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Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides |
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| Institution: | 1. Department of Biotechnology, Lovely Faculty of Technology and Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India;2. School of Basic and Applied Sciences, Raffles University, Alwar, Rajasthan, India;3. Department of Botany, Punjabi University, Patiala, India;4. Department of Plant Physiology, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, 221005, UP, India;5. Department of Botany, H.N.B.Garhwal University, Srinagar, Garhwal, India;6. Department of Computer Science, School of Information Science and Technology, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226025, Uttar Pradesh, India;7. Department of Life Sciences, Presidency University, 86/1 College street, Kolkata, 700076, West Bengal, India |
| 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: | Steviol glycosides Pharmacokinetics Rats Humans ADI terminal elimination constant ADI"} {"#name":"keyword" "$":{"id":"kwrd0050"} "$$":[{"#name":"text" "_":"acceptable daily intake area under the curve from time zero until the last sampling time point AE"} {"#name":"keyword" "$":{"id":"kwrd0070"} "$$":[{"#name":"text" "_":"adverse events AUC"} {"#name":"keyword" "$":{"id":"kwrd0080"} "$$":[{"#name":"text" "_":"area under the plasma concentration-time curve AUC from time zero to infinity AUC to the last quantifiable observation BLQ"} {"#name":"keyword" "$":{"id":"kwrd0110"} "$$":[{"#name":"text" "_":"below the limit of quantification BMI"} {"#name":"keyword" "$":{"id":"kwrd0120"} "$$":[{"#name":"text" "_":"body mass index bw"} {"#name":"keyword" "$":{"id":"kwrd0130"} "$$":[{"#name":"text" "_":"body weight concentration maximum CSAF"} {"#name":"keyword" "$":{"id":"kwrd0150"} "$$":[{"#name":"text" "_":"chemical-specific adjustment factor EE"} {"#name":"keyword" "$":{"id":"kwrd0160"} "$$":[{"#name":"text" "_":"efficacy evaluable population EKG"} {"#name":"keyword" "$":{"id":"kwrd0170"} "$$":[{"#name":"text" "_":"electrocardiogram HBsAg"} {"#name":"keyword" "$":{"id":"kwrd0180"} "$$":[{"#name":"text" "_":"hepatitis B surface antigen IQR"} {"#name":"keyword" "$":{"id":"kwrd0190"} "$$":[{"#name":"text" "_":"interquartile range IRB"} {"#name":"keyword" "$":{"id":"kwrd0200"} "$$":[{"#name":"text" "_":"Institutional Review Board JECFA"} {"#name":"keyword" "$":{"id":"kwrd0210"} "$$":[{"#name":"text" "_":"Joint FAO/WHO Expert Committee on Food Additives LC-MS/MS"} {"#name":"keyword" "$":{"id":"kwrd0220"} "$$":[{"#name":"text" "_":"liquid chromatography-tandem mass spectrometry LLOQ"} {"#name":"keyword" "$":{"id":"kwrd0230"} "$$":[{"#name":"text" "_":"lower limit of quantification LOQ"} {"#name":"keyword" "$":{"id":"kwrd0240"} "$$":[{"#name":"text" "_":"limit of quantification NOAEL"} {"#name":"keyword" "$":{"id":"kwrd0250"} "$$":[{"#name":"text" "_":"no-observed-adverse-effect level PP"} {"#name":"keyword" "$":{"id":"kwrd0260"} "$$":[{"#name":"text" "_":"per protocol population SD"} {"#name":"keyword" "$":{"id":"kwrd0270"} "$$":[{"#name":"text" "_":"standard deviation half-life time to maximum concentration WHO"} {"#name":"keyword" "$":{"id":"kwrd0300"} "$$":[{"#name":"text" "_":"World Health Organization |
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