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  1. #1
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    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://www.rense.com/general67/asdp.htm [ You can contact Dr. Erik
    Millstone for more information on this study: e.p.millstone@sussex.ac.uk ]

    http://www.ramazzini.it/fondazione/d...ameGEO2005.pdf

    " 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."

    http://www.ramazzini.it/eng/fondazio...gli.asp?id=210

    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/d...ameGEO2005.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@ramazzini.it +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@ramazzini.it

    CENTRO DI RICERCA SUL CANCRO - Castello di Bentivoglio, Via Saliceto,
    3-40010 Bentivoglio (BO) - tel. 051.66.40.460 - fax 051 6640223
    crcfr@ramazzini.it
    ************************************************** *************

    http://www.ramazzini.it/fondazione/d...ameGEO2005.pdf

    " 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. "

    http://www.ramazzini.it/fondazione/d...ameGEO2005.pdf

    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@ramazzini.it

    * 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 et* 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@comcast.net 505-501-2298
    1943 Otowi Road Santa Fe, New Mexico 87505 USA
    http://groups.yahoo.com/group/aspartameNM/messages
    group with 186 members, 1,187 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/1045
    http://www.holisticmed.com/aspartame...2-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@holisticmed.com
    Aspartame Toxicity Information Center Mark D. Gold
    12 East Side Drive #2-18 Concord, NH 03301 603-225-2100
    http://www.holisticmed.com/aspartame.../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@drthrasher.org
    Sam-1 Trust, Alto, New Mexico, USA.
    http://www.drthrasher.org/formaldehy..._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@atlas.uoa.gr
    "K.H. Schulpis" <inchildh@otenet.gr> "G.J. Reclos" reklos@otenet.gr

    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@tin.it 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@rcn.com 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
    ****** to Academy Members at Members ****** 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@tin.it

    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) began in 1966.
    This project has included 398 experimental bioassays on 200
    compounds/agents using some 148,000 animals monitored until their
    spontaneous death.
    Among the studies already concluded, 47 agents have shown "clear
    evidence" of carcinogenicity.
    The results have demonstrated for the first time that
    (1) vinyl chloride can cause liver angiosarcoma as well as other tumors;
    (2) benzene is carcinogenic in experimental animals for various tissues
    and organs;
    (3) formaldehyde may produce lymphomas and leukemias; and
    (4) methyl-tert-butyl ether (MTBE), the most common oxygenated additive
    used in gasolines, can cause lymphomas/leukemias.
    Many of the results achieved have led to the introduction of norms and
    measures of primary prevention.
    Publication Types: Historical Article PMID: 12562627


    p. 48 "The sweetening agent aspartame hydrolyzes in the gastrointestinal
    tract to become free methyl alcohol. (25)"
    "(25) Medinsky MA & Dorman DC. 1994; Assessing risks of low-level
    methanol exposure. CIIT Act. 14: 1-7.
    (30) Monte WC. 1984; Aspartame, methanol and the public health.
    Journal Applied Nutrition. Vol 36: 42-54."

    Ann N Y Acad Sci. 2002 Dec; 982: 46-69.
    Results of long-term experimental studies on the carcinogenicity of
    methyl alcohol and ethyl alcohol in rats.
    Soffritti M, Belpoggi F, Cevolani D, Guarino M, Padovani M, Maltoni C.
    Cancer Research Center, European Ramazzini Foundation for Oncology and
    Environmental Sciences, Bologna, Italy. crcfr@tin.it

    Methyl alcohol was administered in drinking water supplied ad libitum at
    doses of 20,000, 5,000, 500, or 0 ppm to groups of male and female
    Sprague-Dawley rats 8 weeks old at the start of the experiment.
    [ Since 11% of aspartame is its methanol component, always quickly released
    into the GI tract upon ingestion, the above methanol levels correspond to
    about
    200,000, 50,000, 5,000, and 0 ppm aspartame levels, while the 2005 aspartame
    levels used were 100,000, 50,000, 10,000, 2,000, 400, 80, and 0 ppm.

