Loading ...
Sorry, an error occurred while loading the content.

Methyl alcohol ingestion as a model etiologic agent in multiple sclerosis, WC Monte, D Glanzman, C Johnston; Methanol induced neuropathology in the mammalian central nervous system, Woodrow C. Monte, Renee Ann Zeising, both reports 1989.12.04: Murray

Expand Messages
  • Rich Murray
    Methyl alcohol ingestion as a model etiologic agent in multiple sclerosis, WC Monte, D Glanzman, C Johnston; Methanol induced neuropathology in the mammalian
    Message 1 of 1 , May 1, 2012
      Methyl alcohol ingestion as a model etiologic agent in multiple
      sclerosis, WC Monte, D Glanzman, C Johnston; Methanol induced
      neuropathology in the mammalian central nervous system, Woodrow C.
      Monte, Renee Ann Zeising, both reports 1989.12.04: Murray 2007.12.28
      posted again Tuesday, May 1, 2012

      Friday, December 28 2007

      [ Over 22 years ago, the Monte methanol/formaldehyde toxicity paradigm
      was launched -- now available as 16 page pdf at
      along with the other references to his two 1989 reports. ]

      [ These two seminal 1989 reports by Prof. Woodrow C. Monte et al are
      also given in this previous post, along his two more recent
      comprehensive reviews in late 2007:

      role of formaldehyde, made by body from methanol from foods and
      aspartame, in steep increases in fetal alcohol syndrome, autism,
      multiple sclerosis, lupus, teen suicide, breast cancer, Nutrition
      Prof. Woodrow C. Monte, retired, Arizona State U., two reviews, 190
      references supplied, Fitness Life, New Zealand 2007 Nov, Dec: Murray
      Wednesday, December 26 2007

      posted again,
      Friday, May 14, 2010

      Wednesday, December 26 2007
      http://health.groups.yahoo.com/group/aspartameNM/message/1498 ]


      Trademarks and copyrights properties of their owners.
      All rights reserved. Woodrow Monte © 2007 - 2007
      Webmaster - Contact the webmaster if you are experiencing any problems
      or have questions about product and or services within this page.
      Designed by Russell David Wilson

      9650 Rockville Pike, Bethesda, MD 20814
      Mail to your Society of membership (APS, ASPET, AAP, AIN)
      ASBMB members send to AIN
      ASCB, BMES and SEBM members send to APS
      ***AAI and ISB members send to AAP
      ***A Oral q Poster q Indifferent
      Final decision regarding presentation format
      is at the discretion of the programing society.
      (Please print in black ink or type. Provide full
      name rather than initials.)
      Woodrow C. Monte, Dept. of Family Resources & Human Development
      Arizona State University, Tempe AZ 85287-2502
      Phone: 602-935-6938 602-935-6938
      (See Minisympgsium and Topic Category Ljsts)
      Auto immunity and
      1 408-4 Immuno deficiency
      2. 795-3 Immunoparm & Toxic
      g . 785-4 Autoimmune Disease
      Is first author graduate student? q Yes ***No

      W. Monte, D. Glanzman, and C. Johnston
      (SPON: S. Hoffman).
      Arizona State University, Tempe, AZ 85287

      Human catalase, unlike that of all other species, does not
      metabolize methyl alcohol (methanol).

      This unfortunate evolutionary deficiency makes_methanol a
      only to humans.

      Methanol is known to be a demyelinating toxin in humans, producing
      symptoms markedly similar to those in multiple sclerosis,
      including bizarre and inconsistent visual field disruptions.

      Human alcohol dehydrogenase metabolizes methanol directly to
      formaldehyde, which actively cross-links native proteins in-situ.

      Such formaldehyde-modified proteins have been shown to induce
      macrophage scavenging at a rate 100 times that of unmodified protein.

      What better method to elicit an autoimmune response than to react
      endogenous proteins with formaldehyde consistently and intermittently
      over a long period of time?

      In our model, the neurotoxic effect of orally-administered methanol was
      visualized in the rat central nervous system using reduced silver
      degeneration staining techniques.

      Following chronic administration for 18-33 days, all experimental
      animals demonstrated massive cellular, axonal and terminal degeneration
      in numerous regions of brain, including cerebellum, hippocampus,
      brainstem nuclei, internal capsule and optic chiasm.

      These results show for the first time that by using sufficiently
      sensitive histological techniques, the neurotoxicity of methanol is
      revealed in the mammalian central nervous system.

      MEMBER'S AFFILIATION (Check one only): j
      q APS q ASBMB q ASPET q AAP q AIN Ifd'AA) q ASCB q BMES q SEBM q ISB
      Submission of signed form indicates acceptance of rules including final
      withdrawal data of December 27, 1989.
      No exception will be made.
      Steven A. Hoffman Member's Name
      Member's Signature
      602-965-7024 602-965-7024 Member's Phone

      Dietary Methanol as a Cause of Multiple Sclerosis

      Human Catalase, unlike that of all other species, cannot detoxify

      This unfortunate evolutionary deficiency makes methanol
      a "poison" only to humans, contradicting Richardson's Rule
      which successfully predicts ethanol as consistently more toxic
      than Methanol in all other species.

      Methanol is known to be a demyelinating toxin in humans.

      The symptoms of chronic methanol poisoning in humans are identical to
      the symptoms of Multiple Sclerosis.

      Even to the bizarre nature and inconsistency of the visual field
      disruptions, thought to be the toxicological marker that sets methanol
      poisoning apart from all other intoxications.

      Human alcohol dehydrogenase metabolizes methanol directly to

      Location of Alcohol dehydrogenase activity in the human brain, though
      individually variable, is generally consistent with MS Plaque distribution.

      The Liver also has ADH activity with concomitant high aldehyde
      dehydrogenase activity.

      Aldehyde dehydrogenase facilitates detoxification of Formaldehyde via
      1-carbon metabolism to CO2.

      Without ready availability of Aldehyde Dehydrogenase, Formaldehyde will
      "immediately" complex with any available protein.

      Formaldehyde treatment of antigens is known to stimulate the immune
      response and is, in fact, the requisite proprietary mechanism normally
      utilized by pharmaceutical companies in the preparation of virus
      proteins for vaccine production.

      Recently sites on macrophages specific to "Formaldehyde Modified
      Protein" have been elucidated.

      Protein modified by formaldehyde are scavenged by macrophages at a rate
      100 times that of unmodified protein.

      What better method to elicit an auto-immune response than to react
      endogenous proteins with Formaldehyde consistently and intermittently
      over a long period of time.

      Although differences in distribution and density of alcohol
      dehydrogenase sites in the brain may account for the great individual
      variability in symptoms and severity of MS and methanol poisoning, it is
      more likely that variability of ethanol levels in the blood may be an
      even more important factor.

      Alcohol Dehydrogenase(ADH) metabolizes ethanol preferentially to
      Methanol by a ratio greater than 9.

      For this reason ethanol is the only known antidote to methanol
      poisoning, its ingestion prevents the conversion to formaldehyde and
      allows methanol to be removed by the kidneys and the lungs.

      There is some indication that endogenous ethanol produced by gut
      fermentation, can be found in the human bloodstream.

      Sobriety testing indicates that there is great variability in these
      residual levels of ethanol, perhaps due to the variation of the
      population of gut flora.

      page 1

      Small amounts of methanol are produced as a result of gut fermentation.

      There are sources of dietary methanol that are substantial enough to
      cause concern.

      Canned fruits and vegetables have been exposed to enough heat to
      liberate methanol from the pectin in the plant cell walls.

      This methanol would normally not be available to the digestive process
      of humans.

      Certain alcoholic beverages are so high in methanol as to not be
      exportable to the United States.

      It is worth noting that countries in which they are produced have the
      highest, per capita incidence of MS.

