aspartameNM : Message: opportunities re BA Magnuson, GA Burdock et al., Aspartame Safety Evaluation 2007 Sept., Critical Reviews in Toxicology: Rich Murray 2008.07.11

opportunities re BA Magnuson, GA Burdock et al., Aspartame Safety Evaluation
2007 Sept., Critical Reviews in Toxicology: Rich Murray 2008.07.11
http://rmforall.blogspot.com/2008_07_01_archive.htm
Friday, July 11, 2008
http://groups.yahoo.com/group/aspartameNM/message/1550
____________________________________________________

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

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

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

http://groups.yahoo.com/group/aspartameNM/messages
group with 127 members, 1,550 posts in a public archive

http://groups.yahoo.com/group/aspartame/messages
group with 1,125 members, 22,796 posts in a public archive
____________________________________________________

[ See also:
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_07_01_archive.htm
Monday, March 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1531 ]

Introduction:

As a volunteer medical layman information activist, ( note that all citizens
are laymen outside the domain of their specific areas of expertise ) who for
over nine years has earnestly provided detailed, long, fair, civil reviews
on the Net of mainly mainstream aspartame toxicity research and related
topics, as well as responsible world media and Net sources, I submit a
version of my 240 KB critical review of an aspartame approving, Ajinomoto
funded review by BA Magnuson, GA Burdock, et al. 2007, (which herein is
designated as "ASE"), to the world public.

I welcome cogent criticism, which usually I will promptly add uncensored to
my public archive.

bias, omissions, incuriosity = opportunity, aspartame safety evaluation,
Magnuson BA, Burdock GA, Williams GM, 7 more, 2007 Sept, Ajinomoto funded 98
pages html [ $ 32 pdf ]: Murray 2007.09.15
http://rmforall.blogspot.com/2007_09_01_archive.html
Saturday, September 15, 2007 240 KB

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

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

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

http://groups.yahoo.com/group/aspartameNM/messages
group with 127 members, 1,550 posts in a public archive

http://groups.yahoo.com/group/aspartame/messages
group with 1,124 members, 22,793 posts in a public archive

My inspiring mentor since January 1999 has been another conscientious
medical layman, Mark David Gold, gives an excellent 13-page critique of ASE
that details undue industry affiliations by the authors and specific faults
in their opus:
http://www.HolisticMed.com/aspartame mgold@...
Aspartame Toxicity Information Center, Mark D. Gold
12 East Side Drive #2-18 Concord, NH 03301 603-225-2100

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

http://www.holisticmed.com/aspartame/burdock/

"Nearly every section of the Magnuson (2007) review has research that is
misrepresented and/or crucial pieces of information are left out.

In addition to the misrepresentation of the research, readers (including
medical professionals) are often not told that this review was funded by the
aspartame manufacturer, Ajinomoto, and the reviewers had enormous conflicts
of interest."

[ See also:

http://groups.yahoo.com/group/aspartameNM/message/957
safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
Murray 2003.01.12 EU Scientific Committee on Food, a whitewash

http://groups.yahoo.com/group/aspartameNM/message/1045
http://www.holisticmed.com/aspartame/scf2002-response.htm
Mark Gold exhaustively critiques European Commission Scientific Committee on
Food re aspartame ( 2002.12.04 ): 59 pages, 230 references ]

www.informaworld.com/smpp/section?content=a781888262&fulltext=713240928 $
32

Bernadene A. Magnuson,
George A. Burdock,
John Doull,
Robert M. Kroes, [deceased]
Gary M. Marsh,
Michael W. Pariza,
Peter S. Spencer,
William J. Waddell,
Ronald Walker,
Gary Murray Williams.
"Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations,
and Toxicological and Epidemiological Studies,"
Critical Reviews in Toxicology, 37(8), 629-727, 2007 Sept [415 references]

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@...;
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. ]
____________________________________________________

details on 6 epidemiological studies since 2004 on diet soda (mainly
aspartame) correlations, as well as 13 other mainstream studies on aspartame
toxicity since summer 2005: Murray 2007.11.14
http://rmforall.blogspot.com/2007_11_01_archive.htm
Wednesday, November 14, 2007
http://groups.yahoo.com/group/aspartameNM/message/1490

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

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

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

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

Abstract

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

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

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

FA elimination is mediated by folic acid.

Neurotoxicity is a common result of chronic alcoholism.

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

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

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

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

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

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

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

When folic acid (1 umol/l) was added with the FA, neuronal death was
prevented. [ umol = micromole ]

Conclusions:
Formic acid may be a significant factor in the neurotoxicity of ethanol
abuse.

This neurotoxicity can be mitigated by folic acid administration at a
clinically relevant dose.

Key Words:
Formic Acid, Folic Acid, Methanol, Neurotoxicity, Alcoholism.

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

St. Michael's Hospital (ACV), Toronto, Canada;

Department of Laboratory Medicine and Pathobiology, (BMK, ACV), Faculty of
Medicine, University of Toronto, Toronto, Ontario, Canada;

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

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

Received for publication May 1, 2007; accepted September 24, 2007.

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

Copyright 2007 by the Research Society on Alcoholism. DOI:
10.1111/j.1530-0277.2007.00541.x
Alcoholism: Clinical and Experimental Research 2007 Dec.
Alcohol Clin Exp Res, Vol. 31, No 12, 2007: pp 2114-2120

NEUROTOXICITY AND BRAIN damage are common concomitants findings of chronic
alcoholism (Carlen and Wilkinson, 1987; Carlen et al., 1981; Harper, 2007).

The cause of ethanol-induced neurotoxicity is still unclear.

We present here a novel hypothesis for neurotoxicity: increased formic acid
(FA) levels produced from methanol (MeOH), whose catabolism is blocked by
ethanol.

Axelrod and Daly (1965) demonstrated the endogenous formation of MeOH from
S-adenosylmethionine (SAM) in the pituitary glands of humans and various
other mammalian species.

Presence of MeOH in the breath of human subjects was reported by Ericksen
and Kulkarni (1963).

Most alcoholic beverages also have a small amount of MeOH as a congener
(Sprung et al., 1988).

As ethanol (EtOH) has a higher affinity for alcohol dehydrogenase (ADH) than
MeOH, EtOH is preferentially metabolized (Mani et al., 1970).

As a result, MeOH accumulation from endogenously produced MeOH, and/or, that
consumed as part of an alcoholic beverage, has been reported in
concentrations up to 2 mmol/l in heavy drinkers (Majchrowicz and Mendelson,
1971).

Toxicity resulting from MeOH consumption is extensively documented in both
humans and animals and has been attributed to its metabolite, FA (Benton and
Calhoun, 1952; Roe, 1946, 1955; Wood, 1912; Wood and Buller, 1904).

The rate of formate oxidation and elimination is dependent on adequate
levels of hepatic folic acid, particularly hepatic tetrahydrofolate (THF)
(Johlin et al., 1987; Tephly and McMartin, 1974).

Significantly higher formate levels were obtained when folate-deficient
animals were exposed to MeOH as compared with folate-sufficient animals (Lee
et al., 1994; McMartin et al., 1975; Noker et al., 1980).

To understand ethanol's toxicity, one must consider FA produced from MeOH,
and its elimination mediated by folic acid.

We postulate that in the chronically drinking patient, we will find higher
levels of FA than in the nondrinking population, and that formate is
neurotoxic.

We also hypothesize that treatment with folic acid, which is a critical
factor in the catabolism of FA, can prevent or diminish FA neurotoxicity.
____________________________________________________

Pondering how to proceed for two months, I realized the value of my
existing opus and modus operandi. It is best to submit this text as a
working preprint, in the public domain, allowing readers to access the
wonderful opportunities today on the Net for immediate, full, unlimited,
detailed, uncensored, global public collaboration, forever archived, freely
accessible, and very conveniently searchable. Thus, the text is a portal to
aid agile readers in hopping quickly in any direction and depth they want,
with hyperlinked references throughout.

The focus here, largely bypassing the isolated fortress islands of vested
interest operations, vainly entrenched to impede open-ended investigation,
shut down debate, defend narrowly construed self-interest, spread confusion,
instill propaganda -- all the dull, tedious, pious pleadings of false
authority, the mistakable artifice of modern PR spin artists, in the service
of criminal capitalism -- is opportunity.

Opportunity is not optional. Just as new collaborations of responsibility
arose in the face of nuclear and thermonuclear bombs after 1945, so again
now with the current chemical catastrophe:

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

http://health.groups.yahoo.com/group/GFCFKids/messages

This group, after nine years, has 12,708 members and 335,599 posts in a
public archive: "This list is unmoderated and unrestricted. The principle
aim of this list is to provide a discussion forum for parents of children on
the autism spectrum who are avoiding gluten and casein and other substances
in their children's diets. "

British Columbia guidelines against "any drinks with artificial sweeteners"
in January 2008 in school vending machines, stores, cafeterias or
fundraisers -- also recently in Ontario and Quebec, Janet Steffenhagen
2007.12.28 Vancouver Sun: Murray 2008.04.10
http://rmforall.blogspot.com/2008_04_01_archive.htm
Thursday, April 10, 2008
http://groups.yahoo.com/group/aspartameNM/message/1537

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

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

http://groups.yahoo.com/group/aspartameNM/message/1341
Connecticut bans artificial sweeteners in schools, Nancy Barnes, New Milford
Times: Murray 2006.05.25

http://groups.yahoo.com/group/aspartameNM/message/1369
Bristol, Connecticut, schools join state program to limit artificial
sweeteners, sugar, fats for 8800 students, Johnny J Burnham, The Bristol
Press: Murray 2006.09.22

Summary:

1. The preceding items indicate a few facets of exponentially evolving
global responses on many levels to chemical catastrophe. AspartameNM was
set up nine years ago to facilitate this process with detailed, thorough,
referenced information, civil discourse based on reason and public evidence,
and openness to dialogue among diverse and opposed points of view. It may
well evolve into a new type of scientific journal, with an unusually broad
membership, allowing fully democratic co-evolution of articles, discussions,
research and public affairs proposals, funding, project implementations,
completely transparent and perpetually archived communication during all
phases, constant sharing of data, conclusions, and open questions to
consider, with constantly co-created traditions of organization,
responsibility, and ownership, naturally allied with other "open source"
service societies, like Wikipedia and Citizendium, and the many 12-Step
communities.

This review exists within and serves this context of a wider global society,
extremely diverse yet complexly unified, aided by service societies not
bound by past concepts: national, political, economic, educational,
governmental, legal, medical, spiritual, scientific. Multiple exponential
emergencies mandate multiple exponential service societies.

Here, it is helpful for the specific case of aspartame toxicity to present
salient capsules, with full references and texts given in the rest of this
text.

