High energy consumption at the button tips of axons and dendrites of nerve cells requires plentiful supply of mitochondria. These are made in the cell body near the nucleus and transported out axions along microtubules with a corresponding return flow of damaged proteins.ref Mitochondria wear out rapidly and are replaced every few weeks. Formaldehyde can damage both the mitochondria and the microtubules.     If the damage rate of mitochondria is high compared to normal replacement rate, the button tips should loose energy supply and soon die - but after a time delay because of the many-hours to couple-day transit time of mitochondria out axons. The half life of methanol in the blood is 2⅓ hours or less, so it is mostly gone by the time lethal shortness of breath begins at 18-24 hours. Muscle twitching or cramps also occur, which might be due to disintegration of button tips with release of stored neurotransmitter vessicles into synaptic gaps.(EHT)     If the damage rate of mitochondria is low compared to normal replacement rate, the axon problem becomes, not axion death, but accumulation of formaldehyde physical damage to microtubule proteins, their tau protein and/or myelin sheath removal. In Alzheimer's disease, cross-links between proteins by polymerized paraformaldehyde are suggested to be what cause the microtubules to knot up in the observed neurofibrillary tangles that eventually rupture the axon, after which phagocytosis of formaldehyde-tagged myelin increases. And the nucleus being damaged and tied to the cell wall was observed as early as 1917, Similarly, outside neurons, it is suggested that paraformaldehyde cross-linking is what causes beta amyloid protein to accumulate into hard insoluble plaques instead of being broken down and eliminated normally. MS seems to be distinguished by myelin sheath damage from the start. In either case, damage is observed to start around small blood vessels and slowly spread outward as predicted.     It has recently been determined that Tau protein lacks secondary structure and is considered to be in a special "worm-like" conformation with high flexibility and with amino acid side groups mostly exposed.Nie2007 Something like this is to be expected, because tau proteins are the binding strands that hold microtubule subunits together. But this unusual structure with amino acid side groups mostly exposed also makes tau protein unusually vulnerable to formaldehyde intra- and inter-protein bonding, from which follows misfolding, polymerization, insolubility and clumping.     And since formaldehyde could effect enzymes and neurotransmitters, there may be reason to expect cases of psychological change, such as depression, well before effects from slow accrual of physical damage. (Monte's epidemiology shows no time delay.) Only very low levels of circulating methanol need be involved, because the brain has 400 miles of capillaries, which gives a lot of surface area for leakage of formaldehyde into brain tissue. A suggestion here is that a major effect might simply be from imposition of extra need for cleaning up of waste products. PST is usually abundant for this purpose, but for individuals with modest or low PST, Induced cleanup load by in situ formaldehyde might lead to a bit higher production of MAO, and thereby reduction in dopamine including to the shell of the nucleus accumbens, resulting in depression. This is a model that can be tested. Is there a class of depression that lifts after only one to three days of avoiding inadvertent methanol and phenolics? [Damage of MAO would not cause depression, because that would be like taking MAOI a known anti-depressant.](EHT)

ADH Oxidizes Methanol To Formaldehyde:

  In situ formaldehyde 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 COOCH₃ side groups that potentially can dissolve off to form methanol. These side groups 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 groups 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 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 often show signs of arthritis and especially arterial plaque identical to modern atherosclerosis.^1,2,3,4 This was likely due to smoked fish and meats and use of fires in confined spaces. The Lancet discussion and several others suggest that maybe humans have always had vulnerability to heart disease not related to modern diets or lack of exercise. They totally miss the smoke factor.

B: High-Level Methanol, 7g/kg, and the Majchrowicz-Mendelson Experiment:

At high enough level, alcohol suppresses 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

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 (one shot of 40%/hr of ethanol) that the human body can dissipate. Ethanol BAC in several volunteers exceed the 0.5% lethal level for non-alcoholics, and at least one hit the 0.63% limit of survivability for alcoholics.

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 quite low to the legal driving limit 0.08% or 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 sensation must relate to the maximum rate of methanol metabolism to formaldehyde. That's with ethanol low and methanol BAC = 12-15 ppm (ethanol BAC < 6-8 times methanol BAC). The authors did not quantify, but the sensation of hangover may persist down to a few ppm BAC of methanol.

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, Jones1986^m389 confirmed the same delayed methanol metabolism synchronous with hangover following a single evening of drinking. The consumption tested was 1.0-1.5 liter+ of 12% wine =120-1800 mL of ethanol in two hours, with blood ethanol levels rising briefly to almost 0.2%.

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/τ_½, with half-life value   τ_½ ethanol = 19 min. This is an awfully short half life for ethanol, but click the above figure. It is what Jones1986 measured for the average of four test subjects, and there is no scatter in his data.

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&Zatman^m115 did experiments with dramatically graphic results showing the inhibition of methanol metabolism by ethanol. A 145 lb male test subject started three mornings the same with 4 mL of methanol on an empty stomach. On two days ethanol was added at 4.5 or 5 hours, the interruption of methanol metabolism being quite pronounced when multiple doses of ethanol were continued every half hour. Also in their report, though given in the wrong units, are ten measurements of τ_{½m dissipatioin} with average 3.0 ±0.1 hr. And they establish that urine methanol concentration is 1.3 ±.07 times that of blood, in agreement with previous findings for ethanol, and suggesting that treatment for accidental methanol poisoning should include plenty of water along with ethanol if dialysis is not available. And they find that τ_{½ m excretion} is about ten times longer than τ_{½ m metabolize}. The Leaf&Zatman results appear to have stimulated the experiments just described by Majchrowicz&Mendelson1971.

A striking example of the antidote effectiveness of ethanol^m489 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 τ_{½ m excretion} / τ_{½ m metaboliz}.  Clearer, is that in the above suicide attempt, the blood level methanol half life was 35 hours.

Summary:  
       τ_{½ ethanol ADH} = 19 min,       τ_{½ ethanol excretion} = 35 hr,               τ_{½ alcohol absorption} ≈ 30‑90 min,    
       τ_{½ methanol ADH} ≈ 2⅓ hr,*     τ_{½ methanol excretion} ≈ 27 hr,*            τ_½ PEG = 5 hr    
        Implied endogenous production rates of ethanol and methanol:
            Jones1986, ethanol:        endogenous BAC / τ_{½ ethanol ADH}     ≈    1.8ppm/15min ≈ 7ppm/hr
            Jones1986, methanol:     endogenous BAC / τ_{½ methanol excretion} ≈ 1.2ppm/2½ hr ≈ .5ppm/hr ??
            Majchrowicz1971 endogenous methanol rise rate during the time its metabolism blocked is >5ppm/24hr ≈ .3ppm/hr
                                                                      *iff methanol BAC ≥ 16 times ethanol BAC or dilution ≤ 20 ppm

C: MLD Methanol Poisoning,  88mg/kg:

The main toxicity mechanism of low-level MLD methanol poisoning and cyanide is the same, effectively asphyxiation due to mitochondrial damage and accompanied by anaerobic lactic acidosis. The difference is that while cyanide acts directly on the cytochrome c oxidase enzyme of mitochondria, it is the formaldehyde metabolized from methanol that acts on the enzyme. So the action of methanol is slow compared to cyanide. And methanol is less effective by about a factor of 20 because some of the formaldehyde is removed by ALDH, especially in the liver. The minimum lethal dose of cyanide is about 0.075 tsp versus about 1.7 tsp for methanol (.37 v 8.5 mL).

Determining the minimum lethal dose for methanol is problematic because the source data 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 or 88 mg/kg of methanol. For a 150 lb or 165 women this scales to 1.5 tsp or 1.69 tsp. Monte uses the first number for MLD. The second is used here because it corresponds to a convenient standard for adult size, someone with 50 liters of body fluids. That's a 165 women or a 150 man.

So for our standard 50 L adult, MLD = 1.69 tsp = 8.46 mL,  which weighs 8.46/.79 = 10.7 g = 0.377 oz,  and corresponds to the already noted 88 mg/kg for women. For men with the same amount of body fluids this is 80 mg/kg.  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.       (Useful units conversion factors are:    1kg=2.21lb,  1tsp=4.93mL,  1oz=28.4g,  densitymethanol=0.79g/mL,  1tsp=98.6drops,  1floz=29.6mL,  1shot=3Tbs=29.6mL,  humanmetabolicrate=1shot/hr40%ethanol.)

D: Very Low Chronic Methanol,  <.3mg/kg,  and Methanol Transport:

What Monte brings to the table is new logic backed by 782+ references and much correlation with data. There are two parts to the Monte-Henzi mechanism for modern disease proliferation. First 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 into cells,^ref and then is converted to in situ 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 retinal pigmented epithelium. The formaldehyde may diffuse within the cell, into mitochondria or out of the cell into interstitial spaces or neighboring cells, but does not last long enough to circulate in the blood system. Some of it is metabolized to formic acid, but much of it combines chemically with protein.

The second part is 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 methoxy 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. About a third of ingested methanol has been metabolized by the time blood methanol concentration peaks at BAC_m after about two hours or a little less. The peak is almost instantaneous for smoke-inhaled methanol.

Here's an introductory calculation for the peak BAC_m that should result from a teaspoon of pure alcohol drunk by an adult, about half the lethal amount. 1 teaspoon = 5mL = .005L, and ⅔ of this is .0033L. For our average adult this .0033L is diluted into 50L of body fluids giving a blood plasma concentration of .000066 = 66 ppm. The methanol concentration in whole blood is lower by the factor of .93 giving BAC_m ≈ 61 ppm.

Here's the calculation for a standard 12 oz can of diet soft drink. It contains 180-200mg of aspartame.^{NutraSweet,Sweeteners} Dissolving of the —OCH₃ methoxy side chain^fig results in 16.5% methanol by weight, or .165x190 = 31mg, which is (31mg)/(79mg/mL) = .04mL, which is .008 tsp (for effectively 110 ppm) of methanol.   As before to get BAC_m divide this .04mL of methanol by 50L of total body fluids and then multiplying by ⅔ and .93, which gives BMC_m = 0.53 ppm.   (Blood plasma is only 1/17 of body fluids, but absorption into body fluids is rapid.)

A two-parameter formula for this time dependence is derived in Appendix D9, which compares favorably with data measured by Stegink1981 for human subjects given aspartame.

    BAC(t) = 0.84 (v_o/V) [t_½dis/(t_½dis - t_½abs)]   [e^{.693t/t_½dis}  - e^{.693t/t_½abs} ]   (Eq.6b, Appendix D9)

Also estimated in Appendix D9 is the amount of accumulation when someone drinks diet soda repeatedly throughout the day. 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 Fleming^SectM 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.
    The original test diabetic women were given 1.8 g/day of aspartame equivalent in quantity to 10 diet soft drinks per day, but probably in capsules.^{m48Part4, pp.181-182} As pointed out with Table 1 there were severe consequences.

Endogenous methanal modeling: In people who have endogenous methanol, production and excretion rates must be in steady state balance, so 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, and long thought to be a key problem chemical of alcohol addiction. Formaldehyde is even more reactive than acetaldehyde, to the point that it can not circulate in the blood.
    Yet while acetaldehyde is considered to be the bad actor of ethanol, today's medical science switches and holds that the bad actor for methanol is formic acid, not formaldehyde.

b) G.D. Searle 1973 Double-Blind Study:   This report is contained in Searle's 1983 petition for use of aspartame in carbonated beverages.^{m48part4,m48all, pp.181-182} The dose level, 1.8 g/day of aspartame, was equivalent to 9 cans/day of diet soft drink. And with aspartame 11 % methanol after digestion that's equivalent to .20g/day = .35mL/day of methanol, which according to Monte's interpretation of patient 17^m16 is about 3.7% of the minimum lethal single dose spread over every day.
    77 diabetic women 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. There is no mention of shortness of breath as occurs in low-level single-dose lethal methanol poisoning.
    Also, hyperplasia and breast adenocarcinoma had been found in laboratory rats fed methanol, but those animal results were withheld from the pathologist reviewing the study.
    The Searle conclusion on the bottom of page 7 of part 4 of the 1983 application reads, "In summary, aspartame appears to be well tolerated by diabetic subjects as a safe sugar substitute."
    But a reading of the 1973 research supports the opposite conclusion. The stroke and breast cancer outcomes suggest validity of the Monte-Henzi model.

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}

click

d) Epidemiology: 1) Fetal Alcohol Syndrome has responded inversely to reduction in drinking 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, some with delay, some not. 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.
    In the other direction of decreasing inadvertent methanol, society's transition from canned to frozen foods correlates with decrease in deaths from MS during the 1970's.
    And most in the news lately,^{WP,NYT,NYT,WP} but probably misinterpreted, is the decrease in incidence of diabetes since 1998-1999. Lower soft drink consumption means decrease in diet sodas.
    A counterexample to this interpretation is that while diet soda consumption has been going down the teen and college suicide rates have been going up.^{HS,Col.Caveat} The answer proposed here involves still another area of medical controversy totally different from Monte and methanol, but it does logically have to be mentioned. A large part of the surge in bottled water and sports drinks like Gatorade has used RF&D colorings. Sorry for the complication, but data dictates.
    Another data factor to track here is that in 2015 Kraft and in 2016 Mars are removing all RF&D's from their brands the way it's been done in the EU since 2010 for all products. EU teen and college suicide rates do not seem to be going up.

