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Highlights • The concept of Margin of Internal Exposure (MOIE) is proposed for route-to-route extrapolation. • It is an extension of the Margin of Exposure (MOE) approach for cosmetics in the EU. • PBK modelling integrates in vitro and in silico predictions of ADME-properties. • The MOIE approach is transparent and facilitates to make uncertainties explicit. • The MOIE can be extended to include in vitro toxicity data in animal-free risk assessment., Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (Cmax), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day.

The Influence of Pregnancy on the Location of the Center of Gravity in Standing Position The purpose of the study was to compare the average location of the center of gravity vertical projection in sagittal plane in women at the beginning of and in advanced pregnancy as well as after delivery. The experiment was performed with the use of a force platform during four test sessions. A group of 44 women (8-16 weeks of pregnancy) participated in the initial test session. In the following sessions the number of the subjects reduced mainly due to medical and childcare problems: 33 women were tested in late pregnancy (2-3 weeks before delivery), and 39 women were tested two and six months after delivery. The results showed the statisticaly significant (p We concluded that the change of the center of gravity location in late pregnancy is temporary and two months after delivery the vertical projection of the center of gravity is located as it was at the beginning of pregnancy.

This work illustrates the use of Physiologically-Based Toxicokinetic (PBTK) modelling for the healthy Caucasian population in in vitro -to- in vivo correlation of kinetic measures of caffeine skin penetration and liver clearance (based on literature experiments), as well as dose metrics of caffeine-induced measured HepaRG toxicity. We applied a simple correlation factor to quantify the in vitro and in vivo differences in the amount of caffeine permeated through the skin and concentration-time profiles of caffeine in the liver. We developed a multi-scale computational approach by linking the PBTK model with a Virtual Cell-Based Assay to relate an external oral and dermal dose with the measured in vitro HepaRG cell viability. The results revealed higher in vivo skin permeation profiles than those determined in vitro using identical exposure conditions. Liver clearance of caffeine derived from in vitro metabolism rates was found to be much slower than the optimised in vivo clearance with respect to caffeine plasma concentrations. Finally, HepaRG cell viability was shown to remain almost unchanged for external caffeine doses of 5–400 mg for both oral and dermal absorption routes. We modelled single exposure to caffeine only.

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.

Antimicrobial agents should be added to lecithin-stabilized submicron emulsions when these preparations are non-sterile products or when packed in multidose containers. Eleven antimicrobials were introduced to a standard submicron emulsion. The emulsions were adjusted to pH 5.0 or 8.2 prior aseptic filtration or thermal sterilization, respectively. The physicochemical stability of the preparations was observed during storage for 2 years at room temperature. Parabens showed the best compatibility but satisfying stability was also observed in emulsions containing phenylethanol, m-cresol and benzalkonium chloride. Partitioning studies revealed poor correlation between aqueous solubility and content of the preservatives in the aqueous phase of the emulsion. Only 1.2% of the total content of benzalkonium chloride was found in this phase and incorporation of this compound into different microscopic structures of the emulsion is proposed as a reason for such effect. Preliminary studies on the efficacy of antimicrobial preservation was performed for emulsions containing parabens, benzalkonium chloride or chlorocresol and the negative results bring conclusion that higher concentration of antimicrobials or their combination may be required for efficient preservation of submicron emulsions.

The European Union’s ban on animal testing for cosmetic ingredients and products has generated a strong momentum for the development of in silico and in vitro alternative methods. One of the focus of the COSMOS project was ab initio prediction of kinetics and toxic effects through multiscale pharmacokinetic modeling and in vitro data integration. In our experience, mathematical or computer modeling and in vitro experiments are complementary. We present here a summary of the main models and results obtained within the framework of the project on these topics. A first section presents our work at the organelle and cellular level. We then go toward modeling cell levels effects (monitored continuously), multiscale physiologically based pharmacokinetic and effect models, and route to route extrapolation. We follow with a short presentation of the automated KNIME workflows developed for dissemination and easy use of the models. We end with a discussion of two challenges to the field: our limited ability to deal with massive data and complex computations.