Methanol is known to be a demyelinating toxin in humans, producing symptoms markedly similar to those in multiple sclerosis

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METHYL ALCOHOL INGESTION AS A MODEL ETIOLOGIC AGENT INMULTIPLE SCLEROSIS.W. Monte, D. Glanzman, and C. Johnston(SPON: S. Hoffman).Arizona State University, Tempe, AZ 85287Human catalase, unlike that of all other species, does notmetabolize methyl alcohol (methanol).This unfortunate evolutionary deficiency makes_methanol aonly to humans.Methanol is known to be a demyelinating toxin in humans, producingsymptoms markedly similar to those in multiple sclerosis,including bizarre and inconsistent visual field disruptions.Human alcohol dehydrogenase metabolizes methanol directly toformaldehyde, which actively cross-links native proteins in-situ.Such formaldehyde-modified proteins have been shown to inducemacrophage scavenging at a rate 100 times that of unmodified protein.What better method to elicit an autoimmune response than to reactendogenous proteins with formaldehyde

consistently and intermittentlyover a long period of time?In our model, the neurotoxic effect of orally-administered methanol wasvisualized in the rat central nervous system using reduced silverdegeneration staining techniques.Following chronic administration for 18-33 days, all experimentalanimals demonstrated massive cellular, axonal and terminal degenerationin numerous regions of brain, including cerebellum, hippocampus,brainstem nuclei, internal capsule and optic chiasm.These results show for the first time that by using sufficientlysensitive histological techniques, the neurotoxicity of methanol isrevealed in the mammalian central nervous system.MEMBER'S AFFILIATION (Check one only): jq APS q ASBMB q ASPET q AAP q AIN Ifd'AA) q ASCB q BMES q SEBM q ISBSubmission of signed form indicates acceptance of rules including finalwithdrawal data of December 27, 1989.No exception will be

made.Steven A. Hoffman Member's NameMember's Signature602-965-7024 Member's PhoneDietary Methanol as a Cause of Multiple SclerosisHuman Catalase, unlike that of all other species, cannot detoxifymethanol.This unfortunate evolutionary deficiency makes methanola "poison" only to humans, contradicting Richardson's Rulewhich successfully predicts ethanol as consistently more toxicthan 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 tothe symptoms of Multiple Sclerosis.Even to the bizarre nature and inconsistency of the visual fielddisruptions, thought to be the toxicological marker that sets methanolpoisoning apart from all other intoxications.Human alcohol dehydrogenase metabolizes methanol directly toFormaldehyde.Location of Alcohol dehydrogenase activity in the

human brain, thoughindividually variable, is generally consistent with MS Plaque distribution.The Liver also has ADH activity with concomitant high aldehydedehydrogenase activity.Aldehyde dehydrogenase facilitates detoxification of Formaldehyde via1-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 immuneresponse and is, in fact, the requisite proprietary mechanism normallyutilized by pharmaceutical companies in the preparation of virusproteins for vaccine production.Recently sites on macrophages specific to "Formaldehyde ModifiedProtein" have been elucidated.Protein modified by formaldehyde are scavenged by macrophages at a rate100 times that of unmodified protein.What better method to elicit an auto-immune response than to

reactendogenous proteins with Formaldehyde consistently and intermittentlyover a long period of time.Although differences in distribution and density of alcoholdehydrogenase sites in the brain may account for the great individualvariability in symptoms and severity of MS and methanol poisoning, it ismore likely that variability of ethanol levels in the blood may be aneven more important factor.Alcohol Dehydrogenase(ADH) metabolizes ethanol preferentially toMethanol by a ratio greater than 9.For this reason ethanol is the only known antidote to methanolpoisoning, its ingestion prevents the conversion to formaldehyde andallows methanol to be removed by the kidneys and the lungs.There is some indication that endogenous ethanol produced by gutfermentation, can be found in the human bloodstream.Sobriety testing indicates that there is great variability in theseresidual levels of ethanol, perhaps

due to the variation of thepopulation of gut flora.page 1Small amounts of methanol are produced as a result of gut fermentation.There are sources of dietary methanol that are substantial enough tocause concern.Canned fruits and vegetables have been exposed to enough heat toliberate methanol from the pectin in the plant cell walls.This methanol would normally not be available to the digestive processof humans.Certain alcoholic beverages are so high in methanol as to not beexportable to the United States.It is worth noting that countries in which they are produced have thehighest, per capita incidence of MS.Although MS occurrence in populations varies with geographical andclimatological consistency, a very believable case can be made fordirect correlation to preformed dietary methanol.page 2METHANOL INDUCED NEUROPATHOLOGYIN THE MAMMALIAN CENTRAL NERVOUS

SYSTEMWoodrow C. Monte Ph.DRenee Ann ZeisingDepartment of Family Resources and Human DevelopmentArizona State University, Tempe, AZ 85287 (U.S.A.)Key words: Methanol--Degeneration--Axon--Rat--Brain--Central Nervous System--NeuropathologyPlease address correspondence to:Woodrow C. MonteDepartment of Family Resources and Human DevelopmentArizona State University, Tempe, Az. 85287SUMMARYThe neurotoxic effect of methyl alcohol (methanol) was visualized in therat central nervous system using reduced silver staining techniques.Following chronic administration of methanol (intubation with 0.95 gm/kgfor 18, 25 or 33 days) all experimental animals showed massive axonaldegeneration in multiple regions of brain, regardless of the duration ofexposure.Histological processing yielded degeneration by-products of fibers withcells 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 opticchiasm.These results show that by using sufficiently sensitiveneurohistological techniques, the neurotoxicity of methyl alcohol isrevealed in the vertebrate central nervous system.INTRODUCTIONMethanol has been widely suggested as a neurotoxin in humans (9, 7),yet the demonstration of such purported toxicity has been difficult toachieve with consistency."Surprisingly low levels" of methanol (14) are known to cause variousand nonspecific neurological complaints, including headache, vertigo,chills, gastric pain, insomnia (23), tinnitus (4), shooting pains inthe lower extremities, and a form of multiple neuritis characterized byparesthesia,

