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Referencing: First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats
In their article "First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed of Sprague-Dawley Rats," Soffritti et al. (2006) present interesting data on the carcinogenic effects of long-term exposure to aspartame, an artificial sweetener, in experimental animals (rats).
Recently, aspartame was supplanted as the leading artificial sweetener by sucralose, marketed in the United States under the trade name Splenda (McNeil Nutritionals, LLC, Ft. Washington, PA). As of 2005, Splenda was reported to have > 50% of the market for artificial sweeteners, while aspartame [Equal (Merisant Company, Chicago, IL); NutraSweet (NutraSweet Property Holdings Inc., Chicago, IL)] had < 20% (Associated Press 2005). Splenda is typically used in sweetener blends, most frequently with acesulfame potassium (CAS RN 55589-62-3) (Sunett; marketed in the United States by Nutrinova, Somerset, NJ).
The Food and Drug Administration's (FDA) multiple approvals of food additive petitions (FAPs) for acesulfame began in 1988 (FDA 1988), and culminated in 1998 with approval of the use of acesulfame in soft drinks (FDA 1998), historically the largest single use of artificial sweeteners. All of the FDA's approvals of FAPs for acesulfame were grounded on the conclusion that safety studies, including long-term animal tests of acesulfame carried out for Hoechst, the manufacturer of the chemical, in the Netherlands in the 1970s, were adequate and the test results indicated safety.
The 1970s tests of acesulfame—two tests carried out in rats and one in mice—are inadequate to establish lack of potential carcinogenicity. Here are a few reasons why the tests are inadequate [Center for Science in the Public Interest (CSPI) 1996]:
* Subchronic tests were not conducted for the rats and mice used in the tests on which the FAPs rested
* It is likely the minimum toxic dose/maximum tolerated dose (MTD) was not achieved in the rat and mouse studies
* Randomization of test groups was not carried out properly
* Mice were held on test for only 80 weeks, rather than the 104 weeks characteristic of NTP bioassays
* Animal husbandry and monitoring of animals on test were evidently poor, as indicated by high disease rates in the animals and extensive autolysis of tissues.
Even with the flaws in design and execution of the Hoechst tests, results indicated an association between treatment with acesulfame and carcinogenesis (CSPI 1996).
Working-level staff members at the FDA identified deficiencies in the acesulfame tests in the 1980s (McLaughlin 1986; Taylor 1986). Thus, an FDA staff member (Taylor 1986) noted in 1986, when the FDA had decided to accept the Hoechst studies, that
The question remains whether these studies are sufficiently definitive or rigorous in light of the potential for widespread, [sic] high exposure to acesulfame K in all group [sic] in the population.
In 1996, the CSPI nominated acesulfame for testing in the National Toxicology Program (NTP) bioassay program (CSPI 1996), and provided the NTP with detailed information on the Hoechst tests and their flaws. Although an individual familiar with test design and implementation could have concluded with ease that the Hoechst tests were not consistent with the criteria established for NTP bioassays or the test guidelines set out in the FDA's Redbook, (FDA 1982) and it was likely that, at some point, many people would be exposed to acesulfame, the NTP rejected CSPI's nomination.
In 2003, the NTP announced the results of tests of both aspartame and acesulfame in genetically modified mice (GMM) (NTP 2005). Both chemicals gave negative results in the tests, carried out in two strains of GMM.
The NTP's final report on those GMM studies (NTP 2005) noted that aspartame and acesulfame had been selected as "negative controls" for validation tests for the GMM models. The chemicals did indeed test negative, but that negative result did not advance our understanding of potential carcinogenicity of acesulfame. Regarding the GMM tests of aspartame and acesulfame, Martha Sandy of the California Environmental Protection Agency, stated that
[N]egative results [in the GMM tests] are not informative as to the test substance's carcinogenicity, and point to the need to conduct standard two-year carcinogenicity studies. At this time, transgenic models cannot replace the two-year bioassay and it would be unwise to list a chemical as safe for human exposure based upon negative results in not yet validated model systems. (Sandy 2003)
The findings of Soffritti et al. (2006) of multipotential carcinogenesis in rats fed aspartame over their lifetimes provide support for Sandy's (2003) statements.
