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explosion in numbers of children with serious food allergies has bewildered experts and parents, Helen Francombe, The Australian 2007.11.17: role of formic acid from methanol in liquors and aspartame, Murray 2007.11.28

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


      The Australian

      November 17, 2007 01:31am AEDT

      The Australian
      Street Address 2 Holt Street, Surry Hills, NSW, 2010, Australia.
      Postal Address GPO Box 4245, Sydney, NSW, 2001, Australia.
      Work Telephone (02) 9288 3000
      Fax (02) 9288 2250
      Email letters@...,

      Rising allergies trend mystifying

      An explosion in numbers of children with serious food allergies has
      bewildered experts and parents,

      writes Helen Francombe | November 17, 2007

      WHEN all Natalie Fine could see of her hospitalised six-month-old baby,
      Lucas, was a small pair of eyes peering out from head-to-toe bandaging,
      she couldn't help wondering what she had done wrong.

      She certainly didn't imagine soy-based formula -- recommended by her
      paediatrician after problems with a dairy-based formula -- could be the
      cause of his severe eczema, infected and requiring IV antibiotics.

      "When I was told he had a soy allergy I felt terrible -- as if I had
      been poisoning him with the formula," says Fine.

      Lucas was also found to have a severe allergy to egg white, and his
      mother was warned that if he came in contact with egg he could have an
      anaphylactic reaction -- the most severe manifestation of allergy which
      can cause swelling of the throat, difficulty breathing, a fall in blood
      pressure and, in some cases, death.

      Given the long list of foods that contain either egg white or soy, Fine
      was hesitant to give her son any food at first. "He lived on rice cereal
      and banana for quite a while," she says.

      Fine has since become more adventurous, but has become adept at reading
      the small print on food packaging, scanning for any mention of egg and soy.

      Fine's family is just one of many in Australia experiencing first-hand
      the effects of the dramatic rise in the numbers of children developing
      food allergies.

      This week the Australasian Society of Clinical Immunology and Allergy
      (ASCIA) found food allergies and other types of allergic disorders are
      rising fast in Australia.

      The report, compiled by Access Economics, found these allergic
      disorders, including hayfever, asthma and others, already cost the
      nation $7.8 billion per year in absenteeism from work and other effects.

      But this is likely to rise sharply, as the 4.1 million Australians
      currently affected -- about one in five of the population -- is expected
      to soar to one in four by 2050.

      While hayfever can be surprisingly debilitating in severe cases, it is
      not going to kill anyone.

      Food allergies, on the other hand, can be fatal -- as witnessed by the
      latest death just this week, when a 25-year-old woman collapsed in
      Brisbane after eating a dim sim containing seafood.

      But the biggest rise in food allergies is being seen not in adults but
      in children under five, as shown by data published in the October issue
      of the Journal of Allergy and Clinical Immunology (2007; 120: 878-84).

      The study found a 5 1/2-fold increase in the rate of Australian hospital
      admissions between 1994 and 2005 for food-related anaphylaxis in the
      under-fives -- a much greater rise than in any other age group.

      Shortages of allergy specialists also mean it can take months for
      parents to get an appointment.

      Similar trends have been observed in the UK and US, but experts are at a
      loss to explain what is causing it.

      "We have more theories and questions than answers," says Raymond
      Mullins, an allergy specialist in Canberra and president-elect of ASCIA.
      "It has something to do with our westernised lifestyle: you just don't
      see it in developing countries."

      The most common causes of food allergy in children are
      cow's milk, egg, peanuts, tree nuts and sesame, he says.

      Food allergy has a significant effect on quality of life for children
      and their parents -- similar to the effect of insulin-dependent diabetes
      in a child, says Mullins. The stress comes from anxiety about the child
      having a reaction, as well as the need for preparation of special meals,
      planning of outings, and liaison with other caregivers such as teachers,
      he says.

      In the Medical Journal of Australia in June (2007; 186: 618-21), Mullins
      reported a 12-fold increase in demand for consultations related to food
      allergies in children over 12 in his practice. "In the same way research
      has helped us identify risk factors to help reduce the risk of sudden
      infant death and heart disease, we need large-scale epidemiological
      studies to work out why allergy is becoming more common and how we can
      prevent it."