2. Aspartame is a triple toxin, since all three of its loosely bound
components along with their complex metabolites are toxic, especially for
the many vulnerable groups who are also long-term, heavy users, above 6 cans
diet soda, 1,200 mg aspartame, daily for years:
Phenylalanine 50%, aspartic acid 39%, methanol 11% -- methanol likewise owes
its toxicity entirely to its rapid conversion in humans to formaldehyde and
thence to formic acid. About 30-40% of the methanol remains in human
tissues as cumulative, toxic products, as yet largely unobserved and
unexplored.

3. It is fruitless to study aspartame without tracking its actual metabolic
fate in specific tissues in individual humans.

4. There is extreme individual variation -- involving genetics, diet, health
status, drugs and medicines, age, sex, stress, other toxins and protective
factors like adaquate folic acid levels.

5. According, studies that focus on averages, such as much of epidemiology
and double blind experimental tests, are completely blind to the realities.

6. Therefore, it is essential to do deep, detailed, exhaustive studies on
individuals, starting with case histories.

7. It is necessary to thoroughly integrate all studies on methanol,
formaldehyde, formic acid, folic acid, acetaldehyde, alcohol hangover,
addiction studies, and all sources of methanol and formaldehyde, including
alcohol drinks, tobacco and wood smoke, air pollution, degradation of
pectins from fruits and vegetables by bacteria in the colon, and the modern
diet and environment. The toxic level of concern for formaldehyde from air
in mobile homes is about the same as the dose from 3 cans of diet soda.

8. Folic acid in most people expedites the safe metabolism of methanol and
formaldehyde, so it must be included in most research. It is urgent to
immediately assess and publicize its value. Its presence in fruits and
vegetables may account for the low level of reported symptoms.

9. There are many, many other such co-factors.

10. Behavioral measures for neurotoxicity show immediate harm at much lower
doses, compared to biochemical and genetic effects.

11. Thus, current safety levels are too high by an order of magnitude or
more for methanol, formaldehyde, formic acid, and so on.

12. During the Stone Age, high levels of methanol from fermented fruit and
of formaldehyde from wood fires may have have helped humans survive fungi,
germs, and viruses. These possible benefits should be evaluated for many
kinds of people and conditions.

13. Thus, evolution may have operated to make alcohol, acetaldehyde,
formaldehyde, and formic acid addictive.

14. A small population in the Stone Age may have evolved overproduction of
brain cells to counter neurotoxicity, leading to larger brains overall and a
thus a major survival gain. Then, overall positive selection pressure would
also promote addiction to nonlethal levels of neurotoxins, as is common
today for caffeine, alcohol, tobacco, cocaine, heroin, marihuana, etc.

15. Formaldehyde is well known as an initial and subsequent trigger for
hypersensitivity, Multiple Chemical Sensitivity.

16. The Comet assay enables fast, inexpensive, subtle measures of genetic
damage from neurotoxins in single cells.

17. ASE reference (Larsen and Richold, 1999): re survey of teenage
diabetics

3.5. "Methanol generated from aspartame is estimated to average 33 mg/day
or 0.55 mg/kg bw/day for a 60-kg individual.

For individuals in the 95th percentile the estimated methanol consumption
figures are 93.9 mg/day or 1.57 mg/kg bw/day for a 60-kg individual." [
three times more than the average ]

[ Thus, 114% of the European ADI of 40 mg/kg bw/day for a 60-kg teenager
gives 2,736 mg aspartame daily, with the 11% methanol 301 mg daily, so 30%
retention of cumulative durable toxic products of formaldehyde and formic
acid would be 90 mg daily -- 2700 mg a month.

About 150 mg methanol impurity in ordinary liquors is a major cause of
"morning after" hangovers, due to the conversion of methanol into
formaldehyde and formic acid, with methanol blood levels
reduced to about 3%, 5 mg/l, 13 h after drinking.

However, almost all of the methanol from aspartame is quickly released into
the blood.

It is urgent to assess the specific health status of this "small
subpopulation" of teenage diabetics who endure these remarkable toxic
exposures.

18. 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
[ highest value 3400 mg ]

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.

18. Besides their recent studies on lifetime aspartame carcinogenicity, the
Ramazzini team in 2002 found similar cancers from studies with alcohol,
acetaldehyde, methanol, and formaldehyde at levels corresponding to those
from conversion from aspartame.

Critique:

Naturally, I want to cut to the chase with pertinent critical comments,
often giving quotes from the ASE text and its 415 references, and then my
comments in square brackets.

ASE 6. "As aspartame is completely hydrolyzed following intake, studies
employing either intraperitoneal administration or direct exposure of cells
in vitro to intact aspartame do not reflect human exposures and therefore,
must be carefully interpreted." [ Spot on! ]

ASE 3.1.1 [ They state that 22 mg ingested aspartame releases 2.4 mg
methanol, Stegink, 1987 -- i.e., which is 11% of the aspartame.

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 times the USA EPA limit for daily formaldehyde in drinking water, 2 mg in
2 L water.

For instance, hangover researchers claim that it is the ~150 mg/L methanol
impurity, about one part in 10,000, twice the level from aspartame in diet
sodas, in dark wines and liquors that, turned into formaldehyde and then
formic acid, is the major cause of the common symptoms of "morning after"
hangover.

In addition, the half-life of methanol in blood is about 2.5 h, (SE Jones
et al. 1987) and hangover symptoms occur 13 hours later, five half-lives, so
by then the methanol blood level is reduced about 32 fold, to about 3 %, or
5 mg/L (YS Woo et al. 2005) -- whereas the methanol from aspartame is
quickly available in full. ]

[ ASE reference 254: Oppermann JA, Muldoon E, Ranney RE.
Metabolism of aspartame in monkeys.
J. Nutrition 1973 Oct; 103(10): 1454-1459. [ free full text via PubMed ]
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680

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

They did not mention that this meant that about 30% of the methanol must
transform into formaldehyde and then into formic acid, both of which must
remain as toxic products in all parts of the body.

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

This study did not monitor long-term use of aspartame. ]

ASE 3.1.5. "Ilback et al. (2003) surveyed 1120 diabetics and reported that
average daily intakes of aspartame by children and adult diabetics were
below the ADI, for both the top 5% and 10% consumers.

Worst-case intakes were calculated for the 10 diabetic children [ 1.1% of
adults and children ] consuming the highest amounts of artificially
sweetened foods and using the highest concentrations of
sweetener allowed in food products.

The worst-case calculation was based on the following assumptions:
(1) All sweeteners found in the diet were replaced by aspartame;
(2) the level of aspartame in foods was the maximum allowed by regulations,
not the concentration actually used in the foods; and
(3) the intake was based on the highest reported consumption of 10 diabetic
children consuming the highest amounts of artificially sweetened foods.

These worst-case calculations showed that consumption by this small
subpopulation would exceed the ADI by only a small percentage (about 114% of
the ADI), and thus the authors concluded that there is a sufficient safety
margin for aspartame, even in high consuming diabetics in a single time
point (Ilback et al., 2003). "

"Therefore, a short period of exposure slightly above the ADI is not
considered to pose any significant risk (Larsen and Richold, 1999)."

ASE 3.3. "Methanol generated from aspartame is estimated to average 33
mg/day or 0.55 mg/kg bw/day for a 60-kg individual.

For individuals in the 95th percentile the estimated methanol consumption
figures are 93.9 mg/day or 1.57 mg/kg bw/day for a 60-kg individual." [
three times more than the average ]

[ Thus, 114% of the European ADI of 40 mg/kg bw/day for a 60-kg teenager
gives 2,736 mg aspartame daily, with the 11% methanol 301 mg daily, so 30%
retention of cumulative durable toxic products of formaldehyde and formic
acid would be 90 mg daily -- 2700 mg a month.

About 150 mg methanol impurity in ordinary liquors is a major cause of
"morning after" hangovers, due to the conversion of methanol into
formaldehyde and formic acid, with methanol blood levels
reduced to about 3%, 5 mg/L, 13 h after drinking.

It is urgent to assess the specific health status of this "small
subpopulation" of teenage diabetics who endure these remarkable toxic
exposures.

Many aspartame reactors used over 12 12-oz cans daily diet soda for years.
At 200 mg each, this is 2400 mg daily aspartame, 264 mg methanol, and at
30%, 80 mg retained formaldehyde and formic acid products -- disposition,
biochemistry, and concentrations unknown as yet to world science.

This fundamental crucial ignorance is hardly grounds for disingenuously
dismissing every one of hundreds of mainstream research reports and
thousands of individual cases by informed professionals and affected people.

Yet, this is all that is offered the ASE review, by a paid expert panel set
up by the Burbank Group, funded by Ajinomoto. Should not the
"remuneration," past or continuing be disclosed, along with any contractual
obligations?

The greatest gift of science to humanity since 1600 is the vision of
unfettered, yet disciplined, curiosity, publicly and respectfully shared,
about all aspects and levels of our infinite reality.

Questions raised generate partial answers, which open up ever expanding
frontiers of more questions, within a overall richness of understanding and
subtlety of communication that is profoundly meaningful, awesomely
beautiful, and of the greatest practical value.

Like all the other previous reviews, invariably committee work at its worst,
the ASE review, fails totally at being curious, at spotting telling details
(where frisky devils cavort), acknowledging fundamental unknowns, and
raising pointed questions to inspire their peers.

Once again, good, intelligent, trained, experienced, dedicated, earnest
scientists have failed themselves and science, by acquiescing to
participation, true, very well paid, in a ceremonial public ritual dance of
groupthink to support vast vested interests.

Once again, the good tidings are immediately proclaimed in a global media
campaign, a Katrina deluge of relentless, repetitious, pious, preaching --
Our witch doctors have met and burned much incense, the baleful concerns are
all laid to rest, so go ye villagers and consume ye yet more in peace.

Once again, but with some progress.

Now, there are many times more references, with ever more on recent studies.

Now, there is explicit discussion, or at least mention, of areas of
ignorance.

Now, at least on the edge of the table of discourse, are closely related
fields of methanol, formaldehyde, formic acid, alcohol hangover, MSG,
additives, tobacco, addiction, vehicle exhaust, diet, genetic variation,
drug interactions, the many new modern diseases, whole population
epidemiology, global data bases mining -- all growing exponentially, all
intimately, instantly linked on the Net.

Now, every match sets off fire.

Now, there are Net groups with permanent, open archives, where citizens and
experts collaborate on every problem, i.e. opportunity.

AspartameNM -------------------- 127 members ---- 1,550 posts
Aspartame ---------------------- 1,124 members --- 22,793 posts
GlutenFreeCaseinFreeKids ---- 12,708 members -- 335,599 posts

The ASE review will ignite a new level of creative world collaboration to
finally remove gratuitous toxins.