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.
   - The ethanol health benefit is both explained by and is proof of Monte-Henzi (also autopsies).
   - The "auto-immune diseases" can't be auto-immune because the target tissue is not all removed.
   - An Alzheimer's brain has the same rubbery feel as one stored in formaldehyde.
   - There was no such disease as multiple scleroses until about 20 years after the invention of canning.
   - The CDC accidentally discards neural tube birth defect data and then follows industry's ranking of the metabolites of methanol when it recommends somewhat dangerous dietary folate. Dr. Monte recommends reduction of methanol intake and not taking folate.
  - He also presents evidence for (true) auto-immune nature of classic Type I diabetes, contrasting that it is not related to today's increasingly common late-onset Type I. What he doesn't point out here but should is that Type I diabetes didn't exist until the invention of canned milk and has grown exponentially ever since.

f) Anatomical Fit: The fit between the Monte-Henzi model and what is observed in several of diseases is good, and to this reviewer sometimes striking, as for atherosclerosis, Alzheimer's and, surprisingly, autism.
    Alzheimer's & MS: The myelin loss begins around the small capillaries exactly as Monte-Henzi suggests. An Alzheimer's brain has the same rubbery feel as a normal brain stored in formaldehyde.
   Arteriosclerosis and specifically Atherosclerosis: Monte-Henzi predicts what is observed. Atheroma is a swelling within the artery walls between the intima and the media that is made up of an accumulation of macrophage cells that have consumed too much oxidized LDL, turned into foam cells and died releasing their partially digested contents as fatty deposit accumulation.
     Autism: Prenatal and lactation exposure to methanol in rat experiments may result in neural tube defects or, less dramatic but still severe, reduced brain size, hemorrhaging and much damage to neurons. The regions most reduced in size, with most hemorrhage and most severe nerve cell loss are the hippocampus, cerebellum and specifically the vermis of the cerebellum. This correlates with the fact that the main locations of ADH in the brain are blood vessel linings and the purkinje cells of the cerebellum.^m637 And on page 206, Monte notes that,   "it has now been discovered the cerebellum is known to be preferentially damaged in human autism,^m622 and the vermis^m570 and hippocampus are the particular areas of the cerebellum most damaged and reduced in volume by the disease.^m571 A recent study of suckling rats fed aspartame showed 'severe' major enzyme changes specifically in their hippocampus.^m623 Another finding in the damaged area of our rat brain was an overabundance of macrophages."     •Not mentioned by Monte, but perhaps most striking to this reviewer is correlation with the (dubious?) finding of reduced cerebellar volume and specifically the vermis in anatomical MRI measurements for ADHD.^{Castellanos2002,video,L (The data analysis involves adjustment of the mean by 14 standard deviations.)}
    Depression: There is no overtly observable anatomy for depression, but if the condition does involve in-situ formaldehyde, it is reasonable that it should be immediate with no delay between cause and effect as in the above comparison plot. Monte-Henzi suggests mental function effects due to low ATP (mitochondrial enzyme damage but sub-lethal dose), and though not discussed by Monte, probably low supply of glucose (transport enzyme damage in capillary epithelial tissue). This would cause an opening of the blood-brain barrier (the tight packing of capillary epithelial cells), possibly allowing entry of problem compounds like excitotoxins. These should all be fast-acting effects.

H: Tephly Science v. Monte Science

The point of departure from Røe1946^{m3trucated, Røe1946m3all} is in three paragraphs in the 1984 methanol metabolism review article by Tephly&McMartin1984.^pdf See also Tephly1991.^pdf  
...being rewritten...this section should expand from the introduction and needs more referencing.

A central debate is 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 base of mainstream thinking in industry, in medicine and in science in general.

Monte says the opposite. The reason formaldehyde doesn't circulate is because it interacts strongly with proteins, and in non-liver tissue this reaction with proteins is significantly faster than metabolism by ALDH. Accidental breathing of formaldehyde would cause systemic damage if it were immediately metabolized to supposedly damaging but also circulating formic acid. But that's not what happens. Formaldehyde inhalation causes mostly lung-related damage.

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.

On the other hand, Monte also points out that formaldehyde is officially classified as a Class 1 carcinogen^m67 and mutagen.^m68

There are several additional factors worth noting. First, for much studied ethanol, mainstream switches the ranking of which metabolic byproduct is more dangerous, the aldehyde (acetaldehyde) being considered more harmful than the carboxylic acid (acetic acid = vinegar).^L9 Acetaldehyde is of great concern in studies of alcoholism. That's the reason details are known about which tissues contain the ADH enzyme. Formaldehyde is more reactive than acetaldehyde—but for the one-carbon alcohol its vinegar-like formic acid is supposed to be the bad actor?

There are three points to add concerning disagreement about why human blood turns acidic during methanol poisoning. Tephly says it is formic acid that makes the blood acidic. The first calculation of whether there is enough formic acid to do this was in the 1940's and negative.   Also, Monty says the most important cause of this acidity is 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.

And further strengthening Motey's point is that one enzyme affects many molecules, not one. 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.

Tephly says monkeys are representative test animals and has several papers on the subject. Monte says that, like other species, monkeys are also 100 times less sensitive to methanol than humans. Human catalase is uniquely ineffective. 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, catalase being 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 damage the cell, or may diffuse out of the cell and cause local damage. 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.
     Particularly unfortunate in this reviewer's estimation is that in his book, p.47 last paragraph, Monte oversimplifies and does not distinguish between methyl ‑CH₃ and methoxy ‑OCH₃ side groups. In private communication he clarifies that, yes, it is the methoxy that formaldehyde forms on DNA or RNA as:   -H + COH₂ -> -OCH₃, not -CH₃. But there is then a separate process mediated by an enzyme readily available in the nucleus that does convert this to methyl.^m225 It can not happen in vitro.

The key here to the potential disruptiveness of formaldehyde to DNA is that the first step of forming an methoxy -OCH₃ is spontaneous and random, and not controlled by an enzyme.

A typical cancer involves 70 or so mutations.

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: Birth Defects,  FDA Tardiness,  FOIA,  Collins Memo

1975   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 FDA internal 1978 review by F.X. Collins of rabbit birth defect studies done by G.D. Searle and Hazelton Laboratories in 1974 and 1975.^m677 Pregnant rabbits were given aspartame on days 6 through 18 of their gestation.

Three things happened. The adult rabbits 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 of .75 or 2 g/kg/day. That's 1/20th and 1/7th per day of the 14.2 g/kg lethal dose of methanol for rabbits. Defects from the higher dose level were quite serious bone abnormalities and hydrocephaly.

In contrast to these withheld 1975 results, Searle published favorable research for human subjects in 1985 in a widely read international ObGyn journal.^m100 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..."

This damagingly false advertisement by aspartame's manufacturer would not have been possible and the political power approval of aspartame might not have succeeded if the FDA had not withheld the early data showing that aspartame is a teratogen capable of causing the most serious class of brain birth defects. The data was released 36 years late and then only because of Monte's Freedom Of Information Act application. There is significant implication here that the FDA may have been cooperating with industry. Another way to say it is that a commercial goal of the regulated is to become part of the regulator.

1987   Also not being used is the teratogen data by Hoque et al. for rats.^m177 Methanol was administered beginning two weeks prior to mating and throughout gestation and lactation as continuous humidity at the rate of 23% of the lethal dose per day for rats (1.28 v 5.6 g/kg). That sounds high, but humans can maintain an ethanol blood alcohol content very near the lethal 0.4% for days with no lasting ill effect other than from overworking the liver. Hoque's rat pups, though, developed

1994   Bolon B, Welsch F & Morgan K found similar results in 1994 but performed far more microscopic inspection and give much more analytic reporting of neurological damage.^278Bolon1994 A significant shortcoming of this paper, though, is that the administered methanol is stated in units of 15,000 ppm humidity, with actual delivered dose level or information to calculate it never stated.

1996   Dorman D & Welsch F, Developmental Toxicity of Methanol in Rodents in Chemical Industry Institute of Toxicology Activities.^m626   Formate found not to be the cause of exencephaly.

2011   A notable anatomical analysis update of the Hoque1987 data is given on pp.206-207, Fig.12.5 of Monte's book. Besides capillary linings, the primary location of ADH in the brain is in the purkinje cells of the cerebellum. The picture shows that in utero exposure to methanol as described can result in a new-born pup with bloody vermis, that apparently occurring after neural tube folding. And notably, the vermis has independently been found to be developmentally deficient in humans with autism.

2011   FOIA release of the 1974 Searle-Hazelton rabbit birth defect data.

2003 NTP-CERHR of HHS (National Toxicology Program Center for the Evaluation of Risks to Human Reproduction)
(The many references here include m93, m549, m550, m551, m552, m553, m627. writeup to be fixed)
The official US expert panel on whether methanol could cause birth defects in humans states that:
  1) Fetuses may be vulnerable if pregnant women are exposed to methanol poisoning,
  2) It is the methanol itself that results in developmental toxicity not one of its metabolites, and
  3) The methanol from normal exposures is too low to cause adverse developmental effects.
The committee was convened circa 1995 and took at least five years to Methanol Institute had veto power over what the committee wrote, and there are several charges that the FDA withheld information from the committee such as the above mentioned Searl-Hazelton rabbit data. Two of the committee members refused to sign the final report and instead wrote separate charges of malfeasance as below. One of them went on to contributed to the 2013 book The Toxicity of Methanol.

How does the Allowable Daily Intake, ADI, compare today with actual intake of aspartame?

For ADI, the guiding rule the FDA is supposed to use is that consumption per day of a food ingredient should be less than 1/100 the dose known to cause any harm in animals. Using the 1974-1975 Searle-Hazelton rabbit data noted above, that would be 7.5 mg/kg/day. And humans are more susceptible to methanol than rabbits by a factor of 75, so one might use 0.1 mg/kg/day. (Rabbit methanol LD50 = 7g/kg, versus human MLD = .09g/kg) But the ADI for aspartame is set by the FDA at 50 mg/kg/day,^ref1,2,3 a rather high by a factor of 6 or more.

Actual consumption of aspartame is usually expressed in units of g/day for an average size person and is typically thought to be < 1 g/day. The 1 g of aspartame is equivalent to 5.6 12 oz cans = 2 L of standard diet soda or about 2.8 cans of orange diet soda, and some people definitely drink more than that. And there are some 3000 aspartame diet products. So here's a g/day table of daily allowance versus consumption:

J: Government Approval of Aspartame by Corporate Political Power

A prime example of President Ronald Reagan's "get government off our backs" policy was the way aspartame became approved for use in foods in July of 1981^L27,L26 and for soft drinks in July of 1983. The initial 1974 approval had been reversed due to concerns that one of the constituent amino acids could disrupt mental function. Unsuccessful scientifically, the developer, G.D. Searle hired a new chairman, Donald Rumsfeld, who was politically connected and became a key player in Reagan's transition team while still chairman at Searle. He oversaw the appointment of Arthur Hayes Hull to head the FDA. Searle reapplied for aspartame approval the day after Reagan was inaugurated, and when the five-member evaluation committee was about to decline the application by a vote of 3 to 2, Hull appointed a sixth member. The committee was then locked 3 to 3, and Hull broke the tie and approved aspartame. A couple years later he was hired by a consulting firm for Searle and Monsanto. There was much revolving door influence, and when Monsanto absorbed Searle in 1985, Rumsfeld reportedly received a $12M bonus.

Historic precedent is in the way leaded gasoline was approved in the mid 1920s.^video,ref G.D. Searle successfully promulgated fake science showing the bad actor of methanol is not formaldehyde and that lab animals are adequate for testing human vulnerability, successfully dismissed death and cancers in its initial human studies,^{m48part4,m48AllVol} and had the support of an anti-regulation, cut-government President. Calvin Coolidge was similarly small-government inclined, and the committee appointed to evaluate the dangers of tetraethyllead was of primarily industry supporters. Standard Oil powered through the science with claims that there was no alternative, that there would be very little lead in the atmosphere, that the amount of lead coming out of engines tested to be less than what was in the fuel, and by hiding the fatalities suffered in its early production plants. The fact is that ethanol also has reduced explosion flame speed allowing increased compression ratio for enhancing engine power, that it burns very clean and that ethanol-gasoline mix is sufficient. But tetraethyllead needed at only one part in 2000 in gasoline was very cheap, costing only a penny per gallon. Like aspartame, tetraethyllead was worth billions, and so the two had similar approval processes.

K: The Aspartame Wars and The Nancy Markle Hoax

Aspartame has always caused concern^EarlyStudies because of its component parts and because of initially unfavorable animal studies. 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, the American Council on Science and Health, the American Cancer Society and others to be Luddite conspiracy theory tied to the "Nancy Markle" email hoax.^{Wiki, ACSH, ACS GIZMO, Garst, Dean, scare}  This doesn't match very well with in-depth histories.^{L17, L16a, L16b}

Was It A Double Hoax?

