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eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV Belsito, Nov 2003: Murray 3.30.4 rmforall

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  • Rich Murray
    ************************************************************ http://groups.yahoo.com/group/aspartameNM/message/1067 eyelid contact dermatitis by formaldehyde
    Message 1 of 1 , Mar 30, 2004
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      eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV
      Belsito, Nov 2003: Murray 3.30.4 rmforall [ 150 KB ]

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

      [ Comments by Rich Murray are in square brackets. To increase the
      readability of the dense, specialized, condensed text of a brief scientific
      letter (usually not peer reviewed), I have added spacing without altering
      text, while correcting minor typos.

      I then offer some critical analyses and extensions of the references, since
      the relevant scientific literature is contaminated by long-term, systematic
      influence by corporate vested interests. ]

      "A 60-year-old Caucasian woman presented with a 6-month history of eyelid

      By strictly avoiding formaldehyde and all formaldehyde releasers for the
      next 3 weeks, she improved only slightly.

      Her problem, however, was subsequently solved when a local pharmacist
      advised her to avoid aspartame.

      She had begun using an aspartame-based artificial sweetener 5 months prior
      to the onset of her dermatitis. [ 12 months of low-level aspartame use until
      stopping. ]

      Within 1 week of discontinuing the aspartame, her eyelid dermatitis resolved
      completely and has not recurred over 18 months without specific

      Our patient was consuming an average of 80 mg (1.13 mg/kg) of aspartame
      daily, well below the levels previously studied."

      [ A packet of tabletop sweetener gives 37 mg aspartame, while a 12 oz diet
      soda gives 200 mg aspartame. An aspartame reactor can have immediate strong
      symtoms from an under-the-tongue wafer with 4 mg aspartame. (Appendix A,
      for comments, abstracts, and links.) ]

      Contact Dermatitis. 2003 Nov; 49(5): 258-9.
      Systemic contact dermatitis of the eyelids caused by formaldehyde derived
      from aspartame?
      Hill AM, Belsito DV. DBelsito@...
      Division of Dermatology, University of Kansas Medical Center, 3901 Rainbow
      Blvd., Kansas City, KS 66160, USA. PMID: 14996049

      A. Michele Hill and Donald V. Belsito
      Division of Dermatology, University of Kansas Medical Center
      3901 Rainbow Blvd., Kansas City, KS 66160, USA [ (Appendix B, for more
      abstracts by Donald V. Belsito, selections, and institutions) ]

      Key Words: allergic contact dermatitis; aspartame; eyelids; formaldehyde;
      systemic contact dermatitis.

      Formaldehyde is a common and ubiquitous contact allergen.
      Sources of exposure include hair and skin care products, cosmetics, topical
      medications, permanent press clothing, cleaning agents, disinfectants, paper
      and even smoke. [ Also, new buildings, mobile homes, furniture, carpets,
      drapes, particleboard, medical facilities, methanol, aspartame, dimethyl
      dicarbonate, dark wines and liquors ]

      Sensitization is reported in between 2.2 and 9.6% of patients patch tested
      [ (Appendix C, for abstracts on rates of formaldehyde sensitivity in control
      groups, as a possible first estimate of the impact of widespread exposure to
      aspartame since 1981.) ]

      Case Report

      A 60-year-old Caucasian woman presented with a 6-month history of eyelid
      A corticosteroid-containing opthalmologic ointment improved but did not
      clear the rash.
      She failed to improve when she discontinued the use of all eyelid cosmetics
      and nail polishes for 2 months.
      She had had a facial dermatitis in 1995, for which she had been patch tested
      and found to be allergic to formaldehyde, quaternium-15 and fragrances.
      She had also had incidental, non-relevant reactions to neomycin and
      Her dermatitis had resolved with a change to formaldehyde-, quaternium-15
      and fragrance-free facial and nail cosmetics.

      There was no personal or family history of atopy or psoriasis.
      Her only oral medication was celecoxib that she had taken for years prior to
      the onset of her blepharitis.
      She had also taken multivitamins, calcium and flaxseed oil for many years.
      She worked as a homemaker and library volunteer. [ It is relevant as to
      whether she had the standard urban diet with high protein and animal fats,
      meats, milk products, some inorganic fruits and vegetables, high sugars,
      and processed foods. Mercury dental amalgams and mercury contaminated fish
      could also play a role. Was her water fluoridated or otherwise
      contaminated? Were there toxic mold exposures in her environment? Was she
      exposed to pesticides in her area? ]

      Her eyelid dermatitis was kept clear with tacrolimus 0.03% ointment X2
      She underwent patch testing to the North American Contact Dermatitis Group
      standard tray, the University of Kansas' supplemental standard tray, and to
      her cosmetics, cleansers, skin and hair care products and topical
      She had relevant positive reactions at days 2 and 4 to formaldehyde (++),
      quaternium-15 (++), diazolidinyl urea (+), DMDM hydantoin (+) and
      imidazolidinyl urea (++), her hair care products and cleansers containing
      multiple sources of these allergens.

      She was extensively instructed in avoidance of formaldehyde and formaldehyde
      releasers, as well as that of her multiple, currently non-relevant
      allergens, including fragrance, benzalkonium chloride, neomycin, bacitracin,
      p-phenylenediamine and black rubber mix. [ As a medical layman, I'm
      disturbed to see all these chemicals that I know nothing about. ]

      By strictly avoiding formaldehyde and all formaldehyde releasers for the
      next 3 weeks, she improved only slightly.

