NIH thinks the idea is too reductionist, and main line research is either looking for genetic factors that can't explain epidemics, or looking for better treatments to use after people are already sick.(AMP,Moonshot) So far, no one can explain the origin of chronic ailment with systemic inflammation.
Interestingly though, a recent publication found that caffeine consumption correlates with low state of inflammation with age and low incidence of chronic ailments.(Furman2017or#B) The theme developed here is that this is not because coffee is good for you but because of what you don't drink if you are a coffee addict.
Woodrow C. Monte published in 2011 what we here call his MTFT model for the way damage can be caused by very low level methanol(Monte2011,web) We rephrase, tabulate and slightly expand the original model. Added are explanations for why the long delay to symptoms with classic methanol poisoning (<2 tsp will kill an adult), why death is not until after the body has removed the methanol, why the symptoms of still lower doses of methanol should be so entirely different from those of classic poisoning, why just a skin swab of methanol will kill an infant, and why endogenous ethanol does not prevent metabolization of sub ppm methanol to formaldehyde.(SeeLindinger1997)
Also, Monte's data comparison plot for Alzheimer's deaths can be expanded to be a predictive tool. His original plot showed that death from Alzheimer's occurs fairly precisely at 14 years after people start using aspartame. So take the data for society's consumption of aspartame and move it forward 14 years to predict Alzheimer's deaths that should happen in the future. The fact that this works and agrees with the latest fifteen years of CDC data is fairly compelling. (Similarly determined latencies for cancers are less precise but average about half a dozen years, the longest being 14 years for thyroid cancer. Monte Figures 11.1 & 11.9)
ADH Oxidizes Methanol To Formaldehyde:Figure 4: The Primary ADH Pathway For Metabolizing Methanol In Humans**
MTFT is claimed here to be a likely driver of today's chronic, non-germ diseases already cited. The word "epidemic" will be used to describe significant sustained rise in incidence rate over many years. In some cases the rise is still continuing and in some is being followed by high plateau. The main surge in new cases of diabetes, for instance, was from 1991 to 2009, but now with 9.3% of Americans afflicted.ref And a 30 years growth of cardiovascular disease has finally leveled off but still causes ¼ of deaths in the US and is spreading throughout the world.
Fruits and vegetables contain pectin, which has oxymethyl (also called methyl ester) side chains that potentially can dissolve off to form methanol. These side chains are normally so tightly bound that digestion can not dislodge them. But heating, enzymes used during juice processing and over ripening or shelf life can dissolve off these side chains and form methanol. USDA studies in the 1950s, for instance, found that methanol content increased by factors of 80-100 when orange and grapefruit juice are canned and stored.m28,m363GF,SectF Cooking would normally boil off the methanol, because its vaporization temperature is only 149°F, but modern rapid containerization after processing and heating, or post heating to kill the germs, traps the methanol in the food product. Here "container" means can, bottle, carton or pouch - as can of cranberry or spinach, bottle of tomato juice, jar of jam, carton of orange juice or vegetable broth or kids juice with straw. Smoked foods and tobacco smoke contain wood alcohol, and aspartame with intentional methanol in each molecule, has become society's super-dose since 1981.MonteDiet Pot-belly stoves and inadequately ventilated fireplaces may contribute as well.
Exposure to methanol by inhalation of smoke is a special case. The very rapid absorption from the lungs into the blood stream is probably faster than the time for absorption from the blood stream into other body fluids. This means that for a brief period dilution is into less fluid than usual making the blood alcohol concentration high. And a jump in methanol-to-ethanol ratio will then turn up the ADH enzyme's rate of production of formaldehyde. A cigarette delivers about 1/6 the amount of methanol as a diet soda, but the peak rate of formaldehyde production may be higher.
Skeletons and CT scans of mummified remains from many eras as far back as 1500 BC sometimes show signs of arthritis and arterial plaque, and one might guess that this was due to fireplace smoke and smoked foods.ref
B: High-Level Methanol, 7g/kg, and the Majchrowicz-Mendelson Experiment:
At high enough level, alcohol supresses the central nervous system and causes breathing to stop. This is at 0.4% BAC for most people,L7 and the same for methanol and ethanol. Alcoholics, though, because of increased activity of an alternative microsomal metabolic pathway, can tolerate up to 0.6% BAC, a number that comes from Majchrowicz-Mendelson1971.m134&A2
The rest of this section is a little technical, reviewing three journal publications. Learned are: 1) Ethanol is an antidote for methanol poisoning. 2) The hangover effect from a binge of ethanol drinking is due to methanol. 3) A cure for hangover is to have a little tiny bit more ethanol. Blood BAC of ethanol needs to be only a fraction of that for methanol to force methanol to be excreted rather than metabolized. 4) Numbers for the half life of methanol and ethanol are tabulated for various conditions.