      Although MS occurrence in populations varies with geographical and
      climatological consistency, a very believable case can be made for
      direct correlation to preformed dietary methanol.

      page 2

      Woodrow C. Monte Ph.D
      Renee Ann Zeising
      Department of Family Resources and Human Development
      Arizona State University, Tempe, AZ 85287 (U.S.A.)
      Key words: Methanol--Degeneration--Axon--Rat--
      Brain--Central Nervous System--Neuropathology
      Please address correspondence to:
      Woodrow C. Monte
      Department of Family Resources and Human Development
      Arizona State University, Tempe, Az. 85287


      The neurotoxic effect of methyl alcohol (methanol) was visualized in the
      rat central nervous system using reduced silver staining techniques.

      Following chronic administration of methanol (intubation with 0.95 gm/kg
      for 18, 25 or 33 days) all experimental animals showed massive axonal
      degeneration in multiple regions of brain, regardless of the duration of

      Histological processing yielded degeneration by-products of fibers with
      cells of origin lying in cerebellar cortex, deep cerebellar nuclei,
      cranial nerve nuclei and the red nucleus.

      Additional regions of axonal degeneration were found in the hippocampus,
      the flocculus, dorsal raphe nucleus, ventral cochlear nuclei,
      retrosplenium, the internal capsule of the corpus striatum and the optic

      These results show that by using sufficiently sensitive
      neurohistological techniques, the neurotoxicity of methyl alcohol is
      revealed in the vertebrate central nervous system.


      Methanol has been widely suggested as a neurotoxin in humans (9, 7),
      yet the demonstration of such purported toxicity has been difficult to
      achieve with consistency.

      "Surprisingly low levels" of methanol (14) are known to cause various
      and nonspecific neurological complaints, including headache, vertigo,
      chills, gastric pain, insomnia (23), tinnitus (4), shooting pains in
      the lower extremities, and a form of multiple neuritis characterized by
      paresthesia, numbness, prickling and shooting pain in the back of the
      hands and forearms as well as edema of the arms.

      Bilateral blindness, nystagmus (20, 10), bladder paresis (7) and
      permanent motor dysfunction (9) are long term neurotoxic sequelae
      following acute poisonings (18).

      The most characteristic signs and symptoms of chronic methyl alcohol
      exposure in humans are diverse visual disturbances with progressive
      contraction of visual fields (23).

      Acute exposure to methanol can also lead to blindness.

      These data are inconsistent on two grounds:

      Reports of both transient and permanent blindness, as well as unilateral
      and bilateral disturbances, have appeared in the clinical literature
      (20, 25).

      Methanol is generally considered to be a cumulative toxin, both due
      to its unusually long half life (estimated to be over thirty five hours
      in humans;(2),
      and to the progressive damage reported in test animals chronically
      exposed to methanol in early studies (10).

      Methanol poisoning of humans is the only known exception to
      "Richardsons' Rule," by which the toxicity of alcohols increases
      directly with the length of the carbon chain (18).

      Unfortunately, little is yet known of the mechanism by which methanol
      exerts its apparently selective cellular toxicity (22).

      There are considerable differences methanol toxicity across species (19).

      For example, the minimum acute lethal dose (MLD) in rat is 9.5 g/kg,
      rabbit 7.0 g/kg and dog is 8 g/kg (19).

      Primates also vary considerably across species and strains, with
      lethality reported to occur in the range of 3-9 g/kg (24).

      Humans have succumbed to doses as low as 100 mg/kg (1);

      blood levels above 115 mg/dl (milligram percent) are generally
      considered lethal (3). {{See footnote 1}}

      Several early studies of chronic methanol exposure have reported,
      although with little substantiation, the occurrence of extensive
      peripheral "nerve damage" (12, 21) and "destruction of the parenchyma
      [sic] cells of the cerebrum" (6) with long term inhalation of methanol
      both in monkeys and in dogs.

      Both the ingestion and the inhalation of methanol have been reported to
      induce behavioral abnormalities (11) and gross neurological teratology
      in rat pups whose dams had been exposed to methanol during gestation (15).

      Similarly, rabbits acutely exposed to methanol showed "thinning and
      focal loss" of myelin, though the nature and extent of the damage was
      not fully described (20).

      Heretofore laboratory animals have not been considered as appropriate
      model systems for the study of methanol toxicity in humans, due to the
      increased methanol tolerance among all lower species thus far examined

      The present experiments addressed the question of whether an adequate
      dose and treatment regimen could provide a reliable animal model of
      methanol neurotoxicity.


      Eight adult male and female Long Evans derived rats weighing between
      200-250 grams were intubated once a day with 20 percent (v/v) spectral
      grade methanol (Sigma Chemical Company, M3641) in glass distilled water
      sufficient to provide 0.95 g/kg body weight (10 percent of the MLD).

      Six control animals received intubation with an equivalent volume of
      glass distilled water.

      Animals were randomly selected for histological examination on day 18,
      25 or 33 of treatment.

      For histology, animals were deeply anesthetized with sodium
      pentobarbital (100 mg/kg), and perfused transcardially with normal
      saline followed by 4% paraformaldehyde, pH adjusted to 7.4.

      Brains were removed from the calvaria and postfixed in the perfusate for
      7-48 days awaiting further analysis.

      On the day before sectioning brains were transferred to 10% sucrose to
      facilitate sectioning.

      Frozen sections were cut at 40 microns and processed for degenerating
      neuronal byproducts using the reduced silver method of Giolli and Pope (8).

      Sections were then mounted on gelatin coated slides, counter stained
      with thionin, cleared and cover slipped.

      Tissue was analyzed and regions of degenerating neuronal byproducts were
      photographed using conventional bright field light microscopic techniques.


      Analyses of degenerating neuronal tissue were performed by three

      All experimental animals showed massive axonal degeneration in numerous
      and widely distributed regions.

      Microscopic analyses indicated degeneration of fibers whose cells of
      origin lay in cerebellar cortex, deep cerebellar nuclei, several cranial
      nerve nuclei and in the red nucleus.

      Of particular interest was the surprising absence of neuronal cell body
      All observable damage was restricted to axons and axon terminals.

      All experimental animals showed massive degeneration throughout the
      medullary layer of the cerebellum.

      The spinocerebellar tracts were so heavily stained with degeneration
      byproducts as to preclude tracing the course of individual fibers.

      The corticospinal tract, rubrospinal tract, the trapezoid body, the
      trigeminal nerve, trigeminal nucleus and particularly the NTST nerve)
      were virtually filled with degenerating fibers.

      Exceptionally heavy degeneration was observed in the flocculus and in
      the ventral-most aspect of the periventricular gray (dorsal raphe nucleus).

      There was also extensive damage to the dorsal and ventral cochlear nuclei.

      The optic chiasm showed patchy areas of degeneration.

      The neocortex was mostly free of degeneration except for the retrosplenium.

      The corpus striatum showed damage only in the isolated fibers of the
      internal capsule.

      The hippocampus exhibited degeneration scattered throughout regions CA 1
      thru CA 4, with some involvement of the dentate leaf.

      The locus and extent of the axonal damage was independent of the
      duration of methanol exposure and of the sex of the experimental animals.

      The thalamus, hypothalamus, cingulate cortex, substantia nigra and the
      reticular formation showed no signs of degeneration in any animal.


      Our present findings indicate that chronic high doses of methanol are
      capable of inducing severe axonal damage in many brain loci of the rat.

      There are surprisingly few published reports of the effect of long term
      methanol exposure in any species, due, in part, to the relatively high
      resistance to methanol found in virtually all lower animals.

      Many of the symptoms of acute and chronic methanol toxicity in humans
      are indicative of neurological damage (perhaps via demyelination).

      There is virtually no literature addressing the long term exposure of
      humans to this ever-increasing environmental contaminant (16) and food
      toxicant (13) which has a particularly high, and as yet unexplained,
      potency toward man.

      It is highly unlikely that this neurological damage is caused by the
      direct effect of methanol itself, but rather by one or more of its
      metabolic products.

      Both formaldehyde and formic acid are far more potent neurotoxins.


