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Abstract

Aspartame, a widely used artificial sweetener, was administered with feed to male and female Sprague-Dawley rats (100-150/sex/group), 8 weeks-old at the start of the experiment, at concentrations of 100,000; 50,000; 10,000; 2,000; 400; 80 and 0 ppm. Treatment lasted until spontaneous death of the animals. In this report we present the first results showing that aspartame, in our experimental conditions, causes a statistically significant, dose-related increase in lymphomas and leukaemias in females. No statistically significant increase in malignant brain tumours was observed among animals from the treated groups as compared to controls.

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... Only at the end of 2011 were final reports of these studies made available on the website of the European Food Safety Authority (EFSA), following the EFSA call for data on APM (launched on June 1, 2011) [EFSA, 2011]. Other studies available in the scientific literature were published in the early 1980s [Ishii, 1981;Ishii et al., 1981] and after 2005[National Toxicology Program, 2005Iwata, 2006]. Between 2005 and 2010 the Ramazzini Institute (RI) published the results of three peer-reviewed, long-term carcinogenicity bioassays, two of which were performed on rats [Soffritti et al., 2005[Soffritti et al., , 2007Belpoggi et al., 2006] and one on mice [Soffritti et al., 2010]. ...
... Other studies available in the scientific literature were published in the early 1980s [Ishii, 1981;Ishii et al., 1981] and after 2005[National Toxicology Program, 2005Iwata, 2006]. Between 2005 and 2010 the Ramazzini Institute (RI) published the results of three peer-reviewed, long-term carcinogenicity bioassays, two of which were performed on rats [Soffritti et al., 2005[Soffritti et al., , 2007Belpoggi et al., 2006] and one on mice [Soffritti et al., 2010]. In 2005 and 2012 the results of two prospective epidemiological studies conducted in the US were published. ...
... The CarcinoGenicity Studies of the Ramazzini Institute on APM shown for the first time that APM administered with feed to Sprague-Dawley rats from 8 weeks of age, throughout their lifespan, causes cancer in both males and females. Results showed a statistically significant dose-related increased incidence of lymphomas/leukemias, pre-neoplastic, and neoplastic lesions of the renal pelvis in females and malignant Schwannomas of peripheral nerves in males [Soffritti et al., 2005Belpoggi et al., 2006]. In 2007, the statistically significant dose-related increase in lymphoma/ leukemia incidence (diagnosed following the same morphological criteria as the first experiment) in Sprague-Dawley rats treated from prenatal life with APM in the feed was confirmed [Soffritti et al., 2007]. ...
Article
Aspartame (APM) is an artificial sweetener used since the 1980s, now present in >6,000 products, including over 500 pharmaceuticals. Since its discovery in 1965, and its first approval by the US Food and Drugs Administration (FDA) in 1981, the safety of APM, and in particular its carcinogenicity potential, has been controversial. The present commentary reviews the adequacy of the design and conduct of carcinogenicity bioassays on rodents submitted by G.D. Searle, in the 1970s, to the FDA for market approval. We also review how experimental and epidemiological data on the carcinogenic risks of APM, that became available in 2005 motivated the European Commission (EC) to call the European Food and Safety Authority (EFSA) for urgent re-examination of the available scientific documentation (including the Searle studies). The EC has further requested that, if the results of the evaluation should suggest carcinogenicity, major changes must be made to the current APM specific regulations. Taken together, the studies performed by G.D. Searle in the 1970s and other chronic bioassays do not provide adequate scientific support for APM safety. In contrast, recent results of life-span carcinogenicity bioassays on rats and mice published in peer-reviewed journals, and a prospective epidemiological study, provide consistent evidence of APM's carcinogenic potential. On the basis of the evidence of the potential carcinogenic effects of APM herein reported, a re-evaluation of the current position of international regulatory agencies must be considered an urgent matter of public health. Am. J. Ind. Med. 9999;1-17, 2014 © 2014 Wiley Periodicals, Inc.
... The paucity of scientific data on the potential long-term carcinogenic risks for human beings using such types of food led the Ramazzini Institute (RI) as of 1985 to develop an integrated set of mega-experiments to test the carcinogenic potential of many common products: beverages like ethyl alcohol (1) and Coca Cola (2); integrators like Vitamin A (3) and Vitamin C and E; contaminants like Mancozeb (4), a well-known fungicide; additives like aspartame and sucralose; and preservatives like formaldehyde (5). Particular interest has been aroused in the scientific community, consumers, the food industry and health-care organizations by recent reports from the RI on the carcinogenic potential of aspartame (APM) which, after saccharine, is the most widely used artificial sweetening agent in the world with over 17,000 tons produced every year (6). Some of APM's trade names are NutraSweet, Equal, or E951 (generally in ingredient lists). ...
... In the first experiment, including 1,800 Sprague-Dawley rats (100-150 per sex/per group), we demonstrated that APM, administered from 8 weeks of age for the life span to Sprague-Dawley rats, induced a significant increased incidence of lymphomas/ leukaemias and of neoplastic lesions of the renal pelvis and ureter in females, and a significant increased incidence of malignant schwannomas of the peripheral nerves in males (6,32,33). ...
... In our laboratory we showed for the first time that APM, administered in the feed from 8 weeks of age until death, causes a significant increased incidence of malignant tumours, in particular lymphomas/ leukaemias in females (6,32,33). ...
Article
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The artificial sweetener aspartame (APM), over two hundred times sweeter than sucrose, is an additive contained in over 6,000 products, including almost 500 drugs. As part of the Ramazzini Institute's mega-experiment projectto test the carcinogenic potential of numerous products commonly used in the diet of millions of people, the Authors report the full results of the lifespan carcinogenicity bioassay on APM administeredin animal feed from foetal life untilnatural death. A total of 470 Sprague-Dawley (SD)rats were divided by number and sex into three different groups of 70-95 animals. APM was administered in their feed at concentrations of2,000, 400 or 0 ppm to simulate a daily APM intake of 100, 20 or 0 mg/kg b.w., respectively. The results have shown: 1) a significantly increased dose-related incidence (p≤0.05) of females bearing benign tumours, particularly in the group of 2,000 ppm (p≤0.05); a significantly increased dose-related incidence (p≤0.01) of males bearing malignant tumours, in particular in the 2,000 ppm group (p≤0.01); 2) a significantly increased dose-related incidence (p≤0.05)of mammary adenocarcinomas in females, particularly in the 2,000 ppm group (p≤0.05); 3)a significantly increased incidence (p≤0.05) of lymphomas/leukaemias in males treated at 2,000ppm; and 4) a significantly increased doserelated incidence (p≤0.01) of lymphomas/leukaemias in females, particularly in the 2,000 ppm group (p≤0.01). Our experimental conditions confirm the carcinogenic potential of APM n rats. The data also show that when the lifespan treatment starts from foetal life the carcinogenic effects are heightened.
... Aspartame induces lymphomas and leukaemias in rats Soffritti et al. (2005) Lifetime carcinogenicity study in rats administering aspartame in diet at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. ...
