Posted: 25 May 2005
Formaldehyde & formic acid from 11% methanol in aspartame
FDA Docket 02P-0317 Recall Aspartame as a Neurotoxic Drug
Dec 9 2002
The work of Jack D. Thrasher, PhD, provides an adequate scientific model and specific biochemical assays for the chronic symptoms of long-term, low-level exposure to formaldehyde, which is well reported in the scientific literature to inevitably be in intimate association with aspartame-methanol-formaldehyde-formic acid metabolism in monkeys.
Confirming evidence and a general theory are given by Pall (2002):
Testable theory of MCS type diseases, vicious cycle of nitric oxide & peroxynitrite: MSG: Formaldehyde-methanol-aspartame: Martin L. Pall: Murray: 12.9.2
Immune system reactions due to formaldehyde from the 11% methanol in aspartame: Thrasher: Tephly: Monte: Murray 9.27.2
Simple tests for immune system reactions due to formaldehyde from the 11% methanol in aspartame: Tholen 9.17.2
http://www.drthrasher.org/formaldehyde_1990.html [full text]
Arch Environ Health 1990 Jul-Aug;45(4):217-23
Immune activation and autoantibodies in humans with long-term inhalation exposure to formaldehyde.
Thrasher JD, Broughton A, Madison R.
Thrasher & Associates, Northridge, California.
Jack D. Thrasher, PhD firstname.lastname@example.org
Sam-1 Trust, PO Box 874 Alto, New Mexico 88312
505-336-8312 fax 425-675-7379
"The patients in our study had symptoms and complaints related to several organs, as described previously, (4,5,9) which were similar to symptoms of workers with multiple chemical sensitivity,(11) cacosmia,(12) and other chemical exposures. (13-15) We report on the differences in humoral and cell-mediated immunity in humans with long-term inhalation exposure to HCHO vs. asymptomatic students (controls) who experienced short-term, periodic exposure to the chemical."
Cacosmia (a.k.a. Multiple Chemical Sensitivity) Details:
"It is recognized that chemicals and therapeutic drugs are associated with a Lupus-like syndrome. (28, 29) The observations made on the patients in this study support this concept."
Since 11% of aspartame (1120 mg in 2L diet soda, 5.6 12-oz cans) is 123 mg methanol (wood alcohol), immediately released into the body after drinking (unlike the large levels of methanol locked up in molecules inside many fruits), 16 times the 7.8 EPA limit for methanol in drinking water. Ingested methanol is then quickly metabolized into formaldehyde, which in turn becomes formic acid, both of which in time become carbon dioxide and water-- however, about 30% of the methanol remains in the body as cumulative durable toxic metabolites of formaldehyde and formic acid-- 37 mg daily, a gram every month (Oppermann, Muldoon, Ranney 1973). As discussed below, if 10% of the methanol accumulates as retained formaldehyde, that is 12.3 mg daily, 61 times the 0.2 mg level of retained formaldehyde, if 10% is retained from the EPA daily limit of 2 mg formaldehyde in drinking water.
The question is: how much of this formaldehyde and formic acid, both deadly, potent, cumulative toxins with complex multiple effects, as much as 6.6 mg total (30% of the 22 mg methanol) from the 200 mg aspartame in a 12-oz can of diet soda, results in various toxic processes in people?
We should find that aspartame reactors and people with Multiple Chemical Sensitivity and related diseases also react to formic acid, to formaldehyde, to methanol, and to aspartame.
Bear in mind that the EPA limit for formaldehyde in drinking water is 1 ppm, or 2 mg daily for a typical daily consumption of 2 L of water.
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
If 10% of the 7.8 mg EPA daily limit for methanol in drinking water, most of which would promptly metabolized into formaldehyde, were to be retained in the body as formaldehyde, that would be .78 mg, in contrast to 10% retention of the 2 mg EPA daily limit for formaldehyde in drinking water, which would be 0.2 mg, about 40 times less. This suggests a contradiction between the EPA limits for methanol and formaldehyde, which in turn suggests that this important topic is not as yet well understood-- the EPA methanol limit may be far too high.
A limit of 2 mg daily of formaldehyde in drinking water for a 60-kg person is .03 mg/kg, roughly equivalent to .03 mg/L, or 0.001 mmol/L, since a mole is 30 grams and 1 mmole is .03 gm = 30 mg. This level is a thousand times less than the 1 mmole/L level that Oyama (2002) found hurt rat cells. However, Martin L. Pall (2002) in his review article cites people with MCS type diseases react to levels 10 to 100 times under the usual reaction levels. Also, formaldehyde accumulates.
