http://groups.yahoo.com/group/aspartameNM/message/1338
Aspartame: The healthy option? Richard A. Lovett, The New Scientist
2006.05.04: Murray 2006.05.08

http://www.newscientist.com/channel/health/mg19025501.700.html

http://www.newscientist.com/contact.ns

Aspartame: The healthy option? 04 May 2006 Richard A. Lovett
Exclusive from New Scientist Print Edition.
Subscribe and get 4 free issues.

[Available to nonsubscribers for $ 4.95, along with 4 mailed issues.]

http://www.newscientist.com/data/images/archive/2550/25501703.jpg

Aspartame: the scares that turned out to be false

rumour ---------- alleged ill effects ------------ what the evidence says

[ Are heavily biased, pejorative terms like "scares", "rumour"
and "alleged" compatible with mutually respectful scientific
discourse about very important, long unsettled public health issues?
Does TNS really want to allay with PR spin operatives,
funded by obvious vested interests?
Does TNS really want to undermine the efforts of informed
professionals to enlist the critical help of their colleagues
regarding substantial scientific findings?
How does it serve the public interest and the scientific process to
focus on the weakest points of evidence?
Why is The New Scientist taking this tact? ]

brain tumors: 1996 study claims that an increase in brain tumour rates
in the US is linked with aspartame in the diet.

Epidemiological study by US National Cancer Institute (NCI) in
2006 finds no link between aspartame and brain tumors.
[ So far, an abstract given at a 15 minute talk, not published or
peer-reviewed, not available for open review, based on crude
estimates of at most a few years of use -- however I agree there is
no convincing epidemiological data in humans for carcinogenicity ]

breast and prostate cancers: 1999 letter to journal suggests
correlation between increasing incidence of breast and prostate
cancer and increased aspartame intake.

Timing of breast and prostate cancer rises incompatible with
aspartame use. NCI's 2006 epidemiological study finds no link
between no link between aspartame and cancer.
[ Please give the references, in order to foster informed debate.
George R. Schwartz's and the NCI claims are both scientifically weak. ]

migraine and headache: Some researchers report that aspartame
triggers headaches in "susceptible people".
[ Use of terms like "susceptible people" obviously conveys the
attitude that there is no need to established the prevalence and
specifics of symptoms in various kinds of vulnerable people, such as those
already depressed, obese, aged, or ill. ]

Numerious small scale studies. No statistically significant association.
[ http://groups.yahoo.com/group/aspartameNM/message/622
Gold: Koehler: Walton: Van Den Eeden: Leon:
aspartame toxicity: Murray 2001.06.04 four double-blind studies ]

epileptic seizures: Many anecdotal reports in online forums and
early animal studies.
Not backed up by randomised controlled trials and FDA studies.
[ Again, terms like "anecdotal reports" are used by PR strategists to
dismiss thousands of citizen accounts, far more than for any other
food additive, which show patterns of symptoms entirely consistent
with chronic, low-level, long-term methanol toxicity.
There is enough alarming evidence to justify a clarion call for
rigorous research into all facets of aspartame (methanol, formaldehyde,
and formic acid) toxicity. The New Scientist could exert very valuable
influence. Please allow an unfettered public debate on your site, fairly
reported in your magazine.


http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 2002.01.17 rmforall
Jerry D Smith, Chris M Terpening,
Siegfried OF Schmidt, and John G Gums
Relief of Fibromyalgia Symptoms Following
Discontinuation of Dietary Excitotoxins.
The Annals of Pharmacotherapy 2001; 35(6): 702-706.
Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL.
BACKGROUND: Fibromyalgia is a common rheumatologic disorder
that is often difficult to treat effectively.
CASE SUMMARY: Four patients diagnosed with fibromyalgia
syndrome for two to 17 years are described.
All had undergone multiple treatment
modalities with limited success. All had complete, or nearly complete,
resolution of their symptoms within months after eliminating monosodium
glutamate (MSG) or MSG plus aspartame from their diet.
All patients were women with multiple comorbidities
prior to elimination of MSG.
All have had recurrence of symptoms whenever MSG is ingested.

Siegfried O. Schmidt, MD Asst. Clinical Prof. siggy@...
Community Health and Family Medicine, U. Florida, Gainesville, FL
Shands Hospital West Oak Clinic Gainesville, FL 32608-3629
352-376-5071 ]

multiple sclerosis: Anti-aspartame websites warn that MS is just
one aspect of "aspartame disease". [ H.J. Roberts, MD , an eminent
clinician, in his many reports and books describes many cases in which
aspartame reactors were misdiagnosed with MS. ]

No evidence. US National Multiple Sclerosis Society in New York
publishes warning to ignore "unsubstantiated claims".
[ Here's a fresh "anecdotal", "unsubstantiated claim" for you to ignore:

http://groups.yahoo.com/group/aspartameNM/message/1336
a mom and her kids in the trenches for 20 years with aspartame:
B. Isbell: Murray 2006.05.07

"Over the next two days, I chewed several pieces of gum.
My depression and anxiety were back with a vengeance,
and I made the connection."...]



Aspartame: The scares that turned out to be false

Note: see below for 5 May update

THINK about what you ate and drank over the last 24 hours,
and chances are you will have swallowed some aspartame.
Perhaps you followed your lunch with a low-calorie yogurt,
washed it down with a diet soda followed
by a stick of sugar-free gum.
Even if you don't have a sweet tooth,
you may have eaten some aspartame.
The sweetener also turns up in some processed savoury snacks
as a flavour enhancer.

