Asya+Popili

Final Paper Chem Info, Asya Popili

"Aspartame and its effects on the human health despite controversies surrounding the sweetener"

__//Table of molecules//__: Fig.1-Aspartame Fig.3-Aspartic Acid Fig.4-Phenylalinine Fig.5-Methanol

In recent years, sugar substitutes became a billion dollar industry. Partially, the reason for such high demand of sugar replacers is due to the American Society’s desire for weight loss through low-sugar foods and beverages which can overall decrease the amount of total calories consumed. Since of the main factors causing obesity in the U.S. is the unhealthy diet, which certainly includes enormous amount of sugar intake, sugar substitutes may be a perfect solution for reducing sugar amounts, and therefore amount of calories per meal and overall food consumption.
 * __//Introduction://__**

There are a lot of different sugar substitutes that gained its popularity right after it was discovered that sweeteners can sweeten the food and beverages just as successful as table sugar does. But the greatest advantage of substitutes over the table sugar is the minimum amount of calories present. In fact, “diet” of “light” products have zero calories (as stated on the food label) present which can give a lot more freedom to enjoy your favorite foods and beverages without the “guilt” or scare of gaining few extra pounds. There are few types of sugar substitutes commonly used. They mainly divide into natural substitutes and those derived artificially. Truth is that often, sugar substitute may have different after taste; some may be a little too sweet, while others may seem a little bitter. Most common natural sugar substitutes and artificial sweeteners used are aspartame, saccharine, acesulfame-K, xylitol,sorbitol, sucralose and stevia, derived from a stevia plant (“What are the best sugar substitutes?”,2012). The main question, however, is sugar substitute such as aspartame, safe to consume it or is it too good to be true? Also what is the daily recommendation regarding the aspartame consumption? And if in case aspartame is dangerous, then what are the side-effects associated with an intake of such sweetener? The most important question that one might ask is, how trust-worthy are those statements claiming that and is there evidence supported by studies that actually confirm the fact that aspartame may be potentially dangerous? There are lot of controversies surrounding the sweetener. Most popular one is that aspartame may cause cancer, headaches, seizures, as well as behavioral and neurological problems. However, there are no direct evidence that proves the toxicity of aspartame.

Aspartame is a very popular sugar substitute that is used in many low-calorie and low-sugar products and beverages. Such products include soda, dairy products such as yogurts and puddings, energy drinks, chewing gum and candy. Aspartame is an artificial sugar sweetener that differs from sucrose, commonly referred to as a table sugar, in many ways. First of all in structure and many physical properties. Aspartame is a methyl ester that binds together amino acid such as L-aspartic acid and L-phenylaniline. The IUPAC name of aspartame is Methyl L-α-aspartyl-L-phenylalaninate which tells us about the structure of the molecule.



Aspartame was discovered by Jim Schlatter, back in 1965. Jim Schlatter was a chemist who worked on a research of a drug development for treating gastric ulcers. The reaction that he performed was. In which the final product was supposed to be Methyl L-α-aspartyl-L-phenylalaninate was an intermediate product that was obtained while preparing the drug. Schlatter accidentally swallowed traces of the product and discovered the sweetness of it (Walters,2001). Later the new synthesized product was analyzed but it wasn’t until 13 years later when aspartame started gaining popularity and be used as a sweetener for the first time (Lajtha,2013). Since then many well-known companies such as Equal and NutraSweet, adopted newly discovered compound and started using it as a sweetener that can be basically added to any food. However, the main distinction of aspartame from sucrose is the fact that it cannot be used in baking due to its properties, primarily instability to high heat (Magnuson,2013). Another interesting fact about aspartame is its sweetness. Aspartame is about up to 200 times sweeter, than regular sucrose, depending on the concentration present. It is known that 1 gram of sucrose has about 4 calories that may add up to hundreds of calories per specific type of food or beverage. Aspartame, on the other hand, is so sweet that only a small amount of it is needed to provide the same amount of sweetness, providing minimum amount of calories. For example, 12oz of diet soft drink has about 0.024g of aspartame which has about 0.096 calories, whereas any regular soft drink might have up to 60g of sugar resulting in much higher calorie intake (up to 240) (Walters,2001).
 * //__Discovery of Aspartame:__//**