I have sent the NTP a new nomination of acesulfame for 2-year bioassay testing (Karstadt 2006).
The author declares that she has no competing financial interests.
Myra L. Karstadt
Department of Environmental and Occupational Health
Drexel University School of Public Health
Associated Press. 2005. Splenda War Turns More Sour Available: http://www.msnbc.msn.com/id/6936203 [accessed 10 July 2006].
CSPI. 1996. Letter from M Karstadt and MF Jacobson, Center for Science in the Public Interest, to Errol Zeiger, National Toxicology Program. Acesulfame, 29 May 1986.
FDA. 1982. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives. Washington, DC:Food and Drug Administration.
FDA (Food and Drug Administration). 1988. Food additives permitted for direct addition to food for human consumption: acesulfame potassium. Final rule. Fed Reg 53: 28379.
FDA (Food and Drug Administration). 1998. Food additives permitted for direct addition to food for human consumption; acesulfame potassium. Final rule. Fed Reg 63(128): 36344–36361
Karstadt M. 2006. Letter from M Karstadt, Drexel University School of Public Health,to S Masten, National Toxicology Program. Nomination of acesulfame potassium for testing in NTP's bioassay program, 1 May 2006.
McLaughlin PJ. 1986. Memorandum from PJ McLaughlin, Food and Drug Administration (FDA), Center for Food Safety and Applied Nutrition, to four participants from Hoechst (registrant of acesulfame) and five participants from FDA. Memorandum of conference; industry/FDA, 19 June 1986.
NTP. 2005. Toxicity Studies of Acesulfame Potassium (CAS No. 55589-62-3) in FVB/N-TgN(v-Ha-ras)Led (Tg.AC) Hemizygous Mice and Carcinogenicity Studies of Acesulfame Potassium in B6.129-Trp53tm1Brd(N5) Haploinsufficient Mice (Feed Studies). NTP GMM2. Research Triangle Park:National Toxicology Program. Available: http://ntp.niehs.nih.gov/files/GMM2_Web.pdf [accessed 10 July 2006].
Sandy MS. 2003. Letter from MS Sandy, California Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, to K Olden, National Toxicology Program/National Institute of Environmental Health Sciences. GMM tests of aspartame and acesulfame, 16 May 2003.
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 114:379–385.
Taylor L. 1986. Memorandum from L Taylor, Food and Drug Administration, to R Lorentzen, Center for Food Safety and Applied Nutrition. Request for CAC Evaluation of the carcinogenic potential of acesulfame potassium; update, 19 June 1986.
Acesulfame Potassium: Soffritti Responds
Karstadt makes an important point regarding the need for more adequate long-term carcinogenicity testing of the artificial sweetener acesulfame K. The issues raised in her letter stimulated me to offer some additional considerations.
As reported in a previous paper (Soffritti et al. 1999), one of the most important issues in environmental and industrial carcinogenesis is how to deal with diffused carcinogenic risks, to which most of the planet's population may be exposed. These carcinogenic risks are represented by a) agents that are slightly carcinogenic at any dose; b) low or extremely low doses of a carcinogenic agent of any kind; or c) mixtures of small doses of carcinogenic agents.
Epidemiologic and experimental studies are fundamental in the identification and quantification of diffused carcinogenic risks, but they must be designed and conducted to be as powerful as possible with adequate methodology. In the case of experimental studies, it is not sufficient to follow the standard protocol used in ordinary experiments. Instead, it is necessary to conduct studies that may be defined as "mega-experiments," using a vast number of animals (at least 200–1,000 per experimental group) in order to express a marked difference in the variation of effects, and exposing the animals in all phases of development to allow the agent to express its full carcinogenic potential.
It is based on this rationale that the European Ramazzini Foundation performed a mega-experiment on 1,800 rats and demonstrated that, in our experimental conditions, aspartame is a multipotential carcinogenic agent (Soffritti et al. 2005; Soffritti et al. 2006).
The results of our study (Soffritti et al. 2005; Soffritti et al. 2006) attracted the attention of the scientific community, consumer and industry associations, and the national and international agencies responsible for food safety. Among various comments, the opinion expressed on 5 May 2006 by the European Food Safety Authority (EFSA 2006) and the general interpretation of an epidemiologic study conducted by the National Cancer Institute (NCI 2006) necessitate comment on our part.