... Flawed, Soffritti (2005) reports on same study. ...
... (2006) Lifetime carcinogenicity study in rats administering aspartame in diet at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The authors report an increased incidence of malignant tumour-bearing animals, with a positive significant trend in both Flawed, Soffritti (2005) reports on same study. sexes, and in particular in females treated at 50,000 ppm compared to controls; an increase in lymphomas-leukemias, with a positive significant trend in both sexes, and in particular in females treated at doses of 400 ppm and above. ...
... No evidence of carcinogenic activity was found. More recently, the three lifetime (two from gestation day 12) exposure studies completed by the Ramazzini Institute have been published each of which the authors concluded that aspartame has carcinogenic potential on the basis of reported incidence of several tumor types, including lymphoreticular tumors and liver tumors (Soffritti et al., 2005(Soffritti et al., , 2010Belpoggi et al., 2006). Finally, a study was identified which assessed effects of aspartame treatment on the incidence of pancreatic acinar carcinoma (Dooley et al., 2017). ...
... A lifetime study was conducted by Soffritti et al. (2005) in Sprague-Dawley rats administered diets which provided 0, 80, 400, 2000, 10,000, 50,000, or 10,0000 ppm aspartame (reported to correspond to 0, 4, 20, 100, 500, 2500, or 5000 mg aspartame/kg body weight/day, respectively; purity > 98%; DKP < 1.5%) from 8 weeks of age until spontaneous death (the last animal died at the age of 159 weeks). Groups of 150 male and 150 female rats were randomly allocated to the control and 3-lowest dose groups (i.e. ...
... Within the above study by Soffritti et al. (2005), the incidences of malignant brain tumors (malignant gliomas, mixed gliomas, medulloblastoma, and malignant meningioma) were reported and were generally sparse, not dose-related, and within the historical range for this laboratory. ...
Article
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The current review assessed cancer studies of aspartame based on a quality appraisal using the Klimisch grading system. Nine studies having complete histopathology were included: three 2-year studies by Searle; three transgenic mice studies by the NTP; three lifetime studies by the Ramazzini Institute. A tenth study limited to brain tumors was not rated. None were determined as Klimisch Code 1 (reliable without restrictions). The Searle studies predated GLP standards but their methodology was comparable; transgenic mouse models are not validated, but are accepted as supporting data. These studies were rated Klimisch Code 2 (reliable with restrictions). The Ramazzini Institute used a lifetime model of their own design that has been questioned due to high rates of spontaneous tumors, issues with tumor type diagnosis and concerns about the impact of chronic infections. As many of these problems could be attributed to using animals that died or were terminated near end of life, along with the other problems noted, these studies were rated Klimisch Code 3 (not reliable). As the Klimisch Code 2 studies demonstrated a lack of carcinogenic potential, and as aspartame is hydrolyzed to common components and lacks genotoxic activity, a conclusion that aspartame is not carcinogenic is supported.
... Dr. Samuels notes the importance of looking at high consumption rather than average. In the NIH-AARP cohort, 3,867 participants reported consuming 1,200 mg or more aspartame daily (equivalent to seven or more 12-oz cans of diet soda), which is the lowest dose that was followed by doubled hematopoietic cancers in female rats in a recent study (4,5). The rates of hematopoietic (n = 12 cases) and brain cancers (n = 3 cases) among our study participants with high consumption, however, were not elevated. ...
... Numerous animal studies to date by independent investigators have not determined aspartame to be carcinogenic (10 -12), and other human studies have not yielded any positive findings (13 -15). Similarly, the European Food Safety Authority (16) and the U.S. Food and Drug Administration (17) concluded from their review of Soffritti et al.'s data (4,5) that the increased number of hematopoietic and other cancers in the aspartame-treated group of rats was probably due to experimental conditions other than aspartame. Animal laboratory and epidemiologic studies each have their strengths and limitations. ...
... The World Health Organization and FAO concluded that AC-K is safe for human consumption, [21] although, several reports [6,13,22] indicate that the AC-K, in similar doses of those reported by these organizations, causes significant genetic damage and has a doseresponse relation. With respect to AS, 24 reports suggest genotoxic activity, 15 of them associate it with malignant tumors in rats and in humans [23][24][25][26][27][28][29][30] and in 13, chromosomal aberrations were detected [24]. The genotoxic effects of the synergic AS-AC-K combination have not been sufficiently discussed. ...
... ASP is not commonly used individually; it is combined with different sweeteners to generate a synergic sweetening effect [42]. The chemically pure form of ASP has been directly related to genotoxic activity and the ability to cause cancer, [24][25][26][27][28][29][30]42] although, Mukhopatahy et al. [24] reported an absence of genotoxicity. Our data indicate that the ASP-AC-K combination possesses genotoxic activity in its commercial form with an apparent dose-response relation. ...
Article
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Genotoxic activity of various concentrations of saccharin, acesulfame-K, aspartame-acesulfame-K and stevia in their commercial form was assessed. Human lymphocytes were exposed to different concentrations of saccharin, acesulfame-K, aspartame-acesulfame-K and stevia for 2 h and then subjected to alkaline comet assay system. Saccharin and the aspartame-acesulfame-K combination showed significant genotoxic activity (P<0.0001). Concentrations 0.5% of acesulfame-K and stevia did not induce significant genetic damage particularly stevia possesses antigenotoxic activity at 5%, 0.5% and 0.05%. Saccharin and the combination of aspartame-acesulfame- K have genotoxic activity and represent a genetic risk for consumers. Acesulfame-K and stevia are harmless and stevia even possesses antigenotoxic activity at concentrations below 5%.
... Perceived problems in RI studies have been central in European Food Safety Authority (EFSA) reviews (EFSA 2006(EFSA , 2009 of RI aspartame bioassay findings of lymphoreticular tumors (Soffritti et al. 2005(Soffritti et al. , 2006b(Soffritti et al. , 2007. The level of inflammatory changes in the lungs of animals in the RI studies has prompted discussions regarding the role of respiratory infections in tumor formation; the ability to discern tumors from inflammatory infiltrates; and the adequacy of RI protocols [Caldwell et al. 2008;Cruzan 2009;EFSA 2006EFSA , 2009National Toxicology Program (NTP) 2011;McConnell 2011a, 2011b;Schoeb et al. 2009]. ...
... U.S. EPA testing guidelines (U.S. EPA 1998) recommend, and NTP cancer bioassays generally employ, four dose groups (control, low, middle, and high). RI cancer bio assays often use four dose groups as well (Soffritti et al. 2002c), but have employed as many as seven for larger bio assays such as the one performed for aspartame (Soffritti et al. 2005(Soffritti et al. , 2006b. ...