This is the purpose of this critical review.

Now, corporations are inevitably competing to maximize the health, energy,
clarity, intelligence, sanity, and creative productivity not only of their
staff, but their customers, and all people.

A huge opportunity: find a safe, inexpensive process to remove all methanol
from alcohol beverages, solving the billion-dollar disease of alcohol
hangovers.

In this regard, it is tragic to delay study of the role of folic acid as a
safe, inexpensive preventive of toxicity from methanol and formaldehyde.

A corporate tipping point: whether to continue the mistake of continuing to
bet the ranch on a single highly profitable, but sadly toxic product, in a
radically uncontrolled information environment that can this year produce an
Enron-level meltdown, with tedious, hundred billion dollar civil and
criminal liabilities, a la tobacco, or immediately shut down the operation,
release all secret files and research, and set up hundred billion dollar
funds to recompense individuals and governments, while funding independent
groups to definitively study the health issues -- which can rapidly lead to
good business opportunities.

Corporations probably best cooperate to expedite this forward moving
retreat.

ASE members and Burdock Group: The ASE review should be made available for
free on the Net, along with the full text of the references and many more
related studies and a open, public archive, unedited public action group for
civil discussion and collaboration.

All financial and secrecy contracts should be made public, along with the
details of the history of meetings and communications, especially how
dissent and conflict were managed.

The ASE review should best evolve into a on-going public collaboration like
Wikipedia or Citizendium. ]

ASE 3.2. "Thus there is no established UL for either aspartic acid or
phenylalanine (Institute of Medicine, 2005)."

ASE 3.3, "Taucher et al. (1995) estimated that humans produce approximately
1000 mg of methanol daily from [pectins in] fruits and vegetables."

[ ASE reference 375:
Taucher J, Lagg A, Hansel A, Vogel W, Lindinger W.
Methanol in human breath.
Alcohol Clin Exp Res. 1995 Oct; 19(5): 1147-50.
Institut fur Ionenphysik, Universitat Innsbruck, Austria.

Using proton transfer reaction-mass spectrometry for trace gas analysis of
the human breath, the concentrations of methanol and ethanol have been
measured for various test persons consuming alcoholic beverages and various
amounts of fruits, respectively.

The methanol concentrations increased from a natural (physiological) level
of approximately 0.4 ppm up to approximately 2 ppm a few hours after eating
about 1/2 kg of fruits, and about the same concentration was reached after
drinking of 100 ml brandy containing 24% volume of ethanol and 0.19% volume
of methanol. [ 24 ml = 61 g ethanol, and 0.19 ml = 0.34 g = 340 mg
methanol ]
PMID: 8561283

The high folic acid levels in many fruits and vegetables may protect most
people from resulting conversion of methanol into formaldehyde and formic
acid. ]

ASE 3.3.1. "Exposure to Formaldehyde From Methanol in Aspartame

As is described later, methanol is metabolized to formaldehyde, which is
rapidly further metabolized."

"For example, the demethylation of the caffeine found in one cup of coffee
produces 30 mg of formaldehyde (Imbus, 1988)."

[ These important, surprising results demand thorough, immediate, definitive
research into the disposition of these apparently highly toxic sources of
methanol (formaldehyde) in various vulnerable groups of people -- rather
than be used as an insipid ploy to insinuate that any methanol from
aspartame is non-issue. ]

[ http://groups.yahoo.com/group/aspartameNM/message/835
ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999:
Murray 2002.05.30

"The EPA recommends that an adult should not drink water containing more
than 1 milligram of formaldehyde per liter of water (1 mg/L) for a lifetime
exposure, and a child should not drink water
containing more than 10 mg/L for 1 day or 5 mg/L for 10 days."

http://groups.yahoo.com/group/aspartameNM/message/1140
EPA Preliminary Remedial Goals, PRGs, 2003 Oct, air and tap water --
methanol, formaldehyde, formic acid -- not mentioned is methanol from
aspartame, dark wines and liquors: Murray 2004.11.20

http://groups.yahoo.com/group/aspartameNM/message/1108
faults in 1999 July EPA 468-page formaldehyde profile: Elzbieta Skrzydlewska
PhD, Assc. Prof., Medical U. of Bialystok, Poland, abstracts -- ethanol,
methanol, formaldehyde, formic acid, acetaldehyde, lipid peroxidation, green
tea, aging: Murray 2004.08.08 2005.07.11 ]

"The 1999 July EPA 468-page formaldehyde profile admits that four states
substantially exceed the federal EPA limit:

Environmental Protection Agency 2.00 mg in 2 L daily drinking water
California and Maine ----------------- 0.06 mg
Maryland ---------------------------- 0.02 mg
New Jersey -------------------------- 0.20 mg"

Maryland's limit is ten times more stringent than the EPA's." ]

[ 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).

Jones AW. wayne.jones@...
Elimination half-life of methanol during hangover.
Pharmacol Toxicol. 1987 Mar; 60(3): 217-20.
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

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

[ DMDC would be a very useful alternative source of methanol for human
studies, as controls to compare with aspartame and wines. ] ]

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

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

ASE 4.1. "Formic acid is ultimately converted to CO2 and water, via the
formation of 10-formyl tetrahydrofolate (Barceloux et al., 2002)."

ASE 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)."

[ In a few pages, I give many details about formaldehyde and formic acid
dispositions in blood and tissues of 4 small monkeys from a single damage
level methanol dose:

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." ]

Ernstg�rd 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@...
http://toxsci.oxfordjournals.org/cgi/content/full/88/1/30 free full text

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

"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., 1988)
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,
Ernstg�rd et al., 1999, 2002; J�rnberg et al., 1996; Nihl�n et al., 1998b)."

"Background levels of methanol were detected in all samples during control
exposure: blood range 9-76 �M/l, saliva 4-76 �M/l, urine 13-86 �M/l, and
exhaled air 0.0005-0.01 �M/l.

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) �M/lat 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."

ASE reference 133: Hantson PE.
[Acute methanol intoxication: physiopathology, prognosis and treatment]
[Article in French]
Bull Mem Acad R Med Belg. 2006;161(6):425-34; discussion 434-6.
D�partement 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

Bebarta VS, Heard K, Dart RC.
Inhalational abuse of methanol products: elevated methanol and formate
levels without vision loss.
Am J Emerg Med. 2006 Oct; 24(6): 725-8.
Department of Emergency Medicine, Wilford Hall Medical Center, San Antonio,
TX, USA. vikbebarta@...

Inhalant abuse of methanol-containing products has increased over the last
decade.

We performed a prospective observational study of 7 subjects who presented
to an ED after inhalant abuse of methanol-containing hydrocarbon products.

Four patients had a methanol level greater than 24 mg/dl and 2 had an anion
gap greater than 17 mEq/l. [ 240 mg/l blood ]

The mean formic acid level was 71 microg/ml, and 1 patient had a level
considered high enough to induce retinal toxicity (>200 microg/ml). [ 71
mg/l blood]

No patient had an abnormal ophthalmologic examination.

All patients were treated with intravenous folate, 2 received alcohol
dehydrogenase blockade, and no patient received hemodialysis or intravenous
bicarbonate.

All patients' acidosis resolved within 4 hours.

The methanol and formic acid levels are lower than those reported after
methanol ingestion.

These preliminary data suggest that inhalant abusers of methanol products
may have significantly elevated methanol and formic acid levels, but are at
low risk for methanol induced complications of visual dysfunction and
refractory acidosis. PMID: 16984844

Hovda KE, Urdal P, Jacobsen D.
Increased serum formate in the diagnosis of methanol poisoning.
J Anal Toxicol. 2005 Sep; 29(6): 586-8.
Department of Acute Medicine, Ullevaal University Hospital,
NO-0407 Oslo, Norway. knov@...

Early diagnosis is essential for successful treatment in methanol poisoning.

Methanol detection by gas chromatography is not available in most hospitals.

Methanol increases the osmolal gap in serum and its metabolite formate
increases the anion gap.

The sensitivity of these indirect diagnostic methods is not good at low
concentrations of methanol or formate.

We therefore studied the usefulness of formate measurement in diagnosing
methanol poisoning.

In 15 patients poisoned with methanol, serum formate was measured
enzymatically on a Cobas Mira analyzer using formate dehydrogenase and
nicotinamid adenine dinucleotid.

Day-to-day coefficient of variation was 5%, and the upper reference limit
was 2 mg/dl (0.4 mmol/l). [ 20 mg/l blood serum = 0.4 mmol/l ]

Methanol was detected in all 15 patients of whom 14 had elevated serum
formate concentrations.

Anion gap was increased in 11 of 11, and osmolal gap in 11 patients of 15
examined.

Metabolic acidosis was present in 12 of 15 patients, but pH was below 7.30
in only 9 of them.

Four patients with no symptoms had formate concentrations in the range 2-38
mg/dl (0.5-8.3 mmol/l), indicating that increased serum formate was a
sensitive indicator of methanol poisoning.
[ 20-380 mg/l blood serum = 0.5-8.3 mmol/l]

Our results proved formate analyzes to be a simple, sensitive, and specific
way of diagnosing methanol poisoning.

Confounders are patients admitted early, or concomitant ethanol ingestion,
and therefore no acidosis.

This problem may, however, be omitted by repeated formate analysis in
patients developing metabolic acidosis. PMID: 16168185

[ 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; R�e, 1982; Tephly and McMartin, 1984)."

"Formaldehyde, as it is highly reactive, forms relatively stable adducts
with cellular constituents (Heck et al., 1983; R�e, 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; R�e, 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."

Mich�le Bouchard *, #,1, michele.bouchard@...;
Robert C. Brunet, # brunet@...
Pierre-Olivier Droz, #
Ga�tan Carrier* gaetan.carrier@...
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

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 ]

http://groups.yahoo.com/group/aspartameNM/message/1067
eyelid contact dermatitis by formaldehyde from aspartame,
AM Hill & DV Belsito, Nov 2003: Murray 2004.03.30 [150 KB]

[ In this 2003 critique, I added a long critique of industry research,
including this study, not in the ASE review:

Biochemical Pharmcacology 1979: 28; 645-649. [ No abstract in PubMed ]
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.
The Toxicology Center, Dept. of Pharmacology,
University of Iowa, Iowa City, Iowa 52242 PMID: 109089

K.E. McMartin and T.R. Tephly, authors of many pro-aspartame studies, in
Biochemical Pharmacology (1979) remarked, "It is now generally accepted that
the toxicity of methanol is due to the formation of toxic metabolites,
either formaldehyde or formic acid."

They put damage doses of methanol into the stomachs of three monkeys, and,
using insensitive tests, found no formaldehyde in many tissues -- except for
a single datum in the midbrain, 1.5 times the detection limit.

