20021225
http://groups.yahoo.com/group/aspartameNM/message/927
Rumsfeld, 1977 head of Searle Corp., got aspartame FDA approval:
Turner: Murray 12.23.2 rmforall
http://www.swankin-turner.com/
Swankin & Turner is a law firm specializing in the areas of regulation
(food and drug, health care, standard setting, antitrust and trade) and
policy (agricultural, insurance, corporate, tax, administrative and
consumer). Established in Washington, D.C. in 1973, it has served a
broad variety of individual and organizational clients, including
national and local business corporations and nonprofit associations.
All attorneys with the firm are members of the District of Columbia bar.
In addition, James Turner is admitted to the Ohio and U.S. Supreme Court
bars; Betsy Lehrfeld is admitted to the California and U.S. Supreme
Court bars; Charles Brown is admitted to the bars of Ohio, West Virginia
and the U.S. Supreme Court; and Chris Turner is admitted to the
Pennsylvania bar.
http://www.swankin-turner.com/aspartame.html
http://www.swankin-turner.com/hist.html
Aspartame/NutraSweet: The History of the Aspartame Controversy
by James Turner, ESQ. Director of the National Institute of Science,
Law, and Public Policy (NISLAPP)
National Institute of Science, Law, and Public Policy
1400 16th Street, NW, Suite 330, Washington, DC 20036
(202) 462-8800 Fax: (202) 265-6564 nislapp@swankin-turner.com
Timeline:
December 1965-- While working on an ulcer drug, James Schlatter, a
chemist at G.D. Searle, accidentally discovers aspartame, a substance
that is 180 times sweeter than sugar yet has no calories.
Spring 1967-- Searle begins the safety tests on aspartame that are
necessary for applying for FDA approval of food additives.
Fall 1967-- Dr. Harold Waisman, a biochemist at the University of
Wisconsin, conducts aspartame safety tests on infant monkeys on behalf
of the Searle Company. Of the seven monkeys that were being fed
aspartame mixed with milk, one dies and five others have grand mal
seizures.
November 1970-- Cyclamate, the reigning low-calorie artificial sweetener
-- is pulled off the market after some scientists associate it with
cancer. Questions are also raised about safety of saccharin, the only
other artificial sweetener on the market, leaving the field wide open
for aspartame.
December 18, 1970-- Searle Company executives lay out a "Food and Drug
Sweetener Strategy' that they feel will put the FDA into a positive
frame of mind about aspartame. An internal policy memo describes
psychological tactics the company should use to bring the FDA into a
subconscious spirit of participation" with them on aspartame and get FDA
regulators into the "habit of saying, "Yes"."
Spring 1971-- Neuroscientist Dr. John Olney (whose pioneering work with
monosodium glutamate was responsible for having it removed from baby
foods) informs Searle that his studies show that aspartic acid (one of
the ingredients of aspartame) caused holes in the brains of infant
mice. One of Searle's own researchers confirmed Dr. Olney's findings in
a similar study.
February 1973-- After spending tens of millions of dollars conducting
safety tests, the G.D. Searle Company applies for FDA approval and
submits over 100 studies they claim support aspartame's safety.
March 5, 1973-- One of the first FDA scientists to review the aspartame
safety data states that "the information provided (by Searle) is
inadequate to permit an evaluation of the potential toxicity of
aspartame". She says in her report that in order to be certain that
aspartame is safe, further clinical tests are needed.
May 1974-- Attorney, Jim Turner (consumer advocate who was instrumental
in getting cyclamate taken off the market) meets with Searle
representatives to discuss Dr. Olney's 1971 study which showed that
aspartic acid caused holes in the brains of infant mice.
July 26, 1974-- The FDA grants aspartame its first approval for
restricted use in dry foods.
August 1974-- Jim Turner and Dr. John Olney file the first objections
against aspartame's approval.
March 24, 1976-- Turner and Olney's petition triggers an FDA
investigation of the laboratory practices of aspartame's manufacturer,
G.D. Searle. The investigation finds Searle's testing procedures shoddy,
full of inaccuracies and "manipulated" test data. The investigators
report they "had never seen anything as bad as Searle's testing."
January 10, 1977-- The FDA formally requests the U.S. Attorney's office
to begin grand jury proceedings to investigate whether indictments
should be filed against Searle for knowingly misrepresenting findings
and "concealing material facts and making false statements" in aspartame
safety tests. This is the first time in the FDA's history that they
request a criminal investigation of a manufacturer.
January 26, 1977-- While the grand jury probe is underway, Sidley &
Austin, the law firm representing Searle, begins job negotiations with
the U.S. Attorney in charge of the investigation, Samuel Skinner.
March 8, 1977-- G. D. Searle hires prominent Washington insider Donald
Rumsfeld as the new CEO to try to turn the beleaguered company around. A
former Member of Congress and Secretary of Defense in the Ford
Administration, Rumsfeld brings in several of his Washington cronies as
top management.
July 1, 1977-- Samuel Skinner leaves the U.S. Attorney's office and
takes a job with Searle's law firm. (see Jan. 26th)
August 1, 1977-- The Bressler Report, compiled by FDA investigators and
headed by Jerome Bressler, is released. The report finds that 98 of the
196 animals died during one of Searle's studies and weren't autopsied
until later dates, in some cases over one year after death. Many other
errors and inconsistencies are noted. For example, a rat was reported
alive, then dead, then alive, then dead again; a mass, a uterine polyp,
and ovarian neoplasms were found in animals but not reported or
diagnosed in Searle's reports.
December 8, 1977-- U.S. Attorney Skinner's withdrawal and resignation
stalls the Searle grand jury investigation for so long that the statue
of limitations on the aspartame charges runs out. The grand jury
investigation is dropped.
June 1, 1979-- The FDA established a Public Board of Inquiry (PBOI) to
rule on safety issues surrounding NutraSweet.
September 30, 1980-- The Public Board of Inquiry concludes NutraSweet
should not be approved pending further investigations of brain tumors in
animals. The board states it "has not been presented with proof of
reasonable certainty that aspartame is safe for use as a food additive."
January 1981-- Donald Rumsfeld, CEO of Searle, states in a sales meeting
that he is going to make a big push to get aspartame approved within the
year. Rumsfeld says he will use his political pull in Washington, rather
than scientific means, to make sure it gets approved.
January 21, 1981-- Ronald Reagan is sworn in as President of the United
States. Reagan's transition team, which includes Donald Rumsfeld, CEO of
G. D. Searle, hand picks Dr. Arthur Hull Hayes Jr. to be the new FDA
Commissioner.
March, 1981-- An FDA commissioner's panel is established to review
issues raised by the Public Board of Inquiry.
May 19, 1981-- Three of six in-house FDA scientists who were responsible
for reviewing the brain tumor issues, Dr. Robert Condon, Dr. Satya
Dubey, and Dr. Douglas Park, advise against approval of NutraSweet,
stating on the record that the Searle tests are unreliable and not
adequate to determine the safety of aspartame.
July 15, 1981-- In one of his first official acts, Dr. Arthur Hayes Jr.,
the new FDA commissioner, overrules the Public Board of Inquiry, ignores
the recommendations of his own internal FDA team and approves NutraSweet
for dry products. Hayes says that aspartame has been shown to be safe
for its' proposed uses and says few compounds have withstood such
detailed testing and repeated close scrutiny.
October 15, 1982-- The FDA announces that Searle has filed a petition
that aspartame be approved as a sweetener in carbonated beverages and
other liquids.
July 1, 1983-- The National Soft Drink Association (NSDA) urges the FDA
to delay approval of aspartame for carbonated beverages pending further
testing because aspartame is very unstable in liquid form. When liquid
aspartame is stored in temperatures above 85 degrees Fahrenheit, it
breaks down into DKP and formaldehyde, both of which are known toxins.
July 8, 1983-- The National Soft Drink Association drafts an objection
to the final ruling which permits the use of aspartame in carbonated
beverages and syrup bases and requests a hearing on the objections. The
association says that Searle has not provided responsible certainty that
aspartame and its' degradation products are safe for use in soft drinks.
August 8, 1983-- Consumer Attorney, Jim Turner of the Community
Nutrition Institute and Dr. Woodrow Monte, Arizona State University's
Director of Food Science and Nutritional Laboratories, file suit with
the FDA objecting to aspartame approval based on unresolved safety
issues.
September, 1983-- FDA Commissioner Hayes resigns under a cloud of
controversy about his taking unauthorized rides aboard a General Foods
jet. (General foods is a major customer of NutraSweet)
Burson-Marsteller, Searle's public relation firm (which also represented
several of NutraSweet's major users), immediately hires Hayes as senior
scientific consultant.
Fall 1983-- The first carbonated beverages containing aspartame are sold
for public consumption.
November 1984-- Center for Disease Control (CDC) "Evaluation of consumer
complaints related to aspartame use." (summary by B. Mullarkey)
November 3, 1987-- U.S. hearing, "NutraSweet: Health and Safety
Concerns," Committee on Labor and Human Resources, Senator Howard
Metzenbaum, chairman.
************************************************************************
http://groups.yahoo.com/group/aspartameNM/message/857
RTM: www.dorway.com: original documents and long reviews of flaws in
aspartame toxicity research 7.31.2 rmforall
http://www.dorway.com/upipart1.txt
UPI reporter Gregory Gordon: 96K 3-part expose Oct 1987
"Survey of aspartame studies: correlation of outcome and funding
sources," 1998, unpublished: http://www.dorway.com/peerrev.html
Walton found 166 separate published studies in the peer reviewed
medical literature, which had relevance for questions of human safety.
The 74 studies funded by industry all (100%) attested to aspartame's
safety, whereas of the 92 non-industry funded studies, 84 (91%)
identified a problem. Six of the seven non-industry funded studies
that were favorable to aspartame safety were from the FDA, which
has a public record that shows a strong pro-industry bias.
Ralph G. Walton, MD, Prof. of Clinical Psychology, Northeastern Ohio
Universities, College of Medicine, Dept. of Psychiatry, Youngstown,
OH 44501, Chairman, The Center for Behavioral Medicine,
Northside Medical Center, 500 Gypsy Lane, P.O. Box 240 Youngstown,
OH 44501 330-740-3621 rwalton193@aol.com
http://www.neoucom.edu/DEPTS/Psychiatry/walton.htm
************************************************************************
Christie D. Michas christiem@messengers-of-messiah.org
Wed, 11 Sep 2002 12:37:51 -0700
>----- Original Message -----
>From: "Mark Douglas Whitaker"
>To:
>Sent: Saturday, August 24, 2002 9:44 PM
>Subject: Rumsfeld's conflict of interest and ASPARTAME: Rumsfeld was
>president of Serle corporation! part of Reagan transition team, and got
>aspartame 'legalized' by appointing a defense department contractor
>(Hayes) as head of FDA!
http://csf.colorado.edu/envtecsoc/2002/msg00440.html
Rumsfeld's conflict of interest and ASPARTAME: Rumsfeld was
president of Searle corporation! part of Reagan transition team, and got
aspartame 'legalized' by appointing a defense department
contractor (Hayes) as head of FDA!
by Mark Douglas Whitaker 25 August 2002 01:45 UTC
summary:
Rumsfeld's conflict of interests and ASPARTAME: Rumsfeld was president
of Searle corporation in 1977, maker of aspartame, then, part of Reagan
transition team, and got aspartame 'legalized' by appointing a defense
department contractor [??] (Hayes) as head of FDA!
A book should be written about American corruption and aspartame.
[also at: http://www.stevia.net/aspartame.htm ]
The Aspartame/NutraSweet Fiasco by James S. Turner
Many health-conscious people believe that avoiding aspartame, found in
over 5000 products under brand names such as Equal and NutraSweet, can
improve their quality of life. The history of this synthetic sweetener's
approval by the U.S. Food and Drug Administration (FDA), including a
long record of consumer complaints and the agency's demonstrated
insensitivity to public concern, suggests they're right.
In October 1980 the Public Board of Inquiry (PBOI) impaneled by the FDA
to evaluate aspartame safety found that the chemical caused an
unacceptable level of brain tumors in animal testing. Based on this
fact, the PBOI ruled that aspartame should not be added to the food
supply.
This ruling capped 15 years of regulatory ineptitude, chicanery and
deception by the FDA and the Searle drug company, aspartame's discoverer
and manufacturer (acquired by Monsanto in 1985), and kicked off another
two decades of maneuvering, manipulating and dissembling by FDA, Searle
and Monsanto.
In 1965, a Searle scientist licked some of a new ulcer drug from his
fingers and discovered the sweet taste of aspartame. Eureka! Selling
this chemical as a food additive to hundreds of millions of healthy
people every day would mean many more dollars than limited sales to the
much smaller group of ulcer sufferers.
Searle, a drug company with little experience in food regulation, began
studies to comply with the law-- but which failed to do so. Its early
tests of the substance showed it produced microscopic holes and tumors
in the brains of experimental mice, epileptic seizures in monkeys, and
was converted by animals into dangerous substances, including
formaldehyde.
In 1974, however, in spite of the information in its files, the FDA
approved aspartame as a dry-foods additive. But the agency also made
public for the first time the data supporting a food-additive decision.
This data was subsequently reviewed by renowned brain researcher John
Olney from Washington University in St. Louis, and other scientists.
Dr. Olney discovered two studies showing brain tumors in rats and
petitioned FDA for a public hearing. Consumer Action for Improved Foods
and Drugs (represented by the author of this piece) also petitioned for
a public hearing based on the approval process having been based on
sloppy science and the product's having reportedly caused epileptic
seizures in monkeys and possible eye damage.
Dr. Olney had already shown that aspartic acid (one aspartame component)
caused microscopic holes in the brains of rats after each feeding.
Aspartame also includes phenylalinine, which causes PKU in a small
number of susceptible children, and methyl, or wood, alcohol which is
neurotoxic in large amounts.
Faced with this array of possible health dangers, FDA granted the
hearing requests. In lieu of withdrawing its aspartame approval, the
agency prevailed on Searle to refrain from marketing the sweetener until
after completion of the hearing process. it then proposed that a Public
Board of Inquiry (PBOI) review the matter.
In July of 1975, as the FDA prepared for the PBOI, an FDA inspector
conducted a routine review of the Searle's Skokie Ill., testing
facilities and found many deviations from proper procedures. This report
led the FDA commissioner to empanel a Special Commissioner's Task Force
to review Searle's labs.
In December of 1975 the Task force reported serious problem with Searle
research on a wide range of products, including aspartame. It found 11
pivotal studies conducted in a manner so flawed as to raise doubts about
aspartame safety and create the possibility of serious criminal
liability for Searle.
The FDA then stayed aspartame's approval. It also contracted, over
serious internal objection, with a group of university pathologists
(paid by Searle) to review most of the studies, set up a task force to
review three studies and asked the U.S. Attorney for Chicago to seek a
grand jury review of the monkey seizure study.
The pathologists paid by Searle only reviewed failure to properly report
data and not the study's design or conduct. They found no serious
problems. The FDA task force found Searle's key tumor safety study
unreliable, but was ignored. The U.S. attorney let the statue of
limitations run out, then (along with two aides) proceeded to join
Searle's law firm.
While these committees met, the FDA organized the PBOI. Searle, the
petitioners and the FDA Bureau of Foods each nominated three members for
the board and the FDA commissioner selected one member from each list.
the board, which convened in January of 1980, rejected petitioners'
request to include the commissioner's task force information in its
deliberations. Still, in October 1980, based on its limited review, the
board blocked aspartame marketing until the tumor studies could be
explained. Unless the commissioner overruled the board, the matter was
closed.
In November 1980, however, the country elected Ronald Reagan President.
Donald Rumsfeld (former congressman from Skokie, former White House
chief of staff, former secretary of defense and since January 1977
president of Searle) joined the Reagan transition team. A full court
press against the board decision began.
In January 1981 Rumsfeld told a sales meeting, according to one
attendee, that he would call in his chips and get aspartame approved by
the end of the year. On January 25th, the day the new president took
office, the previous FDA commissioner's authority was suspended, and the
next month, the commissioner's job went to Dr. Arthur Hull Hayes.
Transition records do not show why the administration chose ***Hayes, a
professor and Defense Department contract researcher.*** In July Hayes,
defying FDA advisors, approved aspartame for dry foods -- his first
major decision. In November 1983 the FDA approved aspartame for soft
drinks -- Hayes' last decision.
In November 1983 Hayes, under fire for accepting corporate gifts, left
the agency and went to Searle's public-relations firm as senior medical
advisor. Later Searle lawyer Robert Shapiro named aspartame NutraSweet.
Monsanto purchased Searle. Rumsfeld received a $12 million bonus.
Shapiro is now Monsanto president.
Shortly after the FDA soft-drink approval, Searle began test marketing,
and complaints began to arrive at the FDA -- of such reactions as
dizziness, blurred vision, headaches, and seizures. The complaints were
more serious than the agency had ever received on any food additive, At
the same time, scientists began looking more closely at this
manufactured chemical sweeetner.
In 1985, the FDA asked the Centers for Disease Control (CDC) to review
the first 650 complaints (there are now over 10,000). CDC found that the
symptoms in approximately 25% of the complainants had stopped and then
restarted, corresponding with their having stopped and then restarted,
either purposely or by accident, aspartame consumption.
The CDC also identified several specific subjects whose symptoms stopped
and started as they stopped and started consuming aspartame. The FDA
discounted the report. The day the FDA released the CDC report, Pepsi
Cola -- having obained an advance copy -- announced its switch to
aspartame with a worldwide media blitz.
Former White House Chief of Staff Rumsfeld owed a debt of gratitude to
former White House confidante and Rumsfeld friend Donald Kendal, Pepsi's
chairman. The Pepsi announcement and aggressive marketing (millions of
gumballs, a red and white swirl, tough contracts) made NutraSweet known
in every home.
At the same time, according to data released in 1995, human brain tumors
like those in the animal studies rose 10% and previously benign tumors
turned virulent. Searle and FDA's deputy commissioner said the data
posed no problem. Two years later this same FDA official became vice
president of clinical research for Searle.
>From 1985 to 1995, researchers did about 400 aspartame studies. They
were divided almost evenly between those that gave assurances and those
that raised questions about the sweetener. Most instructively, Searle
paid for 100% of those finding no problem. All studies paid for by
non-industry sources raised questions.
Given this record, it is little wonder that many health-conscious people
believe avoiding NutraSweet improves their quality of life. If and when
a scientific consensus concludes that aspartame puts some, if not all,
of its consumers at risk, it will be much too late. The point is to eat
safely now. Remember: the brain you save may be your own.
James S. Turner, Esq., is a partner in the 27-year-old Washington, D.C.
consumer-interest law firm of Swankin and Turner. He is the author of
The Chemical Feast: The Nader Report on the Food and Drug
Administration, Making Your Own Baby Food, and a number of law journal
and popular media articles.
************************************************************************
http://www.conspiracyplanet.com/channel.cfm?channelid=55&contentid=107
Conspiracy Planet Mon Dec 23 2002
The Alternative News & History Network
Your Antidote to Media Cartel Propaganda
Rumsfeld Lobbied FDA Approval of Toxic Aspartame by RM NEWS
(Editor's note: Bush just appointed another unindicted criminal, Donald
Rumsfeld, as Secretary of Defense.
>From Secretary of Defense under Gerald Ford to Chairman and CEO of G.D.
Searle (makers of aspartame), to White House Chief of Staff to
Congressman to the board of directors of Amylin Pharmaceuticals, among
other things, this man is apparently really qualified to take over the
position of head of dirty works.
His connections to Ford, Rockefeller, Bush, Cheney, Kissinger, etc. make
him an ideal insider choice.
>From the following website comes this tidbit and much more:
http://www.aspartamekills.com/mpvalley/
ARTIFICIAL SWEETENER ASPARTAME (EQUAL, NUTRASWEET) LINKED TO BREAST
CANCER AND GULF WAR SYNDROME
"On June 1, 1977, Donald Rumsfeld became Chairman and CEO of G.D.
Searle. Rumsfeld, straight out the White House as Gerald Ford's
Secretary of Defense and before that his Chief of Staff, was a heavy gun
for Searle to secure FDA approval of aspartame (Equal, NutraSweet).
A hard-right Republican who served four terms in Congress
(1962-69),Rumsfeld voted against food stamps, Medicare and anti-poverty
funds. Rumsfeld's political ideology encompasses the stockpiling of
chemical weapons,downsizing the Federal government, and eliminating
funding for the Corporation for Public Broadcasting."
And this:
"James Turner, the anti-aspartame advocate alleges that Searle hired
Rumsfeld to handle the aspartame approval difficulties as a "legal
problem rather than a scientific problem."