Article
Full-text available
The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on over 200 compounds. Study design and protocol differences between RI and other laboratories have been suggested by the European Food Safety Authority (EFSA) and others to contribute to controversy regarding cancer hazard findings, principally lymphoma/leukemia diagnoses. Evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization. We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from International authorities. Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not for lymphoma/leukemia of the respiratory tract and neoplasms of the inner ear and cranium. We discuss (1) the implications of the PWG findings, particularly lymphoma diagnostic issues, (2) differences between RI and other laboratory studies that are relevant to evaluating RI cancer bioassays and (3) future work that may help resolve some concerns. We conclude that (1) issues related to respiratory tract infections have complicated diagnoses at that site (i.e., lymphoma/leukemia) and for neoplasms of the inner ear and cranium, and (2) there is consistency and value in RI studies for identification of other chemical-related neoplasia.
... In the gastrointestinal tract, aspartame is metabolized to aspartic acid, phenylalanine and methanol. In vivo studies demonstrated that methanol and formaldehyde, a metabolite of methanol, may be associated with the increase of the incidence of lymphomas and leukemias [15,16]. Furthermore, toxic manifestations, as hypersensitivity reactions and renal tubular acidosis are related to aspartame consumption (or ingestion) [15,16]. ...
... In vivo studies demonstrated that methanol and formaldehyde, a metabolite of methanol, may be associated with the increase of the incidence of lymphomas and leukemias [15,16]. Furthermore, toxic manifestations, as hypersensitivity reactions and renal tubular acidosis are related to aspartame consumption (or ingestion) [15,16]. Despite these facts, the toxicology of this sweetening agent was evaluated by the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) that attributed an Acceptable Daily Intake (ADI) of 40 mg/kg of body weight to aspartame [17]. ...
Article
A simple, accurate, precise, rapid and sensitive capillary zone electrophoresis (CZE) method was developed, optimized and validated for the simultaneous determination of strontium ranelate (antiosteoporetic drug) and aspartame (sweetener excipient) in pharmaceutical formulation for the treatment of postmenopausal osteoporosis. The final optimized conditions obtained were: borate buffer 50 mmol L− 1 at pH 9.4 (BGE), applied potential of 30 kV, temperature set to 35 °C and hydrodynamic injection time of 10 s at a pressure of 50 mbar. The separation was carried out into a fused-silica capillary column (55 cm total length × 75 μm ID) and took less than 8 min. A diode array detector was used for the detection of the anion ranelate and aspartame at 235 and 198 nm, respectively. For both analytes, the method showed linear range from 1 to 40 μg mL− 1, with satisfactory detectability (limits of detection of 0.3 and 0.2 μg mL− 1 for aspartame and ranelate, respectively). In addition, acceptable accuracy, good repeatability and intermediate precision (RSD < 2.6%) were obtained. The feasibility of the method was verified with recovery tests of analytes in the pharmaceutical sample. Recoveries varied from 85 ± 5% to 111 ± 2%, indicating the usefulness and effectiveness of the proposed method.
... In 1997, the Ramazzini Institute (RI) initiated studies to test the potential carcinogenic effects of aspartame (APM) administered with feed; these included a total of 2270 Sprague-Dawley (SD) rats and 852 Swiss mice. In particular, the first experiment tested seven different doses of APM administered in feed to SD rats from 8 weeks of age until spontaneous death (BT6008) (Soffritti et al., 2005Belpoggi et al., 2006). The second study used a similar protocol at the two lowest exposure levels but starting from prenatal life (BT6009) (Soffritti et al., 2007). ...
... To distinguish tumours from normal tissue or Table 1 Aspartame long-term experimental projects performed at the Cesare Maltoni Cancer Research Center of the Ramazzini Institute (RI). Study (a) human equivalent dose (b) BT6008 SD Rat 900 900 1800 8 wks 0,80,400,2000,10000,0,4,20,100,500,2500, 5000 0, 0.08X, 0.4X, 2X, 10X, 50X, 100X 1) Dose-related increase of total malignant tumour in M and F Soffritti et al. (2005) ;Belpoggi et al. (2006); 50000, 100,000 2) Dose-related increase of HLTs in F (from the high dose to 400 ppm) Soffritti et al. (2006) 3 a dose estimates are based on mean body weight and mean feed consumption (mice: 40g b.w. and 5g/day; rat: 400g b.w. and 20g/day food). ...
Article
Lymphomas and leukaemias involving the lung have in some cases been hard to distinguish from respiratory tract infection in Sprague-Dawley (SD) rats from long-term bioassays. In order to differentiate between tumours and immune cell infiltrates, updated pathological criteria and nomenclature were used and immunohistochemistry (IHC) was applied to haematopoietic and lymphoid tissue tumours (HLTs) in the original prenatal long-term Aspartame (APM) study performed by the Ramazzini Institute (RI). All 78 cases of HLTs from treated and control groups were re-examined based on light microscopic morphological characteristics and subjected to a panel of IHC markers including Ki67, CD3, PAX5, CD20, CD68, TdT, CD45, CD14 and CD33. The analysis confirmed the diagnoses of HLTs in 72 cases, identified 3 cases of preneoplastic lesions (lymphoid hyperplasia), and categorized 3 cases as inflammatory lesions. A statistically significant increase in total HLTs (p = 0.006), total lymphomas (p = 0.032) and total leukaemias (p = 0.031) in treated female rats was confirmed (high dose vs control), and a statistically significant linear trend for each HLT type was also observed. After the HLT cases re-evaluation, the results obtained are consistent with those reported in the previous RI publication and reinforce the hypothesis that APM has a leukaemogenic and lymphomatogenic effect.
... In these and many other ways, the Ramazzini study was more thorough, sensitive, reliable and relevant to human exposure than those conducted in accordance with conventional protocols. The authors reported in 2005 that their study: "… demonstrated for the first time that APM [aspartame] is a multipotent [ …] carcinogenic agent …" with dose-related tumour increases in both males and females [50]. In 2010 the Ramazzini team published the results of a study showing that aspartame induced tumours in the livers and lungs of male mice [51]. ...
Article
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Background: A detailed appraisal is provided of the most recent (December 2013) assessment of the safety and/or toxicity of the artificial sweetener aspartame by the European Food Safety Authority's Panel on Food Additives and Nutrient Sources Added to Food. That appraisal is prefaced with a contextualising chronological account drawn from a documentary archive of the key highlights of the antecedent scientific and policy debates concerning this sweetener from the early 1970s onwards. The appraisal focuses specifically on Section 3.2 of the panel's review, which is headed 'Toxicological data of aspartame'. Methods: The methodology of the appraisal focusses on the extent to which the panel was symmetrically alert to possible false positives and false negatives, which in toxicological terms denote misleading indications of possible toxicity or misleading indications of safety. The methodology involved identifying and tabulating the prima facie indications of each of 154 empirical studies, and then comparing them with the way in which the panel chose to interpret the studies' findings, by focussing primarily on whether the panel deemed those studies to be reliable or unreliable. If the panel had been even-handed, the criteria for assessing reliability should have been the same for both putative positive and negative studies. Results: Eighty-one studies were identified that prima facie did not indicate any possible harm, and of those the panel deemed 62 to be reliable and 19 as unreliable. Seventy-three studies were identified that prima facie did indicate possible harm; of those the panel deemed all 73 to be unreliable; none were deemed reliable. A qualitative comparative review of the criteria of appraisal invoked by the panel to judge the reliability of putative negative and positive studies is also provided. Conclusion: The quantitative result indicate that the panel's appraisal of the available studies was asymmetrically more alert to putative false positives than to possible false negatives. The qualitative analysis shows that very demanding criteria were used to judge putative positive studies, while far more lax and forgiving criteria were applied to putative negative studies. Discussion: That quantitative and qualitative patterns are very problematic for a body supposed to prioritise the protection of public health. Given the shortcomings of EFSA's risk assessment of aspartame, and the shortcomings of all previous official toxicological risk assessments of aspartame, it would be premature to conclude that it is acceptably safe. They also imply that the manner in which EFSA panels operate needs to be scrutinised and reformed.
