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Sweeteners pp 311-347 | Cite as

Potential Carcinogenic Risks of Aspartame

  • Morando SoffrittiEmail author
  • Angela Guaragna
  • Marco Manservigi
Reference work entry
Part of the Reference Series in Phytochemistry book series (RSP)

Abstract

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.

Keywords

Aspartame Food additive Carcinogenic bioassay Rat Mice Artificial sweetener Carcinogenic effects EFSA FDA GD-SEARLE 

Abbreviations

ADI

Admitted daily dose

APM

Aspartame

CI

Confidence interval

DKP

5-benzyl-3, 6-dioxo-2 piperazine acetic acid

EFSA

European Food Safety Authority

FDA

Food Drug Administration

GR

Glutathione reductase

GSH

Glutathione

IARC

International Agency for Research on Cancer

MPL

Maximum permitted level

RR

Relative risk

US-NCI

United States – National Cancer Institute

US-NTP

United States – National Toxicology Program

WHO

World Health Organization

Notes

Acknowledgements

A special thanks to Dr. Eva Tibaldi and Dr. Erica Tommasini for their extraordinary technical support during the preparation of the paper.

References

  1. 1.
    Sasaki YF, Kawaguchi S, Kamaya A, Ohshita M, Kabasawa K, Iwama K, Taniguchi K, Tsuda S (2002) The comet assay with 8 mouse organs: results with 39 currently used food additives. Mutat Res 519:103–119CrossRefGoogle Scholar
  2. 2.
    Weihrauch MR, Diehl V (2004) Artificial sweeteners-do they bear a carcinogenic risk? Ann Oncol 15:1460–1465CrossRefGoogle Scholar
  3. 3.
    EFSA (European Food Safety Authority) (2011) Call for scientific data on Aspartame (E 951). Available online http://www.efsa.europa.eu//en/dataclosed/call/110601.htm
  4. 4.
    Prankerd RJ (2002) Aspartame. Anal Profiles Drug Subst Excip 29:7–55Google Scholar
  5. 5.
    EFSA (European Food Safety Authority) (2013) Scientific opinion on the re-evaluation of aspartame (E 951) as a food additive. EFSA J 11(12):3496, 263 pp. doi: 10.2903/j.efsa.2013.3496
  6. 6.
    Schernhammer ES, Bertrand KA, Birmann BM, Sampson L, Willett WW, Feskanich D (2012) Consumption of artificial sweetener-and sugar-containing soda and risk of lymphoma and leukemia in man and woman. Am J Clin Nutr 96:1419–1428CrossRefGoogle Scholar
  7. 7.
    Food and Drug Administration (1981) Aspartame: commissioner’s final decision. Fed Regist 46:38285–38308Google Scholar
  8. 8.
    Food and Drug Administration (1983) Food additives permitted for direct addition to food for human consumption: aspartame. Fed Regist 48:31376–31382Google Scholar
  9. 9.
    Food and Drug Administration (1996) Food additives permitted for direct addition to food for human consumption: aspartame. Fed Regist 61:33654–33656Google Scholar
  10. 10.
    European Parliament and Council (1994) Directive 94/35/EC of 30 June 1994 on sweeteners for use in foodstuffs. Off J L 237:3–12Google Scholar
  11. 11.
    Leung SS, Grant DJ (1997) Solid state stability studies of model dipeptides: aspartame and aspartylphenylalanine. J Pharm Sci 86:64–71CrossRefGoogle Scholar
  12. 12.
    Homler (1984) Aspartame: implications for the food scientist. In: Stegink LD, Filer LJ Jr (eds) Aspartame: physiology and biochemistry, Marcel Dekker Inc. New YorkGoogle Scholar
  13. 13.
    Pattanaargson S, Chuapradit C, Srisukphoraruk S (2001) Aspartame degradation in solutions at various pH conditions. J Food Sci 66:808–809Google Scholar
  14. 14.
    Prodolliet J, Bruelhart M (1993) Determination of aspartame and its major decomposition products in foods. J AOAC Int 76:275–282Google Scholar
  15. 15.
