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 methanol- containing 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 aspartame- containg 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 1952- 1953 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 (anti- bacterial), 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, low- level 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, low- level 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 methanol- laden 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 15.7 26.0 22.4 33.0 70 kg adult 11.2 18.6 16.0 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. Laboratory- detectable 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.