      [ The abstracts and texts of all 190 references are given in pdf form
      at http://www.thetruthaboutstuff.com/articles.shtml

      Many full original texts are provided, annotated by Monte by hand,
      and often collected together as brief reviews of specific topics.

      In Mozilla ThunderBird email client, you can click on the pdf text,
      use Ctr A to highlight the text, and then Ctr C to copy it to the
      Note Pad, and then left click on an email and use Ctr V to paste
      the full text into the email as plain text. ]

      (1) Bennett, I.L., Cary , F.H., Michell , G.L. and Cooper, M.N. (1953)
      Acute Methyl Alcohol Poisoning: A Review Based on Experience in an
      Outbreak of 323 Cases.
      Medicine. 35, 431-463.

      (2) Bergeron, R., Cardinal, J. and Geadah, D. (1982)
      Prevention of Methanol Toxicity by Ethanol Therapy.
      N Engl J Med. 304(24), 1528.

      (3) Berkow, R. (1982)
      Merck Manual. p. 2186 vol. 14.
      Merck and Co Inc., New Jersey.

      (4) Browing, E. (115) Methanol Toxicology:
      In Toxicity and Metabolism of Industrial Solvents.
      p. 315-323. Elsevier Publishing Co., Amsterdam.

      (5) Clay, K.L., Murphy, W.C. and Watkins, W.D. (1975)
      Experimental Methanol Toxicity in the Primate:
      Analysis of Metabolic Acidosis.
      Toxicology and Applied Pharmacology. 34, 49-61.

      (6) Eisenberg, A.A. (1917)
      Visceral Changes in Wood Alcohol Poisoning by Inhalation.
      American Journal of Public Health. 7, 765.

      (7) Erlanson, P., Fritz, H., Hagstam, K. E., Liljenberg, B. (115)
      Tryding, N., Voigt, G.,
      Severe Methanol Intoxication.
      Acta Medica Scand. 177(4), 393-408.

      (8) Giolli, R.A. and Pope, J.E. (1973)
      The Mode of Innervation of the Dorsal Lateral Geniculate Nucleus and the
      Pulvinar of the Rabbit by Axons Arising from the Visual Cortex.
      Journal of Comparative Neur. 147, 129-144.

      (9) Guggenheim, M.A., Couch, R. and Weinberg, W. (1971)
      Motor Dysfunction as a Permanent Complication of Methanol Ingestion.
      Archives of Neurology. 24, 550-554.

      (10) Hunt, R. (1902)
      The Toxicity of Methyl Alcohol.
      John Hopkins Hospital Bulletin. 13, 213-225.

      (11) Infurna, R., Schubin, W. and Weiss, B. (1981)
      Developmental Toxicology of Methanol,
      Toxicologist. 1, 32.

      (12) McCord, C.P. (1931)
      Toxicity of Methyl Alcohol (Methanol) Following Skin Absorption
      and Inhalation.
      Industrial and Engineering Chemistry. 23, 931-936.

      (13) Monte, W.C. (1984)
      Aspartame: Methanol and the Public Health.
      Journal of Applied Nutrition. 36(1), 42-54.

      (14) National Institute for Occupational Safety and Health.
      Health Hazard Evaluation Report No HETA-81-177,178-988:
      NTIS Order No. 1982; PB82-194648: 1-14.

      (15) Nelson, B.K., Brightwell, W.S., MacKenzie, D.R, Khan, A., Burg,
      J.R., Weigel, W.W. and Goad, P.T. (1985)
      Teratological Assessment of Methanol and Ethanol at High Inhalation
      Levels in Rats.
      Fundam Appl Toxicol. 5, 727-736.

      (16) Posner, H.S. (1975)
      Biohazards of Methanol in Proposed New Uses.
      Journal of Toxicology and Environmental Health. 1, 153-171.

      (17) Rao, K.R., Aurora, A.L., Muthaiyan, S. and Ramalrishnan, S. (1977)
      Methanol toxicity -- an experimental study.
      Jawaharlal Inst. Post-Grad. Med. Educ. Res. 2, 1-11.

      (18) Roe, O. (1955)
      The Metabolism and Toxicity of Methanol.
      Parmacological Review. 7, 399-412.

      (19) Roe, O. (1982)
      Species Differences in Methanol Poisoning. I. Minimal Lethal Doses,
      Symptoms, and Toxic Sequelae of Methanol Poisoning in Humans and
      Experimental Animals.
      CRC Critical Reviews in Toxicology. 275-286.

      (20) Roe, O.(1946)
      Methanol Poisoning: Its clinical course, pathogenesis and treatment.
      Acta Medica Scandinavica. 126(Supplement 182), 1-253.

      (21) Scott, E., Helz, M.K. and McCord, C.P. (1933)
      The Histopathology of Methyl Alcohol Poisoning.
      American Journal of Clinical Pathology. 3, 311-319.

      (22) Smith, E.N. and Taylor, R.T. (1982)
      Acute Toxicity of Methanol in the Folate-Deficient Acatalasemic Mouse.
      Toxicology. 25, 271-287.

      (23) U. S. Department of Health, Education, and Welfare.
      Occupational Exposure to Methyl Alcohol:
      HEW Pub. No. (NIOSH) 76-148. March 1976.

      (24) Wimer, W.W., Russell, J.A. and Kaplan, H.L. (1983)
      Alcohols Toxicology: Alcohols Toxicology. p. 1-277.
      Noyes Data Corporation.

      (25) Wood, C.A. and Buller, F. (1904)
      Poisoning by Wood Alcohol.
      Journal of the American Medical Association. 43, 972-977, 1058-1062,
      1117-1123, 1213-91, 1289-1301.

      "Of course, everyone chooses, as a natural priority, to enjoy peace,
      joy, and love by helping to find, quickly share, and positively act
      upon evidence about healthy and safe food, drink, and environment."

      Rich Murray, MA Room For All rmforall@...
      505-501-2298 505-501-2298 1943
      Otowi Road, Santa Fe, New Mexico 87505

      http://RMForAll.blogspot.com new primary archive

      group with 116 members, 1,499 posts in a public archive

      details on 6 epidemiological studies since 2004 on diet soda (mainly
      aspartame) correlations, as well as 14 other mainstream studies on
      aspartame toxicity since summer 2005: Murray 2007.11.27
      Wednesday, November 14, 2007

      Coca-Cola and Cargill Inc., after years of development,
      with 24 patents, will soon sell rebiana (stevia)
      in drinks and foods: Murray 2007.05.31

      Coca-Cola, Cargill Inc., PureCircle global operations market stevia
      for foods and drinks: Murray 2007.11.12

      Souring on fake sugar (aspartame), Jennifer Couzin,
      Science 2007.07.06: 4 page letter to FDA from 12 eminent
      USA toxicologists re two Ramazzini Foundation
      cancer studies 2007.06.25: Murray 2007.07.18

      Artificial sweeteners (aspartame, sucralose) and coloring
      agents will be banned from use in newly-born and baby foods,
      the European Parliament decided: Latvia ban in schools 2006:
      Murray 2007.07.12

      Sainsbury's supermarket chain in UK details its bans of aspartame,
      sodium benzoate, and artificial flavourings and colours: Carol Key,
      Customer Manager: Murray 2007.11.09

      more from The Independent, UK, Martin Hickman, re ASDA
      (unit of Wal-Mart Stores) and Marks & Spencer ban of
      aspartame, MSG, artificial chemical additives and dyes
      to prevent ADHD in kids: Murray 2007.05.16

      ASDA (unit of Wal-Mart Stores WMT.N) and Marks & Spencer
      will join Tesco and also Sainsbury to ban and limit
      aspartame, MSG, artificial flavors dyes preservatives additives,
      trans fats, salt "nasties" to protect kids from ADHD:
      leading UK media: Murray 2007.05.15



      folic acid prevents neurotoxicity from formic acid, made by body from
      methanol impurity in alcohol drinks [ also 11 % of aspartame ], BM
      Kapur, PL Carlen, DC Lehotay, AC Vandenbroucke, Y Adamchik, U. of
      Toronto, 2007 Dec., Alcoholism Cl. Exp. Res.: Murray 2007.11.27
      Wednesday, November 27, 2007

      [ See also:
      Wednesday, November 28, 2007
      explosion in numbers of children with serious food allergies has
      bewildered experts and parents, Helen Francombe, The Australian
      2007.11.17: role of formic acid from methanol in liquors and
      aspartame: Murray 2007.11.28 ]


      Brief Summary:

      Methanol in small amounts is present along with ethanol in beverage
      alcohol. [Murray: and about the same amounts from aspartame diet

      The body's natural enzymes preferentially metabolize ethanol while
      methanol breaks down into highly neurotoxic Formic Acid.

