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safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF: Murray 1.12.3 rmforall: FDA Docket 02P-0317 Recall Aspartame as a Neurotoxic Drug

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  • Rich Murray
    http://groups.yahoo.com/group/aspartameNM/message/957 safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF: Murray 1.12.3 rmforall: FDA Docket 02P-0317 Recall
    Message 1 of 1 , Jan 12, 2003
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      http://groups.yahoo.com/group/aspartameNM/message/957
      safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
      Murray 1.12.3 rmforall:
      FDA Docket 02P-0317 Recall Aspartame as a Neurotoxic Drug

      Please post this to the FDA Dockets website.

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

      Jan 12 2003 How sad and how harmful is this "review", which
      parrots the industry's standard PR lines,
      dismisses without adaquate assessment key contrary studies,
      accepts uncritically very weak supportive studies,
      justifies ignoring thousands of customer and physician reports,
      omits very relevent recent studies,
      are uninformed about new general theories about toxic processes in
      various diseases in the catagory of fibromyalgia and multiple chemical
      sensitivity, and fails to see the urgent need to do
      competent, unbiased, thorough, detailed, and definitive research on the
      actual biochemical disposition of the toxic metabolites of aspartame in
      long-term heavy users, who in unknown numbers develop the typical
      complex serious symptom syndrome, often becoming extremely sensitive to
      doses as small as a single migraine pill, 4 mg aspartame, 2% of the
      aspartame in a single 12-oz diet soda.
      Links to scores of reviews and full texts of studies in the mainstream
      scientific literature are given at the end of this post.

      http://www.foodstandards.gov.uk/multimedia/pdfs/aspartameopinion.pdf
      B-1049 Bruxelles/ B-1049 Brussels- Belgium
      Telephone: exchange (+32-2) 299 11 11 Fax: (+32-2) 299 48 91
      http: europa.eu.int/comm/food/fs/sc/scf/index_en.html
      EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL
      Directorate C-- Scientific Opinions C2-- Management of scientific
      committees II; scientific co-operation and networks
      Scientific Committee on Food SCF/CS/ADD/EDUL/222 Final
      10 December 2002 Opinion of the Scientific Committee on Food:
      Update on the Safety of Aspartame (expressed on 4 December 2002) [p2]

      Terms of Reference
      The Committee is asked to review all new scientific information on
      aspartame not having been examined by the SCF previously, taking into
      account, notably, the literature search carried out in the UK.

      Background
      The intense sweetener, aspartame, is used in a wide range of food
      products in many countries around the world and is authorised for use in
      the EU (E951). It has the following structure:

      The Scientific Committee for Food (SCF) initially evaluated aspartame
      (L-aspartyl-L-phenylalanine methyl ester) during 1984 (SCF, 1985) and
      subsequently during 1988 (SCF, 1989).
      At its 107th meeting in June 1997, the SCF also examined the issue of an
      alleged connection between aspartame and increase in incidence of brain
      tumours in the USA (SCF, 1997).
      Aspartame has also been considered by other bodies including the Joint
      FAO/WHO Expert Committee on Food Additives (JECFA, 1980) the US Food and
      Drug Administration (FDA, 1984), and the UK Committee on Toxicity (COT,
      1992).
      The toxicity data on aspartame were used by the JECFA, SCF and COT to
      establish an Acceptable Daily Intake (ADI) of 40 mg/kg body weight/day
      and an ADI of 50 mg/kg bw/d was established by the FDA.

      An ADI of 7.5 mg/kg bw/d was also established for a minor cyclic
      dipeptide derivative of aspartame, a diketopiperazine (DKP), which
      is formed in some aqueous solutions (JECFA, 1980; SCF, 1985).

      The safety issues that have been raised in the past about aspartame have
      included:
      (1) the possibility of toxicity from methanol, one of the breakdown
      products of aspartame;
      (2) elevations in plasma concentrations of phenylalanine (Phe) and
      aspartic acid, which could result in increased transport of these amino
      acids into the (p3) brain, altering the brain's neurochemical
      composition;
      (3) the possibility of neuroendocrine changes, particularly increased
      concentrations in the brain, synaptic ganglia and adrenal medulla of
      catecholamines derived from Phe and its hydroxylation product, tyrosine;
      and (4) a postulated link with epilepsy and brain tumours.
      All these areas have been addressed in the pre-1988 literature and in
      more recent reviews (Meldrum, 1993; Lajtha et al., 1994; Tschanz et al.,
      1996).
      The safety of aspartame and its metabolic breakdown products
      (phenylalanine, aspartic acid and methanol) has been assessed in humans
      generally and in several subgroups, including healthy infants, children,
      adolescents, adults, obese individuals, diabetics, lactating women, and
      individuals heterozygous for the genetic disease, phenylketonuria (PKU),
      who have a compromised ability to metabolise the essential amino acid,
      Phe.
      Since its approval, aspartame has undergone further investigation
      through clinical and laboratory research, intake studies and
      postmarketing surveillance of anecdotal reports of adverse health
      effects.
      The present review updates the previous SCF opinions in the light of new
      reports on the consumption of aspartame in relation to the onset of
      brain tumours and seizures, headaches, allergies, and changes in
      behaviour and cognitive function.
      Information on the safety of aspartame was available from a variety of
      sources including scientific papers, conference proceedings, abstracts
      and magazine articles.
      This review focuses on papers published in the open scientific
      literature from 1988 to 2001 and draws on the recent extensive review by
      the Agence Française de Sécurité Sanitaire des Aliments (AFSSA, 2002),
      which covered mutagenic, carcinogenic and neurological effects.