numbness, prickling and shooting pain in the back of thehands and forearms as well as edema of the arms.Bilateral blindness, nystagmus (20, 10), bladder paresis (7) andpermanent motor dysfunction (9) are long term neurotoxic sequelaefollowing acute poisonings (18).The most characteristic signs and symptoms of chronic methyl alcoholexposure in humans are diverse visual disturbances with progressivecontraction 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 unilateraland bilateral disturbances, have appeared in the clinical literature(20, 25).Methanol is generally considered to be a cumulative toxin, both dueto its unusually long half life (estimated to be over thirty five hoursin humans;(2),and to the progressive damage reported in test animals

chronicallyexposed to methanol in early studies (10).Methanol poisoning of humans is the only known exception to"Richardsons' Rule," by which the toxicity of alcohols increasesdirectly with the length of the carbon chain (18).Unfortunately, little is yet known of the mechanism by which methanolexerts 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, withlethality 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 generallyconsidered lethal (3). {{See footnote 1}}Several early studies of chronic methanol exposure have reported,although with

little substantiation, the occurrence of extensiveperipheral "nerve damage" (12, 21) and "destruction of the parenchyma[sic] cells of the cerebrum" (6) with long term inhalation of methanolboth in monkeys and in dogs.Both the ingestion and the inhalation of methanol have been reported toinduce behavioral abnormalities (11) and gross neurological teratologyin rat pups whose dams had been exposed to methanol during gestation (15).Similarly, rabbits acutely exposed to methanol showed "thinning andfocal loss" of myelin, though the nature and extent of the damage wasnot fully described (20).Heretofore laboratory animals have not been considered as appropriatemodel systems for the study of methanol toxicity in humans, due to theincreased methanol tolerance among all lower species thus far examined(19).The present experiments addressed the question of whether an adequatedose and treatment regimen could

provide a reliable animal model ofmethanol neurotoxicity.METHODEight adult male and female Long Evans derived rats weighing between200-250 grams were intubated once a day with 20 percent (v/v) spectralgrade methanol (Sigma Chemical Company, M3641) in glass distilled watersufficient to provide 0.95 g/kg body weight (10 percent of the MLD).Six control animals received intubation with an equivalent volume ofglass distilled water.Animals were randomly selected for histological examination on day 18,25 or 33 of treatment.For histology, animals were deeply anesthetized with sodiumpentobarbital (100 mg/kg), and perfused transcardially with normalsaline followed by 4% paraformaldehyde, pH adjusted to 7.4.Brains were removed from the calvaria and postfixed in the perfusate for7-48 days awaiting further analysis.On the day before sectioning brains were transferred to 10% sucrose

tofacilitate sectioning.Frozen sections were cut at 40 microns and processed for degeneratingneuronal byproducts using the reduced silver method of Giolli and Pope (8).Sections were then mounted on gelatin coated slides, counter stainedwith thionin, cleared and cover slipped.Tissue was analyzed and regions of degenerating neuronal byproducts werephotographed using conventional bright field light microscopic techniques.RESULTSAnalyses of degenerating neuronal tissue were performed by threeinvestigators.All experimental animals showed massive axonal degeneration in numerousand widely distributed regions.Microscopic analyses indicated degeneration of fibers whose cells oforigin lay in cerebellar cortex, deep cerebellar nuclei, several cranialnerve nuclei and in the red nucleus.Of particular interest was the surprising absence of neuronal cell bodyinvolvement:All observable

damage was restricted to axons and axon terminals.All experimental animals showed massive degeneration throughout themedullary layer of the cerebellum.The spinocerebellar tracts were so heavily stained with degenerationbyproducts as to preclude tracing the course of individual fibers.The corticospinal tract, rubrospinal tract, the trapezoid body, thetrigeminal nerve, trigeminal nucleus and particularly the NTST nerve)were virtually filled with degenerating fibers.Exceptionally heavy degeneration was observed in the flocculus and inthe 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 theinternal

capsule.The hippocampus exhibited degeneration scattered throughout regions CA 1thru CA 4, with some involvement of the dentate leaf.The locus and extent of the axonal damage was independent of theduration of methanol exposure and of the sex of the experimental animals.The thalamus, hypothalamus, cingulate cortex, substantia nigra and thereticular formation showed no signs of degeneration in any animal.DISCUSSIONOur present findings indicate that chronic high doses of methanol arecapable of inducing severe axonal damage in many brain loci of the rat.There are surprisingly few published reports of the effect of long termmethanol exposure in any species, due, in part, to the relatively highresistance to methanol found in virtually all lower animals.Many of the symptoms of acute and chronic methanol toxicity in humansare indicative of neurological damage (perhaps via

demyelination).There is virtually no literature addressing the long term exposure ofhumans to this ever-increasing environmental contaminant (16) and foodtoxicant (13) which has a particularly high, and as yet unexplained,potency toward man.It is highly unlikely that this neurological damage is caused by thedirect effect of methanol itself, but rather by one or more of itsmetabolic products.Both formaldehyde and formic acid are far more potent neurotoxins.LITERATURE CITED[ The abstracts and texts of all 190 references are given in pdf format http://www.thetruthaboutstuff.com/articles.shtmlMany 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 theNote Pad, and then left click on an

