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

Regul Toxicol Pharmacol. 2016 Aug:79:91-102. doi: 10.1016/j.yrtph.2016.05.017. Epub 2016 May 13.

Abstract

The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 0-4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a no-observed-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ∼8 and ∼20 h after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40-1000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 and 16 mg/kg bw/d is justified.

Keywords: ADI; Humans; Pharmacokinetics; Rats; Steviol glycosides.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • Adult
  • Animals
  • Area Under Curve
  • Biotransformation
  • Diterpenes, Kaurane / blood
  • Diterpenes, Kaurane / pharmacokinetics*
  • Diterpenes, Kaurane / toxicity*
  • Dose-Response Relationship, Drug
  • Female
  • Glucosides / blood
  • Glucosides / pharmacokinetics*
  • Glucosides / toxicity*
  • Glucuronides / pharmacokinetics
  • Half-Life
  • Humans
  • Hydrolysis
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Models, Biological
  • No-Observed-Adverse-Effect Level*
  • Rats
  • Rats, Sprague-Dawley
  • Risk Assessment
  • Species Specificity
  • Sweetening Agents / pharmacokinetics*
  • Sweetening Agents / toxicity*
  • Toxicity Tests / methods*
  • Toxicokinetics*
  • Uncertainty
  • Young Adult

Substances

  • Diterpenes, Kaurane
  • Glucosides
  • Glucuronides
  • Sweetening Agents
  • stevioside