      Exposure assessment
      European Commission report on Food Additive Intake
      In the European Commission report on Dietary Food Additive Intake in the
      European Union (EC, 2001), estimates of intake were calculated using a
      tiered approach.
      Tier 1 is based on theoretical food consumption data and maximum usage
      levels for additives as permitted by relevant Community legislation.
      The second and third tiers refer to assessment at the level of
      individual Member States, combining national data on food consumption
      with the maximum permitted usage levels for the additive (Tier
      2) and
      with its actual usage patterns (Tier 3).
      Aspartame has been examined at Tier 1 for adults and
      at Tier 2 for children.
      Aspartame intakes for adults were estimated at Tier 1 to be 21.3 mg/kg
      bw/day in the European Union. The Tier 1 approach is likely to be an
      overestimate of actual intake even by high level consumers of
      aspartame-sweetened foods.
      More refined intake [p4] estimates (Tier 2) were performed for children.
      Information from individual member states showed that the refined
      estimated intake for children was 1-40% of the ADI.
      Therefore aspartame was excluded from further consideration as both
      adults and children were shown to be unlikely to exceed the ADI of 40
      mg/kg bw.

      Other published intake estimates for European countries
      In addition to the Commission report, a number of reports have been
      published from 1990 onwards with estimates of aspartame intake in
      European countries (Bär and Biermann, 1992; Butchko and Stargel, 2001;
      Garnier-Sagne et al., 2001; Hinson and Nicol, 1992; Leclercq et al.,
      1999; MAFF, 1990 and 1995; Renwick, 1990; Salminen and Penttilä, 1999).

      The table below shows the highest reported intake estimates for
      different age groups of the general population and people with diabetes.
      The data are based on actual food consumption combined with the actual
      sweetener levels present in the foods (equivalent to Tier 3 in the
      Commission report) or the maximum permitted aspartame levels (Tier 2).
      The estimates of intake by mean and high level consumers are fairly
      consistent between European countries even though slightly different
      approaches were used.

      High level consumers, both adults and children, are unlikely to exceed
      the ADI of 40 mg/kg bw for aspartame.

      Special groups such as diabetics that are likely to be high consumers of
      foods containing aspartame are also well below the ADI.

      Therefore, from the available data it appears that no group is likely to
      exceed the ADI for aspartame on a regular basis.

      Table: Highest reported intake estimates for aspartame
      Consumer group
      Country
      Mean consumer intake in mg/kg bw/d
      High level consumer intake in mg/kg bw/d
      (percentile quoted)
      Reference
      Children 1-5 years old UK - 2.8 (90) Hinson & Nicol, 1992
      Children 1-6 years old Finland - <4 (-) Salminen & Penttilä, 1999
      All ages Netherlands - 2.4 7.5 (95) Butchko & Stargel, 2001
      All ages Norway 3.4 - Butchko & Stargel, 2001
      Diabetics* 2-20 years old France 2.4 7.8 (97.5) Garnier-Sagne et
      al., 2001
      Diabetics 2-65 years old UK - 10.1 (97.5) MAFF, 1995
      * using maximum permitted level of sweeteners in different food
      categories (Tier 2 approach). All the other figures are derived using
      actual sweetener levels present in foods. [p5]

      Absorption, distribution, metabolism and excretion
      The metabolism of aspartame and its metabolic breakdown products in
      animals, healthy individuals and in PKU subjects has been
      comprehensively reviewed by Lajtha et al. (1994).

      Aspartame is metabolised by gut esterases and peptidases to three common
      dietary components-- two amino acids (aspartic acid and Phe) and
      methanol.

      Animal studies have demonstrated that the metabolic breakdown products
      of aspartame are absorbed and metabolised similarly whether they are
      given alone or derived from aspartame.

      The extensive presystemic metabolism of aspartame results in little or
      no parent compound reaching the general circulation.

      Initial studies focused on the effects of ingesting single bolus doses
      of aspartame on plasma aspartate and Phe levels and blood methanol
      concentrations in normal adults.

      These studies were done with doses of aspartame approximating current
      levels of dietary exposure (4 and 10 mg/kg bw), doses representative of
      premarketing projections of the high level intake and the ADI (34 and 40
      mg/kg bw respectively), and ‘abuse’ doses of 100, 150 and 200 mg/kg bw
      (Stegink and Filer 1996).

      The plasma Phe concentrations in healthy adults administered various
      doses of aspartame have been compared to values obtained:
      (1) in the fasting and postprandial state;
      (2) in individuals who are heterozygous for PKU; and
      (3) in subjects with various forms of hyperphenylalaninaemia other than
      PKU (Stegink et al 1990; Stegink and Filer, 1996).
      The data indicated that the plasma Phe concentrations after single bolus
      doses (ranging between 4 and 50 mg/kg bw) and repeated doses (30 and
      69 mg/kg bw given as 3 and 8 divided doses respectively) of aspartame
      were generally within the normal postprandial range for this amino acid
      and well below those measured in subjects homozygous for PKU after
      ingestion of aspartame.
      The aspartate component is rapidly metabolised and thus the plasma
      aspartate concentrations are not significantly elevated following
      aspartame doses of 34 to 50 mg/kg bw, whereas plasma Phe concentrations
      may increase depending on dose (Stegink, 1984).
      Methanol is also rapidly metabolised and blood levels are usually
      not detectable unless large bolus doses of aspartame (>50 mg/kg bw) are
      administered.

