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From: Rich Murray on 24 Jun 2008 03:04
M Soffritti of Ramazzini Foundation answers critique by Ajinomoto
funded BA Magnuson and GM Williams re aspartame (methanol)
carcinogenicity,Environmental Health Perspectives 2008 May: Murray
2008.06.24
http://rmforall.blogspot.com/2008_06_01_archive.htm
Tuesday, June 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1543
____________________________________________________


"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(a)comcast.net
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
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http://www.ehponline.org/docs/2008/10881/letter.html

Environmental Health Perspectives (EHP) is a monthly journal of
peer-reviewed research and news on the impact of the environment on
human
health.
EHP is published by the National Institute of Environmental Health
Sciences
and its content is free online.
Print issues are available by paid subscription.

NIEHS NIH DHHS
Current Issue
Cover of Current Issue
Volume 116, Number 5 May 2008

Carcinogenicity of Aspartame in Rats Not Proven
Magnuson B, et al. (More)

Correspondence-in-Press- Disclaimer - Full (PDF)

Correspondence

Letter: Magnuson B, Williams GM
Response: Soffritti M


[ two detailed critiques of industry affiliations and biased science
in 99
page review with 415 references by BA Magnuson, GA Burdock
and 8 more, Critical Reviews in Toxicology, 2007 Sept.: Mark D
Gold 13 page: also Rich Murray 2007.09.15: 2008.03.24
http://rmforall.blogspot.com/2008_03_01_archive.htm
Monday, March 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1531

stevia herbal sweetener to be sold as Truvia (rebiana) by Cargill and
Coca-Cola, if blitz of 12 studies wins FDA approval in 30-90 days:
Murray
2008.05.24
http://rmforall.blogspot.com/2008_05_01_archive.htm
Saturday, May 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1540
[ Extracts ]

Dr Ashley Roberts, Vice-President, Food and Nutrition Group, Cantox
Health
Sciences International, of Mississauga, USA, www.cantox.com
Cantox is the leading international scientific and regulatory
consulting
firm with specialized expertise in the areas of Food & Nutrition,
Pharmaceutical & Healthcare, Chemicals, and Agri, Biotech & Consumer
Products.

For the past 20 years, we have been helping clients resolve complex
scientific and toxicology issues, develop scientific and strategic
regulatory and compliance plans, and facilitate timely regulatory
global
approvals. We optimize success and minimize client risk through broad
expertise and knowledge.

We are ideally equipped to help clients achieve success in a fast-
paced,
changing global market with:

* Offices around the world
* Internationally recognized scientists, regulatory specialists, and
toxicologists
* More than 60 professionals dedicated to the interests of our
clients.

Our lengthy track record of success speaks for itself and today, more
than
70% of our projects come from existing clients or direct referrals.

Cantox -- Protecting Client Interests

We protect client interests while helping our clients achieve
milestones and
bring products to market. Our clients benefit from successful
outcomes,
reduced time to market, and decreased costs. That is why so many
clients
return to Cantox when they have new challenges to overcome.

Our cost-effective, value-added service:

* Streamlines product development programs and eliminates unnecessary
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* Addresses scientific issues prior to and during regulatory review
* Allows faster time to market and timely regulatory approvals

We focus on client success!

Cantox Health Sciences International info(a)cantox.com;
1011 Route 22, West Bridgewater, NEW JERSEY 08807 U.S.A.
Telephone: (908) 429-9202 Fax: (908) 429-9260

http://www.cantox.com/staff.html

Scientific & Regulatory Consultants

Williams GM, GWilliams(a)cantox.com;

Bernadene Magnuson, Ph.D., Senior Scientific and Regulatory Consultant
BMagnuson(a)cantox.com;

Berna Magnuson brings to Cantox an exceptional broad range of skills
and
knowledge in toxicology and food and nutritional sciences.
Her research on diet and cancer, and her work in food toxicology, has
been
recognized internationally.
She is a pioneer in the developing field of food nanoscience, and is
leading
efforts to address issues facing the food industry in the adoption of
this
promising new technology.

Berna received her BSHEc with distinction in food science and
nutrition.
After working in the food industry, she obtained her MSc in Toxicology
from
the University of Saskatchewan, and her PhD in Food and Nutritional
Sciences
from the University of Manitoba.
Her post-doctoral research focused on the pathology and biochemistry
of
colon cancer.
As a university faculty member recently at the University of Maryland,
Berna
led a competitive research program, mentored graduate students, and
taught
courses for over 12 years.

She is now an adjunct professor in nutritional sciences at the
University of
Toronto.

Her research has been published in over 40 peer-reviewed journal
articles
and book chapters, and had led to several patents.
Recently, her work focused on safety assessments of various dietary
ingredients and supplements.
Berna has been elected to numerous leadership positions of the
Institute of
Food Technologists and the Society of Toxicology, and she has been the
recipient of outstanding service awards from both the US FDA and IFT.
She is a member of the editorial board of the Journal of Food
Protection and
an Associate Editor of Food Analytical Methods.
Berna is also a member of the American Association for Cancer
Research, and
is a reviewer for many other toxicology, food science and cancer
journals.

Berna is based in our Mississauga office as a Senior Scientific and
Regulatory Consultant.
Her expertise and knowledge in food science and toxicology will be a
valuable addition to our Food and Nutrition group.

http://www.utoronto.ca/nutrisci/faculty/Magnuson/
Bernadene A. Magnuson, Ph.D.
Adjunct Associate Professor, Department of Nutritional Sciences
Senior Scientific and Regulatory Consultant, Cantox Health Science
International
2233 Argentia Road, Suite 308, Mississauga, ON L5N 2X7
Tel: (905) 542 2900 Fax: (905) 542 1011 BMagnuson(a)cantox.com;
Research
My research interests have been in the area of diet and cancer and I
am now
interested in the new and exciting area of nanotechnology and its role
in
nutrition. ]

Carcinogenicity of Aspartame in Rats Not Proven

Environ Health Perspect. doi:10.1289/ehp.10881 available via
http://dx.doi.org [Online 27 May 2008]

Referencing: Life-Span Exposure to Low Doses of Aspartame Beginning
during
Prenatal Life Increases Cancer Effects in Rats

In their article on lifetime exposure to aspartame in rats, Soffritti
et al.
(2007) purported that their study demonstrated increased carcinogenic
effects in female rats as a result of exposure beginning during
prenatal
life.

We believe that this article (Soffritti et al. 2007) has methodologic
and
conceptual weaknesses that require exposition.

