From: Rich Murray [rmforall@att.net] Sent: Tuesday, September 24, 2002 4:02 AM To: fdadockets@oc.fda.gov Subject: FDA Docket 02P-0317 Aspartame: Methanol and the Public Interest 1984: Monte: Murray 9.23.2 rmforall FDA Docket 02P-0317 Recall Aspartame as a Neurotoxic Drug http://groups.yahoo.com/group/aspartameNM/message/870 Aspartame: Methanol and the Public Interest 1984: Monte: Murray 9.23.2 rmforall Rereading this prescient classic review from 1984, I find its findings are supported in much recent research, so I am again making the full text widely available. [I have put my comments or corrections in square brackets, and spaced the text to ease the reader's task] For instance, I had forgotten this, which answers the industry PR "science" that fruits and vegetables supply much more methanol than does aspartame: Fruit and vegetables contain pectin with variable methyl ester content. However, the human has no digestive enzymes for pectin (6, 25) particularly the pectin esterase required for its hydrolysis to methanol (26). Fermentation in the gut may cause disappearance of pectin (6) but the production of free methanol is not guaranteed by fermentation (3). In fact, bacteria in the colon probably reduce methanol directly to formic acid or carbon dioxide (6) (aspartame is completely absorbed before reaching the colon). Heating of pectins has been shown to cause virtually no demethoxylation; even temperatures of 120 deg C produced only traces of methanol (3). Methanol evolved during cooking of high pectin foods (7) has been accounted for in the volatile fraction during boiling and is quickly lost to the atmosphere (49). Entrapment of these volatiles probably accounts for the elevation in methanol levels of certain fruit and vegetable products during canning (31, 33). Recent research [see links at end of post] supports his focus on the methanol to formaldehyde toxic process: The United States Environmental Protection Agency in their Multimedia Environmental Goals for Environmental Assessment recommends a minimum acute toxicity concentration of methanol in drinking water at 3.9 parts per million, with a recommended limit of consumption below 7.8 mg/day (8). This report clearly indicates 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." (8).... Recently the toxic role of formaldehyde (in methanol toxicity) has been questioned (34). No skeptic can overlook the fact that, metabolically, formaldehyde must be formed as an intermediate to formic acid production (54). Formaldehyde has a high reactivity which may be why it has not been found in humans or other primates during methanol poisioning (59).... If formaldehyde is produced from methanol and does have a reasonable half life within certain cells in the poisoned organism the chronic toxicological ramifications could be grave. Formaldehyde is a known carcinogen (57) producing squamous-cell carcinomas by inhalation exposure in experimental animals (22). The available epidemiological studies do not provide adequate data for assessing the carcinogenicity of formaldehyde in man (22, 24, 57). However, reaction of formaldehyde with deoxyribonucleic acid (DNA) has resulted in irreversible denaturation that could interfere with DNA replication and result in mutation (37).... http://www.dorway.com/wmonte.txt Dr. Woodrow C. Monte Aspartame: methanol, and the public health. Journal of Applied Nutrition 1984; 36 (1): 42-54. (62 references) Professsor of Food Science Director of the Food Science and Nutrition Laboratory Arizona State University, Tempe, Arizona 85287 6411 South River Drive #61 Tempe, Arizona 85283-3337 602-965-6938 woody.monte@asu.edu The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is 112 mg, 10% of the aspartame. The EPA limit for water is 7.8 mg daily for methanol (wood alcohol), a deadly cumulative poison. Many users drink 1-2 L daily. The reported symptoms are entirely consistent with chronic methanol toxicity. (Fresh orange juice has 34 mg/L, but, like all juices, has 16 times more ethanol, which strongly protects against methanol.) [Monte has retired to New Zealand.] ASPARTAME: METHANOL AND THE PUBLIC HEALTH Woodrow C. Monte, Ph.D., R.D.** ABSTRACT Aspartame (L-asparty-L-phenylalanine methyl ester), a new sweetener marketed under the trade name NutraSweet*, releases into the human bloodstream one molecule of methanol for each molecule of aspartame consumed. This new methanol source is being added to foods that have considerably reduced caloric content and, thus, may be consumed in large amounts. Generally, none of these foods could be considered dietary methanol sources prior to addition of aspartame. When diet sodas and soft drinks, sweetened with aspartame, are used to replace fluid loss during exercise and physical exertion in hot climates, the intake of methanol can exceed 250 mg/day or 32 times the Environmental Protection Agency's recommended limit of consumption for this cumulative toxin (8). [7.8 mg daily methanol from 2 L drinking water: 8. Cleland, J.G. and Kingsbury, G.L., Multimedia Environmental Goals For Environmental Assessment. U.S. Environmental Protection Agency: EPA-600/7-77-136b, E-28, November 1977.] There is extreme variation in the human response to acute methanol poisoning, the lowest recorded lethal oral dose being 100 mg/kg, with one individual surviving a dose over ninety times this level (55). Humans, due perhaps to the loss of two enzymes during evolution, are more sensitive to methanol than any