title: Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides.
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.
authors.affiliation: Intertek Scientific & Regulatory Consultancy, 2233 Argentia Rd., Suite 201, Mississauga, ON, L5N 2X7, Canada. Electronic address: ashley.roberts@intertek.com.
authors.forename: Ashley
authors.initials: A
authors.lastname: Roberts
authors.affiliation: Intertek Scientific & Regulatory Consultancy, 2233 Argentia Rd., Suite 201, Mississauga, ON, L5N 2X7, Canada.
authors.forename: Barry
authors.initials: B
authors.lastname: Lynch
authors.affiliation: Intertek Scientific & Regulatory Consultancy, 2233 Argentia Rd., Suite 201, Mississauga, ON, L5N 2X7, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rogerson
authors.affiliation: Faculty of Medicine, Highfield, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Renwick
authors.affiliation: Biofortis Clinical Research, 211 East Lake Street, Addison, IL, 60101, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Kern
authors.affiliation: WIL Research, 1407 George Road, Ashland, OH, 44805-8946, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Coffee
authors.affiliation: Cargill, Incorporated, 15407 McGinty Rd W., Wayzata, MN, 55391, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cuellar-Kingston
authors.affiliation: Cargill, Incorporated, 15407 McGinty Rd W., Wayzata, MN, 55391, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Eapen
authors.affiliation: Cargill, Incorporated, 15407 McGinty Rd W., Wayzata, MN, 55391, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Crincoli
authors.affiliation: The Coca-Cola Company, One Coca-Cola Plaza, Atlanta, GA, 30126, USA.
authors.forename: George
authors.initials: G
authors.lastname: Pugh
authors.affiliation: The Coca-Cola Company, One Coca-Cola Plaza, Atlanta, GA, 30126, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Bhusari
authors.affiliation: PureCircle Limited, 915 Harger Road, Suite 250, Oak Brook, IL, 60523, USA.
authors.forename: Sidd
authors.initials: S
authors.lastname: Purkayastha
authors.affiliation: ToxStrategies, Inc., 2 Reeve Crt #200, St. Helena Island, SC, 29920, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Carakostas
mesh_terms: D000328:Adult; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D045786:Diterpenes, Kaurane / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005960:Glucosides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D020719:Glucuronides / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013045:Species Specificity; D013549:Sweetening Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D066007:Toxicokinetics; D035501:Uncertainty; D055815:Young Adult
chemical_list: D045786:Diterpenes, Kaurane; D005960:Glucosides; D020719:Glucuronides; D013549:Sweetening Agents; C012043:stevioside
keywords: ADI; Humans; Pharmacokinetics; Rats; Steviol glycosides