      Use of high levels of Folic Acid was found to inhibit brain damage
      caused by the methanol.

      The use of Folic Acid during pregnancy has been recommended for
      several years to prevent neural tube defects.

      However, this study indicates that even higher levels of Folic Acid
      can be very beneficial to the developing baby, particularly where
      alcohol exposure is a factor.

      Folic Acid is mandated as an additive to all flour sold in Canada.

      The debate has begun on its required addition to all beverage
      alcohol to help mitigate damage caused to both infants and adults.

      Formic Acid in the Drinking patient and the expectant mother
      Dr. Bhushan M. Kapur
      Departments of Laboratory Medicine,
      St. Michael's Hospital , Toronto, Ontario, Canada


      Methanol is produced endogenously in the pituitary glands of humans
      and is present as a congener in almost all alcoholic beverages.

      Ethanol and methanol are both bio-transformed by alcohol
      dehydrogenase; however, ethanol has greater affinity for the enzyme.

      Since ethanol is preferentially metabolized by the enzyme, it is not
      surprising that trace amounts of methanol, most likely originating
      from both sources, have been reported in the blood of people who drink

      Toxicity resulting from methanol is very well documented in both
      humans and animals and is attributed to its toxic metabolite formic acid.

      To understand ethanol toxicity and Fetal Alcohol Spectrum Disorders,
      it is important to consider methanol and its metabolite, formic acid,
      as potential contributors to the toxic effects of alcohol.

      Accumulation of methanol suggests that alcohol-drinking population
      should have higher than baseline levels of formic acid.

      Our preliminary studies do indeed show this.

      Chronic low-level exposure to methanol has been suggested to impair
      human visual functions.

      Formic acid is known to be toxic to the optic nerve.

      Ophthalmological abnormalities are a common finding in children
      whose mothers used alcohol during pregnancy.

      Formic acid, a low molecular weight substance, either crosses the
      placenta or may be formed in-situ from the water soluble methanol
      that crosses the placenta.

      Embryo toxicity from formic acid has been reported in an animal model.

      To assess neurotoxicity we applied low doses of formic acid
      to rat brain hippocampal slice cultures.

      We observed neuronal death with a time and dose response.

      Formic acid requires folic acid as a cofactor for its elimination.

      Animal studies have shown that when folate levels are low, the
      elimination of formic acid is slower and formate levels are elevated.

      When folic acid was added along with the formic acid to the brain
      slice cultures, neuronal death was prevented.

      Therefore, folate deficient chronic drinkers may be at higher risk
      of organ damage.

      Women who are folic acid deficient and consume alcohol may have
      higher levels of formic acid and should they become pregnant,
      their fetus may be at risk.

      To our knowledge low level chronic exposure to formic acid and its
      relationship to folic acid in men or women who drink alcohol has
      never been studied.

      Our hypothesis is that the continuous exposure to low levels of
      formic acid is toxic to the fetus and may be part of the etiology of
      Fetal Alcohol Spectrum Disorders.


      Alcoholism: Clinical and Experimental Research
      Volume 31 Issue 12 Page 2114-2120, December 2007

      Bhushan M. Kapur, b.kapur@...,
      Arthur C. Vandenbroucke, PhD, FCACB
      Yana Adamchik,
      Denis C. Lehotay, dlehotay@...,
      Peter L. Carlen carlen@...,
      (2007) Formic Acid, a Novel Metabolite of Chronic Ethanol Abuse,
      Causes Neurotoxicity, Which Is Prevented by Folic Acid
      Alcoholism: Clinical and Experimental Research 31 (12), 2114–2120.

      the Department of Clinical Pathology (BMK),
      Sunnybrook Health Science Centre, Division of Clinical Pharmacology
      and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada;

      St. Michael’s Hospital (ACV), Toronto, Canada;
      Department of Laboratory Medicine and Pathobiology (BMK, ACV),
      Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;

      Departments of Medicine (Neurology) and Physiology (YA, PLC),
      Toronto Western Research Institute, University of Toronto,
      Toronto, Ontario, Canada;

      and University of Saskatchewan (DLC), Saskatchewan, Canada.

      Reprint requests: Dr. Bhushan M. Kapur, Department of Clinical
      Pathology, Sunnybrook Health Science Centre, 2075 Bayview Ave,
      Toronto, Ontario, M4N 3M5, Canada; Fax: 416-813-7562; E-Mail:


      Background: Methanol is endogenously formed in the brain and is
      present as a congener in most alcoholic beverages.

      Because ethanol is preferentially metabolized over methanol (MeOH) by
      alcohol dehydrogenase, it is not surprising that MeOH accumulates in
      the alcohol-abusing population.

      This suggests that the alcohol-drinking population will have higher
      levels of MeOH’s neurotoxic metabolite, formic acid (FA).

      FA elimination is mediated by folic acid.

      Neurotoxicity is a common result of chronic alcoholism.

      This study shows for the first time that FA, found in chronic
      alcoholics, is neurotoxic
      and this toxicity can be mitigated by folic acid administration.

      To determine if FA levels are higher in the alcohol-drinking
      population and to assess its neurotoxicity in organotypic hippocampal
      rat brain slice cultures.

      Serum and CSF FA was measured in samples from both ethanol abusing
      and control patients, who presented to a hospital emergency

      FA’s neurotoxicity and its reversibility by folic acid were
      assessed using organotypic rat brain hippocampal slice cultures
      using clinically relevant concentrations.

      Serum FA levels in the alcoholics
      (mean ± SE: 0.416 ± 0.093 mmol/l, n = 23)
      were significantly higher than in controls
      (mean ± SE: 0.154 ± 0.009 mmol/l, n = 82) (p < 0.0002).

      FA was not detected in the controls’ CSF (n = 20),
      whereas it was >0.15 mmol/l in CSF of 3 of the 4 alcoholic cases.

      Low doses of FA from 1 to 5 mmol/l added for 24, 48 or 72 hours to
      the rat brain slice cultures caused neuronal death as measured by
      propidium iodide staining.

      When folic acid (1 ?mol/l) was added with the FA, neuronal death was

      Formic acid may be a significant factor in the neurotoxicity of
      ethanol abuse.
      This neurotoxicity can be mitigated by folic acid administration
      at a clinically relevant dose.


      Peter L Carlen, FRCPC, MD
      Head, Division of Fundamental Neurobiology
      Toronto Western Research Institute (TWRI)

      Senior Scientist, Division of Fundamental Neurobiology
      Toronto Western Research Institute (TWRI)

      Keywords: stroke, gap junctions, synaptic transmission, mitochondria,
      calcium chelators, whole cell patch clamp recordings, fluorescence
      imaging, epilepsy, dementia, fetal alcohol syndrome, brain state

      Research Interests:
      Mechanisms of neural synchrony and entrainment (epilepsy), and
      neurodegenerative processes

      * We have several projects on cellular mechanisms of epilepsy,
      particularly the synchronizing role of electrotonic coupling via gap
      Molecular biological and cellular electrophysiological recording
      techniques are being used to measure the upregulation of gap
      junctional function in several in vitro seizure models, including
      the use of the intact mouse hippocampus preparation.
      Also a project on the pathogenesis of hypoglycemic seizures is in progress.