The 1971 experiment by Majchrowicz and Mendelson was highly informative - but also bold and apparently almost catastrophic. Nineteen long-term male alcoholics from a rehab program were asked to volunteer to return to another bout of their chronic binge drinking with the condition that they agree to have their blood ethanol and methanol measured throughout the incident. They were allowed to self-regulate the amount and duration of drinking except that they were limited to 32 oz/day of 50% whiskey. That's 2.8 times the maximum amount of ethanol that the human body can dissipate (a shot of 40%/hr), and methanol BAC's went up to half the lethal level of 110ppm, so the volunteers, known addicts with a problem, could kill themselves during the experiment if they didn't self-regulate. The binges lasted from 10 to 15 days, and at least one hit the limits of survivability with ethanol peaking at 0.63%.
What Majchrowicz & Mendelson demonstrated dramatically is that when there is significant ethanol in the blood, methanol can rise to high levels from sources internal to the body. And then after the drinking stops and ethanol is going down, this high level of methanol stays constant for many hours. It is not until ethanol BAC drops to 90 ppm and below that the methanol level begins also to drop. That's a delay of 15-18 hours, and significantly, it is when hangover symptoms begin. The peak in hangover symptoms corresponds with the maximum rate of methanol metabolism.
So Majchrowicz & Mendelson suggest that a way to avoid hangover is to not stop drinking precipitously, but instead to sip a small continuous amount of ethanol for several days after the partying. Fifteen years later, Jones1986m389 confirmed the same delayed methanol metabolism synchronous with hangover following a single evening of drinking. The consumption tested was a liter+ of 9.5% wine in two hours, with blood ethanol levels rising only briefly to almost 0.2%.
When no alcohol is being ingested, Jones1986 measured normal endogenous levels of blood alcohols to be about 1.8 for ethanol and 1.2 ppm for methanol. These are at the noise floor of the alcohol breath measurements, and there is no data comparing individuals.
Here are some additional experimental results, simplified for self-consistency but still rather difficult to read:
For high ingested ethanol the body's available ADH enzyme saturates at about 90 ppm = 0.009% BAC. Above this the ethanol dissipation rate is 0.036%/hr, which for an adult with an effective 50L of body fluid (a 150 lb male or 165 lb female) is the well-known shot per hour of 40% whiskey. (1 shot = 1.5 oz = 3Tbs = 45 mL) At saturation and below the dissipation rate is proportional to alcohol concentration and is BAC/τ½, with half-life value τ½ ethanol = 15 min. This is an awfully short half life for ethanol, but click the above figure. It is what Jones1986 measured, and there is no scatter in his data.
One has to be careful about interpreting the 142 min half live given in the Jones1986 plot for methanol, because the ADH enzyme normally has a much higher affinity for ethanol than for methanol. Monty states a sixteen times greater affinity but does not give a reference. This would mean that the methanol is not metabolized and must be excreted, which is slow. As pointed out initially, this affinity for ethanol may be significantly diminished at < ppm dilutions. The Jones half life measured in the 10 ppm region for methanol appears to be slow and will be interpreted here as representing excretion: τ½ m excretion = 142 min ≈ 2⅓ hr.
Original recognition of the trend that ADH has a higher affinity for ethanol was in 1943 during assessment of accidental methanol poisonings, and three additional papers on the subject followed in the late 1940's. Then in 1952 Leaf&Zatmanm115&A1 did experiments with dramatically graphic results showing the inhibition of methanol metabolism by ethanol. They made a couple math mistakes - taking log10 rather than lne, and failing to fit their data to (.93v/V)[exp(t/τabs)-exp(t/τdis] - but one of their results used here is that τ½ m excretion is about ten times longer than τ½ m metabolize. The Leaf&Zatman results appear to have stimulated both the recognition in Røe1955 that ethanol can be used as an antidote for methanol poisoning and the Majchrowicz&Mendelson1971 experiments just described.
A striking example of the antidote effectiveness of ethanolm489 is an attempted suicide in 1982 by a woman who ingested 112 mL of methanol, some 20+ times the minimum lethal dose of ~6 mL for her size. Her methanol BAC responded proportionally, reaching some 23 times the lethal 110 pm of Table 1. But she suffered no injury, poisoning symptoms or abnormal blood measures, without administration of bicarbonate, because she was immediately given and maintained on a high level of ethanol.
And finally, the point that that even excretion of methanol becomes blocked by ethanol if ethanol BAC is high enough. This is implied by interpreting the Majchrowicz&Mendelson1971 plots using
the Leaf&Zatman1952 factor of ten for the ratio τ½ m excretion
/ τ½ m metaboliz. Clearer, is that in the above suicide case, the blood level methanol half life was 35 hours.