Thrasher's report about symptoms from long-term, low-level exposure to formaldehyde gives much the same litany of complex symptoms as aspartame reactors, who often report using 2-4 L daily of diet soda, providing 123-246 mg methanol, resulting in some probable chronic formaldehyde toxicity-- as already discussed, if 10% were retained as formaldehyde, that would give 12-24 mg daily formaldehyde accumulation, about 60-120 times more than the 0.2 mg from 10% retention of the 2 mg EPA daily limit for formaldehyde in drinking water.
Therefore, we can expect to find signs and symptoms of chronic toxicity, especially since there will be a percentage of users who for various reasons are especially vulnerable, from long-term, low-dose formaldehyde exposure in heavy users of aspartame, such as a daily drinking level of 2-4 L diet soda-- of course there are many other dietary sources.
The most common symptoms are, in rough order of occurrence, considering hundreds of case reports:
RTM: Smith, Terpening, Schmidt, Gums:
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. email@example.com
Community Health and Family Medicine, U. Florida, Gainesville, FL
Shands Hospital, West Oak Clinic Gainesville, FL 32608-3629 352-376-5071
Debbie J. Hypes firstname.lastname@example.org 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:
"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.
Aspartame puts formaldehyde adducts into tissues, Part 1/2 full text, Trocho & Alemany 6.26.98
Aspartame puts formaldehyde adducts into tissues, Part 2/2 full text, Trocho & Alemany 6.26.98: Murray 12.22.2
Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde adducts in rats 9.8.2
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 funded 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."
[They repeatedly pass on the ageless industry deceit that the methanol in fruits and vegetables is as biochemically available as that in aspartame-- see the 1984 rebuttal by Monte.]
RTP ties to industry critized by CSPI: Murray: 12.9.2
Aspartame: Methanol and the Public Interest 1984: Monte: Murray 9.23.2
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 poisoning (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)...."
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 email@example.com [now retired in New Zealand]
Life Sci 1991;48(11):1031-41
The toxicity of methanol.
Tephly TR. [a notable pro-aspartame scientist]
Department of Pharmacology, University of Iowa, Iowa City 52242.
Methanol toxicity in humans and monkeys is characterized by a latent period of many hours followed by a metabolic acidosis and ocular toxicity. This is not observed in most lower animals. The metabolic acidosis and blindness is apparently due to formic acid accumulation in humans and monkeys, a feature not seen in lower animals.
The accumulation of formate is due to a deficiency in formate metabolism which is, in turn, related, in part, to low hepatic tetrahydrofolate (H4 folate). An excellent correlation between hepatic H4 folate and formate oxidation rates has been shown within and across species. Thus, humans and monkeys possess low hepatic H4 folate levels, low rates of formate oxidation and accumulation of formate after methanol. Formate, itself, produces blindness in monkeys in the absence of metabolic acidosis. In addition to low hepatic H4 folate concentrations, monkeys and humans also have low hepatic 10-formyl H4 folate dehydrogenase levels, the enzyme which is the ultimate catalyst for conversion of formate to carbon dioxide. This review presents the basis for the role of folic acid-dependent reactions in the regulation of methanol toxicity.
Publication Types: Review, Academic PMID: 1997785
page 1035 "In the past, formaldehyde has often been suggested as the methanol metabolite which produces toxicity (34,35). Today, a great deal of information is available concerning its lack of such a role. The presence of elevated formaldehyde levels in body fluids or tissues following methanol administration has not been observed. No formaldehyde has been detected in blood, urine or tissues obtained from methanol-treated animals (36,37) and, in methanol-poisoned humans, formaldehyde increases have not been observed...About 85% of a low dose of 14C-formaldehyde [radioactive label] is excreted as pulmonary 14CO2 (49,50)..."
49. Biochem. Pharmacol. 13: 1137-1142 (1964).
The metabolic fate of formaldehyde-C14 intraperitoneally administered to the rat.
W. Brock Neely
Biochemical Research Labs, Dow Chemical Co., Midland, Michigan
In one rat, a 60.5 mg/kg dose = 2,000 mmol/kg was injected, and by 48 hours, 82.0% was in the exhaled air as CO2 and 13.9 % was in the urine = total 95.9% excreted, so 4 % was retained in the body. Trocho (1998) put aspartame in the stomachs of rats, and found formaldehyde adducts in liver, kidneys, brain, and retinas.
50. Xenobiotica 1982 Feb;12 (2):119-24
Formaldehyde metabolism by the rat: a re-appraisal.
Mashford PM, Jones AR.
