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Research Notes: Aspartame (NutraSweet, Equal, etc.)This page contains the following:
Aspartame page 2:
Aspartame concerns for those with PWS
The metabolizing of aspartame-derived phenylalanine into tyrosine and phenylpyruvate is possibly of concern for some with PWS, as an incidental study of hypopigmentation in PWS (Butler 1989) found that 39% of those with PWS had elevated plasma phenylalanine and/or tyrosine. Also, I know of an infant with PWS that was initially suspected of having tyrosinemia type I based on his high urinary 4-hydroxyphenylpyruvate and another infant had high plasma tyrosine during his NICU stay. All of this suggests there is a problem with phenylalanine and tyrosine metabolism in at least some with PWS and so aspartame probably is not advisable for them because its ingestion results in the rapid release of free-form phenylalanine into the bloodstream. The eMedicine.com article about hyperphenylalaninemia, for example, notes that "patients should avoid consuming aspartame because phenylalanine is a primary component of aspartame."
There are some other potential issues regarding the use of aspartame by those with PWS (including the possibility that "spikes" in plasma asparatic acid due aspartame consumption can cause hypothalamic lesions and neuronal death), but I have not had the time to research them. In any event, the foregoing points seem adequate to me to warrant a recommendation that those with PWS should probably avoid aspartame. Comments about the asparatame "controversy" It has been noted that the Ramazzini studies are "controversial," but of course not all controversies are equal. For example, the decades-long "debates" about such things as whether or not smoking or asbestos cause lung cancer clearly demonstrate that a well-heeled industry is quite capable of creating an essentially bogus but still difficult to resolve scientific "controversy" when faced with regulatory action that threatens its profits. The standard of scientific proof is high and "perfect" studies are rare given the time and cost constraints that are typically involved, so it is usually easy for a large corporation to hire any number of "experts" to pick at a study's methodology and raise questions about it. The recent Vioxx fiasco and many others also testify to the fact that it is not all that difficult for the scientific literature to be flooded by corporate-funded studies and review articles designed to show the purported "safety" or even supposed "benefits" of a questionable product. Of course, those with an interest in protecting public health don't have such deep financial pockets, so it typically takes many years before enough independent studies are performed to provide conclusive evidence of harm and the "controversy" is finally resolved. PLoS Biology published an excellent article on June 15, 2007, about the plastic industry's response to the work by Fred vom Saal and others showing how hormone-disrupting chemicals such as bisphenol A (BPA) interfere with developmental pathways and even induce obesity. It's an interesting read, as it details the use of many of the same tactics used by the aspartame industry to create the appearance of a "controversy," such as the commissioning of reviews by "independent experts." One example: The [Harvard Center for Risk Analysis] report ... concluded that "the weight of the evidence for low-dose effects [of BPA] is very weak." Industry groups hailed the report as a comprehensive review by independent experts and quickly disseminated its findings. Yet the "comprehensive" report reviewed just 19 of 47 studies available in April 2002, and when it was published more than two years later, three panelists asked not to be listed as authors.
In a 2005 commentary, vom Saal and Claude Hughes, a reproductive endocrinologist who had served on the HCRA panel, argued that the report was already obsolete when it came out. By the end of 2004, they had identified 115 published studies on low doses of bisphenol A. They also found a troubling trend. Ninety percent of government studies found significant effects of bisphenol A at doses below the EPA's lowest adverse effect level, but not a single industry study found any effect. Many of the industry studies, they pointed out, either used a rat strain with very low sensitivity to estrogen or misinterpreted failure to find effects with positive controls. Vom Saal and Hughes urged the EPA to conduct a new risk assessment on bisphenol A.