C: Classic Methanol Poisoning, .03g/kg, and the Minimum Lethal Dose:
Dr. Monte argues that minimum in Minimum Lethal Dose means minimum - one number, not a large range of numbers as often suggested. There is a problem with the source data, though. It tends to be circumstantial from thousands of accidental methanol poisonings during prohibition when the poor and even the rich couldn't be sure of the ethanol versus methanol content of their beverage. And reports of surviving near poisoning from high levels of methanol are probably associated with imbibing both kinds of alcohol together, the ethanol providing protection against the methanol.
Dr. Monte uses the circumstances of patient 17 in a well-documented reportm16 from the Emory University School of Medicine to infer an accurate number for MLD. This was a 21 year old 117 lb female who tasted a tablespoon of 40% methanol whisky and then refused to take any more. She died three days later. Her MLD was .4x3 = 1.2 tsp of methanol. For a 150 lb women this scales to 1.5 tsp, the number Monte uses for MLD.
The number is scaled up a little further here to 1.69 tsp to adjust what here will be used as a "standard" adult size, someone with body fluids totaling about 50 liters. That's an easy number to use for calculations and corresponds to a 165 lb women or a 150 lb man. 1.69 tsp = 8.46 mL, which weighs 8.46/.79 = 10.7 g = 0.377 oz. In terms of g methanol per kg body weight, the lethal dose is about 0.03 g/kg, but a little different for men and women; 0.0324 g/kg for men, 0.0294 g/kg for women. In terms of peak blood alcohol content the lethal methanol level should be about 8.46mL/50L = 169 ppm - but a little lower to account for metabolization during absorption. The modeling of "Absorption-Dissipation Curves" below suggests a 2/3 factor giving about 113 ppm peak BAC.
D: Low-Level Methanol, <.3mg/kg, and Monte's MTFT Model:
What Monte brings to the table is new logic backed by 782+ references and much correlation with data. His mechanism for modern disease proliferation is referred to here as MTFT, Methanol Transported Formaldehyde Toxicity.
There are two parts, "MTF" and "T." The "MTF" is how formaldehyde gets into a variety of tissues. It's too reactive to last long enough to circulate in the blood. But methanol circulates, is passed freely without regulation into cells,ref and then is converted to local non-circulating formaldehyde. Most of the ADH that fosters this conversion is in the liver and stomach, but not all. ADH is also present in the cells of the inner two layers of blood vessel linings, in connective tissue, in mammary epithelium where there is little ALDH and in the retina. The formaldehyde may diffuse within the cell, into mitochondria or out of the cell into interstitial spaces or neighboring cells.
The second "T" part refers to toxic damage caused by formaldehyde when persistently generated in tissue in tiny amounts. There are basically just three or four damage modes, but depending on what tissue is being affected, these manifest as a wide range of disease.
E: Calculations of BAC (Blood Alcohol Concentration)
We use what here will be called the average adult, someone whose body contains V = 50 liters of fluid, which corresponds to about a 150 lb male or a 165 lb female or elderly male. Blood is 93% water, so if the amount of alcohol in body fluids is v', the blood alcohol concentration is BAC = .93v'/V.
The amount of alcohol in body fluids is less than the amount consumed for possibly two reasons. First is metabolization of about 10% of alcohol in the stomach. This does not apply to the effective methanol of aspartame, though, because dissolution of the oxy-methyl side chain to methanol does not occur until fluids reach the duodenum. And it doesn't apply to inhaled methanol in smoke.
The second and larger factor that reduces alcohol volume in body fluids is metabolization of the alcohol, mostly in the liver, during the time while it is being absorbed from the intestines into the blood. Depending on what else has been eaten and whether it is aspartame that has to be digested, the peak in BAC occurs somewhere between less than an hour to as much as two hours after the alcohol/aspartame is consumed. The peak is almost instantaneous for smoke-inhaled methanol.
We denote this delayed maximum BAC as BACm, and to simplify the calculations assume that the amount of alcohol/aspartame consumed is moderate or small so that enzyme saturation does not occur.
Here's an introductory calculation for a teaspoon of pure alcohol drunk by an adult. 1 teaspoon = 5mL = .005L, and if 2/3 of this is diluted into 50L, the over-all blood BAC would be .005/50 = 0.01% = 100 ppm times the 2/3 factor, which gives 67 ppm. And with dilution into only blood plasma, the peak BAC would be 17x67 = 1100 ppm = 0.11%.
Here's the calculation for a standard 12 oz can of diet soft drink. It contains 180-193mg of aspartame.NutraSweet,AspInfo Solution of the methyl esterfig results in 0.13x180mg/(792mg/mL) = .03mL = .00003L (=.61 of a drop) of methanol. Multiplying by 2/3 and dividing by 50L of total body fluids gives only .40 ppm for the over-all BAC. But for dilution into only blood plasma, the peak BAC is 17x0.4 = 6.8ppm, which is some 5-6 times endogenous. (For the larger 198mg number peak BAC would be 7.3ppm.)