First, although the study was a toxicology study, the most important
element -- the reported doses -- are not correct. The doses are
"estimates"
based on assuming constant food consumption of 20 g/day and constant
body
weights of 400 g for each rat from in utero (fetal day 12) to death.
These
assumptions are unrealistic and inaccurate. The doses during the early
growth phase of rats would be much higher because, as is well known,
rats
consume more food per gram of body weight during the rapid growth
phase.
Food consumption and body weight were reportedly measured throughout
the
experiment; however, Soffritti et al. (2007) presented only data
beginning
16 weeks postpartum, when rats reached adult body weight. Therefore
the
authors' conclusions are built on the exposure period for which they
provide
no data.

Second, for a study allegedly designed to assess prenatal exposure,
Soffritti et al. (2007) did not address important details, such as
a) pregnancy history and ages of breeders;
b) number of pregnant dams per dose group;
c) growth and food consumption of mothers during pregnancy and
lactation;
d) pregnancy outcomes;
e) disposition of pups from all mothers and each litter;
f) the origin of the 70 pups;
and g) body weight of pups at birth and during lactation.
These details are typically required to allow other scientists to
assess the
appropriateness of the study design and to repeat the study, if
desired.

The findings are of questionable biological significance for a number
of
reasons.

The lymphoma/leukemia incidences in the high-dose group, which were
the only
significant differences from control, were within or near the reported
historical control ranges.

Similarly, the mammary gland carcinoma incidence in high-dose females
(again, the only significant difference from control) was similar to
historical controls.

In their article, Soffritti et al. (2007) stated that their study
disproved
the conclusions of the European Food Safety Authority (EFSA 2006) that
the
incidences of lymphomas/leukemias observed in the first report
(Soffritti et
al. 2006) were "unrelated to aspartame given the high background
incidence
of chronic inflammatory changes in the lungs ." (EFSA 2006).

The U.S. Food and Drug Administration (FDA 2007) agreed with the EFSA
assessment.

It is not clear to us how this study disproved the EFSA's conclusions.

Soffritti et al. (2007) indicated that the lung was often the site of
lymphoma again in this study, which is not surprising because they
used the
same infected colony.

Studies in the 1960s demonstrated that the progression of chronic
pneumonia
in rats resulted in lymphoid neoplasmas, and elimination of chronic
respiratory disease in rat colonies reduced the incidence of pulmonary
lymphoid neoplasias to near zero (Cotchin and Roe 1967).

Rats with pulmonary infections developed lesions in multiple sites
earlier
than rats free from pulmonary disease (Cotchin and Roe 1967).

The establishment of pathogen-free animal suppliers for toxicity
research
was
impelled for this reason.

Therefore, we believe it is highly likely that the present findings
are due
to infection and not aspartame consumption.

Data do not support the conclusions of Soffritti et al. (2007) that
aspartame has carcinogenic potential at doses near the human level of
exposure.

The authors observed no significant effects at the low-diet level, and
the
actual dose is unknown.

Also, no data were provided on in utero exposure.

Aspartame is completely digested in the gastrointestinal tract into
two
amino acids (phenylalanine and aspartic acid) and methanol, which is
subsequently metabolized to carbon dioxide and water.

In human clinical studies (reviewed by Stegink and Filer 1996), oral
doses
equal to or exceeding the amount that would represent the 99th
percentile of
aspartame intake did not increase plasma aspartate or phenylalanine
levels
in adults or children, or in breast milk from lactating women beyond
normal
postprandial concentrations.

Ratios of fetal/maternal plasma amino acids and transport across the
placental membrane were unchanged in pregnant rabbits that received
1,600 mg
aspartame/kg/day (Ranney et al. 1975).

Thus, a biologically plausible explanation is lacking for Soffritti et
al.'s
(2007) contention that prenatal exposure to aspartame increases cancer
risk.

In summary, considering that there are no significant differences in
cancer
rates between high-dose groups and historical controls, plus the many
deficiencies in the experimental design and data, Soffritti et al.
(2007)
failed to provide convincing evidence of aspartame carcinogenicity.

Given the effort expended by many government review agencies to
document
shortcomings of the first article by this group (Soffritti et al.
2006), it
is disappointing that the editor and reviewers of this paper
(Soffritti et
al. 2007) did not require the authors to address those problems that
appear
again in this study.

Diligence is especially necessary on topics of great public interest
and
relevance because the public is relying upon the scientific community
to
assure that only high quality, well-documented, and controlled studies
appear in peer-reviewed journals.

The authors received payment from the Burdock Group during the
preparation
of an expert review of the safety of aspartame.

The Burdock Group managed the independent review, which was
financially
supported by Ajinomoto Company Inc., a producer of aspartame.

Bernadene Magnuson
Department of Nutrition and Food Science University of Maryland
College Park, Maryland
E-mail: bmagnuso(a)umd.edu;

Gary M. Williams
Department of Pathology
New York Medical College
Valhalla, New York

References

Cotchin E, Roe JFC. 1967.
Pathology of Laboratory Rats and Mice. Oxford,
UK:Blackwell Scientific Publications.

EFSA (European Food Safety Authority). 2006.
Opinion of the Scientific Panel on Food Additives, Flavourings,
Processing
Aids and Materials in Contact with Food (AFC) on a Request from the
Commission Related to a New Long-term Carcinogenicity Study on
Aspartame.
EFSA J 356:1-44. Available:
http://www.efsa.europa.eu/EFSA/Scientific_Opinion/afc_op_ej356_aspartame_en1,2.pdf
[accessed 9 April 2008].

FDA (Food and Drug Administration). 2007.
FDA Statement on European Aspartame Study. Available:
http://www.cfsan.fda.gov/~lrd/fpaspar2.html [accessed 15 August 2007].

Ranney RE, Mares SE, Schroeder RE, Hutsell TC, Raczialowski FM. 1975.
The phenylalanine and tyrosine content of maternal and fetal body
fluids
from rabbits fed aspartame.
Toxicol Appl Pharmacol 32:339-346.

Soffriti M, Belpoggi F, Degli Esposti D, Lambertini L, Tibaldi E,
Rigano A.
2006.
First experimental demonstration of the multipotential carcinogenic
effects
of aspartame administered in the feed to Sprague-Dawley rats.
Environ Health Perspect 114:379-385.

Soffritti M, Belpoggi F, Tibaldi E, Degli Esposti D, Lauriola M. 2007.
Life-span exposure to low doses of aspartame beginning during prenatal
life
increases cancer effects in rats.
Environ Health Perspect 115:1293-1297.

Stegink LD, Filer LJ. 1996.
Effect of aspartame ingestion on plasma aspartate, phenylalanine, and
methanol concentrations in potentially sensitive populations.
In: The Clinical Evaluation of a Food Additive: Assessment of
Aspartame
(Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, eds).
Boca Raton, FL: CRC Press, 87-113.