They did report widespread accumulation of formic acid in five tissues.

The use of inadequate tests is common in industry research that is funded to
claim the safety of profitable toxins.

Since then, industry scientists have been very wary of doing studies on
primates, which all too easily show the dangers to humans.

"Abstract [ not given in PubMed ]: [ My briefer comments are in square
brackets. ]

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

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

No formaldehyde accumulation was observed in the blood and no formaldehyde
was detected in the urine, cerebrospinal fluid, vitreous humor, liver,
kidney, optic nerve, and brain in these monkeys at a time when marked
metabolic acidosis and other characteristics of methanol poisoning were
observed.

Following intravenous infusion into the monkey, formaldehyde was rapidly
eliminated from the blood with a half-life of about 1.5 min and formic acid
levels promptly increased in the blood.

Since formic acid accumulation accounted for the metabolic acidosis and
since ocular toxicity essentially identical to that produced in methanol
poisoning has been described after formate treatment, the predominant role
of formic acid as the major metabolic agent for methanol toxicity is
certified.

Also, results suggest that formaldehyde is not a major factor in the toxic
syndrome produced by methanol in the monkey."

"It is now generally accepted that the toxicity of methanol is due to the
formation of toxic metabolites (1,2), either formaldehyde or formic acid."

So, this is an acute toxicity study, with little relevance for chronic
long-term, low-level exposure.

Monkeys, like people, are susceptible to methanol toxicity.

This team cites their six previous methanol in monkey studies, from 1975 to
1977.

The report is difficult to understand, since the three monkeys were treated
differently, and different assays were used.

For the methanol sensitive, folate-deficient monkey A, the assay used was
the chromatropic acid method, with a detection limit of .025 mmol/l.

None of the five tissues showed any formaldehyde with this assay, except the
midbrain, 0.14 mmol/kg wet weight tissue [ units converted from their 0.14
micromole/gm ] -- just 1.5 times the detection limit of .09 mmol/kg wet
tissue weight (given on p. 648).
[ Since 1 kg of water is 1 liter, 1 mmol/kg is equivalent to 1 mmol/l. ]

Meanwhile, in the methanol sensitive, folate-deficient monkey A, the blood
formate level rose by 18 hours from 0.18 to 10.02 mEq/l. [ I assume that a
mEq is equivalent to a mmol -- let me know if I'm wrong. ]

The formate detection limits for the assays were not given in this report.

The formate level in the vitreous humor of the eye of monkey A was 7.90
mEq/l.

It is well known that formate is extremely damaging to the eye.

For unexplained reasons, formate levels in the five tissues and
cerebrospinal fluid were not measured in the methanol sensitive,
folate-deficient monkey A., in the cerebrospinal fluid of monkey B, or in
the optic nerve of monkey C.

Formaldehyde was not measured in the optic nerve of Monkey A.

The kidney formate level for monkey B was 6.33 and for C was only 0.44, with
no comment or explanation given.

The experiment seems arbitrary, capricious, and erratic.

For monkey A, after 18 hours, the urine formaldehyde level was below
detection level, while urine formate was 115.80 mEq/l -- so much of the
formaldehyde had been converted into formic acid, another cumulative, potent
toxin.

"In the presence of high formate values and definitive evidence of toxicity
in methanol-poisoned monkeys, no measurable formaldehyde was found in the
body tissues that were tested."

It is reasonable to surmise that more sensitive assays would have found
formaldehyde and formate bound to and reacted with a variety of cellular
substances in all tissues -- just as the 1998 Trocho study confirmed.
(Appendix E)

Monkeys B and C were normal, not extra vulnerable to methanol, and were
given 3,000 mg/kg methanol, and samples taken at 18 hr.

Formaldehyde was detected only in the blood of Monkey B, while formate was
found in 8 and 10, respectively, of the 10 fluid and tissue samples in
Monkeys B and C.

For instance, the lowest value of formate, except for zero-time blood, for
each monkey was in the midbrain, 2.16 mmol/kg for Monkey B (24 times the
detection limit for the chromatropic acid method) and 1.02 mmol/kg (1.3
times the detection for the dimedon method) for Monkey C.

This shows accumulation of formate in liver, kidney, optic nerve, cerebrum,
and midbrain.

"Thus, whereas one can associate formate intimately with ocular toxicity in
the monkey, no association of formaldehyde with ocular toxicity can be made
at this time. It is not possible to completely eliminate formaldehyde as a
toxic intermediate because formaldehyde could be formed slowly within cells
and interfere with normal cellular function without ever obtaining levels
that were detectable in body fluids..."

"Acknowledgements -- This research was supported by NIH grant GM 19420 and
GM 12675." [not funded by the industry]

Appendix F:

The exponential fragmentation of science into a fractile structure of ever
more atomized specialties ensures that every expert is a layman outside his
own specialty.

Capable laymen play an essential role by summarizing and integrating
scattered lines of inquiry that certain vested interests have long-term
campaigns for obscuring, since outright opposition would tend to attract
discussion and scrutiny that would soon vitiate billion dollar products.
Most professionals simply do not have the free time to investigate such
arcane, but possibly crucial, details. Capable laymen now join together on
the Net to establish credibility by common sense, polite mobilization of
specialized research, backed by support from informed specialists.

For instance, I started investigating aspartame in early January 1999 and
within two months was being given papers by Woodrow C. Monte and Ralph G.
Walton.

The route of aspartame to methanol to formaldehyde to formic acid is a
classic example. Were this line of inquiry already suspected to be sure to
establish the harmlessness of aspartame, then the industry would have every
motive to spend a few paltry millions to both complete the research in
humans and widely publicize the results.

The fact that on the contrary, there is no industry funded research in
humans at all in the public domain on the specific biochemical and tissue
outcomes of formaldehyde and formic acid from aspartame leads to a
reasonable surmise that the industry has reason to fear, obscure, and derail
this inquiry.

Following the crooked but unmistakable trail of missing research, i.e.,
avoided, ignored, misstated, discounted, obscured, explained away, or simply
never mentioned, is an excellent strategy for uncovering the lurking secret.

In spring 1999, an eminent pro-aspartame scientist Christian Tschanz had
NutraSweet Co. give me their $ 130 review text of their research, "The
Clinical Evaluation of a Food Additive: Assessment of Aspartame" (1996), by
Christian Tschanz, Harriett H. Butchko, W. Wayne Stargel, and Frank N.
Kotsonis, all aspartame stalwarts.

Chapter 5: "Metabolism and Pharmacokinetics of Radiolabeled Aspartame in
Normal Subjects", by Aziz Karim and Thomas Burns, has 10 pages and 10
citations. Page 63, Figure 4, Metabolic products derived from aspartame,
beta-aspartame, and DKP, does not list formaldehyde or formic acid.

The tangle of black arrows includes two paths from Aspartame to Methanol to
"CO2 + Body Constituents". Now, that's pretty good public relations spin,
eh? "Body Constituents", indeed? This is systematic and persistent deceit,
as pernicious as it is profitable.

Aziz Karim, PhD is a "Distinguished Research Fellow and Sr. Director,
Clinical Research, G.D. Searle and Company, Skokie, Illinois", where Thomas
Burns, M.S. is a "Clinical Research Manager".

They state that "in monkeys" with methanol or aspartame labeled in the
methyl ester, both with 14C, "...excretion of 14CO2 in the expired air
occurred to the same extent (about 70% of the 14C dose) with both compounds,
indicating complete hydrolysis of the methyl ester moiety of aspartame
(Figure 6)."

They said nothing about resulting levels in blood plasma, urine, feces, or
any body tissues.

This is the typical commission by omission strategy of industry research on
aspartame.

ASE reference 254:
Oppermann JA, Muldoon E, Ranney RE.
Metabolism of aspartame in monkeys. [ No abstract in PubMed ]
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
http://jn.nutrition.org/cgi/reprint/103/10/1454 free full text

They found that 68.67% of the radioactive methanol in aspartame put into the
stomachs of 3 to 7 kg monkeys was eliminated within 8 hours, with little
additional elimination afterwards, as carbon dioxide in exhaled air and in
the urine.

They did not mention that this meant that about 31.33% of the methanol must
transform into formaldehyde and then into formic acid, both of which must
remain as toxic products in all parts of the body.

They did not report any studies on the distribution of radioactivity in body
tissues, nor give the absolute levels for declining blood plasma proteins.

This study did not monitor long-term use of aspartame, which might reveal
cumulative effects.

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

Two liters daily use of diet soda provides 123 mg methanol, 2 mg/kg for a 60
kg person, a dose of 63 mmole/kg, a thousand times more than the dose in
this study.

By eight hours excretion of the dose in air and urine had leveled off at
67.1 +-2.1% as CO2 in the exhaled air and 1.57+-0.32% in the urine, so 68.7%
was excreted, and 31.3% was retained. [This data is the average of 4
monkeys.] ...the 14C in the feces was negligible." "That fraction not so
excreted (about 31%) was converted to body constituents through the
one-carbon metabolic pool."

"All radioactivity measurements were counted to +-1% accuracy..." This
indicates that the results could not be claimed to have a precision of a
tenth of a percent. OK, so this is a nit-pick -- but I believe espousing
spurious accuracy is a sign of scientific insecurity.

The abstract ends, "It was concluded that aspartame was digested to its
three constituents that were then absorbed as natural constituents of the
diet." Thus, the concept is very subtly insinuated that methanol, as a
constituent of aspartame, is absorbed as a natural constituent of the diet.
"Dietary methanol is derived in large part from fresh fruits and
vetetables." Nowhere in this report, or in the book chapter are mentioned
the dreaded words, "formaldehyde" and "formic acid".

Searle Laboratories team in 1976 reported that in 4 monkeys fed aspartame,
by 12 hours: "...the major fraction (70 %) of the [aspartate] label appeared
in the expired air (Fig.6)... Urinary and fecal 14C\
[ aspartate derived ] amounted to 4 - 6 % of the administered [ aspartate ]
label."

This gives a total of a maximum 76 % excreted aspartate from the aspartame,
indicating that 24 % of this excitotoxin was retained in the body. It is
reasonable to conclude that daily use of aspartame must lead to substantial
accumulation of this excitotoxin, aspartate, in body tissues.

Their 1979 review said: "Aspartame... is hydrolyzed in the gut to yield
aspartic acid, phenylalanine, and methanol.... Aspartate may also be
incorporated into body constituents such as other amino acids, proteins,
pyrimidines, asparagine, and N-acetylaspartic acid."

