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aspartame induces lymphomas and leukaemias in rats, full plain text, M Soffritti, F Belpoggi, DD Esposti, L Lambertini: Ramazzini Foundation study 2005.07.14: main results agree with their previous methanol and formaldehyde studies: Murray 2005.08.19

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  • Rich Murray
    From: Rich Murray To: Cc: ; Graham A Colditz
    Message 1 of 1 , Aug 20, 2005
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      From: "Rich Murray" <rmforall@...>
      To: <kmichels@...>
      Cc: <Bernard.Rosner@...>; "Graham A Colditz" <graham.colditz@...>; <cameron.chumlea@...>; <WWillett@...>

      Subject: aspartame induces lymphomas and leukaemias in rats, full plain text, M Soffritti, F Belpoggi, DD Esposti, L Lambertini: Ramazzini Foundation study 2005.07.14: main results agree with their previous methanol and formaldehyde studies: Murray 2005.08.19
      Date: Friday, August 19, 2005 8:11 PM
       
      2005.08.19  Dear Karin B. Michels and colleagues,
       
      Methanol, which the human body always quickly and largely makes into formaldehyde and then formic acid, which as the 2001 M. Bouchard review makes clear, does lead to substantial retention of cumulative toxic products, is freely supplied as an 11% component of aspartame,  half the dose for diet soda as for dark wines and liquors, where the ~150 mg/liter methanol impurity is agreed by several experts to be the major cause of "morning after" hangover, due to the production of formaldehyde after the ethanol level has dropped enough for the methanol, which has a much longer half-life in the blood, to then be converted by an enzyme into formaldehyde.
       
      Thus, it is plausible that methanol and formaldehyde, substantially provided by various largely unexamined common sources, are unknown and uncontrolled co-factors in symptoms, research, diagnosis, and treatment.
       
      Children who consume French fries are more likely to be life long users of aspartame diet soda and other aspartame products.  It is plausible that they will on average be more sensitized to formaldehyde, acknowledged in 2004 by WHO to be a human carcinogen.
       
      It would probably be easy to run a quick check on diet sodas and cancer and many other diseases on the Nurses Health Study database.
       
      The Ramazzini results and other recent mainstream studies make it evident that this tragic toxicity issue is both urgent and sadly neglected.
       
      In mutual service,  Rich Murray
       
      Rich Murray, MA  Room For All  rmforall@...  505-501-2298
      1943 Otowi Road    Santa Fe, New Mexico 87505   USA
      http://groups.yahoo.com/group/aspartameNM/messages
      group with 146 members, 1,206 posts in a public, searchable archive
      ***************************************************************
       
      http://groups.yahoo.com/group/aspartameNM/message/1186
      aspartame induces lymphomas and leukaemias in rats, full plain text,
      M Soffritti, F Belpoggi, DD Esposti, L Lambertini: Ramazzini Foundation
      study 2005.07.14: main results agree with their previous methanol and
      formaldehyde studies: Murray 2005.08.19
       
      http://groups.yahoo.com/group/aspartameNM/message/1141
      Nurses Health Study can quickly reveal the extent of aspartame (methanol,
      formaldehyde, formic acid) toxicity: Murray 2004.11.21 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1143
      methanol (formaldehyde, formic acid) disposition: Bouchard M et al, full
      plain text, 2001: substantial sources are degradation of fruit pectins,
      liquors, aspartame, smoke: Murray 2005.04.02 rmforall  ]
       
       
      " In rodents and humans,
      APM is metabolised in the gastrointestinal tract
      into three constituents:
      aspartic acid, phenylalanine and methanol 3. "
       
      " These experiments demonstrate that the increase in
      lymphomas and leukaemias,
      observed in the APM study,
      could be related to methanol, a metabolite of APM,
      which is metabolised to formaldehyde and then to formic acid,
      both in humans and rats 3. "
       
      " Yellowing of the coat was observed in animals exposed to APM, mainly at
      the highest concentrations.
       
      This change was previously observed in our laboratory in rats exposed
      to formaldehyde administered with drinking water 9. "
       

      1. The total number of rats was 1800.  1500 were given aspartame.
       
      2. 44 [ 14.7 % ] of the 300 control rats, given no aspartame, developed
      lymphomas and leukemias (hemolymphoreticular neoplasias ), and none had
      malignant brain tumors.
       
      Of 1500 rats given aspartame, 294 [ 19.6 % ] had lymphomas and leukemias
      (hemolymphoreticular neoplasias), and 12 [ 0.8 % ]  had malignant brain
      tumors.
       
      In their previous methanol study, reported Dec 2002, of 200  + 100 = 300
      control rats, given no methanol, there  were 41+ 15  = 56 [ 18.7% ]
      lymphomas and leukemias (hemolymphoreticular neoplasias), while  of 600 +
      100 = 700 rats given methanol, there were 187 + 15 = 202 with the same
      cancers [ 28.9 % ].  They added 100 rats given 15 ppm methanol to their
      Table 3 summarizing the formaldehyde data in their formaldehyde study, in
      which their 200 control rats had 15 of these cancers.
       
      In their previous formaldehyde study, reported Dec 2002, 200 control rats,
      given no formaldehyde, had 15 [ 7.5 %]  lymphomas and leukemias
      (hemolymphoreticular neoplasias),  while of the 600 rats given formaldehyde,
      121 [ 20.3 % ] had these cancers.
       
      Probably, other factors, such as viruses, bacteria, molds, or toxic
      chemicals in the air, water, and food, also facilitate these cancers.
       
       
      News and events
      Istituto Ramazzini
      Collegium Ramazzini
      NEWS AND EVENTS   14 July 2005   Press Release
       
      Results of study on the carcinogenicity of the artificial sweetener
      aspartame
       
      CRC/ERF
       
      Results of study on the carcinogenicity of the artificial sweetener
      aspartame
       
      Summary.
       
      A long-term study to evaluate the potential carcinogenic effects of
      aspartame,
      an artificial sweetener used in more than 6,000 food and pharmaceutical
      products has recently been completed in the experimental laboratories of its
      Cancer Research Center of the European Foundation of Oncology and
      Environmental Sciences "B. Ramazzini" in Bologna, Italy.
       
      The first results of the experiment were reported to the Ministry of Health
      and to the Superior Institute of Health of the Italian government in April
      2005.
       
      In mid-June, these findings were then communicated to
      the European Food Safety Authority,
      the Herbert Irving Comprehensive Cancer Center of Columbia University,
      the National Cancer Institute of the US government,
      and the National Toxicology Program of the US National Institutes of Health.
       
      First results demonstrate that aspartame,
      when administered to rats for the entire life span,
      induces an increase of lymphomas and leukaemias in female rats.
       