      One strategy shown not to be effective for cutting the risk of food
      allergy is avoiding allergenic foods during pregnancy.

      However, many women still think cutting out peanuts and the like at this
      time will help.

      Parents are not the only ones who could be wrong on this issue. The UK
      Department of Health has been advising women to avoid peanuts in
      pregnancy if there is a family history of allergy, but a House of Lords
      report on September 26 said the advice should be withdrawn immediately
      due to a lack of evidence.

      In Australia such elimination diets have not been officially
      recommended, and ASCIA's guidelines advised against them three years
      ago, citing a lack of evidence and the risk of smaller babies if mothers
      undertook elimination diets.

      Despite the guidelines, many of Mullins's patients do exclude
      potentially allergenic foods during pregnancy, probably based on
      information from the media, friends, the internet and community
      mythology, he says.

      However, some academics are worried that excluding foods during
      pregnancy may even make allergy more likely in the child.

      Associate professor Mimi Tang, head of Melbourne's Royal Children's
      Hospital department of immunology, says although we don't understand
      whether sensitisation to foods occurs in pregnancy, the body must be
      exposed to a food for the immune system to become tolerant to it -- so
      avoidance is unlikely to be the right strategy.

      Consistent with this line of thinking is new evidence that delaying
      introduction of solid foods beyond seven months in a baby may increase
      the risk of allergy, she says.

      The question of when to introduce solids is a whole other area of
      confusion and conflicting information -- as Mullins found when he
      compared the advice on this issue from sources such as state health
      departments and infant nutrition companies.

      While many other sources recommend delaying introduction of potentially
      allergenic foods, such as egg and dairy, until 12 months of age if there
      is a family history of allergy, ASCIA advises there is no evidence that
      waiting until the child is more than six months old to introduce these
      foods will reduce the risk of allergy in the long term.

      There is also no good evidence that restricting foods during
      breastfeeding will reduce the risk of food allergy in the child.

      "There has been a perception that avoidance is a good thing if you have
      allergies, but I think this advice will change," he says. Parents should
      keep an eye on the ASCIA website ( www.allergy.org.au ) for up-to-date
      advice that is evidence-based, says Mullins.

      The theory that early exposure to an allergen actually helps a child's
      immune system become tolerant is being tested currently by the LEAP
      (Learning Early About Peanut allergy) study in the UK.

      The researchers will compare the rate of peanut allergy at the age of
      five years in children who were exposed repeatedly to peanut and in
      those who avoided it.

      Tang is studying another strategy, based on the theory that the food
      allergy epidemic is related to a reduction in "good" bacteria in some
      children's gastrointestinal systems -- the "hygiene hypothesis".

      Proponents of this theory suggest we have become too clean for our own
      good and children's immune systems are suffering because of a lack of
      good bacteria. The imbalance possibly causes the child's immune system
      to react inappropriately to certain foods.

      "There is some evidence that children who grew up on farms have lower
      rates of allergy -- particularly if they were exposed to farm animals
      and drank unpasteurised cow's milk," Tang says. "And we know kids with
      allergy problems have lower numbers of good bacteria like bifidobacteria
      and lactobacilli, and higher numbers of pathogenic bacteria, those that
      can cause disease, in their gut flora than healthy children."

      At birth, babies' gastrointestinal systems are sterile, but bacteria
      soon make themselves at home. "For children with allergy problems the
      imbalance in good versus harmful bacteria occurs within the first weeks
      or months of life," says Tang.

      Studies where probiotics (good bacteria) have been taken by mothers in
      the last weeks of pregnancy, and then by their babies in the first
      months of life, have shown a reduction in allergy symptoms for up to
      eight years of age.

      Tang is currently conducting a study to see whether giving a probiotic
      to the mother in the last four weeks of pregnancy is sufficient to gain
      the benefit.

      Until more of our questions about allergy are answered by research, the
      following measures are the best advice for reducing the risk of allergy
      in children with a family history, says Tang:

      do not smoke during pregnancy or around children;

      where possible, breastfeed exclusively for the first four to six months
      of life (if this is not possible, a partially hydrolysed cow's milk
      formula may be used if the child does not have a cow's milk allergy);

      and delay the introduction of solid foods until four to six months.

