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

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  • Rich Murray
    folic acid prevents neurotoxicity from formic acid, made by body from methanol impurity in alcohol drinks [ also 11 % of aspartame ], BM Bhushan, PL Carlen, DC
    Message 1 of 1 , Nov 27, 2007
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      folic acid prevents neurotoxicity from formic acid, made by body from
      methanol impurity in alcohol drinks [ also 11 % of aspartame ], BM
      Bhushan, PL Carlen, DC Lehotay, AC Vandenbroucke, Y Adamchik, U. of
      Toronto, 2007 Dec., Alcoholism Cl. Exp. Res.: Murray 2007.11.27
      http://rmforall.blogspot.com/2007_11_01_archive.htm
      Wednesday, November 27, 2007
      http://groups.yahoo.com/group/aspartameNM/message/1495


      http://www.faslink.org/Formic%20Acid%20Kapur.htm

      Brief Summary:

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

      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

      Abstract

      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 alcohol.

      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.


      http://www.blackwell-synergy.com/doi/abs/10.1111/j.1530-0277.2007.00541.x

      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.
      doi:10.1111/j.1530-0277.2007.00541.x

      From:
      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:
      k.kapur@...,

      Abstract

      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.

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

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

      FA’s neurotoxicity and its reversibility by folic acid were assessed
      using organotypic rat brain hippocampal slice cultures using 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 to the
      rat brain slice cultures caused neuronal death as measured by propidium
      iodide staining.

      When folic acid (1 micromol/l) was added with the FA, neuronal death was
      prevented.

      Conclusions:
      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.


      http://www.uhnresearch.ca/researchers/profile.php?lookup=801

      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
      classification

      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
      junctions.
      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 epilepsy.

      * 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 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

      http://www.clinpharmtox.utoronto.ca/Page60.aspx

      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, Fax +1 416 813 7562
      E-Mail gkoren@..., pharmtox@..., ]

      Kapur B, Koren G. Folic acid fortification of flour: three years later.
      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 calcium.
      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.


      http://www.medicalnewstoday.com/articles/45698.php

      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 (FASD).

      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.
      ----------------------------

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

      Contact: Lorinda Peterson

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

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


      http://www.faslink.org/toc2.htm

      FASlink
      2448 Hamilton Road, Bright's Grove, Ontario, Canada N0N 1C0
      Phone: (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
      failures.
      The largest cause of brain injury in children is prenatal exposure to
      alcohol.
      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 rehabilitation
      programs.

      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
      alcoholics.

      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.

      Research

      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.

      http://www.faslink.org/faslink.htm

      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
      http://listserv.rivernet.net/mailman/listinfo/fas-link

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

      info@... sends 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,
      cites 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."


      http://health.groups.yahoo.com/group/aspartameNM/message/1143

      http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169


      "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."

      http://groups.yahoo.com/group/aspartameNM/message/1143

      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
      http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169
      Toxicological Sciences 64, 169-184 (2001) Copyright © 2001 by the
      Society of Toxicology BIOTRANSFORMATION AND TOXICOKINETIC 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
      Medicine,

      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)."


      http://groups.yahoo.com/group/aspartameNM/message/1286

      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
      disorders.

      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 Swedem 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
      disorders.

      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 ± 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 for
      three individuals who registered 0.01-0.09g/l.

      Ethanol was not measurable in urine samples collected later in the
      morning and early afternoon.

      The peak urinary methanol occurred in the first morning void, when the
      mean concentration after 80 g ethanol was approximately 6-fold higher
      than pre-drinking values.

      [ This is a much greater increase of methanol than the 50 % increase
      that cause roughly similar symptoms in South Koreans, Woo YS, 2005,
      confirming many studies that show that specific genetic differences make
      Asians and American Indians much more vulnerable to inebriation,
      hangover, and addiction. ]

      This compares with a approximately 50-fold increase for the
      5-HTOL/5-HIAA ratio in the first morning void.

