Regulatory toxicology and pharmacology

Harriett H. Butchko, W. Wayne Stargel, C. Phil Comer, Dale A. Mayhew, Christian Benninger, George L. Blackburn, Leo M.J. de Sonneville, Raif S. Geha, Zsolt Hertelendy, Adalbert Koestner, Arthur S. Leon, George U. Liepa, Kenneth E. McMartin, Charles L. Mendenhall, Ian C. Munro, Edward J. Novotny, Andrew G. Renwick, Susan S. Schiffman, Donald L. Schomer, Bennett A. ShaywitzPaul A. Spiers, Thomas R. Tephly, John A. Thomas, Friedrich K. Trefz

Research output: Contribution to journalReview articlepeer-review

147 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)S1-S93
JournalRegulatory Toxicology and Pharmacology
Issue number2 II
StatePublished - Jul 2 2002

Bibliographical note

Funding Information:
In 1996, Olney again raised the issue of aspartame and carcinogenicity. On this occasion, Olney et al. (1996) claimed that the rate of brain tumors increased in the United States concurrent with aspartame use and postulated nitrosation of aspartame as a putative mechanism for a national increase in brain tumor rates. This purported association between aspartame and brain tumors was based on a flawed analysis of selected epidemiological data from the U.S. Surveillance, Epidemiology and End Results (SEER) tumor database maintained by the National Cancer Institute (NCI).

Funding Information:
lithium chloride large neutral amino acid UK Ministry of Agriculture, Fisheries & Food database from U.S. National Library of Medicine MRCA Information Services, Northbrook, Illinois magnetic resonance imaging monosodium glutamate National Cancer Institute N-methyl-D-aspartate Public Board of Inquiry phenylalanine plasma ratio of phenylalanine to the other large neutral amino acids phenylketonuria heterozygotes for phenylketonuria phenylalanine methyl ester profile of mood states portal systemic index pentylenetetrazol radioallergosorbent test EU Scientific Committee for Food U.S. Surveillance, Epidemiology and End Results cognitive battery of aviation-related information processing tasks Stanford sleepiness scale time to mean peak concentration tetrahydrofolate tyrosine Universities Associated for Research and Education in Pathology United States Department of Agriculture Visual analogue mood scales video cassette recorder World Health Organization Weight


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