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

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  • Rich Murray
    http://groups.yahoo.com/group/aspartameNM/message/958 safety of aspartame Part 2/2 12.4.2: EC HCPD-G SCF: Murray 1.12.3 rmforall: FDA Docket 02P-0317 Recall
    Message 1 of 1 , Jan 12, 2003
      safety of aspartame Part 2/2 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

      [ Continued from Part 1/2 ]

      Headache was one of the more common symptoms that was reported to the
      FDA and evaluated by the CDC (Janssen and Van der Heijden, 1988;
      Tollefson, 1988).
      Several studies were carried out to test the potential association
      between aspartame intake and the onset of headaches. Although the
      results of a questionnaire-based study (Lipton et al., 1989) and two
      double-blind out-patient investigations (Koehler and Glaros, 1988; Van
      Den Eeden et al., 1994) employing daily doses of up to 30 mg/kg bw/day
      indicated a potential association between aspartame intakes and [p12]
      headache, it was not possible to deduce causality as the effect of diet
      had not been adequately controlled for and the interpretation of the
      data was complicated by a high drop out rate and a limited experimental

      Another study employing a controlled environment, which was also a
      randomised double-blind placebo-controlled cross-over trial, concluded
      that aspartame was no more likely than placebo to trigger headaches
      (Schiffman et al., 1987). This study consisted of 40 subjects who
      complained of aspartame-related headaches. Subjects received aspartame
      challenges on days three or five at a total dose of 30 mg/kg bw
      (for a 70 kg person); subjects received placebo on the other days. While
      35% of subjects developed headaches while on aspartame, 45% developed
      headaches while on placebo. In addition, no treatment related effects
      were detected in blood pressure, or plasma concentrations of cortisol,
      insulin, glucagon, histamine, epinephrine or norepinephrine. The
      subjects who had headaches had lower plasma concentrations of
      norepinephrine and epinephrine just before the development of headache.
      This study has been criticised for using tightly controlled experimental
      conditions which did not mimic normal life (Edmeads, 1988), but
      Schiffman et al. (1987) argued that the nature of the study and the
      primary focus of the questions raised by CDC dictated that they
      use carefully controlled conditions at a hospital setting.

      The AFSSA (2002) report noted that “Among the possible adverse effects
      of aspartame, researchers have paid particular attention to seizures.

      Several studies have suggested a relationship between the consumption of
      large amounts of aspartame and the triggering of epileptic seizures. In
      an old study (1972), on new-born monkeys (2-3 animals per group) treated
      with doses of aspartame of 1, 3 and 4g/kg bw/day for 52 weeks, epileptic
      seizures were recorded at the highest doses, after 218 days of
      treatment. Thereafter, sporadic convulsions were observed during
      handling of the animals. These symptoms were identical with those
      observed in young monkeys treated with phenylalanine.”

      “In contrast, in a similar study also conducted on young monkeys, no
      effect was observed at doses of aspartame of 2 and 2.7 g/kg bw/day. The
      different results observed in the two studies could be explained by
      differences in the exposure conditions, the food and the state of health
      of the animals (JECFA, 1980).”

      “Walton et al. (1993) reported, in a study conducted on 13 patients
      suffering from depression, that the administration of 30 mg/kg bw/day of
      aspartame for 7 days caused severe side effects in these patients which
      led the authors to conclude that the use of this sweetener in depressive
      patients should be avoided.

      The same author (Walton, 1986) reported a case of 7 epileptic [p13]
      seizures and serious behavioural problems in a woman being treated with
      antidepressants who ingested large quantities of tea containing

      “Wurtman (1985) indicated that the administration of aspartame, due to
      an increase in phenylalanine absorption in the brain, could affect the
      synthesis of catecholamines or serotonin and cause seizures. He based
      his findings on three examples of heavy consumers of ”diet” drinks and
      on experimental studies on animals demonstrating that the consumption of
      aspartame reduced the threshold of sensitivity to chemically induced
      seizures (Maher et al., 1987; Guiso et al.,1988; Pinto et al., 1988).

      Finally Camfield et al. (1992) demonstrated that aspartame could
      increase the duration of certain types of epileptic seizure in

      “The ATIC on the Internet reported a large amount of evidence from
      people who have identified aspartame as the cause of their health
      problems and in particular of seizures. These statements should be taken
      into account but with the reservation that they have not been examined
      according to any academic standard. They may, however, in certain cases,
      reflect the hypersensitivity of certain individuals to aspartame or its

      Effects on seizures have been reported with phenylalanine, aspartic acid
      and methanol but these were under specific conditions (high doses,
      individual sensitivity, types of seizures, etc.) which are not
      representative of the general population and of current use of this
      sweetener in food (Anderson et al., 1996).