      Both methanol and the 5-HTOL/5-HIAA ratio remained elevated above
      pre-drinking baseline values in the second and sometimes even the third
      morning voids.

      Most subjects experienced only mild hangover symptoms after drinking 50
      g ethanol (mean score 2.4 ± 2.6), but the scores were significantly
      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 found
      between the presence of headache, nausea, and vertigo and the urinary
      methanol concentration in the first and second morning voids, whereas
      5-HTOL/5-HIAA correlated with headache and nausea.

      These results show that analysing urinary methanol and 5-HTOL furnishes
      a way to disclose recent drinking after alcohol has no longer been
      measurable by conventional breath-alcohol tests for at least 5-10 h.

      The results also support the notion that methanol may be an important
      factor in the aetiology of hangover. PMID: 9719404
      ////////////////////////////////////////////////////////////



      http://groups.yahoo.com/group/aspartameNM/message/1067
      eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV
      Belsito, Nov 2003: Murray 4.4.4 rmforall [ 150 KB ]

      [ Extracts ]

      McMartin, KE et al 1979, put 3,000 mg/kg methanol in the stomachs of
      small monkeys and, 18 hours later found accumulation of formate in
      liver, kidney, optic nerve, cerebrum, and midbrain in 2 of three monkeys.


      Biochemical Pharmcacology 1979: 28; 645-649.
      Lack of a role for formaldehyde in methanol poisoning in the monkey.
      Kenneth E. McMartin, Gladys Martin-Amat, Patricia E. Noker
      and Thomas R. Tephly
      The Toxicology Center, Dept. of Pharmacology,
      University of Iowa, Iowa City, Iowa 52242

      K.E. McMartin and T.R. Tephly, authors of many pro-aspartame studies, in
      Biochemical Pharmacology (1979) remarked, "It is now generally accepted
      that the toxicity of methanol is due to the formation of toxic
      metabolites, either formaldehyde or formic acid."

      They put damage doses of methanol into the stomachs of three monkeys,
      and, using insensitive tests, found no formaldehyde in many tissues --
      except for a single datum in the midbrain,
      1.5 times their detection limit.

      They did report widespread accumulation of formic acid in five tissues.

      The use of inadequate tests is common in industry research that is
      funded to claim the safety of profitable toxins.

      Since then, industry scientists have been very wary of doing studies on
      primates, which all too easily show the dangers to humans.

      "Abstract [ not given in PubMed ]: [ My briefer comments are in square
      brackets. ]

      Methanol was administered [ by nasogastric tube ] either to untreated
      cynomolgus monkeys [ 2-3.5 kg ] or to a folate-deficient cynomolgus
      monkey which exhibits exceptional sensitivity to the toxic effects of
      methanol.

      Marked formic acid accumulation in the blood and in body fluids and
      tissues was observed.

      No formaldehyde accumulation was observed in the blood and no
      formaldehyde was detected in the urine, cerebrospinal fluid, vitreous
      humor, liver, kidney, optic nerve, and brain in these monkeys at a time
      when marked metabolic acidosis and other characteristics of methanol
      poisoning were observed.

      Following intravenous infusion into the monkey, formaldehyde was rapidly
      eliminated from the blood with a half-life of about 1.5 min and formic
      acid levels promptly increased in the blood.

      Since formic acid accumulation accounted for the metabolic acidosis and
      since ocular toxicity essentially identical to that produced in methanol
      poisoning has been described after formate treatment, the predominant
      role of formic acid as the major metabolic agent for methanol toxicity
      is certified.

      Also, results suggest that formaldehyde is not a major factor in the
      toxic syndrome produced by methanol in the monkey."

      "It is now generally accepted that the toxicity of methanol is due to
      the formation of toxic metabolites (1,2), either formaldehyde or formic
      acid."


      So, this is an acute toxicity study, with little relevance for chronic
      long-term, low-level exposure.

      Monkeys, like people, are susceptible to methanol toxicity.

      This team cites their six previous methanol in monkey studies,
      from 1975 to 1977.

