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
- 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
November 17, 2007 01:31am AEDT
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
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
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,
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
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
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@...,
de Benedictis FM,
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
Professor Mimi Tang mimi.tang@...,
Dr Ralf Heine ralf.heine@...,
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
Med J Aust. 2007 Jun 18; 186(12): 618-21.
Paediatric food allergy trends in a community-based specialist allergy
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
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.
DESIGN, SETTING AND PARTICIPANTS:
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).
MAIN OUTCOME MEASURES:
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@...,
Allen KJ, katie.allen@...,
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
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@...,
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
cows milk, hens egg, soy, peanuts, tree nuts (and seeds), wheat, fish
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
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
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
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
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
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
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
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
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
Mechanisms of neural synchrony and entrainment (epilepsy), and
* 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
Toronto Western Hospital, McLaughlin Pavilion, 12th Floor Rm. 413
399 Bathurst St., Toronto, Ontario Canada M5T 2S8
Phone Numbers 416.603.5800 x5044
Staff and Trainees:
S Sabet Jahromi
Eunji (Ellen) Kang
Zhang (Jane) Zhang
Dr. Bhushan Kapur
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
"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
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
phone: 613 533 6946
department: Pharmacology and Toxicology
name: James F Brien
phone: 613 533 6114
department: Pharmacology and Toxicology, School of Medicine, Psychiatry
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.
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
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
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
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
Intensive family and social service supports for FASD and recovering
Poverty is a result of, and breeds, substance abuse. Deal with it.
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.
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
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
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,
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
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
"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
"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
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
"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
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.
[ 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
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@...,
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
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
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
Also, results suggest that formaldehyde is not<br/><br/>(Message over 64 KB, truncated)