laboratory animal; even the monkey is not generally accepted as a suitable animal model (42). There are no human or mammalian studies to evaluate the possible mutagenic, teratogenic, or carcinogenic effects of chronic administration of methyl alcohol (55). The average intake of methanol from natural sources varies, but limited data suggests an average intake of considerably less than 10 mg/day (8). Alcoholics may average much more, with a potential range of between 0 and 600 mg/day, depending on the source and in some cases the quality of their beverages (15). Ethanol, the classic antidote for methanol toxicity, is found in natural food sources of methanol at concentrations 5 to 500,000 times that of the toxin (Table 1). Ethanol inhibits metabolism of methanol and allows the body time for clearance of the toxin through the lungs and kidneys (40, 46). The question asked is whether uncontrolled consumption of this new sweetener might increase the methanol intake of certain individuals to a point beyond which our limited knowledge of acute and chronic human methanol toxicity can be extrapolated to predict safety. *NutraSweet is a trademark of G.D. Searle & Co. **Director of the Food Science and Nutrition Laboratory Arizona State University Tempe, Arizona 85287 ASPARTAME Aspartame (L-aspartyl-L-phenylalanine methyl ester) has recently been approved as a sweetener for liquid carbonated beverages. It has had wide acceptance as an additive in many dry food applications after Food and Drug Administration approval on July 24, 1981 (48). The Food and Drug Administration, Dr. Richard Wurtman and myself have received well over a thousand written complaints relative to aspartame consumption. [H.J. Roberts, MD has also used many of these reports.] By far, the most numerous of these include dizziness, visual impairment, disorientation, ear buzzing, high SGOT, tunnel vision, loss of equilibrium, severe muscle aches, numbing of extremities, pancreatitis, episodes of high blood pressure, retinal hemorrhaging, menstrual flow changes, and depression. The validity of these complaints has yet to be scientifically evaluated. However, a thorough knowledge of just what makes this new sweetener stand apart from other nutritional substances might aid physicians in making dietary recommendations for their patients. Aspartame (NutraSweet)* is a small molecule made up of three components: Phenylalanine, aspartic acid, and methanol (wood alcohol) (47). When digested, these components are released into the bloodstream (48). Phenylalanine and aspartic acid are both amino acids which are found in natural proteins (14), and under normal circumstances are beneficial, if not essential, for health. Proteins are complex molecules which contain many chemically bonded amino acids. It takes several enzymes to break these bonds and liberate the amino acids. This is a slow process and the amino acids are released gradually into the blood stream (40). The quaternary structure of protein also slows the digestion of these amino acids; the amino acids in the center of the protein molecule aren't released until the outer layers of amino acids on the surface have been swept away. This natural time release process saves the body from large numbers of any one of these 21 amino acids being released into the bloodstream at any one time. Aspartame requires the breaking of only two bonds for absorption (47). This happens very quickly with the potential to raise component blood levels rapidly (52). The methyl ester bond of phenyalanine is the first to cleave due to its susceptibility to pancreatic enzymes (40). This is highly unusual; the methyl esters associated with pectin for instance are completely impervious to all human digestive enzymes (6). AMINO ACID COMPONENTS Phenylalanine Phenylalanine is an essential amino acid, the daily consumption of which is required to maintain life. However, Dr. Richard J. Wurtman, Professor of Neuroendocrine Regulation at the Massachusetts Institute of Technology, presented data to the FDA demonstrating that in humans the feeding of a carbohydrate with aspartame significantly enhances aspartame's positive effect on plasma and brain phenylalanine and tyrosine levels (48 Federal Register at 31379). There are sound scientific reasons to believe that increasing the brain levels of these large neutral amino acids could affect the synthesis of neurotransmitters and in turn affect bodily functions controlled by the autonomic nervous system (61) (e.g., blood pressure). The proven ability of aspartame to inhibit the glucose-induced release of serotonin within the brain may also affect behaviors, such as satiety and sleep (61). Aspartic Acid Aspartic acid, is not an essential amino acid but is normally easily utilized for human metabolism. However, under conditions of excess absorption it has caused endocrine disorders in mammals with markedly elevated plasma levels of luteinizing hormone and testosterone in the rat (52) and release of pituitary gonadotropins and prolactin in the rhesus monkey (58). The amount of luteinizing hormone in the blood is a major determinant of menstrual cycling in the human female (39). METHANOL Methanol (methyl alcohol, wood alcohol), a poisonous substance (60), is added as a component during the manufacture of aspartame (47). This methanol is subsequently released within hours of consumption (51) after hydrolysis of the methyl group of the dipeptide by chymotrypsin in the small intestine (40). Absorption in primates is hastened considerably if the methanol is ingested as free methanol (40) as it occurs in soft drinks after decomposition of aspartame during storage or in other foods after being heated (48). Regardless of whether the aspartame-derived methanol exists in food in its free form or still esterified to phenylalanine, 10% of the weight of aspartame intake of an individual will be absorbed by the blood stream as methanol within hours after consumption (51). [The precise value is 11%.] Methanol has no therapeutic properties and is considered only as a toxicant (20). The ingestion of two teaspoons is considered lethal in humans (19). [~9.4 cc = ~ 30 gm] Methyl alcohol produces the Methyl alcohol syndrome, consistently , only in humans and no other test animal, including monkeys (42, 54). There is a clear difference between "toxicity", which can be produced in every living thing, and the "toxic syndrome" (54). The greater toxicity of methanol to man is deeply rooted in the limited biochemical pathways available to humans for detoxification. The loss of uricase (EC 1.7.3.3.), formyl-tetrahydrofolate synthetase (EC 6.3.4.3.) (42) and other enzymes (18) during evolution sets man apart from all laboratory animals including the monkey (42). There is no generally accepted animal model for methanol toxicity (42, 59). Humans suffer "toxic syndrome" (54) at a minimum lethal dose of <1 gm/kg, much less than that of monkeys, 3-6 g/kg (42, 59). The minimum lethal dose of methanol in the rat, rabbit, and dog is 9, 5, 7, and 8 g/kg, respectively (43); ethyl alcohol is more toxic than methanol to these test animals (43). No human or experimental mammalian studies have been found to evaluate the possible mutagenic, teratogenic or carcinogenic effects of methyl alcohol (55), though a 3.5% chromosomal aberration rate in testicular tissues of grasshoppers was induced by an injection of methanol (51). The United States Environmental Protection Agency in their Multimedia Environmental Goals for Environmental Assessment recommends a minimum acute toxicity concentration of methanol in drinking water at 3.9 parts per million, with a recommended limit of consumption below 7.8 mg/day (8). This report clearly indicates 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." (8) Role of Formaldehyde Recently the toxic role of formaldehyde (in methanol toxicity) has been questioned (34). No skeptic can overlook the fact that, metabolically, formaldehyde must be formed as an intermediate to formic acid production (54). Formaldehyde has a high reactivity which may be why it has not been found in humans or other primates during methanol poisioning (59). The localized retinal production of formaldehyde from methanol is still thought to be principally responsible for the optic papillitis and retinal edema always associated with the toxic syndrome in humans (20). This is an intriguing issue since formaldehyde poisoning alone does not produce retinal damage (20). If formaldehyde is produced from methanol and does have a reasonable half life within certain cells in the poisoned organism the chronic toxicological ramifications could be grave. Formaldehyde is a known carcinogen (57) producing squamous-cell carcinomas by inhalation exposure in experimental animals (22). The available epidemiological studies do not provide adequate data for assessing the carcinogenicity of formaldehyde in man (22, 24, 57). However, reaction of formaldehyde with deoxyribonucleic acid (DNA) has resulted in irreversible denaturation that could interfere with DNA replication and result in mutation (37). Glycerol formal, a condensation product of glycerol and formaldehyde (which may be formed in vivo), is a potent teratogen causing an extremely high incidence of birth defects in laboratory animals (52). Even the staunchest critic of formaldehyde involvement in methanol toxicity admits: "It is not possible to completely eliminate 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." (34) [34. McMartin, K.E., Martin-Amat, G., Noker, P.E. and Tephly, T.R., Lack of a Role for Formaldehyde in Methanol Poisoning in the Monkey. Biochem. Pharm., 28: 645-649 (1978).] Acute Toxicity in Man "Toxic Syndrome" A striking feature of methyl alcohol syndrome is the asymptomatic interval (latent period) which usually lasts 12 to 18 hours after consumption. [This can account for the failure of many laboratory and clinical tests to finds symptoms hours after exposure to aspartame.] This is followed by a rapid and severe acidosis caused partially by the production of formic acid (19). Insufficient formic acid is generated to account for the severity of metabolic acidosis produced and, therefore, other organic acids may also be involved (32). Patients may complain of lethargy, confusion, and impairment of articulation, all frequently encountered signs in moderate central nervous system (CNS) intoxications resulting from other toxic compounds (20). Patients may also suffer leg cramps, back pain, severe headache, abdominal pain, labored breathing, vertigo and visual loss, the latter being a very important clue to making a diagnosis of methanol poisoning (20). Other striking clinical features associated only with the oral administration of methanol are elevated serum amylase and the finding of pancreatitis or pancreatic necrosis on autopsy (20, 55). In fatal cases liver, kidneys and heart may show parenchymatous degeneration. The lungs show desquamation of epithelium, emphysema, edema, congestion and bronchial pneumonia (12). Chronic Human Exposure This is the most important aspect of methanol toxicity to those who are interested in observing the effect of increased methanol consumption on a population. The data presented here were compiled by the Public Health Service. The individuals studied were working in methanol contaminated environments. It is interesting to note that the visual signs always associated with acute toxicity often do not surface under chronic conditions (20). 