      The report is difficult to understand, since the three monkeys were
      treated differently, and different assays were used.

      For the methanol sensitive, folate-deficient monkey A, the assay used
      was the chromatropic acid method, with a detection limit of .025 mmol/L.

      None of the five tissues showed any formaldehyde with this assay, except
      the midbrain, 0.14 mmol/kg wet weight tissue [ units converted from
      their 0.14 micromole/gm -- just 1.5 times the detection limit of .09
      mmol/kg wet tissue weight (given on p. 648).
      [ Since 1 kg of water is 1 L, 1 mmol/kg is equivalent to 1 mmol/L. ]

      Meanwhile, in the methanol sensitive, folate-deficient monkey A, the
      blood formate level rose by 18 hours from 0.18 to 10.02 mEq/L. [ I
      assume that a mEq is equivalent to a mmol -- let me know if I'm wrong. ]

      The formate detection limits for the assays were not given in this report.

      The formate level in the vitreous humor of the eye of monkey A was 7.90
      mEq/L.

      It is well known that formate is extremely damaging to the eye.

      For unexplained reasons, formate levels in the five tissues and
      cerebrospinal fluid were not measured in the methanol sensitive,
      folate-deficient monkey A., in the cerebrospinal fluid of monkey B,
      or in the optic nerve of monkey C.

      Formaldehyde was not measured in the optic nerve of Monkey A.

      The kidney formate level for monkey B was 6.33 and for C was only 0.44,
      with no comment or explanation given.

      The experiment seems arbitrary, capricious, and erratic.

      For monkey A, after 18 hours, the urine formaldehyde level was below
      detection level, while urine formate was 115.80 mEq/L -- so much of the
      formaldehyde had been converted into formic acid, another cumulative,
      potent toxin.

      "In the presence of high formate values and definitive evidence of
      toxicity in methanol-poisoned monkeys, no measurable formaldehyde was
      found in the body tissues that were tested."

      It is reasonable to surmise that more sensitive assays would have found
      formaldehyde and formate bound to and reacted with a variety of cellular
      substances in all tissues -- just as the 1998 Trocho study confirmed.
      (Appendix E)

      Monkeys B and C were normal, not extra vulnerable to methanol, and were
      given 3,000 mg/kg methanol, and samples taken at 18 hr.

      Formaldehyde was detected only in the blood of Monkey B, while formate
      was found in 8 and 10, respectively, of the 10 fluid and tissue samples
      in Monkeys B and C.

      For instance, the lowest value of formate, except for zero-time blood,
      for each monkey was in the midbrain, 2.16 mmol/kg for Monkey B (24 times
      the detection limit for the chromatropic acid method) and 1.02 mmol/kg
      (1.3 times the detection for the dimedon method) for Monkey C.

      This shows accumulation of formate in liver, kidney, optic nerve,
      cerebrum, and midbrain.

      "Thus, whereas one can associate formate intimately with ocular toxicity
      in the monkey, no association of formaldehyde with ocular toxicity can
      be made at this time.

      It is not possible to completely eliminate formaldehyde as a toxic
      intermediate because formaldehyde could be formed slowly within cells
      and interfere with normal cellular function without ever obtaining
      levels that were detectable in body fluids..."

      "Acknowledgements-- This research was supported by NIH grant GM 19420
      and GM 12675." [not funded by the industry]



      Life Sci 1991; 48(11): 1031-41. The toxicity of methanol. Tephly TR.
      Department of Pharmacology, University of Iowa, Iowa City 52242.

      "Abstract:
      Methanol toxicity in humans and monkeys is characterized by a latent
      period of many hours followed by a metabolic acidosis and ocular toxicity.

      This is not observed in most lower animals.

      The metabolic acidosis and blindness is apparently due to formic acid
      accumulation in humans and monkeys, a feature not seen in lower animals.

      The accumulation of formate is due to a deficiency in formate metabolism
      which is, in turn, related, in part, to low hepatic tetrahydrofolate (H4
      folate).