      Genotoxicity and carcinogenicity
      The available mutagenicity and long-term carcinogenicity studies on
      aspartame were recently reviewed by AFSSA (2002). AFSSA noted that:
      “Aspartame is not genotoxic in a reverse mutation test on S.
      typhimurium, in two chromosome aberration tests in vivo on somatic cells
      and in Rodent [p6] dominant lethal test on germ cells (JECFA, 1980).

      Recently, two studies have confirmed the absence of clastogenic
      potential (Durnev et al., 1995; Mukhopadhyay et al., 2000) of the
      compound.”

      The AFSSA report also noted:
      “Trocho et al., (1998) demonstrated that aspartame, radio-labelled on
      the methanol, induced in the liver stable DNA and protein adducts.
      According to these authors, the accumulation of these adducts after
      repeated administration of aspartame could pose problems of toxicity and
      carcinogenicity in the long term. Besides the fact that aspartame at
      high doses has never induced liver cancer in rats, Trocho's studies did
      not identify the radioactivity found in the proteins and DNA.
      Consequently, the formation of adducts of formaldehyde
      on the proteins and nucleic acids from aspartame, in vivo, remains to be
      proved (Tephly, 1999).”

      As regards the long-term studies, the AFSSA report noted that:
      “In a carcinogenicity study on CD-1 mice (FDA, FR 1981), aspartame
      administered in feed at doses of 1, 2 and 4 g/kg bw/day for 110 weeks,
      showed no carcinogenic potential.”

      “Three carcinogenicity studies were conducted in Sprague Dawley and
      Wistar rats. In the first study (1973), post-weaning Sprague Dawley rats
      were fed doses of aspartame corresponding to 1, 2, 4, 6/8 g/kg bw/day
      for 104 weeks (6/8 i.e. dose of 6 was increased during the study to 8
      g/kg bw/day). In the second study (1974), male and female Sprague Dawley
      rats, from a twogeneration study, were exposed during gestation,
      lactation and after weaning for 104 weeks, to doses of 0, 2 and 4 g/kg
      bw/day in their food. The results of these two studies have been widely
      discussed by the scientific community and the regulatory authorities
      (FDA). In the first study, the incidence of brain tumours in the treated
      animals was higher than in the control animals but without any
      dose-response relationship. In contrast, in the second study the
      incidence of tumours in the treated rats was lower than in the control
      group.
      For these reasons, a third study was conducted under conditions of Good
      Laboratory Practice in order to ensure the reliability of the
      experimental data.
      In this third study (Ishii, 1981), groups of male and female Wistar rats
      were given doses of aspartame of 0, 1, 2, 4 g/kg bw/day for 104 weeks.
      Under these conditions, aspartame did not cause any increase in the
      incidence of brain tumours.”

      AFSSA concluded as follows on carcinogenicity:
      “Taking into account all the studies that have been conducted, the
      frequency of spontaneous tumours in laboratory rats, the types of
      tumours observed and the absence of a dose-response relationship, it was
      concluded that aspartame had no carcinogenic potential on the brain in
      experimental animals (FDA FR, 1981-1984; Koestner, 1984; Cornell et al.,
      1984; Flamm, 1997).” [p7]

      Epidemiological data
      Concerning the epidemiological data on brain tumours, the AFSSA (2002)
      report noted that:
      “In 1996, Olney et al. published an article on a possible link between
      the increase in the frequency of brain tumours in humans and the
      consumption of aspartame in the United States. Based on the data from
      the National Cancer Institute (10% of the population) from 1975-1992,
      the authors concluded that there was a significant increase in the
      frequency of brain tumours in the mid-1980s, that is to say the period
      following aspartame came onto the market. The conclusions of this
      epidemiological study have been criticised by a number of scientists who
      questioned the methodology, the use of the data and their
      interpretation (Levy et al., 1996; Linet et al., 1999; Ross, 1998;
      Seife, 1999; Smith et al., 1998). One of the major criticism is that the
      authors only took into account the frequency of brain tumours during a
      selected period (1975-1992). When all the epidemiological data are used
      (1973-1992) a different conclusion is reached, as the frequency of brain
      cancers began to increase in 1973 and stabilised from the mid-1980s
      (Levy et al., 1996). Furthermore, Olney et al. did not provide any
      quantitative or qualitative relationship between the exposure of the
      population to aspartame and the observed frequency of brain tumours.
      Finally, an increase in the incidence of the tumours can have many
      causes including, among others, improvements in diagnostic methods
      (Modan et al., 1992).”

      “More recently, Gurney et al., (1997) published the results of a
      case-control study on the relationship between the consumption of
      aspartame and the frequency of brain tumours. The study covered 56
      patients affected by tumours in childhood and 94 controls. According to
      these authors, no relationship could be established between the
      consumption of aspartame and the frequency of brain tumours.”

      “In France, data on the incidence of and mortality from brain cancers
      were supplied by the FRANCIM network (F. Ménégoz et al., 2001). These
      cancers include meninges tumours and tumours of the brain itself.
      Between 1980 and 1997, the incidence (number of new cases appearing each
      year) of cerebral tumours was relatively stable in men and showed a
      slight increase in women. The trend towards an increase in mortality
      from cancer of the brain and other parts of the nervous system is a
      longstanding one, as it first appeared in 1950 and continues to the
      present day, for both sexes. However, during the last decade, mortality
      in men stabilised and the increase in mortality from brain cancer in
      women was less pronounced than during the preceding period.”

