Aspartame: A Compile of studies

1. Aspartame– Health Benefit or long-term, slow accumulating poison? Part I The Following is an amalgamation of Aspartame studies and related topics, highlighting some of the major findings and mechanisms of how AspartameOperates within the body. If you’re not familiar with my style of presentation and writing style, here is the text code to the colouring. I find it’s easier to pick out the important points, which points are simply facts and identifiers, and which parts are simply informational. Bluetext = Standard information or positive attributable data Yellow = Simple facts, names, places, dates titles, corporations, or neutral information Red = Negative effects or known pathways to illness Orange = Pertaining to Organisations or corporations statements Green = Points of connecting interest (in context)

4. The chairman of the expert panel which assessed the sweetener, Dr AlicIiMortensen, said: ‘This opinionrepresents one of the most comprehensive risk assessments of aspartameever undertaken. ‘It’s a step forward in strengthening consumer confidence in the scientific underpinning of the EU food safety system and the regulation of food additives.’ Aspartamehas come under suspicion as a result of research studies drawing links to everything from allergic reactions to cancer and premature births. However, a study by experts on behalf of the European Food Safety Authority (EFSA), has found it has no harmful effects. EFSA said yesterday: ‘Aspartameand its breakdown products are safe for human consumption at current levels of exposure.’

6. The EFSA Panel on Additives and Nutrient Sources added to Food is made up of excellent experts from a wide range of disciplines who have analysed and assessed all available data. The International Sweeteners Association (ISA) welcomed the EFSA opinion and quoted Professor Andrew Renwick, from the University of Southampton, supporting the decision. ‘People should be confident that the data reviewed is the most up-to-date and that the EFSA opinion is based on all existing scientific facts. Aspartameis a simple compound made from two amino acids and a methyl group, all of which occur naturally in the diet and are consumed in larger amounts from other normal dietary sources.’

10. David G. Hattan, Ph.D.Acting Director, Division of Health Effects Evaluation 13 January 1999 (19 years ago)

15. Aspartame Cancer Risks Revisited Prenatal Exposure May Be Greatest Concern The current limits for acceptable daily intake are set at 50 mg/kg body weight in the United States and 40 mg/kg body weight in Europe. (because it’s a chemical) https://www.cancer.org/cancer/cancer-causes/aspartame.html?_ga=2.190355755.1275091266.1544977048-1810297467.1544977048

18. 1Artificial Sweeteners: A systematic review of metabolic effects in youth (15 pages) - 2010 The initial literature search produced 116 potentially eligible articles. Of these articles, 111 were excluded as they did not meet requirements. An additional 13 articles were identified based on a reference list search of review articles. Our search yielded a total of 18 human studies Evidence of a causal relationship linking artificial sweetener use to weight gain and other metabolic health effects is limited. However, recent animal studies provide intriguing information that supports an active metabolic role of artificial sweeteners. This systematic review examines the current literature on artificial sweetener consumption in children and its health effects. Eighteen studies were identified. Data from large, epidemiologic studies support the existence of an association between artificially-sweetened beverage consumption and weight gain in children…Since their FDA approval, artificial sweeteners and their benefits on metabolic health have been questioned In addition, increased consumption of added caloric sweeteners has been associated with lower diet quality in children (31), perhaps by altering taste preferences toward sweetened foods in place of more healthful foods, such as fruits and vegetables; this mechanism could apply to artificial sweeteners as well. In particular, very little data exist regarding the role of artificial sweetenersinglucose metabolismin children 1Int J Pediatr Obes. 2010 August ; 5(4): 305–312. doi:10.3109/17477160903497027

19. New data from both humans and animal models have provided convincing evidence that artificial sweeteners play an active rolein the gastrointestinal tract, thus providing a mechanistic explanation for observed metabolic effects. Sweet-taste receptors, including the taste receptor T1R family and α-gustducin, respond not only to caloric sugars, such as sucroseand glucose, but also to artificial sweeteners, including sucralose (Splenda™) and acesulfame-K(32,33). In both humans and animals, these receptorshave been shown to be present not only in lingual taste buds, but also in glucagon-like peptide-1 (GLP-1) secretingL cells of the gut mucosa (34–36), where they serve as critical mediators of GLP-1 secretion (36). Mace et al. showed in rat studies that stimulation of intestinal taste receptors with sucralose led to more rapid absorption of sugars from the intestine into the bloodstream (32). We have demonstrated in young healthy volunteers that consumption of diet soda before an oral glucose challenge potentiates GLP-1 secretion, thus potentially altering both gastric emptying and insulin secretion (62). Translating these results into the clinical realm, consumption of an artificial sweetener in conjunction with a sugar-containing food or drink could lead to more rapid sugar absorption, as well as increased GLP-1 and insulin secretion, potentially affecting weight, appetite, and glycemia.