      An excellent correlation between hepatic H4 folate and formate oxidation
      rates has been shown within and across species.

      Thus, humans and monkeys possess low hepatic H4 folate levels, low rates
      of formate oxidation and accumulation of formate after methanol.

      Formate, itself, produces blindness in monkeys in the absence of
      metabolic acidosis.

      In addition to low hepatic H4 folate concentrations, monkeys and humans
      also have low hepatic 10-formyl H4 folate dehydrogenase levels, the
      enzyme which is the ultimate catalyst for conversion of formate to
      carbon dioxide.

      This review presents the basis for the role of folic acid-dependent
      reactions in the regulation of methanol toxicity.
      Publication Types: Review Review, Academic PMID: 1997785"

      p. 1035 "In the past, formaldehyde has often been suggested as the
      methanol metabolite which produces toxicity (34,35).

      Today, a great deal of information is available concerning its lack of
      such a role.

      The presence of elevated formaldehyde levels in body fluids or tissues
      following methanol administration has not been observed.

      No formaldehyde has been detected in blood, urine or tissues obtained
      from methanol-treated animals (36,37) and,
      in methanol-poisoned humans, formaldehyde increases have not been
      observed....

      About 85% of a low dose of 14C-formaldehyde [radioactive label] is
      excreted as pulmonary 14CO2 (49,50)....."

      [ This suggests that 15% of the formaldehyde is indeed retained in the
      body, a very significant result, considering its extreme and complex
      toxicity. ]

      49. W.B. Neely, Biochem. Pharmacol. 13: 1137-1142 (1964).

      50. Xenobiotica 1982 Feb; 12(2): 119-24.
      Formaldehyde metabolism by the rat: a re-appraisal.
      Mashford PM, Jones AR.
      1. The metabolism of [14C]formaldehyde has been investigated in the male
      Sprague-Dawley rat.
      It is extensively oxidized to CO2 and formate, which is excreted in the
      urine.
      2. Two radioactive compounds isolated from the urine of rats dosed with
      [14C]formaldehyde have been identified as N-(hydroxymethyl)urea and
      N,N'-bis-(hydroxymethyl)urea, and shown to be urinary artefacts.
      3. Previous studies of the metabolism of formaldehyde by rats have been
      re-appraised.
      Differences in the rate of oxidation of formaldehyde in various strains
      of rats result in the excretion of different urinary metabolites and, in
      some cases, formaldehyde.
      Excretion of formaldehyde leads to the formation of several artefacts
      depending on the components present in the urine. PMID: 6806997
      ////////////////////////////////////////////////////////////



      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
      http://rmforall.blogspot.com/2007_11_01_archive.htm
      Wednesday, November 14, 2007
      http://groups.yahoo.com/group/aspartameNM/message/1490


      "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 1943 Otowi Road, Santa Fe, New Mexico 87505

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

      http://groups.yahoo.com/group/aspartameNM/messages
      group with 113 members, 1,495 posts in a public archive


      http://rmforall.blogspot.com/2007_09_01_archive.htm
      Saturday, September 15, 2007
      http://groups.yahoo.com/group/aspartameNM/message/1472
      bias, omissions, incuriosity = opportunity, aspartame safety evaluation,
      Magnuson BA, Burdock GA, Williams GM, 7 more, 2007 Sept, Ajinomoto
      funded 98 pages html [$ 32 781888262_content.pdf]: Murray 2007.09.15
      ////////////////////////////////////////////////////////////


      http://groups.yahoo.com/group/aspartameNM/message/1491
      industry scientists praise aspartame safety and benefits in Paris on
      2006.05.30, Herve Nordmann, Andrew G. Renwick, Carlo La Vecchia, Tommy
      Visscher, Jaap Seidell, France Bellisle, Adam Drewnowski, Margaret
      Ashwell, Anne de la Hunty, Sigrid A. Gibson, Alan R. Boobis: Murray
      2007.11.18


      [ This layman review gives detailed access to the gist of six
      epidemiological studies since 2004, two in 2007, that show correlations
      of diet soda (largely aspartame) with health issues.

