Carcinogenicity of Aspartame in Rats Not Proven

Environ Health Perspect. doi:10.1289/ehp.10881 available via http://dx.doi.org [Online 27 May 2008]

Referencing: Life-Span Exposure to Low Doses of Aspartame Beginning during Prenatal Life Increases Cancer Effects in Rats

In their article on lifetime exposure to aspartame in rats, Soffritti et al. (2007) purported that their study demonstrated increased carcinogenic effects in female rats as a result of exposure beginning during prenatal life.

We believe that this article (Soffritti et al. 2007) has methodologic and conceptual weaknesses that require exposition. First, although the study was a toxicology study, the most important element—the reported doses—are not correct. The doses are "estimates" based on assuming constant food consumption of 20 g/day and constant body weights of 400 g for each rat from in utero (fetal day 12) to death. These assumptions are unrealistic and inaccurate. The doses during the early growth phase of rats would be much higher because, as is well known, rats consume more food per gram of body weight during the rapid growth phase. Food consumption and body weight were reportedly measured throughout the experiment; however, Soffritti et al. (2007) presented only data beginning 16 weeks postpartum, when rats reached adult body weight. Therefore the authors' conclusions are built on the exposure period for which they provide no data.

Second, for a study allegedly designed to assess prenatal exposure, Soffritti et al. (2007) did not address important details, such as a) pregnancy history and ages of breeders; b) number of pregnant dams per dose group; c) growth and food consumption of mothers during pregnancy and lactation; d) pregnancy outcomes; e) disposition of pups from all mothers and each litter; f) the origin of the 70 pups; and g) body weight of pups at birth and during lactation. These details are typically required to allow other scientists to assess the appropriateness of the study design and to repeat the study, if desired.

The findings are of questionable biological significance for a number of reasons. The lymphoma/leukemia incidences in the high-dose group, which were the only significant differences from control, were within or near the reported historical control ranges. Similarly, the mammary gland carcinoma incidence in high-dose females (again, the only significant difference from control) was similar to historical controls. In their article, Soffritti et al. (2007) stated that their study disproved the conclusions of the European Food Safety Authority (EFSA 2006) that the incidences of lymphomas/leukemias observed in the first report (Soffritti et al. 2006) were "unrelated to aspartame given the high background incidence of chronic inflammatory changes in the lungs …" (EFSA 2006). The U.S. Food and Drug Administration (FDA 2007) agreed with the EFSA assessment. It is not clear to us how this study disproved the EFSA's conclusions. Soffritti et al. (2007) indicated that the lung was often the site of lymphoma again in this study, which is not surprising because they used the same infected colony. Studies in the 1960s demonstrated that the progression of chronic pneumonia in rats resulted in lymphoid neoplasmas, and elimination of chronic respiratory disease in rat colonies reduced the incidence of pulmonary lymphoid neoplasias to near zero (Cotchin and Roe 1967). Rats with pulmonary infections developed lesions in multiple sites earlier than rats free from pulmonary disease (Cotchin and Roe 1967). The establishment of pathogen-free animal suppliers for toxicity research was impelled for this reason. Therefore, we believe it is highly likely that the present findings are due to infection and not aspartame consumption.

Data do not support the conclusions of Soffritti et al. (2007) that aspartame has carcinogenic potential at doses near the human level of exposure. The authors observed no significant effects at the low-diet level, and the actual dose is unknown. Also, no data were provided on in utero exposure. Aspartame is completely digested in the gastrointestinal tract into two amino acids (phenylalanine and aspartic acid) and methanol, which is subsequently metabolized to carbon dioxide and water. In human clinical studies (reviewed by Stegink and Filer 1996), oral doses equal to or exceeding the amount that would represent the 99th percentile of aspartame intake did not increase plasma aspartate or phenylalanine levels in adults or children, or in breast milk from lactating women beyond normal postprandial concentrations. Ratios of fetal/maternal plasma amino acids and transport across the placental membrane were unchanged in pregnant rabbits that received 1,600 mg aspartame/kg/day (Ranney et al. 1975). Thus, a biologically plausible explanation is lacking for Soffritti et al.'s (2007) contention that prenatal exposure to aspartame increases cancer risk.

In summary, considering that there are no significant differences in cancer rates between high-dose groups and historical controls, plus the many deficiencies in the experimental design and data, Soffritti et al. (2007) failed to provide convincing evidence of aspartame carcinogenicity. Given the effort expended by many government review agencies to document shortcomings of the first article by this group (Soffritti et al. 2006), it is disappointing that the editor and reviewers of this paper (Soffritti et al. 2007) did not require the authors to address those problems that appear again in this study. Diligence is especially necessary on topics of great public interest and relevance because the public is relying upon the scientific community to assure that only high quality, well-documented, and controlled studies appear in peer-reviewed journals.

The authors received payment from the Burdock Group during the preparation of an expert review of the safety of aspartame. The Burdock Group managed the independent review, which was financially supported by Ajinomoto Company Inc., a producer of aspartame.

References

Cotchin E, Roe JFC. 1967. Pathology of Laboratory Rats and Mice. Oxford, UK:Blackwell Scientific Publications.

EFSA (European Food Safety Authority). 2006. Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC) on a Request from the Commission Related to a New Long-term Carcinogenicity Study on Aspartame. EFSA J 356:1–44. Available: http://www.efsa.europa.eu/EFSA/Scientific_Opinion/afc_op_ej356_aspartame_en1,2.pdf [accessed 9 April 2008].