Carcinogenicity of Aspartame: Soffritti Responds

Environ Health Perspect. doi:10.1289/ehp.10881R available via
http://dx.doi.org [Online 27 May 2008]

Magnuson and Williams's letter is substantially a repetition of the
arguments set forth in a recent article (Magnuson et al. 2007), which
was a
"safety evaluation" sponsored entirely by Ajinomoto, the manufacturer
of
aspartame.

Their article (Magnuson et al. 2007) and this letter contain numerous
erroneous statements about the long-term carcinogenesis studies on
aspartame
conducted by the European Ramazzini Foundation (ERF).

First, Magnuson and Williams imply that our findings (Soffritti et al.
2007)
should be discounted because the incidence of lymphomas/leukemias in
the
high-dose group "were within or near the reported historical control
ranges."

As reported in our study (Soffritti et al. 2007), the incidence of
lymphomas/leukemias observed in both sexes treated with 2,000 ppm
aspartame
is nearly double the concurrent control (Soffritti et al. 2007).

The suggestion that concurrent control data should be ignored is
contrary to
the widely accepted standard of good laboratory science.

Second, Magnuson and Williams attribute our findings (Soffritti et al.
2007)
to some kind of bias (i.e., infection) that would affect only treated
animals but not the controls.

We have responded in detail to this hypothesis in our article
(Soffritti et
al. 2007) and in an earlier letter (Soffritti 2006).

To support their assertion, Magnuson and Williams mislead readers by
stating
that "the lung was often the site of lymphoma again in this [second]
study."

However, we actually reported that we observed the diffusion of
neoplastic
tissue not only in the lung but also concurrently in various organs
(liver,
spleen, mediastinal and other lymph nodes). (Soffritti et al. 2007)

Infection as a mode of action for induction of rat lymphoma has been
recently examined by a group of scientists at the National Center for
Environmental Assessment of the U.S. Environmental Protection Agency;

Caldwell et al. (2008) found that a careful examination of available
information does not support the hypothesis that the observed
lymphomas/leukemias in the ERF bioassays are a general effect from
infection.

The reports of chemically-induced lymphomas/leukemias by the ERF seem
to be
chemical specific.

Third, the idea that we must provide a "biologically plausible
explanation"
for human or rodent carcinogens is a time-honored approach to postpone
or
prevent the application of regulatory measures to minimize
carcinogenic
risks.

The reality is that this explanation is quite often unknown, as is, in
general, the mode of action behind the carcinogenic process.

I regard the other questions raised by Magnuson and Williams as
trivial.

For example, whatever the doses at various ages and weights, the
finding of
any effect should be a cause for concern.

Likewise, the authors' observation that some methodologic details were
omitted from the publication certainly does not change the oncologic
results
of this research.

Magnuson and Williams express disappointment that Environmental Health
Perspectives would publish original scientific research by the ERF
after
regulatory agencies went through so much trouble to review our first
aspartame study (Soffritti 2006) only to disagree with our
conclusions.

It is the obligation of the agencies responsible for food safety to
review
any new scientific data available and to make their opinion available
to the
public.

The Food and Drug Administration (FDA) did not make public the
contents of
their review, but rather they issued a short press release a full year
after
the European Food Safety Authority (EFSA) concluded its evaluation,
and
coincidently, just days before I presented new aspartame data in a
lecture
at the Mount Sinai School of Medicine in New York (FDA 2007).

I find it unfortunate that some scientists have such a low tolerance
for
original, independent scientific research;
however, I welcome continued discussion and more importantly,
additional
long-term experimental studies on aspartame and other artificial
sweeteners.

We at the ERF stand behind our results, and we remain convinced that a
review of the current regulations governing the use of aspartame is
necessary to better protect public health.

The author declares he has no competing financial interests.

Morando Soffritti
European Foundation of Oncology and Environmental Sciences, "B.
Ramazzini"
Cesare Maltoni Cancer Research Center, Bologna, Italy
E-mail: crcfr(a)ramazzini.it;

References

Caldwell J, Jinot J, DeVoney D, Gift JS. 2008.
Evaluation of evidence for infection as a mode of action for induction
of
rat lymphoma.
Environ Mol Mutagen 49: 155-164.

FDA (Food and Drug Administration). 2007.
FDA Statement on European Aspartame Study. Available:
http://www.cfsan.fda.gov/~lrd/fpaspar2.html [accessed 12 January
2008].

Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, et
al.
2007.
Aspartame: a safety evaluation based on current use levels,
regulations, and
toxicological and epidemiological studies.
Crit Rev Toxicol 37: 629-727.

Soffritti M. 2006.
Acesulfame potassium: Soffritti responds [Letter].
Environ Health Perspect 114: A516-A519.

Soffritti M, Belpoggi F, Tibaldi E, Degli Esposti D, Lauriola M. 2007.
Life-span exposure to low doses of aspartame beginning during prenatal
life
increases cancer effects in rats.
Environ Health Perspect 115:1293-1297.
____________________________________________________


JC Caldwell et al. 2007 refuted major, widely publicized criticisms
of the
Ramazzini research by the European Food Safety Authority:
Environ Mol Mutagen. 2008 Mar; 49(2): 155-64.
Evaluation of evidence for infection as a mode of action for induction
of
rat lymphoma.
Caldwell JC, Jinot J, DeVoney D, Gift JS.
National Center for Environmental Assessment, U.S. Environmental
Protection
Agency, Washington, DC, USA. caldwell.jane(a)epa.gov;

The European Food Safety Authority (EFSA) released a 2006 report
questioning
the relationship of aspartame exposure with increased incidence of
lymphomas/leukemias in a European Ramazzini Foundation (ERF) rat
study.

The EFSA report suggested that the lymphoma/leukemia findings were
most
likely explained by infection in the rat colony.

The ERF has also conducted the only available long-term oral study of
methyl
tertiary-butyl ether (MTBE).

Thus, using the EFSA report as support, some have now raised questions
about
the human relevance of MTBE-associated hemolymphoreticular tumors
reported
by the ERF in female rats as well as whether their incidence was
elevated
above background levels.

In this report, we discuss the hypothesized mode of action (MOA) of
infection-induced lymphoma and its relevance to MTBE-associated
lymphomas.

We address the relationship of rat strain and study duration to
lymphoma
susceptibility and review evidence of low background rates of this
tumor in
control animals at the ERF, similar survival rates for female rats at
the
ERF and National Toxicology Program (NTP), and chemical- and
gender-specificity of tumor induction for this type of tumor in
studies at
the ERF.

We find that the background incidence of hemolymphoreticular tumors in
female rats in the MTBE study is consistent with contemporaneous
studies at
the ERF and that there is an exposure-related effect, which is
unlikely to
be due to infections.