... However, some studies have suggested that ASBs are also deleterious as regards obesity [15] and type 2 diabetes risk [5]. Moreover, it has also been suggested that long-term consumption of aspartame, used in many ASBs, might be carcinogenic [16]. Aspartame in liquids can quickly break down into methanol, and the subsequent metabolized formaldehyde is a documented carcinogenic substance [17]. ...
Article
Full-text available
The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificial-sweetened beverages (ASB) and fruit juices (FJ), is associated with the risk of different cardiometabolic diseases. It may also be linked to the development of certain types of tumors. We carried out a systematic review and meta-analysis of observational studies aimed at examining the association between sweet beverage intake and cancer risk. Suitable articles published up to June 2020 were sourced through PubMed, Web of Science and SCOPUS databases. Overall, 64 studies were identified, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest sweet beverage intake categories compared to the lowest one. Random effects showed significant positive association between SSB intake and breast (RR: 1.14, 95% CI: 1.01–1.30) and prostate cancer risk (RR: 1.18, 95% CI: 1.10–1.27) and also between FJs and prostate cancer risk (RR: 1.03, 95% CI: 1.01–1.05). Although the statistically significant threshold was not reached, there tended to be positive associations for the following: SSBs and colorectal and pancreatic cancer risk; FJs and breast, colorectal and pancreatic cancer risk; and ASBs and pancreatic cancer risk. This study recommends limiting sweet beverage consumption. Furthermore, we propose to establish a homogeneous classification of beverages and investigate them separately, to better understand their role in carcinogenesis.
... (9,25,33) Moreover, aspartame has received much negative media attention after the release of the study results of the Ramazzini Institute linking aspartame to cancer in rats. (34,35) However, because of severe deficiencies in the study design, the results were declared faulty by other experts, (36,37) and a complete reevaluation of the safety of aspartame in 2013 came to the conclusion that the consumption of aspartame at the current ADI is safe for human health. (38) Nonetheless, consumers may have believed and remembered the negative headlines, as predicted by the negativity bias. ...
Article
Intensive risk assessment is required before the approval of food additives. During this process, based on the toxicological principle of "the dose makes the poison,ˮ maximum usage doses are assessed. However, most consumers are not aware of these efforts to ensure the safety of food additives and are therefore sceptical, even though food additives bring certain benefits to consumers. This study investigated the effect of a short video, which explains the scientific risk assessment and regulation of food additives, on consumers' perceptions and acceptance of food additives. The primary goal of this study was to inform consumers and enable them to construct their own risk-benefit assessment and make informed decisions about food additives. The secondary goal was to investigate whether people have different perceptions of food additives of artificial (i.e., aspartame) or natural origin (i.e., steviolglycoside). To attain these research goals, an online experiment was conducted on 185 Swiss consumers. Participants were randomly assigned to either the experimental group, which was shown a video about the scientific risk assessment of food additives, or the control group, which was shown a video about a topic irrelevant to the study. After watching the video, the respondents knew significantly more, expressed more positive thoughts and feelings, had less risk perception, and more acceptance than prior to watching the video. Thus, it appears that informing consumers about complex food safety topics, such as the scientific risk assessment of food additives, is possible, and using a carefully developed information video is a successful strategy for informing consumers. © 2015 Society for Risk Analysis.
... This study by Italian researchers presented the first results showing that aspartame caused a statistically significant, dose-related increase in lymphomas and leukaemias in females. No significant increase in malignant brain tumours was observed among animals (Soffritti et al., 2005). In the same year, the same research team provided the first compelling experimental evidence for the carcinogenic effects of aspartame at a dose level within range (even less) of human daily intake . ...
... However, the safety of aspartame was renewed by a report suggesting that an increase in the number of people with brain tumors might be associated with the introduction and use of this sweetener in the USA. A study reports that lymphomas and leukemias were induced in rats fed very high doses of aspartame (Soffritti et al., 2005). Saccharin is another artificial sweetener increases incidence of urinary bladder cancer at high doses in male rats. ...
Article
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Aspartame is an artificial sweetener used as an alternate for sugar in several foods and beverages. The study reports that consumption of aspartame containing product could lead to cancer. However, the effect of aspartame on apoptosis process in cancer is not yet understood clearly. HeLa cells were exposed to different concentration (0.01-0.05 mg/ml) of aspartame for 48 h. Cytotoxicity of aspartame on cancer cells were determined by SRB assay. The result indicates no significant changes on cell viability. Aspartame suppress apoptosis process in cancer cells by down-regulation of mRNA expression of tumor suppressor gene p53, and pro-apoptotic gene bax. It up-regulates anti-apoptotic gene bcl-2 mRNA expression. In addition, Ki 67 and PCNA mRNA, and protein expressions were determined. Taking all these together, we conclude that the aspartame may be a potent substance to slow-down the apoptosis process in HeLa cells. Further works are going to understand the biochemical and molecular mechanism of aspartame in cancer cells.
... However, some studies have suggested that ASB are also deleterious for obesity [13] and type 2 diabetes risk [3]. Moreover, some studies showed that long-term consumption of aspartame, used in many ASBs, might be carcinogenic [14]. Aspartame in liquids can quickly break down into methanol, and the subsequent metabolized formaldehyde is a documented carcinogenic substance [15]. ...
Preprint
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The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB) and fruit juices (FJ) is associated with the risk of different cardiometabolic diseases and probably with some tumors as well. We carried out a systematic review and meta-analysis of observational studies aimed at evaluating the association between sweet beverage intake and different types of cancer risk. Suitable papers published up to June 2020 were searched through PubMed, Web of Science and SCOPUS databases, using relevant keywords. Overall, 64 studies were identified for the systematic review, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest compared with the lowest sweet beverage intake categories. Random effects showed significant positive association between SSBs intake and breast (RR: 1.14, 95% CI: 1.01 – 1.30) and prostate cancer risk (RR: 1.18, 95% CI: 1.10 – 1.27), also between FJs and prostate cancer risk (RR: 1.03, 95% CI: 1.01 – 1.05). Associations between SSBs and colorectal and pancreatic cancer risk, FJs and breast, colorectal and pancreatic cancer risk, ASBs and pancreatic cancer risk tended to be positive but did not reach the statistically significant threshold. This study supports the recommendation to limit the consumption of SSBs and FJs for cancer prevention and proposes to further investigate the potential harmful role of ASBs intake in cancer risk.