Aspartame, also known in Europe as E951, is the artificial sweetener
people love to hate.
Since it was approved for food use 25 years ago
it has been linked to pretty much every health scare going,
from brain tumours to insomnia and mood swings.
Each time, the evidence has crumbled under closer scrutiny.

http://www.efsa.eu.int/press_room/media_events/catindex_en.html

http://www.flyonthewall.com/FlyBroadcast/efsa.eu.int/AspartamePressConference/

http://www.efsa.eu.int/science/afc/afc_opinions/1471/afc_op_ej356_aspartame_en1.\
pdf

Now aspartame is under fresh attack.
In 2005 a group of scientists at the European Ramazzini Foundation
in Bentivoglio, near Bologna in Italy, published some new findings.
When the foundation's researchers added aspartame to the diet
of 1500 rats, they saw an increase in the incidence of leukaemias
and lymphomas -- cancers of the blood and lymphatic systems --
particularly among females.
Notably, cancer incidence rose even in rats fed
the equivalent of half the World Health Organization's
acceptable daily intake (ADI) of 40 milligrams of aspartame
per kilogram of body weight.

The report caught the attention of many of the world's food watchdogs.
Despite the succession of scare stories and rumours (see Table),
national and international regulators universally
regard aspartame as safe.
Several, however,
including the European Food Safety Authority (EFSA),
the US Food and Drug Administration (FDA) and some equivalent
national bodies, are currently scrutinizing the Ramazzini Foundation's
findings to see if they stand up.
None has yet come to a conclusion,
but the EFSA has all but finished its "risk assessment" into the study
and is due to report this week.
What it decides may have far-reaching consequences for the food
industry and the millions of people trying to go sugar free.

Aspartame was discovered in 1965 when chemist James Schlatter
accidentally spilt some laboratory reagent on his hands.
Later, when he touched a finger to his lips,
he found that it had an unexpectedly sweet taste.

Gram for gram, the chemical turned out to be
200 times sweeter than sucrose.
Aspartame went on to become a food industry staple
and is now used in more than 6000 products
and consumed by 200 million people worldwide.
Annual production is more than ten thousand tonnes and rising,
and the global industry is worth more than $1 billion a year.

Even before it was approved for food use,
aspartame attracted the attention of scientists interested in the links
between diet and health.
This delayed the compound's approval by the
US Food and Drug Administration,
but after extensive studies failed to find any link between aspartame
and ill health, even in very high doses,
it was licensed by the FDA for dry foods in 1981.

[ In fact, the newly elected President Reagan appointed a new FDA
Commissioner, Arthur Hayes Hull, Jr., who within months overruled
the negative vote of the five-person FDA scientific commitee in order
to mandate the approval of aspartame:

http://www.dorway.com/upipart1.txt
http://groups.yahoo.com/group/aspartameNM/message/262
aspartame expose 96K Oct 1987 Part 1/3:
Gregory Gordon, UPI reporter: Murray 2000.07.10

http://www.dorway.com/enclosur.html
http://groups.yahoo.com/group/aspartameNM/message/53
aspartame history Part 1/4 1964-1976: Gold: Murray 1999.11.06

http://groups.yahoo.com/group/aspartameNM/message/928
revolving door, Monsanto, FDA, EPA: NGIN:
Murray 2002.12.23 ]

The European Union approved the sweetener for all foods in 1994,
and the FDA allowed similarly broad use in 1996.

Burden of proof

The rumours continued in the mid-1990s with claims that
increases in brain tumours and breast cancer
could be linked to the sweetener.
These were demolished when it emerged that the increased incidence
in these diseases had occurred at the same time as aspartame use
had been growing.
If the link had been causal, there should have been a time lag
between mass use and increases in cancers.
Supposed links to depression, bipolar disorder, migraines, insomnia
and panic attacks are still regularly touted online,
but none has ever been backed up with solid scientific evidence.

[ Here are three mainstream double-blind laboratory studies
that show headache:

http://groups.yahoo.com/group/aspartameNM/message/622
Gold: Koehler: Walton: Van Den Eeden: Leon:
aspartame toxicity: Murray 2001.06.04 four double-blind studies

Headache 1988 Feb; 28(1): 10-4
The effect of aspartame on migraine headache.
Koehler SM, Glaros A PMID: 3277925, UI: 88138777
Shirley M. Koehler, PhD 904-858-7651 skoehler@...
http://www.med.umich.edu/abcn/alpha/alpha-K.html#Koehler
Alan Glaros glarosa@... 816-235-2074

They conducted a double-blind study of patients, ages 18-55, who had
a medical diagnosis of classical migraines (normally having 1-3
migraines in 4-weeks), who were not on medications (other than
analgesics), and who suspected that aspartame had a negative effect on
their migraine headaches. The subjects were given 1200 mg daily,
aspartame or placebo, for four weeks, about 17 mg/kg. The placebo
group had no increase in headaches. Approximately half of the subjects (5
of 11) who took aspartame had a large, statistically
significant (p = 0.02), increase in migraine headache frequency,
but not in intensity or duration, compared to baseline or placebo.
Only 11 of 25 subjects completed the program: 8 dropped out, 4 began new
medications, 2 had incomplete records. They were at home.
Since 1/3 of the subjects dropped out, they may have been choosing
to avoid headaches-- were they unpaid? To achieve statistical
signifance with only 11 subjects hints that the incidence rate from
aspartame is very high, about 1/2, for migraine cases who believe
that they are hurt by aspartame.

http://groups.yahoo.com/group/aspartameNM/message/1077
eight depressed people react strongly to aspartame, Prof. Ralph G. Walton,
MD, 1993 double-blind study, full text:
Murray 2004.04.26

Walton, RG, "Adverse reactions to aspartame: double-blind challenge
in patients from a vulnerable population," 1993, with Robert Hudak and
Ruth J. Green-Waite, Biological Psychiatry, 34 (1), 13-17.
Ralph G. Walton, MD, Prof. of Clinical Psychology, Northeastern
Ohio Universities, College of Medicine, Dept. of Psychiatry,
Youngstown, OH 44501, Chairman, The Center for Behavioral Medicine,
Northside Medical Center,
500 Gypsy Lane, P.O. Box 240 Youngstown, OH 44501
330-740-3621 rwalton193@...
http://www.neoucom.edu/DEPTS/Psychiatry/walton.htm

Eight depressed patients, ages 24-60, and five non-depressed controls,
ages 24-56, employed at the hospital, were given for 7 days either
aspartame or a placebo, and then after a 3 day break, given the
opposite. Each got 2100 mg aspartame daily, 30 mg/kg bodyweight,
equal to 10-12 cans of diet soda daily, about a gallon. Despite the
very small number of subjects, the results were dramatic and
statistically significant. The eight depressed patients reported with
aspartame, compared to placebo, much higher levels of nervousness,
trouble remembering, nausea, depression, temper, and malaise.
(For each symptom, p<0.01)
The five normals did not report strong enough differences
between aspartame and placebo to be significant.
Initially, the study was to be on a group of 40, but was halted by the
Institutional Review Board because of severe reactions among 3 of the
depressed patients.