      Probably studies of the correlations at the top 0.1 to 1.0 % level of
      use over periods of years by people in vulnerable groups are needed.

      http://groups.yahoo.com/group/aspartameNM/message/1141
      Nurses Health Study can quickly reveal the extent of aspartame
      (methanol, formaldehyde, formic acid) toxicity: Murray 2004.11.21

      The Nurses Health Study is a bonanza of information about the health of
      probably hundreds of nurses who use 6 or more cans daily of diet soft
      drinks -- they have also stored blood and tissue samples from their
      immense pool of subjects, over 100,000 for decades.

      In total, there are 20 mainstream studies about negative effects with
      aspartame since summer, 2005, listed in this review, included many about
      the detailed biochemistry involved. ]
      ////////////////////////////////////////////////////////////


      http://RMForAll.blogspot.com September 21, 2007
      http://groups.yahoo.com/group/aspartameNM/message/1475

      19,000 people, the 4% of users of aspartame who drink average 5 cans
      daily, have more problems in NIH AARP study of 474,000 people: Murray
      2007.09.21

      This is the first good data about the percentage of aspartame users who
      use over 3 cans daily, averaging 5 cans daily at 200 mg per 12 oz can
      diet soda.

      About 4% of 473,984 is 19,000 people, with a peak intake of 17 cans
      daily, and average 5 cans daily.

      It would be worthwhile to investigate a wide variety of symptoms for the
      0.1% of highest level users, about 500 people.

      For about 200 million USA aspartame users, this would be 200,000 people.

      Table 1 reveals consistent increase in problems from

      --------------------- zero to (400 - 600) to (over 600) mg/d
      aspartame intake:

      % of cohert ---------- 46 -------- 5 -------- 4 %

      mean aspartame mg/d --- 0 -------441 ------ 986

      16+ education -------- 37 ------- 40 ------- 34 %

      diabetes history ------ 3 ------- 22 ------- 26 %

      alcohol g/d ---------- 14 ------- 11 ------- 13

      never smoke ---------- 36 ------- 31 ------- 29 %

      Body Mass Index ------ 26 ------- 29 ------- 29

      18.5 - 25 ------------ 42 ------- 21 ------- 19 %

      30 - 35 -------------- 13 ------- 23 ------- 26 %

      over 35 --------------- 4 ------- 10 ------- 13 %

      Physical activity %:

      under 3-4/mo --------- 32 ------- 32 ------- 37 %

      under 1-2/wk --------- 22 ------- 21 ------- 19 %

      over 3-4/wk ---------- 45 ------- 45 ------- 43 %

      Calories kcal ----- 1,919 ---- 1,855 ---- 2,044 %

      Caffeine mg/d ------- 393 ------ 364 ------ 424

      There do seem to be many increases of problems
      from the second to third row, as mean aspartame use doubles.

      Granted, this is cherry picking the data, selecting interesting patterns.

      Correlations alone do not prove any direction of causation.

      Nevertheless, it may be of value to study the correlations for
      increasing aspartame intake among the 4 % using over 600 mg, the
      equivalent of 3 cans 12-oz cans diet soda daily.
      The average use for this group is 5 cans daily.

      For instance, are a minority of these heavy users displaying the great
      majority of the problems that are reflected in the mean for each level
      of use, with most users only having little or no increase in problems?

      This is a group of about 20,000 people.

