Abstract
Background and objective
The safety of individual low- and no-calorie sweeteners (LNCS) has been well established over decades, yet interest has grown in potential combined effects from concurrent exposure. This study evaluated (a) whether existing cumulative risk assessment (CRA) frameworks are appropriate for LNCS and (b) their applicability to aspartame, saccharin, sucralose, acesulfame-K, steviol glycosides, and cyclamate.
Methods
Regulatory CRA guidance and safety evaluations for each LNCS were reviewed. Toxicological data from repeat-dose and reproductive/developmental studies were synthesized by organ system and effect thresholds. A structured review of human microbiome studies was also conducted. Evidence was assessed for shared structure, target organ toxicity, and mode of action relevant to CRA frameworks.
Results
Existing frameworks rely on grouping chemicals with shared structure or mode of action; however, LNCS lack common structural features, toxicological profiles, and target organ effects. Kidney findings observed at high doses were inconsistent, species-specific, and considered toxicologically insignificant. Microbiome effects were variable, sweetener-specific, and not indicative of cumulative impact.
Conclusions
LNCS do not exhibit properties necessary for cumulative assessment under established CRA methods. Evidence supports no cumulative effects at typical intake levels, reinforcing the adequacy of individual acceptable daily intakes (ADIs) for safety evaluation.
Summary
The current study examined whether current approaches for assessing the combined safety of multiple substances are appropriate for evaluating the cumulative effects of mixtures of low/no calorie sweeteners. Existing cumulative risk assessment (CRA) frameworks rely on grouping chemicals with shared structure or mode of action. However, low/no calorie sweeteners do not share common chemical structure, toxicological profiles, target-organ effects or modes of action to justify grouping them under the estanblished frameworks. The authors therefore concluded that extabslihed CRA approaches are neither appropriate nor informative for sweeteners.
The study also reviewed safety evaluations from food safety authorities globally for six LNCS: aspartame saccharin, sucralose, acesulfame-K, steviol glycosides, and cyclamate. Toxicological data from repeat-dose and reproductive/developmental studies were synthesised by organ system and effect thresholds. Target organ assessment demonstrated lack of adverse effects within and across organ systems supporting an absence of cumulative effects on any target organ from exposure to multiple LNCS.
Finally, a structured review of sweetener-microbiome studies was conducted. The human microbiome evidence base indicated that effects of LNCS on the human gut microbiome are generally limited, inconsistent, and often nonreproducible, particularly at exposure levels at or below their ADIs and relevant to human dietary intake, with no evidence of a common effect across sweeteners.
These findings support the lack of cumulative effects of low/no calorie sweeteners at typical intake levels and reinforce the continued use of Acceptable Dialy Intakes (ADIs) as the basis for the safety evaluation of individual low/no calorie sweeteners rather than applying cumulative risk assessment approaches that are not suited for these substances.