Again, statistical significance with only 8 depressed patients:
"In this study, patients most often began to report significant
symptoms after day 2 or 3." The incidence rate is very high,
indeed, about 1/3. The most common symptoms are entirely typical
of thousands of case histories.

Stephen K. Van Den Eeden, T.D. Koepsell, W.T. Longstreth, Jr,
G. van Belle, J.R. Daling, B. McKnight, "Aspartame ingestion and
headaches: a randomized crossover trial,"
1994, Neurology, 44, 1787-93
Steven K. Van Den Eeden,PhD 550-450-2202 skv@...
Division of Research, Kaiser Permanente Medical Care Program
3505 Broadway, Oakland, CA 94611-5714
http://www.dor.kaiser.org/dorhtml/investigators/Stephen_Van_Den_Eeden.html

In their introduction, they comment:

"In addition, the FDA had received over 5,000 complaints as of July,
1991 in a passive surveillance system to monitor adverse side effects.
(17) Neurologic problems constitute the primary complaints in these
and several other case series, with headaches accounting for
18 to 45 %,depending on the case series reported. (17-19)"

Subjects, ages 18-57, were recruited who believed they got headaches
from aspartame, but were otherwise mentally and physically healthy.
They were paid $ 15 total, and were at home. Of the 44 subjects, 32
contributed data to the 38-day trials: a week of inert placebo, a week
of either aspartame or placebo, followed by a week of the opposite,
and then this two-week cycle repeated.
The daily dose was about 30 mg/kg.
"The proportion of days subjects reported having a headache was
higher during aspartame treatment compared with placebo treatment
(aspartame = 0.33, placebo = 0.24; p = 0.04) (table 5)".
Of the 12 subjects not included in the data, 7 reported adverse
symptoms before withdrawing.

Again, statistical significance with a moderate number of healthy
subjects, willing to be recruited by a newspaper ad, who believed
aspartame hurt them. The number of headaches for each subject
for each treatment week are given: it appears that 4 subjects
had the strongest increase in headaches from the run-in week
or placebo week to their first week on aspartame, jumping from 0 to 5,
1 to 6, 1 to 4, 0 to 5 headaches per week. So, about 4 of the 44
healthy people recruited for the study, who believed aspartame hurt
them, had a stong increase in headaches from the first week of daily
asparame exposure, while 7 reported adverse symptoms before
leaving, a total of 11 out of 44, an incidence ratio of 1/4.

This is sky high, if we consider that, if the incidence ratio for the
about two hundred million users in the USA is 1 of 100, that is 2
million cases. It is plausible that the incidence ratio lies between 1
and 10 out of 100 for continuous daily exposure. These three flames
should have set off alarm bells, with extensive follow-up studies and
much more careful study of thousands of case histories. But these
little flares were adroitly smothered by thick blankets of industry
funded fluff:

http://groups.yahoo.com/group/aspartameNM/message/623
Simmons: Gold: Schiffman: Spiers:
aspartame toxicity: Murray 2001.06.04 ]

Scientific experts are still struggling to understand the ramifications
of the new study.
That's partly because the European Foundation of Oncology and
Environmental Sciences, to give the Ramazzini Foundation its full name,
has performed more than 200 cancer studies in the past 35 years.
Previous Ramazzini studies have led to the revamping of regulations
on the plastic PVC after one of its components
was found to be carcinogenic,
and changes in the rules on petrol after the foundation reported
that the additive MTBE caused cancer.
The study also commands respect because it has been published
in Environmental Health Perspectives (vol 114, p 379),
a peer-reviewed journal published by the
US National Institute of Environmental Health Sciences (NIEHS).

The key finding was that aspartame-fed rats suffered
significantly increased levels of leukaemias and lymphomas
at the sort of doses that some people might be consuming.
A few of the aspartame-fed animals also developed kidney tumours.
Although the numbers of kidney tumours were too small
to show statistical significance, they still caught the attention of the
Ramazzini Foundation's researchers because these cancers are normally
very rare: in the past 20 years of research,
they had only seen single figures of control animals with the disease.
In this study, there were a total of 21 in the 1500 animals
receiving aspartame, and none in the control group.

One of the conclusions that the Ramazzini Foundation highlighted
is that tumours, including three of the kidney cancer cases,
were seen at doses equivalent to
20 milligrams per kilogram of body weight,
or half the acceptable daily intake laid down
by the World Health Organization.
That is 1/50 of the lowest dose tested in any of the studies
conducted when aspartame was being scrutinised for official approval,
and is the equivalent of
around 3 litres of diet soda per day for an average adult.

Unlike many other studies purporting to show the dangers of aspartame, the
finding can't be dismissed on the grounds that animals
are being fed more than any human will ever consume.

"This is in a different league," says Michael Jacobson,
executive director of the Center for Science in the Public Interest (CSPI) a
New York-based consumer group.
People can drink 3 litres of soda a day, he says.
"Many teenage boys do."

Conflicting results

The study remains highly controversial, however,
not least because many people find it hard to understand how
aspartame could be harmful.
Aspartame is a dipeptide, a pair of amino acids joined together.
Amino acids are the basic building blocks of proteins,
and the two that make up aspartame --
aspartic acid and phenylalanine -- are nothing unusual.
Normally, the gut digests peptides into their component amino acids
and metabolises the products just as it does your breakfast eggs.