      The study is currently being published in the European Journal of Oncology
      (available at:
      http://www.ramazzini.it/fondazione/docs/AspartameGEO2005.pdf ) and final
      results will be presented
      at the 3rd international scientific conference of the Collegium Ramazzini,
      "Framing the Future in Light of the Past: Living in a Chemical World",
      to be held in Bologna, Italy from September 18-21, 2005,
      the proceedings of which will be published in
      the Annals of the New York Academy of Sciences.
       
      Communication.
       
      Aspartame is an artificial sweetener consumed by hundreds of millions of
      people worldwide.
       
      It is used in over 6,000 diet products including soft drinks, chewing gum,
      candy, desserts, yogurt as well as in pharmaceuticals, in particular, syrups
      and antibiotics for children.
       
      The average daily intake of aspartame is calculated to be about 2-3 mg/Kg of
      body weight, a figure which increases for children and women of childbearing
      age.
       
      Current daily intake allowed by regulatory bodies is 50 mg/Kg of body weight
      in the US and
      40 mg/Kg of body weight in the European Union.
       
      Prior to the commercialization of aspartame in the 1970s,
      the manufacturers of the compound conducted various experimental studies on
      rats and mice to test its carcinogenicity.
       
      When taken together, the results of these studies were considered negative
      with regard to the carcinogenicity of aspartame.
       
      Doubts were however raised by some in the scientific community about the
      conduct of the experiments and
      the fact that some cases of malignant brain tumors were found among animals
      treated with aspartame
      while none were found among the control group.
       
      Given the limitations of these studies and
      the ever growing use of aspartame throughout the years,
      the European Ramazzini Foundation decided in the late 1990s
      to plan and perform an experiment that would,
      based on the total number of animals used,
      the number of dose levels studied,
      and the conduct of the experiment according to Good Laboratory Practices,
      provide an adequate evaluation of the potential carcinogenic effects of
      aspartame.
       
      The CRC/ERF study was conducted on 1800 rats (900 males, 900 females)
      of the colony used for over 30 years by the Foundation.
       
      In order to simulate daily human intake,
      aspartame was added to the standard rat diet in quantities of
      5000, 2500, 100, 500, 20, 4, and 0 mg/Kg of body weight.
      [ This asserts that humans are twenty times more vulnerable to aspartame
      (methanol, formaldehyde, formic acid) toxicity than rats. ]
       
      Treatment of the animals began at 8 weeks of age and
      continued until spontaneous death.
       
      A complete necropsy and histopathological evaluation of tissues and organs
      was then performed on each deceased animal,
      for a total of over 30,000 slides examined by microscope.
       
      The first results of the experiment show:
       
      1) a dose-related statistically significant increase of lymphomas and
      leukemias in female rats.
      This statistically significant increase was also observed at a dose level of
      20 mg/Kg of body weight,
      a dose inferior to the accepted daily intake permitted by current
      regulations (50-40 mg/Kg of body weight);
       
      2) that the addition of aspartame to the diet induces
      a dose-related reduction in food consumption,
      without however causing a difference in body weight
      between treated and untreated animals.
       
      The above results demonstrate
      for the first time
      that aspartame is a carcinogenic agent,
      capable of inducing lymphomas and leukaemias in female rats,
      including when administered at dose levels very close
      to the acceptable daily intake for humans.
       
      In addition, the data demonstrate that the integration of aspartame into the
      diet did not affect the body weight of treated animals
      compared with untreated animals.
       
      As recognized by the International Agency for Research on Cancer (IARC) of
      the World Health Organization,
      results of long-term bioassays conducted on rodents (rats and mice)
      are highly predictive of carcinogenic risk for humans.
       
      In light of this fact,
      the results of the CRC/ERF study on aspartame call
      for urgent reconsideration of regulations
      governing its use as an artificial sweetener
      in order to better protect public health,
      in particular that of children.
       
      Websites
       
      European Foundation for Oncology and Environmental Sciences "B. Ramazzini"
      www.ramazzini.it/fondazione/eng
       
      3rd international scientific conference of the Collegium Ramazzini
      www.ramazzini.it/living2005
       
      Contact    Kathryn Knowles   Director of Resource Development
      European Foundation of Oncology and Environmental Sciences "B. Ramazzini"
      development@...     +39 0516640460
       
      Home | About us | Research and Activities | Publications | News and Events
      Support the Foundation | Partners | Contact Us | Credits | Versione Italiana
       
      FONDAZIONE "B. RAMAZZINI" - Via Guerrazzi, 18 - 40125 Bologna - tel. 051
      237286 - fax 051 2911679 - fondazione@...
       
      CENTRO DI RICERCA SUL CANCRO - Castello di Bentivoglio, Via Saliceto,
      3-40010 Bentivoglio (BO) - tel. 051.66.40.460 - fax 051 6640223
      crcfr@...
      ***************************************************************
       
       
      "  Conclusions
      In our experimental conditions, it has been demonstrated,
      for the first time, that APM causes a dose-related
      statistically significant increase in lymphomas and leukaemias in females
      at dose levels very near
      those to which humans can be exposed.
       
      Moreover, it can hardly
      be overlooked that at the lowest exposure of 80 ppm,
      there was a 62% increase in lymphomas and leukaemias
      compared to controls, even though this was not statistically significant.
       
      When compared to the concurrent control
      group, an increase in the incidence of these neoplasias
      was also observed in males exposed to the highest dose;
      even though not statistically significant,
      this observation confirms and extends the result in females.
       
      The significance of the increase in haemolymphoreticular
      neoplasias is further reinforced by the following considerations,
      based on the results of experiments performed in the CRC laboratory.
       
      These experiments demonstrate that the increase in
      lymphomas and leukaemias, observed in the APM study,
      could be related to methanol,
      a metabolite of APM, which
      is metabolised to formaldehyde and then to formic acid,
      both in humans and rats 3.
       
      In fact we have shown that:
       
      1) methanol administered in drinking water increased the incidence
       of lymphomas and leukaemias in female rats 11;
       
       2) the same effect was induced in females treated with the
      gasoline oxygenated additive methyl-tert-butyl-ether
      (MTBE), which is also metabolised to methanol 12 ;
       
      and finally
      3) an increase in the incidence of lymphomas and
      leukaemias was also observed in females treated with
      formaldehyde 9, 13.
       
      These results further highlight the important role that
      formaldehyde has on the induction of haematological
      malignancies in rodents.
       
      Moreover, in a recent reevaluation
      of the carcinogenicity of formaldehyde by the International
      Agency for Research on Cancer (IARC),
      strong, although not considered sufficient,
      evidence of an association with leukaemias in humans was found 14.
       
      Since the results of carcinogenicity bioassays in rodents,
      mainly rats and mice, have been shown to be a consistent
      predictor of human cancer risk 15-17,
      the first results of our study
      call for urgent re-examination of permissible exposure
      levels of APM in both food and beverages,
      especially to protect children. "
       
      " 9. Soffritti M, Belpoggi F, Lambertini L, et al.
      Results of longterm experimental studies on the carcinogenicity of
      formaldehyde and acetaldehyde in rats.
      In
      Mehlman MA, Bingham E, Landrigan PJ, et al.
      Carcinogenesis bioassays and protecting public health.
      Commemorating the lifework of Cesare Maltoni and colleagues.
      Ann NY Acad Sci 2002; 982: 87-105.
       
