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Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde adducts in rats 9.8.2 rmforall

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  • Rich Murray
    Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde adducts in rats 9.8.2 rmforall http://groups.yahoo.com/group/aspartameNM/message/864 Marià
    Message 1 of 1 , Sep 8, 2002
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      Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde
      adducts in rats 9.8.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/864

      Marià Alemany <alemany@...>,
      Thomas R. Tephly <thomas-tephly@...>,
      Kenneth E. McMartin <kmcmar@...>,
      Harriett H. Butchko <harriett.h.butchko@...>,
      Susan S. Schiffman <sss@...>,
      Arthur S. Leon <leonx002@...>,
      Christian Benninger <Christian_Benninger@...-heidelberg.de>,
      George L. Blackburn <gblackbu@...>,
      Leo M.J. de Sonneville <lmj.sonneville@...>,
      Raif S. Geha <raif.geha@...>,
      Edward J. Novotny, Jr. <edward.novotny@...>,
      Andrew G. Renwick <agr@...>,
      Donald L. Schomer <dschomer@...>,
      Bennett A. Shaywitz <bennett.shaywitz@...>

      Subject: Re: Murray: Butchko:
      Tephly: critique of Trocho report Apr 2002 8.29.2
      Date: Fri, 30 Aug 2002 09:49:56 +0200
      From: Marià Alemany <alemany@...>
      To: "Rich Murray" <rmforall@...>
      References: 1

      Dear Rich,

      Thank you for the opportunity to say something about the "paper" by
      Tephly that followed our study on the incorporation of
      aspartame-derived methanol label into DNA and protein of rats.
      I don't know if responding to that publication is worth the effort.

      Surprisingly, a serious journal, such as Life Sciences published a
      rebuttal of our previous paper as a normal "research paper", but
      including no new information neither experimental work. This is only a
      sample of the "scientific" power of the advocates of aspartame.

      Anybody can extract conclusions from this anomaly, but it seems to me
      that there was nothing new in that pamphlet that may add information to
      what we already explained in our paper. The responses to the questions
      raised by Tephly are already in our paper, which means that either that
      it was not read or, worst, it was misread.

      The presence of aspartame-derived label in DNA and protein adducts is
      unquestionable and unquestioned, and agrees with previous studies.
      Then, what importance has the mechanism of incorporation? There were
      adducts, and they represent loss of function and mutation.
      That was our thesis.

      The reference to previous studies showing very low levels of
      formaldehyde in blood do not refute our data.
      First of all, measuring formaldehyde is tricky,
      and in any case, the circulating levels would be below the current limit
      of detection for most of the methods used. That is the current
      explanation for the low levels of methanol in plasma after aspartame
      loading: they are zero, using most of the methods available for
      methanol, since the expected levels are currently below the limit of
      detection...

      In addition, it is not logical to expect to find measurable levels of
      formaldehyde in a medium (blood) containing a huge amount of protein.
      Formaldehyde reacts immediately with proteins because it is highly
      reactive: that is the reason why we have found it in cell protein and
      DNA. It is absurd to expect it to forfeit binding with cell proteins
      and go all the way into the bloodstream! Remember that formaldehyde is
      used to preserve corpses precisely because it binds protein (including
      those of putrefactive bacteria) and prevents its degradation.

      The "alternative" point expressed by Tephly, suggesting that aspartame
      methanol-label goes all the way into formic acid and the C1 pathway was
      thoroughly refuted by us, using experimental data.
      There was no labelled methionine nor thymine in protein and DNA
      respectively in the rat protein we recovered from rats treated with
      aspartame. This means--unequivocally-- that the label present in DNA and
      protein adducts was NOT incorporated into amino acids or nucleic acid bases.
      The only explanation for our data was that the label was in the form of
      formaldehyde adducts.

      If this explanation does not satisfy other scientists, they are free to
      repeat the experiment and show where we went wrong, or to probe and
      prove experimentally their hypotheses.

      Otherwise, our results stand unchecked and, consequently, should be
      deemed true.

      I hope that this information will help any attentive reader understand
      why we have left for good this field of study.