FDA (Food and Drug Administration). 2007. FDA Statement on European Aspartame Study. Available: http://www.cfsan.fda.gov/~lrd/fpaspar2.html [accessed 15 August 2007].

Ranney RE, Mares SE, Schroeder RE, Hutsell TC, Raczialowski FM. 1975. The phenylalanine and tyrosine content of maternal and fetal body fluids from rabbits fed aspartame. Toxicol Appl Pharmacol 32:339–346.

Soffriti 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 114:379–385.

Soffritti M, Belpoggi F, Tibaldi E, Degli Esposti D, Lauriola M. 2007. Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats. Environ Health Perspect 115:1293–1297.

Stegink LD, Filer LJ. 1996. Effect of aspartame ingestion on plasma aspartate, phenylalanine, and methanol concentrations in potentially sensitive populations. In: The Clinical Evaluation of a Food Additive: Assessment of Aspartame (Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, eds). Boca Raton, FL:CRC Press, 87–113.

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Carcinogenicity of Aspartame: Soffritti Responds

Environ Health Perspect. doi:10.1289/ehp.10881R available via http://dx.doi.org [Online 27 May 2008]

Magnuson and Williams's letter is substantially a repetition of the arguments set forth in a recent article (Magnuson et al. 2007), which was a "safety evaluation" sponsored entirely by Ajinomoto, the manufacturer of aspartame. Their article (Magnuson et al. 2007) and this letter contain numerous erroneous statements about the long-term carcinogenesis studies on aspartame conducted by the European Ramazzini Foundation (ERF).

First, Magnuson and Williams imply that our findings (Soffritti et al. 2007) should be discounted because the incidence of lymphomas/leukemias in the high-dose group "were within or near the reported historical control ranges." As reported in our study (Soffritti et al. 2007), the incidence of lymphomas/leukemias observed in both sexes treated with 2,000 ppm aspartame is nearly double the concurrent control (Soffritti et al. 2007). The suggestion that concurrent control data should be ignored is contrary to the widely accepted standard of good laboratory science.

Second, Magnuson and Williams attribute our findings (Soffritti et al. 2007) to some kind of bias (i.e., infection) that would affect only treated animals but not the controls. We have responded in detail to this hypothesis in our article (Soffritti et al. 2007) and in an earlier letter (Soffritti 2006). To support their assertion, Magnuson and Williams mislead readers by stating that "the lung was often the site of lymphoma again in this [second] study." However, we actually reported that

we observed the diffusion of neoplastic tissue not only in the lung but also concurrently in various organs (liver, spleen, mediastinal and other lymph nodes). (Soffritti et al. 2007)

Infection as a mode of action for induction of rat lymphoma has been recently examined by a group of scientists at the National Center for Environmental Assessment of the U.S. Environmental Protection Agency; Caldwell et al. (2008) found that

a careful examination of available information does not support the hypothesis that the observed lymphomas/leukemias in the ERF bioassays are a general effect from infection. The reports of chemically-induced lymphomas/leukemias by the ERF seem to be chemical specific.

Third, the idea that we must provide a "biologically plausible explanation" for human or rodent carcinogens is a time-honored approach to postpone or prevent the application of regulatory measures to minimize carcinogenic risks. The reality is that this explanation is quite often unknown, as is, in general, the mode of action behind the carcinogenic process.

I regard the other questions raised by Magnuson and Williams as trivial. For example, whatever the doses at various ages and weights, the finding of any effect should be a cause for concern. Likewise, the authors' observation that some methodologic details were omitted from the publication certainly does not change the oncologic results of this research.

Magnuson and Williams express disappointment that Environmental Health Perspectives would publish original scientific research by the ERF after regulatory agencies went through so much trouble to review our first aspartame study (Soffritti 2006) only to disagree with our conclusions. It is the obligation of the agencies responsible for food safety to review any new scientific data available and to make their opinion available to the public. The Food and Drug Administration (FDA) did not make public the contents of their review, but rather they issued a short press release a full year after the European Food Safety Authority (EFSA) concluded its evaluation, and coincidently, just days before I presented new aspartame data in a lecture at the Mount Sinai School of Medicine in New York (FDA 2007).

I find it unfortunate that some scientists have such a low tolerance for original, independent scientific research; however, I welcome continued discussion and more importantly, additional long-term experimental studies on aspartame and other artificial sweeteners. We at the ERF stand behind our results, and we remain convinced that a review of the current regulations governing the use of aspartame is necessary to better protect public health.

The author declares he has no competing financial interests.

References

Caldwell J, Jinot J, DeVoney D, Gift JS. 2008. Evaluation of evidence for infection as a mode of action for induction of rat lymphoma. Environ Mol Mutagen 49: 155–164.

FDA (Food and Drug Administration). 2007. FDA Statement on European Aspartame Study. Available: http://www.cfsan.fda.gov/~lrd/fpaspar2.html [accessed 12 January 2008].

Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, et al. 2007. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol 37: 629–727.

Soffritti M. 2006. Acesulfame potassium: Soffritti responds [Letter]. Environ Health Perspect 114: A516–A519.

Soffritti M, Belpoggi F, Tibaldi E, Degli Esposti D, Lauriola M. 2007. Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats. Environ Health Perspect 115:1293–1297.