      10. Harris NL, Jaffe ES, Vardiman JW, et al.
      WHO Classification of tumours of haematopoietic and lymphoid tissues:
      Introduction.
      In
      Jaffe ES, Harris NL, Stein H, et al.
      Tumours of haematopoietic and lymphoid tissues.
      Lyon: IARC Press, 2001, 12-3.
       
      11. Soffritti M, Belpoggi F, Cevolani D, et al.
      Results of long-term experimental studies on the carcinogenicity of methyl
      alcohol and ethyl alcohol in rats.
      In
      Mehlman MA, Bingham E, Landrigan PJ, et al.
      Carcinogenesis bioassays and protecting public health.
      Commemorating the lifework of Cesare Maltoni and colleagues.
      Ann NY Acad Sci 2002; 982: 46-69.
       
      12. Belpoggi F, Soffritti M, Maltoni C.
      Methyl-tertiary-butyl ether (MTBE), a gasoline additive, causes testicular
      and lymphohaematopoietic cancers in rats.
      Toxicol Ind Health 1995; 11: 119-49.
       
      13. Soffritti M, Maltoni C, Maffei F, et al.
      Formaldehyde: an experimental multipotent carcinogen.
      Toxicol Ind Health 1989; 5: 699-730.
       
      14. International Agency for Research on Cancer.
      Monographs on the evaluation of the carcinogenic risk of chemicals to
      humans.
      Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxy-2-Propanol.
      Vol. 88 (in press). Available on http://www.iarc.fr.
       
      15. Huff J. Long-term chemical carcinogenesis bioassays predict
      human cancer hazards. Issues, controversies, and uncertainties.
      In
      Bailer JA, Maltoni C, Bailar III JC, et al.
      Uncertainty in the risk assessment of environmental and occupational
      hazards.
      Ann NY Acad Sci 1999; 895: 56-79.
       
      16. Tomatis L, Aitio A, Wilbourn J, et al.
      Human carcinogens so far identified.
      Jpn J Cancer Res 1989; 80: 795-807.
       
      17. Rall DP.
      Can laboratory animal carcinogenicity studies predict cancer in exposed
      children?
      Environ Health Perspect 1995; 103 suppl 6: 173-5. "
       
       
      page 1
       
      Original studies/Studi originali
      General topics/Argomenti generali
       
      Eur. J. Oncol., vol. 10, n. 2, pp. 00-00, 2005 IN PRESS
       
      Aspartame induces lymphomas and leukaemias in rats  *
      L'aspartame induce linfomi e leucemie nei ratti
      Morando Soffritti,
      Fiorella Belpoggi,
      Davide Degli Esposti,
      Luca Lambertini
       
      Cancer Research Centre, European Ramazzini Foundation of Oncology and
      Environmental Sciences, Bologna, Italy
      Received/Pervenuto 15.3.2005 - Accepted/Accettato 11.4.2005
       
      Address/Indirizzo: Dr. Morando Soffritti, Centro di Ricerca sul Cancro,
      Fondazione Europea di Oncologia e Scienze Ambientali "B. Ramazzini",
      Castello di Bentivoglio, 40010 Bentivoglio (BO), Italia - Tel.
      +39/051/6640460 - Fax +39/051/6640223 - E-mail: crcfr@...
       
      * Research supported by European Ramazzini Foundation of Oncology and
      Environmental Sciences, Bologna, Italy
       

      Summary
       
      Aspartame, a widely used artificial sweetener, was administered
      with feed to male and female Sprague-Dawley rats
      (100-150/sex/group),
      8 weeks-old at the start of the experiment,
      at concentrations of 100,000; 50,000; 10,000; 2,000; 400; 80 and 0 ppm.
      Treatment lasted until spontaneous death of the animals.
       
      In this report we present the first results showing that aspartame,
      in our experimental conditions,
      causes a statistically significant, dose-related increase
      in lymphomas and leukaemias in females.
       
      No statistically significant increase in malignant brain tumours was
      observed among animals from the treated groups
      as compared to controls.
      Eur. J. Oncol., 10 (2), 00-00, 2005
       
      Key words: aspartame, artificial sweetener, carcinogenesis,
      rats, lymphoma, leukaemia
       
      Riassunto
       
      L'aspartame, un dolcificante artificiale largamente
      diffuso, è stato somministrato con il mangime a ratti
      Sprague-Dawley, maschi e femmine (100-150/sesso/
      gruppo), di 8 settimane di età all'inizio dell'esperimento,
      a concentrazioni di 100.000; 50.000; 10.000;
      2.000; 400; 80 e 0 ppm.
      Il trattamento è durato fino alla
      morte spontanea degli animali. In questo articolo
      vengono presentati i primi risultati che dimostrano
      come l'aspartame, nelle nostre condizioni sperimentali,
      causa un incremento statisticamente significativo,
      dose-correlato, di linfomi e leucemie nelle femmine.
      Nei gruppi trattati rispetto al controllo non è stato osservato
      nessun aumento statisticamente significativo
      dei tumori maligni del cervello.
      Eur. J. Oncol., 10 (2), 00-00, 2005
       
      Parole chiave: aspartame, dolcificante artificiale, cancerogenesi,
      ratti, linfoma, leucemia
       
      Introduction
       
      Aspartame (APM) is a widely used artificial sweetener
      consumed by hundreds of millions of people around
      the world 1, 2.
       
      It is found in more than 6,000 products, including
      soft drinks, chewing gum, candy, yoghurt, tabletop
      sweeteners and some pharmaceuticals such as vitamins
      and sugar-free cough drops 2.
       
      Dietary surveys, performed among APM consumers,
      have shown that the average APM daily intake in the general
      population ranged from 2 to 3 mg/kg b.w.
      and was even more in children and pregnant women 1.
       
      The Acceptable Daily Intake (ADI) both in the US and in Europe is
      50 and 40 mg/kg b.w., respectively 1.
       
      In rodents and humans,
      APM is metabolised in the gastrointestinal tract
      into three constituents:
      aspartic acid, phenylalanine and methanol 3.
       
      Three long-term feeding carcinogenicity bioassays on
      APM were performed on rats, and one on mice, during the 1970s.
       
      Overall, the carcinogenicity studies were considered negative 4,
      but it must be noted that these studies did not comply
      with the basic requirements which must nowadays be met when testing the
      carcinogenicity potential of a chemical or physical agent.
       
      Because of these limitations,
      we decided to perform a mega-experiment following
      the currently accepted Good Laboratory Practices.
       
      In the present paper we are reporting our first results on
      the incidence of haemolymphoreticular malignancies
      (lymphomas and leukaemias) and malignant brain tumours.
       
