This is a point-by-point rebuttal of U.K. Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) evaluation of aspartame. While I did not receive that list of references, many of the references are self-evident for those familiar with the scientific literature. It appears that the COT is getting its inaccurate information from either the manufacturer Monsanto/Benevia/ NutraSweet and/or the U.S. FDA. (This reported was in response to a request by a U.K. citizen to the MAFF -- Ministry for Agriculture, Fisheries and Food, who in turn routed it to the Department of Health.) The COT statements are prefaced by the ">" symbol. > STATEMENT BY THE COT ON THE SAFETY-IN-USE OF ASPARTAME > > Introduction > > 1. We last fully reviewed aspartame as part of the Food Additives and > Contaminants Committee's review of sweeteners in food in 1982 (1), when > we classified it as acceptable for use in food. We also recommended > that, after allowing for new food manufacturing practices to develop > and the market to stabilise following the implementation of new > regulations and within five years of implementation, information > should be collected so that intake levels in the general population > and In special groups could be measured. The Committee must not have had access to aspartame pre-approval tests which showed among other things: a. Aspartame caused brain cancer in animals when ingested at levels that could be considered equivalent to human ingestion (after correcting for differences in toxicity of aspartame's components). b. The "quality" of the preapproval experiments were so horrendous that FDA officials at the time urged prosecution for fraud. c. The FDA was forced to create the "Good Laboratories" regulations due to the complete lack of quality of the pre-approval studies. d. One FDA investigator stated that the manufacturer "lied and they didn't submit the real nature of their observations...." Other independent reviewers thought that the pre-approval "research was the worst they had ever seen. There were *many* other major problems with the pre-approval studies. Please see the Preapproval "Research" & History of Aspartame FAQ for more detail. Unfortunately, the FDA probably did not provide the officials in the UK with the appropriate documents to make a adequate safety decision. > 2. Since 1982 we have reviewed issues relevant to the safety of > aspartame as they have arisen in the scientific literature. None of > these reviews caused us to alter our advice that aspartame was safe- > in-use In 1989 the Food Advisory Committee considered the results > of surveys carried out by MAFF on the intakes of sweeteners by the > general and diabetic populations (2) and asked us for advice on the > potential risk to health of the levels of intake of aspartame > reported. In view of the large amount of data on aspartame which has > been published in the scientific literature since 1982, we took the > opportunity to conduct a full review of this sweetener. In keeping > with our current policy (3), we have decided to formulate our advice > in terms of an acceptable daily intake (ADI) for aspartame. We have > also taken the opportunity to review the safety of the degradation > product of aspartame, a diketopiperazine derivative (DKP). Since 1982, the manufacturer of aspartame, Monsanto Chemical Company, has flooded the scientific community with poorly designed, improperly conducted studies in an attempt to prove the safety of aspartame. A recent preliminary review of the scientific literature relating to aspartame and its relevence to human safety conducted by Dr. Ralph Walton (Northeastern Ohio College of Medicine) showed that nearly every independent study found problems with aspartame. It is only the industry-funded studies and the FDA reviews that never find a problem with aspartame. The studies conducted and funded by the aspartame manufacturer repeat most of the same major flaws over and over. Unfortunately, for scientists who do not understand the issues regarding the components of aspartame, these flaws are not apparent. It is clear from the rest of this review that the scientists performing the review were not intimately familiar with the scientific literature. I dicuss some of the independent studies which found health problems caused by aspartame throughout my draft scientific/historic review and in the scientific FAQs. > Animal studies reported since 1982 > > 3. We have reviewed the available animal studies on aspartame which > have been published In the scientific literature since our last > review in 1982. These studies have mainly investigated the potential > effects of high doses of aspartame on brain neurotransmitters > and on behaviour. We conclude that adverse neurochemical or neuro- > behavioural effects have only been seen in animal studies using > exposures to aspartame which far exceed extreme intake figures for > the UK. At current intake levels no neurotoxic effects have been > observed or