And this:
"On September 30, 1980, the PBOI voted unanimously to reject the use of
aspartame (Equal, NutraSweet) until additional studies on aspartame's
potential to cause brain tumors could be done.
On January 21, 1981, the day after Ronald Reagan was inaugurated as
President of the United States, Searle Pharmaceuticals reapplied to the
FDA for aspartame (Equal, NutraSweet) approval.
A former G.D. Searle salesperson, Patty Wood-Allott, revealed that
Donald Rumsfeld, president of Searle, told his sales force that, if
necessary, "he would call in all his markers and that no matter what, he
would see to it that aspartame would be approved that year." (mgold,
Gordon, US Senate Record)
>From the Amylin Pharmaceuticals webpage: Donald Rumsfeld Bio
Mr. Rumsfeld is Chairman of the Board of Directors of Gilead
Sciences, Inc. He also serves as a member of the boards of directors
of ABB (Asea Brown Boveri) Ltd., Tribune Company and RAND
Corporation. He is currently Chairman of the Salomon Smith Barney
International Advisory Board. He recently completed service as
Chairman of the U.S. Government Commission to Assess the Ballistic
Missile Threat to the United States. From 1991 to 1996, Mr.
Rumsfeld served as a member of the board of directors of Amylin
Pharmaceuticals. Mr. Rumsfeld was Chairman and Chief Executive
Officer of General Instrument Corporation from October 1990 to
August 1993 and served as a senior advisor to William Blair & Co.,
an investment banking firm, from 1985 to 1990. He was Chief
Executive Officer of G.D. Searle & Co. from 1977 to 1985. Mr.
Rumsfeld formerly served as U.S. Secretary of Defense, White
House Chief of Staff, U.S. Ambassador to NATO, and U.S.
Congressman. He has also served as the President's special envoy to
the Middle East. He is a recipient of the Presidential Medal of
Freedom, the United States' highest civilian award.
************************************************************************
http://groups.yahoo.com/group/aspartameNM/message/928
revolving door, Monsanto, FDA, EPA: NGIN: Murray 12.23.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/912
aspartame: methanol, formaldehyde, formic acid toxicity:
brief review: Murray 12.23.2 rmforall
Rich Murray, MA Room For All rmforall@att.net
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-986-9103
http://groups.yahoo.com/group/aspartameNM/messages
for 930 posts in a public searchable archive
http://groups.yahoo.com/group/aspartameNM/message/862 long review
http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall
It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA daily limit for formaldehyde in
drinking water.
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.
Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/915
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
Wilson: CIIN: 12.12.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/860
RTM: FDA: objections to neotame approval 8.3.2 rmforall 38 pages
http://groups.yahoo.com/group/aspartameNM/message/868
Murray: submit complaints and papers to FDA Docket 02P-0317
by Jan 12 2003: Recall Aspartame as a Neurotoxic Drug 9.20.2 rmforall
http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@aol.com
http://www.sunsentpress.com/ sunsentpress@aol.com
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/926
aspartame puts formaldehyde adducts into tissues, Part 2/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
***********************************************************************
Rumsfeld, 1977 head of Searle Corp., got aspartame FDA approval:
Turner: Murray 12.23.2 rmforall
http://www.swankin-turner.com/
Swankin & Turner is a law firm specializing in the areas of regulation
(food and drug, health care, standard setting, antitrust and trade) and
policy (agricultural, insurance, corporate, tax, administrative and
consumer). Established in Washington, D.C. in 1973, it has served a
broad variety of individual and organizational clients, including
national and local business corporations and nonprofit associations.
All attorneys with the firm are members of the District of Columbia bar.
In addition, James Turner is admitted to the Ohio and U.S. Supreme Court
bars; Betsy Lehrfeld is admitted to the California and U.S. Supreme
Court bars; Charles Brown is admitted to the bars of Ohio, West Virginia
and the U.S. Supreme Court; and Chris Turner is admitted to the
Pennsylvania bar.
http://www.swankin-turner.com/aspartame.html
http://www.swankin-turner.com/hist.html
Aspartame/NutraSweet: The History of the Aspartame Controversy
by James Turner, ESQ. Director of the National Institute of Science,
Law, and Public Policy (NISLAPP)
National Institute of Science, Law, and Public Policy
1400 16th Street, NW, Suite 330, Washington, DC 20036
(202) 462-8800 Fax: (202) 265-6564 nislapp@swankin-turner.com
Timeline:
December 1965-- While working on an ulcer drug, James Schlatter, a
chemist at G.D. Searle, accidentally discovers aspartame, a substance
that is 180 times sweeter than sugar yet has no calories.
Spring 1967-- Searle begins the safety tests on aspartame that are
necessary for applying for FDA approval of food additives.
Fall 1967-- Dr. Harold Waisman, a biochemist at the University of
Wisconsin, conducts aspartame safety tests on infant monkeys on behalf
of the Searle Company. Of the seven monkeys that were being fed
aspartame mixed with milk, one dies and five others have grand mal
seizures.
November 1970-- Cyclamate, the reigning low-calorie artificial sweetener
-- is pulled off the market after some scientists associate it with
cancer. Questions are also raised about safety of saccharin, the only
other artificial sweetener on the market, leaving the field wide open
for aspartame.
December 18, 1970-- Searle Company executives lay out a "Food and Drug
Sweetener Strategy' that they feel will put the FDA into a positive
frame of mind about aspartame. An internal policy memo describes
psychological tactics the company should use to bring the FDA into a
subconscious spirit of participation" with them on aspartame and get FDA
regulators into the "habit of saying, "Yes"."
Spring 1971-- Neuroscientist Dr. John Olney (whose pioneering work with
monosodium glutamate was responsible for having it removed from baby
foods) informs Searle that his studies show that aspartic acid (one of
the ingredients of aspartame) caused holes in the brains of infant
mice. One of Searle's own researchers confirmed Dr. Olney's findings in
a similar study.
February 1973-- After spending tens of millions of dollars conducting
safety tests, the G.D. Searle Company applies for FDA approval and
submits over 100 studies they claim support aspartame's safety.
March 5, 1973-- One of the first FDA scientists to review the aspartame
safety data states that "the information provided (by Searle) is
inadequate to permit an evaluation of the potential toxicity of
aspartame". She says in her report that in order to be certain that
aspartame is safe, further clinical tests are needed.
May 1974-- Attorney, Jim Turner (consumer advocate who was instrumental
in getting cyclamate taken off the market) meets with Searle
representatives to discuss Dr. Olney's 1971 study which showed that
aspartic acid caused holes in the brains of infant mice.
July 26, 1974-- The FDA grants aspartame its first approval for
restricted use in dry foods.
August 1974-- Jim Turner and Dr. John Olney file the first objections
against aspartame's approval.
March 24, 1976-- Turner and Olney's petition triggers an FDA
investigation of the laboratory practices of aspartame's manufacturer,
G.D. Searle. The investigation finds Searle's testing procedures shoddy,
full of inaccuracies and "manipulated" test data. The investigators
report they "had never seen anything as bad as Searle's testing."
January 10, 1977-- The FDA formally requests the U.S. Attorney's office
to begin grand jury proceedings to investigate whether indictments
should be filed against Searle for knowingly misrepresenting findings
and "concealing material facts and making false statements" in aspartame
safety tests. This is the first time in the FDA's history that they
request a criminal investigation of a manufacturer.
January 26, 1977-- While the grand jury probe is underway, Sidley &
Austin, the law firm representing Searle, begins job negotiations with
the U.S. Attorney in charge of the investigation, Samuel Skinner.
March 8, 1977-- G. D. Searle hires prominent Washington insider Donald
Rumsfeld as the new CEO to try to turn the beleaguered company around. A
former Member of Congress and Secretary of Defense in the Ford
Administration, Rumsfeld brings in several of his Washington cronies as
top management.
July 1, 1977-- Samuel Skinner leaves the U.S. Attorney's office and
takes a job with Searle's law firm. (see Jan. 26th)
August 1, 1977-- The Bressler Report, compiled by FDA investigators and
headed by Jerome Bressler, is released. The report finds that 98 of the
196 animals died during one of Searle's studies and weren't autopsied
until later dates, in some cases over one year after death. Many other
errors and inconsistencies are noted. For example, a rat was reported
alive, then dead, then alive, then dead again; a mass, a uterine polyp,
and ovarian neoplasms were found in animals but not reported or
diagnosed in Searle's reports.
December 8, 1977-- U.S. Attorney Skinner's withdrawal and resignation
stalls the Searle grand jury investigation for so long that the statue
of limitations on the aspartame charges runs out. The grand jury
investigation is dropped.
June 1, 1979-- The FDA established a Public Board of Inquiry (PBOI) to
rule on safety issues surrounding NutraSweet.
September 30, 1980-- The Public Board of Inquiry concludes NutraSweet
should not be approved pending further investigations of brain tumors in
animals. The board states it "has not been presented with proof of
reasonable certainty that aspartame is safe for use as a food additive."
January 1981-- Donald Rumsfeld, CEO of Searle, states in a sales meeting
that he is going to make a big push to get aspartame approved within the
year. Rumsfeld says he will use his political pull in Washington, rather
than scientific means, to make sure it gets approved.
January 21, 1981-- Ronald Reagan is sworn in as President of the United
States. Reagan's transition team, which includes Donald Rumsfeld, CEO of
G. D. Searle, hand picks Dr. Arthur Hull Hayes Jr. to be the new FDA
Commissioner.
March, 1981-- An FDA commissioner's panel is established to review
issues raised by the Public Board of Inquiry.
May 19, 1981-- Three of six in-house FDA scientists who were responsible
for reviewing the brain tumor issues, Dr. Robert Condon, Dr. Satya
Dubey, and Dr. Douglas Park, advise against approval of NutraSweet,
stating on the record that the Searle tests are unreliable and not
adequate to determine the safety of aspartame.
July 15, 1981-- In one of his first official acts, Dr. Arthur Hayes Jr.,
the new FDA commissioner, overrules the Public Board of Inquiry, ignores
the recommendations of his own internal FDA team and approves NutraSweet
for dry products. Hayes says that aspartame has been shown to be safe
for its' proposed uses and says few compounds have withstood such
detailed testing and repeated close scrutiny.
October 15, 1982-- The FDA announces that Searle has filed a petition
that aspartame be approved as a sweetener in carbonated beverages and
other liquids.
July 1, 1983-- The National Soft Drink Association (NSDA) urges the FDA
to delay approval of aspartame for carbonated beverages pending further
testing because aspartame is very unstable in liquid form. When liquid
aspartame is stored in temperatures above 85 degrees Fahrenheit, it
breaks down into DKP and formaldehyde, both of which are known toxins.
July 8, 1983-- The National Soft Drink Association drafts an objection
to the final ruling which permits the use of aspartame in carbonated
beverages and syrup bases and requests a hearing on the objections. The
association says that Searle has not provided responsible certainty that
aspartame and its' degradation products are safe for use in soft drinks.
August 8, 1983-- Consumer Attorney, Jim Turner of the Community
Nutrition Institute and Dr. Woodrow Monte, Arizona State University's
Director of Food Science and Nutritional Laboratories, file suit with
the FDA objecting to aspartame approval based on unresolved safety
issues.
September, 1983-- FDA Commissioner Hayes resigns under a cloud of
controversy about his taking unauthorized rides aboard a General Foods
jet. (General foods is a major customer of NutraSweet)
Burson-Marsteller, Searle's public relation firm (which also represented
several of NutraSweet's major users), immediately hires Hayes as senior
scientific consultant.
Fall 1983-- The first carbonated beverages containing aspartame are sold
for public consumption.
November 1984-- Center for Disease Control (CDC) "Evaluation of consumer
complaints related to aspartame use." (summary by B. Mullarkey)
November 3, 1987-- U.S. hearing, "NutraSweet: Health and Safety
Concerns," Committee on Labor and Human Resources, Senator Howard
Metzenbaum, chairman.
************************************************************************
http://groups.yahoo.com/group/aspartameNM/message/857
RTM: www.dorway.com: original documents and long reviews of flaws in
aspartame toxicity research 7.31.2 rmforall
http://www.dorway.com/upipart1.txt
UPI reporter Gregory Gordon: 96K 3-part expose Oct 1987
"Survey of aspartame studies: correlation of outcome and funding
sources," 1998, unpublished: http://www.dorway.com/peerrev.html
Walton found 166 separate published studies in the peer reviewed
medical literature, which had relevance for questions of human safety.
The 74 studies funded by industry all (100%) attested to aspartame's
safety, whereas of the 92 non-industry funded studies, 84 (91%)
identified a problem. Six of the seven non-industry funded studies
that were favorable to aspartame safety were from the FDA, which
has a public record that shows a strong pro-industry bias.
Ralph G. Walton, MD, Prof. of Clinical Psychology, Northeastern Ohio
Universities, College of Medicine, Dept. of Psychiatry, Youngstown,
OH 44501, Chairman, The Center for Behavioral Medicine,
Northside Medical Center, 500 Gypsy Lane, P.O. Box 240 Youngstown,
OH 44501 330-740-3621 rwalton193@aol.com
http://www.neoucom.edu/DEPTS/Psychiatry/walton.htm
************************************************************************
Christie D. Michas christiem@messengers-of-messiah.org
Wed, 11 Sep 2002 12:37:51 -0700
>----- Original Message -----
>From: "Mark Douglas Whitaker"
>To:
>Sent: Saturday, August 24, 2002 9:44 PM
>Subject: Rumsfeld's conflict of interest and ASPARTAME: Rumsfeld was
>president of Serle corporation! part of Reagan transition team, and got
>aspartame 'legalized' by appointing a defense department contractor
>(Hayes) as head of FDA!
http://csf.colorado.edu/envtecsoc/2002/msg00440.html
Rumsfeld's conflict of interest and ASPARTAME: Rumsfeld was
president of Searle corporation! part of Reagan transition team, and got
aspartame 'legalized' by appointing a defense department
contractor (Hayes) as head of FDA!
by Mark Douglas Whitaker 25 August 2002 01:45 UTC
summary:
Rumsfeld's conflict of interests and ASPARTAME: Rumsfeld was president
of Searle corporation in 1977, maker of aspartame, then, part of Reagan
transition team, and got aspartame 'legalized' by appointing a defense
department contractor [??] (Hayes) as head of FDA!
A book should be written about American corruption and aspartame.
[also at: http://www.stevia.net/aspartame.htm ]
The Aspartame/NutraSweet Fiasco by James S. Turner
Many health-conscious people believe that avoiding aspartame, found in
over 5000 products under brand names such as Equal and NutraSweet, can
improve their quality of life. The history of this synthetic sweetener's
approval by the U.S. Food and Drug Administration (FDA), including a
long record of consumer complaints and the agency's demonstrated
insensitivity to public concern, suggests they're right.
In October 1980 the Public Board of Inquiry (PBOI) impaneled by the FDA
to evaluate aspartame safety found that the chemical caused an
unacceptable level of brain tumors in animal testing. Based on this
fact, the PBOI ruled that aspartame should not be added to the food
supply.
This ruling capped 15 years of regulatory ineptitude, chicanery and
deception by the FDA and the Searle drug company, aspartame's discoverer
and manufacturer (acquired by Monsanto in 1985), and kicked off another
two decades of maneuvering, manipulating and dissembling by FDA, Searle
and Monsanto.
In 1965, a Searle scientist licked some of a new ulcer drug from his
fingers and discovered the sweet taste of aspartame. Eureka! Selling
this chemical as a food additive to hundreds of millions of healthy
people every day would mean many more dollars than limited sales to the
much smaller group of ulcer sufferers.
Searle, a drug company with little experience in food regulation, began
studies to comply with the law-- but which failed to do so. Its early
tests of the substance showed it produced microscopic holes and tumors
in the brains of experimental mice, epileptic seizures in monkeys, and
was converted by animals into dangerous substances, including
formaldehyde.
In 1974, however, in spite of the information in its files, the FDA
approved aspartame as a dry-foods additive. But the agency also made
public for the first time the data supporting a food-additive decision.
This data was subsequently reviewed by renowned brain researcher John
Olney from Washington University in St. Louis, and other scientists.
Dr. Olney discovered two studies showing brain tumors in rats and
petitioned FDA for a public hearing. Consumer Action for Improved Foods
and Drugs (represented by the author of this piece) also petitioned for
a public hearing based on the approval process having been based on
sloppy science and the product's having reportedly caused epileptic
seizures in monkeys and possible eye damage.
Dr. Olney had already shown that aspartic acid (one aspartame component)
caused microscopic holes in the brains of rats after each feeding.
Aspartame also includes phenylalinine, which causes PKU in a small
number of susceptible children, and methyl, or wood, alcohol which is
neurotoxic in large amounts.
Faced with this array of possible health dangers, FDA granted the
hearing requests. In lieu of withdrawing its aspartame approval, the
agency prevailed on Searle to refrain from marketing the sweetener until
after completion of the hearing process. it then proposed that a Public
Board of Inquiry (PBOI) review the matter.
In July of 1975, as the FDA prepared for the PBOI, an FDA inspector
conducted a routine review of the Searle's Skokie Ill., testing
facilities and found many deviations from proper procedures. This report
led the FDA commissioner to empanel a Special Commissioner's Task Force
to review Searle's labs.
In December of 1975 the Task force reported serious problem with Searle
research on a wide range of products, including aspartame. It found 11
pivotal studies conducted in a manner so flawed as to raise doubts about
aspartame safety and create the possibility of serious criminal
liability for Searle.
The FDA then stayed aspartame's approval. It also contracted, over
serious internal objection, with a group of university pathologists
(paid by Searle) to review most of the studies, set up a task force to
review three studies and asked the U.S. Attorney for Chicago to seek a
grand jury review of the monkey seizure study.
The pathologists paid by Searle only reviewed failure to properly report
data and not the study's design or conduct. They found no serious
problems. The FDA task force found Searle's key tumor safety study
unreliable, but was ignored. The U.S. attorney let the statue of
limitations run out, then (along with two aides) proceeded to join
Searle's law firm.
While these committees met, the FDA organized the PBOI. Searle, the
petitioners and the FDA Bureau of Foods each nominated three members for
the board and the FDA commissioner selected one member from each list.
the board, which convened in January of 1980, rejected petitioners'
request to include the commissioner's task force information in its
deliberations. Still, in October 1980, based on its limited review, the
board blocked aspartame marketing until the tumor studies could be
explained. Unless the commissioner overruled the board, the matter was
closed.
In November 1980, however, the country elected Ronald Reagan President.
Donald Rumsfeld (former congressman from Skokie, former White House
chief of staff, former secretary of defense and since January 1977
president of Searle) joined the Reagan transition team. A full court
press against the board decision began.
In January 1981 Rumsfeld told a sales meeting, according to one
attendee, that he would call in his chips and get aspartame approved by
the end of the year. On January 25th, the day the new president took
office, the previous FDA commissioner's authority was suspended, and the
next month, the commissioner's job went to Dr. Arthur Hull Hayes.
Transition records do not show why the administration chose ***Hayes, a
professor and Defense Department contract researcher.*** In July Hayes,
defying FDA advisors, approved aspartame for dry foods -- his first
major decision. In November 1983 the FDA approved aspartame for soft
drinks -- Hayes' last decision.
In November 1983 Hayes, under fire for accepting corporate gifts, left
the agency and went to Searle's public-relations firm as senior medical
advisor. Later Searle lawyer Robert Shapiro named aspartame NutraSweet.
Monsanto purchased Searle. Rumsfeld received a $12 million bonus.
Shapiro is now Monsanto president.
Shortly after the FDA soft-drink approval, Searle began test marketing,
and complaints began to arrive at the FDA -- of such reactions as
dizziness, blurred vision, headaches, and seizures. The complaints were
more serious than the agency had ever received on any food additive, At
the same time, scientists began looking more closely at this
manufactured chemical sweeetner.
In 1985, the FDA asked the Centers for Disease Control (CDC) to review
the first 650 complaints (there are now over 10,000). CDC found that the
symptoms in approximately 25% of the complainants had stopped and then
restarted, corresponding with their having stopped and then restarted,
either purposely or by accident, aspartame consumption.
The CDC also identified several specific subjects whose symptoms stopped
and started as they stopped and started consuming aspartame. The FDA
discounted the report. The day the FDA released the CDC report, Pepsi
Cola -- having obained an advance copy -- announced its switch to
aspartame with a worldwide media blitz.
Former White House Chief of Staff Rumsfeld owed a debt of gratitude to
former White House confidante and Rumsfeld friend Donald Kendal, Pepsi's
chairman. The Pepsi announcement and aggressive marketing (millions of
gumballs, a red and white swirl, tough contracts) made NutraSweet known
in every home.
At the same time, according to data released in 1995, human brain tumors
like those in the animal studies rose 10% and previously benign tumors
turned virulent. Searle and FDA's deputy commissioner said the data
posed no problem. Two years later this same FDA official became vice
president of clinical research for Searle.
