Methyl alcohol ingestion as a model etiologic agent in multiple
sclerosis, WC Monte, D Glanzman, C Johnston; Methanol induced
neuropathology in the mammalian central nervous system, Woodrow C.
Monte, Renee Ann Zeising, both reports 1989.12.04: Murray 2007.12.28
http://rmforall.blogspot.com/2007_12_01_archive.htm
Friday, December 28 2007
http://groups.yahoo.com/group/aspartameNM/message/1499

[ These seminal 1989 studies by Prof. Woodrow C. Monte are also given in
this previous post, along his two recent comprehensive reviews:

role of formaldehyde, made by body from methanol from foods and
aspartame, in steep increases in fetal alcohol syndrome, autism,
multiple sclerosis, lupus, teen suicide, breast cancer, Nutrition
Prof. Woodrow C. Monte, retired, Arizona State U., two reviews, 190
references supplied, Fitness Life, New Zealand 2007 Nov, Dec: Murray
2007.12.26
http://rmforall.blogspot.com/2007_12_01_archive.htm
Wednesday, December 26 2007
http://groups.yahoo.com/group/aspartameNM/message/1498 ]


http://www.thetruthaboutstuff.com/pdf/(2)%20FASEB%20Meeting%201990%20Abstract%20\
and%20paper.pdf

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


ABSTRACT MUST BE RECEIVED
AT SOCIETY OFFICE BY MONDAY, DECEMBER 4, 1989.
9650 Rockville Pike, Bethesda, MD 20814
Mail to your Society of membership (APS, ASPET, AAP, AIN)
ASBMB members send to AIN
ASCB, BMES and SEBM members send to APS
***AAI and ISB members send to AAP
ABSTRACT FORM
PRESENTATION PREFERENCE (Check one)
***A Oral q Poster q Indifferent
Final decision regarding presentation format
is at the discretion of the programing society.
MAILING ADDRESS OF FIRST AUTHOR
(Please print in black ink or type. Provide full
name rather than initials.)
Woodrow C. Monte, Dept. of Family Resources & Human Development
Arizona State University, Tempe AZ 85287-2502
Phone: 602-935-6938
SELECT CATEGORY NUMBERS & TITLES
(See Minisympgsium and Topic Category Ljsts)
Auto immunity and
1 408-4 Immuno deficiency
2. 795-3 Immunoparm & Toxic
g . 785-4 Autoimmune Disease
Is first author graduate student? q Yes ***No

METHYL ALCOHOL INGESTION AS A MODEL ETIOLOGIC AGENT IN
MULTIPLE SCLEROSIS.
W. Monte, D. Glanzman, and C. Johnston
(SPON: S. Hoffman).
Arizona State University, Tempe, AZ 85287

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

This unfortunate evolutionary deficiency makes_methanol a
only to humans.

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

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

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

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

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

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

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

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

Dietary Methanol as a Cause of Multiple Sclerosis

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

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

Methanol is known to be a demyelinating toxin in humans.

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

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

Human alcohol dehydrogenase metabolizes methanol directly to
Formaldehyde.

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

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

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

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

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

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

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

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

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

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

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

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

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

page 1

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

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

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

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

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

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

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

page 2

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

SUMMARY

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

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

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

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

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

INTRODUCTION

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

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

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

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

Acute exposure to methanol can also lead to blindness.

These data are inconsistent on two grounds:

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

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

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

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

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

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

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

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

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

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

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

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

Heretofore laboratory animals have not been considered as appropriate
model systems for the study of methanol toxicity in humans, due to the
increased methanol tolerance among all lower species thus far examined
(19).

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

METHOD

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

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

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

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

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

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

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

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

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

RESULTS

Analyses of degenerating neuronal tissue were performed by three
investigators.

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

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

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

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

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

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

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

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

The optic chiasm showed patchy areas of degeneration.

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

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

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

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

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

DISCUSSION

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

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

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

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

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

Both formaldehyde and formic acid are far more potent neurotoxins.