We examine more recent tumor classification schemes for lymphomas,
which
support the combination of lymphoblastic leukemias and lymphomas
reported by
Belpoggi et al. ([1995] Toxicol Ind Health 11: 119-149; [1998] Eur J
Oncol
3: 201-206). Published 2007 Wiley-Liss, Inc. PMID: 18095346
____________________________________________________


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

Dr. Kamal M. Abdo, PhD,
Carlos A. Camargo, Jr., MD, DrPH,
Devra Lee Davis, PhD, MPH,
David E. Egilman MD, MPH,
Samuel S. Epstein, MD,
John R. Froines, PhD,
Dale Hattis, PhD,
Kim Hooper, PhD,
James Huff, PhD,
Michael F. Jacobson, PhD,
Peter F. Infante, DDS, DrPH.
Letter to U.S. FDA commissioner. Questions about the safety of the
artificial sweetener aspartame.
Int J Occup Environ Health. 2007 Oct-Dec; 13(4): 449-50. No abstract
available. PMID: 18085059

" In light of the new aspartame study, which extends and corroborates
the
finding from an earlier study, we urge the FDA to immediately commence
a
careful review of the new study.

Considering how widely aspartame in consumed by young children, as
well as
adults, in the United States and abroad, it is essential that this
review be
done as expeditiously as possible.

If that review confirms that aspartame caused cancer in the laboratory
animals, the FDA must invoke the Delaney amendment and revoke its
approval
for the artificial sweetener. 8 "

www.ramazzini.it/fondazione/pdfUpload/Science_06.07.2007.pdf

SCIENCE VOL 317 6 JULY 2007 page 31

Souring on Fake Sugar

Fearful it causes cancer, 12 U.S. environmental health experts last
week
asked the U.S. Food and Drug Administration (FDA) to review the
potential
health risks of the artificial sweetener aspartame, which appears in
everything from medicines to diet sodas.

A study published last month in Environmental Health Perspectives
found
somewhat more leukemias and lymphomas in male rats receiving less
aspartame
than the recommended maximum for humans;
at higher doses, the rats had a marked increase in cancers throughout
the
body.

Pregnant rats were fed the sweetener, and animals received it once
they'd
been weaned. The work, by scientists at the European Ramazzini
Foundation of
Oncology and Environmental Sciences in Bologna, Italy, is "more
sensitive
and more realistic" than earlier aspartame studies, says James Huff of
the
National Institute of Environmental Health Sciences, who signed onto
the FDA
letter drafted by the Washington, D.C.-based watchdog group
Center for Science in the Public Interest.

But because the study conflicts with earlier work, FDA spokesperson
Michael
Herndon says that the agency finds the study unpersuasive and that
"aspartame is safe."

FDA's European counterpart has not responded publicly to the study.
--
Jennifer Couzin

www.cspinet.org/new/200706251.html
www.cspinet.org/new/200706251_print.html
http://cspinet.org/new/pdf/aspartame_letter_to_fda.pdf
____________________________________________________



(BA Magnuson et al, 2007)

4.1. Animal Studies

Studies in the 1970s by Opperman and coworkers (Oppermann et al.,
1973b;
Ranney et al., 1976; Ranney and Oppermann, 1979; Oppermann and Ranney,
1979)
using radiolabeled aspartame demonstrated that aspartame was first
hydrolyzed to aspartylphenylalanine and methanol by intestinal
esterases,
possibly chymotrypsin......

Methanol is not subject to metabolism within the enterocyte and
rapidly
enters the portal circulation.

The methanol is oxidized in the liver to formaldehyde.

Enzymes involved depend on species: In the rat, the metabolism of
methanol
to formaldehyde is mediated though a catalase-peroxidase system,
whereas in
primates and humans, an alcohol dehydrogenase is responsible.

Formaldehyde is further oxidized to formic acid by formaldehyde
dehydrogenase.

This conversion is very rapid, with formaldehyde having a half-life of
only
one to 2 min, so there is no accumulation of formaldehyde.

Formic acid is ultimately converted to CO2 and water, via the
formation of
10-formyl tetrahydrofolate (Barceloux et al., 2002).


[ not cited in BA Magnuson et al, 2007]
Bull Mem Acad R Med Belg. 2006;161(6):425-34; discussion 434-6.Links
[Acute methanol intoxication: physiopathology, prognosis and
treatment]
[Article in French]
Hantson PE.
Département des Soins Intensifs, Cliniques St-Luc-U.C.L.

Acute methanol poisoning is mainly the consequence of voluntary or
accidental ingestion.

The mortality and morbidity rates remain very high despite intensive
care
therapy.

Methanol by itself is poorly toxic.

Methanol is transformed in the liver into formaldehyde and thereafter
formic
acid.

Metabolic acidosis is the main biological feature of poisoning.

Acidosis is related to formic acid accumulation, and also to a less
extent
to lactate production.

In contrast to rodents, primates are relatively deficient in
tetrahydrofolate reductase and therefore formic acid is usually the
final
metabolite.

Formic acid is able to inhibit cytochrome oxidase activity in the
mitochondria, leading to histotoxic hypoxia.

The most sensitive organs to the effects of formic acid are the brain
and
the visual pathway, while other organs may also be seriously damaged
according to the severity of metabolic acidosis.

Hemodialysis remains indicated for the removal of both methanol and
formic
acid.

Fomepizole is a recently approved antidote.

It appears safe and effective.

Analysis of its cost-effectiveness ratio is still ongoing in methanol
poisoning. PMID: 17288275


[ BA Magnuson et al, 2007]
6.9.2.1 "Formic acid accumulates in the blood because its half-life
(t1/2 =
3.4-6 h) is very much longer than is that of formaldehyde (t1/2 = 1.5
min)
(Hantson et al., 2005).

Formic acid accumulation is considered the mechanism of toxicity of
high
doses of methanol, which induces metabolic acidosis, ophthalmic
toxicity and
central nervous system depression (Barceloux et al., 2002)."

[ Reference 133.
Hum Exp Toxicol. 2005 Feb; 24(2): 55-9.
Formate kinetics in methanol poisoning.
Hantson P, Haufroid V, Wallemacq P.
Department of Intensive Care, Cliniques St-Luc, Université catholique
de
Louvain, Brussels, Belgium. hantson(a)rean.ucl.ac.be;