Dept. of Biochemistry, University of Sidney, Australia
Six rats were injected with a 4 mg/kg dose = 133 mmol/kg, and by 48 hours, 82% was in the exhaled air as CO2, and 7.5% in the urine = total 89.5% excreted, so 10.5% was retained in the body.
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
They found that about 70% of the radioactive methanol in aspartame put into the stomachs of 3 to 7 kg monkeys was eliminated within a day as carbon dioxide in exhaled air and as water in the urine: page 1458
"That fraction not so excreted (about 30%) was converted to body constituents through the one-carbon metabolic pool." They did not mention that this meant that about 30% of the methanol must transform into formaldehyde and then into formic acid, much of which must remain as toxic products in all parts of the body. This study did not monitor long-term use of aspartame."
The low oral dose of aspartame and for methanol was 0.068 mmol/kg, about 1 part per million [ppm] of the acute toxicity level of 2,000 mg/kg, 67,000 mmol/kg, used by McMartin (1979). Two L daily use of diet soda provides 123 mg methanol, 2 mg/kg for a 60 kg person, a dose of 67 mmole/kg, a thousand times more than the dose in this study. By eight hours excretion of the dose in air and urine had leveled off at 67.1 +-2.1% as CO2 in the exhaled air and 1.57+-0.32% in the urine, so 68.7 % was excreted, and 31.3% was retained. [This data is the average of 4 monkeys.]
Aspartame, methanol, formaldehyde, formate toxicity on rat cells:
Oyama, Akaike, et al, Jan 2002: Murray 11.7.2
"While methanol and formate did not affect cell viability in the physiological pH range, formaldehyde at 1-3 mmol/L started to induce cell death. Further increase in formaldehyde concentration produced a dose-dependent decrease in cell viability. Formaldehyde at 1 mmol/L or more greatly reduced cellular content of glutathione, possibly increasing cell vulnerability to oxidative stress."
This study admitted one datum that showed accumulation of formaldehye in the midbrain from an acute toxicity dose of methanol, and widespread accumulation of formic acid in five tissues.
Biochemical Pharmcacology 1979: 28; 645-649.
Lack of a role for formaldehyde in methanol poisoning in the monkey.
Kenneth E. McMartin, Gladys Martin-Amat, Patricia E. Noker and Thomas R. Tephly
The Toxicology Center, Dept. of Pharmacology,
University of Iowa, Iowa City, Iowa 52242
Abstract [not given in PubMed]: [My comments are in square braclets.] Methanol was administered [by nasogastric tube] either to untreated cynomolgus monkeys [2-3.5 kg] or to a folate-deficient cynomolgus monkey which exhibits exceptional sensitivity to the toxic effects of methanol. Marked formic acid accumulation in the blood and in body fluids and tissues was observed. No formaldehyde accumulation was observed in the blood and no formaldehyde was detected in the urine, cerebrospinal fluid, vitreous humor, liver, kidney, optic nerve, and brain in these monkeys at a time when marked metabolic acidosis and other characteristics of methanol poisoning were observed.
Following intravenous infusion into the monkey, formaldehyde was rapidly eliminated from the blood with a half-life of about 1.5 min and formic acid levels promptly increased in the blood. Since formic acid accumulation accounted for the metabolic acidosis and since ocular toxicity essentially identical to that produced in methanol poisoning has been described after formate treatment, the predominant role of formic acid as the major metabolic agent for methanol toxicity is certified.
Also, results suggest that formaldehyde is not a major factor in the toxic syndrome produced by methanol in the monkey.
[So, this is an acute toxicity study, with little relevance for chronic long-term, low-level exposure.
"It is now generally accepted that the toxicity of methanol is due to the formation of toxic metabolites (1,2), either formaldehyde or formic acid."
Monkeys, like people, are susceptible to methanol toxicity.
This team cites their six previous methanol in monkey studies, from 1975 to 1977.
The report is difficult to understand, since the three monkeys were treated differently, and different assays were used.
Monkey A was folate-deficient and thus highly vulnerable to methanol toxicity. This means that the large number of people who are folate-deficient will also be more vulnerable. Blood, urine, and tissue samples were studied 12 hours after the methanol dose of 2,000 mg/kg, when symptoms were visible. Formaldehyde [FM] had decreased in blood from .068 to .038 mmol/L. Note that Oyama, Akaike, et al in 2002 found that 1 mmol/L formaldehyde levels damaged rat cells-- 14 times higher than the initial spike of .068 nmol/L in blood formaldehyde.