      “In France, the epidemiological data from the cancer registers do not
      enable a definitive indication to be given on a possible aspartame-brain
      tumour relationship, but they do show that, at the present time, the
      sale of this food additive in France is not being accompanied by an
      increase in the frequency of brain tumours or increased mortality from
      this disease in the general population.” [p8]

      Reproduction and Developmental toxicity
      The derivation of an ADI for aspartame by JECFA (1980) and the SCF
      (1985) included assessment of single- and multi-generation studies in
      animals that were specifically designed to examine the possible effects
      of aspartame and its metabolic conversion products on reproduction, and
      development, including neuro-development.

      The data used by JECFA (1980) were discussed in more recent reviews
      (Kotsonis and Hjelle, 1996; London and Rorick, 1996; Shaywitz, 1997;
      AFSSA, 2002), but no additional studies were identified which would
      impact on the no-observed-adverse-effect-level (NOAEL).

      Neurological effects Much of the recent interest in the safety of
      aspartame has explored whether its consumption is linked with
      neurological effects. Therefore this end point has been given special
      consideration in this review.

      Shortly after the widespread marketing of aspartame, there were a number
      of anecdotal reports of health effects, which some consumers related to
      their consumption of aspartame-containing products (Hull, 1999). Most of
      the earlier complaints and reports of aspartame-related adverse
      reactions were analysed by experts at the Centres for Disease Control
      (CDC) in Atlanta on behalf of the FDA, who concluded that there was no
      symptom complex that could be assigned to the ingestion of aspartame
      (Janssen and Van der Heijden, 1988; Tollefson, 1988).

      A number of complaints were of a neurological or behavioural type
      (Tollefson, 1988) and these received special consideration, in part
      because experiments in animals have shown that high doses (1000mg/kg bw
      and above in rats) can alter the concentrations of neurotransmitters and
      their precursors within the central nervous system (Lajtha et al.,
      1994).

      As regards the potential effect of aspartame on neurotransmitter levels,
      the underlying hypothesis was that aspartame, as a source of Phe without
      the other large neutral amino acids (LNAA) (i.e. tryptophan, valine,
      leucine, methionine, histidine) which compete for transport across the
      blood-brain barrier, would increase the serum ratio of Phe to the other
      LNAA, thereby selectively increasing Phe concentrations in brain. It
      was further suggested that such increased entry of Phe into the brain
      may result in disturbances in monoaminergic neurotransmission (Wurtman,
      1985).

      A number of animal studies were conducted to determine whether increases
      in plasma Phe concentrations secondary to large doses of aspartame may
      result in changes in brain concentrations of norepinephrine, dopamine,
      or serotonin and their metabolites (reviewed by Schomer et al., 1996;
      Lajtha et al., 1994). Although effects on neurotransmitter levels were
      noted in some acute and repeat-dose studies at high doses in rodents, it
      was apparent that these effects were not consistent or reproducible.

      For instance, acute doses of up to 2000 mg/kg bw/d and repeated doses of
      up to 863 mg/kg bw/d (for 28 days) failed to induce significant changes
      in brain serotonin or dopamine levels and had no effect on seizure
      severity in rats genetically prone to epilepsy (Dailey et al., 1991).

      Some changes in neurotransmitter levels in rodents were also identified
      in some of the older studies on aspartame (Lajtha et al., 1994). In mice
      given aspartame orally at 13,130 and 650 mg/kg bw, increases of 12, 49
      and 47% respectively in norepinephrine were found after 3 hours in the
      hypothalamus; significant increases in norepinephrine in the medulla
      oblongata (in the low- and high-dose group animals) and corpus striatum
      (in the low-dose group animals) were also observed (Coulombe and Sharma,
      1986). However, these increases were not dose-related and were
      accompanied by non-significant changes in serotonin levels.

      Lack of any significant effects on biogenic amine levels, following
      higher bolus doses (1000 mg/kg bw) of aspartame, have also been reported
      in both Sprague-Dawley and Fischer 344 rats (Freeman et al., 1990).
      Glutamic and aspartic acids act as excitatory neurotransmitters at
      glutamate receptor sites to which aspartic acid also shows affinity.

      A more recent study evaluated brain glutamatergic receptor kinetics
      following perinatal exposure to large doses of aspartame (500 mg/kg
      bw/day) (Reilly and Lajtha, 1995). In this study aspartame in drinking
      water was administered to Sprague-Dawley rats throughout gestation and
      lactation. The kinetics of the N-methyl-D-aspartate receptor and total
      glutamatergic binding in cerebral cortex and hippocampus of the
      offspring (20-22 days old) were found to be unaffected by perinatal
      exposure to aspartame. However, statistically significant but reversible
      reductions in glutamic acid levels in both brain regions and of
      aspartate in the hippocampus were noted.

      The same group of workers reported an absence of effects on
      dopaminergic, adrenergic and serotonergic receptor binding kinetics in
      adult rat brain with chronic exposure to aspartame (Reilly et al.,
      1989).