      "We cannot exclude the possibility that higher aspartame consumption
      than that observed in this study may be associated with an elevated risk
      of hematopoietic or brain cancers."

      http://cebp.aacrjournals.org/cgi/content/full/15/9/1654 free full text
      http://cebp.aacrjournals.org/cgi/reprint/15/9/1654 free full text pdf

      Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1654-1659,
      September 2006
      © 2006 American Association for Cancer Research

      Consumption of Aspartame-Containing Beverages and Incidence of
      Hematopoietic and Brain Malignancies

      Unhee Lim 1,
      Amy F. Subar 2, subara@...,
      Traci Mouw 1,
      Patricia Hartge 1,
      Lindsay M. Morton 1,
      Rachael Stolzenberg-Solomon 1,
      David Campbell 3,
      Albert R. Hollenbeck 4
      and Arthur Schatzkin 1

      1 Division of Cancer Epidemiology and Genetics,

      2 Division of Cancer Control and Population Sciences, National Cancer
      Institute, NIH, Department of Health and Human Services;

      3 Information Management Services, Inc., Rockville, Maryland; and

      4 AARP, Washington, District of Columbia

      Requests for reprints: Amy Subar,
      Division of Cancer Control and Population Sciences,
      National Cancer Institute,
      6130 Executive Boulevard, EPN 4005, Rockville, MD 20852-7344.
      Phone: 301-594-0831; Fax: 301-435-3710. E-mail: subara@...,

      BACKGROUND:
      In a few animal experiments, aspartame has been linked to hematopoietic
      and brain cancers.

      Most animal studies have found no increase in the risk of these or other
      cancers.

      Data on humans are sparse for either cancer.

      Concern lingers regarding this widely used artificial sweetener.

      OBJECTIVE:
      We investigated prospectively whether aspartame consumption is
      associated with the risk of hematopoietic cancers or gliomas (malignant
      brain cancer).

      METHODS:
      We examined 285,079 men and 188,905 women ages 50 to 71 years in the
      NIH-AARP Diet and Health Study cohort

      Daily aspartame intake was derived from responses to a baseline
      self-administered food frequency questionnaire that queried consumption
      of four aspartame-containing beverages (soda, fruit drinks, sweetened
      iced tea, and aspartame added to hot coffee and tea) during the past year.

      Histologically confirmed incident cancers were identified from eight
      state cancer registries.

      Multivariable-adjusted relative risks (RR) and 95% confidence intervals
      (CI) were estimated using Cox proportional hazards regression that
      adjusted for age, sex, ethnicity, body mass index, and history of diabetes.

      RESULTS:
      During over 5 years of follow-up (1995-2000), 1,888 hematopoietic
      cancers and 315 malignant gliomas were ascertained.

      Higher levels of aspartame intake were not associated with the risk of
      overall hematopoietic cancer
      (RR for >/=600 mg/d, 0.98; 95% CI, 0.76-1.27),
      glioma (RR for >/=400 mg/d, 0.73; 95% CI, 0.46-1.15;
      P for inverse linear trend = 0.05),
      or their subtypes in men and women.

      CONCLUSIONS:
      Our findings do not support the hypothesis that aspartame increases
      hematopoietic or brain cancer risk. PMID: 16985027

      "We cannot exclude the possibility that higher aspartame consumption
      than that observed in this study may be associated with an elevated risk
      of hematopoietic or brain cancers.

      In the laboratory study with positive findings, animals were fed doses
      starting from 4 mg up to 5,000 mg per kg body weight.

      Significantly elevated lymphomas and leukemias were observed in female
      rats fed 20 mg of aspartame and higher (e.g., 1,200 mg for humans
      weighing 60 kg or 132 lb; refs. 13, 14).

      The reported aspartame intake in our data ranged from 0 to 3,400 mg/d
      with sparse numbers in the upper intake categories
      (1,200 or 2,000 mg/d, which is equivalent to ~7 to 11 cans of soft
      drinks daily) compared with the lowest categories,
      and the associations were similarly null in both men and women."
      ////////////////////////////////////////////////////////////


      http://RMForAll.blogspot.com October 12, 2007
      http://groups.yahoo.com/group/aspartameNM/message/1479
      13,620 seniors using more than 1 can/week artificially sweetened
      [aspartame] soft drinks had 8% higher death risk, 1981-2004,
      Paganini-Hill A, Kawas CH, Corrada MM, U. Southern Cal., Prev. Med. 2007
      April 44(4) 305-10: Murray 2007.10.12

      "Individuals who drank more than 1 can/week of artificially sweetened
      (but not sugar-sweetened) soft drink (cola and other) had an 8 %
      increased risk (95 % CI: 1.01-1.16)."