The United States Calorie Control Council (USCCC) sponsored a survey on the consumption of low-calorie foods and beverages. It showed that a lot of people today consume low-calorie foods and it became their lifestyle rather than diet plan. In fact, it was noted that about 93 million Americans use reduced fat (calories) foods, which is double the number since 1978 (Gunner,1991). But does it actually mean that if aspartame has very little amount of calories comparing to sucrose or to other sugar substitutes, it may lead to weight loss? There was an interesting study conducted in which men and women were given soft drinks sweetened with aspartame and soda with high-fructose syrup, alternated with no soda consumption, for a period of three weeks. It turned out that amount of calories significantly decreased in both men and women but the weight loss alone, was only observed in males. Comparing with the soda sweetened by high fructose syrup, the calorie intake and sugar intake dramatically increased for both sexes. Not a surprise, since one can of soda may have up to 40g of sugar, contributing to 160 calories. So in contrast with sugar sweetened drink, drink containing aspartame may significantly reduce the calorie and sugar intake (Tordoff, 2013). However, in short-term of aspartame consumption it was reported that aspartame may actually increase hunger in humans. What was really shocking is that study showed that chewing a piece of gum containing aspartame, actually increases person’s desire for food.

Fig. 2 (Tordoff,2013)

It was also found that hunger increases after consuming 500ml drink sweetened with aspartame. Therefore based on the study a conclusion may be drawn that even if aspartame may increase the appetite as a short-term effect, in a long-term effect it actually helps reduce the amount of calories and sugar and overall is capable of promoting weight loss (Tordoff, 2013). Figure 1 represents overall results obtained from a study where healthy, normal weight men (9) and women (21) were participating. It clearly represents a slight difference in weight change in both females and males.

Since aspartame is used as a sugar substitute that provides zero calories per gram of the product, it might be a perfect resolution for those suffering from obesity. But also, aspartame is recommended for type 2 diabetes patients. The main reason behind it I he fact that this sugar substitute doesn’t contain carbohydrates which therefore can help control carbohydrate intakes as well as blood glucose levels of patients struggling with diabetes. It is suggested that aspartame is safer in reducing the fall of blood glucose level during exercising in people with type 2 diabetes. There was a study conducted by the Diabetes Association in which the purpose was to investigate the effect of sugar substitute such as aspartame (and fructose) on plasma glucose levels relative to the regular sugar during the exercise in people struggling with type 2 diabetes. The hypothesis of the study was that meals sweetened by sugar substitutes (used aspartame and fructose) will promote a “lower impact of insulin release and glucose response” and therefore regulate the glucose level in bloodstream comparing to the meal sweetened with table sugar (Ferland,2007). In order to investigate and possibly confirm the hypothesis, 14 men with type 2 diabetes were given meals with different macronutrient content and later the effect of insulin levels were analyzed. It turned out that meal containing aspartame gave approximately the same rise in insulin despite the fact that it contained less calories and therefore amount of carbs, as meal containing sucrose. Further in the study, it was observed that severe low blood glucose levels were observed in all patients regardless of the content of the meal. Based on the study, it can be concluded that aspartame didn’t show any significant evidence in helping with reducing the hypoglycemia (low blood glucose levels) for those suffering from diabetes (Ferland,2007). Similar study about the consumption of aspartame in (non-insulin) diabetics showed that there was no difference observed between the sucrose and aspartame. Aspartame didn’t show a difference in the insulin level, as well as glycemic control and glucose tolerance (Colagiuri,1989).