Betty Martini turns out to be the real person who in 2017 still answers the phone where she lives in Duluth, GA, and who did make the said presentation at the World Environmental Conference at Elizabeth City State University, NC, on Nov 30 and Dec 1, 1995.

Her name is not Nancy Markle, and the "hoax" text is a disorganized version of what she actually presented at the conference, a summary from cases of "aspartame sickness" seen with Dr Roberts. The modified text went viral, and for a couple years Betty was getting calls from all over the world at a rate of every two minutes. This led to four file cabinet fulls of letters that are still coming in from people thankful for having quit aspartame.^Anom Betty's web site is Mission Possible, mpwhi.com.

The university contracts & grants office could not confirm that the conference was held at their location because they keep records for only fifteen years. But Betty Martini sent this investigator a copy of her letter of acceptance and direction from the University.^letter The conference was funded by a grant from the Office of Environmental Equity of the EPA.

It is interesting to compare the original version^OrigTxt of Betty Martini's presentation with the hoax version^HoaxTxt by the purported Nancy Markle. (to be continued...lost copy of original)

L: 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

    These endeavors do not acknowledge the epidemic nature of the diseases being addressed or what the word "cure" should mean. The dramatic growth, for instance, of cardiovascular disease over 30 years has finally leveled off in the US due in part to highly effective modern interventions, but heart disease currently still causes about ¼ of all US deaths and is spreading worldwide.^ref,bkup High tech treats sick people but has not solved the epidemic.

    And that's even more true for ADHD (not related to methanol), for which treatment is still only palliative and for which the many heady years of high tech anatomical MRI studies have led to no improvement in outcomes.

    In AMP and moonshot, the terms "cure" and even "cancer vaccine" don't mean what they connote. They mean "treatment," a medication or procedure for sustaining patients already afflicted. The aim is to reverse or mitigate harm, not prevent harm or reverse epidemic growth. (Money mangers should perhaps take special care with terminology so as not to inadvertently misrepresent to the paying public.)

    Monte-Henzi is the opposite. It is about, "primum non nocere"—and about "cure" in a true sense of attempting to explain and therefore reverse the expansive growths of several non-germ diseases.

The billion dollar question:  If not in-situ formaldehyde, what is or are the causal agents of these epidemics, and shouldn't at least half the money go to investigating this larger problem?

M: The NIH AMP^{WashPosta,b,NIHa,b,Progress}

See Section N: NIH, CDC, Congressional Communications

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 Indredavik2007^m572 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 the epidemiology discussion ^table for its delay in getting to the top of the charts, and it does, too, with low chronic in-situ formaldehyde. According to Monte-Henzi, 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 far less than $250M simply by confirming and publicizing already available information.
  a) The body's quick need for insulin after a high-pasta meal can be for more than the amount stored in the liver.[Fig.27.2, p,551, "Human Physiology," by G Pocock & CD RichardsOxford University Press, 1999] So even for people without diabetes, today's diets tend to raise blood sugar levels a little higher than normal, probably resulting in slight but accruing damage to body proteins and trend to onset of diabetes.
  b) Type 1 diabetes is probably a (true) auto-immune response to cows milk before gut closing, as per Monte's references.^Type1
 c) In animal studies prenatal and infant exposure to excitotoxins can cause obesity in the adult.^{Blaylock1994,video}
  d) Weight correlation with diet soft drinks and sweeteners: The initial 1974 Searle/Hazelton studies found that when rabbits were given aspartame for 24 days they ate more and gained weight both during the time of administration of aspartame and after. In the years since, there are many discussions confirming this trend. The modern finding is that aspartame chemically dampens satiation so that people eat more.

N: NIH, CDC & Congressional 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 in situ formaldehyde 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.

...................................
NIH communications posted here for the record on September 10, 2014:
AMP Announcement,         February 4,     2014
Takken to Collins,               February 13             MurrayToTakken, February 24     TakkenToMurray, March 18       both
Takken to Collins,               March 18
Takken to Collins,              April 14
Takken to House Reps,     May 14
Takken to House Reps,     August 15
Warner to Takken,             June 11 & Oct 17

Concerning $1B Moonshot program (no response), so posted mid 2016:
to several Congesmen,             mid 2016

Concerning his glioblastoma (no response), so posted September 11, 2017:
to Sen. John McCain,                 Sept 2017

Concerning Alzheimer's predictions (no response to mail or phone messages), so posted January 11, 2018:
to Dr. Christopher Taylor, CDC,   August 2017

O: Conclusions

The big picture is that too much free enterprise with corporate free speech and invisible propaganda^{Stauber,s,Industry} is bad for health. Industry is often ruthlessly unconscionable when seeking profit, but that is to be expected. The problem is fostering health-costly and other truth distortion to happen by naiveté in Congress and especially the Supreme Court.^{Winkler,w,Cohen,c,CaseDeaton,cd}  The first amendment says "Congress shall make no law...abridging the freedom of speech, or of the press; or the right of the people peaceably to assemble..." This enumeration specifically does not include corporations, but the Supreme Court now grants corporations "personhood" so that they have freedom of speech the same as humans. Much would be accomplished for health with a constitutional amendment clarifying that the word "person" means an actual flesh-and-blood human.
(See for yourself how the Constitution uses the word "person." text search here)

Perhaps more than tobacco and energy, the banking industry versus Brooksley Born is a particularly instructive example. In contrast to Greenspan, Rubin, Summers, Levitt and Congress and to Bill Clinton's popular Republican style deregulation of financials, she proved to be correct during events leading to the crash of 2008. Transparency and anti-fraud regulation are necessary in the derivatives market.

    The conclusion here is that the edibles and methanol industries similarly need transparency, anti-fraud regulation and specifically separation of regulator and regulated to protect we the real people against false science, misleading imagery, manipulation of inclination to consume, questionable ingredients and other profit motive machinations.

    The FDA was established in 1906 and expanded in 1930 because of bad things that were happening, but the badness in profit motive has become more sophisticated and more powerful. What we've seen with regard to methanol since 1900 and especially aspartame since 1980 is ability by the edibles industries to infiltrate regulation; dominate politically; use fronts in medical journals, academia and pro-health independent-looking organizations; elevate researchers getting answers it likes; and even make profitable false science true throughout all research medicine.

Monte’s specific charges of malfeasance are listed here. Be cautious about reacting to what on the surface may look like conspiracy theory. Everything is supported by medical publications, epidemiological data and in a couple cases FOIA forced documents.

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 the U.S. and other governments have not yet learned. ^{Conclusions written 1½ yr before Winkler's 2018 book}

Appendices

Appendix A:  The Fleming Murder Mystery

Introduction:   The amount of methanol in Charles body was twice that in the Gatorade mix bottle he drank 27 hours earlier. And 3½ hours after he got to the hospital his measured blood methanol content was .08% even thought no one ever reported him as having acted drunk or smelling of alcohol.
    Subsection A1 summarizes solid irrefutable facts. They turn out to be of the form "what didn't happen." The following Subsections A2, A3 and A4 are three attempts to solve "then who did it." The possibilities that seem least likely at first turn out to give the better fits to data. A summary table is given at the end of this Appendix A.     summary
    A problem for the prosecution during the trial was that the the amount of methanol measured in Gatorade mix bottles was only a third to a fifth of the stated minimum lethal dose for humans. This appears to have led to several speculations presented by expert witness as fact during the trial, so part of this write up is to review the symptoms of methanol poisoning as determined from medical journal literature. Particularly informative papers are the 250 page Røe1946, which finally brought to a close the first multi-decade era of deaths from methanol in foods and medicines, and Tephly&McMartin1984, especially pages 8-10, which began departure from Røe and initiated the modern era of widespread misunderstanding of methanol.

Case CR0IF01484-01, 1/19/02, Chesterfield, VA:   Diane Fleming was found guilty of using methanol to poison her husband Charles on Sunday, June 11, 2000, and was given a combined sentence of 50 years for first degree murder and for mixing the poison drink. She was in jail for 17 years and then given geriatric parole in early 2018. Here are copies of court documents:
    autopsy report (June 2000) of Charles Fleming by Dr. Marcella Fierro,
    trial transcripts (Feb 2002 trial), in searchable hyper-text format,*
    Chuck's Monday, Diane testimony,
    polygraph test & police report, Diane testimony (gives accurate time for when Gatorade mix was drunk),
    brain/skull anatomy, for understanding autopsy report,
    post-trial affidavit that the crime lab testing was not adequate to detect windshield washer color,
    M. Fierro cancellation of conference call with H.J. Roberts, (March 2004)  Disagreement about aspartame,
    habeas corpus petition 2006 unsuccessful   Carol Gebert and methylamine are not mentioned.
    methylamine the poison? by Carol Gebert et al:   1-Methanol,   2-Creatine,   3-Analytical Chemistry,
    PEG solvent issue by Dr. M. Al-Bayati in 2008.**     Bayati errors and bias     (gives details of 2^nd CT scan).
    Fierro & Saady publication in Forensic Toxicology (Sept, 2011), autopsy pathologist & state toxicologist,
    (Do not have medical records as CT scan reports. Hour of 2nd CT scan on 14th not known but maybe morning or noon.)
*Pertinent information from the Analysis Reports has been included at the beginning of the transcripts.
*The original court document page numbers have been put in <> brackets and left in position in the text.
**Dr. Bayati also had the following additional information: 1) Chuck’s medical record obtained from Chippenham Hospital; 3) toxicology report; 4) case history obtained from Diane covering Chuck’s health and medications used during the eight years prior to his death; 6) H & E stained tissue sections obtained from Chuck’s brain, lung, heart, liver, and kidney microscopically, slides purchased from the medical examiner’s office in Richmond, Virginia.
**Charles was 43 years old, 5' 11'' tall and weighed 170 lb, so the total fluid content of his body was about 57L.

Subsection A1 - Solid Facts:   There are three reasons why the Gatorade-creatine mix that Charles drank at about 7:00pm Sunday evening could not be the source of methanol that killed him.

Subsection A2 - Chronic or Multiple Dose Methanol: The idea that prevailed in court was that there must have been multiple doses or chronic poisoning with methanol that eventually summed to lethal. The data available was:

Just intuition suggests that 120 mL could not be the MLD for a supposedly potent toxin. That much should cause a peak in blood methanol of about (2/3)(120mL/57L) = 0.14%, which is about a third of the 0.4% lethal level of common ethanol.  8.5 mL induces a peak of 110 ppm, more reasonable for a true toxin.)

Expert witnesses all gave inaccurate or strikingly incorrect statements about methanol:
    Joseph Saady, state toxicologist: The minimum lethal dose is "75-120 mL, but less if given over a period of time."   "Methanol can build up over time and reach a lethal threshold."
    Christopher Acker, treating physician: "Charles had had some symptoms for about a month before he came to the emergency room that were, you know, odd symptoms."   "Charles nighttime ethanol could rev up his enzyme level and convert more methanol, or would he be protected?"
    Edward Leaton, consulting physician in autopsy report: "Delayed effects of Methanol are typically seen in 6 to 30 hours and can include restlessness and delirum, as well as course visual changes and I believe vomiting is quite typical of Methanol ingestion."
    John Hyslof, consulting physician: "He normally is on [4 meds], and he just began Creatine."
    Marcella Fierro, state pathologist, autopsy report: "History: Of a previously well athletic man who for the month prior to death complained of some shortness of breath."  "The brain is very soft and shows diffuse swelling. A preliminary cut shows bilateral intercerebral hemorrhages. The fixed brain shows fresh hemorrhage and necrosis involving both basal ganglia and adjacent thalamus. The caudate nuclei show no lesions. The ventricles contain blood clot."  "The brain showed encephalomalacia and the clinically noted intracranial hemorrhages as necrosis and hemorrhage of the bilateral basal ganglia with rupture into the lateral ventricles consistent with methanol poisoning..  "The history, laboratory studies, and pathology are consistent with a death due to profound metabolic acidosis due to acute and likely chronic methanol poisoning."
    Warren Von Schuch, Prosecution closing arguments: "Methanol built up to lethal from multiple poisonings over a period of time."
    Fierro & Saady submission to journal Forensic Toxicology 9 years after the trial: "The victim had a history of using creatine as a nutritional supplement.. Bottles of a sport drink ingested regularly by the victim...were the source of the methanol..* The victim's wife prepared his regular supplement by mixing a large tablespoonful of powdered creatine into 20-fluid-ounce bottles of a popular sports drink.. [Charles had had] a month-long illness of intermittent nausea, vomiting and shortness of breath.. Gastrointestinal distress with nausea and vomiting are initial symptoms of methanol ingestion. The onset of symptoms may occur within 20 min of ingestion.. The recent medical history of the victim and toxicology findings were consistent with a chronic exposure to methanol.. The estimated minimal lethal dose of methanol ranges from 30 to 75 mL for an adult. Therefore, ingestion over a day or two of one to several bottles of the creatine-sports drink mixture with 30 mL of methanol in each would account for the fatal poisoning in this case."  Fierro & Saady have a similarly absolute description for motive.
    M Fierro v. HJ Roberts, 2004: Fierro et al. reject an arranged conference call with Roberts who was stating that Charles death was "due to considerable methanol consumption in the form of aspartame products." *

But according to the trial transcripts:
    Charles had never used creatine before. He had not been drinking Gatorade regularly, or at all. And there was never any “wife preparing his regular supplement.”
    Instead, Charles had tried protein shakes, which didn’t work, so he researched creatine for about a week before deciding to try it on the Sunday of note. He had to visit two stores before finding where to buy it and didn't know if he would like Gatorade. They were reading instructions for how much creatine to mix in (Diane says 1½ tbsp), finding that creatine didn’t dissolve very well apparently needing shaking, and realizing that the taste wasn’t very good so that some cooling was needed. This is from Daine’s testimony and cross examination, so you might counter that she was tilting things to her advantage. But the literal verbiage doesn’t read that way, and testimony from police investigator Ruth Baker confirms that Diane Fleming's account did not change from what she was saying before she knew she was being charged. The trial transcripts have been word processed to make it easy to find and read specific testimony.

