Clinical Briefs

With Comments from Russell H. Greenfield, MD Dr. Greenfield is Medical Director, Carolinas Integrative Health, Carolinas HealthCare System, Charlotte, NC, and Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; he has no financial relationships with companies having ties to the material presented in this continuing education program.

Sweet Sorrow: Risks of Aspartame

Source: Soffritti M, et al. First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats. Environ Health Perspect 2006;114:379-385.

Goal: To evaluate the carcinogenicity of aspartame (APM) in a rat model deemed a consistent predictor of human cancer risk.

Design: Long-term (life span) carcinogenicity bioassay.

Subjects: Sprague-Dawley rats from colony CMCRC/ERF.

Methods: Assumed human daily APM intake ranging from 0 to 5,000 mg/kg was simulated by adding APM to standard rat feed in seven specific concentrations. Sprague-Dawley rats were randomized at 4-5 weeks of age and then permitted to ingest feed ad libitum beginning at 8 weeks of age and continuing until natural death, with control rats consuming the same feed without APM. At death animals underwent complete necropsy and histopathologic evaluation (death of the last animal occurred at the age of 159 weeks).

Results: No significant difference was found in survival or behavior between groups. A significantly positive trend was found for the incidence of malignant tumors in both male and female rats at levels higher than simulated usual human APM intake, but also at levels less than the currently stated acceptable human daily intake. Identified tumors included among others leukemias/lymphomas, brain tumors, and transitional cell carcinomas of the renal pelvis (the latter of which is extremely uncommon in untreated rats).

Conclusion: APM possesses multipotential carcinogenic effects in both male and female Sprague-Dawley rats, a model that has previously predicted human cancer risks.

Study strengths: Large number of animals studied (> 1,800); study continued until natural death of animals (significantly longer duration than prior studies, usually 110 weeks).

Study weakness: Inherent challenge of extrapolating rat data to human experience (though track record of the model seems consistent).

Of note: This study is but one of 32 long-term bioassays assessing carcinogenicity of dietary substances completed at the Cesare Maltoni Cancer Research Center (CMCRC) since 1985, including data on vinyl chloride that led to strict regulation in the United States; FDA approval for limited use of APM occurred in 1981, while approval for use in soft drinks and later as a general sweetener occurred in 1983 and 1996, respectively; APM is the second most commonly used artificial sweetener in the world behind saccharin, with an estimated exposure of > 200 million people; surveys suggest average APM intake in the United States is 2-3 mg/kg/d, slightly higher in children and women of childbearing age (2.5-5.0 mg/kg/d); acceptable daily intake of APM has been set at 50 mg/kg/d; because studies have been ongoing for almost 30 years at CMCRC using specific Sprague-Dawley colonies, significant historical data exist regarding cancer incidence among untreated rats for comparison.

We knew that: APM, the methyl ester of the dipeptide L-aspartyl-L-phenylalanine, is frequently employed as a food additive due to its strong sweet taste (200 times stronger than sucrose); APM is metabolized in the GI tract into three constituents, which are then absorbed into the systemic circulation—aspartate (transformed into alanine + oxaloacetate), phenylalanine (transformed mainly into tyrosine), and methanol (transformed into formaldehyde and then formic acid); a number of APM studies, some supported by the manufacturer of APM, have been reviewed by the FDA over the years and considered negative with regard to carcinogenicity.

Clinical import: Conspiracy theorists have long suspected that APM causes illness in humans, but their quivers have been relatively empty. Health practitioners have had little reason to speak with patients about frequent ingestion of diet soft drinks except to state they would do better to choose beverages with known health benefits. Unfortunately, this well-done animal study brings concerns to light anew. A Feb. 12, 2006, story about this trial published in The New York Times raised additional concerns apart from health-related ones, leaving the reader curious if not truly concerned. The topic has been, and continues to be, a contentious one. Until clarity is attained through further research, however, it seems prudent to advise patients to lessen their intake of products containing APM, if not to steer clear of such products altogether.

What to do with this article: Keep a hard copy in your file cabinet.