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Cancer is defined as: "any disorder of cell growth that results in the invasion and destruction of surrounding healthy tissue by abnormal cells" by the Oxford Dictionary of Biology. It occurs when one or more of the approximately sixty trillion cells in the human body goes haywire and starts to proliferate at a much faster rate than normal cells, gradually taking up the space usually occupied by healthy tissue and failing to perform the functions necessary for survival. Following this the cancer may metastasise to other parts of the body and thus migrate to other organs often leading to death. So why do these cells which generally cooperate so perfectly with each other to allow mutual survival suddenly turn on the rest of the body and seem to opt for its destruction? To put it simply, cancer is the result of malignant mutations in human DNA leading to the production of these unhealthy cells. Research has proven that several substances which humans consume or come into contact with may increase the probability of the formation of cancerous tissue. These substances are known as carcinogens. The objective of this essay is to assess the possible carcinogenic effects of artificial sweeteners. Artificial sweeteners are substances which imitate the taste of sugar (usually sucrose) but have a much lower caloric value. The issue with sucrose is that when it is consumed in excess, the liver has no space to store glucose which is thus converted into fatty acids and distributed through the blood causing the consumer's body weight to increase as the result of adipose tissue production. An increase in insulin as a result of high sugar consumption also prevents the body from burning fats hence perpetuating weight gain. Increased caloric intake can also decrease insulin production or efficiency causing diabetes mellitus. Obesity and diabetes are increasing throughout the world population with 30.6 percent obesity in the US and in the United Kingdom as well as 23.1 percent cases of diabetes in Americans of above the age of 60. Sugar has been targeted as one of the main causes for these conditions and thus the objective is to replace it with a healthier alternative. The problem with these substitutes is that they are artificial and thus challenging for the body to process and possibly linked to diseases such as cancer. As a result of word restrictions the safety of only three of the most commonly used artificial sweeteners will be investigated in this essay: aspartame (APM) which is used in a variety of things from diet sodas to chewing gum, the less well-known acesulfame potassium (acesulfame K) used in, for example, protein supplements and the and the largely forgotten sodium cyclamate which has long been taken of the market in the US and many other countries.
Part A: Aspartame
APM is used as a sugar substitute in several consumer goods most notably all mainstream diet sodas excluding 7-up and Coca-Cola. Aspartame was first created in 1965 by James M. Schlatter, a chemist working for a pharmaceutical company. It was first approved by the United States Food and Drug Administration (USDA) and brought onto the market in 1981 in the US and almost immediately caused a great deal of controversy. It is two hundred times sweeter than sugar and scientifically defined as a methyl ester of the dipeptide of aspartic acid and phenylalanine. There are about 6000 APM containing products on the market worldwide and going a full day without aspartame is an achievement. If you check the label on sugarless gum, diet soda or even prawn cocktail, chances are you will find aspartame (E951 in some countries.) Early studies performed on rats in Japan did not provide any evidence of urinary bladder or brain tumours (Ishii et al)15, (Hagiwara et al)13. Further studies indicated that no DNA damage is caused by the sweetener (Jeffrey et al)14. Then a journal article was published relating increased incidence of brain tumours with aspartame consumption (Olney et al)23. This article stated that the popular substitute's mutagenic properties could cause such cancers and called for further examination. This article also stated that an FDA trial performed on Sprague-Dawley rats had resulted in twelve brain tumours (Olney et al)23 . However, the fact that brain tumours increased at the same time as the sweetener was introduced on the market did not epidemiological make sense as such changes should take several decades to take place (Ross et al)25. Furthermore, later studies also refuted this statement most significantly a case control study performed on children which showed no link between the aspartame and brain tumours (Gurney et al)12. Following this a link was made between aspartame and breast cancer which yet again used an increase in the incidence of this form of neoplasm in the general population (Schwartz et al)26. However it soon became evident that this cancer increase had occurred before