And general technical facts are that:
    The minimum lethal dose of methanol is about 8.5 mL, about two teaspoon fulls.
    Methanol does not accumulate over time. Like ethanol it is metabolized or excreted. The half life of methanol in the body is about 2⅓ hours, so for accumulation buildup to occur from multiple doses, the doses would need to be less than an hour apart. A can of diet soft drink effectively contains ⅔ drop of methanol = .02 mL, which confirmed modeling shows will induce a peak the blood methanol content about an hour-and-a-half later of about 0.4 ppm = .00004 %.
    The latency period of no symptoms after methanol poisoning (with no ethanol present) is 18-24 hours.
        So Charles not feeling well soon after drinking the Gatorade mix was due to something else.
    Indigestion and throwing up are not initial symptoms of methanol poisoning.  Throwing up is usually
        associated with overindulgence of alcohol, but the minimum lethal dose of methanol is only a couple teaspoons.
    Shortness of breath is a typical first symptom of methanol poisoning.
    If shortness of breath is due to methanol it is usually fatal unless ethanol has been quickly administered.
    Though multiple or chronic low-level methanol exposure was touted during the trial, no one seemed to know what the ongoing symptoms of this could be - not shortness of breath, which was mentioned - but instead rosacea, which Charles had but no one paid any attention to.
    The lethality of methanol is not due to the so oft touted formic acid. It is due instead to several effects from formaldehyde and paraformaldehyde that take time to evolve. From formaldehyde: a) Damage of the cytochrome c oxidase enzyme causes both anaerobic metabolism with lactic acid production and death of mitochondria. b) Alteration of proteins chanes identifier tags to "foreign" which stimulating immune system inflammation and phagocytosis, whence the softening of brain tissue, necrosis, myelin loss, buildup of fluids and pressure causing rupture as of the tentorium diaphragm, collapse of ventricles and hemorrhage as to the basal ganglia from sharp ridges on the bottom interior of the skull. From paraformaldehyde links between pairs of amino acids within or between proteins likely inflicts (intra-) tau protein tangle thereby disrupting microtubules and probably inflicting much delayed loss of mitochondrial replacement to neuron button tips and then their eventual death and (inter-) displacement of cell interior structures as attaching the nucleus to the cell wall as happens in ganglion cells of the retina.  The Charles Fleming autopsy with regards to brain tissue did not distinguish between whether encephalomalacia was due to blood supply problems or immune response, did not evaluate phagocyte infiltration, myeilen loss (which often is extensive after methanol poisoning) or in the retina did not determine whether there were tangles and displacements in the interior of ganglion cells as would be typical of methanol poisoning.

In-Court Technical Errors:
    A2b) Inability to detect blue coloring in Gatorade mix:
    The Virginia Department of Forensic Science released a post-trial affidavit stating that its test method was not sensitive enough to discern whether the blue coloring of windshield washer was in the samples of Gatorade mix. It is strange that this information was not presented in court or that there was no attempt to measure the taste additive Bitrex instead.
    Even stranger and more inexcusable is omission of two other methods for detecting windshield washer in Gatorade mix. These are simply taste and visual inspection.
    The picture on the right can be blown up by clicking on it, but even in small size anyone not color blind can fairly easily discern which bottle is which. Two contain 3-4% methanol from windshield washer, and two contain 1½ tablespoon of creatine.  (You figure out whether none contain both.)
    Tasting and spitting out a weak solution of methanol is safe, and when done with these bottles the test was definitive. As pointed out by Carol Gebert, Bitrex is the world’s most bitter substance and since 1995 has been added to wiper fluid to render it undrinkable.
    It should have been known during the trial whether the Gatorade mix bottles did or did not have windshield washer added to them.
    A2c) Should be sick after methanol poisoning (incorrect):
   by Mr. Von Schuch, defense closing, p.87: "See, he drank that Gatorade that Sunday night and then he woke up the next morning and he wasn't feeling good."
    A2d) Multiple sub-lethal doses accrue to lethal (incorrect):
    by Mr. Von Schuch, defense closing, p.87: "Dr. Saady indicated that this builds up in your system, though. It builds up in your system... So, we're talking about a situation where this was not a one-night shot, but whoever did this had been doing it for some period of time. That's the only conclusion you can draw from this. And that certainly is willful, deliberate and premeditated." (How, when or with what she “did it for some period of time” had never been discussed in the proceedings.)
    by Dr. Saady, Virginia State Chief Toxicologist, p.47: But a lesser amount [of methanol is lethal] if given over a period of time."
    by Dr. Saady, Virginia State Chief Toxicologist, p.50: "Q If someone consumes methanol over a period of time, does it build up in the system? A Yes, it does. Q And at some point in time, you would reach a critical mass where it would be sufficient to cause a lethal episode; is that correct? A Yes."
    by Dr. Acker, the hospital physician, p.37: "He had had some symptoms, though, for about a month before he came to the emergency room that were, you know, odd symptoms."
    A2e) Ethanol might make methanol worse (incorrect):
    by Dr. Acker, the hospital physician, p.37: "So, if he was taking ethanol at nighttime at home and then was being given methanol at some point, you know, whether or not the enzyme level would be revved up and he would convert a lot more of the methanol at that point or would he be protected because he had been taking the ethanol during that time period, I guess you would have to ask a toxicologist."
.....

Source of Poison in Gatorade Mix Questionable:  There seem to be three possibilities. 1) Diane might have done it using windshield washer. Or the opposite. Even if there was no poison in the bottle Charles drank, there might have been in the other by the time they were analyzed. 2) Methanol might have dissolved off from side groups of methylated creatine. 3) Most likely is that the compound measured might have actually been methylamine from disassociation of creatine. This is reviewed in Subsection A4.
    Number 1 is tarnished by the highly non-specific presumption in court that Diane must have delivered the poison multiple times. When more than a few hours apart, multiple exposures to methanol to not add and accumulate. And though cross examination of Detective Baker by Defense did not ask the question directly in court, there is some evidence that the jug of windshield washer taken by police had originally been unopened.
    Number 2 is not likely, either, though ten brands of methylated creatine products were available at the time of Charles death and until 2007 when they were removed from the market after complaint from the body building community. The Analysis Reports and evidence in trial refer to GNC Creatine, but the autopsy report states that the bottle brought by police was creatine monohydrate. And calculation of the percent methanol concentration that would result from 1.5 TBS of methylated creatine in 20 oz of fluid gives about a third of what was measured.

Subsection A3 - Methanol Where Charles Worked: We have to more closely consider the unsecured methanol Monday morning about 6-7 am when Charles got to work.

Subsection A4 - Methylamine: Carol Gebert points out that the crime lab's equipment might not have been able to distinguish between methanol and methylamine. The latter is a "component" of creatine and, like methanol, also metabolizes to formaldehyde likely producing similar symptoms of lethality.

And she also points out that methylamine instead of methanol in Charles' blood would explain why no one reported him as acting drunk or smelling of alcohol when he arrived at the hospital with BAC around 0.2%. This and evidence identifying methylamine were presented during the 2006 habeas corpus petition, but apparently in a legally required manner that garbled the science.

There are two problems with this methylamine explanation for Charles' death. Misidentification of the compound being measured does not explain why there was so much of it in his body 27 hours after he drank the Gatorade mix with none in it. Maybe the misidentified compound was only in the aged Gatorade mix bottles, but the hospital blood measurement was correctly of methanol - from some source other than the fresh Gatorade mix Charles drank. The problem with that, as we shall see, is that measured half life during dialysis does not fit methanol

The figures on the left are from Restek Corporation using gas chromatography with two different types of "columns." These are small-diameter tubes with coated interiors through which gasses are blown. The Restek BAC Plus 2 is the one used by the Virginia Department of Forensic Science for measuring methanol in the Gatorade mix bottles and in blood samples from Charles Fleming.

The upper chromatogram demonstrates clear separation of ethanol and methanol from five other compounds that might be in a blood samples. But notably not included in this demonstration of resolution is methylamine.

The Rtx Volatile Amine column is better optimized for distinguishing methanol and metylamine. Experiments with aged creatine-Gatorade mix are planned.

Methylamine is one of the ingredients used in the commercial production of creatine.^ref,patent The process is to mix and heat methylamine and other compounds in an aqueous solution held basic at pH of 7-13. Creatine precipitates out and is then cleaned to make the purified product sold as a diet supplement.

Putting the creatine end product in an acidic solution like Gatorade and letting it sit for a couple weeks is likely to at least partially reverse the production process, methylamine becoming a likely admixture.

Today's standard hospital treatment of methanol poisoning includes dialysis with monitoring of blood methanol content. So the half live of methanol during dialysis and with metabolism blocked by administration or ethanol of fomepizole is known. It's two hours.

Carol Gebert points out that in Charles case, though, the half life of the chemical being measured in his blood during dialysis was about eight hours - about four times too slow. This indicates that it was not methanol, but some other compound instead.

And she points out that what gets really interesting is inconsistency between measurement laboratories. Six samples were taken of Charles' blood. The first three were sent to and analyzed both by the Virginia Department of Forensic Science and by the Pathology Lab at Virginia Commonwealth University. These measurements agree and give the surprising eight hour half life for the chemical being measured.  The last three blood samples, though, were sent to LabCorp, and their analysis each time gave zero for the amount of methanol in Charles blood.

The conclusion has to be that there is a problem somewhere with the lab techniques used for measuring presence of methanol.  Was it methylamine?
 
 

Summary:  The table points out that no single model can explain all the issues. But that can be achieved by drawing the more valid points from all four models.

Most appealing at first is the court finding that the methanol measured to be in Gatorade mix bottles is what killed Charles. But the numbers do not work. The Court finding is based on the false idea that multiple doses of methanol can be added without taking into account its 2⅓ hour metabolic half life. And an even bigger problem is that in 27 hours the amount of poison in Charles body is supposed to have increased. So data forces us to consider other possibilities.

The unreasonable parts of the other three models are that:
• The methylamine model has the same problem about poison increasing over 27 hours.
• Bayati's PEG-hyper-creatine model is riddled with bias and error.
• No one would knowingly drink methanol from the lab at work.

But the only way methanol in Charles body could increase after he drank Gatorade is by his later getting an additional sizable dose. The only candidate source for this is the supply where he worked.

And there is possible or probable motive. PEG may explain why he felt so lousy when he got up and went to work that fateful Monday morning. And he was used to using alcohol every day to feel better.

An explanation for how methanol got into the Gatorade mix might be that there was a problem with particular column used in the gas chromatagraphy measuring equipment. It might not have been able to distinguish between methylamine and methanol. The hospital blood methanol determination was truly of methanol, but the finding of a methyl compound in Gatorade-creatine mix was likely methlamine instead.

(A test is being planned to see whether the Rtx-BAC2 column overlaps the lines from methylamine and methanol.)

Appendix B:  Case Histories with possible involvement of methanol

Ronald Reagan (1911-2004), intestinal and skin cancers 1984 to 1987, Alzheimer's announced Nov 5, 1995. The typical delay time from start of methanol exposure to death by Alzheimer's is 40 years. Reagan died 23 years after starting to use aspartame, but from pneumonia at age 93.)

Reagan had surgical removals of both a benign and a potentially cancerous polyp in 1984, two feet of colon in 1985, two benign polyps in 1987, a small basal cell carcinoma (skin cancer) on his nose and then a larger area of surrounding tissue in 1987, and another basal cell carcinoma on his neck in 1995.^L20,L20b And when his Alzheimer's was announced, it had progressed to stage 6 or 7 out or 7. These are all ailments possibly related to inadvertent methanol consumption, and Monte implies so by pointing out that Reagan was known to carry blue packs of aspartame. It had been re-approved for dry foods in July of 1981 soon after (and because) he had become President earlier that year.