    Animals were kept under observation until spontaneous death.
    Ethyl alcohol was administered by ingestion in drinking water at a
    concentration of 10% or 0% supplied ad libitum to groups of male and
    female Sprague-Dawley rats; breeders and offspring were included in the
    experiment.
    Treatment started at 39 weeks of age (breeders), 7 days before mating,
    or from embryo life (offspring) and lasted until their spontaneous death.
    Under tested experimental conditions, methyl alcohol and ethyl alcohol
    were demonstrated to be carcinogenic for various organs and tissues.
    They must also be considered multipotential carcinogenic agents.
    In addition to causing other tumors, ethyl alcohol induced malignant
    tumors of the oral cavity, tongue, and lips.
    These sites have been shown to be target organs in man by epidemiologic
    studies. Publication Types: Review Review, Tutorial PMID: 12562628


    p. 88 "The sweetening agent aspartame hydrolyzes in the gastrointestinal
    tract to become free methyl alcohol, which is metabolized in the liver
    to formaldehyde, formic acid, and CO2. (11) [Medinsky & Dorman 1994]"

    Ann N Y Acad Sci. 2002 Dec; 982: 87-105.
    Results of long-term experimental studies on the carcinogenicity of
    formaldehyde and acetaldehyde in rats.
    Soffritti M, Belpoggi F, Lambertin L, Lauriola M, Padovani M, Maltoni C.
    Cancer Research Center, European Ramazzini Foundation for Oncology and
    Environmental Sciences, Bologna, Italy. crcfr@tin.it

    Formaldehyde was administered for 104 weeks in drinking water supplied
    ad libitum at concentrations of 1500, 1000, 500, 100, 50, 10, or 0 mg/L
    to groups of 50 male and 50 female Sprague-Dawley rats beginning at
    seven weeks of age.
    Control animals (100 males and 100 females) received tap water only.
    Acetaldehyde was administered to 50 male and 50 female Sprague-Dawley
    rats beginning at six weeks of age at concentrations of 2,500, 1,500,
    500, 250, 50, or 0 mg/L.
    Animals were kept under observation until spontaneous death.
    Formaldehyde and acetaldehyde were found to produce an increase in total
    malignant tumors in the treated groups and showed specific carcinogenic
    effects on various organs and tissues. PMID: 12562630

    Surely the authors deliberately emphasized that aspartame is well-known
    to be a source of formaldehyde, which is an extremely potent, cumulative
    toxin, with complex, multiple effects on all tissues and organs.

    This is even more significant, considering that they have already tested
    aspartame, but not yet released the results: [ comment made spring, 2003 ]

    p. 29-32 Table 1: The Ramazzinni Foundation Cancer Program
    Project of [200] Long-Term Carcinogenicity Bioassays: Agents Studied

    No. No. of Bioassays Species No. Route of Exposure
    108. "Coca-Cola" 4 Rat 1,999 Ingestion, Transplantal Route
    109. "Pepsi-Cola" 1 Rat 400 Ingestion
    110. Sucrose 1 Rat 400 Ingestion
    111. Caffeine 1 Rat 800 Ingestion
    112. Aspartame 1 Rat 1,800 Ingestion

    http://members.nyas.org/events/confe...f_02_0429.html
    Soffritti said that Coca-Cola showed no carcinogenicity.
    ************************************************** ***********

    http://www.annalsnyas.org/content/vol982/issue1/ Table of Contents
    Ann N Y Acad Sci. 2002 Dec; 982: 87-105.
    Results of long-term experimental studies on the carcinogenicity of
    formaldehyde and acetaldehyde in rats.
    Soffritti M, Belpoggi F, Lambertin L, Lauriola M, Padovani M, Maltoni C.
    Cancer Research Center, European Ramazzini Foundation for Oncology and
    Environmental Sciences, Bologna, Italy. crcfr@tin.it
    MORANDO SOFFRITTI, FIORELLA BELPOGGI, LUCA LAMBERTIN, MICHELINA LAURIOLA,
    MICHELA PADOVANI, and CESARE MALTONI