... One approach to overcoming these limitations in design would be to require a lifetime toxicological approach, as has been used by the European Ramazzini Institute for the testing of the carcinogenicity of chemicals (Soffriti et al., 2005). In this approach, duration of toxicity testing protocols would be extended to incorporate administration of chemicals in early lifeideally in utero or even before conception-coupled with lifelong follow-up to natural death. ...
... As part of a project started in 1997 by the Ramazzini Institute in Bologna (Italy) to test the carcinogenic potential of widely used intense artificial sweeteners primarily in aspartame, [23][24][25][26][27][28] a study on the carcinogenic potential of sucralose administered with feed to Swiss mice was undertaken. Because human exposure to sucralose might occur during in utero development and during adolescence and in order to increase the sensitivity of the study, the exposure began prenatally and lasted until death. ...
Article
Background: Sucralose is an organochlorine artificial sweetener approximately 600 times sweeter than sucrose and used in over 4,500 products. Long-term carcinogenicity bioassays on rats and mice conducted on behalf of the manufacturer have failed to show the evidence of carcinogenic effects. Objective: The aim of this study was to evaluate the carcinogenic effect of sucralose in mice, using a sensitive experimental design. Methods: Five groups of male (total n = 457) and five groups female (total n = 396) Swiss mice were treated from 12 days of gestation through the lifespan with sucralose in their feed at concentrations of 0, 500, 2,000, 8,000, and 16,000 ppm. Results: We found a significant dose-related increased incidence of males bearing malignant tumors (p < 0.05) and a significant dose-related increased incidence (p < 0.01) of hematopoietic neoplasias in males, in particular at the dose levels of 2,000 ppm (p < 0.01) and 16,000 ppm (p < 0.01). Conclusions: These findings do not support previous data that sucralose is biologically inert. More studies are necessary to show the safety of sucralose, including new and more adequate carcinogenic bioassay on rats. Considering that millions of people are likely exposed, follow-up studies are urgent.
... As part of a project started in 1997 by the Ramazzini Institute in Bologna (Italy) to test the carcinogenic potential of widely used intense artificial sweeteners primarily in aspartame, [23][24][25][26][27][28] a study on the carcinogenic potential of sucralose administered with feed to Swiss mice was undertaken. Because human exposure to sucralose might occur during in utero development and during adolescence and in order to increase the sensitivity of the study, the exposure began prenatally and lasted until death. ...
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Background: Sucralose is an organochlorine artificial sweetener approximately 600 times sweeter than sucrose and used in over 4,500 products. Long-term carcinogenicity bioassays on rats and mice conducted on behalf of the manufacturer have failed to show the evidence of carcinogenic effects. Objective: The aim of this study was to evaluate the carcinogenic effect of sucralose in mice, using a sensitive experimental design. Methods: Five groups of male (total n = 457) and five groups female (total n = 396) Swiss mice were treated from 12 days of gestation through the lifespan with sucralose in their feed at concentrations of 0, 500, 2,000, 8,000, and 16,000 ppm. Results: We found a significant dose-related increased incidence of males bearing malignant tumors (p < 0.05) and a significant dose-related increased incidence (p < 0.01) of hematopoietic neoplasias in males, in particular at the dose levels of 2,000 ppm (p < 0.01) and 16,000 ppm (p < 0.01). Conclusions: These findings do not support previous data that sucralose is biologically inert. More studies are necessary to show the safety of sucralose, including new and more adequate carcinogenic bioassay on rats. Considering that millions of people are likely exposed, follow-up studies are urgent.
... Aspartame (Molecular formula -C14H18N2O5) is a synthetic sweetener used as an alternate for sugar in food and beverages. The permissible dose of aspartame (on a daily basis) is 40mg/kg BW [1][2][3] . Nevertheless, habitual consumers of aspartame usually exceed this threshold. ...
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Background/Objectives: Aspartame is a synthetic sweetener used as an alternate for sugar in food and beverages. Many research observations and findings have related to adverse health effects of aspartame. The medical symptoms include severe headache, giddiness, gastrointestinal and psychological disturbances. In the present study we have evaluated the genotoxicity of aspartame in two animal models; Drosophila melanogaster and Danio rerio. Methods: In the present study we have evaluated the genotoxicity of aspartame in two animal models; Drosophila melanogaster (Phenotypic analysis and DNA fragmentation assay) and Danio rerio (Embryo toxicity, Fin regeneration and DNA fragmentation assay). The flies and fishes were exposed to 4 concentrations of aspartame (500 mg/ml, 250 mg/ml, 125 mg/ml and 62.5 mg/ml). An important aspect that was considered was to measure the sugar levels (by biochemical analysis) in flies post exposure to aspartame and the same was compared with normal sugar intake and in combinations with coconut oil, sugar and aspartame. The fact of increasing blood glucose level and cholesterol levels has been a regular complaint amongst many diabetics and the usage of aspartame has also been higher in patients with diabetes. Findings: The present biochemical assay was carried out to compare and contrast the difference in glucose levels in flies exposed to increasing concentrations of sugar, oil, aspartame and combinations of sugar+coconut oil, aspartame+coconut oil. The results suggested marked phenotypic changes in flies and distinct shearing of DNA on DNA fragmentation assay in both flies and fishes. The extent of fin regeneration was also found to be reduced with increasing concentrations of aspartame. Embryo toxicity assay in zebra fish demonstrated inactivity, neurological disturbances followed by death. The biochemical analysis revealed the efficiency of aspartame to decrease glucose levels in hemo lymph of flies but the presence of oil hindered the efficacy of aspartame to reduce the glucose levels. Applications: The study reflects the toxicity of aspartame and brings awareness in general public about its risk in regular usage.
... Furthermore, some sweet makers use artificial sweeteners instead of sugars to low their manufacturing cost. Sometimes these sweeteners can cause metabolic misbalance or even cancers [11,12]. So this reagent is a brilliant option to identify the absence of sugars. ...
... Az EU SCF ezt követően 1987-ben, 1988-ban, 2002-ben is megvizsgálta az aszpartámot -utóbbi esetben 500 vizsgálat adatait tekintették át -és biztonságosnak minősítették. A European Rammazzini Foundation on Oncology and Environmental Sciences vizsgálati eredményeinek hatására újra fellángoltak az aggodalmak, mivel állatkísérletekben igazolni vélték az aszpartám leukaemiát és lymphomát indukáló hatását [59,60]. Ennek hatására a Bizottság felkérte az EFSA illetékes tudományos paneljét (AFC), hogy vizsgálja meg az újonnan összegyűjtött bizonyítékokat és állapítson meg új ADI-értéket, amennyiben szükséges. ...