email and use Ctr V to pastethe 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 anOutbreak 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 thePulvinar 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 Absorptionand 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 InhalationLevels 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 andExperimental 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 actupon evidence about healthy and safe food, drink, and environment."Rich Murray, MA Room For All rmforall505-501-2298 1943 Otowi Road, Santa Fe, New Mexico 87505http://RMForAll.blogspot.com new primary archiveaspartameNM/messagesgroup with 116 members, 1,499 posts in a public archivedetails on 6 epidemiological studies since 2004 on diet soda (mainlyaspartame) correlations, as well as 14 other mainstream studies

onaspartame toxicity since summer 2005: Murray 2007.11.27http://rmforall.blogspot.com/2007_11_01_archive.htmWednesday, November 14, 2007aspartameNM/message/1490aspartameNM/message/1438Coca-Cola and Cargill Inc., after years of development,with 24 patents, will soon sell rebiana (stevia)in drinks and foods: Murray 2007.05.31aspartameNMmessage/1488Coca-Cola, Cargill Inc., PureCircle global operations market steviafor foods and drinks: Murray 2007.11.12aspartameNM/message/1453Souring on fake sugar (aspartame), Jennifer Couzin,Science 2007.07.06: 4 page letter to FDA from 12 eminentUSA toxicologists re two Ramazzini Foundationcancer studies 2007.06.25: Murray 2007.07.18aspartameNMmessage/1451Artificial sweeteners (aspartame, sucralose) and

coloringagents will be banned from use in newly-born and baby foods,the European Parliament decided: Latvia ban in schools 2006:Murray 2007.07.12aspartameNM/message/1487Sainsbury's supermarket chain in UK details its bans of aspartame,sodium benzoate, and artificial flavourings and colours: Carol Key,Customer Manager: Murray 2007.11.09aspartameNM/message/1427more from The Independent, UK, Martin Hickman, re ASDA(unit of Wal-Mart Stores) and Marks & Spencer ban ofaspartame, MSG, artificial chemical additives and dyesto prevent ADHD in kids: Murray 2007.05.16http://news.independent.co.uk/uk/health_medical/article2548747.eceaspartameNM/message/1426ASDA (unit of Wal-Mart Stores WMT.N) and Marks & Spencerwill join Tesco and also Sainsbury to ban and limitaspartame, MSG, artificial flavors dyes

preservatives additives,trans fats, salt "nasties" to protect kids from ADHD:leading UK media: Murray 2007.05.15http://en.wikipedia.org/wiki/Aspartame_controversyhttp://en.citizendium.org/wiki/Aspartame//////////////////////////////////////////////////////////////////////folic acid prevents neurotoxicity from formic acid, made by body frommethanol impurity in alcohol drinks [ also 11 % of aspartame ], BMKapur, PL Carlen, DC Lehotay, AC Vandenbroucke, Y Adamchik, U. ofToronto, 2007 Dec., Alcoholism Cl. Exp. Res.: Murray 2007.11.27http://rmforall.blogspot.com/2007_11_01_archive.htmWednesday, November 27, 2007aspartameNM/message/1495[ See also:http://rmforall.blogspot.com/2007_11_01_archive.htmWednesday, November 28, 2007aspartameNM/message/1496explosion in numbers of children with serious food allergies hasbewildered experts

and parents, Helen Francombe, The Australian2007.11.17: role of formic acid from methanol in liquors andaspartame: Murray 2007.11.28 ]http://www.faslink.org/Formic%20Acid%20Kapur.htmBrief Summary:Methanol in small amounts is present along with ethanol in beveragealcohol. [Murray: and about the same amounts from aspartame dietsodas]The body's natural enzymes preferentially metabolize ethanol whilemethanol breaks down into highly neurotoxic Formic Acid.Use of high levels of Folic Acid was found to inhibit brain damagecaused by the methanol.The use of Folic Acid during pregnancy has been recommended forseveral years to prevent neural tube defects.However, this study indicates that even higher levels of Folic Acidcan be very beneficial to the developing baby, particularly wherealcohol 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 beveragealcohol to help mitigate damage caused to both infants and adults.Formic Acid in the Drinking patient and the expectant motherDr. Bhushan M. KapurDepartments of Laboratory Medicine,St. Michael's Hospital , Toronto, Ontario, CanadaAbstractMethanol is produced endogenously in the pituitary glands of humansand is present as a congener in almost all alcoholic beverages.Ethanol and methanol are both bio-transformed by alcoholdehydrogenase; however, ethanol has greater affinity for the enzyme.Since ethanol is preferentially metabolized by the enzyme, it is notsurprising that trace amounts of methanol, most likely originatingfrom both sources, have been reported in the blood of people who drinkalcohol.Toxicity resulting from methanol is very well documented in bothhumans 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 populationshould 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 impairhuman visual functions.Formic acid is known to be toxic to the optic nerve.Ophthalmological abnormalities are a common finding in childrenwhose mothers used alcohol during pregnancy.Formic acid, a low molecular weight substance, either crosses theplacenta or may be formed in-situ from the water soluble methanolthat crosses the placenta.Embryo toxicity from formic acid has been reported in an animal model.To assess neurotoxicity we

applied low doses of formic acidto 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, theelimination of formic acid is slower and formate levels are elevated.When folic acid was added along with the formic acid to the brainslice cultures, neuronal death was prevented.Therefore, folate deficient chronic drinkers may be at higher riskof organ damage.Women who are folic acid deficient and consume alcohol may havehigher 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 itsrelationship to folic acid in men or women who drink alcohol hasnever been studied.Our hypothesis is that the continuous exposure to low levels offormic

