Aspartame, low-calorie sweeteners and disease: Regulatory safety and epidemiological issues (original) (raw)

Introduction

The safety assessment procedure in the case of both natural and synthetic food additives and various contaminants is well established (EFSA, 2011a, EFSA, 2011b, EFSA, 2011c). The first phase involves the identification of the hazard, namely the inherent ability of the molecule to cause damage, using in silico models and various in vitro and in vivo experimental conditions. Recently, the European Food Safety Authority (EFSA) recommended a tiered approach for the testing of food additives that balances data requirements, animal welfare and risk, based on proposed uses and exposure assessment (EFSA, 2012). For aspartame, an extensive database of studies conducted to establish safety-in-use is available.

Regardless of the approach used for evaluation, a health-based guidance value, such as the Acceptable Daily Intake (ADI) for a food additive, is derived from the lowest No-Observed-Adverse-Effect Level (NOAEL), or the BenchMark Dose Lower confidence limit (BMDL) obtained in studies conducted according to internationally recognized test protocols. An ADI is set by dividing the NOAEL or BMDL by an uncertainty factor (usually an uncertainty factor of 100 in the case of animal studies).

The potential health impact posed by the presence of chemical hazards in food is estimated by calculating the likelihood that the consumer will be exposed to a substance and quantifying the extent of such exposure in relation to the health-based guidance value. Exposure assessments combine data on concentrations of a chemical substance present in food with data on the quantity of those foods consumed.

The exposure assessment is intended to cover the population, taking into account the variation in food consumption across countries and between various groups of the population, in particular those considered sensitive such as children and the elderly. This process is often highly conservative if, in the calculation of the exposure, the maximum permitted level in food is used together with the maximum amount of food consumed (worst case approach).

In the present paper, we review key aspects of the toxicity of aspartame and the related epidemiologic evidence.

Section snippets

Regulatory history

Aspartame is a dipeptide artificial sweetener composed of the amino acids phenylalanine and aspartic acid plus a small quantity of methanol (Butchko et al., 2002a, Butchko et al., 2002b). It is 200 times sweeter than sucrose. Since its approval, aspartame has been used in more than 6000 different type of products including soft drinks, dessert mixes, frozen desserts and yogurt, chewable multi-vitamins, breakfast cereals, tabletop sweeteners and pharmaceuticals (Rencüzogullari et al., 2004), and

Toxicity

The acute toxicity of aspartame, tested in rats, mice, rabbits and dogs, was very low. Sub-chronic toxicity was also low. Aspartame was found to be non-genotoxic in in vitro and in vivo studies (Rencüzoğullari et al., 2004, Jeffrey and Williams, 2000, Sasaki et al., 2002, NTP (US National Toxicology Program), 2005).

Since, after ingestion aspartame, is very efficiently hydrolysed, one of the main concerns derives from the products of hydrolysis, comprising about 50% phenylalanine (50%), aspartic

Epidemiological data on cancer

Since the 1970s, when experimental studies on animals reported an excess risk of bladder cancer in rodents treated with extremely high doses of saccharin (Weihrauch and Diehl, 2004), a potential role of low-calorie sweeteners in cancer risk has been widely debated. A few epidemiological studies also found some relationships between saccharin and bladder cancer risk in humans (Howe et al., 1977, Bravo et al., 1987, Sturgeon et al., 1994, Andreatta et al., 2008), but most – and the largest –

Epidemiologic data on vascular events

Information on artificial (and sugar) sweetened beverage consumption and the risk of coronary heart disease (CHD) was provided from the NHS, including 423 cases of CHD among daily users of low-calorie beverages and 301 among daily users of sugar-sweetened beverages (Fung et al., 2009). The study reported RRs of 1.07 (95%, CI 0.96–1.20) for low-calorie beverages and 1.59 (95% CI 0.92–2.74) for sugar-sweetened beverages.

Data from the Northern Manhattan Study showed an association, of borderline

Epidemiological data on preterm delivery

The issue of a possible association between low-calorie sweeteners and the risk of preterm birth was raised in 2010 in a study from the Danish National Birth Cohort (1996–2002), including 59,334 women and a total of 2739 cases of preterm births (<37

weeks) (Halldorsson et al., 2010). The study showed a significant trend of increasing risk for increasing consumption of artificially sweetened carbonated soft drinks, with a RR of 1.78 (95% CI 1.19–2.66) for drinkers of ⩾4 servings/day. The RRs were

Conclusions

Food additive approval is based on a robust hazard and risk characterization, leading to the establishment of an ADI and often a maximum permitted level (MPL) in foods. They must be subjected to a wide range of tests, devised to assess potential risks to the consumer, before they are allowed in food. Tests assess how the additive reacts in the body and also look for any toxic effects at and above the levels the additive is to be used in food. This includes testing to see if there is any chance

Conflict of Interest

The authors declare there are no conflicts of interest.

Acknowledgement

The work of CB, CLV and SG was conducted with the contribution of the Italian Association for Cancer Research (Grant No. 10068).