Carakostas MC, Curry LL, Boileau AC, Brusick DJ. Overview: the history, technical function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and beverages. Food Chem Toxicol. Jul 2008;46(Suppl 7): S1-S10.

Steviol glycosides are intensely sweet compounds derived from the South American plant stevia (Stevia rebaudiana). In June 2008, Wisdom Natural Brands (Phoenix, Arizona) announced that it will market its SweetLeaf® stevia product as a sweetener after self-affirming generally recognized as safe (GRAS) status. Previously, stevia products were only marketed as dietary supplements in the United States.¹ Stevia preparations have been used by natives of Paraguay and Brazil from pre-history and as a sweetener in Japan since the 1970s. Despite commercial and consumer interest, the combination of regulatory issues, safety concerns, and a problematic bitter aftertaste has prevented steviol glycoside sweeteners from becoming more widely marketed in Europe and America. In this review, the authors aim to address safety and specification-related questions regarding steviol glycoside sweeteners raised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and other regulatory agencies.

Most steviol glycoside products currently on the market consist primarily of stevioside or rebaudioside A. The published literature has mainly focused on stevioside. Stevioside and rebaudioside A are structurally similar, the difference being that rebaudioside A has one more glucose moiety. Rebiana is a purified form of rebaudioside A that meets JECFA technical, purity, and safety specifications. Commercial rebiana is manufactured using a validated and reproducible method following Good Manufacturing Practices (GMPs). Rebiana is produced by hot water extraction of stevia leaves followed by filtration and then separation of steviol glycosides with an absorption resin. The resin is eluted with food grade ethanol or methanol, and after drying the end product is a stable white powder.

Rebaudioside A and stevioside are both metabolized in the colon of rats and humans to steviol, which is then absorbed. In humans, steviol is converted to its glucuronide and excreted by the kidneys. Due to this similarity in metabolism, safety studies on stevioside can also be applied to rebaudioside A, according to the authors. Using intake data for existing low-calorie sweeteners, it has been estimated that the adult intake of rebiana should range from an average intake of 1.3 mg/kg bw/day to a high intake of 3.4 mg/kg bw/day (children's intake: 2.1 and 5.0 mg/kg bw/day, respectively). The authors note that these figures are overestimated because they assume a significant market penetration and total substitution of rebiana for other sweeteners.

Studies have indicated that short-term oral intake of steviol glycosides is non-toxic. No oral toxicity has been found in studies lasting up to 13 weeks, but studies over 13 weeks have shown very high doses reduced body weight in rats. This is probably due to taste aversion as has been observed in studies of artificial sweeteners. No systemic toxicity has been observed. Stevioside studies lasting longer than two years have found body weight and survival rate reductions in high-dose (2000 mg/kg bw/day) males, linked to taste aversion and a tumor that is common in aged rats. A 2005 JECFA report concluded that there is no in vitro or in vivo evidence of genotoxic effects for stevioside and rebaudioside A. Studies that have indicated genotoxicity have been plagued by design flaws and other issues, according to the authors. Additional studies have indicated that stevioside is non-carcinogenic, and these results can also be applied to rebaudioside A.

Stevia has been traditionally used as a contraceptive by Matto Grosso Indian tribes in Paraguay, and some animal studies have indicated reproductive effects. However, these studies have design flaws and other limitations, often involving poor characterization of the test materials utilized, according to the authors. More recent animal studies have reported that high purity stevioside and rebaudioside A do not have adverse effects on reproduction or development. Two clinical trials on patients with high blood pressure reported blood pressure reductions after long-term treatment with stevioside. One clinical trial using stevioside found a beneficial effect on postprandial glucose homeostasis in type 2 diabetic patients. These raised concerns about potential risks for normotensive and diabetic consumers. Two randomized, placebo-controlled, double-blind clinical trials were conducted to examine the effects of rebaudioside A on the blood pressure of healthy subjects and on glucose homeostasis in type 2 diabetics. The studies concluded that 1,000 mg/day of rebaudioside A had no clinically significant effects on blood pressure in healthy subjects or on glucose homeostasis or blood lipids in type 2 diabetic patients. No adverse effects were observed in either study. Results from several other similar clinical studies support these findings that no significant effects on blood pressure and blood sugar occur with high steviol glycoside doses delivered over several months.

The authors' conclusion is "high purity rebaudioside A (rebiana) produced under current GMP to food-grade standards, is safe and appropriate for introduction into the global marketplace." The authors are employees or a paid consultant for the Coca-Cola Company or Cargill, Inc.

—Marissa Oppel, MS

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