would be expected. Overall, the results of animal > studies conducted since our previous review give no cause for > concern (4-21). The is the first section where the reviewers make it clear that they have little understanding of the scientific issues involved with aspartame. It is true that very high doses of aspartame were used in animal experiments to produce adverse effects. Many such experiments showed adverse effects from brain cancer in the pre-approval studies to permanent, adverse changes in brain chemistry and behavior. What is not said is that the dose required to produce adverse effect in rodents is many time higher because the main components of aspartame are many times *less* toxic in rodents. For example: Phenylalanine: It takes approximately 60 times less free (unbound to protein) phenyalalnine given to humans to produce similar biochemical changes in the the animal experiments mentioned above. This has been confirmed by every research except the manufacturer's lab. Methanol: It takes 10 times less methanol to kill a human as it does a rodent. In addition, it appears that rodents do not have adverse effects and chronic poisoning from low levels of methanol as do humans. Or, if they do, it may require a dose of much more than 10 times the dose given to humans to cause the same effects. Aspartic Acid: It appears to take 5 times less free (unbound to protein) glutamic acid give to humans to cause "excitotoxic" damage than it does given to rodents. Free aspartic acid is expected to have a similar differnce in toxicity between humans and rodents. DKP and Beta-aspartame are also probably more toxic in humans on a mg/kg basis than in rodents. Now if the components of aspartame act synergistically to produce adverse effects in humans, one would need to multiply the differences of those components to find an equivalent testing dose for rodent. (For example, phenylalanine and methanol --> 60 x 10 = 600 times the dose need to test on rodents for a very rough equivalent.) Even to test the phenylalanine by itself on rodents, one needs to use 60 times more than in humans. The fact that they didn't even mention the hugh difference in toxicity in this review makes a person wonder where they got their information. > Human data > > 4. Metabolism studies on aspartame in four species of animals and in > humans indicate that aspartame is metabolised to its component moieties > methanol, aspartic acid and phenylalanine, with metabolism taking place > largely in the gastrointestinal tract. Again, this leaves out key information. Short studies on low levels of the breakdown component of aspartame, aspartylphenylalanine diketopiperazine (DKP) shows that it is not completely broken down into aspartic acid and phenylalanine because it is measured in the urine. Therefore some (an unknown quantity) is absorbed by the body. One concern that it is partly converted in the GI tract to other chemicals or that some of it is absorbed when high levels are ingested still stand. At least one well-respected neuroscientist suspects that it may be a contribuatory factor to brain tumors. Here again, they didn't even mention the concerns with DKP. They also didn't mention other breakdown products such as beta-aspartame and large amounts of racemized amino acids (at higher temperatures). > The amino acids aspartic acid and phenylalanine are normal components > of dietary protein and methanol is a low level constituent of common > foods. The problem is that these amino acids from aspartame are ingested in *free* form (unbound to proteins) and often in liquid beverages which causes their absorption to be extremely quick. This leads to spikes in the blood levels of these amino acids. No "food" in the history of man has every contained a two free amino acids by itself in a form that can spike the blood levels. Answers to other common industry points brought up can be found in the aspartic acid and phenylalanine section of my draft scientific review. The fact that this COT review compares these amino acids to amino acids in food even though it has long since been proven that they are absorbed and metabolized differently from aspartame is cause for concern. This is especially the case since it is only Monsanto PR statements that try to convince consumers that aspartame breakdown products are absorbed similar to what is found in food (even though their own scientists know that such statements are untrue). Perhaps the reviewers should read the scientific literature before making irrelevant comparisons between aspartame breakdown products and food components. > The amount of methanol contributed to the diet by aspartame is very > low compared with that from other foods eg one pint of orange Juice > would provide more methanol to a three year old child than a 40 > milligram per kilogram bodyweight (mg/kg bw) bolus dose of > aspartame. This is simply incorrect. Food contains methanol, but humans do not have the enzymes to break the methanol