Morando Soffritti, the Ramazzini Foundation's scientific director,
hypothesises that the danger arises because the compound
is slightly more complex than a simple dipeptide:
it is two amino acids with an extra group called a methyl ester
tagged onto the phenylalanine portion.
In the gut, this extra segment becomes methanol,
which a prior Ramazzini study
found to cause lymphomas and leukaemias when added to rats'
drinking water in fairly small doses.

Aspartame's foes have long voiced concern over the methanol factor.
But Lyn Nabors of the Calorie Control Council, a US-based body
representing low-calorie food and drink manufacturers,
doesn't buy it.
We get a lot more methanol from alcoholic and even non-alcoholic drinks, so,
Nabors argues, methanol in the diet is not a problem.
"Six ounces of tomato juice has six times more methanol
than six ounces of diet soda," she says.

Jacobson is also cautious -- although for a different reason.
If aspartame is carcinogenic at such low doses, he wonders,
why haven't we been seeing an epidemic of leukaemias and lymphomas
over the past 25 years?
He is not the only one to ask this question.
Prompted by the Ramazzini findings, a team of epidemiologists
at the US National Cancer Institute (NCI) has scoured
diet-and-cancer data from more than
half a million 50 to 69-year-old men and women.
The conclusion, announced last month at a meeting
of the American Association for Cancer Research in Washington DC,
was that there was no correlation between aspartame consumption
and leukaemias, lymphomas or, for that matter, brain tumours.
The result, Jacobson says, "significantly allays" concerns
raised by the Ramazzini study.

So why the difference between the two studies?
The explanation could lie in the unusual protocol used by the
Italian group.
While most toxicology studies are terminated after two years,
the Ramazzini Foundation's policy is to test compounds
over the entire lifespan of the animals.
Limiting a rat study to two years, says Soffritti,
is like studying humans only to age 55.
Cancer is largely a disease of old age:
in fact, he says, 80 per cent of cancer diagnoses in people
are made in the last one-third of life.

Jacobson notes that the NCI study also omitted elderly people
by focusing entirely on those in their 50s and 60s.

Another difference is that while most studies use, at most,
a few hundred rats, the Ramazzini team's aspartame study
used far more, a minimum of 100 per dose group.

If lifespan studies are such a good idea,
why doesn't everyone do them?
Often it's simply a matter of cost:
a two-year study costs less than waiting until the last rat dies,
after three years or more.
Government studies are often carried out by contract labs,
which need a specified time frame.
The Ramazzini Foundation uses its own labs,
making it easier for it to design studies to outlast the longest-lived rats.

Lifespan studies present methodological problems, too.
Continuing to study animals as they grow very old
raises tricky questions about how much of any observed effect
is caused by a compound and how much is due to normal ageing.
To Nabors, this is reason enough to discount the study.
No major regulatory agency in the US or Europe uses lifetime studies,
she points out, and disregarding the conventional wisdom merely
generates "background noise that just confuses the real outcome",
she says.

But John Bucher, deputy director of environmental toxicology
at NIEHS, argues that there are statistical techniques
that can account for changes due to ageing alone.

Further doubts

Another criticism of the study surrounds the issue of "historical controls",
the technique of using the sum total of a lab's experience with control
groups from all the experiments it has ever conducted.
On the face of it, using historical controls adds weight to the
Ramazzini Foundation's discovery of kidney tumours,
as they reveal just how rare such cancers normally are.

Conversely, it tends to undercut the findings regarding
lymphomas and leukaemia because lymphoma and leukaemia rates
for the control group in the aspartame tests were lower
than the average for the more than 4500 control group animals
used over the last two decades. [ a very cogent critique ]

Historically, Ramazzini's lab has seen about a 13 per cent rate of
leukaemias and lymphomas in its control groups of female rats,
but for the aspartame experiments the rate was only 8.7 per cent.
Compared with that, the 20.0 per cent cancer rate in the
20 mg/kg dose group looks like a substantial increase,
but if the 8.7 per cent was simply a random fluctuation,
much of the apparent effect of aspartame may not be real.
"I would guess that there's a 50:50 chance you are dealing
with a low control group here," Bucher says.

Independent toxicologist F. Jay Murray, who has reviewed other
toxicology studies for both industry and government clients,
points out that low rates of cancer in the experiment's dedicated
control group may not be a blip.
"It's also possible that the background rate of cancer
is really lower for some reason," he says,
like a shift in the formulation of the animals' feed or improvements
in the lab's air quality.
Genetic drift in their bloodline might have made them less susceptible
to these types of tumours.

For critics of the study, the strongest doubts are raised by the fact
that the Ramazzini Foundation appears to be restricting access
to the mountain of data created by this study
with its unusual lifetime protocol.
When traditional rat studies are terminated,
most of the animals are still alive
and can be sacrificed under controlled conditions.
In lifetime studies, animals may die and start decomposing
before lab technicians discover them.
It's desirable to catch animals shortly after they die.
"What you want to know is what condition the animals were in
when they were necropsied," says Murray.

Diagnosis of certain types of tumours is notoriously complicated,
and Nabors challenges the Ramazzini researchers to give photos
of its microscope slides to regulatory agencies
so they can determine whether growths catalogued as tumours
were what they say they were.
Prior to publication of their work in Environmental Health Perspectives,
the Ramazzini team sent scans of about 70 of the 34,000 microscope
slides to the US for review by scientists at the NIEHS's
National Toxicology Program.
There were, apparently, some disagreements between the
American pathologists and their Italian counterparts.
Bucher says they were not substantial,
but Nabors puts a different spin on it.
"We assume those slides were the best,
or they wouldn't have brought them," she says.

The Ramazzini Foundation's dealings with regulatory agencies
have added further fuel to the fire.
Regulatory agencies often subject toxicological studies
to an especially rigorous review, in which reviewers
go through the raw data.
"My experience," Murray says, "is that scientists who have a good study are
usually eager to have other scientists peer review their work."
The Ramazzini Foundation, however, refuses to play ball.