>From 1985 to 1995, researchers did about 400 aspartame studies. They
were divided almost evenly between those that gave assurances and those
that raised questions about the sweetener. Most instructively, Searle
paid for 100% of those finding no problem. All studies paid for by
non-industry sources raised questions.
Given this record, it is little wonder that many health-conscious people
believe avoiding NutraSweet improves their quality of life. If and when
a scientific consensus concludes that aspartame puts some, if not all,
of its consumers at risk, it will be much too late. The point is to eat
safely now. Remember: the brain you save may be your own.
James S. Turner, Esq., is a partner in the 27-year-old Washington, D.C.
consumer-interest law firm of Swankin and Turner. He is the author of
The Chemical Feast: The Nader Report on the Food and Drug
Administration, Making Your Own Baby Food, and a number of law journal
and popular media articles.
************************************************************************
http://www.conspiracyplanet.com/channel.cfm?channelid=55&contentid=107
Conspiracy Planet Mon Dec 23 2002
The Alternative News & History Network
Your Antidote to Media Cartel Propaganda
Rumsfeld Lobbied FDA Approval of Toxic Aspartame by RM NEWS
(Editor's note: Bush just appointed another unindicted criminal, Donald
Rumsfeld, as Secretary of Defense.
>From Secretary of Defense under Gerald Ford to Chairman and CEO of G.D.
Searle (makers of aspartame), to White House Chief of Staff to
Congressman to the board of directors of Amylin Pharmaceuticals, among
other things, this man is apparently really qualified to take over the
position of head of dirty works.
His connections to Ford, Rockefeller, Bush, Cheney, Kissinger, etc. make
him an ideal insider choice.
>From the following website comes this tidbit and much more:
http://www.aspartamekills.com/mpvalley/
ARTIFICIAL SWEETENER ASPARTAME (EQUAL, NUTRASWEET) LINKED TO BREAST
CANCER AND GULF WAR SYNDROME
"On June 1, 1977, Donald Rumsfeld became Chairman and CEO of G.D.
Searle. Rumsfeld, straight out the White House as Gerald Ford's
Secretary of Defense and before that his Chief of Staff, was a heavy gun
for Searle to secure FDA approval of aspartame (Equal, NutraSweet).
A hard-right Republican who served four terms in Congress
(1962-69),Rumsfeld voted against food stamps, Medicare and anti-poverty
funds. Rumsfeld's political ideology encompasses the stockpiling of
chemical weapons,downsizing the Federal government, and eliminating
funding for the Corporation for Public Broadcasting."
And this:
"James Turner, the anti-aspartame advocate alleges that Searle hired
Rumsfeld to handle the aspartame approval difficulties as a "legal
problem rather than a scientific problem."
And this:
"On September 30, 1980, the PBOI voted unanimously to reject the use of
aspartame (Equal, NutraSweet) until additional studies on aspartame's
potential to cause brain tumors could be done.
On January 21, 1981, the day after Ronald Reagan was inaugurated as
President of the United States, Searle Pharmaceuticals reapplied to the
FDA for aspartame (Equal, NutraSweet) approval.
A former G.D. Searle salesperson, Patty Wood-Allott, revealed that
Donald Rumsfeld, president of Searle, told his sales force that, if
necessary, "he would call in all his markers and that no matter what, he
would see to it that aspartame would be approved that year." (mgold,
Gordon, US Senate Record)
>From the Amylin Pharmaceuticals webpage: Donald Rumsfeld Bio
Mr. Rumsfeld is Chairman of the Board of Directors of Gilead
Sciences, Inc. He also serves as a member of the boards of directors
of ABB (Asea Brown Boveri) Ltd., Tribune Company and RAND
Corporation. He is currently Chairman of the Salomon Smith Barney
International Advisory Board. He recently completed service as
Chairman of the U.S. Government Commission to Assess the Ballistic
Missile Threat to the United States. From 1991 to 1996, Mr.
Rumsfeld served as a member of the board of directors of Amylin
Pharmaceuticals. Mr. Rumsfeld was Chairman and Chief Executive
Officer of General Instrument Corporation from October 1990 to
August 1993 and served as a senior advisor to William Blair & Co.,
an investment banking firm, from 1985 to 1990. He was Chief
Executive Officer of G.D. Searle & Co. from 1977 to 1985. Mr.
Rumsfeld formerly served as U.S. Secretary of Defense, White
House Chief of Staff, U.S. Ambassador to NATO, and U.S.
Congressman. He has also served as the President's special envoy to
the Middle East. He is a recipient of the Presidential Medal of
Freedom, the United States' highest civilian award.
************************************************************************
http://groups.yahoo.com/group/aspartameNM/message/928
revolving door, Monsanto, FDA, EPA: NGIN: Murray 12.23.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/912
aspartame: methanol, formaldehyde, formic acid toxicity:
brief review: Murray 12.23.2 rmforall
Rich Murray, MA Room For All rmforall@att.net
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-986-9103
http://groups.yahoo.com/group/aspartameNM/messages
for 930 posts in a public searchable archive
http://groups.yahoo.com/group/aspartameNM/message/862 long review
http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall
It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA daily limit for formaldehyde in
drinking water.
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.
Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/915
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
Wilson: CIIN: 12.12.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/860
RTM: FDA: objections to neotame approval 8.3.2 rmforall 38 pages
http://groups.yahoo.com/group/aspartameNM/message/868
Murray: submit complaints and papers to FDA Docket 02P-0317
by Jan 12 2003: Recall Aspartame as a Neurotoxic Drug 9.20.2 rmforall
http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@aol.com
http://www.sunsentpress.com/ sunsentpress@aol.com
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/926
aspartame puts formaldehyde adducts into tissues, Part 2/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
***********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall Part 1/2
Dec 9 2002 [ Notes by Rich Murray are in square brackets. Pall has 45
items in PubMed since 1969.
The theory is quite complex. Most readers will not be familiar with the
biochemistry. I will focus on the many diseases that may be involved,
more and less, on MSG and on formaldehyde (an inevitable product of
methanol, the 11% component of aspartame), and the prospect for new
diagnostic tests and for treatments for aspartame disease. ]
http://www.wsunews.wsu.edu/detail.asp?StoryID=3281
News Bureau Washington State University wsunews@wsu.edu
Pullman, WA 99164-1040 509/335-3581 FAX: 509/335-2220
See a complete list of news releases on the Web at:
http://wsunews.wsu.edu
Online Experts Directory: http://experts.wsu.edu
9/16/2002
Contact: Sharon Hatch, 509/335-4262, hatch@wsu.edu
Martin L. Pall, 509/335-1246, martin_pall@wsu.edu
WSU Biochemist Suggests Vicious Chemical Cycle May Cause
Multiple Chemical Sensitivity
PULLMAN, Wash. -- In the United States about 10 million people are
afflicted by severe multiple chemical sensitivity. Many MCS sufferers
give up air travel, some must find new work places or move out of their
homes to avoid exposure to certain chemicals. For them, grocery
shopping in the detergent aisle or attending events where someone may
wear perfume is risky. MCS symptoms, which may last for hours or days,
include pain–severe headaches and pain in joints and muscles–fatigue,
dizziness and an impaired ability to think clearly.
The onset of this chronic condition can usually be traced back to an
exposure to certain chemicals. But why the initial exposure results in
an often life-long, incurable condition has been a mystery. In an
article published in the September 2002 issue of the prestigious
publication of the Federation of American Societies of Experimental
Biology, "The FASEB Journal," Washington State University biochemist
Martin Pall suggests that a vicious chemical cycle may be to blame.
Pall's new theory is a fusion of two previous theories about MCS. One
of these, proposed by Pall earlier, states that MCS is produced by
excessive levels of two chemicals in the body–nitric oxide and its
oxidant product - peroxynitrite. He suggested certain mechanisms act to
keep levels of the two compounds elevated, thus producing chronic
changes. The second theory was proposed by Iris Bell, M.D, Ph.D. of the
University of Arizona. She proposed that the central mechanism in MCS
is neural sensitization in the brain.
"What my article reports," said Pall, "is that if you assume both
previous theories are correct, you come up with a fusion that explains
all the most puzzling features of MCS. It explains why MCS is induced
by a previous chemical exposure and why MCS sufferers show such a high
level of sensitivity to a wide range of organic chemicals."
Pall cites many studies that suggest that the initial chemical exposure
creates a hypersensitivity in the neurons in the brain, which react by
creating the two chemicals that cause further hypersensitivity.
"Ordinarily, these activities are highly regulated, acting only on
specific synapses in the brain where they are involved in learning and
memory. The MCS response is produced," said Pall, "when chemical
exposure produces excessive responses over large regions of the brain.
In this way, normal and important mechanisms may act to generate this
chronic illness. Thus, not only is the brain constantly inundated by
chemicals to which it is normally somewhat sensitive, but the brain of
a person suffering from MCS becomes abnormally sensitive to the
chemicals–- from 100 to 1,000 times more sensitive than in an unaffected
person." Two other mechanisms contribute to the sensitivity to by
allowing the offending chemicals to accumulate to higher levels in the
brains of MCS people.
MCS has overlaps with other medical conditions of uncertain mechanism
including chronic fatigue syndrome, fibromyalgia, posttraumatic stress
disorder, and Gulf War syndrome. Pall has proposed similar mechanisms
for all of these conditions. "The notion that a biochemical vicious
cycle may underlie all four is very exciting and, if correct, suggests
that this is a major new paradigm of human disease."
Interrupting this cycle may be the key to effective MCS treatment, said
Pall.
Pall's article is available on the Web at
http://www.fasebj.org/cgi/content-nw/full/16/11/1407/T1.
Access to this site is free to members of the Federation of American
Societies of Experimental Biology, others must pay a $7 access fee.
Comments: Dr. Gunnar Heuser, neurotoxicologist and clinical professor
at UCLA, who has published on brain changes in Chronic Fatigue
Syndrome, stated "I consider Dr. Pall's research a significant
contribution to the science of clinical toxicology and multiple
chemical sensitivity."
Brain Imaging Center, University of California, Irvine, USA.
gheuser@ucla.edu
Dr. Grace Ziem, Maryland physician who practices occupational and
environmental medicine and specializes in chemically-induced illness,
said "I feel that Dr. Pall has done the most important biochemical
research and documentation toward understanding the mechanism of neural
sensitization underlying toxic injury to the brain and this research
has important implications for treatment."
http://www.mcsrr.org/resources/articles/S3.html
DR. GRACE ZIEM'S ENVIRONMENTAL CONTROL PLAN
FOR CHEMICALLY SENSITIVE PATIENTS
16926 Eyler's Valley Road, Emmitsburg MD 21727, 301-241-4346
Albert Donnay
************************************************************************
http://molecular.biosciences.wsu.edu/Faculty/pall.html [photo]
http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm
Novel chronic fatigue syndrome (CFS) theory finally
produces detailed explanations for many CFS observations:
[ This is a detailed summary review, with diagrams, references, and some
hyperlinks. ]
http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm
Fibromyalgia, excessive nitric oxide/peroxynitrite and excessive NMDA
activity [ detailed summary review, with 14 references, including
2. Smith J. D., Terpening C. M., Schmidt S. O. F., Gums J. G. Relief of
fibromyalgia symptoms following discontinuation of dietary excitotoxins.
Ann Pharmacotherapy 2001; 35: 702-706.
http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall ]
************************************************************************
FASEB J 2002 Sep; 16(11): 1407-17
NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and
organic solvents as the mechanism of chemical sensitivity in multiple
chemical sensitivity.
Pall ML. [ 162 references, received 1.3.2 ]
School of Molecular Biosciences, Washington State University,
Pullman, Washington 99164-4660, USA. martin_pall@wsu.edu
http://www.fasebj.org/cgi/content-nw/full/16/11/1407/T1. full text
Access to this site is free to members of the Federation of American
Societies of Experimental Biology, others must pay a $7 access fee.
Multiple chemical sensitivity (MCS) is a condition where previous
exposure to hydrophobic organic solvents or pesticides appears to
render people hypersensitive to a wide range of chemicals, including
organic solvents. The hypersensitivity is often exquisite, with MCS
individuals showing sensitivity that appears to be at least two orders
of magnitude greater than that of normal individuals. This paper
presents a plausible set of interacting mechanisms to explain such
heightened sensitivity.
It is based on two earlier theories of MCS: the elevated nitric
oxide/peroxynitrite theory and the neural sensitization theory. It is
also based on evidence implicating excessive NMDA activity in MCS. Four
sensitization mechanisms are proposed to act synergistically, each
based on known physiological mechanisms:
Nitric oxide-mediated stimulation of neurotransmitter (glutamate)
release;
peroxynitrite-mediated ATP depletion and consequent hypersensitivity of
NMDA receptors;
peroxynitrite-mediated increased permeability of theblood-brain barrier,
producing increased accessibility of organic
chemicals to the central nervous system;
and nitric oxide inhibition of cytochrome P450 metabolism.
Evidence for each of these mechanisms, which may also be involved in
Parkinson's disease, is reviewed. These interacting mechanisms provide
explanations for diverse aspects of MCS and a framework for
hypothesis-driven MCS research. PMID: 12205032
"...exposure to organophosphates or carbamates (1-7)...
hypersensitive... hydrophobic, volatile organic solvents... not to be
centered on an IgE-based allergic mechanism (1)... severe MCS in the
U.S. is ~4% with greatly reduced quality of life for the patient (2)...
less severe problems have been reported in ~15-30% of the population...
chemical sensitivity two or more orders of magnitude greater than do
normal individuals... no known mechanism whereby low levels of chemical
or chemicals of widely varied chemical structure can interact adversely
with numerous organ systems... Chronic fatigue syndrome (CFS),
fibromyalgia (FM), and post-traumatic stress disorder (PTSD)...
overlapping symptoms... preceded by short-term stress, only to be
followed by a chronic condition that typically lasts for years or
decades. Gulf War syndrome... may share a common etiologic mechanism
(16,23-29)... elevated nitric oxide/peroxynitrite mechanism (28-33)...
short-term stress... increases in nitric oxide (29-32)... reacts with
superoxide to form the potent oxidant peroxynitrite... six different
positive feedback loop mechanisms to increase the levels of nitric oxide
and its other precursor, superoxide, which in turn react to form more
peroxynitrite (30)... biochemical vicious cycle is initiated and
maintained that produces the chronic nature of these four conditions...
10 types of supportive evidence are summarized in Table 1...
The second precursor theory to this paper is the neural sensitization
theory origianlly proposed by Bell and co-workers (34)...
[ 34. Iris R. Bell, Miller CS, Schwartz GE.(1992).
An olfactory-limbic model of multiple chemical sensitivity syndrome:
possible relationships to kindling and affective spectrum disorders.
Biol. Psychiatry 1992; 32: 218-242.
35. Bell IR, Baldwin CM, Fernandez M, Schwartz GE.
Neural sensitization model for multiple chemical sensitivity: overview
of theory and empirical evidence.
Toxicol Ind. Health 1999; 15: 295-304. ]
... especially the limbic system... increased long-term synaptic
sensitivity induced by previous electrical and chemical
stimulation...long-term potentiation (LTP)... nitric oxide and the NMDA
[ N-methyl-D-aspartame ] excitatory neurotransmission system are
implicated in LTP, the presumed mechanism of neural sensitization...
increased Ca2+ influx into the cell... Excessive NMDA activity leading
to excessive levels of nitric oxide and peroxynitrite has been
implicated in several neurodegenerative diseases including
amyotrophic lateral sclerosis [ALS], Parkinson's disease, AIDS-related
dementia, stroke, epilepsy, Huntington's disease, and Alzheimer's
disease (67-72)... nitric oxide and peroxynitrite may act through known
mechanisms to increase both the stimulation of and the sensitivity of
NMDA receptors.
...volative organic solvents act in MCS by increasing NMDA activity.
The evidence for this (discussed below) is suggestive but not
conclusive... leading to ATP [ adenosine triphosphate, a primary energy
store and source in cells ] depletion as well... when neurons containing
NMDA receptors have lowered ATP pools, their NMDA receptors become
hypersensitive to stimulation... MCS individuals are often reported to
have low Mg2+ pools (7), and Mg2+ is known to lower NMDA sensitivity
(91).
...Acetylcholline will activate the muscarinic receptors, which are
known to produce increases in nitric oxide... people in buildings that
had been remodeled ("sick building syndrome"), thus exposing the
individuals to outgassing of organic solvents from the building
materials... (infection, physical trauma, and stress) may act to
increase nitric oxide levels (29,30,32)... carbon monoxide... chronic
sequelae (29), with symptoms similar to those in CFS, and carbon
monoxide is reported to induce excessive production of the two
percursors of peroxynitrite: superoxide and nitric oxide (29).
Peroxynitrite... to increase the permeability of the blood-brain barrier
in MCS... to increase chemical access to the CNS and thus increase
chemical sensitivity generated in the CNS...
Miller and Mitzel (6) reported that many MCS patients appear to be
hypersensitive to monosodium glutamate, a potential excitotoxin that can
act to stimulate NMDA receptors (64, 66, 91)...
One organic chemical often implicated in MCS-- formaldehyde... NMDA
stimulation... pain responses... by excessive NMDA activity and
consequent elevated nitric oxide levels...
...Donald Dudley... clinical observations on his MCS patients
(131)... known NMDA antagonist, dextromethorphan, appeared to block the
effects of organic solvents on his MCS patients... on an episodic
basis... stop the reaction before it gets started... Two other
physicians in Washington state,Gordon Baker and David Buscher,...
dextromethorphan for their MCS patients in a similar fashion, with
apparently similar results...
Part of the goal here is to suggest potentially important foci for
hypothesis-driven research, and clearly the many uncertainties in this
part of the hypothesis suggest many such topics of future study.
In her MCS review, [B.A.] Sorg (ref 2, Table 1) lists 18 neurological
symptoms as being found in MCS but lists other symptoms of
cardiovascular (two), respiratory (seven), gastrointestinal (three),
genitourinary (four), musculoskeletal (five), and dermatologic (one)
origin... various other organs appear to be affected in many
cases... inflammatory cytokines... will circulate to a variety of
tissues and have been reported to be induced by organic solvents
(28)... Furthermore,... nitric oxide transport... spreading to other
tissues... [ These many symptoms fit the profile of aspartame disease. ]
2. Sorg BA.
Multiple chemical sensitivity: potential role for neural sensitization.
Crit. Rev. Neurobiol. 1999; 13: 283-316.
...organic solvent exposure is an important risk factor in Parkinson's
disease (148-153)... Excessive NMDA activity is associated with
Parkinson's disease...
...funding for MCS disease is less than a thousandth of that available
for diabetes research... critical need for clear and compelling
hypotheses, consistent with the many reported properties of MCS, to
provide a basis for future research... four proposed consequent
mechanisms... are all expected to act synergistically, producing the
kind of exquisite sensitivity reported in MCS...
I thank Drs. James Satterlee, 'Jay" Wright and Joseph Harding for
helpful discussions."
************************************************************************
28. Pall ML, Satterlee JD.
Elevated nitric oxide/peroxynitrite mechanism for the common etiology
of multiple chemical sensitivity, chronic fatigue syndrome, and
posttraumatic stress disorder.
Ann N Y Acad Sci. 2001 Mar; 933: 323-9. Review. [ 45 references ]
Various types of evidence implicate nitric oxide and an oxidant,
possibly peroxynitrite, in MCS and chemical intolerance (CI). The
positive feedback loops proposed earlier for CFS may explain the chronic
nature of MCS (CI) as well as several of its other reported properties.
These observations raise the possibility that this proposed elevated
nitric oxide/peroxynitrite mechanism may be the mechanism of a new
disease paradigm, answering the question raised by Miller earlier:
"Are we on the threshold of a new theory of disease?"
Publication Types: Review Review, Tutorial PMID: 12000033
"MCS incitants...volatile organics, such as hydrocarbons, chlorinated
hydrocarbons, other organics, and pesticides...benzene (4-6), carbon
tetrachloride (7-9), formaldehyde (10-13), and chlorinated hydrocarbon
pesticides (14). Organophosphate pesticides...Such muscarinic receptor
stimulation is known to produce increases in nitric oxide levels.
(15-18)
...elevated neopterin levels...a biochemical marker...
In one study, several antioxidants were used to treat patients with MCS,
with some apparent success, (23), suggesting that oxidative damage may
have a role in MCS...blood of MCS patients...elevated levels of oxidants
...the serum to have lowers levels of antioxidants, as compared to
controls, (24)...
...stimulation of the limbic system...spontaneous seizures (kindling).