      Materials and methods
       
      The APM used was produced by Nutrasweet and supplied
      by Giusto Faravelli S.p.A., Milan, Italy.
       
      As an active ingredient, its purity was more than 98%.
       
      To simulate an assumed daily intake by humans of
      5,000; 2,500; 500; 100; 20; 4; or 0 mg/kg b.w.,
      APM was added to the standard Corticella diet,
      used for 30 years at the laboratory of
      the Cancer Research Centre (CRC) of the European Ramazzini Foundation (ERF),
      at concentrations of
      100,000; 50,000; 10,000; 2,000; 400; 80; or 0 ppm.
      [ This asserts that humans are twenty times more vulnerable to aspartame
      (methanol, formaldehyde, formic acid) toxicity than rats. ]
       
      APM-treated feed was administered ad libitum to Sprague-Dawley rats
      (100-150/sex/group),
      8 weeks old at the start of the experiment,
      and the treatment lasted until spontaneous death.
       
      Control animals received the same feed without APM.
      The plan of the experiment is shown in Table 1.
       
      page 2 M. Soffritti, F. Belpoggi, D. Degli Esposti, et al. IN PRESS
       
      Table 1 - Long-term carcinogenicity bioassay on aspartame administered with
      feed supplied ad libitum to male (M) and female (F) Sprague-Dawley rats from
      8 weeks of age until spontaneous death.
       
      Plan of the experiment.
      Age at start of treatment was 8 weeks.  Duration was then natural life span.
      Group  Sex (M, F, M+F)  Animals (No) Treatment Dose (ppm) mg/kg b.w. a
      Human ADI equivalent b (X)
       
      I
      ---M 100---------100,000-------5,000------100X
      ---F  100
      M+F 200
       
      II
      ---M 100----------50,000-------2,500-------50X
      ---F 100
       M+F 200
       
      III
      ---M 100----------10,000---------500-------10X
      ---F 100
      M+F  200
       
      IV
      ---M 150-----------2,000---------100--------2X
      ---F 150
      M+F 300
       
      V
      ---M 150-------------400----------20--------0.4X
      ---F 150
      M+F 300
       
      VI
      ---M 150--------------80-----------4---------0.08X
      ---F 150
      M+F 300
       
      VII
      ---M 150---------------0------------0---------0
      ---F 150
      M+F 300
       
      a The daily assumption in mg/kg b.w. was calculated considering the average
      weight of a rat for the duration of the experiment as 400 g,
      and the average consumption of feed as 20 g per day, both for males and
      females
       
      b Considering the Acceptable Daily Intake (ADI) of 50 mg/kg b.w. for humans
      [ This asserts that humans are twenty times more vulnerable to aspartame
      (methanol, formaldehyde, formic acid) toxicity than rats. ]
       

      Male (M) and female (F) rats from the colony of the CRC were used.
      This colony of rats has been employed
      for various experiments in the CRC Laboratory for nearly 30 years.
      Data are available on the tumour incidence among untreated Sprague-Dawley
      rats.
      These animals were monitored for feed, water consumption, and body
      weight, for their life span and, at death, underwent complete necropsy and
      histopathological evaluation (historical controls).
       
      The experiment was conducted according to the Italian law regulating use of
      animals for scientific purposes 5.
       
      After weaning, at 4-5 weeks of age,
      the experimental animals were identified by ear punch,
      randomised in order to have no more than one male and one female from
      each litter in the same group, and housed in groups of 5 in makrolon cages
      (41x25x15 cm), with stainless-steel wire tops and a shallow layer of white
      wood shavings as bedding. The animals were kept in one single room, at 23 ±
      2°C and 50-60% relative humidity.
       
      Once a week for the first 13 weeks, then every two weeks until 110 weeks of
      age, the mean daily drinking water and feed consumption were measured per
      cage, and body weight individually.
      Body weight continued to be measured every 8 weeks until the end of the
      experiment.
       
      Status and behaviour of the animals were examined 3 times daily, and
      they were clinically examined for gross changes every 2 weeks.
      All animals were kept under observation until spontaneous death.
       
      page 3  Aspartame, a leukaemogenic compound IN PRESS
       

      Fig. 1. Mean daily water consumption in male Sprague-Dawley rats
       
      Fig. 2. Mean daily water consumption in female Sprague-Dawley rats
       

      The biophase of the experiment terminated after 151 weeks,
      with the death of the last animal at the age of 159 weeks.
       
      Upon death, the animals underwent complete necropsy.
      Histopathology was routinely performed on the following
      organs and tissues of all animals from each group:
      skin and subcutaneous tissue, mammary gland, the brain (3 sagittal
      sections), pituitary gland, Zymbal glands, salivary glands, Harderian
      glands, cranium (five sections, with oral and nasal cavities and external
      and internal ear ducts), tongue, thyroid, parathyroid, pharynx, larynx,
      thymus and mediastinal lymph nodes, trachea, lung and mainstem bronchi,
      heart, diaphragm, liver, spleen, pancreas, kidneys, adrenal glands,
      oesophagus, stomach (fore and glandular), intestine (four levels), urinary
      bladder, prostate, gonads, interscapular brown fat pad, subcutaneous
      and mesenteric lymph nodes and other organs or tissues with pathological
      lesions.
       
      All organs and tissues were preserved in 70% ethyl alcohol, except for bones
      which were fixed in 10% formalin and then decalcified with 10% formaldehyde
      and 20% formic acid in water solution. The normal specimens were trimmed,
      following the Standard Operating Procedures at the CRC Laboratory: i.e.
      parenchymal organs were dissected through the hilus to expose the widest
      surface, and hollow organs were sectioned across the greatest diameter.
       
      page 4  M. Soffritti, F. Belpoggi, D. Degli Esposti, et al. IN PRESS
       

      Fig. 3. Mean daily feed consumption in male Sprague-Dawley rats
       
      Fig. 4. Mean daily feed consumption in female Sprague-Dawley rats
       

      Any pathological tissue was trimmed through the largest surface, including
      normal adjacent tissue. Trimmed specimens were processed as paraffin blocks,
      and 3-5 micron sections of every specimen were obtained. Sections were
      routinely stained with haematoxylin-eosin.
       
      Statistical analyses were performed using the poly-k test (k = 3). This test
      is a survival-adjusted quantal-response procedure that modifies the
      Cochran-Armitage linear trend test to take survival differences into account
      6-8.
       
      Results
       
      During the experiment no differences were observed among the various groups
      in mean daily water consumption (figs. 1 and 2).
       
      A dose-related difference in feed consumption was observed between the
      various treated groups and the control group in both males and females
      (figs. 3 and 4).
       
      No differences in mean body weight were observed among treated and control
      groups in either males or females (figs. 5 and 6).
       
      No substantial difference in survival was observed among treated and control
      groups, males or females (figs. 7 and 8).
       
      Yellowing of the coat was observed in animals exposed to APM, mainly at the
      highest concentrations.
       