      * In collaboration with Drs. Berj Bardakjian and Frances Skinner,
      the linear and nonlinear electrical and network properties of central
      mammalian neurons in physiological and pathophysiological conditions
      (e.g., epilepsy) are being described by neural modelling techniques.
      We are developing nonlinear techniques for the identification
      different brain states including those associated with anesthesia and

      * In models of stroke and Alzheimer's disease, calcium homeostasis
      and free radical production are under investigation, focusing on the
      role of degenerating mitochondrial function in presynaptic terminals.

      Fluorescence and confocal microscopic imaging of intracellular calcium
      and mitochondrial function coupled with whole cell and field
      electrophysiological recordings are being used.

      * In collaboration with Drs. Bhushan Kapur, James Reynolds and
      James Brien, we are examining the role of formic acid in the causation
      of the brain damage in the fetal alcohol spectrum disorder and its
      rescue by folate.

      Peter L Carlen
      Mailing Address
      Primary Office
      Toronto Western Hospital, McLaughlin Pavilion, 12th Floor Rm. 413
      399 Bathurst St., Toronto, Ontario Canada M5T 2S8
      Email carlen@...,
      Phone Numbers 416.603.5800 416.603.5800 x5044

      Staff and Trainees:
      Yana Adamchik
      Marija Cotic
      Youssef El-Hayek
      S Sabet Jahromi
      Eunji (Ellen) Kang
      Borna Kavousi
      Philip Liang
      Shanthi Mylvaganam
      Marina Samoilova
      Evan Sheppy
      Damian Shim
      Alexandre Tonkikh
      Hui Ye
      Wilson Yu
      Zhang (Jane) Zhang


      Dr. Bhushan Kapur
      Selected Publications

      Kapur BM. Drug Testing Methods and Clinical Interpretation of Test
      Results. In: Carson-Dewitt R, ed. Encyclopedia of Drugs, Alcohol and
      Addictive Behaviour. Vol 1. Macmillian Press; 2001, p. 450-461.

      Kapur B, Hackman R, Selby P, Klein J, Koren G.
      A randomized, double-blind placebo control trial of nicotine
      replacement therapy in pregnancy. Current Therapeutic Research 2001;
      62(4): 274-278.

      Bailey B, Lalkin A, Kapur B, Koren G. Is chronic poisoning with
      acetaminophen in children a frequent occurrence in Toronto?
      Can J Clin Pharmacol 2001; 8(2): 96-101. [Read More]

      Ho E, Collantes A, Kapur B, Moretti M, Koren G. Alcohol and breast
      feeding: Calculation of time to reach zero-level in milk.
      Biol Neonate 2001; 80(3): 219-222. [Read More]
      [ Dr. Gideon Koren
      Division of Clinical Pharmacology and Toxicology, Hospital for Sick
      Children, 555 University Ave., Toronto, Ont. M5G 1X8 (Canada)
      Tel. +1 416 813 5781 +1 416 813 5781
      , Fax +1 416 813 7562
      E-Mail gkoren@..., pharmtox@..., ]

      Kapur B, Koren G. Folic acid fortification of flour: three years
      Can J Clin Pharmacol 2001; 8(2): 91-92. [Read More]

      Ahn E, Kapur B, Koren G. Iron bioavailability in prenatal
      multivitamin supplements with separated and combined iron and
      J Obstet Gynaecol Can 2004; 26(9):809-14. [Read More]

      Railton CJ, Kapur B, Koren G. Subtherapeutic risperidone serum
      concentrations in an adolescent during hemodialysis:
      A pharmacological puzzle.
      Ther Drug Monit 2005; 27(5):558-561. [Read More]

      Lehotay DC, George S, Etter ML, Graybiel K, Eichhorst JC, Fern B,
      Wildenboer W, Selby P, Kapur B.
      Free and bound enantiomers of methadone and its metabolite, EDDP in
      methadone maintenance treatment: Relationship to dosage?
      Clin Biochem 2005; 38(12): 1088-1094. [Read More]

      Langman L, Kapur B. Toxicology -- then and now.
      Clin Biochem 2006; 39(5):498-510.

      Kapur BM, Vandenbroucke A, Adamchik Y, Lehotay DC, Carlen PL.
      Formic acid, a novel metabolite of chronic ethanol abuse:
      neurotoxicity and its prevention by folic acid.
      Submitted to Alcohol Clin Exp Res, April 30, 2007.


      Queen's-led Network Looks At FAS Aiming To Minimize Life-long
      Learning Problems
      Main Category: Pregnancy / Obstetrics News
      Article Date: 24 Jun 2006 - 12:00 PDT

      For the first time researchers are testing to see whether fetal
      exposure to methanol, a contaminant found in many alcoholic beverages,
      plays an important role in causing the life-long learning and
      behavioural problems associated with Fetal Alcohol Spectrum Disorders

      By understanding fetal brain injury caused by exposure to methanol
      and related toxins, an emerging team of researchers is laying the
      groundwork for potential new therapeutic interventions to protect
      fetuses at risk for FASD.

      "The main goal will always be prevention of FASD," says lead
      researcher James Reynolds, Queen's University professor of Toxicology
      and Pharmacology, "but we also have to develop strategies to minimize
      injury to the developing fetus and individualize earlier therapeutic
      interventions for children with pre-natal exposure to alcohol."

      The interdisciplinary research team, which also includes
      James Brien and Doug Munoz from Queen's,
      Peter Carlen (University Health Network),
      Bhushan Kapur (Sunnybrook Hospital)
      and Brenda Stade (St. Michael's Hospital) from Toronto,
      received just under $1.5 million dollars in funding
      from the Canadian Institutes of Health Research.

      The Queen's researchers have found that simple eye movement tasks
      can be used to assess brain function in children with FASD. Since this
      technology is portable, the researchers plan to travel across the
      country to bring the research program into affected communities. "It's
      estimated that the incidence of FASD is about one per cent in the
      general population," Dr. Reynolds says, "but there are regions and
      communities in this country where the population affected by FASD
      increases dramatically."

      Using blood samples from at risk mother-baby pairs, the Toronto team
      members hope to identify biological markers that may predict brain
      injury in the child. At risk babies will be tracked for 24 months
      following birth so researchers can identify early signs of FASD and
      develop aggressive therapeutic interventions at earlier stages to
      minimize the effects on a child's development.

      To understand the underlying mechanisms of this novel hypothesis of
      FASD, the Toronto team members are studying the effects of formic acid
      and folic acid on the biological functions and survival of neurons in
      isolated brain tissue. In parallel studies, the Kingston team will
      assess the efficacy of folic acid supplementation as a potential
      therapeutic intervention in preventing FASD.

      For these researchers, an exciting opportunity has been created by
      linking this study with Queen's University's state-of-the-art Magnetic
      Resonance Imaging (MRI) facility. New experimental procedures being
      developed at Queen's will link eye movement tasks to MRI images of the
      brain, creating an objective and much more specific way to evaluate
      brain function. By isolating individual brain responses, FASD
      researchers hope to gain greater insight into the underlying brain
      injury caused by prenatal exposure to alcohol, leading to more
      specific intervention therapies designed to minimize the affects of FASD.

      "Not all children exposed to alcohol during prenatal life develop
      FASD," adds Dr. Reynolds. "There are other contributing factors
      including genetic predisposition and nutrition during gestation that
      make important contributions to the ultimate outcome. We need a way
      to identify the different sub-groups within the FASD spectrum. This
      research will help us develop the standardized tools we need to
      evaluate and treat children with FASD."

      Article adapted by Medical News Today from original press release.

