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

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

Author information

1
Intertek Scientific & Regulatory Consultancy, 2233 Argentia Rd., Suite 201, Mississauga, ON, L5N 2X7, Canada. Electronic address: ashley.roberts@intertek.com.
2
Intertek Scientific & Regulatory Consultancy, 2233 Argentia Rd., Suite 201, Mississauga, ON, L5N 2X7, Canada.
3
Faculty of Medicine, Highfield, University of Southampton, Southampton, SO17 1BJ, UK.
4
Biofortis Clinical Research, 211 East Lake Street, Addison, IL, 60101, USA.
5
WIL Research, 1407 George Road, Ashland, OH, 44805-8946, USA.
6
Cargill, Incorporated, 15407 McGinty Rd W., Wayzata, MN, 55391, USA.
7
The Coca-Cola Company, One Coca-Cola Plaza, Atlanta, GA, 30126, USA.
8
PureCircle Limited, 915 Harger Road, Suite 250, Oak Brook, IL, 60523, USA.
9
ToxStrategies, Inc., 2 Reeve Crt #200, St. Helena Island, SC, 29920, USA.

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

PMID:
27181453
DOI:
10.1016/j.yrtph.2016.05.017
[Indexed for MEDLINE]

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