"Many people find it hard to understand how a pair of amino acids
like aspartame could be harmful"

Kathryn Knowles, a spokeswoman for the foundation,
rejects any suggestion that it is unwilling to let others double-check
its work, citing the National Toxicology Program's review
as evidence of its openness.
"But we do not think it is appropriate for slides to be reviewed
on data that has already been published.
It's 34,000 slides and eight years of work.
Dr Soffritti is not open to a third party reading a small subset of slides
and issuing an opinion on the study."
Instead, the foundation challenges others to repeat the study.

Jacobson predicts that this is exactly what will happen,
but it will be many years before we have an answer.
"A year to plan, three years to conduct, then another year to analyse,"
he says. "What is that, 2011?"

Soffritti declines to say whether the regulatory agencies
should tighten restrictions on aspartame use.
"We produce data; they produce opinion," he says.

Murray describes the new findings as interesting and potentially
important, but reminds consumers that
"aspartame has a rich history of allegations that turned out to be false".
Perhaps this one will be the same.

Update, 5 May 2006

The European Food Safety Authority announced the results of its risk
assessment at a press conference in Rome, Italy, on Friday 5 May.
It concluded that there was nothing in the Ramazzini Foundation
study to suggest that aspartame is a human carcinogen,
and no need to carry out any further risk assessment.
The acceptable daily intake remains unchanged
at 40 milligrams per kilogram of body weight.

From issue 2550 of New Scientist magazine, 04 May 2006, page 40

http://www.newscientist.com/data/images/archive/2550/25501701.jpg

Drink problem?

The Ramazzini study tested aspartame at 20 mg per kf of body weight per day.
But what does this mean in everyday terms?

To sweeten a litre of soda requires:
525 mg aspartame or 105 gm sucrose
[ 11% methanol yields 58 mg methanol ]

To take in 20 mg/kg body weight of aspartame
a 75 kg person would need:
1,500 mg aspartame = 2.86 litres of diet soda
[ 165 mg methanol ]

To take in 40 mg/kg body weight of aspartame
(the WHO's accepable daily intake),
a 75 kg person would need:
3,000 mg aspartame = 5.72 litres of diet soda
[ 330 mg methanol ]

[ 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 methnol per ounce.

This suggests that alcohol drinkers are more sensitive to methanol
than the average diet soda drinker, some of whom find symptoms
from a third of a diet soda.

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%,
one part in ten thousand). ]

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@...
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).

[ 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 methnol per ounce.

This suggests that alcohol drinkers are more sensitive to methanol
than the average diet soda drinker, some of whom find symptoms
from a third of a diet soda.]

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.]
*******************************************************


http://groups.yahoo.com/group/aspartameNM/message/1337
Comet assay finds DNA damage from sucralose, cyclamate, saccharin,
aspartame in mice: Sasaki YF & Tsuda S Aug 2002:
Murray 2006.05.08

[ Borderline evidence, in this pilot study of 39 food additives,
using test groups of 4 mice, for DNA damage from for stomach, colon,
liver, bladder, and lung 3 hr after oral dose of 2000 mg/kg aspartame,
a very high dose. Methanol is the only component of aspartame that
can lead to DNA damage. ]

http://groups.yahoo.com/group/aspartameNM/message/961
genotoxins, Comet assay in mice: Ace-K, stevia fine; aspartame poor;
sucralose, cyclamate, saccharin bad: Y.F. Sasaki Aug 2002:
Murray 2003.01.27 [A detailed look at the data] ]

http://groups.yahoo.com/group/aspartameNM/message/934
24 recent formaldehyde toxicity [Comet assay] reports:
Murray 2002.12.31

http://groups.yahoo.com/group/aspartameNM/message/961
genotoxins, Comet assay in mice: Ace-K, stevia fine; aspartame poor;
sucralose, cyclamate, saccharin bad: Y.F. Sasaki Aug 2002:
Murray 2003.01.27

This study tests 39 common food additives for DNA damage,
comparing a control group of 4 mice against
test groups of 4 mice each, killed 3 hr and 24 hr
after oral ingestion of up to 2000 mg/kg.

Aspartame has high values for 2000 mg 3 hr for Stomach, Colon,
Liver, Bladder, Lung -- not statistically significant for just 4 mice.

However, there are only 21 unique control groups, with widely varying
values. By using the averages for all 21 control groups to make
comparison with the groups exposed to the food additives, it is easy
to see that many additives cause
about 140% to about 180% to over 300%
of the averages of all control groups for the 8 organs measured.
By using more mice, statistical significance may be easily proved for
most of these easily noticable high values,
which are not significant for just 4 mice.

Mutat Res 2002 Aug 26; 519(1-2): 103-19
The comet assay with 8 mouse organs: results with 39 currently used
food additives. Yu F. Sasaki
Sasaki YF, Kawaguchi S, Kamaya A, Ohshita M, Kabasawa K,
Iwama K, Taniguchi K, Tsuda S.
Laboratory of Genotoxicity, Faculty of Chemical and Biological
Engineering, Hachinohe National College of Technology,
Tamonoki Uwanotai 16-1, Aomori 039-1192, Japan.
yfsasaki-c@...; s.tsuda@...;

We determined the genotoxicity of 39 chemicals currently in use as
food additives. They fell into six categories-- dyes, color fixatives and
preservatives, preservatives, antioxidants, fungicides, and sweeteners.

We tested groups of four male ddY mice once orally with each additive
at up to 0.5xLD(50) or the limit dose (2000 mg/kg) and performed the
comet assay on the glandular stomach, colon, liver, kidney,
urinary bladder, lung, brain, and bone marrow 3 and 24 h after treatment.

Of all the additives, dyes were the most genotoxic. Amaranth, Allura
Red, New Coccine, Tartrazine, Erythrosine, Phloxine, and Rose Bengal
induced dose-related DNA damage in the glandular stomach, colon,
and/or urinary bladder.