acid is toxic to the fetus and may be part of the etiology ofFetal Alcohol Spectrum Disorders.http://www.blackwell-synergy.com/doi/abs/10.1111/j.1530-0277.2007.00541.xAlcoholism: Clinical and Experimental ResearchVolume 31 Issue 12 Page 2114-2120, December 2007Bhushan M. Kapur, b.kapur,Arthur C. Vandenbroucke, PhD, FCACBYana 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 AcidAlcoholism: Clinical and Experimental Research 31 (12), 2114–2120.doi:10.1111/j.1530-0277.2007.00541.xthe Department of Clinical Pathology (BMK),Sunnybrook Health Science Centre, Division of Clinical Pharmacologyand 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 ClinicalPathology, Sunnybrook Health Science Centre, 2075 Bayview Ave,Toronto, Ontario, M4N 3M5, Canada; Fax: 416-813-7562; E-Mail:b.kapur,AbstractBackground: Methanol is endogenously formed in the brain and ispresent as a congener in most alcoholic beverages.Because ethanol is preferentially metabolized over methanol (MeOH) byalcohol dehydrogenase, it is not surprising that MeOH accumulates inthe alcohol-abusing population.This suggests that the alcohol-drinking population will

have higherlevels 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 chronicalcoholics, is neurotoxicand this toxicity can be mitigated by folic acid administration.Objective:To determine if FA levels are higher in the alcohol-drinkingpopulation and to assess its neurotoxicity in organotypic hippocampalrat brain slice cultures.Methods:Serum and CSF FA was measured in samples from both ethanol abusingand control patients, who presented to a hospital emergencydepartment.FA’s neurotoxicity and its reversibility by folic acid wereassessed using organotypic rat brain hippocampal slice culturesusing clinically relevant concentrations.Results: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 tothe rat brain slice cultures caused neuronal death as measured bypropidium iodide staining.When folic acid (1 ?mol/l) was added with the FA, neuronal death wasprevented.Conclusions:Formic acid may be a significant factor in the neurotoxicity ofethanol abuse.This neurotoxicity can be mitigated by folic acid administrationat a clinically relevant dose.http://www.uhnresearch.ca/researchers/profile.php?lookup=801Peter L Carlen, FRCPC, MDHead, Division of Fundamental NeurobiologyToronto Western Research Institute (TWRI)Senior Scientist, Division of Fundamental NeurobiologyToronto Western Research

Institute (TWRI)Keywords: stroke, gap junctions, synaptic transmission, mitochondria,calcium chelators, whole cell patch clamp recordings, fluorescenceimaging, epilepsy, dementia, fetal alcohol syndrome, brain stateclassificationResearch Interests:Mechanisms of neural synchrony and entrainment (epilepsy), andneurodegenerative processes* We have several projects on cellular mechanisms of epilepsy,particularly the synchronizing role of electrotonic coupling via gapjunctions.Molecular biological and cellular electrophysiological recordingtechniques are being used to measure the upregulation of gapjunctional function in several in vitro seizure models, includingthe 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 centralmammalian neurons in physiological and pathophysiological conditions(e.g., epilepsy) are being described by neural modelling techniques.We are developing nonlinear techniques for the identificationdifferent brain states including those associated with anesthesia andepilepsy.* In models of stroke and Alzheimer's disease, calcium homeostasisand free radical production are under investigation, focusing on therole of degenerating mitochondrial function in presynaptic terminals.Fluorescence and confocal microscopic imaging of intracellular calciumand mitochondrial function coupled with whole cell and fieldelectrophysiological recordings are being used.* In collaboration with Drs. Bhushan Kapur, James Reynolds andJames Brien, we are examining the role of formic acid in the causationof the brain damage in the fetal alcohol spectrum disorder and itsrescue by folate.Peter L

CarlenMailing AddressPrimary OfficeToronto Western Hospital, McLaughlin Pavilion, 12th Floor Rm. 413399 Bathurst St., Toronto, Ontario Canada M5T 2S8Email carlen,Phone Numbers 416.603.5800 x5044Staff and Trainees:Yana AdamchikMarija CoticYoussef El-HayekS Sabet JahromiEunji (Ellen) KangBorna KavousiPhilip LiangShanthi MylvaganamMarina SamoilovaEvan SheppyDamian ShimAlexandre TonkikhHui YeWilson YuZhang (Jane) Zhanghttp://www.clinpharmtox.utoronto.ca/Page60.aspxDr. Bhushan KapurSelected PublicationsKapur BM. Drug Testing Methods and Clinical Interpretation of TestResults. In: Carson-Dewitt R, ed. Encyclopedia of Drugs, Alcohol andAddictive 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 nicotinereplacement

therapy in pregnancy. Current Therapeutic Research 2001;62(4): 274-278.Bailey B, Lalkin A, Kapur B, Koren G. Is chronic poisoning withacetaminophen 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 breastfeeding: Calculation of time to reach zero-level in milk.Biol Neonate 2001; 80(3): 219-222. [Read More][ Dr. Gideon KorenDivision of Clinical Pharmacology and Toxicology, Hospital for SickChildren, 555 University Ave., Toronto, Ont. M5G 1X8 (Canada)Tel. +1 416 813 5781, Fax +1 416 813 7562E-Mail gkoren, pharmtox, ]Kapur B, Koren G. Folic acid fortification of flour: three yearslater.Can J Clin Pharmacol 2001; 8(2): 91-92. [Read More]Ahn E, Kapur B, Koren G. Iron bioavailability in prenatalmultivitamin supplements with separated and combined iron

andcalcium.J Obstet Gynaecol Can 2004; 26(9):809-14. [Read More]Railton CJ, Kapur B, Koren G. Subtherapeutic risperidone serumconcentrations 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 inmethadone 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.http://www.medicalnewstoday.com/articles/45698.phpQueen's-led Network