    Saito K, Horie M, Hoshino Y, Nose N, Nakazawa H, Fujita M (1989) Determination of diketopiperazine in soft drinks by high-performance liquid chromatography. J Liq Chromatogr 12:571–582CrossRefGoogle Scholar
  16. 16.
    Prankerd RJ, Stone HW, Sloan KB, Perrin JH (1992) Degradation of aspartame in acidic aqueous media and its stabilization by complexation with cyclodextrins or modified cyclodextrins. Int J Pharm 88:189–199CrossRefGoogle Scholar
  17. 17.
    Opperman J (1984) Aspartame metabolism in animals. In: Stegink LD, Filer LJ Jr (eds) Aspartame. Physiology and biochemistry. Marcel Dekker Inc, New YorkGoogle Scholar
  18. 18.
    Hooper NM, Hesp RJ, Tieku S (1994) Metabolism of aspartame by human and pig intestinal microvillar peptidases. Biochem J 298:635–639CrossRefGoogle Scholar
  19. 19.
    Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, Spencer PS, Waddele WJ, Walker R, Williams GM (2007) Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol 37:629–727CrossRefGoogle Scholar
  20. 20.
    Burgert SL, Anderson DW, Stegink LD, Takeuchi H, Schedl HP (1991) Metabolism of aspartame and its l-phenylalanine methyl ester decomposition products by the porcine gut. Metab Clin Exp 40:612–618CrossRefGoogle Scholar
  21. 21.
    Horton VL, Higuchi MA, Rickert DE (1992) Physiologically based pharmacokinetic model methanol for rats, monkeys and humans. Toxicol Appl Pharmacol 117:26–36CrossRefGoogle Scholar
  22. 22.
    Stagink LD (1984) Aspartame metabolism in humans: acute dosing studies. In: Stagink LD, Filer LJ Jr (eds) Aspartame: physiology and biochemistry. Marcel Dekker Inc, New YorkGoogle Scholar
  23. 23.
    Leon AS, Unninghake DB, Bell C, Rassin DK, Tephly TR (1989) Safety of long-term large doses of aspartame. Arch Intern Med 149:2318–2124CrossRefGoogle Scholar
  24. 24.
    Abhilash M, Sauganth Paul MV, Varghese MV, Nair RH (2011) Effects of long-term intake of aspartame on antioxidant defense status in liver. Food Chem Toxicol 49:1203–1207Google Scholar
  25. 25.
    Abhilash M, Sauganth Paul MV, Varghese MV, Nair RH (2013) Long-term consumption of aspartame and brain antioxidant defense status. Drug Chem Toxicol 39:135–140CrossRefGoogle Scholar
  26. 26.
    NTP (US National Toxicology Program) (2005) NTP report on the toxicology studies of aspartame (CAS No. 22839-47-0) in genetically modified (FVB Tg.AC hemizygous) and B6.129-Cdkn2atm1Rdp (N2) deficient mice and carcinogenicity studies of aspartame in genetically modified [B6.129-Trp53tm1Brd (N5) haploinsufficient] mice (feed studies). National Toxicology Program genetically modified model report, pp 1–222Google Scholar
  27. 27.
    Rencuzogullarj E, Tuylu BA, Topaktas M, Ila HB, Kayraldiz A, Arslan M, Diler SB (2004) Genotoxicity of aspartame. Drug Chem Toxicol 27:257–268CrossRefGoogle Scholar
  28. 28.
    Bandypadhyay A, Ghoshal S, Mukherjee A (2008) Genotoxicity testing of low-calorie sweeteners: aspartame, acesulfame-K and saccharin. Drug Chem Toxicol 31:447–457CrossRefGoogle Scholar
  29. 29.
    Jeffrey AM, Williams GM (2000) Lack of DNA –damaging activity of five non-nutritive sweeteners in the rat hepatocyte/DNA repair assay. Food Chem Toxicol 38:335–338CrossRefGoogle Scholar
  30. 30.
    Kamath S, Vijaynarayana K, Shetty DP, Shetty P (2010) Evaluation of genotoxic potential of aspartame. Pharmacol Online 1:753–769Google Scholar
  31. 31.
    EPA (1984) Good laboratory practices standards in environmental protection agency – fungicides, insecticides and rodenticides Act. 48 federal register 53946. Environmental Protection AgencyGoogle Scholar
  32. 32.