OBJECTIVE:
The objective is to describe the kinetics of formate, the main toxic
metabolite of methanol, in a series of consecutive patients treated in
the
same intensive care unit for severe methanol poisoning.
METHODS:
The charts of the patients admitted between 1987 and 2001 were
reviewed.
Inclusion criteria were: a history of deliberate methanol ingestion,
with a
blood methanol concentration greater than 20 mg/dL (6.2 mmol/L) or a
high
anion gap metabolic acidosis.
Indications for hemodialysis were: blood methanol concentration >50 mg/
dL
(15.8 mmol/L), metabolic acidosis (bicarbonate <15 mmol/L, arterial pH
<7.30), visual toxicity.
Antidotal therapy included ethanol administration in 22 cases, and
fomepizole in three cases.
Serial blood measurements were obtained for pH, bicarbonate, methanol
and
formate.
Endogenous and hemodialysis elimination half-lives were calculated as
t1/2
=0.693/Ke.
Fick principle was applied for hemodialysis clearance calculation.
RESULTS:
The records of 25 methanol poisoned patients were analysed.
Among them, 18 patients had sufficient data to allow accurate
determinations
of formate kinetics.
Formate half-life elimination during hemodialysis was 1.80+/-0.78 h,
which
was statistically different from the values observed before or in the
absence of dialysis (6.04+/-3.26 h, P =0.004).
[ie, range about 2.78 - 9.30 h ]
The mean hemodialysis formate clearance rate calculated in eight cases
was
176+/-43 mL/min.
A rebound in plasma formate concentration was observed in three
patients
after the discontinuation of hemodialysis.
CONCLUSIONS:
In accordance with previous isolated case reports and in contrast with
a
recent case series, our data document that hemodiaysis is effective in
reducing formate elimination half-life.
The impact on clinical outcome is still debatable. PMID: 15850279 ]


[ not cited by BA Magnuson et al, 2007 ]
Kenneth E. McMartin, Gladys Martin-Amat, Patricia E. Noker and Thomas
R.
Tephly
Lack of a role for formaldehyde in methanol poisoning in the monkey.
Biochemical Pharmcacology 1979: 28; 645-649.
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."

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

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


Ernstgård L, Shibata E, Johanson G.
Uptake and disposition of inhaled methanol vapor in humans.
Toxicol Sci. 2005 Nov; 88(1): 30-8. Epub 2005 Aug 10.
Work Environment Toxicology, Institute of Environmental Medicine,
Karolinska
Institutet, Stockholm, Sweden. Lena.Ernstgard(a)imm.ki.se
http://toxsci.oxfordjournals.org/cgi/content/full/88/1/30 free full
text
Lena Ernstgård*,1, Eiji Shibata{dagger} and Gunnar Johanson{ddagger}

* Work Environment Toxicology, Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden;
{dagger} Department of Health and Psycosocial Medicine, Aichi Medical
University School of Medicine, Nagakute-cho, Japan;
and {ddagger} Work Environment Toxicology, Institute of Environmental
Medicine, Karolinska Institutet, Stockholm, Sweden

1 To whom correspondence should be addressed at Work Environment
Toxicology,
Institute of Environmental Medicine, Karolinska Institutet, SE-171 77
Stockholm, Sweden. Fax: +46 8 31 41 24. E-mail:
Lena.Ernstgard(a)imm.ki.se;

"The absorbed dose of methanol ranged from 8.1 to 12.5 mmol in our
subjects."

Methanol is a widely used solvent and a potential fuel for motor
vehicles.

Human kinetic data of methanol are sparse.

As a basis for biological exposure monitoring and risk assessment, we
studied the inhalation toxicokinetics of methanol vapor in four female
and
four male human volunteers during light physical exercise (50 W) in an
exposure chamber.

The relative uptake of methanol was about 50% (range 47-53%).

Methanol in blood increased from a background level of about 20 to 116
and
244 microM/L after 2 h exposure at 0, 100 ppm (131 mg/m3), and 200 ppm
(262
mg/m3), respectively.

Saliva showed substantially higher levels than blood immediately after
exposure.

This difference disappeared in a few minutes; thereafter the
concentrations
and time courses in blood, urine, and saliva were similar, with half
times
of 1.4, 1.7, and 1.3 h, respectively.

The postexposure decrease of methanol in exhaled air was faster, with
a half
time of 0.8 h.

The methanol concentrations were approximately twice as high in all
four
types of biological samples at 200 compared to 100 ppm.

No increase in urinary formic acid was seen in exposed subjects.

Our study indicates non-saturated, dose-proportional kinetics of
methanol up
to 200 ppm for 2 h.

No gender differences were detected.

Similar, parallel patterns were seen with regard to the methanol time
courses in blood, urine, and saliva, whereas the concentration in
exhaled
air decreased markedly faster.

Thus, apart from blood and urine, saliva also seems suitable for
biomonitoring of methanol exposure. PMID: 16093526

"Methanol is also a natural ingredient of various foods such as fresh
fruits, fruit juices, certain vegetables, and the artificial sweetener
aspartame (Kavet and Nauss, 1990; Lindinger et al., 1997; Taucher et
al.,
1995)......The most common health effect of long-term exposure to low
levels
of methanol vapor is CNS and ocular effects. Chronic occupational
exposure
to methanol vapor concentrations of 365-3080 ppm has resulted in
headache,
dizziness, nausea, and blurred vision (IPCS, 1997)."

"Two subjects at a time were exposed at three different times to 100
ppm
(131 mg/m3) or 200 ppm (262 mg/m3) methanol or to clean air for 2 h.

The subjects were exposed in different exposure orders, and exposure
sessions were separated by at least 2 weeks."

"Symptom ratings.

The subjects rated the level of perceived discomfort immediately
before,
during (10, 50, 80, and 104 min), and after (126 and 210 min) each
exposure
session.

Ten questions were answered, related to irritative symptoms
(eyes, nose, and throat or airways), the central nervous system
(headache, fatigue, nausea, dizziness, feeling of intoxication),
difficulty in breathing, and smell of solvent.

The ratings were performed using a 100-mm visual analogue scale
(Kjellberg et al., 1988Go) graded from "not at all" (corresponding to
0 mm)
through "hardly," "slightly," "fairly," "much," to "almost
unbearable" (100
mm).

The same questionnaire has been used in several chamber inhalation
studies
performed with organic solvent vapors in our laboratory (see for
example,
Ernstgård et al., 1999Go, 2002Go; Järnberg et al., 1996Go; Nihlén et
al.,
1998bGo)."

"Background levels of methanol were detected in all samples during
control
exposure: blood range 9-76 µM/L, saliva 4-76 µM/L, urine 13-86 µM/L,
and
exhaled air 0.0005-0.01 µM/L.
[Note the highest levels of background methanol, close to the mean
level of
116 (94-144) microM/L after 2 h exposure at 100 ppm (131 mg/m3).]

For each individual and time point, the exposure-related methanol
concentrations were calculated as the difference between the
concentrations
measured at methanol exposure and that measured at clean air exposure.

No difference between genders was seen with respect to background
methanol
in blood.

Background methanol levels in urine were higher in men than in women
(35.9
vs. 21.5 mcM/L, p = 0.03 in t-test).

Similar difference was seen for saliva (39.3 vs. 19.0 mcM/L, p =
0.008).

Methanol was rapidly absorbed by inhalation.

The relative uptake remained stable throughout the exposure and was
approximately 50% at both exposure levels (range 47-53%) (Table 1).