If someone drinks diet soda repeatedly throughout the day, the mean methanol will build up. Appendix C7 indicates that if the drink spacing is 2.3 hr (equal to the metabolic half life of methanol), the mean BAC rises to about the single-drink overall BAC of 0.4 ppm, but that if the spacing is 1 hr, the mean trends to four times as much or 1.6 ppm. With the closer spacing of consumption, peak plasma BAC is raised to maybe 8 ppm.
There are some people like Charles FlemingAppF who was drinking 10 cans of diet soda during the 12-14 hour day, including two with bourbon in the evening, plus also using aspartame sweetener packs. He was probably also getting tobacco smoke at Phillip Morris where he worked and the typical inadvertent dose of methanol in containerized vegetable & fruit products.
This might have been enough to raise his daytime blood methanol BAC to three or more times the normal endogenous level and to have caused peaks maybe as high as 10 or more times endogenous.
Final note using all 50L of body fluids: The production and excretion rates of endogenous methanol must be in steady state balance, so endogenous production = 50L(1.2ppm/2.3hr) = 50L(½ ppm/hr) = .025mL/hr = 0.5 drop/hr.
G: Monte's Evidence:
a) A Medical Science Inconsistency: The first and second metabolites of alcohols are aldehydes and carboxylic acids. For ethanol these are acetaldehyde and acetic acid. For methanol they are formaldehyde and formic acid. The FDA lists acetic and formic acid as GRAS, generally regarded as safe, food additives. Acetaldehyde is reactive stuff - lethal if it measurable in blood leaving the liver. But formaldehyde is even more reactive than acetaldehyde, so inclined to combine with proteins that it can not circulate in the blood.
b) A.G. Searle 1973 Double-Blind Study: The dose level was equivalent to 10 cans/day of diet soft drink or 3 mL/day of methanol. It was 1.8 g/day of aspartame. 77 diabetic patients were screened to have no other health issue and then about half were given the aspartame and half a placebo. 1/7 of the women given aspartame developed either fatal stroke or breast cancer in 8-11 weeks.
c) Controlled, Repeatable Experiment with Lower-Dose Aspartame: 3-4 cans/day of diet soda has caused granuiomatous panniculitis lumps that after 10 days reached centimeters in size. Then after a period of secession, 200 mg/day of pure aspartame caused return of the condition in a similar period. That's 1/9 the dose level of the double-blind Searl experiment and equivalent to 1.1 cans/day or .033 mL/day of methanol. This was an open experiment done with a single patient, but with a demonstration of repeatability.m228, pp.102‑103
d) Epidemiology: 1) Fetal Alcohol Syndrome has responded inversely to reduction in smoking by pregnant women but proportionally to intake of methanol.
2) Ditto machines turn out to have been sadly unfortunate for teachers.
3) Dr. Monte gives 22 plots showing correlation over time between increase in a disease and society's increasing consumption of methanol. A suggestion here is that it is perhaps better to think of this epidemiologic data as a whole, as one graphic display with 22 curves rising together almost simultaneously. This mass rise is an issue all unto itself. And then Monte puts a plot of increasing aspartame/methanol consumption on the same page and points out correlation, giving reason why rise in some diseases should be delayed but others not. It's not proof, but it is suggestive.
These epidemiologic correlations are with low BAC methanol following the introduction of aspartame in 1981.
e) Phenomenology: Dr. Monte doles out a panoply of insights into disease phenomenology. He spreads these in comments throughout his book, though, so some of his main points are tabulated here to show their scope. Most fundamental perhaps is the distinction between innate-immune and auto-immune. The terminology will be explained later.
f) Anatomical Fit: The fit between MTFT and what is observed in several of diseases is good, and to this reviewer sometimes striking, as for atherosclerosis, Alzheimer's and, surprisingly, autism.
H: Evaluation of Tephly, Stegink & Filer versus Monte
Use of the acronym MTFT focuses exactly on the difference between Monte and much of the rest of the research community represented by the seminal works by Tephly, Stegink & Filerm272&A4, R1&A4b,m121 A central debate, as pointed out, is about which metabolite does the damage, formaldehyde or formic acid.
In test animals in which a lethal dose of formaldehyde is injected directly into the veins, the formaldehyde disappears within minutes,m122 and in people who have drunk formaldehyde to commit suicide it has been impossible to find formaldehyde in their blood by the time they get to a hospital.m236 Tephly says this is because the body's ALDH rapidly metabolizes formaldehyde to formic acid which then can be measured in the blood stream and causes acidity. And when folate is administered, the toxicity of methanol decreases. These three factors prove that the toxic metabolic byproduct of methanol must be formic acid, not formaldehyde. This has become the essence of mainstream thinking, both in industry and in medicine.
MedScape.comref and the Methanol InstituteL8 give nicely concise medical summaries of the Tephly point of view, stating that "After consumption, methanol is converted into formaldehyde and then into formic acid, which causes the blood to become acidic... Methanol poisoning can be treated if diagnosed within 10 to 30 hours of ingestion... Administration of sodium bicarbonate can neutralize formic acid and maintain proper pH balance."