      Best regards.
      ------------------------------
      Prof.Dr. Marià Alemany
      Grup de Recerca Nitrogen-Obesitat
      Departament de Nutrició i Bromatologia
      Facultat de Biologia, Universitat de Barcelona
      Av. Diagonal, 645; 08028 Barcelona Espanya/España/Spain
      tel. +34 93 403 4606; fax: +34 93 403 7064; E-mail: alemany@...
      ***********************************************************

      Full report http://www.presidiotex.com/barcelona/index.html
      Here is research in 1998 by C. Trocho et al, using a very low level of
      aspartame ingestion, 10 mg/kg, for rats, which have a much greater
      tolerance for aspartame than humans. So, the corresponding level for
      humans would be about 1 or 2 mg/kg. (Many headache studies in humans
      used doses of about 30 mg/kg daily.) This proves that aspartame causes
      binding of methanol's product, formaldehyde, a potent, cumulative
      toxin, into tissues. Life Sci June 26 1998; 63(5): 337-49. ["Trok-ho"]

      Formaldehyde derived from dietary aspartame binds to tissue components
      in vivo. Departament de Bioquimica i Biologia Molecular,
      Facultat de Biologia, Universitat de Barcelona, Spain.
      http://www.bq.ub.es/cindex.html
      Línies de Recerca: Toxicitat de l'aspartame
      http://www.bq.ub.es/grupno/grup-no.html
      Sra. Carme Trocho, Sra. Rosario Pardo, Dra. Immaculada Rafecas,
      Sr. Jordi Virgili, Dr. Xavier Remesar,
      Dr. Jose Antonio Fernandez-Lopez,
      Dr. Marià Alemany Fac. Biologia Tel.: (93)4021521, FAX: (93)4021559
      alemany@... [male] bioq@...
      josefer@...
      rafecas@... remesar@...
      Sra. Carme Trocho Fac. Biologia Tel.: (93)4021544, FAX: (93)4021559

      Abstract:
      Adult male rats were given an oral dose of 10 mg/kg aspartame,
      14C-labeled in the methanol carbon. At timed intervals of up to 6
      hours, the radioactivity in plasma and several organs was investigated.
      Most of the radioactivity found (>98% in plasma, >75% in liver) was
      bound to protein. Label present in liver, plasma and kidney was in the
      range of 1-2% of total radioactivity administered per g or mL, changing
      little with time. Other organs (brown and white adipose tissues,
      muscle, brain, cornea and retina) contained levels of label in the
      range of 1/12th to 1/10th of that of liver. In all, the rats retained,
      6 hours after administration, about 5% of the label, half of it in the
      liver.

      The specific radioactivity of tissue protein, RNA and DNA was quite
      uniform. The protein label was concentrated in amino acids, different
      from methionine, and largely coincident with the result of protein
      exposure to labeled formaldehyde. DNA radioactivity was essentially in
      a single different adduct base, different from the normal bases present
      in DNA. The nature of the tissue label accumulated was, thus, a direct
      consequence of formaldehyde binding to tissue structures.

      The administration of labeled aspartame to a group of cirrhotic rats
      resulted in comparable label retention by tissue components, which
      suggests that liver function (or its defect) has little effect on
      formaldehyde formation from aspartame and binding to biological
      components. The chronic treatment of a series of rats with 200 mg/kg
      of non-labeled aspartame during 10 days results in the accumulation of
      even more label when given the radioactive bolus, suggesting that the
      amount of formaldehyde adducts coming from aspartame in tissue proteins
      and nucleic acids may be cumulative.

      It is concluded that aspartame consumption may constitute a hazard
      because of its contribution to the formation of formaldehyde adducts.
      PMID: 9714421, UI: 98378223

      [Extracts]
      The high label presence in plasma and liver is in agreement with the
      carriage of the label from the intestine to the liver via the portal
      vein. The high label levels in kidney and, to a minor extent, in
      brown adipose tissue and brain are probably a consequence of their
      high blood flows (45). Even in white adipose tissue, the levels of
      radioactivity found 6 hours after oral administration were 1/25th
      those of liver. Cornea and retina, both tissues known to metabolize
      actively methanol (21,28) showed low levels of retained label. In any
      case, the binding of methanol-derived carbon to tissue proteins was
      widespread, affecting all systems, fully reaching even sensitive
      targets such as the brain and retina....