      Her problem, however, was subsequently solved when a local pharmacist
      advised her to avoid aspartame.

      She had begun using an aspartame-based artificial sweetener 5 months prior
      to the onset of her dermatitis. [ 12 months of low-level aspartame use until
      stopping. Aspartame reactors discover this possibiliy usually from the Net,
      alternative medicine providers, media, nurses, friends, and pharmacists,
      rarely from physicians. ]

      Within 1 week of discontinuing the aspartame, her eyelid dermatitis resolved
      completely and has not recurred over 18 months without specific treatment.
      [ This quick healing response is typical of cases of low-level use with few
      symptoms. Long-term heavy users , above 2 L, about 6 12-oz cans daily for
      years, often have severe craving and withdrawal symptoms for weeks, with
      gradual recovery for months. H. J. Roberts, MD has summarized over 1200
      cases. (Appendix H) Three recent case reports are added here.
      (Appendix I) ]

      Unfortunately, she refused to undergo rechallenge with the sweetener.
      [ This is usually the case. Commonly, there is inadvertent reexposure,
      with immediate painful symptoms, even with low doses. ]


      The artificical sweetener, aspartame, is consumed by 54% of adults in the
      USA (3).

      It has been reported to cause dry eyes and difficulty in wearing contact
      lenses (3) but never allergic contact dermatitis. [ Reference (3) is given
      in full here. (Appendix H) Roberts H J. Dry eyes from use of aspartame
      (Nutrasweet): Associated insights concerning the Sjogren syndrome.
      The Townsend Letter for Doctors, January 1994. Appendix H also quotes
      several cases of eyelid dermatitis from his review of 1200 cases in
      Aspartame Disease: An Ignored Epidemic (2001). ]

      Aspartame, an L-aspartyl-L-phynylalanine methyl ester, is hydrolysed in the
      intestine to phenylalanine (50%), aspartic acid (40%) and aspartaic acid
      methyl ester (10%).

      The methyl ester is then converted to methyl alcohol (methanol) and carried
      by the portal vein to the liver.

      Methanol is there oxidized to formaldehyde that is converted into formic
      acid (formate) by alcohol dehydrogenase, aldehyde dehydrogenase and the
      microsomal oxidase pathway.

      This occurs not only in the liver, but also in other organs containing high
      levels of these enzymes, including the eye (4,5).

      Formaldehyde binds proteins and nucleic acids, forming adducts difficult to
      eliminate via metabolism.

      Trocho et al. (6) demonstrated the formation of formaldehyde adducts with
      DNA and proteins after administration of 20 mg/kg 14C-labelled aspartame to
      rats, concluding that these adducts were responsible for functional
      alterations of proteins and for DNA mutations leading to autoimmunity, cell
      death or malignant transformation. [ (Appendix E) gives links, comments,
      and quotes for the debate on the key Trocho study. ]

      In contrast to Trocho et al. (6), McMartin et al. (7) studied formaldehyde
      levels after large doses (3,000 mg/kg) of 14C-labelled methanol and
      14C-labelled formaldehyde in monkeys, which unlike rats are sensitive to the
      toxicities of methanol.

      No increased formaldehyde derived from methanol was found.

      High levels of formic acid were found in all monkeys that were given
      methanol or formaldehyde.

      [ (Appendix F) reviews the major studies. Oppermann et al (1973, 1976)
      found that 30% of the methanol from aspartame fed to monkeys remained in
      body tissues, indubitably as toxic products of formaldehyde and formic acid.
      They did not test methanol product retention in humans. McMartin et al
      (1979) reported significant formaldehyde retention in the midbrain of one
      monkey from oral aspartame, and substantial formic acid in liver, kidney,
      optic nerve, cerebrum, and midbrain in two other monkeys. It is clear that
      his formaldehyde assays were too insensitive to give valid measurements.
      There has been a dearth of relevant primate and human studies ever since. ]

      Based on the work of McMartin and al. (7), Tephly (8) concluded that the
      radioactive carbon from methanol, which was found in DNA and protein by
      Trocho et al., was due to the normal physiologic flow of single-carbon units
      through the folate pathway.

      Stegink et al. (9) have shown that doses of 100 mg/kg or greater of
      aspartame are required to increase methanol blood levels (and thus,
      presumable formaldehyde formic acid levels) above control.

      This would be equivalent to consuming 35 cans of diet beverage at one
      sitting for a 70 kg person. [ This is a typical aspartame industry PR ploy,
      well designed to plant the impression that only absurdly huge amounts of
      diet soda might supply damaging amounts of methanol-derived formaldehyde and
      formic acid toxic residuals in body tissues, thus reducing methanol blood
      levels. So, it is a classic red herring tactic to focus on methanol blood

      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 are partially eliminated as 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. [Metabolism of aspartame in monkeys.
      Oppermann JA, Muldoon E, Ranney RE.
      J. Nutrition 1973 Oct; 103(10): 1454-1459.]
      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 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
      (Appendixes D, E, F, G, H, I, J) ]

      Leon et al. (10) studied doses of 75 mg/kg of aspartame daily for 24 weeks
      and found no change in blood or urine methanol levels and no symptoms of
      methanol toxicity.