LITERATURE CITED

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

http://groups.yahoo.com/group/aspartameNM/messages
group with 116 members, 1,499 posts in a public archive

details on 6 epidemiological studies since 2004 on diet soda (mainly
aspartame) correlations, as well as 14 other mainstream studies on
aspartame toxicity since summer 2005: Murray 2007.11.27
http://rmforall.blogspot.com/2007_11_01_archive.htm
Wednesday, November 14, 2007
http://groups.yahoo.com/group/aspartameNM/message/1490

http://groups.yahoo.com/group/aspartameNM/message/1438
Coca-Cola and Cargill Inc., after years of development,
with 24 patents, will soon sell rebiana (stevia)
in drinks and foods: Murray 2007.05.31

http://groups.yahoo.com/group/aspartameNMmessage/1488
Coca-Cola, Cargill Inc., PureCircle global operations market stevia
for foods and drinks: Murray 2007.11.12

http://groups.yahoo.com/group/aspartameNM/message/1453
Souring on fake sugar (aspartame), Jennifer Couzin,
Science 2007.07.06: 4 page letter to FDA from 12 eminent
USA toxicologists re two Ramazzini Foundation
cancer studies 2007.06.25: Murray 2007.07.18

http://groups.yahoo.com/group/aspartameNMmessage/1451
Artificial sweeteners (aspartame, sucralose) and coloring
agents will be banned from use in newly-born and baby foods,
the European Parliament decided: Latvia ban in schools 2006:
Murray 2007.07.12

http://groups.yahoo.com/group/aspartameNM/message/1487
Sainsbury's supermarket chain in UK details its bans of aspartame,
sodium benzoate, and artificial flavourings and colours: Carol Key,
Customer Manager: Murray 2007.11.09

http://groups.yahoo.com/group/aspartameNM/message/1427
more from The Independent, UK, Martin Hickman, re ASDA
(unit of Wal-Mart Stores) and Marks & Spencer ban of
aspartame, MSG, artificial chemical additives and dyes
to prevent ADHD in kids: Murray 2007.05.16
http://news.independent.co.uk/uk/health_medical/article2548747.ece

http://groups.yahoo.com/group/aspartameNM/message/1426
ASDA (unit of Wal-Mart Stores WMT.N) and Marks & Spencer
will join Tesco and also Sainsbury to ban and limit
aspartame, MSG, artificial flavors dyes preservatives additives,
trans fats, salt "nasties" to protect kids from ADHD:
leading UK media: Murray 2007.05.15

http://en.wikipedia.org/wiki/Aspartame_controversy

http://en.citizendium.org/wiki/Aspartame
//////////////////////////////////////////////////////////////////////


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

[ See also:
http://rmforall.blogspot.com/2007_11_01_archive.htm
Wednesday, November 28, 2007
http://groups.yahoo.com/group/aspartameNM/message/1496
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 ]


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

Brief Summary:

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

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

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

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

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

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

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


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

Abstract

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

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

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

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

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

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

Our preliminary studies do indeed show this.

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

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

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

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

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

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

We observed neuronal death with a time and dose response.

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

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

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

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

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

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

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


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

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

Bhushan M. Kapur, b.kapur@...,
Arthur C. Vandenbroucke, PhD, FCACB
Yana Adamchik,
Denis C. Lehotay, dlehotay@...,
Peter L. Carlen carlen@...,
(2007) Formic Acid, a Novel Metabolite of Chronic Ethanol Abuse,
Causes Neurotoxicity, Which Is Prevented by Folic Acid
Alcoholism: Clinical and Experimental Research 31 (12), 2114–2120.
doi:10.1111/j.1530-0277.2007.00541.x

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

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

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

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

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

Abstract

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

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

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

FA elimination is mediated by folic acid.

Neurotoxicity is a common result of chronic alcoholism.

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Bhushan Kapur
Selected Publications

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

----------------------------
Article adapted by Medical News Today from original press release.
----------------------------

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

Contact: Lorinda Peterson

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

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

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

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


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

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

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

FASlink CD -- more than 170 MB of information.

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

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

FASD Overview

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

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

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

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

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

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

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

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

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

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

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

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

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

To ignore the facts does not change the facts.

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


FASD Prevention

Folic acid should be added to all beverage alcohol.

Break the cycle. Properly fund addiction intervention and
rehabilitation
programs.

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

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

Intensive family and social service supports for FASD and recovering
alcoholics.

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

Alcohol Vendors

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

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

Remove all incentives for governments to promote alcohol.