the introduction of aspartame and thus could not be linked to it (Trichopoulos et al)31. The only significant aspartame health study which may prove carcinogenic effects was conducted by Soffritti et al in 2005 at the Cesare Maltoni Research Centre of the Ramazinni foundation on Sprague-Dawley laboratory rats. This study is considered to be more reliable than other studies as it waited till all animals died before the necropsy to test for cancer were performed. The flip-side of this coin was of course that some of the rats would have been deceased too long for an accurate necropsy to be possible. However, this differs from other studies which waited for only two years instead of till the end of the lifespan. All of these experiments were flawed as cancer most often occurs in the later stages of a human being's and thus also of a rat's life. The Italian study also let the rats ingest a more reasonable amount of daily aspartame (the equivalent of three litres of diet soda a day) instead of earlier studies which often used too much or too little. The most significant findings of the Ramazinni experiment were leukaemias in males and females (a blood cancer in which too many blood cells are produced), lymphomas in females (abnormal growths in the lymphatic system), schwannomas (tumours of the nervous system which are benign in 99 percent of cases), renal lesions in females (preneoplastic and neoplastic - neoplastic means growing abnormally - lesions indicate the possibility of renal or urothelial cell carcinomas also known as kidney cancers), and lesions of the olfactory epithelium in males and females (lesions in the nose indicate the possibility of neuroblastoma) (Soffritti et al)28. Furthermore the study found three cases of bladder cancer in the rats which had consumed APM. The study showed a clear positive trend in the total amount of malignant tumours as the doses of aspartame increased which may seem to be rather worrying as this sugar substitute is evidently still on the market. The explication for aspartame's carcinogenicity provided by Morando Soffriti, the scientific director of the Ramazzini Foundation which currently has the most significant studies concerning APM's connection to cancer is that being a dipeptide, APM should be harmless and easy to digest by the human body but it contains a methyl ester which is where it differs from the normal dipeptides we consume on a daily basis. Thus, when the sweetener is digested, this part of the molecule may become methanol which is known to be toxic. However there are very few links between cancer and methanol and it is not truly considered a cancer-causing substance. Even though the small amount of this substance that is released may not ordinarily appear to be sufficient to have such adverse effects, there is no other clear explanation for these symptoms. There is however much debate and controversy around the Ramazzini study and it has therefore been regarded as inaccurate. The European Food Safety Authority (EFSA) and US Food and Drug Administration (FDA) found the APM study troubling enough to re-examine the its results. The two institutions declared that the connection between APM and cancer was a result of the way in which the study was designed and that the incidence of lymphomas and leukaemias was more likely a cause of unrelated circumstances such as lung infections than by the popular sugar substitute. The kidney cancers which were the other significant factor in the study were only relevant to rats and not humans. With these results rebuffed the other cancers were probably just coincidences. Also, the only cancer in women which has drastically increased since aspartame was brought onto the market is lung cancer which has in no way been related to aspartame in any studies. However, Morando Soffritti defends the Ramazzini foundation's study by stating that such pathologies as lung infections are commonly found in rodents and not an indication of an error. Furthermore, he claims that if caused by infection, lymphomas and leukaemias would be found in both females and males. Soffritti also explains that the study claiming aspartame is safe was partially based on an NTP (National Toxicology Program) study which the NTP itself admits may have lacked the sensitivity to find any trace of cancer. There have also been allegations of a conflict of interest in the FDA and EFSA but the reputation of these institutions makes this unlikely. Control studies on Saccharin and APM were performed at the Istituto di Richerche Farmacologiche Mario Negri in Milan, Italy (S. Gallus et al)9. 14,000 patients were interviewed (7,000 with and 7,000 without cancer) on their artificial sweetener consumption. The results did not show any correlation between APM and cancer. Thus, as of yet, there is no concrete evidence of an association between APM and carcinogenesis despite extensive research. The proof currently on offer does however demand further investigation.