      Copyright 2007 News Limited. All times AEST (GMT +10).

      Clin Exp Allergy. 2007 Nov 19; [Epub ahead of print]
      Confirmation of the association between high levels of immunoglobulin E
      food sensitization and eczema in infancy: an international study.
      Hill DJ, dave.hill@...,
      Hosking CS,
      de Benedictis FM,
      Oranje AP,
      Diepgen TL,
      Bauchau V;
      the EPAAC Study Group.
      Murdoch Children's Research Institute, Royal Children's Hospital,
      Melbourne, Vic., Australia. http://www.mcri.edu.au/
      Flemington Road, Parkville VIC 3052 Australia
      T 1300 766 439 / F +61 3 9348 1391 / ABN: 21 006 566 972

      Studies of Australian infants have reported that more than 80 % of those
      with moderate atopic eczema (AE) have high levels of IgE food
      sensitization (IgE-FS) that are commonly associated with IgE food allergy.

      To explore the relationship between high levels of IgE-FS and AE in a
      large cohort of young children with eczema participating in a
      multi-centre, international study.

      Two thousand one hundred and eighty-four subjects (mean age 17.6 months,
      range 11.8-25.4; 1246 males) with active eczema from atopic families
      from 94 centres in 12 countries were studied.

      Clinical history, Scoring Atopic Dermatitis index as a measure of eczema
      severity and CAP-FEIA measurements for total IgE and IgE antibody levels
      to cow milk, egg and peanut were entered into a database.

      If CAP-FEIA levels exceeded previously reported age-specific cut-off
      levels for 95 % positive predictive values (PPVs) for food allergy,
      subjects were defined as having high-risk IgE-FS (HR-IgE-FS).

      Serum was available from 2048 patients; 55.5 % were atopic.

      The frequency of HR-IgE-FS to milk, egg and/or peanut was the greatest
      in patients whose eczema developed in the first 3 months of life and the
      least in those whose eczema developed after 12 months (P<0.0001).

      In a regression analysis to allow for potential confounding factors,
      children with HR-IgE-FS had the most severe eczema and the youngest age
      of onset (P<0.001);
      64 % of infants with severe eczema of onset-age <3 months had HR-IgE-FS.

      Early-onset severe eczema in infancy was associated with HR-IgE-FS.

      Clinical implications Food allergies should be routinely assessed in
      infants with moderate or severe eczema.

      Capsule summary In eczematous infants, the earlier the age of onset, and
      the greater the severity of eczema, the greater the frequency of
      associated high levels of IgE-FS. PMID: 18028467

      Allergy & Immune Disorders
      The Team
      Group leader
      Professor Mimi Tang mimi.tang@...,
      Dr Ralf Heine ralf.heine@...,

      Group members
      Dr Katie Allen - Group Leader
      Christine Axelrad - Research Assistant
      Anne Balloch - Research Officer
      Ms Bin (Amy) Chen - Research Assistant
      Ms Margaret Flood - Research Coordinator
      Mr Timothy Gemetzis - Research Assistant
      Dr David Hill - Research Affiliate
      Ms Johanna Kappers - Research Affiliate
      Ms Alicia Koek - Honours Student
      Miss Jennifer Koplin - PhD Scholar
      Mr Paul Licciardi - Research Assistant
      Ms Li-Jeen Mah - Honours Student
      Rosalie Maxted - Research Affiliate
      Ms Sally Moore - Research Assistant
      Dr Nick Osborne - Postdoctoral Fellow
      Ms Anne Peace - Research Affiliate
      Dr Simon Royce - Postdoctoral Fellow
      Ms Billy Skoric - Research Assistant
      Dr Joanne Smart - Research Affiliate
      Leone Thiele - Research Coordinator

      The Australasian Society of Clinical Immunology and Allergy (ASCIA)
      Executive Officer: Jill Smith
      Mail: PO Box 450, Balgowlah NSW 2093
      Mobile: 425 216 402 Fax: 02 9907 9773
      Email: education@...,

      Med J Aust. 2007 Jun 18; 186(12): 618-21.
      Paediatric food allergy trends in a community-based specialist allergy
      practice, 1995-2006.
      Mullins RJ. Raymond J. Mullins
      John James Medical Centre, Canberra, ACT, Australia.
      http://www.aafa.org/display.cfm?id=9&sub=33 Allergy Capitals
      Asthma and Allergy Foundation of America
      1233 20th Street, NW, Suite 402, Washington, DC 20036
      1.800.727.8462 info@...,

      To examine changing demand for specialist food allergy services for
      children aged 0-5 years over the 12 years from 1995 to 2006 as an index
      of changing prevalence.