from the pectin in whole foods. Recent studies of orange juice clearly show that fresh squeezed orange juice contains less methanol than does aspartame. These studies also show that pasturized orange juice (as is most store-bought orange juice) and concentrate contains much less methanol than even freshly squeezed orange juice and many times less than aspartame. Most other fruit juices contain less free methanol than found in aspartame. But the most important key fact often left out is that it is not so important how much methanol is ingested as it is how much methanol is absorbed *and* converted to formaldehyde. Alcoholic beverages contain an acutely poisonous dose of methanol, but the ethanol in the beverage keeps the methanol from being converted to toxic formaldehyde and formic acid. There have never been studies which show that the low levels of methanol from juices is even fully absorbed or converted to formaldehyde. In fact, if that were the case and one were to believe the industry-stated levels of methanol in certain juices, persons who drank those juices regularly would be experiencing the same chronic methanol toxicity symptoms seen in some methanol-laden factories in industry. Aspartame, which contains no ethanol or other protective factors, has been shown to lead to a spike in plasma methanol levels. Finally, one also has to consider synergistic reactions of aspartame's breakdown products such as methanol plus the excitotoxic amino acid obtained from aspartame. There are other arguments often brought up by the manufacturer in regards to methanol. These arguments are addressed in the Chronic Methanol/Formaldehyde Poisoning From Aspartame FAQ. It is sad to see, however, that the information these reviewers used in regards to methanol is completely inaccurate. > Unchanged aspartame is not likely to be present In the systemic > circulation even at high levels of human dietary Intake (14, 22) I don't have a reference list to see what 14 and 22 refer to, but it would be interesting to see if the researchers used less accurate thin-layer chromatography as the manufacturer often did. There is plenty of concern about the components of aspartame without even considering whether the *whole* molecule is absorbed intact. > We have reviewed the results of the extensive tolerance and > pharmacokinetic studies on aspartame in humans (13-14, 22-40). The > available data Indicate no adverse effects In various human > subpopulations following exposure to aspartame at doses up to 75 > mg/kg bw/day for 24 weeks or up to 135 mg/kg bw/day for a shorter > period. As I stated earlier, all of these studies which didn't find adverse effects were conducted by the aspartame industry. They were all very poorly-designed. Many of them were extremely short (e.g., one day long) and therefore meaningless when considering long-term use (e.g., 2+ years of use). What is quite interesting is that these reviewers totally ignored the independent studies (including double-blind studies) that have found problems with aspartame. (The independent studies were also usually fairly short and one would expect much more severe problems from long-term use.) One wonders if these studies were ignored for political purposes. It becomes even more ridiculous when one considers that they ignored the independent studies when stating that "aspartame has no adverse effects in humans" but later (below) cited one of the independent studies that found adverse effects! There were numerous major flaws in these studies which invalidates every single one of them. Unfortunately, some reviewers rely on the number of studies as opposed to the quality. In the draft scientific/ historic review, I discuss in detail many of the major flaws in these aspartame industry studies which render them useful only for a press releases. It is obvious that the peer review system does not prevent bad research from being published. In COT's statement above they refer to the longest industry-funded aspartame research study in humans -- only six month! They state that aspartame was given at a dose of "75 mg/kg bw/day for 24 weeks..." In order to see just how bad industry studies get, I will point out just a few of the major flaws in this study. The study in question is: Safety of long-term large doses of aspartame. Leon AS et al, Arch Intern Med 1989 Oct; 149:2318-2324. The aspartame was given as *fresh* aspartame (e.g., much less DKP than often found) and in capsules so that the equivalent dosage is many times less than the stated "10 liters of aspartame-laced carbonated beverages." This is because capsule ingestion greatly effects the way aspartame breakdown products are absorbed and metabolized. They gave the aspartame with meals which further reduces the spike in plasma amino acids that might otherwise occur with real-world products. One might guestimate that the equavalent dosage really given was approximately 1-2 liters per day. The aspartame group had 50% more adverse