Food consumption and body weight changes with neotame, a new sweetener with intense taste: differentiating effects of palatability from toxicity in dietary safety studies.

Safety studies done with neotame, a sweetener with intense taste, demonstrate that changes in bodyweight (BW) and BW gain (BWG) are due to reduced food consumption (FC) rather than toxicity. When offered a choice, rats preferred basal diet to diet with relatively low concentrations of neotame. When no choice was available, rats ate less as concentrations increased, demonstrating reduced palatability. Changes in dietary concentrations of neotame resulted in changes in FC. The maximum tolerable doses (MTDs) in rats, dogs, and mice were due to decreases in BWG secondary to poor palatability of diets when neotame concentrations exceeded approximately 35,000 ppm. Concentrations were increased as animals grew to maintain constant dosing on a "mg/kg bw/day" basis. Food conversion efficiency (FCE) was not changed in rats during periods of active growth. The only consistent findings across safety studies were reductions in BW, BWG, and FC with no dose-response in rats, mice, and dogs. In definitive safety studies, there were no adverse findings related to neotame treatment from clinical observations, physical examinations, water consumption, or clinical pathology evaluations; nor was there morbidity, mortality, organ toxicity, macroscopic or microscopic postmortem findings. Analysis of data from long-term studies in Sprague-Dawley rats support the conclusion that changes in FC alone can cause the observed changes in BWG in neotame studies when changes are scaled allometrically [Regul. Toxicol. Pharmacol. (2003)]. Consequently, BW parameters are not appropriate endpoints for setting no-observed-effect levels (NOELs) for neotame.

Long-term food consumption and body weight changes in neotame safety studies are consistent with the allometric relationship observed for other sweeteners and during dietary restrictions.

In long-term safety studies with neotame, a new high-intensity sweetener 7000-13,000 times sweeter than sucrose, the percent changes (%Delta) in body weight gain (BWG) in Sprague-Dawley rats were several-fold greater than the %Delta in overall food consumption (FC). This study investigates the question of whether the changes in BWG were adverse or secondary to small, long-term decrements in FC. The hypothesis tested in Sprague-Dawley rats was that the relationship between long-term %Delta in FC and %Delta in BWG is linear and in a ratio of 1:1. The %Delta in FC were compared to %Delta in BWG after 52 weeks on study in one saccharin (825 rats), two sucralose (480 rats), two neotame (630 rats), and five dietary restriction (>1000 rats) studies. Non-transformed plotting of data points demonstrated an absence of linearity between %Delta in FC and %Delta in BWG; however, log-log evaluation demonstrated a robust (R2=0.97) linear relationship between %Delta in FC and %Delta in BWG. This relationship followed the well-known allometric equation, y=bxa where x is %DeltaFC, y is %DeltaBWG, b is %DeltaBWG when DeltaFC=1, and a is the log-log slope. Thus, in Sprague-Dawley rats at week 52, the long-term relationship between %Delta in FC and %Delta in BWG was determined to be: %DeltaBWG=3.45(%DeltaFC0.74) for males and %DeltaBWG=5.28(%DeltaFC0.68) for females. Sexes were statistically different but study types, i.e., the high-intensity sweeteners saccharin and sucralose versus dietary restriction, were not. The %Delta in BWG are allometrically consistent with the observed %Delta in FC for these high-intensity sweeteners, including neotame. BW parameters are not appropriate endpoints for setting no-observed-effect levels (NOELs) when materials with intense taste are admixed into food. An approach using objective criteria is proposed to delineate BW changes due to toxicity from those secondary to reduced FC.

Effect of repeated presentation on sweetness intensity of binary and ternary mixtures of sweeteners.

The purpose of the present study was to determine the effect of repeated presentation of the same sweet stimulus on sweetness intensity ratings. The sweet stimuli tested in this study were binary and ternary blends of 14 sweeteners that varied widely in chemical structure. A trained panel evaluated the sweetness intensity over four sips of a given mixture presented at 30 s intervals. The individual components in the binary sweetener combinations were intensity-anchored with 5% sucrose, while the individual sweeteners in the ternary mixtures were intensity-anchored with 3% sucrose (according to formulae developed previously). Each self-mixture was also evaluated (e.g. acesulfame-K-acesulfame-K). The main finding of this study was that mixtures consisting of two or three different sweeteners exhibited less reduction in sweetness intensity over four repeated sips than a single sweetener at an equivalent sweetness level. Furthermore, ternary combinations tended to be slightly more effective than binary combinations at lessening the effect of repeated exposure to a given sweet stimulus. These findings suggest that the decline in sweetness intensity experienced over repeated exposure to a sweet stimulus could be reduced by the blending of sweeteners.

Aspartame: review of safety.

Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.