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 (55). The most characteristic signs and symptoms of methyl alcohol poisoning in humans are the various visual disturbances which can occur without acidosis (55) although they unfortunately do not always appear (20). Some of these symptoms are the following: misty vision, progressive contraction of visual fields (vision tunneling), mist before eyes, blurring of vision, and obscuration of vision (20, 55). ALCOHOLICS: CHRONIC METHANOL CONSUMPTION Alcoholics in general, but particularly those who consume large quantities of wine or fruit liqueur, would seem, from the available evidence, to be the only population thus far exposed to consistently high levels of methanol ingestion (Table 1). The high ethanol/methanol ration of alcoholic beverages must have a very significant protective effect, though enzyme kinetics mandate some constant but low level of methanol metabolism. One could speculate that the delicate balance which maintains this defense might be jeopardized by the general nutrition neglect and specifically the folic acid deficiency (21) associated with the meager food intake of some alcoholics. Alcoholics have a much higher incidence of cancer and other degenerative diseases, none of which can be attributed to ethanol alone (56). The fascinating similarities linking unusual clinical features of methanol toxicity and alcoholism are worth noting. Neuritis: Chronic occupational exposure to methanol often produces human complaints of neuritis with paresthesia, numbing, pricking and shooting pains in the extremities (4, 55). Alcoholic polyneuropathy (36) or multiple peripheral neuritis (21) differs symptomatically from the methanol induced syndrome only in its first and often exclusive affinity for legs. The unpleasant sensations of intolerable pain associated with slight tactile stimulation (36) is not an uncommon anecdotal consumer complaint following long term consumption of aspartame. In one such case reported to me, my interpretation of an electromyogram indicated the signs of denervation indicative of alcoholic polyneuropathy (36). The individual's ischemic lactate pyruvate curve, before and after fasting, was flat. Less than six weeks after aspartame consumption ceased the major symptoms subsided and repetition of these tests produced normal responses, although the individual still experienced intermittent pain. Pancreatitis: Methanol is one of the few etiologic factors associated with acute pancreatic inflammation (16, 20). Microscopic findings of pancreatic necrosis on autopsy have been reported after acute oral methanol poisoning (55) which marks the end of the latent period. There is a generally accepted association between alcoholism and pancreatitis. Most patients, however, give a history of 5 to 10 years of heavy drinking before the onset of the first attack (16). The fact that 40% of all cases of acute pancreatitis complaints are attributable to alcoholics (21), however, must be taken into consideration to avoid artifactual association. Pancreatitis has been a complaint associated with aspartame consumption. Methanol and the Heart: A 21-year-old non-drinking male who had been exposed daily to the fine dust of aspartame at the packaging plant he had worked for over a year, was complaining of blurred vision, headaches, dizziness, and severe depression before his sudden death. An autopsy revealed (aside from the organ involvement one might expect from methanol toxicity) myocardial hypertrophy and dilatation with the myocardiopathy and left ventricle involvement reminiscent of alcoholic cardiomyopathy. Alcoholic cardiomyopathy, however, typically occurs in 30-55 year old men who have a history of alcohol intake in quantities comprising 30-50 percent of their daily caloric requirement over a 10 to 15 year period (56). It has been suggested that alcohol is the etiologic factor in at least 50 percent of the cases of congestive cardiomyopathy (56). The significantly lower hospitalization incidence for coronary disease among moderate drinkers than among nondrinkers and the protection to coronary risk afforded the moderate drinker (less than two drinks a day) over the nondrinker (56) seems contradictory. However, if we implicate methanol as the etiologic factor, then clearly the nondrinker is at a disadvantage with a much lower ethanol to methanol ratio (Table 1) when consuming naturally occurring methanol in a diet otherwise equivalent to the drinkers. The chronic alcoholic for reasons already proposed might sacrifice this protection. As mentioned below, high temperature canning as developed late in the 19th century should increase significantly the methanol content of fruits and vegetables. The increased availability and consumption of these food products in various countries over the years may parallel better than most other dietary factors the increase in incidence of coronary disease in their populations. Cigarette