20. A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes (18 pages) - 2011 Discussion To our knowledge, this is the first systematic review of randomized trial evidence that examines comparative sweetener effectiveness in diabetic, overweight/obese, and healthy populations. Sugar alcohols can also be used as sweetener additives and provide less calories per gram than saccharides (sugars). However because sugar alcohols cause gastrointestinal symptoms in some individuals due to incomplete absorption in the small intestine, they may be used less frequently than saccharides. A variety of different saccharidesis commonly used to sweeten foods, such as sucrose, fructose, glucose, maltose, isomaltulose, and fructooligosaccharide(FOS). Despite tremendous interest in hypocaloricsweeteners as a potential tool to prevent obesity and its complications, we found little evidence to support their health benefits as compared to caloric alternatives. Based on analyses of two trials, we found that the inclusion of non-caloric sweeteners in the diet resulted in reduced energy intakecompared to the caloric (sucrose) groups - approximately 500 kcal/day less over 10 weeks or 250 kcal/day over 4 weeks. Also, despite popular belief, no high-quality RCT evidence was found indicating that fructose causes or exacerbates hypertriglyceridemia

21. In theory, substituting non-caloric and lower caloric sweeteners for simple sugars should reduce energy intake and thereby the risk of obesity and its consequences. However, there are a number of reasons why increasing use of non-caloric and lower caloric sweetenersmight not lead to the expected improvements in energy regulation. Non-caloric sweeteners are not known to suppress appetite, and therefore would not reduce the motivation to eat. Furthermore, it has been suggested that the psychobiological signals with non-caloric sweeteners may directly influence physiological regulatory mechanisms and thus further reduce their potential for reducing net energy intake The lack of data on the long-term benefits of non-caloric sweeteners means that it is currently impossible to determine whether these substanceswill improve public health. Wiebe et al. BMC Medicine 2011, 9:123 - Published: 17 November 2011 http://www.biomedcentral.com/1741-7015/9/123

22. Aspartame in conjunction with carbohydrate reduces insulin levels during endurance exercise (4 pages) - 1 August, 2012 Conclusions: The novel finding of this study was that despite a normal insulin response during the ingestion period (at rest), the combination of aspartame and carbohydrate (CA - 0.04% aspartame with 2% maltodextrinand 5% sucrose) led to significantly lower serum insulin levels during exercise than when compared to carbohydrate alone (C - carbohydrate (2% maltodextrinand 5% sucrose) This suggests that the reduction in insulin levels associated with aspartame ingestion observed in the current study may only be seen at a threshold of carbohydrate intake. Although the results of the current study do not provide evidence for an underlying mechanism responsible for the variation in the exercise-induced insulin response, the disparity between insulin levels warrant further investigation with a larger cohort of clinically relevant subject populations Siegler et al. Journal of the International Society of Sports Nutrition 2012, 9:36 Page 4 of 4 http://www.jissn.com/content/9/1/36

23. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain (12 pages) Research Paper - Accepted 24 April 2014 In 1965Aspartamewas discovered by James Schlatterand was approved for use by the FDA in the 1970s. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether or not chronic aspartame (FDA approved Daily Acceptable Intake (ADI) 40 mg / kg bwt) administration could release methanol, and whether or not it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. Aspartame ( l -aspartyl- l -phenylalanine methyl ester) exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, lipid peroxidation levels, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and catalase activity in (aspartameMTX)-treated animals and with a significant decrease in reduced glutathione, glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic markerBaxshowed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain

24. The increase in free radicals could not be ignored as cells can be injured or killed when the ROS generation overwhelms the cellular antioxidant capacity[ 56 ]. The increasein the lipid peroxidation could not be neglected as it is an auto catalytic mechanism leading to oxidative destruction of cellular membranes [ 57 ]. In free radicals production, the thiol glutathione (glycylglutamicacid–cysteine) is the most important cellular free radical scavenging system in the brain. It is essential to point out that even with the FDA approved dosage of (40 mg / kg) similar alteration in the scavenging system was observed. Free radicals can also attack DNA strand to induce breaks and base modifications that can lead to point mutation [ 79 ]. Scaianoet al [19 ] reported that free radicals were responsible for induction of cellular damage that leads to chromosomal aberrations. AlSuhzibani[80], reported that aspartame induces a significant increase of chromosome aberration frequencies in mice compared to control providing a supporting scientific evidence that aspartame is toxic. The involvement of free radicals with tumor suppressor genes and proto-oncogenes suggests their role in the development of different human cancers[81, 82 ]. The report of Soffritti et al. [83] highlighted that aspartame can induce cancer. The aspartame treated animals showed a neuronal shrink age of hippocampal layer due to degeneration of pyramidal cells in this study.

25. Now this is where it gets interesting from The EFSA and FDA’s point of view The ‘controversial’ Italian Megaexperiment

26. First Experimental Demonstration of the MultipotentialCarcinogenic Effects of Aspartame Administered in the Feed to Sprague-DawleyRats MorandoSoffritti, FiorellaBelpoggi, DavideDegliEsposti, Luca Lambertini, Eva Tibaldi, and Anna Rigano CesareMaltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy In this article we present the results of the mega-experiment on the carcinogenicity of APM in which the sweetenerwas administered in feed to Sprague-Dawley rats for the life span. Under particular conditions (extreme pH, high temperature, lengthy storage times), APMmay be contaminated by the diketopiperazine(DKP) cycloaspartylphenylalanine(Butchko et al. 2002a). Initial commercial approval of APM in the United States was granted by the Food and Drug Administration (FDA 1974). The FDA later approved the limited use of APMin solid foods in 1981 and extended this authorization to soft drinks in1983. In the European Union, the safe use of APMwas authorized in 1994(EC Directive 1994). For each molecule of APM, one molecule of each constituent is produced - aspartic acid, phenylalanine, and methanol. After gastrointestinal tract absorption, they are then used, metabolized, and/or excreted by the body following the same metabolic pathways as when consumed through the ordinary diet: aspartate is transformed into alanine plus oxaloacetate (Stegink 1984); phenylalanine is transformed mainly into tyrosine and, to a smaller extent, phenylethylamine and phenylpyruvate (Harper 1984); and methanol is transformed into formaldehyde and then to formic acid (Opperman 1984).

27. Two long-term feeding carcinogenicity bioassays on APMwere performed on rats and one on mice in the early 1970sby the producer Searle & Co. Results were reviewed by the FDAand then summarized in the Federal Register (FDA 1981). To date, the details of the experiments have not been published. In the first study, groups of 40 male and 40 female Sprague-Dawley rats were treated with 1, 2, 4, or 6–8 g/kg bw/day of APMin the diet. The treatment started at 4 weeks of age and lasted for a period of 104 weeks. A control group of 60 rats per sex was fed the same diet without APM. At the end of the treatment, all surviving animals were sacrificed and their brains, as well as other organs (not specified in the report), were examined histologically. Brain tumors were observed in 7of 155(4.5%) exposed males versus 1 of 59 (1.7%) controls, and in 5of 158 (3.2%) exposed females versus 0 of 59 (0%) controls. Overall, the FDA considered the study to be negativewith regard to the carcinogenicity of APM (FDA 1981). In the second study, groups of 40 male and 40 female Sprague-Dawley rats were exposed to APM, Three brain tumors were observed among control males and one among control females. Brain tumors were also observed in two males and one female in the 2 g/kg bw group, and in one male and one female in the 4 g/kg bw group. Again, the FDAconsidered the study to be negative with regard to the carcinogenicity of APM (FDA 1981).