Looks At FAS Aiming To Minimize Life-longLearning ProblemsMain Category: Pregnancy / Obstetrics NewsArticle 24 Jun 2006 - 12:00 PDTFor the first time researchers are testing to see whether fetalexposure to methanol, a contaminant found in many alcoholic beverages,plays an important role in causing the life-long learning andbehavioural problems associated with Fetal Alcohol Spectrum Disorders(FASD).By understanding fetal brain injury caused by exposure to methanoland related toxins, an emerging team of researchers is laying thegroundwork for potential new therapeutic interventions to protectfetuses at risk for FASD."The main goal will always be prevention of FASD," says leadresearcher James Reynolds, Queen's University professor of Toxicologyand Pharmacology, "but we also have to develop strategies to minimizeinjury to the developing fetus and individualize earlier therapeuticinterventions

for children with pre-natal exposure to alcohol."The interdisciplinary research team, which also includesJames 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 fundingfrom the Canadian Institutes of Health Research.The Queen's researchers have found that simple eye movement taskscan be used to assess brain function in children with FASD. Since thistechnology is portable, the researchers plan to travel across thecountry to bring the research program into affected communities. "It'sestimated that the incidence of FASD is about one per cent in thegeneral population," Dr. Reynolds says, "but there are regions andcommunities in this country where the population affected by FASDincreases dramatically."Using blood samples from at risk mother-baby

pairs, the Toronto teammembers hope to identify biological markers that may predict braininjury in the child. At risk babies will be tracked for 24 monthsfollowing birth so researchers can identify early signs of FASD anddevelop aggressive therapeutic interventions at earlier stages tominimize the effects on a child's development.To understand the underlying mechanisms of this novel hypothesis ofFASD, the Toronto team members are studying the effects of formic acidand folic acid on the biological functions and survival of neurons inisolated brain tissue. In parallel studies, the Kingston team willassess the efficacy of folic acid supplementation as a potentialtherapeutic intervention in preventing FASD.For these researchers, an exciting opportunity has been created bylinking this study with Queen's University's state-of-the-art MagneticResonance Imaging (MRI) facility. New experimental procedures

beingdeveloped at Queen's will link eye movement tasks to MRI images of thebrain, creating an objective and much more specific way to evaluatebrain function. By isolating individual brain responses, FASDresearchers hope to gain greater insight into the underlying braininjury caused by prenatal exposure to alcohol, leading to morespecific intervention therapies designed to minimize the affects of FASD."Not all children exposed to alcohol during prenatal life developFASD," adds Dr. Reynolds. "There are other contributing factorsincluding genetic predisposition and nutrition during gestation thatmake important contributions to the ultimate outcome. We need a wayto identify the different sub-groups within the FASD spectrum. Thisresearch will help us develop the standardized tools we need toevaluate and treat children with FASD."----------------------------Article adapted by Medical News Today from original

press release.----------------------------Contacts:Lorinda Peterson, 613-533-3234, lorinda.peterson,Nancy Dorrance, 613-533-2869, dorrance,Contact: Lorinda Petersonname: James N Reynoldsemail: jnr,phone: 613 533 6946campus_extension: 36946department: Pharmacology and Toxicologytype: Facultyname: James F Brienemail: brienj,phone: 613 533 6114campus_extension: 36114department: Pharmacology and Toxicology, School of Medicine,Psychiatrytype: FacultyDr. Douglas P. Munoz doug,Canada Research Chair in NeuroscienceDirector, Centre for Neuroscience StudiesProfessor of Physiology and PsychologyMember, CIHR Group in Sensory-Motor SystemsQueen's University, Kingston, Ontario, Canada K7L 3N6Phone: (613) 533-2111 Fax: (613) 533-6840Dr. Brenda Stade St. Michael’s HospitalFetal Alcohol Spectrum

Disorder Diagnostic Clinic61 Queen Street Toronto, Ontario M5B 1W8Tel: (416) 867- 3655 stadeb,http://www.faslink.org/toc2.htmFASlink2448 Hamilton Road, Bright's Grove, Ontario, Canada N0N 1C0Phone: (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 disorderscaused when a pregnant woman consumes alcoholFASlink CD -- more than 170 MB of information.While "officially" FASD is not a diagnosis but describes the broadrange of disorders caused by prenatal alcohol exposure, the realityis that FASD IS the diagnosis and the other terms are sub-diagnosesdescribing the specific

effects on a specific patient."St. Michael's Hospital, Fetal Alcohol Spectrum Disorder Clinic ispleased to support the work of FASlink.St. Michael's FASD Clinic views FASlink as an essential service forour clients.We are fortunate to partner with FASlink in our attempt to improvethe lives of individuals and their families with FASD.Dr. Brenda Stade, St. Michael's FASD Clinic" St. Michael's Hospitalis a teaching hospital affiliated with The University of Toronto.FASD OverviewInvisible Disabilities -- An individual’s place, and success, insociety is almost entirely determined by neurological functioning.A child with a brain injury is unable to meet the expectations ofparents, family, peers, school, career and can endure a lifetime offailures.The largest cause of brain injury in children is prenatal exposure toalcohol.Often the neurological damage goes undiagnosed, but not unpunished.There

