Magnuson, B. A., Burdock, G. A., Doull, J., Kroes, R. M., Marsh, G. M., Pariza, M.W., Spencer, P.S., Waddell, W. J., Walker R., Williams, G.M.
Aspartame: A safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Critical Reviews in Toxicology. 2007; 37(8): 629-727.
Abstract
Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.
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Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, de Sonneville LM, Geha RS, Hertelendy Z, Koestner A, Leon AS, Liepa GU, McMartin KE, Mendenhall CL, Munro IC, Novotny EJ, Renwick AG, Schiffman SS, Schomer DL, Shaywitz BA, Spiers PA, Tephly TR, Thomas JA, Trefz FK.
Aspartame: review of safety. Regul Toxicol Pharmacol. 2002 Apr; 35(2 Pt 2):S1-93.
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.
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British Medical Journal 2004; 329:755-756 (2 October)
Editorial (complete text below)
Aspartame and its effects on health
The sweetener has been demonized unfairly in sections of the press and several websites
The European population of 375 million consumes about 2000 tonnes annually of aspartame (NutraSweet, Canderel) an artificial sweetener, which contains two amino acids-aspartic acid and phenylalanine.(1) It is 180-200 times sweeter than sucrose, and almost half a million extra tonnes of sugar would therefore be needed to generate the same sweetness. Was the world screaming for all this sweetness, and what has it done to us? Anyone searching the web on aspartame, launched in 1981 by Monsanto, the manufacturer of NutraSweet, will find a vast catalogue of frightening personal accounts attributing multiple health disasters to exposure to aspartame.(1) Although no orchestrated public outcry about aspartame has taken place, much sensationalist journalism has been published mostly on websites . In contrast, aspartame marketing implies that it embodies a healthy way of life and avoids obesity. Are these claims of hazards and benefits supported by evidence?
Evidence does not support links between aspartame and cancer, hair loss, depression, dementia, behavioural disturbances, or any of the other conditions appearing in websites. Agencies such as the Food Standards Agency, European Food Standards Authority, and the Food and Drug Administration have a duty to monitor relations between foodstuffs and health and to commission research when reasonable doubt emerges. Aspartame's safety was convincing to the European Scientific Committee on Food in 1988,(2) but proving negatives is difficult, and it is even harder to persuade vocal sectors of the public whose opinions are fuelled more by anecdote than by evidence. The Food Standards Agency takes public concerns very seriously and thus pressed the European Scientific Committee on Food to conduct a further review, encompassing over 500 reports, in 2002. It concluded from biochemical, clinical, and behavioural research that the acceptable daily intake of 40 mg/kg/day of aspartame remained entirely safe-except for people with phenylketonuria.(3)
Does aspartame embody a healthy way of life and avoid obesity? In most Western countries sugar provides around 10% of total calories (about 200 kcal (837 kJ), or 50 g daily). If this were entirely replaced by a non-nutritive, non-caloric sweetener such as aspartame then obesity could indeed be vanquished-assuming these calories are not replaced due to stimulation of appetite. We eat about 5 g aspartame annually, equivalent to another kg of sucrose, whose 4000 kcal (16 740 kJ) could generate 0.5 kg gain in weight. But evidence that aspartame prevents weight gain or obesity is generally inconclusive, (4, 5) although in children, the consumption of sugar sweetened soft drinks relates notably to increasing obesity, whereas increasing "diet" drinks or fruit juice is inversely related to weight gain.(6)
Dietary recommendations for the management of diabetes conclude that up to 10% of total energy can safely come from sugars but that artificial sweeteners may help avoid weight gain.(7, 8) When sugar is consumed as a sweetener it is chemically identical with the sugar found in fruits, which we are promoting keenly, and its metabolic effects are no different if consumed in reasonable amounts even by people with diabetes.(8) Most evidence points to fat as the main dietary culprit in obesity, and one counterargument to the use of artificial sweetener instead of sugar includes evidence that high sugar diets tend to be lower in fat.(9) Displacing saturated fat would offer particular advantages by reducing risk of heart disease.(10) Carried to extremes, large amounts of sucrose will increase triglycerides, a key component of the metabolic syndrome, and turn the tables back towards promoting heart disease. Its fructose component is responsible for this hazard.(11)
Artificial sweeteners are promoted to prevent dental caries, as sugars form the main substrate for mouth bacteria. However, avoiding sugar does not reduce dental caries dramatically in regions with high levels of caries.(3) The dominant factors are fluoride deficiency and prolonged exposure to sugar between meals. If children consume sweetened drinks between meals or suck on sweet foods, resulting in prolonged periods of exposure to sugar, then replacing the sugar with artificial sweeteners in such products has some rationale. Children exposed to heavily sweetened foods develop a "sweet palate," but those who take the plunge and take unsweetened drinks may prefer them, which seems a better solution.(12)
Why has aspartame been demonised by the world's press and countless websites? Monsanto was in the public eye, accused of enthusiastic dissemination of genetically modified plants and foods. People resent interference with foods, and synthetic food components are regarded with suspicion. However, aspartame comprises just two amino acids (aspartic acid and phenylalanine). Could this present a risk? Phenylalanine is a natural amino acid, and is toxic only in patients who have phenylketonuria.