28. Origin:  The *AlbinoSprague Dawley® outbred model was developed by Sprague Dawley, Inc. NIHreceived stock from Sprague Dawley, Inc in 1945. The rats are maintained as an outbred closed colony. Taconic received stock from the NIHAnimal Genetic Resource in 1970. The rats were refreshed with NIH Genetic Resource stock in 1998. Epidemiologic studies to evaluate the relationship between APM intake and cancer development in humansare not currently available. For these reasons, and in light of the ever increasing diffusion of APM in the diet of industrialized countries (particularly in products consumed by young children and pregnant women), we considered it important to perform a mega-experiment following today’s internationally recognized good laboratory practices forcarcinogenicity bioassays and, more specifically, the life-spancarcinogenicity bioassaydesign followed for many years at the **CMCRCand described in previous publications (Soffritti et al. 1999, 2002c). *https://www.taconic.com/rat-model/sprague-dawley **https://core.ac.uk/display/23825323 **http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.411.2255

29. No evident behavioural changes were observed among treated animals compared with controls. In animals exposed to the highest dose of APM, yellowing of the coat was observed; this change had previously been observedin our laboratory in rats exposed to formaldehydeadministered with drinking water (Soffritti et al. 2002b). Tumor types that contributed most are presented below. Lymphomas/leukaemias. The data on the occurrence of lymphomas/leukaemias, reported in Tables 2 and 3, indicate that APM causes a significant positive trend in males (p ≤ 0.05) and in females (p ≤ 0.01). Compared with untreated control groups, the increased incidence of lymphomas/leukaemiasin treated femaleswas statistically significant at doses of 100,000(p ≤ 0.01), 50,000 (p ≤ 0.01), 10,000 (p ≤ 0.05), 2,000 (p ≤ 0.05), or 400 ppm (p ≤ 0.01). The most frequent histocytotypesobserved in the experiment were lymphoimmunoblastic lymphomas, mainly involving lungand mediastinal/peripheral nodes, and histiocyticsarcomas, involving mainly lung, liver, spleen, and nodes. The differential diagnoses were based on the morphologic criteriafollowed in our laboratory for several decadesand are in line with the guidelines of the International Classification of Rodent Tumors [International Agency for Research on Cancer (IARC) 1993].

30. A dose related increase in the incidence of dysplastic hyperplasiasand dysplastic papillomas of the renal pelvis and ureter was observed in females. Carcinomasin femalesoccurred with a positive trend(p ≤ 0.05), and the incidenceinfemalesexposed at 100,000 ppm was significantly higher(p ≤ 0.05) compared with the controls.

31. Although transitional cell carcinomas of the renal pelvis and ureter are extremely rare in male and female untreated rats, the APM male and female groups had a total of 21 transitional cell carcinomas of the renal pelvis, whereas the controls had none. Malignant schwannomas of peripheral nerves. Metastases of cranial nerve malignant schwannomaswere observed in three malestreated at the highest dose. The metastaseswere found in submandibular lymph nodes in two cases, and the tumor metastasized to the lung and liver in one case. Preneoplastic and neoplastic lesions of the olfactory epithelium. Incidence of hyperplasia of the olfactory epithelium increased with a significantpositive trendin males and females. Among femalestreated at the highest dose, one case of dysplastic hyperplasia, one adenoma, and one olfactory neuroblastomawere observed. The neuroblastomainvaded the cranium, compressing the forebrain, and was positive for chromogranin A immunohistochemical staining. Malignant brain tumors. Concerning the incidence of malignant tumors in the brain, 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 femaleAPM-treated groups, whereas none were observed in controls.

32. The results of the study show for the first time that APM (Aspartame), in our experimental conditions, causes a) an increased incidence of malignant-tumor–bearing animals with a positive significant trend inmales and in females, in particular those females treated at 50,000 ppm b) an increase in lymphomas and leukemiaswith a positive significant trend in both males and females, in particular in femalestreated at doses of 100,000 (p ≤ 0.01), 50,000 (p ≤ 0.01), 10,000 (p ≤ 0.05), 2,000 (p ≤ 0.05), or 400 ppm

