Carcinogenesis Advance Access published March 10, 2016 Carcinogenesis, 2016, 1–2 doi:10.1093/carcin/bgw025 Advance Access Publication Date: February 24, 2016 Letter to the Editor

letter to the editor

Aspartame, a bittersweet pill Moreno Paolini*, Fabio Vivarelli, Andrea Sapone and Donatella Canistro

To whom correspondence should be addressed. Tel: +39 051 2091806; Fax: +39 051 2096331; Email: [email protected]

*

Abstract For the first time, the aspartame case shows how a corporation decided to ban an artificial ingredient in the wake of public opinion notwithstanding the regulatory assurance claims that it is safe. PepsiCo Inc. made an unprecedented decision most likely based on life-span carcinogenicity bioassay studies from the Cesare Maltoni Cancer Research Center of the Ramazzini Institute (CMCRC/RI), which provide consistent evidence of aspartame’s carcinogenicity in rodents. Although CMCRC/ RI experiments have been criticized for not complying with Organisation for Economic Co-operation and Development (OECD) guidelines, the newly launched aspartame-free soft drink may not be an isolated case. In the light of vinyl chloride-, formaldehyde- or benzene-associated carcinogenicity discovered for the first time by CMCRC/RI in the same way, it seems the guidelines need to be re-evaluated to avoid the credibility of international regulatory agencies being compromised by consumer opinion.

Summary PepsiCo banned aspartame notwithstanding the regulatory assurance claim that it is safe. This unprecedented decision is based on the positivity of rodent life-span carcinogenicity studies, despite experiments do not complying with OECD. A re-evaluation of guidelines seems necessary. Addressing consumer concerns on artificial sweeteners perceived as toxic and reversing slumping diet soda sales, PepsiCo Inc. made an unprecedented decision and banned aspartame (APM) from Diet Pepsi. Although this choice is paradoxically at variance with current regulations stating that APM is safe, this new ‘aspartame-free’ soft drink could be a Trojan horse for other corporations. While the Wall Street Journal has ascribed this case to APMinduced glucose intolerance (1), consumer concerns are more probably based on life-span carcinogenicity bioassay studies from the Cesare Maltoni Cancer Research Center of the Ramazzini Institute (CMCRC/RI) which provide consistent evidence of APM’s carcinogenicity in rodents (2,3). More recently, these data were cautiously supported by the Brigham and Women’s Hospital and Harvard epidemiological studies on diet soda (4). Several concerns about CMCRC/RI experiments were raised by the European Food Safety Authority (EFSA, Parma, Italy) (5)

including the inappropriate large numbers of animals, the lifelong treatment duration and the prenatal exposure not complying with OECD guidelines recommending adult animals and 24 months’ exposure. Up to now, regulatory agencies for safety requirements have recommended that carcinogenicity bioassays last 2  years (104 weeks) starting the treatment at 6–8 weeks of age until 110 weeks, a period representing about 2/3 of the animals’ lifespan. The intense criticisms against the methodological ‘flaws’ of CMCRC/RI studies should appear secondary with the respect to the magnitude of the results and their relative impact on the public health. The RI’s study which showed a significant increase in the dose-related incidence rate of liver and lung cancer in mice consuming APM (6) was considered by EFSA inadequate to provide evidence of any carcinogenic effect of APM. In this case, the concern raised up was based on the general consensus in scientific community that mouse hepatic and lung tumours, if induced by non-genotoxic compounds, can be irrelevant for human risk assessment. Beyond discussion on this point, the question here should have been: how a statistically significant dose-related increase in liver and lung cancer in APM-treated animals, compared to concurrent controls, could not be consider scientifically relevant?

Received: October 7, 2015; Revised: February 10, 2016; Accepted: February 17, 2016 © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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Department of Pharmacology and Biotechnology, Alma Mater Studiorum, University of Bologna, via Irnerio 48 40126, Bologna, Italy

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the PepsiCo demonstrated, the question should be how to best proceed in order to defence public health. We believe that a re-evaluation of APM along with OECD guidelines is necessary to avoid the credibility of the international regulatory agencies being compromised by consumer opinion.

