Title: Alternative Sweeteners

352 Olinger and Pepper
lycerate levels and a NADH-mediated reduction of oxidized glutathione in erythrocytes
(198–202). This latter effect may be particularly relevant in the tens of
millions of people that are affected by different degrees of glucose-6-phosphate
dehydrogenase deficiency, which as such causes little concern but which predisposes
to radical-induced pathology under certain conditions (drug therapy, sepsis,
shock). Whether a reported effective treatment of cardiac arrhythmias with xylitol
is also related to a shift to a more reduced status is not known (203,204).
Although a large number of studies indicate the absence of adverse side
effects with parenteral xylitol administration, some authors advise against the use
of xylitol because of the possibility of increased serum lactic acid, uric acid,
and bilirubin concentrations (205,206) and because of the possible deposition of
calcium oxalate crystals in the kidney and in the brain (207–210). However,
regarding the occurrence of renocerebral oxalosis in association with xylitol infusions,
it is noteworthy that in most of these cases the recommended maximum
daily dose and/or infusion rate was surpassed. If xylitol is infused at recommended
rates (0.25 g/kg/hr and 3g/kg/day) (211) and in combination with
glucose and fructose, such complications are not likely to occur more frequently
than in patients not treated with xylitol (212–214). In general, no adverse side
effects are observed if these recommendations are observed. Contrary to fructose,
sorbitol, and glucose, a metabolic intolerance to xylitol is not known.
X. TOXICITY AND TOLERANCE
The results of animal tests for acute toxicity have indicated that xylitol is of very
low toxicity by all routes of administration. Conventional tests for embryotoxicity
and teratogenicity and for adverse effects on reproduction have given entirely
negative results. Similarly, both in vitro and in vivo tests for mutagenicity and
clastogenicity have given uniformly negative results (215).
Long-term studies in animals for safety evaluation have included 2-year
treatment of rats, mice, and dogs. In these studies, xylitol was tested at a maximum
dose level of 20% of the diet. Although the findings of these animal studies
generally supported the safety of oral xylitol, some observations required further
investigation. These observations were urinary tract calculi in mice and a slight
increase in the incidence of adrenal medullary pheochromocytomas in male rats
(216).
The results of subsequent studies and additional data from experiments with
other polyols and lactose demonstrated, however, that the adverse effects observed
in mice and rats are generic in nature and lack significance for safety
evaluation in humans because of the species specificity of the underlying mechanisms
(19,20,217–220).