Additional examples of formic acid proponents among medical professionals showed up in references for this web page, such as the toxicologist/pathologist with 20 years experience and 40 journal articles who reviewed the Diane Fleming murder conviction. He argues that the evidence for conviction is inadequate,Bayati because they did not "...measure formic acid in Chuck's blood and urine to confirm that Chuck's acidosis was caused by the accumulation of formic acid. ...Formic acid is the major metabolite of methanol that causes acidosis in humans and should be measured whenever methanol poisoning is suspected." And in the three-author 1994 study of birth defects in rats, the authors say,278Bolon1994 "Studies showing that adult rodents with a reduced capacity to detoxify formate (the putative methanol-derived neurotoxicant) develop functional and structural changes that are comparable to those observed in adult human patients with methanol toxicity (Makar and Tephly, '77; Eells, '91), while normal rodents are resistant because they metabolize formate efficiently (Roe,'82)."
Monte says the opposite, a) that formaldehyde is so reactive it rapidly combines with tissue and therefore can not enter the blood stream or be measured in circulation. People suffering from inhaling formaldehyde have primarily lung-related damage, not systemic illness. Then concerning methanol, he points out two additional features. b1) Methanol doesn't react with tissue and can circulate in the blood. b2) When it reaches tissues containing the ADH enzyme, it is converted to non-circulating reactive formaldehyde at those locations, usually diffusing not more than a distance of a few cell diameters. This is being dubbed here as MTF. Besides the liver, these locations of ADH include blood vessel linings, mammary tissue and connective tissues that produce collagen, including bone. The liver has enough ALDH to process formaldehyde with little harm, but not other ADH tissues, especially mammary tissue, so formaldehyde toxicity occurs. It is this mechanism for inflicting dispersed damage that here is called MTFT.
Monte devotes several paragraphs at the end of Chapter 4 to point out: that the FDA classifies formic acid as a harmless GRAS "Generally Recognized As Safe" food additive with a lethal dose level about the same as table salt,m365 that though commonly used in foods there is no recorded death due to its consumption in the last 100 years, that formic acid administered to monkeys causes no damage,m106 that he has used formic acid on salad when he ran out of vinegar, and that it can be found in the bloodstream only for those who have been poisoned with a very large lethal dose of methanol.
And it is perhaps worth noting that for much studied ethanol, mainstream finding switches the ranking of which metabolic byproduct is more dangerous, the aldehyde or the carboxylic acid. For ethanol, with the same enzymes acting as in Figure 2, it is the aldehyde (acetaldehyde) that is more reactive than the carboxylic acid (acetic acid = vinegar).L9 And the reason details are known about which tissues contain the ADH enzyme is because of concern about acetaldehyde.
There is also disagreement about why human blood turns acidic during methanol poisoning and whether monkeys are suitable animals for testing human sensitivity to methanol.
Tephly says it is formic acid that makes the blood acidic. But Monty says this acidity is from two causes, the more important being formaldehyde's powerful negative effect on cellular oxidation function. (Formaldehyde is 100 times more powerful than formate in inhibiting of cytochrome oxidase.m676) As mitochondrial enzymes become impaired, anaerobic respiration ensues, which results in lactic acid. And an observable fact in methanol poisoning is that lactic acid is measurable in the blood before formic acid can be detected and before acidosis develops. Also, note that for each methanol molecule converted to formaldehyde that causes damage to a mitochondrial enzyme, the lasting end effect will be per second, not just per molecule.
And an estimate the Ph change from formic acid alone. If this is done using Monte's number for MLD, 8 mL, the calculated number is too small. Normal blood Ph is 7.4 ± 0.5, and in severe acidosis methanol poisoning like that of Appendix F, blood Ph may go as low as 7.07.
Tephly says monkeys are representative test animals. Monte says that, like other species, monkeys are also 100 times less sensitive to methanol than humans, because of a genetic anomaly of human catalase.
The issue of monkey susceptibility to methanol is one this reviewer doesn't yet fully understand. Tephly has several papers on the subject, and thrashing through that will be a study. But Monte's basic claims appears to stand: Catalase is the primary and ADH a secondary enzyme for oxidizing alcohol in all species from yeasts to primates - except for humans. In humans a genetic anomaly marginalizes the effectiveness catalase, leaving ADH the primary enzyme for oxidizing alcohol. And a particularly critical distinction here is location geometry, catalase being located inside peroxisomes that constrain reactive chemicals, but ADH being located throughout the cytosol of a cell. This means that in humans, but not other species, the formaldehyde produced in cells containing ADH is free to diffuse throughout the cell and to some extent out the cell wall. There is a reason for humans to be orders of magnitude more susceptible to methanol than all other species.
