EURL ECVAM strategy for achieving 3Rs impact in the assessment of toxicokinetics and systemic toxicity

Information on human toxicokinetics plays an important role in the safety assessment of chemicals, even though there are few data requirements in the EU regulatory framework. While existing EU test methods and OECD test guidelines are mostly based on animal procedures, there are increasing opportunities to achieve a 3Rs impact in this area by exploiting modern developments. For example, whole-body toxicokinetic information can be obtained by using physiologically-based toxicokinetic (PBTK) models that integrate data generated by in vitro methods for absorption, distribution, metabolism and excretion (ADME). The development of an infrastructure providing access to such models and their underlying data needs to be accompanied by the establishment of standards for human in vitro ADME methods, the development of guidance on the development and application of such models and the creation of regulatory incentives. Taking these needs into account, this report describes the EURL ECVAM strategy to achieve a 3Rs impact in the area of toxicokinetics and systemic toxicity. The proposed activities are expected to lay the foundation for a risk assessment approach that is increasingly based on human data. Implementation of the strategy will rely on the coordinated efforts of multiple stakeholders.JRC.I.5-Systems Toxicolog

Assessment of Mixtures - Review of Regulatory Requirements and Guidance

Humans and the environment are continuously exposed to a multitude of substances via different routes of exposure. However, the risk assessment of chemicals for regulatory purposes does not generally take into account the “real life” exposure to multiple substances, but mainly relies on the assessment of individual compounds. This report summarizes the different methodologies that are used to assess the toxic effects of mixtures (Chapter 1). It also provides an overview of current legislation in the EU that deals with the safety assessment of chemicals in different matrices and whether, and if so to what extent, the current legislation addresses the toxicological risk of mixtures (Chapter 2). Relevant Guidance Documents from the EU and other countries (USA, Canada) and international organisations (such as the WHO or the OECD) are also included in the review (Chapter 3).JRC.I.5 - Systems Toxicolog

Comparison of muscle strength, sprint power and aerobic capacity in adults with and without cerebral palsy

Objective: To compare: (i) muscle strength, sprint power and maximal aerobic capacity; and (ii) the correlations between these variables in adults with and without cerebral palsy. Design: Cross-sectional study. Subjects: Twenty adults with and 24 without cerebral palsy. Methods: Isometric and isokinetic knee extension strength, sprint power (mean power over the 30s (P30)), peak aerobic power output (POpeak) and oxygen uptake (VO2peak) were determined. Regression analysis was used to investigate correlations between parameters. Results: Adults with cerebral palsy had significantly lower strength (53-69%) and P30 (67%) than adults without cerebral palsy, but similar POpeak and VO2peak. In adults without cerebral palsy the only significant correlations, albeit weak, were between P30 and isometric (R-2=0.34) or isokinetic strength (R-2=0.20), as well as the correlation between P30 and VOpeak (R-2=0.26) or POpeak (R-2=0.36). Stronger correlations were found in the group with cerebral palsy between P30 and isometric (R-2=0.52) and isokinetic strength (R-2=0.71) and between P30 and VOpeak (R-2=0.75) or POpeak (R-2=0.94). Conclusion: In contrast to aerobic capacity, strength and P30 are reduced in (active) people with cerebral palsy. Stronger correlations were found between strength, P30 and POpeak in adults with cerebral palsy. Therefore, muscle strength may be the limiting factor in adults with cerebral palsy for activities involving the lower extremities, such as cycling

The course of the radial nerve in the distal humerus: A novel, anatomy based, radiographic assessment