But in a September 25, 1983, news article the president of the University of Tennessee Student Government Association quotes Reagan as telling her, "I decided there was no reason I should be putting artificial sweeteners in it [my coffee] because we don't know what is in them." (From the Ronald Reagan Library^ref) So the time period during which Reagan used aspartame sweetener was likely 1981 to late 1983. That is a possible good timing fit for his physical ailments but probably not the onset of his dementia which may have started earlier. There is, though, some small possibility that he might have had access to aspartame earlier than 1981 through his involvement with the producing company's CEO, and he appears to have had motivation in his dislike for government regulation. Approval for use of aspartame in dry foods had been granted and then withdrawn seven years before his Presidency.

He had pledged during his campaign to resign if he developed dementia, but there is debate about what actually happened. Ronald Reagan was president Jan 20, 1981-1989, and it wasn't until six years later that he announced having Alzheimer's. His four doctors say there was no dementia impairment during his presidential tenure.^ref But perhaps missing here are copies of the standard mini-mental evaluation forms that must have been used.^{MiniMentalTest, ScoringTable1} Scoring is roughly: 0-9 severe, 10-19 moderate, 20-25 mild Alheimer's, and during the physicals Reagan had before his Nov 1994 announcement there must have a progression of dementia ratings leading up to the announced 6 or 7. Some, including his son,^ref say that Reagan showed early signs of Alzheimer's while he was still in office. There was confusion during a 1984 debate. Others point out that the President forgot the names of cabinet officers, trusted aides and visiting dignitaries, that in Brazil, he toasted the people of Bolivia and that sometimes he couldn't answer questions until cued by Nancy.^L22

This reviewer remembers one that doesn't get discussed, a muddling and security breach of the highest order that no fully mentally competent person would make. In the first few weeks of his administration Reagan said publicly that as President he could recall in-flight nuclear ICBM's. That can't be literally true, but it probably did reveal publicly for the first time that US ICBM's are vulnerable to self destruction by means of a secret code radio link. This was a little before his administration's approval of aspartame for dry foods, and if one interprets it as onset dementia, it could not have been caused by aspartame unless he had a pre-approval supply.

So Reagan's campaign slogan, "Get Government Off Our Backs,"^L22 may have had personal costs, but it was clearly both a brilliant political winner and a shaping of government policy with profound and very long-lasting results. Many still expect to pay lower taxes, and the sentiment, "I love my country, it's the Government I'm afraid of. God Bless America", still resonates in bulk email 30 years later. The action though, for "government off our backs," was arguably more for big corporations and some religious organizations than for individuals. Corporations got deregulation and political sentiment for more - loosening of liability-to-asset ratios from 5:1 to 30:1, tightening of bankruptcy law allowing banks to issue credit cards and loans with lower risk, repeal of the Glass-Steagall and Bank Holding Company acts,^L23 strengthening of corporate personhood and weakening of class action. Much of the change was a momentum Reagan started but was implemented under the following supposedly Democratic Clinton administration and in the Supreme Court. The so-called "supply side economics" with tax cuts supposed to raise government income from stimulation of the economy was basically just renamed Kenesian economics with a bit of Laffer justification. Trouble is that Laffer's caveat that taxes be nearly equal to differential income^Laffer is always forgotten. And also, high liability-to-asset ratio means that most of the money in circulation is con money prone to rapid vaporization, as became evident in the 2008 economic collapse. But the Reagan mood for anti-tax Laffer economics and deregulation still abounds as per Brownback in Kansas and the swell of conservatives in Congress. He was very successful in establishing trend.

A prime example of Reagan's "get government off our backs" policy was the way aspartame became approved for use in foods in July of 1981 ^{L17, L16a, L16b} and for soft drinks in July of 1983. The initial 1974 approval had been reversed due to concerns that one of the constituent amino acids could disrupt mental function. Unsuccessful scientifically, the developer, G.D. Searle hired a new chairman, Donald Rumsfeld, who was politically connected and became a key player in Reagan's transition team while still chairman at Searle. He oversaw the appointment of Arthur Hayes Hull to head the FDA. Searle reapplied for aspartame approval the day after Reagan was inaugurated, and when the FDA's Hull-appointed evaluation committee was about to decline the application by a vote of 3 to 2, Hull appointed a sixth member. The committee was then locked 3 to 3, and Hull broke the tie and approved aspartame. A couple years later he was hired by a consulting firm for Searle and Monsanto. And when Monsanto absorbed Searle in 1985, Rumsfeld reportedly received a $12M bonus.

Reagan had much conviction and true believer conviction in his policies. That's part of what made him "the great communicator." So why would he ever come to question the ingredients of the sweetener he had fostered approval for and that he liked to use? Where did the caution come from? Was it medical advice from his doctors? Is there an early record of "mini-mental" exams? And did he have access to aspartame before its approval date?

Donald Trump:

Apparently all presidents from Ronald Reagan on have used aspartame. Age 70 when he assumed office, Donald Trump Jr. is old enough to be showing aspartame's methanol effects from cardiovascular to mental.

His physical exam in January of 2017 showed moderate plaque buildup in coronary arteries (atherosclerosis), very likely related to methanol as outlined in Sections D-1 and G-f . And in her book "The Dangerous Case of Donald Trump," psychiatrist Bandy X Lee cites several abnormal brain-function characteristics two of which cold likely be related to damage by methanol - disordered decision-making and confusion about facts. [The other three that Lee lists are more like a list of adult ADHD symptoms caused by artificial food additives such as aspartame and colorings - little impulse control, difficulty foreseeing consequences and an insatiable need for affirmation.]

What is clear is that Trump likes Diet Coke and apparently consumes something like 12 cans per day. ^{ref1, ref2} It's not good for the body or brain. He's apparently not a dual alcoholic like Charles Fleming, but one wonders.

Steve Jobs: (1955-2011), endocrine pancreatic cancer diagnosed fall of 2003:^{L28, L29} Ashton Kutcher, actor in hospital with pancreatic problems after experimenting with Steve Jobs fruitarian diet:^{L30, L31}

Less known is that Steve Jobs hands were always in motion, that he bit his nails, had an erratic mercurial personality, had mood swings from ecstatic to depressed and was prone to brutal attacks without warning but not uncommonly might break down and cry. And there are occasional references to hyperactive, bipolar and manic depressive. (p. 157, 261, 266, 271, 272, 274 etc.; "Steve Jobs," by Walter Isaacson) Steve Jobs is well known for his unusual diet emphasizing "raw" vegetarian fruits, starchless vegetables and edible green leaves plus "fasting," which seems to have meant partial, not total fasting.^L32 For a while at college he made his own carrot juice and at one point turned "a sunset-like orange hue." He eventually expanded to "vegan" and would eat omelets, goat cheese and salmon mousse, but continued to sometimes eat nothing but apples or nothing but greens for a week at a time, and he remained throughout his life very fond of fruit smoothies and juices.

In 1982 he had the Mac team's office refrigerator restocked, replacing sodas with Odwalla organic orange and carrot juices, and the next year in new quarters their company kitchen was well stocked with Odwalla. Odwalla juices were also stocked at Next in 1987. He was often seen over the years with a bottle of Odwalla or SmartWater. It's not clear how much he took to energy drinks, but from 2008 on his doctor would provided them.

Odwalla was founded in 1980 and for the first 16 years sold "raw" unpasteurized fruit juices. The company wanted to keep as much of the fruit's taste and essential nutrients and enzymes as possible, but in 1996 had to switch to using flash pasteurization after of an E. Coli infestation in apple products. Odwalla is now part of the Minute Maid division of the Coca-Cola Company, selling for $181 million in 2001. Its product line includes Proteins, Quenchers, Fruit Smoothies, Superfood blends, and energy bars. SmartWater is distilled water with calcium, magnesium and potassium added. It is distributed by Glacéau, formerly Energy Brands which was founded in 1996 and also bought by CocaCola Co - for $4.1 billion in 2007 - and then expanded to the UK, Australia, France and Argentina. There are many unnaturally flavored, colored and sweetened products, and the company has been sued by CSPI and ruled against by the UK for deceptive or false advertising of its products as "nutritious" or a "healthful alternative" to soft drinks. The only product from this company that Steve Jobs is known to have used is SmartWater. So at least in the seven years from 1996 to the time of his pancreatic cancer diagnosis in 2003, Steve Jobs appears to have been imbibing considerable quantities of fruit and vegetable juices containing methanol in the way Monte describes.

The pancreas is an interesting organ with regards to Monte-Henzi in-situ formaldehyde because it has two parts with markedly different abundance of capillary supply. 1-2% is endocrine and receives 10-15% of the pancreatic blood flow. These are the islets of Langerhans that release insulin and three other sugar-control enzymes into the blood stream. The other 98-99% of the pancreas is exocrine releasing digestive enzymes through the bile ducts. The high-vascular endocrine part of the pancreas should be more vulnerable to Monte-Henzi than the low-vascular exocrine part. It consists of 1000-2000 tiny islets of Langerhans scattered throughout the rest of the 5-6" long pancreas.

It might not be surprising then that there is "evidence for a greater pancreatic cancer risk with a high intake of fruit and juices but not with a high intake of sodas."^L40

Steve Jobs had very unusual PNET (pancreatic neuroendocrine tumor) that starts in the islets of Langerhans.^{L34a, L34b} And "the genes most frequently mutated in PNETs are odd. They don't seem to control growth directly; rather they seem to affect the way cells regulate genes." ^{L35, Mukherjee}   Both features fit Monte-Henzi.

- - - - - - - -
   There are two ways that Steve's high-fruit, high-carbohydrate diet might also explain his constant motion hyperactivity, mood swings and feeling good after fasts - salicylate and Candida albicans.

One might expect Steve to avoid artificial coloring, preservative and flavoring. One thing for sure, though, is that he was ingesting huge quantities of salicylate in fruits. And after the artificial additives, salicylate is the next most important food ingredient to remove in the Feingold regimen for alleviating hyperactivity/ADHD.

A second thing for sure about Steve Jobs diet is that it was decidedly high carbohydrate, making Candidaisis a possibility. A table of hyperactive and manic-depressive swings due to food and chemical reactions was first developed in the late 1940's by Clinical Ecologists. Reason for the correlation began to emerge in 1981 when C. Orion Truss outlined how antibiotics, high carbohydrate diets and chemicals are likely to sometimes upset the balance of microflora growing in the gut with dominance tilting to unfriendly yeasts. Candida albicans is leader of the pack, so overgrowth is commonly dubbed "Candidaisis." It is said to initiate systemic changes in two ways - 1) by increasing permeability of the gut lining and 2) by releasing toxins like acetaldehyde into the blood stream. The first makes strange or severe reactions likely to foods and partially digested foods like opiate peptides. The second means subtle disparate systemic dysfunctions including damage to enzyme production pathways. One of the last "Clinical Ecologists" wrote a book titled "The "5-Day Allergy Relief System," basically a fasting technique that can be interpreted now as killing off intestinal fungal overgrowth, which may be what Steve Jobs was doing with his fasts.

It would be interesting to know whether Steve had large use of of antibiotics somewhere in his early life. And it would be interesting to know more about Ashton Kutcher. How much was he getting into Steve Jobs' containerized fruit and vegetable products, and what does he mean by, "My pancreas levels were completely out of whack"? Did his official medical diagnosis make a distinction between the two parts of the pancreas?

Art Buchwald: (1925-2007), stroke 2000, aneurysm and leg amputation 2005, kidney failure 2005-7:

All four conditions could relate to Monte-Henzi in-situ formaldehyde. He was a little over weight and on lithium, which makes one thirsty, so he was high-volume user of diet soft drinks.

Art Buchwald chose not to continue dialysis and moved into a hospice in early 2006. But, inexplicably, his kidney degradation slowed, as described in "Heaven Can Wait". As you can tell in the way he writes, priorities change when someone checks into a hospice, but then his perspective revived ("worry about Bush again") when he didn't die and was able to check out of the hospice. It appears possible that during the low he lost concern about weight and stopped using diet soft drinks for a while. This is only a guess, but there is no other candidate explanation for why his disease progression halted, and the potential of in-situ formaldehyde as a common factor in all his ailments can be taken to add some credence to the diet soft drink issue.

Others it might be interesting to know more about:
*Arthur Hayes Hull, Jr (1933-2010), lukemia:
*Donald Rumsfeld (1932-2021) multiple melanomas, maybe mental degradation^L43
Teresa Brewer (1931-2007) myelin-degenerative PSP^L41
Opera singer with pulmonary hypertension^L42
Ashton Kutcher, actor in movie about Steve Jobs
  (*Key figures in the political process for aspartame approval)

Appendix C:  Non-Aspartame Diet Soft Drinks

As of 2015, diet RC Cola is the only "zero-calorie" soft drink with neither aspartame nor acesulfame potassium. There are four with no aspartame but with acesulfame potassium - Coke Diet with Splenda, Pepsi Next, Diet Pepsi, Caffeine Free Diet pepsi and Diet Pepsi with Wild Cherry.