For people, 11% of aspartame (1120 mg in 2L diet soda, 5.6 12-oz cans) is 123 mg methanol (wood alcohol), immediately released into the body after drinking (unlike the large levels of methanol locked up in molecules inside many fruits), then quickly transformed into formaldehyde, which in turn becomes aspartic acid, both of which in time become carbon dioxide and water-- however, about 30% of the methanol remains in the body as cumulative durable toxic metabolites of formaldehyde and formic acid-- 37 mg daily, a 1.1 gm monthly.
For the average 60-kg person, the daily dose of methanol from 2 L of diet soda is 2 mg/kg. To create a rough estimate, we imagine the whole body to be 60 kg water-- then the daily dose of methanol would be 2 mg/L, about 67 mmol/L, quickly metabolized into formaldehyde and then into formic acid. The formaldehyde dose would temporarily be about 67 times more than the lowest level of 1 mmol/L that Oyama found hurt rat cells. This is a very rough estimate, since the formaldehyde concentrates in many tissues. Toxicity would result from accumulation of a daily fraction of the methanol as formaldehyde and formic acid metabolites, reacted with body chemicals. If 30% of the daily methanol dose is retained in this way, then that would be .6 mg/kg daily accumulation, 18 mg/kg monthly = 18 ppm.
Formaldehyde adducts concentrate in the brain, liver, kidneys, and retinas, according to the Trocho study on aspartame-fed rats. So, symptoms would evolve in these organs. The amount of accumulated formaldehyde can only grow with daily exposure. It is reasonable to surmise that the body's defenses will deteriorate, and allergic sensitivity will grow. Some heavy users report an actual addiction. Those who quit often report fast recurrence of symptoms upon inadvertent re-exposure to small amounts, such as the 6-8 mg aspartame in a stick of chewing gum.
The assay used was the chromatropic acid method, with a detection limit of .025 mmol/L. None of the five tissues showed any formaldehyde with this assay, except the midbrain, 0.14 mmol/kg wet weight tissue [units converted from their 0.14 micromole/gm]-- just 1.5 times the detection limit of .09 mmol/kg wet tissue weight (given on p. 648).
[Since 1 kg of water is 1 L, 1 mmol/kg is equivalent to 1 mmol/L.]
Meanwhile, the blood formate level rose by 12 hours from .180 to 10.02 mEq/L. [I assume that a mEq is equivalent to a mmol-- let me know if I'm wrong.] The formate detection limits for the assays were not given in this report. The formate level in the vitreous humor of the eye was 7.90 mEq/L. It is well known that formate is extremely damaging to the eye. For unexplained reasons, formate levels in the five tissues were not measured.
After 12 hours, the urine formaldehyde level was below detection level, while urine formate was 115.80 mEq/L-- so much of the formaldehyde had been converted into formic acid, another cumulative, potent toxin.
"In the presence of high formate values and definitive evidence of toxicity in methanol-poisoned monkeys, no measurable formaldehyde was found in the body tissues that were tested."
It is reasonable to surmise that more sensitive assays would have found formaldehyde and formate bound to and reacted with a variety of cellular substances in all tissues-- just as the 1998 Trocho study confirmed.
Often, pro-aspartame studies have titles and summaries that are not supported by a close study of the details:
Flawed test for aspartame DNA damage: Jeffrey & Williams 2000: Murray: 11.20.2
Monkeys B and C were normal, not extra vulnerable to methanol, and were given 3,000 mg/kg methanol, and samples taken at 18 hr. Formaldehyde was detected only in the blood of Monkey B, while formate was found in 8 and 10, respectively, of the 10 fluid and tissue samples in Monkeys B and C. For instance, the lowest value of formate, except for zero-time blood, for each monkey was in the midbrain, 2.16 mmol/kg for Monkey B (24 times the detection limit for the chromatropic acid method) and 1.02 mmol/kg (1.3 times the detection for the dimedon method) for Monkey C. This shows accumulation of formate in liver, kidney, optic nerve, cerebrum, and midbrain.]
"Thus, whereas one can associate formate intimately with ocular toxicity in the monkey, no association of formaldehyde with ocular toxicity can be made at this time. 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 were detectable in body fluids..."
"Acknowledgements-- This research was supported by NIH grant GM 19420 and GM 12675." [Not funded by the industry]
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray: Wilson: CIIN: 12.12.2
Rich Murray: Professional House Doctors: Singer: EPA: CPSC:
Formaldehyde toxicity 6.10.1
Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts 6.25.1
Rich Murray: Gold: Koehler: Walton: Van Den Eeden: Leon:
Aspartame toxicity 6.4.1
Rich Murray: Simmons: Gold: Schiffman: Spiers:
Aspartame toxicity 6.4.1
Aspartame: methanol, formaldehyde, formic acid toxicity: Brief review: Murray 12.10.2