Part B: Acesulfame Potassium
Acesulfame Potassium (Acesulfame K) is another widely used artificial sweetener. It was discovered in 1967 by a German chemist called Karl Klauss at Hoechst AG and was not generally approved in the United States until 2003, taking into account studies performed by Hoechst, making it a 'new generation' sugar substitute. It is currently found in approximately 5,000 products worldwide. The slightly bitter after taste of this substitute causes it to often be mixed with other sweeteners to achieve better taste. The most popular of these combinations is Acesulfame K and sucralose (another artificial sweetener) because they cancel out each other's after tastes. The most significant argument against Acesulfame K is that many experts believe that insufficient studies have been performed to be able to judge over the sweetener's safeness. Studies performed at the University of Calcutta showed that at low-level ingestion there were no toxic side-effects to Acesulfame K (A. Mukherjee and J Chakrabati et al)1. However, they stated that, at a high dose, chromosome aberrations could be caused by this sweetener (A. Mukherjee and J Chakrabati et al)1. This was confirmed by experiments D.G Mayer et al performed on Chinese hamsters which indicated increased micronucleated erythrocytes and chromosome aberrations (A. Mukherjee and J Chakrabati et al)1. This could be related to cancer and therefore caution is necessary when dealing with this substitute. Nonetheless, all reliable sources such as the FDA and the USDA dismiss this research in their evaluations of Acesulfame K safety and have declared that there is no evidence of carcinogenicity in this substance. Another study performed on hemizygous and haploinsufficient mice by the National Toxicity Program (NTP) was published as a report in October 2005. In this experiment, the tested rats were fed up to 3 percent Acesulfame K in their diet whereas the control group were fed none. Both types of rats were fed the sweetener for nine months, 15 tissue sites were examined and genetic toxicology tests were performed. The experiment concluded that the survival of both rat types was not affected by the Acesulfame K. There was no increase in micronucleated erythrocytes which would have indicated toxic by-product, and no signs of carcinogenicity were encountered. The NTP does however acknowledge the limitations of their experiments and that wider analysis should occur to ascertain Acesulfame K's safety. There is however much controversy concerning the amount of reliable tests performed on Acesulfame K. When the FDA accepted the tests performed on rats at Hoechst, the first producer of the sweetener and the experiment performed by the NTP as sufficient evidence of the sweetener's safety. On the other hand, Myra L. Karstadt from the Drexel School of Public Health in Pennsylvania argues strongly against this in an opinion article. She declares that tests were not performed subchronically, test groups were not adequately randomised, the rats were not fed sufficient Acesulfame K for the effect to be toxic, and they were not tested for sufficient time. If she is correct about the mistakes made in this study, there is no concrete evidence of Acesulfame K's safety. Morando Soffritti of the Ramazzini foundation believes that a mega-experiment, similar to the one he used to test aspartame, should be performed to test Acesulfame K's safety. However, until such a study is concluded, there is no solid evidence supporting the notion of Acesulfame K's carcinogenicity.