Funding All sources of financial were provided by a grant from the Italian Ministry of Education, University and Research. Conflict of Interest Statement: None declared.

References 1. Suez, J. et al. (2014) Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, 514, 181–186. 2. Belpoggi, F. et al. (2006) Results of long-term carcinogenicity bioassay on Sprague-Dawley rats exposed to aspartame administered in feed. Ann. N. Y. Acad. Sci., 1076, 559–577. 3. Soffritti, M. et  al. (2010) Aspartame administered in feed, beginning prenatally through life span, induces cancers of the liver and lung in male Swiss mice. Am. J. Ind. Med., 53, 1197–1206. 4. Schernhammer, E.S. et al. (2012) Consumption of artificial sweetenerand sugar-containing soda and risk of lymphoma and leukemia in men and women. Am. J. Clin. Nutr., 96, 1419–1428. 5. EFSA (2013) Scientific opinion on the re-evaluation of aspartame (E 951) as a food additive. EFSA J., 11, 263. 6. Soffritti, M. et  al. (2010) Aspartame administered in feed, beginning prenatally through life span, induces cancers of the liver and lung in male Swiss mice. Am. J. Ind. Med., 53, 1197–1206. 7. Soffritti, M. et  al. (2014) The carcinogenic effects of aspartame: The urgent need for regulatory re-evaluation. Am. J. Ind. Med., 57, 383–397. 8. Soffritti, M. et al. (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. 9. Soffritti, M. et al. (2007) Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats. Environ. Health Perspect., 115, 1293–1297. 10. World Health Organization, International Agency for the Research on Cancer. (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (International Report 14/002). http://monographs.iarc. fr/ENG/Publications/internrep/14-002.pdf (10 February 2016, date last accessed).

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We should keep in mind that studies on mice, in order to demonstrate chemical/physical agent exposure safety, are still required by international agencies such as EPA and IARC, even for non-genotoxic agents. Again, it was claimed that the high background of infection in the RI colony, could have affected cancer rates and survival. However, allowing animals to spontaneously die, infectious pathologies frequently occurred, and, more important, looking at the data on the control group, the survival rate fell in the range of expected survival (7). As properly discussed by CMCRC/RI researchers in the recent rebuttal of EFSA criticisms targeting their studies (7), a standard 2-year bioassay could not elucidate the life-span potential carcinogenetic effects. Indeed such studies may lose important information especially in cases of agents with a long latency time as well as weak carcinogens. Safety bioassays should better reproduce the real human situation in which consumers may be exposed to a chemical compound throughout life and hence increase their sensitivity to assess the overall carcinogenic potential. Discussing about RI studies, the key issue is that the risk associated to APM consumption, was confirmed by independent experiments involving different animal models, among which, the most remarkable, probably were those carried out in rats (2,8). In both, an increased incidence of lymphomas-leukemia raised up, and, the subsequent long-term carcinogenicity bioassay (9), reinforced further the data on the APM’s multipotental carcinogenicity, even at a dose level close to the human ADI. It is significant that vinyl chloride, formaldehyde and benzene, today recognized as human carcinogens, were discovered for the first time by CMCRC/RI, and like APM their carcinogenicity emerged only after more than 2 years of life. To reinforce our claim, we recall that the demand for greater clarify on the safety of artificial sweeteners was also backed by the International Agency for Research on Cancer (IARC, Lyon, France) that found it necessary to include APM among the high priority substances due for re-evaluation by the Agency in the coming years (10). Since over the past few years troubling findings concerning APM consumption in both animals and human have been brought to light, and the regulatory agencies did not give reassuring answers to the anxieties of consumers, as the decision by

Aspartame, a bittersweet pill.

For the first time, the aspartame case shows how a corporation decided to ban an artificial ingredient in the wake of public opinion notwithstanding t...
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