Article
Nowadays low calorie or intesive sweeteners are getting more and more popular. These sweeteners can be placed to the market and used as food additives according to the recent EU legislation. In the meantime news are coming out one after the other stating that many of these artificial intensive sweeteners can cause cancer - the highest risk has been attributed to aspartam. Low calorie sweeteners, just like all the other additives can be authorized after strickt risk assessment procedure according to the recent food law. Only after the additive has gone through these procedure can be placed to the list of food additives, which contains not only the range of food these additives can be used, but also the recommended highest amount of daily consumption. European Food Safety Authority considering the latest scientific examination results, evaluates regularly the safety of sweeteners authorized earlier. Until now there is no evidence found to question the safety of the authorized intensive sweeteners. Orv. Hetil., 2016, 157(Suppl. 1), 14-28.
... [233] Since then, the evidence for a relationship between long-term aspartame use and the increase in lymphomas/leukemias in animal models have been reported. [233,234] It is thus highly probable that similar carcinogenic events could occur in humans as a result of regular intake of aspartame; however, further investigations focusing on the safety of aspartame and its breakdown products (aspartic acid, methanol, phenylalanine) are required to provide conclusive evidence. ...
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Colorectal cancer (CRC) is a very common and lethal disease worldwide. The etiology of the disease includes genetic and environmental factors. Among environmental factors, the dietary habits are considered to be easily changeable regarding preventing the CRC. Although there is still a long road to cover the gaps in knowledge on nutritional determinants and dietary pattern on the CRC risk, several dietary suggestions and goals could be summarized. Diets high in energy, consumption of red meat or processed meat, food with high glycemic index (carbohydrates, snack food, frying fast food, and sugar-sweetened drinks, sweets), exceed intake of salt (NaCl), low daily water intake (< 4 cups per day) have been linked to an increased CRC risk. In contrast, consumption of white meat, as well as plant and fish oils with a high omega-3 PUFAs to omega-6 PUFAs ratio might even reduce the occurrence of CRC. A fiber-rich diet can lower the CRC risk up to 50%. Diet rich in vitamin B6, C, D, E, folic acid, selenium, and magnesium has also been considered to reduce the CRC risk. General unhealthy lifestyle which results in overweight and obesity-related syndromes (chronic inflammation, type 2 diabetes) can promote CRC. However, in many cases, the results are inconsistent and depend on multiple interdependent factors, i.e., ethnic, anthropometric, gender, age, hormonal, environmental. In addition to dietary habits, all these agents are suggested to modify the risk of CRC.
... Out of 209 carcinogenesis bioassays at our laboratories, 49 (23%) were carcinogenic (24) and among them 8 increased hemolymphoreticular malignancies. Out of these, 3 were caused these lesions in males and femalesformaldehyde (16), mancozeb (25), and di-isopropylether (26) and 5 only in females-toluene (27), methyl alcohol (28), methyl tert-butyl ether (29), tert-amylmethyl-ether (26), and aspartame (30)(31)(32). A Pathology Working Group convened by the U.S. National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS) to independently evaluate these lesions, and decided some diagnostic differences for certain lymphomas localized in lungs of experimental animals (33). ...
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Recent advances in molecular biology and pathology have opened new opportunities for refining our knowledge of pathophysiologic events and biomarkers. Particular interest in applying these novel methods to current and archived tissues collected in experimental and epidemiological/clinical studies is evident. Until now, it has not always been possible to use archived alcohol-fixed paraffin-embedded (AFPE) tissues for immunohistochemisty (IHC), because AFPE slices and blocks were not often amenable to standard IHC methods. In order to solve this problem, we developed a simple method of post-fixation, which allows to use, on AFPE slices, standard IHC protocols already used for formalin-fixed paraffin-embedded (FFPE) samples. For the assessment of post-fixation processing and to test the feasibility of IHC, we selected the spleen from Sprague-Dawley rats as a demonstrative tissue. Antibodies to PAX5, CD3, CD68 and Ki-67, were tested on FFPE, AFPE and AFPE post-fixed spleen samples. The specificity of antibodies to bind different epitopes expressed in spleen tissue was maintained in FFPE and AFPE post-fixed sections, according to anatomical localization. Post-fixation of AFPE samples did not affect tissue morphology and IHC results were comparable to the FFPE sections in terms of sensitivity, specificity and intensity of staining. In addition to providing an opportunity to use archived tissues, this new post-fixation method would dramatically reduce the use of formaldehyde during histopathology procedures, thus minimizing worker exposure to this dangerous carcinogenic substance.
... Administration at 50 mg per kg body weight (Soffritti, Belpoggi, Esposti, & Lambertini, 2005) Another study found that when aspartame was administered to male and female Sprague-Dawley rats from the 12th day of fetal life until natural death there was a significant dose-related increase of malignant tumors in the male animals. Researchers also found a significant increase in incidence of lymphomas/leukemias in males and females, and significant dose-related increase in incidence of mammary cancer in females (Soffritti, Belpoggi, Tibaldi, Esposti, & Lauriola, 2007). ...
... the incidence of brain malignant tumors, it should be noted that, as previously reported (Soffritti et al. 2005), 12 malignant tumors (10 gliomas, 1 medulloblastoma and 1 meningioma) were observed, without dose relationship, in male and female APM-treated groups, while none were observed in controls. The increase in lymphomas-leukemias in APM-treated females could be related to its metabolite methanol, which is in turn metabolized to formaldehyde in both humans and rats (Ranney et al. 1976). ...
... The foundation for such concern is uncertain, as studies on the impact of artificially sweetened beverages on weight gain, diabetes, and cardio-metabolic disease have produced mixed results [14,[20][21][22][23][24][25][26][27][28][29]. Furthermore, while selected studies in animal models suggest increased incidence of certain cancers with artificial sweetener exposure [30,31], epidemiologic studies in humans have not demonstrated such relationships [32][33][34][35]. ...
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Purpose Observational studies have demonstrated increased colon cancer recurrence and mortality in states of excess energy balance, as denoted by factors including sedentary lifestyle, diabetes, increased dietary glycemic load, and increased intake of sugar-sweetened beverages. Nonetheless, the relation between artificially sweetened beverages, a popular alternative for sugar-sweetened beverages, and colon cancer recurrence and survival is unknown. Methods We analyzed data from 1,018 patients with stage III colon cancer who prospectively reported dietary intake during and after chemotherapy while enrolled in a National Cancer Institute-sponsored trial of adjuvant chemotherapy. Using Cox proportional hazards regressions, we assessed associations of artificially sweetened beverage intake with cancer recurrence and mortality. Results Patients consuming one or more 12-ounce servings of artificially sweetened beverages per day experienced an adjusted hazard ratio for cancer recurrence or mortality of 0.54 (95% confidence interval, 0.36 to 0.80) when compared to those who largely abstained (Ptrend = .004). Similarly, increasing artificially sweetened beverage intake was also associated with a significant improvement in both recurrence-free survival (Ptrend = .005) and overall survival (Ptrend = .02). Substitution models demonstrated that replacing a 12-ounce serving of a sugar-sweetened beverage with an isovolumetric serving of an artificially sweetened beverage per day was associated with a 23% lower risk of cancer recurrence and mortality (relative risk, 0.77; 95% confidence interval, 0.63 to 0.95; P = .02). Conclusion Higher artificially sweetened beverage consumption may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer. This association may be mediated by substitution for sugar-sweetened alternatives. Further studies are needed to confirm these findings.