The gulf over DNA methylation is even more broadly based. Nature's process does not involve formaldehyde, but instead takes a methyl group from a methionine amino acid side chain of SAM and transfers it to replace a hydrogen at a precisely exact location on DNA, 99.98% of the time on a cytosine (C) nucleotide that is followed by a guanine (G), and simultaneously on both strands. In lab work with DNA in test tubes, addition of formaldehyde causes cross-linking between DNA and protein, not methylation. So there is reason to be skeptical when first hearing Monte's assertion that in vivo formaldehyde causes DNA methylation.
The key here to the potential disruptiveness of formaldehyde to DNA is that the first step of forming an oxymethyl -OCH3 is spontaneous and random, and not controlled by an enzyme.
And here are a couple speculations by this reviewer. The one-time metabolization of 0.4 ppm of methanol in an adult will produce some 1015 molecules of non-hepatic formaldehyde inside the cells of blood vessel linings, mammary and connective tissues. Healing is not immediate, so damage might likely accrue when the process is repeated every day several times a day for years. The brain, for instance, has 400 miles of capillaries meaning a lot of exposure, and the myelin damage observed in Alzheimer's disease occurs first around capillaries and then spreads outward. Random methylation of DNA by the reoccurring formaldehyde is another possibility, but it takes a while to accrue the 70 or so mutations of a typical cancer.
Also, it may be relevant that arsenic is being discovered to cause life-threatening diseases when exposure is long term at about 10 ppm in well water. The disease locations for this arsenic poisoning are not the same as those for methanol, but are a subset.(Discover magazine, Oct.2013) And it is interesting that the many forms of arsenic all involve methyl attachments.
I: FDA Correct Appraisal or Undue Withholding?
Another thing Monte brings to the table for the first time is the result of a Freedom-of-Information-Act request he knew to make because of difficulty reviewing documents at the FDA in 1983.L10, pp.iv&v Released in 2011, the document is an internal 1978 review by F.X. Collins of rabbit birth defect studies done by A.G. Searle and Hazelton Laboratories in 1974 and 1975.m677&A5 When pregnant rabbits were given aspartame on days 6 through 18 of their gestation, three things happened. They ate more and gained weight both during the time of administration of aspartame and after. Conception rate decreased slightly depending on dose. And their offspring had defects at rates of ½ or 2+ percent depending on dose level, but brain tissue was not analyzed microscopically for neurologic damage.
Dose level is a central issue in whether it was proper for Searle/Hazelton and then the FDA to withhold this data. Was too much aspartame administered to the rabbits or was it a dose level that scales to a range of normal for humans? The FDA's general recommendation is that consumption per day of a food ingredient should be less than 1/100 the dose known to cause any harm in animals. Also, in these experiments looking for effects, the dose administered is high compared to what humans are susceptible to, because rabbits are relatively immune to methanol.
Scaled for weight, the dose levels given to the rabbits were equivalent for a 150 lb (68 kg) human, to either 51 or 136 g/day of aspartame, and these two data points extrapolate to low birth defect rate at 23 g/day. The FDA's generally recommended limit would then be something like ¼ to ½ g/day of aspartame if the 1974 data were used. The current ADI for aspartame is set at 3.4 g/day.L11,L12 Less than 1 g/day is said to be the average amount of aspartame Americans consume, but there are some 3000 aspartame diet products, and 5.6 12 oz cans or one 2L bottle of diet soda contains 1 g of aspartame.
In contrast to these withheld 1974 results, Searle published favorable research for human subjects in 1985 in an international ObGyn journal.m100&A6 The report says, "Acute loading studies have been performed in human beings... No evidence of risk to the fetus was developed... Aspartame does not readily cross the placenta..."
Something is highly inconsistent here. The published results are totally favorable and in a journal optimal for encouraging aspartame consumption. The withheld results are the opposite, unfavorable, and would likely have prevented the approval of aspartame, or so Monte claims. His personal experience is of a fire in early 1990. His house was totaled and he regained consciousness in the hospital after too much smoke inhalation. This was two years after publication of birth defects in rats fed methanol, and the fire inspector reported many cigarette buts around a tree nearby the house, indicating stalking surveillance.
[Monte's methanol studies in rats were reported as Hoque1988,177 plus there is a post-publication update on pp.206&207 of Monte's book that gives improved analysis.
The methanol was delivered during pregnancy and gestation as continuous humidity @ 1.28 g/kg per day, which Hoque states as equivalent to 3 liters of aspartame soft drink per day for adult humans (but this reviewer calculates to be much higher).
Both the offspring and the mother rats were damaged. A notable correlation with the data is that besides capillary linings, the primary location of ADH in the brain is in the purkinje cells of the cerebellum. (See pp.206-207, Fig.12.5 for other anatomical analysis and correlation with autism.)]