    FDA (2000) Toxicological principles for the safety assessment of food ingredients: FDA Redbook 2000: section IV.B.1. General guidelines for designing and conducting toxicity studies. Nov 2003. Food and Drug Administration, Washington, DC, p 18Google Scholar
  33. 33.
    OECD (2009) Guideline for the testing of chemicals. Test guideline 451: carcinogenicity studies. Organization for Economic Cooperation and Development, Sep 2009. Paris,  p 15Google Scholar
  34. 34.
    Soffritti M, Belpoggi F, Minardi F, Bua L, Maltoni C (1999) Mega-experiments to identify and assess diffuse carcinogenic risks. Ann N Y Acad Sci 895:34–55CrossRefGoogle Scholar
  35. 35.
    Soffritti M, Belpoggi F, Minardi F, Maltoni C (2002) Ramazzini foundation cancer program: history and major projects, life-span carcinogenicity bioassay design, chemicals studied, and results. Ann N Y Acad Sci 982:26–45CrossRefGoogle Scholar
  36. 36.
    Melnick RL, Thayer KA, Bucher JR (2008) Conflicting views on chemical carcinogenesis arising from the design and evaluation of rodent carcinogenicity studies. Environ Health Perspect 116:130–135CrossRefGoogle Scholar
  37. 37.
    Ishii H (1981) Incidence of brain tumors in rats fed aspartame. Toxicol Lett 7:433–437CrossRefGoogle Scholar
  38. 38.
    Iwata S (2006) Histopathological examination in a carcinogenicity study of SC-18862 in Wistar rats. Ajinomoto, unpublished reportGoogle Scholar
  39. 39.
    Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L (2005) Aspartame induces lymphomas and leukemias in rats. Eur J Oncol 10:107–116Google Scholar
  40. 40.
    Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L, Tibaldi E, Rigano A (2006) First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats. Environ Health Perspect 114:379–385Google Scholar
  41. 41.
    Soffritti M, Belpoggi F, Tibaldi E, Degli Esposti D, Lauriola M (2007) Life-span exposure to low doses of aspartame beginning during pre-natal life increases cancer effects in rats. Environ Health Perspect 115:1293–1297CrossRefGoogle Scholar
  42. 42.
    Soffritti M, Belpoggi F, Manservigi M, Tibaldi E, Lauriola M, Falcioni L, Bua L (2010) Aspartame administered in feed, beginning pre-natally through life-span, induces cancers of the liver and lung in male Swiss mice. Am J Ind Med 53:1197–1206CrossRefGoogle Scholar
  43. 43.
    Hardell L, Mild KH, Pahlson A, Hallquist A (2001) Ionizing radiation, cellular telephones and the risk for brain tumours. Eur J Cancer Prev 10:523–529CrossRefGoogle Scholar
  44. 44.
    Bunin GR, Kushi LH, Gallagher PR, Rorke-Adams LB, McBride ML, Cnaan A (2005) Maternal diet during pregnancy and its association with medulloblastoma in children: a children’s oncology group study (United States). Cancer Causes Control 16:877–891CrossRefGoogle Scholar
  45. 45.
    Lim U, Subar AF, Mouw T, Hartge P, Morton LM, Stolzenberg-Solomon R, Campbell D, Hollenbeck AR, Schatzkin A (2006) Consumption of aspartame-containing beverages and incidence of hematopoietic and brain malignancies. Cancer Epidemiol Biomark Prev 15:1654–1659Google Scholar
  46. 46.
    Soffritti M, Padovani M, Tibaldi E, Falcioni L, Manservisi F, Belpoggi F (2014) The carcinogenic effects of aspartame: the urgent need for regulatory re-evaluation. Am J Ind Med 57:383–397CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Morando Soffritti
    • 1
    Email author
  • Angela Guaragna
    • 2
  • Marco Manservigi
    • 3
  1. 1.Clinical Center of Cancer PreventionRamazzini InstituteBolognaItaly
  2. 2.Clinical Center of Cancer PreventionBolognaItaly
  3. 3.Cesare Maltoni Cancer Research CenterBolognaItaly

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