are strategies that can work to help the child with an FASDcompensate for some difficulties.Early diagnosis and intensive intervention and tutoring can dowonders, but the need for a supportive structure is permanent.Report on FASD -- Exposure Rates, Results of Prenatal Exposure toAlcohol, and Incidence Markers -- Bruce Ritchie - February 2, 2007(PDF download 1.2 MB)37% of babies have been exposed to multiple episodes of bingedrinking (5+ drinks per session) during pregnancy.An additional 42% have been multiply exposed to 1 to 4 drinks persession during pregnancy.Prenatal alcohol exposure has been linked to more than 60 diseaseconditions, birth defects and disabilities.Damage is a diverse continuum from mild intellectual and behaviouralissues to profound disabilities or premature death.Prenatal alcohol damage varies due to volume ingested, timing duringpregnancy, peak blood alcohol

levels, genetics and environmental factors.For example, ethanol was found to interact with over 1000 genes andcell events, including cell signalling, transport and proliferation.Serotonin suppression causes loss of neurons and glia, inducingexcessive cell death during normal programmed death (apoptosis) ortriggering apoptosis at inappropriate times leading to smaller orabnormal brain structures with fewer connections between brain cells,leading to fewer cells for dopamine production, leading to problemswith addiction, memory, attention and problem solving, and morepronounced conditions such as schizophrenia.Approximately 20% of Canadian school age children are receivingspecial education services, most for conditions of the typesknown to be caused by prenatal alcohol exposure.As FASD is a diverse continuum, issues range fromalmost imperceptible to profound.It is somewhere in the middle that the

issues attract the attentionof parents, educators, medical and social work professionals, andeventually the justice system.Most of the issues that attract sufficient attention are behaviouraland performance issues.It is probable that about 15% of children are significantly enoughaffected by prenatal alcohol exposure to require special education.As they become adults, FASD does not disappear but the issues ofyouth translate into ongoing problems in family relationships,employment, mental health and justice conflicts.The cost to the individuals affected, their families and society areenormous 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 isadversely related to child behavior.The effect was observed at average exposure levelsas low as

1 drink per week.FASD PreventionFolic acid should be added to all beverage alcohol.Break the cycle. Properly fund addiction intervention andrehabilitationprograms.Identify women at risk of having children with FASD and intervene.Meconium testing for Fatty Acid Ethyl Esters should be mandatory forevery birth.Intensive family and social service supports for FASD and recoveringalcoholics.Poverty is a result of, and breeds, substance abuse. Deal with it.Alcohol VendorsThe beverage alcohol industry pays less than 1% of the total damagescaused by their products. Increase taxes on beverage alcohol.All tax revenue to be returned to support rehabilitation programs andvictims 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

advertisingAlcohol must be served with food.Breathalyzers in all alcohol establishmentsBan alcohol sales incentives, contests, games.Ban "Happy Hour" discounted promotions. They encourage binge drinking.Public EducationEducate 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 alcoholis to make your brain take a hike.ResearchBetter 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 relateddocuments and serves more than 400,000 visitors annually.The FASlink Discussion Forum shares 50 to 100 letters dailyand

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.http://www.faslink.org/faslink.htmThe FASlink Discussion Forum is a free Internet maillist forindividuals, families and professionals who deal with Fetal AlcoholSpectrum 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 tohttp://listserv.rivernet.net/mailman/listinfo/fas-linkOnce you have d, to send mail to the FASlink members,send it to: fas-linkinfo 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 aspartameis quickly turned into formaldehyde.An expert review by a competent, unbiased team,led by M. Bouchard, 2001, with references, many from aspartameindustry funded studies, states that about 30 - 40 % of the methanolremains in the body as unknown, durable reaction products.J. Nutrition 1973 Oct; 103(10): 1454-1459. Metabolism of aspartame inmonkeys. Oppermann JA, Muldoon E, Ranney RE. Dept. of Biochemistry,Searle Laboratories, Division of G.D. Searle and Co.Box 5110, Chicago, IL 60680They found that about 70 % of the radioactive methanol in

aspartameput into the stomachs of 3 to 7 kg monkeys was eliminated within 8hours, with little additional elimination,as carbon dioxide in exhaled air and as water in the urineThey did not report any studies on the distribution of radioactivityin body tissues, except that blood plasma proteins after 4 daysheld 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 2,000mg/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 hadleveled off at 67.1 +-2.1 % as CO2 in the exhaled airand 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 bodyconstituents through the one-carbon metabolic pool.""All radioactivity measurements were counted to +-1 % accuracy..."The abstract ends, "It was concluded that aspartame was digestedto its three constituents that were then absorbed as naturalconstituents of the diet."http://health.aspartameNM/message/1143http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169"Exposure to methanol also results from the consumption of certainfoodstuffs (fruits, fruit juices, certain vegetables, aspartamesweetener, roasted coffee, honey) and alcoholic beverages (HealthEffects Institute, 1987; Jacobsen et al., 1988).""Experimental studies on the detailed time profiles followingcontrolled repeated exposures to methanol are lacking.""Thus, in monkeys and

plausibly humans, a much larger fraction ofbody formaldehyde is rapidly converted to unobserved forms ratherthan passed on to formate and eventually CO2.""However, the volume of distribution of formate was larger thanthat of methanol, which strongly suggests that formate distributesin body constituents other than water, such as proteins."aspartameNM/message/1143methanol (formaldehyde, formic acid) disposition: Bouchard M et al,full plain text, 2001: substantial sources are degradation of fruitpectins, liquors, aspartame, smoke: Murray 2005.04.02http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169Toxicological Sciences 64, 169-184 (2001) 2001 by theSociety of Toxicology BIOTRANSFORMATION AND TOXICOKINETICA Biologically Based Dynamic Model for Predicting the Dispositionof Methanol and Its Metabolites in Animals and HumansMichèle Bouchard *, ^,1,