      Behaviour, Cognition and Mood
      Some years ago, it was hypothesised that aspartame, primarily due to its
      content of Phe, could have an effect on human behaviour, cognition, and
      possibly on measures of physiological function (Wurtman, 1985). However,
      no consistent and reproducible effects were observed in a number of
      older animal studies investigating the effects of aspartame on
      neurotransmitter levels. [p10]

      Only a limited number of studies on behavioural aspects in animals have
      been published in the last ten years. A proportion of these focused on
      seizure activity but a causal link with aspartame could not be
      established; no adverse effects on other aspects of behaviour and
      cognition were reported in experimental animals when aspartame was given
      at oral dose levels of up to 2000 mg/kg bw/day (Yirmiya et al., 1989;
      Tilson et al., 1991; Mullenix et al., 1991; Vitulli et al., 1996; LaBuda
      and Hale, 2000; Goerss et al., 2000).

      A number of anecdotal reports in humans were received by the
      manufacturers of aspartame in early to mid 1980's relating to a variety
      of symptoms following the marketing of aspartame in the USA. About
      two-thirds of these symptoms fell into the neurobehavioural category
      (Butchko and Stargel, 2001). These consisted mostly of headaches (see
      below), mood alterations, insomnia, and dizziness. More than 500
      reports were received by CDC, and almost half underwent follow-up and
      evaluation.
      A post-marketing surveillance system was developed by the NutraSweet
      company (Butchko and Kotsonis, 1994; Butchko et al., 1996), which was
      followed by scientific research on these neurological symptoms (see
      below).

      A number of scientific studies were carried out in healthy and
      potentially sensitive individuals, including children, to test whether
      the consumption of aspartame was associated with behavioural and
      cognitive changes. The potentially sensitive individuals studied were,
      heterozygotes for PKU, individuals suffering from depression, Attention
      Deficit Disorder (ADD), Parkinson’s Disease, epilepsy or other
      suspected seizures. They included double-blind studies in children
      (Saravis et al., 1990; Shaywitz et al., 1994) in which no effects were
      observed on behaviour, mood or learning when aspartame was given as a
      drink at single and multiple doses of 34 mg/kg bw/day for up to two
      weeks.

      The longer term study of Shaywitz et al.(1994) examined the effect of
      aspartame in children with ADD and included an assessment of
      liver function as well as measurement of plasma levels of amino acids,
      serotonin and monoamine metabolites.

      Treatment-related effects were also absent in a study of preschool
      children who were given aspartame at 32 mg/kg bw/day and described as
      sugar sensitive by their parents (Wolraich et al., 1994).

      A number of double-blind behavioural studies of variable quality in
      healthy adults, involving single and repeated administrations of
      aspartame have also been conducted. No treatment-related effects were
      noted in tests on a range of cognitive parameters in studies employing
      single administrations of aspartame at doses of up to 60 mg/kg
      bw/day (Lieberman et al., 1988; Lapierre et al., 1990; Pivonka and
      Grunewald, 1990; Stokes et al., 1991, 1994).

      However, it can be argued that single dosing studies employing high
      amounts of aspartame do not reflect typical consumption patterns.
      A number of longer term studies with a double-blind design involving
      multiple dosing in healthy individuals also failed to highlight any
      treatment-related adverse effects on [p11] behaviour (Spiers et al.,
      1998; Leon et al., 1989).

      As noted with shorter-term studies, no treatment-related effects on
      behaviour were noted even when aspartame was tested at 74 mg/kg bw/day
      for periods extending up to 24 weeks. Although Phe concentrations
      increased significantly as a result of treatment with aspartame, there
      were no significant effects noted on behaviour, mood or
      electroencephalogram (EEG) patterns, nor on a comprehensive battery of
      clinical laboratory tests. Headache was the most frequently reported
      adverse effect in placebo- and aspartame-treated groups but there were
      no significant differences noted between groups.

      Several subpopulations of individuals who may potentially be sensitive
      to aspartame have also been studied. From a double-blind study with a
      cross-over design in 13 depressed patients, Walton et al. (1993)
      concluded that aspartame (30 mg/kg bw/day for 7 days) increased the
      frequency and severity of adverse experiences in these individuals.
      These authors concluded that the use of aspartame in individuals with
      mood disorder should be discouraged. However, it is difficult to
      interpret this study since the authors numerically combined unrelated
      adverse effects to show a statistically significant result in depressed
      patients and only a limited number of subjects were available for
      evaluation due to premature termination of the study.

      The effect of aspartame on behaviour, cognition and EEG patterns has
      also been investigated in PKU heterozygotes. Older studies in PKU
      homozygotes and those heterozygous for the condition have been reviewed
      elsewhere (de Sonneville and Benninger, 1996, and references therein).
      Overall, the authors concluded that aspartame did not affect cognitive
      function and EEG profiles in either the general population or those
      heterozygous for PKU.

      In a more recent double-blind study, which included assessment of plasma
      amino acid levels and EEG patterns (Trefz et al., 1994), the subjects
      ingested aspartame (15 or 45 mg/kg bw/day) and placebo for 12 weeks. The
      battery of behavioural tests included tests for short-term memory,
      reaction time and various attention tasks. Although headaches were among
      the mild adverse symptoms reported, there was no statistically
      significant difference between treatments. There was a significant rise
      in Phe in the high-dose group in contrast to the low-dose group and this
      was also the case for the ratio of Phe to LNAA. However, aspartame had
      no significant effect on cognitive function or EEG profiles.
      [ Continued on Part 2/2 ]
      http://groups.yahoo.com/group/aspartameNM/message/958

      http://groups.yahoo.com/group/aspartameNM/message/932
      aspartame: methanol, formaldehyde, formic acid toxicity:
      brief review: Murray 1.10.3 rmforall

      http://groups.yahoo.com/group/aspartameNM/messages
      for 958 posts in a public searchable archive

      http://groups.yahoo.com/group/aspartameNM/message/910
      formaldehyde & formic acid from methanol in aspartame:
      Murray: 12.9.2 rmforall