... Furthermore, some sweet makers use artificial sweeteners instead of sugars to low their manufacturing cost. Sometimes these sweeteners can cause metabolic misbalance or even cancers [11,12]. So this reagent is a brilliant option to identify the absence of sugars. ...
Article
The main aim of the study is develop a cost effective device to detect glucose, protein and specific gravity of substance. A glass capillary tube with diameter 0.5mm and height 100mm was utilized. Height rise for different well-known fluid for that capillary tube is marked. The Benedict's reagent and Coomassie brilliant blue G250 was tested on cotton thread towards its inert state for these two reagents. At the opposite end of the tube a cotton thread was inserted which contended Benedict's reagent and Bradford Reagent (Coomassie brilliant blue G250) socked and dried on the thread. The device was tested the glucose sensitivity and protein sensitivity. This is a multipurpose device and can also be used to detect diabetes and kidney malfunction. Moreover, it can be applicable to circle round the cause which may kill the person by measuring blood specific gravity in its height rise scale. Moreover, it is the fastest, handy and most economic device which can find whether there is any chemical substitute for glucose or whether the water is pure for drinking purpose.
... On the other hand, there are opponent studies such [12,15] who reported a controversial correlative analysis suggesting that an increase in the incidence of brain tumours in industrialized countries may be linked to aspartame consumption. It caused a statistically significant, dose-related increase in lymphomas and leukaemias in female rats [13]. Aspartame's multipotential carcinogenicity at a dose level close to the acceptable daily intake for humans. ...
Article
Aims/Background Human sweet taste receptor structure is predicted and was further evaluate using experimental result. This would enable receptor-based docking and pharmacophore studies since no structure, experimental or predicted model, for complete subunits of human sweet taste receptor (hSTR) is available till date.Methods Different homology modelling as well as threading-based tools were employed for structure prediction of individual domains (amino terminal domain (ATD), cysteine rich domain (CRD) and transmembrane domain (TMD)) and complete subunit structure. Finally, complete subunits structure was built from combinations of individual domain models. These predicted models were validated and further evaluated using docking and interaction analysis of the experimentally studied sweet molecules.Results/ConclusionhSTR Modelling through threading based tools was of poor quality with the exception of ITASSER software that predicted models with greater than 90% residues in energetically favourable environment. Among homology based software, CPH Model, SWISS Model and Prime predicted hSTR model of acceptable quality with more than 95% residues in energetically favourable environment. This model can be used for receptor-based pharmacophore modelling or searching newer sweet molecules.
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As sucrose has been implicated in healthrelated problems such as obesity and diabetes, awareness of a safe natural non-sugar sweetener has increased. Brazzein is the intensely sweet-tasting plant protein which consists of 54 amino acids. In this study, brazzein was expressed in Lactobacillus spp., probiotics, which are widely used in food industry. Three Lactobacillus spp. (Lb. paracasei KLB58, Lb. plantarum KLB213, and Lb. reuteri KCTC3594) were electrotransformed with pMSP3545::Braht which contains brazzein gene along with nisin-controlled expression (NICE) system. Brazzein expression in Lactobacillus spp. was confirmed by Western blot analysis. Overall, higher expression rate was obtained with nisin concentration of 25–40 ng/mL.
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Background: Excitotoxins are a class of substances usually amino acids or their derivatives that normally act as neurotransmitters in brain but in excessive amounts lead to over excitation of neurons leading to a state of exhaustion & death. Over 70 types of excitotoxins have been identified so far and many have a free access to our body in form of taste enhancing food additives like monosodium glutamate, aspartame, sodium casienate etc. They have been implicated for the development of a wide variety of neurological disorders like Alzheimer`s disease , Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and even for early ageing. Objective:The purpose of this review is to sort out truth about extent of involvement of excitotoxins in neurodegeneration from the massive propaganda against them wherein they have been implicated in almost all disorders of unknown etiology. Method: A comprehensive search strategy was developed incorporating both the peer reviewed,non peer reviewed literature and electronic databases like Medline. These were scrutinized and relevant research papers were examined. Conclusion : There is considerable evidence based research pertaining to the neurodegenerative effect of excitotoxins to the human brain. Yet the autonomous food regulating bodies like FDA refuse to recognize the immediate and long term danger to the public caused by the use of such excitotoxic food additives. Thus only means of protecting oneself from such type of neurological damage is to consume only unprocessed, fresh, whole, organic foodstuffs.
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Aspartame is an artificial sweetner added to many low-calorie foods. The safety of aspartame remains controversial even though there are many studies on its risks. In this study, to understand the physiological effects of trace amounts of artificial sweetners on cells, the effects of aspartame on apoptosis were investigated using a PC12 cell system. In addition, the mechanism of apoptosis induced by aspartame in PC12 cells and effects on apoptotic factors such as cytochrome c, apoptosis-inducing factor, and caspase family proteins were studied by Western blotting and RT-PCR. Aspartame-induced apoptosis in PC12 cells in a dose-dependent manner. In addition, aspartame exposure increased the expressions of caspases 8 and 9, and cytochrome c. These results indicate that aspartame induces apoptosis mainly via mitochondrial pathway involved in apoptosis due to oxigen toxicity.
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Low-calorie sweeteners (sometimes referred to as non-nutritive sweeteners, artificial sweeteners, or sugar substitutes) are ingredients added to foods and beverages to provide sweetness without adding a significant amount of calories. Their role in weight management is wiy known but their role in maintaining dental health is still hidden. The present article discusses about the well known artificial as well as natural sweeteners and their importance in maintaining dental health. Besides this microbes can also be used as a novel approach for the production of natural sweeteners.
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Dietary foods without sugar or so-called "specific for diabetics" are not essential in the Diabetes Mellitus treatment and can even be totally excluded from their diet. However, these foods are highly consumed by diabetics and have a strong impact in their social life as a substitute for sucrose palatability and provision sweetness pleasure. The replacement of sucrose by sweeteners can help the diabetics to better accomplish the nutrition therapy advised by their nutritionist and help them in weight control. This is an important factor, especially in the treatment of type 2 Diabetes Mellitus, since in some sweeteners products, the energy value is negligible.
Chapter
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of non-nutritive sweeteners for the prevention or treatment of being overweight or obesity.
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Il concetto di “nutrizione sana” pervade in maniera ormai capillare il mondo moderno e i flussi d’informazione che lo caratterizzano; è sufficiente inserire questa coppia di termini in un motore di ricerca come Google, per esempio, per ottenere più di 20 milioni di risultati.