reactions after six months, but it seems this result wasn't to the liking of the industry-funded researchers so they created numerous categories of toxicity reactions. As an example, a difference in adverse reactions between two groups of 150 reactions to 100 reactions would be statistically significant. But if you separate the reactions into many categories, the difffernce in reactions in one particular category of (say) 3 reactions to 2 reactions is not statistically significant. This is the game they played. In addition, they chose healthy adults (for less susceptibility) and then eliminated a group of women (for no *legitimate* reason) that have reported a higher percentage of the aspartame toxicity reactions. They measured the plasma amino acids, methanol, and formate at the wrong times so that no spike in these levels would be seen. The methanol test used was not sensitive enough to see a spike even if it had occurred at the right time. The formate testing procedures used are "nortoriously inaccurate" (as described by one researcher), the urine formate measurements are thought to be a poor indicator of low-level formaldehyde exposure (from methanol for example), and these values weren't even presented. Finally, they threw in a bunch of useless tests which, I admit, make the results *sound* more impressive, and MAGIC -- you now have a press release in the guise of "scientific research." It is important to keep in mind that 6 months of ingesting the equivalent of 1-2 liters of aspartame by certain healthy people is likely to produce a significant increase in toxicity reactions. However, much of the more severe damage will not be clinically evident until years after aspartame use has begun. That is what is being experienced in the U.S. > Pharmacokinetic studies have established that both large acute bolus > doses and repeated doses of aspartame result in plasma levels of its > components which are considered safe. "Considered safe" by the manufacturer. The US EPA and the overwhelming majority of scientists studying the methanol issue have not deemed ongoing, low-level exposure to the highly toxic methanol to be safe -- even at levels found in aspartame. Several well respected neuroscientists are questioning the "safety" of the plasma levels of amino acids caused by the quick absorption of aspartic acid and phenylalanine, especially when they are ingested on an ongoing basis. Many researchers have concerns about other aspartame breakdown products such as aspartylphenylalanine diketopiperazine (DKP) and have concerns about synergistic reactions such as those discussed on the Chronic Methanol/Formaldehyde Poisoning From Aspartame FAQ. There is no independent evidence to support such safety of these breakdown product, especially in long-term use, but the evidence showing the dangers is growing as can be seen in the draft scientific/historic review, the scientific FAQs and all of the independent scientific research. > 5. We are aware of anecdotal reports linking aspartame with a variety > of adverse effects such as headache, seizures and behavioural > difficulties in children. I sincerely hope that are aware of more than just those "anecdotal" reports, especially from long-term use. They should add death, depression, vision loss, slurred speech, memory loss, anxiety attacks, severe dizziness, nausea, muscle spasms, chronic fatigue, weight gain, insomnia, joint pain, asthma, severe migraines, convulsions, worsening parkinson's tremors, MS-like symptoms, and many, many other reported problems. Aspartame is not ingested in the UK at the same levels as in the US -- at least not yet. So, your population's problems are only just beginning. It is a *major* problem in the U.S as discussed in detail in the Reported Aspartame Toxicity Effects FAQ. > In the US, reports on adverse reactions associated with aspartame > Ingestion are collected by the US Food and Drug Administration via > a toll-free telephone number and reported quarterly. These quarterly > reports are made available to the Department of Health. Occasional > consumer complaints of adverse reactions In the UK received by > Nutrasweet are also made available to the Department. We have > reviewed these reports. Most of the frequently reported symptoms were > mild and are common background symptoms In the general population. Seizures and convulsions were one of the more common reports. Most people would not consider these mild. Vomitting and nausea, abdominal pain and cramps, vision loss, and memory loss were also frequently reported. I do not consider these "mild" symptoms either, especially if they occur for years before (if) the cause is detected. I have been receiving letters of severe health problems/damage caused by long-term use. I don't consider those mild either. Government agencies with political agendas sometimes are not 100% honest about toxicity problems. The U.S. FDA has been caught refusing to forward aspartame toxicity reaction