      This causal relationship between aspartame and epileptic seizures has
      been refuted by a large number of scientists who base their opinions on
      numerous experimental studies conducted on laboratory animals or on
      clinical or tolerance studies in humans (Anderson et al., 1996; Gaull,
      1985; Rowan et al., 1995; Shaywitz et al., 1994; Tollefson et al., 1992;
      1993; Dailey et al., 1991; Zhi et al., 1989; Sze, 1989; Tilson et al.,

      “The Epilepsy Institute in the USA has also concluded that aspartame is
      not the cause of epileptic seizures (Congressional Record, June 20,

      In the United States various consumer complaints about aspartame have
      been collected by the Special Nutritionals Adverse Event Monitoring
      System (SN/AEMS). The sources of these reports were the FDA, federal and
      local health agencies, consumers and health professionals. Of 2621 side
      effects reported, concerning 3451 products, some ten cases concerned
      preparations concerning aspartame (mixtures also containing vitamins,
      amino acids and various nutritional supplements). The effects reported
      included seizures, death, nervous and cardiac symptoms, oedema and

      Still in the United States, the Center for Disease Control assessed 517
      complaints about aspartame (1983). The symptoms reported were headaches,
      mood changes, insomnia, abdominal pain, nausea, convulsions, etc… These
      symptoms are observed frequently in the general population. Although it
      might be possible that certain individuals are particularly sensitive to
      aspartame, these data, which relate to a large number of people, have
      not enabled any relationship to be demonstrated between the consumption
      of aspartame and the occurrence of convulsive seizures.”

      Other effects [p14]
      Idiosyncratic reactions described as allergic-like (hives, rashes) were
      reported by some consumers to CDC in response to aspartame (Tollefson,

      However, the results of a multi-centre, randomised, double-blind,
      placebo-controlled, cross-over study in individuals who were convinced
      they were allergic to aspartame indicated that aspartame and its
      conversion products are no more likely than placebo to cause
      urticaria and angio-oedema (Geha et al., 1993).

      This finding was supported by the outcome of another study, which also
      demonstrated that alleged allergic reactions to aspartame were not
      reproducible under blinded conditions (Garriga et al., 1991).
      However as with the Geha et al. (1993) study, the authors reported major
      difficulties in enrolling subjects with a history of
      allergy/hypersensitivity reactions to aspartame.

      A number of other studies focused on the effects of aspartame on hunger
      and food intake (Rolls and Shide, 1996) and in the control of body
      weight (Kanders et al., 1996). Sensory and post-ingestion experience
      with aspartame was reported by these reviewers not to be associated with
      increased energy intake or increases in body weight.

      Since the SCF’s extensive reviews of aspartame were carried out in 1984
      and 1988 (SCF, 1985, 1989), the objective of the present review was to
      identify any more recent data suggesting there might be additional
      endpoints requiring evaluation or effects at lower doses than those
      previously considered. To this end, consideration has been given to
      aspects of metabolism and toxicity as well as to clinical studies
      conducted to address the reported adverse effects of aspartame in
      healthy and potentially sensitive individuals.

      Consideration has also been given to recent estimates of intake.
      Aspartame is unique among the intense sweeteners in that the intake of
      its component parts can be compared with intakes of the same substances
      from natural foods. It is clear that the consumption of aspartame
      represents only a minor source of aspartic acid, Phe or methanol in the
      diet (Renwick, 1990). The available estimates of intake of aspartame by
      mean and high level consumers are fairly consistent among European
      countries, even though different approaches were used for the
      assessment. They show that intakes in high level consumers, including
      adults, children, and diabetics of all ages, range up to 10 mg/kg bw/day
      and thus are unlikely to exceed the current ADI for aspartame of 40
      mg/kg bw established by the SCF (1985, 1989).

      Studies both in healthy subjects and in PKU heterozygotes confirm the
      SCF’s earlier conclusion (SCF, 1989) that despite the plasma variations
      in Phe levels following single and repeated administrations of
      aspartame, Phe levels generally remain within normal postprandial
      limits. [p15]

      In 1996, a report suggesting a connection between aspartame and an
      increase in the incidence of brain tumours in the USA was published
      (Olney et al., 1996).