Dr Pepper and 7-Up "Naturally Sweetened" have half the usual calories and neither aspartame nor acesulfame potassium.

The word "diet" for soft drinks used to always mean sweetened with aspartame. But since mid 1914 there is no correlation. "Diet" now means non-aspartame for RC and Pepsi but with aspartame for all other zero-calorie brands.

But to remove aspartame or improve its taste, the majors use acesulfame potassium, which has a methyl side chain less likely to dissolve off than the methoxy side chain or "methyl ester" of aspartame. What they didn't do is use the newer super-sweet version of aspartame, advantame, at 1/200 concentration, which should effectively solved the methanol problem.

2017 update: Zevia: Stevia Leaf extract, tartaric acid and natural flavors.   Hansen's natural soda: splenda.   Diet Rite sodas: sucralose, acesulfame potassium and potassium benzoate but no aspartame.   Diet RC Cola can not be purchased anywhere.

Appendix D:  Additional Details

D2 - Neotame and Advantame versus Aspartame:   Neotame (2002) and Advantame (2014) are derivatives of Aspartame designed with rather impressive chemical engineering to be both sweeter and resistant to digestive enzymes. This is accomplished by adding a side chain on the dipeptide.

They are sweeter than aspartame by factors of about 40 and 200 respectively, and they are "non-nutritive" because only 10% of the dipeptide is split apart and metabolized. 90% of the dipeptide remains intact and is too large to be absorbed through the gut lining. 40% is passed in the urine and 50% in the feces. (Information from a now defunct web site that was called neotame-sweetener.com.)

The methyl ester (methyl group linked by an oxygen) causing sweetness is still digested and split off as methanol in the same way as with aspartame, but so little of the new sweeteners would have to be used that the formaldehyde health problem would be reduced. Replacing aspartame with advantame would reduce the amount of methanol by 1/100 and the amino acids by 1/2000.

And the new sweeteners have been approved for use by the FDA for some time (July, 2002 and May, 2014),^ref so one wonders why they are not being used in diet products.

The savings in calories and cost are insignificant, because there is only one calorie in a standard 12 oz aspartame-sweetened diet soda and because most of cost is probably already in delivery and handling. The manufacturers point out (a legal requirement in labeling) that neotame and advantame are acceptable for people with PKU (phenylketonuria),^ref but that is a rare genetic disorder. Perhaps more significant are mitigation of both the methanol problem and of the original concern with aspartame about brain damage caused by aspartic acid in test animals. But those are advantages the manufacturers are not going to advertise.

The hesitation of product manufacturers seems to be to avoid reigniting the considerable controversy that has surrounded aspartame. And in fact, what is happening is that a significant portion of American shoppers are becoming more health conscious. Sales of once beloved heavily-processed packaged foods are crumbling. Kraft, which counts processed cheese as its biggest seller, saw profits plunge more than 60 percent in 2014.^ref Consumption of diet soft drinks and soft drinks in general is also declining because of growing public concern about artificial sweeteners and calories.^ref Beverage manufacturers have responded with diet soft drinks sweetened with more natural plant-based stevia, Coca-Cola Life and Pepsi True available respectively since about May and November, 2014. See Appendix E for newer list.

Coca-Cola and Pepsi tout only 60 calories per 8 oz bottle. But that needs to be compared to the usual 124-189 calories for a standard 12 oz can of soda. The new diet sodas are more natural and somewhat diet.

Simultaneously there are many buyers for increasingly dyed and flavored products like the brightly colored and spiked drinks so prominent in gas stations, stores and vending machines, so the consumables producers have to meat dual and conflicting objectives. But given todays demand for both natural and low-calorie from a significant fraction of the buying public, one might expect some industrial effort to justify advantame or to develop a cost-effective production process for L-glucose, the more-natural non-digestible mirror image of normal glucose.^a,b The corporate competition was considerable of a couple decades ago when the goal was to find a cost-effective production process for high fructose corn syrup.

D3 - Avoiding Hangover: The MajchrowiczMendelson1971 prescription for how to avoid hangover is not as well known as it should be. That may be because it is a bit counter-intuitive and also because is probably particularly difficult for alcoholics. The rule simply put is: Don't stop the drinking abruptly.

More specifically, with additions from Monte: 1) Take a little but no more than half a shot of 10% alcohol like clockwork every few hours for two or three days. 2) Start the sipping before the hangover would be due to start, as by alarm clock toward the end of the first night of sleep after the binge, or immediately upon waking in the morning. 3) During the binge do not eat or drink containerized fruit or vegetable juices or products - including don't mix them into your alcohol. 4) Maybe not worth the trouble, but an option this reviewer suggests, would be to momentarily heat any fruit juices you want to use to 150 ºF before recooling and imbibing them. 5) Majchrowicz&Mendelson pointed out that Bourbon has more methanol content than other ethanol beverages and found the amount enough to make hangover a bit worse, but only slightly. So either don't use it or heat it briefly to 150 ºF, too, before using.             This is not a prescription to continue the high-consumption binge.

The underlying logic here is that hangover is due to methanol, not ethanol, and that the alcohol metabolizing enzyme ADH has much more affinity for ethanol than for methanol. The presence of a little ethanol prevents metabolization of methanol to formaldehyde, the methanol then being excreted by the slower processes of sweating, respiration and urination. That's why ethanol is an antidote for methanol poisoning.

Then MajchrowiczMendelson1971, when combined with LeafZatman1952, goes a little further. If BAC of ethanol is above 0.1%, it blocks all avenues of disposal for methanol, both metabolization and excretion, so that the BAC of methanol just keeps building with time. That's why the soused binge drinker, who typically quits alcohol abruptly after days or a couple weeks, has such terrible after effects or sometimes dies. The alcoholic binge drinker must follow the HH prescription for avoiding hangover.

The conclusion that methanol causes hangover, not ethanol, could be tested if someone would imbibe a tiny bit of methanol with no ethanol. Less than a teaspoon would probably do it, as Jones1986 points out, but there is no ethical way to do such a direct test. The blood measurements data of Majchrowicz&Mendelson1952 are good enough.

There are four corollaries. 1) Something short of hangover easily happens - waking up restless. 2) Ethanol as an antidote for methanol poisoning is in use in the medical community. 3) Regular imbibing of ethanol has health benefit. The health benefit of ethanol has some folk-lore recognition but meets official resistance. The condition here called dual-alcohol pseudo addiction is unknown and not pointed out even by Monte.

D4 - Nightshades & Arthritis:

The nightshade family of foods all contain inflammatory nicotinic compounds and simply removing those and allergenic foods from the diet is often sufficient to arrest the redness, pain and progression of osteoarthritis.["Nightshade Vegetables" by Craig Sams, "Arthritis and Joint Health" by Kathleen Burnes, and "Arthritis, Little Known Treatments" by Anthony di Fabio] Susceptibility seems to increase with age.

D5 - Fitful Sleep and the Rebound Effect:   Alcohol helps one go to sleep, but many also find that after going to sleep easily, they have trouble staying asleep.^study It's probably a sub-hangover effect, the time of waking up being when the methanol starts being metabolized. Again counterintuitive, a slight bit of ethanol should help, say a teaspoon of vodka.

D6 - Ethanol Health Benefit:  
    Studies show health benefit from daily consumption of ethanol with two shots per day of 40% whisky or equivalent optimal. Between two to three shots/day is the break even point, and three or more per day is detrimental,^{KlatskySciAm2003, m179Klatsky1981} except alcoholics have perfect circulatory systems and no atheroma anywhere at all.(Monte's book pp.100-102 discussion of autopsies)

The reason has to do with ethanol being an antidote for methanol and the fact that many people, inadvertently and unbeknownst to them, are regularly consuming a little methanol. Presence of ethanol occupies the ADH enzyme, limiting its ability to oxidizing methanol to formaldehyde.

But in what way is ethanol beneficial for limiting ADH action on methanol, short term or long term? The answer can not come from data, because the health benefit data just quoted is too coarse to distinguish when the ethanol is consumed or even whether one shot is as beneficial as two.

The suggestion here is that the most useful protection from ethanol is probably prevention of the epithelial formaldehyde surge discussed in the Introduction. For that, one needs about a teaspoon of wine or a quarter teaspoon of whiskey at the same time as meals, snacks and smokes. The danger period is minutes, not hours - basically eating time plus the time for methanol to diffuse from blood plasma through capillary walls into more voluminous body fluids. After that the Blood Alcohol Concentration of methanol is not likely to be dominated by normal endogenous sources.

Ethanol health benefit is described in the literature in terms of a phrase this reviewer does not like, "U-shaped curve." The term was apparently first coined by Klatsky, is used in at least three references 229, 301 & 303, and is referred to 87 times by Monte in his book "While Science Sleeps". Monte even tries to force the reader to get out pencil and paper and draw a U-shaped curve. That seems to be misplaced ire since his general public, especially those who drink, is already aware of and inclined to like the idea of methanol health benefit. If there are non-believers who need to be convinced, they are more likely in the medical community than the general public.

An inherent problem with the phrase "U-shaped curve" is that one ends up trying to describe something positive using negative terminology. The data collected by Klatsky and others is statistics about deaths, a negative, but the results these researchers are trying to describe is something positive, fewer deaths. So the proposal here is to define a positive quantity to talk about, "Ethanaol Health Benefit" = the percentage of fewer deaths from drinking versus not drinking:

Excerpts from Table 3 of 179Klatsky1981 are shown here on the right. He and others make the point that a small regular amount of alcohol helps to mitigate the greatest single killer, cardiovascular disease.

What Monte provides is an explanation for why. Even if there have been other factors like trans fats (no longer GRAS since Nov. 2013), Monte-Henzi in-situ formaldehyde appears to be killing people. Keeping a little ethanol in the veins partially alleviates this by tying up ADH and reducing the oxidation of methanol into formaldehyde in non-liver tissue. This is both an explanation for the methanol health benefit and a confirmation of the Monte-Henzi model.

The new form of table and graph below and to the right highlight three points usually not discussed or missed in reading of the data. 1) The greatest methanol health benefit is for breast cancer. This might be expected because Monte points out that of the non-liver tissues with ADH, mammary tissue has the least ALDH.  2) The liver is not harmed by low-level ethanol and might even be helped a little.  3) The pancreas, though, is harmed by low-level ethanol, and rather severely. This is not related to in-situ formaldehyde because most of the pancreas is low-vascular, and deaths relating to diabetes are typically attributed to non-alcohol causes. Something else not identified is going on.

      More Recent Studies Showing Ethanol Health Benefit:   Non-drinkers had a four times higher risk for rheumatoid arthritis than the heaviest drinkers,^m642   versus "Cigarette smoking is now the most conclusively established environmental risk factor for rheumatoid arthritis." ^m332
"...marked highly significant negative association between alcohol consumption and SLE [lupus]... which becomes stronger with higher weekly intake of alcohol." ^m73
Osteoporotic Fracture due to low bone density shows an ethanol health benefit.^m295
cardiovascular diseases,^m176
myocardial infarction,^m485
coronary heart disease, angina pectoris,^m172
dementia.^m534

      Ethanol Health Benefit and Monte's Approach:   Monte's regimen is twofold - to avoid inadvertent intake of methanol, and to sustain a low-level intake of medicinal ethanol. But the latter is not a logical conclusion from the available data. The proof of ethanol health benefit is based on samplings of people who are presumably ingesting inadvertent methanol. And it seems likely that if one is following Monte's regimen of avoiding inadvertent methanol, there may be little need for the additional regimen of medicinal ethanol.

D7 - "Dual Alcoholism" :   People whose inadvertent intake of methanol is significant should be vulnerable to needing ethanol on a regular basis. This is the three-pack-a-day smoker or a diet soda guzzler. The good side of ethanol is that it blocks the formation of formaldehyde by preventing oxidation of methanol. But inherently this must also mean an elevated level of methanol in body fluids by about a factor of 10 that we here call "methanol storage." Then if there is stoppage of ethanol intake, there should be a temporary higher rate of formaldehyde production than from the steady stream of diet sodas alone.

This storage factor is because in steady state conditions, the blood level of methanol is proportional to it's half life. Or to say this differently, below saturation the dissipation rate is BAC/τ_½, and this has to match the steady input. Ethanol shutting down the methanol oxidation pathway means that the methanol τ_½ changes and becomes long. The time constant ratio measured by Leaf&Zatman1952 is a factor of 10.

Heavy smokers and diet drink guzzlers clearly do not not get enough methanol for them to recognize a feeling equivalent to full-blown hangover. But with methanol storage an added factor, it is not unreasonable to expect some of them to feel maybe somehow a little better if they sip their ethanol on a regular or daily basis.

Standard alcohol addiction is a true, strong addiction that the afflicted can not break and at worst manifests in binge or extreme days-on-end binge drinking. Dual alcoholics are not so irrevocably afflicted and should potentially be able to break their need for ethanol if they knew to stop their inadvertent intake of methanol. They are hooked, at least initially, only in the sense of daily need for some ethanol, not days-on-end binge drinking of a lot of ethanol.