smoke, a known coronary risk factor, contains four times as much methanol as formaldehyde and only traces of ethanol. ETHANOL AND FOLIC ACID The importance of ethanol as an antidote to methanol toxicity in humans is very well established in the literature (46, 55). The timely administration of ethanol is still considered a vital part of methanol poisoning management (11, 12, 19, 20, 50). Ethanol slows the rate of methanol's conversion to formaldehyde and formate, allowing the body time to excrete methanol in the breath and urine. Inhibition is seen in vitro even when the concentration of ethyl alcohol was only 1/16th that of methanol (62). The inhibitory effect is a linear function of the log of the ethyl alcohol concentration, with a 72% inhibition rate at only a 0.01 molar concentration of ethanol (2, 46). Oxidation of methanol, like that of ethanol, proceeds independently of the blood concentration, but at a rate only one seventh (20) to one fifth (12) that of ethanol. Folacin may play an important role in the metabolism of methanol by catalyzing the elimination of formic acid (41). If this process proves to be as protective for humans as has been shown in other organisms (50, 38) it may account, in part, for the tremendous variability of human responses to acute methanol toxicity. Folacin is a nutrient often found lacking in the normal human diet, particularly during pregnancy and lactation (14). METHANOL CONTENT OF ASPARTAME SWEETENED BEVERAGES An average aspartame-sweetened beverage would have a conservative aspartame content of about 555 mg/liter (48, 51) and therefore, a methanol equivalent of 56 mg/liter (56 ppm). For example, if a 25 kg child consumed on a warm day, after exercising, two-thirds of a two-liter bottle of soft drink sweetened with aspartame, that child would be consuming over 732 mg of aspartame (29 mg/kg). This alone exceeds what the Food and Drug Administration considers the 99+ percentile daily consumption level of aspartame (48). The child would also absorb over 70 mg of methanol from that soft drink. This is almost ten times the Environmental Protection Agency's recommended daily limit of consumption for methanol [in water]. To look at the issue from another perspective, the literature reveals death from consumption of the equivalent of 6 gm of methanol (55, 59). It would take 200 12 oz. cans of soda to yield the lethal equivalent of 6 gm of methanol. According to FDA regulations, compounds added to foods that are found to cause some adverse health effect at a particular usage level are actually permitted in foods only at much lower levels. The FDA has established these requirements so that an adequate margin of safety exists to protect particularly sensitive people and heavy consumers of the chemical. Section 170.22 of Title 21 of the Code of Federal Regulations mandates that this margin of safety by 100-fold below the "highest no-effect" level. If death has been caused by the methanol equivalent of 200 12 oz. cans of aspartame sweetened soda, one hundredth of that level would be two cans of soda. The relationship of the lethal dose to the "highest no effect" level has tragically not been determined for methanol (9, 11) but assuming very conservatively that the level is one tenth of the lethal dose, the FDA regulations should have limited consumption to approximately 2.4 ounces of aspartame sweetened soft drink per day. [Published case reports show severe reactions to tiny doses of aspartame in some reactors: 1.5, 4, or 6-8 mg aspartame, while a 12 oz can of diet soda provides about 200 mg aspartame.] The FDA allows a lower safety margin only when "evidence is submitted which justifies use of a different safety factor." (21.C.F.R.170.22) No such evidence has been submitted to the FDA for methanol. Thus, not only have the FDA's requirements for acute toxicity not been met, but also, no demonstration of chronic safety has been made. The fact that methyl alcohol appears in other natural food products increases greatly the danger of chronic toxicity developing by adding another unnatural source of this dangerous cumulative toxin to the food system. NATURAL SOURCES OF METHANOL Methanol does appear in nature. To determine what impact the addition of a toxin will have on an environment it is very helpful to accurately determine the background levels of consumption. Fruit and vegetables contain pectin with variable methyl ester content. However, the human has no digestive enzymes for pectin (6, 25) particularly the pectin esterase required for its hydrolysis to methanol (26). Fermentation in the gut may cause disappearance of pectin (6) but the production of free methanol is not guaranteed by fermentation (3). In fact, bacteria in the colon probably reduce methanol directly to formic acid or carbon dioxide (6) (aspartame is completely absorbed before reaching the colon). Heating of pectins has been shown to cause virtually no demethoxylation; even temperatures of 120? C produced only traces of methanol (3). Methanol evolved during cooking of high pectin foods (7) has been accounted for in the volatile fraction during boiling and is quickly lost to the atmosphere (49). Entrapment of these volatiles probably accounts for the elevation in methanol levels of certain fruit and vegetable products during canning (31, 33). In the recent denial by the Food and Drug Administration of my request for a public hearing on this issue (13), the claim is made by them that methanol occurs