    Formaldehyde was administered for 104 weeks in drinking water supplied ad
    libitum at concentrations of 1500, 1000, 500, 100, 50, 10, or 0 mg/L to
    groups of 50 male and 50 female Sprague-Dawley rats beginning at seven weeks
    of age. Control animals (100 males and 100 females) received tap water only.
    Acetaldehyde was administered to 50 male and 50 female Sprague-Dawley rats
    beginning at six weeks of age at concentrations of 2,500, 1,500, 500, 250,
    50, or 0 mg/L.
    Animals were kept under observation until spontaneous death.
    Formaldehyde and acetaldehyde were found to produce an increase in total
    malignant tumors in the treated groups and showed specific carcinogenic
    effects on various organs and tissues. PMID: 12562630


    Ann N Y Acad Sci. 2002 Dec; 982: 46-69.
    Results of long-term experimental studies on the carcinogenicity of methyl
    alcohol and ethyl alcohol in rats.
    Soffritti M, Belpoggi F, Cevolani D, Guarino M, Padovani M, Maltoni C.
    Cancer Research Center, European Ramazzini Foundation for Oncology and
    Environmental Sciences, Bologna, Italy. crcfr@tin.it
    MORANDO SOFFRITTI, FIORELLA BELPOGGI, DANIELA CEVOLANI, MARINA GUARINO,
    MICHELA PADOVANI, and CESARE MALTONI

    Methyl alcohol was administered in drinking water supplied ad libitum at
    doses of 20,000, 5,000, 500, or 0 ppm to groups of male and female
    Sprague-Dawley rats 8 weeks old at the start of the experiment.
    Animals were kept under observation until spontaneous death.
    Ethyl alcohol was administered by ingestion in drinking water at a
    concentration of 10% or 0% supplied ad libitum to groups of male and female
    Sprague-Dawley rats;
    breeders and offspring were included in the experiment.
    Treatment started at 39 weeks of age (breeders),
    days before mating,
    or from embryo life (offspring)
    and lasted until their spontaneous death.
    Under tested experimental conditions,
    methyl alcohol and ethyl alcohol were demonstrated to be carcinogenic for
    various organs and tissues.
    They must also be considered multipotential carcinogenic agents.
    In addition to causing other tumors,
    ethyl alcohol induced malignant tumors of the oral cavity, tongue, and lips.
    These sites have been shown to be target organs in man by epidemiologic
    studies. Publication Types: Review Review, Tutorial PMID: 12562628


    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

    http://www.epa.gov/iris/subst/0305.htm
    also http://www.china-pops.net/enwww/IRIS...subst/0305.htm 1998.05.05

    USA Environmental Protection Agency EPA
    Integrated Risk Information System IRIS

    This site explains that the harmful rat dose of 500 mg/kg body weight per
    day was divided
    by 10 for "interspecies extrapolation" (the higher vulnerability of
    humans than rats),
    by 10 for "range of sensitivity" (the variation of individual human
    vulnerability), and
    by 10 for "subchronic to chronic exposure" (the increased danger from
    lifetime as compared to the 3 month exposure in the rat test),
    giving a total reduction of 10x10x10 = 1000 for the UF = Uncertainty Factor.

    The human Oral RfD is the rat Oral RfD divided by 1000, so
    500 mg/kg/day is reduced to 0.5 mg/kg/day , so that the allowed dose for a
    60 kg human is 30 mg oral methanol daily.

    Moreover, a recent study found that after 4 months of moderate oral
    aspartame, 12 rats took four times longer to finish a simple, one-turn
    maze-- an alarming level of neurotoxicity:

    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

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

    Rats that had received aspartame (250 mg/kg/day) in the drinking water
    for 3 or 4 months showed a significant increase in time to reach the reward
    in the T-maze, suggesting a possible effect on memory due to the artificial
    sweetener."

    [ The 2005 Ramazzini study found that 2 years ingested aspartame at 20, 100,
    500, 2,500, and 5,000 mg/kg levels all produced a significant, substantial
    increase in female rats of lymphomas and leukaemias by the time of natural
    death. ]

    The 11% methanol component of aspartame is immediately released in the GI
    tract, so these rats were being exposed to only 27.5 mg/kg/day methanol.