      It is certain that high levels of aspartame use, above 2 liters daily
      for months and years, must lead to chronic formaldehyde-formic acid
      toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
      cans) is 123 mg methanol (wood alcohol), immediately released into the
      body after drinking (unlike the large levels of methanol locked up in
      molecules inside many fruits), then quickly transformed into
      formaldehyde, which in turn becomes formic acid, both of which in
      time become carbon dioxide and water-- however, about 30% of the
      methanol remains in the body as cumulative durable toxic metabolites of
      formaldehyde and formic acid-- 37 mg daily, a gram every month.
      If 10% of the methanol is retained as formaldehyde, that would give 12
      mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
      from 10% retention of the 2 mg EPA daily limit for formaldehyde in
      drinking water.

      Bear in mind that the EPA limit for formaldehyde in
      drinking water is 1 ppm,
      or 2 mg daily for a typical daily consumption of 2 L of water.

      http://groups.yahoo.com/group/aspartameNM/message/835
      RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
      5.30.2 rmforall

      This long-term low-level chronic toxic exposure leads to typical
      patterns of increasingly severe complex symptoms, starting with
      headache, fatigue, joint pain, irritability, memory loss, and leading to
      vision and eye problems and even seizures. In many cases there is
      addiction. Probably there are immune system disorders, with a
      hypersensitivity to these toxins and other chemicals.

      Confirming evidence and a general theory are given by Pall (2002):
      http://groups.yahoo.com/group/aspartameNM/message/909
      testable theory of MCS type diseases, vicious cycle of nitric oxide &
      peroxynitrite: MSG: formaldehyde-methanol-aspartame:
      Martin L. Pall: Murray: 12.9.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/946
      Functional Therapeutics in Neurodegenerative Disease Part 1/2:
      Perlmutter 7.15.99: Murray 1.10.3 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/915
      formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
      Wilson: CIIN: 12.12.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/934
      24 recent formaldehyde toxicity [Comet assay] reports:
      Murray 12.31.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/935
      comet assay finds DNA damage from sucralose, cyclamate, saccharin in
      mice: Sasaki YF & Tsuda S Aug 2002: Murray 1.1.3 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/938
      aspartame harms mice brain cells: Hetle & Eltervaag: 2001 thesis
      abstract: Sonnewald 1995 study, full text: Murray 1.5.3 rmforall

      http://www.dorway.com/tldaddic.html 5-page review
      Roberts HJ Aspartame (NutraSweet) addiction.
      Townsend Letter 2000 Jan; HJRobertsMD@...
      http://www.sunsentpress.com/ sunsentpress@...
      Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
      800-814-9800 561-588-7628 561-547-8008 fax

      http://groups.yahoo.com/group/aspartameNM/message/782
      RTM: Smith, Terpening, Schmidt, Gums:
      full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall
      Jerry D Smith, Chris M Terpening, Siegfried OF Schmidt, and John G Gums
      Relief of Fibromyalgia Symptoms Following
      Discontinuation of Dietary Excitotoxins.
      The Annals of Pharmacotherapy 2001; 35(6): 702–706.
      Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL, USA.

      http://groups.yahoo.com/group/aspartameNM/message/846
      Migraine MLT-Down: an unusual presentation of migraine
      in patients with aspartame-triggered headaches.
      Newman LC, Lipton RB Headache 2001 Oct; 41(9): 899-901.
      [Merck 10-mg Maxalt-MLT, for migraine, has 3.75 mg aspartame,
      while 12 oz diet soda has 200 mg.]

      http://groups.yahoo.com/group/aspartameNM/message/855
      RTM: Blumenthall & Vance:
      aspartame chewing gum headaches Nov 1997 7.28.2 rmforall
      Harvey J. Blumenthal, MD, Dwight A Vance, RPh
      Chewing Gum Headaches.
      Headache 1997 Nov-Dec; 37(10): 665-6.

      http://groups.yahoo.com/group/aspartameNM/message/925
      aspartame puts formaldehyde adducts into tissues, Part 1/2
      full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/926
      aspartame puts formaldehyde adducts into tissues, Part 2/2
      full text, Trocho & Alemany 6.26.98: Murray 12.22.2 rmforall

      http://ww.presidiotex.com/barcelona/index.html
      Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X,
      Fernandez-Lopez JA, Alemany M ["Trok-ho"]
      Formaldehyde derived from dietary aspartame binds to tissue
      components in vivo. Life Sci 1998 Jun 26; 63(5): 337-49.
      Departament de Bioquimica i Biologia Molecular, Facultat de Biologia,
      Universitat de Barcelona, Spain.

      http://groups.yahoo.com/group/aspartameNM/message/864
      Murray: Butchko, Tephly, McMartin: Alemany: aspartame formaldehyde
      adducts in rats 9.8.2 rmforall
      Prof. Alemany vigorously affirms the validity of the Trocho study
      against criticism:
      Butchko, HH et al [24 authors], Aspartame: review of safety.
      Regul. Toxicol. Pharmacol. 2002 April 1; 35 (2 Pt 2): S1-93, review
      available for $35, [an industry paid organ]. Butchko:
      "When all the research on aspartame, including evaluations in both the
      premarketing and postmarketing periods, is examined as a whole, it is
      clear that aspartame is safe, and there are no unresolved questions
      regarding its safety under conditions of intended use."
      [They repeatedly pass on the ageless industry deceit that the methanol
      in fruits and vegetables is as as biochemically available as that in
      aspartame-- see the 1984 rebuttal by Monte, below.]