And during 2008-2009 there was withholding of information from an especially convened FDA committee.(pp.196&197,Ch12) The Center for the Evaluation of Risks to Human Reproduction found methanol to be a potential developmental toxicant in humans and several times stated that humans are more susceptible to methanol than animals. But two committee members refused to sign the final CERHR report on methanol an accusation being:
(For what it's worth, here's a news article about industrial influence.)
J: The Aspartame Wars still ongoing since 1970
Aspartame has always caused concern because of early animal studies and because of its component parts. One of the amino acid components of aspartame can act as a neurotransmitter, and the methanol component has long been regarded by some as suspicious. By now, though, aspartame is so widely used and so widely claimed to be safe that linking it to a long, disparate list of ailments is said by Wikipedia, ACSH and others to be Luddite conspiracy theory tied to the "Nancy Markle" email hoax.L13,L14,L15 Etc. by Garst.ref This doesn't match very well with in-depth histories.L16,L17
Aspartame's approval by corporate power can also be compared to that for leaded gasoline. Standard Oil powered through the science with the claim that there would be so little lead put in the atmosphere. G.D. Searle powered through the science by changing it. Monte balderdash sensationalism as some say? Maybe. But naysayers tend to dismiss before knowing what Monte is saying.
Government will invest $121M in a $230M program to foster a period of cooperation between normally competing pharmaceutical corporations. The four diseases to be addressed are: Alzheimer's, Type II diabetes, rheumatoid arthritis and lupus. The reason given for why a new approach is needed is that research has so far not been able to find cures for some of the world's most devastating diseases. The objective is, "to try to increase the odds of picking the right targets to go after for the next generation of drug development."
This can be taken as an admission of failure in research to date and that the new research goal is being scaled back. The announced goal is not to find what is causing the dramatic increase in disease or to turn back that increase, but rather try to be able to treat cases as they occur. (9.3% of Americans now have diabetes.)
And at the same time in mental as opposed to physical disease a similar admission is occurring. The way for research to address ADHD is being reexamined. This reviewer is quite sure that ADHD with comorbid conditions is due to an entirely separate cause, but is forced to admit that there might possibly be some relationship to methanol as mentioned above in reference to the cerebellar vermis. [There is also Indredavik2007m572 linking prenatal smoking (with its methanol) to ADHD.]
There appears to be repetition in the NIH AMP of a mistake already made at the onset of the human genome project. It was anticipated then that the heritability of common conditions like heart disease would be explained by correlation with a small set of common genetic variants. That didn't and couldn't happen, not for diseases showing epidemic expansion.
In the pure sciences when there have been decades of research thrashing, resolution has often been by fundamental paradigm change in how to think about the problem, a better known example being explanation of the baffling 1887 Michelson-Morley experiment by a combination of the 1905 special theory of relativity and the 1925 Schröedinger equation. Maybe today's decades of failure in research medicine is similarly lacking some concept fundamental. A common feature of the four diseases to be addressed in the AMP is that they all can be interpreted as relating to Monte's distinction between innate-immune and auto-immune.
Alzheimer's stands out in Figure 6 for its delay in getting to the top of the charts, and it does, too, in MTFT. According to Monte's model, Alzheimer's involves two toxicity mechanisms that should reasonably take time to effect - first innate-immune myelin removal starting at the predicted and observed location immediately around capillaries, and then at further distance, linking of protein giving the observed rubbery feel. Buildup at long diffusion distance should take a while to manifest, so it is reasonable that Alzheimer's should have taken longer to get to the top three in the charts. Contrast this to the fast action already discussed for depression. A new paradigm?
For diabetes, disease prevention might be facilitated with with far less than $250M simply by confirming and publicizing already available information.
L: NIH Communications
My letter of March 18, 2014, was perhaps too polite and indirect, to be clear. What I really said is that: Dr. Murray's Feb 24 letter contains errors in every paragraph. So that of all the verbiage, what stands as valid statements are feelings, not technical critique. He assesses MTFT to be unscientific and too reductionist.
I was also too polite and indirect in my initial February 13 letter to the laureate director, too—with criticism of his newly announced AMP program indirect and left to attachments where apparently no one saw tham. I didn't get blunt about stating that these are director level issues until April 14.
The goal stated in the AMP announcement is to find medications for treating individuals. But nothing is said about the more basic issue of today's epidemic incidence rates as a whole. Shouldn't an exploratory development program at NIH seek to find why the disease are surging and how to drive the incidence rates back down to normal normal? The AMP doesn't. Its goal is to treat people after they are sick.
For $121M there is a lot missing. The NIH director does not respond.
M: Moonshot & AMP Working Wrong Problem (written summer of 2016)
President Obama, with NCI and NIH council, will be asking Congress in mid 2016 to fund a new $1B "moonshot" cancer initiative.4,5,SciAm
And NIH in 2014 invested $350M in a program called AMP with a goal of finding treatments for today's four worst modern ailments.1a,1b,2,3
Dr. Monte's findings are counterintuitive. The usual reaction is that things like apple sauce, canned green beans, orange juice or a diet soft drink can’t have much methanol in them, are government approved, and besides, people have been eating and drinking these kinds of products for a long time without showing any signs of methanol poisoning.