    The EPA IRIS on 1998.05.05 used a 1986 90 day rat study to find a
    No-Observed-Effect Level (NOEL) value of 500 mg/kg/day, which, divided by
    1000, became their human long-term safe methanol level of 0.5 mg per kg body
    weight per day, which for a 60 kg average person is 30 mg methanol daily,
    for oral exposure.

    However, the rat level is 18 times greater than that for the level of
    dramatic memory loss and clear-cut brain changes found by McConnaughey M,
    May 2004.

    This suggests reducing the human long-term safe level twenty times to
    .025 mg/kg/day = 25 micrograms per kg body weight per day,
    which for a 60 kg average person is 1.5 mg oral methanol per day.

    Since methanol from any source, once in the human blood stream, is always
    quickly and largely turned into formaldehyde and then formic acid, resulting
    in durable retained cumulative complex toxic products, this implies a
    somewhat smaller formaldehyde ingestion limit. A third of the methanol
    would lead to a limit of 0.5 mg ingested and inhaled formaldehyde daily for
    a 60 kg average person.


    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

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

    Dark wines and liquors, as well as aspartame, provide similar levels of
    methanol, above 100 mg daily, for long-term heavy users. Methanol is
    inevitably largely turned into formaldehyde, and thence largely into formic
    acid.

    Both products are toxic, and at this level of use, about 2 L daily,
    almost six 12-oz cans of diet drink, are above recent lifetime EPA
    safety limits in tap water for methanol and formaldehyde of respectively,
    for a 60 kg person, 30 mg and 9 mg daily. The 1999 EPA level for
    formaldehyde in drinking water was 1 ppm, while recent WHO levels are 2.6
    ppm.

    The immediate health effects for dark wines and liquors are the infamous
    "morning after" hangover, for which many informed experts cite as the major
    cause the conversion of the methanol impurity, over one part in ten thousand
    (red wine has 128 mg/L methanol), into formaldehyde and formic acid.
    Everyone knows the complex progression of symptoms at this level of
    long-term, chronic toxicity.

    Aspartame reactors have a very similar progression.

    If 1% of all people exposed to aspartame are heavy users with symptoms, then
    there would easily be about 2 million cases in the USA alone.

    This is a public health emergency.

    At the very least, professionals and the public should be alerted to
    investigate their own exposure, and be given a chance to try a very safe,
    simple, inexpensive treatment for complex, intractable, progressive
    symptoms -- reducing or eliminating their intake.

    There are as well, many safe substances that prevent or treat the
    toxicities -- for example, high folic acid levels expedite the elimination
    of formaldehyde.

    These toxicities are largely uncontrolled co-factors that affect every
    disease and must confuse and impede many health research programs on all
    levels.

    People in high-pressure, critical occupations, such as pilots, nuclear plant
    operators, and national leaders, should certainly be alerted.

    Also, two careful studies show substantial methanol release from degradation
    of pectins by bacteria in the colon from fruits and vegetables -- a topic
    that deserves careful, thorough research.

    Due to my bias, based on detailed reviews by Monte WC (1984)
    and by Mark D Gold (2003), for months I have been discounting the
    startlingly high methanol levels reported in the abstract for Lindinger W
    (1997). I had been reducing the values in their abstract from g to mg, an
    unwarrented "correction" by a factor of a thousand, only to find that
    thefull text study and their many related studies supply expert, robust
    results:

    Alcohol Clin Exp Res. 1997 Aug; 21(5): 939-43.
    Endogenous production of methanol after the consumption of fruit.
    Lindinger W, Taucher J, Jordan A, Hansel A, Vogel W.
    Institut fur Ionenphysik, Leopold Franzens Universitat Innsbruck, Austria.