ASE reference 276:
Ranney RE, Oppermann JA.
A review of the metabolism of the aspartyl moiety of aspartame in
experimental animals and man.
J Environ Pathol Toxicol. 1979 Mar-Apr; 2(4): 979-85.
Department of Drug Metabolism and Radiochemistry,
Searle Laboratories, Skokie, Illinois.
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680

Aspartame (3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester;
the methyl ester of aspartylphenylalanine, SC-18862) is hydrolyzed in the
gut to yield aspartic acid, phenylalanine, and methanol.

This review of the literature describes the metabolic paths followed by
aspartate in its conversion to CO2 or its incorporation into body
constituents.

About 70 percent of 14C from [asp-14C]-aspartame is converted in the monkey
to 14CO2.

Some of the aspartate is converted at the intestinal mucosal level to
alanine by decarboxylation.

This amino acid may be oxidized to CO2 by entering the tricarboxylic acid
cycle via pyruvate and acetyl CoA.

In addition, transamination of aspartate to oxaloacetate permits this
product also to enter the tricarboxylic acid cycle.

Aspartate may also be incorporated into body constitutents such as other
amino acids, proteins, pyrimidines, asparagine, and N-acetylaspartic acid.

It is concluded that the aspartate moiety of aspartame is metabolized in a
manner similar to that of dietary aspartic acid. Publication Types: Review
PMID: 376770

J. A. Oppermann et al, plus F.G. McMahon of Tulane University Medical
School, published a follow-up study, "Comparative metabolism of aspartame in
experimental animals and humans", J. Toxicology and Environmental Health 2:
441-451, 1976.

The abstract says, "Hydrolysis of the methyl group by intestinal esterases
yielded methanol, which was oxidized in the one-carbon metabolic pool to
CO2."

"The hypothetical pathways of metabolism, which aspartame was expected to
follow, are diagrammed in Fig. 1.... The principle used to test the validity
of this hypothetical description of the metabolism of aspartame..."

Figure 1. shows in an nice orderly sequence that: (a) MeOH ---> one-carbon
metabolic pool ---> CO2 + formyl metabolites .

Meanwhile, this sentence jumps from p. 441 to 442 under Figure 1., "The
absorbed methanol would be incorporated into the one-carbon pool and would
be converted [ page jump in sentence ] primarily to CO2 (Makar et.al., 1968;
Tephly et al, 1964), although a small fraction might be incorporated into
body constituents."

The graphs present the same methanol in monkey data as in 1973, but the
nowhere is the specific percentage of exhaled CO2 mentioned.

Methanol and aspartame were also given to a few [ unspecified ] number of
rats: "The major fraction of the 14C was excreted in the expired air (Fig.
2)...Plasma levels of 14C reached a peak [ absolute data not given ] at
about 3 hr..."

In this follow-up report, for methanol and the methyl group in aspartame,
excretion in urine and feces were not mentioned in either the former monkey
or the new rat studies, the absolute plasma levels were not given, and, of
course, no measures were taken of 14C in body tissues.

The only hint of the possible role of formaldehyde and formic acid was the
rather diffident term "formyl metabolites" in Figure 1.

Overall, we see consistent patterns of avoiding any focus on the actual
disposition of extremely toxic formaldehyde and formic acid, both persistent
and cumulative, products in body tissues.

Subtle equivocation and qualification was expressed by such words as
"hypothetical", "was expected to follow", "would be", "primarily", "although
a small fraction might be incorporated into body constituents", "major
fraction".

Methanol from aspartame was not studied in the other species: rabbits, dogs,
and humans.

It pays to investigate early studies, because then the coverup was less well
organized, more patchy.

The loosely organized world-wide exponential growth of science ensures that
the line of inquiry of methanol to formaldehyde and formic acid will pop up
here and there, but no one is encouraged to make the connection with
aspartame, widely proclaimed as "the most thoroughly tested food additive in
history" -- until the momentous, unheralded Trocho study established
explosive results in June 1998. (Appendix E)

C. Trocho (1998): "In all, the rats retained, 6 hours after administration,
about 5 % of the label, half of it in the liver."

They used a very low level of aspartame ingestion, 10 mg/kg, for rats, which
have a much greater tolerance for aspartame than humans.

So, the corresponding level for humans would be about 1 or 2 mg/kg.

Many headache studies in humans used doses of about 30 mg/kg daily.

http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1 of 2 full text,
Trocho & Alemany 1998.06.26: Murray 2002.12.22

Sra. Carme Trocho, Sra. Rosario Pardo, Dra. Immaculada Rafecas, Sr. Jordi
Virgili, Dr. Xavier Remesar, Dr. Jose Antonio Fernandez-Lopez, Dr. Mari�
Alemany [male]
Formaldehyde derived from dietary aspartame binds to tissue components in
vivo.
Life Sci June 26 1998; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular,
Facultat de Biologia, Universitat de Barcelona, Spain.
http://www.bq.ub.es/cindex.html L�nies de Recerca: Toxicitat de
l'aspartame http://www.bq.ub.es/grupno/grup-no.html
Fac. Biologia Tel.: (93)4021544, Fac. Biologia Tel.: (93)4021521, FAX:
(93)4021559
Sra. Carme Trocho "Trok-ho" FAX: (93)4021559 alemany@...;
bioq@...;
http://ww.presidiotex.com/barcelona/index.html full text

Abstract:

Adult male rats were given an oral dose of 10 mg/kg aspartame, 14C-labeled
in the methanol carbon.
[ 1.1 mg/kg methanol, with likely 30% retained as durable toxic cumulative
products of formaldehyde and formic acid, 0.3 mg/kg. ]

At timed intervals of up to 6 hours, the radioactivity in plasma and several
organs was investigated.

Most of the radioactivity found (>98 % in plasma, >75 % in liver) was bound
to protein.

Label present in liver, plasma and kidney was in the range of 1-2 % of total
radioactivity administered per g or ml, changing little with time.

Other organs (brown and white adipose tissues, muscle, brain, cornea and
retina) contained levels of label in the range of 1/12th to 1/10th of that
of liver.

In all, the rats retained, 6 hours after administration, about 5% of the
label, half of it in the liver.

The specific radioactivity of tissue protein, RNA and DNA was quite uniform.

The protein label was concentrated in amino acids, different from
methionine, and largely coincident with the result of protein exposure to
labeled formaldehyde.

DNA radioactivity was essentially in a single different adduct base,
different from the normal bases present in DNA.

The nature of the tissue label accumulated was, thus, a direct consequence
of formaldehyde binding to tissue structures.

The administration of labeled aspartame to a group of cirrhotic rats
resulted in comparable label retention by tissue components, which suggests
that liver function (or its defect) has little effect on formaldehyde
formation from aspartame and binding to biological components.

The chronic treatment of a series of rats with 200 mg/kg of non-labeled
aspartame during 10 days results in the accumulation of even more label when
given the radioactive bolus, suggesting that the amount of formaldehyde
adducts coming from aspartame in tissue proteins and nucleic acids may be
cumulative.

It is concluded that aspartame consumption may constitute a hazard because
of its contribution to the formation of formaldehyde adducts. PMID: 9714421

[ Extracts ]
"The high label presence in plasma and liver is in agreement with the
carriage of the label from the intestine to the liver via the portal vein.

The high label levels in kidney and, to a minor extent, in brown adipose
tissue and brain are a consequence of their high blood flows (45).

Even in white adipose tissue, the levels of radioactivity found 6 hours
after oral administration were 1/25th those of liver.

Cornea and retina, both tissues known to metabolize actively methanol
(21,28) showed low levels of retained label.

In any case, the binding of methanol-derived carbon to tissue proteins was
widespread, affecting all systems, fully reaching even sensitive targets
such as the brain and retina....

The amount of label recovered in tissue components was quite high in all the
groups, but especially in the NA rats.

In them, the liver alone retained, for a long time, more than 2 % of the
methanol carbon given in a single oral dose of aspartame, and the rest of
the body stored an additional 2 % or more.

These are indeed extremely high levels for adducts of formaldehyde, a
substance responsible of chronic deleterious effects (33), that has also
been considered carcinogenic (34,47).

The repeated occurrence of claims that aspartame produces headache and other
neurological and psychological secondary effects -- more often than not
challenged by careful analysis -- (5, 9, 10, 15, 48) may eventually find at
least a partial explanation in the permanence of the formaldehyde label,
since formaldehyde intoxication can induce similar effects (49).

The cumulative effects derived from the incorporation of label in the
chronic administration model suggests that regular intake of aspartame may
result in the progressive accumulation of formaldehyde adducts.

It may be further speculated that the formation of adducts can help to
explain the chronic effects aspartame consumption may induce on sensitive
tissues such as brain (6, 9, 19, 50).

In any case, the possible negative effects that the accumulation of
formaldehyde adducts can induce is, obviously, long-term.

The alteration of protein integrity and function may needs some time to
induce substantial effects.

The damage to nucleic acids, mainly to DNA, may eventually induce cell death
and/or mutations.

The results presented suggest that the conversion of aspartame methanol into
formaldehyde adducts in significant amounts in vivo should to be taken into
account because of the widespread utilization of this sweetener.

Further epidemiological and long-term studies are needed to determine the
extent of the hazard that aspartame consumption poses for humans."

Jack Dwayne Thrasher, Alan Broughton, Roberta Madison.
Immune activation and autoantibodies in humans with long-term inhalation
exposure to formaldehyde.
Archives of Environmental Health. 1990; 45: 217-223.
http://www.drthrasher.org/formaldehyde_1990.html full text

"Immune activation, autoantibodies, and anti-HCHO-HSA antibodies are
associated with long-term formaldehyde inhalation." PMID: 2400243

"Inhalation exposure to formaldehyde (HCHO) is associated with symptoms of
irritation to mucous membranes, (1,2) chronic health problems (e.g., asthma,
(2) nasopharyngeal cancer, (3) and multiple subjective health complaints.
(4,5)

Recent observations have shown that both humoral-and cell-mediated
immunologic mechanisms occur in humans with long-term HCHO exposure.

Antibodies of all isotypes to HCHO conjugated human serum albumin (HCHO-HSA)
are demonstrable in HCHO anaphylaxis, (6) hemodialysis patients, (7) mobile
home residents, (4) persons with occupational exposures, (5,8) office
workers, (9) and in persons in other environments. (4)

In addition, changes in cell-mediated immunity include increases in
eosinophils, basophils, and T-suppressor cells following acute exposure of
patients with HCHO asthma. (10)

Moreover, individuals with multiple subjective health complaints associated
with long-term HCHO inhalation have evidence of immune activation and the
presence of autoantibodies. (4,5)

The patients in our study had symptoms and complaints related to several
organs, as described previously, (4,5,9) which were similar to symptoms of
workers with multiple chemical sensitivity,(11) cacosmia,(12) and other
chemical exposures. (13-15)

We report on the differences in humoral and cell-mediated immunity in humans
with long-term inhalation exposure to HCHO vs. asymptomatic students
(controls) who experienced short-term, periodic exposure to the chemical."

