The obesity epidemic brought sharp focus onto population diets in Western industrialised countries, with recent emphasis on extrinsic, added sugars in particular. Extrinsic sugars do contribute to the development of overweight and obesity, insofar as they drive an energy surplus together with other energy-dense dietary constituents [1]. While the crux of the issue is increased overall caloric consumption in the diet, the evidence suggests that under free-living conditions, the primary issue with extrinsic sugars is that they are added to the diet without any compensatory reduction in energy intake [2]. Increasing the proportion of sugar in the diet under ad libitum conditions drives increased adiposity where calories are not reduced from other sources [2].

This has generated interest in the use of non-nutritive sweeteners [NNS], which encompasses both synthetic artificial sweeteners [AS] and non-caloric sweeteners of natural origin, as a strategy to reduce calorie intake in the population [3]. However, despite extensive toxicology studies, pre and post-market research, significant concerns continue to be raised in relation to the safety and efficacy of artificial sweeteners [4]. The most common concerns articulated relate to potential carcinogenic effects, contributions to weight gain, stimulation of blood glucose, activation of brain reward circuitry and stimulation of hunger or appetite [5].

For the purposes of this article, we’ll focus on AS only, specifically looking at acesulfame-K, aspartame, saccharin, and sucralose, which are the main AS in use [5]. This group of compounds fall under the umbrella of AS, as they can all be defined as having a greater sweetness intensity than sugar, allowing low levels to be added to foods and drinks as a caloric substitute [6]. However, the individual compounds all vary in sweetness potency, duration of sweetness, aftertaste, and mouth feel due to their structural differences, and have different pharmacokinetic profiles which warrant consideration of their health effects individually, and not under the umbrella term ‘AS’ [6].

 

Regulatory Processes and Approval for Use

This is an important first step in separating fact from fiction and fear in relation to AS: understanding the regulatory process and how the Acceptable Daily Intake [ADI] for any food additive is set. Compounds are not simply unleashed into the food environment for human consumption without regulatory authorities conducting safety evaluations, contrary to what many conspiracy theorists would like to believe. The AS listed above are approved for use in the U.S. by the Food and Drug Administration [FDA] and in the European Union [EU] through the European Food Standards Agency [EFSA], through a process involving submission of both scientific technical data and safety data [6][8].

Technical data relates to the chemical composition of the compound, source and manufacturing methods, stability of the compound across a range of food matrices, and sensory properties [6][8]. In addition, the full range of studies on safety must be contained in the submission process inclusive of the anticipate daily intake in the population, within different ages groups, from all dietary sources [6][8]. This safety information is derived from animal toxicology studies, which have specific directions for the type and design of studies required based on a system of “Concern Levels”: AS are considered a high concern level due to their potential high exposure in the population, and toxicity potential [6][8]. As a result of this concern level, studies must be conducted in animals with a similar pharmacokinetic profile to humans, and will assess both toxicity thresholds and sub-chronic toxicity for effects on reproduction, development, genotoxicity, carcinogenicity, and immunotoxicity [6].

Following animal toxicology studies, the “No Observable Adverse Effect Level” [NOAEL] is established, based on the lowest threshold of any toxicity observed in safety studies [7]. The ADI is then set by dividing the NOAEL by an uncertainty factor of 100 [7]. The technical data comes into play in assessing the potential health impact of the compound in the food supply, as exposure assessments combine data on the anticipated intake by reference to the concentrations of the compound in food/drinks together with the quantity of those foods/drinks consumed [7]. Like the establishment of the ADI, this is a very conservative assessment, particularly for children and the elderly, combining the maximum permitted level of the compound in foods together with the maximum level of consumption of food/drink [7].

 

The ADI & NOAEL vs. Consumption Levels

Putting this information into some context, the NOAEL for aspartame was set at 4g/kg/bw/day from long-term animal toxicology studies [7][8]. The ADI was then set at 50mg/kg in the U.S., or the equivalent of a 60kg adult consuming 4L of artificially sweetened soft drinks containing the maximum level of aspartame permitted under regulation [7]. Of course, no one food or drink contains the maximum permitted level of an AS; in the case of aspartame, average estimated intake is 1/10 the ADI [4mg/kg] while the highest quintiles of consumption still don’t exceed 30% of the ADI, with the 90th percentile consuming an average of 10mg/kg/d [9][10] Note that we are assessing consumption by reference to the ADI, not the NOAEL: even assuming an adult did consume the ADI for aspartame, that dose would still be 1/100 of the NOAEL, the lowest dose without any effect in long-term animal toxicology studies [7].

Diet Coke
35 cans of Diet Coke

For saccharin, a common sweetener found in sweetener packs under brand names like ‘Sweet-N-Low’, the ADI is 5mg/kg/bw/d: to reach the ADI you would have to drink 800 12floz cans of diet soda sweetened with saccharin [11]. For acesulfame-K, the ADI is 15mg/kg, and average consumption in the U.S is 20% of the ADI over the course of a lifetime [11]. Sucralose, commonly known as ‘Splenda’, has an ADI of 5mg/kg and is one of the most widely used AS, ubiquitous in food and drink products: there is no bioaccumulation of sucralose [9]. There is an important point to make in light of the significant gap between toxicity and consumption: just because something has toxic potential doesn’t mean it is. There is a lower toxicity threshold for vitamin A, copper, or selenium than AS. What many people are falling prey to is a differentiation made only on the basis of the nature fallacy: that because AS are “artificial”, they are inherently negative in their health effects.

The ADI and NOAEL are important when we consider the purported adverse effects of AS: for example, a recent study looking at neurotoxic effects of aspartame used doses of 500mg/kg and 1,000mg/kg in rats [12], or 2,400% greater than the ADI and thus of no relevance to either established safety thresholds or population levels of consumption. Nonetheless, concerns over AS for human consumption remain, so due diligence is warranted in assessing human health effects.

 

AS & Carcinogenicity

Of the AS approved for use in the U.S., saccharin, aspartame, and acesulfame-K have the most concerns over potential carcinogenicity. Concerns in relation to saccharin arose from animal toxicology studies in which bladder cancer developed in rats administered high doses, however, further research found that the carcinogenic mechanisms identified in rodents were not applicable in humans, and no associations between saccharin consumption and cancer in humans have been found in subsequent studies [11][13].

Research on aspartame is generally controversial due to the strong associations between study outcomes and funding source: industry funded studies all attest to safety, while 92% of independently funded studies report adverse health effects, particularly in relation to body weight, diabetes/glucose regulation [14]. These inconsistencies mandated the need for an unbiased meta-analysis of empirical evidence in relation to the aforementioned issues, and cancer. A 2015 meta-analysis of carcinogenic bioassay rodent studies concluded that there was no significant relationship between various experimental doses of aspartame and occurrence of malignant tumors [14]. This is consistent with human observational epidemiology [7].

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