33. c) a statistically significant increased incidence, with a positive significant trend (p ≤ 0.01), of transitional cell carcinomas of the renal pelvis and ureter and their precursors (dysplasias) in females treated at 100,000 (p ≤ 0.01), 50,000 (p ≤ 0.01), 10,000 (p ≤ 0.01), 2,000 (p ≤ 0.05), or 400 ppm (p ≤ 0.05); and d) an increased incidenceof malignant schwannomasof peripheral nerves with a positive trend (p ≤ 0.05) in males. The results of this mega-experimentindicate that APMis a multi-potential carcinogenic agent, even at a daily dose of 20 mg/kg body weight, much less than the current acceptable daily intake. The increasein lymphomas/leukemiasin APM-treatedfemalescould be related to its metabolite methanol, which is in turn metabolizedto formaldehydein both humans and rats (Ranney et al. 1976). The important role of formaldehydein the induction of hematologic malignancies in rodents is further highlighted by these results. In a recent re-evaluation of the carcinogenicity of formaldehydeby the IARC(in press), strong (although not considered sufficient) evidence of an association between formaldehyde exposure and leukemias in humans was found. To investigate if the other two metabolites of APMare responsible for inducing these lesions, it is of paramount importance to perform adequate life-spancarcinogenicitystudies on aspartic acid orphenylalanine. Also illustrated in Environ Health Perspectives 114:379–385 (March 2006) Volume 114. doi:10.1289/ehp.8711 - Availablevia http://dx.doi.org/ [Online 17 November 2005]

34. Additional findings, investigative routes to follow and interesting avenues for further research are presented below: • T-Maze performance affecting memory • Muscarinic receptor densities in frontal cortex, mid cortex (mid-brain), posterior cortex, hippocampus, hypothalmusand cerebellum • Increase of Oxidative stress biomarkers such as Creatine, Uric Acid and carcninogenesis • Isoprostane and Proglastin stimulation and raised AST, ALT, LDHlevels (kidney and liver function) • Deep Transcranial Magnetic Resonance and other high frequency RF signal may • Stimulate production of beta-endorphins, a reward neurotransmitter attributed to opiate and drug dependency • White Sugar raises Triglycerides which are a precursor to heart disease • Nitrites and Nitrates may also be co-factors to carcinogenic progress • Methanol, Formaldehyde (and the Aldehyde family as a whole) and Formic Acid (Formate) may also be attributed to carcinogenicity progression • Alterations in regional concentrations of Catecholamine (amines) • Folate deficiency due to aspartameand its metabolitemethanol • Decrease in levels of Co-Enzyme Q10 (50% in 6 months), alpha-tocopheroland Glutothionereserves (ubiquinone allows regeneration of a-tocopherol) • Uses GLUT 4 receptor – Ascorbic Acid uses the GLU T 1 poathway • Effects arecompounded (unknown levels)whenmixed with Acesulfame K

35. Immunoreactive beta-endorphin increases after an aspartame chocolate drink in healthy human subjects Abstract: Plasma beta-endorphin concentrations were more elevated after the aspartame drink than after sucroseor fasting, while insulin increased after drinking as much with aspartame as with sucrose. We suggest that the increase in beta-endorphin after aspartameedulcorated chocolate is related with insulin secretion in the absence of marked changes in blood glucose or with a direct effect of aspartame itself on beta-endorphin liberation. 1Chronic aspartame affects T-maze performance, brain cholinergic receptors and Na+,K+-ATPase in rats Abstract: The midbrain was the only area where preparations from aspartame-treated rats showed a significant increase in Na(+),K(+)-ATPase activity. It can be concluded from these data that long-term consumption of aspartame can affect T-maze performance in rats and alter receptor densities or enzymes in brain. 1https://www.researchgate.net/publication/8547552_Chronic_aspartame_affects_Tmaze_performance_brain_cholinergic_receptors_and_NaK-ATPase_in_rats

36. Chronic cola drinking induces metabolic and cardiac alterations in rats April 26, 2011 In the present study, long-term drinking of regular cola beverage resulted in weight gain, mild hyperglycemia and marked hypertriglyceridemia. Changes in plasma triglycerides were also associated with the consumption of diet cola. Importantly, reversal of most parameters was observed after switching back from cola to water. DecreasedCoQ10 levels have been suggested to be a useful biomarker of oxidative stress [13]. CoQ10 mainly accumulates in the liver and in cell membranes, where it acts as an endogenous antioxidant [14], and plasma levels of CoQ10 are well correlated with liver stores. It is conceivable that reduced plasma levels of CoQ10found after 6 monthsof cola drinking in our ratsmight reflect the exhaustion of the protective response mechanism to sustained oxidative stress induced by chronic carbohydrate ingestion. Long term ingestion of a hypercalorichyperglycemic diet leads to obesity and increased lipid peroxidation and induces oxidative stress by compromising the mitochondrial redox metabolism In summary, in this animalmodel, oxidative stress, overweight, hypertriglyceridemia, mild hyperglycemia, systolic hypertension and echocardiographic alterations (heart rate increases) occurred as a consequence of chronic drinking of cola beverages in rats. Most of these changes reversed after washout to tap water. Source: |www.wjgnet.com - World Journal of W J C Cardiology