Another health concern regarding aspartame is that aspartame may affect people struggling from epilepsy seizures. It is believed that due to aspartame’s molecular composition, it may provoke a seizure when given a dose of 1000 mg per kg of the product, which is said to be equivalent to about 400 drinks sweetened with aspartame (Fischer,2013). There was a different research study regarding the same issue, in which infants monkeys were receiving a daily dose of aspartame (3,000mg per kg of a body) for a period of 9 months. The results obtained showed that there were no significant changes in animal’s behavior, as well as physical changes and the occurrence of seizures wasn’t observed (Fischer,2013). These were the results obtained from study in animals, so now the main question is whether aspartame can affect people the same way and potentially cause seizures in people having epilepsy. Since 1984, there were a lot of customer complaints regarding the use and effects of aspartame, from which 137 cases involved occurrence seizures in individuals struggling from epilepsy. Right after that, the FDA was involved since it is responsible for monitoring and regulating compounds that may affect population’s health. After an investigation, the FDA decided that there was no direct link between aspartame and seizures (Fischer,2013). Therefore due to the lack of the evidence, it cannot be stated that aspartame can directly cause seizures. Again, the main conclusion of the study regarding the negative effect of aspartame in different areas of the human’s body system is that aspartame can be dangerous only if not consumed properly, meaning in extremely high doses of the sweetener.

An interesting study involving aspartame was conducted on rats. The goal of the experiment was to investigate how continues ingestion of aspartame will affect “locomotor” activity, behavior and anxiety in rats. Rats were given orally a daily dose containing (75mg per kg of a body) aspartame for a period of 90 days (Ashok,2013). In this research study, three groups of male rats were used and each group was given different chemicals, a control group, MTX (methotrexate-treated group) and Aspartame+MTX (aspartame + methotrexate-treated group). After the experiment was finished, few conclusions were made. First it can be concluded that aspartame may interfere with rat’s behavior. Rats that were fed with aspartame showed a significant decrease in mobility, however, vigorous behavior such as jumping and running wasn’t observed. Secondly it was concluded that aspartame may have effect on the brain but it was also noted that methanol which is released by aspartame may interfere with the sweetener and “contribute” to the result regarding the effect of aspartame on the brain activity and the behavior of rats. Overall, research study showed that there is a slight possibility of aspartame altering the brain function as well as behavior as a long-term effect but further studies are required.

The Food and Drug Administration first allowed the use of aspartame in 1981 and it was limited to use only on dry fruits. Later, FDA also approved aspartame use in carbonated soft beverages and then vitamins as well as in breath mints, fruit juices and dairy products. When aspartame is used as a sweetener, FDA requires the company to indicate the presence of aspartame and it also requires the company to have a label which notifies customers of the presence of phenylalanine ("FDA Statement on European Aspartame Study",2007).The main reason behind this is the phenylketonuria abbreviated as PKU. Individuals diagnosed with this disease are intolerant to aspartame due to the presence of phenylalanine. People who have the disease have already high level of phenylalanine in their body, and therefore they need to follow the diet restricting phenylalanine (Lajtha,2013). Symptoms associated with the disease may include severe problems which include behavior, personality and neurological problems. Those who have the PKU disease are not able to metabolize phenylalanine which is one of the three main components of the molecule of aspartame. Therefore, consumption of aspartame may lead to serious health problems to those who are prone to the disease. The acceptable daily intake of aspartame that an individual may consume daily also known as (ADI), was established by the FDA and the European Drug Safety to be 50mg per kg of a person’s weight and 40mg/kg respectively (“Aspartame”, 2011).For example, for an adult weighting 65kg, the daily recommended dose of aspartame should not go over 3,250mg according to the FDA regulations.
 * //__The FDA requirements:__//**