Vom Saal and Hughes's call for a new risk assessment triggered another [American Plastics Counsel]-sponsored report on bisphenol A, this time from Gradient Corporation. In 2006, Gradient issued its "updated weight of the evidence evaluation," which the authors called an extension of the HCRA report. And like the HCRA report, the review often cited studies that lacked positive controls or used the insensitive rat strain to conclude that bisphenol A produces no adverse effect on any endpoint. In one case, the authors acknowledged a finding of decreased sperm counts, but argued that it was unclear whether such an effect could be considered adverse. In reviewing evidence of chromosomal abnormalities, the report excluded a much-publicized study by geneticist Patricia Hunt - which showed that low levels of bisphenol A trigger substantial increases in improper chromosome segregation - on the grounds that the study didn't measure a developmental or reproductive endpoint. The authors did not explain how chromosomally abnormal oocytes might produce normal individuals.
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After publishing her results, Hunt says, industry "paid people to read our paper and provide talking points, things they could use to say, 'Well, we aren't really sure about this, and well, they didn't do that, and this is suspicious.' It was such a learning experience for me because I had never had a piece of my work scrutinized in such detail, and I always thought my scientific peers were going to be the ones who were going to be most critical.” Hunt had been "peripherally aware" of the disputes between academics studying endocrine disruption and industry, "but you never knew whether these people were credible scientists or not, and then when you step your own foot into it and you watch, industry really did try to run damage control on our work."
Similar to the "controversy" about bisphenol A, a review of published peer-reviewed studies about aspartame prepared by Ralph Walton, Chair of the Department of Psychiatry at Northeastern Ohio University College of Medicine, for the TV program 60 Minutes found that "[o]f the 166 studies felt to have relevance for questions of human safety, 74 had Nutrasweet industry related funding and 92 were independently funded. One hundred percent of the industry funded research attested to aspartame's safety, whereas 92% of the independently funded research identified a problem. A bibliography supplied by the Nutrasweet Company included many studies of questionable validity and relevance, with multiple instances of the same study being cited up to 6 times." The summary report of the "First European conference on aspartame: Putting safety and benefits into perspective" published in the journal Food and Chemical Toxicology has been cited as evidence of aspartame's safety; however, it should be noted that the conference was funded by the International Sweeteners Association (see, e.g., the European Food Information Council (EUFIC)). In addition, the lead author of the summary, Andrew Renwick, apparently has never conducted any primary toxicological research into aspartame; instead his "expertise" about aspartame seems to be focused more along the lines of producing various Nutrasweet- and ISA-sponsored review articles (see, e.g., Butchko 2002) and attending ISA-sponsored conferences (see, e.g., this about an ISA-funded conference in India). Such review articles, along with industry-funded conferences and subsequent "conference reports" in various scientific journals, are well-worn tactics used by industries seeking to avoid adverse regulatory action (see, e.g., the Oct-Dec 2005 issue of the International Journal of Occupational and Environmental Health - which was entirely devoted to the corporate corruption of the scientific process with regard to public health issues). The timing of the ISA conference (about nine months after the publication of the first Ramazzini study) and the rather unusual emphasis in the summary report on knocking the study suggest that the conference was at least in part an effort at damage control by the aspartame industry. The citation by Renwick (in the summary report) to the European Food Safety Authority's (EFSA) response to the first Ramazzini study is similarly not very persuasive. As the London Guardian reported in May 2006, Dr. Susan Barlow, the chair of the EFSA's emergency advisory panel on aspartame following publication of the first Ramazzini study, had a serious conflict of interest given that she works for the International Life Sciences Institute (ILSI), a notorious corporate front group that is funded by artificial sweetener manufacturers including Nutrasweet (and its parent company, Monsanto) and major aspartame users such as Coca-Cola, PepsiCo and Nestle. Other members of the EFSA panel also apparently had conflicts of interest involving the aspartame industry. It is also worth noting that the National Toxicology Program (NTP) at the U.S. National Institute of Environmental Health Sciences apparently holds the Ramazzini Foundation in high regard, as the NTP has conducted 21 interlaboratory