      The dose used in Leon's study is 25 times the 90th percentile daily
      consumption of aspartame (11). [ Appendix E gives an abstract by Davoli
      (1986), using a properly sensitive assay, that proved a temporary rise in
      blood methanol levels in humans from a single aspartame dose. Trocho
      pointed out that formaldehyde adducts are persistent and thus cumulative. It
      is reasonable to state that with long-term chronic formaldehyde exposure, it
      may take a long time to both accumulate adducts and develop markedly
      increased sensitivity and a series of complex symptoms . Adequate studies
      would have to test substantial exposures over a year or longer with large
      numbers of vulnerable types of people and record all symptoms. ]

      Our patient was consuming an average of 80 mg (1.13 mg/kg) of aspartame
      daily, well below the levels previously studied.
      [ A packet of tabletop sweetener gives 37 mg aspartame, while a 12 oz diet
      soda gives 200 mg aspartame. An aspartame reactor can have immediate strong
      symtoms from an under-the-tongue wafer with 4 mg aspartame. (Appendix A,
      for comments, abstracts, and links.) ]

      However, it is possible that the eye, with its high level of metabolic
      activity, could be affected by methanol (and subsequently formaldehyde)
      released from these low levels of aspartame and respond as a localized
      target organ to minute amounts of her known allergen, formaldehyde, or its
      metabolite, formate.

      It is also possible that the amplifying effects of cell-mediated immunity
      might detect trace amounts of a chemical not identified by more standard
      assays, such as blood or urine levels. [ (Appendix D gives Thrasher's data
      about immune system reactions from long-term, low-level formaldehyde
      exposure, while Martin Pall gives a complex general theory, specifically
      discussing formaldehyde as a major trigger.)

      http://www.drthrasher.org/formaldehyde_1990.html full text Jack Dwayne
      Thrasher, Alan Broughton, Roberta Madison. Immune activation and
      autoantibodies in humans with long-term inhalation exposure to formaldehyde.
      Archives of Environmental Health. 1990; 45: 217-223. "Immune activation,
      autoantibodies, and anti-HCHO-HSA antibodies are associated with long-term
      formaldehyde inhalation." PMID: 2400243

      Confirming evidence and a general theory are given by Pall (2002):
      testable theory of MCS type diseases, vicious cycle of nitric oxide &
      peroxynitrite: MSG: formaldehyde-methanol-aspartame: Martin L. Pall: Murray:
      12.9.2 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. PMID: 12205032 [ 162 references, received 1.3.2 ]
      School of Molecular Biosciences, Washington State University,
      Pullman, Washington 99164-4660, USA. martin_pall@... ]

      Such a hypothesis might explain why her dermatitis was limited to the
      eyelids and give clinical support to Trocho's theory of formaldehyde

      Unfortunately, without rechallenging her with aspartame, we cannot test this

      Nonetheless, her long-lasting remission following discontinuation of
      aspartame intake suggests that its breakdown to formaldehyde may have been a
      possible mechanism for her prior blepharitis.


      1. Christophersen J, Menne' T, Tanghoj P, Andersen K E, Brandrup F.
      Clinical patch test data evaluated by multivariate analysis.
      Contact Dermatitis 1989: 21: 291-299.

      2. Fransway AF, Schmitz N A.
      The problem of preservation in the 1990s.
      II. Formaldehyde and formaldehyde-releasing biocides: incidences of
      cross-reactivity and the significance of the positive response to
      Am J Contact Dermat. 1991: 2: 78-88.

      3. Roberts H J. Dry eyes from use of aspatame (Nutrasweet):
      Associated insights concerning the Sjogren syndrome.
      The Townsend Letter for Doctors, January 1994. [ full text in Appendix H ]

      4. Murray T G, Burton T C, Rajani C, Lewandowski M F,
      Burke J M, Eells J T.
      Methanol poisoning: A rodent model with structural and functional evidence
      for reinal involvement.
      Arch Opthalmol 1991: 109: 1012-1016.

      5. Eells J T.
      Methanol-induced visual toxicity in the rat.
      J. Pharmacol Exp Ther 1991: 257: 56-63.

      6. Trocho C., Pardo R, Fafecas I, Virgili J, Remesar X,
      Fernandez-Lopez, J A.
      Formaldehyde derived from dietary aspartame binds to tissue components in
      Life Sci 1998 1988: 63: 337-349. [ abstract and quotes in Appendix E )

      7. McMartin K E, Mrtin-Amat G, Noker P E, Tephly T R.
      Lack of a role for formaldehyde in methanol poisoning in the monkey.
      Biochem Pharmacol 1979: 28: 645-649. [ abstract, quotes, discussion, related
      studies in Appendix F ]

      8. Tephly T R: Comments on the purported generation of formaldehyde from
      the sweetener aspartame.
      Life Sci 1999: 65: 157-160. [ letter, usually not peer-reviewed,
      abstract in Appendix E ]

      9. Stegink L D, Brummel M C, McMartin-Amat G., Filer L J, Baker G L,
      Tephly T R.
      Blood methanol concentrations in normal adult subjects administered abuse
      doses of aspatame.
      J Toxicol Environ Health 1981: 7: 281-290.