All seven dyes induced DNA damage in the gastrointestinal organs at a
low dose (10 or 100mg/kg).

Among them, Amaranth, Allura Red, New Coccine, and Tartrazine
induced DNA damage in the colon
at close to the acceptable daily intakes (ADIs).

Two antioxidants (butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT)), three fungicides (biphenyl, sodium
o-phenylphenol, and thiabendazole), and four sweeteners (sodium
cyclamate, saccharin, sodium saccharin, and sucralose)
also induced DNA damage in gastrointestinal organs.

Based on these results, we believe that more extensive assessment of
food additives in current use is warranted. PMID: 12160896


Also tested were acesulfame K, aspartame, stevia, and glycyrrhizin --
which all came out nonsignificant, while, as the abstract mentions,
sodium cyclamate had 4, saccharin 3, sucralose 3,
and sodium saccharin 5 significant results.

Each test condition had just 4 mice, and, according to the text, each
additive had its own control group of 4 mice. However, there are only
21 unique sets of control groups, with 8 sets used once, 10 sets used
twice, 2 sets used 3 times, and 1 set used 4 times, a total of 38 food
additives listed [Sodium erythorbic acid was left out of Table 2, while
mentioned in the report 3 times, "...erythorbic acid and its sodium salt
did not increase DNA damage in any of the organs studied."].

Aspartame was assigned the control group that had the highest levels of
Migration of damaged nuclear DNA for Liver and Bladder,
and the second highest for Brain.

The same control group was used for the xanthene dye, erythrosinc,
which had Migration as high as 42.4+-2.17 um [micro-meter],
measured on 50 nuclei from stomach cells, 3 hours after ingestion.
So, the high control groups values had no effect on
the statistical analysis for erythrosinc.

The available range of the 21 control groups ranged for the Liver from
1.1 to 3.6 um. For aspartame, the Liver Migration, the average length
of the "comet" tail of damaged, broken DNA pulled out of 50 Liver cell
nuclei by an electric field for 15 minutes, was, average of 4 mice:

control value used 3.59+-0.50 um [1.1 to 3.6 range in 21 controls]
2000 mg/kg 3 hr 3.26+-0.16 um
2000 mg/kg 24 hr 0.57+-0.22 um

The 3 hr aspartame test value was about the same as the control value.
This may be discordant with the Trocho (1998) findings that rats given
200 mg/kg oral doses of aspartame for 11 days, about the same total
dose, had accumulation of formaldehyde adducts, bound to DNA, RNA, and
proteins, in liver, kidneys, brain, retinas, and other tissues, at about the
same total dose, spread over 11 days.

Appying the lowest available control group liver level 1.06+-0.12 um
would make the aspartame level of 3.26+-0.16 um significant
[ratio 3.1].

How significant is a ratio of about 2?
I found two examples in the data, where P<.05 existed for BHT, Bladder,
1000 mg/kg, 3 hr:
10.9+-1.32 vs control 4.77+-0.40 [range 3.6 to 7.1 for 21 controls],
[ratio 2.3]
and sodium cyclamate, Stomach, 1000 mg/kg, 3 hr:
12.2+-1.38 vs control 6.37+-0.57 [range 4.3 to 8.6 for 21 controls]
[ratio 1.9].

However, not significant was:
sodium saccharin, Liver, 2000 mg/kg, 3 hr:
5.95+-2.42 vs control 1.94+-0.36 [range 1.1 to 3.6 for 21 controls]
[ratio 3.1], since the +- error was 33% of the test value. So, if the
data for 4 mice is scattered, then the mean value of the test group has
to be over 3 times that of the control group to be significant.

For Liver, 5 of the 21 control groups, with values 1.67, 1.63, 1.29,
1.06, 1.65 would make some 3 hr aspartame values
approach or reach significance.

Ratios about 2 for different tissues with aspartame that would be close
to significant would exist for many of the 21 control groups:
Stomach 1 Colon 5 Liver 5 Bladder 11 Lung 5 .

The aspartame values at 3 hr are compared with
the mean values for the 21 control groups:

Somach ----- Colon ---- Liver ----- Kidney ---- Bladder ---

DNA Migration at 3 hr from 2000 mg/kg dose
8.49+-0.48; 9.18+-0.56; 3.26+-0.16; 1.91+-0.26; 10.7+-2.77;

mean of 21 control groups
6.31-------- 5.81 ------- 2.15 -------- 2.25 ------- 5.40 ------

range of values for 21 control groups
4.3--8.6 ---- 4.0--8.1 --- 1.1--3.6 ---- 1.2--2.9 --- 3.6--7.1

ratio == DNA Migration/control mean
1.4 ---------- 1.6 -------- 1.5 --------- 0.9 --------- 2.0 ------


Lung -------- Brain ------- Bone [marrow]

DNA Migration at 3 hr from 2000 mg/kg dose
4.13+-1.26; 0.37+-0.70; 1.01+-0.59;

2.61 ------- 1.48 -------- 1.12 ------- mean of 21 control groups

1.6--4.7 --- 0.8--2.6 ---- 0.6--1.9 --- range for 21 control groups

1.6 -------- 0.3 ---------- 0.9 --- ratio DNA Migration/control mean

Wouldn't the average of all the 21 control groups be the best control
values to use? What would then be the appropriate statistical test?
How many mice would it take to reach significance for the 5 tissues with
ratios over 1.4: Stomach, Colon, Liver, Bladder, Lung?

Aspartame at 24 hours had levels too low to reach significance with any
of the 21 control groups.

However, people who are heavy users of aspartame for years are bound to
accumulate toxic metabolites of the three components of aspartame:
methanol 11%, phenylalanine 50%, aspartic acid 29%, all genotoxic
[Trocho (1998), Karakis (1998)].

Comparing the mean control values to the values for the other 7
sweeteners:
Best is acesulfame K, with no significant or high values.