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The aim of this chapter was to address the issue of uses and overuses of additives with consequent impacts on human health. Modern food additives have an important role in food production. At present, the number of individuals engaged in food primary production is dramatically decreasing; on the other hand, consumers seems to search for many food choices, including ready-to-eat foods, with annexed higher safety and hygiene standards (and food additives may be a concern). The most part of consumers have still confidence in the work of official commissions in defense of food safety; on the other hand, some people may find deem discrepancies between their own sense of security and the complex of laws or practices in defense of the human health. Main worries concern the enormous economic power of certain multinational groups in the field of food production; the absolute discretion of Committees to judge eligible or not eligible available researches on certain food additives; the choice of research methods and the lack of studies concerning synergist effects of different food additives.
Chapter
Aspartame is an intense artificial sweetener with a sweet test approximately 200 times that of sucrose and used as additive in more than 6,000 products. Aspartame was invented by GD-Searle in 1965 and submitted for pre-marketing safety evaluation in early 1980s. The studies conducted by GD-Searle to evaluate the potential carcinogenic risks of aspartame did not show any effect. Because of the great commercial diffusion of aspartame, in 1997 the Ramazzini Institute started a large experiments project on rodents to test the carcinogenic effects of aspartame in our experimental model with more sensitive characteristics, namely large number of rats and mice, observation until natural death. Overall the project included the study of 2,270 rats and 852 mice starting the treatment from prenatal life or in mature age and lasting all life. These studies have shown that aspartame is a carcinogenic agent inducing a significant dose-related increased incidence of several types of malignant tumors and, among them, haematological neoplasias. Later this effect was confirmed by an epidemiological study conducted by a group of the Harvard University.
Chapter
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Aspartame [SC-18862; 3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester, the methyl ester of aspartylphenylalanine] is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. The metabolism of aspartame has been studied in mice, rats, rabbits, dogs, monkeys, and humans. The compound was digested in all species in the same way as are natural constituents of the diet. Hydrolysis of the methyl group by intestinal esterases yielded methanol, which was oxidized in the one-carbon metabolic pool to CO2. The resultant dipeptide was split at the mucosal surface by dipeptidases and the free amino acids were absorbed. The aspartic acid moiety was transformed in large part to CO2 through its entry into the tricarboxylic acid cycle. Phenylalanine was primarily incorporated into body protein either unchanged or as its major metabolite, tyrosine.
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The linear trend test in proportions is frequently used to analyze the results of animal carcinogenicity experiments. This test has two major advantages over other frequently used tests; it is easily understood and it is simple to calculate. This test, however, fails to correct for treatment-related differences in survival across the experimental groups. A test which is a simple modification of the linear trend test in proportions and which has the same advantages is proposed to correct for differences in survival. The results of this modified test are compared to those of the linear trend test in proportions, the incidental tumor test, the logistic regression score test, the life table test, and the truncated trend test using information on the incidence of combined alveolar/bronchiolar adenomas or carcinomas in female B6C3F1 mice exposed to vinylcyclohexene diepoxide.
Article
Male and female Sprague-Dawley rats of different ages at the start of the experiments (12 day embryos, and 7 and 25 weeks old) were administered formaldehyde in drinking water at different doses (2,500 or 1,500, 1,000, 500, 100, 50, 10, 0 ppm). An increased incidence of leukemias and of gastro-intestinal tu mors was observed in formaldehyde treated rats. Gastro-intestinal tumors are exceptionally rare in the rats of the colony used. These results, together with the ones obtained by other Authors on rats exposed by inhalation to formaldehyde, indicate that this compound is an experimental multipotential carcinogen. The experimental results presented in this report give scientific support to the epidemiological observation of a higher incidence of leukemias and of gastro-intestinal cancers among the people occu pationally exposed.
Article
Statistical tests of carcinogenicity are shown to have varying degrees of robustness to the effects of mortality. Mortality induced by two different mechanisms is studied--mortality due to the tumor of interest, and mortality due to treatment independent of the tumor. The two most commonly used tests, the life-table test and the Cochran-Armitage linear trend test, are seen to be highly sensitive to increases in treatment lethality using small-sample simulations. Increases in tumor lethality are seen to affect the performance of commonly used prevalence tests such as logistic regression. A simple survival-adjusted quantal response test appears to be the most robust of all the procedures considered.
Article
A key to the prevention of childhood cancer is the control of carcinogens to which children are exposed. The first step in this process is to identify those chemicals that are likely to cause cancer in children. The best way to identify carcinogens, today, is the use of the rodent lifetime cancer test--the bioassay. The test has vocal critics, but is adequately reliable if properly used. Perhaps the major criticism concerns the use of the maximum tolerated dose as the highest dose tested. Critics claim that this dose causes cellular killing. The resultant cellular proliferation "fixes" preexisting mutations that can lead to cancer. This occurs but in a small fraction of the tests, and the high dose is necessary to achieve statistical sensitivity. All human carcinogens have been shown, when properly studied, to be carcinogenic in rodents. Many human carcinogens were first shown to cause cancer in rodent tests. Regulators rarely ban chemicals that have been demonstrated to be carcinogenic. Further, most chemicals in use today have not been properly tested. The potential errors in the rodent cancer test seem small when compared to the errors in the economic projections of the effects of restricting chemicals. Although not perfect, the rodent cancer test, when used properly, can help protect our children, and us, from cancer.
Article
Long-term carcinogenesis bioassays are the most valued and predictive means for identifying potential carcinogenic hazards of various agents to humans. Agents may be chemicals, chemical mixtures, multiple chemicals, combinations of chemicals, residues and contaminants, commercial products and formulations, and various exposure circumstances. Life-styles, dietary factors, and occupational exposure circumstances are very difficult, but not totally impossible, to evaluate experimentally. Historically, the first chemical bioassay took place in the early part of this century: Yamagiwa and Ichikawa in 1915, showed that coal tar applied experimentally to rabbit ears caused skin carcinomas. Since then, nearly 1500-2000 bioassays of one sort or another have been carried out. Importantly, however, some of these bioassays must be considered inadequate for judging the absence of carcinogenicity, since there were various limitations on the way they were performed: too few animals, too short a duration, too low exposure concentrations, too limited pathology, as examples. Thus, each bioassay must be critically evaluated, especially those reported to be negative, because "false negatives" are certainly more hazardous to human health than are "false positives". Likewise, one must be careful not to discount bioassay results simply because a target organ in rodents may not have a direct counterpart in humans (e.g., Zymbal glands), or because an organ site in rodents may not be a major site of cancers in humans (e.g., mouse liver). The design and conduct of a bioassay is not simple, however, and one must be fully aware of possible pitfalls as well as viable and often necessary alternatives. Similarly, evaluating results and interpreting findings must be approached with the utmost objectivity and consistency. These and other select issues, controversies, and uncertainties possibly encountered in long-term bioassays are covered in this paper. One fact remains abundantly clear: for every known human carcinogen that has been tested adequately in laboratory animals, the findings of carcinogenicity are concordant.
Article
Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. 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.
Carcinogenesis bioassays and protecting public health. Commemorating the lifework of Cesare Maltoni and colleagues
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Attuazione della direttiva n. 86/609/CEE in materia di protezione degli animali utilizzati a fini sperimentali o ad altri fini scientifici. Supplemento ordinario alla
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