[ http://lassesen.com/cfids/cacosmia.htm
Cacosmia (a.k.a. Multiple Chemical Sensitivity) Details:
* Chemical odour intolerance induced headache, itching eyes, irritated or
congested nose, dry and/or sore throat, cough, dizziness, and itching or
rash.
* Cacosmics reported increased prevalence of physician-diagnosed nasal
allergies, breast cysts, hypothyroidism, sinusitis, food sensitivities,
irritable bowel, and migraine headache. Resource: http://www.mcsrr.org ]

"Symptoms.
All patients in this study had sought continuous medical attention because
of multiple organ symptoms involving the central nervous system (CNS)
(headaches, memory loss, difficulty completing tasks,
dizziness), upper- and lower-respiratory symptoms, skeletal-muscle
complaints, and gastroenteritis.

Three common symptoms were expressed:
[1.] and initial flu-like illness from which they had not fully recovered;
[2.] chronic fatigue; and
[3.] an olfactory sensitivity to ambient conditions containing low
concentrations of chemicals. (4,9,11)"

"It is recognized that chemicals and therapeutic drugs are associated with a
Lupus-like syndrome. (28,29 ) The observations made on the patients in this
study support this concept."

"Five groups of subjects exposed to HCHO, who gave informed consent, were
included in this study.
[1.] Controls consisted of students of chiropractic medicine (16 males, 12
females), mean age = 29 +- 9 y) exposed to HCHO for 13 h/wk for 28 wk while
studying human anatomy.
Immunologic tests were performed 12 mo following the last classroom
exposure.
No measurements of HCHO concentrations were made.
It is assumed that classroom ambient concentrations were at least 0.43 ppm.
(1)

The students stated that during exposure they experienced eye, nose and
throat irritation and that there was a pungent odor of HCHO.

They did not have residual health complaints (symptoms), and they were
asymptomatic at the time blood was taken.

[2.] Mobile home residents consisted of 19 patients (6 males, 13 females),
mean age 41+-20 y) who currently lived in mobile homes. The patients had
lived in their environments for 2-7 y and reported multiple symptoms. (4,9)
Measured HCHO concentrations ranged from 0.05 to 0.5 ppm at the time blood
samples were taken.

[3.] Office workers included 21 patients (5 males, 16 females, mean age of
40 +-10 y) who worked in new office buildings where there was inadequate
ventilation (closed buildings). The patients had multiple health
complaints. (9) It was determined from medical histories that their
symptoms commenced with employment, waned when away from work (i.e.,
weekends, holidays, vacations) and became worse upon return to work. No HCO
measurements were done; however, closed buildings have ambient
concentrations ranging from 0.01 to 0.77 ppm. (1,16)

[4.] This group included 21 patients (10 males, 11 females, mean age of 35
+ -17 y) who had multiple symptoms and who had been removed from their
original sources of HCHO exposure (mobile homes
and/or particleboard subflooring) for at least 1 y. The HCHO concentrations
measured during their exposures ranged from 0.14 to 0.81 ppm.

[5.] Ocupationally exposed patients (6 males, 2 females, mean age of 45
+ -11 y) had HCHO exposures from the following: biology and human anatomy
classes, mortuary, pathology, physical therapy, formica furniture
(particleboard), and carbonless copy paper. Information on six of these
patients was previously published. (5)"

"In conclusion, measurements of changes in WBCs, T cells, and H/S ratios in
individuals with apparent chemical sensitivities appear to be inadequate
immune parameters to examine.

If one assumes that these individuals respond immunogically to environmental
chemicals, investigations into autoimmunity and immune activation and
perturbations in the interleukins, luekotreines, prostglandins, and other
immunologic mediators appear to be fruitful areas for further research.
(29-32)

Thus, it appears that HCHO sensitivity is a real phenomenon and requires
further research. (4,27-32 )" ]

ASE 6.5. "Therefore, aspartame is considered to have no reproductive or
teratogenic activity, and no effect on lactation.

In these studies, effects have been observed at exceedingly high doses, and
were secondary to reduced body weights."

[ Thrasher JD, Kilburn KH. toxicologist1@...
Embryo toxicity and teratogenicity of formaldehyde. [100 references]
Arch Environ Health 2001 Jul-Aug; 56(4): 300-11.
Sam-1 Trust, Alto, New Mexico, USA. (702) 987-4590 (505) 937-1150
http://www.drthrasher.org/formaldehyde_embryo_toxicity.html full text

"The major difference is that the Japanese demonstrated the incorporation of
FA and its metabolites into the placenta and fetus. The quantity of
radioactivity remaining in maternal and fetal tissues
at 48 hours was 26.9 % of the administered dose." [ Ref. 14-16 ] The DNA
fraction contained 20 % and 50% of total incorporated radioactivity in the
maternal and fetal liver at 6 and 24 hours when compared to the acid
insoluble fraction (Fig. 1). Of primary interest is that the incorporated
radioactivity persisted longer in the fetal liver and brain when compared to
the mothers."

Abstract:

C-14 [radioactive labelled] formaldehyde crosses the placenta and enters
fetal tissues.
The incorporated radioactivity is higher in fetal organs (i.e., brain and
liver) than in maternal tissues.
The incorporation mechanism has not been studied fully, but formaldehyde
enters the single-carbon cycle and is incorporated as a methyl group into
nucleic acids and proteins.

Also, formaldehyde reacts chemically with organic compounds (e.g.,
deoxyribonucleic acid, nucleosides, nucleotides, proteins, amino acids) by
addition and condensation reactions, thus forming adducts and
deoxyribonucleic acid-protein crosslinks.

The following questions must be addressed:
What adducts (e.g., N-methyl amino acids) are formed in the blood following
formaldehyde inhalation?
What role do N-methyl-amino adducts play in alkylation of nuclear and
mitochondrial deoxyribonucleic acid, as well as mitochondrial peroxidation?

The fact that the free formaldehyde pool in blood is not affected following
exposure to the chemical does not mean that formaldehyde is not involved in
altering cell and deoxyribonucleic acid characteristics beyond the nasal
cavity.

The teratogenic effect of formaldehyde in the English literature has been
sought, beginning on the 6th day of pregnancy (i.e., rodents)
(Saillenfait AM, et al. Food Chem Toxicol 1989, pp 545-48;
Martin WJ. Reprod Toxicol 1990, pp 237-39;
Ulsamer AG, et al. Hazard Assessment of Chemicals; Academic Press,
1984, pp 337-400;
and U.S. Department of Health and Human Services. Toxicological Profile
of Formaldehyde; ATSDR, 1999 [references 1-4, respectively, herein]).

The exposure regimen is critical and may account for the differences in
outcomes. Pregnant rats were exposed
(a) prior to mating,
(b) during mating,
(c) or during the entire gestation period.
These regimens
(a) increased embryo mortality;
(b) increased fetal anomalies (i.e., cryptochordism and aberrant
ossification centers);
(c) decreased concentrations of ascorbic acid; and
(d) caused abnormalities in enzymes of mitochondria, lysosomes, and the
endoplasmic reticulum.

The alterations in enzymatic activity persisted 4 mo following birth.

In addition, formaldehyde caused metabolic acidosis, which was augmented by
iron deficiency.

Furthermore, newborns exposed to formaldehyde in utero had abnormal
performances in open-field tests.

Disparities in teratogenic effects of toxic chemicals are not unusual.
For example, chlorpyrifos has not produced teratogenic effects in rats when
mothers are exposed on days 6-15
(Katakura Y, et al. Br J Ind Med 1993, pp 176-82
[reference 5 herein]) of gestation
(Breslin WJ, et al. Fund Appl Toxicol 1996, pp 119-30;
and Hanley TR, et al. Toxicol Sci 2000, pp 100-08
[references 6 and 7, respectively, herein]).

However, either changing the endpoints for measurement or exposing neonates
during periods of neurogenesis (days 1-14 following birth) and during
subsequent developmental periods produced adverse effects. These effects
included neuroapoptosis, decreased deoxyribonucleic acid and ribonucleic
acid synthesis, abnormalities in adenylyl cyclase cascade, and
neurobehavioral effects
(Johnson DE, et al. Brain Res Bull 1998, pp 143-47;
Lassiter TL, et al. Toxicol Sci 1999, pp 92-100;
Chakraborti TK, et al. Pharmacol Biochem Behav 1993, pp 219-24;
Whitney KD, et al. Toxicol Appl Pharm 1995, pp 53-62;
Chanda SM, et al. Pharmacol Biochem Behav 1996, pp 771-76;
Dam K, et al. Devel Brain Res 1998, pp 39-45;
Campbell CG, et al. Brain Res Bull 1997, pp 179-89;
and Xong X, et al. Toxicol Appl Pharm 1997, pp 158-74
[references 8-15, respectively, herein]).

Furthermore, the terata caused by thalidomide is a graphic human example in
which the animal model and timing of exposure were key factors
(Parman T, et al. Natl Med 1999, pp 582-85;
and Brenner CA, et al. Mol Human Repro 1998, pp 887-92
[references 16 and 17, respectively, herein]).

Thus, it appears that more sensitive endpoints (e.g., enzyme activity,
generation of reactive oxygen species, timing of exposure) for the
measurement of toxic effects of environmental agents on embryos,
fetuses, and neonates are more coherent than are gross terata observations.

The perinatal period from the end of organogenesis to the end of the
neonatal period in humans approximates the 28th day of gestation to 4 wk
postpartum. Therefore, researchers must investigate
similar stages of development (e.g., neurogenesis occurs in the 3rd
trimester in humans and neonatal days occur during days 1-14 in rats and
mice, whereas guinea pigs behave more like humans).

Finally, screening for teratogenic events should also include exposure of
females before mating or shortly following mating. Such a regimen is
fruitful inasmuch as environmental agents cause adverse effects.
Publication Types: Review Review, Tutorial PMID: 11572272

Discussion and Analysis of the Papers:

FA was distributed to all organs in the adult, the placenta and fetus (Table
1), which was similar to that reported in male F344 rats, guinea pigs and
monkeys. (25,26).

The major difference is that the Japanese demonstrated the incorporation of
FA and its metabolites into the placenta and fetus. The quantity of
radioactivity remaining in maternal and fetal tissues at 48 hours was 26.9%
of the administered dose.

The DNA fraction contained 20 % and 50% of total incorporated radioactivity
in the maternal and fetal liver at 6 and 24 hours when compared to the acid
insoluble fraction (Fig. 1).

Of primary interest is that the incorporated radioactivity persisted longer
in the fetal liver and brain when compared to the mothers.