Good is glycyrrhizin (derived from licorice), two 1.4 ratios for Stomach
and Brain.

Next is stevia, with one high value [above ratio 1.4],
9.48+-1.99 for Bladder, 2000 mg 3 hr, ratio 1.8 .

Aspartame has high values for 2000 mg 3 hr for Stomach, Colon,
Liver, Bladder, Lung.

Sucralose has 3 significant values and 13 high values, for Stomach,
Colon, Kidney, Bladder, Lung, Brain.

Sodium cyclamate has 4 significant values and 10 high values for
Stomach, Colon, Liver, Kidney, Bladder, Lung, Brain, Bone.

Saccharin has 3 highly significant values for Colon, and 13 high values
for Stomach, Colon, Kidney, Lung, Brain, Bone.

Sodium saccharin has 5 highly significant values for Stomach and Colon, and
14 high values for Stomach, Liver, Kidney, Bladder, Lung, Brain, Bone.

We should keep in mind that toxicity in humans involves many vulnerable
groups, years of daily use, often evolution of hypersensitivity, and complex
interactions with a multitude of foods, additives, other
toxins, foods, and infections.

Some of the dye data was earlier published in Tsuda (2001):
Toxicol Sci 2001 May; 61(1): 92-9
DNA damage induced by red food dyes orally administered to pregnant and male
mice.
Tsuda S, Murakami M, Matsusaka N,
Kano K, Taniguchi K, Sasaki YF.
Laboratory of Veterinary Public Health, Department of Veterinary
Medicine, Faculty of Agriculture, Iwate University, Ueda 3-18-8,
Morioka, Iwate 020-8550, Japan. s.tsuda@...

We determined the genotoxicity of synthetic red tar dyes currently used
as food color additives in many countries, including JAPAN: For the
preliminary assessment, we treated groups of 4 pregnant mice
(gestational day 11) once orally at the limit dose (2000 mg/kg) of
amaranth (food red No. 2), allura red (food red No. 40), or acid red
(food red No. 106), and we sampled brain, lung, liver, kidney, glandular
stomach, colon, urinary bladder, and embryo 3, 6, and 24 h after treatment.

We used the comet (alkaline single cell gel electrophoresis) assay to
measure DNA damage. The assay was positive in the colon 3 h after the
administration of amaranth and allura red and weakly positive in the
lung 6 h after the administration of amaranth.

Acid red did not induce DNA damage
in any sample at any sampling time.

None of the dyes damaged DNA in other organs or the embryo.

We then tested male mice with amaranth, allura red, and a related
color additive, new coccine (food red No. 18).
The 3 dyes induced DNA
damage in the colon starting at 10 mg/kg.

Twenty ml/kg of soaking liquid from commercial red ginger pickles,
which contained 6.5 mg/10 ml of new coccine, induced DNA
damage in colon, glandular stomach, and bladder.

The potencies were compared to those of other rodent carcinogens.
The rodent hepatocarcinogen p-dimethylaminoazobenzene
induced colon DNA damage at 1 mg/kg,
whereas it damaged liver DNA only at 500 mg/kg.

Although 1 mg/kg of N-nitrosodimethylamine
induced DNA damage in liver and bladder,
it did not induce colon DNA damage.
N-nitrosodiethylamine at 14 mg/kg
did not induce DNA damage in any organs examined.
Because the 3 azo additives we examined
induced colon DNA damage at a very low dose,
more extensive assessment of azo additives is warranted.
PMID: 11294979

http://groups.yahoo.com/group/aspartameNM/message/935
comet assay finds DNA damage from sucralose, cyclamate, saccharin
in mice: Sasaki YF & Tsuda S Aug 2002: Murray 2003.01.01

The Single Cell Gel Assay is able to detect single-strand and
double-strand DNA breaks in individual eukaryotic cells;
requires small numbers of cells (<20,000 per sample);
can detect DNA damage from low levels of toxic or physical insults;
and is rapid, simple and efficient.
In this assay, cells are treated with the agent of interest,
embedded in agarose on a histological slide,
the cell membranes are lysed,
and the slides are placed in an electric field.
If the DNA has single or double-strand breaks,
it will flow out of the cells and move toward the anode,
causing the cell and its DNA to resemble a comet.
The more DNA released from the cell, the greater the DNA damage.
A computerized imaging system is used to score and measure
the comets.
The Comet assay is not FDA approved as a human medical test,
so it is not covered by insurance.
It is used in many human research studies.

http://cometassay.com/ Comet Assay Interest Group

http://www.ems-us.org/index.asp Environmental Mutagen Society

http://www.helix3-inc.com/comet-assay.html

Addendum:
summarizing the mean +- variation values for the 21 control groups,
for each tissue, giving the smallest variation and the largest.

Stomach --- Colon ------ Liver ------ Kidney ----- Bladder

4.90+-0.26; 4.49+-0.19; 1.91+-0.19; 1.81+-0.13; 5.89+-0.24;
-- 5% ------- 4% ------- 10% -------- 7% -------- 4% -----

5.55+-1.26; 7.91+-1.95; 1.29+-0.69; 1.73+-0.96; 5.68+-1.30;
- 23% ------- 25% ------- 53% ------- 56% ------- 23% -----

Lung ------- Brain ------- Bone [marrow]

2.44+-0.17; 2.58+-0.40; 1.16+-0.15;
-- 7% ------- 16% ------- 13% ------

2.56+-1.04; 1.09+-1.09; 0.75+-0.75;
- 41% ------ 100% ---- 100% ------

We have +- mean variation, for the 21 control groups of 4 mice, from 4
to 100%. What causes this variation, for a specific strain of mice,
with the same diet, environment, and age? Are there a number of
genotoxins in the laboratory diet, with the mice exhibiting many genetic
susceptibilities? Are there genotoxic infections?