reports, forwarding them to the AIDS Hotline, turning away people trying to report toxicity reactions, stopping recording adverse reaction reports and later declaring they received less than 10 such reports during that year (even though independent organizations sometimes receive that many toxicity reaction reports within one or two days!). > The most common adverse symptom reported was headache, which > accounted for approximately 20% of all complaints in the US. Actually, these account for 18.41% of the complaints. But headaches refer to migraines as well. In addition, many people who ingest aspartame report getting severe, debilitating headaches hours or even days after aspartame ingestion (since it is a toxicity reaction and is sometimes delayed). These debilitating headaches can go on for years before the link between aspartame and the headaches is recognized. Therefore, "headaches" does not necessarily refer to mild headaches that are often found in the general population. One reason that headaches are so commonly reported is that it is easier (although still difficult) to link aspartame to headaches than it is some other much more serious health problems. Persons who get MS-like symptoms, brain cancer, vision loss, etc., etc. would have a much more difficult time recognizing whether aspartame caused or contributed to their health problems. That is one reason they are reported less frequently than headaches. It is also difficult for the public to recognize the cause of their problems when governmental agencies put out inaccurate information about aspartame. > Two studies have investigated the relationship between aspartame > and headache (41-42). Both were double blind, cross over studies. > The results differed markedly from each other. In one study 40 > subjects, who had previously complained about the effects of > aspartame containing products, were hospitalised and entered > into a six day study programme. The conclusions from this study were > that the incidence of headache from aspartame and placebo was > equivalent. The is a deceptive presentation of the first study. The first study was co-designed by the manufacturer of aspartame (G.D. Searle -- now owned by Monsanto). It was conducted by a consultant to G.D. Searle at the G.D. Searle Center at Duke University. The Center was being run by a former G.D. Searle director. The "six day study programme" amounted to only ***one day*** of ingesting aspartame. There were other major flaws such as the fact that the aspartame was fresh (i.e., without common breakdown products such as DKP and beta-aspartame), was encapsulated so that absorption of the amino acids and methanol was slowed considerably allowing the body time to eliminate the excess, the diet of the subjects were changed during the study, there was no information presented about the frequency of headaches when aspartame was ingested in real life or about the typical latency period of any of the subjects (who had obviously not ingested aspartame recently). The latency period is very important because independent researchers are in agreement that it often takes weeks, months, or sometimes years of aspartame ingestion before toxicity reactions and chronic health problems are experienced. A one day study like this should simply be laughed off. Unfortunately, the aspartame manufacturer has conducted so many of these short studies that it confuses honest scientists trying to understand the issues. It concerns me that the reviewers did not see fit to discuss some of these flaws. > In the second study migraine sufferers, who considered that they > were adversely affected by aspartame, were recruited by newspaper > adverts. Only 11 of 25 subjects recruited finished the study. > Because of the high drop-out rate, the conclusions of this study > are necessarily tentative. However, it was considered that the > ingestion of aspartame by migraine sufferers may cause a significant > increase in the frequency of migraine In some subjects. More > studies are needed to confirm the impression gained from this latter > study that aspartame, in common with some other food substances, may > need to be avoided by a sub-group of migraine sufferers. In this independent study, the subject ingested aspartame for *28 times* longer than in the industry study. The fact that there was a high dropout rate is irrellevant. Any study that lasts 13 weeks and requires subjects to perform recordkeeping will lead to a high dropout rate. All that is important is that there was a large, statistically *significant* increase in migraines due to aspartame. The researchers also noted that "several subjects experienced an increase in unusual symptoms during their headache activity (e.g., dizziness, inability to see well, feeling 'shaky')." One wonders what one year, 5 years, or 20 years of aspartame ingestion will do to these people. Even if their are not obvious acute reactions, the silent damage cause by aspartame components is