      The amount of label recovered in tissue components was quite high in
      all the groups, but especially in the NA rats. In them, the liver alone
      retained, for a long time, more than 2 % of the methanol carbon given
      in a single oral dose of aspartame, and the rest of the body stored an
      additional 2 % or more. These are indeed extremely high levels for
      adducts of formaldehyde, a substance responsible of chronic deleterious
      effects (33), that has also been considered carcinogenic (34,47). The
      repeated occurrence of claims that aspartame produces headache and
      other neurological and psychological secondary effects-- more often
      than not challenged by careful analysis-- (5,9,10,15,48) may eventually
      find at least a partial explanation in the permanence of the
      formaldehyde label, since formaldehyde intoxication can induce similar
      effects (49).

      The cumulative effects derived from the incorporation of label in the
      chronic administration model suggests that regular intake of aspartame
      may result in the progressive accumulation of formaldehyde adducts. It
      may be further speculated that the formation of adducts can help to
      explain the chronic effects aspartame consumption may induce on
      sensitive tissues such as brain (6,9,19,50). In any case, the possible
      negative effects that the accumulation of formaldehyde adducts can
      induce is, obviously, long-term. The alteration of protein integrity
      and function may needs some time to induce substantial effects. The
      damage to nucleic acids, mainly to DNA, may eventually induce cell
      death and/or mutations. The results presented suggest that the
      conversion of aspartame methanol into formaldehyde adducts in
      significant amounts in vivo should to be taken into account because
      of the widespread utilization of this sweetener. Further
      epidemiological and long-term studies are needed to determine the
      extent of the hazard that aspartame consumption poses for humans.
      ***********************************************************

      Life Sci 1999; 65(13): PL157-60. [letter, not peer reviewed]
      Comments on the purported generation of formaldehyde and adduct
      formation from the sweetener aspartame.
      Tephly TR Thomas R. Tephly 319-335-7979 thomas-tephly@...
      ttephly@... Department of Pharmacology
      The University of Iowa, Iowa City 52242, USA.

      A recent paper by Trocho et al. (1) describes experiments meant to
      show that formaldehyde adducts are formed when rats are administered
      the sweetener aspartame. These authors assume that the methanol carbon
      of aspartame generates formaldehyde which then forms adducts with
      protein, DNA, and RNA. Doses employed range widely. In this letter,
      studies which have been published previously and which were not cited
      by these authors are reviewed in order to put into perspective the
      disposition of methanol and formaldehyde in monkeys
      and humans, species relevant to the toxicity of methanol
      and its toxic metabolite, formic acid.
      PMID: 10503962, UI: 99431287

      A number of pro-aspartame studies by Tephly and associates, invariably
      funded by the aspartame industry (Monsanto, NutraSweet) are criticized
      in detail at:

      "Scientific Abuse in Aspartame Research"
      http://www.holisticmed.com/aspartame/abuse/methanol.html
      Aspartame Toxicity Information Center Mark D. Gold
      www.HolisticMed.com/aspartame 603-225-2100
      mgold@... 12 East Side Drive #2-18 Concord, NH 03301
      ***********************************************************

      pages S36 to S41 of S1 to S93

      Safety of Methanol from Aspartame and the Diet

      [Thomas R. Tephly (Methanol) thomas-tephly@...
      Department of Pharmacology, The University of Iowa, Iowa City, Iowa

      Kenneth E. McMartin (Methanol) kmcmar@...
      Department of Pharmacology and Therapeutics, Louisiana State University]

      page S39 [Extract]

      Evaluation of Recent Issues Regarding Methanol Safety from Aspartame

      Trocho et al. (1998) concluded from a study in rats
      that aspartame may be hazardous because formaldehyde
      adducts from aspartame may accumulate in
      tissue proteins and nucleic acids. However, according
      to Tephly (1999), the dose of aspartame used in the
      study (20 mg/kg body wt =2 mg of methanol/kg body wt)
      would not yield blood methanol concentrations outside
      control values. Further, the administration of aspartame
      at 200 mg/kg body wt (equal to that in a single bolus
      of about 25 liters of beverage sweetened 100% with
      aspartame) to adult humans results in no detectable
      increase in blood formate concentrations (Stegink
      et al., 1981). Administration of [14 C] methanol itself at
      3000 mg/kg body wt to monkeys produces no detectable
      [14 C] formaldehyde in body fluids and tissues (McMartin
      et al., 1979), while there is ample accumulation of formate.
      An alternative explanation for tissue incorporation
      of label from [14 C] aspartame as described by Trocho
      et al. (1998) would be incorporation into amino acids
      and nucleotides via one-carbon moieties from the folate-dependent
      metabolism of formate. The lack of formaldehyde
      accumulation at very high doses of methanol
      question considerably the conclusion that formaldehyde
      adducts are forming from low doses of methanol (derived
      from high doses aspartame). Thus, Tephly (1999)
      concluded, “the normal flux of one-carbon moieties
      whether derived from pectin, aspartame, or fruit juices
      is a physiologic phenomenon and not a toxic event.”

      page S1 0273-2300/02 $35.00
      C 2002 Elsevier Science (USA) All rights reserved.