(25-29) ... inhibitor of nitric oxide synthase activity blocked the
characteristic sensitization response. (30-36)...arginine,...stimulated
the response. (32)...nitric oxide has an essential role in producing
neural sensitization and kindling...MCS."
***********************************************************************
29. Pall ML.
Common etiology of posttraumatic stress disorder, fibromyalgia, chronic
fatigue syndrome and multiple chemical sensitivity via elevated nitric
oxide/peroxynitrite. [ 93 references, received 10.19.0 ]
Med Hypotheses. 2001 Aug; 57(2): 139-45.
Three types of overlap occur among the disease states chronic fatigue
syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS)
and posttraumatic stress disorder (PTSD). They share common symptoms.
Many patients meet the criteria for diagnosis for two or more of these
disorders and each disorder appears to be often induced by a relatively
short-term stress which is followed by a chronic pathology, suggesting
that the stress may act by inducing a self-perpetuating vicious cycle.
Such a vicious cycle mechanism has been proposed to explain the
etiology of CFS and MCS, based on elevated levels of nitric oxide and
its potent oxidant product, peroxynitrite. Six positive feedback loops
were proposed to act such that when peroxynitrite levels are elevated,
they may remain elevated. The biochemistry involved is not highly
tissue-specific, so that variation in symptoms may be explained by a
variation in nitric oxide/peroxynitrite tissue distribution.
The evidence for the same biochemical mechanism in the etiology of PTSD
and FM is discussed here, and while less extensive than in the case of
CFS and MCS, it is nevertheless suggestive. Evidence supporting the role
of elevated nitric oxide/peroxynitrite in these four disease states is
summarized, including induction of nitric oxide by common apparent
inducers of these disease states, markers of elevated nitric
oxide/peroxynitrite in patients and evidence for an inductive role of
elevated nitric oxide in animal models.
This theory appears to be the first to provide a mechanistic explanation
for the multiple overlaps of these disease states and it also explains
the origin of many of their common symptoms and similarity to both Gulf
War syndrome and chronic sequelae of carbon monoxide toxicity. This
theory suggests multiple studies that should be performed to further
test this proposed mechanism. If this mechanism proves central to the
etiology of these four conditions, it may also be involved in other
conditions of currently obscure etiology and criteria are suggested for
identifying such conditions. PMID: 11461161
"...The NMDA receptors are receptors for the amino acid glutamate and
the toxicity of excessive glutamate is mediated through these receptors
and specifically through their action in increasing the synthesis of
both nitric acid and peroxynitrite (20-26). In animal models of PTSD,
severe stress induces considerable oxidative damage, probably through
the action of peroxynitrite-induced oxidative chain reactions. Reported
oxidative changes include glutathione depletion, increases in lipid
peroxide levels and changes in the levels of antioxidant enzymes
(27-29)...
...The most characteristic symptoms in FM are muscle and joint pain and
tender points. It is well documented that nitric oxide stimulates many
but not all nociceptors (see, for example, refs 55-59) and I propose
that, as in the case of migraine headaches (58-59), much of the pain in
FM may be generated by elevated nitric oxide...
...Tissue hypoxia generated by excessive exercise...through increased
synthesis of superoxide, the other precusor of peroxynitrite (12 and see
below.)...
...symtoms of carbon monoxide (CO) toxicity include essentially all of
the overlapping symptoms typical of CFS, MCS, PTSD and FM, including
fatigue, headache, dizziness, memory impairmant, cognitive dysfunction,
weakness, vertigo and sleep deprivation (66-76). Many victims of CO
show chronic symptoms, lasting from many months to years after both CO
exposure has terminated and CO levels in the blood have returned to
normal (66, 67, 69-73)... [ These same symptom patterns are also
characteristic of aspartame reactors. ]
I suggest nine such criteria:
1. A pattern of possible induction by a short-term stress preceding a
chronic pathology.
2. Uncertain etiology.
3. Association with CFS, MCS, FM and/or PTSD.
4. Elevated tissue levels of nitric oxide/peroxynitrite.
5. Elevated levels of inflammatory cytokines.
6. Elevated levels of oxidants and lowered levels of antioxidants.
7. Chronic inflammation.
8. Chemical hypersensitivity.
9. Effective treatment wtih local glucocorticoid exposure.
...Glucocorticoids are used to treat such diseases as asthma and
psoriasis and are known to repress the synthesis of the inductible
nitric oxide synthase (92, 93). [ This gives many suggestions for
biochemical assays and treatments for aspartame reactors. ]
...grant from the Air Force Office for Scientific Research."
***********************************************************************
30. Pall ML.
Elevated, sustained peroxynitrite levels as the cause of chronic
fatigue syndrome. [ 125 references, received 7.29.98 ]
Med Hypotheses. 2000 Jan; 54(1): 115-25.
The etiology of chronic fatigue syndrome (CFS) has been both obscure and
highly contentious, leading to substantial barriers to both clear
diagnosis and effective treatment. I propose here a novel hypothesis of
CFS in which either viral or bacterial infection induces one or more
cytokines, IL-1beta IL-6, TNF-alpha and IFN-gamma.
These induce nitric oxide synthase(iNOS), leading to increased nitric
oxide levels. Nitric oxide, in turn, reacts with superoxide radical to
generate the potent oxidant peroxynitrite.
Multiple amplification and positive feedback mechanisms are proposed by
which once peroxynitrite levels are elevated, they tend to be
sustained at a high level. This proposed mechanism may lower the HPA
axis activity and be maintained by consequent lowered glucocorticoid
levels. Similarities are discussed among CFS and autoimmune and other
diseases previously shown to be associated with elevated peroxynitrite.
Multiple pharmacological approaches to the treatment of CFS are
suggested by this hypothesis. PMID: 10790736
"...widely discussed notion that post-viral fatigue syndrome (2) is a
form of chronic fatigue syndrome... overall notion of post-infectious
fatigue syndrome (4)....
"Peroxynitrite, OONO-, is a powerful oxidant formed from the reaction of
two relatively nonreactive free radicals, nitric oxide (*NO) and
superoxide (*OO-)... (10-12)... Nitric oxide is synthesized by three
different isozymes of nitric oxide synthase, two of which are
constitutive, eNOS and nNOS and one of which is highly inducible, iNOS.
It is the inducible iNOS isozyme which has the most central role in this
hypothesis. iNOS is higly induced in many cell types in response to four
different inflammatory cytokines... which are, in turn, induced by viral
infection or the presence of bacterial antigens... infections can lead
to the induction of high levels of iNOS, greatly increasing the levels
of nitric oxide and leading to a great increase in the levels of
peroxynitrite... this occurs in sepsis... mitochondrial and energy
metabolism dysfunction is one of the most important consequences of
elevated peroxynitrite (10, 11, 21-23).
...increasing Ca2+ levels will increase nitric oxide synthesis...
...such disease states as atherosclerosis, myocarditis, nephritis, and a
wide variety of automimmune diseases.
...uveoretinitis... rheumatoid arthritis, type I diabetes, multiple
sclerosis, systemic lupus erythrematosis... each show their own
characteristic distribution of peroxynitrite elevation as shown by such
measures as nitrotyrosine distribution in proteins or iNOS expression
pattern... A number of reports suggest that the
hypothalamic-pituitary-adrenal (HPA) axis may have lowered activity in
CFS patients and that this lowered activity may be responsible for many
of the characteristic symptoms of CFS (5, 47-55). These reports suggest
that lowered responsiveness of the hypothalalmus may be an important
cause of CFS and that the resulting lowered levels of glucocorticoids
may be responsible for many of the symptoms of CFS... What is
intriguing, however is that the low levels of glucocorticoids, produced
by low HPA axis activity in CFS patients, may have a substantial role in
the proposed sustained elevation of both inflammatory cytokine levels
and nitric oxide/peroxynitrite levels. Glucorticoids have long been
known to suppress both immune and inflammatory responses... to inhibit
induction of both the inducible nitric oxide synthase (iNOS) in multiple
tissues and also the induction of the inflammatory cytokines...
...one of the primary targets of peroxynitrite is the mitochodrion...
This predicts that energy metabolism disfunction should be
characteristic of CFS... measurements of phosphorylation
activity... mitochondrial structural changes as seen in the electron
microscope (78-84)... urine of CFS patients... two TCA cycle
intermediates, succinate and cis-aconitate, were both found to be
elevated in CFS patients (85, 86)... succinic dehydrogenase activity...
has been reported to be low (78, 80)... [ Unrelenting fatigue is often
part of aspartame disease. ] ...a CFS patient who had accumulated
unusual deletions in his mitochondrial DNA (82).... [ Formaldehyde from
the 11% methanol component of aspartame forms DNA adducts. ]
...polyunsaturated essential fatty acids are low in CFS patients (87)
may also be explained because the lipid peroxidation induced by
elevated peroxynitrite (10-12, 22) preferentially oxidizes such
polyunsaturated fatty acids...
...CFS patients have been reported to suffer from low NK syndrome,
characterized by low serum levels of cystine and glutamine (88). Low NK
syndrome is also found in several diseases characterized by elevated
peroxynitrite levels, including sepsis, Crohn's disease, ulcerative
colitis, AIDS dementia patients and some forms of cancer (89)...
...possible pharmacological intervention...
1. ...ubiquinone (coenzyme Q10) and carnitine may improve mitochondrial
function in CFS....
2. Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin and
ibuprofen, have been reported to inhibit iNOS induction (91,92)...
3. Cell permeable superoxide dismutase mimetic agents...such as MnTBAP
to lower superoxide levels (93, 94)...
4. ...lower the induction of iNOS... vitamin D derivatives (95),
epigallocatechin-3-gallate and genistein... protein tyrosine kinase
inhibitors... linomide, a drug used to treat autoimmune disease (101),
and terpenoids (102).
5. ...antioxidants...
a. ...gamma-tocopherol...
b. N-acetyl cysteine...
c. Flavonoids... epigallocatechin gallate (107)... and genistein...
These two are found in high amounts in green tea and soy products,
respectively....
d. Ascorbic acid acts as a peroxynitrite scavenger, in addition to its
general activity as an antioxidant (108, 109)....
e. Many antioxidants have been shown to inhibit NF-kB activity...
6. Arginine... inhibit... nitric oxide synthrase enzymes... (19,20)...
7. ...Some inhibitors of NF-kB activity, such as TLCK or PDTC, act
indirectly as protease inhibitors or by other mechanisms... (113, 114).
...genistein...
8. Allopurinol is a well-documented inhibitor of xanthine
oxidase/xanthine dehydrogenase activity and has been widely used to
treat gout and other diseases... numerous flavonoids...
9. ...inhibitors of this enzyme... poly(ADP-ribose) synthase... have
been shown to improve cellular survival when challenged by peroxynitrite
(36-38).
This paper is dedicated to the memory of Stephanie Pall.
...neopterin levels are elevated to the urine or serum of CFS patients
(66, 119, 120)... closely linked to the induction of the inducible
nitric oxide synthase (123-125)... important, if indirect, evidence for
nitric oxide elevation in CFS patients..."
[Continued on Part 2/2]
*********************************************************************
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall Part 1/2
Dec 9 2002 [ Notes by Rich Murray are in square brackets. Pall has 45
items in PubMed since 1969.
The theory is quite complex. Most readers will not be familiar with the
biochemistry. I will focus on the many diseases that may be involved,
more and less, on MSG and on formaldehyde (an inevitable product of
methanol, the 11% component of aspartame), and the prospect for new
diagnostic tests and for treatments for aspartame disease. ]
http://www.wsunews.wsu.edu/detail.asp?StoryID=3281
News Bureau Washington State University wsunews@wsu.edu
Pullman, WA 99164-1040 509/335-3581 FAX: 509/335-2220
See a complete list of news releases on the Web at:
http://wsunews.wsu.edu
Online Experts Directory: http://experts.wsu.edu
9/16/2002
Contact: Sharon Hatch, 509/335-4262, hatch@wsu.edu
Martin L. Pall, 509/335-1246, martin_pall@wsu.edu
WSU Biochemist Suggests Vicious Chemical Cycle May Cause
Multiple Chemical Sensitivity
PULLMAN, Wash. -- In the United States about 10 million people are
afflicted by severe multiple chemical sensitivity. Many MCS sufferers
give up air travel, some must find new work places or move out of their
homes to avoid exposure to certain chemicals. For them, grocery
shopping in the detergent aisle or attending events where someone may
wear perfume is risky. MCS symptoms, which may last for hours or days,
include pain–severe headaches and pain in joints and muscles–fatigue,
dizziness and an impaired ability to think clearly.
The onset of this chronic condition can usually be traced back to an
exposure to certain chemicals. But why the initial exposure results in
an often life-long, incurable condition has been a mystery. In an
article published in the September 2002 issue of the prestigious
publication of the Federation of American Societies of Experimental
Biology, "The FASEB Journal," Washington State University biochemist
Martin Pall suggests that a vicious chemical cycle may be to blame.
Pall's new theory is a fusion of two previous theories about MCS. One
of these, proposed by Pall earlier, states that MCS is produced by
excessive levels of two chemicals in the body–nitric oxide and its
oxidant product - peroxynitrite. He suggested certain mechanisms act to
keep levels of the two compounds elevated, thus producing chronic
changes. The second theory was proposed by Iris Bell, M.D, Ph.D. of the
University of Arizona. She proposed that the central mechanism in MCS
is neural sensitization in the brain.
"What my article reports," said Pall, "is that if you assume both
previous theories are correct, you come up with a fusion that explains
all the most puzzling features of MCS. It explains why MCS is induced
by a previous chemical exposure and why MCS sufferers show such a high
level of sensitivity to a wide range of organic chemicals."
Pall cites many studies that suggest that the initial chemical exposure
creates a hypersensitivity in the neurons in the brain, which react by
creating the two chemicals that cause further hypersensitivity.
"Ordinarily, these activities are highly regulated, acting only on
specific synapses in the brain where they are involved in learning and
memory. The MCS response is produced," said Pall, "when chemical
exposure produces excessive responses over large regions of the brain.
In this way, normal and important mechanisms may act to generate this
chronic illness. Thus, not only is the brain constantly inundated by
chemicals to which it is normally somewhat sensitive, but the brain of
a person suffering from MCS becomes abnormally sensitive to the
chemicals–- from 100 to 1,000 times more sensitive than in an unaffected
person." Two other mechanisms contribute to the sensitivity to by
allowing the offending chemicals to accumulate to higher levels in the
brains of MCS people.
MCS has overlaps with other medical conditions of uncertain mechanism
including chronic fatigue syndrome, fibromyalgia, posttraumatic stress
disorder, and Gulf War syndrome. Pall has proposed similar mechanisms
for all of these conditions. "The notion that a biochemical vicious
cycle may underlie all four is very exciting and, if correct, suggests
that this is a major new paradigm of human disease."
Interrupting this cycle may be the key to effective MCS treatment, said
Pall.
Pall's article is available on the Web at
http://www.fasebj.org/cgi/content-nw/full/16/11/1407/T1.
Access to this site is free to members of the Federation of American
Societies of Experimental Biology, others must pay a $7 access fee.
Comments: Dr. Gunnar Heuser, neurotoxicologist and clinical professor
at UCLA, who has published on brain changes in Chronic Fatigue
Syndrome, stated "I consider Dr. Pall's research a significant
contribution to the science of clinical toxicology and multiple
chemical sensitivity."
Brain Imaging Center, University of California, Irvine, USA.
gheuser@ucla.edu
Dr. Grace Ziem, Maryland physician who practices occupational and
environmental medicine and specializes in chemically-induced illness,
said "I feel that Dr. Pall has done the most important biochemical
research and documentation toward understanding the mechanism of neural
sensitization underlying toxic injury to the brain and this research
has important implications for treatment."
http://www.mcsrr.org/resources/articles/S3.html
DR. GRACE ZIEM'S ENVIRONMENTAL CONTROL PLAN
FOR CHEMICALLY SENSITIVE PATIENTS
16926 Eyler's Valley Road, Emmitsburg MD 21727, 301-241-4346
Albert Donnay
************************************************************************
http://molecular.biosciences.wsu.edu/Faculty/pall.html [photo]
http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm
Novel chronic fatigue syndrome (CFS) theory finally
produces detailed explanations for many CFS observations:
[ This is a detailed summary review, with diagrams, references, and some
hyperlinks. ]
http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm
Fibromyalgia, excessive nitric oxide/peroxynitrite and excessive NMDA
activity [ detailed summary review, with 14 references, including
2. Smith J. D., Terpening C. M., Schmidt S. O. F., Gums J. G. Relief of
fibromyalgia symptoms following discontinuation of dietary excitotoxins.
Ann Pharmacotherapy 2001; 35: 702-706.
http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall ]
************************************************************************
FASEB J 2002 Sep; 16(11): 1407-17
NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and
organic solvents as the mechanism of chemical sensitivity in multiple
chemical sensitivity.
Pall ML. [ 162 references, received 1.3.2 ]
School of Molecular Biosciences, Washington State University,
Pullman, Washington 99164-4660, USA. martin_pall@wsu.edu
http://www.fasebj.org/cgi/content-nw/full/16/11/1407/T1. full text
Access to this site is free to members of the Federation of American
Societies of Experimental Biology, others must pay a $7 access fee.
Multiple chemical sensitivity (MCS) is a condition where previous
exposure to hydrophobic organic solvents or pesticides appears to
render people hypersensitive to a wide range of chemicals, including
organic solvents. The hypersensitivity is often exquisite, with MCS
individuals showing sensitivity that appears to be at least two orders
of magnitude greater than that of normal individuals. This paper
presents a plausible set of interacting mechanisms to explain such
heightened sensitivity.
It is based on two earlier theories of MCS: the elevated nitric
oxide/peroxynitrite theory and the neural sensitization theory. It is
also based on evidence implicating excessive NMDA activity in MCS. Four
sensitization mechanisms are proposed to act synergistically, each
based on known physiological mechanisms:
Nitric oxide-mediated stimulation of neurotransmitter (glutamate)
release;
peroxynitrite-mediated ATP depletion and consequent hypersensitivity of
NMDA receptors;
peroxynitrite-mediated increased permeability of theblood-brain barrier,
producing increased accessibility of organic
chemicals to the central nervous system;
and nitric oxide inhibition of cytochrome P450 metabolism.
Evidence for each of these mechanisms, which may also be involved in
Parkinson's disease, is reviewed. These interacting mechanisms provide
explanations for diverse aspects of MCS and a framework for
hypothesis-driven MCS research. PMID: 12205032
"...exposure to organophosphates or carbamates (1-7)...
hypersensitive... hydrophobic, volatile organic solvents... not to be
centered on an IgE-based allergic mechanism (1)... severe MCS in the
U.S. is ~4% with greatly reduced quality of life for the patient (2)...
less severe problems have been reported in ~15-30% of the population...
chemical sensitivity two or more orders of magnitude greater than do
normal individuals... no known mechanism whereby low levels of chemical
or chemicals of widely varied chemical structure can interact adversely
with numerous organ systems... Chronic fatigue syndrome (CFS),
fibromyalgia (FM), and post-traumatic stress disorder (PTSD)...
overlapping symptoms... preceded by short-term stress, only to be
followed by a chronic condition that typically lasts for years or
decades. Gulf War syndrome... may share a common etiologic mechanism
(16,23-29)... elevated nitric oxide/peroxynitrite mechanism (28-33)...
short-term stress... increases in nitric oxide (29-32)... reacts with
superoxide to form the potent oxidant peroxynitrite... six different
positive feedback loop mechanisms to increase the levels of nitric oxide
and its other precursor, superoxide, which in turn react to form more
peroxynitrite (30)... biochemical vicious cycle is initiated and
maintained that produces the chronic nature of these four conditions...
10 types of supportive evidence are summarized in Table 1...
The second precursor theory to this paper is the neural sensitization
theory origianlly proposed by Bell and co-workers (34)...
[ 34. Iris R. Bell, Miller CS, Schwartz GE.(1992).
An olfactory-limbic model of multiple chemical sensitivity syndrome:
possible relationships to kindling and affective spectrum disorders.
Biol. Psychiatry 1992; 32: 218-242.
35. Bell IR, Baldwin CM, Fernandez M, Schwartz GE.
Neural sensitization model for multiple chemical sensitivity: overview
of theory and empirical evidence.
Toxicol Ind. Health 1999; 15: 295-304. ]
... especially the limbic system... increased long-term synaptic
sensitivity induced by previous electrical and chemical
stimulation...long-term potentiation (LTP)... nitric oxide and the NMDA
[ N-methyl-D-aspartame ] excitatory neurotransmission system are
implicated in LTP, the presumed mechanism of neural sensitization...
increased Ca2+ influx into the cell... Excessive NMDA activity leading
to excessive levels of nitric oxide and peroxynitrite has been
implicated in several neurodegenerative diseases including
amyotrophic lateral sclerosis [ALS], Parkinson's disease, AIDS-related
dementia, stroke, epilepsy, Huntington's disease, and Alzheimer's
disease (67-72)... nitric oxide and peroxynitrite may act through known
mechanisms to increase both the stimulation of and the sensitivity of
NMDA receptors.