      This change was previously observed in our laboratory in rats exposed
      to formaldehyde administered with drinking water 9.
       
      The occurrence of lymphomas and leukaemias among male and female rats in
      treated and control groups is shown in Table 2.
       
      page 5 Aspartame, a leukaemogenic compound IN PRESS
       

      Fig. 5. Mean body weights in male Sprague-Dawley rats
       
      Fig. 6. Mean body weights in female Sprague-Dawley rats
       

      The data indicate that APM causes a statistically significant increase in
      the incidence of lymphomas and leukaemias in females, at concentrations of
      100,000 (p= 0.01);
        50,000 (p= 0.01);
        10,000 (p= 0.05);
          2,000 (p= 0.01) and
             400 (p= 0.01) ppm
      as compared to untreated controls.
      This increase is dose-related (p= 0.05).
       
      Although not statistically significant,
      an increase was also observed in females treated with 80 ppm and
      in males treated with the highest dose.
       
      The haemolymphoreticular neoplasias observed in the experiment include:
      lymphoblastic lymphoma and leukaemia,
      lymphocytic lymphoma,
      lymphoimmunoblastic lymphoma,
      histiocytic sarcoma and monocytic leukaemia,
      myeloid leukaemia.
       
      The most frequent type of neoplasia was the lymphoimmunoblastic lymphoma
      (figs. 9 and 10).
       
      Lymphomas and leukaemias are considered together,
      since both solid and circulating phases are present in many lymphoid
      neoplasms, and distinction between them is artificial 10.
       
      The occurrence of brain malignancies is shown in Table 3.
       
      Sparse malignant brain tumours were observed
      among males and females in the treated groups and
      none in the controls.
       
      page 6  M. Soffritti, F. Belpoggi, D. Degli Esposti, et al. IN PRESS
       

      Fig. 7. Survival in male Sprague-Dawley rats
       
      Fig. 8. Survival in female Sprague-Dawley rats
       

      page 7 Aspartame, a leukaemogenic compound IN PRESS
       

      Fig. 9. Lymphoimmunoblastic lymphoma in a female rat administered
      80 ppm aspartame in feed (lung). HE X 25
       
      Fig. 10. A detail of the lymphoimmunoblastic lymphoma shown in fig. 9.
      HE X 400
       

      In our historical controls over the last 20 years,
      when we consider groups of 100 or more animals per sex
      (1934 males and 1957 females),the overall incidence of lymphomas and
      leukaemias in males is 21.8% (8.0-30.9) and
      in females 13.4% (7.0-18.4) .
       

      The overall incidence of malignant brain tumours is
      1.7% (0-5.0) in males and
      0.7% (0-2.0) in females respectively.
       
      page 8 M. Soffritti, F. Belpoggi, D. Degli Esposti, et al. IN PRESS
       

      Table 2 - Long-term carcinogenicity bioassay on aspartame administered with
      feed supplied ad libitum to male (M) and female (F) Sprague-Dawley rats from
      8 weeks of age until spontaneous death.                Incidence of
      lymphomas and leukaemias
       

      Table 3 - Long-term carcinogenicity bioassay on aspartame administered with
      feed supplied ad libitum to male (M) and female (F) Sprague-Dawley rats from
      8 weeks of age until spontaneous death. Incidence of malignant brain tumors
      b
       

      Group (100-150 rats each)  Dose (ppm)  Animals with lymphomas and leukaemias
      Animals with malignant brain tumours (No, %, No, %)  @
       
      I-----100,000-ppm-29--------29.0-------1-------1.0
      ---------------------25--------25.0**----1-------1.0
      ---------------------54--------27.0-------2-------1.0
       
      II-----50,000-ppm-20--------20.0-------2-------2.0
      ---------------------25--------25.0**----1-------1.0
      ---------------------45--------22.5-------3-------1.5
       
      III----10,000-ppm-15--------15.0-------0--------0
      --------------------19--------19.0*------1--------1.0
      --------------------34--------17.0-------1--------0.5
       
      IV------2,000-ppm-33-------22.0-------2--------1.3
      ---------------------28-------18.7*------1--------0.7
      ---------------------61-------20.3-------3--------1.0
       
      V---------400-ppm-25-------16.7-------0--------0
      ---------------------30-------20.0**-----0--------0
      ---------------------55-------18.3--------0--------0
       
      VI---------80-ppm-23 -------15.3-------2-------1.3
      ---------------------22 -------14.7-------1-------0.7
      ---------------------45-------15.0--------3-------1.0
       
      VII---------0-ppm-31--------20.7-------0-------0 [control groups]
      --------------------13---------8.7--------0-------0
      --------------------44--------14.7--------0-------0
       
      @ The malignancies observed were:
      10 malignant gliomas or mixed gliomas,
       1 medulloblastoma, and
       1 malignant meningioma
       
      *   Statistically significant p= 0.05;
      ** Statistically significant p= 0.01 using poly-k test (k = 3)
       

      Conclusions
       
      In our experimental conditions,
      it has been demonstrated,
      for the first time,
      that APM causes a dose-related statistically significant increase
      in lymphomas and leukaemias in females
      at dose levels very near
      those to which humans can be exposed.
       
      Moreover, it can hardly
      be overlooked that at the lowest exposure of 80 ppm,
      there was a 62% increase in lymphomas and leukaemias
      compared to controls,
      even though this was not statistically significant.
       
      When compared to the concurrent control group,
      an increase in the incidence of these neoplasias
      was also observed in males exposed to the highest dose;
      even though not statistically significant, this observation
      confirms and extends the result in females.
       
      The significance of the increase in haemolymphoreticular neoplasias
      is further reinforced by the following considerations,
      based on the results of experiments performed in the CRC laboratory.
       
      These experiments demonstrate that the increase in
      lymphomas and leukaemias,
      observed in the APM study,
      could be related to methanol, a metabolite of APM,
      which is metabolised to formaldehyde and then to formic acid,
      both in humans and rats 3.
       
      In fact we have shown that:
       
      1) methanol administered in drinking water increased
      the incidence of lymphomas and leukaemias in female rats 11;
       
       2) the same effect was induced in females treated with the
      gasoline oxygenated additive methyl-tert-butyl-ether
      (MTBE), which is also metabolised to methanol 12;
       
      and finally
      3) an increase in the incidence of lymphomas and leukaemias was also
      observed in females treated with formaldehyde 9, 13.
       
      These results further highlight the important role that formaldehyde has on
      the induction of haematological malignancies in rodents.
       
      Moreover, in a recent reevaluation of the carcinogenicity of formaldehyde by
      the International Agency for Research on Cancer (IARC), strong,
      although not considered sufficient,
      evidence of an association with leukaemias in humans was found 14.
       
      Since the results of carcinogenicity bioassays in rodents,
      mainly rats and mice, have been shown to be
      a consistent predictor of human cancer risk 15-17,
      the first results of our study call for urgent re-examination
      of permissible exposure levels of APM in both food and beverages,
      especially to protect children.
       