      Regulatory Toxicology and Pharmacology 35, S1–S93 (2002)
      doi:10.1006/rtph.2002.1542, available online at
      http://www.idealibrary.com $ 35.00
      Aspartame: Review of Safety
      Harriett H. Butchko 1
      Medical and Scientific Affairs, The NutraSweet Company,
      Mt. Prospect, Illinois
      W. Wayne Stargel
      Research and Development, The NutraSweet Company,
      Mt. Prospect, Illinois

      C. Phil Comer
      Graystone Associates, Inc., Macon, Georgia
      Dale A. Mayhew
      Regulatory Affairs, The NutraSweet Company, Mt. Prospect, Illinois
      Christian Benninger (EEGs and Cognitive Function in PKU Heterozygotes)
      Department of Pediatrics, University of Heidelberg, Heidelberg, Germany
      George L. Blackburn (Appetite, Food Intake, and Weight Control)
      Department of Surgery, Beth Israel Deaconess Medical Center, Harvard
      Medical School, Boston, Massachusetts
      Leo M. J. de Sonneville (Neuropsychological Function and Phenylalanine)
      Departments of Pediatrics and Neurology, Vrije Universiteit, Medical
      Center, Amsterdam, The Netherlands
      Raif S. Geha (Allergy)
      Division of Immunology, The Children’s Hospital, Harvard Medical School,

      Boston, Massachusetts
      Zsolt Hertelendy (Liver Disease)
      Division of Pharmaceutical Sciences, College of Pharmacy, University of
      Cincinnati, Cincinnati, Ohio
      Adalbert Koestner (Brain Tumors)
      Department of Veterinary Biosciences, Ohio State University School of
      Veterinary Medicine, Columbus, Ohio
      Arthur S. Leon (Long-Term Safety in Humans)
      Division of Kinesiology, College of Education and Human Development and
      Department of Medicine, The Medical School,
      University of Minnesota, Minneapolis, Minnesota
      George U. Liepa (Renal Disease)
      Department of Human, Environmental, and Consumer Resources, Eastern
      Michigan University, Ypsilanti, Michigan
      Kenneth E. McMartin (Methanol)
      Department of Pharmacology and Therapeutics, Louisiana State University
      Medical Center, Shreveport, Louisiana
      Charles L. Mendenhall (Liver Disease)
      Digestive Diseases Section, Department of Veterans Affairs Medical
      Center, Cincinnati, Ohio
      1 To whom correspondence should be addressed at Medical and Scientific
      Affairs, The NutraSweet Company, 699 Wheeling Road, Mt.
      Prospect, IL 60056. Fax: (847) 463-1755. E-mail:
      harriett.h.butchko@....

      page S2 BUTCHKO ET AL.

      Ian C. Munro (Preface)
      Cantox Health Sciences, Inc., Mississauga, Ontario, Canada
      Edward J. Novotny (Seizures and EEGs)
      Department of Pediatrics and Neurology, Yale University School of
      Medicine, New Haven, Connecticut
      Andrew G. Renwick (Preface)
      Department of Pharmacology, University of Southampton, Southampton,
      United Kingdom
      Susan S. Schiffman (Headaches)
      Department of Psychiatry, Duke University Medical Center, Durham, North
      Carolina
      Donald L. Schomer (Neurochemistry, Seizures and EEGs, Behavior,
      Cognitive Function, and Mood)
      Department of Neurology, Division of Neurophysiology and Epilepsy, Beth
      Israel Deaconess Medical Center,
      Harvard Medical School, Boston, Massachusetts
      Bennett A. Shaywitz (Behavior, Cognitive Function, Mood in Children,
      Seizures, and EEGs)
      Departments of Pediatrics, Neurology, and Child Study, Yale University
      School of Medicine, New Haven, Connecticut
      Paul A. Spiers (Behavior, Cognition, and Mood)
      Department of Psychiatry, Boston University School of Medicine, and
      Clinical Research Center,
      Massachusetts Institute of Technology, Boston, Massachusetts
      Thomas R. Tephly (Methanol)
      Department of Pharmacology, The University of Iowa, Iowa City, Iowa
      John A. Thomas (Metabolism and Endocrine)
      Department of Pharmacology, The University of Texas Health Science
      Center at San Antonio, San Antonio, Texas
      Friedrich K. Trefz (Phenylketonuria)
      Department of Pediatrics, Children’s Hospital of Reutlingen, University
      of Tubingen, Reutlingen, Germany
      Received January 8, 2002