The blood methanol concentrations reached 116 (94-144) mcM/L after 2 h
exposure at 100 ppm and 244 (228-260) µM/L at 200 ppm methanol.

These levels are consistent with linear, nonsaturated metabolism of
methanol.

Linear (i.e., dose-proportional) kinetics is also indicated when
comparing
the AUC (0-6 h) of blood methanol at the different exposure levels
(Fig.
1A).

Blood methanol increased in a monoexponential fashion during exposure
(Fig.
2A).

The postexposure decline was also monoexponential, considering the
background methanol.

According to the toxicokinetic model, the elimination half time in
blood was
about 1.4 h, and the apparent total clearance 0.2-0.3 l/min.

The steady-state level of methanol at continuous exposure to methanol
was
calculated to be 186 and 394 mcM at 100 and 200 ppm, respectively
(Table 1),
again an indication of linear kinetics."


"The average rating of irritation and CNS symptoms during exposure to
methanol never exceeded that corresponding to "somewhat" (26 mm).

There was no significant difference in symptoms ratings between
methanol
exposure and control.

However, the women rated significantly higher than the men during
exposure
to 200 ppm of methanol in three of the symptoms, namely irritation in
throat
or airways (p = 0.047), fatigue (p = 0.014), and nausea (p = 0.045).

At the control condition the women rated significantly higher than men
with
respect to irritation in the nose (p = 0.038)."

"We saw no increase in the symptom ratings after exposure to 100 or to
200
ppm of methanol compared to control exposure in our study.

This is in agreement with the findings of Muttray and colleagues
(2001) who
found no differences in symptoms in 12 healthy volunteers exposed to
20 and
200 ppm methanol for 4 h.

However, it is noteworthy that women rated significantly higher than
men for
three symptoms, namely headache, fatigue, and nausea, at 200 ppm
methanol.

In addition, and in line with our previous experience (Ernstgård et
al.,
2002), women rated significantly higher than men for irritation in the
nose
at the control condition."


"The excretion of formic acid was seemingly not affected by exposure
up to
200 ppm methanol

Similar findings have been reported by other investigators (Chuwers et
al.,
1995; d'Alessandro et al., 1994; Lee et al., 1992; Osterloh et al.,
1996).

The absorbed dose of methanol ranged from 8.1 to 12.5 mmol in our
subjects.

Assuming complete conversion to formic acid and excretion in urine
within 24
h, the same amount should be recovered in urine.

These amounts cannot be distinguished from the highly variable
background
excretion of formic acid of 19-332 mmol.

In conclusion, formic acid is not a useful biomarker for low-dose
methanol
exposure."


Int Arch Occup Environ Health. 2001 Jan; 74(1): 43-8.
Acute effects on the human EEG after an external exposure to 200 ppm
methanol.
Muttray A, Kürten R, Jung D, Schicketanz KH, Konietzko J.
Institut für Arbeits-, Sozial- und Umweltmedizin der Johannes
Gutenberg-Universität Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz,
Germany. amuttray(a)mail.uni-mainz.de;

OBJECTIVES:
Even low concentrations of organic solvents may cause acute effects on
the
human central nervous system.

The German MAK (threshold limit value) of methanol is 200 ppm.

The aim of this study was to investigate whether acute exposure to 200
ppm
methanol causes adverse effects, measured by EEG, and moreover,
whether it
is possible to differentiate between sedative and excitatory effects
with
this method.

METHODS:
Twelve healthy subjects were exposed for 4 h to 200 ppm and to 20 ppm
(control) in an exposure chamber in a cross-over design.

The EEG was recorded before (reference) and at the end of each
exposure
with, the subject's eyes closed and opened and during a choice
reaction test
(color word stress test).

Spectral power was calculated by fast Fourier transformation.

Subjective symptoms and effects of blinding with 20 ppm methanol were
assessed by questionnaires.

RESULTS:
The study was a single-blind one.

During subjects' exposure to 200 ppm, their scores for prenarcotic and
irritating symptoms were not different from controls.

In the closed-eye condition of subjects, the spectral power of the
theta-band and of some electrodes of the delta-band was significantly
less
at the end of exposure to 200 ppm, than that of controls.

In the open-eye condition and during the color word stress test no
significant changes were found.

CONCLUSION:
The changes in the theta-band suggest a slight excitatory effect of
200 ppm
methanol.

The effect was weak, as scores of acute symptoms did not change.

With respect to our results, it is not necessary for the MAK value to
be
decreased. PMID: 11196080
____________________________________________________


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 2005.01.05

Michèle Bouchard *, #,1, michele.bouchard(a)umontreal.ca;
Robert C. Brunet, # brunet(a)dms.umontreal.ca;
Pierre-Olivier Droz, #
Gaétan Carrier* gaetan.carrier(a)umontreal.ca;
A Biologically Based Dynamic Model for Predicting the Disposition of
Methanol and Its Metabolites in Animals and Humans
Toxicological Sciences 64, 169-184 (2001)
http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169 free full
text

It is remarkable how little is known about the disposition of
formaldehyde
and formic acid in human tissues, according to a sober review by
Bouchard M,
2001:

"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)."

"A biologically based dynamic model was developed to simulate the
uptake and
disposition of methanol and its metabolites (formaldehyde, formate,
CO2) in
animals and humans."

"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)."

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

"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."

"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..."

"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)...

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."
____________________________________________________


6.3.2 Lifetime Studies

[ The ASE review has devoted section 6.3.2 to many detailed criticisms
of
the two Ramazzini lifetime cancer rat studies.

As a medical layman, never educated in biochemistry, I am not
qualified to
address these matters, and I welcome comments pro and con, which I
will put
on my aspartameNM group public archive:

aspartameNM(a)yahoogroups.com

I am qualified, however, to remind scientists that effective
collaboration
between opposed viewpoints has to based on an ethic of going out of
one's
way to present the best expressions by others of their evidence.

In fact, the Ramazzini Foundation has a large network of eminent
supporters,
some of whom have taken an unusual public position in support of their
two
cancer studies:

Abdo KM, Camargo CA Jr, Davis D, Egilman D, Epstein SS, Froines J,
Hattis D,
Hooper K, Huff J, Infante PF, Jacobson MF, Teitelbaum DT, Tickner JA.
Letter to U.S. FDA commissioner. Questions about the safety of the
artificial sweetener aspartame.
Int J Occup Environ Health. 2007 Oct-Dec; 13(4): 449-50. No abstract
available. PMID: 18085059

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


In addition, Ramazzini Foundation proved carcinogenity by similar
studies in
Dec., 2002 for alcohol, aldehyde, methanol, and formaldehyde, and the
results are very compatible with their first aspartame cancer study,
2005,
and with their second aspartame study, 2007:

http://groups.yahoo.com/group/aspartameNM/message/1186
aspartame induces lymphomas and leukaemias in rats,
free full plain text, M Soffritti, F Belpoggi, DD Esposti, L
Lambertini,
2005 April, 2005.07.14: main results agree with their previous
methanol
and formaldehyde studies, Murray 2005.07.19

""Yellowing of the coat was observed in animals exposed to APM, mainly
at
the highest concentrations.