Iatrogenic nerve injury during fracture surgery of the upper arm is a well-known complication. Prevention of this type of injuries would be of great value. The literature describes several methods to reduce this type of injury, but no perfect solution is at hand. In this study we introduce a new radiographic evaluation of the course and variation of the radial nerve in the distal part of the humerus in relation to bony landmarks as observed on a plain (trauma) radiographs. Aim of this new approach is to reduce the chance of iatrogenic nerve injury by defining of a danger zone in the distal upper arm regarding the radial nerve and hence give an advise for future implant fabrication. Methods and findings: Measurements were done on both arms of ten specially embalmed specimens. Arms were dissected and radiopaque wires attached to the radial nerve in the distal part of the upper arm. Digital radiographs were obtained to determine the course of the radial nerve in the distal 20 cm of the humerus in relation to bony landmarks; medial epicondyle and capitellum-trochlea projection (CCT). Analysis was done with ImageJ and Microsoft Excel software. We also compared humeral nail specifications from different companies with the course of the radial nerve to predict possible radial nerve damage. Results: The distance from the medial epicondyle to point where the radial nerve bends from posterior to lateral was 142 mm on AP radiographs and 152 mm measured on the lateral radiographs. The average distance from the medial epicondyle to point where the radial nerve bends from lateral to anterior on AP radiographs was 66 mm. On the lateral radiographs where the nerve moves away from the anterior cortex 83 mm to the center of capitellum and trochlea (CCT). The distance from the bifurcation of the radial nerve into the posterior interosseous nerve (PIN) and superficial radial nerve was 21 mm on AP radiographs and 42 mm on the lateral radiographs (CCT). Conclusions: The course of the radial nerve in the distal part of the upper arm has great variety. Lateral fixation is relatively safe in a zone between the center of capitellum-trochlea and 48 mm proximal to this point. The danger zone in lateral fixation is in-between 48–122 mm proximal from CCT. In anteroposterior direction; distal fixation is dangerous between 21–101 mm measured from the medial epicondyle. The more distal, the more medial the nerve courses making it more valuable to iatrogenic damage. The IMN we compared with our data all show potential risk in case of (blind) distal locking, especially from lateral to medial direction

Evaluation of the availability and applicability of computational approaches in the safety assessment of nanomaterials: Final report of the Nanocomput project

This is the final report of the Nanocomput project, the main aims of which were to review the current status of computational methods that are potentially useful for predicting the properties of engineered nanomaterials, and to assess their applicability in order to provide advice on the use of these approaches for the purposes of the REACH regulation. Since computational methods cover a broad range of models and tools, emphasis was placed on Quantitative Structure-Property Relationship (QSPR) and Quantitative Structure-Activity Relationship (QSAR) models, and their potential role in predicting NM properties. In addition, the status of a diverse array of compartment-based mathematical models was assessed. These models comprised toxicokinetic (TK), toxicodynamic (TD), in vitro and in vivo dosimetry, and environmental fate models. Finally, based on systematic reviews of the scientific literature, as well as the outputs of the EU-funded research projects, recommendations for further research and development were also made. The Nanocomput project was carried out by the European Commission’s Joint Research Centre (JRC) for the Directorate-General (DG) for Internal Market, Industry, Entrepreneurship and SMEs (DG GROW) under the terms of an Administrative Arrangement between JRC and DG GROW. The project lasted 39 months, from January 2014 to March 2017, and was supported by a steering group with representatives from DG GROW, DG Environment and the European Chemicals Agency (ECHA).JRC.F.3-Chemicals Safety and Alternative Method

On the propagation of pressure and flow waves through the patient specific arterial system

