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

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides
Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides
The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 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 1,000 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 hours 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 40-1,000 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 to 16 mg/kg bw/d is justified.
0273-2300
91-102
Roberts, Ashley
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Lynch, Barry
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Rogerson, Rebecca
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Renwick, Andrew
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Kern, Hua
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Coffee, Matthew
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Cueller-Kingston, Nicole
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Eapen, Alex
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Crincoli, Christine
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Pugh Jr., George
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Bhusari, Sachin
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Purkayastha, Sidd
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Carakostas, Michael
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Roberts, Ashley
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Lynch, Barry
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Rogerson, Rebecca
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Renwick, Andrew
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Kern, Hua
0a339359-94d3-45f2-badb-d1e1dd9f98d2
Coffee, Matthew
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Cueller-Kingston, Nicole
5c9c9d8a-af7a-4be0-b410-3f76bca390f2
Eapen, Alex
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Crincoli, Christine
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Pugh Jr., George
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Bhusari, Sachin
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Purkayastha, Sidd
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Carakostas, Michael
6cf3164d-cf43-4b78-8065-fe6dc60ef712

Roberts, Ashley, Lynch, Barry, Rogerson, Rebecca, Renwick, Andrew, Kern, Hua, Coffee, Matthew, Cueller-Kingston, Nicole, Eapen, Alex, Crincoli, Christine, Pugh Jr., George, Bhusari, Sachin, Purkayastha, Sidd and Carakostas, Michael (2016) Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides. Regulatory Toxicology and Pharmacology, 76, 91-102. (doi:10.1016/j.yrtph.2016.05.017).

Record type: Article

Abstract

The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 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 1,000 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 hours 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 40-1,000 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 to 16 mg/kg bw/d is justified.

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Roberts et al manuscript 2016.pdf - Accepted Manuscript
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Accepted/In Press date: 11 May 2016
e-pub ahead of print date: 13 May 2016
Published date: August 2016
Organisations: Faculty of Medicine

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Local EPrints ID: 399646
URI: http://eprints.soton.ac.uk/id/eprint/399646
ISSN: 0273-2300
PURE UUID: 0642c628-27f2-4c36-85b8-72a06262e113

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Date deposited: 22 Aug 2016 10:04
Last modified: 07 Oct 2020 06:03

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Contributors

Author: Ashley Roberts
Author: Barry Lynch
Author: Rebecca Rogerson
Author: Andrew Renwick
Author: Hua Kern
Author: Matthew Coffee
Author: Nicole Cueller-Kingston
Author: Alex Eapen
Author: Christine Crincoli
Author: George Pugh Jr.
Author: Sachin Bhusari
Author: Sidd Purkayastha
Author: Michael Carakostas

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