carcinogenesis bioassays with it. In addition, a 2002 article in the Annals of the New York Academy of Sciences by John R. Bucher, deputy director of environmental toxicology at the NTP, had this to say about the Ramazzini Foundation: "NTP and Ramazzini Foundation bioassay designs differ in several aspects, but bioassays at both institutions provide chemical-specific information for predicting human carcinogens, thus providing for protection of public health. ... The scientific community and the public owe a huge debt of gratitude to Dr. Cesare Maltoni of the [Ramazzini] European Foundation of Oncology and Environmental Sciences and to Dr. David P. Rall of the National Institute of Environmental Health Sciences for their foresight and wisdom in creating and nurturing these bioassay programs." (Dr. Maltoni, the founder of the Ramazzini Foundation, was the first to demonstrate the carcinogenicity of vinyl chloride and benzene and was an internationally respected expert in the identification of workplace carcinogens.) In a New York Times article on February 12, 2006, Bucher similarly called the design of the Ramazzini study "impressive" and "thorough," and said that he did not think the fact that rats were allowed to live until their natural deaths had skewed the results. Dr. Jose Russo, director of the breast cancer and environmental research center at the Fox Chase Cancer Center in Philadelphia, was also quoted by the Times as saying that lifetime studies are "ideal" but that they are not done often, partly because they are more expensive than limited-time tests. Given the conflicts of interests involving the EFSA panel, it seems worthwhile to mention Soffritti's rebuttal to the panel's dismissal of the Ramazzini study: "As reported in a previous paper (Soffritti et al. 1999), one of the most important issues in environmental and industrial carcinogenesis is how to deal with diffused carcinogenic risks, to which most of the planet's population may be exposed. These carcinogenic risks are represented by a) agents that are slightly carcinogenic at any dose; b) low or extremely low doses of a carcinogenic agent of any kind; or c) mixtures of small doses of carcinogenic agents.
"Epidemiologic and experimental studies are fundamental in the identification and quantification of diffused carcinogenic risks, but they must be designed and conducted to be as powerful as possible with adequate methodology. In the case of experimental studies, it is not sufficient to follow the standard protocol used in ordinary experiments. Instead, it is necessary to conduct studies that may be defined as "mega-experiments," using a vast number of animals (at least 2001,000 per experimental group) in order to express a marked difference in the variation of effects, and exposing the animals in all phases of development to allow the agent to express its full carcinogenic potential.
"It is based on this rationale that the European Ramazzini Foundation performed a mega-experiment on 1,800 rats and demonstrated that, in our experimental conditions, aspartame is a multipotential carcinogenic agent (Soffritti et al. 2005; Soffritti et al. 2006).
"The results of our study (Soffritti et al. 2005; Soffritti et al. 2006) attracted the attention of the scientific community, consumer and industry associations, and the national and international agencies responsible for food safety. Among various comments, the opinion expressed on 5 May 2006 by the European Food Safety Authority (EFSA 2006) and the general interpretation of an epidemiologic study conducted by the National Cancer Institute (NCI 2006) necessitate comment on our part.
"In examining the raw data of our study, the EFSA (2006) observed a high incidence of chronic pulmonary inflammation in males and females in both treated groups and in the control group. Based on this observation, it was concluded that "the increased incidence of lymphomas/leukemias reported in treated rats was unrelated to aspartame, given the high background incidence of chronic inflammatory changes in the lungs . . . ." In my opinion, this conclusion is bizarre for the following reasons:
"First, the EFSA (2006) overlooked the fact that the study was conducted until the natural death of the rodents. It is well known that infectious pathologies are part of the natural dying process in both rodents and humans.
"Second, if the statistically significant increased incidence of lymphomas/leukemias observed were indeed caused by an infected colony, one would expect to observe an increased incidence of lymphomas/leukemias not only in females but also in males. The EFSA (2006) did not comment on this discrepancy in their logic.
"Finally, in support of the hypothesis regarding the safety of aspartame, the EFSA (2006) cited the negative results of recent carcinogenicity studies carried out in transgenic mice by the NTP; the ESFA did not mention that, because the NTP studies on genetically altered mice were performed using a new experimental model, the NTP subcommittee unanimously agreed "there is uncertainty whether the study possessed sufficient sensitivity to detect a carcinogenic effect" (NTP 2005).