Aspartame metabolizes to three main components, such as phenylalanine, methanol and aspartate when injected orally (Jansseen,2013). It mostly consists of phenylalinine (50%), aspartic acid (40%) and only a little bit of methanol(10%)(Humphries,2008). A lot of controversies around aspartame were born due to the structural components of the sweetener Components include aspartic acid (aspartate), methanol, and phenylalanine. Component that raises the most concern is methanol that can be toxic to the human body if consumed in large quantities. The most well-known side effect due to the methanol toxicity is the loss of sight, in other words-blindness. It was believed that due to the fact that aspartame metabolizes to methanol, it may cause a lot of harm to the public. However, there was no actual evidence of methanol toxicity from aspartame. Let’s look at aspartame’s metabolism components separately.
 * //__Structural Components of aspartame:__//**

__//Aspartic Amino Acid//__:

Fig. 3 Aspartic Acid (“ChemSpider”,2013) Aspartic acid is a nonessential amino acid which human body is able to produce from the oxaloacedic acids (“L-aspartic acid”,2013).It was investigated in the studies, primarily on mice and rats, that after the oral intake of aspartic acid, it was shown that the amino acid is capable of “inducing neuronal necrosis in the arcuate nucleous in the brain of an animal ( Jansseen,2013). In rats and rabbits, the study showed that the lethal dose of aspartic acid was shown to be 5000mg per kg of the body weight. And mice (infants) who were fed aspartic acid showed the absence of some neurons in the nucleus. Another effect of aspartame that was observed was that in rats after the injection of the acid, the change frequency of breathing was observed as well change in inspiratory flow rate (Jansseen,2013). Aspartic acid was pronounced to be neurotoxic, meaning it can damage nerve cells in animals. However, according to a different study done on the human body, it was observed that aspartic acid doesn’t cause nerve damage if consumed adequately, within the normal daily consumption allowance. //__Phenylalanine__//:

Fig. 4 Phenylalinine (“Chem Spider”,2013)

Phenylalanine is an essential amino acid that is needed for human’s body. It is relatively safe and doesn’t cause toxicity. However, it is believed that a large consumption of phenylalanine may negatively affect pregnant women. High doses of phenylalanine are closely linked to birth defects (“Phenylalinine”,2013). Therefore it is recommended that pregnant women consume regular amount of phenylalanine present in food, without phenylalanine supplements. When phenylalanine enters the body, it metabolizes to tyrosine. Since tyrosine is a direct precursor to brain transmitters, phenylalanine may potentially affect transmitters and therefore function of the human’s brain (Janssen,2013).

__//Methanol//__ : Fig.5 Methanol (“Chem Spider”,2013)

Truth is that small amount of methanol is present in many products. In fact soda containing aspartame instead of sugar also contains small amount of methanol present just as juices filled with sugar do. It was calculated that with the use of aspartame (40mg per kg of body weight according to the FDA) an individual will consume about 4.4mg of methanol, since aspartame consists of 10% of methanol (Janssen,203). So based on the analysis of the molecules that aspartame consists of, it can be concluded that all of them may be harmful to humans if not consumed appropriately, with the daily dose recommended by the FDA.