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

End all alcohol advertising

Alcohol must be served with food.

Breathalyzers in all alcohol establishments

Ban alcohol sales incentives, contests, games.

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

Public Education

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

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

Have youth design anti-alcohol programs targeting youth.

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

Research

Better diagnostic tools for the full range of FASD damage.

True incidence and scaling of FASD damage.

Chemically turn-off addiction center in brain.

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

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

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

Bruce Ritchie is the Moderator.

To join FASlink, go to
http://listserv.rivernet.net/mailman/listinfo/fas-link

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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


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

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


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

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

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

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

http://groups.yahoo.com/group/aspartameNM/message/1143
methanol (formaldehyde, formic acid) disposition: Bouchard M et al,
full plain text, 2001: substantial sources are degradation of fruit
pectins, liquors, aspartame, smoke: Murray 2005.04.02

http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169
Toxicological Sciences 64, 169-184 (2001) Copyright © 2001 by the
Society of Toxicology BIOTRANSFORMATION AND TOXICOKINETIC
A Biologically Based Dynamic Model for Predicting the Disposition
of Methanol and Its Metabolites in Animals and Humans

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

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

Received May 10, 2001; accepted August 28, 2001

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This pathway contributes to a long-term unobserved compartment.

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

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

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

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

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

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

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

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

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

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

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

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


http://groups.yahoo.com/group/aspartameNM/message/1286
methanol products (formaldehyde and formic acid) are main cause of
alcohol hangover symptoms [same as from similar amounts of methanol,
the 11% part of aspartame]: YS Woo et al, 2005 Dec: Murray 2006.01.20

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

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

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

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

They did not have any previous histories of psychiatric or medical
disorders.

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

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

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

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

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

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

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

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

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


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

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

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

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

They did not have any previous histories of psychiatric or medical
disorders.

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

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

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

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

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

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

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


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

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

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

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

The first morning urine void collected 6-11 h after bedtime as a rule
contained measurable amounts of ethanol, being 0.09 ± 0.03 g/l
(mean ± SD) after 50 g and 0.38 ± 0.1 g/l after 80 g ethanol.

The corresponding breath-alcohol concentrations were zero, except for
three individuals who registered 0.01-0.09g/l.

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

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

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

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

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

Most subjects experienced only mild hangover symptoms after drinking
50 g ethanol (mean score 2.4 ± 2.6), but the scores were
significantly higher after drinking 80 g (7.8 ± 7.1).

The most common symptoms were headache, drowsiness, and fatigue.

A highly significant correlation (r = 0.62-0.75, P <0.01) was found
between the presence of headache, nausea, and vertigo and the urinary
methanol concentration in the first and second morning voids, whereas
5-HTOL/5-HIAA correlated with headache and nausea.

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

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


initiating aspartame article on Citizendium democratic professional
world encyclopedia -- opportunities for all citizens and groups:
Murray 2007.11.20
http://groups.yahoo.com/group/aspartameNM/message/1492
http://rmforall.blogspot.com/2007_11_01_archive.htm
Tuesday, November 20, 2007

http://groups.yahoo.com/group/aspartameNM/message/1486
labs now quickly at low cost measure 100 exhaled gases at 1 part per
trillion levels in a single breath to instantly reveal opportunities
to study diseases and toxicities, possibly methanol and formaldehyde
from vehicle exhaust, wood and tobacco smoke, fruits and vegetables,
dark wines and liquors, aspartame: Murray 2007.11.08

http://groups.yahoo.com/group/aspartameNM/message/1340
aspartame groups and books: updated research review of 2004.07.16:
Murray 2006.05.11

Donald Rumsfeld CEO 1977-85 G.D. Searle & Co., got new President
Reagan to prohibit FDA opposition to aspartame 1981.01.25,
history by lawyer James S. Turner: Murray 2007.10.29
http://groups.yahoo.com/group/aspartameNM/message/1483

what experts say about aspartame and Abby Cormack, New Zealand:
Betty Martini 2007.08.13: Murray 2007.11.22
http://rmforall.blogspot.com/2007_11_01_archive.htm
Thursday, November 22, 2007
http://groups.yahoo.com/group/aspartameNM/message/1493


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

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