in fruit juices at an average of 140 parts per million (a range of between 15-640 parts per million). This often used average originates from an informative table in a conference paper presented by Francot and Geoffroy (15). The authors explain that the data presented in the table "may not" represent their work but "other authors" (15). There is no methodology given nor is the original source cited and only the identity of the lowest methanol source, grape juice (12 ppm), and the highest, black currant (680 ppm), are revealed. The other 22 samples used to generate this disarmingly high average are left completely to the imagination. The authors conclude their paper by insisting that "the content of methanol in fermented or non-fermented beverages should not be of concern to the fields of human physiology and public health." They imply that wines "do not present any toxicity" due to the presence of certain natural protective substances (15). When they present their original data relating to the methanol content of French wines (range 14-265 ppm) or when the methanol content of any alcoholic beverage is given, the ration of methanol to ethanol is also presented. Of the wines they tested, the ratio associated with the highest methanol content (265 ppm) indicates over 262 times as much ethanol present as methanol. The scientific literature indicates that a fair estimate of methanol content of commonly consumed fruit juices is on the order of 40 parts per million (Table 1). Stegink, et al. Points out that some neutral spirits contain as much as 1.5 grams/liter of methanol (51); what is not mentioned is the fact that if these spirits are at least 60 proof (30% ethanol) this still represents the presence of over 200 molecules of ethanol for every molecule of methanol that is digested. An exhaustive search of the present literature indicates that no testing of natural substances has ever shown methanol appearing alone; in every case ethanol is also present, usually, in much higher concentrations (15, 27, 28, 30, 31, 35, 44, 45). Fresh orange juices can have very little methanol (0.8 mg/liter), and have a concomitant ethyl alcohol content of 380 mg/liter (28). Long term storage in cans has a tendency to cause an increase in these levels, but even after three years of storage, testing has revealed only 62 mg/liter of methanol, with an ethanol content of 484 mg/liter. This is a ratio of almost eight times ethanol/methanol (28). Testing done recently in Spain showed orange juice with 33 mg/liter methanol and 651 mg/liter ethanol (20/1 ratio) (45). The range for grapefruit juices are similar, ranging from 0.2 mg methanol/liter (27) to 43 mg methanol/liter (27). The lowest ratio of any food item was found in canned grapefruit sections with 50-70 mg/liter methanol and 200-400 mg/liter ethanol (27), thus averaging six molecules ethanol for every molecule of methanol. This high ethanol to methanol ratio, even at these low ethanol concentrations, may have some protective effect. As stated previously, ethanol slows the rate of methanol's conversion to formaldehyde and formate allowing the body time to excrete methanol in the breath and urine. Inhibition is seen in vitro even when the concentration of ethyl alcohol was only 1/16th that of methanol (62). The inhibitory effect is a linear function of the log of the ethyl alcohol concentration, with a 72% inhibition rate at only a 0.01 molar concentration of ethanol (2). Therefore if a liter of a high methanol content orange juice is consumed, with 33 mg/liter of methanol and a 20/1 ration of ethanol/methanol, only one molecule of methanol in 180 will be metabolized into dangerous metabolites until the majority of the ethanol has been cleared from the bloodstream. If a similar amount of methanol equivalent from aspartame were consumed, there would be no competition (46). Another factor reducing the potential danger associated with methanol from natural juices is that they have an average caloric density of 500 Kcal/liter and high osmolarity which places very definite limits to their consumption level and rate. Data obtained in a Department of Agriculture survey of the food intake of a statistically sampled group of over 17,000 consumers nationwide (1), indicate that the 17.6% of the population that consume orange juice daily take in an average of 185.5 gm of that juice. These statistics indicate that 1.1% of the population consume an average of 173.9 gm of grapefruit juice while only 1.8% drink approximately 201 gm of tomato juice daily. Table 1 shows that under normal conditions these individuals would only be expected to consume between 1 and 7 mg of methanol a day from these sources. Even if an individual consumed two juices in the same day or a more exotic juice such as black currant, there would still be some protection afforded by the ethanol present in these natural juices. Consumption of aspartame sweetened drinks at levels commonly used to replace lost fluid during exercise yields methanol intake between 15 and 100 times these normal intakes (Table 1). This is comparable to that of "winos" but without the metabolic reprieve afforded by ethanol. An alcoholic consuming 1500 calories a day from alcoholic sources alone may consume between 0 and 600 mg of methanol each day depending on his choice of beverages (Table 1). The consumption of aspartame sweetened soft drinks or other beverages is not limited by either calories or osmolarity, and can equal the daily