      http://groups.yahoo.com/group/aspartameNM/message/911
      RTP ties to industry criticized by CSPI: Murray: 12.9.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/939
      aspartame (aspartic acid, phenylalanine) binding to DNA:
      Karikas July 1998: Murray 1.5.3 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://groups.yahoo.com/group/aspartameNM/message/622
      Rich Murray: Gold: Koehler: Walton: Van Den Eeden: Leon:
      aspartame toxicity 6.4.1 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/623
      Rich Murray: Simmons: Gold: Schiffman: Spiers:
      aspartame toxicity 6.4.1 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/870
      Aspartame: Methanol and the Public Interest 1984:
      Monte: Murray 9.23.2 rmforall

      Dr. Woodrow C. Monte Aspartame: methanol, and the public health.
      Journal of Applied Nutrition 1984; 36 (1): 42-54.
      (62 references) Professsor of Food Science
      Director of the Food Science and Nutrition Laboratory
      Arizona State University, Tempe, Arizona 85287
      6411 South River Drive #61 Tempe, Arizona 85283-3337
      602-965-6938 woody.monte@... [now retired in New Zealand]
      The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is
      112 mg, 10% of the aspartame. The EPA limit for water is 7.8 mg daily
      for methanol (wood alcohol), a deadly cumulative poison. Many users
      drink 1-2 L daily. The reported symptoms are entirely consistent
      with chronic methanol toxicity. (Fresh orange juice has 34 mg/L, but,
      like all juices, has 16 times more ethanol, which strongly protects
      against methanol.)

      "Fruit and vegetables contain pectin with variable methyl ester
      content. However, the human has no digestive enzymes for pectin (6, 25)
      particularly the pectin esterase required
      for its hydrolysis to methanol (26).

      Fermentation in the gut may cause disappearance of pectin (6) but the
      production of free methanol is not guaranteed by fermentation (3). In
      fact, bacteria in the colon probably reduce methanol directly to formic
      acid or carbon dioxide (6) (aspartame is completely absorbed before
      reaching the colon). Heating of pectins has been shown to cause
      virtually no demethoxylation; even temperatures of 120 deg C produced
      only traces of methanol (3). Methanol evolved during cooking of high
      pectin foods (7) has been accounted for in the volatile fraction during
      boiling and is quickly lost to the atmosphere (49).
      Entrapment of these volatiles probably accounts for the elevation in
      methanol levels of certain fruit and vegetable products
      during canning (31, 33)."

      Recent research [see links at end of post] supports his focus on the
      methanol to formaldehyde toxic process:

      "The United States Environmental Protection Agency in their Multimedia
      Environmental Goals for Environmental Assessment recommends a minimum
      acute toxicity concentration of methanol in drinking water at 3.9 parts
      per million, with a recommended limit of consumption below 7.8 mg/day
      (8). This report clearly indicates that methanol:

      "is considered a cumulative poison
      due to the low rate of excretion once it is absorbed.
      In the body, methanol is oxidized to formaldehyde and
      formic acid; both of these metabolites are toxic." (8)....

      Recently the toxic role of formaldehyde (in methanol toxicity) has been
      questioned (34). No skeptic can overlook the fact that, metabolically,
      formaldehyde must be formed as an intermediate to formic acid
      production (54).

      Formaldehyde has a high reactivity which may be why it
      has not been found in humans or other primates during methanol
      poisioning (59)....

      If formaldehyde is produced from methanol and does have a reasonable
      half life within certain cells in the poisoned organism the chronic
      toxicological ramifications could be grave.

      Formaldehyde is a known
      carcinogen (57) producing squamous-cell carcinomas by inhalation
      exposure in experimental animals (22). The available epidemiological
      studies do not provide adequate data for assessing the carcinogenicity
      of formaldehyde in man (22, 24, 57).

      However, reaction of formaldehyde
      with deoxyribonucleic acid (DNA) has resulted in irreversible
      denaturation that could interfere with DNA replication and result in
      mutation (37)...."

      http://www.dorway.com/barua.html
      Dr. J. Barua (ophthalmic surgeon), Dr. Arun Bal (surgeon)
      Emerging facts about aspartame.
      Journal Of The Diabetic Association Of India 1995; 35 (4):
      (79 references) barua@...
      "...the total amount of methanol absorbed will be approximately
      10% of aspartame ingested. An EPA assessment of methanol states
      that methanol, 'is considered a cumulative poison due to the low rate
      of excretion once it is absorbed. The absorbed methanol is then
      slowly converted to formaldehyde...'"
      "Reaction of formaldehyde with DNA has been observed,
      by spectrophotometry and electron microscopy, to result in
      irreversible denaturation."
      "DKP has been implicated in the occurence of brain tumors."

      http://groups.yahoo.com/group/aspartameNM/message/943
      aspartame, cell phones, brain cancer July 1999 Hardell:
      Murray 1.9.3 rmforall
      http://www.medscape.com/MedGenMed/braintumors
      Lennart Hardell, M.D., PhD, in 1999 reported in Sweden that both
      cell phone use and heavy aspartame use correlate with increased
      brain cancers lennart.hardell@... +46 19 602 15 46

      http://www.truthinlabeling.org/ Truth in Labeling Campaign [MSG]
      Adrienne Samuels, PhD The toxicity/safety of processed
      free glutamic acid (MSG): a study in suppression of information.
      Accountability in Research 1999; 6: 259-310. 52-page review
      P.O. Box 2532 Darien, Illinois 60561
      858-481-9333 adandjack@...