      The SCF considered this report and concluded that the data did not
      support the proposed biphasic increase in the incidence of brain tumours
      (SCF, 1997).

      The issue had also been considered earlier by the FDA and by the UK
      Committee on Carcinogenicity of Chemicals in Food, Consumer Products and
      the Environment (COC). The FDA stated that analysis of the National
      Cancer Institute database on cancer incidence in the USA did not support
      an association between the use of aspartame and increased incidence of
      brain tumours (FDA, 1996). The COC agreed that the findings provided no
      evidence of the proposed biphasic increase in the incidence or either
      all brain tumours or selected tumour types in the USA during the 1980’s
      and concluded that the data published by Olney et al. did not raise any
      concerns with regard to the use of aspartame in the UK (COC, 1996).

      The recent review by AFSSA (2002) covered all the original experimental
      studies and concluded that aspartame and DKP are not genotoxic and that
      none of the carcinogenicity tests on rodents indicate a relationship
      between treatment with aspartame and the appearance of brain tumours.

      The Committee agrees with this conclusion concerning the experimental

      AFSSA also reviewed more recent publications on the human
      epidemiological data and concluded that “The epidemiological study by
      Olney et al., which suggested a link between the placing on the market
      of aspartame and a possible increase in the frequency of brain cancers
      in humans, did not provide any scientific evidence to justify or
      demonstrate a basis for this suggestion; to date it has not been
      confirmed.” (AFSSA, 2002).

      The Committee agrees with this view and reaffirms its conclusion of
      1997 (SCF, 1997).

      The Committee has also reviewed the study by Trocho et al. (1998), who
      reported the occurrence of stable DNA and protein adducts in the liver
      of rats following aspartame administration. The Committee noted that the
      study used aspartame radiolabelled on the methanol portion, and that
      during metabolism of aspartame in the gut, radiolabelled methanol will
      be split off and enter the body’s one-carbon pool, with the potential to
      appear anywhere there is methylation. The Committee therefore agrees
      with the analysis of Tephly (1999) that formation of DNA adducts has not
      been demonstrated.

      AFSSA (2002) has also evaluated the scientific literature on epilepsy
      and EEG anomalies and concluded that there is a lack of evidence, based
      on the current state of knowledge, which would enable a causal link to
      be established between the consumption of aspartame and the occurrence
      of epileptic seizures or anomalies on an electro-encephalogram. The
      Committee agrees with this conclusion of AFSSA.

      The present review also addressed the data on other neurological
      endpoints including cognition, mood and behaviour. Although the data
      varied in quality, evidence for a causal relationship between aspartame
      consumption and these endpoints could not be [p16] established.

      The Committee noted that despite targeted animal studies, no consistent
      effects of aspartame on neurotransmitters or their precursors have been
      Studies have also been specifically designed to follow up individuals
      reporting that they were sensitive to aspartame during post-marketing
      surveillance, together with studies on individuals, including children,
      who, because of underlying medical conditions, might be considered
      sensitive to aspartame. Aspartame administration did not induce changes
      in behaviour, cognition, mood or learning.

      The data on headaches received special consideration as this was a
      commonly reported symptom during postmarketing surveillance. The data on
      headaches vary in quality, but the one well, controlled double-blind,
      cross-over trial showed that aspartame was no more likely than placebo
      to be associated with headaches.

      Studies on allergic-like reactions in individuals who themselves
      reported such reactions to aspartame have not confirmed their occurrence
      when later studied under controlled conditions.

      The Committee concluded that on the basis of its review of all the data
      in animals and humans available to date, there is no evidence to suggest
      that there is a need to revise the outcome of the earlier risk
      assessment or the ADI previously established for aspartame. [p17]

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      aspartame: methanol, formaldehyde, formic acid toxicity:
      brief review: Murray 1.10.3 rmforall

      for 958 posts in a public searchable archive

      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.

      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):
      testable theory of MCS type diseases, vicious cycle of nitric oxide &
      peroxynitrite: MSG: formaldehyde-methanol-aspartame:
      Martin L. Pall: Murray: 12.9.2 rmforall

      Functional Therapeutics in Neurodegenerative Disease Part 1/2:
      Perlmutter 7.15.99: Murray 1.10.3 rmforall

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