J Toxicol Sci. 2002 Dec; 27 Suppl 1: 1-8.
[Genotoxicity studies of stevia extract and steviol by the comet assay]
[Article in Japanese]
Sekihashi K, Saitoh H, Sasaki Y. yfsasaki-c@...
Safety Research Institute for Chemical Compounds Co., Ltd.,
363-24 Shin-ei, Kiyota-ku, Sapporo 004-0839, Japan.

The genotoxicity of steviol, a metabolite of stevia extract, was evaluated
for its genotoxic potential using the comet assay.
In an in vitro study, steviol at 62.5, 125, 250, and 500 micrograms/ml
did not damage the nuclear DNA of TK6 and WTK1 cells in the
presence and absence of S9 mix.
In vivo studies of steviol were conducted
by two independent organizations.
Mice were sacrificed 3 and 24 hr after one oral administration of steviol
at 250, 500, 1000, and 2000 mg/kg.
DNA damage in multiple mouse organs was measured by the comet
assay as modified by us.
After oral treatment, stomach, colon, liver, kidney and testis DNA were
not demaged.
The in vivo genotoxicity of stevia extract was also evaluated for its
genotoxic potential using the comet assay.
Mice were sacrificed 3 and 24 hr after oral administration of stevia
extract at 250, 500, 1000, and 2000 mg/kg.
Stomach, colon and liver DNA were not damaged.
As all studies showed negative responses, stevia extract and steviol are
concluded to not have DNA-damaging activity in cultured cells and
mouse organs. PMID: 12533916
*******************************************************


http://groups.yahoo.com/group/aspartameNM/message/1106
hangover research relevant to toxicity of 11% methanol in aspartame
(formaldehyde, formic acid): Calder I (full text): Jones AW:
Murray 2004.08.05 rmforall

Since no adaquate data has ever been published on the exact
disposition of toxic metabolites in specific tissues in humans of the
11% methanol component of aspartame, the many studies on
morning-after hangover from the methanol impurity in alcohol drinks
are the main available resource to date.

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%,
one part in ten thousand).

http://groups.yahoo.com/group/aspartameNM/message/1100
research on aspartame (methanol, formaldehyde, formic acid) toxicity:
Murray 2004.07.19 rmforall


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@...
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).

[ 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 methnol per ounce.

This suggests that alcohol drinkers are more sensitive to methanol
than the average diet soda drinker, some of whom find symptoms
from a third of a diet soda.]

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.]
*******************************************************


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 2005.05.30 2005.07.24 rmforall

"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]."

"However, the severe toxic effects are usually associated with the
production and accumulation of formic acid, which causes metabolic
acidosis 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://www.toxsci.oupjournals.org/cgi/content/full/64/2/169 full text

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 *, #, michele.bouchard@...

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
Fax: (514) 343-2200

# 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
*******************************************************


http://groups.yahoo.com/group/aspartameNM/message/1328
migraine from sucralose, Bigal ME & Krymchantowski AV,
Headache 2006 March; formaldehyde from 11% methanol part of
aspartame or from red wine causes same toxicity (hangover) harm:
Murray 2006.05.04

http://groups.yahoo.com/group/aspartameNM/message/1329
aspartame or MSG affects circadian rhythms in rats, two studies,
P. Subramanian, T. Manivasagam et al 2004:
Murray 2006.04.27


"Of course, everyone chooses, as a natural priority,
to actively find, quickly share, and positively act upon the facts
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://groups.yahoo.com/group/aspartameNM/messages
group with 73 members, 1,338 posts in a public, searchable archive
http://RMForAll.blogspot.com http://AspartameNM.blogspot.com

Dark wines and liquors, as well as aspartame, provide
similar levels of methanol, above 120 mg daily, for
long-term heavy users, 2 L daily, about 6 cans.

Within hours, methanol is inevitably largely turned into formaldehyde,
and thence largely into formic acid -- the major causes of the dreaded
symptoms of "next morning" hangover.

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). If 30% of the methanol is turned
into formaldehyde, the amount of formaldehyde, 37 mg,
is 18.5 times the USA EPA limit for daily formaldehyde in
drinking water, 2.0 mg in 2 L average daily drinking water.

Any unsuspected source of methanol, which the body always quickly
and largely turns into formaldehyde and then formic acid, must be
monitored, especially for high responsibility occupations, often with
night shifts, such as pilots and nuclear reactor operators.

http://groups.yahoo.com/group/aspartameNM/message/1052
DMDC: Dimethyl dicarbonate 200mg/L in drinks adds
methanol 98 mg/L [ becomes formaldehyde in body ]: EU Scientific
Committee on Foods 2001.07.12: Murray 2004.01.22

http://groups.yahoo.com/group/aspartameNM/message/1291
European Food Safety Authority to decide aspartame safety by May:
caffeine diet drinks cause female hypertension, WC Winkelmayer et al,
JAMA 2005.11.09: PubMed lists 50 items for "diet soft drinks" since
2004 Oct.: Murray 2006.01.24

http://groups.yahoo.com/group/aspartameNM/message/1279
all three aspartame metabolites harm human erythrocyte [red blood cell]
membrane enzyme activity, KH Schulpis et al, two studies in 2005, Athens,
Greece, 2005.12.14: 2004 research review,
RL Blaylock: Murray 2006.01.14

http://groups.yahoo.com/group/aspartameNM/message/939
aspartame (aspartic acid, phenylalanine) binding to DNA:
Karikas July 1998: Murray 2003.01.05 rmforall
Karikas GA, Schulpis KH, Reclos GJ, Kokotos G
Measurement of molecular interaction of aspartame and
its metabolites with DNA. Clin Biochem 1998 Jul; 31(5): 405-7.
Dept. of Chemistry, University of Athens, Greece
http://www.chem.uoa.gr gkokotos@...;
K.H. Schulpis inchildh@...; G.J. Reclos reklos@...;

http://groups.yahoo.com/group/aspartameNM/message/1271
combining aspartame and quinoline yellow, or MSG and brilliant blue,
harms nerve cells, eminent C. Vyvyan Howard et al, 2005
education.guardian.co.uk, Felicity Lawrence: Murray 2005.12.21
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