      Retrospective analysis of the records of 1489 children aged 0-5 years
      referred to a community-based specialist allergy practice in the
      Australian Capital Territory (population, about 0.33 million).

      Trends in demand for assessment for food allergy, dietary triggers and
      severity over 12 years, compared with Australian hospital morbidity data.

      47 % (697/1489) of 0-5 year-old children seen in private practice had
      food allergy (175 with food-associated anaphylaxis),
      most commonly to peanut, egg, cows milk and cashew.

      Over 12 years, the number of children in this age group evaluated each
      year increased more than fourfold, from 55 cases in 1995 to 240 in 2006.

      There was no change in the proportion diagnosed with allergic rhinitis
      in 1995 and 2006 (14.5% and 13.3%, respectively),
      urticaria (14.5 % and 12.9 %)
      or atopic eczema (54.5 % and 57.0 %).

      By contrast, the proportion with asthma dropped from 33.7 % in 1995 to
      12.5 % in 2006
      and the number with food allergy increased 12-fold, from 11 to 138
      patients (and from 20.0 % to 57.5 % of children seen).

      The number with food anaphylaxis increased
      from five to 37 children (9.0 % to 15.4 %) over the same period.

      There were similar trends in age-adjusted Australian hospital admission
      rates for anaphylaxis in children aged 0-4 years, which increased from
      39.3 to 193.8 per million population between the financial years 1993-94
      and 2004-05, a substantially greater increase than for older age groups,
      or for the population as a whole (36.2 to 80.3 per million population).

      There is an urgent need for coordinated systematic studies of the
      epidemiology of food allergy in Australia, to ascertain risk factors and
      guide public health policy.

      An increased prevalence of food allergy has implications for public
      health and medical workforce planning and availability of allergy
      services in Australia. PMID: 17576175

      J Pediatr. 2007 Oct; 151(4): 359-63. Epub 2007 Aug 6.
      Comment in: J Pediatr. 2007 Oct; 151(4): 331-3.
      IgE food sensitization in infants with eczema attending a dermatology
      Hill DJ, dave.hill@...,
      Heine RG, ralf.heine@...,
      Hosking CS,
      Brown J,
      Thiele L,
      Allen KJ, katie.allen@...,
      Su J,
      Varigos G,
      Carlin JB. jbcarlin@...,
      Murdoch Children's Research Institute, Melbourne, Australia.

      Because community-based studies, which report IgE food sensitization
      (IgE-FS) in more than 80% of infants with moderate atopic eczema, may be
      influenced by referral bias, we assessed the prevalence of IgE-FS in a
      cohort of infants with moderate atopic eczema attending a dermatology
      department clinic.

      Consecutive infants (n = 51, 39 males; median age, 34 weeks; range, 20
      to 51 weeks) with moderate atopic eczema referred to a
      university-affiliated dermatology department were studied prospectively.

      Clinical history and eczema severity were documented.

      IgE-FS was assessed by the skin prick test (SPT; n = 51) and
      food-specific serum IgE antibodies (CAP-FEIA test; n = 41).

      IgE-FS was diagnosed if the SPT or CAP-FEIA level exceeded the >95 %
      predictive reference cutoff for positive food challenges.

      Based on SPT, 44 of 51 infants (86%;
      95 % confidence interval [CI] = 74 % to 94 %)
      had IgE-FS (cow's milk, 16 %; egg, 73 %; peanut, 51 %).

      Using age-specific 95%-predictive cutoff values,
      CAP-FEIA identified 34 of 41 infants
      (83 %; 95 % CI = 68 % to 93 %)
      with IgE-FS (cow's milk, 23 %; egg, 80 %).