      10. Leon A S, Hunninghake D B, Bell C, Rassin D K, Tephly T R.
      Safety of long-term large doses of aspartame.
      Arch Intern Med 1989: 149: 2318-2324.

      11. Tschanz C., Butachko H, Stargel W, Kotsonis F N (eds).
      The Clinical Evaluation of a Food Additive: Assessment of Aspartame
      Boca Raton: CRC Press, 1996.

      Appendix A:

      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: Murray 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@...

      RTM: Blumenthall & Vance:
      aspartame chewing gum headaches Nov 1997 7.28.2 rmforall

      Harvey J. Blumenthal, MD, Dwight A Vance, RPh
      Chewing Gum Headaches. Headache 1997 Nov-Dec; 37(10): 665-6.
      Department of Neurology, University of Oklahoma College of Medicine,
      Tulsa, USA. neurotulsa@...
      Aspartame, a popular dietetic sweetener, may provoke headache in some
      susceptible individuals. Herein, we describe three cases of young women
      with migraine who reported their headaches could be provoked by chewing
      gum sweetened with aspartame. [ 6-8 mg aspartame per stick chewing gum ]

      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
      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
      All have had recurrence of symptoms whenever MSG is ingested.
      PMID: 11408989

      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

      Several recent pro-aspartame reviews simply ignore these reports by eminent
      mainstream researchers, as well as the tidal surge of complaints by users.

      safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
      Murray 1.12.3 rmforall EU Scientific Committee on Food, a whitewash

      Mark Gold exhaustively critiques European Commission Scientific
      Committee on Food re aspartame (12.4.2): 59 pages, 230 references

      J Am Diet Assoc. 2004 Feb; 104(2): 255-75.
      Position of the American Dietetic Association: use of nutritive and
      nonnutritive sweeteners.
      American Dietetic Association. PMID: 14760578

      critique of aspartame review by American Dietetic Association Feb 2004:
      Murray 4.1.4 rmforall

      "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@...

      http://groups.yahoo.com/group/aspartame/messages 770 members 16,692 posts ]

      Appendix B:

      D. V. Belsito has 71 items in PubMed since 1982.

      Donald (Don) V. Belsito, MD Professor, Division Director Dermatology
      +1 913 588-3840 fax +1 913 588-4060 DBelsito@...
      Main Phone Number: (913) 588-6028 Fax Number: (913) 588-8300
      Mailing Address: 4008 Wescoe Pavilion Mail Stop 2025
      3901 Rainbow Boulevard, Kansas City, KS 66160-7319 USA

      The University of Kansas Medical Center
      3901 Rainbow Boulevard, Kansas City, KS 66160
      913-588-5000, 913-588-7963 TDD KU Medical Center is a
      campus of the University of Kansas and is affiliated with The University of
      Kansas Hospital. The School of Medicine has a campus in Wichita.

      University of Kansas Medical Center Research Institute
      3901 Rainbow Boulevard, Kansas City, KS 66160-7702 USA
      Phone: 913-588-1242 Fax: 913-588-5729 lkemble@...

      The University of Kansas Medical Center comprises the School of Medicine,
      School of Allied Health, School of Nursing, and an independently run
      hospital with 415 staffed beds. KUMC is a regional health center treating
      approximately 35,000 emergency room patients, 17,000 inpatients, and more
      than 180,000 outpatients per year. KUMC is a 35 building, 50 acre campus
      with a staff of nearly 5,000 employees.

      The University of Kansas Medical Center Research Institute is a private,
      non-profit corporation established to promote and support medical research.
      The Division of Clinical Trials at the Research Institute serves as the
      central liaison between the pharmaceutical industry, faculty investigators
      at KUMC, and the Institutional Review Board. The Division of Clinical Trials
      also assists the sponsor with identifying suitable clinical investigators.

      Dermatologic Manifestations of Neurologic Disease
      Authored by Theresa Conologue, DO, Staff Physician, Department of
      Dermatology, National Capital Consortium/Walter Reed Army Medical Center
      Coauthored by Jeffrey Meffert, MD, Program Director, Dermatology Service,
      San Antonio Uniformed Services Health Education Consortium.
      Theresa Conologue, DO, is a member of the following medical societies:
      Association of Military Surgeons of the US
      Edited by Donald Belsito, MD, Program Director, Professor, Department of
      Internal Medicine, Division of Dermatology, University of Kansas; Richard
      Vinson, MD, Chief, Department of Dermatology, William Beaumont Medical
      Center; Jeffrey P Callen, MD, Chief, Professor, Department of Internal
      Medicine, Division of Dermatology, University of Louisville School of
      Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of
      Dermatology, Brown University; and Dirk M Elston, MD, Consulting Staff,
      Department of Dermatology, Geisinger Medical Center
      Author's Email: Theresa Conologue, DO Editor's Email: Donald Belsito, MD
      eMedicine Journal, March 19 2003, Volume 4, Number 3
      INTRODUCTION Section 2 of 12

      Many disorders have a combination of neurologic and dermatologic findings in
      patients. This chapter provides an overview of neurocutaneous disorders and
      organizes them into clinically relevant groupings of use to the practicing