Food labelling of sweetener is contentious. Six artificial sweeteners are permitted in Europe, each with an acceptable daily intake. Consumers cannot be expected to alculate cumulative daily intakes of each. Instead, manufacturers are encouraged to use cocktails of sweeteners so it becomes difficult for anyone to reach the acceptable daily intake of any sweetener individually-adults need at least 10 cans of a drink fully sweetened with aspartame alone to reach the acceptable daily intake of 40 mg/kg/day. When using combinations of sweeteners, even high level consumers rarely exceed 10 mg/day. Intakes over 1g/day were needed to alter brain neurotransmitters and provoke seizures in monkeys, and randomised controlled trials of high doses in humans have not shown any behavioural or other effects.(13, 14) The cynical conclusion is that there is probably too much sweetness and never enough light, and the public probably needs protection against misleading websites.
Michael E J Lean, Professor
Division of Developmental Medicine, University of Glasgow, Royal Infirmary, Queen Elizabeth Building, Glasgow G31 2ER
Catherine R Hankey, Lecturer, University Department of Human Nutrition
Division of Developmental Medicine, University of Glasgow, Royal Infirmary, Queen Elizabeth Building, Glasgow G31 2ER
Competing interests: None declared.
References
1. AspartameInformation Center. www.aspartame.org
2. European Commission. Health and Consumer Protection Directorate-General, Scientific Committee on Food. Opinion of the scientific committee on food: update on the safety of aspartame. SCF, 10 December 2002.
3. Navia JM. Carbohydrates and dental health. Amer J Clin Nutr 1994;59: 719-27.
4. Tordoff MG, Alleva AM. Effect of drinking soda sweetened with aspartame or high fructose corn syrup on food intake and body weight. Amer J Clin Nutr 1990;51: 963-9.
5. Drewnowski A. Review: intense sweeteners and energy density of foods: implications for weight control. Eur J Clin Nutr 1999;53: 757-63.
6. Ludwig DS, Peterson, Gortmaker SL. Relation between consumption of sugar sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 2001;357: 505-8.
7. Nutrition Sub-Committee, British Diabetic Association. Dietary recommendations for people with diabetes. An update for the 1990's. J Hum Nutr Diet 1991;4: 393-412.
8. Diabetes and Nutrition Study Group (DNSG) of the European Association for the study of diabetes. Recommendations for the nutritional management of patients with diabetes mellitus. Eur J Clin Nutr 2000;54: 353-5.
9. BoltonSmith C, Woodward M. Dietary composition and fat to sugar ratios in relation to obesity. Int J Obes 1994;18: 820-8.
10. Puska P, Vartiainen E, Tuomilehto J, Salomaa V, Nissinen A. Changes in premature deaths in Finland: successful long-term prevention of cardiovascular diseases. Bull WHO 1998;76: 419-2.
11. Hollenbeck CB. Dietary fructose effects on lipoprotein metabolism and risk for coronary artery disease. Am J Clin Nutr 1993;58: 800s-809s.
12. Birch LL. Development of food preferences. Annu Rev Nutr 1999;19: 41-62.
13. Wolraich ML, Lindgren SD, Stumbo PJ, Stegink LD, Appelbaum MI, Kiritsy MC. Effects of diets high in sucrose or aspartame on the behaviour and cognitive performance of children. N Eng J Med 1994;330: 301-7.
