Assessment of the carcinogenicity of stevioside in F344 rats

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

“…The only effects noted in the steviol glycoside animal toxicity studies have been related to decreases in body weight gain, which have previously been described for a number of other sweetener products including sucralose and neotame as result of palatability, caloric reduction, and subtle decrements in food consumption at study initiation (Carakostas et al, 2008). The results reported in the Toyoda et al (1997) publication which is the study that has been used historically to derive the ADI for steviol glycosides, may also support a higher ADI. The authors considered the mid dose to be the NOAEL on the basis that the top dose had a slightly reduced body weight gain and a significant decrease in survival rate.…”

“…This uncertainty factor can be reduced further to 1 based on comparative Cmax data from rats and man. As a consequence using a CSAF supports a higher ADI value for steviol glycosides of 6 to 16 mg/kg bw/d depending upon the use of either AUC or Cmax data, when using the 400 mg/kg/d NOAEL from the chronic study on stevioside (Toyoda et al, 1997).…”

“…The decrease in survival was postulated to result from an increase in large granular lymphocytic type leukemia which was a common finding in the testing laboratory as well as in all laboratories using the F344 rat. Since the incidence of large granular lymphocytic type leukemia was found to be within the historical control range and given that noting that the presence of this neoplasm is now interpreted quite differently (Thomas et al, 2007) than at the time of the Toyoda et al (1997), there is no indication of a treatment-related effect. In addition, as recently discussed by Maronpot et al (2016), this neoplasm is a result of the species-strain specific biology of the F344 rat and is of little relevance to human risk assessment.…”

“…The ADI using the CSAF would range between 6 and 16 mg/kg/d using the AUC and Cmax data, whereas the ADI using the animal subchronic studies ranges between 7 and 20 mg/kg bw/d steviol equivalents based on 13-and 4-week rat studies, respectively. The CSAF taken together with the higher NOAEL of 800 mg steviol equivalents/kg bw/d from the Toyoda et al (1997) study yields an ADI range of 12 to 32 mg/kg/d using the AUC and Cmax data, respectively. Table 1 for the number of individual animals with quantifiable concentrations.…”

“…This approach was employed recently in European Food Safety Authority (EFSA, 2015) to include rubusoside and to allow any combination of 11 steviol glycosides on the basis of a common metabolic fate so long as steviol glycosides comprised ≥95% of the mixture. The current ADI of 0-4 mg steviol equivalents/kg body weight (bw)/day was based on a no-observed-adverse-effect level (NOAEL) of 400 mg/kg bw/d identified from a chronic study of stevioside in rats (Toyoda et al, 1997). The ADI is thought to be particularly conservative given the existence of other subchronic toxicity studies on steviol glycosides in which no adverse effects were noted at much higher doses than the NOAEL identified in the chronic rat study (Curry and Roberts, 2008;Nikiforov and Eapen, 2008).…”