      Center for Drug Evaluation
      Dermatologic and Opthalmic Drugs Advisory Commitee
      Thursday, November 4, 1999
      Ballroom, Hilton Hotel, 620 Perry Parkway, Taithersburg Maryland
      Guest Speaker: Donald Belsito, M.M.
      6516 Aberdeen Road, Mission Hills, KS 66208

      Dr. Donald Belsito, professor of Dermatology at the University of Kansas in
      Lawrence and a member of the North American Contact Dermatitis Group, notes,
      "Nickel allergies are on the increase - from 10.5 % cited in studies done
      from 1985 to 1989 to 14.3 % in studies done in 1996. More men are showing up
      with nickel allergies; coincidentally more men are having their bodies
      pierced. This indicates a possible correlation between piercing and
      allergies to nickel." In addition to setting off allergic reactions, Dr.
      Belsito, notes, "Piercing cartilage around the top of the ear poses greater
      risks than piercing the lobe. Cartilage is an inert material with very
      little blood supply and takes a long time to heal from the puncture. Also,
      when cartilage becomes infected, it is difficult to treat because of its low
      blood supply.

      "Also, the growth of overwhelming scars known as keloids can occur and the
      condition is particularly prevalent among African Americans," says Dr.
      Belsito, adding, "Keloids can grow to be as big as the ear itself. The cure
      requires administering medication that reduces the tendency to develop
      scars. If scars do develop, they need to be removed by a plastic surgeon.
      The risk, of course, is that people who tend to scar, may not fare well in
      surgery which can promote new scar tissue." When it comes to protecting the
      consumer, Dr. Belsito adds, "I think hypoallergenic is a bad term since it
      only tells you that the product is manufactured without an ingredient to
      which most people are allergic. But it doesn't tell you other possible
      allergy provoking ingredients. For example, some rubber gloves labeled
      hypoallergenic are made without certain chemicals. However, these gloves
      could be made of latex which is lethal to some people."

      Drs. Bendetsen, Scheinman and Belsito favor legislation governing body
      piercing due to the risk of nickel allergies, loss of sensation and
      communicable diseases resulting from poor sterilization procedures. To date,
      Arizona, California, Georgia, Michigan and Washington have passed
      legislation requiring parental consent for body piercing if you are a minor.
      Several states including Delaware, Missouri, Texas and Hawaii have
      legislation pending.

      D. V. Belsito has 9 additional items that include formaledhyde in PubMed:

      2. Ravis SM, Shaffer MP, Shaffer CL, Dehkhaghani S, Belsito DV.
      Glutaraldehyde-induced and formaldehyde-induced allergic contact dermatitis
      among dental hygienists and assistants.
      J Am Dent Assoc. 2003 Aug; 134(8): 1072-8. PMID: 12956347

      3: Thompson TR, Belsito DV.
      Regional variation in prevalence and etiology of allergic contact
      Am J Contact Dermat. 2002 Dec; 13(4): 177-82. PMID: 12478532

      4: Rietschel RL, Mathias CG, Fowler JF Jr, Pratt M, Taylor JS, Sherertz EF,
      Marks JG Jr, Belsito DV, Storrs FJ, Maibach HI, Fransway AF, Deleo VA;
      North American Contact Dermatitis Group.
      Relationship of occupation to contact dermatitis: evaluation in patients
      tested from 1998 to 2000.
      Am J Contact Dermat. 2002 Dec; 13(4): 170-6. PMID: 12478531

      5: Deleo VA, Taylor SC, Belsito DV, Fowler JF Jr, Fransway AF, Maibach HI,
      Marks JG Jr, Mathias CG, Nethercott JR, Pratt MD, Reitschel RR, Sherertz EF,
      Storrs FJ, Taylor JS.
      The effect of race and ethnicity on patch test results.
      J Am Acad Dermatol. 2002 Feb; 46(2 Suppl Understanding): S107-12.
      PMID: 11807472

      6: Suneja T, Belsito DV.
      Comparative study of Finn Chambers and T.R.U.E. test methodologies in
      detecting the relevant allergens inducing contact dermatitis.
      J Am Acad Dermatol. 2001 Dec; 45(6): 836-9. PMID: 11712026

      7: Suneja T, Belsito DV.
      Thimerosal in the detection of clinically relevant allergic contact
      J Am Acad Dermatol. 2001 Jul; 45(1): 23-7. PMID: 11423830

      8: Shaffer MP, Belsito DV.
      Allergic contact dermatitis from glutaraldehyde in health-care workers.
      Contact Dermatitis. 2000 Sep; 43(3): 150-6. Review. PMID: 10985631

      9: Marks JG, Belsito DV, DeLeo VA, Fowler JF Jr, Fransway AF, Maibach HI,
      Mathias CG, Nethercott JR, Rietschel RL, Sherertz EF, Storrs FJ,
      Taylor JS.
      North American Contact Dermatitis Group patch test results for the
      detection of delayed-type hypersensitivity to topical allergens.
      J Am Acad Dermatol. 1998 Jun; 38(6 Pt 1): 911-8. PMID: 9631997

      10: Fowler JF Jr, Skinner SM, Belsito DV.
      Allergic contact dermatitis from formaldehyde resins in permanent press
      clothing: an underdiagnosed cause of generalized dermatitis.
      J Am Acad Dermatol. 1992 Dec; 27(6 Pt 1): 962-8. PMID: 1479102