...volative organic solvents act in MCS by increasing NMDA activity.
The evidence for this (discussed below) is suggestive but not
conclusive... leading to ATP [ adenosine triphosphate, a primary energy
store and source in cells ] depletion as well... when neurons containing
NMDA receptors have lowered ATP pools, their NMDA receptors become
hypersensitive to stimulation... MCS individuals are often reported to
have low Mg2+ pools (7), and Mg2+ is known to lower NMDA sensitivity
(91).
...Acetylcholline will activate the muscarinic receptors, which are
known to produce increases in nitric oxide... people in buildings that
had been remodeled ("sick building syndrome"), thus exposing the
individuals to outgassing of organic solvents from the building
materials... (infection, physical trauma, and stress) may act to
increase nitric oxide levels (29,30,32)... carbon monoxide... chronic
sequelae (29), with symptoms similar to those in CFS, and carbon
monoxide is reported to induce excessive production of the two
percursors of peroxynitrite: superoxide and nitric oxide (29).
Peroxynitrite... to increase the permeability of the blood-brain barrier
in MCS... to increase chemical access to the CNS and thus increase
chemical sensitivity generated in the CNS...
Miller and Mitzel (6) reported that many MCS patients appear to be
hypersensitive to monosodium glutamate, a potential excitotoxin that can
act to stimulate NMDA receptors (64, 66, 91)...
One organic chemical often implicated in MCS-- formaldehyde... NMDA
stimulation... pain responses... by excessive NMDA activity and
consequent elevated nitric oxide levels...
...Donald Dudley... clinical observations on his MCS patients
(131)... known NMDA antagonist, dextromethorphan, appeared to block the
effects of organic solvents on his MCS patients... on an episodic
basis... stop the reaction before it gets started... Two other
physicians in Washington state,Gordon Baker and David Buscher,...
dextromethorphan for their MCS patients in a similar fashion, with
apparently similar results...
Part of the goal here is to suggest potentially important foci for
hypothesis-driven research, and clearly the many uncertainties in this
part of the hypothesis suggest many such topics of future study.
In her MCS review, [B.A.] Sorg (ref 2, Table 1) lists 18 neurological
symptoms as being found in MCS but lists other symptoms of
cardiovascular (two), respiratory (seven), gastrointestinal (three),
genitourinary (four), musculoskeletal (five), and dermatologic (one)
origin... various other organs appear to be affected in many
cases... inflammatory cytokines... will circulate to a variety of
tissues and have been reported to be induced by organic solvents
(28)... Furthermore,... nitric oxide transport... spreading to other
tissues... [ These many symptoms fit the profile of aspartame disease. ]
2. Sorg BA.
Multiple chemical sensitivity: potential role for neural sensitization.
Crit. Rev. Neurobiol. 1999; 13: 283-316.
...organic solvent exposure is an important risk factor in Parkinson's
disease (148-153)... Excessive NMDA activity is associated with
Parkinson's disease...
...funding for MCS disease is less than a thousandth of that available
for diabetes research... critical need for clear and compelling
hypotheses, consistent with the many reported properties of MCS, to
provide a basis for future research... four proposed consequent
mechanisms... are all expected to act synergistically, producing the
kind of exquisite sensitivity reported in MCS...
I thank Drs. James Satterlee, 'Jay" Wright and Joseph Harding for
helpful discussions."
************************************************************************
28. Pall ML, Satterlee JD.
Elevated nitric oxide/peroxynitrite mechanism for the common etiology
of multiple chemical sensitivity, chronic fatigue syndrome, and
posttraumatic stress disorder.
Ann N Y Acad Sci. 2001 Mar; 933: 323-9. Review. [ 45 references ]
Various types of evidence implicate nitric oxide and an oxidant,
possibly peroxynitrite, in MCS and chemical intolerance (CI). The
positive feedback loops proposed earlier for CFS may explain the chronic
nature of MCS (CI) as well as several of its other reported properties.
These observations raise the possibility that this proposed elevated
nitric oxide/peroxynitrite mechanism may be the mechanism of a new
disease paradigm, answering the question raised by Miller earlier:
"Are we on the threshold of a new theory of disease?"
Publication Types: Review Review, Tutorial PMID: 12000033
"MCS incitants...volatile organics, such as hydrocarbons, chlorinated
hydrocarbons, other organics, and pesticides...benzene (4-6), carbon
tetrachloride (7-9), formaldehyde (10-13), and chlorinated hydrocarbon
pesticides (14). Organophosphate pesticides...Such muscarinic receptor
stimulation is known to produce increases in nitric oxide levels.
(15-18)
...elevated neopterin levels...a biochemical marker...
In one study, several antioxidants were used to treat patients with MCS,
with some apparent success, (23), suggesting that oxidative damage may
have a role in MCS...blood of MCS patients...elevated levels of oxidants
...the serum to have lowers levels of antioxidants, as compared to
controls, (24)...
...stimulation of the limbic system...spontaneous seizures (kindling).
(25-29) ... inhibitor of nitric oxide synthase activity blocked the
characteristic sensitization response. (30-36)...arginine,...stimulated
the response. (32)...nitric oxide has an essential role in producing
neural sensitization and kindling...MCS."
***********************************************************************
29. Pall ML.
Common etiology of posttraumatic stress disorder, fibromyalgia, chronic
fatigue syndrome and multiple chemical sensitivity via elevated nitric
oxide/peroxynitrite. [ 93 references, received 10.19.0 ]
Med Hypotheses. 2001 Aug; 57(2): 139-45.
Three types of overlap occur among the disease states chronic fatigue
syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS)
and posttraumatic stress disorder (PTSD). They share common symptoms.
Many patients meet the criteria for diagnosis for two or more of these
disorders and each disorder appears to be often induced by a relatively
short-term stress which is followed by a chronic pathology, suggesting
that the stress may act by inducing a self-perpetuating vicious cycle.
Such a vicious cycle mechanism has been proposed to explain the
etiology of CFS and MCS, based on elevated levels of nitric oxide and
its potent oxidant product, peroxynitrite. Six positive feedback loops
were proposed to act such that when peroxynitrite levels are elevated,
they may remain elevated. The biochemistry involved is not highly
tissue-specific, so that variation in symptoms may be explained by a
variation in nitric oxide/peroxynitrite tissue distribution.
The evidence for the same biochemical mechanism in the etiology of PTSD
and FM is discussed here, and while less extensive than in the case of
CFS and MCS, it is nevertheless suggestive. Evidence supporting the role
of elevated nitric oxide/peroxynitrite in these four disease states is
summarized, including induction of nitric oxide by common apparent
inducers of these disease states, markers of elevated nitric
oxide/peroxynitrite in patients and evidence for an inductive role of
elevated nitric oxide in animal models.
This theory appears to be the first to provide a mechanistic explanation
for the multiple overlaps of these disease states and it also explains
the origin of many of their common symptoms and similarity to both Gulf
War syndrome and chronic sequelae of carbon monoxide toxicity. This
theory suggests multiple studies that should be performed to further
test this proposed mechanism. If this mechanism proves central to the
etiology of these four conditions, it may also be involved in other
conditions of currently obscure etiology and criteria are suggested for
identifying such conditions. PMID: 11461161
"...The NMDA receptors are receptors for the amino acid glutamate and
the toxicity of excessive glutamate is mediated through these receptors
and specifically through their action in increasing the synthesis of
both nitric acid and peroxynitrite (20-26). In animal models of PTSD,
severe stress induces considerable oxidative damage, probably through
the action of peroxynitrite-induced oxidative chain reactions. Reported
oxidative changes include glutathione depletion, increases in lipid
peroxide levels and changes in the levels of antioxidant enzymes
(27-29)...
...The most characteristic symptoms in FM are muscle and joint pain and
tender points. It is well documented that nitric oxide stimulates many
but not all nociceptors (see, for example, refs 55-59) and I propose
that, as in the case of migraine headaches (58-59), much of the pain in
FM may be generated by elevated nitric oxide...
...Tissue hypoxia generated by excessive exercise...through increased
synthesis of superoxide, the other precusor of peroxynitrite (12 and see
below.)...
...symtoms of carbon monoxide (CO) toxicity include essentially all of
the overlapping symptoms typical of CFS, MCS, PTSD and FM, including
fatigue, headache, dizziness, memory impairmant, cognitive dysfunction,
weakness, vertigo and sleep deprivation (66-76). Many victims of CO
show chronic symptoms, lasting from many months to years after both CO
exposure has terminated and CO levels in the blood have returned to
normal (66, 67, 69-73)... [ These same symptom patterns are also
characteristic of aspartame reactors. ]
I suggest nine such criteria:
1. A pattern of possible induction by a short-term stress preceding a
chronic pathology.
2. Uncertain etiology.
3. Association with CFS, MCS, FM and/or PTSD.
4. Elevated tissue levels of nitric oxide/peroxynitrite.
5. Elevated levels of inflammatory cytokines.
6. Elevated levels of oxidants and lowered levels of antioxidants.
7. Chronic inflammation.
8. Chemical hypersensitivity.
9. Effective treatment wtih local glucocorticoid exposure.
...Glucocorticoids are used to treat such diseases as asthma and
psoriasis and are known to repress the synthesis of the inductible
nitric oxide synthase (92, 93). [ This gives many suggestions for
biochemical assays and treatments for aspartame reactors. ]
...grant from the Air Force Office for Scientific Research."
***********************************************************************
30. Pall ML.
Elevated, sustained peroxynitrite levels as the cause of chronic
fatigue syndrome. [ 125 references, received 7.29.98 ]
Med Hypotheses. 2000 Jan; 54(1): 115-25.
The etiology of chronic fatigue syndrome (CFS) has been both obscure and
highly contentious, leading to substantial barriers to both clear
diagnosis and effective treatment. I propose here a novel hypothesis of
CFS in which either viral or bacterial infection induces one or more
cytokines, IL-1beta IL-6, TNF-alpha and IFN-gamma.
These induce nitric oxide synthase(iNOS), leading to increased nitric
oxide levels. Nitric oxide, in turn, reacts with superoxide radical to
generate the potent oxidant peroxynitrite.
Multiple amplification and positive feedback mechanisms are proposed by
which once peroxynitrite levels are elevated, they tend to be
sustained at a high level. This proposed mechanism may lower the HPA
axis activity and be maintained by consequent lowered glucocorticoid
levels. Similarities are discussed among CFS and autoimmune and other
diseases previously shown to be associated with elevated peroxynitrite.
Multiple pharmacological approaches to the treatment of CFS are
suggested by this hypothesis. PMID: 10790736
"...widely discussed notion that post-viral fatigue syndrome (2) is a
form of chronic fatigue syndrome... overall notion of post-infectious
fatigue syndrome (4)....
"Peroxynitrite, OONO-, is a powerful oxidant formed from the reaction of
two relatively nonreactive free radicals, nitric oxide (*NO) and
superoxide (*OO-)... (10-12)... Nitric oxide is synthesized by three
different isozymes of nitric oxide synthase, two of which are
constitutive, eNOS and nNOS and one of which is highly inducible, iNOS.
It is the inducible iNOS isozyme which has the most central role in this
hypothesis. iNOS is higly induced in many cell types in response to four
different inflammatory cytokines... which are, in turn, induced by viral
infection or the presence of bacterial antigens... infections can lead
to the induction of high levels of iNOS, greatly increasing the levels
of nitric oxide and leading to a great increase in the levels of
peroxynitrite... this occurs in sepsis... mitochondrial and energy
metabolism dysfunction is one of the most important consequences of
elevated peroxynitrite (10, 11, 21-23).
...increasing Ca2+ levels will increase nitric oxide synthesis...
...such disease states as atherosclerosis, myocarditis, nephritis, and a
wide variety of automimmune diseases.
...uveoretinitis... rheumatoid arthritis, type I diabetes, multiple
sclerosis, systemic lupus erythrematosis... each show their own
characteristic distribution of peroxynitrite elevation as shown by such
measures as nitrotyrosine distribution in proteins or iNOS expression
pattern... A number of reports suggest that the
hypothalamic-pituitary-adrenal (HPA) axis may have lowered activity in
CFS patients and that this lowered activity may be responsible for many
of the characteristic symptoms of CFS (5, 47-55). These reports suggest
that lowered responsiveness of the hypothalalmus may be an important
cause of CFS and that the resulting lowered levels of glucocorticoids
may be responsible for many of the symptoms of CFS... What is
intriguing, however is that the low levels of glucocorticoids, produced
by low HPA axis activity in CFS patients, may have a substantial role in
the proposed sustained elevation of both inflammatory cytokine levels
and nitric oxide/peroxynitrite levels. Glucorticoids have long been
known to suppress both immune and inflammatory responses... to inhibit
induction of both the inducible nitric oxide synthase (iNOS) in multiple
tissues and also the induction of the inflammatory cytokines...
...one of the primary targets of peroxynitrite is the mitochodrion...
This predicts that energy metabolism disfunction should be
characteristic of CFS... measurements of phosphorylation
activity... mitochondrial structural changes as seen in the electron
microscope (78-84)... urine of CFS patients... two TCA cycle
intermediates, succinate and cis-aconitate, were both found to be
elevated in CFS patients (85, 86)... succinic dehydrogenase activity...
has been reported to be low (78, 80)... [ Unrelenting fatigue is often
part of aspartame disease. ] ...a CFS patient who had accumulated
unusual deletions in his mitochondrial DNA (82).... [ Formaldehyde from
the 11% methanol component of aspartame forms DNA adducts. ]
...polyunsaturated essential fatty acids are low in CFS patients (87)
may also be explained because the lipid peroxidation induced by
elevated peroxynitrite (10-12, 22) preferentially oxidizes such
polyunsaturated fatty acids...
...CFS patients have been reported to suffer from low NK syndrome,
characterized by low serum levels of cystine and glutamine (88). Low NK
syndrome is also found in several diseases characterized by elevated
peroxynitrite levels, including sepsis, Crohn's disease, ulcerative
colitis, AIDS dementia patients and some forms of cancer (89)...
...possible pharmacological intervention...
1. ...ubiquinone (coenzyme Q10) and carnitine may improve mitochondrial
function in CFS....
2. Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin and
ibuprofen, have been reported to inhibit iNOS induction (91,92)...
3. Cell permeable superoxide dismutase mimetic agents...such as MnTBAP
to lower superoxide levels (93, 94)...
4. ...lower the induction of iNOS... vitamin D derivatives (95),
epigallocatechin-3-gallate and genistein... protein tyrosine kinase
inhibitors... linomide, a drug used to treat autoimmune disease (101),
and terpenoids (102).
5. ...antioxidants...
a. ...gamma-tocopherol...
b. N-acetyl cysteine...
c. Flavonoids... epigallocatechin gallate (107)... and genistein...
These two are found in high amounts in green tea and soy products,
respectively....
d. Ascorbic acid acts as a peroxynitrite scavenger, in addition to its
general activity as an antioxidant (108, 109)....
e. Many antioxidants have been shown to inhibit NF-kB activity...
6. Arginine... inhibit... nitric oxide synthrase enzymes... (19,20)...
7. ...Some inhibitors of NF-kB activity, such as TLCK or PDTC, act
indirectly as protease inhibitors or by other mechanisms... (113, 114).
...genistein...
8. Allopurinol is a well-documented inhibitor of xanthine
oxidase/xanthine dehydrogenase activity and has been widely used to
treat gout and other diseases... numerous flavonoids...
9. ...inhibitors of this enzyme... poly(ADP-ribose) synthase... have
been shown to improve cellular survival when challenged by peroxynitrite
(36-38).
This paper is dedicated to the memory of Stephanie Pall.
...neopterin levels are elevated to the urine or serum of CFS patients
(66, 119, 120)... closely linked to the induction of the inducible
nitric oxide synthase (123-125)... important, if indirect, evidence for
nitric oxide elevation in CFS patients..."
[Continued on Part 2/2]
*********************************************************************
[Continued from Part 1/2]
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall Part 2/2
31. Pall, ML.
Levels of nitric oxide synthase product citrulline are elevated in sera
of chronic fatigue syndrome patients.
J. Chronic Fatigue Syndr. 2002; 10(3/4): 37-41. [ 7 references ]
www.cfs.inform.dk/
http://www.cfs.inform.dk/Hypoteser/pall02.pdf free full text
Serum levels of citrulline, a product of nitric oxide synthase activity,
were measured in 36 CFS patients.
Serum citrulline levels were found to be significantly eleveated in CFS
patients and, in addition, there was a trend towards higher levels in
CFS patients with stronger symptoms.
These results provide support for the view that nitric oxide synthesis
activity tends to be elevated in CFS patients, thus supporting a
prediction of the elevated nitric oxide/peroxynitrite theory of CRS
etiology.
"INTRODUCTION
Chronic fatigue syndrome (CFS) is reported to impact a large number of
different biochemical, physiological and immunological properties in
patients, ranging from mitochondrial/energy metabolism to circulatory
function to neuroendocrine function to natural killer cell function
(discussed in 1,2). Similarly a wide range of symptoms are commonly
reported (3). One of the central questions facing CFS researchers is how
these diverse characteristics may be impacted by a single etiologic
mechanism.
A wide-ranging theory of CFS is the elevated nitric
oxide/peroxynitrite theory, which is supported by 12 different
biochemical/physiological observations about CFS (1,2,4) and explains
many of the diverse symptoms in this condition through known biochemical
and physiological mechanisms (2).
The same basic etiology may also explain the properties of three
conditions that overlap with CFS: multiple chemical
sensitivity, fibromyalgia and posttraumatic stress disorder (5,6).
According to this theory, CFS is initiated by stresses such as infection
that lead to elevated levels of nitric oxide and its oxidant product,
peroxynitrite. Peroxynitrite acts through several positive feedback
loops to elevate the levels of both of its precursors, nitric oxide and
superoxide, which will then react with each other to form more
peroxynitrite. In this way, a biochemical vicious cycle is initiated and
maintained with that vicious cycle being responsible for the chronic
nature of CFS.
According to this view, infection acts by inducing inflammatory
cytokines which induce, in turn, the inducible nitric oxide synthase
(iNOS). However, the chronic phase of CFS may be maintained through the
action of both iNOS and the other nitric oxide synthase isozymes, nNOS
and eNOS (1). A number of studies have reported that during the chronic
phase of CFS, both inflammatory cytokines that induce the iNOS gene are
elevated and that the marker for iNOS activity, neopterin levels, are
also elevated in CFS (references in 1,2,4). However, because both iNOS
and the other NOS isozymes are proposed to be involved in the chronic
phase of CFS, it is important to measure a marker of overall nitric
oxide synthesis, not just iNOS activity.
Because nitric oxide is unstable in vivo, nitric oxide synthase activity
in vivo is usually measured by either of two different markers. Either
nitrate/nitrite levels are measured because these are produced through
the degradation of nitric oxide and its oxidant product, peroxynitrite,
or L-citrulline levels are measured.
Because nitrate/nitrite levels are
elevated by diets including such foods as green vegetables and sausages
and other preserved meat and fish products, it is essential to closely
control the diet of people for whom nitrate/nitrite measurements are to
reflect NOS activity.
Citrulline, the coproduct of nitric oxide synthase activity, is stable
and its levels are much less likely to be perturbed by diet, as compared
with nitrate/nitrite, and may therefore be a preferred measurement
for this reason. In a recent study by Larson et al. (7), the citrulline
levels in the cerebrospinal fluid of fibromyalgia patients were reported
to be elevated, allowing them to infer that nitric oxide synthesis was
elevated in the central nervous systems of fibromyalgia patients as
compared with controls. In the current study, the serum levels of
citrulline of CFS patients are compared with those of controls and also
found to be elevated."
"7. Larson AA, Glovengo SL, Russell U, et al. Changes in the
concentration of amino acids in the cerebrospinal fluid that correlate
with pain in patients with fibromyalgia. Pain 2000; 87: 201-211."
************************************************************************
33. Pall ML.
Cobalamin [vitamin B12] used in chronic fatigue syndrome therapy is a
nitric oxide scavenger.
J. Chronic Fatigue Syndr. 2001; 8(2): 39-44. [ 38 references ]
Cobalamin (vitamin B12) in the form of hydrooxocobalamin or
cyanocobalamin injections has been widely used to treat chronic fatigue
syndrome (CFS).