bouchmic,Robert C. Brunet, ^^ brunet,Pierre-Olivier Droz, ^and Gaétan Carrier * gaetan.carrier,* Department of Environmental and Occupational Health, Faculty ofMedicine,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 deRecherches Mathématiques, Faculté des arts et des sciences,Université de Montréal, P.O. Box 6128, Main Station, Montréal,Québec, Canada, H3C 3J71 To whom correspondence should be addressed at Département de santéenvironnementale 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 theproduction and accumulation of formic acid, which causes metabolicacidosis and visual impairment that can lead to blindness and deathat 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 welldocumented, little is known about the chronic effects of low exposuredoses, which are of interest in view of the potential use of methanolas an engine fuel and current use as a solvent and chemical intermediate.Gestational exposure studies in pregnant rodents (mice and rats) havealso shown that high methanol inhalation exposures5000 or 10,000 ppm and more, 7 h/day during days 6 or 7 to 15 ofgestation) can induce birth defects (Bolon et al., 1993; IPCS, 1997;Nelson et al., 1985).""The corresponding average elimination half-life of absorbedmethanol through

metabolism to formaldehyde was estimated to be1.3, 0.7-3.2, and 1.7 h.""Inversely, in monkeys and in humans,a larger fraction of body burden of formaldehydeis 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 eliminatedmainly by metabolism (70 to 97% of absorbed dose) and only a smallfraction is eliminated as unchanged methanol in urine and in theexpired air (< 3-4%) (Dorman et al., 1994; Horton et al., 1992).Systemic methanol is extensively metabolized by liver alcoholdehydrogenase and catalase-peroxidase enzymes to formaldehyde,which is in turn rapidly oxidized to formic acid by formaldehydedehydrogenase enzymes (Goodman and Tephly, 1968; Heck et al., 1983;Røe, 1982; Tephly and McMartin, 1984).Under

physiological conditions, formic acid dissociates to formateand hydrogen ions.Current evidence indicates that, in rodents, methanol is convertedmainly by the catalase-peroxidase system whereas monkeys and humansmetabolize methanol mainly through the alcohol dehydrogenase system(Goodman and Tephly, 1968; Tephly and McMartin, 1984).Formaldehyde, as it is highly reactive, forms relatively stableadducts with cellular constituents (Heck et al., 1983; Røe, 1982).""The whole body loads of methanol, formaldehyde, formate, andunobserved 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 notdeemed necessary.""According to model predictions, congruent with the data in theliterature (Dorman et al., 1994; Horton et al., 1992), a certainfraction of formaldehyde is readily oxidized

to formate, a majorfraction 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 ofHorton et al. (1992) and Dorman et al. (1994) show that,once formed, a substantial fraction of formaldehyde is converted tounobserved 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 endogenousmolecules (Heck et al., 1983; Røe, 1982) or is incorporated in thetetrahydrofolic-acid-dependent one-carbon pathway to become thebuilding block of a number of synthetic pathways(Røe, 1982; Tephly and McMartin, 1984).That substantial amounts of methanol metabolites or by-products areretained for a long time is verified by Horton et al. (1992) whoestimated that 18 h

following an iv injection of 100 mg/kg of14C-methanol in male Fischer-344 rats, only 57% of the dose waseliminated 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-hinhalation exposure to 900 ppm of 14C-methanol vapors in femalecynomolgus monkeys, only 23 % of the absorbed 14C-methanol waseliminated from the body.These findings are corroborated by the data of Heck et al. (1983)showing that 40 % of a 14C-formaldehyde inhalation dose remainedin the body 70 h postexposure.In the present study, the model proposed rests on acute exposuredata, where the time profiles of methanol and its metabolites weredetermined only over short time periods (a maximum of 6 h ofexposure and a maximum of 48 h postexposure).This does not allow observation of the slow releasefrom the long-term components.It is to be

noted that most of the published studies on the detaileddisposition kinetics of methanol regard controlled short-term (ivinjection or continuous inhalation exposure over a few hours) methanolexposures 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 followingcontrolled repeated exposures to methanol are lacking.""Thus, in monkeys and plausibly humans, a much larger fraction ofbody formaldehyde is rapidly converted to unobserved forms ratherthan passed on to formate and eventually CO2.""However, the volume of distribution of formate was larger than thatof methanol, which strongly suggests that

formate distributes in bodyconstituents other than water, such as proteins.The closeness of our simulations to the available experimental dataon the time course of formate blood concentrations is consistentwith the volume of distribution concept (i.e., rapid exchangesbetween the nonblood pool of formate and blood formate).""Also, background concentrations of formate are subject to wideinterindividual variations (Baumann and Angerer, 1979; D'Alessandroet al., 1994; Franzblau et al., 1995; Heinrich and Angerer, 1982;Lee et al., 1992; Osterloh et al., 1996; Sedivec et al., 1981)."aspartameNM/message/1286methanol products (formaldehyde and formic acid) are main cause ofalcohol hangover symptoms [same as from similar amounts of methanol,the 11% part of aspartame]: YS Woo et al, 2005 Dec: Murray 2006.01.20Addict Biol. 2005 Dec;10(4): 351-5.Concentration changes of

methanol in blood samples during anexperimentally 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 mentalsymptoms that occur between 8 and 16 hours after drinking alcohol.After inducing experimental hangover in normal individuals, wemeasured the methanol concentration prior to and after alcoholconsumption and we assessed the association between the hangovercondition 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 medicaldisorders.The blood ethanol concentration prior to the alcohol intake(2.26+/-2.08) was not significantly different from that 13 hoursafter the alcohol consumption