a major cause for concern. > Claims that aspartame causes other adverse effects, such as > behavioural effects or seizures, have not been substantiated > in controlled studies in humans (13, 43-49). Behavioral effects and changes in EEG readings have been seen in independent studies which tend to be far less flawed than the industry studies cited above. Most of the industry studies are extremely short, use a different product for testing than what people purchase, and in the case of seizure tests, they test subjects who are taking anti-seizure medication during the study (among the many other flaws)! How anyone can take these studies seriously is beyond me. > In fact, as Indicated in a recent report, researchers trying to > carry out such studies can encounter difficulties in recruiting > sufficient individuals with a history of adverse reactions to > aspartame to make the studies viable (50). That's funny. An independent researcher was able to easily come up with plenty of subjects after just one ad. In fact, this independent research walked off the industry-sponsored study referred to above because he felt that they weren't interested in properly testing aspartame. There are thousands upon thousands of reports being made to the FDA, various organizations, and researchers. Most people who have suffered from chronic health problems due to aspartame prefer not to become "guinea pigs." However, there are willing subjects out there for researchers who are actually interested in properly studying the issue. >Phenylketonuria > >.... > > 7. People who inherit one of the genes for PKU (termed PKU > heterozygotes) have a somewhat reduced ability to metabolise dietary > pheylalanine. The tolerance and pharmacokinetic studies cited in > paragraph 4 include studies In these individuals and the results > indicate that, like normal individuals, they are not at risk of > adverse effects from aspartame at intakes up to the acceptable > daily intake (ADI, see below). Blatantly untrue. They have no research that shows that long-term (i.e., one year or more) ingestion of aspartame is safe for these individuals (or anyone else for that matter). And the short industry studies on PKU heterozygotes are full of major flaws. This statement is just wishful thinking on the part of the reviewers -- and that is why there is no citation here. > Fetal toxicity due to phenylalanine > > 8. Since maternal hyperphenylalaninaemia Is associated with mental > retardation in the fetus, high maternal plasma levels of phenylalanine > are hazardous to the fetus (52). In the US, the National > Collaboration Study for Maternal Phenylketonuria has recommended > that during pregnancy blood phenylalanine levels should not exceed > 380 umol/l (13). Recently, it has been shown that the birthweights > and head circumferences of infants born to a group of PKU women > were inversely related to the maternal phenylalanine concentrations > around the time of conception (53, 54). However, at plasma > phenylalanine concentrations below 300 - 400 umol/l, these parameters > were within the normal range. Thus although these data could be > taken to suggest that there is no threshold for subtle adverse effects > in the fetus from high maternal phenylalanine concentrations, we > consider there must be a effective threshold, particularly since > hypophenylalaninaemia is also harmful to the fetus. Another bunch of inaccurate statements not completely supported by the scientific literature. In the February 11, 1995 issue of The Lancet researchers Isabel Smith and Sarah Tillotson state that there is no threshold: "for every 100 umol/L rise in phenylalanine, [there] is a clinically important change." The researchers at the Children's Hospital in Boston concur in response that there is no threshold at 400 umold/L. In addition, a relatively few tests are conducted when determining if offspring exposed to high phenylalanine levels are different in any way. To state, based on little more than a couple of tests and mostly wishful thinking, that quadrupling the levels of fetal brain phenylalanine during pregnancy has no adverse effects is negligent in my opinion. Finally, the very important issues of fetal damage and aspartic acid and methanol cannot be discounted. See the draft scientific/historic review for more information. > Studies in PKU heterozygotes indicate that after high bolus doses > of aspartame (10-20 mg/kg bw) or even following repeated doses of > 10 mg/kg bw/day aspartame given every hour for eight hours (55), > plasma phenylalanine concentrations do not exceed 200 umol/l. > Thus we are satisfied that fetotoxic effects due to phenylalanine > would not result from ingestion of aspartame by normal individuals > or by PKU heterozygotes at the ADI (see paragraph 11). To put 10 mg/kg bw/day in perspective, a 30 kg child drinking three cans of diet soda per day (and no other aspartame-containing products) will be ingesting double the 10 mg/kg bw/day. It is