      References
       
      1. Butchko HH, Stargel WW, Comer CP, et al.
      Preclinical safety evaluation of aspartame.
      Regul Toxicol Pharmacol 2002; 35: S7-S12.
       
      2. Aspartame Information Center.
      Available on http://www.aspartame.org, 2004.
       
      3. Ranney RE, Opperman JA, Maldoon E, et al.
      Comparative metabolism of aspartame in experimental animals and humans.
      Toxicol Environ Health 1976; 2: 441-51.
       
      4. Food and Drug Administration. Aspartame:
      Commissioner's Final Decision; 1981 Fed Regist 46, 38285-308.
       
      5. Repubblica Italiana.
      Decreto Legislativo 116.
      Attuazione della direttiva n. 86/609/CEE in materia di protezione degli
      animali utilizzati a fini sperimentali o ad altri fini scientifici.
      Supplemento ordinario alla Gazzetta Ufficiale 1992; 40: 5-25.
       
      page 9 Aspartame, a leukaemogenic compound IN PRESS
       
      6. Bailer AJ, Portier CJ.
      Effects of treatment-induced mortality and tumor-induced mortality on tests
      for carcinogenicity in small samples.
      Biometrics 1988; 44: 417-31.
       
      7. Portier CJ, Bailer AJ.
      Testing for increased carcinogenicity using a survival-adjusted quantal
      response test. Fundam Appl Toxicol 1989; 12: 731-7.
       
      8. Piergorsh WW, Bailer AJ.
      Statistics for environmental biology and toxicology.
      London: Chapman, 1997.
       
      9. Soffritti M, Belpoggi F, Lambertini L, et al.
      Results of longterm experimental studies on the carcinogenicity of
      formaldehyde and acetaldehyde in rats.
      In
      Mehlman MA, Bingham E, Landrigan PJ, et al. Carcinogenesis bioassays and
      protecting public health. Commemorating the lifework of Cesare Maltoni
      and colleagues.
      Ann NY Acad Sci 2002; 982: 87-105.
       
      10. Harris NL, Jaffe ES, Vardiman JW, et al.
      WHO Classification of tumours of haematopoietic and lymphoid tissues:
      Introduction.
      In
      Jaffe ES, Harris NL, Stein H, et al.
      Tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press, 2001,
      12-3.
       
      11. Soffritti M, Belpoggi F, Cevolani D, et al.
      Results of long-term experimental studies on the carcinogenicity of methyl
      alcohol and ethyl alcohol in rats.
      In
      Mehlman MA, Bingham E, Landrigan PJ, et al.
      Carcinogenesis bioassays and protecting public health.
      Commemorating the lifework of Cesare Maltoni and colleagues.
      Ann NY Acad Sci 2002; 982: 46-69.
       
      12. Belpoggi F, Soffritti M, Maltoni C.
      Methyl-tertiary-butyl ether (MTBE), a gasoline additive, causes testicular
      and lymphohaematopoietic cancers in rats.
      Toxicol Ind Health 1995; 11: 119-49.
       
      13. Soffritti M, Maltoni C, Maffei F, et al.
      Formaldehyde: an experimental multipotent carcinogen.
      Toxicol Ind Health 1989; 5: 699-730.
       
      14. International Agency for Research on Cancer.
      Monographs on the evaluation of the carcinogenic risk of chemicals to
      humans. Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxy-2-Propanol.
      Vol. 88 (in press).  Available on http://www.iarc.fr.
       
      15. Huff J.
      Long-term chemical carcinogenesis bioassays predict human cancer hazards.
      Issues, controversies, and uncertainties.
      In
      Bailer JA, Maltoni C, Bailar III JC, et al.
      Uncertainty in the risk assessment of environmental and occupational
      hazards.
      Ann NY Acad Sci 1999; 895: 56-79.
       
      16. Tomatis L, Aitio A, Wilbourn J, et al.
      Human carcinogens so far identified.
      Jpn J Cancer Res 1989; 80: 795-807.
       
      17. Rall DP.
      Can laboratory animal carcinogenicity studies predict cancer in exposed
      children?
      Environ Health Perspect 1995; 103 suppl 6: 173-5.
       
      page 10 M. Soffritti, F. Belpoggi, D. Degli Esposti, et al. IN PRESS
      ***************************************************************
       
      Here I have combined fairly equivalent data from their aspartame, methanol,
      and formaldehyde studies.  Aspartame groups were 100-150 rats each, methanol
      100 rats each, and formaldehyde 50 rats each (formaldehyde control groups
      100 rats each).
       
      Aspartame and methanol are directly comparable, since the 11% methanol
      component of aspartame upon ingestion is immediately and fully released into
      the GI tract, and then much of that quickly turned into formaldehyde and
      then formic acid, both of which account for the toxicity of methanol.
       
      Fully 11% of aspartame is methanol--  1,120 mg aspartame  in 2 L diet soda,
      almost six 12-oz cans,  gives 123 mg methanol (wood alcohol).   If 30% of
      the methanol is turned into formaldehyde, the amount of formaldehyde, 37 mg,
      is 18 times the USA EPA limit for daily formaldehyde in drinking water, 2 mg
      in 2 L
      water.
       
      For instance, hangover researchers claim that it is the ~150 mg/L methanol
      impurity, about one part in 10,000, twice the level from aspartame in diet
      sodas,  in dark wines and liquors that, turned into formaldehyde and then
      formic acid, is the major cause of the dreadful symptoms of "morning after"
      hangover:
       
      http://groups.yahoo.com/group/aspartameNM/message/1143
      methanol (formaldehyde, formic acid) disposition: Bouchard M et al, full
      plain text, 2001: substantial sources are degradation of fruit pectins,
      liquors, aspartame, smoke: Murray 2005.04.02 rmforall
       
      J. Nutrition 1973 Oct; 103(10): 1454-1459.
      Metabolism of aspartame in monkeys.
      Oppermann JA, Muldoon E, Ranney RE.
      Dept. of Biochemistry, Searle Laboratories,
      Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
      They found that about 70% of the radioactive methanol in aspartame put into
      the stomachs of 3 to 7 kg monkeys was eliminated within 8 hours, with little
      additional elimination,  as carbon dioxide in exhaled air and as water in
      the urine.
      They did not mention that this meant that about 30% of the methanol must
      transform into formaldehyde and then into formic acid, both of which must
      remain as toxic products in all parts of the body.
      They did not report any studies on the distribution of radioactivity in body
      tissues, except that blood plasma proteins after 4 days held 4% of the
      initial methanol.
      This study did not monitor long-term use of aspartame.
       