    After the consumption of fruit, the concentration of methanol in the human
    body increases by as much as an order of magnitude.
    This is due to the degradation of natural pectin (which is esterified with
    methyl alcohol) in the human colon.
    In vivo tests performed by means of proton-transfer-reaction mass
    spectrometry show that consumed pectin in either a pure form (10 to 15 g)
    or a natural form (in 1 kg of apples) induces a significant increase of
    methanol in the breath (and by inference in the blood) of humans.
    The amount generated from pectin (0.4 to 1.4 g) [ 400 to 1400 mg ]
    is approximately equivalent to the total daily endogenous production
    (measured to be 0.3 to 0.6 g/day) [ 300 to 600 mg ]
    or that obtained from 0.3 liters of 80-proof brandy
    (calculated to be 0.5 g). [ 500 mg ]
    This dietary pectin may contribute to the development
    of nonalcoholic cirrhosis of the liver. PMID: 9267548

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

    Using proton transfer reaction-mass spectrometry for trace gas analysis of
    the human breath, the concentrations of methanol and ethanol have been
    measured for various test persons consuming alcoholic beverages and various
    amounts of fruits, respectively.
    The methanol concentrations increased from a natural (physiological) level
    of approximately 0.4 ppm up to approximately 2 ppm a few hours after eating
    about 1/2 kg of fruits,
    and about the same concentration was reached after drinking of 100 ml brandy
    containing 24% volume of ethanol and 0.19% volume of methanol.
    [ In 100 ml brandy, 19 gr ethanol and 150 mg methanol.
    A pound of fruit gives about as much methanol as 2 L (nearly 6 cans) diet
    soda. ]
    PMID: 8561283

    I urge Channing Laboratory and its participating universities to rapidly
    mount an in-house study to study the Nurses Health Study database for the
    hundreds of nurses who are long-term users, above 6 cans diet drinks daily,
    for correlations with every disease, as well as ubiquitous co-factors like
    wine and liquor, cigarette smoke, and fruits and vegetables. It could
    vastly serve the world public health to make the initial findings widely
    available immediately. The disparaged issue of aspartame toxicity could be
    swiftly made legitimate, and the resulting progress on all levels remarkably
    accelerated.

    A single scientist could do this.

    Comments pro and con are welcome. A convenient venue would be
    the moderated Usenet group: bionet.toxicology.


    http://groups.yahoo.com/group/aspartameNM/message/1184
    corporate corruption of health sciences, International Journal of
    Occupational and Environmental Health, entire issue, 2005 Oct-Dec: Gary N
    Greenburg, OEM-L: aspartame (methanol, formaldehyde, formic acid) toxicity,
    Murray 2005.07.14

    http://groups.yahoo.com/group/aspartameNM/message/1155
    continuing aspartame debate in British Medical Journal, John Biffra, Bob
    Dowling, Nick Finer, Ian J Gordon: Murray 2005.02.09 rmforall

    http://groups.yahoo.com/group/aspartameNM/message/782
    RTM: Smith, Terpening, Schmidt, Gums:
    full text: aspartame, MSG, fibromyalgia 2002.01.17 rmforall
    Jerry D Smith, Chris M Terpening, Siegfried OF Schmidt, and John G Gums
    Relief of Fibromyalgia Symptoms Following
    Discontinuation of Dietary Excitotoxins.
    The Annals of Pharmacotherapy 2001; 35(6): 702-706.
    Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL, USA.
    BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is
    often difficult to treat effectively.
    CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome
    for two to 17 years are described.
    All had undergone multiple treatment
    modalities with limited success. All had complete, or nearly complete,
    resolution of their symptoms within months after eliminating monosodium
    glutamate (MSG) or MSG plus aspartame from their diet.
    All patients were women with multiple comorbidities
    prior to elimination of MSG.
    All have had recurrence of symptoms whenever MSG is ingested.

    Siegfried O. Schmidt, MD Asst. Clinical Prof. siggy@shands.ufl.edu
    Community Health and Family Medicine, U. Florida, Gainesville, FL
    Shands Hospital West Oak Clinic Gainesville, FL 32608-3629
    352-376-5071
    ************************************************** ************
    Send blank post to: <br />aspartameNM-subscribe@onelist.com to join<br />free,open, list with searchable archives for toxicity issues.<br />Richard \"Rich\" T. Murray Room For All 1943 Otowi Road Santa Fe, NM 87505<br />rmforall@comcast.net 505-501-2298

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