Hydroxocobalamin is a nitric oxide scavenger and is proposed here to act
as such a scavenger in CFS treatment. Its possible efficacy in CFS
treatment, if further substantiated, may provide confirmation of a
prediction of the elevated nitric oxide/peroxynitrite theory of CFS
etiology. This interpreation of the possible role of cobalamin in CFS
treatment suggests a useful perspective for confirming and optimizing
this treatment.
***********************************************************************
http://www.immunesupport.com/library/showarticle.cfm?ID=2976
http://www.imunologie.cz/kveten01_6.htm
New Theory on Explanations for Chronic Fatigue Syndrome
by Dr. Martin L. Pall http://www.ImmuneSupport.com
02-13-2001 Editor's Note: Dr. Martin L. Pall, Ph.D., received
his Ph.D. in Biochemistry and genetics from Caltech after
receiving his B.A. degree at Johns Hopkins University. He is
a professor of biochemistry and Basic Medical Sciences at
Washington State University. He teaches medical students
and is the chief instructor at Washington State University in
the medical biochemistry course for first year medical students.
Dr. Pall writes that he came down with CFS in June/July
1997 after a severe bout of Varicella zoster infection. "My
CFS was diagnosed by my primary care physician and my
case did meet the 1994 CDC criteria. So this was, in many
ways, a typical case of post-viral fatigue syndrome, sudden
onset. However, I have had an excellent recovery, over about
a year and a half (possibly due to self-medication?), and
consider myself cured. So, I don't view myself as a CFS
patient. It was only after recovery from the severe cognitive
dysfunction that I was able to dedicate myself to
understanding the basis of CFS."
I asked Dr. Pall about his comment that he considers
himself cured. Is he not afraid of a relapse in the future?
Also, to what does he attribute the 'cure' and how does he
stay healthy? This is his response:
I became ill with CFS in June/July 1997 and spent most of
July and August in bed trying to recuperate. The following
semester, I was able to perform at a minimal level in my
teaching, taking lot's of sick leave, living from day to day, as
most of us do. I self medicated on several things (more
about that later) but had little apparent improvement.
However, the following winter, I did improve substantially and
by May was doing very well, not completely recovered but
maybe 80% recovered. A year later, I considered myself
completely recovered although I am still self-medicating, not
wanting to take any chances of having a relapse.
Specifically, over the past two summers, I have been able to
go on a series of fairly taxing Sierra Club hikes with no
post-exertional malaise. That is quite distinct from my earlier
condition where I could only walk (slowly) circa 50 yards
before having to sit down for a long rest.
My self medication was primarily with antioxidants (natural
mixed tocopherols, vitamin C, selenium, some carotenoids,
calcium/magnesium supplement, Ginkgo extract and
coenzyme Q10). I also tried some black currant seed oil and
some choline/inositol supplements - I did not think these
helped but maybe I was wrong? I am very careful with my
diet, eating nutritionally rich foods and antioxidant-rich foods
(it would take a book to tell you all about the food issue). I
did not have any GI tract problems so was able to tolerate
both the supplements and a wide variety of foods.
The most dramatic effects that I saw, appeared to be from
the Ginkgo extract (this over a period of two or more months,
however) and, following that, from the Co Q10 , the latter of
which was a dramatic, within 24 hours, recovery of cognitive
function. I have never had a problem with cognitive
dysfunction since that time and am still taking the Co Q10. I
am aware that most others who have tried Co Q10 have not
had as favorable a response, and I can only think that my
body was primed, possibly by the other supplements and
foods, to be ready to respond to it.
I have been running a clinical trial/pilot study with a
physician (Dr. Albert G. Corrado) using a series of
supplements based on my theory, and the results have been
both encouraging and discouraging -- encouraging because
essentially everyone who was on the trial and was able to
tolerate most of the supplements reported an improvement
but all reported a modest improvement, over a 150 day
period. So no one was cured over that time. I met yesterday
with a group of PWCS [Persons With Chemical Sensitivity],
a few of whom were on the trial, and
we are seeing some continued improvement (most people
opted to continue on the supplements after the trial was
officially completed, suggesting that they felt that the
supplements were helpful). One person even reported that
she was "almost normal" now about 13 months after starting
on the supplements. So, maybe there is hope.
With regard to your question about a possible relapse, that
is, of course, the nightmare of all us who have largely or
partially recovered from CFS. All I can say is that over the
past two years, I have functioned on a completely normal
level -- but then, I am still self-medicating and plan to
continue doing so indefinitely. Some of the hikes I have been
on have been quite taxing -- 8 1/2 to 9 mile fairly tough hikes,
with substantial elevation gains -- and the results have been
some fatigue afterwards, but normal fatigue, just requiring
normal resting. So I am hopeful that this functional recovery
is permanent.
Novel chronic fatigue syndrome (CFS) theory finally
produces detailed explanations for many CFS observations
A novel theory of the cause of CFS has been published
which is supported by diverse biochemical and physiological
observations of CFS, while providing explanations for five of
most difficult puzzles about this medical condition. The
theory has been published by Dr. Martin L. Pall (Professor of
Biochemistry and Basic Medical Sciences, Washington
State University) in several publications (1-4,9).
The theory starts with the observation that infections that
precede and may therefore induce CFS and related
conditions act to induce excessive production of
inflammatory cytokines that induce, in turn, the inducible
nitric oxide synthase (iNOS). This enzyme, in turn,
synthesizes excessive amounts of nitric oxide which reacts
with another compound (superoxide) to produce the potent
oxidant peroxynitrite. Peroxynitrite acts via six known
biochemical mechanisms to increase the levels of both nitric
oxide and superoxide which react to produce more
peroxynitrite. In this way, once peroxynitrite levels are
elevated, they may act to continue the elevation, thus
producing a self-sustaining vicious cycle. It is this cycle,
according to the theory, that maintains the chronic
symptoms of CFS and it is this cycle, therefore, that must
be interrupted to effectively treat this condition.
************************************************************************
http://www.ImmuneSupport.com/library/showarticle.cfm/id/4072
The Poisoning of America: The Rise of 'Mystery' Illnesses Including
Chronic Fatigue Syndrome, Fibromyalgia, and Gulf War Syndrome
ImmuneSupport.com 11-13-2002 By Jason Alexander Uttley
"Gulf War Syndrome... Fibromyalgia... Chronic Fatigue Syndrome... At the
heart of this horrific story lies a group of antibiotics called the
fluoroquinolones. Among the more common of these medications are:
ciprofloxacin (Cipro), levofloxacin (Levaquin), norfloxacin
(Noroxin), ofloxacin (Floxin), and trovafloxacin (Trovan).... Such
conditions include Irritable Bowel Syndrome, Multiple Chemical
Sensitivity Syndrome, Chronic Myofascial Pain Syndrome, and
Peripheral Neuropathy.... Just like all the other conditions mentioned
previously their symptoms often include: joint pain, muscle
stiffness/aches, tendon pain, dizziness, disorientation, burning and
tingling sensations, numbness, diarrhea, sensory sensitivities, and
brain fog." [ All these symptoms are common in aspartame disease. This
suggests that Pall may be on the right track with a theory that many CFS
type diseases share a common etiology. ]
***********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/912
aspartame: methanol, formaldehyde, formic acid toxicity:
brief review: Murray 12.10.2 rmforall
Rich Murray, MA Room For All rmforall@att.net
1943 Otowi Road, Santa Fe NM 87505 USA 505-986-9103
http://groups.yahoo.com/group/aspartameNM/messages
for 929 posts in a public searchable archive
http://groups.yahoo.com/group/aspartameNM/message/862 long review
Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall
It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA limit for formaldehyde in drinking
water.
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.
http://groups.yahoo.com/group/aspartameNM/message/860
RTM: FDA: objections to neotame approval 8.3.2 rmforall 38 pages
http://groups.yahoo.com/group/aspartameNM/message/868
Murray: submit complaints and papers to FDA Docket 02P-0317
by Jan 12 2003: Recall Aspartame as a Neurotoxic Drug 9.20.2 rmforall
http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@aol.com
http://www.sunsentpress.com/ sunsentpress@aol.com
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax
http://groups.yahoo.com/group/aspartameNM/message/669
1038-page medical text "Aspartame Disease: An Ignored Epidemic"
published May 30 2001 $ 85.00 postpaid data from 1200 cases
available at http://www.amazon.com
over 600 references from standard medical research
http://www.aspartameispoison.com/contents.html 34 chapters
http://groups.yahoo.com/group/aspartameNM/message/859
RTM: Roberts: the life work of a brilliant clinician:
aspartame toxicity 8.2.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/926
aspartame puts formaldehyde adducts into tissues, Part 2/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://ww.presidiotex.com/barcelona/index.html
Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X,
Fernandez-Lopez JA, Alemany M ["Trok-ho"]
Formaldehyde derived from dietary aspartame binds to tissue
components in vivo. Life Sci 1998 Jun 26; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia,
Universitat de Barcelona, Spain.
http://www.presidiotex.com/barcelona/index.html
Maria Alemany, PhD (male) alemany@porthos.bio.ub.es
http://groups.yahoo.com/group/aspartameNM/message/864
Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde
adducts in rats 9.8.2 rmforall
Prof. Alemany vigorously affirms the validity of the Trocho study
against criticism:
Butchko, HH et al [24 authors], Aspartame: review of safety.
Regul. Toxicol. Pharmacol. 2002 April 1; 35 (2 Pt 2): S1-93, review
available for $35, [an industry paid organ]. Butchko:
"When all the research on aspartame, including evaluations in both the
premarketing and postmarketing periods, is examined as a whole, it is
clear that aspartame is safe, and there are no unresolved questions
regarding its safety under conditions of intended use."
[They repeatedly pass on the ageless industry deceit that the methanol
in fruits and vegetables is as as biochemically available as that in
aspartame-- see the 1984 rebuttal by Monte, below.]
http://groups.yahoo.com/group/aspartameNM/message/911
RTP ties to industry criticized by CSPI: Murray: 12.9.2 rmforall
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall Part 2/2
31. Pall, ML.
Levels of nitric oxide synthase product citrulline are elevated in sera
of chronic fatigue syndrome patients.
J. Chronic Fatigue Syndr. 2002; 10(3/4): 37-41. [ 7 references ]
www.cfs.inform.dk/
http://www.cfs.inform.dk/Hypoteser/pall02.pdf free full text
Serum levels of citrulline, a product of nitric oxide synthase activity,
were measured in 36 CFS patients.
Serum citrulline levels were found to be significantly eleveated in CFS
patients and, in addition, there was a trend towards higher levels in
CFS patients with stronger symptoms.
These results provide support for the view that nitric oxide synthesis
activity tends to be elevated in CFS patients, thus supporting a
prediction of the elevated nitric oxide/peroxynitrite theory of CRS
etiology.
"INTRODUCTION
Chronic fatigue syndrome (CFS) is reported to impact a large number of
different biochemical, physiological and immunological properties in
patients, ranging from mitochondrial/energy metabolism to circulatory
function to neuroendocrine function to natural killer cell function
(discussed in 1,2). Similarly a wide range of symptoms are commonly
reported (3). One of the central questions facing CFS researchers is how
these diverse characteristics may be impacted by a single etiologic
mechanism.
A wide-ranging theory of CFS is the elevated nitric
oxide/peroxynitrite theory, which is supported by 12 different
biochemical/physiological observations about CFS (1,2,4) and explains
many of the diverse symptoms in this condition through known biochemical
and physiological mechanisms (2).
The same basic etiology may also explain the properties of three
conditions that overlap with CFS: multiple chemical
sensitivity, fibromyalgia and posttraumatic stress disorder (5,6).
According to this theory, CFS is initiated by stresses such as infection
that lead to elevated levels of nitric oxide and its oxidant product,
peroxynitrite. Peroxynitrite acts through several positive feedback
loops to elevate the levels of both of its precursors, nitric oxide and
superoxide, which will then react with each other to form more
peroxynitrite. In this way, a biochemical vicious cycle is initiated and
maintained with that vicious cycle being responsible for the chronic
nature of CFS.
According to this view, infection acts by inducing inflammatory
cytokines which induce, in turn, the inducible nitric oxide synthase
(iNOS). However, the chronic phase of CFS may be maintained through the
action of both iNOS and the other nitric oxide synthase isozymes, nNOS
and eNOS (1). A number of studies have reported that during the chronic
phase of CFS, both inflammatory cytokines that induce the iNOS gene are
elevated and that the marker for iNOS activity, neopterin levels, are
also elevated in CFS (references in 1,2,4). However, because both iNOS
and the other NOS isozymes are proposed to be involved in the chronic
phase of CFS, it is important to measure a marker of overall nitric
oxide synthesis, not just iNOS activity.
Because nitric oxide is unstable in vivo, nitric oxide synthase activity
in vivo is usually measured by either of two different markers. Either
nitrate/nitrite levels are measured because these are produced through
the degradation of nitric oxide and its oxidant product, peroxynitrite,
or L-citrulline levels are measured.
Because nitrate/nitrite levels are
elevated by diets including such foods as green vegetables and sausages
and other preserved meat and fish products, it is essential to closely
control the diet of people for whom nitrate/nitrite measurements are to
reflect NOS activity.
Citrulline, the coproduct of nitric oxide synthase activity, is stable
and its levels are much less likely to be perturbed by diet, as compared
with nitrate/nitrite, and may therefore be a preferred measurement
for this reason. In a recent study by Larson et al. (7), the citrulline
levels in the cerebrospinal fluid of fibromyalgia patients were reported
to be elevated, allowing them to infer that nitric oxide synthesis was
elevated in the central nervous systems of fibromyalgia patients as
compared with controls. In the current study, the serum levels of
citrulline of CFS patients are compared with those of controls and also
found to be elevated."
"7. Larson AA, Glovengo SL, Russell U, et al. Changes in the
concentration of amino acids in the cerebrospinal fluid that correlate
with pain in patients with fibromyalgia. Pain 2000; 87: 201-211."
************************************************************************
33. Pall ML.
Cobalamin [vitamin B12] used in chronic fatigue syndrome therapy is a
nitric oxide scavenger.
J. Chronic Fatigue Syndr. 2001; 8(2): 39-44. [ 38 references ]
Cobalamin (vitamin B12) in the form of hydrooxocobalamin or
cyanocobalamin injections has been widely used to treat chronic fatigue
syndrome (CFS).
Hydroxocobalamin is a nitric oxide scavenger and is proposed here to act
as such a scavenger in CFS treatment. Its possible efficacy in CFS
treatment, if further substantiated, may provide confirmation of a
prediction of the elevated nitric oxide/peroxynitrite theory of CFS
etiology. This interpreation of the possible role of cobalamin in CFS
treatment suggests a useful perspective for confirming and optimizing
this treatment.
***********************************************************************
http://www.immunesupport.com/library/showarticle.cfm?ID=2976
http://www.imunologie.cz/kveten01_6.htm
New Theory on Explanations for Chronic Fatigue Syndrome
by Dr. Martin L. Pall http://www.ImmuneSupport.com
02-13-2001 Editor's Note: Dr. Martin L. Pall, Ph.D., received
his Ph.D. in Biochemistry and genetics from Caltech after
receiving his B.A. degree at Johns Hopkins University. He is
a professor of biochemistry and Basic Medical Sciences at
Washington State University. He teaches medical students
and is the chief instructor at Washington State University in
the medical biochemistry course for first year medical students.
Dr. Pall writes that he came down with CFS in June/July
1997 after a severe bout of Varicella zoster infection. "My
CFS was diagnosed by my primary care physician and my
case did meet the 1994 CDC criteria. So this was, in many
ways, a typical case of post-viral fatigue syndrome, sudden
onset. However, I have had an excellent recovery, over about
a year and a half (possibly due to self-medication?), and
consider myself cured. So, I don't view myself as a CFS
patient. It was only after recovery from the severe cognitive
dysfunction that I was able to dedicate myself to
understanding the basis of CFS."
I asked Dr. Pall about his comment that he considers
himself cured. Is he not afraid of a relapse in the future?
Also, to what does he attribute the 'cure' and how does he
stay healthy? This is his response:
I became ill with CFS in June/July 1997 and spent most of
July and August in bed trying to recuperate. The following
semester, I was able to perform at a minimal level in my
teaching, taking lot's of sick leave, living from day to day, as
most of us do. I self medicated on several things (more
about that later) but had little apparent improvement.
However, the following winter, I did improve substantially and
by May was doing very well, not completely recovered but
maybe 80% recovered. A year later, I considered myself
completely recovered although I am still self-medicating, not
wanting to take any chances of having a relapse.
Specifically, over the past two summers, I have been able to
go on a series of fairly taxing Sierra Club hikes with no
post-exertional malaise. That is quite distinct from my earlier
condition where I could only walk (slowly) circa 50 yards
before having to sit down for a long rest.
My self medication was primarily with antioxidants (natural
mixed tocopherols, vitamin C, selenium, some carotenoids,
calcium/magnesium supplement, Ginkgo extract and
coenzyme Q10). I also tried some black currant seed oil and
some choline/inositol supplements - I did not think these
helped but maybe I was wrong? I am very careful with my
diet, eating nutritionally rich foods and antioxidant-rich foods
(it would take a book to tell you all about the food issue). I
did not have any GI tract problems so was able to tolerate
both the supplements and a wide variety of foods.
The most dramatic effects that I saw, appeared to be from
the Ginkgo extract (this over a period of two or more months,
however) and, following that, from the Co Q10 , the latter of
which was a dramatic, within 24 hours, recovery of cognitive
function. I have never had a problem with cognitive
dysfunction since that time and am still taking the Co Q10. I
am aware that most others who have tried Co Q10 have not
had as favorable a response, and I can only think that my
body was primed, possibly by the other supplements and
foods, to be ready to respond to it.
I have been running a clinical trial/pilot study with a
physician (Dr. Albert G. Corrado) using a series of
supplements based on my theory, and the results have been
both encouraging and discouraging -- encouraging because
essentially everyone who was on the trial and was able to
tolerate most of the supplements reported an improvement
but all reported a modest improvement, over a 150 day
period. So no one was cured over that time. I met yesterday
with a group of PWCS [Persons With Chemical Sensitivity],
a few of whom were on the trial, and
we are seeing some continued improvement (most people
opted to continue on the supplements after the trial was
officially completed, suggesting that they felt that the
supplements were helpful). One person even reported that
she was "almost normal" now about 13 months after starting
on the supplements. So, maybe there is hope.
With regard to your question about a possible relapse, that
is, of course, the nightmare of all us who have largely or
partially recovered from CFS. All I can say is that over the
past two years, I have functioned on a completely normal
level -- but then, I am still self-medicating and plan to
continue doing so indefinitely. Some of the hikes I have been
on have been quite taxing -- 8 1/2 to 9 mile fairly tough hikes,
with substantial elevation gains -- and the results have been
some fatigue afterwards, but normal fatigue, just requiring
normal resting. So I am hopeful that this functional recovery
is permanent.
Novel chronic fatigue syndrome (CFS) theory finally
produces detailed explanations for many CFS observations
A novel theory of the cause of CFS has been published
which is supported by diverse biochemical and physiological
observations of CFS, while providing explanations for five of
most difficult puzzles about this medical condition. The
theory has been published by Dr. Martin L. Pall (Professor of
Biochemistry and Basic Medical Sciences, Washington
State University) in several publications (1-4,9).
The theory starts with the observation that infections that
precede and may therefore induce CFS and related
conditions act to induce excessive production of
inflammatory cytokines that induce, in turn, the inducible
nitric oxide synthase (iNOS). This enzyme, in turn,
synthesizes excessive amounts of nitric oxide which reacts
with another compound (superoxide) to produce the potent
oxidant peroxynitrite. Peroxynitrite acts via six known
biochemical mechanisms to increase the levels of both nitric
oxide and superoxide which react to produce more
peroxynitrite. In this way, once peroxynitrite levels are
elevated, they may act to continue the elevation, thus
producing a self-sustaining vicious cycle. It is this cycle,
according to the theory, that maintains the chronic
symptoms of CFS and it is this cycle, therefore, that must
be interrupted to effectively treat this condition.