"Interestingly, the same scrutiny applied to our study has not been applied to a recent abstract published by Lim et al. (2006) from the NCI diet questionnaire survey (NCI 2006) in which self-reported aspartame consumption showed no increases in either leukemia/lymphomas or in brain cancer. These results have been used by industry, the EFSA, and others to argue that aspartame is not a risk for humans, in spite of our animal study results. Without specific information on each individual's consumption rate and duration it is difficult to assess the power of the survey, in spite of the large number of participants. The second related issue is whether aspartame is an early- or late-stage carcinogen. If it is an early-stage initiator of cancer, then reporting the lack of effects in older individuals who have not consumed aspartame since early childhood would be expected to show little or no increased cancer (Hoel 1985).
Citation has been also made to the letter in the journal Environmental Health Perspectives (EHP), Aspartame Not Linked to Cancer by Eyassu G. Abegaz of Aginomoto Corporate Services, which is mostly comprised of quotes from the EFSA opinion. As Soffritti tersely noted in his response: "As communicated in his letter, Abegaz represents Ajinomoto Corporate Services LLC. Ajinomoto, which holds 45% of the market share for worldwide aspartame production (Ajinomoto 2006), is well known for its aggressive and effective defense of its commercial interests. The action by Abegaz to reproduce portions of the opinion issued by the European Food Safety Authority (2006) regarding the results of our long-term carcinogenesis bioassay on aspartame (Soffritti et al. 2006) is clearly specious." Lim's epidemiological study purportedly showing no increase in rates of leukemia, lymphoma and brain cancer in aspartame users is also cited. The study initially sounds impressive due to its large study size (473,000), but a careful reading reveals it has several serious limitations: 1. Aspartame use was determined by self-reporting of the consumption of four aspartame-containing beverage categories (soda, fruit drinks, sweetened iced tea, and hot coffee and tea) during the previous year (1995). Apparently those who eschewed aspartame-sweetened beverages but consumed aspartame via food, chewing gum, candy, medications, etc. were classified as part of the non-aspartame-using control group. In other words, it appears that a group of known aspartame users was being compared with another group containing an unknown but probably large number of aspartame users.
2. The study population was aged 50 to 71 years but aspartame was only approved for use in 1981, which means that at the beginning of the study, the longest term users had only consumed aspartame for a maximum of 14 years (that is, starting from age 36-57). Adding to that the follow-up period (1995 to 2000) during which the number of cancers were counted, it is clear that the longest possible use of aspartame among the study participants was 19 years. In other words, what the study may have determined was the cancer rate for those who started consuming aspartame in middle adulthood and continued such consumption for 19 years; however, even that finding is highly questionable given the problem raised in point #1, that is, that aspartame users weren't being compared to non-aspartame users but against a group that contained an unknown number of aspartame users. In any event, the study certainly had no ability to quantify cancer risk in those who start consuming aspartame in childhood or early adulthood, or those who have consumed it for more than 19 years, and as such has very limited value. Of course, those severe limitations certainly didn't hamper the aspartame industry from widely trumpeting that it "proved" there is no connection between aspartame consumption and cancer.