__**//Methanol metabolites: formaldehyde and formate//**__ Methanol can sometimes be accidentally ingested instead of ethanol, which can cause severe toxicity, blindness, serious neurological problems and death. It is believed that methanol can severely damage the liver cells due to the fact that methanol metabolizes further. Once ingested, methanol metabolizes to formaldehyde(known as a carcinogen) and later oxidizes into the formate accompanied with the formation of hydrogen peroxide and superoxide anion (Skrzydlewska,1999). It is believed that formate is the “source” of toxicity and not methanol itself, which can cause serious health problems if used in large quantities (Skrzydlewska,1999). There was a study done in the effect of methanol in the cells, it showed that cell activity decreased as a result of methanol presence. Also, it was shown that once formaldehyde metabolized from aspartame enters the body, it may be distributed to many organs and tissues and therefore potentially damage the cells. But how much of formaldehyde can actually damage the cells, and how much aspartame would be needed to for it to be toxic? In a study conducted in Japan, the main purpose was to analyze the effect of methanol, formaldehyde and formate on cell’s viability to possibly answer the question regarding the toxicity of aspartame due to its metabolites (Oyama,2001). In the experiment, rat’s thymocytes cells were used, which were divided into three groups and each treated with different chemical. The results were the following: cells treated with methanol (100mmol/L) for a period of three consecutive hours didn’t show any difference in the cell’s viability. Cells treated with formaldehyde (3-30mml/L) show an increase in the amount of dead cells while treatment with formate (3mmol/L, comparing to 1mmol/L) showed a significant increase of dead cells (Oyama,2001).It was believed that formate gave such results due to the reduction of the pH level but once it was adjusted, the result showed that formate essentially had no effect on cells. Therefore formaldehyde was the only chemical that had affected the cell’s viability. Even if formaldehyde can be toxic at concentration of 1mml/L or more, it is very unlikely that its concentration will be reached. The main reason for that is the fact that concentration of injected aspartame was less than 1mmol/L. Therefore it was concluded that after methanol metabolizes to formaldehyde, its concentration is so small that it cannot be considered toxic. In fact it was shown that concentration of methanol from a dose of aspartame (150-200mg/kg of body, comparing to 40mg of recommended intake) resulted in less than 1mml/L. Therefore the final conclusion of the research study on the effect of methanol on cells is that formaldehyde indeed can be toxic, but even with the enormous amount of aspartame used, methanol’s concentration and therefore formaldehyde’s will be less than needed to cause damage (Oyama,2001).

Fig.6 "Effects of formaldehyde, methanol and formate on cell's viability" (Oyama,2001)

Benzaldehyde can be formed in the presence of aspartame and ascorbic acid. Benzaldehyde is a chemical compound that is widely used in many industries, such (in a food flavoring), pharmaceuticals, and cosmetics as well as in the industrial field.It was anounced safe in the U.S. But if not used appropriately it can be toxic. The oral LD(50) in rats and mice ranged from 800-2850mg.kg of a body. In the same study, during the 16week research study, rats who were given 10,000 ppm, didn’t show any signs of toxicity (Andersen,2006). But the evidence show that benzaldehyde is not toxic to humans in small doses. The most common preparation of benzaldehyde is by the chloronation reaction of toluene to benzyl chloride with is then hydrolyzed to benzoic aldehyde. In a study conducted by G. Lawrence and D.Yuan, benzaldehyde was prepared from aspartame in the presence of ascorbic acid, catalyzed by Cu(II) under acidic conditions (Lawrence,1996). Ascorbic acid, also known as vitamin C, is naturally found in many foods and bevarages.It mentions that the reaction itself has no impact on public health, but rather it is a new interesting and unique way of preparing the product. The study also proposed the reaction mechanisms of the formation of benzaldehyde from aspartame and this reaction became a new way of synthesizing benzaldehyde.
 * //__Benzaldehyde formation from aspartame:__//**

Conclusion can be drawn that aspartame is pretty safe to use in used as directed, according to the FDA regulations. A lot of studies were conducted but the evidence of aspartame being a dangerous and toxic compound were not found.Aspartame is a safe sugar substitute, according to the evidence provided.However, there is controversy about the potential health hazards of the sugar substitute that may lead to cancer. According to Arthur Evangelista, former FDA regulator, aspartame is a very dangerous artificial sweetener. He mentions few studies done on the effect of aspartame conducted on humans and rats. His final conclusion is that aspartame is a toxin which leads to altered brain function as well as nerve damage and organs complications(Evangelista,2004). Behavioral studies aspartame effects were conducted on different species including humans, rats, mice and rabbits. According to studies, aspartame is safe and there is no neurotoxic effect in the brain if used within the recommended intake established by the FDA. Long-term studies showed no significant behavioral changes in humans and symptoms associated with the intake of aspartame were observed.
 * //__Conclusion:__//**


 * __//References://__**

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