      Males
      Females
      Males + Females
       
              Animals with lymphomas and leukaemias [hemolymphoreticular
      neoplasias]
      % of each group of animals
       
      Group
      100 rats each
       
      aspartame dose a
      equivalent methanol dose (11% of aspartame)
      roughly equivalent formaldehyde dose (30% of methanol)
       
      --------------------20,000-40.0
      ----------------------------28.0 #^
      --------------------------- 34.0
       
      I--100,000-29.0
      ------------25.0**
      ------------27.0
       
      II---50,000-0.0-----5,000-36.0-1,500-46.0 **
      ------------25.0**---------24.0--------20.0*
      ------------22.5------------30.0--------33.0
       
      ----------------------------------1,000-22.0*
      -----------------------------------------22.0*
      -----------------------------------------22.0
       
      ------------------------------------500-24.0*
      -----------------------------------------14.0
      -----------------------------------------19.0
       
      III-10,000-15.0
      -----------19.0*
      -----------17.0
       
      -----------------------500-35.0
      ----------------------------24.0
      ----------------------------29.5
       
      -----------------------100-26.0**
      ----------------------------16.0
      ----------------------------21.0
       
      -------------------------------------50-20.0
      -----------------------------------------14.0
      -----------------------------------------17.0
       
      IV---2,000-22.0
      -------------18.7*
      -------------20.3
       
      V-------400-16.7
      --------------20.0**
      --------------18.3
      -------------------------------------10--8.0
      ----------------------------------------10.0
      -----------------------------------------9.0
       
      -----------------------15-20.0 [-50 rats ]
      ---------------------------10.0 [-50 rats ]
      ---------------------------15.0 [100 rats ]
       
      VI-------80-15.3
      --------------14.7
      --------------15.0
       
      VII--------0-20.7-------0-28.0------0--8.0 [ control groups ]
      ---------------8.7---------13.0----------7.0
      --------------14.7---------20.5----------7.5
       
      a Considering the life-span average weight of a rat (male and female) as 400
      g and the average consumption of food as 20 g per day
       
      *   aspartame, statistically significant p= 0.05;
      ** aspartame, statistically significant p= 0.01 using poly-k test (k = 3)
       
      # methanol, p<0.05 using X2 test
      ^ methanol, p<0.05 using Cochrane-Armitage test for dose-response
      relationship
       
      *   formaldemyde, p<0.05 using X2 test
      ** formaldehyde,  p<0.01 using X2 test
       
      The control groups vary widely, with the percentage of rats with these most
      common cancers, present at natural death, ranging from 7.0% to 28.0%.
      A layman can only speculate as to the possible causes in a uniform
      population of rats in the same huge laboratory facility for decades, such as
      various
      viruses, bacteria, or molds, or variable impurities in the tap water.
       
      Formaldehyde at 50 ppm shows a doubling of the percentage of rats with these
      cancers, for groups of just 50 rats.  It is a safe bet that studies using
      groups of 100 to 200 rats would establish significance at this 50 ppm level,
      which in turn would mandate the reduction of the present USA EPA level
      (1999) from 1 ppm for lifetime exposure to formaldehyde in drinking water to
      0.05 ppm, since the human limit is estimated by dividing the lowest harmful
      animal level by 1000.
      The various standards for methanol and formaldehyde are not in harmony:
       
      http://groups.yahoo.com/group/aspartameNM/message/835
      ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999:
      Murray 2002.05.30 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1108
      faults in 1999 July EPA 468-page formaldehyde profile:
      Elzbieta Skrzydlewska PhD, Assc. Prof., Medical U. of Bialystok, Poland,
      abstracts -- ethanol, methanol, formaldehyde, formic acid, acetaldehyde,
      lipid peroxidation, green tea, aging: Murray 2004.08.08 2005.07.11
       
      http://groups.yahoo.com/group/aspartameNM/message/1140
      EPA Preliminary Remedial Goals, PRGs, 2003 Oct, air and tap water --
      methanol, formaldehyde, formic acid -- not mentioned is methanol from
      aspartame, dark wines and liquors: Murray 2004.11.20 rmforall
       

      We can grasp the main picture by studying the results at a high level of
      exposure:
       
      II--50,000-20.0------5,000-36.0-1,500--46.0**
      ------------25.0**-----------24.0--------20.0*
      ------------22.5-------------30.0---------33.0
       
      The results amount to 1.3 to 5.75 times their control group levels.
      Aspartame, methanol, and formaldehyde results broadly agree.
      Unknown factors are causing differences between males and females.
      ***************************************************************
       
      Rich Murray, MA  Room For All  rmforall@...  505-501-2298
      1943 Otowi Road    Santa Fe, New Mexico 87505   USA
      http://groups.yahoo.com/group/aspartameNM/messages
      group with 146 members, 1,206 posts in a public, searchable archive
       
      http://groups.yahoo.com/group/aspartameNM/message/1186
      aspartame induces lymphomas and leukaemias in rats, free full plain text, M
      Soffritti, F Belpoggi, DD Esposti, L Lambertini, 2005 April, 2005.07.14:
      main results agree with their previous methanol and formaldehyde studies,
      Murray 2005.07.19
       
      http://groups.yahoo.com/group/aspartameNM/message/1185
      Ramazzini Institute (Italy) lifetime study with 1800 rats shows aspartame at
      human use levels causes cancer (methanol, formaldehyde, formic acid), M
      Soffritti and F Belpoggi: Felicity Lawrence, The Guardian (UK): Murray
      2005.07.15
       
      http://groups.yahoo.com/group/aspartameNM/message/1189
      Michael F Jacobson of CSPI now and in 1985 re aspartame toxicity, letter to
      FDA Commissioner Lester Crawford; California OEHHA aspartame critique
      2004.03.12; Center for Consumer Freedom denounces CSPI: Murray 2004.07.27
       
      http://groups.yahoo.com/group/aspartameNM/message/1045
      http://www.holisticmed.com/aspartame/scf2002-response.htm
      Mark Gold exhaustively critiques European Commission Scientific
      Committee on Food re aspartame ( 2002.12.04 ): 59 pages, 230 references
       
      http://www.HolisticMed.com/aspartame    mgold@...
      Aspartame Toxicity Information Center    Mark D. Gold
      12 East Side Drive #2-18 Concord, NH 03301     603-225-2100
      http://www.holisticmed.com/aspartame/abuse/methanol.html
      "Scientific Abuse in Aspartame Research"
       
      Gold points out that industry methanol assays were too insensitive to
      properly measure blood methanol levels.  ]
       
      Fully 11% of aspartame is methanol--  1,120 mg aspartame  in 2 L diet soda,
      almost six 12-oz cans,  gives 123 mg methanol (wood alcohol).   If 30% of
      the methanol is turned into formaldehyde, the amount of formaldehyde is 18
      times the USA EPA limit for daily formaldehyde in drinking water, 2 mg in 2
      L water.
       
      http://groups.yahoo.com/group/aspartameNM/message/835
      ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999:
      Murray 2002.05.30 rmforall
       