water loss of an individual (which for active people in a state like Arizona can exceed 5 liters). The resultant daily methanol intake might then rise to unprecedented levels. Methanol is a cumulative toxin (8) and for some clinical manifestations it may be a human-specific toxin. CONCLUSION Simply because methanol is found "naturally" in foods, we can not dismiss the need for carefully documented safety testing in appropriate animal models before allowing a dramatic increase in its consumption. We know nothing of the mutagenic, teratogenic or carcinogenic effect of methyl alcohol on man or mammal (55, 59). Yet, if predictions are correct (5), it won't be long before an additional 2,000,000 pounds of it will be added to the food supply yearly (53). Must this, then, constitute our test of its safety? REFERENCES 1. 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Self, R., Casey, J.C., Swain, T., The Low-Boiling Volatiles of Cooked Foods. Chem. And Indust., 863-864 (1963). 50. Smith, E.N. and Taylor, R.T., Acute Toxicity of Methanol in the Folate-Deficient Acatalasemic Mouse. Toxicology, 25: 271-287 (1982). 51. Staples, R.E., Teratogenicity of Formaldehyde. Formaldehyde Toxicity. J.E. Gibson, Ed., Hemisphere Publishing Company pp 51-60 (1983). 52. Stegink, L.D., Brummel, M.C., McMartin, K., Martin-Amat, G., Filer, L.J., Jr., Baker, G.L. and Tephly, T.R., Blood Methanol Concentrations in Normal Adult Subjects Administered Abuse Doses of Aspartame. J. Toxicol. Environ. Health, 7: 281-290 (1981). 53. Strittmatter, P. and Ball, E.G., Formaldehyde Dehydrogenase, A Glutathione-Dependent Enzyme System. J. Biol. Chem., 213: 445-461 (1955). 54. Tephly, T.R., Watkins, W.D. and Goodman, J.I., The Biochemical Toxicology of Methanol. Essays Toxicol., 5: 149-177 (1974). 55. 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Zatmann, L.J., The Effect of Ethanol on the Metabolism of Methanol in Man. Biochem. J., 40: 67-68 (1946). TABLE I AVAILABLE METHANOL IN VARIOUS BEVERAGES Methanol mg/liter Caloric Density Calories/Liter Methanol (mg.) Consumed per 1000 Calories Ratio Ethanol (wt.)/Ethanol (wt.) Methanol (mg.) Consumption per day Juices *Orange, fresh (28) 1 470 2 475 1 *Orange, fresh (45) 33 470 70 20 6 *Orange, fresh (31) 34 470 72 16 6 *Orange, Canned (28) 31 470 66 15 6 *Grapefruit, fresh (27) 1 400 1 2000 1 *Grapefruit (31) 43 400 108 5 7 *Grapefruit, Canned (31) 27 400 68 9 5 Grape (15) 12 660 18 - - Alcoholic Beverages Beer (4.5%) 0 400 - - - Grain Alcohol (55) 1 2950 1 500000 - Bourbon, 100 proof (55) 55 2950 19 9090 - Rum, 80 proof (15) 73 2300 32 5000 - Wines (French) (15) White 32 800 44 2500 - Rose 78 800 98 1000 - Red 128 800 160 667 - Pear 188 1370 137 250 - Wines (American) (30) Low 50 800 62 2500 - High 325 800 406 385 - Aspartame sweetened Beverages (48) 2 Liters 5 Liters Uncarbonated Drinks (48) 55 8 6875 0 110 mg 275 mg Cola (Carbonated) (48) 56 8 7000 0 112 mg 280 mg Orange (Carbonated) (48) 91 8 11375 0 182 mg 455 mg Aspartame, pure 25000 *17.6% of U.S. Population consume an average of 185.5 gm. of Orange Juice a day (1) * 1.1% of U.S. Population consume an average of 173.9 gm. of Grapefruit Juice a day (1) ************************************************************** http://ww.presidiotex.com/barcelona/index.html Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X, Fernandez-Lopez JA, Alemany M ["Trok-ho"] Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Life Sci 1998 Jun 26; 63(5): 337-49. Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. http://www.presidiotex.com/barcelona/index.html Maria Alemany, PhD (male) alemany@porthos.bio.ub.es http://groups.yahoo.com/group/aspartameNM/message/864 Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde adducts in rats 9.8.2 rmforall Prof. Alemany vigorously affirms the validity of the Trocho study against criticism: Butchko, HH et al [24 authors], Aspartame: review of safety. Regul. Toxicol. Pharmacol. 2002 April 1; 35 (2 Pt 2): S1-93, review available for $35, [an industry paid organ]. Butchko: "When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use." http://groups.yahoo.com/group/aspartameNM/message/867 Murray: Thatcher: simple tests for immune system reactions due to formaldehyde from the 11% methanol in aspartame: Tholen 9.17.2 rmforall http://www.drthrasher.org/formaldehyde_embryo_toxicity.html Arch Environ Health 2001 Jul-Aug; 56(4): 300-11 Embryo toxicity and teratogenicity of formaldehyde. Thrasher JD, Kilburn KH. http://groups.yahoo.com/group/aspartameNM/message/628 Rich Murray: Professional House Doctors: Singer: EPA: CPSC: formaldehyde toxicity 6.10.1 rmforall http://groups.yahoo.com/group/aspartameNM/message/863 Murray: Wilson: CIIN: EPA: Gold: Thrasher & Kilburn: Shaham: formaldehyde toxicity 8.22.2 rmforall http://groups.yahoo.com/group/aspartameNM/message/645 Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts 6.25.1 rmforall http://groups.yahoo.com/group/aspartameNM/message/622 Rich Murray: Gold: Koehler: Walton: Van Den Eeden: Leon: aspartame toxicity 6.4.1 rmforall http://groups.yahoo.com/group/aspartameNM/message/623 Rich Murray: Simmons: Gold: Schiffman: Spiers: aspartame toxicity 6.4.1 rmforall ********************************************************** Serious symptom syndrome summary: Aspartame (NutraSweet, Equal, Canderel, Benevia) is reported by scientific studies and case histories to be toxic: * headaches * many body and joint pains (or burning, tingling, tremors, twitching, spasms, cramps, or