true that 10 mg/kg every hour is alot. However, fetal brain levels can be as much as four times the mother's blood plasma levels. To suddenly spike fetal brain levels of phenylalanine and hope that there is no subtle brain changes/damage to the developing child is, once again, negligent. Once again, this discussion ignores the affects of aspartic acid spikes and methanol which by themselves or synergistically may cause fetal damage. It is very important to remember that changes or damage to fetal brain development may not be readily apparent at birth. In fact, the damage seen to young animals when given excitotoxic amino acids (e.g., aspartic acid, glutamic acid) in free form is such that it is only recognized upon close microscopic examination of the brain tissue *or* by waiting until after the animal reaches puberty and activates (to a larger extent) that area of the brain that was damaged. > Validity of early studies on aspartame > > 9. Aspartame was first submitted for approval in the UK by G.D. > Searle and Co. in 1974. In 1975, a task force of the US Food and > Drug Administration (FDA), investigating Searle laboratory > practices, questioned the quality of the data in certain aspartame > studies. During 1977 and 1978, FDA inspectors investigated 3 of > these studies in detail and a further 10 studies were investigated > by an independent US organisation, the Universities Associated for > Research and Education in Pathology (UAREP) (56). These investigations > concluded that although there were discrepancies in the conduct of > some, of these studies, they did not invalidate the studies or their > conclusions. To see how poorly this review looks at the evidence, here is the testimony of the *lead scientist* heading the 1977/78 FDA investigation that the reviewers cite above: ************* 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: "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: "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 UAREP reviewers only looked to see if the studies were conducted at all and if the slides misrepresented the results presented to the FDA; they didn't look at the horrendous quality of the studies: *********** 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.' *********** It turns out that even the limited review performed by UAREP had inaccuracies. That's not surprising since G.D. Searle hired UAREP to perform the "review." See the Preapproval "Research" & History of Aspartame FAQ for more details. The above excerpts from the Preapproval "Research" & History of Aspartame FAQ don't even begin to describe the horrendous conduct of G.D. Searle in the pre-approval experiments. Please see the Preapproval "Research" & History of Aspartame FAQ to get a sense of the utter confusion that was rampant in G.D. Searle labs during the pre-approval experiments. > Aspartame was subsequently permitted for use in the US. A subsequent > investigation of the FDA's approval process followed for aspartame by > the US General Accounting Office concluded that the process was > satisfactory (57). The GAO report specifically stated that "we did not evaluate the interpretation of scientific issues on the studies used for aspartame's approval, nor did we determine aspartame's safety; we do not have the necessary expertise." Basically, all the GAO did in this report was determine whether hearings were held at appropriate times, not whether the "scientific" decisions made any sense. > 10. Since 1982 questions have been asked on a number of occasions > about the decision to accept the early animal studies on aspartame > and while our review was in progress we received a submission on > this (58). It is agreed that by current standards there were flaws > in the conduct of some of the early animaltoxicity studies on > aspartame. However, we accept the conclusions of the detailed FDA > and UAREP investigations, i.e. that the flaws do not invalidate the > conclusions of the studies and that they can be accepted as part > of the safety evaluation of aspartame. It should be noted that in > forming our view on the safety-in-use of aspartame, we took into > account not only the standard animal toxicity studies but also the > known metabolic profile in humans (paragraph 4) and the many human > studies on aspartame. "Flaws" hardly described these animal studies. They were about to be prosecuted for fraud because the conduct was so ridiculous. See the Preapproval "Research" & History of Aspartame FAQ to see why they weren't prosecuted. The UAREP "investigation" was hardy an investigation at all, but merely a G.D. Searle attempt to prove that studies were conducted (no matter how poor they were). This was admitted to by the president of UAREP. A series of FDA hearings concluded that the pre-approval studies were horrendous and unacceptable. The FDA evaluatuation cited by this review was discussed by the head scientist, Jaqueline Verrett above. Basically what they did in the review was