This change was previously observed in our laboratory in rats exposed
to formaldehyde administered with drinking water 9."

http://groups.yahoo.com/group/aspartameNM/message/1441
Lifetime exposure to low doses of aspartame beginning during prenatal
life
increases cancer effects in rats, Morando Soffritti et al, European
Ramazzini Foundation, USA EPA Environmental Health Perspectives
2007.06.13
free full text 24 pages: Murray 2007.06.16
www.ehponline.org/members/2007/10271/10271.pdf free full text 24 pages

Soffritti M, Belpoggi F, Lambertini L, Lauriola M.
Results of long-term experimental studies on the carcinogenicity of
formaldehyde and acetaldehyde in rats. In: Mehlman MA, Bingham E,
Landrigan
PJ, et al.
Carcinogenesis bioassays and protecting public health.
Commemorating the lifework of Cesare Maltoni and colleagues.
Ann NY Acad Sci 2002; 982: 87-105.

Formaldehyde was administered for 104 weeks in drinking water supplied
ad
libitum at concentrations of 1500, 1000, 500, 100, 50, 10, or 0 mg/L
to
groups of 50 male and 50 female Sprague-Dawley rats beginning at seven
weeks
of age. Control animals (100 males and 100 females) received tap
water
only.

Acetaldehyde was administered to 50 male and 50 female Sprague-Dawley
rats
beginning at six weeks of age at concentrations of 2,500, 1,500, 500,
250,
50, or 0 mg/L. Animals were kept under observation until spontaneous
death.
Formaldehyde and acetaldehyde were found to produce an increase in
total
malignant tumors in the treated groups and showed specific
carcinogenic
effects on various organs and tissues. PMID: 12562630

Soffritti M, Belpoggi F, Cevolani D, Guarino M, Padovani M, Maltoni C.
Results of long-term experimental studies on the carcinogenicity of
methyl
alcohol and ethyl alcohol in rats. In: Mehlman MA, Bingham E,
Landrigan PJ,
et al.
Carcinogenesis bioassays and protecting public health.
Commemorating the lifework of Cesare Maltoni and colleagues.
Ann NY Acad Sci 2002; 982: 46-69.

Cancer Research Center, European Ramazzini Foundation for Oncology and
Environmental Sciences, Bologna, Italy. crcfr(a)ramazzini.it

Methyl alcohol was administered in drinking water supplied ad libitum
at
doses of 20,000, 5,000, 500, or 0 ppm to groups of male and female
Sprague-Dawley rats 8 weeks old at the start of the experiment.
Animals were kept under observation until spontaneous death.
Ethyl alcohol was administered by ingestion in drinking water at a
concentration of 10% or 0% supplied ad libitum to groups of male and
female
Sprague-Dawley rats; breeders and offspring were included in the
experiment.
Treatment started at 39 weeks of age (breeders), 7 days before mating,
or
from embryo life (offspring) and lasted until their spontaneous death.
Under tested experimental conditions, methyl alcohol and ethyl alcohol
were
demonstrated to be carcinogenic for various organs and tissues.
They must also be considered multipotential carcinogenic agents.
In addition to causing other tumors, ethyl alcohol induced malignant
tumors
of the oral cavity, tongue, and lips.
These sites have been shown to be target organs in man by
epidemiologic
studies. Publication Types: Review Review, Tutorial PMID: 12562628


Here I have combined fairly equivalent data from their two aspartame,
one
methanol, and one formaldehyde studies. Aspartame groups were 100-150
rats
each, methanol 100 rats each, and formaldehyde 50 rats each
(formaldehyde
control groups 100 rats each).

Aspartame and methanol are directly comparable, since the 11% methanol
component of aspartame upon ingestion is immediately and fully
released into
the GI tract, and then much of that quickly turned into formaldehyde
and
then formic acid, both of which account for the toxicity of methanol.

Comparison of two aspartame, one methanol, one formaldehyde studies:

Males
Females
Males + Females

Animals with lymphomas and leukaemias [hemolymphoreticular neoplasias]
% of
each group of animals

Group
100 rats each
70 rats each 2nd cancer study 2007

aspartame dose ppm a
[400 ppm in 20 gm feed = 20 mg/kg rat body weight for 0.4 kg rats)

--------equivalent methanol dose (11% of aspartame)
----------------roughly equivalent formaldehyde dose (30% of methanol)

------------------------20,000-40.0
---------------------------------28.0 #^
-------------------------------- 34.0

I--100,000-29.0
-------------25.0**
-------------27.0

II--50,000--0.0--------5,000-36.0---1,500-46.0 **
-------------25.0**------------24.0------------20.0*
-------------22.5---------------30.0------------33.0

-------------------------------------------1,000-22.0*
---------------------------------------------------22.0*
---------------------------------------------------22.0

---------------------------------------------500-24.0*
--------------------------------------------------14.0
--------------------------------------------------19.0

III-10,000-15.0
-------------19.0*
-------------17.0

--------------------------500-35.0
--------------------------------24.0
--------------------------------29.5

---------------------------100-26.0**
---------------------------------16.0
---------------------------------21.0

---------------------------------------------50-20.0
-------------------------------------------------14.0
-------------------------------------------------17.0

IV---2,000-22.0
-------------18.7*
-------------20.3

------2,000-17.1 70 rats, 2nd study 2007
-------------31.4
-------------24.3


V------400-16.7
-------------20.0**
-------------18.3

--------400-15.7 70 rats, 2nd study 2007
-------------17.1
-------------16.4


---------------------------------------------10--8.0
-------------------------------------------------10.0
--------------------------------------------------9.0

----------------------------15-20.0 [-50 rats ]
--------------------------------10.0 [-50 rats ]
--------------------------------15.0 [100 rats ]

VI------80-15.3
-------------14.7
-------------15.0

VII-------0-20.7------------0-28.0--------0--8.0 [ control groups ]
---------------8.7--------------13.0------------7.0
--------------14.7--------------20.5-----------7.5

-----------0--9.5 2nd cancer study 2007 95 rats each control group
-------------12.6
-------------11.0 190 rats, combined male and female control groups

a ppm Considering the life-span average weight of a rat (male and
female) as
400 g and the average consumption of food as 20 g per day

* aspartame, statistically significant p= 0.05;
** aspartame, statistically significant p= 0.01 using poly-k test (k =
3)

# methanol, p<0.05 using X2 test
^ methanol, p<0.05 using Cochrane-Armitage test for dose-response
relationship

* formaldemyde, p<0.05 using X2 test
** formaldehyde, p<0.01 using X2 test

The control groups vary widely, with the percentage of rats with these
most
common cancers, present at natural death, ranging from 7.0% to 28.0%.

