title: The acute effects of daily nicotine intake on heart rate--a toxicokinetic and toxicodynamic modelling study.
abstract: Joint physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) modelling was applied to simulate concentration-time profiles of nicotine, a well-known stimulant, in the human body following single and repeated dosing. Both kinetic and dynamic models were first calibrated by using in vivo literature data for the Caucasian population. The models were then used to estimate the blood and liver concentrations of nicotine in terms of the Area Under Curve (AUC) and the peak concentration (Cmax) for selected exposure scenarios based on inhalation (cigarette smoking), oral intake (nicotine lozenges) and dermal absorption (nicotine patches). The model simulations indicated that whereas frequent cigarette smoking gives rise to high AUC and Cmax in blood, the use of nicotine-rich dermal patches leads to high AUC and Cmax in the liver. Venous blood concentrations were used to estimate one of the most common acute effects, mean heart rate, both at rest and during exercise. These estimations showed that cigarette smoking causes a high peak heart rate, whereas dermal absorption causes a high mean heart rate over 48h. This study illustrates the potential of using PBTK/TD modelling in the safety assessment of nicotine-containing products.
authors: Systems Toxicology Unit and EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, 21027 Ispra, VA, Italy; University of Milano Bicocca, Dep. of Earth and Environmental Sciences, Piazza della Scienza 1, Milano, Italy; TUM, Wissenschaftszentrum Weihenstephan für Ernährung und Landnutzung, Department für Biowissenschaften, Weihenstephaner Steig 23, 85350 Freising, Germany. Electronic address: Monika.Gajewska@ec.europa.eu.
authors: M
authors: M
authors: Gajewska
authors: Systems Toxicology Unit and EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, 21027 Ispra, VA, Italy.
authors: A
authors: A
authors: Worth
authors: University of Milano Bicocca, Dep. of Earth and Environmental Sciences, Piazza della Scienza 1, Milano, Italy.
authors: C
authors: C
authors: Urani
authors: TUM, Wissenschaftszentrum Weihenstephan für Ernährung und Landnutzung, Lehrstuhl für Systemverfahrenstechnik, Weihenstephaner Steig 23, 85350 Freising, Germany.
authors: H
authors: H
authors: Briesen
authors: TUM, Wissenschaftszentrum Weihenstephan für Ernährung und Landnutzung, Department für Biowissenschaften, Weihenstephaner Steig 23, 85350 Freising, Germany; Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Molecular EXposomics (MEX), Ingolstädter Landstr.1, D-85764 Neuherberg, Germany.
authors: K-W
authors: KW
authors: Schramm
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002138:Calibration; D015444:Exercise / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009538:Nicotine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D012869:Skin Absorption; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D014018:Tissue Distribution; D061485:Tobacco Use Cessation Devices; D057968:Transdermal Patch
chemical_list: D009538:Nicotine
keywords: Nicotine; Physiologically-based toxicodynamic (PBTD) modelling; Physiologically-based toxicokinetic (PBTK) modelling