      http://www.msgmyth.com/ Debby Anglesey <avenger@...>
      Battling the "MSG Myth", A Survival Guide and Cookbook - $19.00
      P.O. Box 895 Richland, WA 99352 509-735-3397

      http://groups.yahoo.com/group/aspartameNM/message/97
      Lancet website aspartame letter 7.29.99:
      Excitotoxins 1999 Part 1/3 Blaylock: Murray 1.14.0 rmforall
      The Medical Sentinel Journal 1999 Fall; (95 references)

      Russell L. Blaylock, MD 601-982-1175 Madison, Mississippi
      http://www.bioterrorismbook.com/ "Bioterrorism: How You Can Survive"
      Advanced Nutritional Concepts,LLC PO Box 2670 Ridgeland, MS 39158-2670
      http://www.dorway.com/blayenn.html
      "Excitotoxins: The Taste that Kills", 1977, 298 p., 493 references.
      "Health and Nutrition Secrets that can save your life", 2002, 459 p.,
      558 + 30 references, $ 30 http://www.healthpress.com/
      goodbooks@... PO Box 37470 Albuquerque, NM 87176
      505-888-1394 fax 505-888-1521 Kathleen Frazier, Publisher

      George R. Schwartz, MD "In Bad Taste: The MSG Syndrome", 1988, 123 p.

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

      "Survey of aspartame studies: correlation of outcome and funding
      sources," 1998, unpublished: http://www.dorway.com/peerrev.html
      Walton found 166 separate published studies in the peer reviewed
      medical literature, which had relevance for questions of human safety.
      The 74 studies funded by industry all (100%) attested to aspartame's
      safety, whereas of the 92 non-industry funded studies, 84 (91%)
      identified a problem.
      Ralph G. Walton, MD, Prof. of Clinical Psychology, Northeastern Ohio
      Universities, College of Medicine, Dept. of Psychiatry, Youngstown,
      OH 44501, Chairman, The Center for Behavioral Medicine,
      Northside Medical Center, 500 Gypsy Lane, P.O. Box 240 Youngstown,
      OH 44501 330-740-3621 rwalton193@...
      http://www.neoucom.edu/DEPTS/Psychiatry/walton.htm

      http://groups.yahoo.com/group/aspartameNM/message/857
      RTM: www.dorway.com: original documents and long reviews of flaws in
      aspartame toxicity research 7.31.2 rmforall

      http://www.dorway.com/upipart1.txt
      UPI reporter Gregory Gordon: 96K 3-part expose Oct 1987

      http://groups.yahoo.com/group/aspartameNM/message/53
      aspartame history Part 1/4 1964-1976: Gold: Murray 11.6.9: rmforall

      http://google.com gives 133,000 websites for "aspartame" , while
      http://groups.google.com/ finds on 700 MB of posts from 20-years of
      Usenet groups, 75,700 posts, and
      http://www.AllTheWeb.com gives 261,750, the top three being leading and
      very well informed volunteer anti-aspartame sites.
      http://teoma.com/index.asp gives 34,100 websites.
      http://www.ncbi.nlm.nih.gov/PubMed/ lists 719 aspartame items.

      http://www.dorway.com/tldaddic.html 5-page review
      Roberts HJ Aspartame (NutraSweet) addiction.
      Townsend Letter 2000 Jan; HJRobertsMD@...
      http://www.sunsentpress.com/ sunsentpress@...
      Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
      800-814-9800 561-588-7628 561-547-8008 fax

      http://groups.yahoo.com/group/aspartameNM/message/669
      1038-page medical text "Aspartame Disease: An Ignored Epidemic"
      published May 30 2001 $ 85.00 postpaid data from 1200 cases
      available at http://www.amazon.com
      over 600 references from standard medical research
      http://www.aspartameispoison.com/contents.html 34 chapters

      Roberts, Hyman J., 1924- ,
      Useful insights for diagnosis, treatment and public heath: an updated
      anthology of original research, 2002, 798 pages,
      Palm Beach Institute for Medical Research, Inc.
      P.O. Box 17799, West Palm Beach, FL 33416
      fax 561-547-8008 dr.roberts@...
      aspartame disease pages 627-685, 778-780 .

      http://groups.yahoo.com/group/aspartameNM/message/859
      RTM: Roberts: the life work of a brilliant clinician:
      aspartame toxicity 8.2.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/790
      RTM: Moseley:
      review Roberts "Aspartame Disease: An Ignored Epidemic" 2.7.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/876
      hyperthyroidism (Graves disease) in George and Barbara Bush, 1991--
      aspartame toxicity? Roberts 1997: Murray 10.9.2 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/950
      aspartame & diabetes: Roberts 8.9.94:
      Murray 1.11.3 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/951
      aspartame & eye problems: Roberts Jan 1994: Murray 1.11.3 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/304
      aspartame and brain cancers: Roberts 1991: Murray 9.15.0

      http://groups.yahoo.com/group/aspartameNM/message/883
      three texts by H.J. Roberts, 1958, 1971, 1979: Murray 1.2.3 rmforall

      http://groups.yahoo.com/group/aspartameNM/message/880
      Roberts, 45 clinical research reports in mainstream journals:
      Murray 10.20.2 rmforall
      ************************************************************************
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