      DEDICATION
      The authors dedicate this supplement to the memories of Lewis D.
      Stegink, Ph.D., and L. J. Filer, Jr., M.D.,
      Ph.D., from the University of Iowa. Their early research on aspartame
      metabolism in humans formed the basis for
      much of the future research on aspartame that is discussed in this
      supplement. Their objectivity and long-standing
      dedication to science as well as their medical and scientific expertise
      are greatly missed.
      ***********************************************************

      Rich Murray, MA Room For All rmforall@...
      1943 Otowi Road, Santa Fe NM 87505 USA 505-986-9103

      http://groups.yahoo.com/group/aspartameNM/messages
      for 864 posts in a public searchable archive

      http://groups.yahoo.com/group/aspartameNM/message/861 brief review

      http://groups.yahoo.com/group/aspartameNM/message/862 long review

      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/830
      RTM: Tholen: Diet Coke has 5 ppm formaldehyde from aspartame
      5.29.2 rmforall [~200 mg aspartame in 12-oz diet soda]
      For 6 cans of diet soda, this is 5 times the daily limit of 1 PPM for
      formaldehyde in drinking water, set by the EPA.
      http://www.geocities.com/aspartame_survivors/tholen.html
      For a science project, Randy Tholen, age 11, paid $ 180 to have
      six cans of Diet Coke analyzed on Mar 7 2002 by Bill Katz 952-942-1774
      at Braun Intertec Corporation Lab
      Braun Intertec Corporation http://www.brauncorp.com/
      (800) 279-6100 (952) 941-5600 fax (952) 833-4701
      Mail: 6875 Washington Ave. S. Minneapolis, MN 55439
      E-Mail: Webmaster@...

      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@...
      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@... 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/846
      RTM: aspartame in Merck Maxalt-MLT worsens migraine,
      AstraZeneca Zomig, Eli Lilly Zyprexa,
      J&J Merck Pepcid AC (Famotidine 10mg) Chewable Tab,
      Pfizer Cool Mint Listerine Pocketpaks 7.16.2 rmforall
      Migraine MLT-Down: an unusual presentation of migraine
      in patients with aspartame-triggered headaches.
      Newman LC, Lipton RB Headache 2001 Oct; 41(9): 899-901.
      [Merck 10-mg Maxalt-MLT, for migraine, has 3.75 mg aspartame,
      while 12 oz diet soda has 200 mg.]
      Headache Institute, St. Lukes-Roosevelt Hospital Center, New York, NY
      Department of Neurology newmanache@...
      Albert Einstein College of Medicine, Bronx, NY
      Innovative Medical Research RLipton@...

      Mark D. Gold has a fine, detailed analysis, "Scientific Abuse in
      Methanol / Formaldehyde Research Related to Aspartame" at:
      http://www.holisticmed.com/aspartame/abuse/methanol.html#discussion
      http://www.HolisticMed.com/aspartame 603-225-2100
      Aspartame Toxicity Information Center Mark D. Gold
      mgold@... 12 East Side Drive #2-18 Concord, NH 03301
      http://www.holisticmed.com/aspartame/abuse/methanol.html
      "Scientific Abuse in Aspartame Research"

      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/863
      Murray: Wilson: CIIN: EPA: Gold: Thrasher & Kilburn: Shaham:
      formaldehyde toxicity 8.22.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/645
      Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts
      6.25.1 rmforall

      http://google.com gives 105,000 websites for "aspartame" , while
      http://groups.google.com/ finds on 700 MB of posts from 20-years of
      Usenet groups, 72,300 posts, and
      http://www.AllTheWeb.com gives 177,012, the top four being leading and
      very well informed volunteer anti-aspartame sites.
      http://www.ncbi.nlm.nih.gov/PubMed/ lists 714 aspartame items.
      ***********************************************************
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