************************************************************************
http://www.ImmuneSupport.com/library/showarticle.cfm/id/4072
The Poisoning of America: The Rise of 'Mystery' Illnesses Including
Chronic Fatigue Syndrome, Fibromyalgia, and Gulf War Syndrome
ImmuneSupport.com 11-13-2002 By Jason Alexander Uttley
"Gulf War Syndrome... Fibromyalgia... Chronic Fatigue Syndrome... At the
heart of this horrific story lies a group of antibiotics called the
fluoroquinolones. Among the more common of these medications are:
ciprofloxacin (Cipro), levofloxacin (Levaquin), norfloxacin
(Noroxin), ofloxacin (Floxin), and trovafloxacin (Trovan).... Such
conditions include Irritable Bowel Syndrome, Multiple Chemical
Sensitivity Syndrome, Chronic Myofascial Pain Syndrome, and
Peripheral Neuropathy.... Just like all the other conditions mentioned
previously their symptoms often include: joint pain, muscle
stiffness/aches, tendon pain, dizziness, disorientation, burning and
tingling sensations, numbness, diarrhea, sensory sensitivities, and
brain fog." [ All these symptoms are common in aspartame disease. This
suggests that Pall may be on the right track with a theory that many CFS
type diseases share a common etiology. ]
***********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/912
aspartame: methanol, formaldehyde, formic acid toxicity:
brief review: Murray 12.10.2 rmforall
Rich Murray, MA Room For All rmforall@att.net
1943 Otowi Road, Santa Fe NM 87505 USA 505-986-9103
http://groups.yahoo.com/group/aspartameNM/messages
for 929 posts in a public searchable archive
http://groups.yahoo.com/group/aspartameNM/message/862 long review
Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall
It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA limit for formaldehyde in drinking
water.
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.
http://groups.yahoo.com/group/aspartameNM/message/860
RTM: FDA: objections to neotame approval 8.3.2 rmforall 38 pages
http://groups.yahoo.com/group/aspartameNM/message/868
Murray: submit complaints and papers to FDA Docket 02P-0317
by Jan 12 2003: Recall Aspartame as a Neurotoxic Drug 9.20.2 rmforall
http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@aol.com
http://www.sunsentpress.com/ sunsentpress@aol.com
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax
http://groups.yahoo.com/group/aspartameNM/message/669
1038-page medical text "Aspartame Disease: An Ignored Epidemic"
published May 30 2001 $ 85.00 postpaid data from 1200 cases
available at http://www.amazon.com
over 600 references from standard medical research
http://www.aspartameispoison.com/contents.html 34 chapters
http://groups.yahoo.com/group/aspartameNM/message/859
RTM: Roberts: the life work of a brilliant clinician:
aspartame toxicity 8.2.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/926
aspartame puts formaldehyde adducts into tissues, Part 2/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://ww.presidiotex.com/barcelona/index.html
Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X,
Fernandez-Lopez JA, Alemany M ["Trok-ho"]
Formaldehyde derived from dietary aspartame binds to tissue
components in vivo. Life Sci 1998 Jun 26; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia,
Universitat de Barcelona, Spain.
http://www.presidiotex.com/barcelona/index.html
Maria Alemany, PhD (male) alemany@porthos.bio.ub.es
http://groups.yahoo.com/group/aspartameNM/message/864
Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde
adducts in rats 9.8.2 rmforall
Prof. Alemany vigorously affirms the validity of the Trocho study
against criticism:
Butchko, HH et al [24 authors], Aspartame: review of safety.
Regul. Toxicol. Pharmacol. 2002 April 1; 35 (2 Pt 2): S1-93, review
available for $35, [an industry paid organ]. Butchko:
"When all the research on aspartame, including evaluations in both the
premarketing and postmarketing periods, is examined as a whole, it is
clear that aspartame is safe, and there are no unresolved questions
regarding its safety under conditions of intended use."
[They repeatedly pass on the ageless industry deceit that the methanol
in fruits and vegetables is as as biochemically available as that in
aspartame-- see the 1984 rebuttal by Monte, below.]
http://groups.yahoo.com/group/aspartameNM/message/911
RTP ties to industry criticized by CSPI: Murray: 12.9.2 rmforall
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from 11% methanol in aspartame:
Murray: 12.9.2 rmforall
Dec 9 2002
The work of Jack D. Thrasher, PhD, provides an adequate scientific
model and specific biochemical assays for the chronic symptoms of
long-term, low-level exposure to formaldehyde, which is well reported
in the scientific literature to inevitably be in intimate association
with aspartame-methanol-formaldehyde-formic acid metabolism in monkeys.
Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/872
immune system reactions due to formaldehyde from the 11% methanol in
aspartame: Thrasher: Tephly: Monte: Murray 9.27.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/867
Murray: Thrasher:
simple tests for immune system reactions due to formaldehyde from the
11% methanol in aspartame: Tholen 9.17.2 rmforall
http://www.drthrasher.org/formaldehyde_1990.html [full text]
Arch Environ Health 1990 Jul-Aug;45(4):217-23
Immune activation and autoantibodies in humans
with long-term inhalation exposure to formaldehyde.
Thrasher JD, Broughton A, Madison R.
Thrasher & Associates, Northridge, California.
http://www.drthrasher.org
Jack D. Thrasher, PhD toxicology@drthrasher.org
Sam-1 Trust, PO Box 874 Alto, New Mexico 88312
505-336-8312 fax 425-675-7379
"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."
Since 11% of aspartame (1120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), 16 times the 7.8 EPA limit for methanol
in drinking water. Ingested methanol is then quickly metabolized into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month
(Oppermann, Muldoon, Ranney 1973). As discussed below, if 10% of the
methanol accumulates as retained formaldehyde, that is 12.3 mg daily, 61
times the 0.2 mg level of retained formaldehyde, if 10% is retained from
the EPA daily limit of 2 mg formaldehyde in drinking water.
The question is: how much of this formaldehyde and formic acid, both
deadly, potent, cumulative toxins with complex multiple effects, as
much as 6.6 mg total (30% of the 22 mg methanol) from the 200 mg
aspartame in a 12-oz can of diet soda, results in various toxic
processes in people?
We should find that aspartame reactors and people with Multiple Chemical
Sensitivity and related diseases also react to formic acid, to
formaldehyde, to methanol, and to aspartame.
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
If 10% of the 7.8 mg EPA daily limit for methanol in drinking water,
most of which would promptly metabolized into formaldehyde, were to
be retained in the body as formaldehyde, that would be .78 mg, in
contrast to 10% retention of the 2 mg EPA daily limit for formaldehyde
in drinking water, which would be 0.2 mg, about 40 times less.
This suggests a contradiction between the EPA limits for methanol and
formaldehyde, which in turn suggests that this important topic is not
as yet well understood-- the EPA methanol limit may be far too high.
A limit of 2 mg daily of formaldehyde in drinking water for a 60-kg
person is .03 mg/kg, roughly equivalent to .03 mg/L, or 0.001 mmol/L,
since a mole is 30 grams and 1 mmole is .03 gm = 30 mg. This level is a
thousand times less than the 1 mmole/L level that Oyama (2002) found
hurt rat cells. However, Martin L. Pall (2002) in his review article
cites people with MCS type diseases react to levels 10 to 100 times
under the usual reaction levels. Also, formaldehyde accumulates.
Thrasher's report about symptoms from long-term, low-level exposure to
formaldehyde gives much the same litany of complex symptoms as
aspartame reactors, who often report using 2-4 L daily of diet soda,
providing 123-246 mg methanol, resulting in some probable chronic
formaldehyde toxicity-- as already discussed, if 10% were retained as
formaldehyde, that would give 12-24 mg daily formaldehyde accumulation,
about 60-120 times more than the 0.2 mg from 10% retention of the 2 mg
EPA daily limit for formaldehyde in drinking water.
Therefore, we can expect to find signs and symptoms of chronic toxicity,
especially since there will be a percentage of users who for various
reasons are expecially vulnerable, from long-term, low-dose formaldehyde
exposure in heavy users of aspartame, such as a daily drinking level of
2-4 L diet soda-- of course there are many other dietary sources.
The most common symptoms are, in rough order of
occurence, considering hundreds of case reports: * headaches
* many body and joint pains (or burning, tingling, tremors, twitching,
spasms, cramps, or numbness) * fever, fatigue
* "mind fog", "feel unreal", poor memory, confusion, anxiety,
irritability, depression, mania, insomnia, dizziness, slurred speech,
ringing in ears, sexual problems, poor vision, hearing, or taste
* red face, itching, rashes, burning eyes or throat,
dry mouth or eyes, mouth sores * hair loss
* obesity, bloating, edema, anorexia,
poor or excessive hunger or thirst * breathing problems
* nausea, diarrhea or constipation * coldness * sweating
* racing heart, high blood pressure, erratic blood sugar levels
* seizures * birth defects * brain cancers * addiction
* aggrivates diabetes, autism, ADHD, allergies,
and interstitial cystitis (bladder pain).
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall
Jerry D Smith, Chris M Terpening, Siegfried OF Schmidt, and John G Gums
Relief of Fibromyalgia Symptoms Following
Discontinuation of Dietary Excitotoxins.
The Annals of Pharmacotherapy 2001; 35(6): 702–706.
Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL, USA.
BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is
often difficult to treat effectively.
CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome
for two to 17 years are described.
All had undergone multiple treatment
modalities with limited success. All had complete, or nearly complete,
resolution of their symptoms within months after eliminating monosodium
glutamate (MSG) or MSG plus aspartame from their diet.
All patients were women with multiple comorbidities
prior to elimination of MSG.
All have had recurrence of symptoms whenever MSG is ingested.
Siegfried O. Schmidt, MD Asst. Clinical Prof. siggy@shands.ufl.edu
Community Health and Family Medicine, U. Florida, Gainesville, FL
Shands Hospital
West Oak Clinic Gainesville, FL 32608-3629 352-376-5071
Debbie J. Hypes painfreeliving@aol.com 304-872-4141 (Case # 1 of 4)
P.O Box 25 Lookout, WV 25868-0025 She has about 1,000 on her local
mailing list, and has been a volunteer activist since 1997. Her guide
first came out in 1997: http://www.Pain-Free-Living.net
"The Food Plan: How To Do It" $ 5 by mail, free by email.
Her sister Darlene, now 47, cured her own severe fibromyalgia in 1995
by using an elimination diet, and then Debbie also cured herself by
1997. Their doctor, Siegfried Schmidt, paying attention, tried it on
two selected women, who got well, and are his third and fourth cases.
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/926
aspartame puts formaldehyde adducts into tissues, Part 2/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://ww.presidiotex.com/barcelona/index.html full text
Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X,
Fernandez-Lopez JA, Alemany M ["Trok-ho"]
Formaldehyde derived from dietary aspartame binds to tissue
components in vivo. Life Sci 1998 Jun 26; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia,
Universitat de Barcelona, Spain.
http://www.presidiotex.com/barcelona/index.html
Maria Alemany, PhD (male) alemany@porthos.bio.ub.es
http://groups.yahoo.com/group/aspartameNM/message/864
Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde
adducts in rats 9.8.2 rmforall
Prof. Alemany vigorously affirms the validity of the Trocho study
against criticism:
Butchko, HH et al [24 authors], Aspartame: review of safety.
Regul. Toxicol. Pharmacol. 2002 April 1; 35 (2 Pt 2): S1-93, review
available for $35, [an industry funded organ]. Butchko:
"When all the research on aspartame, including evaluations in both the
premarketing and postmarketing periods, is examined as a whole, it is
clear that aspartame is safe, and there are no unresolved questions
regarding its safety under conditions of intended use."
[They repeatedly pass on the ageless industry deceit that the methanol
in fruits and vegetables is as as biochemically available as that in
aspartame-- see the 1984 rebuttal by Monte.]
http://groups.yahoo.com/group/aspartameNM/message/911
RTP ties to industry critized by CSPI: Murray: 12.9.2 rmforall
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/870
Aspartame: Methanol and the Public Interest 1984:
Monte: Murray 9.23.2 rmforall
Rereading this prescient classic review from 1984, I find its findings
are supported in much recent research, so I am again making the full
text widely available.
[I have put my comments or corrections in square brackets, and spaced
the text to ease the reader's task]
For instance, I had forgotten this, which answers the industry PR
"science" that fruits and vegetables
supply much more methanol than does aspartame:
"Fruit and vegetables contain pectin
with variable methyl ester content.
However, the human has no digestive enzymes for pectin (6, 25)
particularly the pectin esterase required
for its hydrolysis to methanol (26).
Fermentation in the gut may cause disappearance of pectin (6) but the
production of free methanol is not guaranteed by fermentation (3). In
fact, bacteria in the colon probably reduce methanol directly to formic
acid or carbon dioxide (6) (aspartame is completely absorbed before
reaching the colon). Heating of pectins has been shown to cause
virtually no demethoxylation; even temperatures of 120 deg C produced
only traces of methanol (3). Methanol evolved during cooking of high
pectin foods (7) has been accounted for in the volatile fraction during
boiling and is quickly lost to the atmosphere (49).
Entrapment of these volatiles probably accounts for the elevation in
methanol levels of certain fruit and vegetable products
during canning (31, 33)."
Recent research [see links at end of post] supports his focus on the
methanol to formaldehyde toxic process:
"The United States Environmental Protection Agency in their Multimedia
Environmental Goals for Environmental Assessment recommends a minimum
acute toxicity concentration of methanol in drinking water at 3.9 parts
per million, with a recommended limit of consumption below 7.8 mg/day
(8). This report clearly indicates that methanol:
"is considered a cumulative poison
due to the low rate of excretion once it is absorbed.
In the body, methanol is oxidized to formaldehyde and
formic acid; both of these metabolites are toxic." (8)....
Recently the toxic role of formaldehyde (in methanol toxicity) has been
questioned (34). No skeptic can overlook the fact that, metabolically,
formaldehyde must be formed as an intermediate to formic acid
production (54).
Formaldehyde has a high reactivity which may be why it
has not been found in humans or other primates during methanol
poisioning (59)....
If formaldehyde is produced from methanol and does have a reasonable
half life within certain cells in the poisoned organism the chronic
toxicological ramifications could be grave.
Formaldehyde is a known
carcinogen (57) producing squamous-cell carcinomas by inhalation
exposure in experimental animals (22). The available epidemiological
studies do not provide adequate data for assessing the carcinogenicity
of formaldehyde in man (22, 24, 57).
However, reaction of formaldehyde
with deoxyribonucleic acid (DNA) has resulted in irreversible
denaturation that could interfere with DNA replication and result in
mutation (37)...."
http://www.dorway.com/wmonte.txt
Dr. Woodrow C. Monte Aspartame: methanol, and the public health.
Journal of Applied Nutrition 1984; 36 (1): 42-54.
(62 references) Professsor of Food Science
Director of the Food Science and Nutrition Laboratory
Arizona State University, Tempe, Arizona 85287
6411 South River Drive #61 Tempe, Arizona 85283-3337
602-965-6938 woody.monte@asu.edu [now retired in New Zealand]
***********************************************************************
Life Sci 1991;48(11):1031-41
The toxicity of methanol.
Tephly TR. [a notable pro-aspartame scientist]
Department of Pharmacology, University of Iowa, Iowa City 52242.
Methanol toxicity in humans and monkeys is characterized by a latent
period of many hours followed by a metabolic acidosis and
ocular toxicity. This is not observed in most lower animals. The
metabolic acidosis and blindness is apparently due to formic acid
accumulation in humans and monkeys, a feature not seen in lower
animals.
The accumulation of formate is due to a deficiency in
formate metabolism which is, in turn, related, in part, to low hepatic
tetrahydrofolate (H4 folate). An excellent correlation between
hepatic H4 folate and formate oxidation rates has been shown within and
across species. Thus, humans and monkeys possess low
hepatic H4 folate levels, low rates of formate oxidation and
accumulation of formate after methanol. Formate, itself, produces
blindness in monkeys in the absence of metabolic acidosis. In addition
to low hepatic H4 folate concentrations, monkeys and humans
also have low hepatic 10-formyl H4 folate dehydrogenase levels, the
enzyme which is the ultimate catalyst for conversion of formate
to carbon dioxide. This review presents the basis for the role of folic
acid-dependent reactions in the regulation of methanol toxicity.
Publication Types: Review Review, Academic PMID: 1997785
page 1035 "In the past, formaldehyde has often been suggested as the
methanol metabolite which produces toxicity (34,35). Today, a great
deal of information is available concerning its lack of such a role.
The presence of elevated formaldehyde levels in body fluids or tissues
following methanol administration has not been observed.
No formaldehyde has been detected in blood, urine or tissues obtained
from methanol-treated animals (36,37) and, in methanol-poisoned humans,
formaldehyde increases have not been observed....
About 85% of a low dose of 14C-formaldehyde [radioactive label] is
excreted as pulmonary 14CO2 (49,50)....."
49. Biochem. Pharmacol. 13: 1137-1142 (1964).
The metabolic fate of formaldehyde-C14 intraperitoneally administered
to the rat.
W. Brock Neely
Biochemical Research Labs, Dow Chemical Co., Midland, Michigan
In one rat, a 60.5 mg/kg dose = 2,000 mmol/kg was injected, and by 48
hours, 82.0% was in the exhaled air as CO2 and 13.9 % was in the urine
= total 95.9% excreted, so 4 % was retained in the body. Trocho (1998)
put aspartame in the stomachs of rats, and found formaldehyde adducts
in liver, kidneys, brain, and retinas.
50. Xenobiotica 1982 Feb;12(2):119-24
Formaldehyde metabolism by the rat: a re-appraisal.
Mashford PM, Jones AR.
Dept. of Biochemistry, University of Sidney, Australia
Six rats were injected with a 4 mg/kg dose = 133 mmol/kg, and by 48
hours, 82% was in the exhaled air as CO2, and 7.5% in the urine = total
89.5% excreted, so 10.5% was retained in the body.
***********************************************************************
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
They found that about 70% of the radioactive methanol in aspartame put
into the stomachs of 3 to 7 kg monkeys was eliminated within a day as
carbon dioxide in exhaled air and as water in the urine: page 1458
"That fraction not so excreted (about 30%) was converted to body
constituents through the one-carbon metabolic pool." They did not
mention that this meant that about 30% of the methanol must transform
into formaldehyde and then into formic acid, much of which must remain
as toxic products in all parts of the body. This study did not monitor
long-term use of aspartame.
The low oral dose of aspartame and for methanol was 0.068 mmol/kg,
about 1 part per million [ppm] of the acute toxicity level of 2,000
mg/kg, 67,000 mmol/kg, used by McMartin (1979). Two L daily use of
diet soda provides 123 mg methanol, 2 mg/kg for a 60 kg person, a dose
of 67 mmole/kg, a thousand times more than the dose in this study.
By eight hours excretion of the dose in air and urine had leveled off
at 67.1 +-2.1% as CO2 in the exhaled air and 1.57+-0.32% in the urine,
so 68.7 % was excreted, and 31.3% was retained. [This data is the
average of 4 monkeys.]
***********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/885
aspartame, methanol, formaldehyde, formate toxicity on rat cells:
Oyama, Akaike, et al, Jan 2002: Murray 11.7.2 rmforall
"While methanol and formate did not affect cell viability in the
physiological pH range, formaldehyde at 1-3 mmol/L started to induce
cell death. Further increase in formaldehyde concentration produced a
dose-dependent decrease in cell viability.
Formaldehyde at 1 mmol/L or more greatly reduced cellular content of
glutathione, possibly increasing cell vulnerability to oxidative
stress."
***********************************************************************
This study admitted one datum that showed accumulation of formaldehye
in the midbrain from an acute toxicity dose of methanol, and widespread
accumulation of formic acid in five tissues.
Biochemical Pharmcacology 1979: 28; 645-649.
Lack of a role for formaldehyde in methanol poisoning in the monkey.
Kenneth E. McMartin, Gladys Martin-Amat, Patricia E. Noker
and Thomas R. Tephly
The Toxicology Center, Dept. of Pharmacology,
University of Iowa, Iowa City, Iowa 52242
Abstract [not given in PubMed]: [My comments are in square braclets.]
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.
[So, this is an acute toxicity study, with little relevance for chronic
long-term, low-level exposure.
"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."
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.
Monkey A was folate-deficient and thus highly vulnerable to methanol
toxicity. This means that the large number of people who are
folate-deficient will also be more vulnerable. Blood, urine, and
tissue samples were studied 12 hours after the methanol dose of 2,000
mg/kg, when symptoms were visible. Formaldehyde [FM] had decreased in
blood from .068 to .038 mmol/L. Note that Oyama, Akaike, et al in 2002
found that 1 mmol/L formaldehyde levels damaged rat cells-- 14 times
higher than the initial spike of .068 nmol/L in blood formaldehyde.
For people, 11% of aspartame (1120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes aspartic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a 1.1 gm monthly.
For the average 60-kg person, the daily dose of methanol from 2 L of
diet soda is 2 mg/kg. To create a rough estimate, we imagine the whole
body to be 60 kg water-- then the daily dose of methanol would be 2
mg/L, about 67 mmol/L, quickly metabolized into formaldehyde and then
into formic acid. The formaldehyde dose would temporarily be about 67
times more than the lowest level of 1 mmol/L that Oyama found hurt rat
cells. This is a very rough estimate, since the formaldehyde
concentrates in many tissues. Toxicity would result from accumulation
of a daily fraction of the methanol as formaldehyde and formic acid
metabolites, reacted with body chemicals. If 30% of the daily methanol
dose is retained in this way, then that would be .6 mg/kg daily
accumulation, 18 mg/kg monthly = 18 ppm.