numbness) * fever, fatigue * "mind fog", "feel unreal", poor memory, confusion, anxiety, irritability, depression, mania, insomnia, dizziness, slurred speech, ringing in ears, sexual problems, poor vision, hearing, or taste * red face, itching, rashes, burning eyes or throat, dry mouth or eyes, mouth sores * hair loss * obesity, bloating, edema, anorexia, poor or excessive hunger or thirst * breathing problems * nausea, diarrhea or constipation * coldness * sweating * racing heart, high blood pressure, erratic blood sugar levels * seizures * birth defects * brain cancers * addiction * aggrivates diabetes, autism, ADHD, allergies, and interstitial cystitis (bladder pain) ********************************************************** Rich Murray, MA Room For All rmforall@att.net 1943 Otowi Road, Santa Fe NM 87505 USA 505-986-9103 http://groups.yahoo.com/group/aspartameNM/messages for 871 posts in a public searchable archive http://groups.yahoo.com/group/aspartameNM/message/871 aspartame toxicity brief review: Murray 9.23.2 rmforall http://groups.yahoo.com/group/aspartameNM/message/862 long review http://groups.yahoo.com/group/aspartameNM/message/860 RTM: FDA: objections to neotame approval 8.3.2 rmforall 38 pages http://groups.yahoo.com/group/aspartameNM/message/868 Murray: submit complaints and papers to FDA Docket 02P-0317 by Jan 12 2003: Recall Aspartame as a Neurotoxic Drug 9.20.2 rmforall http://www.dorway.com/tldaddic.html 5-page review Roberts HJ Aspartame (NutraSweet) addiction. Townsend Letter 2000 Jan; HJRobertsMD@aol.com http://www.sunsentpress.com/ sunsentpress@aol.com Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416 800-814-9800 561-588-7628 561-547-8008 fax http://groups.yahoo.com/group/aspartameNM/message/669 1038-page medical text "Aspartame Disease: An Ignored Epidemic" published May 30 2001 $ 85.00 postpaid data from 1200 cases available at http://www.amazon.com over 600 references from standard medical research http://www.aspartameispoison.com/contents.html 34 chapters http://groups.yahoo.com/group/aspartameNM/message/859 RTM: Roberts: the life work of a brilliant clinician: aspartame toxicity 8.2.2 rmforall http://groups.yahoo.com/group/aspartameNM/message/790 RTM: Moseley: review Roberts "Aspartame Disease: An Ignored Epidemic" 2.7.2 rmforall http://groups.yahoo.com/group/aspartameNM/message/782 RTM: Smith, Terpening, Schmidt, Gums: full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall Jerry D Smith, Chris M Terpening, Siegfried OF Schmidt, and John G Gums Relief of Fibromyalgia Symptoms Following Discontinuation of Dietary Excitotoxins. The Annals of Pharmacotherapy 2001; 35(6): 702–706. Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL, USA. BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is often difficult to treat effectively. CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome for two to 17 years are described. All had undergone multiple treatment modalities with limited success. All had complete, or nearly complete, resolution of their symptoms within months after eliminating monosodium glutamate (MSG) or MSG plus aspartame from their diet. All patients were women with multiple comorbidities prior to elimination of MSG. All have had recurrence of symptoms whenever MSG is ingested. Siegfried O. Schmidt, MD Asst. Clinical Prof. siggy@shands.ufl.edu Community Health and Family Medicine, U. Florida, Gainesville, FL Shands Hospital West Oak Clinic Gainesville, FL 32608-3629 352-376-5071 Debbie J. Hypes painfreeliving@aol.com 304-872-4141 (Case # 1 of 4) P.O Box 25 Lookout, WV 25868-0025 She has about 1,000 on her local mailing list, and has been a volunteer activist since 1997. Her guide first came out in 1997: http://www.Pain-Free-Living.net "The Food Plan: How To Do It" $ 5 by mail, free by email. Her sister Darlene, now 47, cured her own severe fibromyalgia in 1995 by using an elimination diet, and then Debbie also cured herself by 1997. Their doctor, Siegfried Schmidt, paying attention, tried it on two selected women, who got well, and are his third and fourth cases. http://groups.yahoo.com/group/aspartameNM/message/846 RTM: aspartame in Merck Maxalt-MLT worsens migraine, AstraZeneca Zomig, Eli Lilly Zyprexa, J&J Merck Pepcid AC (Famotidine 10mg) Chewable Tab, Pfizer Cool Mint Listerine Pocketpaks 7.16.2 rmforall Migraine MLT-Down: an unusual presentation of migraine in patients with aspartame-triggered headaches. Newman LC, Lipton RB Headache 2001 Oct; 41(9): 899-901. [Merck 10-mg Maxalt-MLT, for migraine, has 3.75 mg aspartame, while 12 oz diet soda has 200 mg.] Headache Institute, St. Lukes-Roosevelt Hospital Center, New York, NY Department of Neurology newmanache@aol.com Albert Einstein College of Medicine, Bronx, NY Innovative Medical Research RLipton@IMRInc.com http://groups.yahoo.com/group/aspartameNM/message/855 RTM: Blumenthall & Vance: aspartame chewing gum headaches Nov 1997 7.28.2 rmforall Harvey J. Blumenthal, MD, Dwight A Vance, RPh Chewing Gum Headaches. Headache 1997 Nov-Dec; 37(10): 665-6. Department of Neurology, University of Oklahoma College of Medicine, Tulsa, USA. neurotulsa@aol.com Aspartame, a popular dietetic sweetener, may provoke headache in some susceptible individuals. Herein, we describe three cases of young women with migraine who reported their headaches could be provoked by chewing gum sweetened with aspartame. [6-8 mg aspartame per stick chewing gum] **********************************************************