      Lorinda Peterson, 613-533-3234 613-533-3234
      , lorinda.peterson@...,
      Nancy Dorrance, 613-533-2869 613-533-2869
      , dorrance@...,

      Contact: Lorinda Peterson

      name: James N Reynolds
      email: jnr@...,
      phone: 613 533 6946 613 533 6946
      campus_extension: 36946
      department: Pharmacology and Toxicology
      type: Faculty

      name: James F Brien
      email: brienj@...,
      phone: 613 533 6114 613 533 6114
      campus_extension: 36114
      department: Pharmacology and Toxicology, School of Medicine,
      type: Faculty

      Dr. Douglas P. Munoz doug@...,
      Canada Research Chair in Neuroscience
      Director, Centre for Neuroscience Studies
      Professor of Physiology and Psychology
      Member, CIHR Group in Sensory-Motor Systems
      Queen's University, Kingston, Ontario, Canada K7L 3N6
      Phone: (613) 533-2111 (613) 533-2111
      Fax: (613) 533-6840

      Dr. Brenda Stade St. Michael’s Hospital
      Fetal Alcohol Spectrum Disorder Diagnostic Clinic
      61 Queen Street Toronto, Ontario M5B 1W8
      Tel: (416) 867- 3655 stadeb@...,


      2448 Hamilton Road, Bright's Grove, Ontario, Canada N0N 1C0
      Phone: (519) 869-8026 (519) 869-8026
      E-mail: info@...,

      Fetal Alcohol Spectrum Disorders (FASD),
      Fetal Alcohol Syndrome (FAS),
      Fetal Alcohol Effects (FAE),
      Partial Fetal Alcohol Syndrome (pFAS),
      Alcohol Related Neurodevelopmental Disorders (ARND),
      Static Encephalopathy (alcohol exposed) (SE)
      and Alcohol Related Birth Defects (ARBD)
      are all names for a spectrum of disorders
      caused when a pregnant woman consumes alcohol

      FASlink CD -- more than 170 MB of information.

      While "officially" FASD is not a diagnosis but describes the broad
      range of disorders caused by prenatal alcohol exposure, the reality
      is that FASD IS the diagnosis and the other terms are sub-diagnoses
      describing the specific effects on a specific patient.

      "St. Michael's Hospital, Fetal Alcohol Spectrum Disorder Clinic is
      pleased to support the work of FASlink.
      St. Michael's FASD Clinic views FASlink as an essential service for
      our clients.
      We are fortunate to partner with FASlink in our attempt to improve
      the lives of individuals and their families with FASD.
      Dr. Brenda Stade, St. Michael's FASD Clinic" St. Michael's Hospital
      is a teaching hospital affiliated with The University of Toronto.

      FASD Overview

      Invisible Disabilities -- An individual’s place, and success, in
      society is almost entirely determined by neurological functioning.
      A child with a brain injury is unable to meet the expectations of
      parents, family, peers, school, career and can endure a lifetime of
      The largest cause of brain injury in children is prenatal exposure to
      Often the neurological damage goes undiagnosed, but not unpunished.

      There are strategies that can work to help the child with an FASD
      compensate for some difficulties.
      Early diagnosis and intensive intervention and tutoring can do
      wonders, but the need for a supportive structure is permanent.

      Report on FASD -- Exposure Rates, Results of Prenatal Exposure to
      Alcohol, and Incidence Markers -- Bruce Ritchie - February 2, 2007
      (PDF download 1.2 MB)

      37% of babies have been exposed to multiple episodes of binge
      drinking (5+ drinks per session) during pregnancy.

      An additional 42% have been multiply exposed to 1 to 4 drinks per
      session during pregnancy.

      Prenatal alcohol exposure has been linked to more than 60 disease
      conditions, birth defects and disabilities.

      Damage is a diverse continuum from mild intellectual and behavioural
      issues to profound disabilities or premature death.

      Prenatal alcohol damage varies due to volume ingested, timing during
      pregnancy, peak blood alcohol levels, genetics and environmental factors.

      For example, ethanol was found to interact with over 1000 genes and
      cell events, including cell signalling, transport and proliferation.

      Serotonin suppression causes loss of neurons and glia, inducing
      excessive cell death during normal programmed death (apoptosis) or
      triggering apoptosis at inappropriate times leading to smaller or
      abnormal brain structures with fewer connections between brain cells,
      leading to fewer cells for dopamine production, leading to problems
      with addiction, memory, attention and problem solving, and more
      pronounced conditions such as schizophrenia.

      Approximately 20% of Canadian school age children are receiving
      special education services, most for conditions of the types
      known to be caused by prenatal alcohol exposure.

      As FASD is a diverse continuum, issues range from
      almost imperceptible to profound.
      It is somewhere in the middle that the issues attract the attention
      of parents, educators, medical and social work professionals, and
      eventually the justice system.
      Most of the issues that attract sufficient attention are behavioural
      and performance issues.

      It is probable that about 15% of children are significantly enough
      affected by prenatal alcohol exposure to require special education.
      As they become adults, FASD does not disappear but the issues of
      youth translate into ongoing problems in family relationships,
      employment, mental health and justice conflicts.
      The cost to the individuals affected, their families and society are
      enormous and as a society, we cannot afford to ignore them.

      To ignore the facts does not change the facts.

      Most girls are 2 to 3 months pregnant before they find out.
      Maternal prenatal alcohol consumption even at low levels is
      adversely related to child behavior.
      The effect was observed at average exposure levels
      as low as 1 drink per week.

      FASD Prevention

      Folic acid should be added to all beverage alcohol.

      Break the cycle. Properly fund addiction intervention and

      Identify women at risk of having children with FASD and intervene.

      Meconium testing for Fatty Acid Ethyl Esters should be mandatory for
      every birth.

      Intensive family and social service supports for FASD and recovering

      Poverty is a result of, and breeds, substance abuse. Deal with it.

      Alcohol Vendors

      The beverage alcohol industry pays less than 1% of the total damages
      caused by their products. Increase taxes on beverage alcohol.

      All tax revenue to be returned to support rehabilitation programs and
      victims of alcohol.

      Remove all incentives for governments to promote alcohol.

      End all government supports for beverage alcohol industry, including
      "wine and beer tourism".

      End all alcohol advertising

      Alcohol must be served with food.

      Breathalyzers in all alcohol establishments

      Ban alcohol sales incentives, contests, games.

      Ban "Happy Hour" discounted promotions. They encourage binge drinking.

      Public Education

      Educate the public that addiction is a medical issue not a moral failure.

      Educate children from a very young age about dangers of alcohol.

      Have youth design anti-alcohol programs targeting youth.

      The ONLY purpose of beverage alcohol
      is to make your brain take a hike.


      Better diagnostic tools for the full range of FASD damage.

      True incidence and scaling of FASD damage.

      Chemically turn-off addiction center in brain.

      FASlink began online in 1995.
      FASlink's website contains more than 110,000 searchable FASD related
      documents and serves more than 400,000 visitors annually.
      The FASlink Discussion Forum shares 50 to 100 letters daily
      and compiles the papers and discussions into the FASlink Archives.
      Our membership is worldwide but most are in Canada and the USA,
      from the most remote locations to urban centers.


      The FASlink Discussion Forum is a free Internet maillist for
      individuals, families and professionals who deal with Fetal Alcohol
      Spectrum Disorders.
      FASlink provides support and information 24/7.
      FASlink has the largest archive of FASD information in the world.
      FASlink serves parents (birth, foster and adoptive), caregivers,
      adults with FASD, doctors, teachers, social workers, lawyers,
      students and government policy makers, etc.

      Bruce Ritchie is the Moderator.

      To join FASlink, go to

      Once you have subscribed, to send mail to the FASlink members,
      send it to: fas-link@...

      info@... email directly to the Moderator, Bruce Ritchie

      The aspartame content of two liters diet soda, 5.6 12-oz cans,
      is 1,120 mg, releasing 11 % as 123 mg methanol.

      Usually, there is not a concurrent larger amount of ethanol taken,
      which would prevent the production of formaldehyde.

      So, the methanol from any aspartame
      is quickly turned into formaldehyde.

      An expert review by a competent, unbiased team,
      led by M. Bouchard, 2001, with references, many from aspartame
      industry funded studies, states that about 30 - 40 % of the methanol
      remains in the body as unknown, durable reaction products.