take each study which had mutiple outrageous problems and look at each problem individually. When the problems are looked at together, the studies would be laughed out of any independent scientific evaluation, but by treating each "flaw" as if it was the only flaw in the study, the politically-motivated FDA reviewers could claim that it didn't affect the results of the study. > Acceptable Daily Intake > > 11. With one exception, the available standard animal toxicity studies > on aspartame Indicate a no observable adverse effect level of 4 g/kg > bw/day (28). Again, this is ridiculous because the components of aspartame are much more toxic in humans than they are in rodents. Numerous animal studies showed adverse effects at levels below 4 g/kg bw/day. This is clearly seen in the phenylalanine and aspartic acid sections of the draft scientific/historic review. It almost sounds like this information was made up out of nothing. It is certainly not backed up by the science. 4 g/kg bw/day of aspartame contains over 40 times the methanol a worker would absorb from working 8 hours in a methanol-laden chemical plant. It contains easily enough aspartic acid to cause brain damage in rodents. I dare these reviews to ingest 4 g/kg of aspartame in solution for even one month and see if they're alive after that. I'd like to see what citation #28 is. > Application of the usual safety factor of 100 would lead to an ADI > of 40 mg/kg bw/day aspartame. In the rabbit, which was used as a > second species in teratology studies, administration of 4 g/kg bw/day > could not be achieved but the available metabolism and toxicological > data on aspartame is sufficient for this not to be of concern. > Tolerance studies in humans in which 40 mg/kg bw aspartame has been > administered as a bolus dose show that the resultant blood > concentrations of aspartame components do not give any cause for > concern. Therefore, taking the animal and human data together, we > recommend an ADI (1992) of 0-40 mg/kg bw/day for aspartame. It's funny that the reviewers mention the rabbit studies. One of the pre-approval studies which G.D. Searle was supposed to be prosecuted for fraud on was a rabbit study. G.D. Searle's own independent expert on teratology stated that their rabbit studies were worthless. See the Preapproval "Research" & History of Aspartame FAQ for more details. The 40 mg/kg bolus doses are one day experiments! Not worth much for anything but a press release. 40 mg/kg of aspartame will lead to a large spike in plasma methanol levels, aspartic acid levels, and phenylalanine levels. The dangers of such *regular ingestion* is clear in the adverse reaction reports, in the independent research, and in the study of the individual components of aspartame by independent researchers. > Diketopiperazine > > 12. On storage and particularly in aqueous solution, aspartame > breaks down to a diketopiperazine derivative (DKP; aspartyl > phenylalanine diketopiperazine) by hydrolysis and cyclisation. A > variety of cyclic dipeptide derivatives can be found in many > protein-rich foods and many of these dipeptides contain > phenylalanine (59,60). In pharmacokinetic studies in humans, DKP > has been detected In some subjects during the placebo phase, > indicating that it is a naturally occurring dietary and/or > endogenous substance (61). While some DKPs can be found in foods, this particular DKP is not found in foods -- at least it has never been shown to be in foods. There are no properly-conducted, medium-term or long-term human studies looking at the effects of the particular DKP found in aspartame. There is alot of wishful thinking on the manufacturer's part that it is safe. Reknowned neuroscientist, Dr. John Olney, has shown extreme concern about the potential dangers of long-term ingestion of this particular DKP. It is desparation on the part of the manufacturer to claim that this particular chemical is "safe" simply because different chemicals that have a similar physical structure are safe. > 13. Substantial animal toxicity data presented on DKP at the time > of last review give no cause for concern (28). Metabolic studies > in humans both normal subjects and PKU heterozygotes, indicate that > DKP is poorly absorbed after oral administration and that which is > absorbed is excreted unchanged in the urine (28,62). Since DKP > performs no technological function in food and is essentially > equivalent to a contaminant, we consider it appropriate to set a > tolerable daily Intake (TDI) rather than an ADI for this substance. > We recommend a TDI(1992) of 0-7.5 mg/kg bw/day for DKP. This is only partially relevant because there may be a large difference between animal and human toxicity as has been shown for the other components. In addition, most of the animal DKP tests were the pre-approval tests which were of laughable quality (at best). Mark D. Gold mgold@holisticmed.com http://www.holisticmed.com/ http://www.holisticmed.com/aspartame/