Also, since FA is a precursor of a number of biological compounds, it would
have been of prime interest to determine what fraction resulted from either
metabolic incorporation or from chemical reactivity of FA (e.g. crosslinks,
adduction, methylation) with biological molecules (DNA, proteins,
polypeptide, amino acids, etc.).

FA undergoes addition (adducts and alkylation) and condensation (methene
bridges) reactions with proteins and amino acids (27) as well as nucleic
acids and nucleosides/tides. (28) It is a mutagen, crosslinking agent and
an immunogen (28-30).

Free FA concentrations in the blood are 2.24+- 0.07 (rats), 1.84+- 0.15
(Rhesus monkeys) and 2.61+- 0.14 (humans) ug/g of blood [ppm], which did not
change following either acute or subchronic inhalation of FA. (31,32)

Thus, it appears that additional information is required on addition and
condensation products of amino acids, polypeptides, nucleoside, etc., of the
blood, generated by FA exposure.

An increase of N-methyl amino acids would produce endogenous FA, which may
have a significant role in mitotic and apoptosis processes.

FA generators are responsible for FA formation in tumors and have an
impairment of liver antioxidant mechanisms and functional integrity of
mitochondria. (33-41)

FA had adverse effects on zygotes/embryos and bone marrow cells (Tables 2
and 3). The embryos showed cytological injury and high rate of mortality,
while bone marrow cells had increased rates of chromosome aberrations and
aneuploidy.

Similar observations on chromosomes of peripheral lymphocytes have been
reported for anatomy and mortuary students. (42-44) Classroom exposure to
FA at 1.5 to 3.17 mg/m3 was associated with
increased frequency of sister chromatid exchanges, aberrations and
micronuclei. Concentrations less 1 mg/m3 had no effect on lymphocyte
chromosomes, but caused micronuclei in nasal and oral exfoliative cells and
changes in lymphocyte subsets (increase in CD19 and decreases in CD4, CD5
and H/S ratio. (45,46)

With respect to the effect of FA on embryos additional research is needed.

FA is an alkylating agent. Treatment of C3H transplacentally with
N-ethyl-N-nitrosourea (alkylating agent) has caused primordial germ cell
mutations. (47)

Also, treatment of female mice within hours after mating with ethyl
methanesulfanate, ethyl nitrosourea and ethylene oxide resulted in fetal
deaths and malformations. (48-51)

Thus, further investigation into the zygote/embryonic effects of FA should
follow the protocols established for other alkylating agents with attention
to the role of potential methyl donors, e.g. N-methyl amino acids.

FA exposure throughout gestation caused a decreased DNA and RNA
concentrations, increased weights of bodies and organs (thymus, heart,
kidneys and adrenals) and decreased in the weights of lung and liver (Table
3).

Microscopy and histochemical observations revealed other abnormalities:
involution of lymphoid tissue, numerous extra-medullary hemopoietic centers,
decreased glycogen content (myocardium) and liver, decreased AA content of
whole fetus and fetal and maternal liver.

AA is an antioxidant, produced from glucuronate via the uronic acid pathway,
which also is the intermediary route for synthesis of pentoses.

The decreased AA content may have resulted from either the utilization of AA
as an antioxidant or by interference (inhibition?) of the uronic pathway.

It is difficult to interpret the meaning of the decreased DNA and the
increased RNA contents of the organs. However, treatment of adult male rats
by FA injection was reported to decrease the DNA content of testis and
prostate and a decrease of protein content of the prostate and epididymus.
(52)

Cytopathology of organs and alterations of mitochondria, ER and lysosome
enzymatic were observed in fetuses following FA inhalation (Table 4). Organ
cytopathology included increased ploidy, micronecrotic loci, extramedullary
hematopoeitec enters, and degeneration of kidney glomeruli. Concomitant were
changes in enzymatic activity of as follows: mitochondria (MDH, SDH, LDH
decreased, while GDH increased); ER and lysosomes (ATPase increased while
inosine diphosphatase and b-glucorinidase decreased). The impairment lasted
in the organs to 4 months of age. In addition, N-acetylneuraminic
concentration increased in maternal and fetal tissues. The changes in the
enzymatic activity and N-acetyleneuraminic acid correlated with increased
fetal mortality. Finally, the development of postnatal behavior was also
adversely affected (Table 6).

FA has effects on mitochondrial enzymes, glutathione concentrations and bile
production in the liver of many species, including humans. (53)

FA inhibits the uptake of phosphate by mitochondria, (54,55) and causes the
release of GPT, SDH, GSSG and malondialdehyde into the perfusate of isolated
livers. (56)

Intraperitoneal injection results in a 2-fold increase in bile and a
significant decrease in glutathione of the liver, lungs and brains. (57)

An electron microscopic investigation of the perfused isolated livers showed
destruction of the mitochondria (ruptured membranes, loss of the cristae)
and some damage to the endoplasmic reticulum. (56)

The protection of the liver from FA toxicity appears to be dependent upon
glutathione by formation of the adduct S-hydroxymethylglutathione. (58)

Thus, the observed effect of FA on mitochondrial and ER functions during
embryo/fetal development is also demonstrable in the adult liver.

FA caused preimplantation, prenatal and postnatal abnormalities.

The prenatal effects were demonstrable as anomalies and aberrancies in blood
buffering capacity with metabolic (formate?) acidosis.

The major anomalies were an increased frequency of cryptochordism, a
decrease/delay in ossification centers of the hyoid, metacarpus and
metatarsal bones, delay in eruption of incisors and a decrease in body
weight.

Blood pH decreased in the fetus, while the pCO2 (hypercapnia) increased in
the fetus and the mother.
The true bicarbonates and CO2 were unaffected by FA alone, but increased
with iron-deficiency in the fetus and mother.

The presence of iron-induced deficiency augmented these abnormalities, along
with increased embryo mortality.

The postnatal effect of FA was tested by maze performance. Open field tests
demonstrated an increase in motor activity, increase in standing and
appearance of emotion. In sexually mature rats there was an increase in
search activity.

FA is metabolized to formate.

Alcohols, particularly methanol and ethanol, are metabolized to formate and
lactate via an aldehyde.

The toxicity of alcohols and formalin in humans and animals includes
metabolic acidosis (59-61).

Alcohol toxicity generates free radicals, cause an increase in
malondialdehyde, and induce lipid peroxidation resulting in DNA single
strand breaks (62-66).

FA and alcohols probably affect embryos and the fetus via mitochondrial
damage.

Ethanol and environmental agents trigger apoptotic neurodegeneration in the
developing brain (67,68).

Oxygen stress, such as that caused by free radical generation, is associated
with apoptotic cell death and fragmentation of mitochondrial genome (69-71).

Moreover, FA via formaldehyde generators, e.g. alkylating agents, initiates
apoptosis (72-74).
Mitochondria are the suicide organelles and control apoptosis (75-78).

Thus, subtle birth defects (autism, low birth weight, fetal alcohol
syndrome, etc.) are probably best understood by investigating in utero
oxidative stress and mitochondrial damage, rather than by standard FA
teratogenic research (79-83). ]

ASE references 293, 294, 295 were published studies by HJ Roberts.

[ Roberts HJ
Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@...
http://www.sunsentpress.com/ sunsentpress@...
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax
http://www.dorway.com/tldaddic.html 5-page review full text

http://groups.yahoo.com/group/aspartameNM/message/669
1038-page medical text "Aspartame Disease: An Ignored Epidemic"
published May 30 2001 $ 60.00 postpaid data from 1200 cases
available at http://www.amazon.com
over 600 references from standard medical research

http://groups.yahoo.com/group/aspartameNM/message/790
Moseley: review Roberts "Aspartame Disease: An Ignored Epidemic": Murray
2002.07.02

http://groups.yahoo.com/group/aspartameNM/message/883
three texts by H.J. Roberts, 1958, 1971, 1979: Murray 2002.11.06

http://groups.yahoo.com/group/aspartameNM/message/880
Roberts 45 clinical research reports in mainstream journals: Murray
2002.10.20 ]

ASE 6.4.2.3. [ They stretched to argue away this study, and concluded with
a grudging admission:

"There are two studies that, when using only one dose and only one measure
of learning, interpreted their findings to indicate an impairment of
learning by aspartame at doses of 250 and 500 mg/kg/day." ]

ASE 6.4.2.3. " Recently, Christian et al. (2004) used a T-maze to test for
memory loss in male Sprague-Dawley rats receiving aspartame (250 mg/kg
bw/day) in drinking water for 120 days.

Twelve rats per group were tested periodically during the treatment period
for the time required to find a reward (chocolate) in the T-maze.

Rats were tested every 2 weeks.

Although no differences were noted during the measurements occurring
approximately every 2 weeks up to about 72 weeks, rats receiving aspartame
took significantly longer to find the reward after 90 days.

The next measurement shown is at 120 days, when rats again took longer to
find the reward.

Rats were then killed and levels of brain cholinergic receptors and
NaK-ATPase levels were determined.

Muscarinic cholinergic receptor density, measured using radiolabeled
quinuclindinyl benzilate, was significantly higher in several areas of the
brain of rats receiving aspartame compared to rats receiving only water.

NaK-ATPase levels were similar in all areas of the brain, except for the
midbrain where levels were higher in aspartame-treated rats.

The authors (Christian et al., 2004) speculate that the increase in time to
find a reward in the T-maze indicates that chronic aspartame consumption
results in memory loss and this was mediated by the change in cholinergic
receptor density.

However, they also acknowledge that the relationship between memory and
receptor density is not well understood.

The authors suggest that an alternative explanation for the increased time
in the T-maze test is that rats treated with aspartame may have a reduced
desire for the chocolate reward.

As rats do not recognize aspartame as a sweet substance, it is not clear how
this may occur.

One possibility is that as aspartame is also used to modify the flavors of
other substances (when given below the sweetness threshold in humans), it is
possible that while the rats might not taste aspartame as sweet, aspartame
could have modified the taste of the chocolate (e.g., making it more
bitter).

Major limitations of this study are the use of only one tool or task to
measure memory and the use of only one dose of aspartame.

The majority of studies designed to detect an effect of aspartame on
learning or memory have used multiple doses and multiple tests to evaluate
these parameters.

These studies report no effect, at doses as high as 4% aspartame in the
diet, even when exposed from conception to 90 days postnatally.

Higher doses have been reported to affect various indices of learning
behavior.

There are two studies that, when using only one dose and only one measure of
learning, interpreted their findings to indicate an impairment of learning
by aspartame at doses of 250 and 500 mg/kg/day.

In summary, well-designed studies using a range of approaches to evaluate
learning and memory consistently demonstrate no effect of aspartame
consumption at levels up to 4000 mg/kg/day, indicating little likelihood
that aspartame will have an effect on memory or learning in humans."