      J. Nutrition 1973 Oct; 103(10): 1454-1459. Metabolism of aspartame in
      monkeys. Oppermann JA, Muldoon E, Ranney RE. Dept. of Biochemistry,
      Searle Laboratories, Division of G.D. Searle and Co.
      Box 5110, Chicago, IL 60680

      They found that about 70 % of the radioactive methanol in aspartame
      put into the stomachs of 3 to 7 kg monkeys was eliminated within 8
      hours, with little additional elimination,
      as carbon dioxide in exhaled air and as water in the urine

      They did not report any studies on the distribution of radioactivity
      in body tissues, except that blood plasma proteins after 4 days
      held 4 % of the initial methanol.

      The low oral dose of aspartame and for methanol was 0.068 mmol/kg,
      about 1 part per million [ppm] of the acute toxicity level of 2,000
      mg/kg, 67,000 mmol/kg, used by McMartin (1979).

      Two L daily use of diet soda provides 123 mg methanol,
      2 mg/kg for a 60 kg person, a dose of 67 mmole/kg,
      a thousand times more than the dose in this study.

      By eight hours excretion of the dose in air and urine had
      leveled off at 67.1 +-2.1 % as CO2 in the exhaled air
      and 1.57+-0.32 % in the urine, so 68.7 % was excreted,
      and 31.3 % was retained.

      This data is the average of 4 monkeys.
      "...the 14C in the feces was negligible."

      "That fraction not so excreted (about 31%) was converted to body
      constituents through the one-carbon metabolic pool."
      "All radioactivity measurements were counted to +-1 % accuracy..."

      The abstract ends, "It was concluded that aspartame was digested
      to its three constituents that were then absorbed as natural
      constituents of the diet."



      "Exposure to methanol also results from the consumption of certain
      foodstuffs (fruits, fruit juices, certain vegetables, aspartame
      sweetener, roasted coffee, honey) and alcoholic beverages (Health
      Effects Institute, 1987; Jacobsen et al., 1988)."

      "Experimental studies on the detailed time profiles following
      controlled repeated exposures to methanol are lacking."

      "Thus, in monkeys and plausibly humans, a much larger fraction of
      body formaldehyde is rapidly converted to unobserved forms rather
      than passed on to formate and eventually CO2."

      "However, the volume of distribution of formate was larger than
      that of methanol, which strongly suggests that formate distributes
      in body constituents other than water, such as proteins."

      methanol (formaldehyde, formic acid) disposition: Bouchard M et al,
      full plain text, 2001: substantial sources are degradation of fruit
      pectins, liquors, aspartame, smoke: Murray 2005.04.02

      Toxicological Sciences 64, 169-184 (2001) Copyright © 2001 by the
      A Biologically Based Dynamic Model for Predicting the Disposition
      of Methanol and Its Metabolites in Animals and Humans

      Michèle Bouchard *, ^,1, bouchmic@...,
      Robert C. Brunet, ^^ brunet@...,
      Pierre-Olivier Droz, ^
      and Gaétan Carrier * gaetan.carrier@...,
      * Department of Environmental and Occupational Health, Faculty of
      Université de Montréal, P.O. Box 6128, Main Station, Montréal,
      Québec, Canada, H3C 3J7;
      ^ Institut Universitaire romand de Santé au Travail,
      rue du Bugnon 19, CH-1005, Lausanne, Switzerland, and
      ^^ Département de Mathématiques et de Statistique and Centre de
      Recherches Mathématiques, Faculté des arts et des sciences,
      Université de Montréal, P.O. Box 6128, Main Station, Montréal,
      Québec, Canada, H3C 3J7

      1 To whom correspondence should be addressed at Département de santé
      environnementale et santé au travail, Université de Montréal,
      P.O. Box 6128, Main Station, Montréal, Québec, H3C 3J7, Canada.
      Fax: (514) 343-2200.

      Received May 10, 2001; accepted August 28, 2001

      "However, the severe toxic effects are usually associated with the
      production and accumulation of formic acid, which causes metabolic
      acidosis and visual impairment that can lead to blindness and death
      at blood concentrations of methanol above 31 mmol/l
      (Røe, 1982; Tephly and McMartin, 1984; U.S. DHHS, 1993).

      Although the acute toxic effects of methanol in humans are well
      documented, little is known about the chronic effects of low exposure
      doses, which are of interest in view of the potential use of methanol
      as an engine fuel and current use as a solvent and chemical intermediate.

      Gestational exposure studies in pregnant rodents (mice and rats) have
      also shown that high methanol inhalation exposures
      5000 or 10,000 ppm and more, 7 h/day during days 6 or 7 to 15 of
      gestation) can induce birth defects (Bolon et al., 1993; IPCS, 1997;
      Nelson et al., 1985)."

      "The corresponding average elimination half-life of absorbed
      methanol through metabolism to formaldehyde was estimated to be
      1.3, 0.7-3.2, and 1.7 h."

      "Inversely, in monkeys and in humans,
      a larger fraction of body burden of formaldehyde
      is rapidly transferred to a long-term component.

      The latter represents the formaldehyde that
      (directly or after oxidation to formate)
      binds to various endogenous molecules..."

      "Animal studies have reported that systemic methanol is eliminated
      mainly by metabolism (70 to 97% of absorbed dose) and only a small
      fraction is eliminated as unchanged methanol in urine and in the
      expired air (< 3-4%) (Dorman et al., 1994; Horton et al., 1992).

      Systemic methanol is extensively metabolized by liver alcohol
      dehydrogenase and catalase-peroxidase enzymes to formaldehyde,
      which is in turn rapidly oxidized to formic acid by formaldehyde
      dehydrogenase enzymes (Goodman and Tephly, 1968; Heck et al., 1983;
      Røe, 1982; Tephly and McMartin, 1984).

      Under physiological conditions, formic acid dissociates to formate
      and hydrogen ions.

      Current evidence indicates that, in rodents, methanol is converted
      mainly by the catalase-peroxidase system whereas monkeys and humans
      metabolize methanol mainly through the alcohol dehydrogenase system
      (Goodman and Tephly, 1968; Tephly and McMartin, 1984).

      Formaldehyde, as it is highly reactive, forms relatively stable
      adducts with cellular constituents (Heck et al., 1983; Røe, 1982)."

      "The whole body loads of methanol, formaldehyde, formate, and
      unobserved by-products of formaldehyde metabolism were followed.

      Since methanol distributes quite evenly in the total body water,
      detailed compartmental representation of body tissue loads was not
      deemed necessary."

      "According to model predictions, congruent with the data in the
      literature (Dorman et al., 1994; Horton et al., 1992), a certain
      fraction of formaldehyde is readily oxidized to formate, a major
      fraction of which is rapidly converted to CO2 and exhaled,
      whereas a small fraction is excreted as formic acid in urine.

      However, fits to the available data in rats and monkeys of
      Horton et al. (1992) and Dorman et al. (1994) show that,
      once formed, a substantial fraction of formaldehyde is converted to
      unobserved forms.

      This pathway contributes to a long-term unobserved compartment.

      The latter, most plausibly, represents either the formaldehyde that
      (directly or after oxidation to formate) binds to various endogenous
      molecules (Heck et al., 1983; Røe, 1982) or is incorporated in the
      tetrahydrofolic-acid-dependent one-carbon pathway to become the
      building block of a number of synthetic pathways
      (Røe, 1982; Tephly and McMartin, 1984).

      That substantial amounts of methanol metabolites or by-products are
      retained for a long time is verified by Horton et al. (1992) who
      estimated that 18 h following an iv injection of 100 mg/kg of
      14C-methanol in male Fischer-344 rats, only 57% of the dose was
      eliminated from the body.

      From the data of Dorman et al. (1994) and Medinsky et al. (1997),
      it can further be calculated that 48 h following the start of a 2-h
      inhalation exposure to 900 ppm of 14C-methanol vapors in female
      cynomolgus monkeys, only 23 % of the absorbed 14C-methanol was
      eliminated from the body.