      Aspartame is made of phenylalanine (50% by weight) and aspartic acid (39%),
      both ordinary amino acids, bound loosely together by methanol (wood alcohol,
      11%).   The readily released methanol from aspartame is within hours turned
      by the liver into formaldehyde and then formic acid, both potent, cumulative
      toxins.
       

      http://groups.yahoo.com/group/aspartameNM/message/1182
      Joining together: short review: research on aspartame (methanol,
      formaldehyde, formic acid) toxicity: Murray 2005.07.08 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1071
      research on aspartame (methanol, formaldehyde, formic acid) toxicity: Murray
      2004.04.29 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1143
      methanol (formaldehyde, formic acid) disposition: Bouchard M et al, full
      plain text, 2001: substantial sources are degradation of fruit pectins,
      liquors, aspartame, smoke: Murray 2005.04.02 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1131
      genotoxicity of aspartame in human lymphocytes 2004.07.29 full plain text,
      Rencuzogullari E et al, Cukurova University, Adana, Turkey 2004 Aug: Murray
      2004.11.06 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1088
      Murray, full plain text & critique: chronic aspartame in rats affects
      memory, brain cholinergic receptors, and brain chemistry, Christian B,
      McConnaughey M et al, 2004 May: 2004.06.05 rmforall
       
      http://groups.yahoo.com/group/aspartameNM/message/1067
      eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV
      Belsito, Nov 2003: Murray 2004.03.30 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.  toxicology@...
      Sam-1 Trust, Alto, New Mexico, USA.
      http://www.drthrasher.org/formaldehyde_embryo_toxicity.html   full text
       
      http://groups.yahoo.com/group/aspartameNM/message/939
      aspartame (aspartic acid, phenylalanine) binding to DNA:
      Karikas July 1998: Murray 2003.01.05 rmforall
      Karikas GA, Schulpis KH, Reclos GJ, Kokotos G
      Measurement of molecular interaction of aspartame and
      its metabolites with DNA. Clin Biochem 1998 Jul; 31(5): 405-7.
      Dept. of Chemistry, University of Athens, Greece
      http://www.chem.uoa.gr   gkokotos@...
      "K.H. Schulpis" <inchildh@...>  "G.J. Reclos" reklos@...
       
      http://groups.yahoo.com/group/aspartameNM/message/1052
      DMDC: Dimethyl dicarbonate 200mg/L in drinks adds methanol 98 mg/L
      [ becomes formaldehyde in body ]:  EU Scientific Committee on Foods
      2001.07.12:  Murray 2004.01.22 rmforall
       

      Clearly, Europe has placed the issue of aspartame toxicity on the table
      as a legitimate, urgent issue for evidence-based public discussion.
       
      Perhaps this shift in the climate of opinion is due to:
      European Ramazzini Foundation, led by Morando Soffritti, MD.
      crcfr@...  Cancer Research Center, European Ramazzini Foundation for
      Oncology and Environmental Sciences, Bentivoglio Castle, 40010
      Bentivoglio (BO), Italy.  +39-051-6640460 fax +39-051-6640223
       
      Annuals of the New York Academy of Science. 2002 Dec; Vol. 982:
       
      The RF research program was started in 1966 by the eminent Cesare
      Maltoni, (1930-2001):
       p. 6  "Maltoni was known for his meticulous and carefully documented
      experiments.
      He studied 198 chemicals and agents and conducted 394 separate experiments
      using 138,281 animals.
      Of the 135 agents studied,
      68.9% were found to be carcinogenic,
      5.92% showed borderline carcinogenicity,
      and 25.18% were found to be noncarcinogenic in the animals tested."
      Often, the hundreds to thousands of rats in each study were exposed daily
      for two years and then thoroughly examined for cancers after their later
      natural deaths.
       
      http://www.nyas.org/books/vols/v982.html
      Annals of the New York Academy of Sciences
      Carcinogenesis Bioassays and Protecting Public Health:
      Commemorating the Lifework of Cesare Maltoni and Colleagues
      Edited by Myron A. Mehlman (Collegium Ramazzini, Princeton, NJ);
      [Dept. of Environmental Medicine, The Mount Sinai Medical Center, New
      York City, mehlman@... 609-683-4750]
      Eula Bingham (University of Cincinnati College of Medicine, Cincinnati, OH);
      Philip J. Landrigan (Mount Sinai School of Medicine, New York, NY);
      Morando Soffritti, Fiorella Belpoggi, European Ramazzini Foundation;
      Ronald L. Melnick, National Institute of Environmental Health Sciences,
      Research Triangle Park, NC
       
      Proceedings of an April 29-30, 2002 Academy conference.
      Volume 982 ISBN 1-57331-406-4
      231 pages 14 papers 0 posters  Price: $135.00
      Member Price *:  $15.00   December 2002
       
      Long-term experimental carcinogenesis studies are the cornerstone of
      human health protection and risk assessment for drugs and chemicals.
      Great contributions to the development of bioassay methodology and the
      understanding of the mechanisms of carcinogenesis were made by Professor
      Cesare Maltoni at the European Foundation of Oncology and Environmental
      Sciences "B. Ramazzini," Bologna, Italy.
      This volume is based on a conference that was held on the first anniversary
      of Professor Maltoni's death to honor him and to celebrate the work on
      carcinogenesis bioassays carried out at the Ramazzini Foundation Cancer
      Research Center in Italy and at the National Toxicology Program, NIEHS, in
      the United States.
      Papers include reviews of previously unreported findings and discussion
      of the continued utility of such studies for the protection of public
      health.
      Full text of volume 837 and forward is available at Annals
      Online to Academy Members at Members Online and to subscribing
      libraries. New York Academy of Sciences  2 East 63rd St., NY, NY 10021
       
      "(3) formaldehyde may produce lymphomas and leukemias..."
       
      Ann N Y Acad Sci. 2002 Dec; 982: 26-45.
      Ramazzini Foundation cancer program: history and major projects,
      life-span carcinogenicity bioassay design, chemicals studied, and results.
      Soffritti M, Belpoggi F, Minardi F, Maltoni C.
      Cancer Research Center, European Ramazzini Foundation for Oncology and
      Environmental Sciences, Bologna, Italy. crcfr@...
       
      The Ramazzini Foundation research program was started over thirty years
      ago.  The features of this program are:
      (1) systematic and integrated project design;
      (2) consistency over time;
      (3) homogeneity of approach: key members of the team remain unchanged;
      and (4) choice to work on new frontiers of scientific research.
      The program centers mainly on three projects:
      Project 1: experimental carcinogenicity bioassays;
      Project 2: experimental anticarcinogenesis assays to identify factors
      and active principles (compounds) capable of opposing the onset of
      tumors while being suitable for preventive/chemopreventive intervention;
      Project 3: epidemiological studies, both descriptive and analytical, on
      tumor incidence and mortality in persons professionally and
      environmentally exposed to industrial carcinogenic risks.
      The project involving experimental carcinogenicity bioassays for the
      identification of exogenous carcinogens (environmental and industrial
      above all) beg

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