Title: Alternative Sweeteners

174 Kinghorn et al.
sulting in the improvement of taste quality for both natural sweeteners. In addition,
stevioside has been found to be synergistic with aspartame, cyclamate, and
acesulfame K, but not with saccharin (1).
VI. METABOLISM
Only limited data are available on the in vitro and in vivo metabolism of stevioside
and other S. rebaudiana sweet constituents. An initial investigation in which
stevioside and rebaudioside A were degraded to steviol by rat intestinal flora in
vitro was reviewed previously (1). Steviol has also been found as a major metabolite
of stevioside when a tritiated form of the compound was fed to Wistar rats
at an oral dose of 125 mg/kg. The biological half-life of stevioside was estimated
to be 24 hr, and 125 hr after compound administration, the highest percentages
of radioactivity were found in the feces, followed by expired air and urine. It was
concluded that although a portion of orally administered stevioside was excreted
unchanged in the feces of the rat, most of it was degraded by the intestinal bacterial
flora to steviol, steviolbioside, and glucose, which were then absorbed in the
cecum. Absorbed glucose was metabolized and excreted in the expired air as
carbon dioxide and water, whereas steviol was conjugated in the liver and excreted
into the bile. It was also inferred from the results of biliary and fecal
excretion that enterohepatic circulation of steviol occurred (2). More recently,
the distribution of [ 131 I]-stevioside has been reported in rats after IV administration,
and within 2 hr, 52% of the radioactivity was present in the bile, which
consisted of [ 131 I]-iodosteviol (47% of total radioactivity), unchanged [ 131 I]-stevioside
(37%), and an unidentified metabolite (15%) (21).
Despite the widespread use of S. rebaudiana extracts containing stevioside
as sweeteners in foods in Japan, the metabolism of this substance in humans does
not seem to have been investigated to date.
VII. SAFETY STUDIES
A. Toxicity Studies in Rodents
Previous acute, subacute, and chronic toxicity studies carried out in Japan in rats
on S. rebaudiana extracts with various stevioside levels have not resulted in the
demonstration of any significant toxic effects (1, 2). In one of several toxicity
studies carried out more recently, stevioside was fed to F344 rats at various levels
(0.31, 0.62, 1.25, 2.5, and 5%) for 13 weeks. A concentration of 5% in the diet
was considered to be the maximum tolerable dose of stevioside for a proposed
2 year carcinogenicity study in rats. Although lactic dehydrogenase and singlecell
necrosis of the liver were increased in male animals treated with stevioside,