      Appendix C:

      "Sensitization is reported in between 2.2 and 9.6% of patients patch tested

      Widespread use of aspartame since 1981 must cause some of the formaldehyde
      sensitization found in many studies of control groups, so I offer a relevant
      abstract, which is the only data I know of that starts to assess
      the prevalence of aspartame disease in otherwise healthy people:

      "One (2 percent) control subject had a reaction to glutaraldehyde, and one
      other (2 percent) had a reaction to formaldehyde." "51 nondental
      professionals "

      Aspartame use must sensitize some users. This study's control group hints
      that about 2% of a control group of 51 professionals showed a sensitivity to
      formaldehyde in a skin patch test. Are there any data for nonusers of

      J Am Dent Assoc. 2003 Aug; 134(8): 1072-8.
      Glutaraldehyde-induced and formaldehyde-induced allergic contact dermatitis
      among dental hygienists and assistants.
      Ravis SM, Shaffer MP, Shaffer CL, Dehkhaghani S, Belsito DV.
      University of Miami, USA.

      BACKGROUND: Research has found that among health care workers, dental
      personnel are especially likely to have reactions to glutaraldehyde and
      METHODS: The authors conducted patch test evaluations with a voluntary
      cohort of randomly recruited, healthy dental hygienists, or DHs,
      and dental assistants, or DAs, and nondental professionals
      to determine the incidence of glutaraldehyde-induced and
      formaldehyde-induced allergic contact dermatitis, or ACD;
      the potential for coreactivity between glutaraldehyde and formaldehyde; and
      the correlation between training methods in safe handling of sterilizing
      solutions and the sensitivity to glutaraldehyde and formaldehyde among DHs
      and DAs.
      RESULTS: The researchers enrolled 101 DHs and DAs and 51 nondental
      professionals in the study.
      All except one DH/DA subject were female.
      The dental subjects' mean age was 34.3 +/- standard deviation of 10.7 years;
      the nondental subjects', 33.8 +/- 11.0 years.
      DHs and DAs had worked in their profession for a mean of 11.0 +/- 9.3 years.
      Among the dental professionals, 80 (79.2 percent) had had a known exposure
      to cold sterilizing solutions, while the remainder were unable to provide a
      known history of exposure.
      Eleven (10.9 percent) dental professionals had clear reactions to
      four (4.0 percent) were questionably allergic to glutaraldehyde, and
      two (2 percent) were definitively allergic to formaldehyde.
      One (2 percent) control subject had a reaction to glutaraldehyde, and
      one other (2 percent) had a reaction to formaldehyde.
      CONCLUSIONS AND CLINICAL: IMPLICATIONS: The authors found a statistically
      significant disparity in the rates of glutaraldehyde sensitivity among
      healthy DHs and DAs versus healthy control subjects (10.9 percent versus 2
      percent reactively; P = .02).
      They found no evidence of cross-reactivity between glutaraldehyde and
      formaldehyde. The preponderance of reactions among the DHs and DAs suggests
      that their present safety practices are largely ineffective in protecting
      against sensitization to glutaraldehyde in sterilizing solutions. PMID:

      Appendix D:

      formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
      Wilson: CIIN: 12.12.2 rmforall

      Thrasher (2001): "The major difference is that the Japanese demonstrated
      the incorporation of FA and its metabolites into the placenta and fetus.
      The quantity of radioactivity remaining in maternal and fetal tissues
      at 48 hours was 26.9% of the administered dose." [Ref. 14-16]

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

      Environ Health Perspect. 2003 Sep; 111(12): 1461-4.
      Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity:
      central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.
      Pall ML.
      School of Molecular Biosciences, 301 Abelson Hall, Washington State
      University, Pullman, WA 99164, USA. martin_pall@...

      The elevated nitric oxide/peroxynitrite and the neural sensitization
      theories of multiple chemical sensitivity (MCS) are extended here to propose
      a central mechanism for the exquisite sensitivity to organic solvents
      apparently induced by previous chemical exposure in MCS.
      This mechanism is centered on the activation of N-methyl-D-aspartate (NMDA)
      receptors by organic solvents producing elevated nitric oxide and
      peroxynitrite, leading in turn to increased stimulating of and
      hypersensitivity of NMDA receptors.
      In this way, organic solvent exposure may produce progressive sensitivity to
      organic solvents.
      Pesticides such as organophosphates and carbamates may act via muscarinic
      stimulation to produce a similar biochemical and sensitivity response.
      Accessory mechanisms of sensitivity may involve both increased blood-brain
      barrier permeability, induced by peroxynitrite, and cytochrome P450
      inhibition by nitric oxide. The NMDA hyperactivity/hypersensitivity and
      excessive nitric oxide/peroxynitrite view of MCS provides answers to many of
      the most puzzling aspects of MCS while building on previous studies and
      views of this condition. PMID: 12948884

      http://www.drthrasher.org/formaldehyde_1990.html full text Jack Dwayne
      Thrasher, Alan Broughton, Roberta Madison. Immune activation and
      autoantibodies in humans with long-term inhalation exposure to formaldehyde.
      Archives of Environmental Health. 1990; 45: 217-223. "Immune activation,
      autoantibodies, and anti-HCHO-HSA antibodies are associated with long-term
      formaldehyde inhalation." PMID: 2400243