37. Consumption of artificial sweetener– and sugar-containing soda and risk of lymphoma and leukaemia in men and women - 2012 Aspartame, especially in liquids (8), quickly breaks down into its 3 main ingredients (methanol, aspartic acid, and phenylalanine) if stored near or above room temperature (3), and the formaldehyde metabolized from methanol is a documented human carcinogen(9). A recent megaexperimentin 1800 rats tested at aspartamedoses much lower than the currently acceptable daily intake (5ADI) for humans (10) reported a dose-dependent increase in lymphomas, leukemias, and transitional renal cell tumors. This report provoked a review by several European agencies, including the European Food Safety Authority Panel on Food Additives, Flavors, Processing Aids and Materialsand the European Food and Safety Agency (EFSA), which concludedthat there is “no reason to revise the previously established ADI for aspartameof40 mg/kg body weight” (11). In the United States, the ADI for aspartameis set at 50 mg/kg body weight (6). (9) International Agency for Research on Cancer Working Group. Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropan-2-ol. In: WHO, ed. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon, France: IARC, WHO, 2006.

38. RESULTS A total of 47,810 men contributed 784,461 person-years to this analysis, and 77,218 women contributed 1,493,935 person-years. At the final dietary assessment in 2002, 53% of men and 54% of women reported diet soda consumption with mean intakes of 5.7 and 5.3 servings/wk, respectively. The mean daily aspartame intake in consumers at the final dietary assessment was 114 mg in the HPFS (Health Professionals Follow-Up Study and 102 mg in the NHS (Nurses’ Health Study) In men, risk of NHL(Non-Hodgkin Lymphoma) was significantly elevated for subjects who consumed 1 serving diet soda/d (RR: 1.31; 95% CI: 1.01, 1.72) compared with in subjectswho reported no consumption. Risk was even greater for the consumption of 2 servings diet soda/d, and the association showed a linear trend For multiple myeloma, risk increased linearly with increased consumption of diet soda in men(P-trend = 0.009) and was significantly elevated for subjects who consumed 1 serving/d Diet soda was not associated with risk of multiple myeloma in women, and a significant heterogeneity was observed between cohorts for the linear trend

39. Although aspartamewas approved for use in the United States in 1981and was used as the sole artificial sugar sweetener in Diet Coke soda (The Coca-Cola Company), which was the most commonly used diet soda at the time, beginning in 1983, most other diet sodas in the 1980s used both aspartame and saccharin for sweetness. Aspartamebecame most broadly used in sodasin 1992when its patent expired (Searle & Co.) and the price dropped significantly. We hypothesized that the sex differences we observed may have been due to the recognized higher enzymatic activity of alcohol dehydrogenase type I (ADH) in men, which possibly induced higher conversion rates from methanol to the carcinogenic substrate formaldehyde. DISCUSSION In the most comprehensive long-term epidemiologic study, to our knowledge, to evaluate the association between aspartameintake and cancer riskin humans, we observed a positive association between diet soda and total aspartame intake and risks of NHLand multiple myeloma in menand leukemiain both men and women. A higher consumption of regular sugar-sweetened soda was associated with higher risk of NHL and multiple myeloma in menbut not in women. US Food and Drug Administration. Aspartame: Commissioner’s final decision. Fed Reg 1981;46(142):38285–308.

40. Extremely high nitrite concentrations may react with a variety of amino acids, including aspartame, whichgenerate compounds with mutagenic properties under certain conditions. However, these mechanisms are not unique to aspartame. The primary food sources of phenylalanineand aspartic acid are meats, fish, and dairy foods, and diet soda adds a minor amount to the total. In a previous analysis, we showed animal protein to be associated with increased risk of NHL in womenin the NHS(35). Another, more speculative explanation could be that men are more susceptible to the effects of aspartame, perhaps because of differences in enzyme activity; the only human enzyme that is capable of metabolizing methanol, one of the breakdown products of aspartame, to formaldehyde is ADH (44). Previous studies reported that ADH activity was significantly higher in men than in women (45), and increased alcohol consumption was associated with decreased ADH activityin men (24, 46), which slowed down the conversion of methanol to formaldehyde and formate(47, 48). Although it is still being debated whether methanol, by itself, is carcinogenic in humans (49), in 2006the International Agency for Cancer Research (IARC) classifiedformaldehyde as a class 1 definite carcinogen, with likely carcinogenic effects for leukemia and other tumors(9). 9. International Agency for Research on Cancer Working Group. Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropan-2-ol. In: WHO, ed. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon, France: IARC, WHO, 2006. 35. Zhang S, Hunter DJ, Rosner BA, Colditz GA, Fuchs CS, Speizer FE, Willett WC. Dietary fat and protein in relation to risk of non-Hodgkin’s lymphoma among women. J Natl Cancer Inst1999;91:1751–8.

