{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:32:15Z","timestamp":1790415135332,"version":"4.1.0"},"reference-count":47,"publisher":"American Chemical Society (ACS)","issue":"3","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":4425,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation has conducted a long-term bioassay on aspartame (APM), a widely used artificial sweetener. APM was administered with feed to 8-week-old Sprague-Dawley rats (100\u2013150\/sex\/group), at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The treatment lasted until natural death, at which time all deceased animals underwent complete necropsy. Histopathologic evaluation of all pathologic lesions and of all organs and tissues collected was routinely performed on each animal of all experimental groups. The results of the study show for the first time that APM, in our experimental conditions, causes a) an increased incidence of malignant-tumor\u2013bearing animals with a positive significant trend in males (p \u2264 0.05) and in females (p \u2264 0.01), in particular those females treated at 50,000 ppm (p \u2264 0.01); b) an increase in lymphomas and leukemias with a positive significant trend in both males (p \u2264 0.05) and females (p \u2264 0.01), in particular in females treated at doses of 100,000 (p \u2264 0.01), 50,000 (p \u2264 0.01), 10,000 (p \u2264 0.05), 2,000 (p \u2264 0.05), or 400 ppm (p \u2264 0.01); c) a statistically significant increased incidence, with a positive significant trend (p \u2264 0.01), of transitional cell carcinomas of the renal pelvis and ureter and their precursors (dysplasias) in females treated at 100,000 (p \u2264 0.01), 50,000 (p \u2264 0.01), 10,000 (p \u2264 0.01), 2,000 (p \u2264 0.05), or 400 ppm (p \u2264 0.05); and d) an increased incidence of malignant schwannomas of peripheral nerves with a positive trend (p \u2264 0.05) in males. The results of this mega-experiment indicate that APM is a multipotential carcinogenic agent, even at a daily dose of 20 mg\/kg body weight, much less than the current acceptable daily intake. On the basis of these results, a reevaluation of the present guidelines on the use and consumption of APM is urgent and cannot be delayed.<\/jats:p>","DOI":"10.1289\/ehp.8711","type":"journal-article","created":{"date-parts":[[2005,11,16]],"date-time":"2005-11-16T13:17:33Z","timestamp":1132147053000},"page":"379-385","source":"Crossref","is-referenced-by-count":203,"title":["First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats"],"prefix":"10.1021","volume":"114","author":[{"given":"Morando","family":"Soffritti","sequence":"first","affiliation":[{"name":"Cesare Maltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorella","family":"Belpoggi","sequence":"additional","affiliation":[{"name":"Cesare Maltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide Degli","family":"Esposti","sequence":"additional","affiliation":[{"name":"Cesare Maltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lambertini","sequence":"additional","affiliation":[{"name":"Cesare Maltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Tibaldi","sequence":"additional","affiliation":[{"name":"Cesare Maltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rigano","sequence":"additional","affiliation":[{"name":"Cesare Maltoni Cancer Research Center, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2005,11,17]]},"reference":[{"key":"2026081810333759100_micit1","author":"Armitage"},{"key":"2026081810333759100_micit2","author":"Aspartame Information Center"},{"key":"2026081810333759100_micit3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.2307\/2531856","article-title":"Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples","volume":"44","author":"Bailer","year":"1988","journal-title":"Biometrics"},{"key":"2026081810333759100_micit4","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1177\/074823379501100202","article-title":"Methyl-tertiary-butyl ether (MTBE), a gasoline additive, causes testicular and lymphohaematopoietic cancers in rats","volume":"11","author":"Belpoggi","year":"1995","journal-title":"Toxicol Ind Health"},{"key":"2026081810333759100_micit5","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1006\/rtph.2002.1542","article-title":"Preclinical safety evaluation of aspartame","volume":"35","author":"Butchko","year":"2002","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026081810333759100_micit6","first-page":"S13","article-title":"Intake of aspartame vs the acceptable daily intake","volume":"35","author":"Butchko","year":"2002","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026081810333759100_micit7","first-page":"5","article-title":"Attuazione della direttiva n. 86\/609\/CEE in materia di protezione degli animali utilizzati a fini sperimentali o ad altri fini scientifici [in Italian]","volume":"40","author":"Decreto Legislativo 116","year":"1992","journal-title":"Supplemento ordinario alla Gazzetta Ufficiale"},{"key":"2026081810333759100_micit8","first-page":"3","article-title":"Directive 94\/35\/EC of 30 June 1994 on sweeteners for use in foodstuffs","volume":"237","author":"EC Directive 35","year":"1994","journal-title":"Official Journal L"},{"key":"2026081810333759100_micit9","first-page":"27317","article-title":"Food additives permitted in food for human consumption: aspartame","volume":"39","author":"FDA (Food and Drug Administration)","year":"1974","journal-title":"Fed Reg"},{"key":"2026081810333759100_micit10","first-page":"38285","article-title":"Aspartame: commissioner\u2019s final decision","volume":"46","author":"FDA (Food and Drug Administration)","year":"1981","journal-title":"Fed Reg"},{"key":"2026081810333759100_micit11","first-page":"31376","article-title":"Food additives permitted for direct addition to food for human consumption: aspartame","volume":"48","author":"FDA (Food and Drug Administration)","year":"1983","journal-title":"Fed Reg"},{"key":"2026081810333759100_micit12","first-page":"33654","article-title":"Food additives permitted for direct addition to food for human consumption; 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