      "Inhalation exposure to formaldehyde (HCHO)
      is associated with symptoms of irritation to mucous membranes, (1,2)
      chronic health problems (e.g., asthma, (2) nasopharyngeal cancer, (3)
      and multiple subjective health complaints. (4,5) )
      Recent observations have shown that both humoral-and cell-mediated
      immunologic mechanisms occur in humans with long-term HCHO exposure.
      Antibodies of all isotypes to HCHO conjugated human serum albumin (HCHO-HSA)
      are demonstrable in HCHO anaphylaxis, (6) hemodialysis patients, (7) mobile
      home residents, (4) persons with occupational exposures, (5,8) office
      workers, (9) and in persons in other environments. (4)
      In addition, changes in cell-mediated immunity include increases in
      eosinophils, basophils, and T-suppressor cells following acute exposure of
      patients with HCHO asthma. (10)
      Moreover, individuals with multiple subjective health complaints associated
      with long-term HCHO inhalation have evidence of immune activation and the
      presence of autoantibodies. (4,5)

      The patients in our study had symptoms and complaints related to several
      organs, as described previously, (4,5,9) which were similar to symptoms of
      workers with multiple chemical sensitivity,(11) cacosmia,(12) and other
      chemical exposures. (13-15) We report on the differences in humoral and
      cell-mediated immunity in humans with long-term inhalation exposure to HCHO
      vs. asymptomatic students (controls) who experienced short-term, periodic
      exposure to the chemical."
      [ http://lassesen.com/cfids/cacosmia.htm
      Cacosmia (a.k.a. Multiple Chemical Sensitivity) Details:
      * Chemical odour intolerance induced headache, itching eyes, irritated or
      congested nose, dry and/or sore throat, cough, dizziness, and itching or
      * Cacosmics reported increased prevalence of physician-diagnosed nasal
      allergies, breast cysts, hypothyroidism, sinusitis, food sensitivities,
      irritable bowel, and migraine headache. Resource: http://www.mcsrr.org ]

      "Symptoms. All patients in this study had sought continuous medical
      attention because of multiple organ symptoms involving the central nervous
      system (CNS) (headaches, memory loss, difficulty completing tasks,
      dizziness), upper- and lower-respiratory symptoms, skeletal-muscle
      complaints, and gastroenteritis. Three common symptoms
      were expressed:
      [1.] and initial flu-like illness from which they had not fully
      recovered; [2.] chronic fatigue; and [3.] an olfactory sensitivity to
      ambient conditions containing low concentrations of chemicals. (4,9,11)"

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

      "Five groups of subjects exposed to HCHO,
      who gave informed consent, were included in this study.
      [1.] Controls consisted of students of chiropractic medicine
      (16 males, 12 females), mean age = 29 +- 9 y) exposed to HCHO
      for 13 h/wk for 28 wk while studying human anatomy. Immunologic tests
      were performed 12 mo following the last classroom exposure.
      No measurements of HCHO concentrations were made.
      It is assumed that classroom ambient concentrations were at least
      0.43 ppm. (1) The students stated that during exposure they experienced
      eye, nose and throat irritation and that there was a pungent odor of
      HCHO. They did not have residual health complaints (symptoms), and
      they were asymptomatic at the time blood was taken.
      [2.] Mobile home residents consisted of 19 patients (6 males, 13 females),
      mean age 41+-20 y) who currently lived in mobile homes. The patients had
      lived in their environments for 2-7 y and reported multiple symptoms. (4,9)
      Measured HCHO concentrations ranged from 0.05 to 0.5 ppm at the time
      blood samples were taken.
      [3.] Office workers included 21 patients
      (5 males, 16 females, mean age of 40 +-10 y)
      who worked in new office buildings where there was inadequate ventilation
      (closed buildings). The patients had multiple health complaints. (9)
      It was determined from medical histories that their symptoms commenced
      with employment, waned when away from work (i.e., weekends, holidays,
      vacations) and became worse upon return to work.
      No HCO measurements were done; however, closed buildings have ambient
      concentrations ranging from 0.01 to 0.77 ppm. (1,16)
      [4.] This group included 21 patients (10 males, 11 females,
      mean age of 35 + -17 y) who had multiple symptoms and who had been
      removed from their original sources of HCHO exposure (mobile homes
      and/or particleboard subflooring) for at least 1 y. The HCHO
      concentrations measured during their exposures ranged from 0.14 to 0.81 ppm.
      [5.] Ocupationally exposed patients
      (6 males, 2 females, mean age of 45 + -11 y)
      had HCHO exposures from the following: biology and human
      anatomy classes, mortuary, pathology, physical therapy, formica
      furniture (particleboard), and carbonless copy paper. Information on
      six of these patients was previously published. (5)"

      "In conclusion, measurements of changes in WBCs, T cells, and H/S
      ratios in individuals with apparent chemical sensitivities appear to be
      inadequate immune parameters to examine. If one assumes that these
      individuals respond immunogically to environmental chemicals,
      investigations into autoimmunity and immune activation and
      perturbations in the interleukins, luekotreines, prostglandins, and
      other immunologic mediators appear to be fruitful areas for further
      research. (29-32) Thus, it appears that HCHO sensitivity is a real
      phenomenon and requires further research. (4,27-32 )"