      These findings are corroborated by the data of Heck et al. (1983)
      showing that 40 % of a 14C-formaldehyde inhalation dose remained
      in the body 70 h postexposure.

      In the present study, the model proposed rests on acute exposure
      data, where the time profiles of methanol and its metabolites were
      determined only over short time periods (a maximum of 6 h of
      exposure and a maximum of 48 h postexposure).

      This does not allow observation of the slow release
      from the long-term components.

      It is to be noted that most of the published studies on the detailed
      disposition kinetics of methanol regard controlled short-term (iv
      injection or continuous inhalation exposure over a few hours) methanol
      exposures in rats, primates, and humans (Batterman et al., 1998;
      Damian and Raabe, 1996; Dorman et al., 1994; Ferry et al., 1980;
      Fisher et al., 2000; Franzblau et al., 1995; Horton et al., 1992;
      Jacobsen et al., 1988; Osterloh et al., 1996; Pollack et al., 1993;
      Sedivec et al., 1981; Ward et al., 1995; Ward and Pollack, 1996).

      Experimental studies on the detailed time profiles following
      controlled repeated exposures to methanol are lacking."

      "Thus, in monkeys and plausibly humans, a much larger fraction of
      body formaldehyde is rapidly converted to unobserved forms rather
      than passed on to formate and eventually CO2."

      "However, the volume of distribution of formate was larger than that
      of methanol, which strongly suggests that formate distributes in body
      constituents other than water, such as proteins.

      The closeness of our simulations to the available experimental data
      on the time course of formate blood concentrations is consistent
      with the volume of distribution concept (i.e., rapid exchanges
      between the nonblood pool of formate and blood formate)."

      "Also, background concentrations of formate are subject to wide
      interindividual variations (Baumann and Angerer, 1979; D'Alessandro
      et al., 1994; Franzblau et al., 1995; Heinrich and Angerer, 1982;
      Lee et al., 1992; Osterloh et al., 1996; Sedivec et al., 1981)."

      methanol products (formaldehyde and formic acid) are main cause of
      alcohol hangover symptoms [same as from similar amounts of methanol,
      the 11% part of aspartame]: YS Woo et al, 2005 Dec: Murray 2006.01.20

      Addict Biol. 2005 Dec;10(4): 351-5.
      Concentration changes of methanol in blood samples during an
      experimentally induced alcohol hangover state.
      Woo YS, Yoon SJ, Lee HK, Lee CU, Chae JH, Lee CT, Kim DJ.
      Chuncheon National Hospital, Department of Psychiatry,
      The Catholic University of Korea, Seoul, Korea. [ Han-Kyu Lee ]

      A hangover is characterized by the unpleasant physical and mental
      symptoms that occur between 8 and 16 hours after drinking alcohol.

      After inducing experimental hangover in normal individuals, we
      measured the methanol concentration prior to and after alcohol
      consumption and we assessed the association between the hangover
      condition and the blood methanol level.

      A total of 18 normal adult males participated in this study.

      They did not have any previous histories of psychiatric or medical

      The blood ethanol concentration prior to the alcohol intake
      (2.26+/-2.08) was not significantly different from that 13 hours
      after the alcohol consumption (3.12+/-2.38).

      However, the difference of methanol concentration between the day
      of experiment (prior to the alcohol intake) and the next day
      (13 hours after the alcohol intake) was significant
      (2.62+/-1.33/l vs. 3.88+/-2.10/l, respectively).

      [ So, the normal methanol level was 2.62 mg per liter,
      and increasing that by 50% = 1.3 mg per liter to 3.88 mg per liter
      caused hangover symptoms.

      The human body has about 5.6 liters blood, so adding 1.3 mg per liter
      gives an estimate of 7.3 mg added methanol, as much as 4 oz diet soda.

      Diet soda is about 200 mg aspartame per 12 oz can, which is 22 mg
      (11 % methanol), 1.83 mg methanol per ounce.

      Also, this 50 % increase in blood methanol that caused roughly
      similar symptoms in South Koreans, Woo YS, 2005, as in men in Sweden
      who had a 6-fold increase in urine methanol, confirms many studies
      that show that specific genetic differences make Asians and American
      Indians much more vulnerable to inebriation, hangover, and addiction
      than Europeans. Bendtsen P, Jones AW, Helander A. 1998 ]

      A significant positive correlation was observed between the changes
      of blood methanol concentration and hangover subjective scale score
      increment when covarying for the changes of blood ethanol level
      (r=0.498, p<0.05).

      This result suggests the possible correlation of methanol as well as
      its toxic metabolite to hangover. PMID: 16318957

      [ The "toxic metabolite" of methanol is formaldehyde, which in turn
      partially becomes formic acid -- both potent cumulative toxins
      that are the actual cause of the toxicity of methanol.]

      Int J Neurosci. 2003 Apr; 113(4): 581-94. The effects of alcohol
      hangover on cognitive functions in healthy subjects. Kim DJ, Yoon SJ,
      Lee HP, Choi BM, Go HJ. Department of Psychiatry, College of Medicine,
      Catholic University of Korea, Buchon City, Kyunggi Do, Korea.

      A hangover is characterized by the constellation of unpleasant
      physical and mental symptoms that occur between 8 and 16 h after
      drinking alcohol.

      We evaluated the effects of experimentally-induced alcohol hangover
      on cognitive functions using the Luria-Nebraska Neuropsychological Battery.

      A total of 13 normal adult males participated in this study.

      They did not have any previous histories of psychiatric or medical

      We defined the experimentally-induced hangover condition at 13 h
      after drinking a high dose of alcohol (1.5 g/kg of body weight).

      We evaluated the changes of cognitive functions before drinking
      alcohol and during experimentally-induced hangover state.

      The Luria-Nebraska Neuropsychological Battery was administrated
      in order to examine the changes of cognitive functions.

      Cognitive functions, such as visual, memory, and intellectual process
      functions, were decreased during the hangover state.

      Among summary scales, the profile elevation scale was also increased.

      Among localization scales, the scores of left frontal, sensorimotor,
      parietal-occipital dysfunction, and right parietal-occipital scales
      were increased during the hangover state.

      These results indicate that alcohol hangovers have a negative effect
      on cognitive functions, particularly on the higher cortical and visual
      functions associated with the left hemisphere and right posterior
      hemisphere. Publication Types: Clinical Trial PMID: 12856484

      Alcohol Alcohol. 1998 Jul-Aug; 33(4): 431-8. Urinary excretion of
      methanol and 5-hydroxytryptophol as biochemical markers of recent
      drinking in the hangover state.
      Bendtsen P, prebe@...,
      Jones AW,
      Helander A. Anders.Helander@...,
      Drug Dependence Unit, University Hospital, Linkoping, Sweden.

      Twenty healthy social drinkers (9 women and 11 men) drank either
      50 g of ethanol (mean intake 0.75 g/kg) or 80 g (mean 1.07 g/kg)
      according to choice as white wine or export beer in the evening
      over 2 h with a meal.

      After the end of drinking, at bedtime, in the following morning after
      waking-up, and on two further occasions during the morning and early
      afternoon, breath-alcohol tests were performed and samples of urine
      were collected for analysis of ethanol and methanol and the
      5-hydroxytryptophol (5-HTOL) to 5-hydroxyindol-3-ylacetic acid
      (5-HIAA) ratio.

      The participants were also asked to quantify the intensity of hangover
      symptoms (headache, nausea, anxiety, drowsiness, fatigue, muscle aches,
      vertigo) on a scale from 0 (no symptoms) to 5 (severe symptoms).

      The first morning urine void collected 6-11 h after bedtime as a rule
      contained measurable amounts of ethanol, being 0.09 ±<br/><br/>(Message over 64 KB, truncated)
    Your message has been successfully submitted and would be delivered to recipients shortly.