14. Butchko HH, Stargel WW. Aspartame: scientific evaluation in the postmarketing period. Reg Toxic Pharma 2001;34: 221-233
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Leon AS, Hunninghake DB, Bell C, Rassin DK, Tephly TR. Safety of long-term large doses of aspartame. Arch Intern Med. 1989 Oct; 149(10):2318-24.
Safety of long-term administration of 75 mg/kg of aspartame per day was evaluated with the use of a randomized, double-blind, placebo-controlled, parallel-group design in 108 male and female volunteers aged 18 to 62 years. Subjects received either aspartame or placebo in capsule form three times daily for 24 weeks. No persistent changes over time were noted in either group in vital signs; body weight; results of standard laboratory tests; fasting blood levels of aspartame's constituent amino acids (aspartic acid and phenylalanine), other amino acids, and methanol; or blood formate levels and 24-hour urinary excretion of formate. There also were no statistically significant differences between groups in the number of subjects experiencing symptoms or in the number of symptoms per subject. These results further document the safety of the long-term consumption of aspartame at doses equivalent to the amount of aspartame in approximately 10 L of beverage per day.
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Butchko HH, Stargel WW. Aspartame: scientific evaluation in the postmarketing period. Regul Toxicol Pharmacol. 2001 Dec; 34(3):221-33.
Prior to marketing, the safety of the high-intensity sweetener aspartame for its intended uses as a sweetener and flavor enhancer was demonstrated by the results of over 100 scientific studies in animals and humans. In the postmarketing period, the safety of aspartame was further evaluated through extensive monitoring of intake, postmarketing surveillance of anecdotal reports of alleged health effects, and additional research to evaluate these anecdotal reports and other scientific issues. The results of the extensive intake evaluation in the United States, which was done over an 8-year period, and the results of studies done in other countries demonstrated intakes which were well below the acceptable daily intakes set by the FDA and regulatory bodies in other countries, as well as the Joint FAO/WHO Expert Committee on Food Additives. Evaluation of the anecdotal reports of adverse health effects, the first such system for a food additive, revealed that the reported effects were generally mild and also common in the general population and that there was no consistent or unique pattern of symptoms that could be causally linked to consumption of aspartame. Finally, the results of the extensive scientific research done to evaluate these allegations did not show a causal relationship between aspartame and adverse effects. Thus, the weight of scientific evidence confirms that, even in amounts many times what people typically consume, aspartame is safe for its intended uses as a sweetener and flavor enhancer.
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Aspartame. Review of safety issues. Council on Scientific Affairs. JAMA. 1985 Jul 19; 254(3):400-2.
[No authors listed]
This report examines the safety issues related to the nutritive sweetener aspartame, including possible toxic effects of aspartame's component amino acids, aspartic acid and phenylalanine, and its major decomposition products, methanol and diketopiperazine, and the potential synergistic effect of aspartame and dietary carbohydrate on brain neurochemicals. Available evidence suggests that consumption of aspartame by normal humans is safe and is not associated with serious adverse health effects. Individuals who need to control their phenylalanine intake should handle aspartame like any other source of phenylalanine.
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Yost DA. Clinical safety of aspartame. Am Fam Physician. 1989 Feb; 39(2):201-6.
Aspartame is a synthetic sweetener commonly used in soft drinks and many foods. Even with high doses, the metabolites of this sweetener do not accumulate in toxic amounts. To date, no definite symptom complex has been connected with aspartame, and it is considered safe for use in all populations, including diabetics, phenylketonuric heterozygotes and pregnant women.
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Frey GH. Use of aspartame by apparently healthy children and adolescents. J Toxicol Environ Health. 1976 Nov; 2(2):401-15.
This study was conducted to determine the effects and the differences, if any, resulting from the ingestion of aspartame (sweetener) versus sucrose. A 13-wk, double-blind study was conducted using 126 apparently healthy children and adolescents as panelists. Individuals were randomly assigned in a double-blind design to aspartame or sucrose in each of five age groups; dosage levels were assigned according to age and weight groups. Physical examinations and special eye examinations were performed at the beginning and end of the study. Other parameters determined including laboratory tests of liver and renal function, hematologic status, and plasma levels of phenylalanine and tyrosine. Clinically significant differences in laboratory parameters measured could not be demonstrated; all mean values were within normal limits. No unusual findings were observed in phenylalanine or tyrosine levels. All phenylpyruvic acid and methanol determinations were negative. No important physical changes occurred, and no product-related side effects were reported.
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