Mice," American Journal of Clinical Nutrition, Voolume 26, page 803-813. Westlund, Karin N., et al., 1992. "Glutamate-Immunoreactive Terminals Synapse on Primate Spinothalamic Tract Cells," Journal of Comparative Neurology, Volume 322, page 519527. White, Jonathan W., 1950. "Composition of a Volatile Fraction of Apples," Food Research, Volume 15, page 6878. Wilson, Steve, 1985. "Sweet Suspicions," Television broadcast and interviews regarding aspartame. Transcript in Congressional Record (1985b, page S10826-S10827) Wolf-Novak, Louise C., Lewis D. Stegink, et al., 1990. "Aspartame Ingestion With and Without Carbohydrate in

Phenylketonuric and Normal Subjects: Effect on Plasma Concentrations of Amino Acids, Glucose, and Insulin." Metabolism, Volume 39, No. 4, page 391-396, April, 1990. Wolin, Meyer J., Terry L. Miller, 1993. "Bacterial Strains from Human Feces That Reduce CO2 to Acetic Acid," Applied and Environmental Microbiology, Volume 59, No. 11, page 3551-3556. Wolraich, Mark L., 1985. "Effects of Surose Ingestion on the Behavior of Hyperactie Boys," Journal of Pediatrics, Volume 106, page 675-681. Wolraich, Mark L., et al., 1994. "Effects of Diets High in Sucrose or Aspartame on the Behavior and Cognitive Performance of Children," The New England Journal of Medicine, Volume 330, No. 5, page 301-307. Wood, David R., Fred W. Reimherr, Paul H. Wender, 1985. "Treatment of Attention Deficit Disorder With DLPhenylalanine," Psychiatry Research, Volume 16, page 21-26. Wurtman, Richard J., 1983a. "Effects of Aspartame and Glucose on Rat Brain Amino Acids and Serotonin," New England Journal of Medicine, Volume 309, No. 7, page 429430. Wurtman, Richard J., 1983b. "Neurochemical Changes Following High-Dose Aspartame With Dietary Carbohydrates," New England Journal of Medicine, Volume 309, page 429-430. Wurtman, Richard J., 1985a. "Aspartame: Possible Effect on Seizure Susceptibility," The Lancet, Volume 2, page 1060. Wurtman, Richard J., 1985b. Statement of Richard J. Wurtman, Professor of Neuroscience, Massachusetts Institute of Technology to "U.S. Senate Hearing Before the Committee on Labor and Human Resources, "Saccharin Study and Labeling Act Amendments of 1985," April 2, 1985, page 119121. Wurtman, Richard J., 1987. Testimony and Statement of Richard J. Wurtman, Professor of Neuroscience, Massachusetts Institute of Technology to U.S. Senate Committee on Labor and Human Resources, November 3, 1987 regarding "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, page 339-359. Wurtman, Richard J., Tomothy J. Maher, 1988. "General Discussion: Calculation of the Aspartame Dose for Rodents that Produces Neurochemical Effects Comparable to Those Occurring in People," Dietary Phenylalanine and Brain Function. Proceedings of the First International Meeting on Dietary Phenylalanine and Brain Function, Washington, D.C., May 8-10, 1987. Center for Brain Sciences and Metabolism Charitable Trust, P.O. Box 64, Kendall Square, Cambridge, MA 02142. Reprinted in "Dietary Phenyalalnine and Brain Function," c1988, Birkhauser, Boston, MA USA. Yaryura-Tobias, J.A., B. Heller, H. Spatz, E. Fischer, 1974.

"Phenylalanine for Endogenous Depression," Journal of Orthomolecular Psychiatry, Volume 3, No. 2, page 80-81. Yu, P.H., D.M. Zuo, 1993. "Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase deads to cytotoxic damage in endothelial cells. Possible consequences for diabetes," Diabetes, Volume 42, No. 4, page 594-603. Yokogoshi, H., et al., 1984. "Effects of aspartame and glocose administration on brain and plasma levels of large neutral amino acids and brain 5-hydroxy-indoles." American Journal of Clinical Nutrition, Volume 40, page 1-7. Ziem, G.E., V.J. Castleman, 1989. "Threshold Limit Values: Historical Perspectives and Current Practice," Journal of Occupational Medicine, Volume 31, page 910-918.