[ ASE reference 52:

http://groups.yahoo.com/group/aspartameNM/message/1088
chronic aspartame in rats affects memory, brain cholinergic receptors, and
brain chemistry, Christian B, McConnaughey M et al, 2004 May, full plain
text & critique: Murray 2004.06.05

Christian B, McConnaughey K, Bethea E, Brantley S, Coffey A, Hammond L,
Harrell S, Metcalf K, Muehlenbein D, Spruill W, Brinson L, McConnaughey M.
Chronic aspartame affects T-maze performance, brain cholinergic receptors
and Na(+),K(+)-ATPase in rats.
Pharmacol Biochem Behav. 2004 May; 78(1): 121-7.
Department of Pharmacology, Brody School of Medicine,
East Carolina University, Greenville, NC 27858, USA;
North Carolina School of Science and Mathematics, Durham, NC 27811.
http://www.ecu.edu/pharmacology/faculty/mcconnaughey.html
Mona M. McConnaughey, Ph.D. Research Assistant Professor
Department: PHARMACOLOGY & TOXICOLOGY
Office: Brody Medical Science 6E-120A 252-744-2756
MCCONNAUGHEYM@...

This study demonstrated that chronic aspartame consumption in rats can lead
to altered T-maze performance and increased muscarinic cholinergic receptor
densities in certain brain regions.

Control and treated rats were trained in a T-maze to a particular side and
then periodically tested to see how well they retained the learned response.

Rats that had received aspartame (250 mg/kg/day) [ 27.5 mg methanol, and at
30%, 8.25 mg formaldehyde and formic acid retention ] in the drinking water
for 3 or 4 months showed a significant increase in time to reach the reward
in the T-maze, suggesting a possible effect on memory due to the artificial
sweetener.

Using [(3)H]quinuclidinyl benzilate (QNB) (1 nM) to label muscarinic
cholinergic receptors and atropine (10(-6) M) to determine nonspecific
binding in whole-brain preparations, aspartame-treated rats showed a 31 %
increase in receptor numbers when compared to controls.
In aspartame-treated rats, there was a significant increase in muscarinic
receptor densities in the frontal cortex, midcortex, posterior cortex,
hippocampus, hypothalamus and cerebellum of 80 %, 60 %, 61 %, 65 %, 66 % and
60 %, respectively.

The midbrain was the only area where preparations from aspartame-treated
rats showed a significant increase in Na(+),K(+)-ATPase activity.

It can be concluded from these data that long-term consumption of aspartame
can affect T-maze performance in rats and alter receptor densities or
enzymes in brain. PMID: 15159141

This extraordinary result demands replication, because it implies a much
lower No Observed Effect Level (NOEL), which is customarily divided by 1000
to set an Acceptible Daily Limit for humans.

A formaldehyde NOEL of about 8 mg/kg bw/day would set a human formaldehyde
ADL much lower at .008 mg/kg bw/day, which for a 60 kg person would be 0.5
mg daily, if 30 % retention of formaldehyde and formic acid durable
cumulative toxic products is allowed.

Recall that 12 cans daily diet soda gives 2400 mg aspartame, 264 mg
methanol, and at 30% retention of formaldehyde and formic acid cumulative
durable toxic products, 80 mg daily, 160 times the ADL
suggested by the results of Christian et al, 2004.

A single 12-oz can of diet soda gives 200 mg aspartame, 22 mg methanol, and
toxic products 7 mg, 13 times above this possible ADL.

Accordingly, we should give much more respectful attention to the thousands
of case reports of toxic symptoms, especially neurological, by professionals
and citizens. ]

ASE 6.4.2.4. "Effects on Aggression.

Male Long-Evans rats received single intraperitoneal injections of 0, 200,
400, and 800 mg/kg bw aspartame in vehicle (saline plus Tween 80) and then
were exposed to an intruder rat and observed for aggression (Goerss et al.,
2000).

Eleven rats were tested with all aspartame doses delivered in ascending then
descending order with a minimum of 1 day between tests.

Contrary to an expected enhancement of aggressive behavior based on the
hypothesis that aspartame is neuroexcitatory, when rats received aspartame
doses of 200 mg/kg bw or higher, the time to attack an intruder rat
increased, the number of bites decreased, and fewer rats engaged in
aggressive attacks.

Rats treated with 200 and 400 mg/kg bw aspartame had higher levels of
serotonin (5-hydroxytryptamine) and its metabolite, 5-hydroxyindolacetic
acid, in the brain compared to rats receiving vehicle, but this effect was
not evident in rats treated with 800 mg/kg bw aspartame.

Dopamine and its metabolites, dihydroxyphenylacetic acid and homovanillic
acid, were not affected by aspartame treatments.

The authors (Goerss et al., 2000) were unable to explain how aspartame
administration would result in increased serotonin levels in these groups.

The rationale for intraperitoneal administration of aspartame was not given.

An intraperitoneal exposure is an irrelevant route of administration when
aspartame is extensively metabolized prior to absorption, and the only human
exposure is via oral administration.

In summary, there has been extensive investigation of the possibility of
neurotoxic effects due to consumption of aspartame.

The data from these studies, in general, do not support the hypothesis that
aspartame in the human diet will affect neuronal function, learning or
behavior."

[ This 2000 study demands careful replication, using even lower oral doses,
determination of the actual disposition of toxic metabolites in specific
tissues, and more tests of behavioral changes. Dimethyl dicarbonate would
make an ideal control.

It's possible that the toxic effects of intraperitoneal injection of
aspartame were depressing the rat's overall energy level.

Anxiety, restlessness, and irritability, or depression, fatigue, and dulled
affect are major symptoms for aspartame reactors and alcohol hangover.

Behavioral studies may confirm the very low ADL of 4.8 mg formaldehyde for a
60 kg person, as reasonably suggested by the results from Christian et al,
2004.

It is not surprising that researchers are not readily funded to do simple,
low cost, fast studies that would compel steep limitations on billions of
dollars annual business of world vested interests for products ranging from
diet and alcohol beverages to buildings and mobile homes to methanol vehicle
fuels, and perhaps an entire new field of concerns about the otherwise ideal
fruits and vegetables. ]

ASE 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@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@...

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

* formaldehyde, 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.

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@...

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

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
____________________________________________________

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/2007_09_01_archive.htm
September 21, 2007
http://groups.yahoo.com/group/aspartameNM/message/1475

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.

Table 1 reveals consistent increase in problems from

--------------------- zero to (400-600) to (over 600) mg/d
aspartame intake:

% of cohort ------------ 46 --------- 5 -------- 4 %

mean aspartame mg/d --- 0 -------441 ------ 986

16+ education ---------- 37 ------- 40 ------- 34 %

diabetes history ---------- 3 ------- 22 ------- 26 %

alcohol g/d -------------- 14 ------- 11 ------- 13

never smoke ------------ 36 ------- 31 ------- 29 %

Body Mass Index ------- 26 ------- 29 ------- 29

18.5 - 25 --------------- 42 ------- 21 ------- 19 %

30 - 35 ----------------- 13 ------- 23 ------- 26 %

over 35 ----------------- 4 ------- 10 ------- 13 %

Physical activity %:

under 3-4/mo ----------- 32 ------- 32 ------- 37 %

under 1-2/wk ----------- 22 ------- 21 ------- 19 %

over 3-4/wk ------------ 45 ------- 45 ------- 43 %

Calories kcal -------- 1,919 ---- 1,855 ---- 2,044 %

Caffeine mg/d --------- 393 ------ 364 ------ 424

There do seem to be many increases of problems from the second to third row,
as mean aspartame use doubles.

Granted, this is cherry picking the data, selecting interesting patterns.

Correlations alone do not prove any direction of causation.

Nevertheless, it may be of value to study the correlations for increasing
aspartame intake among the 4 % using over 600 mg, the equivalent of 3 cans
12-oz cans diet soda daily. The average use for this group is 5 cans daily.

For instance, are a minority of these heavy users displaying the great
majority of the problems that are reflected in the mean for each level of
use, with most users only having little or no increase in problems?

This is a group of about 20,000 people.

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

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

Cancer Epidemiol Biomarkers Prev. 2006 Sep; 15(9): 1654-9.
Comment in:
Cancer Epidemiol Biomarkers Prev. 2007 Jul; 16(7): 1527-8;
author reply 1528-9.
Consumption of aspartame-containing beverages and incidence of hematopoietic
and brain malignancies.
Lim U, Subar AF, Mouw T, Hartge P, Morton LM, Stolzenberg-Solomon R,
Campbell D, Hollenbeck AR, Schatzkin A.
Division of Cancer Control and Population Sciences, National Cancer
Institute, 6130 Executive Boulevard, EPN 4005, Rockville, MD 20852-7344,
USA. PMID: 16985027

Unhee Lim 1,
Amy F. Subar 2, subara@...,
Traci Mouw 1,
Patricia Hartge 1,
Lindsay M. Morton 1,
Rachael Stolzenberg-Solomon 1,
David Campbell 3,
Albert R. Hollenbeck 4
and Arthur Schatzkin 1

1 Division of Cancer Epidemiology and Genetics,

2 Division of Cancer Control and Population Sciences, National Cancer
Institute, NIH, Department of Health and Human Services;

3 Information Management Services, Inc., Rockville, Maryland; and

4 AARP, Washington, District of Columbia

Requests for reprints: Amy Subar,
Division of Cancer Control and Population Sciences,
National Cancer Institute,
6130 Executive Boulevard, EPN 4005, Rockville, MD 20852-7344.
Phone: 301-594-0831; Fax: 301-435-3710. E-mail: subara@...,

http://cebp.aacrjournals.org/cgi/content/full/15/9/1654 free full text

BACKGROUND:
In a few animal experiments, aspartame has been linked to hematopoietic and
brain cancers.

Most animal studies have found no increase in the risk of these or other
cancers.

Data on humans are sparse for either cancer.

Concern lingers regarding this widely used artificial sweetener.

OBJECTIVE:
We investigated prospectively whether aspartame consumption is associated
with the risk of hematopoietic cancers or gliomas
(malignant brain cancer).

METHODS:
We examined 285,079 men and 188,905 women ages 50 to 71 years in the
NIH-AARP Diet and Health Study cohort

Daily aspartame intake was derived from responses to a baseline
self-administered food frequency questionnaire that queried consumption of
four aspartame-containing beverages (soda, fruit drinks, sweetened iced tea,
and aspartame added to hot coffee and tea) during the past year.

Histologically confirmed incident cancers were identified from eight state
cancer registries.

Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI)
were estimated using Cox proportional hazards regression that adjusted for
age, sex, ethnicity, body mass index, and history of diabetes.

RESULTS:
During over 5

(Message over 64k, truncated.)

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