D8 - Methalic Index, Colonic Bacteria, and Endogenous Methanol:   No or very little pectin should reach the colon, but if it does, bacteria there will clearly produce methanol.^Siragusa1988 On the other hand, the upper intestine often contains an abundance of methylated compounds, but for most of these, has very little ability to hydrolyze.

Analogous to "glycemic index," there must be what one could call a "methalic index" for how much blood methanol rises due to methylated foods. The methyl groups in pectin are tightly bound, but one would expect some small quantity to eventually be broken down and cause low, slow rise in methanol BAC. And if some pectin does reach the colon, that would result in a particularly delayed and spread out effect. Compounds like caffeine and thobromine that may be absorbed in toto into the blood stream but then have some slow hepatic breakdown would also have low methalic index. The methyl group in aspartame is a relatively weakly bound, though, is hydrolyzed quite rapidly by digestive enzymes, and should cause BAC rise almost as quickly as the actual methanol in containerized fruit and vegetable products. Aspartame has high methalic index.

The specter is often raised that the obvious lack of harm from abundant methylation in pectin and caffeine should mean that aspartame, too, must cause no harm. That corroborates the initial calculation given here that the peak blood methanol from a can of diet soft drink is at or below normal endogenous and so must cause no harm. But the methylated foods have low methalic index, and any blood methanol effect they infuse is both low and low-pass filtered. Perhaps it is fair to turn the obvious argument upside down and examine the normalcy of today's endogenous levels. Could today's endogenous be a little high and like aspartame also harmful, compared to evolutionary standards?
    (A pituitary? enzyme has been mentioned as a possible minor source of endogenous methanol.)

D9 - Formulas for Blood Alcohol Concentration:   Some publication somewhere must list the equations for sub-saturation absorption and dissipation of orally ingested compounds into the blood system. But this is not easy to find, and notably, the two sources of data for methanol give neither reference nor equations, Stegink1981 and Leaf&Zatman1952.   Theoretical curves should be parameter fit to measured curves.

So this reviewer set about to derive the equations. It seemed as though this should be easy because intuition suggests in advance that there is little more than just the difference in two exponentials, e^-δt ‑ e^-αt, where α and δ are absorption and dissipation parameters related to half lives t_½a and t_½d. But it turns out that a coefficient α/(δ-α) derives from first principles, which is more complicated than one might at first expect.

We model the physiologic problem with sequential dual decay indicated at the right. Simplifying assumptions are:

1) We assume there is just one absorption process with rate equal to that of the small intestine and don''t try to account for the short time that rate of absorption is different in the stomach. Probably more significant is that up to 10% of ethanol may be metabolized in the stomach before absorption into the blood, so we use this same factor for methanol. Volume parameters used are V for total fluids in the body, v_o for the amount of alcohol consumed and .9v_o for the amount absorbed. The fluid fraction of the blood is 93%, so if all the alcohol in the small intestine were immediately absorbed, the starting blood alcohol concentration would be
            BAC_o = .84 v_o / V                                                                (Eq.1)
V ≈ 50 liters for a 150 lb male or 165 lb female. But if v_o is given in units of mL of alcohol per kg of body weight, use V ≈ 68 L/kg for males and 75 L/kg for females.

2) Absorption of alcohol from the intestines is a transfer, not a diffusion process, so that rate of absorption into blood and body fluids is independent of blood concentration and is proportional to only the amount of alcohol in the intestines. The rate of decrease of alcohol volume v₁(t) in the intestines is
            dv₁/dt = -α v₁(t),                     (t≠0)                                        (Eq.2)
as indicated in the figure, which with boundary condition v₁(t=0) = v_o gives the solution
            v₁(t) = v_o e^-αt,         t ≥ 0,     α = .693 / t_½a                            (Eq.3)
                   = 0,                  t < 0

3) Two delta's will be used. Written out, delta(t-t') is a function of time, the Dirac delta function. Written as a symbol δ is the body's metabolic dissipation constant for methanol. Assuming that δ is constant means there is either no ethanol present or at least that the amount of ethanol is not changing.
    We also assume that alcohol levels are below saturation so that dissipation of alcohol in the intestines is proportional to the amount present. Absorption from the intestines has to be added, giving the equation
            dv/dt = -δ v(t) + α v₁           δ = .693 / t_½d                            (Eq.4)
The standard canonical form for writing this kind of homogeneous differential equation is
            dv/dt + δ v(t)  =  α v_o e^-αt  ≡  f(t)                                         (Eq.5)
Here the terms on the left containing v(t) and its derivatives describe a system and ways that it could behave, while the expression the right is a driver of the system forcing it into one behavior. The Green's function method of solution is in two steps. First solve for the system's impulse response function G(t-t') at present time t when it has been pulsed with a delta function at a previous time t'. Then do a convolution to apply the actual f(t) of interest. G(t-t') satisfies a modification of Eq.5,
            dG(t-t')/dt + δ G(t-t')  =  delta(t-t'),                                       (Eq.6)
where delta(t-t') is zero everywhere except for t=t' where it is infinite but has integral value of one. The solution is:
            G(t-t')  =  e^-δ(t-t'),     t > t'                                                      (Eq.7a)
            G(t-t')  =  0,             t < t'                                                      (Eq.7b)
The simple dissipation system responds with exponential decay. Response only after the impulse is called causality.

The solution for Eq.5 is the sum of responses at present time t from pings from all previous times t', the convolution
            v(t) = ∫dt' G(t-t') f(t')
                  = .9v_o α   _o^t∫ dt' e^-δ(t-t') e^-αt'                 Limits on ∫ set by Eqs. 3 & 7.
                  = .9v_o α   e^-δt   ₀^t∫ dt' e^(δ-α)t'
                  = .9v_o [α/(δ-α)]   (e^-αt - e^-δt)                                           (Eq.8)
Now dividing by V and multiplying by .93 to get concentration in whole blood gives:

            BAC(t) =  BAC_o [α/(α-δ)]  [ e^-αt - e^-δt ]                      (Eq.9)

                      = 0.84 (vo/V) [t½d/(t½d - t½a)]   [e.693t/t½d  -  e.693t/t½a ]     (Eq.9b)

            BAC_max = BAC_o r^r/(1-r)   is at   δt_m = [r/(r-1)] ln(r),   r = δ/α       (Eq.10)

α = δ doesn't occur in nature, but the math formula for that case is
            BAC( t, α=δ )   = BAC_o α t e^-αt                                               (Eq.11)

Plots are given in the click expandable figure at the right.
Next need to do a parameter fit to the available data.

Note that in the Stegink1981 data the peaks for the two higher doses are delayed. This is probably because the blood methanol concentrations are beginning to saturate the ADH enzyme, so curve fit should be for the lower curve that was for a dose of about 13 drops of methanol. Evidently t_½a ≈ ½ hour and t_½d ≈ 3 hours, giving r ≈ ⅙ and BAC_max ≈ 0.7 BAC_o = ½ v_o/V.    [Or if metabolism in the stomach were not included, this would be ⅔ v_o/V.]
    (The summary of literature above was t_½d = 19min and 2⅓hr for ethanol and methanol, and t_½a = 30-90 min for ethanol.

Now need to solve for v₁(t) and v(t) when there is yeast production of alcohol in the colon. There are two ways, steady state with this production always having existed, and with transients from this production starting at time zero.

D10 - Removing Methanol From Commercial Products:   This should be fairly easy to do using a scaled-back version of the low-pressure, low-heat process used for producing juice concentrate. Home-use dehydrators use 95-155°F and time to remove water. The commercial process uses low pressure and a tall column to remove water quickly in a continuous process. That also undesirably removes essences, vitamin C and oils which have to be added back. The vapor pressure of methanol, though, is so low that it should be removable without affecting the rest of the product. 110 °F and ⅓ atmosphere would suffice. For juices and vegetables this might be just an extension to already used flash pasteurization before sealing of bottles, cartons or cans. For cigarettes and tobacco products the FDA might not face legal restraints.

D11 - Aspartame Half Life In Carbonated Drinks:   The pH of carbonated soft drinks is optimal for stability of aspartame in liquids, but the methyl group tends to hydrate off, forming methanol and leaving the amino acid pair with no taste. The Searle 1983 petition data plotted at the right shows soda aspartame half lives of 30 weeks at room temperature and 110 weeks when refrigerated. In the trunk of a car at 150 degrees a quarter of the time this would drop to something like four weeks.

D12 - Desert Storm Post-Traumatic Stress Disorder:   Some are concerned that PTSD may have been caused in part by diet soft drinks exposed to desert heat. This is incorrect. The amount and rate of methanol absorbed into the blood per can is the same no matter whether the aspartame hydration disassociation is in the can or in the duodenum. The main difference should be taste.

D13 - ßPhenylketonuria (PKU):   Some people can not process phenylalanine. Buildup of this amino acid in the body can cause mental and other serious damage.^ref

D14 - Delivery Agents:   Chemistry tricks are needed when products are not very water soluble.
    PEG is a commonly used solvent in many consumer products like colorings and medicine. It is also now used in one of the forms of e-cigarettes to make the vapor smoke. It does have GRAS status, but the Bayati report might suggest trouble ahead for others like Charles Fleming who take a lot of medications containing PEG and perhaps especially for non-smoke smokers.
    Attaching an alcohol molecule seems to be another way of making a compound more soluble, as is done with both aspartame sweetener and creatine body-building compound. The latter can be bought on line unmodified, with ethyl or with methyl attachment - but aspartame is produced with only a methyl attachment. It's a simple dehydrolysis bond that is easily broken apart during digestion when a water molecule returns to free the alcohol.
    Aspartame is a di-peptide (L-phenylalanine plus L-aspartic acid) plus a methyl group and has no sweet taste without the alcohol. It's discovery stimulated much investigation of other di-peptides and compounds for possible use as sweeteners, and though none are listed, the use of ethyl attachment must surely have been evaluated. It is only methyl compounds that are listed, though. [(Chapters 1 & 2 of "Aspartame: Physiology and Biochemistry," ed. LD Stenik & LJ Filer Jr, (Marcel Dekker, Inc., 1984)] Perhaps an attached ethanol is even less stable than an attached methanol.

Appendix E:  Experiments

(Most of this appendix was written in early 2014 as a response to NIH Dr. Murray's last paragraph about need for further research. The first three were added in October, 2015.)

Alzheimer's Plaque:   Chemically, what causes the rubbery feel of an Alzheimer's brain? Monte points out that when a brain is to be preserved it is put in approximately an equal volume of formaldehyde. Then in half a day the formaldehyde is gone, with no change in brain size, and the brain texture has changed from delicate to a rubbery toughness. So Is formaldehyde or paraformaldehyde causing protein binding and misfolding in the brains of Alzheimer's patients?
    "Plaque" just means lump of something abnormal. "Amyloid" means aggregate of misfolded and insoluble proteins or protein sub-pieces called peptides. Proteins sometimes do just naturally ball up incorrectly, especially if they are made as two pieces that are later put together, and there are cellular enzymes for removing these mistakes. But misfolded peptides have to be water soluble for enzymes to be able to act on them, and sometimes misfolding can be severe enough to causes insolubility. Aggregation is normal for hydrophobic molecules in a water medium.
    "Beta amyloid" or Aβ plaques are from a specific membrane protein concentrated on synaptic endings. So far, little is know about the beneficial role of this protein, but a lot is known about what can go wrong with it, so it's named for that. Amyloid beta precursor protein is 365 to 770 amino acids long but in Alzheimer's patients gets broken down into peptides 37 to 49 amino acid long. These are insoluble, aggregate, and form Aβ plaques.

Petri Dish Amyloid Plaque:   What would happen if a little formaldehyde were added to the media as perhaps by blowing a small stream of vapor?   Gaytan2015^ref,orig

Cadaver HGH - Prions v. Formaldehyde?:   An early source of human growth hormone from 1958 to 1985 was extraction from the pituitary glands of cadavers. This turned out to be unfortunately prion contaminated and to sometimes cause CJD, the human variant of mad cow disease. As of 2012, incidence rates have been 6.3% in France, 3.6% in the UK and 0.4% in the US, with peak incubation period of 20 years.
    In addition to prion protein, many of the autopsies showed unexpected moderate to severe plaques of amyloid-β peptide typical of that seen in Alzheimer's disease. The Aβ deposition was not co-localized with the prion-protein deposition, and Aβ deposition in pituitary glands was found as well. There was no correlation with pathogenic mutations for early-onset Alzheimers.   Jaunmuktane2015^ref,orig
    Neurosurgery and invasive electroencephalography devices have also sometimes induced Aβ plaques, and seeding of Aβ pathology has been demonstrated in primates and mice by CNS or peripheral inoculation with Alzheimer's disease brain homogenate.
    The authors suggest that the precursor of an abnormal protein that triggers Alzheimer's disease could perhaps be transmitted from person to person through the transfer of tissue or certain specialized medical or surgical procedures.
    But instead, could the Aβ plaque discovered in these early HGH and a few surgery patients have been due to formaldehyde in the embalming of source cadavers, or due to formaldehyde used with disinfected instruments?