      Appendix E:

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

      They used a very low level of aspartame ingestion, 10 mg/kg, for rats, which
      have a much greater tolerance for aspartame than humans. So, the
      corresponding level for humans would be about 1 or 2 mg/kg. (Many headache
      studies in humans used doses of about 30 mg/kg daily.)

      aspartame puts formaldehyde adducts into tissues, Part 1/2
      full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall

      http://ww.presidiotex.com/barcelona/index.html full text
      Formaldehyde derived from dietary aspartame binds to tissue components in
      Life Sci June 26 1998; 63(5): 337-49.
      Departament de Bioquimica i Biologia Molecular,
      Facultat de Biologia, Universitat de Barcelona, Spain.
      http://www.bq.ub.es/cindex.html 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 [male]
      Fac. Biologia Tel.: (93)4021521, FAX: (93)4021559
      Sra. Carme Trocho "Trok-ho" Fac. Biologia Tel.: (93)4021544,
      FAX: (93)4021559
      alemany@... bioq@... josefer@...
      rafecas@... remesar@...

      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
      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

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

      [ Extracts ]
      "The high label presence in plasma and liver is in agreement with the
      carriage of the label from the intestine to the liver via the portal vein.
      The high label levels in kidney and, to a minor extent, in brown adipose
      tissue and brain are 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."

      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 in (Appendix G). ]
      In the same report, Schiffman concludes on page S49, not citing any
      research after 1997, "Thus, the weight of the scientific evidence
      indicates that aspartame does not cause headache."
      Dr. Susan S. Schiffman, Dept. of Psychiatry, Duke University
      sss@... 919-684-3303, 660-5657

      RTP ties to industry criticized by CSPI: Murray: 12.9.2 rmforall

      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

      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

      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@...

      Life Sci 1999; 65(13): PL157-60. [ letter, usually 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"
      Aspartame Toxicity Information Center Mark D. Gold
      www.HolisticMed.com/aspartame 603-225-2100
      mgold@... 12 East Side Drive #2-18 Concord, NH 03301

      Gold points out that industry methanol assays were too insensitive to
      properly measure blood methanol levels.

      Davoli: aspartame causes rise in blood methanol 1986: Mario Negri
      Institute for Pharmacological Research: Murray 10.30.99 rmforall

      Davoli, E., Cappellini L, Airoldi L, Fanelli R, 1986.
      "Serum Methanol Concentrations in Rats and in Men
      After a Single Dose of Aspartame,"
      Food and Chemical Toxicology, Volume 24, No. 3, page 187-189.

      Serum methanol concentrations were measured in rats and in humans
      given oral aspartame.
      The dose given to rats was the FDA's projected 99th percentile daily intake
      for humans, assuming aspartame were to replace all sucrose sweeteners in the
      diet (34 mg/kg).
      Four male adult volunteers each received 500 mg, equivalent to 6-8.7 mg/kg,
      which is approximately the FDA's estimate of mean daily human consumption.
      Both treatments caused a rise in serum methanol.
      In rats the mean peak value was 3.1 mg/litre 1 hr after administration;
      serum methanol returned to endogenous values 4 hr after treatment.
      In the men, the mean rise over endogenous values was 1.06 mg/litre after 45
      Two hours after treatment, serum methanol had returned to basal levels.
      The temporary serum methanol increase showed peak values within the range of
      individual basal levels. PMID: 3957170, UI: 86166135
      Enrico Davoli has 22 citations in PubMed.

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

      Harriett H. Butchko 1
      Medical and Scientific Affairs, The NutraSweet Company,
      Mt. Prospect, Illinois
      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. harriett.h.butchko@....
      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
      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
      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

      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.

      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
      questions 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." (Next, Appendix F critiques the McMartin
      study.) ]

      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@...>

      Appendix F:

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

      Capable laymen play an essential role by summarizing and integrating
      scattered lines of inquiry that certain vested interests have long-term
      campaigns for obscuring, since outright opposition would tend to attract
      discussion and scrutiny that would soon vitiate billion dollar products.
      Most professionals simply do not have the free time to investigate such
      arcane, but possibly crucial, details. Capable laymen now join together on
      the Net to establish credibility by common sense, polite mobilization of
      specialized research, backed by support from informed specialists. For
      instance, I started investigating aspartame in early January 1999 and within
      two months was being given papers by Woodrow C. Monte and Ralph G.Walton.

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

      The fact that on the contrary, there is no industry funded research in
      humans at all in the public domain on the specific biochemical and tissue
      outcomes of formaldehyde and formic acid from aspartame leads to a
      reasonable surmise that the industry has reason to fear, obscure, and derail
      this inquiry. Following the crooked but unmistakable trail of missing
      research, i.e., avoided, ignored, misstated, discounted, obscured, explained
      away, or simply never mentioned, is an excellent strategy for uncovering the
      lurking secret.

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

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

      The tangle of black arrows includes two paths from Aspartame to Methanol to
      "CO2 + Body Constituents". Now, that's pretty good public relations spin,
      eh? "Body Constituents", indeed? This is systematic and persistent deceit,
      as pernicious as it is profitable. Aziz Karim, PhD is a "Distinguished
      Research Fellow and <br/><br/>(Message over 64 KB, truncated)
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