      Forty-six (90 %) infants had IgE-FS
      to at least 1 food item by either SPT or CAP-FEIA.

      Atopic eczema was found to be closely associated with IgE-FS in infants
      attending a dermatology department. PMID: 17889069

      Med J Aust. 2006 Oct 2; 185(7): 394-400.
      4. Food allergy in childhood.
      Allen KJ, katie.allen@...,
      Hill DJ,
      Heine RG. ralf.heine@...,
      Department of Allergy and Immunology, Royal Children's Hospital,
      Melbourne, Victoria, Australia. katie.allen@...

      Food allergies in children present with a wide spectrum of clinical
      manifestations, including anaphylaxis, urticaria, angioedema, atopic
      dermatitis and gastrointestinal symptoms (such as vomiting, diarrhoea
      and failure to thrive).

      Symptoms usually begin in the first 2 years of life, often after the
      first known exposure to the food.

      Immediate reactions (occurring between several minutes and 2 hours after
      ingestion) are likely to be IgE-mediated and can usually be detected by
      skin prick testing (SPT) or measuring food-specific serum IgE antibody

      Over 90 % of IgE-mediated food allergies in childhood are caused by
      eight foods:
      cows milk, hens egg, soy, peanuts, tree nuts (and seeds), wheat, fish
      and shellfish.

      Anaphylaxis is a severe and potentially life-threatening form of
      IgE-mediated food allergy that requires prescription of self-injectable

      Delayed-onset reactions (occurring within several hours to days after
      ingestion) are often difficult to diagnose.

      They are usually SPT negative, and elimination or challenge protocols
      are required to make a definitive diagnosis.

      These forms of food allergy are not usually associated with anaphylaxis.

      The mainstay of diagnosis and management of food allergies is correct
      identification and avoidance of the offending antigen.

      Children often develop tolerance to cows milk, egg, soy and wheat by
      school age, whereas allergies to nuts and shellfish are more likely to
      be lifelong. PMID: 17014410

      free full text

      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
      Wednesday, November 27, 2007


      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


      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.


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

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

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

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

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

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

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


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

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

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

      FA elimination is mediated by folic acid.

      Neurotoxicity is a common result of chronic alcoholism.

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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


      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
      Ther Drug Monit 2005; 27(5):558-561. [Read More]

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

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

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


      Queen's-led Network Looks At FAS Aiming To Minimize Life-long Learning
      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.

      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@...,


      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
      We are fortunate to partner with FASlink in our attempt to improve the
      lives of individuals and their families with FASD.
      Dr. Brenda Stade, St. Michael's FASD Clinic" St. Michael's Hospital is a
      teaching hospital affiliated with The University of Toronto.

      FASD Overview

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

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

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

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

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

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

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

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

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

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

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

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

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

      To ignore the facts does not change the facts.

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

      FASD Prevention

      Folic acid should be added to all beverage alcohol.

      Break the cycle. Properly fund addiction intervention and rehabilitation

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

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

      Intensive family and social service supports for FASD and recovering

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

      Alcohol Vendors

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

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

      Remove all incentives for governments to promote alcohol.

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

      End all alcohol advertising

      Alcohol must be served with food.

      Breathalyzers in all alcohol establishments

      Ban alcohol sales incentives, contests, games.

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

      Public Education

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

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

      Have youth design anti-alcohol programs targeting youth.

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


      Better diagnostic tools for the full range of FASD damage.

      True incidence and scaling of FASD damage.

      Chemically turn-off addiction center in brain.

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


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

      To join FASlink, go to

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

      info@... 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

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

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



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

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

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

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


      methanol (formaldehyde, formic acid) disposition: Bouchard M et al, full
      plain text, 2001: substantial sources are degradation of fruit pectins,
      liquors, aspartame, smoke: Murray 2005.04.02
      Toxicological Sciences 64, 169-184 (2001) Copyright © 2001 by the
      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

      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,

      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

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

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

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

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

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

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


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

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

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

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

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

      They did not have any previous histories of psychiatric or medical

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

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

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

      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

      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)

      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

      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

      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<br/><br/>(Message over 64 KB, truncated)
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