For pre-operative decision making in cardiovascular surgery, patient-specific physiological data are needed. These data (e.g. pressure, flow and wall shear stress) can be obtained using a computational model of the arterial system. Because of the high computational costs involved with fully three-dimensional models of the total arterial tree, one-dimensional wave propagation models are more suited to provide clinically relevant information. Current models of the arterial system are based on assumptions concerning the frictional and convection forces in the one-dimensional momentum balance that yield an inaccurate representation of the physiological situation. Moreover, the constitutive law, relating the local pressure to the local cross-sectional area, is usually based on purely elastic material properties of the arterial wall, whereas arteries are known to possess viscoelastic properties as well. Furthermore, standard one-dimensional wave propagation methods are based on the assumption of fluid flow through straight or slightly tapered vessels where the velocity component in the radial direction is negligibly small with respect to its axial counterpart. In pathological regions such as stenoses and aneurysms these assumption do not hold. In the current study, a one-dimensional wave propagation model is developed, using an approximate velocity profile function to provide an estimate for the frictional forces and the non-linear term. The resulting wall shear stress and convection forces are compared to the analytical solution for pulsatile flow in a rigid tube showing good agreement. With respect to the arterial wall, a constitutive law, based on the viscoelastic behaviour of the standard linear solid model is introduced, that relates the local cross-sectional area of the vessel lumen to the local blood pressure. The resulting one-dimensional wave propagation model is validated by a comparison to data obtained from an experimental setup, modelling fluid flow through straight and tapered polyurethane vessels. In order to apply the one-dimensional wave propagation model to patient-specific arterial systems, a bifurcation model is implemented to relate the pressure and flow of the parent artery to the pressure and flow of the child arteries. Also, terminal impedances based on a three-element Windkessel model are introduced to obtain appropriate boundary conditions at the truncated ends of the arterial network. Furthermore, to accurately model the fluid dynamics near pathological regions, such as stenoses and aneurysms, relations between the pressure drop and flow characteristics as a function of the local geometry are developed. These relations are based on the results of a computational study of blood flow through two-dimensional axisymmetric stenoses and aneurysm models. The final model is applied to an idealised arterial network known from literature to investigate the influence of the different model assumptions made on the pressure, the flow and on the wall shear stress. The pressure and flow waves computed using the approximate velocity profile function, show only moderate changes with respect to those obtained using Poiseuille profiles. The resulting wall shear stress, however, does differ significantly. The introduced viscoelastic properties of the arterial wall are shown to significantly contribute to the pressure and flow wave attenuation and the influence of a femoral stenoses and an abdominal aortic aneurysms has been demonstrated. In conclusion, the resulting one-dimensional wave propagation model can be used to obtain clinically relevant information that may be crucial in surgical planning

Guidance on safety evaluation of sources of nutrients and bioavailability of nutrient from the sources

Whenever new substances are proposed for use as sources of nutrients in food supplements, foods for the general population or foods for specific groups, EFSA is requested by the European Commission to perform an assessment of their safety and of the bioavailability of the nutrient from the proposed source. This guidance describes the scientific data required to allow an evaluation of the safety of the source within the established framework for risk assessment of food additives and novel food ingredients and the bioavailability of the nutrient from this source. This document is arranged in five main sections: one on technical data aimed at characterising the proposed source and at identifying potential hazards resulting from its manufacture and stability in food; one on existing authorisations and evaluation, providing an overview of previous assessments on the proposed source and their conclusions; one on proposed uses and exposure assessment section, allowing an estimate of the dietary exposure to the source and the nutrient based on the proposed uses and use levels; one on toxicological data, describing approaches which can be used to identify (in conjunction with data on manufacture and composition) and to characterise hazards of the source and any relevant breakdown products; the final section on bioavailability focuses on determining the extent to which the nutrient from the proposed source is available for use by the body in comparison with one or more forms of the same nutrient that are already permitted for use on the positive lists. This guidance document should replace the previous guidance issued by the Scientific Committee for Food and published in 2001

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2013-April 2014)

The EURL ECVAM status report provides an update on the progress made in the development, validation and regulatory acceptance of alternative methods and approaches since the last report published in April 2013. It is informing on ongoing research and development activities, validation studies, peer reviews, recommendations, strategies and international acceptance of alternative methods and approaches. R&D activities are ongoing for the complex endpoints where the toxicological processes and the mechanistic understanding have not been sufficiently elucidated yet and for which 3Rs solutions are more difficult to find. On the other hand, good progress In the validation and regulatory acceptance is made in areas where non-animal alternative methods have been developed and validated and where the focus lies in an intelligent combination/ integration of the various non-animal approaches.JRC.I.5-Systems Toxicolog