In summary, it seems rather clear that the aspartame industry has diligently engaged in a deliberate effort to create the impression of a "controversy" about the results of the Ramazzini studies (as well as others that show aspartame can have toxic effects). However, the fact remains that underneath the appearance of a "debate" about aspartame's safety, there is no real scientific controversy about the fact that major metabolites of aspartame are toxic in the human body. As such, the real issue is not whether or not carcinogenicity is one of those toxic effects but whether or not it is advisable, particularly for children with PWS, to engage in chronic, low-level ingestion of something that breaks down in toxins such as methanol, formaldehyde and formic acid. Personally, I think don't think it is. Historical materials about the FDA's approval of aspartame Testimony of M. Jacqueline Verrett, Ph.D., U.S. Senate Committee on Labor and Human Resources, November 3, l987 From l957-l977 I was employed as a Biochemist/Toxicologist in what is now designated the Center for Food Safety and Applied Nutrition of the Food and Drug Administration. During this time my duties were twofold: 1) evaluation of experimental data submitted to FDA in support of the safety of a wide variety of chemicals and processes (such as irradiation) intended for food additive use directly and indirectly, as well as data pertaining to various contaminants such as mycotoxins, pesticides, and also some drugs; 2) a variety of research pertinent to FDA's mission, and for the most part devoted to the overall toxicity and more specifically to teratogenic (birth-deforming) capabilities of several hundred substances that may be broadly classified as food additives, both direct and indirect, or as food contaminants. In the early l970's, I examined the animal studies submitted by G.D. Searle and Co. on aspartame prior to the initial approval by FDA in l974. While I cannot recall any specific examples, it was my overall impression that these studies raised numerous questions in a number of areas that needed to be resolved before approval of aspartame for any food additive use. In l977 I served as a member of an FDA team (from the Bureau of Foods) which was charged with examining three studies (the rat DKP long-term study, and aspartame teratology studies in mice and rats) to determine if they were 'authentic'. We were instructed to incorporate the findings of the FDA task force investigation of Searle (Bressler Report) and to determine whether alterations and adjustments to the data engendered by inclusion and consideration of these discrepancies resulted in significantly different results from those presented in the original Searle submission. This authentication was hence intended to verify that the submitted data had not been altered, that it reflected the actual outcome of the study, and that it did not change substantially, particularly in a statistical sense, the various parameters from which the conclusion of safety had been derived. Our analysis of the data in this manner revealed that in these three studies no substantial change resulted, although in numerous instances a definitive answer could not be arrived at because of basic inadequacies and improper procedures used in the execution of these studies. I wish to emphasize at this point that we were specifically instructed not to be concerned with, or comment upon, the overall validity of the study - this was to be done in a subsequent review carried out at the Bureau level. It is apparent that that review, on a point by point basis, discarded or ignored the problems and deficiencies outlined in this Team Report, and concluded that, even in toto, these problems were insufficient to render the study invalid. It also appears that the serious departures from acceptable toxicological protocols that were noted in the reevaluation of these studies were also discounted. At this point it might be helpful to mention some of the deficiencies and improper procedures encountered: no protocol was written until the study was well underway; animals were not permanently tagged to avoid mixups; changes were introduced in some laboratory methods during the study with inadequate documentation; there was sporadic monitoring and/or inadequate reporting of food consumption and animal weights; tumors were removed and the animals returned to the study; animals were recorded as dead, but subsequent records, after varying periods of time indicated the same animal was still alive (almost certain evidence of mixups); many animal tissues were autolyzed (decomposed) before any postmortem examinations were performed; and finally, of extreme importance, in the DKP study there was evidence, including pictures, that the diets were not homogeneous and that the animals could discriminate between feed and the included DKP. Almost any single one of these aberrations would suffice to negate a study designed to assess the safety of a food additive, and most certainly a combination of many such improper practices would, since the results are bound to be compromised. It is unthinkable that any reputable toxicologist, giving a completely objective evaluation of data resulting from such a study, could conclude anything other than that the study was uninterpretable and worthless, and should be repeated. This is especially important for an additive such as aspartame, which is equally vital since DKP is a major breakdown product of aspartame in liquid media. Not only is aspartame being used in the absence of basic toxicity information, but there is also no data to assess the toxicity of the interactions of DKP with the excess phenylalanine generated, with any other metabolite of aspartame, and its interactions with other additives, drugs, or other chemicals which may be present simultaneously in persons exposed to high levels of DKP in presweetened liquids such as diet drinks. While I have not been involved in aspartame safety matters since the team effort described previously, a brief examination of studies completed and currently underway seems to indicate that the subject studies have not been repeated, so the safety questions remain unanswered. It would appear that the safety of aspartame (and its breakdown products) has still not been satisfactorily determined, since many of the flaws cited in the studies referred to here were also present in other studies submitted by Searle. |