Catalase Mutation - When and Why?:   Other primates such as gorillas seem to eat more fruit and probably overly-ripe fruit than pre-modern humans. This suggests that they might have higher levels of endogenous methanol, that they have more need of their form of catalase that is effective on methanol, that the human form of catalase has some other sort of advantage, and that the mutation of human catalase probably occurred after the evolutionary split between the species and diets. Can these expectations be proven with DNA analysis?

Monte Henzi - Excitotoxin Synergism:   One apparent possibility concerns supply of glucose to the brain. Glucose does not pass through the blood-brain barrier directly but instead is transported through cells of the capillary linings by special transport molecules. The interior of these cells is also exactly a location where formaldehyde is generated by ADH-mediated oxidation of methanol, so it is possible that the glucose transport molecules could become degraded and the supply of glucose to the brain reduced. But a compensation response for brain hypoglycemia is known to be increased permeability of the blood-brain barrier, the tightly packed cells of the capillary walls spread apart a little. This could allow (large molecule amino acid) excitotoxins to enter the brain, with a cascade of effects possibly following.^{Blaylock1994,video} Could animal studies with high-BAC methanol determine whether Monte Henzi - Excitotoxin Synergism does actually occur?

Gut Premeability: Similarly, does in-situ formaldehyde decrease absorption of nutrients through the epithelial cells of the intestine?.

Demyelination Healing:   There are at least two demyelination diseases that, if survived, tend to self-heal — Guillain-Barré syndrome thought to be due to an autoimmune attack on peripheral nerves, and another caused by bacteria that I can't remember the name of. Why doesn't multiple sclerosis tend to similarly self-heal? Or to put this differently, would it, if treated with methanol avoidance and continuous antidote as per Monte's proposal? And would Guillain-Barré syndrome be more responsive to the same than the usually employed plasmapheresis?

Fibromyalgia v. Lupus:   There is no mention in the book at all to fibromyalgia. But it is similar enough to lupus that distinguishing diagnosis is difficult,^L18 and in principle it would seem that Monte-Henzi should relate to both. The symptoms of fibromyalgia, however, do not respond to immunosuppressants while lupus symptoms do. Does this relate to Monte's distinction between auto-immune and innate-immune, and is fibromyalgia an aspect of in-situ formaldehyde?

Endogenous Methanol:   Much exploration needed. The simplest experiment would be to analyze blood samples from patients who switch diet back and forth on about a two-day schedule between high fruit and vegetable and then none.   Food methalic indices could be inferred from in vitro experiments.   Is there any kind of condition, compound or drug side effect that might increase the passage of methylated compounds to the colon?

Endogenous Methanol and Disulfiram:   Disulfiram is used to treat alcoholics. It blocks the action of ALDH on ascetaldehyde causing the aldehyde to build up and make the a person feel terrible if they drink ethanol. Similarly, disulfiram should also cause an increase in formaldehyde, the first metabolic product of endogenous methanol. Is disulfiram a little dangerous even if the alcoholic drinks no alcohol?

Is dual-alcohol pseudo addiction a real phenomenon?

Other Aldehyde-Protein Bonds:   Does the innate immune system recognize other aldehyde-bondings to protein?

Sucralose And Other Sweeteners:   Sucralose is a form of chlorinated sucrose (table sugar = glucose-fructose disaccharide) that does not break down very well by hydration in digestion, probably because the chlorine replacements block enzymatic fit. Most of it stays a disaccharide too large to be absorbed through the gut lining and so has no caloric effect. But some fraction of it must be hydrolyzed resulting in chlorinated glucose and fructose in the blood stream. Could these chlorinated monosaccharides be harmful in some sort of subtle, low-level, long-term effect like low-level methanol? (Common brand names of sucralose-based sweeteners are Splenda, Sukrana, SucraPlus, Candys, Cukren and Nevella. Sucralose is 320 to 1000 times as sweet as sucrose, twice as sweet as saccharin and three times a sweet as aspartame. And it is stable under heat and over a broad range of Ph conditions.)

Ancient Cardiovascular Disease:   Some ancient mummies show a significant incidence of cardiovascular disease.^L19 How much smoked fish or food were they eating and how much fire smoke were they exposed to?

Parameters It Would Be Nice To Know:   Many of the papers on animal and human testing with methanol do not give blood concentrations, rise times or fall times. And for the many methylated food compounds there seems to be not enough precision in what is known about how much methanol breaks off during digestion or in the liver. Caffeine and theobromine seem to be in this category.^L How rapidly or slowly are their methyl groups converted to methanol, and how do these time constants compare to the ADH half life of methanol, and what blood concentration results? The methyl group on aspartame seems to be very rapidly hydrolyzed yielding methanol quickly absorbed into the blood. What are the rates? And the same for the abundant methyl groups in pectin foods. They are tightly bound according to Monte, but what are the hydrolization time constants during digestion or in the blood?
  What are the timing effects for methanol to pass from the blood stream into inter-cellular spaces and then into cells, and does this effect the initial BAC calculation given in Foreword 1 or otherwise effect the concentration of methanol in the cell walls of capillaries?



    This table and accompanying discussion from the Beverage Institute shows the problem that occurs when too little is known about metabolic rates and related concentration levels. It becomes easy to say that methyl groups, methanol, phenylalanine and aspartic acid are abundant everywhere, which is normal, so not to worry.

Appendix F:  Diet Recommendations; Ornish-Fuhrman-Gundry...

The long-touted mantra^ref to avoid cholesterol and saturated fats is crumbling. It may have been in part a 1960's purchase by the sugar industry in the first place,^{ref, refcpy} and founding research on saturated fats looks now as though it involved cherry picking of data.^ref Cholesterol is being dropped from US dietary guidelines,^ref and doing so is backed by a 2006 study of nearly 50,000 women showing that a low-fat diet did not protect them from heart disease or stroke,^ref and a 2014 meta-analysis involving 76 studies and 600,000 participants reaching similar conclusion.^ref The understanding of dietary fats is changing.

The suggestion here is that these studies may be somewhat invalid and may not really provide firm conclusion, because they do not meter inadvertant trace chronic methanol consumption in their test populations. The Monte-Henzi in-situ formaldehyde model holds that the plaque that clogs arteries is formaldehyde-tagged cholesterol only, not just cholesterol, and that the formaldehyde is created inside cells of blood vessel linings by metabolism there of methanol.

Researchers are fairly sure that there must be something involving cholesterol that triggers macrophages and inflammation, and there has been a lot of searching and looking for the bad actor. But the formaldehyde tag of the Monte-Henzi model is way too small to be seen by microscopes by a factor of 600-800. And samples are always corrupted either by having been preserved in formaldehyde or for fresh tissue by formaldehyde fixative during slide preparation.

Dean Ornish's article and book in 1990 began an earlier revolution in thinking about how to treat heart disease - dropping the 1950s recommendation of bed rest, and moving instead to lifestyle change with mild exercise and mostly plant-based foods. This has become called "intensive cardiac rehabilitation," and since 2010 Medicare and Medicaid reimburse three-days of ICR training from a choice of three facilities.^ref

Dr. Joel Fuhrman recommends essentially the same diet. He puts more emphasis on micronutrients as including details about onions and mushrooms, and is a little more circumspect about being essentially vegetarian. Ornish pointed out at the onset that excess protein leaches calcium from bone. Neither is aware of the link between nightshades, inflammation and arthritis. Fuhrman's first book in 2003 sold over a million copies, and he continues public outreach and media presentations such as the video below.

Perhaps key is that much of Monte's recommendation to avoid methanol is inadvertently included by Ornish and Fuhrman even though they are unaware of it. The suggestion here is that this makes their results more valid than the studies cited above. Ornish and Fuhrman show that if avoidance of saturated fats is combined with low methanol and other dietary factors, there is then benefit for preventing or even reversing heart disease.

At this point we need to distinguish between prevention, cessation and remission. Avoidance of methanol is recommended first as a method of disease prevention. Then second, if disease has already begun, introduction of methanol avoidance should tend to halt progression of non-cancer or advanced-degeneration diseases. But whether methanol avoidance might sometimes foster remission or cure is unknown and probably depends on the type of disease. It's a guess, but methanol avoidance might help to resolve conditions like depression, late-onset partial Type I diabetes, lupus or rheumatoid arthritis - and maybe arteriosclerosis, or kidney failure - but not advanced Alzheimer's or arthritis.

Ornish-Fuhrman go beyond Monte and attempt to not just halt disease progression but also to optimize nutrients for body self healing. In the video, for instance, Dr. Fuhrman points out a micronutrient effect of increasing an enzyme that limits capillary growth expansion in tumors. Weight normalization and its benefits are automatic by eating for health, not for weight reduction as in the Atkin diet. Ornish and Furhman do not claim anything like universal success, but they do both independently state that some patients previously given up as lost to a variety of severe diseases do on their regimen sometimes achieve disease remission or cure.

Appendix G:  Biochemistry 101: (an incomplete draft of tutorial information)

Points that will be covered in this appendix when it is finished are:
          how molecular bonds are formed by removing water,
          where the methanol comes from in pectin and aspartame,
          how sugar can damage protein, and
          why glucose is least damaging

G-1: Glucose Production In Plants

The multi-step process in plants for making glucose from carbon dioxide and water can be summarized as
                6CO₂ + 6H₂O + energy   -->   C₆H₁₂O₆ + 6O₂,
where C, O and H stand for atoms of carbon, oxygen and hydrogen and C₆H₁₂O₆ is glucose.

To do this, the first step is the natural formation of carbonic acid when water is exposed to carbon dioxide,
                Step 1:   H₂O + CO₂ --> OC(OH)₂.
Osmotic pressure drives water upward into leaves, and pores on the bottom side of the leaves allow in carbon dioxide.

More remarkable are the next two steps.  It is the OC(OH)₂ carbonic acid that is acted on in photosynthesis, basically forming formaldehyde.
                Step 2:   OC(OH)₂       + energy   -->   HCOH             +   O₂
                              carbonic acid + energy   -->   formaldehyde + oxygen

The formaldehyde is then almost immediately bundled five or six at a time to form larger single sugar molecules,
                Step 3:   6(H-C-OH)   -->   C₆H₁₂O₆
                    six formaldehyde   -->   one glucose
which here we draw as

The lines represent covalent bonds, which is the sharing of an electron between two atoms so as to fill quantum mechanical orbitals. The orbital-filling bonding requirements are C 4, O 2, H 1, that is, carbon needs four bonds, oxygen needs two and hydrogen needs one sharing bond.
      —OH means —O—H.
      A double line represents sharing of two electrons.

G-2: Ring Glucose,   α vs. β,   Polysaccharides

In water solution, though, the linear form of glucose exists less than 1 % of the time. Glucose spends most of its time as a ring with the linear form double-bond oxygen replaced by an oxygen with two single bonds. As this folding occurs, an OH from carbon 5 moves up to carbon 1. But this could be to either side of carbon 1, which is the distinction between α and β glucose. Polymer chains are formed by connecting carbon 1 on one ring with carbon 4 on the next with an H₂O removed. There are two types of these glycosidic bonds, α(1→4) in starch and glycogen and β(1→4) in cellulose.

G-3: The Three Common Hexose Monosaccharides And Combinations

Glucose, galactose and fructose are all C₆H₁₂O₆ but with slight differences in three dimensional structure. In galactose the positions of OH and H are reversed on carbon #4, and in fructose the double bond oxygen is moved down to carbon #2. These are the only saccharides readily absorbed across the gut lining into the bloodstream. Disaccharides and longer are too large.  β glucose does not respond to the transporter molecule, which makes it a natural low calorie sweetener, but it's too expensive to produce. The cost-effective low-cal sweetener is sucrose, which is table sugar with three —OH replaced by chlorine, which prevents digestive enzymes from breaking it down into its monosaccharide components.

Of these three digestible monosaccharides, it is only glucose at controlled low concentrations that is transported in the blood. It is apparently the one least likely to inflict damage to proteins by random attachment. Fructose with reactive —OH sticking out more in the plane of the ring is some ten times more likely to form glycolytic bonds with protein, and apparently to prevent this, the liver either converts and stores glucose as glycogen or releases some of it as glucose. Abnormally high blood sugar (glucose) concentration damages proteins, and a 2-3 month average of effect on hemoglobin is used in the modern A1C test for diabetes. (An A1C level > 6.5 % indicates diabetes, and 5.7—6.4 % prediabetes. Below 5.7 is considered normal.)

The complex sugars and starches are polymerized versions of glucose, fructose and galactose. Pectin is polymerized galacturonic acid, which is galactose with its side -CH2OH replaced by -COOH or methylated -COOCH3.

G-4: The glycositic bond

The glycositic bond to form polysaccharides involves removing a water molecule as joining carbons 1 to 4.

G-5: Difference In Long Chain Polysaccharides     (This section not complete and may contain errors)

Methyl cellulose                                         Pectin              
   
Other thickeners

All widely used in food stuffs, cosmetics, medicines and personal products.