This web page summarizes Monte's evidence that, yes, tiny amounts of methanol if repeated appear to cause harm. And this harm should come with symptoms totally different from that of Classical methanol poisoning. Here's an outline:
Figure 2 serves as an introduction to Monte’s huge complaint. Researchers at the University of Iowa Medical School confirmed and published three (mis)concepts about methanol toxicity. These just happened to be beneficial for achieving approval of aspartame, and the works just happened to be funded by A.G. Searle Corp, the developer. Most important for approval were that the toxicity of methanol should not relate to formaldehyde and that the lethality not be too severe. This promulgation of faux science was in the early 1980’s and is still with us today, apparently vested even in referees for peer review journals.
We call it faux science both because it is incorrect and because it’s hold and tenure seems rather strange. You don’t need research to know that at least some of it is wrong. Formic acid, the promulgated and still identified bad guy with regards to methanol, is essentially just vinegar and classed by the FDA as a GRAS food additive. It can't be what makes methanol so lethal.
The approach here for presenting Monte's complaint is again rather the opposite of what he uses. His book does not cite the journal articles of Tephly et al. But in Section H here, the writings of the opponents are referenced, put side beside, and compared point by point. It's rather like watching a fencing match but with the outcome being credibility of science. Guess who wins.
Several examples are given in Section H to point out how the Tephly et al. teachings are still believed, but perhaps the most interesting and saddest place to read about this is in the murder trial reviewed in Appendix F. Another reason to read Appendix F is to get oriented to the strangeness of how methanol works in the human body.
The big picture is that too much free enterprise and corporate free speech are bad for health. Start with Brooksley Born. She proved to be correct, that transparency and anti-fraud regulation are necessary in the derivatives market. But that was just about money. The conclusion here is that for the edibles industry anti-fraud enforcement needs to be extended to protect both truth in science and the image making that entices consumption.
Monte’s MTFT model has not been and can not be tested directly. That’s because there is no animal model, and because it would be unethical to use humans in potentially debilitating experiments.
So proof has to come from epidemiology, inadvertent human experiments and a model with scientific self-consistency. The summary of Monte's evidence is given here in Sections G and H.
Three problems with Monte's book have been addressed. First, his thinking is too "out of the box" for the scientific community (Sect L, 2/25/14 & 3/18/14), but hopefully the present introduction will serve as a bridge for that problem. Second, writing style has been changed to more of a compressed reference document. And third, a few technical gaps in Monte's presentation have been filled in. Those usually started in attempts to prove him wrong but after study always ended up reinforcing his logic.
Monte’s charges of corporate, scientific, political, agency and scientific malfeasance with general scientific naivety are at first too broad to believe. But after much consideration, reading of his cited documents and note of funding sources, this reviewer has to conclude that his charges are both objective and correct, that:
Further, Monte's charges probably don't go far enough. The machinations he exposes are, after all, pretty much just the flow from "normal" economic forces, and are, arguably, just an oft-seen repeat. Most familiar, perhaps, are some of the misrepresentations by big tobacco and energy, industries that compete in power with the US Government and even use government as in trade negotiations.
If there is any change with time it is increased sophistication in hiding manipulation. Though the US does not have assassinations as in Latin America, disregard for consumer well-being is an imbedded historical constant, the vested interest of corporations being profit, not health. Large industries - like those for energy, tobacco, pharmaceuticals, foods and banking - get return from spending lots of money on advertising, congressional influence, infiltration of regulation, research done their way, and general promulgation of their point of view which may mean subtle denigration of their opposition.
Edibles need to be appealing and convenient (achieved partly with coloring and preservatives), tasty (typically achieved with salt, sugar, fat and flavorings or flavor enhancers) and also be healthy (achieved with advertising). The health image staple, milk, for instance, tastes good because of its animal fat and sugar, but is nutrient depleted after being heated twice, and wonderfully appealing "all-natural" ice cream is an even bigger contrast in image and fact.
A huge, under-recognized new economic force for corporate profitability since WW II is ability to influence inclination to consume. More consumption, whether of food, ice cream, news, cars or borrowed money, is more profit. And aspartame is just one of many, many edibles successfully projected as desirable and healthy, in this case by reducing calories especially for diabetics.
Capitalistic Government makes free enterprise less free only after learning the hard way what is necessary. But today's epidemics of chronic, non-germ diseases are negative experience from which government has not yet learned.
And a final more personal conclusion: A young researcher inclined to be aloof of industry is probably not facing a bright academic career with funding and publications. There aren't many survivors like Monte, and he is having a hard time being heard or publishing in leading journals. I have come to ignore the sometimes stridency in his charges and to critique only the substance of what he writes.