      "The increased death risk with consumption of artificially sweetened,
      but not sugar-sweetened, soft drinks suggests an effect of the sweetener
      rather than other components of the soft drinks, although residual
      confounding remains a possibility."

      Prev Med. 2007 Apr; 44(4): 305-10. Epub 2006 Dec 29.
      Non-alcoholic beverage and caffeine consumption and mortality: the
      Leisure World Cohort Study.
      Paganini-Hill A, annliahi@...,
      Kawas CH, ckawas@...,
      Corrada MM. mcorrada@...,
      Department of Preventive Medicine, Keck School of Medicine of the
      University of Southern California, CA, USA.

      OBJECTIVE:
      To examine the effects of non-alcoholic beverage and caffeine
      consumption on all-cause mortality in older adults.

      METHODS:
      The Leisure World Cohort Study is a prospective study of residents of a
      California retirement community.

      A baseline postal health survey included details on coffee, tea, milk,
      soft drink, and chocolate consumption.

      Participants were followed for 23 years (1981-2004).

      Risk ratios (RRs) of death were calculated using Cox regression for 8644
      women and 4980 men (median age at entry, 74 years) and adjusted for age,
      gender, and multiple potential confounders.

      RESULTS:
      Caffeine consumption exhibited a U-shaped mortality curve.

      Moderate caffeine consumers had a significantly reduced risk of death
      (multivariable-adjusted RR = 0.94, 95 % CI: 0.89, 0.99 for 100-199 mg/day
      and RR = 0.90, 95 % CI: 0.85, 0.94 for 200-399 mg/day
      compared with those consuming <50 mg/day).

      Individuals who drank more than 1 can/week of artificially sweetened
      (but not sugar-sweetened) soft drink (cola and other) had an 8 %
      increased risk (95 % CI: 1.01-1.16).

      Neither milk nor tea had a significant effect on mortality after
      multivariable adjustment.

      CONCLUSIONS:
      Moderate caffeine consumption appeared beneficial in reducing risk of death.

      Attenuation in the observed associations between mortality and intake of
      tea and milk with adjustment for potential confounders suggests that
      such consumption identifies those with other mortality-associated
      lifestyle and health risks.

      The increased death risk with consumption of artificially sweetened, but
      not sugar-sweetened, soft drinks suggests an effect of the sweetener
      rather than other components of the soft drinks, although residual
      confounding remains a possibility. PMID: 17275898


      Age Ageing. 2007 Mar; 36(2): 203-9.
      Type of alcohol consumed, changes in intake over time and mortality: the
      Leisure World Cohort Study.
      Paganini-Hill A, Kawas CH, Corrada MM.
      Department of Preventive Medicine,
      Keck School of Medicine of University of Southern California, USA.
      annliahi@...

      BACKGROUND:
      modifiable behavioural risk factors including smoking and alcohol
      consumption are major contributing or actual causes of mortality.

      OBJECTIVE:
      to examine the effect of alcohol intake on all-cause mortality in older
      adults.

      Design and SETTING:
      prospective population-based cohort study of residents of a California,
      United States retirement community.

      SUBJECTS:
      8,877 women and 5,101 men (median age, 74 years) who in the early 1980s
      completed a postal health survey incluing details on alcohol consumption.

      METHODS:
      participants were followed for 23 years (1981-2004) including two
      follow-up questionnaires (in 1992 and 1998) asking about current alcohol
      intake.

      Age-adjusted and multivariate-adjusted risk ratios of death and 95 %
      confidence intervals were calculated separately for men and women, using
      proportional hazard regression.

      RESULTS:
      of the 8,644 women and 4,980 men with complete information on the
      variables of interest and potential confounders,
      6,930 women and 4,456 men had died (median age, 87 years).

      Both men and women who drank<br/><br/>(Message over 64 KB, truncated)
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