In examining the raw data of our study, the EFSA (2006) observed a high incidence of chronic pulmonary inflammation in males and females in both treated groups and in the control group. Based on this observation, it was concluded that "the increased incidence of lymphomas/leukemias reported in treated rats was unrelated to aspartame, given the high background incidence of chronic inflammatory changes in the lungs . . . ." In my opinion, this conclusion is bizarre for the following reasons:
First, the EFSA (2006) overlooked the fact that the study was conducted until the natural death of the rodents. It is well known that infectious pathologies are part of the natural dying process in both rodents and humans.
Second, if the statistically significant increased incidence of lymphomas/leukemias observed was indeed caused by an infected colony, one would expect to observe an increased incidence of lymphomas/leukemias not only in females but also in males. The EFSA (2006) did not comment on this discrepancy in their logic.
Finally, in support of the hypothesis regarding the safety of aspartame, the EFSA (2006) cited the negative results of recent carcinogenicity studies carried out in transgenic mice by the NTP; the ESFA did not mention that, because the NTP studies on genetically altered mice were performed using a new experimental model, the NTP subcommittee unanimously agreed "there is uncertainty whether the study possessed sufficient sensitivity to detect a carcinogenic effect" (NTP 2005).
Interestingly, the same scrutiny applied to our study has not been applied to a recent abstract published by Lim et al. (2006) from the NCI diet questionnaire survey (NCI 2006) in which self-reported aspartame consumption showed no increases in either leukemia/lymphomas or in brain cancer. These results have been used by industry, the EFSA, and others to argue that aspartame is not a risk for humans, in spite of our animal study results. Without specific information on each individual's consumption rate and duration it is difficult to assess the power of the survey, in spite of the large number of participants. The second related issue is whether aspartame is an early- or late-stage carcinogen. If it is an early-stage initiator of cancer, then reporting the lack of effects in older individuals who have not consumed aspartame since early childhood would be expected to show little or no increased cancer (Hoel 1985).
The safety—in particular, the noncarcinogenicity—of today's most widely diffused artificial sweeteners and their blends is largely based on studies conducted decades ago. I second Karstadt's nomination of acesulfame K for further study; however, I add that it should be evaluated using a long-term mega-experiment.
The author declares he has no competing financial interests.
Cesare Maltoni Cancer Research Center
European Foundation of Oncology and Environmental Sciences
EFSA (European Food Safety Authority). 2006. Opinion of the Scientific Panel AFC Related to a New Long-Term Carcinogenicity Study on Aspartame. Available: http://www.efsa.eu.int/science/afc/afc_opinions/1471_en.html [accessed 1 June 2006].
Hoel DG. 1985. Epidemiology and the inference of cancer mechanisms. Natl Cancer Inst Monogr 67: 199–203.
NCI (National Cancer Institute). 2006. NIH-AARP Diet and Health Study. Available: http://dietandhealth.cancer.gov/ [accessed 1 June 2006].
NTP. 2005. 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 on Aspartame in Genetically Modified B6.129-Trp53tm1Brd (N5) Haploinsufficient Mice (Feed Studies). Technical report GMM1. Research Triangle Park, NC:National Toxicology Program. Available: http://ntp.niehs.nih.gov/files/GMM1_Web.pdf [accessed 11 July 2006].
Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L. 2005. Aspartame induces lymphomas and leukaemias in rats. Eur J Oncol 10:107–116.
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 114:379–385.
Soffritti M, Belpoggi F, Minardi F, Bua L, Maltoni C. 1999. Mega-experiments to identify and assess diffuse carcinogenic risks. Ann NY Acad Sci 895:34–55.
Lim U, Subar AF, Mouw T, Hartge P, Morton LM, Stolzenberg-Solomon R, et al. 2006. Prospective study of aspartame-containing beverages and risk of hematopoietic and brain cancers [Abstract]. In: Proceedings of the 97th AACR Annual Meeting, 1–5 April 2006, Washington, DC. Available: http://www.aacr.org/default.aspx?p=6036 [accessed 11 July 2006].
Environmental Health Perspectives Volume 114, Number 9, September 2006
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