Formaldehyde adducts concentrate in the brain, liver, kidneys, and
retinas, according to the Trocho study on aspartame-fed rats. So,
symptoms would evolve in these organs. The amount of accumulated
formaldehyde can only grow with daily exposure. It is reasonable to
surmise that the body's defenses will deteriorate, and allergic
sensitivity will grow. Some heavy users report an actual addiction.
Those who quit often report fast recurrence of symptoms upon
inadvertent reexposure to small amounts, such as the 6-8 mg aspartame
in a stick of chewing gum.
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 L, 1 mmol/kg is equivalent to 1 mmol/L.]
Meanwhile, the blood formate level rose by 12 hours from .180 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 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 were not measured.
After 12 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.
Often, pro-aspartame studies have titles and summaries that are not
supported by a close study of the details:
http://groups.yahoo.com/group/aspartameNM/message/891
flawed test for aspartame DNA damage: Jeffrey & Williams 2000: Murray:
11.20.2 rmforall
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 becasue 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]
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/915
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
Wilson: CIIN: 12.12.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/628
Rich Murray: Professional House Doctors: Singer: EPA: CPSC:
formaldehyde toxicity 6.10.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/645
Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts
6.25.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/622
Rich Murray: Gold: Koehler: Walton: Van Den Eeden: Leon:
aspartame toxicity 6.4.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/623
Rich Murray: Simmons: Gold: Schiffman: Spiers:
aspartame toxicity 6.4.1 rmforall
***********************************************************************
formaldehyde & formic acid from 11% methanol in aspartame:
Murray: 12.9.2 rmforall
Dec 9 2002
The work of Jack D. Thrasher, PhD, provides an adequate scientific
model and specific biochemical assays for the chronic symptoms of
long-term, low-level exposure to formaldehyde, which is well reported
in the scientific literature to inevitably be in intimate association
with aspartame-methanol-formaldehyde-formic acid metabolism in monkeys.
Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/872
immune system reactions due to formaldehyde from the 11% methanol in
aspartame: Thrasher: Tephly: Monte: Murray 9.27.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/867
Murray: Thrasher:
simple tests for immune system reactions due to formaldehyde from the
11% methanol in aspartame: Tholen 9.17.2 rmforall
http://www.drthrasher.org/formaldehyde_1990.html [full text]
Arch Environ Health 1990 Jul-Aug;45(4):217-23
Immune activation and autoantibodies in humans
with long-term inhalation exposure to formaldehyde.
Thrasher JD, Broughton A, Madison R.
Thrasher & Associates, Northridge, California.
http://www.drthrasher.org
Jack D. Thrasher, PhD toxicology@drthrasher.org
Sam-1 Trust, PO Box 874 Alto, New Mexico 88312
505-336-8312 fax 425-675-7379
"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."
Since 11% of aspartame (1120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), 16 times the 7.8 EPA limit for methanol
in drinking water. Ingested methanol is then quickly metabolized into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month
(Oppermann, Muldoon, Ranney 1973). As discussed below, if 10% of the
methanol accumulates as retained formaldehyde, that is 12.3 mg daily, 61
times the 0.2 mg level of retained formaldehyde, if 10% is retained from
the EPA daily limit of 2 mg formaldehyde in drinking water.
The question is: how much of this formaldehyde and formic acid, both
deadly, potent, cumulative toxins with complex multiple effects, as
much as 6.6 mg total (30% of the 22 mg methanol) from the 200 mg
aspartame in a 12-oz can of diet soda, results in various toxic
processes in people?
We should find that aspartame reactors and people with Multiple Chemical
Sensitivity and related diseases also react to formic acid, to
formaldehyde, to methanol, and to aspartame.
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
If 10% of the 7.8 mg EPA daily limit for methanol in drinking water,
most of which would promptly metabolized into formaldehyde, were to
be retained in the body as formaldehyde, that would be .78 mg, in
contrast to 10% retention of the 2 mg EPA daily limit for formaldehyde
in drinking water, which would be 0.2 mg, about 40 times less.
This suggests a contradiction between the EPA limits for methanol and
formaldehyde, which in turn suggests that this important topic is not
as yet well understood-- the EPA methanol limit may be far too high.
A limit of 2 mg daily of formaldehyde in drinking water for a 60-kg
person is .03 mg/kg, roughly equivalent to .03 mg/L, or 0.001 mmol/L,
since a mole is 30 grams and 1 mmole is .03 gm = 30 mg. This level is a
thousand times less than the 1 mmole/L level that Oyama (2002) found
hurt rat cells. However, Martin L. Pall (2002) in his review article
cites people with MCS type diseases react to levels 10 to 100 times
under the usual reaction levels. Also, formaldehyde accumulates.
Thrasher's report about symptoms from long-term, low-level exposure to
formaldehyde gives much the same litany of complex symptoms as
aspartame reactors, who often report using 2-4 L daily of diet soda,
providing 123-246 mg methanol, resulting in some probable chronic
formaldehyde toxicity-- as already discussed, if 10% were retained as
formaldehyde, that would give 12-24 mg daily formaldehyde accumulation,
about 60-120 times more than the 0.2 mg from 10% retention of the 2 mg
EPA daily limit for formaldehyde in drinking water.
Therefore, we can expect to find signs and symptoms of chronic toxicity,
especially since there will be a percentage of users who for various
reasons are expecially vulnerable, from long-term, low-dose formaldehyde
exposure in heavy users of aspartame, such as a daily drinking level of
2-4 L diet soda-- of course there are many other dietary sources.
The most common symptoms are, in rough order of
occurence, considering hundreds of case reports: * headaches
* many body and joint pains (or burning, tingling, tremors, twitching,
spasms, cramps, or numbness) * fever, fatigue
* "mind fog", "feel unreal", poor memory, confusion, anxiety,
irritability, depression, mania, insomnia, dizziness, slurred speech,
ringing in ears, sexual problems, poor vision, hearing, or taste
* red face, itching, rashes, burning eyes or throat,
dry mouth or eyes, mouth sores * hair loss
* obesity, bloating, edema, anorexia,
poor or excessive hunger or thirst * breathing problems
* nausea, diarrhea or constipation * coldness * sweating
* racing heart, high blood pressure, erratic blood sugar levels
* seizures * birth defects * brain cancers * addiction
* aggrivates diabetes, autism, ADHD, allergies,
and interstitial cystitis (bladder pain).
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall
Jerry D Smith, Chris M Terpening, Siegfried OF Schmidt, and John G Gums
Relief of Fibromyalgia Symptoms Following
Discontinuation of Dietary Excitotoxins.
The Annals of Pharmacotherapy 2001; 35(6): 702–706.
Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL, USA.
BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is
often difficult to treat effectively.
CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome
for two to 17 years are described.
All had undergone multiple treatment
modalities with limited success. All had complete, or nearly complete,
resolution of their symptoms within months after eliminating monosodium
glutamate (MSG) or MSG plus aspartame from their diet.
All patients were women with multiple comorbidities
prior to elimination of MSG.
All have had recurrence of symptoms whenever MSG is ingested.
Siegfried O. Schmidt, MD Asst. Clinical Prof. siggy@shands.ufl.edu
Community Health and Family Medicine, U. Florida, Gainesville, FL
Shands Hospital
West Oak Clinic Gainesville, FL 32608-3629 352-376-5071
Debbie J. Hypes painfreeliving@aol.com 304-872-4141 (Case # 1 of 4)
P.O Box 25 Lookout, WV 25868-0025 She has about 1,000 on her local
mailing list, and has been a volunteer activist since 1997. Her guide
first came out in 1997: http://www.Pain-Free-Living.net
"The Food Plan: How To Do It" $ 5 by mail, free by email.
Her sister Darlene, now 47, cured her own severe fibromyalgia in 1995
by using an elimination diet, and then Debbie also cured herself by
1997. Their doctor, Siegfried Schmidt, paying attention, tried it on
two selected women, who got well, and are his third and fourth cases.
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/926
aspartame puts formaldehyde adducts into tissues, Part 2/2
full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall
http://ww.presidiotex.com/barcelona/index.html full text
Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X,
Fernandez-Lopez JA, Alemany M ["Trok-ho"]
Formaldehyde derived from dietary aspartame binds to tissue
components in vivo. Life Sci 1998 Jun 26; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia,
Universitat de Barcelona, Spain.
http://www.presidiotex.com/barcelona/index.html
Maria Alemany, PhD (male) alemany@porthos.bio.ub.es
http://groups.yahoo.com/group/aspartameNM/message/864
Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde
adducts in rats 9.8.2 rmforall
Prof. Alemany vigorously affirms the validity of the Trocho study
against criticism:
Butchko, HH et al [24 authors], Aspartame: review of safety.
Regul. Toxicol. Pharmacol. 2002 April 1; 35 (2 Pt 2): S1-93, review
available for $35, [an industry funded organ]. Butchko:
"When all the research on aspartame, including evaluations in both the
premarketing and postmarketing periods, is examined as a whole, it is
clear that aspartame is safe, and there are no unresolved questions
regarding its safety under conditions of intended use."
[They repeatedly pass on the ageless industry deceit that the methanol
in fruits and vegetables is as as biochemically available as that in
aspartame-- see the 1984 rebuttal by Monte.]
http://groups.yahoo.com/group/aspartameNM/message/911
RTP ties to industry critized by CSPI: Murray: 12.9.2 rmforall
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/870
Aspartame: Methanol and the Public Interest 1984:
Monte: Murray 9.23.2 rmforall
Rereading this prescient classic review from 1984, I find its findings
are supported in much recent research, so I am again making the full
text widely available.
[I have put my comments or corrections in square brackets, and spaced
the text to ease the reader's task]
For instance, I had forgotten this, which answers the industry PR
"science" that fruits and vegetables
supply much more methanol than does aspartame:
"Fruit and vegetables contain pectin
with variable methyl ester content.
However, the human has no digestive enzymes for pectin (6, 25)
particularly the pectin esterase required
for its hydrolysis to methanol (26).
Fermentation in the gut may cause disappearance of pectin (6) but the
production of free methanol is not guaranteed by fermentation (3). In
fact, bacteria in the colon probably reduce methanol directly to formic
acid or carbon dioxide (6) (aspartame is completely absorbed before
reaching the colon). Heating of pectins has been shown to cause
virtually no demethoxylation; even temperatures of 120 deg C produced
only traces of methanol (3). Methanol evolved during cooking of high
pectin foods (7) has been accounted for in the volatile fraction during
boiling and is quickly lost to the atmosphere (49).
Entrapment of these volatiles probably accounts for the elevation in
methanol levels of certain fruit and vegetable products
during canning (31, 33)."
Recent research [see links at end of post] supports his focus on the
methanol to formaldehyde toxic process:
"The United States Environmental Protection Agency in their Multimedia
Environmental Goals for Environmental Assessment recommends a minimum
acute toxicity concentration of methanol in drinking water at 3.9 parts
per million, with a recommended limit of consumption below 7.8 mg/day
(8). This report clearly indicates that methanol:
"is considered a cumulative poison
due to the low rate of excretion once it is absorbed.
In the body, methanol is oxidized to formaldehyde and
formic acid; both of these metabolites are toxic." (8)....
Recently the toxic role of formaldehyde (in methanol toxicity) has been
questioned (34). No skeptic can overlook the fact that, metabolically,
formaldehyde must be formed as an intermediate to formic acid
production (54).
Formaldehyde has a high reactivity which may be why it
has not been found in humans or other primates during methanol
poisioning (59)....
If formaldehyde is produced from methanol and does have a reasonable
half life within certain cells in the poisoned organism the chronic
toxicological ramifications could be grave.
Formaldehyde is a known
carcinogen (57) producing squamous-cell carcinomas by inhalation
exposure in experimental animals (22). The available epidemiological
studies do not provide adequate data for assessing the carcinogenicity
of formaldehyde in man (22, 24, 57).
However, reaction of formaldehyde
with deoxyribonucleic acid (DNA) has resulted in irreversible
denaturation that could interfere with DNA replication and result in
mutation (37)...."
http://www.dorway.com/wmonte.txt
Dr. Woodrow C. Monte Aspartame: methanol, and the public health.
Journal of Applied Nutrition 1984; 36 (1): 42-54.
(62 references) Professsor of Food Science
Director of the Food Science and Nutrition Laboratory
Arizona State University, Tempe, Arizona 85287
6411 South River Drive #61 Tempe, Arizona 85283-3337
602-965-6938 woody.monte@asu.edu [now retired in New Zealand]
***********************************************************************
Life Sci 1991;48(11):1031-41
The toxicity of methanol.
Tephly TR. [a notable pro-aspartame scientist]
Department of Pharmacology, University of Iowa, Iowa City 52242.
Methanol toxicity in humans and monkeys is characterized by a latent
period of many hours followed by a metabolic acidosis and
ocular toxicity. This is not observed in most lower animals. The
metabolic acidosis and blindness is apparently due to formic acid
accumulation in humans and monkeys, a feature not seen in lower
animals.
The accumulation of formate is due to a deficiency in
formate metabolism which is, in turn, related, in part, to low hepatic
tetrahydrofolate (H4 folate). An excellent correlation between
hepatic H4 folate and formate oxidation rates has been shown within and
across species. Thus, humans and monkeys possess low
hepatic H4 folate levels, low rates of formate oxidation and
accumulation of formate after methanol. Formate, itself, produces
blindness in monkeys in the absence of metabolic acidosis. In addition
to low hepatic H4 folate concentrations, monkeys and humans
also have low hepatic 10-formyl H4 folate dehydrogenase levels, the
enzyme which is the ultimate catalyst for conversion of formate
to carbon dioxide. This review presents the basis for the role of folic
acid-dependent reactions in the regulation of methanol toxicity.
Publication Types: Review Review, Academic PMID: 1997785
page 1035 "In the past, formaldehyde has often been suggested as the
methanol metabolite which produces toxicity (34,35). Today, a great
deal of information is available concerning its lack of such a role.
The presence of elevated formaldehyde levels in body fluids or tissues
following methanol administration has not been observed.
No formaldehyde has been detected in blood, urine or tissues obtained
from methanol-treated animals (36,37) and, in methanol-poisoned humans,
formaldehyde increases have not been observed....
About 85% of a low dose of 14C-formaldehyde [radioactive label] is
excreted as pulmonary 14CO2 (49,50)....."
49. Biochem. Pharmacol. 13: 1137-1142 (1964).
The metabolic fate of formaldehyde-C14 intraperitoneally administered
to the rat.
W. Brock Neely
Biochemical Research Labs, Dow Chemical Co., Midland, Michigan
In one rat, a 60.5 mg/kg dose = 2,000 mmol/kg was injected, and by 48
hours, 82.0% was in the exhaled air as CO2 and 13.9 % was in the urine
= total 95.9% excreted, so 4 % was retained in the body. Trocho (1998)
put aspartame in the stomachs of rats, and found formaldehyde adducts
in liver, kidneys, brain, and retinas.
50. Xenobiotica 1982 Feb;12(2):119-24
Formaldehyde metabolism by the rat: a re-appraisal.
Mashford PM, Jones AR.
Dept. of Biochemistry, University of Sidney, Australia
Six rats were injected with a 4 mg/kg dose = 133 mmol/kg, and by 48
hours, 82% was in the exhaled air as CO2, and 7.5% in the urine = total
89.5% excreted, so 10.5% was retained in the body.
***********************************************************************
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
They found that about 70% of the radioactive methanol in aspartame put
into the stomachs of 3 to 7 kg monkeys was eliminated within a day as
carbon dioxide in exhaled air and as water in the urine: page 1458
"That fraction not so excreted (about 30%) was converted to body
constituents through the one-carbon metabolic pool." They did not
mention that this meant that about 30% of the methanol must transform
into formaldehyde and then into formic acid, much of which must remain
as toxic products in all parts of the body. This study did not monitor
long-term use of aspartame.
The low oral dose of aspartame and for methanol was 0.068 mmol/kg,
about 1 part per million [ppm] of the acute toxicity level of 2,000
mg/kg, 67,000 mmol/kg, used by McMartin (1979). Two L daily use of
diet soda provides 123 mg methanol, 2 mg/kg for a 60 kg person, a dose
of 67 mmole/kg, a thousand times more than the dose in this study.
By eight hours excretion of the dose in air and urine had leveled off
at 67.1 +-2.1% as CO2 in the exhaled air and 1.57+-0.32% in the urine,
so 68.7 % was excreted, and 31.3% was retained. [This data is the
average of 4 monkeys.]
***********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/885
aspartame, methanol, formaldehyde, formate toxicity on rat cells:
Oyama, Akaike, et al, Jan 2002: Murray 11.7.2 rmforall
"While methanol and formate did not affect cell viability in the
physiological pH range, formaldehyde at 1-3 mmol/L started to induce
cell death. Further increase in formaldehyde concentration produced a
dose-dependent decrease in cell viability.
Formaldehyde at 1 mmol/L or more greatly reduced cellular content of
glutathione, possibly increasing cell vulnerability to oxidative
stress."
***********************************************************************
This study admitted one datum that showed accumulation of formaldehye
in the midbrain from an acute toxicity dose of methanol, and widespread
accumulation of formic acid in five tissues.
Biochemical Pharmcacology 1979: 28; 645-649.
Lack of a role for formaldehyde in methanol poisoning in the monkey.
Kenneth E. McMartin, Gladys Martin-Amat, Patricia E. Noker
and Thomas R. Tephly
The Toxicology Center, Dept. of Pharmacology,
University of Iowa, Iowa City, Iowa 52242
Abstract [not given in PubMed]: [My comments are in square braclets.]
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.
[So, this is an acute toxicity study, with little relevance for chronic
long-term, low-level exposure.
"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."
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.
Monkey A was folate-deficient and thus highly vulnerable to methanol
toxicity. This means that the large number of people who are
folate-deficient will also be more vulnerable. Blood, urine, and
tissue samples were studied 12 hours after the methanol dose of 2,000
mg/kg, when symptoms were visible. Formaldehyde [FM] had decreased in
blood from .068 to .038 mmol/L. Note that Oyama, Akaike, et al in 2002
found that 1 mmol/L formaldehyde levels damaged rat cells-- 14 times
higher than the initial spike of .068 nmol/L in blood formaldehyde.
For people, 11% of aspartame (1120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes aspartic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a 1.1 gm monthly.
For the average 60-kg person, the daily dose of methanol from 2 L of
diet soda is 2 mg/kg. To create a rough estimate, we imagine the whole
body to be 60 kg water-- then the daily dose of methanol would be 2
mg/L, about 67 mmol/L, quickly metabolized into formaldehyde and then
into formic acid. The formaldehyde dose would temporarily be about 67
times more than the lowest level of 1 mmol/L that Oyama found hurt rat
cells. This is a very rough estimate, since the formaldehyde
concentrates in many tissues. Toxicity would result from accumulation
of a daily fraction of the methanol as formaldehyde and formic acid
metabolites, reacted with body chemicals. If 30% of the daily methanol
dose is retained in this way, then that would be .6 mg/kg daily
accumulation, 18 mg/kg monthly = 18 ppm.
Formaldehyde adducts concentrate in the brain, liver, kidneys, and
retinas, according to the Trocho study on aspartame-fed rats. So,
symptoms would evolve in these organs. The amount of accumulated
formaldehyde can only grow with daily exposure. It is reasonable to
surmise that the body's defenses will deteriorate, and allergic
sensitivity will grow. Some heavy users report an actual addiction.
Those who quit often report fast recurrence of symptoms upon
inadvertent reexposure to small amounts, such as the 6-8 mg aspartame
in a stick of chewing gum.
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 L, 1 mmol/kg is equivalent to 1 mmol/L.]
Meanwhile, the blood formate level rose by 12 hours from .180 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 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 were not measured.
After 12 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.
Often, pro-aspartame studies have titles and summaries that are not
supported by a close study of the details:
http://groups.yahoo.com/group/aspartameNM/message/891
flawed test for aspartame DNA damage: Jeffrey & Williams 2000: Murray:
11.20.2 rmforall
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 becasue 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]
**********************************************************************
http://groups.yahoo.com/group/aspartameNM/message/915
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
Wilson: CIIN: 12.12.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/628
Rich Murray: Professional House Doctors: Singer: EPA: CPSC:
formaldehyde toxicity 6.10.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/645
Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts
6.25.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/622
Rich Murray: Gold: Koehler: Walton: Van Den Eeden: Leon:
aspartame toxicity 6.4.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/623
Rich Murray: Simmons: Gold: Schiffman: Spiers:
aspartame toxicity 6.4.1 rmforall
***********************************************************************