Part C: Sodium Cyclamate
Sodium Cyclamate is an artificial sweetener that was discovered in 1937 and approved in 1951. It has been banned in the US but is still in use in some other countries like Germany. The issue with cyclamate is that it converts into a metabolite called cyclohexylamine which is toxic and could explain carcinogenicity. A study performed in 1969 showed an increase in bladder carcinomas in rats which were fed Cyclamate (S. Wagner et al)32. Further research found testicular atrophy in Cyclamate fed mice. Because of this Cyclamate was banned in 1970 and still remains banned in the US today. However many countries regarded the evidence that this study provided as incomplete and Cyclamate is still legal in about 50 countries including the UK and all the nations of the European Union. All of the studies following the 1969 testing indicated that Cyclamate and its metabolite cyclohexylamine are completely harmless to humans. Studies concerning the intake of intense sweeteners proved that cyclohexylamine was metabolised by the bacteria that form the microflora of the human gut (A.G. Renwick et al)24. Even the American National Academy of Sciences declared Cyclamate as safe. Nonetheless, an experiment performed on rats tested several sodium salts including sodium cyclamate and indicated increased amounts of bladder tumours when the substitute was consumed (Cohen et al)5. A 24 year study conducted between 1970 and 1994 by using non-human primates seemed to prove that cyclamate stimulated carcinogenesis as the monkeys who had consumed it had malignancies and the ones that had not did not (Takayama et al)30. However because the tumours found were not overwhelming and were normal in monkeys the conclusion was that cancer is not caused by cyclamate. This is proof that Cyclamate is not carcinogenic as the few tumours found in the monkeys did not correspond with the results of the Wagner and Cohen studies thus proving the likely falsehood of the two earlier studies. Nonetheless, the Takayama experiment was much criticised for its limitations, mainly the low amount of monkeys used in testing which is considered as insufficient to reach a conclusive result (Huff and Tomatis et al)14. 10 experiments on various laboratory animals where conducted between 1969 and 1989 in an attempt to reproduce the experiment which lead to the ban. However none of these studies were successful at achieving similar results. Testicular atrophy had also been found in rats and which was linked to the cyclohexylamine (Gaunt et al)10, (James et al)16. However, after the studies concerning the metabolic digestion of the sweetener and the lack of a correlation with these studies in primates, this argument was also discarded. Gradually, the countries that had joined the US in banning Cyclamate including Canada legalised it as they realised that the evidence on Cyclamate's safety outnumbered and outclassed that of the contrary. Several more studies were conducted to test for cancer and other conditions possibly caused by the sweetener but none of these attained any positive results. Stubbornly, the FDA refused to accept these experiments and adhered to the 1969 experiment. In 1989 there was a great call for the legalisation of Cyclamate lead by Abott laboratories and the legalisation of the chemical had been anticipated. At this time, even the director of toxicological services at the FDA, Robert Scheuplein, admitted that he had "no reluctance in saying that with Cyclamate we made a mistake." However, the petition for Cyclamate's legalisation was turned down and for the next three decades the issue was effectively ignored by the US and its institutions. Now the reason for Cyclamate's ban is "not related to cancer." The actual reason for this is not clear but a speculative guess would be that the FDA has decided that there is not sufficient evidence of Cyclamate's safety. It is a mystery why such a sugar substitute is held off the market while more controversial sweeteners with fewer studies to support their safety like aspartame and Acesulfame K are still on it and a reconsideration of the FDA's decision might improve the situation.
It is evident from this essay that there is no concrete evidence of carcinogenicity in any of the three artificial sweeteners discussed. This however proves nothing but that insufficient research has been conducted. It is evident that the studies conducted on Aspartame are as of yet inconclusive as various reliable sources have conflicting views on this. Acesulfame Potassium has been declared safe by the FDA and the USDA but both Morando Soffritti and Myra L. Karstadt are convinced that there is not sufficient evidence for such an approval. It is possible that they are mistaken and there is nothing to worry about but the views of experts should never be disregarded completely. Ironically, Sodium Cyclamate appears be the safest of the three sweeteners as all experiments following the 1969 study indicated that these results were flawed. However, Cyclamate remains banned while the more controversial Aspartame and Acesulfame K are still on the market. It is clear that the sweetener that should be avoided the most is Aspartame closely followed by Acesulfame K. The Ramazzini studies have been internationally disregarded as inaccurate yet there is no apparent mistake in their testing that would explain a faulty outcome and no more recent experiments have been conducted in order to disprove the outcome. There is no real proof of the carcinogenicity of Acesulfame K which is why it comes second to Aspartame. Nevertheless, it is clear that the amount of studies performed on this sweetener is inadequate and thus it is also necessary to minimize its consumption. In essence, there is no reason to stop consuming artificial sweeteners completely as the evidence is nowhere near concrete but limitation is the best method to apply. Cancer is caused by many things: salt, meat and even the sugar that the sweeteners substitute. There is one thing which all results have in common and that is that if cancer is caused by artificial sweeteners this is only a significant risk when they are consumed in copious amounts.
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