41. A limitation of our study is that the measurement of aspartame intake is necessarily imperfect for 2 primary reasons. First, we did not have complete assessment of each single dietary item that may have contained aspartame; however, we are confident that we captured close to 95% of all aspartameintake by adding diet soda consumption and aspartame consumption via sweetener packets (19, 20). Other sources of aspartameintakeare minor contributors to overall aspartame intake. Second, the assessment of aspartame intake is imperfect because there are multiple sources in the diet that must be self-reported. Another, rather unique strength of this study, besides its large sample size, was that we effectively captured lifetime exposure to aspartamebecause we have been assessing diet soda consumption intake since aspartame was first allowed into the food supply. In conclusion, these observational data provide some support for findings from a recent animal experiment that suggested positive associations between aspartame intake and NHL, multiple myeloma, and leukemia, particularly in men. Because this is, to our knowledge, the first large-scale observational human study to report associations between diet soda and aspartame intake and these cancer types, our results necessarily require confirmation in other large cohorts.

42. Consumption of Artificially-Sweetened Soft Drinks in Pregnancy and Risk of Child Asthma and Allergic Rhinitis - February 27, 2013 Ekaterina Maslova, Marin Strøm, Sjurdur F. Olsen, Thorhallur I. Halldorsson1 In our prospective study of the relation between maternal intake of artificially-sweetened beverages during pregnancy and development of child allergic disease, we found that artificially-sweetened beverages moderately increased risk of asthma and allergic rhinitis both in early and later childhood. These results appeared stronger for carbonated beverages. We did not find similar results for sugar-sweetened beverages, suggesting that artificial sweeteners, rather than other additives and aromatic compounds in soft drinks, may play a role in the development of allergic diseases. Aspartamedid decrease antigen-induced histamine release from cultured mouse mast cells after long-term exposure only. The authors could not fully explain the origin of this effect but speculated that by increasing mast cell proliferation, it made mast cells less responsive to anaphylactic stimulation. Furthermore, while the majority of these studies involved aspartame; other artificial sweeteners, such as acesulfame-K, sucralose, or saccharine, need to be considered as potential active agents. Soft drinks often contain a mixture of different sweeteners. The predominant sweeteners in soft drinks appearing on the Danish market are aspartame and acesulfame-K[26].

43. 1EFFECT OF LONG-TERM CONSUMPTION OF ASPARTAME ON BODY WEIGHT, BLOOD GLUCOSE, LIPID PROFILE, AND KIDNEY AND LIVER FUCTION IN RATS Conclusion: The administration of APM (Aspartame) during 4 monthsshowed adeleterious effect on the kidneys and liver function. Besides that, a combination of atheroscleroticeffects were also observed, as well as, a general increased exposure to oxidative stress, as demonstrated by isoprostane levels elevation. The sweetener consumption increased the liver lipoperoxidation and the risk of carcinogenesis. The kidney’s function was also affected. Therefore, APMwasconsidered unsafe to be included in the diet. Taken together, these results suggest that the long use of APM may be harmful in humans. Artificial sweeteners consumption may cause migraines or headache, skin eruptions, muscle dysfunction, depression, weight gain, liver and kidney toxicity, multiple sclerosis, blurred vision, respiratory problems, cancers, allergies, seizures andimmune system dysfunction. 1https://www.researchgate.net/publication/327140449_EFFECT_OF_LONGtERM_CONSUMPTION_OF_ASPARTAME_ON_BODY_WEIGHT_BLOOD_GLUCOSE_LIPID_PROFILE_AND_KIDNEY_AND_LIVER_FUCTION_IN_RATS August 2018