(3.12+/-2.38).However, the difference of methanol concentration between the dayof 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 litercaused hangover symptoms.The human body has about 5.6 liters blood, so adding 1.3 mg per litergives 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 roughlysimilar symptoms in South Koreans, Woo YS, 2005, as in men in Swedenwho had a 6-fold increase in urine methanol, confirms many studiesthat show that specific genetic differences make Asians and AmericanIndians

much more vulnerable to inebriation, hangover, and addictionthan Europeans. Bendtsen P, Jones AW, Helander A. 1998 ]A significant positive correlation was observed between the changesof blood methanol concentration and hangover subjective scale scoreincrement 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 asits toxic metabolite to hangover. PMID: 16318957[ The "toxic metabolite" of methanol is formaldehyde, which in turnpartially becomes formic acid -- both potent cumulative toxinsthat are the actual cause of the toxicity of methanol.]Int J Neurosci. 2003 Apr; 113(4): 581-94. The effects of alcoholhangover 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 unpleasantphysical and mental symptoms that occur between 8 and 16 h afterdrinking alcohol.We evaluated the effects of experimentally-induced alcohol hangoveron 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 medicaldisorders.We defined the experimentally-induced hangover condition at 13 hafter drinking a high dose of alcohol (1.5 g/kg of body weight).We evaluated the changes of cognitive functions before drinkingalcohol and during experimentally-induced hangover state.The Luria-Nebraska Neuropsychological Battery was administratedin order to examine the changes of cognitive functions.Cognitive functions, such as visual, memory, and intellectual processfunctions, 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 scaleswere increased during the hangover state.These results indicate that alcohol hangovers have a negative effecton cognitive functions, particularly on the higher cortical and visualfunctions associated with the left hemisphere and right posteriorhemisphere. Publication Types: Clinical Trial PMID: 12856484Alcohol Alcohol. 1998 Jul-Aug; 33(4): 431-8. Urinary excretion ofmethanol and 5-hydroxytryptophol as biochemical markers of recentdrinking 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 either50 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 eveningover 2 h with a meal.After the end of drinking, at bedtime, in the following morning afterwaking-up, and on two further occasions during the morning and earlyafternoon, breath-alcohol tests were performed and samples of urinewere collected for analysis of ethanol and methanol and the5-hydroxytryptophol (5-HTOL) to 5-hydroxyindol-3-ylacetic acid(5-HIAA) ratio.The participants were also asked to quantify the intensity of hangoversymptoms (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 rulecontained measurable amounts of ethanol, being 0.09 ± 0.03 g/l(mean ± SD) after 50 g and 0.38 ± 0.1 g/l after 80 g ethanol.The corresponding breath-alcohol

concentrations were zero, except forthree individuals who registered 0.01-0.09g/l.Ethanol was not measurable in urine samples collected later in themorning and early afternoon.The peak urinary methanol occurred in the first morning void, whenthe mean concentration after 80 g ethanol was approximately 6-foldhigher than pre-drinking values.[ This is a much greater increase of methanol than the 50 % increasethat cause roughly similar symptoms in South Koreans, Woo YS, 2005,confirming many studies that show that specific genetic differencesmake Asians and American Indians much more vulnerable to inebriation,hangover, and addiction. ]This compares with a approximately 50-fold increase for the5-HTOL/5-HIAA ratio in the first morning void.Both methanol and the 5-HTOL/5-HIAA ratio remained elevated abovepre-drinking baseline values in the second and sometimes even thethird morning

voids.Most subjects experienced only mild hangover symptoms after drinking50 g ethanol (mean score 2.4 ± 2.6), but the scores weresignificantly higher after drinking 80 g (7.8 ± 7.1).The most common symptoms were headache, drowsiness, and fatigue.A highly significant correlation (r = 0.62-0.75, P <0.01) was foundbetween the presence of headache, nausea, and vertigo and the urinarymethanol concentration in the first and second morning voids, whereas5-HTOL/5-HIAA correlated with headache and nausea.These results show that analysing urinary methanol and 5-HTOLfurnishes a way to disclose recent drinking after alcohol has nolonger been measurable by conventional breath-alcohol tests for atleast 5-10 h.The results also support the notion that methanol may be an importantfactor in the aetiology of hangover. PMID:

9719404//////////////////////////////////////////////////////////////////////initiating aspartame article on Citizendium democratic professionalworld encyclopedia -- opportunities for all citizens and groups:Murray 2007.11.20aspartameNM/message/1492http://rmforall.blogspot.com/2007_11_01_archive.htmTuesday, November 20, 2007aspartameNM/message/1486labs now quickly at low cost measure 100 exhaled gases at 1 part pertrillion levels in a single breath to instantly reveal opportunitiesto study diseases and toxicities, possibly methanol and formaldehydefrom vehicle exhaust, wood and tobacco smoke, fruits and vegetables,dark wines and liquors, aspartame: Murray 2007.11.08aspartameNM/message/1340aspartame groups and books: updated research review of 2004.07.16:Murray 2006.05.11Donald Rumsfeld CEO 1977-85

G.D. Searle & Co., got new PresidentReagan to prohibit FDA opposition to aspartame 1981.01.25,history by lawyer James S. Turner: Murray 2007.10.29aspartameNM/message/1483what experts say about aspartame and Abby Cormack, New Zealand:Betty Martini 2007.08.13: Murray 2007.11.22http://rmforall.blogspot.com/2007_11_01_archive.htmThursday, November 22, 2007aspartameNM/message/1493aspartameNM/message/1141Nurses Health Study can quickly reveal the extent of aspartame(methanol, formaldehyde, formic acid) toxicity: Murray 2004.11.21The Nurses Health Study is a bonanza of information about the healthof probably hundreds of nurses who use 6 or more cans daily of dietsoft drinks -- they have also stored blood and tissue samplesfrom their immense pool of subjects, over 100,000 for decades.

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