A layman can only speculate as to the possible causes in a uniform
population of rats in the same huge laboratory facility for decades,
such as
various viruses, bacteria, or molds, or variable impurities in the tap
water.

Formaldehyde at 50 ppm shows a doubling of the percentage of rats with
these
cancers, for groups of just 50 rats.

It is a safe bet that studies using groups of 100 to 200 rats would
establish significance at this 50 ppm level, which in turn would
mandate the
reduction of the present USA EPA level (1999) from 1 ppm for lifetime
exposure to formaldehyde in drinking water to 0.05 ppm, since the
human
limit is estimated by dividing the lowest harmful animal level by
1000.

The various standards for methanol and formaldehyde are not in
harmony:

We can grasp the main picture by studying the results at a high level
of
exposure:

II--50,000--0.0--------5,000-36.0----1,500-46.0 **
-------------25.0**------------24.0------------20.0*
-------------22.5---------------30.0------------33.0

The results amount to 1.3 to 5.75 times their control group levels.
Aspartame, methanol, and formaldehyde results broadly agree.
Unknown factors are causing differences between males and females.
____________________________________________________



http://groups.yahoo.com/group/aspartameNM/message/1475
19,000 people, the 4 % of users of aspartame who drink average 5 cans
daily, have more problems in NIH AARP study of 474,000 people: Murray
2007.09.21
http://RMForAll.blogspot.com September 21, 2007


Table 1. NIH-AARP Diet and Health Study aspartame intake levels from
beverages, 1995-2000 (N = 473,984)
[ adapted from article -- a 12-oz can diet soda has 200 mg aspartame ]

0 - under 100 - 100-200 - 200-400 - 400-600 - 600-1200 - over 1200 mg/
d

cohort %
46 ------- 25 ------ 13 ------ 7 -------- 5 -- about 3 --- under 1


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

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

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

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


re "A Few too Many", Joan Acocella, The New Yorker, long review of
hangover
research 2008.05.26 -- same levels of formaldehyde and formic acid in
FEMA
trailers and other sources (aspartame, dark wines and liquors, tobacco
smoke): Murray 2008.06.05
http://rmforall.blogspot.com/2008_06_01_archive.htm
Thursday, June 5, 2008
http://groups.yahoo.com/group/aspartameNM/message/1541


formaldehyde and formic acid in FEMA trailers and other sources
(aspartame,
dark wines and liquors, tobacco smoke): Murray 2008.01.30
http://rmforall.blogspot.com/2008_01_01_archive.htm
Wednesday, January 30, 2008
http://groups.yahoo.com/group/aspartameNM/message/1508

The FEMA trailers give about the same amount of formaldehyde and
formic acid
daily as from a quart of dark wine or liquor, or two quarts (6 12-oz
cans)
of aspartame diet soda, from their over 1 tenth gram methanol impurity
(one
part in 10,000), which the body quickly makes into formaldehyde and
then
formic acid -- enough to be the major cause of "morning after" alcohol
hangovers.

Methanol and formaldehyde and formic acid also result from many fruits
and
vegetables, tobacco and wood smoke, heater and vehicle exhaust,
household
chemicals and cleaners, cosmetics, and new cars, drapes, carpets,
furniture,
particleboard, mobile homes, buildings, leather... so all these
sources add
up and interact with many other toxic chemicals.
____________________________________________________


methanol impurity in alcohol drinks [ and aspartame ] is turned into
neurotoxic formic acid, prevented by folic acid, re Fetal Alcohol
Syndrome,
BM Kapur, DC Lehotay, PL Carlen at U. Toronto, Alc Clin Exp Res 2007
Dec.
plain text: detailed biochemistry, CL Nie et al. 2007.07.18: Murray
2008.02.24
http://rmforall.blogspot.com/2008_02_01_archive.htm
Sunday, February 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1524

http://www.newyorker.com/reporting/2008/05/26/080526fa_fact_acocella?currentPage=all

Annals Of Drinking
A Few Too Many
Is there any hope for the hung over?
by Joan Acocella May 26, 2008 themail(a)newyorker.com;

"Wayne Jones, of the Swedish National Laboratory of Forensic Medicine"
[ http://groups.yahoo.com/group/aspartameNM/message/1469
highly toxic formaldehyde, the cause of alcohol hangovers, is
made by the body from 100 mg doses of methanol from
dark wines and liquors, dimethyl dicarbonate, and aspartame:
Murray 2007.08.31 ]

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.
http://www.cuk.ac.kr/eng/ sysop(a)catholic.ac.kr
Songsin Campus: 02-740-9714 Songsim Campus: 02-2164-4116
Songeui Campus: 02-2164-4114
http://www.cuk.ac.kr/eng/sub055.htm eight hospitals

[ 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).

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.]

This study by Jones AW (1987) found next-morning hangover
from red wine with 100 to 150 mg methanol
(9.5 % w/v ethanol, 100 mg/l methanol, 0.01 %).
Fully 11% of aspartame is methanol --
1,120 mg aspartame in 2 L diet soda,
almost six 12-oz cans, gives 123 mg methanol (wood alcohol).

Pharmacol Toxicol. 1987 Mar; 60(3): 217-20.
Elimination half-life of methanol during hangover.
Jones AW. wayne.jones(a)RMV.se;
Department of Forensic Toxicology,
University Hospital, SE-581 85 Linkoping, Sweden.

This paper reports the elimination half-life of methanol in human
volunteers.
Experiments were made during the morning after the subjects had
consumed 1000-1500 ml red wine
(9.5 % w/v ethanol, 100 mg/l methanol)
the previous evening. [ 100 to 150 mg methanol ]
The washout of methanol from the body
coincided with the onset of hangover.
The concentrations of ethanol and methanol in blood were
determined indirectly by analysis of end-expired alveolar air.
In the morning when blood-ethanol dropped
below the Km of liver alcohol dehydrogenase (ADH)
of about 100 mg/l (2.2 mM),
the disappearance half-life of ethanol was 21, 22, 18 and 15 min.
in 4 test subjects respectively.
The corresponding elimination half-lives of methanol
were 213, 110, 133 and 142 min. in these same individuals.
The experimental design outlined in this paper can be used
to obtain useful data on elimination kinetics of methanol
in human volunteers without undue ethical limitations.
Circumstantial evidence is presented to link methanol
or its toxic metabolic products, formaldehyde and formic acid,
with the pathogenesis of hangover. PMID: 3588516 ]
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